Pancreatic Enzyme Use Reduces Pancreatitis Frequency in Children With Acute Recurrent or Chronic Pancreatitis: A Report From INSPPIRE.

INTRODUCTION: Among children who suffer from acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP), acute pancreatitis (AP) episodes are painful, often require hospitalization, and contribute to disease complications and progression. Despite this recognition, there are currently no interventions to prevent AP episodes. In this retrospective cohort study, we assessed the impact of pancreatic enzyme therapy (PERT) use on clinical outcomes among children with pancreatic-sufficient ARP or CP. METHODS: Children with pancreatic-sufficient ARP or CP in the INSPPIRE-2 cohort were included. Clinical outcomes were compared for those receiving vs not receiving PERT, as well as frequency of AP before and after PERT. Logistic regression was used to study the association between development of AP episodes after starting PERT and response predictors. RESULTS: Among 356 pancreatic-sufficient participants, 270 (76%) had ARP, and 60 (17%) received PERT. Among those on PERT, 42% did not have a subsequent AP episode, during a mean 2.1 years of follow-up. Children with a SPINK1 mutation ( P = 0.005) and those with ARP (compared with CP, P = 0.008) were less likely to have an AP episode after starting PERT. After initiation of PERT, the mean AP annual incidence rate decreased from 3.14 down to 0.71 ( P < 0.001). DISCUSSION: In a retrospective analysis, use of PERT was associated with a reduction in the incidence rate of AP among children with pancreatic-sufficient ARP or CP. These results support the need for a clinical trial to evaluate the efficacy of PERT to improve clinical outcomes among children with ARP or CP.

Pancreatitis-Associated Medication Use in Hospitalized Pediatric and Young Adult Patients With Acute Pancreatitis.

OBJECTIVE: The objective of this study is (1) to describe the prevalence of pancreatitis-associated medication (PAM) use at admission and discharge in pediatric and young adult patients hospitalized with acute pancreatitis (AP) and (2) to describe the prevalence of PAM use at admission in patients classified as having idiopathic AP. STUDY DESIGN: A single-center retrospective study of patients <21 years who were hospitalized with AP or acute recurrent pancreatitis from March 2015 to July 2017 was performed. Charts were reviewed for demographic data, etiology of pancreatitis, comorbidities, and use of PAMs at admission and discharge. PAMs were defined and scored based on an evidence-based classification system, with class I PAMs having strongest evidence for causation. Standard descriptive statistics were used to report prevalence data. RESULTS: Our cohort was comprised of 119 patients; 50% of patients were using a PAM at admission and 67% were taking a PAM at discharge, reflecting a significant change (P = 0.0009); 44% of patients classified as having idiopathic pancreatitis were taking a PAM on admission, reflecting a possibly missed role of medication in their presentation. Comorbidities significantly associated with PAM use included seizure disorder (P = 0.005) and oncologic disease (P = 0.005). The most commonly used class I PAMs were omeprazole, trimethoprim-sulfamethazole, valproic acid, and 6-mercaptopurine. The increase in prevalence of PAM use at discharge compared to admission was partially driven by addition of omeprazole to the outpatient medication regimen during the hospital stay (P = 0.07). CONCLUSION: Medications likely play an under-recognized role in pediatric AP. The practice of using proton pump inhibitors in management of AP warrants further study.

Small Gene Networks Delineate Immune Cell States and Characterize Immunotherapy Response in Melanoma.

Single-cell technologies have elucidated mechanisms responsible for immune checkpoint inhibitor (ICI) response, but are not amenable to a clinical diagnostic setting. In contrast, bulk RNA sequencing (RNA-seq) is now routine for research and clinical applications. Our workflow uses transcription factor (TF)-directed coexpression networks (regulons) inferred from single-cell RNA-seq data to deconvolute immune functional states from bulk RNA-seq data. Regulons preserve the phenotypic variation in CD45+ immune cells from metastatic melanoma samples (n = 19, discovery dataset) treated with ICIs, despite reducing dimensionality by >100-fold. Four cell states, termed exhausted T cells, monocyte lineage cells, memory T cells, and B cells were associated with therapy response, and were characterized by differentially active and cell state-specific regulons. Clustering of bulk RNA-seq melanoma samples from four independent studies (n = 209, validation dataset) according to regulon-inferred scores identified four groups with significantly different response outcomes (P < 0.001). An intercellular link was established between exhausted T cells and monocyte lineage cells, whereby their cell numbers were correlated, and exhausted T cells predicted prognosis as a function of monocyte lineage cell number. The ligand-receptor expression analysis suggested that monocyte lineage cells drive exhausted T cells into terminal exhaustion through programs that regulate antigen presentation, chronic inflammation, and negative costimulation. Together, our results demonstrate how regulon-based characterization of cell states provide robust and functionally informative markers that can deconvolve bulk RNA-seq data to identify ICI responders.

Impact of Trainee Involvement on Pediatric ERCP Procedures: Results From the Pediatric ERCP Initiative.

This study examines the role of trainee involvement with pediatric endoscopic retrograde cholangiopancreatography (ERCP) and whether it affects the procedure's success, post-procedural adverse outcomes, and duration. A secondary analysis of the Pediatric ERCP Database Initiative, an international database, was performed. Consecutive ERCPs on children <19 years of age from 18 centers were entered prospectively into the database. In total 1124 ERCPs were entered into the database, of which 320 (28%) were performed by trainees. The results showed that the presence of trainees did not impact technical success ( P = 0.65) or adverse events rates ( P = 0.43). Rates of post-ERCP pancreatitis, pain, and bleeding were similar between groups ( P > 0.05). Fewer cases involving trainees were in the top quartile (>58 minutes) of procedural time (19% vs 26%; P = 0.02). Overall, our findings indicate trainee involvement in pediatric ERCP is safe.

Pediatric ERCP in the Setting of Acute Pancreatitis: A Secondary Analysis of an International Multicenter Cohort Study.

Previous studies have demonstrated the safety of performing endoscopic retrograde cholangiopancreatography (ERCP) in the pediatric population; however, few have addressed the outcomes of children undergoing ERCP during acute pancreatitis (AP). We hypothesize that ERCP performed in the setting of AP can be executed with similar technical success and adverse event profiles to those in pediatric patients without pancreatitis. Using the Pediatric ERCP Database Initiative, a multi-national and multi-institutional prospectively collected dataset, we analyzed 1124 ERCPs. One hundred and ninety-four (17%) of these procedures were performed in the setting of AP. There were no difference in the procedure success rate, procedure time, cannulation time, fluoroscopy time, or American Society of Anesthesiology class despite patients with AP having higher American Society of Gastrointestinal Endoscopy grading difficulty scores. This study suggests that ERCP can be safely and efficiently performed in pediatric patients with AP when appropriately indicated.

Endoscopy and Pediatric Pancreatitis.

Children and adolescents are increasingly impacted by pancreatic disease. Interventional endoscopic procedures, including endoscopic retrograde cholangiopancreatography) and endoscopic ultrasonography, are integral to the diagnosis and management of many pancreatic diseases in the adult population. In the past decade, pediatric interventional endoscopic procedures have become more widely available, with invasive surgical procedures now being replaced by safer and less disruptive endoscopic interventions.

Quality Improvement Initiative to Improve Timing of Enteral Feeds in Pediatric Acute Pancreatitis.

BACKGROUND: Acute pancreatitis (AP) represents a significant disease burden in the pediatric population. The management of AP includes fluid resuscitation, pain management, and early enteral feeds. Contrary to old dogma, early enteral feeding has been shown to improve outcomes and reduce hospital length of stay (LOS), yet uptake of this approach has not been standardized. Our aim was to standardize the management of AP, increasing the percentage of patients receiving early enteral nutrition from 40% to 65% within 12 months. METHODS: Between January 2013 and September 2021, we conducted a quality improvement initiative among patients hospitalized with AP. Interventions included the development of a clinical care pathway, integration of an AP order set, and physician education. Our primary outcome was the percentage of patients receiving enteral nutrition within 48 hours of admission, and our secondary outcome was hospital LOS. Balancing measures included hospital readmission rates. RESULTS: A total of 652 patients were admitted for AP during the project, of which 322 (49%) were included after pathway implementation. Before pathway development, the percentage of patients receiving early enteral nutrition was 40%, which increased significantly to 84% after our interventions. This improvement remained stable. Median LOS decreased significantly from 5.5 to 4 days during this timeframe. Our balancing measure of readmission rates did not change during the project period. CONCLUSIONS: Through multiple interventions, including the implementation of an AP clinical pathway, we significantly increased the proportion of patients receiving early enteral nutrition and decreased hospital LOS without increasing hospital readmission rates.

Technical Outcomes in Pediatric Endoscopic Retrograde Cholangiopancreatography: Data from an International Collaborative.

OBJECTIVES: Endoscopic retrograde cholangiopancreatography (ERCP) in adults has been extensively studied through multicenter prospective studies. Similar pediatric studies are lacking. The Pediatric ERCP Database Initiative (PEDI) is a multicenter collaborative aiming to evaluate the indications and technical outcomes in pediatric ERCPs. METHODS: In this prospective cohort study, data were recorded for pediatric ERCPs performed across 15 centers. A pre-procedure, procedure, 2-week post-procedure follow-up, and adverse event form were completed for each ERCP performed. Univariate and stepwise linear regression was performed to identify factors associated with technically successful procedures and adverse events. RESULTS: A total of 1124 ERCPs were performed on 857 patients from May 1, 2014 to May 1, 2018. The median age was 13.5 years [interquartile range (IQR) 9.0-15.7]. Procedures were technically successful in the majority of cases (90.5%) with success more commonly encountered for procedures with biliary indications [odds ratio (OR) 4.2] and less commonly encountered for native papilla anatomy (OR 0.4) and in children <3 years (OR 0.3). Cannulation was more often successful with biliary cannulation (95.9%) compared to pancreatic cannulation via the major papilla (89.6%, P < 0.0001) or minor papilla (71.2%, P < 0.0005). The most commonly identified adverse events included post-ERCP pancreatitis (5%), pain not related to post-ERCP pancreatitis (1.8%), and bleeding (1.2%). Risk factors for the development of each were identified. CONCLUSIONS: This large prospective study demonstrates that ERCP is reliable and safe in the pediatric population. It highlights the utility of PEDI in evaluating the technical outcomes of pediatric ERCPs and demonstrates the potential of PEDI for future studies in pediatric ERCPs.

Urine Proteomics Reveals Sex-Specific Response to Total Pancreatectomy With Islet Autotransplantation.

OBJECTIVES: Total pancreatectomy with islet autotransplantation (TPIAT) is a surgical option for refractory chronic pancreatitis-related pain. Despite the known clinical implications of TPIAT, the molecular effects remain poorly investigated. We performed the first hypothesis-generating study of the urinary proteome before and after TPIAT. METHODS: Twenty-two patients eligible for TPIAT were prospectively enrolled. Urine samples were collected the week before and 12 to 18 months after TPIAT. The urine samples were prepared for bottom-up label-free quantitative proteomics using the "MStern" protocol. RESULTS: Using 17 paired samples, we identified 2477 urinary proteins, of which 301 were significantly changed post-TPIAT versus pre-TPIAT. Our quantitative analysis revealed that the molecular response to TPIAT was highly sex-specific, with pronounced sex differences pre-TPIAT but minimal differences afterward. Comparing post-TPIAT versus pre-TPIAT, we found changes in cell-cell adhesion, intracellular vacuoles, and immune response proteins. After surgery, immunoglobulins, complement proteins, and cathepsins were increased, findings that may reflect glomerular damage. Finally, we identified both known and novel markers for immunoglobulin A nephropathy after 1 patient developed the disease 2 years after TPIAT. CONCLUSIONS: We found distinct changes in the urinary proteomic profile after TPIAT and the response to TPIAT is highly sex-specific.

Environmental Factors Affecting Covid-19 Dynamics: A Study in Bengaluru City of Karnataka State of India.

The horrifying and fast spreading COVID-19 pandemic has shocked India and in fact the entire world to its core. Indian Government has taken all the possible preventive steps to contain the wider spread of this highly contagious disease but the second wave in the month of April, 2021 has turned this strong country in a helpless position. In this paper, the effect of environmental factors like temperature and air quality index on the new confirmed cases along with recovered cases has been seen in Bengaluru Urban district of Karnataka State of India. Regression analysis has been carried out with the help of SPSS software. The outcomes from the paper will definitely give some valuable insights for the researchers around the world in their future combat measures.

Confluence of law enforcement, mental health, and race.

Disparities in victimization by law enforcement for both people of color and individuals with mental health disorders is gaining national attention following the deaths of George Floyd, Sandra Bland, TAmir Rice, and many others. Despite this, the discussion around the intersectionality of race, psychiatric illness, and law enforcement is still in its infancy, the purpose of this article is to discuss the confluence of race and psychiatric illness as vulnerabilities in various contacts with law enforcement in order to further highlight this issue and to ignite further needed research on this topic. Possible solutions such as police-hiring practices, bias training, and trauma-informed policing will be discussed.

Triple gallbladder with heterotopic gastric mucosa: a case report.

BACKGROUND: Triple gallbladder is a rare congenital anomaly of the biliary tract that can be associated with heterotopic tissue. Gallbladder triplication results from the failure of rudimentary bile ducts to regress during embryological development, and can be difficult to distinguish from Todani type II choledochal cysts and biliary duplication cysts. CASE PRESENTATION: A 2-year-old patient presented to our institution with intermittent abdominal pain for 1 year. She had elevated transaminases with imaging concerning for a choledochal cyst. After assessment with magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography, she was diagnosed with a gallbladder multiplication and a common bile duct stricture. She underwent laparoscopic cholecystectomy, which confirmed the diagnosis of triple gallbladder. One of the three gallbladders demonstrated heterotopic gastric mucosa on final pathology, including at the cystic duct margin. Follow up testing with a technetium 99 m scan demonstrated a subtle focus of increased activity in the right upper abdomen at the expected location of the common bile duct, concerning for the presence of residual gastric mucosa. The patient remains well without abdominal pain. CONCLUSIONS: We describe the first case of heterotopic gastric mucosa in a triple gallbladder in a young patient presenting with chronic abdominal pain. We also demonstrate the safety and feasibility of laparoscopic cholecystectomy in young children with triple gallbladder. Finally, we propose an interdisciplinary approach to the management of common bile duct strictures in the setting of ectopic acid secretion, involving a combination of medical management, endoscopic intervention, and possible salvage laparoscopic Roux-en-Y hepaticojejunostomy.

Predictors of Prolonged Fluoroscopy Exposure in Pediatric Endoscopic Retrograde Cholangiopancreatography: Results From the Large Pediatric Endoscopic Retrograde Cholangiopancreatography Database Initiative Multicenter Cohort.

BACKGROUND AND AIMS: Ionizing radiation exposure during endoscopic retrograde cholangiopancreatography (ERCP) is an important quality issue especially in children. We aim to identify factors associated with extended fluoroscopy time (FT) in children undergoing ERCP. METHODS: ERCP on children <18 years from 15 centers were entered prospectively into a REDCap database from May 2014 until May 2018. Data were retrospectively evaluated for outcome and quality measures. A univariate and step-wise linear regression analysis was performed to identify factors associated with increased FT. RESULTS: 1073 ERCPs performed in 816 unique patients met inclusion criteria. Median age was 12.2 years (interquartile range [IQR] 9.3-15.8). 767 (71%) patients had native papillae. The median FT was 120 seconds (IQR 60-240). Factors associated with increased FT included procedures performed on patients with chronic pancreatitis, ERCPs with American Society of Gastrointestinal Endoscopy (ASGE) difficulty grade >3, ERCPs performed by pediatric gastroenterologist (GI) with adult GI supervision, and ERCPs performed at non-free standing children's hospitals. Hispanic ethnicity was the only factor associated with lower FT. CONCLUSION: Several factors were associated with prolonged FTs in pediatric ERCP that differed from adult studies. This underscores that adult quality indicators cannot always be translated to pediatric patients. This data can better identify children with higher risk for radiation exposure and improve quality outcomes during pediatric ERCP.

Clinical Characteristics and Short-Term Outcomes of Children With Asparaginase-Associated Pancreatitis.

OBJECTIVES: Acute pancreatitis is a significant toxicity of l-asparaginase, a chemotherapeutic agent used to treat acute lymphoblastic leukemia. This case series describes the short-term clinical course and disposition of patients who developed asparaginase-associated pancreatitis (AAP) at one quaternary pediatric center. METHODS: Clinical data, including laboratory data, inpatient and intensive care unit (ICU) days, imaging findings, presence of complications such as need for ventilation, dialysis, and the development of pleural effusions, and mode of nutrition were abstracted from the medical record of patients with AAP. Pediatric criteria were used to classify episode severity based on the development of organ failure and local complications, such as pancreatic necrosis. RESULTS: Between 2005 and 2015, 34 patients had AAP with 43 distinct episodes of pancreatitis. The median inpatient length of stay was 10 days (range 2-65). Seven episodes (16.3%) required intensive care unit (ICU)-level care. Seventeen episodes (39.5%) were severe based on the development of organ failure or presence of pancreatic necrosis. Total parenteral nutrition (TPN) was used in 17 episodes (39.5%); for 34 episodes (79.1%), patients were discharged on entirely oral feeds. Antibiotics were administered in 20 episodes (46.5%). Pancreatic necrosis was identified within the first week in 12 episodes (27.9%). There were no deaths due to AAP. CONCLUSIONS: The clinical course varies widely among patients with AAP. Over one-third of the patients in this series developed severe pancreatitis. Although the prognosis of AAP is generally good, many patients develop systemic complications of AAP, requiring TPN or ICU-level care.

Prevalence of dyspnoea and usage of opioids in managing dyspnoea in advanced cancer patients: a longitudinal observational multi-centre study from India.

Context: Breathlessness is one of the devastating symptoms experienced by patients with advanced cancer and can be very challenging to manage. Objectives: To find the point prevalence of dyspnoea in advanced cancer patients presenting to palliative care out-patient clinics, and the usage of opioids in palliation of dyspnoea. Methods: We conducted a prospective observational study among all consecutive patients presenting to the outpatient clinics of six cancer centres in India from different parts of the country. In addition to routinely documented demographic and clinical data from patient charts, study investigators collected information on the Edmonton Symptom Assessment System, Cancer Dyspnoea Scale (CDS) and European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 15 Palliative Care. We calculated the prevalence of dyspnoea and documented the usage of opioids in palliation of dyspnoea using tests of differences across patient characteristics. Results: Between May 1, 2019, and April 30, 2020, 5,541 patients were screened for eligibility, and 288 were enrolled (48 patients from each of the six centres). We analysed the data of 288 patients, of which 36.4% had dyspnoea, with 28.5% with moderate to a severe degree (>4/10). Tiredness and loss of appetite were found to have associations with dyspnoea which were statistically significant on multivariate analysis. Standard palliative care management and routine usage of opioids preceded improvement in dyspnoea scores, CDS scores and quality of life scores throughout 7 days. Conclusion: Dyspnoea is a common symptom in advanced cancer patients, presenting to outpatient clinics, and routine documentation of dyspnoea with appropriate usage of opioids helps in mitigation. Key message: The article suggests that breathlessness is a common problem in advanced cancer patients and opioid prescription preceded symptom improvements in such patients.

Structural Barriers Associated with the Intersection of Traumatic Stress and Gun Violence: A Case Example of New Orleans.

Gun violence drastically increased in urban cities following the ease of shutdown restrictions associated with the Coronavirus Pandemic. The association of gun violence and COVID-19 has highlighted the importance of taking a public health perspective, particularly as it relates to impacts on the Black community. In this article we discuss macro-level factors and community traumas in the city of New Orleans, an area that has had longstanding issues related to gun violence. Community structural issues, traumatic stress from disasters, and recommendations to address disparities in social determinants of health are discussed.

Myeloid-Derived Suppressor Cells: A Propitious Road to Clinic.

Myeloid-derived suppressor cells (MDSC) are important regulators of immune responses in cancer. They represent a relatively stable form of pathologic activation of neutrophils and monocytes and are characterized by distinct transcriptional, biochemical, functional, and phenotypical features. The close association of MDSCs with clinical outcomes in cancer suggests that these cells can be an attractive target for therapeutic intervention. However, the complex nature of MDSC biology represents a substantial challenge for the development of selective therapies. Here, we discuss the mechanisms regulating MDSC development and fate and recent research advances that have demonstrated opportunities for therapeutic regulation of these cells. SIGNIFICANCE: MDSCs are attractive therapeutic targets because of their close association with negative clinical outcomes in cancer and established biology as potent immunosuppressive cells. However, the complex nature of MDSC biology presents a substantial challenge for therapeutic targeting. In this review, we discuss those challenges and possible solutions.

Acute pancreatitis in children: a review with clinical perspectives to enhance imaging interpretation.

Pediatric acute pancreatitis has distinct etiologic, clinical and prognostic characteristics in contrast to the adult form of the disease. This review offers a comprehensive imaging update that emphasizes the importance of recognizing specific findings that are relevant from the clinical standpoint. Knowledge of these features facilitates communication among multidisciplinary team members and ultimately could lead to the improved care of pediatric acute pancreatitis patients.

Resolving cellular systems by ultra-sensitive and economical single-cell transcriptome filtering.

Single-cell transcriptomics suffer from sensitivity limits that restrict low abundance transcript identification, affects clustering and can hamper downstream analyses. Here, we describe Constellation sequencing (Constellation-Seq), a molecular transcriptome filter that delivers two orders of magnitude sensitivity gains by maximizing read utility while reducing the data sparsity and sequencing costs. The technique reliably measures changes in gene expression and was demonstrated by resolving rare dendritic cell populations from a peripheral blood mononuclear cell sample sample and exploring their biology with extreme resolution. The simple and powerful method is fully compatible with standard scRNA-Seq library preparation protocols and can be used for hypothesis testing, marker validation or investigating pathways.

Medical Management of Chronic Pancreatitis in Children: A Position Paper by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Pancreas Committee.

ABSTRACT: This position paper summarizes the current understanding of the medical management of chronic pancreatitis (CP) in children in light of the existing medical literature, incorporating recent advances in understanding of nutrition, pain, lifestyle considerations, and sequelae of CP. This article complements and is intended to integrate with parallel position papers on endoscopic and surgical aspects of CP in children. Concepts and controversies related to pancreatic enzyme replacement therapy (PERT), the use of antioxidants and other CP medical therapies are also reviewed. Highlights include inclusion of tools for medical decision-making for PERT, CP-related diabetes, and multimodal pain management (including an analgesia ladder). Gaps in our understanding of CP in children and avenues for further investigations are also reviewed.