Duhamel Versus Swenson Pull-Through for Total Colonic Aganglionosis: A Multi-Institutional Study.

BACKGROUND: Total colonic aganglionosis (TCA) is a rare variant of Hirschsprung disease (HD) where the colon and portion of distal ileum lack ganglion cells. Most pediatric use either a straight ileoanal (Swenson or Yancey-Soave) or a short Duhamel pull-through for TCA. There are no large studies comparing these techniques. We aimed to compare short-and medium-term outcomes between these approaches. METHOD: A retrospective review was performed among children with TCA from 2001 to 2019 undergoing a primary Duhamel or Swenson pull-through across three large children's hospitals. Patients undergoing redo and patients with greater than 30 % small bowel aganglionosis were excluded. We gathered data on demographics, operative approach, and outcomes at one, two, and three years. Continuous variables were analyzed with t-tests and categorical variables with Chi square or Fisher's tests. RESULTS: There were 54 patients, with 26 (48 %) undergoing Duhamel and 28 (52 %) undergoing Swenson pull-through. There were no differences in sex, age, medical comorbidities, or operative details, including age at pull-through, laparoscopic vs open, length of involved small bowel, and operative time. Length of stay and post-operative complications were not different. Three years after pull-through, patients undergoing Duhamel had fewer stools per day (1-3 stools 69.6 % vs 14.3 %, p = 0.003) and were less likely to be prescribed fiber supplementation (4.2 % vs 43.8 %, p = 0.003). There were no differences in irrigations, botulinum toxin administration, loperamide, or HD admissions. CONCLUSION: Both Duhamel and straight pull-throughs are safe for treatment of TCA, with acceptable short- and medium-term outcomes. Further studies on patient-reported outcomes are necessary to examine long-term differences. LEVEL OF EVIDENCE: III.

Synthetic augmentation of bilirubin metabolism in human pluripotent stem cell-derived liver organoids.

UGT1A1 (UDP glucuronosyltransferase family 1 member A1) is the primary enzyme required for bilirubin conjugation, which is essential for preventing hyperbilirubinemia. Animal models lack key human organic anion transporting polypeptides with distinct epigenetic control over bilirubin metabolism, necessitating a human model to interrogate the regulatory mechanism behind UGT1A1 function. Here, we use induced pluripotent stem cells to develop human liver organoids that can emulate conjugation failure phenotype. Bilirubin conjugation assays, chromatin immunoprecipitation, and transcriptome analysis elucidated the role of glucocorticoid antagonism in UGT1A1 activation. This antagonism prevents the binding of transcriptional repressor MECP2 at the expense of NRF2 with associated off-target effects. Therefore, we introduced functional GULO (L-gulonolactone oxidase) in human organoids to augment intracellular ascorbate for NRF2 reactivation. This engineered organoid conjugated more bilirubin and protected against hyperbilirubinemia when transplanted in immunosuppressed Crigler-Najjar syndrome rat model. Collectively, we demonstrate that our organoid system serves as a manipulatable model for interrogating hyperbilirubinemia and potential therapeutic development.

Fluorescent-guided surgery and the use of indocyanine green sentinel lymph node mapping in the pediatric and young adult oncology population.

BACKGROUND: Technetium-99 (99m Tc) lymphoscintigraphy with blue dye injection is an accepted method for sentinel lymph node (SLN) mapping, but blue dye has known adverse effects, and injection of 99m Tc may increase time under anesthesia for pediatric patients. Indocyanine green (ICG) may serve as an adjunct to assist with visibility and identification of SLNs. We hypothesized that sensitivity of ICG was similar to blue dye in SLN biopsies. METHODS: Thirty patients (36 procedures with 96 total specimens) underwent preoperative intradermal injection of 99m Tc, followed by intradermal injection of isosulfan blue and ICG. Test characteristics of blue dye, ICG, and 99m Tc included sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: ICG had a sensitivity of 87% and PPV of 83% for detection of 99m Tc-hot lymph nodes; blue dye had a sensitivity of 44% and PPV of 97%. For detection of pathologically confirmed lymph nodes, ICG had a sensitivity of 84% and a positive predictive value (PPV) of 91%. 99m Tc had a sensitivity of 82% and a PPV of 94%. ICG had no significant difference in odds of being positive in pathology-confirmed lymph nodes compared to 99m Tc (odds ratio [OR], 0.818; 95% confidence interval [CI], 0.3-2.172; p = .823) and had higher odds than isosulfan blue (OR, 0.025, 95% CI, 0.001-0.148; p < .001). CONCLUSION: This study established the efficacy of ICG as an adjunct to SLNB in the pediatric and young adult population. ICG was safe, more efficacious than blue dye, and may obviate the need for lymphoscintigraphy in selected patients resulting in reduced time under anesthesia.

Quality of Life Outcomes for Patients Who Underwent Conventional Resection and Liver Transplantation for Locally Advanced Hepatoblastoma.

Hepatoblastoma is the most common malignant liver tumor of childhood, with liver transplant and extended resection used as surgical treatments for locally advanced tumors. Although each approach has well-described post-operative complications, quality-of-life outcomes have not been described following the two interventions. Long-term pediatric survivors of hepatoblastoma who underwent conventional liver resection or liver transplantation at a single institution from January 2000-December 2013 were recruited to complete quality-of-life surveys. Survey responses for the Pediatric Quality of Life Generic Core 4.0 (PedsQL, n = 30 patient and n = 31 parent surveys) and Pediatric Quality of Life Cancer Module 3.0 (PedsQL-Cancer, n = 29 patient and n = 31 parent surveys) were collected from patients and parents. The mean total patient-reported PedsQL score was 73.7, and the parent-reported score was 73.9. There were no significant differences in scores on the PedsQL between patients who underwent resection compared to those who underwent transplantation (p > 0.05 for all comparisons). On the PedsQL-Cancer module, procedural anxiety scores were significantly lower for patients who underwent resection as compared to transplant (M = 33.47 points less, CI [-60.41, -6.53], p-value 0.017). This cross-sectional study demonstrates that quality of life outcomes are overall similar among patients receiving transplants and resections. Patients who received a resection reported worse procedural anxiety.

The national rate of malignancy among Bethesda III, IV, and V thyroid nodules is higher than expected: A NSQIP analysis.

BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology was formalized in 2007 to stratify cytologic specimens based on their risk of malignancy. Several studies have reported significant variations between their institutional rate of malignancy compared to the Bethesda System for Reporting Thyroid Cytopathology. The objective of this study was to determine the national rate of malignancy for Bethesda III, Bethesda IV, and Bethesda V thyroid nodules. METHODS: From 2016 to 2019, patients with preoperative thyroid cytopathology and pathology results in National Surgical Quality Improvement database were included. The rate of malignancy was compared to the median the Bethesda System for Reporting Thyroid Cytopathology 2017, and risk factors associated with malignancy were identified for Bethesda III, Bethesda IV, and Bethesda V specimens. RESULTS: In total, 13,121 patients with preoperative cytopathology and postresection pathology were identified. The national rate of malignancy was significantly higher than the Bethesda System for Reporting Thyroid Cytopathology 2017 for Bethesda III (36.2% vs 12.0%, P < .01), Bethesda IV (36.7% vs 25.0%, P < .01), and Bethesda V (91.1% vs 52.5%, P < .01) specimens. Male sex was significantly associated with malignancy in Bethesda III, Bethesda IV, and Bethesda V nodules (Bethesda III, odds ratio: 1.20, [1.01-1.42]; Bethesda IV, odds ratio: 1.47, [1.27-1.71]; Bethesda V, odds ratio: 1.28, [1.03-1.58]). Younger age was associated with malignancy in Bethesda III patients under 55 (odds ratio: 1.23, [1.06-1.42]), Bethesda IV patients under 42 (odds ratio: 1.23, [1.06-1.43]), and Bethesda V patients aged less than 47 (odds ratio: 1.38, [1.15-1.67]). CONCLUSIONS: This is the largest cohort study to describe the national rate of malignancy for Bethesda III, IV, and V specimens in the United States. These results reveal the national rate of malignancy is higher than the implied rate of malignancy reported to patients based on the Bethesda System for Reporting Thyroid Cytopathology. We recommend counseling patients regarding this increased rate of malignancy to set appropriate expectations after surgical intervention.

10 Year Analysis of Pediatric Surgery Fellowship Match and Operative Experience: Concerning Trends?

OBJECTIVE: This paper aims to evaluate the pediatric surgery training pipeline vis-à-vis the pediatric surgery match and operative experience of pediatric surgery fellows. SUMMARY OF BACKGROUND DATA: Pediatric surgery remains a competitive surgical subspecialty. However, there is concern that operative experience for pediatric surgery fellows is changing. This paper examines the selectivity of the pediatric surgery match, along with the operative experience of pediatric surgery fellows to characterize the state of pediatric surgery training. METHODS: The pediatric surgery fellowship match was analyzed from the National Resident Matching Program data from 2010 to 2019. Selectivity among fellowships was compared using analysis of variance with Dunnett test. Operative log data for pediatric fellows was analyzed using the Accreditation Council for Graduate Medical Education case logs from 2009 to 2019. Linear regression analysis was used to evaluate trends in operative volume over time. RESULTS: Pediatric surgery had the highest proportion of unmatched applicants (47.2% ± 5.3%) and lowest proportion of unfilled positions (1.4% ± 1.6%) when compared to other National Resident Matching Program surgical fellowships. Accreditation Council for Graduate Medical Education case log analysis revealed a statistically significant decrease in cases for graduating fellows (-5.3 cases/year, P < 0.05). Total index cases decreased (-4.7 cases/year, P < 0.01, R 2 = 0.83) such that graduates in 2019 completed 59 fewer index operations than graduates in 2009. CONCLUSION: Although pediatric surgery fellowship remains highly selective there has been a decline in the operative experience for graduating fellows. This highlights the need for evaluation of training paradigms and operative exposure in pediatric surgery to ensure the training of competent pediatric surgeons.

Thoracoscopy vs thoracotomy for the management of metastatic osteosarcoma: A Pediatric Surgical Oncology Research Collaborative Study.

Complete surgical resection of pulmonary metastatic disease in patients with osteosarcoma is crucial to long-term survival. Open thoracotomy allows palpation of nodules not identified on imaging but the impact on survival is unknown. The objective of this study was to compare overall survival (OS) and pulmonary disease-free survival (DFS) in children who underwent thoracotomy vs thoracoscopic surgery for pulmonary metastasectomy. A multi-institutional collaborative group retrospectively reviewed 202 pediatric patients with osteosarcoma who underwent pulmonary metastasectomy by thoracotomy (n = 154) or thoracoscopy (n = 48). Results were analyzed by Kaplan-Meier survival estimates and multivariate Cox proportional hazard regression models. With median follow-up of 45 months, 135 (67.5%) patients had a pulmonary relapse and 95 (47%) patients were deceased. Kaplan-Meier analysis showed no significant difference in 5-year pulmonary DFS (25% vs 38%; P = .18) or OS (49% vs 42%, P = .37) between the surgical approaches of thoracotomy and thoracoscopy. In Cox regression analysis controlling for other factors impacting outcome, there was a significantly increased risk of mortality (HR 2.11; P = .027; 95% CI 1.09-4.09) but not pulmonary recurrence (HR 0.96; P = .90; 95% CI 0.52-1.79) with a thoracoscopic approach. However, in the subset analysis limited to patients with oligometastatic disease, thoracoscopy had no increased risk of mortality (HR 1.16; P = .62; 0.64-2.11). In conclusion, patients with metastatic osteosarcoma and limited pulmonary disease burden demonstrate comparable outcomes after thoracotomy and thoracoscopy for metastasectomy. While significant selection bias in these surgical cohorts limits the generalizability of the conclusions, clinical equipoise for a randomized clinical trial in patients with oligometastatic disease is supported.

Catching the red eye: A retrospective review of factors associated with retinal hemorrhage in child physical abuse.

BACKGROUND/PURPOSE: Accurate identification of child physical abuse is crucial during the evaluation of injured children. Retinal hemorrhages (RH) are used for diagnosis, but clear criteria for screening with direct fundoscopic exam are lacking. We sought to identify key factors associated with RH to guide evaluations. METHODS: Electronic medical records for patients <1 year of age presenting to a Level I Pediatric Trauma Center with unwitnessed head injury from January 2015 to December 2018 were retrospectively reviewed. Multivariable logistic regression was used to identify factors associated with RH. RESULTS: Two hundred and seventy-six patients were included; 63% underwent direct fundoscopic examination, of which 23% were positive and 77% were negative for RH. Unscreened patients tended to be older and have isolated skull fractures. Multivariable regression analysis revealed that abnormal GCS and subdural hemorrhage were positively associated with a diagnosis of retinal hemorrhage, while isolated skull fracture was negatively associated. CONCLUSIONS: Children under 1 year of age with subdural hemorrhage have a greater risk of associated RH and should undergo routine screening with direct fundoscopic examination. Conversely, those with isolated skull fractures may not require an ophthalmology consultation. Standardized screening protocols may help reduce the risk of missing child physical abuse. LEVEL OF EVIDENCE: III (Diagnostic Test).

Characterizing Early Inpatient Death After Trauma.

BACKGROUND: There is a paucity of data to predict early death or futility after trauma. The objective of this study was to characterize the laboratory values, blood product administration, and hospital disposition for patients with trauma who died within 72 h of admission. METHODS: All deaths within 72 h of admission over a 5-y period at a level I trauma center were reviewed. Blood transfusion within the first 4 h of arrival and patient disposition from the emergency department to the operating room (OR), surgical intensive care unit, or the neuroscience intensive care unit (NSICU) were analyzed. Kaplan-Meier curves were generated to determine time to death. RESULTS: A total of 622 subjects were identified; 39.5% died in the emergency department, 10.6% went directly to the OR, 13.6% were admitted to the surgical intensive care unit, and 29.7% admitted to the NSICU. Of these subjects, 201 (32.2%) patients received blood within the first 4 h. By 24 h, early blood transfusion was associated with more rapid death for patients who were admitted to the NSICU (80% versus 60% mortality, P = 0.01) but not for patients taken directly to the OR (80% versus 70% mortality, P = 0.2). Admission coagulopathy by international normalized ratio (P < 0.01), but not anemia (P = 0.64) or acidosis (P = 0.45), correlated with a shorter time to death. In contrast, laboratory values obtained at 4 h after admission did not correlate with time to death. CONCLUSIONS: Our data demonstrate that admission coagulation derangement and need for early blood product transfusion are the two factors most associated with early death after injury, particularly in those patients with traumatic brain injury. These data will help construct future models for futility of continued care in patients with trauma.

Perinatal Lead (Pb) Exposure and Cortical Neuron-Specific DNA Methylation in Male Mice.

: Lead (Pb) exposure is associated with a wide range of neurological deficits. Environmental exposures may impact epigenetic changes, such as DNA methylation, and can affect neurodevelopmental outcomes over the life-course. Mating mice were obtained from a genetically invariant C57BL/6J background agouti viable yellow Avy strain. Virgin dams (a/a) were randomly assigned 0 ppm (control), 2.1 ppm (low), or 32 ppm (high) Pb-acetate water two weeks prior to mating with male mice (Avy/a), and this continued through weaning. At age 10 months, cortex neuronal nuclei were separated with NeuN⁺ antibodies in male mice to investigate neuron-specific genome-wide promoter DNA methylation using the Roche NimbleGen Mouse 3x720K CpG Island Promoter Array in nine pooled samples (three per dose). Several probes reached p-value < 10-5 , all of which were hypomethylated: 12 for high Pb (minimum false discovery rate (FDR) = 0.16, largest intensity ratio difference = -2.1) and 7 for low Pb (minimum FDR = 0.56, largest intensity ratio difference = -2.2). Consistent with previous results in bulk tissue, we observed a weak association between early-life exposure to Pb and DNA hypomethylation, with some affected genes related to neurodevelopment or cognitive function. Although these analyses were limited to males, data indicate that non-dividing cells such as neurons can be carriers of long-term epigenetic changes induced in development.

Does clinical improvement of symptomatic degenerative lumbar disease impact obesity?

OBJECTIVE Obesity and low-back pain associated with degenerative spondylosis or spondylolisthesis are common comorbid conditions. Many patients report that the pain and disability associated with degenerative lumbar disease are key factors in their inability to lose weight. The aim of this retrospective study was to determine if there is an association between improved functional status and weight loss following a successful transforaminal lumbar interbody fusion (TLIF) procedure. METHODS A retrospective cohort study of patients who underwent single-level TLIF was performed. Inclusion criteria were preoperative body mass index (BMI) greater than 30 kg/m2, achievement of minimum clinically important difference in the Oswestry Disability Index (ODI, defined as improvement of 15 points), and minimum 1-year postoperative followup BMI. Preoperative and postoperative BMI, ODI, and visual analog scale (VAS) scores were compared. A subgroup analysis of patients who achieved substantial clinical benefit (SCB, defined as a net improvement of 18.8 points on the ODI) was also performed. RESULTS A total of 56 patients met the inclusion criteria. The mean age of the study population was 55.6 ± 13.7 years. The mean preoperative BMI was 34.8 ± 4.6 kg/m2, the mean preoperative ODI was 66.2 ± 10.1, and the mean preoperative VAS score was 7.1 ± 1.7. The mean change in ODI was -33.1 ± 13.5 (p < 0.01) and the mean change in the VAS score was -4.1 ± 2.1 (p < 0.01). The mean change in BMI was +0.15 ± 2.1 kg/m2 (range -4.2 to +6.5 kg/m2; p = 0.6). SCB was achieved in 46 patients on the ODI. The mean preoperative BMI for patients with SCB was 34.8 ± 4.8 kg/m2, and the mean postoperative BMI was 34.7 ± 5.0 kg/m2. The mean change in BMI was -0.03 ± 1.9 kg/m2 (p = 0.9). CONCLUSIONS Despite successful surgical intervention via TLIF with achievement of improved function and pain, obese patients did not have significant change in weight postoperatively.

Multi-focal sequencing of a diffuse intrinsic pontine glioma establishes PTEN loss as an early event.

Improved molecular understanding is needed for rational treatment of diffuse intrinsic pontine gliomas (DIPG). Here, using multi-focal paired tumor and germline exome DNA and RNA sequencing, we uncovered phosphatase and tensin homolog (PTEN) loss as a clonal mutation in the case of a 6-year-old boy with a diffuse intrinsic pontine glioma, and incorporated copy number alteration analyses to provide a more detailed understanding of clonal evolution in diffuse intrinsic pontine gliomas. As well, using the PedcBioPortal, we found alterations in PTEN in 16 of 326 (4.9%) cases of pediatric high-grade glioma (3 of 154 (1.9%) brainstem) for which full sequencing data was available. Our data strengthens the association with PTEN loss in diffuse intrinsic pontine gliomas and provides further argument for the inclusion of PTEN in future targeted sequencing panels for pediatric diffuse intrinsic pontine gliomas and for the development and optimization of mTOR/PI3K inhibitors with optimal central nervous system penetration.

Associations of cumulative Pb exposure and longitudinal changes in Mini-Mental Status Exam scores, global cognition and domains of cognition: The VA Normative Aging Study.

BACKGROUND: Lead (Pb) exposure has been associated with poorer cognitive function cross-sectionally in aging adults, however the association between cumulative Pb exposure and longitudinal changes in cognition is little characterized. METHODS: In a 1993-2007 subcohort of the VA Normative Aging Study (Mini-mental status exam (MMSE) n=741; global cognition summary score n=715), we used linear mixed effects models to test associations between cumulative Pb exposure (patella or tibia bone Pb) and repeated measures of cognition (MMSE, individual cognitive tests, and global cognition summary). Cox proportional hazard modeling assessed the risk of an MMSE score falling below 25. RESULTS: Among men 51-98 at baseline, higher patella Pb concentration (IQR: 21µg/g) was associated with -0.13 lower baseline MMSE (95% CI: -0.25, -0.004) and faster longitudinal MMSE decline (-0.016 units/year, 95% CI: -0.032, -0.0004) over 15 years. Each IQR increase in patella Pb was associated with increased risk of a MMSE score below 25 (HR=1.21, 95% CI: 0.99, 1.49; p=0.07). There were no significant associations between Pb and global cognition (both baseline and longitudinal change). Patella Pb was associated with faster longitudinal decline in Word List Total Recall in the language domain (0.014 units/year, 95% CI: -0.026, -0.001) and Word List Delayed Recall in the memory domain (0.014 units/year, 95% CI: -0.027, -0.002). We found weaker associations with tibia Pb. CONCLUSIONS: Cumulative Pb exposure is associated with faster declines in MMSE and Word List Total and Delayed Recall tests. These findings support the hypothesis that Pb exposure accelerates cognitive aging.

Using the bias from flow to elucidate single DNA repair protein sliding and interactions with DNA.

We perform single-molecule spatial tracking measurements of a DNA repair protein, the C-terminal domain of Ada (C-Ada) from Escherichia coli, moving on DNA extended by flow. The trajectories of single proteins labeled with a fluorophore are constructed. We analyze single-protein dwell times on DNA for different flow rates and conclude that sliding (with essentially no hopping) is the mechanism of C-Ada motion along stretched DNA. We also analyze the trajectory results with a drift-diffusion Langevin equation approach to elucidate the influence of flow on the protein motion; systematic variation of the flow enables one to estimate the microscopic friction. We integrate the step-size probability distribution to obtain a version of the fluctuation theorem that articulates the relation between the entropy production and consumption under the adjustable drag (i.e., bias) from the flow. This expression allows validation of the Langevin equation description of the motion. Comparison of the rate of sliding with recent computer simulations of DNA repair suggests that C-Ada could conduct its repair function while moving at near the one-dimensional diffusion limit.