Adipose Triglyceride Lipase-Mediated Adipocyte Lipolysis Exacerbates Acute Pancreatitis Severity in Mouse Models and Patients.

Dyslipolysis of adipocytes has played a critical role in various diseases. Adipose triglyceride lipase (ATGL) is a rate-limiting enzyme in adipocyte autonomous lipolysis. However, whether the degree of adipocyte lipolysis relates to the prognoses in acute pancreatitis (AP) and the role of ATGL-mediated lipolysis in the pathogenesis of AP remain elusive. The visceral adipose tissue consumption rate in the acute stage was measured in both patients with AP and mouse models. Lipolysis levels and ATGL expression were detected in caerulein-induced AP models. CL316,243, a lipolysis stimulator, and adipose tissue-specific ATGL knockout mice were used to further investigate the role of lipolysis in AP. The ATGL-specific inhibitor, atglistatin, was used in C57Bl/6N and ob/ob AP models. This study found that increased visceral adipose tissue consumption rate in the acute phase was independently associated with adverse prognoses in patients with AP, which was validated in mice AP models. Lipolysis of adipocytes was elevated in AP mice. Stimulation of lipolysis could aggravate AP. Genetic blockage of ATGL specifically in adipocytes was able to alleviate the damage to AP. The application of atglistatin could effectively protect against AP in both lean and obese mice. These findings demonstrated that ATGL-mediated adipocyte lipolysis exacerbates AP and highlighted the therapeutic potential of ATGL as a drug target for AP.

Balanced Solution versus Normal Saline in Predicted Severe Acute Pancreatitis: A Stepped Wedge Cluster Randomized Trial.

OBJECTIVE: To compare the effect of balanced multielectrolyte solutions(BMES) versus normal saline(NS) for intravenous fluid on chloride levels and clinical outcomes.in patients with predicted severe acute pancreatitis (pSAP). SUMMARY BACKGROUND DATA: Isotonic crystalloids are recommended for initial fluid therapy in acute pancreatitis, but whether the use of BMES in preference to NS confers clinical benefits is unknown. METHODS: In this multicenter, stepped-wedge, cluster-randomized trial, we enrolled patients with pSAP (APACHE II score ≥8 and C-reactive protein >150 mg/L) admitted within 72 hours of the advent of symptoms. The study sites were randomly assigned to staggered start dates for one-way crossover from the NS phase (NS for intravenous fluid) to the BMES phase(Sterofudin for intravenous fluid). The primary endpoint was the serum chloride concentration on trial day3. Secondary endpoints included a composite of clinical and laboratory measures. RESULTS: Overall, 259 patients were enrolled from eleven sites to receive NS(n=147) or BMES(n=112). On trial day3, the mean chloride level was significantly lower in patients who received BMES(101.8 mmol/L(SD4.8) versus 105.8 mmol/L(SD5.9), difference -4.3 mmol/L [95%CI -5.6 to -3.0 mmol/L];P<0.001). For secondary endpoints, patients who received BMES had less systemic inflammatory response syndrome(19/112,17.0% versus 43/147,29.3%, P=0.024) and increased organ failure-free days (3.9 d(SD2.7) versus 3.5days(SD2.7), P<0.001) by trial day7. They also spent more time alive and out of ICU(26.4 d(SD5.2) versus 25.0days(SD6.4), P=0.009) and hospital(19.8 d(SD6.1) versus16.3days(SD7.2), P<0.001) by trial day30. CONCLUSIONS: Among patients with pSAP, using BMES in preference to NS resulted in a significantly more physiological serum chloride level, which was associated with multiple clinical benefits(Trial registration number: ChiCTR2100044432).

Significant but partial lipoprotein lipase functional loss caused by a novel occurrence of rare LPL biallelic variants.

BACKGROUND: Lipoprotein lipase (LPL) plays a crucial role in triglyceride hydrolysis. Rare biallelic variants in the LPL gene leading to complete or near-complete loss of function cause autosomal recessive familial chylomicronemia syndrome. However, rare biallelic LPL variants resulting in significant but partial loss of function are rarely documented. This study reports a novel occurrence of such rare biallelic LPL variants in a Chinese patient with hypertriglyceridemia-induced acute pancreatitis (HTG-AP) during pregnancy and provides an in-depth functional characterization. METHODS: The complete coding sequences and adjacent intronic regions of the LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes were analyzed by Sanger sequencing. The aim was to identify rare variants, including nonsense, frameshift, missense, small in-frame deletions or insertions, and canonical splice site mutations. The functional impact of identified LPL missense variants on protein expression, secretion, and activity was assessed in HEK293T cells through single and co-transfection experiments, with and without heparin treatment. RESULTS: Two rare LPL missense variants were identified in the patient: the previously reported c.809G > A (p.Arg270His) and a novel c.331G > C (p.Val111Leu). Genetic testing confirmed these variants were inherited biallelically. Functional analysis showed that the p.Arg270His variant resulted in a near-complete loss of LPL function due to effects on protein synthesis/stability, secretion, and enzymatic activity. In contrast, the p.Val111Leu variant retained approximately 32.3% of wild-type activity, without impacting protein synthesis, stability, or secretion. Co-transfection experiments indicated a combined activity level of 20.7%, suggesting no dominant negative interaction between the variants. The patient's post-heparin plasma LPL activity was about 35% of control levels. CONCLUSIONS: This study presents a novel case of partial but significant loss-of-function biallelic LPL variants in a patient with HTG-AP during pregnancy. Our findings enhance the understanding of the nuanced relationship between LPL genotypes and clinical phenotypes, highlighting the importance of residual LPL function in disease manifestation and severity. Additionally, our study underscores the challenges in classifying partial loss-of-function variants in classical Mendelian disease genes according to the American College of Medical Genetics and Genomics (ACMG)'s variant classification guidelines.

Impact of therapeutic plasmapheresis on the duration of organ failure in patients with hypertriglyceridemia-associated acute pancreatitis.

BACKGROUND: Plasmapheresis is widely used for severe hypertriglyceridemia-associated acute pancreatitis (HTG-AP) to remove excessive triglycerides from plasma. This study aimed to evaluate whether plasmapheresis could improve the duration of organ failure in HTG-AP patients. METHODS: We analyzed a cohort of patients from a multicenter, prospective, long-running registry (the PERFORM) collecting HTG-AP patients admitted to the study sites within 72 h from the onset of symptoms. This study was based on data collected from November 2020 to March 2023. Patients who had organ failure at enrollment were involved in the analyses. The primary outcome was time to organ failure resolution within 14 days. Multivariable Cox regression model was used to evaluate the association between plasmapheresis and time to organ failure resolution. Directed acyclic graph (DAG) was used to identify potential confounders. RESULTS: A total of 122 HTG-AP patients were included (median [IQR] sequential organ failure assessment (SOFA) score at enrollment, 3.00 [2.00-4.00]). Among the study patients, 46 underwent plasmapheresis, and 76 received medical treatment. The DAG revealed that baseline serum triglyceride, APACHE II score, respiratory failure, cardiovascular failure, and renal failure were potential confounders. After adjusting for the selected confounders, there was no significant difference in time to organ failure resolution between patients undergoing plasmapheresis and those receiving exclusive medical treatment (HR = 1.07; 95%CI 0.68-1.68; P = 0.777). Moreover, the use of plasmapheresis was associated with higher ICU requirements (97.8% [45/46] vs. 65.8% [50/76]; OR, 19.33; 95%CI 2.20 to 169.81; P = 0.008). CONCLUSIONS: In HTG-AP patients with early organ failure, plasmapheresis was not associated with accelerated organ failure resolution compared to medical treatment but may be associated with more ICU admissions. TRIAL REGISTRATION: The PERFORM study was registered in the Chinese Clinical Trial Registry (ChiCTR2000039541). Registered 30 October 2020.

Differences in glucose homeostasis and islet injury among diverse mice strains post acute pancreatitis.

Diverse animal models have been used to study postpancreatitis diabetes mellitus (PPDM) development; however, no study has yet conducted a comparative analysis of the specific differences in glucose homeostasis and islet injury between these models. Therefore, we investigated the differences in pancreatic islet injury and glucose homeostasis among diverse strains in a cerulein-induced acute pancreatitis (AP) model to determine the appropriate animal model for PPDM. BALB/cJ, C57BL/6J, C57BL/6 N, and FVB/NJ mice were administered cerulein to induce AP. Serum amylase levels, pancreatic acinar injury, blood glucose homeostasis, islet function, and islet injury were measured and analyzed. All strains exhibited elevated amylase secretion post pancreatitis, and BALB/cJ, C57BL/6J, and C57BL/6 N mice exhibited sex-related differences. All strains exhibited pancreatic acinar injury post pancreatitis but mostly recovered within 15 days. Overall, glucose homeostasis remained balanced post pancreatitis in all strains compared to that in the control groups, except in FVB/NJ male and female mice, which exhibited an imbalance in glucose homeostasis on day 7 post pancreatitis. All the strains, except BALB/cJ mice, exhibited a decline in Homeostasis model assessment-ß(HOMA-ß) values post pancreatitis, with significant decrease in C57BL/6J females and FVB/NJ males. Islet size decreased post pancreatitis in all strains, except BALB/cJ mice. Pancreatic islet insulin secretion levels significantly decreased in male FVB/NJ mice post pancreatitis onset and did not recover within 15 days. Therefore, FVB/NJ male mice are a useful model for studying PPDM.

Association of energy delivery with short-term survival in mechanically ventilated critically ill adult patients: a secondary analysis of the NEED trial.

BACKGROUND AND AIMS: The optimal energy delivery for mechanically ventilated patients is controversial, particularly during the first week of ICU admission. This study aimed to investigate the association between different caloric adequacy and 28-day mortality in a cohort of critically ill adults on mechanical ventilation. METHODS: This is a secondary analysis of a multicenter, cluster-randomized controlled trial. Eligible patients were divided into four quartiles (Q1-Q4) according to caloric adequacy calculated by the actual average daily energy delivery during the first seven days of ICU stay divided by energy requirement as a percentage. Cox proportional hazards models were used to examine the impact of different quartiles of caloric adequacy on 28-day mortality in the whole cohort and subgroups with different nutritional risk status at enrollment. RESULTS: A total of 1587 patients were included in this study, with an overall 28-day mortality of 15.8%. The average caloric adequacy was 26.3 ± 11.9% (Q1), 52.5 ± 5.5% (Q2), 71.7 ± 6.4% (Q3), 107.0 ± 22.2% (Q4), respectively (p < 0.001 among quartiles). Compared with Q1, Q3 was associated with lower mortality in the unadjusted model (hazard ratio [HR] = 0.536; 95% confidence interval [CI], 0.375-0.767; P = 0.001) and adjusted model (adjusted HR = 0.508; 95% CI, 0.339-0.761; P = 0.001). This association remained valid in the subgroup of high nutritional risk patients (unadjusted HR = 0.387; 95% CI, 0.238-0.627; P < 0.001 and adjusted HR = 0.369; 95% CI, 0.216-0.630; P < 0.001, respectively), but not in those with low risk. CONCLUSIONS: Energy delivery near the 70% energy requirements in the first week of ICU stay was associated with reduced 28-day mortality among mechanically ventilated critically ill patients, especially in patients with high nutrition risk at admission.

Dynamic nomogram for predicting infected pancreatic necrosis in female patients of childbearing age with hypertriglyceridemia-induced acute pancreatitis.

BACKGROUND: Hypertriglyceridemia is a common cause of acute pancreatitis. Pregnant women are at risk of developing hypertriglyceridemia-induced acute pancreatitis (HTG-AP); however, whether pregnancy increases the risk of infected pancreatic necrosis (IPN) is unknown. AIM: We aimed to assess the association between pregnancy and IPN. METHODS: This 10-year retrospective cohort study was conducted at Jinling Hospital. Adult female patients of childbearing age with HTG-AP between January 2013 and September 2022 were screened. Logistic regression analyses were performed to assess the risk factors for IPN. Patients admitted within 7 days were assigned to the training and validation sets to develop a dynamic nomogram for IPN prediction. RESULTS: 489 patients were included, and 144 developed IPN. Logistic regression analyses revealed pregnancy (OR: 2.578 95% CI: 1.474-4.510) as an independent risk factor for IPN. Gestation weeks, ARDS, albumin level, and serum creatinine level were selected as the predictors of the dynamic nomogram for IPN prediction, with good discrimination in the training set (AUC 0.867 95% CI: 0.794-0.940) and validation set (AUC 0.957 95% CI: 0.885-1.000). CONCLUSION: Pregnancy increases the risk of IPN in adult patients of childbearing age with HTG-AP, and the dynamic nomogram may help risk stratification for IPN.

AAV-mediated hepatic LPL expression ameliorates severe hypertriglyceridemia and acute pancreatitis in Gpihbp1 deficient mice and rats.

GPIHBP1 plays an important role in the hydrolysis of triglyceride (TG) lipoproteins by lipoprotein lipases (LPLs). However, Gpihbp1 knockout mice did not develop hypertriglyceridemia (HTG) during the suckling period but developed severe HTG after weaning on a chow diet. It has been postulated that LPL expression in the liver of suckling mice may be involved. To determine whether hepatic LPL expression could correct severe HTG in Gpihbp1 deficiency, liver-targeted LPL expression was achieved via intravenous administration of the adeno-associated virus (AAV)-human LPL gene, and the effects of AAV-LPL on HTG and HTG-related acute pancreatitis (HTG-AP) were observed. Suckling Gpihbp1-/- mice with high hepatic LPL expression did not develop HTG, whereas Gpihbp1-/- rat pups without hepatic LPL expression developed severe HTG. AAV-mediated liver-targeted LPL expression dose-dependently decreased plasma TG levels in Gpihbp1-/- mice and rats, increased post-heparin plasma LPL mass and activity, decreased mortality in Gpihbp1-/- rat pups, and reduced the susceptibility and severity of both Gpihbp1-/- animals to HTG-AP. However, the muscle expression of AAV-LPL had no significant effect on HTG. Targeted expression of LPL in the liver showed no obvious adverse reactions. Thus, liver-targeted LPL expression may be a new therapeutic approach for HTG-AP caused by GPIHBP1 deficiency.

HDL inhibits pancreatic acinar cell NLRP3 inflammasome activation and protect against acinar cell pyroptosis in acute pancreatitis.

BACKGROUND AND PURPOSE: Recent clinical studies have shown that serum high-density lipoprotein (HDL) levels are correlated with acute pancreatitis (AP) severity. We aimed to investigate the role of HDL in pancreatic necrosis in AP. EXPERIMENTAL APPROACH: ApoA-I is the main constitution and function component of HDL. The roles of healthy human-derived HDL and apoA-I mimic peptide D4F were demonstrated in AP models in vivo and in vitro. Constitutive Apoa1 genetic inhibition on AP severity, especially pancreatic necrosis was assessed in both caerulein and sodium taurocholate induced mouse AP models. In addition, constitutive (Casp1-/-) and acinar cell conditional (Pdx1CreNlrp3Δ/Δ and Pdx1CreGsdmdΔ/Δ) mice were used to explore the effects of HDL on acinar cell pyroptosis in AP. KEY RESULTS: Apoa1 knockout dramatically aggravated pancreatic necrosis. Human-derived HDL protected against acinar cell death in vivo and in vitro. We found that mimic peptide D4F also protected against AP very well. Constitutive Casp1 or acinar cell-conditional Nlrp3 and Gsdmd genetic inhibition could counteract the protective effects of HDL, implying HDL may exert beneficial effects on AP through inhibiting acinar cell pyroptosis. CONCLUSION AND IMPLICATIONS: This work demonstrates the protective role of HDL and apoA-I in AP pathology, potentially driven by the inhibition of NLRP3 inflammasome signaling and acinar cell pyroptosis. Mimic peptides have promise as specific therapies for AP.

The East Asian-specific LPL p.Ala288Thr (c.862G > A) missense variant exerts a mild effect on protein function.

BACKGROUND: Lipoprotein lipase (LPL) is the key enzyme responsible for the hydrolysis of triglycerides. Loss-of-function variants in the LPL gene are associated with hypertriglyceridemia (HTG) and HTG-related diseases. Unlike nonsense, frameshift and canonical GT-AG splice site variants, a pathogenic role for clinically identified LPL missense variants should generally be confirmed by functional analysis. Herein, we describe the clinical and functional analysis of a rare LPL missense variant. METHODS: Chinese patients with HTG-associated acute pancreatitis (HTG-AP) were screened for rare nonsense, frameshift, missense or canonical GT-AG splice site variants in LPL and four other lipid metabolism-related genes (APOC2, APOA5, GPIHBP1 and LMF1) by Sanger sequencing. The functional consequences of the LPL missense variant of interest were characterized by in vitro expression in HEK-293T and COS-7 cells followed by Western blot and LPL activity assays. RESULTS: Five unrelated HTG-AP patients were found to be heterozygous for a rare East Asian-specific LPL missense variant, c.862G > A (p.Ala288Thr). All five patients were adult males, and all were overweight and had a long history of alcohol consumption. Transfection of LPL wild-type and c.862G > A expression vectors into two cell lines followed by Western blot analysis served to exclude the possibility that the p.Ala288Thr missense variant either impaired protein synthesis or increased protein degradation. Contrary to a previous functional study that claimed that p.Ala288Thr had a severe impact on LPL function (reportedly having 36% normal activity), our experiments consistently demonstrated that the variant had a comparatively mild effect on LPL functional activity, which was mediated through its impact upon LPL protein secretion (~ 20% reduced secretion compared to wild-type). CONCLUSIONS: In this study, we identified the East Asian-specific LPL c.862G > A (p.Ala288Thr) missense variant in five unrelated HTG-AP patients. We demonstrated that this variant exerted only a relatively mild effect on LPL function in two cell lines. Heterozygosity for this LPL variant may have combined with alcohol consumption to trigger HTG-AP in these patients.

Frameshift coding sequence variants in the LPL gene: identification of two novel events and exploration of the genotype-phenotype relationship for variants reported to date.

BACKGROUND: Lipoprotein lipase (LPL) is the rate-limiting enzyme for triglyceride hydrolysis. Homozygous or compound heterozygous LPL variants cause autosomal recessive familial chylomicronemia syndrome (FCS), whereas simple heterozygous LPL variants are associated with hypertriglyceridemia (HTG) and HTG-related disorders. LPL frameshift coding sequence variants usually cause complete functional loss of the affected allele, thereby allowing exploration of the impact of different levels of LPL function in human disease. METHODS: All exons and flanking intronic regions of LPL were Sanger sequenced in patients with HTG-related acute pancreatitis (HTG-AP) or HTG-AP in pregnancy. Previously reported LPL frameshift coding sequence variants were collated from the Human Gene Mutation Database and through PubMed keyword searching. Original reports were manually evaluated for the following information: zygosity status of the variant, plasma LPL activity of the variant carrier, disease referred for genetic analysis, patient's age at genetic analysis, and patient's disease history. SpliceAI was employed to predict the potential impact of collated variants on splicing. RESULTS: Two novel rare variants were identified, and 53 known LPL frameshift coding sequence variants were collated. Of the 51 variants informative for zygosity, 30 were simple heterozygotes, 12 were homozygotes, and 9 were compound heterozygotes. Careful evaluation of the 55 variants with respect to their clinical and genetic data generated several interesting findings. First, we conclude that 6-7% residual LPL function could significantly delay the age of onset of FCS and reduce the prevalence of FCS-associated syndromes. Second, whereas a large majority of LPL frameshift coding sequence variants completely disrupt gene function through their "frameshift" nature, a small fraction of these variants may act wholly or partly as "in-frame" variants, leading to the generation of protein products with some residual LPL function. Third, we identified two candidate LPL frameshift coding sequence variants that may retain residual function based on genotype-phenotype correlation or SpliceAI-predicted data. CONCLUSIONS: This study reported two novel LPL variants and yielded new insights into the genotype-phenotype relationship as it pertains to LPL frameshift coding sequence variants.

Clinical and Genomic Characteristics of Carbapenem-Resistant Klebsiella pneumoniae Isolates from Acute Pancreatitis with Infection in China.

BACKGROUND: The aim of the study was to provide a clinical treatment reference for acute pancreatitis (AP) with infection, we analyzed the clinical and genomic characteristic of carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates from AP with infection in China. METHODS: Our clinical database was retrospectively analyzed with focus on the carbapenem-resistant characteristics among AP with infection in our Intensive Care Unit (ICU). Whole-genome sequencing (WGS) was used to analyze the antibiotic resistance gene, and antimicrobial susceptibility testing (AST) was performed to study the relevant phenotype in vitro. The CRISPR-Cas9 system was used to verify the relevant phenotype. RESULTS: Based on 2,211 AST data of 627 AP patients with infection, CRKP had the highest proportion among carbapenem-resistant Enterobacteriaceae (CRE), at 37.8% for imipenem and 45.3% for meropenem. WGS revealed key ß-lactamase genes, specifically blaCTX-M-15, blaCTX-M-65, blaKPC-2, blaLAP-2, blaNDM-5, blaTEM-181, blaOXA-1, and blaSHV. A total of 31.3% of CRKP were NDM-5-KPC-2-producing strains, and NDM-5-producing CRKP was resistant to imipenem/meropenem combined with avibactam, with an MIC of 512 mg/L. In addition, after knocking out blaKPC-2 and blaNDM-5, NDM-5-producing and KPC-2-producing CRKP had the same resistance level to imipenem/ meropenem. CONCLUSIONS: We first provided key insights into the clinical and genomic characteristic of CRKP in AP with infection and then made it clear that NDM-5 and KPC-2 had the same resistance level to carbapenems.

Catheter-directed thrombolysis versus systemic anticoagulation in the treatment of symptomatic splanchnic venous thrombosis secondary to acute pancreatitis: a retrospective cohort study.

BACKGROUND: Catheter-directed thrombolysis (CDT) has been an important therapy and seems effective in patients with splanchnic venous thrombosis (SVT) secondary to some diseases, but this intervention hasn't been formally evaluated in the setting of acute pancreatitis (AP). METHODS: This was a retrospective study enrolled patients between January 2013 and December 2018. AP patients who developed SVT-induced symptoms, including intractable ascites and/or enteral nutrition intolerance, were included. Demographics, SVT associated parameters, clinical features and outcomes, long-term quality of life evaluated by using SF-36 questionnaire were compared between CDT group and systemic anticoagulation (SAC) group. RESULTS: 6 patients underwent CDT and 17 received SAC. Patients in CDT group had a higher recanalization rate (100% versus 35.3%; p = 0.014) and shorter time to symptoms resolution (median 8 days versus. 31.5 days, p = 0.004). Mortality and length of hospital stay were comparable between two groups. The association analysis indicated that CDT use exerted a significantly beneficial effect on recanalization rate (risk ratio, 2.833; 95% CI, 1.489 to 5.393; p = 0.002) and time to symptoms resolution (mean difference, -33.333; 95% CI, -64.612 to -2.055; p = 0.038). No SVT-related symptoms recurrence was recorded in survivors at six-month follow-up. There was no statistical difference in either item of SF-36 questionnaire between two groups. CONCLUSIONS: Compared with SAC, CDT may facilitate vascular recanalization and shorten symptom resolution for symptomatic SVT.

Recurrence rates and risk factors for recurrence after first episode of acute pancreatitis: A systematic review and meta-analysis.

BACKGROUND: There are a certain number of acute pancreatitis (AP) patients who may suffer from multiple episodes and develop recurrent acute pancreatitis (RAP), but recurrence rates and associated risk factors for RAP vary significantly in the published literature. METHODS: We searched PubMed, Web of Science, Scopus, and Embase databases to identify all publications reporting AP recurrence until October 20th, 2022. Meta-analysis and meta-regression were performed to calculate the pooled estimates using the random-effects model. RESULTS: A total of 36 studies met the inclusion criteria and all were used in pooled analyses. The overall rate of recurrence after first-time AP was 21% (95% CI, 18%- 24%), and pooled rates in biliary, alcoholic, idiopathic, and hypertriglyceridemia etiology patients were 12%, 30%, 25%, and 30%, respectively. After managing underlying causes post-discharge, the recurrence rate decreased (14% versus 4% for biliary, 30% versus 6% for alcoholic, and 30% versus 22% for hypertriglyceridemia AP). An increased risk of recurrence was reported in patients with a smoking history (odds ratio [OR] = 1.99), alcoholic etiology (OR = 1.72), male sex (hazard ratio [HR] = 1.63), and local complications (HR = 3.40), while biliary etiology was associated with lower recurrence rates (OR = 0.38). CONCLUSION: More than one-fifth of AP patients experienced recurrence after discharge, with the highest recurrence rate in alcoholic and hypertriglyceridemia etiologies, and managing underlying causes post-discharge was related to decreased incidence. In addition, smoking history, alcoholic etiology, male gender, and presence of local complications were independent risks for the recurrence.

Early Plasmapheresis Among Patients With Hypertriglyceridemia-Associated Acute Pancreatitis.

Importance: The incidence of hypertriglyceridemia-associated acute pancreatitis (HTG-AP) is increasing. Plasmapheresis is theoretically effective in removing triglyceride from plasma, but whether it confers clinical benefits is unclear. Objective: To assess the association between plasmapheresis and the incidence and duration of organ failure among patients with HTG-AP. Design, Setting, and Participants: This is an a priori analysis of data from a multicenter, prospective cohort study with patients enrolled from 28 sites across China. Patients with HTG-AP were admitted within 72 hours from the disease onset. The first patient was enrolled on November 7th, 2020, and the last on November 30th, 2021. The follow-up of the 300th patient was completed on January 30th, 2022. Data were analyzed from April to May 2022. Exposures: Receiving plasmapheresis. The choice of triglyceride-lowering therapies was at the discretion of the treating physicians. Main Outcomes and Measures: The primary outcome was organ failure-free days to 14 days of enrollment. Secondary outcomes included other measures for organ failure, intensive care unit (ICU) admission, duration of ICU and hospital stays, incidence of infected pancreatic necrosis, and 60-day mortality. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analyses were used to control potential confounders. Results: Overall, 267 patients with HTG-AP were enrolled (185 [69.3%] were male; median [IQR] age, 37 [31-43] years), among whom 211 underwent conventional medical treatment and 56 underwent plasmapheresis. PSM created 47 pairs of patients with balanced baseline characteristics. In the matched cohort, no difference was detected concerning organ failure-free days between patients undergoing plasmapheresis or not (median [IQR], 12.0 [8.0-14.0] vs 13.0 [8.0-14.0]; P = .94). Moreover, more patients in the plasmapheresis group required ICU admission (44 [93.6%] vs 24 [51.1%]; P < .001). The IPTW results conformed to the results from the PSM analysis. Conclusions and Relevance: In this large multicenter cohort study of patients with HTG-AP, plasmapheresis was commonly used to lower plasma triglyceride. However, after adjusting for confounders, plasmapheresis was not associated with the incidence and duration of organ failure, but with increased ICU requirements.

Nomogram development and validation for predicting minimally invasive step-up approach failure in infected necrotizing pancreatitis patients: a retrospective cohort study.

BACKGROUND: Previous studies have shown that minimally invasive treatment for infected necrotizing pancreatitis (INP) may be safer and more effective than open necrosectomy (ON), but ON is still irreplaceable in a portion of INP patients. Furthermore, there is a lack of tools to identify INP patients at risk of minimally invasive step-up approach failure (eventually received ON or died), which may enable appropriate treatment for them. Our study aims to identify risk factors that can predict minimally invasive step-up approach failure in INP patients and to develop a nomogram for early prediction. METHODS: Multivariate logistic regression was performed to evaluate the association between minimally invasive step-up approach failure and factors regarding demographics, disease severity, laboratory index, and the location of extrapancreatic necrotic collections. A novel nomogram was developed, and its performance was validated both internally and externally by its discrimination, calibration, and clinical usefulness. RESULTS: There were 267, 89, and 107 patients in the training, internal, and external validation cohorts, respectively. Multivariate logistic regression demonstrated that the computed tomography severity index (CTSI) greater than 8 points, Acute Physiology and Chronic Health Evaluation II (APACHE II) score of 16 points or more, early spontaneous bleeding, fungi infection, granulocyte and platelet decrease within 30 days of acute pancreatitis onset, and extrapancreatic necrosis collection located in small bowel mesentery were independent risk factors for minimally invasive step-up approach failure. The area under the curve and coefficient of determination ( R2 ) of the nomogram constructed from the above factors were 0.920 and 0.644, respectively. The Hosmer-Lemeshow test showed that the model had good fitness ( P =0.206). In addition, the nomogram performed well in both the internal and external validation cohorts. CONCLUSIONS: The nomogram had a good performance in predicting minimally invasive step-up approach failure, which may help clinicians distinguish INP patients at risk of minimally invasive step-up approach failure early.

Association between pretreatment lymphocyte count and efficacy of immune-enhancing therapy in acute necrotising pancreatitis: a post-hoc analysis of the multicentre, randomised, placebo-controlled TRACE trial.

Background: Immune-enhancing thymosin alpha 1 (Tα1) therapy may reduce infected pancreatic necrosis (IPN) in acute necrotising pancreatitis (ANP). However, the efficacy might be impacted by lymphocyte count due to the pharmacological action of Tα1. In this post-hoc analysis, we tested the hypothesis that pre-treatment absolute lymphocyte count (ALC) determines whether patients with ANP benefit from Tα1 therapy. Methods: A post-hoc analysis of data from a multicentre, double-blind, randomised, placebo-controlled trial testing the efficacy of Tα1 therapy in patients with predicted severe ANP was performed. Patients from 16 hospitals of China were randomised to receive a subcutaneous injection of Tα1 1.6 mg every 12 h for the frst 7 days and 1.6 mg once a day for the following 7 days or a matching placebo during the same period. Patients who discontinued the Tα1 regimen prematurely were excluded. Three subgroup analyses were conducted using the baseline ALC (at randomisation), and the group allocation was maintained as intention-to-treat. The primary outcome was the incidence of IPN 90 days after randomisation. The fitted logistic regression model was applied to identify the range of baseline ALC where Tα1 therapy could exert a maximum effect. The original trial is registered with ClinicalTrials.gov, NCT02473406. Findings: Between March 18, 2017, and December 10, 2020, a total of 508 patients were randomised in the original trial, and 502 were involved in this analysis, with 248 in the Tα1 group and 254 in the placebo group. Across the three subgroups, there was a uniform trend toward more significant treatment effects in patients with higher baseline ALC. Within the subgroup of patients with baseline ALC≥0.8 × 10ˆ9/L (n = 290), the Tα1 therapy significantly reduced the risk of IPN (covariate adjusted risk difference, -0.12; 95% CI, -0.21,-0.02; p = 0.015). Patients with baseline ALC between 0.79 and 2.00 × 10ˆ9/L benefited most from the Tα1 therapy in reducing IPN (n = 263). Interpretation: This post-hoc analysis found that the efficacy of immune-enhancing Tα1 therapy on the incidence of IPN may be associated with pretreatment lymphocyte count in patients with acute necrotising pancreatitis. Funding: National Natural Science Foundation of China.

Involvement of transverse mesocolon is associated with development of colonic fistula in patients with acute necrotizing pancreatitis.

BACKGROUND: Involvement of transverse mesocolon (TM) during acute necrotizing pancreatitis(ANP) indicates that inflammation has spread from retroperitoneal space to peritoneum. Nevertheless, the impact of TM involvement, as confirmed by contrast-enhanced computed tomography (CECT), on local complications and clinical outcomes was poorly investigated. PURPOSE: This study aimed to explore the association between CECT-diagnosed TM involvement and the development of colonic fistula in a cohort of ANP patients. METHODS: This is a single-center, retrospective cohort study involving ANP patients admitted from January 2020 to December 2020. TM involvement was diagnosed by two experienced radiologists. The study subjects were enrolled consecutively and divided into two groups: TM involvement and non-TM involvement. The primary outcome was colonic fistula during the index admission. Clinical outcomes were compared between the two groups, and the association between the TM involvement and the development of colonic fistula was assessed using multivariable analysis to adjust for baseline unbalances. RESULTS: A total of 180 patients with ANP were enrolled, and 86 (47.8%) patients had TM involvement. The incidence of the colonic fistula is significantly higher in patients with TM involvement (16.3% vs. 5.3%;p = 0.017). Moreover, the length of hospital stay was 24(13,68) days in patients with TM involvement and 15(7,31) days in those not (p = 0.001). Analysis of multivariable logistic regression revealed that TM involvement is an independent risk factor for the development of colonic fistula (odds ratio: 10.253, 95% CI: 2.206-47.650, p = 0.003). CONCLUSION: TM involvement in ANP patients is associated with development of colonic fistula in ANP patients.

Detection of potential pathogen in pancreatic fluid aspiration with metagenomic next-generation sequencing in patients with suspected infected pancreatic necrosis.

BACKGROUND: Timely and accurate microbial diagnosis is important in managing patients with infected pancreatic necrosis (IPN). AIMS: To evaluate the diagnostic performance of Metagenomic next-generation sequencing (mNGS) in patients with suspected IPN. METHODS: The clinical data of 40 patients with suspected IPN who underwent CT-guided pancreatic fluid aspiration were retrospectively analyzed. Microbial culture and mNGS were simultaneously applied to identify the potential pathogens. The diagnostic performance of the mNGS was assessed by sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: The mNGS report can be obtained significantly earlier than culture methods (42 (36-62 h) vs. 60 (42-124 h), P = 0.032). Across all the study samples, seven species of bacteria and two species of fungi were reported accordingly to the culture results, while 22 species of bacteria and two species of fungi were detected by mNGS. The sensitivity, specificity, NPV, and PPV of mNGS were 88.0%, 100%, 83.33%, and 100%, respectively. CONCLUSIONS: The diagnostic accuracy of mNGS in patients with suspected IPN is satisfactory. Moreover, mNGS may broaden the range of identifiable infectious pathogens and provide a more timely diagnosis.

Prediction of infected pancreatic necrosis in acute necrotizing pancreatitis by the modified pancreatitis activity scoring system.

OBJECTIVES: Infected pancreatic necrosis (IPN) is a significant complication of acute necrotizing pancreatitis (ANP). Early identification of patients at high risk of IPN would enable appropriate treatment, but there is a lack of valid tools. This study aimed to assess the performance of the Pancreatitis Activity Scoring System (PASS) and its modifications (by removing or reducing the weight of opioid usage) in predicting IPN in a cohort of predicted severe ANP patients. METHODS: Data was prospectively collected in the TRACE trial (2017-2020) involving 16 sites across China. The predictive performance of PASS, modified PASS (mPASS), and conventional indices were assessed by the area under the receiver operating characteristic curve (AUC), Hosmer-Lemeshow C-test, Brier score, and Fagan's nomogram. Multivariate logistic regression analysis (MLRA) was used to define the relationship between the best-performing PASS/mPASS model and IPN. RESULTS: A total of 508 subjects were enrolled (median age, 43 years; 62.8% males) in the original trial, and 122 developed IPN (24%) within 90 days after randomization. Compared with non-IPN patients, the scores of PASS and its modified models were significantly higher in the IPN patients (all p < 0.001). Among the PASS and its modifications, mPASS-4 had the largest AUC, the lowest Brier score, and good calibration. The mPASS-4 model demonstrated an AUC of 0.752 in predicting IPN (the optimal cut-off for the mPASS-4 was 292.5) and outperformed the conventional indices. The MLRA results showed that mPASS-4 >292.5 was an independent risk factor of IPN (OR: 3.6, 95% CI: 2.1-6.3). CONCLUSION: The PASS and its modifications during the first week of ANP onset predict the development of IPN, with mPASS-4 performing best. The mPASS-4 model simplifies the original PASS, increasing the likelihood of clinical implementation.