Congenital anomalies and predisposition to severe COVID-19 among pediatric patients in the United States.

BACKGROUND AND OBJECTIVE: Congenital heart defects are known to be associated with increased odds of severe COVID-19. Congenital anomalies affecting other body systems may also be associated with poor outcomes. This study is an exhaustive assessment of congenital anomalies and odds of severe COVID-19 in pediatric patients. METHODS: Data were retrieved from the COVID-19 dataset of Cerner® Real-World Data for encounters from March 2020 to February 2022. Prior to matching, the data consisted of 664,523 patients less than 18 years old and 927,805 corresponding encounters with COVID-19 from 117 health systems across the United States. One-to-one propensity score matching was performed, and a cumulative link mixed-effects model with random intercepts for health system and patients was built to assess corresponding associations. RESULTS: All congenital anomalies were associated with worse COVID-19 outcomes, with the strongest association observed for cardiovascular anomalies (odds ratio [OR], 3.84; 95% CI, 3.63-4.06) and the weakest association observed for anomalies affecting the eye/ear/face/neck (OR, 1.16; 95% CI, 1.03-1.31). CONCLUSIONS AND RELEVANCE: Congenital anomalies are associated with greater odds of experiencing severe symptoms of COVID-19. In addition to congenital heart defects, all other birth defects may increase the odds for more severe COVID-19. IMPACT: All congenital anomalies are associated with increased odds of severe COVID-19. This study is the largest and among the first to investigate birth defects across all body systems. The multicenter large data and analysis demonstrate the increased odds of severe COVID19 in pediatric patients with congenital anomalies affecting any body system. These data demonstrate that all children with birth defects are at increased odds of more severe COVID-19, not only those with heart defects. This should be taken into consideration when optimizing prevention and intervention resources within a hospital.

Center Volume and Survival Relationship for Neonates With Congenital Diaphragmatic Hernia Treated With Extracorporeal Life Support.

OBJECTIVES: Literature is emerging regarding the role of center volume as an independent variable contributing to improved outcomes. A higher volume of index procedures may be associated with decreased morbidity and mortality. This association has not been examined for the subgroup of infants with congenital diaphragmatic hernia (CDH) receiving extracorporeal life support (ECLS). Our study aims to examine the risk-adjusted association between center volume and outcomes in CDH-ECLS neonates, hypothesizing that higher center volume confers a survival advantage. DESIGN: Multicenter, retrospective comparative study using the Extracorporeal Life Support Organization database. SETTING: One hundred twenty international pediatric centers. PATIENTS: Neonates with CDH managed with ECLS from 2000 to 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The cohort included 4,985 neonates with a mortality rate of 50.6%. For the 120 centers studied, mean center volume was 42.4 ± 34.6 CDH ECLS cases over the 20-year study period. In an adjusted model, higher ECLS volume was associated with lower odds of mortality: odds ratio (OR) 0.995 (95% CI, 0.992-0.999; p = 0.014). For an increase in one sd in volume, that is, 1.75 cases annually, the OR for mortality was lower by 16.7%. Volume was examined as a categorical exposure variable where low-volume centers (fewer than 2 cases/yr) were associated with 54% higher odds of mortality (OR, 1.54; 95% CI, 1.03-2.29) compared with high-volume centers. On-ECLS complications (mechanical, neurologic, cardiac, hematologic metabolic, and renal) were not associated with volume. The likelihood of infectious complications was higher for low- (OR, 1.90; 95% CI, 1.06-3.40) and medium-volume (OR, 1.87; 95% CI, 1.03-3.39) compared with high-volume centers. CONCLUSIONS: In this study, a survival advantage directly proportional to center volume was observed for CDH patients managed with ECLS. There was no significant difference in most complication rates. Future studies should aim to identify factors contributing to the higher mortality and morbidity observed at low-volume centers.

A pilot study of multi-modal pain management for same-day discharge after minimally invasive repair of pectus excavatum (Nuss procedure) in children.

BACKGROUND: Despite advancements in minimally invasive repair of pectus excavatum (MIRPE), Nuss procedure, postoperative pain control remains challenging. This report covers a multimodal regimen using bilateral single-shot paravertebral block (PVB) and bilateral thoracoscopic intercostal nerve (T3-T7) cryoablation, leading to significant reduction in length of stay (LOS) and high rate of same-day discharge. METHODS: This is a comparative study of pain management protocols for patients undergoing the Nuss procedure at a single center from 2016 through 2020. All patients underwent the the same surgical technique for the treatment of pectus excavatum at a single center. Patients received bilateral PVB with continuous infusion (Group 1, n = 12), bilateral PVB with infusion and right-side cryoablation (Group 2, n = 9), or bilateral single-shot PVB and bilateral cryoablation (Group 3, n = 17). The primary outcome was LOS with focus on same-day discharge, and the secondary outcome was decreased opioid usage. RESULTS: Eleven of 17 patients in Group 3 (65%) (bilateral single-shot PVB and bilateral cryoablation) were discharged the same day as surgery. The remaining Group 3 patients were discharged the following day with no complications or interventions. Compared to Group 1 (no cryoablation), Group 3 had shorter LOS (median 4.4 days vs. 0.7 days, respectively, p < 0.001) and significantly decreased median opioid use on the day of surgery (0.92 mg/kg vs. 0.47 mg/kg, p = 0.006). CONCLUSION: Findings demonstrate the feasibility of multimodal pain management for same-day discharge after the Nuss procedure. Future multisite studies are needed to investigate the superiority of this approach to established methods. LEVEL OF EVIDENCE: III.

A Novel VACTERL Assessment Tool to Facilitate Counseling for Expectant Families.

INTRODUCTION: VACTERL is defined as 3 or more of the following congenital defects: vertebral, anorectal, cardiac, tracheoesophageal (TE), renal, and limb. The purpose of this study was to create an easy-to-use assessment tool to help providers counsel expecting families regarding the likelihood of additional anomalies and postnatal outcomes. METHODS: Employing the Kids' Inpatient Database from 2003-2016, neonates (<29 days old) with VACTERL were identified using ICD-9-CM and ICD-10-CM codes. For each unique combination of VACTERL, multivariable logistic regression was used to estimate inpatient mortality, and Poisson regression was used to estimate length-of-stay during the initial hospitalization. RESULTS: The assessment tool used in this study is available at https://choc-trauma.shinyapps.io/VACTERL. 1,886 of 11,813,782 (0.016%) neonates presented with VACTERL. 32% weighed <1,750 g, and 239 (12.7%) died prior to discharge. Associated with mortality were limb anomaly (1.8 [1.01-3.22], p < 0.05), prematurity (1.99 [1.14-3.47], p < 0.02), and weight <1,750 g (2.19 [1.25-3.82], p < 0.01). Median length-of-stay was 14 days (IQR: 7-32). Associated with increased length-of-stay were cardiac defect (1.47 [1.37-1.56], p < 0.001), vertebral anomaly (1.1 [1.05-1.14], p < 0.001), TE fistula (1.73 [1.66-1.81], p < 0.001), anorectal malformation (1.12 [1.07-1.16], p < 0.001), and weight <1,750 g (1.65 [1.57-1.73], p < 0.001). CONCLUSION: This novel assessment tool may help providers counsel families confronting a VACTERL diagnosis.

Inborn Versus Outborn Delivery in Neonates With Congenital Diaphragmatic Hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a morbid and potentially fatal condition that challenges providers. The aim of this study is to compare outcomes in neonates with prenatally diagnosed CDH that are inborn (delivered in the institution where definitive care for CDH is provided) versus outborn. METHODS: Prenatally diagnosed CDH cases were identified from the Congenital Diaphragmatic Hernia Study Group (CDHSG) database between 2007 and 2019. Using risk adjustment based on disease severity, we compared inborn versus outborn status using baseline risk and multivariable logistic regression models. The primary endpoint was mortality and the secondary endpoint was need for extracorporeal life support (ECLS). RESULTS: Of 4195 neonates with prenatally diagnosed CDH, 3087 (73.6%) were inborn and 1108 (26.4%) were outborn. There was no significant difference in birth weight, gestational age, or presence of additional congenital anomalies. There was no difference in mortality between inborn and outborn infants (32.6% versus 33.8%, P = 0.44) or ECLS requirement (30.9% versus 31.5%, P = 0.73). Among neonates requiring ECLS, outborn status was a risk factor for mortality (OR 1.51, 95% CI 1.13-2.01, P = 0.006). After adjusting for post-surgical defect size, which is not known prenatally, outborn status was no longer a risk factor for mortality for infants requiring ECLS. CONCLUSIONS: Risk of mortality and need for ECLS for inborn CDH patients is not different to outborn infants. Future studies should be directed to establishing whether highest risk infants are at risk for worse outcomes based on center of birth.

A Nested Mixed Effects Multicenter Model Examining the Risk Factors for Pediatric Trauma Return Visits Within 72 Hours.

BACKGROUND: Return visits within 72 h are an important metric in evaluating the performance of emergency rooms. This has not been well studied in the pediatric trauma population. We sought to determine novel risk factors for return visits to the emergency department (ED) after trauma that may assist in identifying patients most at risk of revisit. METHODS: We used the Cerner Health Facts Database to retrieve data from 34 EDs across the United States that care for pediatric trauma patients aged <15 y. The data consist of 610,845 patients and 816,571 ED encounters. We retrieved variables encompassing demographics, payor, current and past health care resource utilization, trauma diagnoses, other diagnoses/comorbidities, medications, and surgical procedures. We built a nested mixed effects logistic regression model to provide statistical inference on the return visits. RESULTS: Traumas resulting from burns and corrosion, injuries to the shoulder and arms, injuries to the hip and legs, and trauma to the head and neck are all associated with increased odds of returning to the ED. Patients suffering from poisoning relating to drugs and other biological substances and patients with trauma to multiple body regions have reduced odds of returning to the ED. Longer ED length of stay and prior health care utilization (ED or inpatient) are associated with increased odds of a return visit. The sex of the patient and payor had a statistically significant effect on the risk of a return visit to the ED within 72 h of discharge. CONCLUSIONS: Certain traumas expose patients to an increased risk for return visits to the ED and, as a result, provide opportunity for improved quality of care. Targeted interventions that include education, observation holds, or a decision to hospitalize instead of discharge home may help improve patient outcomes and decrease the rate of ED returns. LEVEL OF EVIDENCE: III (Prognostic and Epidemiology).

Analysis of Unintentional Falls in Pediatric Population and Predictors of Morbidity.

INTRODUCTION: Unintentional falls are a leading cause of pediatric traumatic injury. This study evaluates clinical outcomes of fall-related injuries in children under the age of 10. METHODS: The National Trauma Database was queried for children who experienced an unintentional fall. Patients were stratified by age in two groups: 1-5 and 6-10 years old. The primary outcome was post discharge extension of care, defined as transfer to skilled nursing facility or rehabilitation center after discharge from the hospital. Descriptive statistics and a multivariable logistic regression analysis were used to compare the two groups. RESULTS: From 2009 to 2016, a total of 8,277 pediatric patients experienced an unintentional fall, with 93.6% of patients being discharged home. Falls were more common in younger children, with greater odds of post discharge extension of care. Predictors of increased associated risk of extended medical care included intracranial hemorrhage (OR 1.05, 95% CI 1.03-1.06) and thoracic injuries (OR 1.03, 95% CI 1.00-1.1.05) (P< 0.05). Mortality in pediatric patients suffering unintentional falls was a rare event occurring in 0.7% of cases in children 1-5 years old and 0.4% of children 6-10 years old. CONCLUSION: The majority of children experiencing an unintentional fall are discharged home, with mortality being very rare. However, younger age is prone to more severe and serious injury patterns. Intracranial hemorrhage and thoracic injury were a predictor of need for extended medical care.

Risk Factors for Hemolysis During Extracorporeal Life Support for Congenital Diaphragmatic Hernia.

BACKGROUND: Neonates receiving extracorporeal life support (ECLS) for congenital diaphragmatic hernia (CDH) require prolonged support compared with neonates with other forms of respiratory failure. Hemolysis is a complication that can be seen during ECLS and can lead to renal failure and potentially to worse outcomes. The purpose of this study was to identify risk factors for the development of hemolysis in CDH patients treated with ECLS. METHODS: The Extracorporeal Life Support Organization database was used to identify infants with CDH (2000-2015). The primary outcome was hemolysis (plasma-free hemoglobin >50 mg/dL). Potentially associated variables were identified in the data set. Descriptive statistics and a series of nested multivariable logistic regression models were used to identify associations between hemolysis and demographic, pre-ECLS, and on-ECLS factors. RESULTS: There were 4576 infants with a mortality of 52.5%. The overall mean rate of hemolysis was 10.5% during the study period. In earlier years (2000-2005), the hemolysis rates were 6.3% and 52.7% for roller versus centrifugal pumps, whereas in later years (2010-2015), they were 2.9% and 26.5%, respectively. The fully adjusted model demonstrated that the use of centrifugal pumps was a strong predictor of hemolysis (odds ratio: 6.67, 95% confidence interval: 5.14-8.67). In addition, other risk factors for hemolysis included low 5-min Apgar score, on-ECLS complications (renal, metabolic, and cardiovascular), and duration of ECLS. CONCLUSIONS: In our cohort of CDH patients receiving ECLS over 15 y, the use of centrifugal pumps increased over time, along with the rate of hemolysis. Patient- and treatment-level risk factors were identified contributing to the development of hemolysis.

Effect of pump type on outcomes in neonates with congenital diaphragmatic hernia requiring ECMO.

PURPOSE: With the exception of neonatal respiratory failure, most centers are now using centrifugal over roller-type pumps for the delivery of extracorporeal membrane oxygenation (ECMO). Evidence supporting the use of centrifugal pumps specifically in infants with congenital diaphragmatic hernia (CDH) remains lacking. We hypothesized that the use of centrifugal pumps in infants with CDH would not affect mortality or rates of severe neurologic injury (SNI). METHODS: Infants with CDH were identified within the ELSO registry (2000-2016). Patients were then divided into those undergoing ECMO with rollertype pumps or centrifugal pumps. Patients were matched based on propensity score (PS) for the ECMO pump type based on pre-ECMO covariates. This was done for all infants and separately for each ECMO mode, venovenous (VV) and venoarterial (VA) ECMO. RESULTS: We identified 4,367 infants who were treated with either roller or centrifugal pumps from 2000-2016. There was no difference in mortality or SNI between the two pump types in any of the groups (all infants, VA-ECMO infants, VV-ECMO infants). However, there was at least a six-fold increase in the odds of hemolysis for centrifugal pumps in all groups: all infants (odds ratio [OR] 6.99, p<0.001), VA-ECMO infants (OR 8.11, p<0.001 and VV-ECMO infants (OR 9.66, p<0.001). CONCLUSION: For neonates with CDH requiring ECMO, there is no survival advantage or difference in severe neurologic injury between those receiving roller or centrifugal pump ECMO. However, there is a significant increase in red blood cell hemolysis associated with centrifugal ECMO support.

Foramen of Winslow hernia: a minimally invasive approach.

Hernias through the foramen of Winslow comprise 8 % of all internal hernias and the majority contain incarcerated bowel. Clinical signs are often non-specific and delay in diagnosis associated with a mortality rate that approaches 50 %. Management is urgent surgical reduction with bowel decompression and resection of devitalized bowel. A foramen of Winslow hernia (FWH) has traditionally been managed via an exploratory laparotomy incision and the vast majority of cases describe an open approach. We describe a minimally invasive approach to the management of an incarcerated FWH requiring decompression and bowel resection.

Racial Disparity among Youth Decedents of Legal Intervention Trauma.

BACKGROUND: Legal intervention trauma (LIT) is defined as injury due to any encounter with law enforcement. This study investigates associations between demographics, violent status, and law enforcement tactics among youth decedents of LIT. STUDY DESIGN: Decedents of LIT age 26 years or younger were identified using the CDC's National Violent Death Reporting System from 2003 to 2018. Decedents were classified as "violent" if they possessed a weapon, were committing a violent crime, or if law enforcement reported justified use of force. All others were classified as "nonviolent." Law enforcement tactics were stratified into "lethal" (firearm with standard ammunition) or "less lethal" (any other) force. Differences in the racial distribution across these classifications were assessed using chi-square tests of proportions. RESULTS: We identified 1,281 youth decedents of LIT; of which, 92.5% met violent criteria. Black youths were less likely than White youths to possess a weapon (71.6% vs 77.4%, p = 0.02) and were not more likely to be committing a violent crime (63.6% vs 60.4%, p = 0.27). They were, however, more likely than White youths to experience force reported as justified by law enforcement (89.9% vs 82.4%, p = 0.002) and to experience exclusively lethal force not preceded by less-lethal tactics (94.0% vs 88.7%, p = 0.001). Among the subset of 85 cases where law enforcement reported justified use of force despite the decedent not possessing a weapon or committing a violent crime, the precipitating event was more often a traffic stop for Black youths than for White youths (28.5% vs 6.66%, p = 0.02). CONCLUSIONS: These findings indicate a racial disparity among youth decedents of LIT.

Minorities struggle to advance in academic medicine: A 12-y review of diversity at the highest levels of America's teaching institutions.

BACKGROUND: Blacks, Hispanics, and women are underrepresented in academic medicine. This study sought to identify recent trends in the academic appointments of underrepresented groups at all levels of academic medicine. METHODS: This was a retrospective cross-sectional analysis of the Association of American Medical Colleges' data on faculty at U.S. medical schools from 1997 to 2008. The distribution across race and gender at different academic ranks (instructor, assistant professor, associate professor, and full professor) and the leadership positions of chairperson and dean were calculated for each year of the study. RESULTS: Averaged over the 12-y study period, whites accounted for 84.76% of professors, 88.26% of chairpersons, and 91.28% of deans. Asians represented 6.66% of professors, 3.52% of chairpersons, and 0% of deans. Blacks represented 1.25% of professors, 2.69% of chairpersons, and 4.94% of deans. Hispanics represented 2.76% of professors, 3.37% of chairpersons, and 2.91% of deans. Women represented 14.7% of professors, 9.2% of chairpersons, and 9.3% of deans. Overall, there was a net positive increase in the percentage of minority academic physicians in this study period, but at the current rate, it would take nearly 1000y for the proportion of black physicians to catch up to the percentage of African Americans in the general population. Additionally, year-by-year analysis demonstrates that there was a reduction in the percentage of each minority group for the last 2y of this study, in 2007 and 2008. CONCLUSIONS: Minorities, including Asian Americans, and women remain grossly underrepresented in academic medicine. Blacks have shown the least progress during this 12-y period. The disparity is greatest at the highest levels (professor, chairperson, and dean) of our field. We must redouble our efforts to recruit, retain, and advance minorities in academic medicine.

Can universal coverage eliminate health disparities? Reversal of disparate injury outcomes in elderly insured minorities.

BACKGROUND: Health outcome disparities in racial minorities are well documented. However, it is unknown whether such disparities exist among elderly injured patients. We hypothesized that such disparities might be reduced in the elderly owing to insurance coverage under Medicare. We investigated this issue by comparing the trauma outcomes in young and elderly patients in California. METHODS: A retrospective analysis of the California Office of Statewide Health Planning and Development hospital discharge database was performed for all publicly available years from 1995 to 2008. Trauma admissions were identified by International Classification of Disease, Ninth Revision, primary diagnosis codes from 800 to 959, with certain exclusions. Multivariate analysis examined the adjusted risk of in-hospital mortality in young (<65 y) and elderly (≥65 y) patients, controlling for age, gender, injury severity as measured by the survival risk ratio, Charlson comorbidity index, insurance status, calendar year, and teaching hospital status. RESULTS: A total of 1,577,323 trauma patients were identified. Among the young patients, the adjusted odds ratio of death relative to non-Hispanic whites for blacks, Hispanics, Asians, and Native Americans/others was 1.2, 1.2, 0.90, and 0.78, respectively. The corresponding adjusted odds ratios of death for elderly patients were 0.78, 0.87, 0.92, and 0.61. CONCLUSIONS: Young black and Hispanic trauma patients had greater mortality risks relative to non-Hispanic white patients. Interestingly, elderly black and Hispanic patients had lower mortality risks compared with non-Hispanic whites.

Demystifying sample-size calculation for clinical trials and comparative effectiveness research: the impact of low-event frequency in surgical clinical research.

BACKGROUND: Type II error, or not meeting sample-size requirement, has been identified as an issue in the surgical literature. The root of this problem is the low frequency of events in the majority of surgical clinical research. This exponentially increases the sample size needed to achieve statistical significance. METHODS: The methodology and mechanics of sample-size calculations are presented to demonstrate how sample-size requirements change based on baseline event rate and relative reduction in event rate. These concepts are then illustrated using real-life clinical scenarios. RESULTS: If a hypothetical baseline event rate is 1 % and the event rate in the experimental group is 0.5 % (therefore representing a 50 % reduction), then the total number of study patients required is 10,130. If the baseline event rate is 1 %, and the event rate in the experimental group is 0.9 % (a 10 % reduction), then the total number of study patients required is 299,410. CONCLUSIONS: Sample-size calculations are affected by the frequency of the event or events of interest. Given advances in clinical medicine, many clinical outcomes of interest occur at very low frequencies. These low frequencies exponentially increase the sample size required to find statistically significant differences, making randomized clinical trials difficult to conduct properly. Surgical clinical researchers should advocate for the establishment of robust, prospective, large, multi-institutional clinical databases along with the establishment of proper outcomes research methodology as a way to augment randomized trials.

Single-center comparison of outcomes between laparoscopic appendectomy and transumbilical laparoscopic assisted appendectomy.

PURPOSE: Appendectomy is the most common pediatric emergency surgery performed to date. This study compared outcomes between laparoscopic appendectomy (LA) and transumbilical laparoscopic assisted appendectomy (TULAA) for 1154 uncomplicated patients across 5 years at a single institution. Primary outcomes include length of stay (LOS), post-operative complications, pain score, and operating room (OR) time. METHODS: Demographic and clinical data was collected for 1154 eligible patients treated for uncomplicated appendicitis between August 2014-October 2019, with 830 patients in the LA group, and 324 in the TULAA group. Mixed effects modeling procedure using logistic and linear regression examined the effect of surgery type on the four primary outcomes after adjustment for potential clustering effect of surgeon and confounding factors. RESULTS: Of 1154 patients, 62.7% were male, and mean (SD) age was 10.9 (3.6) years. Median [IQR] LOS was 28.0 h [22.0, 36.0], mean (SD) OR time was 29.0 (10.0) minutes, and median [IQR] pain at maximum level was 5.5 (2.7). The complication rate overall was <5.0% and did not differ between TULAA and LA groups (p > 0.05). OR time was reduced by an average of 5.2 min in the TULAA group (p < 0.001), pain did not differ between groups overall (p > 0.05), and patients were more likely to be discharged within 24 h in patients who underwent TULAA (OR = 5.3 [1.6, 17.4], p = 0.007). CONCLUSION: Retrospective analysis of 1154 pediatric appendectomies, found no difference in complications between single- and three-incision laparoscopic procedures (TULAA vs. LA). Findings suggest TULAA is a safe procedure for acute appendicitis in pediatrics. LEVEL OF EVIDENCE: IV.

The RON-receptor regulates pancreatic cancer cell migration through phosphorylation-dependent breakdown of the hemidesmosome.

The recepteur d'origine nantais (RON) receptor tyrosine kinase is overexpressed and stimulates invasive growth in pancreatic cancer cells, yet the mechanisms that underlie RON-mediated phenotypes remain poorly characterized. To better understand RON function in pancreatic cancer cells, we sought to identify novel RON interactants using multidimensional protein identification analysis. These studies revealed plectin, a large protein of the spectrin superfamily, to be a novel RON interactant. Plectin is a multifunctional protein that complexes with integrin-ß4 (ITGB4) to form hemidesmosomes, serves as a scaffolding platform crucial to the function of numerous protein signaling pathways and was recently described as an overexpressed protein in pancreatic cancer (Bausch D et al., Clin Cancer Res 2010; Kelly et al., PLoS Med 2008;5:e85). In this study, we demonstrate that on exposure to its ligand, macrophage-stimulating protein, RON binds to plectin and ITGB4, which results in disruption of the plectin-ITGB4 interaction and enhanced cell migration, a phenotype that can be recapitulated by small hairpin ribosomal nucleic acid (shRNA)-mediated suppression of plectin expression. We demonstrate that disruption of plectin-ITGB4 is dependent on RON and phosphoinositide-3 (PI3) kinase, but not mitogen-activated protein kinase (MEK), activity. Thus, in pancreatic cancer cells, plectin and ITGB4 form hemidesmosomes which serve to anchor cells to the extracellular matrix (ECM) and restrain migration. The current study defines a novel interaction between RON and plectin, provides new insight into RON-mediated migration and further supports efforts to target RON kinase activity in pancreatic cancer.

Variation across centers in standardized mortality ratios for congenital diaphragmatic hernia receiving extracorporeal life support.

BACKGROUND: We sought to elucidate the degree of variation across centers by calculating center-specific standardized mortality ratios (SMRs) for infants with congenital diaphragmatic hernia (CDH) requiring extracorporeal life support (ECLS). METHODS: The Extracorporeal Life Support Organization (ELSO) registry data (2000-2019) were used to estimate SMRs. Center-specific SMRs and their 95% confidence intervals (CIs) were used to identify centers with mortality as significantly worse (SW), significantly better (SB), or not different (ND) relative to the median standardized mortality rate. RESULTS: We identified 4,223 neonates with CDH from 109 centers. SMRs were risk-adjusted for pre-ECLS case-mix (birthweight, sex, race, 5 min Apgar, blood gases, gestational age, hernia side, prenatal diagnosis, pre-ECLS arrest, and comorbidities). Observed (unadjusted) mortality rates across centers varied substantially (range: 14.3%-90.9%; interquartile range [IQR]: 42.9%-62.1%). Thirteen centers (11.9%) had SB SMRs< 1 (SMR 0.52 to 0.84), 7 centers (6.4%) had SW SMRs>1 (SMR 1.25 to 1.43), and 89 centers (81.7%) had SMRs ND relative to the median SMR rate across all centers (i.e., SMR not different from one). Descriptive analyses demonstrated that SB centers had a lower proportion of cases with renal complications, infectious complications and discontinuation of ECLS owing to complications, as well as differences in pre-ECLS treatments and timing of CDH repair, compared to SW and ND centers. CONCLUSION: This study specifically identified ECLS centers with higher and lower survival for patients with CDH, which may serve as a benchmark for institutional quality improvement. Future studies are needed to identify those specific processes at those centers that leads to favorable outcomes with the goal of improving care globally. LEVEL OF EVIDENCE: Level III.

Development and validation of machine learning models for the prediction of blunt cerebrovascular injury in children.

BACKGROUND: Blunt cerebrovascular injury (BCVI) is a rare finding in trauma patients. The previously validated BCVI (Denver and Memphis) prediction model in adult patients was shown to be inadequate as a screening option in injured children. We sought to improve the detection of BCVI by developing a prediction model specific to the pediatric population. METHODS: The National Trauma Databank (NTDB) was queried from 2007 to 2015. Test and training datasets of the total number of patients (885,100) with complete ICD data were used to build a random forest model predicting BCVI. All ICD features not used to define BCVI (2268) were included within the random forest model, a machine learning method. A random forest model of 1000 decision trees trying 7 variables at each node was applied to training data (50% of the dataset, 442,600 patients) and validated with test data in the remaining 50% of the dataset. In addition, Denver and Memphis model variables were re-validated and compared to our new model. RESULTS: A total of 885,100 pediatric patients were identified in the NTDB to have experienced blunt pediatric trauma, with 1,998 (0.2%) having a diagnosis of BCVI. Skull fractures (OR 1.004, 95% CI 1.003-1.004), extremity fractures (OR 1.001, 95% 1.0006-1.002), and vertebral injuries (OR 1.004, 95% CI 1.003-1.004) were associated with increased risk for BCVI. The BCVI prediction model identified 94.4% of BCVI patients and 76.1% of non-BCVI patients within the NTDB. This study identified ICD9/ICD10 codes with strong association to BCVI. The Denver and Memphis criteria were re-applied to NTDB data to compare validity and only correctly identified 13.4% of total BCVI patients and 99.1% of non BCVI patients. CONCLUSION: The prediction model developed in this study is able to better identify pediatric patients who should be screened with further imaging to identify BCVI. LEVEL OF EVIDENCE: Retrospective diagnostic study-level III evidence.

The role of race in pediatric legal intervention as a cause of injury.

BACKGROUND: Previous studies have assessed the prevalence and nature of traumatic injuries due to legal intervention in adults. The purpose of this study is to characterize and understand legal intervention trauma in children. METHODS: The National Trauma Data Bank (NTDB) was queried from 2007 to 2015. Patients (0-18 years old) who sustained injuries due to legal intervention were compared to those injured from other causes in the general NTDB population. Descriptive statistics were used to characterize the study population. Multivariate logistic regression models were utilized to predict firearm trauma and mortality. RESULTS: 622 patients sustained injuries involving legal intervention. Compared to general NTDB pediatric population, those who sustained legal intervention injuries were more likely to be older (age 16.5 vs. 10.6, p < 0.01), male (91.96% vs. 34.95%, p < 0.01), test positive for illegal drugs (64.64% vs. 38.35%, p < 0.01) or alcohol (26.36% vs. 17.25%, p < 0.01), and be African-American (44.37% vs. 17.00%, p < 0.01), Latino (22.82% vs. 15.10%, p < 0.01), or Native American (0.96% vs.. 0.94%, p < 0.01). Logistic regression models identified an 11% increased odds (95% CI 1.02-1.21, p = 0.02) of death among African-Americans when compared to other racial groups receiving legal intervention trauma. African-American status was associated with a 12% increased odds (95% CI 1.02-1.22, p = 0.01) of firearm trauma when compared to other racial groups receiving legal intervention trauma. CONCLUSION: Legal intervention-related pediatric trauma disproportionately affects the African-American population. This is particularly pronounced in cases of firearm related injuries. LEVEL OF EVIDENCE: III.

IGF1-R signals through the RON receptor to mediate pancreatic cancer cell migration.

The RON receptor tyrosine kinase (RTK) is overexpressed in the majority of pancreatic cancers, yet its role in pancreatic cancer cell biology remains to be clarified. Recent work in childhood sarcoma identified RON as a mediator of resistance to insulin-like growth factor receptor (IGF1-R)-directed therapy. To better understand RON function in pancreatic cancer cells, we sought to identify novel RON interactants. Using multidimensional protein identification analysis, IGF-1R was identified and confirmed to interact with RON in pancreatic cancer cell lines. IGF-1 induces rapid phosphorylation of RON, but RON signaling did not activate IGF-1R indicating unidirectional signaling between these RTKs. We next demonstrate that IGF-1 induces pancreatic cancer cell migration that is RON dependent, as inhibition of RON signaling by either shRNA-mediated RON knockdown or by a RON kinase inhibitor abrogated IGF-1 induced wound closure in a scratch assay. In pancreatic cancer cells, unlike childhood sarcoma, STAT-3, rather than RPS6, is activated in response to IGF-1, in a RON-dependent manner. The current study defines a novel interaction between RON and IGF-1R and taken together, these two studies demonstrate that RON is an important mediator of IGF1-R signaling and that this finding is consistent in both human epithelial and mesenchymal cancers. These findings demand additional investigation to determine if IGF-1R independent RON activation is associated with resistance to IGF-1R-directed therapies in vivo and to identify suitable biomarkers of activated RON signaling.