Patient-reported use of pancreatic enzyme replacement treatment (PERT) in pancreatic cancer in New Zealand and Australia: a cross-sectional survey study.

PURPOSE: This study investigated pancreatic enzyme replacement therapy (PERT) use in people diagnosed with pancreatic cancer in New Zealand (NZ) and Australia (AU). METHODS: A cross-sectional survey study was conducted using a mixed-media campaign to recruit people with pancreatic cancer and collect information about current PERT use. The questionnaire gathered data on participant demographics, awareness of PERT, prescribing practices and efficacy of enzyme replacement. RESULTS: Over 300 people with pancreatic cancer were recruited, 135 from New Zealand and 199 from Australia. Every region, state and territory was represented except for the West Coast (NZ) and the Northern Territory (AU), the lowest populated areas in both countries. In New Zealand, 60% of participants had heard about PERT, compared to 69.3% in Australia. Dosing regimens were inconsistent in both countries, with 18% and 27% of participants being prescribed PERT considered best practice in New Zealand and Australia, respectively. Before PERT commencement, 70% of participants experienced symptoms of malabsorption, with all symptoms improving after therapy was established. The majority of participants were compliant with their medication. CONCLUSION: PERT use in pancreatic cancer in New Zealand and Australia was highly variable and not compliant with international guidelines in which PERT is recommended as standard therapy. Enzyme replacement is effective for improving the symptoms of malabsorption in patients with pancreatic cancer. Clinician education may be needed to help improve the use of PERT in people with pancreatic cancer.

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).

Optimizing prediction models for pancreatic fistula after pancreatectomy: Current status and future perspectives.

Postoperative pancreatic fistula (POPF) is a frequent complication after pancreatectomy, leading to increased morbidity and mortality. Optimizing prediction models for POPF has emerged as a critical focus in surgical research. Although over sixty models following pancreaticoduodenectomy, predominantly reliant on a variety of clinical, surgical, and radiological parameters, have been documented, their predictive accuracy remains suboptimal in external validation and across diverse populations. As models after distal pancreatectomy continue to be progressively reported, their external validation is eagerly anticipated. Conversely, POPF prediction after central pancreatectomy is in its nascent stage, warranting urgent need for further development and validation. The potential of machine learning and big data analytics offers promising prospects for enhancing the accuracy of prediction models by incorporating an extensive array of variables and optimizing algorithm performance. Moreover, there is potential for the development of personalized prediction models based on patient- or pancreas-specific factors and postoperative serum or drain fluid biomarkers to improve accuracy in identifying individuals at risk of POPF. In the future, prospective multicenter studies and the integration of novel imaging technologies, such as artificial intelligence-based radiomics, may further refine predictive models. Addressing these issues is anticipated to revolutionize risk stratification, clinical decision-making, and postoperative management in patients undergoing pancreatectomy.

Critical appraisal of machine learning prognostic models for acute pancreatitis: protocol for a systematic review.

Acute pancreatitis (AP) is an acute inflammatory disorder that is common, costly, and is increasing in incidence worldwide with over 300,000 hospitalizations occurring yearly in the United States alone. As its course and outcomes vary widely, a critical knowledge gap in the field has been a lack of accurate prognostic tools to forecast AP patients' outcomes. Despite several published studies in the last three decades, the predictive performance of published prognostic models has been found to be suboptimal. Recently, non-regression machine learning models (ML) have garnered intense interest in medicine for their potential for better predictive performance. Each year, an increasing number of AP models are being published. However, their methodologic quality relating to transparent reporting and risk of bias in study design has never been systematically appraised. Therefore, through collaboration between a group of clinicians and data scientists with appropriate content expertise, we will perform a systematic review of papers published between January 2021 and December 2023 containing artificial intelligence prognostic models in AP. To systematically assess these studies, the authors will leverage the CHARMS checklist, PROBAST tool for risk of bias assessment, and the most current version of the TRIPOD-AI. (Research Registry ( http://www.reviewregistry1727 .).

Lymphatic Uptake of a Highly Lipophilic Protease Inhibitor Prodrug from a Lipid-Based Formulation is Limited by Instability in the Intestine.

Dabigatran etexilate (DABE) is a lipophilic double alkyl ester prodrug of dabigatran (DAB) which is a serine protease inhibitor used clinically as an anticoagulant. Recently, translocation of serine protease enzymes, including trypsin, from the gut into the mesenteric lymph and then blood has been associated with organ failure in acute and critical illnesses (ACIs). Delivery of DABE into mesenteric lymph may thus be an effective strategy to prevent organ failure in ACIs. Most drugs access the mesenteric lymph in low quantities following oral administration, as they are rapidly transported away from the intestine via the blood. Here, we examine the potential to deliver DABE into the mesenteric lymph by promoting association with lymph lipid transport pathways via co-administration with a lipid-based formulation (LBF). A series of self-emulsifying LBFs were designed and tested in vitro for their potential to form stable DABE loaded emulsions and keep DABE solubilised and stable over time in simulated gastrointestinal conditions. The LBFs were found to form fine emulsions with a droplet size of 214 ± 30 nm and DABE was stable in the formulation. The stability of DABE in vitro in simulated intestinal conditions, plasma and lymph samples was also evaluated to ensure stability in collected samples and to evaluate whether the prodrug is likely to release active DAB. Ultimately, a highly uniform and stable self-emulsifying Type III A LBF of DABE was chosen for progression into in vivo studies in male Sprague Dawley rats to confirm the lymphatic uptake and plasma pharmacokinetics. Both in vitro and in vivo in plasma and lymph, DABE was rapidly converted to an intermediate and DAB. The main species present in vivo in both plasma and lymph was DAB and mass transport of DABE and DAB in lymph was minimal (∼0.5 % of dose). Importantly, the concentration of DABE in lymph was substantially (20-176 fold) higher than in plasma, supporting that if the prodrug were stable and did not convert to DAB in the intestine, it would be lymphatically transported. Future studies will therefore focus on optimizing the design of the prodrug and formulation to improve stability during absorption and further promote lymphatic uptake.

Opioid analgesia and severity of acute pancreatitis: An international multicentre cohort study on pain management in acute pancreatitis.

BACKGROUND: The effect of analgesic modalities on short-term outcomes in acute pancreatitis remains unknown. However, preclinical models have raised safety concerns regarding opioid use in patients with acute pancreatitis. OBJECTIVE: This study aimed to assess the association between analgesics, particularly opioids, and severity and mortality in hospitalised patients with acute pancreatitis. METHODS: This prospective multicentre cohort study recruited consecutive patients admitted with a first episode of acute pancreatitis between April 1 and 30 June 2022, with a 1-month follow-up. Data on aetiology, clinical course, and analgesic treatment were collected. The primary outcome was the association between opioid analgesia and acute pancreatitis severity, which was analysed using univariate and multivariate analyses. RESULTS: Among a total of 1768 patients, included from 118 centres across 27 countries, 1036 (59%) had opioids administered on admission day, and 167 (9%) received opioids after admission day. On univariate analysis, moderately severe or severe acute pancreatitis was associated with male sex, Asian ethnicity, alcohol aetiology, comorbidity, predicted severe acute pancreatitis, higher pain scores, longer pain duration and opioid treatment (all p < 0.001). On multivariate analysis, comorbidity, alcohol aetiology, longer pain duration and higher pain scores increased the risk of moderately severe or severe acute pancreatitis (all p < 0.001). Furthermore, opioids administered after admission day (but not on admission day) doubled the risk of moderately severe or severe disease (OR 2.07 (95% CI, 1.29-3.33); p = 0.003). Opioid treatment for 6 days or more was an independent risk factor for moderately severe or severe acute pancreatitis (OR 3.21 (95% CI, 2.16-4.79; p < 0.001). On univariate analysis, longer opioid duration was associated with mortality. CONCLUSION: Opioid treatment increased the risk of more severe acute pancreatitis only when administered after admission day or for 6 days or more. Future randomised studies should re-evaluate whether opioids might be safe in acute pancreatitis.

Luminal Delivery of Pectin-Modified Oxygen Microbubbles Mitigates Rodent Experimental Intestinal Ischemia.

INTRODUCTION: Ischemic gut injury is common in the intensive care unit, impairs gut barrier function, and contributes to multiorgan dysfunction. One novel intervention to mitigate ischemic gut injury is the direct luminal delivery of oxygen microbubbles (OMB). Formulations of OMB can be modified to control the rate of oxygen delivery. This project examined whether luminal delivery of pectin-modified OMB (OMBp5) can reduce ischemic gut injury in a rodent model. METHODS: The OMBp5 formulation was adapted to improve delivery of oxygen along the length of small intestine. Adult Sprague-Dawley rats (n = 24) were randomly allocated to three groups: sham-surgery (SS), intestinal ischemia (II), and intestinal ischemia plus luminal delivery of OMBp5 (II + O). Ischemia-reperfusion injury was induced by superior mesenteric artery occlusion for 45 min followed by reperfusion for 30 min. Outcome data included macroscopic score of mucosal injury, the histological score of gut injury, and plasma biomarkers of intestinal injury. RESULTS: Macroscopic, microscopic data, and intestinal injury biomarker results demonstrated minimal intestinal damage in the SS group and constant damage in the II group. II + O group had a significantly improved macroscopic score throughout the gut mucosa (P = 0.04) than the II. The mean histological score of gut injury for the II + O group was significantly improved on the II group (P ≤ 0.01) in the proximal intestine only, within 30 cm of delivery. No differences were observed in plasma biomarkers of intestinal injury following OMBp5 treatment. CONCLUSIONS: This proof-of-concept study has demonstrated that luminal OMBp5 decreases ischemic injury to the proximal small intestine. There is a need to improve oxygen delivery over the full length of the intestine. These findings support further studies with clinically relevant end points, such as systemic inflammation and vital organ dysfunction.

Best supportive care in advanced pancreas cancer: a systematic review to define a patient-care bundle.

BACKGROUND: The majority of patients with pancreatic adenocarcinoma (PDAC) have advanced disease at presentation, preventing treatment with curative intent. Management of these patients is often provided by surgical teams for whom there are a lack of widely accepted strategies for care. The aim of this study was to conduct a systematic review to identify key issues in patients with advanced PDAC and integrate the evidence to form a care bundle checklist for use in surgical clinics. METHODS: A systematic review of the literature was performed regarding best supportive care for advanced PDAC according to the PRISMA guidelines. Interventions pertaining to supportive care were included whilst preventative and curative treatments were excluded. A narrative review was planned. RESULTS: Forty-four studies were assessed and four themes were developed: (i) Pain is an undertreated symptom, requiring escalating analgesics and sometimes invasive modalities. (ii) Health-related quality of life necessitates optimisation by involving family, carers and multi-disciplinary teams. (iii) Malnutrition and weight loss can be mitigated with early assessment, replacement therapies and resistance exercise. (iv) Biliary and duodenal obstruction can often be relieved by endoscopic/radiological interventions with surgery rarely required. CONCLUSION: This is the first systematic review to evaluate the different types of interventions utilized during best supportive care in patients with advanced PDAC. It provides a comprehensive care bundle for surgeons that informs management of the common issues experienced by patients within a multidisciplinary environment.

COX2 inhibitor use and type 2 diabetes treatment intensification: A registry-based cohort study.

AIM: This study examined the association between cyclooxygenase-2 inhibitor (COX2i) use and diabetes progression in people with type 2 diabetes. METHODS: We conducted a nation-wide cohort study using an Australian diabetes registry linked to medication dispensing data. We assessed time to diabetes treatment intensification among new users of COX2i compared to mild opioids. Inverse probability of treatment-weighted Cox regression models were used to adjust for age, sex, time since diabetes diagnosis, comorbidities, and socio-economic disadvantage. We conducted several sensitivity analyses, including per-protocol analyses and comparing use of any NSAID to mild opioids. RESULTS: There were 8,071 new users of COX2i and 7,623 of mild opioids with 4,168 diabetes treatment intensifications over a median follow-up of 1.6 years. Use of COX2i was associated with decreased risk of treatment intensification when compared to mild opioids (HR 0.91, 95 %CI 0.85-0.96). The results were not significant in the per-protocol analyses. Use of any NSAID was associated with a lower risk of treatment intensification compared to mild opioids (HR 0.90, 95 %CI 0.85-0.96). CONCLUSIONS: Treatment with COX2i may be associated with a modest decreased risk of diabetes treatment intensification compared to mild opioids. Future clinical studies are required to confirm whether COX2 inhibition has clinically significant benefits for glycaemic control.

Prognostic significance of organ failure and infected pancreatic necrosis in acute pancreatitis: An updated systematic review and meta-analysis.

OBJECTIVES: In patients with acute pancreatitis (AP), minimally invasive treatment and the step-up approach have been widely used to deal with infected pancreatic necrosis (IPN) in the last decade. It is unclear whether IPN has become a less important determinant of mortality relative to organ failure (OF). We aimed to statistically aggregate recent evidence from published studies to determine the relative importance of IPN and OF as determinants of mortality in patients with AP (PROSPERO: CRD42020176989). METHODS: Relevant studies were sourced from MEDLINE and EMBASE databases. Relative risk (RR) or weighted mean difference (WMD) was analyzed as outcomes. A two-sided P value of less than 0.05 was regarded as statistical significance. RESULTS: Forty-three studies comprising 11 601 patients with AP were included. The mortality was 28% for OF patients and 24% for those with IPN. Patients with OF without IPN had a significantly higher risk of mortality compared to those with IPN but without OF (RR 3.72, P < 0.0001). However, patients with both OF and IPN faced the highest risk of mortality. Additionally, IPN increased length of stay in hospital for OF patients (WMD 28.75, P = 0.032). CONCLUSION: Though IPN remains a significant concern, which leads to increased morbidity and longer hospital stay, it is a less critical mortality determinant compared to OF in AP.

Recruitment of participants with pancreatic cancer to a mixed media study for optimal recruitment in an Australasian survey of pancreatic enzyme replacement.

BACKGROUND: Pancreatic cancer is relatively rare and aggressive, with digestion and malabsorption issues often leading to significant weight loss. Recruitment of people with this malignancy into studies can be challenging, and innovative methods need to be explored to improve recruitment rates. AIM: To describe a mixed media methodology and the outcomes used to recruit patients to participate in a binational survey. METHODS: The details of the mixed media method used to identify and recruit people with pancreatic cancer are described. This method was used to investigate pancreatic enzyme replacement therapy use in people with pancreatic cancer across Australia and Aotearoa New Zealand. RESULTS: The mixed media approach was successful in reaching 334 participants from a range of ethnicities and regions. Results showed that social media platforms were notably more efficient and cost-effective than radio and newspaper but required additional expertise, including graphic design and media strategy knowledge. CONCLUSIONS: Social media is an effective and efficient method of recruiting people with pancreatic cancer to a national survey. Studies using media to recruit patients may need to include team members with a range of skills.

Predicting pancreatic fistula after central pancreatectomy using current fistula risk scores for pancreaticoduodenectomy and distal pancreatectomy.

BACKGROUND: The incidence of clinically relevant postoperative pancreatic fistula (CR-POPF) after central pancreatectomy (CP) is high, yet an effective predictive method is currently lacking. This study aimed to predict CR-POPF after CP by utilizing existing fistula risk scores (FRSs) for pancreaticoduodenectomy (PD) and distal pancreatectomy (DP). METHODS: A retrospective analysis was conducted on patients undergoing CP at our institution between January 2010 and July 2022. The primary outcome was CR-POPF (grade B/C) according to the 2016 International Study Group of Pancreatic Surgery definition. To establish predictive models for CR-POPF after CP, we combined the FRSs for PD and DP using a calculation formula that considers the probability of the union of two events. As a result, we obtained twelve central FRS (C-FRS) models. The performance of each C-FRS was assessed using the area under the curves (AUC) and calibration plots. RESULTS: A total of 115 patients undergoing CP were included. Among them, 38 (33%) were male, with a median age of 53 years. CR-POPF occurred in 35 (30.4%) patients, specifically 33 (28.7%) with grade B and 2 (1.7%) with grade C. Multivariate analysis showed that body mass index (BMI) [odds ratio (OR) 1.260, 95% confidence interval (CI) 1.039-1.528, P = 0.019), pancreatic thickness at the cephalic transection site (OR 1.228, 95% CI 1.074-1.405, P = 0.003), cephalic main pancreatic duct (MPD) size (OR 41.872, 95%CI 7.614-230.265, P < 0.001), and distal MPD size (OR 0.142, 95% CI 0.036-0.561, P = 0.005) were independent predictive factors for CR-POPF. Discrimination was generally acceptable for all C-FRS models, with an AUC ranging from 0.748 (DISPAIR-a-FRS: 95% CI, 0.659-0.824) to 0.847 (Intraop-D-a-FRS: 95% CI, 0.768-0.907). The models were calibrated with adequate Brier scores ranging from 0.157 to 0.183. The performance in all subgroups was similar as that of the entire cohort. Three preoperative risk groups (low, intermediate, and high) were identified based on the clinical applicability of the Preop-D-Roberts-FRS, with corresponding incidences of CR-POPF as 0% (0/24), 30% (21/70), and 66.7% (14/21), respectively. CONCLUSION: The derived C-FRS models show potential for accurately predicting the development of CR-POPF after CP. However, further validation studies are required to determine the most effective model. In the meantime, the Preop-D-Roberts-FRS is recommended for clinical practice due to its ease of use and preoperative predictability.

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.

Kidney Lymphatics.

Following significant advances in lymphatic biology, the important role of kidney lymphatics in kidney function and dysfunction is now being more fully appreciated. Kidney lymphatics begin in the cortex as blind-ended lymphatic capillaries and then coalesce into larger lymphatics that follow the main blood vessels out through the kidney hilum. Their function in draining interstitial fluid, macromolecules, and cells underpins their important role in kidney fluid and immune homeostasis. This article provides a comprehensive overview of recent and more established research findings on kidney lymphatics and the implications of these findings for kidney function and disease. The use of lymphatic molecular markers has greatly expanded our knowledge of the development, anatomy, and pathophysiology of kidney lymphatics. Significant recent discoveries include the diverse embryological source of kidney lymphatics, the hybrid nature of the ascending vasa recta, and the effects of lymphangiogenesis on kidney diseases such as acute kidney injury and renal fibrosis. On the basis of these recent advances, there is now an opportunity to link information from across multiple research disciplines to drive a new era of lymphatic-targeted therapies for kidney disease. © 2023 American Physiological Society. Compr Physiol 13:4945-4984, 2023.

A core set of quality performance indicators for HPB procedures: a global consensus for hepatectomy, pancreatectomy, and complex biliary surgery.

BACKGROUND: Surgery for hepatopancreaticobiliary (HPB) conditions is performed worldwide. This investigation aimed to develop a set of globally accepted procedural quality performance indicators (QPI) for HPB surgical procedures. METHODS: A systematic literature review generated a dataset of published QPI for hepatectomy, pancreatectomy, complex biliary surgery and cholecystectomy. Using a modified Delphi process, three rounds were conducted with working groups composed of self-nominating members of the International Hepatopancreaticobiliary Association (IHPBA). The final set of QPI was circulated to the full membership of the IHPBA for review. RESULTS: Seven "core" indicators were agreed for hepatectomy, pancreatectomy, and complex biliary surgery (availability of specific services on site, a specialised surgical team with at least two certified HPB surgeons, a satisfactory institutional case volume, synoptic pathology reporting, undertaking of unplanned reintervention procedures within 90 days, the incidence of post-procedure bile leak and Clavien-Dindo grade ≥III complications and 90-day post-procedural mortality). Three further procedure specific QPI were proposed for pancreatectomy, six for hepatectomy and complex biliary surgery. Nine procedure-specific QPIs were proposed for cholecystectomy. The final set of proposed indicators were reviewed and approved by 102 IHPBA members from 34 countries. CONCLUSIONS: This work presents a core set of internationally agreed QPI for HPB surgery.

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.

Predicting Persistent Acute Respiratory Failure in Acute Pancreatitis: The Accuracy of Two Lung Injury Indices.

BACKGROUND/AIMS: Early and accurate identification of patients with acute pancreatitis (AP) at high risk of persistent acute respiratory failure (PARF) is crucial. We sought to determine the accuracy of simplified Lung Injury Prediction Score (sLIPS) and simplified Early Acute Lung Injury (sEALI) for predicting PARF in ward AP patients. METHODS: Consecutive AP patients in a training cohort from West China Hospital of Sichuan University (n = 912) and a validation cohort from The First Affiliated Hospital of Nanchang University (n = 1033) were analyzed. PARF was defined as oxygen in arterial blood/fraction of inspired oxygen < 300 mmHg that lasts for > 48 h. The sLIPS was composed by shock (predisposing condition), alcohol abuse, obesity, high respiratory rate, low oxygen saturation, high oxygen requirement, hypoalbuminemia, and acidosis (risk modifiers). The sEALI was calculated from oxygen 2 to 6 L/min, oxygen > 6 L/min, and high respiratory rate. Both indices were calculated on admission. RESULTS: PARF developed in 16% (145/912) and 22% (228/1033) (22%) of the training and validation cohorts, respectively. In these patients, sLIPS and sEALI were significantly increased. sLIPS ≥ 2 predicted PARF in the training (AUROC 0.87, 95% CI 0.84-0.89) and validation (AUROC 0.81, 95% CI 0.78-0.83) cohorts. sLIPS was significantly more accurate than sEALI and current clinical scoring systems in both cohorts (all P < 0.05). CONCLUSIONS: Using routinely available clinical data, the sLIPS can accurately predict PARF in ward AP patients and outperforms the sEALI and current existing clinical scoring systems.

Position statement on the definition, incidence, diagnosis and outcome of acute on chronic pancreatitis.

BACKGROUND: Acute on chronic pancreatitis (ACP) is a relatively common condition, but there are significant gaps in our knowledge on the definition, incidence, diagnosis, treatment and prognosis. METHODS: A systematic review that followed PICO (Population; Intervention; Comparator; Outcome) recommendation for quantitative questions and PICo (Population, Phenomenon of Interest, Context) for qualitative research was done to answer 10 of the most relevant questions about ACP. Quality of evidence was judged by the GRADE criteria (Grades of Recommendation, Assessment, Development and Evaluation). The manuscript was sent for review to 12 international experts from various disciplines and continents using a Delphi process. RESULTS: The quality of evidence, for most statements, was low to very low, which means that the recommendations in general are only conditional. Despite that, it was possible to reach strong levels of agreement by the expert panel for all 10 questions. A new consensus definition of ACP was reached. Although common, the real incidence of ACP is not known, with alcohol as a major risk factor. Although pain dominates, other non-specific symptoms and signs can be present. Serum levels of pancreatic enzymes may be less than 3 times the upper limit of normal and cross-sectional imaging is considered more accurate for the diagnosis in many cases. It appears that it is less severe and with a lower mortality risk than acute pancreatitis. CONCLUSIONS: Although the evidence base is poor, this position statement provides a foundation from which to advance management of ACP.

The Anti-Tubercular Aminolipopeptide Trichoderin A Displays Selective Toxicity against Human Pancreatic Ductal Adenocarcinoma Cells Cultured under Glucose Starvation.

Pancreatic ductal adenocarcinoma remains a highly debilitating condition with no effective disease-modifying interventions. In our search for natural products with promising anticancer activity, we identified the aminolipopeptide trichoderin A as a potential candidate. While it was initially isolated as an antitubercular peptide, we provide evidence that it is also selectively toxic against BxPC-3 and PANC-1 human pancreatic ductal adenocarcinoma cells cultured under glucose deprivation. This has critical implications for the pancreatic ductal adenocarcinoma, which is characterized by nutrient deprivation due to its hypovascularized network. We have also successfully simplified the trichoderin A peptide backbone, allowing greater accessibility to the peptide for further biological testing. In addition, we also conducted a preliminary investigation into the role of peptide lipidation at the N-terminus. This showed that analogues with longer fatty acyl chains exhibited superior cytotoxicity than those with shorter acyl chains. Further structural optimization of trichoderin A is anticipated to improve its biological activity, whilst ongoing mechanistic studies to elucidate its intracellular mechanism of action are conducted in parallel.