Juvenile polyposis syndrome in children: The impact of SMAD4 and BMPR1A mutations on clinical phenotype and polyp burden.

OBJECTIVE: A constitutional disease-causing variant (DCV) in the SMAD4 or BMPR1A genes is present in 40%-60% of patients with juvenile polyposis syndrome (JPS). The aim of this study was to characterize the clinical course and polyp burden in children with DCV-positive JPS compared to DCV-negative JPS. METHODS: Demographic, clinical, genetic, and endoscopic data of children with JPS were compiled from eight international centers in the ESPHGAN/NASPGHAN polyposis working group. RESULTS: A total of 124 children with JPS were included: 69 (56%) DCV-negative and 55 (44%) DCV-positive (53% SMAD4 and 47% BMPR1A) with a median (interquartile range) follow-up of 4 (2.8-6.4) years. DCV-positive children were diagnosed at an older age compared to DCV-negative children [12 (8-15.7) years vs. 5 (4-7) years, respectively, p < 0.001], had a higher frequency of family history of polyposis syndromes (50.9% vs. 1.4%, p < 0.001), experienced a greater frequency of extraintestinal manifestations (27.3% vs. 5.8%, p < 0.001), and underwent more gastrointestinal surgeries (16.4% vs. 1.4%, p = 0.002). The incidence rate ratio for the development of new colonic polyps was 6.15 (95% confidence interval 3.93-9.63, p < 0.001) in the DCV-positive group compared to the DCV-negative group, with an average of 12.2 versus 2 new polyps for every year of follow-up. There was no difference in the burden of polyps between patients with SMAD4 and BMPR1A mutations. CONCLUSIONS: This largest international cohort of pediatric JPS revealed that DCV-positive and DCV-negative children exhibit distinct clinical phenotype. These findings suggest a potential need of differentiated surveillance strategies based upon mutation status.

Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules.

Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type- and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.

Availability and utilization of endoscopic retrograde cholangiopancreatography at children's hospitals.

OBJECTIVES: No study has explored whether availability of endoscopic retrograde cholangiopancreatography (ERCP) is adequate and equitable across US children's hospitals. We hypothesized that ERCP availability and utilization differs by geography and patient factors. METHODS: Healthcare encounter data from 2009 to 2019 on children with pancreatic and biliary diseases from the Pediatric Health Information System were analyzed. ERCP availability was defined as treatment at a hospital that performed pediatric ERCP during the year of service. RESULTS: From 2009 to 2019, 37,946 children (88,420 encounters) had a potential pancreatic or biliary indication for ERCP; 7066 ERCPs were performed. The commonest pancreatic diagnoses leading to ERCP were chronic (47.2%) and acute pancreatitis (43.2%); biliary diagnoses were calculus (68.3%) and obstruction (14.8%). No ERCP was available for 25.0% of pancreatic encounters and 8.1% of biliary encounters. In multivariable analysis, children with public insurance, rural residence, or of Black race were less likely to have pancreatic ERCP availability; those with rural residence or Asian race were less likely to have biliary ERCP availability. Black children or those with public insurance were less likely to undergo pancreatic ERCP where available. Among encounters for calculus or obstruction, those of Black race or admitted to hospitals in the West were less likely to undergo ERCP when available. CONCLUSIONS: One-in-four children with pancreatic disorders and one-in-12 with biliary disorders may have limited access to ERCP. We identified racial and geographic disparities in availability and utilization of ERCP. Further studies are needed to understand these differences to ensure equitable care.

Enhanced microwave assisted pyrolysis of waste rice straw through lipid extraction with supercritical carbon dioxide.

A combination of supercritical carbon dioxide (scCO2) extraction and microwave-assisted pyrolysis (MAP) have been investigated for the valorisation of waste rice straw. ScCO2 extraction of rice straw led to a 0.7% dry weight yield of lipophilic molecules, at elevated temperatures of 65 °C and pressures of 400 bar. Lipid compositions (fatty acids, fatty alcohol, fatty aldehydes, steroid ketones, phytosterols, n-alkanes and wax esters) of the waxes obtained by scCO2 were comparable to those obtained Soxhlet extraction using the potentially toxic solvent n-hexane. ScCO2 extraction positively influenced the pyrolysis heating rate, with a rate of 420 K min-1 for particles of 500-2000 µm, compared to 240 K min-1 for the same particle size of untreated straw. Particle size significantly affected cellulose decomposition and the distribution of pyrolysis products (gaseous, liquid and char), highlighting the importance of selecting an adequate physical pre-treatment. TG and DTG of the original rice straw and resulting biochar produced indicated that cellulose was completely decomposed during the MAP. While a rapid pressure change occurred at ∼120 °C (size > 2000 µm) and ∼130 °C (size 500-2000 µm) during MAP and was associated with the production of incondensable gas during cellulose decomposition, this takes place at significantly lower temperatures than those observed with conventional pyrolysis, 320 °C. Wax removal by scCO2 influences the dielectric properties of the straw, enhancing microwave absorption with rapid heating rates and elevated final pyrolysis temperatures, illustrating the benefits of combining these sustainable technologies within a holistic rice straw biorefinery.

Endoscopy in pediatric polyposis syndromes: why, when and how.

Single or multiple polyps are frequently encountered during colonoscopy among children and adolescents and may be indicative of hereditary polyposis syndrome (HPS). The management of children with single or multiple polyps is guided by the number of polyps, their distribution and the histological findings. Children with HPS carry a high risk of complications, including intestinal and extra-intestinal malignancies. The goals of surveillance in pediatric HPS are to treat symptoms, monitor the burden of polyps and prevent short- and long-term complications. Therefore, the management of children with HPS is based on therapeutic endoscopy. The strategy of therapeutic endoscopy is a careful assessment and characterization of the polyps and performing polypectomies using advanced endoscopic techniques. A multidisciplinary approach, comprising clinical, interventional endoscopy, cancer surveillance and support of familial and emotional aspects is essential in the management of children with HPS.

Endoscopist experience with pediatric recurrent and intentional foreign body ingestion (RIFBI): Management considerations and future directions.

OBJECTIVES AND STUDY: Accidental foreign body ingestion (FBI) is a common pediatric referral concern. In contrast, recurrent and intentional FBI (RIFBI) is infrequent and associated with greater endoscopic and surgical intervention in adults. Although pediatric guidelines exist for FBI, the risk and therapeutic implications of RIFBI are not addressed. An anonymous international survey on pediatric gastroenterologist experience with RIFBI was distributed. METHODS: A 33-item REDCap© survey was distributed via email to pediatric gastroenterologists identified through mailing and email lists obtained from pediatric gastroenterology professional organizations. RESULTS: During 9-12/2021 we accrued 202 completed surveys. Respondents were from 27 countries and across the career span. Eighty percent reported experience with RIFBI; 74% reported seeing ≤ 3 patients with RIFBI within the past 24 months and 4% reported seeing ≥ 6. Of those who treated RIFBI, 38% reported an average number of annual ingestions per patient was ≥5. Frequent morbidity but not mortality was reported. Half reported adherence to FBI guidelines. Later-career endoscopists treated RIFBI more aggressively than accidental ingestion. Ninety-six percent noted that patients with RIFBI had psychiatric comorbidities. Providers at academic medical centers reported referring to behavioral health more than those in other settings. CONCLUSION: Most gastroenterologists surveyed reported encountering RFBI several times a year and in patients with psychiatric comorbidities. Greater likelihood of adverse outcomes associated with endoscopy was reported. Most reported referral to behavioral health and few had RIFBI management protocols. A broader spectrum of psychologic comorbidities in the pediatric population with RIFBI, notably depression and autism spectrum disorder, were reported.

Small Intestinal Polyp Burden in Pediatric Peutz-Jeghers Syndrome Assessed through Capsule Endoscopy: A Longitudinal Study.

The management of pediatric Peutz-Jeghers Syndrome (PJS) focuses on the prevention of intussusception complicating small intestinal (SI) polyposis. This hinges on the accurate appraisal of the polyp burden to tailor therapeutic interventions. Video Capsule Endoscopy (VCE) is an established tool to study SI polyps in children, but an in-depth characterization of polyp burden in this population is lacking. Methods: We performed a retrospective longitudinal cross-sectional analysis of VCE studies in pediatric PJS patients at our institution (CMKC) from 2010 to 2020. Demographic, clinical, and VCE findings reported by three reviewers in tandem were accrued. Polyp burden variables were modeled as functions of patient and study characteristics using linear mixed models adjusted for clustering. Results: The cohort included 15 patients. The total small bowel polyp count and largest polyp size clustered under 30 polyps and <20 mm in size. Luminal occlusion correlated closely with the estimated polyp size. Polyp distribution favored proximal (77%) over distal (66%) small bowel involvement. The adjusted largest polyp size was greater in males. Double Balloon Enteroscopy was associated with a decreased polyp burden. Conclusions: The polyp burden in pediatric PJS patients favors the proximal third of the small intestine, with relatively small numbers and a polyp size amenable to resection through enteroscopy. Male gender and older age were related to an increased polyp burden.

Don't Look Back and Spray! Risk of Endoscope Adhesion with Hemospray Application in Retroflexion in a Pediatric Patient.

Although the vast majority of recognized pediatric upper gastrointestinal bleeding (GIB) resolves spontaneously, gastrointestinal hemorrhage is the most common indication for urgent or emergent therapeutic endoscopy in pediatric practice. The application of hemostatic powders, including TC-325 (Hemospray, Cook Medical, Winston-Salem, NC, USA), has shown considerable impact on the control of acute bleeding, with the advantage of potentially covering an extensive area and requiring less technical expertise. We report a case of transient adherence of an esophagogastroduodenoscopy following Hemospray application in a 22-month-old with upper GIB. Our experience does not detract from the significant gains in the management of pediatric GIB from Hemospray; however, it does raise a cautionary note toward the application technique utilized.

Polyps and Polyposis Syndromes in Children: Novel Endoscopic Considerations.

Polypectomy is the most common therapeutic endoscopic intervention in children. Management of sporadic juvenile polyps is limited to polypectomy to resolve symptoms, whereas polyposis syndromes pose a multidisciplinary challenge with broader ramifications. In preparation for polypectomy, there are key patient, polyp, endoscopy unit, and provider characteristics that factor into the likelihood of success. Younger age and multiple medical comorbidities increase the risk of adverse outcomes, classified as intraoperative, immediate postoperative, and delayed postoperative complications. Novel techniques, including cold snare polypectomy, can significantly decrease adverse events but a more structured training process for polypectomy in pediatric gastroenterology is needed.

Gastric cancer in the pediatric population, a multicenter cross-sectional analysis of presentation and coexisting comorbidities.

OBJECTIVES: Solid tumors of the stomach in children are rare, adenocarcinoma being most frequently reported. Risk factors and clinical presentation are poorly understood. We undertook a nationwide database analysis to evaluate pediatric CA stomach presentation, comorbidities, and metastatic pattern. METHODS: The Cerner Health Facts Database® (CHFD) was queried for pediatric age range (1-21) patients, 2010-2017 inclusive. The pediatric gastric cancer cohort was defined by ICD9 and ICD 10 CM diagnoses attributable to primary (non-GIST, non-hematologic) solid tumors of the stomach limited to diagnosis priority < 5 and validated by filtering for supportive diagnoses. Demographic characteristics, comorbidities, before and throughout the medical record were analyzed and compared to the base population. RESULTS: The cohort included 333 patients from a base population of 9.6 million children. The M:F ratio was 1.15:1, mean age at diagnosis was 11.8 years. Stomach cancer was most prevalent in non-Hispanic whites, less in Asians and African Americans. Symptoms included abdominal pain, vomiting, anemia, diarrhea and weight loss. Reflux symptoms, esophagitis, gastritis, including H. pylori and duodenitis were reported in 10.2%. Obesity, obesity-related comorbidities, tobacco exposure and family history of colonic polyps, gastrointestinal and breast cancer were all more prevalent (P < 0.0001) in the cohort. DISCUSSION: We defined patient demographic characteristics, anatomic distribution in a large cohort of children with solid tumors of the stomach. Reported symptoms in our cohort are similar to those observed in adults. Associated comorbidities which may reflect risk factors include obesity, tobacco exposure and family history of intestinal polyps and malignancy.

Microbiome insights into pediatric familial adenomatous polyposis.

BACKGROUND: Individuals with familial adenomatous polyposis (FAP) harbor numerous polyps with inevitable early progression to colon cancer. Complex microbiotic-tumor microenvironment perturbations suggest a dysbiotic relationship between polyp and microbiome. In this study, we performed comprehensive analyses of stool and tissue microbiome of pediatric FAP subjects and compared with unaffected cohabiting relatives through 16S V4 region amplicon sequencing and machine learning platforms. RESULTS: Within our FAP and control patient population, Firmicutes and Bacteroidetes were the predominant phyla in the tissue and stool samples, while Proteobacteria dominated the polyp/non-polyp mucosa. A decline in Faecalibacterium in polyps contrasted with a decline in Bacteroides in the FAP stool. The alpha- and beta-diversity indices differed significantly within the polyp/non-polyp groups, with a concurrent shift towards lower diversity in polyps. In a limited 3-year longitudinal study, the relative abundance of Proteobacteria and Fusobacteria was higher in polyps compared to non-polyp and stool specimens over time. Through machine learning, we discovered that Archaeon_enrichment_culture_clone_A13, Micrococcus_luteus, and Eubacterium_hallii in stool and PL-11B10, S1-80, and Blastocatellaceae in tissues were significantly different between patients with and without polyps. CONCLUSIONS: Detection of certain bacterial concentrations within stool or biopsied polyps could serve as adjuncts to current screening modalities to help identify higher-risk patients.

Understanding molecular mechanisms and predicting phenotypic effects of pathogenic tubulin mutations.

Cells rely heavily on microtubules for several processes, including cell division and molecular trafficking. Mutations in the different tubulin-α and -ß proteins that comprise microtubules have been associated with various diseases and are often dominant, sporadic and congenital. While the earliest reported tubulin mutations affect neurodevelopment, mutations are also associated with other disorders such as bleeding disorders and infertility. We performed a systematic survey of tubulin mutations across all isotypes in order to improve our understanding of how they cause disease, and increase our ability to predict their phenotypic effects. Both protein structural analyses and computational variant effect predictors were very limited in their utility for differentiating between pathogenic and benign mutations. This was even worse for those genes associated with non-neurodevelopmental disorders. We selected tubulin-α and -ß disease mutations that were most poorly predicted for experimental characterisation. These mutants co-localise to the mitotic spindle in HeLa cells, suggesting they may exert dominant-negative effects by altering microtubule properties. Our results show that tubulin mutations represent a blind spot for current computational approaches, being much more poorly predicted than mutations in most human disease genes. We suggest that this is likely due to their strong association with dominant-negative and gain-of-function mechanisms.

Effect of harvest time on the compositional changes in essential oils, cannabinoids, and waxes of hemp (Cannabis sativa L.).

Demand for cannabinoid is growing, with the global market expected to reach $9.69 billion by 2025. Understanding how chemical composition changes in hemp at different harvest times is crucial to maximizing this industrial crop value. Important compositional changes in three different compound classes (essential oils, cannabinoids, and lipids) from inflorescences (tops), leaves, and stems of hemp (Cannabis sativa L., Finola variety) at different harvesting stages have been investigated. Over 85% of the total extracts from the tops were cannabinoids, while leaves demonstrated the greatest quantities of wax ester and sterols. Essential oil and cannabinoid increased in tops until full flowering (third harvest), reaching 2030 µg g-1 and 39 475 µg g-1, respectively. Cannabinoids decreased at seed maturity (final harvest) to 26 969 µg g-1. This demonstrates the importance of early harvesting to maximize cannabidiol (CBD), which is highly sought after for its therapeutic and pharmacological properties. A total of 21 161 µg g-1 of CBD was extracted from the tops at full flowering (third harvest); however, a significant increase (63%) in the banned psychoactive tetrahydrocannabinol (THC) was observed from budding (157 µg g-1 of biomass) to the full flowering (9873 µg g-1 of biomass). Harvesting the tops after budding is preferable due to the high CBD content and low amounts of THC.

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.

Demographics of children with feeding difficulties from a large electronic health record database.

BACKGROUND: Feeding difficulties are among the most common concerns expressed by parents in younger children. However, few studies have reported on the characteristics of patients with clinically significant feeding diagnoses. The aim of the current study is to describe the characteristics of patients diagnosed with feeding difficulties including concurrent conditions, age, and sex, sampled nationwide utilizing the Cerner Health Facts Database. METHODS: We identified patients with a diagnosis of feeding difficulties (ICD-9 783.3 or ICD-10 R63.3), age 7 months to 17 years, with an outpatient visit between 2010 and 2017. The demographics and complex clinical conditions of this population were categorized. The cohort was then collapsed into a matrix defining recognized phenotype codes for ICD-9 and ICD-10 diagnoses to identify associated conditions. RESULTS: We identified 39,674 patients (0.95%) representing 101,684 encounters from 68 health systems across the United States; 43% of patients were female. Gastrointestinal conditions were the most common, followed by malnutrition, developmental and behavioral diagnoses, and neurologic conditions. CONCLUSIONS: This study is one of the most robust studies defining the prevalence, demographic characteristics, and phenotypic profiling of patients with feeding difficulties. Our observations have implications on screening and resource allocation to recognize and manage this poorly understood population.