Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH individuals, including 1,064 child-parent trios and 6,133 ancestry-matched, unaffected controls for the genome-wide association study. We identify candidate CDH variants in 15 genes, including eight novel genes, through deleterious de novo variants. We further identify two genomic loci contributing to CDH risk through common variants with similar effect sizes among Europeans and Latinx. Both loci are in putative transcriptional regulatory regions of developmental patterning genes. Estimated heritability in common variants is ∼19%. Strikingly, there is no significant difference in estimated polygenic risk scores between isolated and complex CDH or between individuals harboring deleterious de novo variants and individuals without these variants. The data support a polygenic model as part of the CDH genetic architecture.

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.

Unintended Perioperative Hypothermia and Surgical Site Infection in Children.

INTRODUCTION: Unintended perioperative hypothermia is associated with surgical site infection (SSI) in adults, prompting exhaustive efforts to maintain perioperative normothermia. Although these efforts are also made for pediatric patients, the association between hypothermia and SSI has not been demonstrated in children. We sought to determine whether perioperative hypothermia and other risk factors and clinical outcomes are associated with SSI in the pediatric population. MATERIALS AND METHODS: This case-control study took place from January 2014 through December 2016 and included patients at a National Surgical Quality Improvement Program-participant academic children's hospital. All surgical patients were included in this retrospective analysis. SSI rates were determined. A univariate analysis was performed to determine clinical factors associated with SSI. A multivariate regression analysis was then performed to determine the predictive effect of minimum perioperative temperature for SSI. RESULTS: This study included 3541 patients, of which 92 (2.6%) developed SSI. A univariate analysis showed associations among SSI and higher perioperative temperatures, surgical specialty of otolaryngology and general surgery, and wound classification (American Society of Anesthesiologists [ASA] classification III and IV). A multivariate analysis determined the odds of SSI increased by a factor of 1.6 for every 1°C increase in minimum perioperative temperature. CONCLUSIONS: Unintended perioperative hypothermia in our pediatric patients was inversely associated with SSI. This finding suggests that pediatric SSI prevention may not require the efforts made for adult patients to maintain normothermia.

The Relationship Between Neonatal Surgery, Postpartum Depression, and Infant Clinical Course.

OBJECTIVE: Postpartum depression (PPD) affects 10-15% of mothers in the general population, and studies show increased incidence for mothers of infants with serious health conditions. This study investigates incidence of PPD in mothers of surgical patients in the neonatal intensive care unit (NICU) and characterizes these patients' clinical and neurodevelopmental outcomes. METHODS: This retrospective cohort study analyzed Nebraska's Tracking Infant Progress Statewide (TIPS) database and referring hospital medical records from February 2013 to June 2018. Upon NICU discharge, children were referred to the TIPS program, with scheduled follow-up appointments at approximately 6 months corrected age. All patients seen in NICU follow-up clinic with recorded scores for maternal Edinburgh postnatal depression screen (EPDS) were eligible except infants with congenital heart disease as this cohort was previously studied. Patients were stratified into groups based on presence or absence of a general surgical procedure within the first 6 months of life and positive (≥ 10) or negative (< 10) EPDS score. Statistical analyses assessed for significant differences between groups regarding gestational age, birth weight, maternal age, length of NICU stay (LOS), number of days on a ventilator, payment method, ethnicity, developmental testing, and rate of referral for early intervention services. RESULTS: Of 436 patients, 83 were surgical patients (16 with positive EPDS; 19.3% incidence), and 353 were non-surgical patients (44 with positive EPDS; 12.5% incidence). Statistical analysis showed no significant relationship between neonatal surgery and positive EPDS (χ2 = 2.6, p = 0.1). While the surgical cohort had longer LOS and days on ventilator, maternal EPDS did not predict these factors. In the surgical cohort, mothers of children not independent on oral feeding at discharge were more likely to screen positive for depression (7/14, 50% vs. 7/61, 11%; p < 0.05). CONCLUSION: Mothers of surgical patients are not significantly more likely to screen positive for post-partum depression compared to other NICU mothers. This underscores the importance of routine screening for PPD in mothers of both surgical and non-surgical NICU patients in order to identify parents and children at risk.

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.

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.

Intrusion Characteristics of Three Bone Cements for Tibial Component of Total Knee Arthroplasty in a Cadaveric Bone Model.

The purpose of this study was to evaluate and compare the intrusion characteristics of Simplex-HV to Simplex-P and Palacos-R in cadaveric proximal tibial bone. Eighteen fresh-frozen cadaver proximal tibiae were examined with standard arthroplasty tibial cuts. Each tibia was randomly assigned to receive one of the three bone cements for use with finger packing technique. Sagittal sections were prepared and analyzed using digital photography and stereoscopic micrographs to evaluate cement intrusion characteristics. The cement penetration depth was measured from the tibial bone cut surface, which did not include the cement thickness under the tibial base plate. Significant differences were detected in the bone cement penetration between the three cements. Penetration was increased using the Simplex-HV (average, 2.7 mm; range, 2.0-3.0 mm) compared with Simplex-P (average, 2.2 mm) and Palacos-R (average, 1.8 mm). These depths approximate to 3.7, 3.2, and 2.8 mm of total cement penetration, respectively. The data suggest that high-viscosity bone cement may provide good fixation of the tibial component of a total knee arthroplasty when using the finger packing technique.

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.

Comparative Analysis of Topical Versus Intravenous Administration of Epsilon-Aminocaproic Acid on Blood Management in Total Knee Arthroplasty.

Introduction: Although the use of antifibrinolytics to reduce perioperative blood loss during total knee arthroplasty (TKA) has shown unequivocal benefit in regard to blood conservation, the best route of administration remains in question. This study tested the hypothesis that topical delivery of epsilon-aminocaproic acid (EACA) was superior to intravenous (IV) administration in the setting of primary TKA. Methods: This cross-sectional study included a six-year retrospective chart review of TKA patients done by a single surgeon. Post-operative hemoglobin levels and the incidence of blood transfusions were compared among three patient subgroups: no EACA, topical EACA, or IV EACA. Key outcome measures included post-operative hemoglobin, need for post-operative transfusion, and length of hospital stay. Results: Of the 668 patients included in this study, 351 (52.5%) received IV EACA, 298 (44.6%) received topical EACA, and 19 (2.8%) received no EACA. For the three-way comparisons, significant differences were observed for post-operative mean hemoglobin on day one (p < 0.001), day two (p < 0.001), and day three (p = 0.004), with consistently higher means for participants in the topical group. Eight patients required transfusions in the IV EACA group, but none were needed in the topical EACA group (p = 0.027). Length of stay was shortest for patients in the topical group, with 66% hospitalized for two days, while 84% of the IV group remained hospitalized for three days (p < 0.001). Conclusions: The topical delivery of EACA is superior to IV administration with respect to blood conservation for patients undergoing primary TKA.

Operative management of urachal remnants: An NSQIP based study of postoperative complications.

PURPOSE: The identification of urachal remnants is occurring more in infancy. Despite evidence that nonoperative management is effective, operative management remains common and has a high complication rate. We sought to determine if the complication rate after urachal resection is associated with age. METHODS: Patients undergoing urachal remnant resection were identified from ACS NSQIP Pediatric from 2013 to 2017. Exclusion criteria included emergent operations, contaminated wounds, and any additional procedures. Patients were compared based on complication rates, need for reoperation or readmission, and length of stay. RESULTS: A complication occurred in 16 of 476 patients (3.3%), 6 (1.3%) had reoperation, and 11 (2.3%) were readmitted. The median age for patients requiring reoperation was lower (0.1 years) than those not (1.3 years; p = 0.004). The median age of those readmitted was lower (0.4 years) than those not (1.4 years, p = 0.03), and a weak trend of longer length of stay in younger patients was identified (ρ = -0.16, p < 0.001). CONCLUSIONS: Operative management of younger patients resulted in greater risk of reoperation, readmission, and longer length of stay. Given that nonoperative management is effective, it may be of benefit to delay resection of urachal remnants to after 1 year of age. STUDY TYPE: Treatment study. LEVEL OF EVIDENCE: Level III.

Exploring the gender gap: Letters of recommendation to pediatric surgery fellowship.

BACKGROUND: Letters of recommendation (LoR) are considered one of the most important predictors of matching into a pediatric surgery fellowship. We determined if gendered differences exist in LoR written for resident candidates. METHODS: A retrospective review of blinded LoR to a fellowship program between 2015 and 2017 was performed. RESULTS: Of the 364 LoR reviewed for 49 female and 48 male applicants, male surgeons wrote 82.5% of letters. Male LoR contained more agentic terms (p = 0. 042), first name occurrences (p = 0.0082) and phrase "future success" (p = 0.015). Female letters included more socio-communal phrases (p = 0. 010) and 5% referenced a spouse's accomplishments vs. 0% of male letters. Male LoR contained more active possessive language (p-0. 027); ie: "he published", "he presented". We found no difference in an applicant's research experience (p = 0.06) or leadership qualities (p = 0. 067). CONCLUSION: Gender differences exist in LoR written for fellowship applicants applying to a highly competitive subspecialty.

Comparative outcomes of right versus left congenital diaphragmatic hernia: A multicenter analysis.

BACKGROUND: Congenital diaphragmatic hernia (CDH) occurs in 1 out of 2500-3000 live births. Right-sided CDHs (R-CDHs) comprise 25% of all CDH cases, and data are conflicting on outcomes of these patients. The aim of our study was to compare outcomes in patients with right versus left CDH (L-CDH). METHODS: We analyzed a multicenter prospectively enrolled database to compare baseline characteristics and outcomes of neonates enrolled from January 2005 to January 2019 with R-CDH vs. L-CDH. RESULTS: A total of 588, 495 L-CDH, and 93 R-CDH patients with CDH were analyzed. L-CDHs were more frequently diagnosed prenatally (p=0.011). Lung-to-head ratio was similar in both cohorts. R-CDHs had a lower frequency of primary repair (p=0.022) and a higher frequency of need for oxygen at discharge (p=0.013). However, in a multivariate analysis, need for oxygen at discharge was no longer significantly different. There were no differences in long-term neurodevelopmental outcomes assessed at two year follow up. There was no difference in mortality, need for ECMO, pulmonary hypertension, or hernia recurrence. CONCLUSION: In this large series comparing R to L-CDH patients, we found no significant difference in mortality, use of ECMO, or pulmonary complications. Our study supports prior studies that R-CDHs are relatively larger and more often require a patch or muscle flap for repair. TYPE OF STUDY: Prognosis study LEVEL OF EVIDENCE: Level II.

Paint and wait management of giant omphaloceles.

Management of the very large defect or those in patients with severe comorbidities has evolved to the use of methods that result in escharification and eventual skin coverage over the viscera. This treatment strategy employs principles that were described in the early 20th century. This review will describe the history, principles, methods, and outcomes from the so called 'paint and wait' management of omphalocele.

Conservative management of urachal anomalies.

PURPOSE: The purpose of this study was to evaluate trends in management of urachal anomalies at our institution and the safety of nonoperative care. METHODS: Based on our experience managing urachal remnants from 2000 to 2010 (reported in 2012), we adopted a more conservative approach, including preoperative antibiotic use, refraining from using voiding cystourethrograms (VCUG), postponing surgery until at least six months of age, and considering nonoperative management. A retrospective analysis of urachal anomaly cases was conducted (2011-2016) to assess trends in practice. Charts indicating anomalies of the urachus were pulled and trends in management (nonoperative versus surgical treatment), VCUG and antibiotic use, and outcomes were reviewed. RESULTS: Data from 2000-2010 and 2013-2016 were compared. Our findings indicate care has shifted towards nonoperative management. A smaller proportion of patients from 2013-2016 was treated surgically compared to 2000-2010. Patients receiving nonoperative treatment exhibited lower rates of complication relative to surgically managed cases. VCUGs were eliminated as a diagnostic tool for evaluating urachal anomalies. Prophylactic preoperative antibiotic use was standardized. No patients with a known urachal remnant presented later with an abscess or sepsis. CONCLUSIONS: We find that a shift towards nonoperative treatment of urachal anomalies did not adversely affect overall outcomes. We recommend observing minimally symptomatic patients, especially those under six months old. STUDY TYPE: Performance improvement. LEVEL OF EVIDENCE: Level IV.

Comparison of short bowel syndrome acquired early in life and during adolescence.

BACKGROUND: Prolonged survival in pediatric patients with short bowel syndrome (SBS) is now possible because of parenteral nutrition and small bowel transplantation. We hypothesized that there may be important differences between adult patients who developed SBS during early childhood and those who develop this as adolescents. METHODS: Sixty-seven patients between the ages of 16 and 40 years were studied. Thirty patients developing SBS younger than 12 years comprised the pediatric group (PG), 37 developing SBS at age 13 to 25 constituted the adolescent group (AG). RESULTS: Midgut volvulus (n=11) was the most common cause in the PG followed by gastroschisis (n=5), intestinal atresia (n=5), and necrotizing enterocolitis (n=4). The most common cause of SBS in the AG was trauma (n=13), followed by tumors (n=7) and postoperative complications (n=5). A similar portion in each group had intestinal remnants less than 60 cm (69% vs. 58%), however, the PG was more likely to have a colon remnant (97% vs. 71%, P<0.05), and less likely to have an ostomy (7% vs. 47%, P<0.05). Patients in PG were followed significantly longer than AG (246+/-67 vs. 90+/-58 months, P<0.05). A similar portion of the patients require long-term parenteral nutrition (86% vs. 84%) or have undergone intestinal transplant (28% vs. 23%). Significantly more pediatric patients had negative height z scores when compared with the adolescents. CONCLUSIONS: Acknowledging the inherent biases created in defining the two groups, pediatric patients developing SBS early in life seem to be similar to those who develop SBS as adolescents with regards to long-term outcome, despite differences in origin and intestinal anatomy.

The Cost of Routine Follow-Up in Total Joint Arthroplasty and the Influence of These Visits on Treatment Plans.

INTRODUCTION: Many physicians recommend annual or biennial visits after total hip and knee arthroplasty (THA and TKA). This study sought to establish the cost of a post-operative visit to both the health care system and patient and identify if these visits altered patient management. METHODS: A prospective cohort study was conducted using patients presenting for follow-up after THA or TKA from April through December 2016. All surgeries were performed by a single orthopaedic surgeon in Wichita, Kansas. All eligible subjects that met the inclusion criteria received and completed a questionnaire about the personal cost of the visit and their assessment of their function and outcome after total joint arthroplasty. The physician also completed a questionnaire that examined the cost of the visit to the health care system and whether the clinical or radiographic findings altered patient management. RESULTS: Fifty-six patients participated with an average length of follow- up of 4.5 ± 4.1 years since surgery. The average patient cost was $135.20 ± $190.53 (range, $1.65 - $995.88), and the average visit time for the patient was 3.9 ± 2.9 hours. Eighty percent of patients reported no pain during the clinic encounter, and 11% reported loss of function. Eighty-four percent thought the visit was necessary. Physician time for each visit lasted 12.9 ± 3.7 minutes (range, 10 - 20 minutes). Only 9% of patient encounters resulted in an alteration in patient management. This occurred at an average follow-up time of 3.6 ± 1.8 years after the index procedure. The average cost of each visit to the health care system at large was $117.31 ± 60.53 (range, $93.90 - $428.28). CONCLUSIONS: The findings of this study advise total joint patients and orthopaedic surgeons regarding the cost of routine post-operative appointments and whether these visits alter patient management. The majority of the routine follow-up visits after THA and TKA did not result in an alteration in patient management, but added substantial cost to the health care system.

Does Surgical Volume Influence the Need for Second Surgery? A Pilot Study.

OBJECTIVE: To examine outcomes of pediatric thyroidectomy in the context of training background, institution, and experience of the surgeon. STUDY DESIGN: Case series with chart review. SETTING: A tertiary academic medical center and a pediatric hospital. SUBJECTS AND METHODS: Eighty-one thyroidectomy patients younger than 18 years. Outcomes were major complications (recurrent laryngeal nerve injury, permanent hypocalcemia, and wound infection), length of stay (LOS), and need for repeat surgery. RESULTS: Eighty-one patients, 39 from the University of Nebraska Medical Center and 42 from the Children's Hospital and Medical Center-Omaha, were identified over a 12-year time period. No difference was found in surgeon training (otolaryngology/head and neck surgery vs general/pediatric surgery) for complications (1 vs 1, odds ratio [OR] = 0.76, 95% confidence interval [CI] = [0.05, 13.1]), LOS >1 day (5 vs 13, OR = 0.39, 95% CI = [0.13, 1.24]), or need for second surgery (4 vs 7, OR = 1.47, 95% CI = [0.39, 5.49]). Higher surgeon volume (≥12 surgeries) was found to be significant for decreased need for second surgery (3 vs 8, OR = 6.67, 95% CI = [1.57, 27.17]). Patients of higher-volume surgeons were 4.2 times more likely to stay in the hospital 1 day or less compared with those patients operated on by surgeons with less experience (7 vs 11, 95% CI = [1.59, 15.0]). CONCLUSIONS: Need for second surgery in pediatric thyroidectomy may be predicted by surgical volume.

Mutations in BMPR2 are not present in patients with pulmonary hypertension associated with congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a prevalent major congenital anomaly with significant morbidity and mortality. Thirty to 40% mortality in CDH is largely attributed to pulmonary hypoplasia and pulmonary hypertension (PH). We hypothesized that the underlying genetic risk factors for hereditary PH are shared with CDH associated PH. METHODS: Participants were recruited as part of the Diaphragmatic Hernia Research & Exploration; Advancing Molecular Science (DHREAMS) study, a prospective cohort of neonates with a diaphragmatic defect enrolled from 2005 to 2012. PH affected patients with available DNA for sequencing had one of the following: moderate or severe PH on echocardiography at 3months of age; moderate of severe PH at 1month of age with death occurring prior to the 3month echocardiogram; or on PH medications at 1month of age. We sequenced the coding regions of the hereditary PH genes bone morphogenetic protein receptor type II (BMPR2), caveolin 1 (CAV1) and potassium channel subfamily K, member 3 (KCNK3) to screen for mutations. RESULTS: There were 29 CDH patients with PH including 16 males and 13 females. Sequencing of BMPR2, CAV1, and KCNK3 coding regions did not identify any pathogenic variants in these genes. TYPE OF STUDY: Prognosis study LEVEL OF EVIDENCE: Level IV.

Global Outreach Using a Systematic, Competency-Based Training Paradigm for Inguinal Hernioplasty.

Importance: Sustainable, capacity-building educational collaborations are essential to address the global burden of surgical disease. Objective: To assess an international, competency-based training paradigm for hernia surgery in underserved countries. Design, Setting, and Participants: In this prospective, observational study performed from November 1, 2013, through October 31, 2015, at 16 hospitals in Brazil, Ecuador, Haiti, Paraguay, and the Dominican Republic, surgeons completed initial training programs in hernia repair, underwent interval proficiency assessments, and were appointed regional trainers. Competency-based evaluations of technical proficiency were performed using the Operative Performance Rating Scale (OPRS). Maintenance of proficiency was evaluated by video assessments 6 months after training. Certified trainees received incentives to document independent surgical outcomes after training. Main Outcomes and Measures: An OPRS score of 3.0 (scale of 1 [poor] to 5 [excellent]) indicated proficiency. Secondary outcomes included initial vs final scores by country, scores among surgeons trained by the regional trainers (second-order trainees), interval scores 6 months after training, and postoperative complications. Results: A total of 20 surgeon trainers, 81 local surgeons, and 364 patients (343 adult, 21 pediatric) participated in the study (mean [SD] age, 47.5 [16.3] years; age range, 16-83 years). All 81 surgeons successfully completed the program, and all 364 patients received successful operations. Mean (SD) OPRS scores improved from 4.06 (0.87) before the initial training program to 4.52 (0.57) after training (P < .001). No significant variation was found by country in final scores. On trainee certification, 20 became regional trainers. The mean (SD) OPRS score among 53 second-order trainees was 4.34 (0.68). After 6-month intervals, the mean (SD) OPRS score among participating surgeons was 4.34 (0.55). The overall operative complication rate during training series was 1.1%. Conclusions and Relevance: Competency-based training helps address the global burden of surgical disease. The OPRS establishes an international standard of technical assessment. Additional studies of long-term surgeon trainer proficiency, community-specific quality initiatives, and expansion to other operations are warranted.