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Background and Aims: Acute non-variceal upper gastrointestinal bleeding (UGIB) is associated with significant morbidity and mortality. Our aim was to evaluate the incidence, management, risk factors and outcomes of acute non-variceal UGIB in a population-based study from Hungary. Methods: The present prospective one–year study involved six major community hospitals in Western Hungary covering a population of 1,263,365 persons between January 1 and December 31, 2016. Data collection included demographics, comorbidities endoscopic management, Glasgow-Blatchford score (GBS), Rockall score (RS) transfusion requirements, length of hospital stay and mortality. Results: 688 cases of acute non-variceal UGIB were included with an incidence rate of 54.4 (95%CI: 50.5-58.6) per 100,000 per year. Endoscopy was performed within 12 hours in 71.8%. 5.3% of the patients required surgical treatment and the overall mortality was 13.5%. Weekend presentation was associated with increased transfusion requirements (p=0.047), surgery (p=0.016) and mortality (p=0.021). Presentation with hemodynamic instability or presence of comorbidities was associated with transfusion (p7points), while mortality was best predicted by the post-endoscopic RS (AUC:0.75; cut-off: RS >5points). Conclusions: Incidence rates of acute non-variceal UGIB in Western Hungary are in line with international trends. Longer pre-hospital time, comorbidities, hemodynamic instability, weekend presentation, treatment with anticoagulants or non-steroidal anti-inflammatory drugs was associated with worse outcomes.

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious drug-related adverse event. To identify pharmacogenomic markers of MRONJ associated with bisphosphonate therapy, we conducted a genomewide association study (GWAS) meta-analysis followed by functional analysis of 5,008 individuals of European ancestry treated with bisphosphonates, which includes the largest number of MRONJ cases to date (444 cases and 4,564 controls). Discovery GWAS was performed in randomly selected 70% of the patients with cancer and replication GWAS was performed in the remaining 30% of the patients with cancer treated with intravenous bisphosphonates followed by meta-analysis of all 3,639 patients with cancer. GWAS was also performed in 1,369 patients with osteoporosis treated with oral bisphosphonates. The lead single-nucleotide polymorphism (SNP), rs2736308 on chromosome 8, was associated with an increased risk of MRONJ with an odds ratio (OR) of 2.71 and 95% confidence interval (CI) of 1.90–3.86 (P=3.57*10−8) in the meta-analysis of patients with cancer. This SNP was validated in the MRONJ GWAS in patients with osteoporosis (OR: 2.82, 95% CI: 1.55–4.09, P=6.84*10−4). The meta-analysis combining patients with cancer and patients with osteoporosis yielded the same lead SNP rs2736308 on chromosome 8 as the top SNP (OR: 2.74, 95% CI: 2.09–3.39, P=9.65*10−11). This locus is associated with regulation of the BLK, CTSB, and FDFT1 genes, which had been associated with bone mineral density. FDFT1 encodes a membrane-associated enzyme, which is implicated in the bisphosphonate pathway. This study provides insights into the potential mechanism of MRONJ.

Background Data about the right ventricular (RV) mechanics adaptation to volume overload in patients with repaired tetralogy of Fallot (rToF) are limited. Accordingly, we sought to assess the mechanics of the functional remodeling occurring in the RV of rToF with severe pulmonary regurgitation. Methods We used three-dimensional transthoracic echocardiography (3DTE) to obtain RV data sets from 33 rToF patients and 30 age- and sex- matched controls. A 3D mesh model of the RV was generated, and RV global and regional longitudinal (LS) and circumferential (CS) strain components, and the relative contribution of longitudinal (LEF), radial (REF) and anteroposterior (AEF) wall motion to global RV ejection fraction (RVEF) were computed using the ReVISION method. Results Corresponding to decreased global RVEF (45 ± 6% vs 55 ± 5%, p 0.05) and AEF (0.38 ± 0.09 vs 0.39 ± 0.04, p > 0.05) to global RVEF was similar to controls. Accordingly, rToF patients showed lower 3D RV global LS (-16.94 ± 2.9 vs -23.22 ± 2.9, p 0.05). Conclusions 3DTE allows a quantitative evaluation of the mechanics of global RVEF. In rToF with chronic volume overload, the relative contribution of the longitudinal shortening to global RVEF is affected more than either the radial or the anteroposterior components.

Összefoglaló. Bevezetés: Az akut varixeredetű gastrointestinalis vérzés napjainkban is jelentős morbiditással és mortalitással jár. Célkitűzés: Célunk az akut varixeredetű felső gastrointestinalis vérzések incidenciájának, ellátási folyamatainak és kimeneteli tényezőinek átfogó felmérése volt. Módszer: Prospektív, multicentrikus vizsgálatunk keretében hat nyugat-magyarországi gasztroenterológiai centrum bevonásával elemeztük az ott diagnosztizált és kezelt, varixvérző betegek adatait. Rögzítettük a demográfiai, az anamnesztikus, a diagnosztikus, valamint a terápiát és a betegség kimenetelét érintő adatokat. Minden beteg esetében kockázat- és predikcióbecslést végeztünk a Glasgow–Blatchford Score (GBS), a pre- és posztendoszkópos Rockall Score (RS) és az American Society of Anesthesiologists (ASA) Score alapján. Eredmények: A vizsgált egyéves periódusban (2016. 01. 01. és 2016. 12. 31. között) 108, akut varixeredetű gastrointestinalis vérzést találtunk (átlagéletkor: 59,6 év). Endoszkópos terápiára 57,4%-ban került sor, 39,8% sclerotherapiában, 18,5% ligatióban részesült. Transzfúziót a betegek 76,9%-a igényelt. A teljes halálozás 24,1% volt. A transzfúziós igény vonatkozásában a legmagasabb prediktív értékű a GBS volt (AUC: 0,793; cut-off: GBS >8 pont). Az ASA-pontszám szignifikáns összefüggést mutatott a transzfúzió-szükséglettel (OR 7,6 [CI 95% 2,7–21,6]; pKövetkeztetés: Nyugat-Magyarországon magas az akut varixeredetű vérzés előfordulási gyakorisága. Az ASA-pontszám és a GBS jó prediktív faktor a betegségkimenetel és a transzfúziós igény vonatkozásában. A megfigyelt magas mortalitás és az endoszkópos ligatio alacsony aránya indokolja a kezelési stratégiák optimalizálását akut varixeredetű gastrointestinalis vérzés esetén. Orv Hetil. 2021; 162(31): 1252–1259. Summary. Introduction: Acute variceal gastrointestinal bleeding is associated with significant morbidity and mortality. Objective: Our aim was to evaluate the characteristics and prognostic factors in the management of acute upper gastrointestinal bleeding in a large multi-center study from Hungary. Method: This prospective one-year study (between January 1, 2016 and December 31, 2016) involved six community hospitals in Western Hungary. Data collection included demographic characteristics, vital signs at admission, comorbidities, medications, time to hospital admission and endoscopy, laboratory results, endoscopic management, risk assessment using Glasgow–Blatchford Score (GBS), Rockall Score (RS) and the American Society of Anesthesiologists (ASA) Physical Status Score, transfusion requirements, length of hospital stay and mortality. Results: 108 cases (male: 69.4%) of acute variceal gastrointestinal bleeding were registered during the 1-year period. Endoscopic therapeutic intervention was performed in 57.4%. On initial endoscopy, 39.8% of the patients were treated with sclerotherapy and 18.5% had ligation. 76.9% of the patients required blood transfusion. The overall mortality (including in-hospital bleedings) was 24.1%. The GBS predicted transfusions (AUC: 0.793; cut-off: GBS >8 points). The ASA Score was associated with transfusion (OR 7.6 [CI 95% 2.7–21.6]; pConclusion: Incidence rates of acute variceal gastrointestinal bleeding in Western Hungary are high. The ASA Score, GBS predicted outcomes and transfusion requirements. The observed high mortality rates, coupled with relatively low rates of endoscopic ligation, warrant optimization of management strategies in acute variceal gastrointestinal bleeding. Orv Hetil. 2021; 162(31): 1252–1259.

This is the second of a series of two articles reporting the European Crohn’s and Colitis Organisation [ECCO] evidence-based consensus on the management of adult patients with ulcerative colitis [UC]. The first article is focused on medical management, and the present article addresses medical treatment of acute severe ulcerative colitis [ASUC] and surgical management of medically refractory UC patients, including preoperative optimisation, surgical strategies, and technical issues. The article provides advice for a variety of common clinical and surgical conditions. Together, the articles represent an update of the evidence-based recommendations of the ECCO for UC.

The prevalence of inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis, in Canada, is over 0.75% in 2021. Many individuals with IBD are immunocompromised. Consequently, the World Health Organization’s declaration of a global pandemic uniquely impacted those with IBD. Crohn’s and Colitis Canada (CCC) formed the COVID-19 and IBD Taskforce to provide evidence-based guidance during the pandemic to individuals with IBD and their families. The Taskforce met regularly through the course of the pandemic, synthesizing available information on the impact of COVID-19 on IBD. At first, the information was extrapolated from expert consensus guidelines, but eventually, recommendations were adapted for an international registry of worldwide cases of COVID-19 in people with IBD. The task force launched a knowledge translation initiative consisting of a webinar series and online resources to communicate information directly to the IBD community. Taskforce recommendations were posted to CCC’s website and included guidance such as risk stratification, management of immunosuppressant medications, physical distancing, and mental health. A weekly webinar series communicated critical information directly to the IBD community. During the pandemic, traffic to CCC’s website increased with 484,755 unique views of the COVID-19 webpages and 126,187 views of the 23 webinars, including their video clips. CCC’s COVID-19 and IBD Taskforce provided critical guidance to the IBD community as the pandemic emerged, the nation underwent a lockdown, the economy reopened, and the second wave ensued. By integrating public health guidance through the unique prism of a vulnerable population, CCC’s knowledge translation platform informed and protected the IBD community.

Inflammatory bowel disease (IBD) is a disease that results from dysregulation of the immune system and frequently requires medications that can affect the immune response to infections; therefore, it was imperative to quickly understand the risk of coronavirus disease 2019 (COVID-19) infection on persons living with IBD and how that risk may be increased by commonly used IBD medications. The IBD research community in Canada and beyond quickly established collaborative efforts to better understand the specific risk posed by COVID-19 on persons with IBD. We learned that IBD itself was not a risk factor for death or serious complications of COVID-19, and that most commonly used drug classes (with the notable exception of corticosteroids) do not increase the risk of COVID-19-related adverse outcomes. The risk factors for serious complications and death from COVID-19 appear to be similar to those identified in the wider population; those being advanced age, having pre-existing heart or lung disease, and smoking. We recommend that persons with IBD do not alter their course of therapy to avoid complications of COVID-19, though the indiscriminate use of corticosteroids should be avoided. Persons with IBD should follow the same public health recommendations as the general population to reduce their personal risk of acquiring COVID-19.

BACKGROUND Fucosyltransferase 2 (FUT2) participates in intestinal antigen secretion and bacterial adherence. FUT2 homozygous nonsense mutations (FUT2M) and subsequent nonsecretor status is associated with Crohn's disease (CD). The common null allele is rs601338. We assessed the relationship between FUT2M and disease course. METHODS In consecutive adult CD outpatients, clinical, biochemical, and genetic data were collected at baseline visits. Patients were longitudinally followed over 5 years. The primary outcome analyzed the relationship between FUT2M and rates of CD patients in persistent steroid-free clinical remission requiring neither surgery, biologics, nor immunomodulators. RESULTS Sixty-two CD patients were recruited. FUT2M homozygotes (rs601338 or any mutation in linkage disequilibrium) were detected in 27% of CD (17/62). Patients with rs601338 mutations had higher rates of the primary outcome (homozygous: 46.6%, heterozygous: 28.0%, wild-type: 5.3%, P=0.02). Similar findings existed for CD patients with homozygous mutations in any single-nucleotide polymorphism for FUT2 (homozygous: 41.2%, heterozygous: 25.9%, wild-type: 5.6%, P=0.04). On multivariable analysis, rs601338 mutation was associated with the primary outcome (odds ratio=3.4, 95% confidence interval: 1.3-8.7, P=0.01), while other parameters were not. Mutation of rs601338 was associated with lower rates of penetrating disease (homozygous: 13.3%, heterozygous: 28.0%, wild-type: 52.6%, P=0.05) and particularly in high-risk patients (homozygous: 0%, heterozygous: 37.5%, wild-type: 83.3%, P=0.01). CONCLUSIONS FUT2 mutation status is associated with a favorable clinical course in CD. Further confirmatory studies are needed.

Our aim was to assess the regional right ventricular (RV) shape changes in pressure and volume overload conditions and their relations with RV function and mechanics. The end-diastolic and end-systolic RV endocardial surfaces were analyzed with three-dimensional echocardiography (3DE) in 33 patients with RV volume overload (rToF), 31 patients with RV pressure overload (PH), and 60 controls. The mean curvature of the RV inflow (RVIT) and outflow (RVOT) tracts, RV apex and body (both divided into free wall (FW) and septum) were measured. Zero curvature defined a flat surface, whereas positive or negative curvature indicated convexity or concavity, respectively. The longitudinal and radial RV wall motions were also obtained. rToF and PH patients had flatter FW (body and apex) and RVIT, more convex interventricular septum (body and apex) and RVOT than controls. rToF demonstrated a less bulging interventricular septum at end-systole than PH patients, resulting in a more convex shape of the RVFW (r = − 0.701, p

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse drug reaction. Our previous whole-exome sequencing study found SIRT1 intronic region single-nucleotide polymorphism (SNP) rs7896005 to be associated with MRONJ in cancer patients treated with intravenous (iv) bisphosphonates (BPs). This study aimed to identify causal variants for this association. In silico analyses identified three SNPs (rs3758391, rs932658, and rs2394443) in the SIRT1 promoter region that are in high linkage disequilibrium (r2 > 0.8) with rs7896005. To validate the association between these SNPs and MRONJ, we genotyped these three SNPs on the germline DNA from 104 cancer patients of European ancestry treated with iv BPs (46 cases and 58 controls). Multivariable logistic regression analysis showed the minor alleles of these three SNPs were associated with lower odds for MRONJ. The odds ratios (95% confidence interval) and p values were 0.351 (0.164-0.751; p = 0.007) for rs3758391, 0.351 (0.164-0.751; p = 0.007) for rs932658, and 0.331 (0.157-0.697; p = 0.0036) for rs2394443, respectively. In the reporter gene assays, constructs containing rs932658 with variant allele A had higher luciferase activity than the reference allele, whereas constructs containing SNP rs3758391 and/or rs2394443 did not significantly affect activity. These results indicate that the promoter SNP rs932658 regulates the expression of SIRT1 and presumably lowers the risk of MRONJ by increasing SIRT1 expression. © 2020 American Society for Bone and Mineral Research (ASBMR).

BACKGROUND Intracardiac blood cysts are an exceedingly rare occurrence in adulthood. Detailed imaging modalities aid in the diagnosis of such incidental lesions and procedure planning. METHODS We report the case of a 51-year-old male accusing dyspnea on exertion as a sole symptom which led to the discovery of multiple cardiac anomalies, namely, severe aortic valve insufficiency on a bicuspid aortic valve, ascending aortic aneurysm, a cystic mass on the tricuspid valve, patent foramen ovale, and an occluded right coronary artery. RESULTS The disorders were managed in a single surgical intervention, the resected mass being confirmed as a blood cyst. CONCLUSIONS Our case presents a unique association of cardiac disorders, including a highly uncommon intracardiac blood-filled cyst, and underlines the importance of multimodality imaging and interdisciplinary approach in the successful management of such complex cases.

Inflammatory bowel disease (IBD) is a chronic condition that significantly affects the quality of life of its patients. Biologic drugs have been the mainstay treatment in the management of IBD patients but despite their significant contribution, there remains a proportion of patients that do not respond or lose response to treatment. Therapeutic drug monitoring (TDM) involves measuring levels of serum drug concentrations and anti-drug antibodies. TDM of biologic drugs initially emerged to understand treatment failure in other immune mediated inflammatory diseases. This was then introduced in IBD to rationalize primary non-response or secondary loss of response, given that low serum drug concentrations or the formation of anti-drug antibodies are variably associated with treatment failure. The aim of this narrative review is to provide an overview regarding the current use of TDM in clinical practice and to present the evidence available regarding its use in both proactive and reactive clinical settings in preventing and managing treatment failure. This review also presents the existing evidence regarding the association of various clinical outcomes with specific thresholds of drug concentrations, in everyday practice. A narrative review of published articles and conference abstracts regarding the use of TDM in IBD management, through an electronic search using PubMed and ScienceDirect. TDM has proven to be superior and more cost effective in guiding management of patients with treatment failure compared to empiric dose escalation or change in treatment. Despite a trend towards an association between clinical outcomes and drug concentrations, proactive TDM based strategies have not been shown to achieve clear benefit in long-term outcomes. In the clinical setting, TDM has proven to be useful in managing IBD patients, and its use in the reactive setting, as an additional tool to help manage patients with treatment failure, is being promoted as newer guidelines and consensus groups implement TDM as part of the management plan.

From March through December 2020, 100 autopsies were performed (Semmelweis University, Budapest, Hungary), with chart review, of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection demonstrated by real-time reverse-transcription polymerase chain reaction testing (mean age, 74.73 years, range 40–102 years; 50 males, mean age 71.96 years, and 50 females, mean age 77.5 years). Classified by the date of death, 21 cases were from the pandemic’s “first wave” (March through July) and 79 from the “second wave” (August through December). Three mortality categories were defined by relevance of SARS-CoV-2 infection: (1) “strong” association (n=57), in which COVID-19 was primary responsible for death; (2) “contributive” association (n=27), in which a pre-existing condition independent of COVID-19 was primary responsible for death, albeit with substantial COVID-19 co-morbidity; (3) “weak” association (n=16), in which COVID-19 was minimally or not at all responsible for death. Distributions among categories differed between the first wave, in which the “contributive” association cases dominated (strong: 24%, contributive: 48%, weak: 28%), and the second wave, in which the “strong” association cases dominated (strong: 66%, contributive: 21%, weak: 13%). Charted co-morbidities included hypertension (85 %), cardiovascular diseases (71 %), diabetes (40 %), cerebrovascular diseases (31 %), chronic respiratory diseases (30 %), malignant tumors (20 %), renal diseases (19 %), diseases of the central nervous system (15 %), and liver diseases (6 %). Autopsy evaluation analyzed alterations on macroscopy as well as findings on microscopy of scanned and scored sections of formalin-fixed, paraffin-embedded tissue samples (50–80 blocks/case). Severity of histological abnormalities in the lung differed significantly between “strong” and “contributive” (pp

Contains fulltext : 249977.pdf (Publisher’s version ) (Closed access) BACKGROUND: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies. METHODS: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as β blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977. FINDINGS: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; p(interaction)=0·18). A similar result was seen for β blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; p(interaction)=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus β blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; p(interaction)=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups. INTERPRETATION: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy. FUNDING: Boehringer Ingelheim and Eli Lilly and Company.

Optimal management of patients with ulcerative colitis (UC) requires the accurate, objective assessment of disease activity. We aimed to determine how strong patient-reported outcomes, clinical scores and symptoms correlate with endoscopy and biomarkers for assessment of disease activity in patients with UC. Consecutive patients with UC followed at the McGill University IBD Center and referred for endoscopy (surveillance or flare) were included prospectively between September 2018 and August 2020. Patient-reported outcome (PRO2), partial Mayo, Simple Clinical Colitis Activity Index (SCCAI), Mayo endoscopic subscore (MES) and Baron and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scores were calculated. C-reactive protein (CRP) and fecal calprotectin (FCAL) were collected. A total of 171 patients with UC [age: 49(IQR:38–61) years, female: 46.2%, 57.3% extensive disease, 42.7% on biologicals] were included prospectively. Rectal bleeding (RBS), stool frequency (SF) subscore of 0, or total PRO2 remission (RBS0 and SF ≤ 1), partial Mayo (≤ 2) and SCCAI (≤ 2.5) remission were similarly associated with mucosal healing defined by MES (0 or ≤ 1), Baron (0 or ≤ 1) or UCEIS (≤ 3) scores in ROC analysis (AUC:0.93–0.72). There was a moderate-to-strong agreement between MES Baron and UCEIS (K = 0.91–0.41). A UCEIS of ≤ 3 was identified as the best cutoff to clinical or endoscopic remission. Agreement between CRP and clinical remission or endoscopic healing (MES/Baron) was poor (K ~ 0.2), while agreement between FCAL and RBS-PRO2 or MES/Baron/UCEIS was moderate to strong (K = 0.44–0.70). Agreement between RBS, SF, PRO2, partial Mayo and SCCAI in predicting endoscopic healing was moderate to strong, while no clinically meaningful difference was found in accuracy across the scores and definitions. FCAL, but not CRP, was associated to clinical and endoscopic remission.

BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab for maintenance of remission in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, placebo-controlled, double-blind, phase 3 study (LAUREL) across 111 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. During open-label induction, participants received subcutaneous etrolizumab 105 mg once every 4 weeks. Participants who had clinical response at week 10 (MCS with ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) proceeded into the double-blind maintenance phase and were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or matched placebo until week 62. Randomisation was stratified by baseline concomitant treatment with corticosteroids, treatment with immunosuppressants, baseline disease activity, and week 10 remission status. All participants and study site personnel were masked to treatment assignment. The primary endpoint was remission at week 62 (MCS ≤2, with individual subscores ≤1, and rectal bleeding subscore of 0) among patients with a clinical response at week 10, measured in the modified intention-to-treat population (all randomised patients who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, NCT02165215, and is now closed to recruitment. FINDINGS: Between Aug 12, 2014, and June 4, 2020, 658 patients were screened for eligibility and 359 were enrolled into the induction phase. 214 (60%) patients had a clinical response at week 10 and were randomly assigned to receive etrolizumab (n=108) or placebo (n=106) in the maintenance phase. 80 (74%) patients in the etrolizumab group and 42 (40%) in the placebo group completed the study through week 62. Four patients in the placebo group did not receive study treatment and were excluded from the analyses. At week 62, 32 (29·6%) of 108 patients in the etrolizumab group and 21 (20·6%) of 102 in the placebo group were in remission (adjusted treatment difference 7·7% [95% CI -4·2 to 19·2]; p=0·19). A greater proportion of patients reported one or more adverse events in the placebo group (82 [80%] of 102) than in the etrolizumab group (70 [65%] of 108); the most common adverse event in both groups was ulcerative colitis (16 [15%] patients in the etrolizumab group and 37 [36%] in the placebo group). Ten (9%) patients in the etrolizumab group and eight (8%) in the placebo group reported one or more serious adverse events. No deaths were reported in either treatment group. INTERPRETATION: No significant differences were observed between maintenance etrolizumab and placebo in the primary endpoint of remission at week 62 among patients who had a clinical response at week 10. Etrolizumab was well tolerated in this population and no new safety signals were identified. FUNDING: F Hoffmann-La Roche. ispartof: LANCET GASTROENTEROLOGY & HEPATOLOGY vol:7 issue:1 pages:28-37 ispartof: location:Netherlands status: published

Aims While global longitudinal strain (GLS) is considered to be a sensitive marker of left ventricular (LV) function, it is significantly influenced by loading conditions. We hypothesized that global myocardial work index (GMWI), a novel marker of LV function, may show better correlation with load‐independent markers of LV contractility in rat models of pressure‐induced or volume overload‐induced heart failure. Methods and results Male Wistar rats underwent either transverse aortic constriction (TAC; n = 12) or aortocaval fistula creation (ACF; n = 12), inducing LV pressure or volume overload, respectively. Sham procedures were performed to establish control groups (n = 12/12). Echocardiographic loops were obtained to determine GLS and GMWI. Pressure‐volume analysis with transient occlusion of the inferior caval vein was carried out to calculate preload recruitable stroke work (PRSW), a load‐independent ‘gold‐standard’ parameter of LV contractility. Myocardial samples were collected to assess interstitial and perivascular fibrosis area and also myocardial atrial‐type natriuretic peptide (ANP) and brain‐type natriuretic peptide (BNP) relative mRNA expression. Compared with controls, GLS was substantially lower in the TAC group (−7.0 ± 2.8 vs. −14.5 ± 2.5%; P

Autoimmune pancreatitis is a rare, distinct and increasingly recognized form of chronic inflammatory pancreatic disease secondary to an underlying autoimmune mechanism. We report on a 14-year-old boy who developed autoimmune pancreatitis, while he was under treatment with eltrombopag for chronic immune thrombocytopenia. Therapy with corticosteroids resulted in complete remission of both. This is the first report on the co-occurrence of autoimmune pancreatitis and chronic immune thrombocytopenia in childhood, and clinicians should be aware of this rare association, because early diagnosis and therapy of autoimmune pancreatitis may prevent severe complications.

New data suggest that incidence and prevalence of inflammatory bowel diseases [IBD] are still increasing worldwide, and approximately 0.2% of the European population suffer from IBD at the present time. Medical therapy and disease management have evolved significantly in recent decades, with an emphasis on tight objective monitoring of disease progression and a treat-to-target approach in Europe and also worldwide, aiming to prevent early bowel damage and disability. Surgery rate declined over time in Europe, with 10–30% of CD and 5–10% of UC patients requiring a surgery within 5 years. The health economic burden associated with IBD is high in Europe. Direct health care costs [approximately €3500 in CD and €2000 in UC per patient per year] have shifted from hospitalisation and surgery towards drug-related expenditures with the increasing use of biologic therapy and other novel agents, and substantial indirect costs arise from work productivity loss [approximately €1900 per patient yearly]. The aim of this paper is to provide an updated review of the burden of IBD in Europe by discussing current data on epidemiology, disease course, risk for surgery, hospitalisation, and mortality and cancer risks, as well as the economic aspects, patient disability, and work impairment, by discussing the latest population-based studies from the region.

Funder: UK Dementia Research Institute, Amyotrophic lateral sclerosis overlapping with frontotemporal dementia (ALS/FTD) is a fatal and currently untreatable disease characterized by rapid cognitive decline and paralysis. Elucidating initial cellular pathologies is central to therapeutic target development, but obtaining samples from presymptomatic patients is not feasible. Here, we report the development of a cerebral organoid slice model derived from human induced pluripotent stem cells (iPSCs) that recapitulates mature cortical architecture and displays early molecular pathology of C9ORF72 ALS/FTD. Using a combination of single-cell RNA sequencing and biological assays, we reveal distinct transcriptional, proteostasis and DNA repair disturbances in astroglia and neurons. We show that astroglia display increased levels of the autophagy signaling protein P62 and that deep layer neurons accumulate dipeptide repeat protein poly(GA), DNA damage and undergo nuclear pyknosis that could be pharmacologically rescued by GSK2606414. Thus, patient-specific iPSC-derived cortical organoid slice cultures are a reproducible translational platform to investigate preclinical ALS/FTD mechanisms as well as novel therapeutic approaches.

Background and Aims: Anemia is a common complication of inflammatory bowel diseases (IBD), as well as a predictor of poor outcomes. The aim of this study was to determine the prevalence of anemia over time and the management of moderate to severe anemia at a tertiary referral IBD center. Methods: We retrospectively reviewed the occurrence of anemia at the time of referral or diagnosis and during follow-up at the McGill University Health Centre IBD center. Consecutive patients presenting with an outpatient visit between July and December 2016 and between December 2018 and March 2019 were included. Disease characteristics, biochemistry and medical management, including the need for intravenous iron therapy were recorded. Results: 1,356 Crohn’s disease (CD) and 1,293 ulcerative colitis (UC) patients [disease duration: 12 (IQR: 6-22) and 10 (IQR: 5-19) years respectively] were included. The prevalence of moderate to severe anemia at referral/diagnosis (15.4% and 8.5%) and during follow-up (11.1% and 8.1%) were higher in CD than in UC patients. In CD, previous resective surgery, perianal disease and elevated C-reactive protein (CRP) at assessment, while in UC steroid therapy, an elevated CRP and fecal calprotectin at assessment were associated with anemia in a multivariate analysis. Anemia improved by >2g/dL in 56.5% after 4-6 weeks (intravenous iron dose >1000 mg in 87% of patients). Conclusion: Anemia occurred frequently in this IBD cohort, at referral to the center and during follow-up, and contributes to the burden of IBD in referral populations. Most patients were assessed for anemia regularly and with accurate anemia workup; however, the targeted management of moderate to severe anemia was suboptimal.

Aims Preferring side branch of coronary sinus during cardiac resynchronization therapy (CRT) implantation has been empirical due to the limited data on the association of left ventricular (LV) lead position and long‐term clinical outcome. We evaluated the long‐term all‐cause mortality by LV lead non‐apical positions and further characterized them by interlead electrical delay (IED). Methods and results In our retrospective database, 2087 patients who underwent CRT implantation were registered between 2000 and 2018. Those with non‐apical LV lead locations were classified into anterior (n = 108), posterior (n = 643), and lateral (n = 1336) groups. All‐cause mortality was assessed by Kaplan–Meier and Cox analyses. Echocardiographic response was measured 6 months after CRT implantation. During the median follow‐up time of 3.7 years, 1150 (55.1%) patients died—710 (53.1%) with lateral, 78 (72.2%) with anterior, and 362 (56.3%) with posterior positions. When we investigated the risk of all‐cause mortality, there was a significantly lower rate of death in patients with lateral LV lead location when compared with those with an anterior (P

AIM The aim was to explore the subjective health expectations (sHE) of patients with Crohn's disease (CD) for both the near future and the elderly. METHOD A cross-sectional survey was performed in four gastroenterology centres in Hungary. Consecutive outpatients with CD with age ≥ 18 were recruited. Socio-demographic and disease characteristics were recorded and the Crohn's Disease Activity Index (CDAI), Perianal Disease Activity Index, Patients' Global Assessment (PGA) and current pain visual analogue scale (VAS) were assessed. Subjective life expectancy (sLE) was explored and compared to statistical life expectancy. Current health and sHE for 1 year ahead and for ages 60/70/80/90 were assessed using the descriptive system of the EQ-5D-3L. RESULTS In all, 206 patients (54.9% men) with a mean age of 34.7 (SD 10.5 years) and disease duration of 10.5 (SD 6.3) years were studied. The CDAI score was 110.5 (SD 77.0) and 66% were treated by biologic drugs. Mean current EQ-5D-3L score was 0.80 (SD 0.17) and patients expected a 0.05 (SD 0.15) improvement within a year (P

Absztrakt: Az őszi és téli meghűléses időszakban sokan vásárolnak különböző, vény nélkül kapható, megfázás elleni készítményeket, ezen belül is nagy számban paracetamol- (más néven acetaminofén-) tartalmú szereket. A paracetamol különböző típusú fájdalmak (fejfájás, migrén, meghűlés-láz okozta fájdalom, fogfájás, menstruációs fájdalom stb.) enyhítésére szolgáló, igen népszerű, a nemopioid típusú analgetikumok közé sorolható hatóanyag, amely többek között tabletta, kúp és oldat formájában is elérhető a gyógyszertárakban. Magyarországon 2020-ban 86, törzskönyvezett paracetamoltartalmú készítmény van forgalomban. A paracetamol alkalmazása biztonságos és hatékony, amennyiben az előírásnak megfelelően használják. Közleményünkben három olyan esetet mutatunk be, amelyben a beteg halála összefüggésbe hozható a paracetamol alkalmazásával. Mindhárom, krónikus alkoholizmusban szenvedő beteg (34, 42 és 51 évesek) rövid idővel a kórházba kerülés után elhunyt. Vizsgálataink során három betegből származó, összesen kilenc szérumminta került feldolgozásra. A paracetamolnak és metabolitjainak együttes meghatározása enzimatikus módszerrel (Roche assay) történt, míg a paracetamol specifikus mérésére tandem-tömegspektrométerrel kapcsolt szuperkritikus folyadékkromatográfot (SFC–MS/MS) alkalmaztunk. Enzimatikus meghatározással mindegyik mintában terápiás koncentrációt mutattunk ki. SFC–MS/MS módszerrel történt meghatározás esetén egy betegtől származó négy mintában a terápiás tartománynál alacsonyabb paracetamolkoncentrációkat mértünk. A paracetamolterápia alkalmazása krónikus alkoholizmusban szenvedő betegek esetén fokozott kockázatot jelent. A klinikai toxikológiai gyakorlatban a paracetamol meghatározására használt enzimatikus módszer eredményét a máj- és vesefunkciós paraméterekkel együttesen szükséges értékelni, mert krónikus alkoholizmusban szenvedő betegek esetén az enzimatikus módszerrel kapott terápiás tartományba eső koncentráció nem zárja ki a paracetamoltoxicitást. Orv Hetil. 2020; 161(40): 1720–1723.

Colorectal cancer is a clinically and molecularly heterogeneous disease. Currently, extended RAS and BRAF mutation testing is obligatory in routine clinical practice before starting any treatment in the metastatic setting. Treatment decision making also includes assessment of the clinical condition of the patient, definition of the treatment goal, and consideration of the primary tumor site. Biological treatment is part of the first-line drug combination unless contraindicated. Mutational status is significantly associated with the outcome of patients and is strongly predictive for anti-EGFR-targeted therapy. The prognosis of RAS mutant CRC is clearly inferior to wild-type cases. RAS remains an elusive target, and specific treatment options are not yet available. Recently, promising results of a direct KRAS G12C inhibitor have been reported; however, further confirmation is needed. The biomarker landscape in mCRC is evolving; new promising markers are awaited with the chance of more precise targeted treatment.

Background/Aims: Latent tuberculosis screening is mandatory prior to initiating anti-tumor necrosis factor (anti-TNF) medications. Guidelines recommend interferon-gamma release assays (IGRA) as first line screening method for the general population. Studies provided conflicting evidence on IGRA and tuberculin skin test (TST) performance in inflammatory bowel disease (IBD) patients. We assessed test concordance and the effects of immunosuppression on their performance in IBD patients.Methods: We searched MEDLINE, Embase and Cochrane databases (2011–2018) for studies testing TST and IGRA in IBD. Primary outcome was TST and IGRA concordance. Secondary outcomes were effects of immunosuppressive therapy on performance. Immunosuppression defined as either steroids, thiopurine, methotrexate or cyclosporine use. We used the pooled random effects model to adjust for heterogeneity analyzed using (I2–Q statistics). We compared the fixed model to exclude smaller study effects.Results: Sixteen studies (2,488 patients) were included. Pooled TST and IGRA concordance was 85% (95% confidence interval [CI], 81%–88%; P=0.01). Effects of immunosuppression were reported in 8 studies (814 patients). The odds ratio of testing positive by IGRA decreased to 0.57 if immunosuppressed (95% CI, 0.31–1.03; P=0.06). The odds ratio of testing positive by TST if immunosuppressed was 1.14 (95% CI, 0.61–2.12; P=0.69). The fixed model yielded similar results, however the negative effect of immunosuppression on IGRA reached statistical significance (P=0.01).Conclusions: While concordance was 85% between TST and IGRA, the performance of IGRA seems to be negatively affected by immunosuppression. Given the importance of detecting latent tuberculosis prior to anti-TNF initiation, further randomized controlled trials comparing the performance of TST and IGRA in IBD patients are needed.

Absztrakt: Bevezetés: Jelenleg nem áll rendelkezésünkre specifikus kuratív kezelés vagy vakcina az új koronavírus-2 (COVID–19, SARS-CoV-2) kezelésére. A súlyos citokinvihar-szindrómával társuló COVID–19-fertőzés kezelésére sürgősen szükséges alternatív kezelési megoldást találni. Célkitűzés: A convalescens plazmaterápia alkalmazása más, súlyos vírusfertőzések kezelésében a túlélés javulását eredményezte, és ígéretes terápiás megközelítés lehet súlyos COVID–19-betegek számára. Módszer: Két kritikus állapotú, COVID–19-fertőzött beteg convalescens friss fagyasztott plazmával történő kezelését mutatjuk be. Eredmények: A plazmaterápia megkezdésekor mindkét beteg gépi lélegeztetésre szorult, és antivirális kezelésben, valamint maximális szupportív ellátásban részesült. A COVID–19-fertőzésből nemrég felépült és a súlyos akut légúti distressz szindrómát okozó koronavírus-2 elleni immunglobulin-G-t termelő donorokból 3 × 200 ml convalescens plazma transzfúzióját alkalmaztuk. A convalescens plazma transzfúzióját követően mindkét betegnél javult az oxigénszaturáció, és a gyulladásos értékeket jelző paraméterek csökkenést mutattak. A convalescens plazma adását megelőző paraméterekhez viszonyítva növekedett a lymphocytaszám, és csökkent az interleukin-6-szint. Mindkét betegnél 2 héten belül megszüntethető volt a gépi lélegeztetés. Nem észleltünk a convalescens plazma adása során súlyos mellékhatást. Következtetések: Megfigyelésünk alapján a convalescens plazmával történő terápia jól tolerálható volt, és javíthatja a betegek gyógyulási arányát. A convalescens plazmával való kezelés optimális dózisának, időpontjának és klinikai előnyeinek meghatározására további nagy, kontrollált vizsgálatok szükségesek. Közleményünk megírásának célja az első két, hazánkban convalescens plazmával sikeresen kezelt, kritikus állapotú COVID–19-fertőzött beteg kórtörténetének bemutatása. Orv Hetil. 2020; 161(27): 1111–1121.

Immunomodulator monotherapy is an important component in the treatment of inflammatory bowel disease (IBD). However, there is conflicting literature about thiopurines maintaining long-term remission in patients with active IBD. To determine the durable clinical remission rate in adults with Crohn’s disease (CD) or ulcerative colitis (UC) on thiopurine monotherapy over 5 years. We performed a retrospective analysis of adult patients identified at McGill University Health Centre from 2009 to 2012. We included IBD patients who initiated thiopurine monotherapy and were in remission for at least 3 months (Harvey–Bradshaw Index (HBI) 5 in CD and pMS > 2 in UC. There were 148 patients included in the study (100 CD; 48 UC). At 5 years, 23% (34/148) patients remained in clinical remission on thiopurine monotherapy (25 CD and 9 UC patients). Thirty-three percent (33/100) of CD and 46% (22/48) of UC patients relapsed while on thiopurines. There was no difference in relapse rates between CD and UC patients. Eighty-four percent (42/50) of patients with CD with side effects and all UC (17/17) patients who experienced side effects discontinued the drug. This analysis demonstrates that there is poor sustainability of clinical remission in IBD patients on thiopurine monotherapy given that a high proportion of patients discontinue thiopurines due to either relapse or side effects.

Aims The PREPARE‐MVR study (PRediction of Early PostoperAtive Right vEntricular failure in Mitral Valve Replacement/Repair patients) sought to investigate the alterations of right ventricular (RV) contraction pattern in patients undergoing mitral valve replacement/repair (MVR) and to explore the associations between pre‐operative RV mechanics and early post‐operative RV dysfunction (RVD). Methods and results We prospectively enrolled 42 patients (63 ± 11 years, 69% men) undergoing open‐heart MVR. Transthoracic three‐dimensional (3D) echocardiography was performed pre‐operatively, at intensive care unit discharge, and 6 months after surgery. The 3D model of the RV was reconstructed, and RV ejection fraction (RVEF) was calculated. We decomposed the motion of the ventricle to compute longitudinal ejection fraction (LEF) and radial ejection fraction (REF). Pulmonary artery catheterization was performed to monitor RV stroke work index (RVSWi). RVEF was slightly decreased after MVR [52 (50–55) vs. 51 (46–54)%; P = 0.001], whereas RV contraction pattern changed notably. Before MVR, the longitudinal shortening was the main contributor to global systolic RV function [LEF/RVEF vs. REF/RVEF; 0.53 (0.47–0.58) vs. 0.33 (0.22–0.42); P

Background Vitamin D metabolism and obesity have been linked by several studies, however the reason for this association is unclear. Our objective was to investigate potential correlations between genetic variants in key enzymes of vitamin D metabolism and the body mass index on a representative and random sample of Hungarian adults. Methods Altogether 462 severely vitamin D deficient individuals were studied at the end of winter in order to decrease environmental and maximize any relevant genetic effect. Furthermore, participants with lifestyle factors known to affect vitamin D homeostasis were also excluded. We selected 23 target SNPs in five genes that encode key proteins of vitamin D metabolism (NADSYN1, GC, CYP24A1, CYP2R1, VDR). Results Variants in 2 genetic polymorphisms; rs2853564 (VDR) and rs11023374 (CYP2R1) showed a significant association with participants‘ BMI. These associations survived further adjustment for total-, free-, or bioactive-25(OH) vitamin D levels, although the variance explained by these 2 SNPS in BMI heterogeneity was only 3.2%. Conclusion Our results show two novel examples of the relationship between genetics of vitamin D and BMI, highlighting the potential role of vitamin D hormone in the physiology of obesity.

Absztrakt: Az elmúlt hónapokban pandémiához vezető, Kínából induló, új koronavírus okozta megbetegedés (COVID–19) rámutatott az emberiség kiszolgáltatottságára. Aktuálisan a COVID–19 kezelésére randomizált kontrollált vizsgálattal igazolt hatékonyságú, törzskönyvezett gyógyszer nem áll rendelkezésre. A súlyos akut légúti tünetegyüttest okozó koronavírus-2 (SARS-CoV-2) a jelen munka írásáig – a legóvatosabb becslések szerint is – közel 4 millió fertőzésért és megközelítőleg 300 000 halálesetért felelős. A patomechanizmus mélyebb megismerése fedte fel, hogy a fatális esetek hátterében az immunválasz diszregulációja, a citokinvihar-szindróma (CRS) áll. Eddigi ismereteink alapján a COVID–19-ben kialakuló citokinvihar sarkalatos szereplője az interleukin-6 (IL6). Esetleírások és kis betegcsoportokon végzett vizsgálatok eredményei alapján az IL6 monoklonális antitest gátló terápia (tocilizumab) eredményesnek mutatkozik a citokinvihar kezelésében. A szerzők egy eset leírása kapcsán foglalják össze a legfrissebb ismereteket a COVID–19 terápiájával kapcsolatosan. A jelen esetismertetés súlyos COVID–19-ben szenvedő betegben kialakult CRS sikeres terápiáját mutatja be, melynek során – a szerzők tudomása szerint – hazánkban elsőként került sor tocilizumab alkalmazására infektológiai osztályon. Orv Hetil. 2020; 161(26): 1070–1077.

Absztrakt: A szemgödörbe került idegen testek műtéti eltávolítására, az ezek során kialakult komplikációk kezelésére, illetve gyógyítására jelenleg Magyarországon nincs protokoll. Annak ellenére, hogy sokszor több szakma bevonása szükséges, orbitasebészeti centrum országosan nem került kialakításra. Kettős esetbemutatásunk célja rávilágítani a fenti esetek fontosságára, műtéti szemlélet kialakítására, illetve az esetleges komplikációk felismerésére, megoldására legfőképp szerves idegen testek esetén olyan esetben is, ha több fej-nyaki anatómiai régió érintett, létfontosságú szervekkel együtt. Orv Hetil. 2020; 161(21): 889–894.

De-escalation of immunomodulators and biologic agents in inflammatory bowel disease is frequently discussed with patients and must weigh the risk of continued medical therapy with the risk of disease recurrence. Risk factors for disease flare after withdrawal of inflammatory bowel disease medications such as disease activity at de-escalation, disease prognostic features, and prior course of disease have been identified predominately in retrospective studies, allowing for risk stratification of patients. This review evaluates the published literature regarding therapeutic de-escalation and provides a framework for physicians to apply this to clinical practice. Prospective trials are underway and planned, which should provide further insight into this treatment paradigm and better inform patient selection for this strategy.

Absztrakt: Bevezetés: Számos tanulmány vizsgálta az emlőrákkal diagnosztizált nők kötődési stílusát, és az eddigi eredmények rámutatnak arra, hogy a betegek életminőségének és a gyógyulás optimális feltételeinek biztosítása érdekében fontos figyelembe venni a kötődési mintázat és a kapcsolati jellemzők közötti összefüggéseket is. Célkitűzés és módszer: A jelen tanulmányban emlőrákkal diagnosztizált nők kötődési stílusát (n = 135) kívánjuk felmérni, és összehasonlítani emlőrákkal nem diagnosztizált nők csoportjával (n = 137) a felnőttkori kötődés, szorongás és elkerülés dimenziói mentén. Vizsgáljuk továbbá a felnőttkori kötődés jellemzőinek összefüggéseit a szubjektív egészségi állapottal, valamint a párkapcsolattal és a szexuális kapcsolattal való elégedettség között. Eredmények: A diagnosztizált csoportra a kötődési mintázat szempontjából magasabb elkerülés, továbbá rosszabb szubjektív egészségi állapot, alacsonyabb kapcsolati és szexuális elégedettség volt jellemző. A magasabb elkerülés és a magasabb szorongás is alacsonyabb kapcsolati elégedettséget jelzett előre, míg a szexuális elégedettség az emlőrák diagnózisával mutatott negatív, a szubjektív egészségi állapottal pedig pozitív összefüggést. Következtetés: Eredményeink arra utalnak, hogy az emlőrákkal diagnosztizált nők kötődési mintázata, emellett pedig szubjektív egészségi állapota is szerepet játszhat párkapcsolati és szexuális elégedettségükben. A páciensek testi, lelki és kapcsolati jellemzőinek figyelemmel kísérése és támogatása hozzájárulhat a jobb életminőség eléréséhez. Orv Hetil. 2020; 161(13): 510–518.

BACKGROUND Emergency situations in inflammatory bowel diseases (IBD) put significant burden on both the patient and the healthcare system. AIM To prospectively measure Quality-of-Care indicators and resource utilization after the implementation of the new rapid access clinic service (RAC) at a tertiary IBD center. METHODS Patient access, resource utilization and outcome parameters were collected from consecutive patients contacting the RAC between July 2017 and March 2019 in this observational study. For comparing resource utilization and healthcare costs, emergency department (ED) visits of IBD patients with no access to RAC services were evaluated between January 2018 and January 2019. Time to appointment, diagnostic methods, change in medical therapy, unplanned ED visits, hospitalizations and surgical admissions were calculated and compared. RESULTS 488 patients (Crohn’s disease: 68.4%/ulcerative colitis: 31.6%) contacted the RAC with a valid medical reason. Median time to visit with an IBD specialist following the index contact was 2 d. Patients had objective clinical and laboratory assessment (C-reactive protein and fecal calprotectin in 91% and 73%). Fast-track colonoscopy/sigmoidoscopy was performed in 24.6% of the patients, while computed tomography/magnetic resonance imaging in only 8.1%. Medical therapy was changed in 54.4%. ED visits within 30 d following the RAC visit occurred in 8.8% (unplanned ED visit rate: 5.9%). Diagnostic procedures and resource utilization at the ED (n = 135 patients) were substantially different compared to RAC users: Abdominal computed tomography was more frequent (65.7%, P < 0.001), coupled with multiple specialist consults, more frequent hospital admission (P < 0.001), higher steroid initiation (P < 0.001). Average medical cost estimates of diagnostic procedures and services per patient was $403 CAD vs $1885 CAD comparing all RAC and ED visits. CONCLUSION Implementation of a RAC improved patient care by facilitating easier access to IBD specific medical care, optimized resource utilization and helped avoiding ED visits and subsequent hospitalizations.

Most case series of patients with ischemic stroke (IS) and COVID-19 are limited to selected centers or lack 3-month outcomes. The aim of this study was to describe the frequency, clinical and radiological features, and 3-month outcomes of patients with IS and COVID-19 in a nationwide stroke registry. From the Swiss Stroke Registry (SSR), we included all consecutive IS patients ≥18 years admitted to Swiss Stroke Centers or Stroke Units during the first wave of COVID-19 (25 February to 8 June 2020). We compared baseline features, etiology, and 3-month outcome of SARS-CoV-2 polymerase chain reaction-positive (PCR+) IS patients to SARS-CoV-2 PCR- and/or asymptomatic non-tested IS patients. Of the 2341 IS patients registered in the SSR during the study period, 36 (1.5%) had confirmed COVID-19 infection, of which 33 were within 1 month before or after stroke onset. In multivariate analysis, COVID+ patients had more lesions in multiple vascular territories (OR 2.35, 95% CI 1.08-5.14, p = 0.032) and fewer cryptogenic strokes (OR 0.37, 95% CI 0.14-0.99, p = 0.049). COVID-19 was judged the likely principal cause of stroke in 8 patients (24%), a contributing/triggering factor in 12 (36%), and likely not contributing to stroke in 13 patients (40%). There was a strong trend towards worse functional outcome in COVID+ patients after propensity score (PS) adjustment for age, stroke severity, and revascularization treatments (PS-adjusted common OR for shift towards higher modified Rankin Scale (mRS) = 1.85, 95% CI 0.96-3.58, p = 0.07). In this nationwide analysis of consecutive ischemic strokes, concomitant COVID-19 was relatively rare. COVID+ patients more often had multi-territory stroke and less often cryptogenic stroke, and their 3-month functional outcome tended to be worse.

Wilms tumor; Pediatric; Renal tumor Tumor de Wilms; Pediatría; Tumor renal Tumor de Wilms; Pediatria; Tumor renal Background: The SIOP-Renal Tumor Study Group (RTSG) does not advocate invasive procedures to determine histology before the start of therapy. This may induce misdiagnosis-based treatment initiation, but only for a relatively small percentage of approximately 10% of non-Wilms tumors (non-WTs). MRI could be useful for reducing misdiagnosis, but there is no global consensus on differentiating characteristics. Purpose: To identify MRI characteristics that may be used for discrimination of newly diagnosed pediatric renal tumors. Study type: Consensus process using a Delphi method. Population: Not applicable. Field strength/sequence: Abdominal MRI including T1- and T2-weighted imaging, contrast-enhanced MRI, and diffusion-weighted imaging at 1.5 or 3 T. Assessment: Twenty-three radiologists from the SIOP-RTSG radiology panel with ≥5 years of experience in MRI of pediatric renal tumors and/or who had assessed ≥50 MRI scans of pediatric renal tumors in the past 5 years identified potentially discriminatory characteristics in the first questionnaire. These characteristics were scored in the subsequent second round, consisting of 5-point Likert scales, ranking- and multiple choice questions. Statistical tests: The cut-off value for consensus and agreement among the majority was ≥75% and ≥60%, respectively, with a median of ≥4 on the Likert scale. Results: Consensus on specific characteristics mainly concerned the discrimination between WTs and non-WTs, and WTs and nephrogenic rest(s) (NR)/nephroblastomatosis. The presence of bilateral lesions (75.0%) and NR/nephroblastomatosis (65.0%) were MRI characteristics indicated as specific for the diagnosis of a WT, and 91.3% of the participants agreed that MRI is useful to distinguish NR/nephroblastomatosis from WT. Furthermore, all participants agreed that age influenced their prediction in the discrimination of pediatric renal tumors. Data conclusion: Although the discrimination of pediatric renal tumors based on MRI remains challenging, this study identified some specific characteristics for tumor subtypes, based on the shared opinion of experts. These results may guide future validation studies and innovative efforts. This work was supported by a grant (Grant Number 341) from the Stichting Kinderen Kankervrij (KiKa).

ObjectivesTo investigate the cardiovascular consequences of SARS-CoV-2 infection in highly trained, otherwise healthy athletes using cardiac magnetic resonance (CMR) imaging and to compare our results with sex-matched and age-matched athletes and less active controls.MethodsSARS-CoV-2 infection was diagnosed by PCR on swab tests or serum immunoglobulin G antibody tests prior to a comprehensive CMR examination. The CMR protocol contained sequences to assess structural, functional and tissue-specific data.ResultsOne hundred forty-seven athletes (94 male, median 23, IQR 20–28 years) after SARS-CoV-2 infection were included. Overall, 4.7% (n=7) of the athletes had alterations in their CMR as follows: late gadolinium enhancement (LGE) showing a non-ischaemic pattern with or without T2 elevation (n=3), slightly elevated native T1 values with or without elevated T2 values without pathological LGE (n=3) and pericardial involvement (n=1). Only two (1.4%) athletes presented with definite signs of myocarditis. We found pronounced sport adaptation in both athletes after SARS-CoV-2 infection and athlete controls. There was no difference between CMR parameters, including native T1 and T2 mapping, between athletes after SARS-CoV-2 infection and the matched athletic groups. Comparing athletes with different symptom severities showed that athletes with moderate symptoms had slightly greater T1 values than athletes with asymptomatic and mildly symptomatic infections (pConclusionAmong 147 highly trained athletes after SARS-CoV-2 infection, cardiac involvement on CMR showed a modest frequency (4.7%), with definite signs of myocarditis present in only 1.4%. Comparing athletes after SARS-CoV-2 infection and healthy sex-matched and age-matched athletes showed no difference between CMR parameters, including native T1 and T2 values.

Tofacitinib is an oral Janus kinase inhibitor. Although it contributes to the induction and maintenance of clinical remission of patients with moderate-to-severe ulcerative colitis, various malignancies have been reported after the use of this small molecule. We report a rare case of biopsy-proven Kaposi sarcoma in a patient with complex biological-resistant ulcerative colitis after 2 years of treatment with tofacitinib. Kaposi sarcoma lesions spontaneously regressed after tofacitinib was discontinued. Given the concern of potential risk of malignancy associated with this agent, we believe that specialists should be aware of this rare but serious possible adverse event.

Current guidelines state that systemic inflammation, together with endothelial dysfunction, calcification, and hypercoagulability, predispose to premature atherosclerosis in patients with inflammatory bowel disease (IBD). We assessed whether IBD can affect aortic stiffness, a well-recognized vascular biomarker and an independent risk factor for cardiovascular (CV) disease (CVD) in several populations. Recent studies reported that aortic stiffness is increased in adults with IBD compared with matched controls. This association is dependent on inflammatory burden and disease duration, and is reduced by antitumor necrosis factor therapy. Considered together, current findings suggest that increased aortic stiffness is an extraintestinal manifestation of IBD. This is clinically relevant since measuring aortic stiffness in patients with IBD could improve risk assessment, especially in those without established CVD. Moreover, effective control of inflammation could lower CV risk in patients with IBD by reducing aortic stiffness. Further longitudinal studies are needed to better clarify (i) the relationship between disease duration and irreversible changes of the arterial wall, (ii) the clinical characteristics of patients with IBD that have an increased arterial stiffness at least in part reversible, and (iii) whether arterial stiffness is useful to evaluate the efficacy of immunosuppressive therapy.

Aims The aim of this study was to determine the contemporary use of reperfusion therapy in the European Society of Cardiology (ESC) member and affiliated countries and adherence to ESC clinical practice guidelines in patients with ST-elevation myocardial infarction (STEMI). Methods and results Prospective cohort (EURObservational Research Programme STEMI Registry) of hospitalized STEMI patients with symptom onset Conclusions The use of reperfusion therapy for STEMI in the ESC member and affiliated countries was high. Primary PCI was the most frequently used treatment and associated total in-hospital mortality was below 5%. However, there was geographic variation in the use of primary PCI, which was associated with differences in in-hospital mortality.

Biological drugs revolutionized the treatment of inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis. However, not all clinically eligible patients have access to biologicals due to significant costs and budget impact. Biosimilars are highly comparable to their originator product in terms of clinical efficacy and safety. Biosimilars are priced 15-75% lower than their reference product, which makes them a less costly alternative and is expected to offer better patients access to biologicals. The total projected cost savings are significant. If the achieved budget savings were used to cover more biological therapy, several additional IBD patients could be treated. Currently, the main barriers to the increasing uptake of biosimilars are the few incentives of the key stakeholders, while physicians’ and patients’ skepticism towards biosimilars seems to be changing. Over the coming years, biosimilars are expected to gain a growing importance in the treatment of IBD, contributing to a better access to treatment, improving population-level health gain and sustainability of health systems. This review summarizes the results of the literature on the economic considerations of biosimilars in IBD and the role of biosimilar infliximab in the treatment of IBD.

AIM To test the cross-immunogenicity of anti-CT-P13 IBD patients' sera to CT-P13/infliximab originator and the comparative antigenicity evoked by CT-P13/infliximab originator sera. METHODS Sera of patients with IBD with measurable anti-CT-P13 antibodies were tested for their cross-reactivity to 5 batches of infliximab originator and CT-P13. Anti-drug antibody positive sera from treated patients were used to compare antigenic epitopes. RESULTS All 42 anti-CT-P13 and 37 anti-infliximab originator IBD sera were cross-reactive with infliximab originator and CT-P13 respectively. Concentration of anti-drug antibodies against infliximab originator or CT-P13 were strongly correlated both for IgG1 and IgG4 (P

Introduction Iron metabolism determines the oxygen transport of the blood, thereby affecting the exercise capacity and performance. In patients with heart failure iron deficiency is a major risk factor that predicts and influences patient's quality of life. In athletes diagnosing iron deficiency is also extremely important as it determines sport performance. Purpose Our aim is to study the correlation of iron metabolism parameters with exercise capacity in athletes. Methods Cardiopulmonary exercise test (CPET) was performed as part of detailed sports cardiology screening. We studied in athletes the changes of iron metabolism parameters (serum iron, transferrin, total iron-binding capacity (TIBC), ferritin) and correlation with the exercise physiology parameters. Results Our measurements were performed on 105 top athletes: swimmers (n=58,55%; male = 29; junior = 30; 20,4±4,6 y), football players (n=47, 45%; junior = 6; 23,2±5,4 y). Laboratory test verified hemoglobin (male = 153,8±9,4; female = 141,2±7,7 g/L; p Conclusion Diagnosing iron deficiency in athletes, complete iron panel containing ferritin is required. According to our results iron status determines performance, therefore iron deficiency screening and iron supplementation is essential. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): - Supported by the ÚNKP-20-3-I New National Excellence Program of the Ministry for Innovation and Technology from the Source of the National Research, Development and Innovation Fund - The research was financed by the Thematic Excellence Programme (2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary, within the framework of the Therapeutic Development and Bioimaging programmes of the Semmelweis University.

Lysosomal degradation, the common destination of autophagy and endocytosis, is one of the most important elements of eukaryotic metabolism. The small GTPases Rab39A and B are potential new effectors of this pathway, as their malfunction is implicated in severe human diseases like cancer and neurodegeneration. In this study, the lysosomal regulatory role of the single Drosophila Rab39 ortholog was characterized, providing valuable insight into the potential cell biological mechanisms mediated by these proteins. Using a de novo CRISPR-generated rab39 mutant, we found no failure in the early steps of endocytosis and autophagy. On the contrary, we found that Rab39 mutant nephrocytes internalize and degrade endocytic cargo at a higher rate compared to control cells. In addition, Rab39 mutant fat body cells contain small yet functional autolysosomes without lysosomal fusion defect. Our data identify Drosophila Rab39 as a negative regulator of lysosomal clearance during both endocytosis and autophagy.

Colorectal malignancies are a leading cause of cancer death. Despite large-scale genomic efforts, DNA mutations do not fully explain malignant evolution. Here we study the co-evolution of the genome and epigenome of colorectal tumours at single-clone resolution using spatial multi-omic profiling of individual glands. We collected 1,373 samples from 30 primary cancers and 9 concomitant adenomas and generated 1,212 chromatin accessibility profiles, 527 whole-genomes and 297 whole-transcriptomes. We found positive selection for DNA mutations in chromatin modifier genes and recurrent chromatin changes in regulatory regions of cancer drivers with otherwise no mutation. Genome-wide alterations in transcription factor binding accessibility involved CTCF, downregulation of interferon, and increased accessibility for SOX and HOX, indicating developmental genes reactivation. Epigenetic aberrations were heritable, distinguishing adenomas from cancers. Mutational signature analysis showed the epigenome influencing DNA mutation accumulation. This study provides a map of (epi)genetic tumour heterogeneity, with fundamental implications for understanding colorectal cancer biology.

Background and Objectives: No data are available on whether the heritability of left ventricle (LV) systolic and diastolic parameters are independent of each other. Therefore, our aim was to assess the magnitude of common and independent genetic and environmental factors defining LV systolic and diastolic function. Materials and Methods: We analyzed 184 asymptomatic twins (65% female, mean age: 56 ± 9 years). Transthoracic echocardiography was performed to measure LV systolic (global longitudinal and circumferential strain, basal and apical rotation) and diastolic (early diastolic velocity of mitral inflow and lateral mitral annulus tissue, deceleration time and early diastolic strain rate) parameters using conventional and speckle-tracking echocardiography. Genetic structural equation models were evaluated to quantify the proportion of common and specific genetic (Ac, As) and environmental factors (Ec, Es) contributing to the phenotypes. Results: LV systolic parameters had no common genetic or environmental heritability (Ac range: 0–0%, Ec range: 0–0%, As range: 57–77%, Es range: 24–43%). Diastolic LV parameters were mainly determined by common genetic and environmental effects (Ac range: 9–40%, Ec range: 11–49%, As range: 0–29%, Es range: 0–51%). Systolic parameters had no common genetic or environmental factors (Ac = 0%, Ec = 0%) with diastolic metrics. Conclusions: Systolic LV parameters have a strong genetic predisposition to any impact. They share no common genetic or environmental factors with each other or with diastolic parameters, indicating that they may deteriorate specifically to given effects. However, diastolic functional parameters are mainly affected by common environmental influences, suggesting that pathological conditions may deteriorate them equally. Estimation of the genetic and environmental influence and interdependence on systolic and diastolic LV function may help the understanding of the pathomechanism of different heart failure classification types.