Real-world experience with glucagon-like peptide 2 analogues in patients with short bowel syndrome and chronic intestinal failure: results from an international survey in expert intestinal failure centers.

BACKGROUND AND AIMS: Glucagon-like peptide 2 (GLP-2) analogues are the first available disease-modifying treatments for patients with intestinal failure (IF) due to short bowel syndrome (SBS). Efficacy in terms of reduction of parenteral support (PS) has been demonstrated in multiple studies and real-world reports. However, it remains unclear how many patients are eligible to receive the treatment, when treatment is started after intestinal resection, how treatment efficacy is assessed outside of clinical trials, and how the treatment is modified in case of non-response or adverse events. The aim of this study was to investigate the real-world management of patients treated with GLP-2 analogues in expert centers around the world. METHODS: A survey questionnaire was developed by a multidisciplinary working group consisting of 52 questions related to various aspects of multidisciplinary care of SBS-IF patients. The 17 questions related to the use of GLP-2 analogues in clinical practice were analyzed for this study. The online survey was sent to 33 participating centers in a phase 3 study of a long-acting GLP-2 analogue. Only responses from countries with access to commercially available GLP-2 analogues were included in the study. A descriptive analysis was performed for each question. Results are presented as median (interquartile range). RESULTS: The responses from the 19 expert IF centers with access to GLP-2 analogues indicated that 10 (10-20) % of patients with SBS-IF were treated with a GLP-2 analogue, which was less than the number of eligible patients (30 (25-40) %). In most centers (10 centers, 53%), GLP-2 therapy was started 6-12 months after the last intestinal resection, with 5 centers (26%) starting later (12-24 months). Multiple parameters were used in combination to determine the response to GLP-2 analogues of which the three most common were >20% decrease in PS (95%), at least 1 day of PS reduction per week (84%) and increased urinary output (68%). In non-responders GLP-2 therapy was stopped within the first year by 67% of the centers. Finally, strategies in case of significant adverse events include stopping the GLP-2 analogue (used by 79% of experts), dose reduction (67%) and temporary treatment interruption (62%). CONCLUSION: The results of this survey completed by expert IF centers show the real-life use of GLP-2 analogues in clinical practice. Key learning points identified include the accounting for a period of intestinal adaptation before starting GLP-2 analogues and not stopping the treatment too early in case of non-response. The best strategy in case of adverse effects should be studied further.

Airborne microplastic monitoring: Developing a simplified outdoor sampling approach using pollen monitoring equipment.

A novel, yet simple, airborne microplastic (MP) sampling approach using global pollen monitoring equipment was applied to identify, characterise and quantify outdoor airborne MPs for the first time. Modification of Burkard spore trap tape adhesive provided particle capture and facilitated downstream spectroscopy analysis. 36 polymer types were identified from a total of 21 days sampling using Burkard spore traps at two locations (United Kingdom and South Africa). MPs were detected in 95 % of daily samples. Mean MP particle levels were 2.0 ± 0.9 MP m-3 (11 polymer types) in Hull (U.K.), during March, 2.9 ± 2.0 MP m-3 (16 types) in Hull in July, and 11.0 ± 5.7 MP m-3 (29 types) in Gqeberha, (S.A.) in August 2023. The most abundant polymer type was nylon (Gqeberha). The approach was compared with two passive sampling methods whereby 27 polymer types were identified and of these, 6 types were above the limit of quantification (LOQ), with poly(methacrolein:styrene) (PMA/PS) the most abundant. Irregularly shaped MPs < 100 µm in length were predominant from all sampling approaches. For the first time, airborne MPs were chemically characterised and quantified using volumetric pollen sampling equipment, representing a viable approach for future airborne MP monitoring.

MSA: scalable DNA methylation screening BeadChip for high-throughput trait association studies.

The Infinium DNA Methylation BeadChips have significantly contributed to population-scale epigenetics research by enabling epigenome-wide trait association discoveries. Here, we design, describe, and experimentally verify a new iteration of this technology, the Methylation Screening Array (MSA), to focus on human trait screening and discovery. This array utilizes extensive data from previous Infinium platform-based epigenome-wide association studies (EWAS). It incorporates knowledge from the latest single-cell and cell type-resolution whole genome methylome profiles. The MSA is engineered to achieve scalable screening of epigenetics-trait association in an ultra-high sample throughput. Our design encompassed diverse human trait associations, including those with genetic, cellular, environmental, and demographical variables and human diseases such as genetic, neurodegenerative, cardiovascular, infectious, and immune diseases. We comprehensively evaluated this array's reproducibility, accuracy, and capacity for cell-type deconvolution and supporting 5-hydroxymethylation profiling in diverse human tissues. Our first atlas data using this platform uncovered the complex chromatin and tissue contexts of DNA modification variations and genetic variants linked to human phenotypes.

No Effect of Methylnaltrexone on Acute Pancreatitis Severity: A Multicenter Randomized Controlled Trial.

INTRODUCTION: Opioids used to manage severe pain in acute pancreatitis (AP) might exacerbate the disease through effects on gastrointestinal and immune functions. Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, may counteract these effects without changing analgesia. METHODS: This double-blind, randomized, placebo-controlled trial included adult patients with AP and systemic inflammatory response syndrome at 4 Danish centers. Patients were randomized to receive 5 days of continuous intravenous methylnaltrexone (0.15 mg/kg/d) or placebo added to the standard of care. The primary end point was the Pancreatitis Activity Scoring System score after 48 hours of treatment. Main secondary outcomes included pain scores, opioid use, disease severity, and mortality. RESULTS: In total, 105 patients (54% men) were randomized to methylnaltrexone (n = 51) or placebo (n = 54). After 48 hours, the Pancreatitis Activity Scoring System score was 134.3 points in the methylnaltrexone group and 130.5 points in the placebo group (difference 3.8, 95% confidence interval [CI] -40.1 to 47.6; P = 0.87). At 48 hours, we found no differences between the groups in pain severity (0.0, 95% CI -0.8 to 0.9; P = 0.94), pain interference (-0.3, 95% CI -1.4 to 0.8; P = 0.55), and morphine equivalent doses (6.5 mg, 95% CI -2.1 to 15.2; P = 0.14). Methylnaltrexone also did not affect the risk of severe disease (8%, 95% CI -11 to 28; P = 0.38) and mortality (6%, 95% CI -1 to 12; P = 0.11). The medication was well tolerated. DISCUSSION: Methylnaltrexone treatment did not achieve superiority over placebo for reducing the severity of AP.

A preclinical model of TB meningitis to determine drug penetration and activity at the sites of disease.

Tuberculosis meningitis (TBM) is essentially treated with the first-line regimen used against pulmonary tuberculosis, with a prolonged continuation phase. However, clinical outcomes are poor in comparison, for reasons that are only partially understood, highlighting the need for improved preclinical tools to measure drug distribution and activity at the site of disease. A predictive animal model of TBM would also be of great value to prioritize promising drug regimens to be tested in clinical trials, given the healthy state of the development pipeline for the first time in decades. Here, we report the optimization of a rabbit model of TBM disease induced via inoculation of Mycobacterium tuberculosis into the cisterna magna, recapitulating features typical of clinical TBM: neurological deterioration within months post-infection, acid-fast bacilli in necrotic lesions in the brain and spinal cord, and elevated lactate levels in cerebrospinal fluid (CSF). None of the infected rabbits recovered or controlled the disease. We used young adult rabbits, the size of which allows for spatial drug quantitation in critical compartments of the central nervous system that cannot be collected in clinical studies. To illustrate the translational value of the model, we report the penetration of linezolid from plasma into the CSF, meninges, anatomically distinct brain areas, cervical spine, and lumbar spine. Across animals, we measured the bacterial burden concomitant with neurological deterioration, offering a useful readout for drug efficacy studies. The model thus forms the basis for building a preclinical platform to identify improved regimens and inform clinical trial design.

Wild mouse gut microbiota limits initial tuberculosis infection in BALB/c mice.

Mouse models are critical tools in tuberculosis (TB) research. Recent studies have demonstrated that the wild mouse gut microbiota promotes host fitness and improves disease resistance. Here we examine whether the wild mouse gut microbiota alters the immunopathology of TB in BALB/c mice. Conventional BALB/c mice (LabC) and mice born to germ-free BALB/c mothers reconstituted with the wild mouse gut microbiota (WildR) were used in our studies. WildR mice controlled initial TB infection better than LabC mice. The microbial gut communities of LabC mice and WildR mice had similar richness but significantly different composition prior to infection. TB reduced the gut community richness in both cohorts while differences in community composition remained indicating a general TB-induced dysbiosis. The wild mouse gut microbiota did not alter the typical lung histopathology of TB in the BALB/c model that includes unstructured immune cell infiltrates with infected foamy macrophages invading alveolar spaces. Animals of both cohorts mounted robust T cell responses in lungs and spleen with lower absolute counts of CD4 and CD8 T cells in lungs of WildR mice during acute infection, corresponding with observed differences in pathogen load. In summary, LabC mice and WildR mice showed largely overlapping TB immunopathology and pathogen kinetics, with WildR mice controlling early acute infection better than LabC mice.

Real-World Management of High Stool Output in Patients with Short Bowel Syndrome: An International Multicenter Survey.

BACKGROUND: International practice guidelines for high-stool-output (HSO) management in short bowel syndrome (SBS) are available, but data on implementation are lacking. This study describes the approach used to manage HSO in SBS patients across different global regions. METHODS: This is an international multicenter study evaluating medical management of HSO in SBS patients using a questionnaire survey. Thirty-three intestinal-failure centers were invited to complete the survey as one multidisciplinary team. RESULTS: Survey response rate was 91%. Dietary recommendations varied based on anatomy and geographic region. For patients without colon-in-continuity (CiC), clinical practices were generally consistent with ESPEN guidelines, including separation of fluid from solid food (90%), a high-sodium diet (90%), and a low-simple-sugar diet (75%). For CiC patients, practices less closely followed guidelines, such as a low-fat diet (35%) or a high-sodium diet (50%). First-line antimotility and antisecretory medications were loperamide and proton-pump inhibitors. Other therapeutic agents (e.g., pancreatic enzymes and bile acid binders) were utilized in real-world practices, and usage varied based on intestinal anatomy. CONCLUSION: Expert centers largely followed published HSO-management guidelines for SBS patients without CiC, but clinical practices deviated substantially for CiC patients. Determining the reasons for this discrepancy might inform future development of practice guidelines.

Effects of a peripherally acting µ-opioid receptor antagonist for the prevention of recurrent acute pancreatitis: study protocol for an investigator-initiated, randomized, placebo-controlled, double-blind clinical trial (PAMORA-RAP trial).

BACKGROUND: Acute and chronic pancreatitis constitute a continuum of inflammatory disease of the pancreas with an increasing incidence in most high-income countries. A subset of patients with a history of pancreatitis suffer from recurrence of acute pancreatitis attacks, which accelerate disease progression towards end-stage chronic pancreatitis with loss of exocrine and endocrine function. There is currently no available prophylactic treatment for recurrent acute pancreatitis apart from removing risk factors, which is not always possible. Pain is the primary symptom of acute pancreatitis, which induces the endogenous release of opioids. This may further be potentiated by opioid administration for pain management. Increased exposure to opioids leads to potentially harmful effects on the gastrointestinal tract, including, e.g. increased sphincter tones and decreased fluid secretion, which may impair pancreatic ductal clearance and elevate the risk for new pancreatitis attacks and accelerate disease progression. Peripherally acting µ-opioid receptor antagonists (PAMORAs) have been developed to counteract the adverse effects of opioids on the gastrointestinal tract. We hypothesize that the PAMORA naldemedine will reduce the risk of new pancreatitis attacks in patients with recurrent acute pancreatitis and hence decelerate disease progression. METHODS: The study is a double-blind, randomized controlled trial with allocation of patients to either 0.2 mg naldemedine daily or matching placebo for 12 months. A total of 120 outpatients will be enrolled from five specialist centres in Denmark and Sweden. The main inclusion criteria is a history of recurrent acute pancreatitis (minimum of two confirmed pancreatitis attacks). The primary endpoint is time to acute pancreatitis recurrence after randomization. Secondary outcomes include changes in quality of life, gastrointestinal symptom scores, new-onset diabetes, exocrine pancreatic insufficiency, disease severity, health care utilization, adherence to treatment, and frequency of adverse events. Exploratory outcomes are included for mechanistic linkage and include the progression of chronic pancreatitis-related findings on magnetic resonance imaging (MRI) and changes in circulating blood markers of inflammation and fibrosis. DISCUSSION: This study investigates if naldemedine can change the natural course of pancreatitis in patients with recurrent acute pancreatitis and improve patient outcomes. TRIAL REGISTRATION: EudraCT no. 2021-000069-34. CLINICALTRIALS: gov NCT04966559. Registered on July 8, 2021.

A multidisciplinary team evaluation of management guidelines for adult short bowel syndrome.

BACKGROUND & AIMS: An international, multidisciplinary management working group (MWG) convened to review clinically useful short bowel syndrome (SBS) literature and identify gaps and inconsistencies in the management of adults with SBS. METHODS: Using nominal group technique for literature review, key publications were identified, discussed, and ranked by importance related to management of SBS. Gaps in management recommendations for SBS were identified upon critical review of the selected publications. RESULTS: Five guidelines, seven review articles, one series of six articles, and one single center series were selected and prioritized for their importance to SBS management. Evaluation of the articles by the MWG identified ten gaps and opportunities to standardize and improve SBS management. CONCLUSION: The main practice areas in need of more definitive guidelines are the management of high stool output and strategies to improve absorption of medications, nutrients, and fluids. An understanding of current real-world clinical practices related to these gaps could allow for development of best practice standards and improve patient-focused care.

Characteristics of adult intestinal failure centers: An international multicenter survey.

BACKGROUND: Current guidelines recommend that patients with chronic intestinal failure (CIF) should be managed by a multidisciplinary team (MDT). However, the characteristics of real-world IF centers and the patients they care for are lacking. The study aims to describe IF center characteristics as well as characteristics of patients with CIF across different global regions. METHODS: This is an international multicenter study of adult IF centers using a survey. The questionnaire survey included questions regarding program and patient characteristics. Thirty-three investigational centers were invited to participate. Each center was asked to answer the survey questions as one MDT. RESULTS: The survey center response rate was 91%. The median number of patients with CIF per center was 128 (range, 30-380). The most common disciplines reported were gastroenterologist (93%), dietitian (90%), nurse (83%), and advanced practitioner (nurse practitioner and physician assistant, 77%). There were centers that did not have a pharmacist, surgeon, psychologist, and social worker (30%, 37%, 60%, and 70%, respectively). The median full-time equivalents (FTEs) per 100 patients were 1.1 for nurses, 1 for dietitians, 1 for advanced practitioners, and 0.9 for gastroenterologists. Short bowel syndrome was the most common cause of CIF (50%) followed by intestinal dysmotility (20%). CONCLUSION: The majority of centers were managing around 100 patients with CIF. Despite the widespread use of the MDT, there are some variances in team characteristics. Gastroenterologists were the most common physicians supporting MDTs. In IF centers, one FTE of each core discipline was supported to manage 100 patients with CIF.

Pharmacokinetics of Glepaglutide, A Long-Acting Glucagon-Like Peptide-2 Analogue: A Study in Healthy Subjects.

BACKGROUND AND OBJECTIVE: Glepaglutide is a novel, long-acting, glucagon-like peptide-2 analogue in a stable aqueous formulation for subcutaneous dosing to treat patients with short bowel syndrome. This study was conducted primarily to characterise the pharmacokinetics of glepaglutide in healthy subjects. METHODS: In this open-label, partially randomised, parallel-group study, healthy subjects were evenly randomised to glepaglutide 5 or 10 mg dosed subcutaneously once weekly for 6 weeks or to a single intravenous infusion of glepaglutide 1 mg. Each group comprised 15 subjects. Blood samples were drawn to determine plasma concentrations of the parent drug and its two main metabolites. Concentrations of glepaglutide were calculated as the sum of these three analytes. Citrulline was included as a pharmacodynamic biomarker. Safety was assessed throughout the study. RESULTS: From a comparison of pharmacokinetic parameters following subcutaneous versus intravenous dosing, it is concluded that the pharmacokinetics of glepaglutide following subcutaneous dosing are primarily determined by slow release of the two main glepaglutide metabolites from a subcutaneous depot. For subcutaneous dosing once weekly, the two main metabolites accounted for >98% of the overall glepaglutide exposure at steady state, with the parent drug contributing to less than 1% of exposure. The estimated mean (95% confidence interval) effective half-life for glepaglutide 5 and 10 mg was 124 (73-185) h and 88 (31-146) h, respectively. There was an increase in the citrulline concentration for both glepaglutide subcutaneous dose levels. No safety issues were identified. CONCLUSIONS: Slow release of active metabolites following subcutaneous dosing leads to a significantly protracted pharmacokinetic profile for glepaglutide. These results support that once- or twice-weekly subcutaneous dosing of glepaglutide could be an efficacious therapy for intestinal rehabilitation. GOV IDENTIFIER: NCT03279302.

Characteristics of chronic intestinal failure in the USA based on analysis of claims data.

BACKGROUND: This study investigated the prevalence, characteristics, and management of patients with chronic intestinal failure (CIF) in the United States in 2012-2020, based on parenteral support (PS) prescription claims and healthcare utilization. METHODS: Patients with CIF were identified from the Integrated DataVerse® claims database if they had at least two PS prescriptions within 6 months and a relevant diagnosis. Analysis included prevalence and characteristics of patients with CIF, their travel distance to receive PS prescriptions, and the distribution of PS providers and their prescribing history. RESULTS: Up to 24,048 patients with CIF were identified, equivalent to 75 patients per million. CIF affected people of all ages, being more prevalent in women than in men. Many providers signed PS orders for small patient groups over short time periods, whereas few providers signed PS orders for large patient groups long term, indicating a lack of centralization. The distribution of PS providers suggested a disparity in healthcare coverage in rural vs urban areas, leading to patients traveling considerable distances to receive PS prescriptions. This may be exacerbated by a decline of providers with expertise in CIF and nutrition. CONCLUSIONS: Healthcare disparities for patients with CIF have likely been obscured by the lack of CIF-specific diagnostic and procedure codes, obliging providers to code for their patients under other codes. Effective policy changes, including centralized care, revision of reimbursement models, and expansion of nutrition-focused education in addition to the newly introduced International Classification of Diseases codes, are needed to provide the best care for patients.

Learning the representation of surrogate safety measures to identify traffic conflict.

Traffic conflict can be identified by the presence of evasive actions or the amount of temporal (spatial) proximity measures like time-to-collision (TTC). However, it is not enough to use only one kind of measures in some scenarios and it is hard to set a threshold for those measures. This paper proposed a method to identify traffic conflict by learning the representation of TTC and driver maneuver profiles with deep unsupervised learning and clustering the representations into traffic conflict and non-conflict clusters. We first trained a transformer encoder to encode sequences of surrogate safety measures into some latent space with unsupervised pre-training. Second, we identified informative clusters in the latent space by calculating the statistic summaries and visualizing trajectory pairs of each cluster. Some clusters are interpreted as traffic conflict clusters because they have small TTC, large deceleration rate and intertwining trajectories and they can be further interpreted as rear-end or angle conflicts. Moreover, the identified traffic conflicts contain critical conditions from the two vehicles in an interaction and one vehicle perceives them as abnormal and takes evasive action to avoid crashes.

Nanomolar EP4 receptor potency and expression of eicosanoid-related enzymes in normal appearing colonic mucosa from patients with colorectal neoplasia.

BACKGROUND: Aberrations in cyclooxygenase and lipoxygenase (LOX) pathways in non-neoplastic, normal appearing mucosa from patients with colorectal neoplasia (CRN), could hypothetically qualify as predisposing CRN-markers. METHODS: To test this hypothesis, biopsies were obtained during colonoscopy from macroscopically normal colonic mucosa from patients with and without CRN. Prostaglandin E2 (PGE2) receptors, EP1-4, were examined in Ussing-chambers by exposing biopsies to selective EP receptor agonists, antagonists and PGE2. Furthermore, mRNA expression of EP receptors, prostanoid synthases and LOX enzymes were evaluated with qPCR. RESULTS: Data suggest that PGE2 binds to both high and low affinity EP receptors. In particular, PGE2 demonstrated EP4 receptor potency in the low nanomolar range. Similar results were detected using EP2 and EP4 agonists. In CRN patients, mRNA-levels were higher for EP1 and EP2 receptors and for enzymes prostaglandin-I synthase, 5-LOX, 12-LOX and 15-LOX. CONCLUSIONS: In conclusion, normal appearing colonic mucosa from CRN patients demonstrates deviating expression in eicosanoid pathways, which might indicate a likely predisposition for early CRN development and furthermore that PGE2 potently activates high affinity EP4 receptor subtypes, supporting relevance of testing EP4 antagonists in colorectal neoplasia management.

Towards Machine Vision for Insect Welfare Monitoring and Behavioural Insights.

Machine vision has demonstrated its usefulness in the livestock industry in terms of improving welfare in such areas as lameness detection and body condition scoring in dairy cattle. In this article, we present some promising results of applying state of the art object detection and classification techniques to insects, specifically Black Soldier Fly (BSF) and the domestic cricket, with the view of enabling automated processing for insect farming. We also present the low-cost "Insecto" Internet of Things (IoT) device, which provides environmental condition monitoring for temperature, humidity, CO2, air pressure, and volatile organic compound levels together with high resolution image capture. We show that we are able to accurately count and measure size of BSF larvae and also classify the sex of domestic crickets by detecting the presence of the ovipositor. These early results point to future work for enabling automation in the selection of desirable phenotypes for subsequent generations and for providing early alerts should environmental conditions deviate from desired values.

Dapiglutide, a novel dual GLP-1 and GLP-2 receptor agonist, attenuates intestinal insufficiency in a murine model of short bowel.

BACKGROUND: Extensive intestinal resection may lead to short bowel (SB) syndrome, resulting in intestinal insufficiency or intestinal failure (IF). Intestinal insufficiency and IF involve deficiency of the proglucagon-derived hormones glucagon-like peptide-1 (GLP-1) and GLP-2. Two major problems of SB are epithelial surface loss and accelerated transit. Standard treatment now targets intestinal adaptation with a GLP-2 analogue to enlarge absorptive surface area. It is possible that additional benefit can be gained from a combination of GLP-1 and GLP-2 activity, with the aim to enlarge intestinal surface area and slow intestinal transit. METHODS: The GLP-1- and GLP-2-specific effects of the novel dual GLP-1 receptor (GLP-1R) and GLP-2 receptor (GLP-2R) agonist dapiglutide (rINN) were characterized in rodents. Furthermore, in a murine SB model of intestinal insufficiency with 40% ileocecal resection, the influence of dapiglutide on intestinal growth, body weight, food intake, volume status, and stool water content was tested against vehicle and sham-operated male mice. RESULTS: Dapiglutide significantly improves oral glucose tolerance, reduces intestinal transit time, and promotes intestinal growth. In the SB mouse model, dapiglutide promotes body weight recovery, despite unchanged intake of liquid diet. Dapiglutide promotes significant intestinal growth, as indicated by significantly increased villus height as well as intestinal length. Furthermore, dapiglutide reduces stool water losses, resulting in reduced plasma aldosterone. CONCLUSION: Dapiglutide possesses specific and potent GLP-1R and GLP-2R agonist effects in rodents. In the murine SB model, combined unimolecular GLP-1R and GLP-2R stimulation with dapiglutide potently attenuates intestinal insufficiency and potentially also IF.

Molecular Diversity Assessment using Chemotypes.

BACKGROUND: Many techniques to design chemical libraries for screening have been put forward over time. General use libraries are still important when screening against novel targets, and their design has relied on the use of molecular descriptors. In contrast, chemotype or scaffold analysis has been used less often. OBJECTIVE: We describe a simple method to assess chemical diversity based on counts of the chemotypes that offers an alternative to model chemical diversity. We describe a simple method to assess chemical diversity based on counts of the chemotypes that offers an alternative to model chemical diversity based on computed molecular properties. We show how chemotype counts can be used to evaluate the diversity of a library and compare diversity selection algorithms. We demonstrate an efficient compound selection algorithm based on chemotype analysis. METHODS: We use automated chemotype perception algorithms and compare them to traditional techniques for diversity analysis to check their effectiveness in designing diverse libraries for screening. RESULTS: The best type of molecular fingerprints for diversity selection in our analysis are extended circular fingerprints, but they can be outperformed by the use of a chemotype diversity algorithm, which can be more intuitive than traditional techniques based on molecular descriptors. Chemotype- -based algorithms retrieve a larger share of the chemotypes contained in a library when picking a subset of the chemicals in a collection. CONCLUSIONS: Chemotype analysis offers an alternative for the generation of a general-purpose screening library as it maximizes the number of chemotypes present in a subset with the smallest number of compounds. The applications of methods based on chemotype analysis that does not resort to the use of molecular descriptors are a very promising but seldom explored area of chemoinformatics.

Effects of the peripherally acting µ-opioid receptor antagonist methylnaltrexone on acute pancreatitis severity: study protocol for a multicentre double-blind randomised placebo-controlled interventional trial, the PAMORA-AP trial.

BACKGROUND: Moderate to severe acute pancreatitis (AP) is associated with a high rate of complications and increased mortality, yet no targeted pharmacologic treatment currently exists. As pain is a dominant symptom in AP, patients are exposed to excess levels of both endo- and exogenous opioids, which may have harmful effects on the course of AP. This trial investigates the effects of the peripherally acting µ-opioid receptor antagonist (PAMORA) methylnaltrexone on disease severity and clinical outcomes in patients with moderate to severe AP. METHODS: PAMORA-AP is a multicentre, investigator-initiated, double-blind, randomised, placebo-controlled, interventional trial, which will be conducted at four referral centres for acute pancreatitis in Denmark. Ninety patients with early-onset AP (pain onset within 48 h) as well as predicted moderate to severe disease (two or more systemic inflammatory response syndrome criteria upon admission) will be prospectively included. Subsequently, participants will be randomised (1:1) to intravenous treatment with either methylnaltrexone or matching placebo (Ringer's lactate) during 5 days of admission. The primary endpoint will be the group difference in disease severity as defined and measured by the Pancreatitis Activity Scoring System (PASS) score 48 h after randomisation. Secondary endpoints include daily PASS scores; disease severity according to the Atlanta classification; quantification of need for analgesics, nutritional support, intravenous fluid resuscitation and antibiotics; duration of hospital admissions, readmission rates and mortality. Pain intensity and gut function will be self-reported using validated questionnaires. Exploratory endpoints include circulating levels of pro-and anti-inflammatory markers, polyethylene glycol recovery from the urine, circulating levels of blood markers of intestinal permeability, the prevalence of pancreatic complications on computed tomography (CT) scans, and colon transit time assessed using a CT-based radiopaque marker method. DISCUSSION: This trial aims to evaluate the PAMORA methylnaltrexone as a novel targeted pharmacotherapy in patients with moderate to severe AP with the potential benefit of improved patient outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04743570 . Registered on 28 January 2021. EudraCT 2020-002313-18.