Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma.

INTRODUCTION: Only a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate. MATERIALS AND METHODS: We scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase. RESULTS: The C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10-8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1. CONCLUSION: We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.

Combined use of indomethacin and hydration is the best conservative approach for post-ERCP pancreatitis prevention: A network meta-analysis.

OBJECTIVES: Post-ERCP pancreatitis (PEP) is a life-threatening complication. Given the lack of a causative treatment for pancreatitis, it is of vital importance to minimize this risk of PEP. Multi-target preventive therapy may be the best choice for PEP prevention as disease development is multifactorial. AIM: We aimed to assess the efficacy of a combination of indomethacin and hydration - type and amount - for PEP prevention via a network meta-analysis. METHODS: Through a systematic search in three databases, we searched all randomized controlled trials involving hydration and indomethacin and ranked the PEP preventive efficacy with a Bayesian network meta-analysis using the PRISMA for Network Meta-Analyses (PRISMA-NMA) guideline. The RoB2 tool was used for risk of bias assessment, surface under the cumulative ranking curve (SUCRA) for ranking and PROSPERO for the study protocol [reg. no. CRD42018112698]. We used risk ratios (RR) for dichotomous data with 95% credible intervals (95% CrI). RESULTS: The quantitative analysis included 7559 patients from 24 randomized controlled trials. Based on the SUCRA values, a combination of lactated Ringer's and indomethacin is more effective than single therapy with a 94% certainty. The percent relative risk ratios estimate preventive efficacy 70-99% higher for combinations than single therapies. Aggressive hydration with indomethacin (SUCRA 100%) is also significantly more effective than all other interventions (percent relative effect 94.3-98.1%). CONCLUSIONS: A one-hit-on-each-target therapeutic approach is recommended in PEP prevention with an easily accessible combination of indomethacin and aggressive hydration for all average and high-risk patients without contraindication.

Early occurrence of pseudocysts in acute pancreatitis - A multicenter international cohort analysis of 2275 cases.

BACKGROUND: Pseudocysts being the most frequent local complications of acute pancreatitis (AP) have substantial effect on the disease course, hospitalization and quality of life of the patient. Our study aimed to understand the effects of pre-existing (OLD-P) and newly developed (NEW-P) pseudocysts on AP. METHODS: Data were extracted from the Acute Pancreatitis Registry organized by the Hungarian Pancreatic Study Group (HPSG). 2275 of 2461 patients had uploaded information concerning pancreatic morphology assessed by imaging technique. Patients were divided into "no pseudocyst" (NO-P) group, "old pseudocyst" (OLD-P) group, or "newly developed pseudocyst" (NEW-P) groups. RESULTS: The median time of new pseudocyst development was nine days from hospital admission and eleven days from the beginning of the abdominal pain. More NEW-P cases were severe (15.9% vs 4.7% in the NO-P group p < 0.001), with longer length of hospitalization (LoH) (median: 14 days versus 8 days, p < 0.001), and were associated with several changed laboratory parameters. OLD-P was associated with male gender (72.2% vs. 56.1%, p = 0.0014), alcoholic etiology (35.2% vs. 19.8% in the NO-P group), longer hospitalization (median: 10 days, p < 0.001), a previous episode of AP (p < 0.001), pre-existing diagnosis of chronic pancreatitis (CP) (p < 0.001), current smoking (p < 0.001), and increased alcohol consumption (unit/week) (p = 0.014). CONCLUSION: Most of the new pseudocysts develop within two weeks. Newly developing pseudocysts are associated with a more severe disease course and increased length of hospitalization. Pre-existing pseudocysts are associated with higher alcohol consumption and smoking. Because CP is more frequently associated with a pre-existing pseudocyst, these patients need closer attention after AP.

Early changes in laboratory parameters are predictors of mortality and ICU admission in patients with COVID-19: a systematic review and meta-analysis.

Despite the growing knowledge of the clinicopathological features of COVID-19, the correlation between early changes in the laboratory parameters and the clinical outcomes of patients is not entirely understood. In this study, we aimed to assess the prognostic value of early laboratory parameters in COVID-19. We conducted a systematic review and meta-analysis based on the available literature in five databases. The last search was on July 26, 2020, with key terms related to COVID-19. Eligible studies contained original data of at least ten infected patients and reported on baseline laboratory parameters of patients. We calculated weighted mean differences (WMDs) for continuous outcomes and odds ratios (ORs) with 95% confidence intervals. 93 and 78 studies were included in quantitative and qualitative syntheses, respectively. Higher baseline total white blood cell count (WBC), C-reactive protein (CRP), lactate-dehydrogenase (LDH), creatine kinase (CK), D-dimer and lower absolute lymphocyte count (ALC) (WMDALC = - 0.35 × 109/L [CI - 0.43, - 0.27], p < 0.001, I2 = 94.2%; < 0.8 × 109/L, ORALC = 3.74 [CI 1.77, 7.92], p = 0.001, I2 = 65.5%) were all associated with higher mortality rate. On admission WBC, ALC, D-dimer, CRP, LDH, and CK changes could serve as alarming prognostic factors. The correct interpretation of laboratory abnormalities can guide therapeutic decisions, especially in early identification of potentially critical cases. This meta-analysis should help to allocate resources and save lives by enabling timely intervention.

Recurrent acute pancreatitis induced by 5-ASA and azathioprine in ulcerative colitis.

Drug-induced acute pancreatitis (DIAP) is an often-neglected entity where the disorder is the consequence of the toxic effects of various agents applied to treat potentially life-threatening conditions, such as inflammatory bowel disease. Here, we present the case of a male patient with ulcerative colitis with a history of two episodes of recurrent acute pancreatitis. After excluding other potential causes, we suspected DIAP since the patient received 5-aminosalycilate (5-ASA) prior to the first episode and, one year later, azathioprine (AZA) prior to the second episode. The causative effect of AZA was confirmed by performing a re-challenge with a reduced dose. While both episodes of DIAP had a mild disease course, they were associated with acute relapse of ulcerative colitis. Last seen, the patient was asymptomatic. With this case, we would like to highlight the importance and diagnostic difficulties of DIAP in the background of recurrent cases when common etiological factors of acute pancreatitis are excluded.

Hypertriglyceridemia-induced acute pancreatitis: A prospective, multicenter, international cohort analysis of 716 acute pancreatitis cases.

BACKGROUND: Hypertriglyceridemia is the third most common cause of acute pancreatitis (AP). It has been shown that hypertriglyceridemia aggravates the severity and related complications of AP; however, detailed analyses of large cohorts are contradictory. Our aim was to investigate the dose-dependent effect of hypertriglyceridemia on AP. METHODS: AP patients over 18 years old who underwent triglyceride measurement within the initial three days were included into our cohort analysis from a prospective international, multicenter AP registry operated by the Hungarian Pancreatic Study Group. Data on 716 AP cases were analyzed. Six groups were created based on the highest triglyceride level (<1.7 mmol/l, 1.7-2.19 mmol/l, 2.2-5.59 mmol/l, 5.6-11.29 mmol/l, 11.3-22.59 mmol/l, ≥22.6 mmol/l). RESULTS: Hypertriglyceridemia (≥1.7 mmol/l) presented in 30.6% of the patients and was significantly and dose-dependently associated with younger age and male gender. In 7.7% of AP cases, hypertriglyceridemia was considered as a causative etiological factor (≥11.3 mmol/l); however, 43.6% of these cases were associated with other etiologies (alcohol and biliary). Hypertriglyceridemia was significantly and dose-dependently related to obesity and diabetes. The rates of local complications and organ failure and maximum CRP level were significantly and dose-dependently raised by hypertriglyceridemia. Triglyceride above 11.3 mmol/l was linked to a significantly higher incidence of moderately severe AP and longer hospital stay, whereas triglyceride over 22.6 mmol/l was significantly associated with severe AP as well. CONCLUSION: Hypertriglyceridemia dose-dependently aggravates the severity and related complications of AP. Diagnostic workup for hypertriglyceridemia requires better awareness regardless of the etiology of AP.

Antibiotic therapy in acute pancreatitis: From global overuse to evidence based recommendations.

BACKGROUND: Unwarranted administration of antibiotics in acute pancreatitis presents a global challenge. The clinical reasoning behind the misuse is poorly understood. Our aim was to investigate current clinical practices and develop recommendations that guide clinicians in prescribing antibiotic treatment in acute pancreatitis. METHODS: Four methods were used. 1) Systematic data collection was performed to summarize current evidence; 2) a retrospective questionnaire was developed to understand the current global clinical practice; 3) five years of prospectively collected data were analysed to identify the clinical parameters used by medical teams in the decision making process, and finally; 4) the UpToDate Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system was applied to provide evidence based recommendations for healthcare professionals. RESULTS: The systematic literature search revealed no consensus on the start of AB therapy in patients with no bacterial culture test. Retrospective data collection on 9728 patients from 22 countries indicated a wide range (31-82%) of antibiotic use frequency in AP. Analysis of 56 variables from 962 patients showed that clinicians initiate antibiotic therapy based on increased WBC and/or elevated CRP, lipase and amylase levels. The above mentioned four laboratory parameters showed no association with infection in the early phase of acute pancreatitis. Instead, procalcitonin levels proved to be a better biomarker of early infection. Patients with suspected infection because of fever had no benefit from antibiotic therapy. CONCLUSIONS: The authors formulated four consensus statements to urge reduction of unjustified antibiotic treatment in acute pancreatitis and to use procalcitonin rather than WBC or CRP as biomarkers to guide decision-making.

Incidence of recurrent and chronic pancreatitis after acute pancreatitis: a systematic review and meta-analysis.

Background: Acute pancreatitis (AP) has a high incidence, and patients can develop recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) after AP. Objectives: We aimed to estimate the pooled incidence rates (IRs), cumulative incidences, and proportions of RAP and CP after AP. Design: A systematic review and meta-analysis of studies reporting the proportion of RAP and CP after AP. Data sources and methods: The systematic search was conducted in three (PubMed, EMBASE, and CENTRAL) databases on 19 December 2023. Articles reporting the proportion of RAP or CP in patients after the first and multiple episodes of AP were eligible. The random effects model was used to calculate the pooled IR with 95% confidence intervals (CIs). The I 2 value assessed heterogeneity. The risk of bias assessment was conducted with the Joanna Briggs Institute Critical Appraisal Tool. Results: We included 119 articles in the quantitative synthesis and 29 in the IRs calculations. Our results showed that the IR of RAP in adult patients after AP was 5.26 per 100 person-years (CI: 3.99-6.94; I 2 = 93%), while in children, it was 4.64 per 100 person-years (CI: 2.73-7.87; I 2 = 88%). We also found that the IR of CP after AP was 1.4 per 100 person-years (CI: 0.9-2; I 2 = 75%), while after RAP, it increased to 4.3 per 100 person-years (CI: 3.1-6.0; I 2 = 76%). The risk of bias was moderate in the majority of the included studies. Conclusion: Our results showed that RAP affects many patients with AP. Compared to patients with the first AP episode, RAP leads to a threefold higher IR for developing CP. Trial registration: Our protocol was registered on PROSPERO (CRD42021283252).

Morphology of the papilla can predict procedural safety and efficacy of ERCP-a systematic review and meta-analysis.

Endoscopic Retrograde Cholangiopancreatography (ERCP) is the primary therapeutic procedure for pancreaticobiliary disorders, and studies highlighted the impact of papilla anatomy on its efficacy and safety. Our objective was to quantify the influence of papilla morphology on ERCP outcomes. We systematically searched three medical databases in September 2022, focusing on studies detailing the cannulation process or the rate of adverse events in the context of papilla morphology. The Haraldsson classification served as the primary system for papilla morphology, and a pooled event rate with a 95% confidence interval was calculated as the effect size measure. Out of 17 eligible studies, 14 were included in the quantitative synthesis. In studies using the Haraldsson classification, the rate of difficult cannulation was the lowest in type I papilla (26%), while the highest one was observed in the case of type IV papilla (41%). For post-ERCP pancreatitis, the event rate was the highest in type II papilla (11%) and the lowest in type I and III papilla (6-6%). No significant difference was observed in the cannulation failure and post-ERCP bleeding event rates between the papilla types. In conclusion, certain papilla morphologies are associated with a higher rate of difficult cannulation and post-ERCP pancreatitis.

The risk of developing splanchnic vein thrombosis in acute pancreatitis increases 3 days after symptom onset: A systematic review and meta-analysis.

BACKGROUND: Splanchnic vein thrombosis is a complication of acute pancreatitis (AP) and is likely often underdiagnosed. OBJECTIVES: We aimed to understand the time course and risk factors of splanchnic vein thrombosis in the early phase of AP. METHODS: A systematic search was conducted using the PRISMA guidelines (PROSPERO registration CRD42022367578). Inclusion criteria were appropriate imaging techniques in adult AP patients, studies that reported splanchnic vein thrombosis data from the early phase, and reliable information on the timing of imaging in relation to the onset of pancreatitis symptoms or hospital admission. The proportion of patients with thrombosis with 95% confidence intervals (CI) was calculated using random-effects meta-analyses, and multiple subgroup analyses were performed. RESULTS: Data from 1951 patients from 14 studies were analyzed. The proportion of patients with splanchnic vein thrombosis within 12 days after symptom onset was 0.13 (CI 0.07-0.23). The occurrence was lowest at 0.06 (CI 0.03-0.1) between 0 and 3 days after symptom onset, and increased fourfold to 0.23 (CI 0.16-0.31) between 3 and 11 days. On hospital admission, the proportion of patients affected was 0.12 (CI 0.02-0.49); it was 0.17 (CI 0.03-0.58) 1-5 days after admission. The prevalence in mild, moderate, and severe AP was 0.15 (CI 0.05-0.36), 0.26 (CI 0.15-0.43), and 0.27 (CI 0.17-0.4), respectively. Alcoholic etiology (0.31, CI 0.13-0.58) and pancreatic necrosis (0.55, CI 0.29-0.78, necrosis above 30%) correlated with increased SVT prevalence. CONCLUSION: The risk of developing splanchnic vein thrombosis is significant in the early stages of AP and may affect up to a quarter of patients. Alcoholic etiology, pancreatic necrosis, and severity may increase the prevalence of splanchnic vein thrombosis.

Low molecular weight heparin decreases mortality and major complication rates in moderately severe and severe acute pancreatitis-a systematic review and meta-analysis.

Background: Routine anticoagulation therapy in acute pancreatitis (AP) is not recommended by the guidelines in the field, although it is frequently used in clinical practice. Objectives: We aimed to analyze the efficacy and safety of adding anticoagulants therapy to AP management. Methods: The systematic search was performed in three databases on the 14th of October 2022 without restrictions. Randomized controlled trials (RCTs) and observational studies that reported the differences in the outcomes of AP for patients receiving anticoagulants (intervention group) in addition to the standard of care (SOC), compared to patients managed by SOC alone (control group), were eligible. A random-effects model was used to calculate the pooled odds ratios (OR) and mean differences (MD) with the corresponding 95%-confidence intervals (CI). We performed subgroup analysis for study design and disease severity, among other criteria. Results: Of the 8,223 screened records, we included eight in the meta-analysis. Except one, all studies reported on low-molecular-weight heparin (LMWH). Both RCTs and observational studies reported results in favor of the LMWH group. Subgroup RCTs' analysis revealed significantly decreased odds of mortality [OR 0.24; 95%CI 0.17-0.34] and multiple organ failure [OR 0.32; 95%CI 0.17-0.62] in the intervention group. Moreover, the need for endoscopic or surgical interventions [OR 0.41; 95%CI 0.28-0.61] were significantly reduced by LMWH. The subgroup analyzes for moderate and severe cases, respectively, yielded similar results. Due to limited data, we could no perform subgroup analysis for mild cases. Conclusion: LMWH therapy reduces major complication rates in moderate and severe AP. Across all identified RCTs, LMWH were initiated early after AP diagnosis and improved its prognosis.

Metabolic-associated fatty liver disease is associated with acute pancreatitis with more severe course: Post hoc analysis of a prospectively collected international registry.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is a proven risk factor for acute pancreatitis (AP). However, NAFLD has recently been redefined as metabolic-associated fatty liver disease (MAFLD). In this post hoc analysis, we quantified the effect of MAFLD on the outcomes of AP. METHODS: We identified our patients from the multicentric, prospective International Acute Pancreatitis Registry of the Hungarian Pancreatic Study Group. Next, we compared AP patients with and without MAFLD and the individual components of MAFLD regarding in-hospital mortality and AP severity based on the revised Atlanta classification. Lastly, we calculated odds ratios (ORs) with 95% confidence intervals (CIs) using multivariate logistic regression analysis. RESULTS: MAFLD had a high prevalence in AP, 39% (801/2053). MAFLD increased the odds of moderate-to-severe AP (OR = 1.43, CI: 1.09-1.89). However, the odds of in-hospital mortality (OR = 0.89, CI: 0.42-1.89) and severe AP (OR = 1.70, CI: 0.97-3.01) were not higher in the MAFLD group. Out of the three diagnostic criteria of MAFLD, the highest odds of severe AP was in the group based on metabolic risk abnormalities (OR = 2.68, CI: 1.39-5.09). In addition, the presence of one, two, and three diagnostic criteria dose-dependently increased the odds of moderate-to-severe AP (OR = 1.23, CI: 0.88-1.70, OR = 1.38, CI: 0.93-2.04, and OR = 3.04, CI: 1.63-5.70, respectively) and severe AP (OR = 1.13, CI: 0.54-2.27, OR = 2.08, CI: 0.97-4.35, and OR = 4.76, CI: 1.50-15.4, respectively). Furthermore, in patients with alcohol abuse and aged ≥60 years, the effect of MAFLD became insignificant. CONCLUSIONS: MAFLD is associated with AP severity, which varies based on the components of its diagnostic criteria. Furthermore, MAFLD shows a dose-dependent effect on the outcomes of AP.

In-Hospital Patient Education Markedly Reduces Alcohol Consumption after Alcohol-Induced Acute Pancreatitis.

Although excessive alcohol consumption is by far the most frequent cause of recurrent acute pancreatitis (AP) cases, specific therapy is still not well established to prevent recurrence. Generally, psychological therapy (e.g., brief intervention (BI)) is the cornerstone of cessation programs; however, it is not yet widely used in everyday practice. We conducted a post-hoc analysis of a prospectively collected database. Patients suffering from alcohol-induced AP between 2016 and 2021 received 30 min BI by a physician. Patient-reported alcohol consumption, serum gamma-glutamyl-transferase (GGT) level, and mean corpuscular volume (MCV) of red blood cells were collected on admission and at the 1-month follow-up visit to monitor patients' drinking habits. Ninety-nine patients with alcohol-induced AP were enrolled in the study (mean age: 50 ± 11, 89% male). A significant decrease was detected both in mean GGT value (294 ± 251 U/L vs. 103 ± 113 U/L, p < 0.001) and in MCV level (93.7 ± 5.3 U/L vs. 92.1 ± 5.1 U/L, p < 0.001) in patients with elevated on-admission GGT levels. Notably, 79% of the patients (78/99) reported alcohol abstinence at the 1-month control visit. Brief intervention is an effective tool to reduce alcohol consumption and to prevent recurrent AP. Longitudinal randomized clinical studies are needed to identify the adequate structure and frequency of BIs in alcohol-induced AP.

Early prediction of acute necrotizing pancreatitis by artificial intelligence: a prospective cohort-analysis of 2387 cases.

Pancreatic necrosis is a consistent prognostic factor in acute pancreatitis (AP). However, the clinical scores currently in use are either too complicated or require data that are unavailable on admission or lack sufficient predictive value. We therefore aimed to develop a tool to aid in necrosis prediction. The XGBoost machine learning algorithm processed data from 2387 patients with AP. The confidence of the model was estimated by a bootstrapping method and interpreted via the 10th and the 90th percentiles of the prediction scores. Shapley Additive exPlanations (SHAP) values were calculated to quantify the contribution of each variable provided. Finally, the model was implemented as an online application using the Streamlit Python-based framework. The XGBoost classifier provided an AUC value of 0.757. Glucose, C-reactive protein, alkaline phosphatase, gender and total white blood cell count have the most impact on prediction based on the SHAP values. The relationship between the size of the training dataset and model performance shows that prediction performance can be improved. This study combines necrosis prediction and artificial intelligence. The predictive potential of this model is comparable to the current clinical scoring systems and has several advantages over them.

EASY-APP: An artificial intelligence model and application for early and easy prediction of severity in acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is a potentially severe or even fatal inflammation of the pancreas. Early identification of patients at high risk for developing a severe course of the disease is crucial for preventing organ failure and death. Most of the former predictive scores require many parameters or at least 24 h to predict the severity; therefore, the early therapeutic window is often missed. METHODS: The early achievable severity index (EASY) is a multicentre, multinational, prospective and observational study (ISRCTN10525246). The predictions were made using machine learning models. We used the scikit-learn, xgboost and catboost Python packages for modelling. We evaluated our models using fourfold cross-validation, and the receiver operating characteristic (ROC) curve, the area under the ROC curve (AUC), and accuracy metrics were calculated on the union of the test sets of the cross-validation. The most critical factors and their contribution to the prediction were identified using a modern tool of explainable artificial intelligence called SHapley Additive exPlanations (SHAP). RESULTS: The prediction model was based on an international cohort of 1184 patients and a validation cohort of 3543 patients. The best performing model was an XGBoost classifier with an average AUC score of 0.81 ± 0.033 and an accuracy of 89.1%, and the model improved with experience. The six most influential features were the respiratory rate, body temperature, abdominal muscular reflex, gender, age and glucose level. Using the XGBoost machine learning algorithm for prediction, the SHAP values for the explanation and the bootstrapping method to estimate confidence, we developed a free and easy-to-use web application in the Streamlit Python-based framework (http://easy-app.org/). CONCLUSIONS: The EASY prediction score is a practical tool for identifying patients at high risk for severe AP within hours of hospital admission. The web application is available for clinicians and contributes to the improvement of the model.

Metabolic Associated Fatty Liver Disease Is Associated With an Increased Risk of Severe COVID-19: A Systematic Review With Meta-Analysis.

Background: The most common pre-existing liver disease, the metabolic dysfunction-associated fatty liver disease (MAFLD) formerly named as non-alcoholic fatty liver disease (NAFLD), may have a negative impact on the severity of COVID-19. This meta-analysis aimed to evaluate if MAFLD or NAFLD are associated with a more severe disease course of COVID-19. Methods: A systematic search was performed in five databases for studies comparing severity, the rate of intensive care unit (ICU) admission, and mortality of COVID-19 patients with and without MAFLD or NAFLD. In meta-analysis, pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results: Altogether, we included nine studies in our quantitative and qualitative synthesis. MAFLD was associated with an increased risk of severe COVID-19 compared to the non-MAFLD group (28 vs. 13%, respectively; OR = 2.61, CI: 1.75-3.91). Similarly, in the NAFLD vs. non-NAFLD comparison, NAFLD proved to be a risk factor as well (36 vs. 12%, respectively; OR = 5.22, CI: 1.94-14.03). On the other hand, NAFLD was not associated with an increased risk of ICU admission (24 vs. 7%, respectively; OR = 2.29, CI: 0.79-6.63). We were unable to perform meta-analysis to investigate the association of MAFLD with the rate of ICU admission and with mortality. Conclusion: In conclusion, patients with MAFLD and NAFLD showed a more severe clinical picture in COVID-19. Our results support the importance of close monitoring of COVID-19 patients with MAFLD. Further research is needed to explore the cause of increased severity of COVID-19 in MAFLD.

Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Angiotensin-Converting Enzyme 2 Levels: A Comprehensive Analysis Based on Animal Studies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen of coronavirus disease 2019 (COVID-19), caused the outbreak escalated to pandemic. Reports suggested that near 1-3% of COVID-19 cases have a fatal outcome. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are widely used in hypertension, heart failure and chronic kidney disease. These drugs have been reported to upregulate angiotensin converting enzyme 2 (ACE2) which produces Ang (1-7), the main counter-regulatory mediator of angiotensin II. This enzyme is also known as the receptor of SARS-CoV-2 promoting the cellular uptake of the virus in the airways, however, ACE2 itself proved to be protective in several experimental models of lung injury. The present study aimed to systematically review the relationship between ACEI/ARB administration and ACE2 expression in experimental models. After a comprehensive search and selection, 27 animal studies investigating ACE2 expression in the context of ACEI and ARB were identified. The majority of these papers reported increased ACE2 levels in response to ACEI/ARB treatment. This result should be interpreted in the light of the dual role of ACE2 being a promoter of viral entry to cells and a protective factor against oxidative damage in the lungs.

Granulocyte and monocyte apheresis as an adjunctive therapy to induce and maintain clinical remission in ulcerative colitis: a systematic review and meta-analysis.

OBJECTIVE: The goal of treatment in ulcerative colitis (UC) is to induce and maintain remission. The addition of granulocyte and monocyte apheresis (GMA) to conventional therapy may be a promising therapeutic alternative. In this meta-analysis, we aimed to assess the efficacy and safety profile of GMA as an adjunctive therapy. DESIGN: Systematic review and meta-analysis. METHODS: We searched four databases (MEDLINE, Embase, Web of Science and Cochrane Central Register of Controlled Trials) for randomised or minimised controlled trials which discussed the impact of additional GMA therapy on clinical remission induction and clinical remission maintenance compared with conventional therapy alone. Primary outcomes were clinical remission induction and maintenance, secondary outcomes were adverse events (AEs) and steroid-sparing effect. ORs with 95% CIs were calculated. Trial Sequential Analyses were performed to adjusts for the risk of random errors in meta-analyses. RESULTS: A total of 11 studies were eligible for meta-analysis. GMA was clearly demonstrated to induce and maintain clinical remission more effectively than conventional therapy alone (598 patients: OR: 1.93, 95% CI 1.28 to 2.91, p=0.002, I2=0.0% for induction; 71 patients: OR: 8.34, 95% CI 2.64 to 26.32, p<0.001, I2=0.0% for maintenance). There was no statistically significant difference in the number of AEs (OR: 0.27, 95% CI 0.05 to 1.50, p=0.135, I2=84.2%). CONCLUSION: GMA appears to be more effective as an adjunctive treatment in inducing and maintaining remission in patients with UC than conventional therapy alone. PROSPERO REGISTRATION NUMBER: CRD42019134050.

Diabetes Mellitus Increases the Risk of Hepatocellular Carcinoma After Direct-Acting Antiviral Therapy: Systematic Review and Meta-Analysis.

Background: Hepatitis C virus (HCV)-infected patients treated with direct-acting antivirals (DAAs) are still at risk of developing hepatocellular carcinoma (HCC) after sustained virologic response (SVR). This study aimed to investigate the role of diabetes mellitus (DM) as a potential predictive risk factor in developing de novo HCC in HCV-infected patients after DAA treatment. Methods: This study was registered on PROSPERO under registration number CRD42021230457. We performed a systematic search in four medical databases from inception through November 3rd, 2020. Studies were eligible if they reported on HCV-infected patients treated with DAAs and compared the frequency of de novo HCC in patients with and without DM. We calculated pooled odds ratios, unadjusted (UHR), and adjusted hazard ratios (AHR) with 95% confidence intervals (CIs) in meta-analysis. Results: We included 30 articles in our systematic review and meta-analysis. DM proved to be a significant risk factor of HCC in DAA-treated HCV patients in unadjusted (UHR = 1.44, CI: 1.15-1.79) and adjusted analyses (AHR = 1.31, CI: 1.06-1.62). In the group of patients achieving SVR after DAA therapy, DM increased the risk of HCC in unadjusted (UHR = 1.3, CI: 1.09-1.51) analysis; however, in adjusted results, the risk was non-significant (AHR = 1.07, CI: 0.89-1.28). In patients with advanced liver fibrosis, DM was a risk factor for HCC in adjusted (AHR = 1.36, CI: 1.03-1.8), but not in unadjusted analysis (UHR = 1.11, CI: 0.8-1.42). Conclusions: DM is an independent risk factor of de novo HCC after DAA treatment in HCV-infected patients. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=230457, identifier: CRD42021230457.

Endoscopic ultrasound-guided ethanol and radiofrequency ablation of pancreatic insulinomas: a systematic literature review.

BACKGROUND: Insulinoma is the most common neuroendocrine neoplasm of the pancreas, characterised by hypoglycaemic symptoms. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) and ethanol ablation (EUS-EA) are novel methods for treating insulinoma.We aimed to perform a systematic review to assess the efficacy and safety of EUS-guided ablation techniques for pancreatic insulinomas. METHODS: We systematically searched for articles detailing EUS-guided ablations of insulinomas. We performed a qualitative analysis and summarised data on the efficacy and safety of EUS-RFA and EUS-EA techniques. RESULTS: In total, we identified 35 case reports and case series describing 75 patients with insulinomas treatment with EUS-guided ablation. Twenty-seven patients were treated with EUS-RFA, 47 patients with EUS-EA, and 1 patient received EUS-EA and EUS-RFA in the same session. In total, 84 insulinomas were ablated (EUS-RFA: 31, EUS-EA: 53). Most insulinomas were in the head of the pancreas (40%). The clinical success rate for EUS-guided ablation techniques was 98.5%. The median glucose level was 1.95 (Q1-Q3: 1.69-2.13) mmol/L before ablation compared to 6.20 (Q1-Q3: 5.30-7.05) mmol/L after treatment. The median insulin and C-peptide levels before and after RFA/EA were 230 (Q1-Q2: 120-257) pmol/L and 41 (Q1-Q2 35-42) pmol/L; 2077 (Q1-Q2 1644-2459) pmol/L and 819 (Q1-Q2 696-1072) pmol/L, respectively. There were eleven adverse events: seven abdominal pain, two mild acute pancreatitis, one necrotising acute pancreatitis and one local hematoma. All patients recovered, and there were no periprocedural deaths. CONCLUSIONS: EUS-guided ablation of insulinoma seems to be a safe and effective treatment and is an alternative to surgical resection in selected cases.