Detailed Characteristics of Post-discharge Mortality in Acute Pancreatitis.

BACKGROUND & AIMS: The in-hospital survival of patients suffering from acute pancreatitis (AP) is 95% to 98%. However, there is growing evidence that patients discharged after AP may be at risk of serious morbidity and mortality. Here, we aimed to investigate the risk, causes, and predictors of the most severe consequence of the post-AP period: mortality. METHODS: A total of 2613 well-characterized patients from 25 centers were included and followed by the Hungarian Pancreatic Study Group between 2012 and 2021. A general and a hospital-based population was used as the control group. RESULTS: After an AP episode, patients have an approximately threefold higher incidence rate of mortality than the general population (0.0404 vs 0.0130 person-years). First-year mortality after discharge was almost double than in-hospital mortality (5.5% vs 3.5%), with 3.0% occurring in the first 90-day period. Age, comorbidities, and severity were the most significant independent risk factors for death following AP. Furthermore, multivariate analysis identified creatinine, glucose, and pleural fluid on admission as independent risk factors associated with post-discharge mortality. In the first 90-day period, cardiac failure and AP-related sepsis were among the main causes of death following discharge, and cancer-related cachexia and non-AP-related infection were the key causes in the later phase. CONCLUSION: Almost as many patients in our cohort died in the first 90-day period after discharge as during their hospital stay. Evaluation of cardiovascular status, follow-up of local complications, and cachexia-preventing oncological care should be an essential part of post-AP patient care. Future study protocols in AP must include at least a 90-day follow-up period after discharge.

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.

Early infection is an independent risk factor for increased mortality in patients with culture-confirmed infected pancreatic necrosis.

BACKGROUND: Mortality in infected pancreatic necrosis (IPN) is dynamic over the course of the disease, with type and timing of interventions as well as persistent organ failure being key determinants. The timing of infection onset and how it pertains to mortality is not well defined. OBJECTIVES: To determine the association between mortality and the development of early IPN. METHODS: International multicenter retrospective cohort study of patients with IPN, confirmed by a positive microbial culture from (peri) pancreatic collections. The association between timing of infection onset, timing of interventions and mortality were assessed using Cox regression analyses. RESULTS: A total of 743 patients from 19 centers across 3 continents with culture-confirmed IPN from 2000 to 2016 were evaluated, mortality rate was 20.9% (155/734). Early infection was associated with a higher mortality, when early infection occurred within the first 4 weeks from presentation with acute pancreatitis. After adjusting for comorbidity, advanced age, organ failure, enteral nutrition and parenteral nutrition, early infection (≤4 weeks) and early open surgery (≤4 weeks) were associated with increased mortality [HR: 2.45 (95% CI: 1.63-3.67), p < 0.001 and HR: 4.88 (95% CI: 1.70-13.98), p = 0.003, respectively]. There was no association between late open surgery, early or late minimally invasive surgery, early or late percutaneous drainage with mortality (p > 0.05). CONCLUSION: Early infection was associated with increased mortality, independent of interventions. Early surgery remains a strong predictor of excess mortality.

Design and validation of a patient-reported outcome measure scale in acute pancreatitis: the PAN-PROMISE study.

OBJECTIVE: This study aimed to develop and validate a patient-reported outcome measure (PROM) in acute pancreatitis (AP) as an endpoint centred on the patient. DESIGN: A PROM instrument (PAtieNt-rePoRted OutcoMe scale in acute pancreatItis, an international proSpEctive cohort study, PAN-PROMISE scale) was designed based on the opinion of patients, professionals and an expert panel. The scale was validated in an international multicentre prospective cohort study, describing the severity of AP and quality of life at 15 days after discharge as the main variables for validation. The COSMIN (COnsensus-based Standards for the selection of health status Measurement INstruments) methodology was applied. Both the design and validation stages considered the content and face validity of this new instrument; the metric properties of the different items, reliability (reproducibility and internal consistence), the construct, structural and criterion validity, responsiveness and interpretability of this scale. RESULTS: PAN-PROMISE consists of a seven-item scale based on the symptoms that cause the most discomfort and concern to patients with AP. The validation cohort involved 15 countries, 524 patients. The intensity of symptoms changed from higher values during the first 24 hours to lower values at discharge and 15 days thereafter. Items converged into a unidimensional ordinal scale with good fit indices. Internal consistency and split-half reliability at discharge were adequate. Reproducibility was confirmed using test-retest reliability and comparing the PAN-PROMISE score at discharge and 15 days after discharge. Evidence is also provided for the convergent-discriminant and empirical validity of the scale. CONCLUSION: The PAN-PROMISE scale is a useful tool to be used as an endpoint in clinical trials, and to quantify patient well-being during the hospital admission and follow-up. TRIAL REGISTRATION NUMBER: NCT03650062.

Pharmacological inhibition of the mitochondrial Ca2+ uniporter: Relevance for pathophysiology and human therapy.

Mitochondrial Ca2+ uptake has long been considered crucial for meeting the fluctuating energy demands of cells in the heart and other tissues. Increases in mitochondrial matrix [Ca2+] drive mitochondrial ATP production via stimulation of Ca2+-sensitive dehydrogenases. Mitochondria-targeted sensors have revealed mitochondrial matrix [Ca2+] rises that closely follow the cytoplasmic [Ca2+] signals in many paradigms. Mitochondrial Ca2+ uptake is mediated by the Ca2+ uniporter (mtCU). Pharmacological manipulation of the mtCU is potentially key to understanding its physiological significance, but no specific, cell-permeable inhibitors were identified. In the past decade, as the molecular identity of the mtCU was brought to light, efforts have focused on genetic targeting. However, in the cells/animals that are able to survive impaired mtCU function, robust compensatory changes were found in the mtCU as well as other mechanisms. Thus, the discovery, through chemical library screens on normal and mtCU-deficient cells, of new small-molecule inhibitors with improved cell permeability and specificity might offer a better chance to test the relevance of mitochondrial Ca2+ uptake. Success with the development of small molecule mtCU inhibitors is also expected to have clinical impact, considering the growing evidence for the role of mitochondrial Ca2+ uptake in a variety of diseases, including heart attack, stroke and various neurodegenerative disorders. Here, we review the progress in pharmacological targeting of mtCU and illustrate the challenges in this field using data obtained with MCU-i11, a new small molecule inhibitor.

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.

Glucose levels show independent and dose-dependent association with worsening acute pancreatitis outcomes: Post-hoc analysis of a prospective, international cohort of 2250 acute pancreatitis cases.

BACKGROUND: Metabolic risk factors, such as obesity, hypertension, and hyperlipidemia are independent risk factors for the development of various complications in acute pancreatitis (AP). Hypertriglyceridemia dose-dependently elicits pancreatotoxicity and worsens the outcomes of AP. The role of hyperglycemia, as a toxic metabolic factor in the clinical course of AP, has not been examined yet. METHODS: We analyzed a prospective, international cohort of 2250 AP patients, examining associations between (1) glycosylated hemoglobin (HbA1c), (2) on-admission glucose, (3) peak in-hospital glucose and clinically important outcomes (mortality, severity, complications, length of hospitalization (LOH), maximal C-reactive protein (CRP)). We conducted a binary logistic regression accounting for age, gender, etiology, diabetes, and our examined variables. Receiver Operating Characteristic Curve (ROC) was applied to detect the diagnostic accuracy of the three variables. RESULTS: Both on-admission and peak serum glucose are independently associated with AP severity and mortality, accounting for age, gender, known diabetes and AP etiology. They show a dose-dependent association with severity (p < 0.001 in both), mortality (p < 0.001), LOH (p < 0.001), maximal CRP (p < 0.001), systemic (p < 0.001) and local complications (p < 0.001). Patients with peak glucose >7 mmol/l had a 15 times higher odds for severe AP and a five times higher odds for mortality. We found a trend of increasing HbA1c with increasing LOH (p < 0.001), severity and local complications. CONCLUSIONS: On-admission and peak in-hospital glucose are independently and dose-dependently associated with increasing AP severity and mortality. In-hospital laboratory control of glucose and adequate treatment of hyperglycemia are crucial in the management of AP.

Endoscopic and surgical drainage for pancreatic fluid collections are better than percutaneous drainage: Meta-analysis.

BACKGROUND: Pancreatic pseudocyst (PP) and walled-off necrosis can be managed endoscopically, percutaneously or surgically, but with diverse efficacy. AIMS & METHODS: A comprehensive literature search was carried out from inception to December 2018, to identify articles which compared at least two of the three kinds of treatment modalities, regarding the mortality, clinical success, recurrence, complications, cost and length of hospitalisation (LOH). RESULTS: The outcomes of endoscopic (ED) and percutaneous drainage (PD) were comparable in six articles. The clinical success of endoscopic intervention was better considering any types of fluid collections (OR = 3.36; 95% confidence interval (CI) 1.48, 7.63; p = 0.004). ED was preferable regarding recurrence of PP (OR = 0.23; 95% CI 0.08, 0.66; p = 0.006). Fifteen articles compared surgical intervention with ED. Significant difference was found in postoperative LOH (WMD (days) = -4.61; 95%CI -7.89, -1.33; p = 0.006) and total LOH (WMD (days) = -3.67; 95%CI -5.00, -2.34; p < 0.001) which favored endoscopy, but ED had lower rate of clinical success (OR = 0.54; 95% CI 0.35, 0.85; p = 0.007) and higher rate of recurrence (OR = 1.80; 95% CI 1.16, 2.79; p = 0.009) in the treatment of PP. Eleven studies compared surgical and percutaneous intervention. PD resulted in higher rate of recurrence (OR = 4.91; 95% CI 1.82, 13.22; p = 0.002) and lower rate of clinical success (OR = 0.13; 95% CI 0.07, 0.22, p < 0.001). CONCLUSION: Both endoscopy and surgery are preferable over percutaneous intervention, furthermore endoscopic treatment is associated with shorter hospitalisation than surgery.

Development of disturbance of consciousness is associated with increased severity in acute pancreatitis.

BACKGROUND: Disturbance of consciousness (DOC) may develop in acute pancreatitis (AP). In clinical practice, it is known that DOC may worsen the patient's condition, but we have no exact data on how DOC affects the outcome of AP. METHODS: From the Hungarian Pancreatic Study Groups' AP registry, 1220 prospectively collected cases were analyzed, which contained exact data on DOC, included patients with confusion, delirium, convulsion, and alcohol withdrawal, answering a post hoc defined research question. Patients were separated to Non-DOC and DOC, whereas DOC was further divided into non-alcohol related DOC (Non-ALC DOC) and ALC DOC groups. For statistical analysis, independent sample t-test, Mann-Whitney, Chi-squared, or Fisher exact test were used. RESULTS: From the 1220 patients, 47 (3.9%) developed DOC, 23 (48.9%) cases were ALC DOC vs. 24 (51.1%) Non-ALC DOC. Analysis between the DOC and Non-DOC groups showed a higher incidence of severe AP (19.2% vs. 5.3%, p < 0.001), higher mortality (14.9% vs. 1.7%, p < 0.001), and a longer length of hospitalization (LOH) (Me = 11; IQR: 8-17 days vs. Me = 9; IQR: 6-13 days, p = 0.049) respectively. Patients with ALC DOC developed more frequently moderate AP vs. Non-ALC DOC (43.5% vs. 12.5%), while the incidence of severe AP was higher in Non-ALC vs. ALC DOC group (33.3% vs. 4.4%) (p < 0.001). LOH showed a tendency to be longer in Non-ALC DOC compared to ALC DOC, respectively (Me:13; IQR:7-20 days vs. Me:9.5; IQR:8-15.5 days, p = 0.119). CONCLUSION: DOC during AP is associated with a higher rate of moderate and severe AP and increases the risk of mortality.

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.

Eosinophil Counts in the Small Intestine and Colon of Children Without Apparent Gastrointestinal Disease: A Meta-analysis.

The aim of the current study was to review the available data regarding eosinophil density in healthy tissue specimen originating from lower gastrointestinal segments to support suggested diagnostic cutoffs widely used in clinical practice. A systematic search was performed in 3 different databases. Calculations were made with Comprehensive MetaAnalysis software using random-effects model. Cell number measurements were pooled using the random-effects model and displayed on forest plots. Summary point estimations, 95% confidence intervals (CIs), and 95% prediction intervals (PIs) were calculated. The cumulative mean cell numbers were 8.26 (95% CI 4.71-11.80) with PI of 0-25.32 for the duodenum, 11.52 (95% CI 7.21-15.83) with PI 0-60.64 for the terminal ileum, and 11.10/ high-power field (HPF) (95% CI 9.11-13.09) with PI of 0.96 to 21.23 in the large intestine and the rectum (HPF area = 0.2 mm). Previous studies included control patients with irritable bowel syndrome and functional gastrointestinal disorders. As mucosal eosinophils have a role in their pathomechanism, those patients should have been excluded. A critical point of interpreting reported data is that HPF is relative to the technical parameters of the microscopes; therefore, it is important to report findings in cell/mm. The present meta-analysis does not support the higher (>20) or lower (<10) cutoff values for healthy tissue eosinophil number. In contrast to the esophagus, there is no normal cutoff eosinophil density in the small intestine and the colon. A prospective, multicenter study to establish normal mucosal eosinophil density is clearly needed.

Meta-Analysis of Early Nutrition: The Benefits of Enteral Feeding Compared to a Nil Per Os Diet Not Only in Severe, but Also in Mild and Moderate Acute Pancreatitis.

The recently published guidelines for acute pancreatitis (AP) suggest that enteral nutrition (EN) should be the primary therapy in patients suffering from severe acute pancreatitis (SAP); however, none of the guidelines have recommendations on mild and moderate AP (MAP). A meta-analysis was performed using the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P). The following PICO (problem, intervention, comparison, outcome) was applied: P: nutrition in AP; I: enteral nutrition (EN); C: nil per os diet (NPO); and O: outcome. There were 717 articles found in Embase, 831 in PubMed, and 10 in the Cochrane database. Altogether, seven SAP and six MAP articles were suitable for analyses. In SAP, forest plots were used to illustrate three primary endpoints (mortality, multiorgan failure, and intervention). In MAP, 14 additional secondary endpoints were analyzed (such as CRP (C-reactive protein), WCC (white cell count), complications, etc.). After pooling the data, the Mann-Whitney U test was used to detect significant differences. Funnel plots were created for testing heterogeneity. All of the primary endpoints investigated showed that EN is beneficial vs. NPO in SAP. In MAP, all of the six articles found merit in EN. Analyses of the primary endpoints did not show significant differences between the groups; however, analyzing the 17 endpoints together showed a significant difference in favor of EN vs. NPO. EN is beneficial compared to a nil per os diet not only in severe, but also in mild and moderate AP.

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).

Psychological intervention improves quality of life in patients with early-stage cancer: a systematic review and meta-analysis of randomized clinical trials.

The effectiveness of psychological interventions (PI) for malignant diseases is controversial. We aimed to investigate the effect of PI on survival and quality of life (QoL) in patients with cancer. We performed a systematic search of MEDLINE, Cochrane, and Embase databases to identify randomized controlled trials comparing PI to standard care (PROSPERO registration number CRD42021282327). Outcomes were overall survival (OS), recurrence-free survival (RFS), and different domains of QoL. Subgroup analysis was performed based on the provider-, type-, environment-, duration of intervention; cancer stage, and type. Pooled hazard ratios (HR) and standardized mean difference (SMD) with 95% confidence intervals (CI) were calculated using a random-effects model. The OS and RFS did not differ significantly between the two groups (OS:HR = 0.97; CI 0.87-1.08; RFS:HR = 0.99; CI 0.84-1.16). However, there was significant improvement in the intervention group in all the analyzed domains of QoL; in the global (SMD = 0.65; CI 0.35-0.94), emotional (SMD = 0.64; CI 0.33-0.95), social (SMD = 0.32; CI 0.13-0.51) and physical (SMD = 0.33; CI 0.05-0.60) domains. The effect of PI on QoL was generally positive immediately, 12 and 24 weeks after intervention, but the effect decreased over time and was no longer found significant at 48 weeks. The results were better in the breast cancer group and early stages of cancer. PIs do not prolong survival, but they significantly improve the QoL of cancer patients. PI should be added as standard of care 3-4 times a year, at least for patients with early-stage cancer.

Increased risk of adverse events in patients with low-on clopidogrel platelet reactivity after percutaneous coronary intervention: A systematic review and meta-analysis.

BACKGROUND: Clinical evidence has been controversial regarding the influence of low platelet reactivity (LPR), ischemic and bleeding outcomes among patients receiving coronary stent implantation. Hence, the present study performed a meta-analysis to systematically evaluate the significance of LPR on adverse cardiovascular events. METHODS: MEDLINE, EMBASE and CENTRAL databases were searched up to November 2020 for relevant studies including patients with acute coronary syndrome undergoing percutaneous coronary intervention. LPR was the exposed arm while the non-LPR group represented the control. The primary outcome of interest was bleeding risk including major and minor bleeding events. Secondary outcomes included all-cause mortality, repeated revascularization, nonfatal myocardial infarction, and stent thrombosis. Study-level outcomes were evaluated in random-effect models. RESULTS: A total of 20 studies with 19,064 patients were included. Pooled analysis showed that LPR was associated with an increased bleeding risk (relative risk [RR] 2.80, 95% confidence interval [CI] 1.95-4.02, p < 0.01). Patients with LPR had a lower risk of non-fatal myocardial infarction (RR 0.59, 95% CI 0.38-0.91, p < 0.05) and of serious vascular events (RR 0.50, 95% CI 0.30-0.84, p < 0.01). CONCLUSIONS: Low platelet reactivity is associated with an increased bleeding risk of patients who underwent coronary stent implantation. The results suggest possible benefits of this marker in risk stratification, with potential improvement in risk prediction. There are potential advantages using combinations with other factors in prediction models, however, they require further study. PROSPERO registration number: CRD42019136393).

MICU1 controls the sensitivity of the mitochondrial Ca2+ uniporter to activators and inhibitors.

Mitochondrial Ca2+ homeostasis loses its control in many diseases and might provide therapeutic targets. Mitochondrial Ca2+ uptake is mediated by the uniporter channel (mtCU), formed by MCU and is regulated by the Ca2+-sensing gatekeeper, MICU1, which shows tissue-specific stoichiometry. An important gap in knowledge is the molecular mechanism of the mtCU activators and inhibitors. We report that all pharmacological activators of the mtCU (spermine, kaempferol, SB202190) act in a MICU1-dependent manner, likely by binding to MICU1 and preventing MICU1's gatekeeping activity. These agents also sensitized the mtCU to inhibition by Ru265 and enhanced the Mn2+-induced cytotoxicity as previously seen with MICU1 deletion. Thus, MCU gating by MICU1 is the target of mtCU agonists and is a barrier for inhibitors like RuRed/Ru360/Ru265. The varying MICU1:MCU ratios result in different outcomes for both mtCU agonists and antagonists in different tissues, which is relevant for both pre-clinical research and therapeutic efforts.

One in four patients with gastrointestinal bleeding develops shock or hemodynamic instability: A systematic review and meta-analysis.

BACKGROUND: Hemodynamic instability and shock are associated with untoward outcomes in gastrointestinal bleeding. However, there are no studies in the existing literature on the proportion of patients who developed these outcomes after gastrointestinal bleeding. AIM: To determine the pooled event rates in the available literature and specify them based on the bleeding source. METHODS: The protocol was registered on PROSPERO in advance (CRD42021283258). A systematic search was performed in three databases (PubMed, EMBASE, and CENTRAL) on 14th October 2021. Pooled proportions with 95%CI were calculated with a random-effects model. A subgroup analysis was carried out based on the time of assessment (on admission or during hospital stay). Heterogeneity was assessed by Higgins and Thompson's I2 statistics. The Joanna Briggs Institute Prevalence Critical Appraisal Tool was used for the risk of bias assessment. The Reference Citation Analysis (https://www.referencecitationanalysis.com/) tool was applied to obtain the latest highlight articles. RESULTS: We identified 11589 records, of which 220 studies were eligible for data extraction. The overall proportion of shock and hemodynamic instability in general gastrointestinal bleeding patients was 0.25 (95%CI: 0.17-0.36, I2 = 100%). In non-variceal bleeding, the proportion was 0.22 (95%CI: 0.14-0.31, I2 = 100%), whereas it was 0.25 (95%CI: 0.19-0.32, I2 = 100%) in variceal bleeding. The proportion of patients with colonic diverticular bleeding who developed shock or hemodynamic instability was 0.12 (95%CI: 0.06-0.22, I2 = 90%). The risk of bias was low, and heterogeneity was high in all analyses. CONCLUSION: One in five, one in four, and one in eight patients develops shock or hemodynamic instability on admission or during hospitalization in the case of non-variceal, variceal, and colonic diverticular bleeding, respectively.

Suprapapillary Biliary Stents Have Longer Patency Times than Transpapillary Stents-A Systematic Review and Meta-Analysis.

BACKGROUND AND STUDY AIMS: Endoscopic biliary stent placement is a minimally invasive intervention for patients with biliary strictures. Stent patency and function time are crucial factors. Suprapapillary versus transpapillary stent positioning may contribute to stent function time, so a meta-analysis was performed in this comparison. METHODS: A comprehensive literature search was conducted in the CENTRAL, Embase, and MEDLINE databases to find data on suprapapillary stent placement compared to the transpapillary method via endoscopic retrograde cholangiopancreatography in cases of biliary stenosis of any etiology and any stent type until December 2020. We carried out a meta-analysis focusing on the following outcomes: stent patency, stent migration, rate of cholangitis and pancreatitis, and other reported complications. RESULTS: Three prospective and ten retrospective studies involving 1028 patients were included. Suprapapillary stent placement appeared to be superior to transpapillary stent positioning in patency (weighted mean difference = 50.23 days, 95% CI: 8.56, 91.98; p = 0.0.018). In a subgroup analysis of malignant indications, suprapapillary positioning showed a lower rate of cholangitis (OR: 0.34, 95% CI: 0.13, 0.93; p = 0.036). Another subgroup analysis investigating metal stents in a suprapapillary position resulted in a lower rate of pancreatitis (OR: 0.16, 95% CI: 0.03, 0.95; p = 0.043) compared to transpapillary stent placement. There was no difference in stent migration rates between the two groups (OR: 0.67, 95% CI: 0.17, 2.72; p = 0.577). CONCLUSIONS: Based on our results, suprapapillary biliary stenting has longer stent patency. Moreover, the stent migration rate did not differ between the suprapapillary and transpapillary groups.

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.