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Digestive Diseases and Sciences Aug 2023The small intestinal bacterial overgrowth (SIBO) in acute pancreatitis correlates with the severity of the disease. However, corresponding studies on the microbial...
OBJECTIVE
The small intestinal bacterial overgrowth (SIBO) in acute pancreatitis correlates with the severity of the disease. However, corresponding studies on the microbial composition of the duodenal mucosa of patients are uncommon.
METHODS
Duodenal mucosal biopsies were collected by gastroscopy from 16 patients with mild acute pancreatitis (the Ap group) and 16 healthy individuals (the control group) and subjected to histological studies as well as bacterial 16S rRNA gene sequencing. Caerulein and L-arginine were used to induce mild acute pancreatitis (MAP) and severe acute pancreatitis (SAP) in mice, respectively, and their pancreas and duodenum were collected for histological studies.
RESULTS
H&E analysis displayed no significant pathological damage in the descending duodenum of patients with acute pancreatitis compared with that of the controls. Immunofluorescence and Real-time PCR revealed that the expressions of tight junction proteins (TJPs) in duodenal mucosa were decreased in acute pancreatitis. The results of the alpha diversity analysis revealed no significant difference between the two groups, while LEfSe and the random forest revealed a few differences, indicating that the descending duodenum mucosal microbiota changed slightly in patients with mild acute pancreatitis. We observed the pathological changes and the expression of TJPs in the duodenum in the three groups of mice and found that SAP mice had more severe pathological damage in the duodenum. Furthermore, the expression of TJPs in the duodenum was lower in the MAP and SAP groups of mice compared to control mice, but it was similar in both groups.
CONCLUSION
Patients with mild acute pancreatitis had mild duodenal barrier dysfunction and slight changes in duodenal mucosal microbiota.
Topics: Humans; Acute Disease; RNA, Ribosomal, 16S; Pancreatitis; Duodenum; Intestinal Mucosa; Tight Junction Proteins; Microbiota
PubMed: 37258979
DOI: 10.1007/s10620-023-07948-8 -
Gastroenterology Oct 2023Although transient bacteremia is common during dental and endoscopic procedures, infections developing during sterile diseases like acute pancreatitis (AP) can have...
BACKGROUND & AIMS
Although transient bacteremia is common during dental and endoscopic procedures, infections developing during sterile diseases like acute pancreatitis (AP) can have grave consequences. We examined how impaired bacterial clearance may cause this transition.
METHODS
Blood samples from patients with AP, normal controls, and rodents with pancreatitis or those administered different nonesterified fatty acids (NEFAs) were analyzed for albumin-unbound NEFAs, microbiome, and inflammatory cell injury. Macrophage uptake of unbound NEFAs using a novel coumarin tracer were done and the downstream effects-NEFA-membrane phospholipid (phosphatidylcholine) interactions-were studied on isothermal titration calorimetry.
RESULTS
Patients with infected AP had higher circulating unsaturated NEFAs; unbound NEFAs, including linoleic acid (LA) and oleic acid (OA); higher bacterial 16S DNA; mitochondrial DNA; altered β-diversity; enrichment in Pseudomonadales; and increased annexin V-positive myeloid (CD14) and CD3-positive T cells on admission. These, and increased circulating dead inflammatory cells, were also noted in rodents with unbound, unsaturated NEFAs. Isothermal titration calorimetry showed progressively stronger unbound LA interactions with aqueous media, phosphatidylcholine, cardiolipin, and albumin. Unbound NEFAs were taken into protein-free membranes, cells, and mitochondria, inducing voltage-dependent anion channel oligomerization, reducing ATP, and impairing phagocytosis. These were reversed by albumin. In vivo, unbound LA and OA increased bacterial loads and impaired phagocytosis, causing infection. LA and OA were more potent for these amphipathic interactions than the hydrophobic palmitic acid.
CONCLUSIONS
Release of stored LA and OA can increase their circulating unbound levels and cause amphipathic liponecrosis of immune cells via uptake by membrane phospholipids. This impairs bacterial clearance and causes infection during sterile inflammation.
Topics: Humans; Acute Disease; Pancreatitis; Fatty Acids, Nonesterified; Oleic Acid; Inflammation; Albumins; Phosphatidylcholines
PubMed: 37263302
DOI: 10.1053/j.gastro.2023.05.034 -
Gastroenterology Sep 2023The 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...
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.
Topics: Humans; Pancreatitis; Patient Discharge; Acute Disease; Aftercare; Cachexia; Retrospective Studies
PubMed: 37247642
DOI: 10.1053/j.gastro.2023.05.028 -
Lipids in Health and Disease Dec 2023The prevalence of hypertriglyceridaemia-induced acute pancreatitis (HTG-AP) is increasing due to improvements in living standards and dietary changes. However,...
BACKGROUND
The prevalence of hypertriglyceridaemia-induced acute pancreatitis (HTG-AP) is increasing due to improvements in living standards and dietary changes. However, currently, there is no clinical multifactor scoring system specific to HTG-AP. This study aimed to screen the predictors of HTG-SAP and combine several indicators to establish and validate a visual model for the early prediction of HTG-SAP.
METHODS
The clinical data of 266 patients with HTG-SAP were analysed. Patients were classified into severe (N = 42) and non-severe (N = 224) groups according to the Atlanta classification criteria. Several statistical analyses, including one-way analysis, least absolute shrinkage with selection operator (LASSO) regression model, and binary logistic regression analysis, were used to evaluate the data.
RESULTS
The univariate analysis showed that several factors showed no statistically significant differences, including the number of episodes of pancreatitis, abdominal pain score, and several blood diagnostic markers, such as lactate dehydrogenase (LDH), serum calcium (Ca), C-reactive protein (CRP), and the incidence of pleural effusion, between the two groups (P < 0.000). LASSO regression analysis identified six candidate predictors: CRP, LDH, Ca, procalcitonin (PCT), ascites, and Balthazar computed tomography grade. Binary logistic regression multivariate analysis showed that CRP, LDH, Ca, and ascites were independent predictors of HTG-SAP, and the area under the curve (AUC) values were 0.886, 0.893, 0.872, and 0.850, respectively. The AUC of the newly established HTG-SAP model was 0.960 (95% confidence interval: 0.936-0.983), which was higher than that of the bedside index for severity in acute pancreatitis (BISAP) score, modified CT severity index, Ranson score, and Japanese severity score (JSS) CT grade (AUC: 0.794, 0.796, 0.894 and 0.764, respectively). The differences were significant (P < 0.01), except for the JSS prognostic indicators (P = 0.130). The Hosmer-Lemeshow test showed that the predictive results of the model were highly consistent with the actual situation (P > 0.05). The decision curve analysis plot suggested that clinical intervention can benefit patients when the model predicts that they are at risk for developing HTG-SAP.
CONCLUSIONS
CRP, LDH, Ca, and ascites are independent predictors of HTG-SAP. The prediction model constructed based on these indicators has a high accuracy, sensitivity, consistency, and practicability in predicting HTG-SAP.
Topics: Humans; Pancreatitis; Severity of Illness Index; Acute Disease; Ascites; Retrospective Studies; Prognosis; Biomarkers; C-Reactive Protein; Hypertriglyceridemia
PubMed: 38066493
DOI: 10.1186/s12944-023-01984-z -
Nutrients Oct 2023The ketogenic diet (KD) has emerged as a popular weight-loss regimen in recent years. However, it has been confirmed to elicit a mild inflammatory response in the...
The ketogenic diet (KD) has emerged as a popular weight-loss regimen in recent years. However, it has been confirmed to elicit a mild inflammatory response in the intestinal epithelium and exacerbate various digestive disorders. The severity of acute pancreatitis (AP) is closely associated with the permeability of the intestinal epithelium and gut microbiota, yet the impact of KD on acute pancreatitis remains unclear. In this study, we induced acute pancreatitis using L-arginine in mice fed with KD. The consumption of KD resulted in an elevation of lipopolysaccharide-binding protein (LBP), accompanied by upregulated cytokines (IL-1a, IL-5, IL-12, MIP-1a, and Rantes) and dysfunction of the intestinal barrier both in control and AP groups. The bloom of and was observed as a specific profile of gut microbiota in KD-fed mice with AP, along with downregulation of carbohydrate metabolism and depletion of short-chain fatty acids (SCFAs). Antibiotic decontamination reduced the cytokine storm and tissue necrosis but did not significantly improve the integrity of the intestinal barrier in KD-fed mice with AP. The overgrowth of in feces and in colonic tissue appears to explain the limitation of antibiotic treatment to aggravate acute pancreatitis. Butyrate supplementation attenuated the depletion of SCFAs, promoted the intestinal barrier, and reduced the necrotic area in AP mice. The bloom of and the correlated increase in tryptophan metabolism explain the therapeutic potential of butyrate supplements for acute pancreatitis. In conclusion, our findings suggest that the ketogenic diet exacerbates acute pancreatitis through its impact on the gut microbiota and subsequent disruption of the intestinal barrier, while butyrate supplementation reverses this effect.
Topics: Mice; Animals; Butyrates; Pancreatitis; Diet, Ketogenic; Acute Disease; Fatty Acids, Volatile; Mice, Inbred C57BL
PubMed: 37892502
DOI: 10.3390/nu15204427 -
BMC Surgery Sep 2023This study aimed to construct predictive models for the risk of sepsis in patients with Acute pancreatitis (AP) using machine learning methods and compared optimal one... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
This study aimed to construct predictive models for the risk of sepsis in patients with Acute pancreatitis (AP) using machine learning methods and compared optimal one with the logistic regression (LR) model and scoring systems.
METHODS
In this retrospective cohort study, data were collected from the Medical Information Mart for Intensive Care III (MIMIC III) database between 2001 and 2012 and the MIMIC IV database between 2008 and 2019. Patients were randomly divided into training and test sets (8:2). The least absolute shrinkage and selection operator (LASSO) regression plus 5-fold cross-validation were used to screen and confirm the predictive factors. Based on the selected predictive factors, 6 machine learning models were constructed, including support vector machine (SVM), K-nearest neighbour (KNN), multi-layer perceptron (MLP), LR, gradient boosting decision tree (GBDT) and adaptive enhancement algorithm (AdaBoost). The models and scoring systems were evaluated and compared using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and the area under the curve (AUC).
RESULTS
A total of 1, 672 patients were eligible for participation. In the training set, 261 AP patients (19.51%) were diagnosed with sepsis. The predictive factors for the risk of sepsis in AP patients included age, insurance, vasopressors, mechanical ventilation, Glasgow Coma Scale (GCS), heart rate, respiratory rate, temperature, SpO2, platelet, red blood cell distribution width (RDW), International Normalized Ratio (INR), and blood urea nitrogen (BUN). The AUC of the GBDT model for sepsis prediction in the AP patients in the testing set was 0.985. The GBDT model showed better performance in sepsis prediction than the LR, systemic inflammatory response syndrome (SIRS) score, bedside index for severity in acute pancreatitis (BISAP) score, sequential organ failure assessment (SOFA) score, quick-SOFA (qSOFA), and simplified acute physiology score II (SAPS II).
CONCLUSION
The present findings suggest that compared to the classical LR model and SOFA, qSOFA, SAPS II, SIRS, and BISAP scores, the machine learning model-GBDT model had a better performance in predicting sepsis in the AP patients, which is a useful tool for early identification of high-risk patients and timely clinical interventions.
Topics: Humans; Acute Disease; Retrospective Studies; Pancreatitis; Sepsis; Systemic Inflammatory Response Syndrome
PubMed: 37658375
DOI: 10.1186/s12893-023-02151-y -
The Lancet. Respiratory Medicine Feb 2024Around 500 000 people worldwide develop rifampicin-resistant tuberculosis each year. The proportion of successful treatment outcomes remains low and new treatments are... (Randomized Controlled Trial)
Randomized Controlled Trial
Short oral regimens for pulmonary rifampicin-resistant tuberculosis (TB-PRACTECAL): an open-label, randomised, controlled, phase 2B-3, multi-arm, multicentre, non-inferiority trial.
BACKGROUND
Around 500 000 people worldwide develop rifampicin-resistant tuberculosis each year. The proportion of successful treatment outcomes remains low and new treatments are needed. Following an interim analysis, we report the final safety and efficacy outcomes of the TB-PRACTECAL trial, evaluating the safety and efficacy of oral regimens for the treatment of rifampicin-resistant tuberculosis.
METHODS
This open-label, randomised, controlled, multi-arm, multicentre, non-inferiority trial was conducted at seven hospital and community sites in Uzbekistan, Belarus, and South Africa, and enrolled participants aged 15 years and older with pulmonary rifampicin-resistant tuberculosis. Participants were randomly assigned, in a 1:1:1:1 ratio using variable block randomisation and stratified by trial site, to receive 36-80 week standard care; 24-week oral bedaquiline, pretomanid, and linezolid (BPaL); BPaL plus clofazimine (BPaLC); or BPaL plus moxifloxacin (BPaLM) in stage one of the trial, and in a 1:1 ratio to receive standard care or BPaLM in stage two of the trial, the results of which are described here. Laboratory staff and trial sponsors were masked to group assignment and outcomes were assessed by unmasked investigators. The primary outcome was the percentage of participants with a composite unfavourable outcome (treatment failure, death, treatment discontinuation, disease recurrence, or loss to follow-up) at 72 weeks after randomisation in the modified intention-to-treat population (all participants with rifampicin-resistant disease who received at least one dose of study medication) and the per-protocol population (a subset of the modified intention-to-treat population excluding participants who did not complete a protocol-adherent course of treatment (other than because of treatment failure or death) and those who discontinued treatment early because they violated at least one of the inclusion or exclusion criteria). Safety was measured in the safety population. The non-inferiority margin was 12%. This trial is registered with ClinicalTrials.gov, NCT02589782, and is complete.
FINDINGS
Between Jan 16, 2017, and March 18, 2021, 680 patients were screened for eligibility, of whom 552 were enrolled and randomly assigned (152 to the standard care group, 151 to the BPaLM group, 126 to the BPaLC group, and 123 to the BPaL group). The standard care and BPaLM groups proceeded to stage two and are reported here, post-hoc analyses of the BPaLC and BPaL groups are also reported. 151 participants in the BPaLM group and 151 in the standard care group were included in the safety population, with 138 in the BPaLM group and 137 in the standard care group in the modified intention-to-treat population. In the modified intention-to-treat population, unfavourable outcomes were reported in 16 (12%) of 137 participants for whom outcome was assessable in the BPaLM group and 56 (41%) of 137 participants in the standard care group (risk difference -29·2 percentage points [96·6% CI -39·8 to -18·6]; non-inferiority and superiority p<0·0001). 34 (23%) of 151 participants receiving BPaLM had adverse events of grade 3 or higher or serious adverse events, compared with 72 (48%) of 151 participants receiving standard care (risk difference -25·2 percentage points [96·6% CI -36·4 to -13·9]). Five deaths were reported in the standard care group by week 72, of which one (COVID-19 pneumonia) was unrelated to treatment and four (acute pancreatitis, suicide, sudden death, and sudden cardiac death) were judged to be treatment-related.
INTERPRETATION
The 24-week, all-oral BPaLM regimen is safe and efficacious for the treatment of pulmonary rifampicin-resistant tuberculosis, and was added to the WHO guidance for treatment of this condition in 2022. These findings will be key to BPaLM becoming the preferred regimen for adolescents and adults with pulmonary rifampicin-resistant tuberculosis.
FUNDING
Médecins Sans Frontières.
Topics: Adult; Adolescent; Humans; Rifampin; Acute Disease; Pancreatitis; Tuberculosis, Multidrug-Resistant; Moxifloxacin; Linezolid; Nitroimidazoles
PubMed: 37980911
DOI: 10.1016/S2213-2600(23)00389-2 -
United European Gastroenterology Journal Oct 2023There is a noteworthy overlap between the clinical picture of biliary acute pancreatitis (AP) and the 2018 Tokyo guidelines currently used for the diagnosis of... (Review)
Review
BACKGROUND
There is a noteworthy overlap between the clinical picture of biliary acute pancreatitis (AP) and the 2018 Tokyo guidelines currently used for the diagnosis of cholangitis (AC) and cholecystitis (CC). This can lead to significant antibiotic and endoscopic retrograde cholangiopancreatography (ERCP) overuse.
OBJECTIVES
We aimed to assess the on-admission prevalence of AC/CC according to the 2018 Tokyo guidelines (TG18) in a cohort of biliary AP patients, and its association with antibiotic use, ERCP and clinically relevant endpoints.
METHODS
We conducted a secondary analysis of the Hungarian Pancreatic Study Group's prospective multicenter registry of 2195 AP cases. We grouped and compared biliary cases (n = 944) based on the on-admission fulfillment of definite AC/CC according to TG18. Aside from antibiotic use, we evaluated mortality, AC/CC/AP severity, ERCP performance and length of hospitalization. We also conducted a literature review discussing each criteria of the TG18 in the context of AP.
RESULTS
27.8% of biliary AP cases fulfilled TG18 for both AC and CC, 22.5% for CC only and 20.8% for AC only. Antibiotic use was high (77.4%). About 2/3 of the AC/CC cases were mild, around 10% severe. Mortality was below 1% in mild and moderate AC/CC patients, but considerably higher in severe cases (12.8% and 21.2% in AC and CC). ERCP was performed in 89.3% of AC cases, common bile duct stones were found in 41.1%.
CONCLUSION
Around 70% of biliary AP patients fulfilled the TG18 for AC/CC, associated with a high rate of antibiotic use. Mortality in presumed mild or moderate AC/CC is low. Each of the laboratory and clinical criteria are commonly fulfilled in biliary AP, single imaging findings are also unspecific-AP specific diagnostic criteria are needed, as the prevalence of AC/CC are likely greatly overestimated. Randomized trials testing antibiotic use are also warranted.
Topics: Humans; Acute Disease; Anti-Bacterial Agents; Pancreatitis; Prospective Studies; Tokyo; Guidelines as Topic
PubMed: 37464535
DOI: 10.1002/ueg2.12402 -
Cell Death & Disease Aug 2023Acinar cell dedifferentiation is one of the most notable features of acute and chronic pancreatitis. It can also be the initial step that facilitates pancreatic cancer...
Acinar cell dedifferentiation is one of the most notable features of acute and chronic pancreatitis. It can also be the initial step that facilitates pancreatic cancer development. In the present study, we further decipher the precise mechanisms and regulation using primary human cells and murine experimental models. Our RNAseq analysis indicates that, in both species, early acinar cell dedifferentiation is accompanied by multiple pathways related to cell survival that are highly enriched, and where SLC7A11 (xCT) is transiently upregulated. xCT is the specific subunit of the cystine/glutamate antiporter system x. To decipher its role, gene silencing, pharmacological inhibition and a knock-out mouse model were used. Acinar cells with depleted or reduced xCT function show an increase in ferroptosis relating to lipid peroxidation. Lower glutathione levels and more lipid ROS accumulation could be rescued by the antioxidant N-acetylcysteine or the ferroptosis inhibitor ferrostatin-1. In caerulein-induced acute pancreatitis in mice, xCT also prevents lipid peroxidation in acinar cells. In conclusion, during stress, acinar cell fate seems to be poised for avoiding several forms of cell death. xCT specifically prevents acinar cell ferroptosis by fueling the glutathione pool and maintaining ROS balance. The data suggest that xCT offers a druggable tipping point to steer the acinar cell fate in stress conditions.
Topics: Humans; Animals; Mice; Acinar Cells; Acute Disease; Ferroptosis; Pancreatitis; Reactive Oxygen Species; Glutamic Acid
PubMed: 37604805
DOI: 10.1038/s41419-023-06063-w -
Revista de Gastroenterologia de Mexico... 2023Acute pancreatitis (AP) and recurrent acute pancreatitis (RAP) are conditions, whose incidence is apparently on the rise. Despite the ever-increasing evidence regarding...
Acute pancreatitis (AP) and recurrent acute pancreatitis (RAP) are conditions, whose incidence is apparently on the rise. Despite the ever-increasing evidence regarding the management of AP in children and adults, therapeutic actions that could potentially affect having a poor prognosis in those patients, especially in the pediatric population, continue to be carried out. Therefore, the Asociación Mexicana de Gastroenterología convened a group of 24 expert pediatric gastroenterologists from different institutions and areas of Mexico, as well as 2 pediatric nutritionists and 2 specialists in pediatric surgery, to discuss different aspects of the epidemiology, diagnosis, and treatment of AP and RAP in the pediatric population. The aim of this document is to present the consensus results. Different AP topics were addressed by 6 working groups, each of which reviewed the information and formulated statements considered pertinent for each module, on themes involving recommendations and points of debate, concerning diagnostic or therapeutic approaches. All the statements were presented and discussed. They were then evaluated through a Delphi process, with electronic and anonymous voting, to determine the level of agreement on the statements. A total of 29 statements were formulated, all of which reached above 75% agreement in the first round of voting.
Topics: Adult; Humans; Child; Adolescent; Pancreatitis; Consensus; Acute Disease; Mexico
PubMed: 37336694
DOI: 10.1016/j.rgmxen.2023.04.011