The Neutrophil.

Neutrophils are immune cells with unusual biological features that furnish potent antimicrobial properties. These cells phagocytose and subsequently kill prokaryotic and eukaryotic organisms very efficiently. Importantly, it is not only their ability to attack microbes within a constrained intracellular compartment that endows neutrophils with antimicrobial function. They can unleash their effectors into the extracellular space, where, even post-mortem, their killing machinery can endure and remain functional. The antimicrobial activity of neutrophils must not be misconstrued as being microbe specific and should be viewed more generally as biotoxic. Outside of fighting infections, neutrophils can harness their noxious machinery in other contexts, like cancer. Inappropriate or dysregulated neutrophil activation damages the host and contributes to autoimmune and inflammatory disease. Here we review a number of topics related to neutrophil biology based on contemporary findings.

"An urgent need for transition of care programs for adolescents and young adults with neurogastroenterology and motility disorders".

Transition of Care for Adolescents and Young Adults (AYA) with Neurogastroenterology & Motility (NGM) Disorders.

Persistent and newly developed gastrointestinal symptoms after surgery for intestinal malrotation in children: Dysmotility or disorders of gut and brain interaction?

OBJECTIVES: Surgery for intestinal malrotation (IM) aims to correct the defect and improve symptoms; however, many have persistent gastrointestinal (GI) symptoms postoperatively. We evaluated the incidence, clinical presentation, and long-term outcomes of children with surgically repaired IM and its possible association with disorders of gut and brain interaction (DGBI). METHODS: Multicenter retrospective study was conducted in patients from 0 to 21 years old, who had surgery for IM from 2000 to 2021 across three pediatric tertiary care centers. Data analyzed included demographics, time to diagnosis, idiopathic diagnosis, incidental diagnosis, postoperative follow-up, surgical time, and the need for surgery including bowel detorsion. Outcome variables were the presence of postoperative GI symptoms and DGBIs, and overall resolution of symptoms. We also evaluated the potential association of demographics and other included variables with our outcome variables. RESULTS: Ninety-two patients with surgically corrected IM were included, 54% were male, and median age of diagnosis and surgical correction was 4.9 and 7.8 months, respectively. Median follow-up after surgery was 64 months. A total of 77% had postoperative GI symptoms, and notably, 78% of patients without symptoms before surgery (incidental diagnosis) developed GI symptoms postoperatively and 27% of patients met Rome IV criteria for a one or more DGBI. No factors were associated to the presence of postoperative symptoms or DGBIs in multivariate analysis. Female gender was the only factor associated with lack of resolution of symptoms at follow-up. CONCLUSION: Pediatric IM is commonly associated with postoperative GI symptoms and DGBI well beyond surgery. An increased awareness about the prevalence of DGBI in these patients may help reach a prompt and accurate diagnosis, and improve their quality of life.

Ineffective esophageal motility: Characterization and outcomes across pediatric neurogastroenterology and motility centers in the United States.

OBJECTIVES: Ineffective esophageal motility (IEM) on high-resolution manometry (HRM) is not consistently associated with specific clinical syndromes or outcomes. We evaluated the prevalence, clinical features, management, and outcomes of pediatric IEM patients across the United States. METHODS: Clinical and manometric characteristics of children undergoing esophageal HRM during 2021-2022 were collected from 12 pediatric motility centers. Clinical presentation, test results, management strategies, and outcomes were compared between children with IEM and normal HRM. RESULTS: Of 236 children (median age 15 years, 63.6% female, 79.2% Caucasian), 62 (23.6%) patients had IEM, and 174 (73.7%) patients had normal HRM, with similar demographics, medical history, clinical presentation, and median symptom duration. Reflux monitoring was performed more often for IEM patients (25.8% vs. 8.6%, p = 0.002), but other adjunctive testing was similar. Among 101 patients with follow-up, symptomatic cohorts declined in both groups in relation to the initial presentation (p > 0.107 for each comparison) with management targeting symptoms, particularly acid suppression. Though prokinetics were used more often and behavioral therapy less often in IEM (p ≤ 0.015 for each comparison), symptom outcomes were similar between IEM and normal HRM. Despite a higher proportion with residual dysphagia on follow-up in IEM (64.0% vs. 39.1%, p = 0.043), an alternate mechanism for dysphagia was identified more often in IEM (68.8%) compared to normal HRM (27.8%, p = 0.017). CONCLUSIONS: IEM is a descriptive manometric pattern rather than a clinical diagnosis requiring specific intervention in children. Management based on clinical presentation provides consistent symptom outcomes.

Neurogastroenterology and Motility Disorders of the Gastrointestinal Tract in Cystic Fibrosis.

PURPOSE OF REVIEW: To discuss all the various motility disorders impacting people with Cystic Fibrosis (PwCF) and provide diagnostic and management approaches from a group of pediatric and adult CF and motility experts and physiologists with experience in the management of this disease. RECENT FINDINGS: Gastrointestinal (GI) symptoms coexist with pulmonary symptoms in PwCF regardless of age and sex. The GI manifestations include gastroesophageal reflux disease, esophageal dysmotility gastroparesis, small bowel dysmotility, small intestinal bacterial overgrowth syndrome, distal idiopathic obstruction syndrome, constipation, and pelvic floor disorders. They are quite debilitating, limiting the patients' quality of life and affecting their nutrition and ability to socialize. This genetic disorder affects many organ systems and is chronic, potentially impacting fertility and future family planning, requiring a multidisciplinary approach. Our review discusses the treatments of motility disorders in CF, their prevalence and pathophysiology. We have provided a framework for clinicians who care for these patients that can help to guide their clinical management.

Association of Anxiety and Gastrointestinal Comorbidities in Repeat Hospital Admissions in Pediatric Cyclic Vomiting Syndrome.

INTRODUCTION: Cyclic vomiting syndrome (CVS) is a functional gastrointestinal disorder with recurrent episodes of intense nausea and vomiting and thus may require frequent hospitalizations. There is paucity of data exploring the association of psychiatric and gastrointestinal comorbidities in repeat hospitalizations among pediatric patients with CVS. METHODS: We analyzed the Pediatric Health Information System database and included all patients up to 18 years of age with a diagnosis of CVS between 2016 and 2020. We excluded patients with chronic conditions, which mimic CVS. The primary outcome variable was 90-day admission rate, which was defined as a visit to emergency department or admission to observation/inpatient unit with a primary diagnosis of CVS within 90 days after an index CVS hospitalization. RESULTS: We evaluated a total of 2,604 hospitalizations represented by 1,370 unique individuals. The overall 90-day admission rate was 28.5%, which steadily decreased from 35.7% in 2016 to 23% in 2019 ( P < 0.001). Patients in the repeat hospitalization cohort were slightly older and more often men. Patients with repeat admissions had an increased proportion of anxiety and other gastrointestinal disorders. Multivariable logistic regression showed that anxiety, gastroesophageal reflux disease, functional dyspepsia, and abdominal migraine were associated with increased odds of repeat admissions. DISCUSSION: Ninety-day admission rates in pediatric CVS are decreasing overall, although still contributing to significant healthcare expenditure. Anxiety and gastrointestinal comorbidities were associated with increased risk of repeat admissions. Further prospective studies are needed to better understand the complex interactions of these comorbidities and their management affecting the natural course of CVS.

Evaluation and Management of Postsurgical Patient With Hirschsprung Disease Neurogastroenterology & Motility Committee: Position Paper of North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN).

Children with Hirschsprung disease have postoperative long-term sequelae in defecation that contribute to morbidity and mortality and significantly impact their quality of life. Pediatric patients experience ongoing long-term defecation concerns, which can include fecal incontinence (FI) and postoperative obstructive symptoms, such as constipation and Hirschsprung-associated enterocolitis. The American Pediatric Surgical Association has developed guidelines for management of these postoperative obstructive symptoms and FI. However, the evaluation and management of patients with postoperative defecation problems varies among different pediatric gastroenterology centers. This position paper from the Neurogastroenterology & Motility Committee of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition reviews the current evidence and provides suggestions for the evaluation and management of postoperative patients with Hirschsprung disease who present with persistent defecation problems.

A Gastroenterologist's Guide to Care Transitions in Cystic Fibrosis from Pediatrics to Adult Care.

Cystic Fibrosis is a chronic disease affecting multiple systems, including the GI tract. Clinical manifestation in patients can start as early as infancy and vary across different age groups. With the advent of new, highly effective modulators, the life expectancy of PwCF has improved significantly. Various GI aspects of CF care, such as nutrition, are linked to an overall improvement in morbidity, lung function and the quality of life of PwCF. The variable clinical presentations and management of GI diseases in pediatrics and adults with CF should be recognized. Therefore, it is necessary to ensure efficient transfer of information between pediatric and adult providers for proper continuity of management and coordination of care at the time of transition. The transition of care is a challenging process for both patients and providers and currently there are no specific tools for GI providers to help ensure a smooth transition. In this review, we aim to highlight the crucial features of GI care at the time of transition and provide a checklist that can assist in ensuring an effective transition and ease the challenges associated with it.

Analysis of Neurogastrointestinal and Motility Disorders From the National Pediatric Database (Kid's Inpatient Database): Exploring Demographic Access and Outcomes.

OBJECTIVES: Pediatric neurogastroenterology and motility (PNGM) disorders impose a significant impact on health-related quality of life and cost of health care in children and adolescents. The detailed understanding of its burden across demographic groups is unknown. The objective of our study is to characterize the demographic and hospitalization trends of patients undergoing PNGM tests. METHODS: We used Healthcare Cost and Utilization Project (HCUP) Inpatient Database (KID) for years 2003-2016 to perform a trend analysis in US hospitalizations for International Classification of Diseases (ICD)-9 and -10 Clinical Modification (CM)-identified PNGM studies in patients (<18 years of age) with elective admission and a length of stay (LOS) <3 days. The hospitalization rates were analyzed by year, hospital region, facility type, and patient sociodemographic characteristics. Multivariable logistic regression was used to examine factors influencing the receipt of motility studies. RESULTS: There was an overall increase trend in hospitalizations, rates of PNGM studies, and median hospital charges from 2003 to 2016. Patients with private insurance and living in the high-income zip codes were more likely to receive a PNGM study compared with those with governmental insurance and lower income area. Although the race was not found to influence the receipt of the study, a major difference in the LOS was noted across the regions. CONCLUSIONS: There are income- and insurance-based differences in the rates of inpatient PNGM studies. PNGM studies significantly add to health care burden. Standardization of PNGM practices across the country may decrease the LOS and associated expenses. Future analysis should include ambulatory PNGM services to understand combined inpatient and outpatient trends.

A Guide to Establishing a Pediatric Neurogastroenterology and Motility Program.

ABSTRACT: The purpose of this document is to provide guidance for establishing a pediatric neurogastroenterology and motility (PNGM) program, including considerations for personnel, equipment, and physical space requirements, and business planning, from members of the neurogastroenterology and motility (NGM) Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) who have developed PNGM programs at various institutions. A business plan defining the needs for required personnel, dedicated physical space, procedures, clinical care, and equipment storage is a prerequisite. Thoughtful logistical planning should address provider schedules, clinical visits, procedure coordination, and prior authorization processes. A business-plan outlining equipment purchase with projected costs, revenue generation, and goals for future growth is desirable for obtaining institutional support, which is imperative to building a successful PNGM program.

Pediatric Neurogastroenterology and Motility Services in North America: Neurogastroenterology and Motility Survey Report.

ABSTRACT: To characterize the current availability and scope of pediatric neurogastroenterology and motility (PNGM) services in North America (NA), the NASPGHAN-NGM committee distributed a self-reporting survey through the NASPGHAN bulletin board and mailing listserv, to compile a list of NA centers offering PNGM services, PNGM training, and the types of diagnostic and therapeutic PNGM procedures and services. We received responses that 54 centers in NA offer some form of PNGM services. Previously, the NASPGHAN website had last updated information from 2015 listing 36 centers in the USA and 2 in Canada. The American Neurogastroenterology and Motility Society (ANMS) website had 16 PNGM centers listed in NA in 2021. Neither of these resources capture additional information regarding training, research, advanced diagnostics, and therapeutics, and all available PNGM services. Our data highlights the growth in the field of PNGM services, and the variability of their distribution throughout the continent.

Evaluation of the Effectiveness of In-line Immobilized Lipase Cartridge in Enterally Fed Patients With Cystic Fibrosis.

BACKGROUND: Pancreatic insufficiency occurs in most patients with cystic fibrosis (CF) contributing to malnutrition. In the United States, 3600 patients with CF require enteral feeding (EF). Oral pancreatic enzymes are commonly used with EF, despite not being designed or approved for this use. An immobilized lipase cartridge (ILC) for extracorporeal digestion of enteral feedings was developed. The sponsor provided it to patients via a structured program, which we evaluated to assess the effectiveness of the ILC on nutritional status. METHODS: The program provided the ILC to patients prescribed the device while reimbursement efforts were ongoing. Baseline anthropometric data were obtained and subsequent measurements of height, weight, and body mass index (BMI) were collected at 6 and 12 months. RESULTS: Inclusion criteria were met by 100 patients (age = 0--45 years). Over 12 months of use in patients >2 years of age (n = 93), there were significant improvements seen in height and weight z-scores with improvement trend seen in BMI. The frequency of achieving the 50th percentile increased steadily for weight and BMI from baseline to 12 months but not for height. CONCLUSIONS: This evaluation of a program to assist patient access to ILC demonstrates that better growth is possible over standard of care. The association of ILC use with significant improvements in anthropometric parameters over a 12-month period in people with CF demonstrates the effectiveness of ILC as rational enzyme therapy during enteral feedings.

Correction to: Developing real-world comparators for clinical trials in chemotherapy-refractory patients with gastric cancer or gastroesophageal junction cancer.

ping real-world comparators for.

Developing real-world comparators for clinical trials in chemotherapy-refractory patients with gastric cancer or gastroesophageal junction cancer.

BACKGROUND: There are few third-line or later (3L+) treatment options for advanced/metastatic (adv/met) gastric cancer/gastroesophageal junction cancers (GC/GEJC). 3L+ Nivolumab demonstrated encouraging results in Asian patients in the ATTRACTION-2 study compared with placebo (12-month survival, 26% vs 11%), and in Western patients in the single-arm CheckMate 032 study (12-month survival, 44%). This analysis aimed to establish comparator cohorts of US patients receiving routine care in real-world (RW) clinical practice. METHODS: A 2-step matching process generated RW cohorts from Flatiron Health's oncology database (January 1, 2011-April 30, 2017), for comparison with each trial: (1) clinical trial eligibility criteria were applied; (2) patients were frequency-matched with trial arms for baseline variables significantly associated with survival. Median overall survival (OS) was calculated by Kaplan-Meier analysis from last treatment until death. RESULTS: Of 742 adv/met GC/GEJC patients with at least 2 prior lines of therapy, matching generated 90 US RW ATTRACTION-2-matched patients (median OS: 3.5 months) versus 163 ATTRACTION-2 placebo patients (median OS: 4.1 months), and 100 US RW CheckMate 032-matched patients (median OS: 2.9 months) versus 42 CheckMate 032 nivolumab-treated patients (median OS: 8.5 months). Baseline characteristics were generally similar between clinical trial arms and RW-matched cohorts. CONCLUSIONS: We successfully developed RW cohorts for comparison with data from clinical trials, with comparable baseline characteristics. Survival in US patients receiving RW care was similar to that seen in Asian patients receiving placebo in ATTRACTION-2; survival with nivolumab in CheckMate 032 appeared favorable compared with US RW clinical practice.

Glycaemic and non-glycaemic efficacy of once-weekly GLP-1 receptor agonists in people with type 2 diabetes.

WHAT IS KNOWN AND OBJECTIVE: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may confer a range of benefits for people with type 2 diabetes (T2D), which is reflected through their position within diabetes treatment guidelines. The objective of this narrative review is to explore the efficacy data of once-weekly (QW) GLP-1 RAs in terms of glycaemic control, body weight reduction, cardiovascular (CV) outcomes and potential renal protective effects to assist pharmacists and other healthcare professionals (HCPs) in treatment discussions with patients. METHODS: This a narrative review focused on 31 clinical trials involving the Phase 3 clinical programmes of the QW GLP-1 RAs dulaglutide, exenatide extended-release (ER) and semaglutide subcutaneous (s.c.). RESULTS AND DISCUSSION: The clinical trials were divided by their comparator arms and examined for trends. All QW GLP-1 RAs were superior to placebo for reductions in glycated haemoglobin (HbA1c ) and body weight. Data regarding QW GLP-1 RAs versus metformin were limited, likely due to metformin's use as the first-line pharmacologic for T2D. In the robust head-to-head trials of QW versus QW GLP-1 RAs, semaglutide s.c. was superior to both dulaglutide and exenatide ER regarding HbA1c and body weight; however, QW versus once-daily GLP-1 RA trials had mixed results depending on the comparators. Finally, in QW GLP-1 RA versus insulin trials, all QW GLP-1 RAs were as effective as insulin, particularly when hypoglycaemia and body weight were also considered. CV outcome trials demonstrated benefits in major adverse CV events and renal outcomes for semaglutide and dulaglutide. WHAT IS NEW AND CONCLUSION: This review collates recently published data and previously published Phase 3 results to allow pharmacists and other HCPs to understand all of the efficacy data available and the corresponding impact on treatment guidelines. QW GLP-1 RAs are emerging as important therapeutic options for people with T2D as they offer a spectrum of benefits extending beyond glycaemic control, but it is important to be aware of their efficacy differences when prescribing and discussing them with patients.

Diagnostic accuracy of non-contrast magnetic resonance enterography in detecting active bowel inflammation in pediatric patients with diagnosed or suspected inflammatory bowel disease to determine necessity of gadolinium-based contrast agents.

BACKGROUND: Pediatric patients with inflammatory bowel disease (IBD) are at increased risk of gadolinium deposition given the potential need for multiple contrast-enhanced magnetic resonance enterography (MRE) exams over their lifetime. OBJECTIVE: To determine whether gadolinium-based contrast agents are necessary in assessing active bowel inflammation on MRE in pediatric patients with known or suspected IBD. MATERIALS AND METHODS: We conducted a retrospective study of 77 patients (7-18 years; 68.8% male) with known (n=58) or suspected (n=19) IBD and endoscopy with biopsy performed within 30 days of MRE without and with contrast evaluated bowel and non-bowel findings. During three visual analysis sessions, two radiologists reviewed pre-, post-, and pre-/post-contrast MRE images. A third radiologist independently reviewed 27 studies to assess inter-reader reliability. We used Cohen kappa (κ), Fleiss kappa, (κF), McNemar test, and sensitivity and specificity to compare MRE readings to combined endoscopic/histopathological findings (the reference standard). RESULTS: The pre- and pre-/post-contrast-enhanced MRE vs. combined endoscopic/histopathological results had moderate agreement (85.7%; κ 0.713, P<0.001; P-value 0.549). Compared to combined endoscopy/histopathology, pre- vs. pre-/post-contrast sensitivity (67%, confidence interval [CI] 0.53-0.79 vs. 67%, CI 0.53-0.79) and specificity (80%, CI 0.59-0.92 vs. 68%, CI 0.46-0.84) varied little (κ 0.42, P<0.001 and κ 0.32, P=0.003, respectively). The three readers had moderate agreement (85.2%; κ 0.695, P=0.001; P-value 0.625). More penetrating complications were identified following contrast administration (P-value 0.04). CONCLUSION: Use of a contrast agent does not improve the detection of active inflammation in the terminal ileum and colon compared to non-contrast MRE, although use of a contrast agent does aid in the detection of penetrating disease.

Nonglycemic Outcomes of Antidiabetic Medications.

IN BRIEF The number of medications used to treat diabetes has increased dramatically in the past 15 years. With so many options that have shown significant A1C improvement, it is important to consider side effects, precautions, and additional benefits these agents may offer. This article is a review of some of the most compelling literature available on the nonglycemic benefits of sulfonylureas, thiazolidinediones, biguanides, glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase 4 inhibitors, and sodium-glucose cotransporter 2 inhibitors. Other classes of antihyperglycemic agents, such as dopamine agonists, meglitinides, and amylin agonists, are not discussed in this article.

Neutrophils drive alveolar macrophage IL-1ß release during respiratory viral infection.

BACKGROUND: Alveolar macrophages are sentinels of the airways that must exhibit immune restraint to innocuous antigens but elicit a robust inflammatory response to pathogenic threats. How distinction between these dichotomous functions is controlled is poorly defined.Neutrophils are the first responders to infection, and we hypothesised that they may free alveolar macrophages from their hyporesponsive state, promoting their activation. Activation of the inflammasome and interleukin (IL)-1ß release is a key early inflammatory event that must be tightly regulated. Thus, the role of neutrophils in defining inflammasome activation in the alveolar macrophage was assessed. METHODS: Mice were infected with the X31 strain of influenza virus and the role of neutrophils in alveolar macrophage activation established through administration of a neutrophil-depleting (1A8) antibody. RESULTS: Influenza elicited a robust IL-1ß release that correlated (r=0.6849; p<0.001) with neutrophil infiltrate and was ablated by neutrophil depletion. Alveolar macrophages were shown to be the prominent source of IL-1ß during influenza infection, and virus triggered the expression of Nod-like receptor protein 3 (NLRP3) inflammasome and pro-IL-1ß in these cells. However, subsequent activation of the inflammasome complex and release of mature IL-1ß from alveolar macrophages were critically dependent on the provision of a secondary signal, in the form of antimicrobial peptide mCRAMP, from infiltrating neutrophils. CONCLUSIONS: Neutrophils are critical for the activation of the NLRP3 inflammasome in alveolar macrophages during respiratory viral infection. Accordingly, we rationalise that neutrophils are recruited to the lung to confront a viable pathogenic threat and subsequently commit alveolar macrophages to a pro-inflammatory phenotype to combat infection.

Absorption and Safety With Sustained Use of RELiZORB Evaluation (ASSURE) Study in Patients With Cystic Fibrosis Receiving Enteral Feeding.

OBJECTIVES: Pancreatic insufficiency (PI) and malabsorption of fats lead to reduced caloric intake, inability to maintain weight, and increased gastrointestinal symptoms. Thus, enteral nutrition (EN) is used in patients with cystic fibrosis (CF) and poor nutritional status. The current study evaluated safety, tolerability, and improvement of fatty acid (FA) status in red blood cell (RBC) membranes, a marker of long-term FA absorption, with an in-line digestive cartridge (RELiZORB) that hydrolyzes fat in enteral formula. METHODS: Patients with CF receiving EN participated in a multicenter, 90-day open-label study during which RELiZORB was used with overnight EN. The primary endpoint was change over time in RBC uptake of docosahexaenoic acid (DHA)+ eicosapentaenoic acid (EPA). Gastrointestinal symptoms were collected to evaluate safety and tolerability. Several clinical and anthropometric parameters were also assessed throughout the study. RESULTS: A total of 36 subjects completed the study with a mean age of 13.8 years, body mass index of 17.7 and 6.2 years mean use of overnight EN. Fat absorption significantly improved as shown by increased RBC levels of DHA+EPA, improved ω-6/ω-3 ratio, and increased plasma levels of DHA+EPA. RELiZORB use was not associated with any unanticipated adverse events. CONCLUSIONS: RELiZORB use was found to be safe, well tolerated, and resulted in increased levels of FAs in RBCs and plasma. This is the first prospective study to show EN can improve FA abnormalities in CF. Because improvement in omega-3 levels has been shown to help pulmonary and inflammatory status as well as anthropometric parameters in CF, RELiZORB may have important long-term therapeutic benefits in patients with CF.