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Noémi Zádori,1,2 Dávid Németh,1 Levente Frim,1 Nóra Vörhendi,1,2 Lajos Szakó,1,2 Szilárd Váncsa,1– 3 Péter Hegyi,1– 3 József Czimmer1,4 1Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; 2János Szentágothai Research Centre, University of Pécs, Pécs, Hungary; 3Centre for Translational Medicine, Semmelweis University, Budapest, Hungary; 4Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, HungaryCorrespondence: József Czimmer, First Department of Medicine, University of Pécs Medical School, Ifjúság street 13, Pécs, H-7624, Hungary, Email czimmer.jozsef@pte.huIntroduction: Dyspeptic symptoms are frequent in the general population, with a high socioeconomic burden. Helicobacter pylori (H. pylori) might be a possible etiological factor; however, it is also common in H. pylori negative gastritis. Clarification of the underlying aetiology might be beneficial to set up the optimal treatment strategy for dyspepsia and chronic gastritis (CG) itself. We aimed to assess the prevalence of dyspeptic symptoms in patients with H. pylori negative CG and explore autoimmunity’s possible role.Methods: This retrospective study included data from patients with H. pylori negative CG. Exclusion criteria were (1) acute gastritis; (2) reactive gastropathy; (3) subjects without any serology testing results; (4) H. pylori positivity; (5) presence of atrophy, intestinal metaplasia (IM), gastroesophageal reflux disease (GERD), ulcer, or cancer. The following endpoints were assessed (1) the rate of dyspepsia-like symptoms; (2) association between dyspepsia and autoimmune disease-related seromarker positivity (AISP); (3) frequency of other symptoms in CG and its association with AISP; (4) location of the inflammation and its association with AISP.Results: From a total of 285 patients, 175 were included in this study. Among these patients, 95 experienced dyspeptic symptoms (54.29%) and were associated more with AISP (p = 0.012), especially with celiac seropositivity (p = 0.045), anti-neutrophil cytoplasmic antibody (ANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) positivity (p = 0.043). A significant association was not found with other tested autoimmune (AI)-related antibody positivity.Conclusion: Positivity of seromarkers of autoimmune diseases in chronic gastritis may predispose to have dyspeptic symptoms and may be the causative factor behind some cases of uninvestigated dyspepsia. These data suggest that further prospective studies are needed to clarify whether screening for autoantibodies in patients with dyspepsia is cost-effective and helps the earlier diagnosis of autoimmune diseases.Keywords: chronic gastritis, autoimmunity, auto-antibody, dyspepsia

Background and Aims: The underlying aetiology of chronic gastritis (CG) often remains unknown due to its underrated significance in clinical practice. However, the role of chronic inflammation of the stomach in the development of atrophy, intestinal metaplasia (IM) and eventually of gastric cancer is well documented. We aimed to explore the possible aetiological factors of CG, determine the prevalence of systemic autoimmune disorders in patients with CG of unknown aetiology, and clarify the role of autoantibodies in the development of precancerous lesions in the stomach., Methods: This is a retrospective, cross-sectional study, conducted from January 2016 to January 2020, including data from 175 patients with CG. Exclusion criteria were: (1) acute gastritis; (2) reactive gastropathy; (3) gastric cancer; (4) subjects without any serology testing results; and (5) Helicobacter pylori positivity. The primary endpoint was a composite endpoint involving gastric atrophy and IM., Results: Fifty-five per cent of patients with CG had autoantibodies. Systemic lupus erythematosus (SLE)-related antibodies were positive in most of the cases, including antinuclear antibody (ANA) positivity, which was found in 19.13% of the patients. Autoimmune positivity was shown to be associated with precancerous lesions in the stomach (p<0.001): IM, atrophy and IM with atrophy. Anti-parietal cell antibody positivity seems to be a significant risk factor for IM and IM with atrophy. Autoimmune thyroiditis-related antibodies and ANA positivity by itself were only associated with atrophy; SLE-related antibodies and inflammatory bowel diseases related antibodies (ASCA and ANCA) correlated either with IM or with atrophy. No significant relation was found between any other investigated autoimmune disease-related antibodies and precancerous lesions., Conclusions: Autoimmune positivity often underlies gastritis of unknown aetiology and predisposes to precancerous lesions in the stomach. These antibodies can serve as non-invasive markers for the of optimal timing of an endoscopic follow-up strategy. Furthermore, CG can be an early symptom of a systemic autoimmune disorder.

Background/objectives: Acute recurrent pancreatitis (ARP) due to alcohol and/or tobacco abuse is a preventable disease which lowers quality of life and can lead to chronic pancreatitis. The REAPPEAR study aims to investigate whether a combined patient education and cessation programme for smoking and alcohol prevents ARP., Methods and Analysis: The REAPPEAR study consists of an international multicentre randomised controlled trial (REAPPEAR-T) testing the efficacy of a cessation programme on alcohol and smoking and a prospective cohort study (REAPPEAR-C) assessing the effects of change in alcohol consumption and smoking (irrespective of intervention). Daily smoker patients hospitalised with alcohol-induced acute pancreatitis (AP) will be enrolled. All patients will receive a standard intervention priorly to encourage alcohol and smoking cessation. Participants will be subjected to laboratory testing, measurement of blood pressure and body mass index and will provide blood, hair and urine samples for later biomarker analysis. Addiction, motivation to change, socioeconomic status and quality of life will be evaluated with questionnaires. In the trial, patients will be randomised either to the cessation programme with 3-monthly visits or to the control group with annual visits. Participants of the cessation programme will receive a brief intervention at every visit with direct feedback on their alcohol consumption based on laboratory results. The primary endpoint will be the composite of 2-year all-cause recurrence rate of AP and/or 2-year all-cause mortality. The cost-effectiveness of the cessation programme will be evaluated. An estimated 182 participants will be enrolled per group to the REAPPEAR-T with further enrolment to the cohort., Ethics and Dissemination: The study was approved by the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (40394-10/2020/EÜIG), all local ethical approvals are in place. Results will be disseminated at conferences and in peer-reviewed journals., Trial Registration Number: NCT04647097., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Gastric cancer is one of the most common cancers worldwide, with a high mortality rate. The potential etiological role of autoimmune (AI) disorders has been described in gastric cancer; however, the literature is controversial. This study aims to provide a comprehensive summary of the association between autoimmune disorders and the incidence of gastric cancer., Methods: This study was registered on PROSPERO under registration number CRD42021262875. The systematic literature search was conducted in four scientific databases up to May 17, 2021. Studies that reported standardized incidence rate (SIR) of gastric cancer in autoimmune disorders were eligible. We calculated pooled SIRs with 95% confidence intervals (CIs) in this meta-analysis., Results: We included 43 articles describing 36 AI disorders with data of 499,427 patients from four continents in our systematic review and meta-analysis. Significantly increased incidence of gastric cancer was observed in dermatomyositis (SIR = 3.71; CI: 2.04, 6.75), pernicious anemia (SIR = 3.28; CI: 2.71, 3.96), inflammatory myopathies (SIR = 2.68; CI:1.40; 5.12), systemic lupus erythematosus (SIR = 1.48; CI: 1.09, 2.01), diabetes mellitus type I (SIR = 1.29; CI:1.14, 1,47), and Graves' disease (SIR = 1.28; CI: 1.16, 1.41). No significant associations could be found regarding other AI disorders., Conclusions: Pernicious anemia, Graves' disease, dermatomyositis, diabetes mellitus type I, inflammatory myopathies, and systemic lupus erythematosus are associated with higher incidence rates of gastric cancer. Therefore, close gastroenterological follow-up or routinely performed gastroscopy and application of other diagnostic measures may be cost-effective and clinically helpful for patients diagnosed with these autoimmune diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zádori, Szakó, Váncsa, Vörhendi, Oštarijaš, Kiss, Frim, Hegyi and Czimmer.)

Introduction: Sepsis and septic shock have mortality rates between 20% and 50%. In sepsis, the immune response becomes dysregulated, which leads to an imbalance between proinflammatory and anti-inflammatory mediators. When standard therapeutic measures fail to improve patients' condition, additional therapeutic alternatives are applied to reduce morbidity and mortality. One of the most recent alternatives is extracorporeal cytokine adsorption with a device called CytoSorb. This study aims to compare the efficacy of standard medical therapy and continuous extracorporeal cytokine removal with CytoSorb therapy in patients with early refractory septic shock. Furthermore, we compare the dosing of CytoSorb adsorber device changed every 12 or 24 hours., Methods and Analysis: It is a prospective, randomised, controlled, open-label, international, multicentre, phase III study. Patients fulfilling the inclusion criteria will be randomly assigned to receive standard medical therapy (group A) or-in addition to standard treatment-CytoSorb therapy. CytoSorb treatment will be continuous and last for at least 24 hours, CytoSorb adsorber device will be changed every 12 (group B) or 24 hours (group C). Our primary outcome is shock reversal (no further need or a reduced (≤10% of the maximum dose) vasopressor requirement for 3 hours) and time to shock reversal (number of hours elapsed from the start of the treatment to shock reversal).Based on sample size calculation, 135 patients (1:1:1) will need to be enrolled in the study. A predefined interim analysis will be performed after reaching 50% of the planned sample size, therefore, the corrected level of significance (p value) will be 0.0294., Ethics and Dissemination: Ethics approval was obtained from the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (OGYÉI/65049/2020). Results will be submitted for publication in a peer-reviewed journal., Trial Registration Number: NCT04742764; Pre-results., Competing Interests: Competing interests: ZMo is one of the medical directors at CytoSorbents Europe., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The prevalence of familial hypercholesterolemia (FH) is about 1 in 200-500 in the general population, but approximately less than 1% of those affected are actually diagnosed. One of the most promising approaches to treat FH is utilizing human monoclonal antibodies. This is a case study describing a 47-year-old male patient who presented to the Emergency Department with acute abdominal pain caused by severe hypertriglyceridemia (HTG)-induced acute pancreatitis (AP). We report the steps necessary for establishing the right diagnosis and the management of HTG-induced AP, which are inevitable for the reduction of severity and mortality. This case study shows that hypercholesterolemia is an underdiagnosed and potentially lethal disease. Once diagnosed, all measures should be considered to control blood cholesterol and lipid levels. The decision to administer PCSK9 inhibitors should not be solely based on economical calculation, but rather individual factors should also be considered to weigh the risk/benefit ratio., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 by S. Karger AG, Basel.)

Background: Coronavirus disease 2019 (COVID-19) is an infection with possible serious consequences. The plasma of recovered patients might serve as treatment, which we aim to assess in the form of a prospective meta-analysis focusing on mortality, multi-organ failure, duration of intensive care unit stay, and adverse events., Methods: A systematic search was conducted to find relevant registered randomized controlled trials in five trial registries. A comprehensive search will be done continuously on a monthly basis in MEDLINE (via PubMed), Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science to find the results of previously registered randomized controlled trials. The selection will be done by two independent authors. Data extraction will be carried out by two other independent reviewers. Disagreements will be resolved by a third investigator. An update of the search of the registries and the first search of the databases will be done on the 21st of July. Data synthesis will be performed following the recommendations of the Cochrane Collaboration. In the case of dichotomous outcomes (mortality and organ failure), we will calculate pooled risk ratios with a 95% confidence interval (CI) from two-by-two tables (treatment Y/N, outcome Y/N). Data from models with multivariate adjustment (hazard ratios, odds ratio, risk ratio) will be preferred for the analysis. P less than 0.05 will be considered statistically significant. In the case of ICU stay, weighted mean difference with a 95% confidence interval will be calculated. Heterogeneity will be tested with I 2 , and χ 2 tests. Meta-analysis will be performed if at least 3 studies report on the same outcome and population., Discussion: Convalescent plasma therapy is a considerable alternative in COVID-19, which we aim to investigate in a prospective meta-analysis.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with an overall 5-year survival of approximately 8%. The success in reducing the mortality rate of PDAC is related to the discovery of new therapeutic agents, and to a significant extent to the development of early detection and prevention programmes. Patients with new-onset diabetes mellitus (DM) represent a high-risk group for PDAC as they have an eightfold higher risk of PDAC than the general population. The proposed screening programme may allow the detection of PDAC in the early, operable stage. Diagnosing more patients in the curable stage might decrease the morbidity and mortality rates of PDAC and additionally reduce the burden of the healthcare., Methods and Analysis: This is a prospective, multicentre observational cohort study. Patients ≥60 years old diagnosed with new-onset (≤6 months) diabetes will be included. Exclusion criteria are (1) Continuous alcohol abuse; (2) Chronic pancreatitis; (3) Previous pancreas operation/pancreatectomy; (4) Pregnancy; (5) Present malignant disease and (6) Type 1 DM. Follow-up visits are scheduled every 6 months for up to 36 months. Data collection is based on questionnaires. Clinical symptoms, body weight and fasting blood will be collected at each, carbohydrate antigen 19-9 and blood to biobank at every second visit. The blood samples will be processed to plasma and analysed with mass spectrometry (MS)-based metabolomics. The metabolomic data will be used for biomarker validation for early detection of PDAC in the high-risk group patients with new-onset diabetes. Patients with worrisome features will undergo MRI or endoscopic ultrasound investigation, and surgical referral depending on the radiological findings. One of the secondary end points is the incidence of PDAC in patients with newly diagnosed DM., Ethics and Dissemination: The study has been approved by the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (41085-6/2019). We plan to disseminate the results to several members of the healthcare system includining medical doctors, dietitians, nurses, patients and so on. We plan to publish the results in a peer-reviewed high-quality journal for professionals. In addition, we also plan to publish it for lay readers in order to maximalise the dissemination and benefits of this trial., Trial Registration Number: ClinicalTrials.gov NCT04164602., Competing Interests: Competing interests: BK and AMG are employees of Metanomics Health GmbH, Germany., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We aimed to perform a systematic search and meta-analysis to evaluate the prognostic value of on-admission liver function tests and pre-existing liver diseases on the clinical course of coronavirus disease 2019 (COVID-19). Methods: The study was registered on PROSPERO (CRD42020182902). We searched five databases between 01/01/2020 and 04/23/2020. Studies that reported on liver-related comorbidities and/or laboratory parameters in patients with COVID-19 were included. The main outcomes were COVID-19 severity, intensive care unit (ICU) admission, and in-hospital mortality. Analysis of predictive models hierarchical summary receiver-operating characteristic (HSROC) was conducted with a 95% confidence interval (CI). Results: Fifty studies were included in the meta-analysis. High specificity was reached by acute liver failure associated by COVID-19 (0.94, 95% CI: 0.71-0.99) and platelet count (0.94, 95% CI: 0.71-0.99) in the case of mortality; chronic liver disease (CLD) (0.98, 95% CI: 0.96-0.99) and platelet count (0.82, 95% CI: 0.72-0.89) in the case of ICU requirement; and CLD (0.97, 95% CI: 0.95-0.98), chronic hepatitis B infection (0.97, 95% CI: 0.95-0.98), platelet count (0.86, 95% CI: 0.77-0.91), and alanine aminotransferase (ALT) (0.80, 95% CI: 0.66-0.89) and aspartate aminotransferase (AST) (0.84, 95% CI: 0.77-0.88) activities considering severe COVID-19. High sensitivity was found in the case of C-reactive protein (CRP) for ICU requirement (0.92, 95% CI: 0.80-0.97) and severe COVID-19 (0.91, 95% CI: 0.82-0.96). Conclusion: On-admission platelet count, ALT and AST activities, CRP concentration, and the presence of acute and CLDs predicted the severe course of COVID-19. To highlight, pre-existing liver diseases or acute liver injury associated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection plays an important role in the prediction of mortality., (Copyright © 2020 Váncsa, Hegyi, Zádori, Szakó, Vörhendi, Ocskay, Földi, Dembrovszky, Dömötör, Jánosi, Rakonczay, Hartmann, Horváth, Erőss, Kiss, Szakács, Németh, Hegyi and Pár.)

Introduction: Inflammatory bowel diseases (IBD) are among the most common chronic illnesses diagnosed in childhood. Transition from paediatric to adult care is a crucial phase. The implementation of joint visits during the transition period in IBD is widely recommended, however, strong evidence supporting their benefit is still missing. In this trial, we aim to prove the superiority of joint visits compared with usual care in improving transition outcomes of adolescents with IBD., Methods and Analysis: This is a randomised controlled two-arm multicentre trial. A minimum of 160 adolescents with IBD aged between 16.75 and 17 years will be recruited from Hungarian tertiary IBD centres. After randomisation, eligible subjects in the intervention arm attend a total of four joint visits with adult and paediatric gastroenterologist between the ages of 17 and 18. In the control arm, adolescents meet only the paediatric gastroenterologist, but there is a balanced consultation between the two gastroenterologist regarding the patient's treatment plan. Patients in both groups receive the same training and education, the only determinative difference between the two arms is the presence of the adult gastroenterologist at the joint visits. Data will be collected at inclusion, at transfer and 12 months post-transfer. Primary outcome is the change in health-related quality of life measured with the IMPACT-III questionnaire at 1 year after transfer. Secondary outcomes include the number of patients not lost to follow-up, healthcare utilisation, disease activity, medication adherence, self-efficacy, transition readiness and patient's satisfaction. To compare the results of the two patient groups, two-sample T-test and Mann-Whitney test will be applied., Ethics and Dissemination: The Scientific and Research Ethics Committee of the Hungarian Medical Research Council approved this study (50457-2/2019/EKU). Findings will be disseminated at conferences and in medical journals., Trial Registration Number: NCT04290156., Competing Interests: Competing interests: None declared. Principal investigators of each study sites decline any financial and other competing interests., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Early reports indicate that COVID-19 may require intensive care unit (ICU) admission in 5-26% and overall mortality can rise to 11% of the recognised cases, particularly affecting the elderly. There is a lack of evidence-based targeted pharmacological therapy for its prevention and treatment. We aim to compare the effects of a World Health Organization recommendation-based education and a personalised complex preventive lifestyle intervention package (based on the same WHO recommendation) on the outcomes of the COVID-19., Methods: PROACTIVE-19 is a pragmatic, randomised controlled clinical trial with adaptive "sample size re-estimation" design. Hungarian population over the age of 60 years without confirmed COVID-19 will be approached to participate in a telephone health assessment and lifestyle counselling voluntarily. Volunteers will be randomised into two groups: (A) general health education and (B) personalised health education. Participants will go through questioning and recommendation in 5 fields: (1) mental health, (2) smoking habits, (3) physical activity, (4) dietary habits, and (5) alcohol consumption. Both groups A and B will receive the same line of questioning to assess habits concerning these topics. Assessment will be done weekly during the first month, every second week in the second month, then monthly. The composite primary endpoint will include the rate of ICU admission, hospital admission (longer than 48 h), and mortality in COVID-19-positive cases. The estimated sample size is 3788 subjects per study arm. The planned duration of the follow-up is a minimum of 1 year., Discussion: These interventions may boost the body's cardiovascular and pulmonary reserve capacities, leading to improved resistance against the damage caused by COVID-19. Consequently, lifestyle changes can reduce the incidence of life-threatening conditions and attenuate the detrimental effects of the pandemic seriously affecting the older population., Trial Registration: The study has been approved by the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (IV/2428- 2 /2020/EKU) and has been registered at clinicaltrials.gov ( NCT04321928 ) on 25 March 2020.

Introduction: Acute pancreatitis (AP) is a life-threatening inflammatory disease of the exocrine pancreas which needs acute hospitalisation. Despite its importance, we have significant lack of knowledge whether the lifestyle factors elevate or decrease the risk of AP or influence the disease outcome. So far, no synthetising study has been carried out examining associations between socioeconomic factors, dietary habits, physical activity, chronic stress, sleep quality and AP. Accordingly, LIFESPAN identifies risk factors of acute pancreatitis and helps to prepare preventive recommendations for lifestyle elements., Methods and Analysis: LIFESPAN is an observational, multicentre international case-control study. Participating subjects will create case and control groups. The study protocol was designed according to the SPIRIT guideline. Patients in the case group (n=1700) have suffered from AP (alcohol-induced, n=500; biliary, n=500; hypertriglyceridemiainduced, n=200; other, n=500); the control group subjects have no AP in their medical history. Our study will have three major control groups (n=2200): hospital-based (n=500), population-based (n=500) and aetiology-based (alcohol, n=500; biliary, n=500 and hypertriglyceridemia, n=200). All of them will be matched to the case group individually by gender, age and location of residence. Aggregately, 3900 subjects will be enrolled into the study. The study participants will complete a complex questionnaire with the help of a clinical research administrator/study nurse. Analysis methods include analysis of the continuous and categorical values., Ethics and Dissemination: The study has obtained the relevant ethical approval (54175-2/2018/EKU) and also internationally registered (ISRCTN25940508). After obtaining the final conclusions, we will publish the data to the medical community and will also disseminate our results via open access., Trial Registration Number: ISRCTN25940508; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: According to the literature, early cholecystectomy is necessary to avoid complications related to gallstones after an initial episode of acute biliary pancreatitis (ABP). A randomised, controlled multicentre trial (the PONCHO trial) revealed that in the case of gallstone-induced pancreatitis, early cholecystectomy was safe in patients with mild gallstone pancreatitis and reduced the risk of recurrent gallstone-related complications, as compared with interval cholecystectomy. We hypothesise that carrying out a sphincterotomy (ES) allows us to delay cholecystectomy, thus making it logistically easier to perform and potentially increasing the efficacy and safety of the procedure., Methods/design: EMILY is a prospective, randomised, controlled multicentre trial. All patients with mild ABP, who underwent ES during the index admission or in the medical history will be informed to take part in EMILY study. The patients will be randomised into two groups: (1) early cholecystectomy (within 6 days after discharge) and (2) patients with delayed (interval) cholecystectomy (between 45 and 60 days after discharge). During a 12-month period, 93 patients will be enrolled from participating clinics. The primary endpoint is a composite endpoint of mortality and recurrent acute biliary events (that is, recurrent ABP, acute cholecystitis, uncomplicated biliary colic and cholangitis). The secondary endpoints are organ failure, biliary leakage, technical difficulty of the cholecystectomy, surgical and other complications., Ethics and Dissemination: The trial has been registered internationally ISRCTN 10667869, and approved by the relevant organisation, the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (EKU/2018/12176-5)., Trial Registration Number: ISCRTN 10667869; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)