Mechanisms of spinophilin-dependent pancreas dysregulation in obesity.

Spinophilin is an F-actin binding and protein phosphatase 1 (PP1) targeting protein that acts as a scaffold of PP1 to its substrates. Spinophilin knockout (Spino-/-) mice have decreased fat mass, increased lean mass, and improved glucose tolerance, with no difference in feeding behaviors. Although spinophilin is enriched in neurons, its roles in nonneuronal tissues, such as ß cells of the pancreatic islets, are unclear. We have corroborated and expanded upon previous studies to determine that Spino-/- mice have decreased weight gain and improved glucose tolerance in two different models of obesity. We have identified multiple putative spinophilin-interacting proteins isolated from intact pancreas and observed increased interactions of spinophilin with exocrine, ribosomal, and cytoskeletal protein classes that normally act to mediate peptide hormone production, processing, and/or release in Leprdb/db and/or high-fat diet-fed (HFF) models of obesity. In addition, we have found that spinophilin interacts with proteins from similar classes in isolated islets, suggesting a role for spinophilin in the pancreatic islet. Consistent with a pancreatic ß cell type-specific role for spinophilin, using our recently described conditional spinophilin knockout mice, we found that loss of spinophilin specifically in pancreatic ß cells improved glucose tolerance without impacting body weight in chow-fed mice. Our data further support the role of spinophilin in mediating pathophysiological changes in body weight and whole body metabolism associated with obesity. Our data provide the first evidence that pancreatic spinophilin protein interactions are modulated by obesity and that loss of spinophilin specifically in pancreatic ß cells impacts whole body glucose tolerance.NEW & NOTEWORTHY To our knowledge, these data are the first to demonstrate that obesity impacts spinophilin protein interactions in the pancreas and identify spinophilin specifically in pancreatic ß cells as a modulator of whole body glucose tolerance.

Patterns and Outcomes of Epoprostenol Use in Infants with Congenital Diaphragmatic Hernia Requiring Extracorporeal Life Support.

OBJECTIVE: To describe our experience utilizing epoprostenol for pulmonary hypertension (PH) in infants with congenital diaphragmatic hernia (CDH) requiring extracorporeal life support (ECLS). STUDY DESIGN: We retrospectively reviewed infants diagnosed with CDH who required ECLS at our institution from 2013 to 2023. Data collected included demographics, disease characteristics, medication administration patterns, and hospital outcomes. We first compared infants who received intravenous epoprostenol and those who did not. Among infants who received epoprostenol, we compared survivors and nonsurvivors. χ² test/Fisher's exact and Mann-Whitney tests were used, with significance defined at P < .05. RESULTS: Fifty-seven infants were included; 40 (70.2%) received epoprostenol. Infants receiving epoprostenol had lower observed/expected total fetal lung volume (O/E TFLV) on magnetic resonance imaging (20 vs 26.2%, P = .042) as well as higher prenatal frequency of liver-up (90 vs 64.7%, P = .023) and "severe" classification (67.5 vs 35.3%, P = .007). Survival with and without epoprostenol was comparable (60% vs 64%, P = .23). Of those receiving epoprostenol, both survivors and nonsurvivors had similar prenatal indicators of disease severity. Most (80%) of hernia defects were classified as type C/D and 68% were repaired <72 hours after ECLS cannulation. The median age at initiation of epoprostenol was day of life 6 (IQR: 4, 7) in survivors and 8 (IQR: 7, 16) in nonsurvivors (P = .012). Survivors had shorter ECLS duration (11 vs 20 days, P = .049). Of nonsurvivors, refractory PH was the cause of death for 13 infants (81%). CONCLUSIONS: In infants with CDH requiring ECLS, addition of epoprostenol appears promising and earlier initiation may affect survival.

Impact of Prior Abdominal Procedures on Peritoneal Dialysis Catheter Outcomes: Findings From the North American Peritoneal Dialysis Catheter Registry.

RATIONALE & OBJECTIVE: A history of prior abdominal procedures may influence the likelihood of referral for peritoneal dialysis (PD) catheter insertion. To guide clinical decision making in this population, this study examined the association between prior abdominal procedures and outcomes in patients undergoing PD catheter insertion. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adults undergoing their first PD catheter insertion between November 1, 2011, and November 1, 2020, at 11 institutions in Canada and the United States participating in the International Society for Peritoneal Dialysis North American Catheter Registry. EXPOSURE: Prior abdominal procedure(s) defined as any procedure that enters the peritoneal cavity. OUTCOMES: The primary outcome was time to the first of (1) abandonment of the PD catheter or (2) interruption/termination of PD. Secondary outcomes were rates of emergency room visits, hospitalizations, and procedures. ANALYTICAL APPROACH: Cumulative incidence curves were used to describe the risk over time, and an adjusted Cox proportional hazards model was used to estimate the association between the exposure and primary outcome. Models for count data were used to estimate the associations between the exposure and secondary outcomes. RESULTS: Of 855 patients who met the inclusion criteria, 31% had a history of a prior abdominal procedure and 20% experienced at least 1 PD catheter-related complication that led to the primary outcome. Prior abdominal procedures were not associated with an increased risk of the primary outcome (adjusted HR, 1.12; 95% CI, 0.68-1.84). Upper-abdominal procedures were associated with a higher adjusted hazard of the primary outcome, but there was no dose-response relationship concerning the number of procedures. There was no association between prior abdominal procedures and other secondary outcomes. LIMITATIONS: Observational study and cohort limited to a sample of patients believed to be potential candidates for PD catheter insertion. CONCLUSION: A history of prior abdominal procedure(s) does not appear to influence catheter outcomes following PD catheter insertion. Such a history should not be a contraindication to PD. PLAIN-LANGUAGE SUMMARY: Peritoneal dialysis (PD) is a life-saving therapy for individuals with kidney failure that can be done at home. PD requires the placement of a tube, or catheter, into the abdomen to allow the exchange of dialysis fluid during treatment. There is concern that individuals who have undergone prior abdominal procedures and are referred for a catheter might have scarring that could affect catheter function. In some institutions, they might not even be offered PD therapy as an option. In this study, we found that a history of prior abdominal procedures did not increase the risk of PD catheter complications and should not dissuade patients from choosing PD or providers from recommending it.

Temporal Trends of Neonatal Surgical Conditions in Texas and Accessibility to Pediatric Surgical Care.

INTRODUCTION: Texas consistently accounts for approximately 10% of annual national births, the second highest of all US states. This temporal study aimed to evaluate incidences of neonatal surgical conditions across Texas and to delineate regional pediatric surgeon accessibility. METHODS: The Texas Birth Defects Registry was queried from 1999 to 2018, based on 11 well-established regions. Nine disorders (30,476 patients) were identified as being within the operative scope of pediatric surgeons: biliary atresia (BA), pyloric stenosis (PS), Hirschsprung's disease, stenosis/atresia of large intestine/rectum/anus, stenosis/atresia of small intestine, tracheoesophageal fistula/esophageal atresia, gastroschisis, omphalocele, and congenital diaphragmatic hernia. Annual and regional incidences were compared (/10,000 births). Statewide pediatric surgeons were identified through the American Pediatric Surgical Association directory. Regional incidences of neonatal disorder per surgeon were evaluated from 2010 to 2018 as a surrogate for provider disparity. RESULTS: PS demonstrated the highest incidence (14.405/10,000), while BA had the lowest (0.707/10,000). Overall, incidences of PS and BA decreased significantly, while incidences of Hirschsprung's disease and small intestine increased. Other diagnoses remained stable. Regions 2 (48.24/10,000) and 11 (47.79/10,000) had the highest incidence of neonatal conditions; Region 6 had the lowest (34.68/10,000). Three rural regions (#2, 4, 9) lacked pediatric surgeons from 2010 to 2018. Of regions with at least one surgeon, historically underserved regions (#10, 11) along the Texas-Mexico border consistently had the highest defect per surgeon rates. CONCLUSIONS: There are temporal and regional differences in incidences of neonatal conditions treated by pediatric surgeons across Texas. Improving access to neonatal care is a complex issue that necessitates collaborative efforts between state legislatures, health systems, and providers.

Is There Still a Role for Peritoneal Drains in Neonatal Pneumoperitoneum? A Single-Center Experience.

INTRODUCTION: Although pneumoperitoneum from necrotizing enterocolitis or spontaneous intestinal perforation is a surgical emergency, risk stratification to determine which neonates benefit from initial peritoneal drainage (PD) is lacking. METHODS: Using a single-center retrospective review of very low birth weight neonates under 1500 g who underwent PD for pneumoperitoneum (January 2015 to December 2023) from necrotizing enterocolitis or spontaneous intestinal perforation, two cohorts were created: drain "responders" (patients managed definitively with PD; includes placement of a second drain) and "nonresponders" (patients who underwent subsequent laparotomy or died after PD). Antenatal/postnatal characteristics, periprocedural clinical data, and hospital outcomes were compared between responders and nonresponders using Student's t-test, chi-squared test, or Kruskal-Wallis test as appropriate, with P < 0.05 considered significant. RESULTS: Fifty-six neonates were included: 31 (55%) drain responders and 25 (45%) nonresponders. Birth weight, gestational age, sex, ethnicity, use of postnatal steroids, and enteral feeds were similar between the cohorts. Nonresponders had higher base deficits (-3.4 versus -5.0, P = 0.032) and FiO2 (0.25 versus 0.52, P = 0.001) after drain placement. Drain responders had significantly shorter lengths of stay (89 versus 148 days, P = 0.014) and lower mortality (6.4% versus 56%, P < 0.001). A subgroup analysis of the nonresponders showed no differences in birth weight, vasopressor requirement, FiO2, or postdrain base deficit between nonresponders who had a drain alone versus laparotomy following drain placement. CONCLUSIONS: PD remains a viable initial therapy for pneumoperitoneum in premature very low birth weight neonates (< 1500 g), demonstrating clinical response in more than half. Ongoing clinical assessment and judgment is imperative after drain placement to ensure continued clinical improvement.

Use of modern three-dimensional imaging models to guide surgical planning for local control of pediatric extracranial solid tumors.

INTRODUCTION: In complex pediatric surgical oncology, surgical planning is contingent upon data gathered from preoperative imaging. Three-dimensional (3D) modeling and printing has been shown to be beneficial for adult presurgical planning, though pediatric literature is less robust. The study reviews our institutional experience with the use of 3D image segmentation and printed models in approaching resection of extracranial solid tumors in children. METHODS: This is a single institutional series from 2021 to 2023. Models were based on computed tomography and magnetic resonance imaging studies, optimized for 3D imaging. The feasibility and creation of the models is reviewed, including specific techniques, software, and printing materials from our institution. Clinical implications for surgical planning are also described, along with detailed preoperative and intraoperative images. RESULTS: 3D modeling and printing was performed for four pediatric patients diagnosed with extracranial solid tumors. Diagnoses included Ewing sarcoma, hepatoblastoma, synovial sarcoma, and osteosarcoma. No intraoperative complications or discrepancies with the preoperative 3D-printed model were noted. No evidence of local recurrence was identified in any patient thus far. CONCLUSION: Our institutional series demonstrates a wide spectrum of clinical application for 3D modeling and printing technology within pediatric surgical oncology. This technology may aid in surgical planning for both resection and reconstruction, can be applied to a diverse breadth of diagnoses, and may potentially augment patient and/or family education about their condition.

A modern approach to multiple pulmonary resections in children with recurrent metastatic pulmonary disease.

Implications of repeated resections of pulmonary metastasis (PM) are not well documented in the modern era. Fifteen children underwent two (n = 8), three (n = 3), or four or more (n = 3) resections (total = 38 procedures), most commonly for osteosarcoma (71%). Operative approach included muscle-sparing thoracotomy (71%), non-muscle-sparing thoracotomy (18%), and video-assisted thoracoscopy (11%). Median resected nodules per procedure was four (range = 1-95). Prolonged air leaks were the most common postoperative complication (29%). Median hospital stay was 4 days, and no children were discharged with or have required oxygen. Event-free survival is 67% at median follow-up time of 54 months, with an overall survival rate of 64%. Repeat resection of PM appears to be well tolerated, without prolonged hospital stays or compromised pulmonary function.

Modern surgical strategies in pediatric neuroblastoma: Evolving approaches and treatment principles.

Neuroblastoma, the most common extracranial solid tumor in children under the age of 5, has been described as early as the 19th century, and its complexity has continued to intrigue researchers, as well as medical and surgical specialists. At one end of the phenotypic spectrum, neuroblastoma is self-limiting with minimal to no intervention required, while on the opposite end exists the challenge of refractory disease despite aggressive management and toxic systemic treatments. The goal of this review is to describe a comprehensive surgical perspective and contemporary approach to neuroblastoma.

Effect of Calcium and Vitamin D Supplementation (Dairy vs. Pharmacological) on Bone Health of Underprivileged Indian Children and Youth with Type-1 Diabetes: A Randomized Controlled Trial.

BACKGROUND: Bone health is affected by chronic childhood disorders including type-1 diabetes mellitus (T1DM). We conducted this randomized controlled trial with the objective of investigating the effect of 1-year supplementation of vitamin-D with milk or with pharmacological calcium on bone mass accrual in underprivileged Indian children and youth with T1DM. METHODS: 5 to 23year old (n = 203) underprivileged children and youth with T1DM were allocated to one of three groups: Milk (group A-received 200 ml milk + 1000 international unit (IU) vitamin-D3/day), Calcium supplement (group B-received 500 mg of calcium carbonate + 1000 IU of vitamin-D3/day) or standard of care/control (group C). Anthropometry, clinical details, biochemistry, diet (3-day 24-h recall), physical activity (questionnaires adapted for Indian children) and bone health parameters (using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography- DXA and pQCT respectively) were evaluated at enrolment and end of 12 month intervention. RESULTS: Total body less head(TBLH) bone mineral content (BMC(g)) and bone mineral density (BMD(gm/cm2)) were significantly higher at end of study in girls in both supplemented groups (TBLHBMC-A-1011.8 ±â€¯307.8, B-983.2 ±â€¯352.9, C-792.8 ±â€¯346.8. TBLHBMD-A-± 0.2, B-0.8 ±â€¯0.2, C-0.6 ±â€¯0.2, p < 0.05). Z score of lumbar spine bone mineral apparent density of supplemented participants of both sexes was significantly higher than controls (Boys- A-0.7 ±â€¯1.1, B-0.6 ±â€¯1.4, C- -0.7 ±â€¯1.1; Girls- A-1.1 ±â€¯1.1, B-0.9 ±â€¯3.4, C- -1.7 ±â€¯1.3, p < 0.05). A significantly higher percentage increase was found in cortical thickness in girls in both supplemented groups (A-17.9 ±â€¯28.6, B-15.3 ±â€¯16.5, C-7.6 ±â€¯26.2); the differences remained after adjusting for confounders. CONCLUSION: Supplementation with milk or pharmacological calcium (+vitaminD3) improved bone outcomes-particularly geometry in children with T1DM with more pronounced effect in girls. Pharmacological calcium may be more cost effective in optimising bone health in T1DM in resource limited settings.

Global variability of vascular and peritoneal access for chronic dialysis.

AIM: Vascular and peritoneal access are essential elements for sustainability of chronic dialysis programs. Data on availability, patterns of use, funding models, and workforce for vascular and peritoneal accesses for dialysis at a global scale is limited. METHODS: An electronic survey of national leaders of nephrology societies, consumer representative organizations, and policymakers was conducted from July to September 2018. Questions focused on types of accesses used to initiate dialysis, funding for services, and availability of providers for access creation. RESULTS: Data from 167 countries were available. In 31 countries (25% of surveyed countries), >75% of patients initiated haemodialysis (HD) with a temporary catheter. Seven countries (5% of surveyed countries) had >75% of patients initiating HD with arteriovenous fistulas or grafts. Seven countries (5% of surveyed countries) had >75% of their patients starting HD with tunnelled dialysis catheters. 57% of low-income countries (LICs) had >75% of their patients initiating HD with a temporary catheter compared to 5% of high-income countries (HICs). Shortages of surgeons to create vascular access were reported in 91% of LIC compared to 46% in HIC. Approximately 95% of participating countries in the LIC category reported shortages of surgeons for peritoneal dialysis (PD) access compared to 26% in HIC. Public funding was available for central venous catheters, fistula/graft creation, and PD catheter surgery in 57%, 54% and 54% of countries, respectively. CONCLUSION: There is a substantial variation in the availability, funding, workforce, and utilization of vascular and peritoneal access for dialysis across countries regions, with major gaps in low-income countries.