Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

The need for early Kasai portoenterostomy: a Western Pediatric Surgery Research Consortium study.

PURPOSE: The purpose of this study was to investigate factors impacting transplant-free survival among infants with biliary atresia. METHODS: A multi-institutional, retrospective cohort study was performed at nine tertiary-level children's hospitals in the United States. Infants who underwent Kasai portoenterostomy (KP) from January 2009 to May 2017 were identified. Clinical characteristics included age at time of KP, steroid use, surgical approach, liver pathology, and surgeon experience. Likelihood of transplant-free survival (TFS) was evaluated using logistic regression, adjusting for patient and surgeon-level factors. Secondary outcomes at 1 year included readmission, cholangitis, reoperation, mortality, and biliary clearance. RESULTS: Overall, 223 infants underwent KP, and 91 (40.8%) survived with their native liver. Mean age at surgery was 63.9 days (± 24.7 days). At 1 year, 78.5% experienced readmission, 56.9% developed cholangitis, 3.8% had a surgical revision, and 5 died. Biliary clearance at 3 months was achieved in 76.6%. Controlling for patient and surgeon-level factors, each additional day of age toward operation was associated with a 2% decrease in likelihood of TFS (OR 0.98, 95% CI 0.97-0.99). CONCLUSION: Earlier surgical intervention by Kasai portoenterostomy at tertiary-level centers significantly increases likelihood for TFS. Policy-level interventions to facilitate early screening and surgical referral for infants with biliary atresia are warranted to improve outcomes.

Courtesy Authorship Practices Among First and Senior Authors: Evaluation of Motivations, Gender Bias, and Inequities.

OBJECTIVES: A courtesy author is an individual who has not met authorship criteria but is listed as an author. This practice is common and often seen as victimless. Because publications are used for funding and promotion decisions, it is critical to understand biases in this practice. METHODS: An anonymous survey was conducted from March to October 2020 of first and senior authors of publications from 2014 to 2015 in 8 surgical journals. Authors were surveyed about demographic data, practice setting, and courtesy author practices. RESULTS: Three hundred forty-one authors responded (16% response rate). 75% were from academic practice settings. 14% reported adding courtesy authors 5 or more times in the past year. Courtesy authors were more often male (80%, P = 0.023), older (75%), and of higher academic rank (65%) than first/senior authors. All author groups were >75% white. When a reason was reported, 46% added a courtesy author due to avoid retaliation; 64% to avoid awkwardness. 26% expected reciprocal authorship offers. 92% of respondents acknowledge understanding International Committee of Medical Journal Editors authorship criteria. Women were less common among those added from goodwill than those added from fear (P = 0.039.) When courtesy authors were of a lower rank than first/senior authors, they were nearly twice as likely to be female (P = 0.0056) or non-white (P = 0.0184.). CONCLUSION: Courtesy authors were more often male, older, and higher rank than first/senior authors. Fear of career consequences was a major motivator for including courtesy authors. Understanding the motivations and pressures leading to courtesy authorship will help to correct this practice.

Minimizing Variance in Gastroschisis Management Leads to Earlier Full Feeds in Delayed Closure.

BACKGROUND: Limited guidance exists regarding appropriate timing for feed initiation and advancement in gastroschisis. We hypothesized that implementation of a gastroschisis management protocol would allow for standardization of antibiotic and nutritional treatment for these patients. METHODS: We conducted a retrospective comparison of patients with simple gastroschisis at two pediatric hospitals before and after initiation of our gastroschisis care protocol. Complicated gastroschisis and early mortality were excluded. The control group extended from January 2012 to January 2014 and the protocol group from July 2014 to July 2016. Variables of interest included time to feed initiation, time to goal feeds, length of stay, and National Surgical Quality Improvement Program-defined complications. We performed a subgroup analysis for primary versus delayed gastroschisis closure. Statistical analyses, including F-tests for variance, were conducted in Prism. RESULTS: Forty-seven patients with simple gastroschisis were included (control = 22, protocol = 25). Protocol compliance was 76% with no increase in complication rates. There was no difference in length of stay or time from initiation to full feeds overall between the control and protocol groups. However, neonates who underwent delayed closure reached full feeds significantly earlier, averaging 9 d versus 15 d previously (P = 0.04). CONCLUSIONS: For infants undergoing delayed closure, the time to full feeds in this group now appears to match that of patients undergoing primary closure, indicating that delayed closure should not be a reason for slower advancement. Additional studies are needed to assess the impact of earlier full enteral nutrition on rare complications and rates of necrotizing enterocolitis.

Attitudes Affecting Decision-Making for Use of Radiologic Enteral Contrast in the Management of Pediatric Adhesive Small Bowel Obstruction: A Survey Study of Pediatric Surgeons.

BACKGROUND: Pediatric surgeons are often asked to treat clinical problems for which little high-quality data exist. For adults with adhesive small bowel obstruction (ASBO), water soluble contrast-based protocols are used to guide management. Little is known about their utility in children. We aimed to better understand key factors in clinical decision-making processes and integration of adult based data in pediatric surgeon's approach to ASBO. METHODS: We administered a web-based survey to practicing pediatric surgeons at institutions comprising the Western Pediatric Surgery Research Consortium. RESULTS: The response rate was 69% (78/113). Over half of respondents reported using contrast protocols to guide ASBO management either routinely or occasionally (n = 47, 60%). Common themes regarding the incorporation of adult-based data into clinical practice included the need to adapt protocols for pediatric patients, the dearth of pediatric specific data, and the quality of the published adult evidence. CONCLUSIONS: Our findings demonstrate that pediatric surgeons use contrast-based protocols for the management of ASBO despite the paucity of pediatric specific data. Furthermore, our survey data help us understand how pediatric surgeons incorporate adult based evidence into their practice.

De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders.

Congenital diaphragmatic hernia (CDH) is a severe birth defect that is often accompanied by other congenital anomalies. Previous exome sequencing studies for CDH have supported a role of de novo damaging variants but did not identify any recurrently mutated genes. To investigate further the genetics of CDH, we analyzed de novo coding variants in 362 proband-parent trios including 271 new trios reported in this study. We identified four unrelated individuals with damaging de novo variants in MYRF (P = 5.3x10(-8)), including one likely gene-disrupting (LGD) and three deleterious missense (D-mis) variants. Eight additional individuals with de novo LGD or missense variants were identified from our other genetic studies or from the literature. Common phenotypes of MYRF de novo variant carriers include CDH, congenital heart disease and genitourinary abnormalities, suggesting that it represents a novel syndrome. MYRF is a membrane associated transcriptional factor highly expressed in developing diaphragm and is depleted of LGD variants in the general population. All de novo missense variants aggregated in two functional protein domains. Analyzing the transcriptome of patient-derived diaphragm fibroblast cells suggest that disease associated variants abolish the transcription factor activity. Furthermore, we showed that the remaining genes with damaging variants in CDH significantly overlap with genes implicated in other developmental disorders. Gene expression patterns and patient phenotypes support pleiotropic effects of damaging variants in these genes on CDH and other developmental disorders. Finally, functional enrichment analysis implicates the disruption of regulation of gene expression, kinase activities, intra-cellular signaling, and cytoskeleton organization as pathogenic mechanisms in CDH.

Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes.

PURPOSE: Congenital diaphragmatic hernia (CDH) is associated with significant mortality and long-term morbidity in some but not all individuals. We hypothesize monogenic factors that cause CDH are likely to have pleiotropic effects and be associated with worse clinical outcomes. METHODS: We enrolled and prospectively followed 647 newborns with CDH and performed genomic sequencing on 462 trios to identify de novo variants. We grouped cases into those with and without likely damaging (LD) variants and systematically assessed CDH clinical outcomes between the genetic groups. RESULTS: Complex cases with additional congenital anomalies had higher mortality than isolated cases (P = 8 × 10-6). Isolated cases with LD variants had similar mortality to complex cases and much higher mortality than isolated cases without LD (P = 3 × 10-3). The trend was similar with pulmonary hypertension at 1 month. Cases with LD variants had an estimated 12-17 points lower scores on neurodevelopmental assessments at 2 years compared with cases without LD variants, and this difference is similar in isolated and complex cases. CONCLUSION: We found that the LD genetic variants are associated with higher mortality, worse pulmonary hypertension, and worse neurodevelopment outcomes compared with non-LD variants. Our results have important implications for prognosis, potential intervention and long-term follow up for children with CDH.

Significant practice variability exists in the prevention of venous thromboembolism in injured children: results from a joint survey of the Pediatric Trauma Society and the Trauma Center Association of America.

BACKGROUND/PURPOSE: The purpose of this study was to characterize current practices to prevent venous thromboembolism (VTE) in children and measure adherence to recent joint consensus guidelines from the Pediatric Trauma Society and Eastern Association for the Surgery of Trauma (PTS/EAST). METHODS: An 18-question survey was sent to the membership of PTS and the Trauma Center Association of American. Responses were compared with Chi-square test. RESULTS: One hundred twenty-nine members completed the survey. Most respondents were from academic (84.5%), Level 1 pediatric (62.0%) trauma centers. Criteria for VTE prophylaxis varied between hospitals with freestanding pediatric trauma centers significantly more likely to stratify children by risk factors than adult trauma centers (p = 0.020). While awareness of PTS/EAST guidelines (58.7% overall) was not statistically different between hospital types (44% freestanding adult, 52% freestanding pediatric, 71% combined adult pediatric, p = 0.131), self-reported adherence to these guidelines was uniformly low at 37.2% for all respondents. Lastly, in three clinical scenarios, respondents chose VTE screening and prophylaxis plans in accordance with a prospective application of PTS/EAST guidelines 55.0% correctly. CONCLUSION: Currently no consensus regarding the prevention of VTE in pediatric trauma exists. Prospective application of PTS/EAST guidelines has been limited, likely due to poor quality of evidence and a reliance on post-injury metrics. Results of this survey suggest that further investigation is needed to more clearly define the risk of VTE in children, evaluate, and prospectively validate alternative scoring systems for VTE prevention in injured children. LEVEL OF EVIDENCE: N/A-Survey.

Analysis of Gender-based Differences in Surgery Faculty Compensation, Promotion, and Retention: Establishing Equity.

OBJECTIVES: The objectives of this study were to evaluate gender-based differences in faculty salaries before and after implementation of a university-wide objective compensation plan, Faculty First (FF), in alignment with Association of American Medical Colleges regional median salary (AAMC-WRMS). Gender-based differences in promotion and retention were also assessed. SUMMARY BACKGROUND DATA: Previous studies demonstrate that female faculty within surgery are compensated less than male counterparts are and have decreased representation in higher academic ranks and leadership positions. METHODS: At a single institution, surgery faculty salaries and work relative value units (wRVUs) were reviewed from 2009 to 2017, and time to promotion and retention were reviewed from 1998 to 2007. In 2015, FF supplanted specialty-specific compensation plans. Salaries and wRVUs relative to AAMC-WRMS, time to promotion, and retention were compared between genders. RESULTS: Female faculty (N = 24) were compensated significantly less than males were (N = 62) before FF (P = 0.004). Female faculty compensation significantly increased after FF (P < 0.001). After FF, female and male faculty compensation was similar (P = 0.32). Average time to promotion for female (N = 29) and male faculty (N = 82) was similar for promotion to associate professor (P = 0.49) and to full professor (P = 0.37). Promotion was associated with significantly higher retention for both genders (P < 0.001). The median time of departure was similar between female and male faculty (P = 0.73). CONCLUSIONS: A university-wide objective compensation plan increased faculty salaries to the AAMC western region median, allowing correction of gender-based salary inequity. Time to promotion and retention was similar between female and male faculty.

Increased burden of de novo predicted deleterious variants in complex congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is a serious birth defect that accounts for 8% of all major birth anomalies. Approximately 40% of cases occur in association with other anomalies. As sporadic complex CDH likely has a significant impact on reproductive fitness, we hypothesized that de novo variants would account for the etiology in a significant fraction of cases. We performed exome sequencing in 39 CDH trios and compared the frequency of de novo variants with 787 unaffected controls from the Simons Simplex Collection. We found no significant difference in overall frequency of de novo variants between cases and controls. However, among genes that are highly expressed during diaphragm development, there was a significant burden of likely gene disrupting (LGD) and predicted deleterious missense variants in cases (fold enrichment = 3.2, P-value = 0.003), and these genes are more likely to be haploinsufficient (P-value = 0.01) than the ones with benign missense or synonymous de novo variants in cases. After accounting for the frequency of de novo variants in the control population, we estimate that 15% of sporadic complex CDH patients are attributable to de novo LGD or deleterious missense variants. We identified several genes with predicted deleterious de novo variants that fall into common categories of genes related to transcription factors and cell migration that we believe are related to the pathogenesis of CDH. These data provide supportive evidence for novel genes in the pathogenesis of CDH associated with other anomalies and suggest that de novo variants play a significant role in complex CDH cases.

A definition of gentle ventilation in congenital diaphragmatic hernia: a survey of neonatologists and pediatric surgeons.

Ventilation practices have changed significantly since the initial reports in the mid 1980 of successful use of permissive hypercapnia and spontaneous ventilation [often called gentle ventilation (GV)] in infants with congenital diaphragmatic hernia (CDH). However, there has been little standardization of these practices or of the physiologic limits that define GV. We sought to ascertain among Diaphragmatic Hernia Research and Exploration; Advancing Molecular Science (DHREAMS) centers' GV practices in the neonatal management of CDH. Pediatric surgeons and neonatologists from DHREAMS centers completed an online survey on GV practices in infants with CDH. The survey gathered data on how individuals defined GV including ventilator settings, blood gas parameters and other factors of respiratory management. A total of 87 respondents, from 12 DHREAMS centers completed the survey for an individual response rate of 53% and a 92% center response rate. Approximately 99% of the respondents defined GV as accepting higher carbon dioxide (PCO2) and 60% of the respondents also defined GV as accepting a lower pH. There was less consensus about the use of sedation and neuromuscular blocking agents in GV, both within and across the centers. Acceptable pH and PCO2 levels are broader than the goal ranges. Despite a lack of formal standardization, the results suggest that GV practice is consistently defined as the use of permissive hypercapnia with mild respiratory acidosis and less consistently with the use of sedation and neuromuscular blocking agents. GV is the reported practice of surveyed neonatologists and pediatric surgeons in the respiratory management of infants with CDH.

Whole exome sequencing identifies de novo mutations in GATA6 associated with congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a common birth defect affecting 1 in 3000 births. It is characterised by herniation of abdominal viscera through an incompletely formed diaphragm. Although chromosomal anomalies and mutations in several genes have been implicated, the cause for most patients is unknown. METHODS: We used whole exome sequencing in two families with CDH and congenital heart disease, and identified mutations in GATA6 in both. RESULTS: In the first family, we identified a de novo missense mutation (c.1366C>T, p.R456C) in a sporadic CDH patient with tetralogy of Fallot. In the second, a nonsense mutation (c.712G>T, p.G238*) was identified in two siblings with CDH and a large ventricular septal defect. The G238* mutation was inherited from their mother, who was clinically affected with congenital absence of the pericardium, patent ductus arteriosus and intestinal malrotation. Deep sequencing of blood and saliva-derived DNA from the mother suggested somatic mosaicism as an explanation for her milder phenotype, with only approximately 15% mutant alleles. To determine the frequency of GATA6 mutations in CDH, we sequenced the gene in 378 patients with CDH. We identified one additional de novo mutation (c.1071delG, p.V358Cfs34*). CONCLUSIONS: Mutations in GATA6 have been previously associated with pancreatic agenesis and congenital heart disease. We conclude that, in addition to the heart and the pancreas, GATA6 is involved in development of two additional organs, the diaphragm and the pericardium. In addition, we have shown that de novo mutations can contribute to the development of CDH, a common birth defect.

Chronic cervical esophageal foreign bodies in children: surgical approach after unsuccessful endoscopic management.

OBJECTIVES: We reviewed the surgical management of chronic cervical esophageal foreign bodies (CCEFBs) in a pediatric population after failed endoscopic retrieval. METHODS: A descriptive analysis via a retrospective chart review of patients with CCEFBs who failed initial endoscopic management was performed between 2008 and 2013. Details were recorded regarding presenting symptoms, time from symptom onset to diagnosis of the CCEFB, surgical approach, and complications. RESULTS: Three patients with CCEFBs unsuccessfully managed with endoscopy were identified. The range of ages at diagnosis was 14 months to 4.5 years. The foreign bodies (FBs) were present for at least 1 month before diagnosis (range, 1 to 10 months). Respiratory symptoms were predominant in all cases. Neck exploration with removal of the FB was performed in each case. Complications included esophageal stricture necessitating serial dilations (patient 1), left true vocal fold paresis that resolved spontaneously (patient 3), and tracheoesophageal fistula with successful endoscopic closure (patient 3). No long-term sequelae were experienced. CONCLUSIONS: A high index of suspicion is required to recognize CCEFBs in children with respiratory distress. Although endoscopic management remains the first-line treatment, it may fail or may not be possible because of transmural FB migration. In this setting, neck exploration with FB removal is a safe and effective alternative.

Morbidity and mortality associated with liver resections for primary malignancies in children.

PURPOSE: Liver resection (LR) is a high-risk procedure with limited data in the pediatric surgical literature regarding short-term outcomes. Our aim was to characterize the patient population and short-term outcomes for children undergoing LR for malignancy. METHODS: We studied 126 inpatient admissions for children ≤20 years of age undergoing LR in 2009 using the Kids' Inpatient Database. Patients had a principal diagnosis of a primary hepatic malignancy and LR listed as one of the first five procedures. Transplantations were excluded. Complications were defined by ICD-9 codes. High-volume centers performed at least 5 LR. RESULTS: The mean age was 5.83 years. The morbidity and mortality rates were 30.7 and 3.7%, respectively. The most common causes of morbidity were digestive system complications (7.4%), anemia (7.3%), and respiratory complications (3.8%). 43.9% received a blood product transfusion. The average length of stay was 10.04 days. When compared to low-volume centers, high-volume centers increased the likelihood of a complication fourfold (P = 0.011) but had 0% mortality (P = 0.089). CONCLUSION: LR remains a procedure fraught with multiple complications and a significant mortality rate. High-volume centers have a fourfold increase in likelihood of complications compared to low-volume centers and may be related to extent of hepatic resection.

Variants in GATA4 are a rare cause of familial and sporadic congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is characterized by incomplete formation of the diaphragm occurring as either an isolated defect or in association with other anomalies. Genetic factors including aneuploidies and copy number variants are important in the pathogenesis of many cases of CDH, but few single genes have been definitively implicated in human CDH. In this study, we used whole exome sequencing (WES) to identify a paternally inherited novel missense GATA4 variant (c.754C>T; p.R252W) in a familial case of CDH with incomplete penetrance. Phenotypic characterization of the family included magnetic resonance imaging of the chest and abdomen demonstrating asymptomatic defects in the diaphragm in the two "unaffected" missense variant carriers. Screening 96 additional CDH patients identified a de novo heterozygous GATA4 variant (c.848G>A; p.R283H) in a non-isolated CDH patient. In summary, GATA4 is implicated in both familial and sporadic CDH, and our data suggests that WES may be a powerful tool to discover rare variants for CDH.

De novo copy number variants are associated with congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a common birth defect with significant morbidity and mortality. Although the aetiology of CDH remains poorly understood, studies from animal models and patients with CDH suggest that genetic factors play an important role in the development of CDH. Chromosomal anomalies have been reported in CDH. METHODS: In this study, the authors investigated the frequency of chromosomal anomalies and copy number variants (CNVs) in 256 parent-child trios of CDH using clinical conventional cytogenetic and microarray analysis. The authors also selected a set of CDH related training genes to prioritise the genes in those segmental aneuploidies and identified the genes and gene sets that may contribute to the aetiology of CDH. RESULTS: The authors identified chromosomal anomalies in 16 patients (6.3%) of the series including three aneuploidies, two unbalanced translocation, and 11 patients with de novo CNVs ranging in size from 95 kb to 104.6 Mb. The authors prioritised the genes in the CNV segments and identified KCNA2, LMNA, CACNA1S, MYOG, HLX, LBR, AGT, GATA4, SOX7, HYLS1, FOXC1, FOXF2, PDGFA, FGF6, COL4A1, COL4A2, HOMER2, BNC1, BID, and TBX1 as genes that may be involved in diaphragm development. Gene enrichment analysis identified the most relevant gene ontology categories as those involved in tissue development (p=4.4×10(-11)) or regulation of multicellular organismal processes (p=2.8×10(-10)) and 'receptor binding' (p=8.7×10(-14)) and 'DNA binding transcription factor activity' (p=4.4×10(-10)). CONCLUSIONS: The present findings support the role of chromosomal anomalies in CDH and provide a set of candidate genes including FOXC1, FOXF2, PDGFA, FGF6, COL4A1, COL4A2, SOX7, BNC1, BID, and TBX1 for further analysis in CDH.

Multi-institutional analysis of long-term symptom resolution after cholecystectomy for biliary dyskinesia in children.

PURPOSE: Current literature for resolution of abdominal pain after cholecystectomy in children with biliary dyskinesia shows variable outcomes. We sought to compare early outcomes with long-term symptom resolution in children. METHODS: Telephone surveys were conducted on children who underwent cholecystectomy for biliary dyskinesia between January 2000 and January 2011 at two centers. Retrospective review was performed to obtain demographics and short-term outcomes. RESULTS: Charts of 105 patients' age 7.9-19 years were reviewed; 80.9 % were female. All were symptomatic with an ejection fraction (EF) <35 % or pain with cholecystokinin administration. At the postoperative visit, 76.1 % had resolution of symptoms. Fifty-six (53.3 %) patients were available for follow-up at median 3.7 (1.1-10.7) years. Of these, 34 (60.7 %) reported no ongoing abdominal pain. Of the 22 patients with persistent symptoms, satisfaction score was 7.3 ± 2.7 (scale of 1-10) and 19 (86.4 %) were glad that they had a cholecystectomy performed. EF, body mass index percentile (BMI %), and pain with cholecystokinin (CCK) were not predictive of ongoing pain at either follow-up periods. CONCLUSION: Short-term symptom resolution in children undergoing cholecystectomy for biliary dyskinesia is not reflective of long-term results. Neither EF, BMI % nor pain with CCK was predictive of symptom resolution. The majority of patients with ongoing complaints do not regret cholecystectomy.

Guidelines for Opioid Prescribing in Children and Adolescents After Surgery: An Expert Panel Opinion.

Importance: Opioids are frequently prescribed to children and adolescents after surgery. Prescription opioid misuse is associated with high-risk behavior in youth. Evidence-based guidelines for opioid prescribing practices in children are lacking. Objective: To assemble a multidisciplinary team of health care experts and leaders in opioid stewardship, review current literature regarding opioid use and risks unique to pediatric populations, and develop a broad framework for evidence-based opioid prescribing guidelines for children who require surgery. Evidence Review: Reviews of relevant literature were performed including all English-language articles published from January 1, 1988, to February 28, 2019, found via searches of the PubMed (MEDLINE), CINAHL, Embase, and Cochrane databases. Pediatric was defined as children younger than 18 years. Animal and experimental studies, case reports, review articles, and editorials were excluded. Selected articles were graded using tools from the Oxford Centre for Evidence-based Medicine 2011 levels of evidence. The Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument was applied throughout guideline creation. Consensus was determined using a modified Delphi technique. Findings: Overall, 14 574 articles were screened for inclusion, with 217 unique articles included for qualitative synthesis. Twenty guideline statements were generated from a 2-day in-person meeting and subsequently reviewed, edited, and endorsed externally by pediatric surgical specialists, the American Pediatric Surgery Association Board of Governors, the American Academy of Pediatrics Section on Surgery Executive Committee, and the American College of Surgeons Board of Regents. Review of the literature and guideline statements underscored 3 primary themes: (1) health care professionals caring for children who require surgery must recognize the risks of opioid misuse associated with prescription opioids, (2) nonopioid analgesic use should be optimized in the perioperative period, and (3) patient and family education regarding perioperative pain management and safe opioid use practices must occur both before and after surgery. Conclusions and Relevance: These are the first opioid-prescribing guidelines to address the unique needs of children who require surgery. Health care professionals caring for children and adolescents in the perioperative period should optimize pain management and minimize risks associated with opioid use by engaging patients and families in opioid stewardship efforts.

Small cell ovarian carcinoma: a rare, aggressive tumor masquerading as constipation in a teenager with a fatal outcome.

SUMMARY: A 16-year-old female presented with symptoms consistent with constipation with no constitutional symptoms. Multiple different laxatives were attempted over 4 months and were unsuccessful. This thin female developed an impressively distended, nonacute abdomen within a 2-week period. Histology demonstrated a stage IV small cell carcinoma of the ovary. Her disease initially responded to treatment, but ultimately she relapsed and failed to respond to 2 other chemotherapy combinations, which were based on limited success found in the literature. She ultimately passed away 13 months after the diagnosis, demonstrating the poor prognosis and rapid spread of this rare disease.

Validation of Shock Index Pediatric-Adjusted for children injured in warzones.

BACKGROUND: Shock Index Pediatric-Adjusted (SIPA) has been used to predict injury severity and outcomes after civilian pediatric trauma. We hypothesize that SIPA can predict the need for blood transfusion and emergent surgery among pediatric patients injured in warzones, where resources are limited and accurate triage is essential. METHODS: Retrospective review of the DoD Trauma Registry for all patients 17 years or younger, from 2008 to 2015. Shock Index Pediatric-Adjusted was determined using vital signs recorded upon arrival to the initial level of care. Patients were classified into two groups (normal vs. elevated SIPA) using age-specific threshold values. The need for blood product transfusion (BPT) within 24 hours and emergent surgical procedures (ESP) was compared between groups. Intensive care unit admission, injury severity, and mortality were also compared. Regression analysis was performed to evaluate the relationship between SIPA and primary outcomes. RESULTS: There were 2,121 patients included with a mean Injury Severity Score of 12 ± 10. The mechanism of injury was penetrating (63%), blunt (25%), and burns (12%). Patients with an elevated SIPA (43%) had a significantly greater need for BPT (49.2% vs. 25.0%) and ESP (22.9% vs. 16.0%), as well as mortality (10.3% vs. 4.8%) and intensive care unit admission (49.9% vs. 36.1%), all p less than 0.001. Regression analysis confirmed an elevated SIPA as independently associated with both BPT (odds ratio, 2.36; 95% confidence interval, 1.19-2.94; p < 0.001) and ESP (odds ratio, 1.29; 95% confidence interval, 1.01-1.64; p = 0.044). CONCLUSION: This is the first study of SIPA in pediatric warzone trauma. Elevated SIPA is associated with significantly increased need for BPT and emergent surgery and may therefore serve as a valuable tool for planning and triage in austere settings. LEVEL OF EVIDENCE: Prognostic/epidemiological, Level III.