Surgical management of complicated Crohn's disease.

Surgical management of pediatric Crohn's disease is fundamentally palliative, aiming to treat the sequalae of complicated disease while preserving intestinal length. Multidisciplinary discussion of risk factors and quality of life should take place prior to operative intervention. Though the surgical management of pediatric Crohn's disease is largely based on the adult literature, there are considerations specific to the pediatric population - notably disease and treatment effects on growth and development. Intrabdominal abscess is approached with percutaneous drainage when feasible, reserving surgical intervention for the patient who is unstable or failing medical therapy. Pediatric patients with fibrostenotic disease should be considered for strictureplasty when possible, for maximum preservation of bowel length. Patients with medically refractory Crohn's proctocolitis should be treated initially with fecal diversion without proctocolectomy.

In utero delivery of miRNA induces epigenetic alterations and corrects pulmonary pathology in congenital diaphragmatic hernia.

Structural fetal diseases, such as congenital diaphragmatic hernia (CDH) can be diagnosed prenatally. Neonates with CDH are healthy in utero as gas exchange is managed by the placenta, but impaired lung function results in critical illness from the time a baby takes its first breath. MicroRNA (miR) 200b and its downstream targets in the TGF-ß pathway are critically involved in lung branching morphogenesis. Here, we characterize the expression of miR200b and the TGF-ß pathway at different gestational times using a rat model of CDH. Fetal rats with CDH are deficient in miR200b at gestational day 18. We demonstrate that novel polymeric nanoparticles loaded with miR200b, delivered in utero via vitelline vein injection to fetal rats with CDH results in changes in the TGF-ß pathway as measured by qRT-PCR; these epigenetic changes improve lung size and lung morphology, and lead to favorable pulmonary vascular remodeling on histology. This is the first demonstration of in utero epigenetic therapy to improve lung growth and development in a pre-clinical model. With refinement, this technique could be applied to fetal cases of CDH or other forms of impaired lung development in a minimally invasive fashion.

Clinical Practices Following Train-The-Trainer Trauma Course Completion in Uganda: A Parallel-Convergent Mixed-Methods Study.

BACKGROUND: Despite the growth of trauma training courses worldwide, evidence for their impact on clinical practice in low- and middle-income countries (LMICs) is sparse. We investigated trauma practices by trained providers in Uganda using clinical observation, surveys, and interviews. METHODS: Ugandan providers participated in the Kampala Advanced Trauma Course (KATC) from 2018 to 2019. Between July and September of 2019, we directly evaluated guideline-concordant behaviors in KATC-exposed facilities using a structured real-time observation tool. We conducted 27 semi-structured interviews with course-trained providers to elucidate experiences of trauma care and factors that impact adoption of guideline-concordant behaviors. We assessed perceptions of trauma resource availability through a validated survey. RESULTS: Of 23 resuscitations, 83% were managed without course-trained providers. Frontline providers inconsistently performed universally applicable assessments: pulse checks (61%), pulse oximetry (39%), lung auscultation (52%), blood pressure (65%), pupil examination (52%). We did not observe skill transference between trained and untrained providers. In interviews, respondents found KATC personally transformative but not sufficient for facility-wide improvement due to issues with retention, lack of trained peers, and resource shortages. Resource perception surveys similarly demonstrated profound resource shortages and variation across facilities. CONCLUSIONS: Trained providers view short-term trauma training interventions positively, but these courses may lack long-term impact due to barriers to adopting best practices. Trauma courses should include more frontline providers, target skill transference and retention, and increase the proportion of trained providers at each facility to promote communities of practice. Essential supplies and infrastructure in facilities must be consistent for providers to practice what they have learned.

Improving Surgical Research Capacity in Low- and Middle-Income Countries: Can Episodic Data Collection Reliably Estimate Perioperative Mortality?

OBJECTIVE: The aim of this study was to empirically determine the optimal sample size needed to reliably estimate perioperative mortality (POMR) in different contexts. SUMMARY BACKGROUND DATA: POMR is a key metric for measuring the quality and safety of surgical systems and will need to be tracked as surgical care is scaled up globally. Continuous collection of outcomes for all surgical cases is not the standard in high-income countries and may not be necessary in low- and middle-income countries. METHODS: We created simulated datasets to determine the sampling frame needed to reach a given precision. We validated our findings using data collected at Mulago National Referral Hospital in Kampala, Uganda. We used these data to create a tool that can be used to determine the optimal sampling frame for a population based on POMR rate and target POMR improvement goal. RESULTS: Precision improved as the sampling frame increased. However, as POMR increased, lower sampling percentages were needed to achieve a given precision. A total of 357 eligible cases were identified in the Mulago database with an overall POMR rate of 14%. Precision of ±10% was achieved with 34% sampling, and precision of ±25% was obtained at 9% sampling. Using simulated datasets, a tool was created to determine the minimum sample percentage needed to detect a given mortality improvement goal. CONCLUSIONS: Reliably tracking POMR does not require continuous data collection. Data driven sampling strategies can be used to decrease the burden of data collection to track POMR in resource-constrained settings.

Intra-amniotic Injection of Poly(lactic-co-glycolic Acid) Microparticles Loaded with Growth Factor: Effect on Tissue Coverage and Cellular Apoptosis in the Rat Model of Myelomeningocele.

BACKGROUND: Myelomeningocele (MMC) is a devastating congenital neurologic disorder that can lead to lifelong morbidity and has limited treatment options. This study investigates the use of poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) loaded with fibroblast growth factor (FGF) as a platform for in utero treatment of MMC. STUDY DESIGN: Intra-amniotic injections of PLGA MPs were performed on gestational day 17 (E17) in all-trans retinoic acid-induced MMC rat dams. MPs loaded with fluorescent dye (DiO) were evaluated 3 hours after injection to determine incidence of binding to the MMC defect. Fetuses were then treated with PBS or PLGA particles loaded with DiO, bovine serum albumin, or FGF and evaluated at term (E21). Fetuses with MMC defects were evaluated for gross and histologic evidence of soft tissue coverage. The effect of PLGA-FGF treatment on spinal cord cell death was evaluated using an in situ cell death kit. RESULTS: PLGA-DiO MPs had a binding incidence of 86% and 94% 3 hours after injection at E17 for doses of 0.1 mg and 1.2 mg, respectively. Incidence of soft tissue coverage at term was 19% (4 of 21), 22% (2 of 9), and 83% (5 of 6) for PLGA-DiO, PLGA-BSA, and PLGA-FGF, respectively. At E21, the percentage of spinal cord cells positive for in situ cell death was significantly higher in MMC controls compared with wild-type controls or MMC pups treated with PLGA-FGF. CONCLUSION: PLGA MPs are an innovative minimally invasive platform for induction of soft tissue coverage in the rat model of MMC and may reduce cellular apoptosis.

Financing Pediatric Surgery: A Provider's Perspective from the Global Initiative for Children's Surgery.

BACKGROUND: Half the world's population is at risk of catastrophic health expenditure (CHE, out-of-pocket spending of more than 10% of annual expenditure) should they require surgery. Protection against CHE is a key indicator of successful health care delivery and has been identified as a priority area by the Global Initiative for Children's Surgery (GICS). Data specific to pediatric surgical patients is limited. This study examines the financial risks for pediatric surgical patients and their families from a provider's perspective. METHODS: We surveyed GICS members about the existing financial protection mechanisms and estimated expenditures for their patients. Questions were structured based on the National Surgical, Obstetric and Anesthesia Planning Surgical Indicators and finalized based on multi-institutional consensus between high-income country and low-and middle-income country (LMIC) providers. Chi-squared test, Fisher's exact test and student's t-test were used as appropriate. RESULTS: Among 107 respondents, 72.4% were from low income or lower-middle income (LIC/LMIC) countries, and 55.1% were attending or consultant physicians. Families were most likely to decline surgery in LIC/LMIC due to inability to afford treatment (mean Likert = 3.77 ± 1.06). The odds of incurring CHE after children's surgery are up to 17 times greater in LIC/LMIC (P = 0.001, unadjusted OR 17.28, 95%CI 2.13-140.02). Over 50% of families of children undergoing major surgery in these settings face CHE. An estimated 5.1% of providers in LIC/LMIC and 56.2% (P < 0.001) of providers in UMIC/HIC reported that families are able to pay for their direct medical costs with the assistance available to them and were more likely to sell assets (74.4% vs. 33.3%, P = 0.005). CONCLUSION: Patients in LMICs are at greater risk for CHE and have less financial risk protection than their HIC counterparts. Given this disparity, intervention is needed to make safe surgery affordable for children worldwide.

Pediatric surgical quality improvement in low- and middle-income countries: What data to collect?

BACKGROUND: As surgical access expands in low- and middle-income countries, risk-adjusted outcomes data are needed to measure and improve surgical quality. Existing data collection tools in high-income countries are complex and may be burdensome to implement in low and middle income countries. This study determined the minimum dataset needed for adequate risk adjustment to predict perioperative mortality using data collected in a low- and middle-income countries. METHODS: All patients admitted to the pediatric surgery ward at Mulago National Referral Hospital in Kampala, Uganda, from January 1, 2014 through December 31, 2018 were included. Studies were performed modelling the effects of reducing data granularity and reducing number of variables on the area under the receiver operating curve. RESULTS: Of the 3,194 patients included, 1,941(61%) were male, 957(30%) were neonates, 1,714 (54%) had an operation, and the overall mortality rate was 14%. Granularity reduction analyses found that measuring age in ranges was equivalent to recording age in days (area under the receiver operating curve = 0.776; 95% confidence interval, 0.754%-0.798%, vs 0.815, 95% confidence interval, 0.794%-0.837%). Variable reduction analyses found that models with 3 predictor variables (diagnosis, procedure, and district) reached a maximum area under the receiver operating curve of 0.915 (95% confidence interval, 0.903%-0.928%), which was equivalent to the model using all available predictor variables (area under the receiver operating curve = 0.932; 95% confidence interval, 0.922%-0.943%). For all 3-variable models, the primary diagnosis contributed most to predictive ability (P < .001). CONCLUSION: Effective risk adjustment for perioperative mortality can be performed in low and middle income countries using minimal, objective variables often already part of the patient's medical record. This approach can be used by clinicians, hospital administrators, and policymakers low- and middle-income countries looking to begin data collection to track and improve patient outcomes.

Engineering alginate microparticles for optimized accumulation in fetal rat myelomeningocele.

INTRODUCTION: Intraamniotic microparticle injection is a novel technique for the treatment of myelomeningocele (MMC) in which microparticles are delivered in-utero in a minimally invasive fashion to bind to and protect the exposed spinal cord. This technique could offer earlier intervention and greater access to prenatal treatment of MMC. Here we demonstrate progress on the engineering of the microparticles to promote binding to the MMC defect. We hypothesized that when the particle's surface charge was decreased and delivery concentration increased, particles would bind to the MMC defect more frequently and more specifically. METHODS: Alginate microparticles underwent surface modification to alter the particle charge. Dye-loaded alginate, alginate- dextran sulfate, and alginate- chitosan were injected on e17 into the amnion of a rat model of MMC and the incidence of successful binding and specificity of particle binding to the MMC defect were calculated. Specificity of binding was described using a defect-to-skin brightness ratio based on specimen imaging. Comparisons were made with chi-square, p< 0.05 marked significance. RESULTS: There was no difference in the incidence of successful binding at e17 with 0.6 mg/fetal kg between the three tested alginate particles. However, alginate- dextran sulfate bound most specifically to the defect (p< 0.05). Alginate-dextran sulfate also demonstrated more frequent binding at higher doses than lower doses (79% at 1.2 mg/kg vs 38% at 0.6 mg/kg and 24% at 0.8 mg/kg, p< 0.01 for both). Specificity was not sacrificed at higher dose injections: defect-to-skin brightness ratio of 5.4 at 1.2 mg/kg vs 1.8 at 0.6 mg/kg (p< 0.05) CONCLUSION: We demonstrate that the intraamniotic injection of alginate-dextran sulfate microparticles at high concentration bind more frequently and more specifically to MMC defects than the previously tested unmodified alginate microparticles.

A narrative review of in utero gene therapy: advances, challenges, and future considerations.

The field of in utero gene therapy (IUGT) represents a crossroad of technologic advancements and medical ethical boundaries. Several strategies have been developed for IUGT focusing on either modifying endogenous genes, replacing missing genes, or modifying gene transcription products. The list of candidate diseases such as hemoglobinopathies, cystic fibrosis, lysosomal storage disorders continues to grow with new strategies being developed as our understanding of their respective underlying molecular pathogenesis increases. Treatment in utero has several distinct advantages to postnatal treatment. Biologic and physiologic phenomena enable the delivery of a higher effective dose, generation of immune tolerance, and the prevention of phenotypic onset for genetic diseases. Therapeutic technology for IUGT including CRISPR-Cas9 systems, zinc finger nucleases (ZFN), and peptide nucleic acids (PNAs) has already shown promise in animal models and early postnatal clinical trials. While the ability to detect fetal diagnoses has dramatically improved with developments in ultrasound and next-generation sequencing, treatment options remain experimental, with several translational gaps remaining prior to implementation in the clinical realm. Complicating this issue, the potential diseases targeted by this approach are often debilitating and would otherwise prove fatal if not treated in some manner. The leap from small animals to large animals, and subsequently, to humans will require further vigorous testing of safety and efficacy.

Nanoparticles for delivery of agents to fetal lungs.

Fetal treatment of congenital lung disease, such as cystic fibrosis, surfactant protein syndromes, and congenital diaphragmatic hernia, has been made possible by improvements in prenatal diagnostic and interventional technology. Delivery of therapeutic agents to fetal lungs in nanoparticles improves cellular uptake. The efficacy and safety of nanoparticle-based fetal lung therapy depends on targeting of necessary cell populations. This study aimed to determine the relative distribution of nanoparticles of a variety of compositions and sizes in the lungs of fetal mice delivered through intravenous and intra-amniotic routes. Intravenous delivery of particles was more effective than intra-amniotic delivery for epithelial, endothelial and hematopoietic cells in the fetal lung. The most effective targeting of lung tissue was with 250nm Poly-Amine-co-Ester (PACE) particles accumulating in 50% and 44% of epithelial and endothelial cells. This study demonstrated that route of delivery and particle composition impacts relative cellular uptake in fetal lung, which will inform future studies in particle-based fetal therapy.

Pulmonary Metastasis of Low-risk Perinatal Neuroblastoma After Resection: Implications for Surveillance.

In the wake of the Children's Oncology Group (COG) ANBL00P2 trial and the ongoing ANBL1232 trial, an increasing number of children with neonatal neuroblastoma are being managed nonoperatively. We report the case of a patient with low-risk, non-MYCN amplified, neuroblastoma that was diagnosed and resected in the neonatal period but subsequently developed pulmonary metastases by the age of 7 months. Though rare, the possibility of low-risk disease metastasizing during surveillance should be recognized and may not be identified by current protocols.

Development of an Operative Trauma Course in Uganda-A Report of a Three-Year Experience.

BACKGROUND: Trauma is a leading cause of morbidity and mortality in low-income countries. Improved health care systems and training are potential avenues to combat this burden. We detail a collaborative and context-specific operative trauma course taught to postgraduate surgical trainees practicing in a low-resource setting and examine its effect on resident practice. METHOD: Three classes of second year surgical residents participated in trainings from 2017 to 2019. The course was developed and taught in conjunction with local faculty. The most recent cohort logged cases before and after the course to assess resources used during initial patient evaluation and operative techniques used if the patient was taken to theater. RESULTS: Over the study period, 52 residents participated in the course. Eighteen participated in the case log study and logged 117 cases. There was no statistically significant difference in patient demographics or injury severity precourse and postcourse. Postcourse, penetrating injuries were reported less frequently (40 to 21% P < 0.05) and road traffic crashes were reported more frequently (39 to 60%, P < 0.05). There was no change in the use of bedside interventions or diagnostic imaging, besides head CT. Of patients taken for a laparotomy, there was a nonstatistically significant increase in the use of four-quadrant packing 3.4 to 21.7%) and a decrease in liver repair (20.7 to 4.3%). CONCLUSIONS: The course did not change resource utilization; however, it did influence clinical decision-making and operative techniques used during laparotomy. Additional research is indicated to evaluate sustained changes in practice patterns and clinical outcomes after operative skills training.

Burden and Outcomes of Neonatal Surgery in Uganda: Results of a Five-Year Prospective Study.

BACKGROUND: Ninety-four percent of congenital anomalies occur in low- and middle-income countries. In Uganda, only three pediatric surgeons and three pediatric anesthesiologists serve more than 20 million children. This study estimates burden, outcomes, coverage, and economic benefit of neonatal surgical conditions in Uganda. METHODS: A prospectively collected database was reviewed for neonatal surgical admissions from January 1, 2012, to December 31, 2017, at the only two sites with specialist pediatric surgical coverage. Outcomes were compared with high-income countries. Met and unmet need were estimated using disability-adjusted life years. Economic benefit was estimated using a value of statistical life-year approach. RESULTS: For 1313 neonatal admissions, the median age of presentation was 3 d, overall mortality was 36%, and median distance traveled was 40 km. Anorectal malformations were most common (18%). Postoperative mortality was 24%. Mortality was significantly associated with surgical intervention (P < 0.0001). Met need was 4181 disability-adjusted life years per year, which corresponds to a $3.5 million net economic benefit to Uganda, with a potential additional benefit of $153 million if unmet need were fully addressed. Approximately 2% of the total need is met by the health care system. CONCLUSIONS: Neonatal surgery is associated with improved survival for most conditions. Despite increases in workforce and infrastructure, a limited proportion of the need for neonatal surgery is currently being met. This is multifactorial, including lack of access to surgical care and severe shortages of workforce and infrastructure. Current and potential economic benefit to Uganda appears substantial.

Design, implementation and long-term follow-up of a context specific trauma training course in Uganda: Lessons learned and future directions.

BACKGROUND: The Kampala Advanced Trauma Course (KATC) was developed in 2007 due to a locally identified need for an advanced trauma training curriculum for the resource-constrained setting. We describe the design, implementation and evaluation of the course. METHODS: The course has been delivered to over 1,000 interns rotating through surgery at Mulago National Referral Hospital. Participants from 2013 to 2016 were surveyed after completion of the course. RESULTS: The KATC was developed with local faculty and includes didactic and simulation modules. Over 50% of survey respondents reported feeling confident performing and teaching 7 of 11 course skills and felt the most relevant skill was airway management(30.2%). Participants felt least confident managing head trauma(26.4%). Lack of equipment(52.8%) was identified as the most common barrier to providing trauma care. CONCLUSIONS: Providers are confident with most skill sets after taking the KATC. Minimal dependence on instructors from high-income countries has kept the course sustainable and maximized local relevance.