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).

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.

Recurrence of hypertriglyceridemia-associated acute pancreatitis: A multicenter, prospective cohort study.

OBJECTIVES: There are scarce prospective data on recurrent hypertriglyceridemia-associated acute pancreatitis (HTG-AP). This study aimed to investigate the incidence, potential prognostic factors, and clinical relevance of recurrent HTG-AP. METHODS: This study is a multicenter, prospective cohort study. Adult patients with the first HTG-AP attack enrolled in the PERFORM registry between November 2020 and December 2021 were involved. All the study patients were followed up for more than two years with a two-round schedule. The Cox proportional-hazards model was applied to analyze the potential factors. Quality of life was evaluated using the EuroQol five-dimensional five-level health scale (EQ-5D-5L). RESULTS: A total of 184 patients from 25 sites were included in the study, and 161 patients completed the two-round follow-up. Among them, the mean follow-up time for the study patients was 31±4 months, and the incidence rate of recurrent HTG-AP attack was 23 % (37/161). All patients with recurrent episodes required readmission to the hospital. The EQ visual analog scale (VAS) score was significantly lower in patients with recurrent episodes compared to those without (76±10 vs. 82±12; P = 0.02) at the latest follow-up. Age <40 years old (hazard ratio [HR], 3.6; 95 % confidence interval [CI], 1.5-8.7; P = 0.004) and a history of diabetes (HR, 2.6; 95 %CI, 1.3-5.1; P = 0.005) were identified as potential predictor factors for recurrence. CONCLUSIONS: Recurrence of HTG-AP is common, especially for younger patients with diabetes. Recurrence necessitated additional hospital readmissions and was associated with compromised quality of life.

Nutrition therapy in critically ill patients with severe acute pancreatitis.

A significant proportion of patients (10%-20%) with acute pancreatitis develop severe acute pancreatitis characterized by pancreatic necrosis, systemic inflammation, and organ failure, commonly requiring intensive care unit (ICU) admission. In this specific population, nutrition therapy is more challenging than that in the general ICU population, primarily because of inevitable gastrointestinal involvement by pancreatic inflammation. In this review, we discussed several key aspects of nutrition therapy in this population, including key pathophysiology that may impede nutrition therapy, the timing and implementation of enteral nutrition and parenteral nutrition, the importance of specific nutrient supplements, and the long-term outcomes that may be addressed by nutrition therapy.

Investigation of the migration of natural organic matter-iron-antimony nano-colloids in acid mine drainage.

Colloids can potentially affect the efficacy of traditional acid mine drainage (AMD) treatment methods such as precipitation and filtration. However, it is unclear how colloids affect antimony (Sb) migration in AMD, especially when natural organic matter (NOM) is present. To conduct an in-depth investigation on the formation and migration behavior of NOM, iron (Fe), Sb and NOM-Fe-Sb colloids in AMD, experiments were performed under simulated AMD conditions. The results demonstrate significant variations in the formation of NOM-Fe-Sb colloids (1-3-450 nm) as the molar ratio of carbon to iron (C/Fe) increases within acidic conditions (pH = 3). Increasing the C/Fe molar ratio from 0.1 to 1.2 resulted in a decrease in colloid formation but an increase in particulate fraction. The distribution of colloidal Sb, Sb(III), and Fe(III) within the NOM-Fe-Sb colloids decreased from 68 % to 55 %, 72 % to 57 %, and 68 % to 55 %, respectively. Their distribution in the particulate fraction increased from 28 % to 42 %, 21 % to 34 %, and 8 % to 27 %. XRD, FTIR, and SEM-EDS analyses demonstrated that NOM facilitates the formation and crystallization of Fe3O4 and FeSbO4 crystalline phases. The formation of the colloids depended on pH. Our results indicate that NOM-Fe-Sb colloids can form when the pH ≤ 4, and the proportion of colloidal Sb fraction within the NOM-Fe-Sb colloids increased from 9 % to a maximum of 73 %. Column experiments show that the concentration of NOM-Fe-Sb colloids reaches its peak and remains stable at approximately 3.5 pore volumes (PVs), facilitating the migration of Sb in the porous media. At pH ≥ 5, stable NOM-Fe-Sb colloids do not form, and the proportion of colloidal Sb fraction decreases from 7 % to 0 %. This implies that as pH increases, the electrostatic repulsion between colloidal particles weakens, resulting in a reduction in the colloidal fraction and an increase in the particulate fraction. At higher pH values (pH ≥ 5), the repulsive forces between colloidal particles nearly disappear, promoting particle aggregation. The findings of this study provide important scientific evidence for understanding the migration behavior of NOM-Fe-Sb colloids in AMD. As the pH gradually shifts from acidic to near-neutral pH during the remediation process of AMD, these results could be applied to develop new strategies for this purpose.

Immune-Enhancing Treatment among Acute Necrotizing Pancreatitis Patients with Metabolic Abnormalities: A Post Hoc Analysis of a Randomized Clinical Trial.

Background/Aims: : Metabolic syndrome is common in patients with acute pancreatitis and its components have been reported to be associated with infectious complications. In this post hoc analysis, we aimed to evaluate whether metabolic abnormalities impact the effect of immune-enhancing thymosin alpha-1 (Tα1) therapy in acute necrotizing pancreatitis (ANP) patients. Methods: : All data were obtained from the database for a multicenter randomized clinical trial that evaluated the efficacy of Tα1 in ANP patients. Patients who discontinued the Tα1 treatment prematurely were excluded. The primary outcome was 90-day infected pancreatic necrosis (IPN) after randomization. Three post hoc subgroups were defined based on the presence of hyperglycemia, hypertriglyceridemia, or both at the time of randomization. In each subgroup, the correlation between Tα1 and 90-day IPN was assessed using the Cox proportional-hazards regression model. Multivariable propensity-score methods were used to control potential bias. Results: : Overall, 502 participants were included in this post hoc analysis (248 received Tα1 treatment and 254 received matching placebo treatment). Among them, 271 (54.0%) had hyperglycemia, 371 (73.9%) had hypertriglyceridemia and 229 (45.6%) had both. Tα1 therapy was associated with reduced incidence of IPN among patients with hyperglycemia (18.8% vs 29.7%: hazard ratio, 0.80; 95% confidence interval, 0.37 to 0.97; p=0.03), but not in the other subgroups. Additional multivariate regression models using three propensity-score methods yielded similar results. Conclusions: : Among ANP patients with hyperglycemia, immune-enhancing Tα1 treatment was associated with a reduced risk of IPN (ClinicalTrials.gov, Registry number: NCT02473406).

Early systemic anticoagulation reduces hospital readmission in acute necrotizing pancreatitis patients: A retrospective cohort study.

BACKGROUND: Early systemic anticoagulation (SAC) is a common practice in acute necrotizing pancreatitis (ANP), and its impact on in-hospital clinical outcomes had been assessed. However, whether it affects long-term outcomes is unknown. This study aimed to evaluate the effect of SAC on 90-day readmission and other long-term outcomes in ANP patients. METHODS: During January 2013 and December 2018, ANP patients admitted within 7 days from the onset of abdominal pain were screened. The primary outcome was 90-day readmission after discharge. Cox proportional-hazards regression model and mediation analysis were used to define the relationship between early SAC and 90-day readmission. RESULTS: A total of 241 ANP patients were enrolled, of whom 143 received early SAC during their hospitalization and 98 did not. Patients who received early SAC experienced a lower incidence of splanchnic venous thrombosis (SVT) [risk ratio (RR) = 0.40, 95% CI: 0.26-0.60, P < 0.01] and lower 90-day readmission with an RR of 0.61 (95% CI: 0.41-0.91, P = 0.02) than those who did not. For the quality of life, patients who received early SAC had a significantly higher score in the subscale of vitality (P = 0.03) while the other subscales were all comparable between the two groups. Multivariable Cox regression model showed that early SAC was an independent protective factor for 90-day readmission after adjusting for potential confounders with a hazard ratio of 0.57 (95% CI: 0.34-0.96, P = 0.04). Mediation analysis showed that SVT mediated 37.0% of the early SAC-90-day readmission causality. CONCLUSIONS: The application of early SAC may reduce the risk of 90-day readmission in the survivors of ANP patients, and reduced SVT incidence might be the primary contributor.

Quantification of the effect of biochar application on heavy metals in paddy systems: Impact, mechanisms and future prospects.

Biochar (BC) has shown great potential in remediating heavy metal(loid)s (HMs) contamination in paddy fields. Variation in feedstock sources, pyrolysis temperatures, modification methods, and application rates of BC can result in great changes in its effects on HM bioavailability and bioaccumulation in soil-rice systems and remediation mechanisms. Meanwhile, there is a lack of application guidelines for BC with specific properties and application rates when targeting rice fields contaminated with certain HMs. To elucidate this topic, this review focuses on i) the effects of feedstock type, pyrolysis temperature, and modification method on the properties of BC; ii) the changes in bioavailability and bioaccumulation of HMs in soil-rice systems applying BC with different feedstocks, pyrolysis temperatures, modification methods, and application rates; and iii) exploration of potential remediation mechanisms for applying BC to reduce the mobility and bioaccumulation of HMs in rice field systems. In general, the application of Fe/Mn modified organic waste (OW) derived BC for mid-temperature pyrolysis is still a well-optimized choice for the remediation of HM contamination in rice fields. From the viewpoint of remediation efficiency, the application rate of BC should be appropriately increased to immobilize Cd, Pb, and Cu in rice paddies, while the application rate of BC for immobilizing As should be <2.0 % (w/w). The mechanism of remediation of HM-contaminated rice fields by applying BC is mainly the direct adsorption of HMs by BC in soil pore water and the mediation of soil microenvironmental changes. In addition, the application of Fe/Mn modified BC induced the formation of iron plaque (IP) on the root surface of rice, which reduced the uptake of HM by the plant. Finally, this paper describes the prospects and challenges for the extension of various BCs for the remediation of HM contamination in paddy fields and makes some suggestions for future development.

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.

U-shaped association between serum triglyceride levels and mortality among septic patients: An analysis based on the MIMIC-IV database.

BACKGROUND: Sepsis is characterized by upregulated lipolysis in adipose tissue and a high blood triglyceride (TG) level. It is still debated whether serum TG level is related to mortality in septic patients. The aim of this study is to investigate the association between serum TG level and mortality in septic patients admitted to the intensive care unit (ICU). METHODS: Data from adult septic patients (≥18 years) admitted to the ICU for the first time were obtained from the Multiparameter Intelligent Monitoring in Intensive Care IV (MIMIC-IV) database. The patients' serum TG levels that were measured within the first week after ICU admission were extracted for statistical analysis. The endpoints were 28-day, ICU and in-hospital mortality. RESULTS: A total of 2,782 septic patients were included. Univariate analysis indicated that the relationship between serum TG levels and the risk of mortality was significantly nonlinear. Both the Lowess smoothing technique and restricted cubic spline analyses revealed a U-shaped association between serum TG levels and mortality among septic patients. The lowest mortality rate was associated with a serum TG level of 300-500 mg/dL. Using 300∼500 mg/dL as the reference range, we found that both hypo-TG (<300 mg/dL) and hyper-TG (≥500 mg/dL) were associated with increased mortality. The result was further adjusted by Cox regression with and without the inclusion of some differential covariates. CONCLUSIONS: There was a U-shaped association between serum TG and mortality in septic ICU patients. The optimal concentration of serum TG levels in septic ICU patients is 300-500 mg/dL.

PFKFB3 promotes sepsis-induced acute lung injury by enhancing NET formation by CXCR4hi neutrophils.

CXCR4hi neutrophils, which are a subset of neutrophils with high CXCR4 expression, are important contributors to sepsis-induced acute lung injury (ALI). PFKFB3, a key glycolysis gene, plays an essential role in neutrophil inflammatory activation. However, the specific involvement of PFKFB3 in sepsis-induced ALI remains unclear. Here, we observed that PFKFB3 was upregulated in CXCR4hi neutrophils and facilitated sepsis-induced ALI. Mechanistically, we observed that PFKFB3 promoted sepsis-induced ALI by enhancing neutrophil extracellular trap (NET) formation by CXCR4hi neutrophils. Further study indicated that PFKFB3 promoted NET formation by upregulating glycolytic metabolism in CXCR4hi neutrophils. In summary, our study uncovered a new mechanism by which CXCR4hi neutrophils trigger sepsis-induced ALI by promoting NET formation, which is supported by PFKFB3-mediated glycolytic metabolism.

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.

Role of PFKFB3-driven glycolysis in sepsis.

Sepsis is still the leading cause of death as a result of infection. Metabolic disorder plays a vital role in sepsis progression. Glycolysis intensification is the most characteristic feature of sepsis-related metabolic disorders. The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) is a critical engine that controls the rate of glycolysis. Recent studies have revealed that sepsis accelerates the rate of PFKFB3-driven glycolysis in different cells, including macrophages, neutrophils, endothelial cells and lung fibroblasts. Furthermore, increased PFKFB3 is closely related to the excessive inflammatory response and high mortality in sepsis. Interestingly, inhibition of PFKFB3 alone or in combination has also shown great potential in the treatment of sepsis. Therefore, an improved understanding of the canonical and noncanonical functions of PFKFB3 may provide a novel combinatorial therapeutic target for sepsis. This review summarizes the role of PFKFB3-driven glycolysis in the regulation of immunocyte activation and nonimmune cell damage in sepsis. In addition, we present recent achievements in the development of PFKFB3 drugs and discuss their potential therapeutic roles in sepsis.KEY MESSAGESepsis induces high expression of PFKFB3 in immunocytes and nonimmune cells, thereby enhancing cellular glycolytic flux.PFKFB3-driven glycolysis reprogramming is closely related to an excessive inflammatory response and high mortality in sepsis.Inhibition of PFKFB3 alone or in combination provides a novel combinatorial therapeutic target for sepsis.

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.

Early mean absolute lymphocyte count in acute necrotizing pancreatitis is associated with infected pancreatic necrosis.

OBJECTIVES: Peripheral absolute lymphocyte count (ALC) has the potential to predict infected pancreatic necrosis (IPN), but requires verification. This study aimed to assess whether early mean absolute lymphocyte count is associated with the development of IPN in ANP patients using pooled data from a multicenter, randomized controlled trial and a retrospective study. METHODS: The study subjects are from the TRACE trial and a single-center cohort study. ALC during the first seven days was used to define early mean ALC. The entire cohort was then divided into quartiles of early mean ALC. Multivariable Cox proportional hazards regression (MCPHR) model was used to assess the association between early mean ALC and 90-day IPN. RESULTS: A total of 660 patients (median age, 44 years; 63.8 % males) were included and 157 (23.8 %) developed IPN within a 90-day period. The median (interquartile range, IQR) of the early mean ALC is 1.07 (0.80-1.36). All the study subjects were evenly divided into 4 groups: quartile-1 (0.33-0.79*10^9/L), quartile-2 (0.80-1.06*10^9/L), quartile-3 (1.07-1.36*10^9/L) and quartile-4 (1.37-4.01*10^9/L). The incidence of 90-day IPN was 38.3 %, 25.7 %, 19.2 % and 12.2 % for each group, respectively. In the MCPHR model, the lowest early mean ALC (quartile-1) was found to be an independent risk factor of 90-day IPN with a hazard ratio (95 %CI) of 2.21 (1.28-3.81) compared to the highest mean ALC(quartile-4) group. CONCLUSION: Among patients with ANP, early mean ALC was significantly associated with the development of IPN. Preventive strategies should be considered in patients with reduced ALC.

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.

GPIHBP1 autoantibody is an independent risk factor for the recurrence of hypertriglyceridemia-induced acute pancreatitis.

BACKGROUND: GPIHBP1, a glycolipid-anchored protein of capillary endothelial cells, is a crucial partner for lipoprotein lipase (LPL) in plasma triglyceride metabolism. GPIHBP1 autoantibodies block LPL binding to GPIHBP1 and lead to severe hypertriglyceridemia (HTG) and HTG-induced acute pancreatitis (HTG-AP). We sought to define the incidence of GPIHBP1 autoantibodies in patients with HTG-AP. OBJECTIVE: We determined the incidence of GPIHBP1 autoantibody in HTG-AP patients, and compared the clinical features and long-term outcomes between GPIHBP1 autoantibody-positive and negative groups. METHODS: An enzyme-linked immunosorbent assay was used to screen for GPIHBP1 autoantibody in 116 HTG-AP patients hospitalized from Jan 1, 2015 to Aug 31, 2019. All patients were followed up for 24 months. The primary outcome was the recurrence rate of HTG-AP during the two-year follow-up period. The incidence of recurrent episodes was analyzed by the Kaplan-Meier method and multivariable Cox regression was used to identify risk factors. RESULTS: GPIHBP1 autoantibodies were present in 17 of 116 study patients (14.66%). The 2-year recurrence rate of HTG-AP was much higher in the GPIHBP1 autoantibody-positive group (35%, 6 in 17) than in the negative group (4%, 4 in 99). The multivariable Cox regression analysis showed that GPIHBP1 autoantibody was an independent risk factor for HTG-AP recurrence in two years. CONCLUSIONS: The presence of GPIHBP1 autoantibody is common in patients with HTG-AP, and is an independent risk factor for two-year recurrence of HTG-AP.

Immune enhancement in patients with predicted severe acute necrotising pancreatitis: a multicentre double-blind randomised controlled trial.

PURPOSE: Infected pancreatic necrosis (IPN) is a highly morbid complication of acute necrotising pancreatitis (ANP). Since there is evidence of early-onset immunosuppression in acute pancreatitis, immune enhancement may be a therapeutic option. This trial aimed to evaluate whether early immune-enhancing Thymosin alpha 1 (Tα1) treatment reduces the incidence of IPN in patients with predicted severe ANP. METHODS: We conducted a multicentre, double-blind, randomised, placebo-controlled trial involving ANP patients with an Acute Physiology and Chronic Health Evaluation II (APACHE II) score ≥ 8 and a computed tomography (CT) severity score ≥ 5 admitted within 7 days of the advent of symptoms. Enrolled patients were assigned to receive a subcutaneous injection of Tα1 1.6 mg every 12 h for the first 7 days and 1.6 mg once a day for the subsequent 7 days or matching placebos (normal saline). The primary outcome was the development of IPN during the index admission. RESULTS: A total of 508 patients were randomised, of whom 254 were assigned to receive Tα1 and 254 placebo. The vast majority of the participants required admission to the intensive care unit (ICU) (479/508, 94.3%). During the index admission, 40/254(15.7%) patients in the Tα1 group developed IPN compared with 46/254 patients (18.1%) in the placebo group (difference -2.4% [95% CI - 7.4 to 5.1%]; p = 0.48). The results were similar across four predefined subgroups. There was no difference in other major complications, including new-onset organ failure (10.6% vs. 15%), bleeding (6.3% vs. 3.5%), and gastrointestinal fistula (2% vs. 2.4%). CONCLUSION: The immune-enhancing Tα1 treatment of patients with predicted severe ANP did not reduce the incidence of IPN during the index admission.