Understanding the Burden of Pediatric Traumatic Injury in Uganda: A Multicenter, Prospective Study.

INTRODUCTION: Traumatic injury is responsible for eight million childhood deaths annually. In Uganda, there is a paucity of comprehensive data describing the burden of pediatric trauma, which is essential for resource allocation and surgical workforce planning. This study aimed to ascertain the burden of non-adolescent pediatric trauma across four Ugandan hospitals. METHODS: We performed a descriptive review of four independent and prospective pediatric surgical databases in Uganda: Mulago National Referral Hospital (2012-2019), Mbarara Regional Referral Hospital (2015-2019), Soroti Regional Referral Hospital (SRRH) (2016-2019), and St Mary's Hospital Lacor (SMHL) (2016-2019). We sub-selected all clinical encounters that involved trauma. The primary outcome was the distribution of injury mechanisms. Secondary outcomes included operative intervention and clinical outcomes. RESULTS: There was a total of 693 pediatric trauma patients, across four hospital sites: Mulago National Referral Hospital (n = 245), Mbarara Regional Referral Hospital (n = 29), SRRH (n = 292), and SMHL (n = 127). The majority of patients were male (63%), with a median age of 5 [interquartile range = 2, 8]. Chiefly, patients suffered blunt injury mechanisms, including falls (16.2%) and road traffic crashes (14.7%) resulting in abdominal trauma (29.4%) and contusions (11.8%). At SRRH and SMHL, from which orthopedic data were available, 27% of patients suffered long-bone fractures. Overall, 55% of patients underwent surgery and 95% recovered to discharge. CONCLUSIONS: In Uganda, non-adolescent pediatric trauma patients most commonly suffer injuries due to falls and road traffic crashes, resulting in high rates of abdominal trauma. Amid surgical workforce deficits and resource-variability, these data support interventions aimed at training adult general surgeons to provide emergency pediatric surgical care and procedures.

Treatment abandonment in children with Wilms tumor at a national referral hospital in Uganda.

INTRODUCTION: The incidence of pediatric Wilms' tumor (WT) is high in Africa, though patients abandon treatment after initial diagnosis. We sought to identify factors associated with WT treatment abandonment in Uganda. METHODS: A cohort study of patients < 18 years with WT in a Ugandan national referral hospital examined clinical and treatment outcomes data, comparing children whose families adhered to and abandoned treatment. Abandonment was defined as the inability to complete neoadjuvant chemotherapy and surgery for patients with unilateral WT and definitive chemotherapy for patients with bilateral WT. Patient factors were assessed via bivariate logistic regression. RESULTS: 137 WT patients were included from 2012 to 2017. The mean age was 3.9 years, 71% (n = 98) were stage III or higher. After diagnosis, 86% (n = 118) started neoadjuvant chemotherapy, 59% (n = 82) completed neoadjuvant therapy, and 55% (n = 75) adhered to treatment through surgery. Treatment abandonment was associated with poor chemotherapy response (odds ratio [OR] 4.70, 95% confidence interval [CI] 1.30-17.0) and tumor size > 25 cm (OR 2.67, 95% CI 1.05-6.81). CONCLUSIONS: Children with WT in Uganda frequently abandon care during neoadjuvant therapy, particularly those with large tumors with poor response. Further investigation into the factors that influence treatment abandonment and a deeper understanding of tumor biology are needed to improve treatment adherence of children with WT in Uganda.

Met and Unmet Need for Pediatric Surgical Access in Uganda: A Country-Wide Prospective Analysis.

INTRODUCTION: Children's surgical access in low and low-middle income countries is severely limited. Investigations detailing met and unmet surgical access are necessary to inform appropriate resource allocation. MATERIALS AND METHODS: Surgical volume, outcomes, and distribution of pediatric general surgical procedures were analyzed using prospective pediatric surgical databases from four separate regional hospitals in Uganda. The current averted burden of surgical disease through pediatric surgical delivery in Uganda and the unmet surgical need based on estimates from high-income country data was calculated. RESULTS: A total of 8514 patients were treated at the four hospitals over a 6-year period corresponding to 1350 pediatric surgical cases per year in Uganda or six surgical cases per 100,000 children per year. The majority of complex congenital anomalies and surgical oncology cases were performed at Mulago and Mbarara Hospitals, which have dedicated pediatric surgical teams (P < 0.0001). The averted burden of pediatric surgical disease was 27,000 disability adjusted life years per year, which resulted in an economic benefit of approximately 23 million USD per year. However, the average case volume performed at the four regional hospitals currently represents 1% of the total projected pediatric surgical need. CONCLUSIONS: This investigation is one of the first to demonstrate the distribution of pediatric surgical procedures at a country level through the use of a prospective locally created database. Significant disease burden was averted by local pediatric and adult surgical teams, demonstrating the economic benefit of pediatric surgical care delivery. These findings support several ongoing strategies to increase pediatric surgical access in Uganda.

Implementation of ultrasound and fast magnetic resonance imaging pathway reduces computed tomography utilization in children with suspected appendicitis.

PURPOSE: Computed tomography (CT) is still used in the imaging diagnosis of acute appendicitis in children at many hospitals. We implemented an ultrasound (US) and fast magnetic resonance imaging (MRI) pathway for suspected appendicitis at our institution with the goal of reducing radiation exposure in children. METHODS: All children (< 18 years old) who underwent appendectomy between January 2011 and July 2021 were reviewed. Data were collected on all imaging studies performed. In December 2015, we initiated an imaging pathway for suspected acute appendicitis. US was the initial imaging study, and a rapid protocol MRI was performed if US was equivocal. Those could not tolerate MRI underwent CT. We evaluated the difference in percentage of patients who underwent CT before and after pathway initiation. RESULTS: 554 patients who underwent appendectomy did not have prior imaging studies on presentation to our hospital and were included in analysis. After initiating the pathway, the use of abdominal US increased from 87% (220 of 254) to 97% (291 of 300, p < 0.0001) and the use of MRI increased by 100% (0 MRIs pre-protocol, 90 of 300 patients post-protocol, p < 0.0001). CT utilization decreased significantly from 32% (82 of 254) to 2% (6 of 300, p < 0.0001). CONCLUSION: Embracing a new US and rapid MRI pathway to evaluate pediatric patients with suspected acute appendicitis resulted in significant reduction in CT utilization and therefore radiation exposure.

Standing Intravenous Acetaminophen Is Associated With a Reduction of Post-operative Opioid Use in Infants Aged Less Than 1 Year Treated on the Acute Care Floor.

INTRODUCTION: Given the negative clinical effects opiates can have, the search for alternative forms of analgesia to treat post-operative pain continues. We implemented an opiate reduction strategy using standing intravenous (IV) acetaminophen for infants aged less than 1 y who underwent abdominal or anorectal surgery and recovered on the acute care floor. MATERIALS AND METHODS: Infants were administered standing IV acetaminophen every 6 h for a minimum of 48 h as the main form of post-operative analgesia. Pain severity was objectively scored using the Face, Legs, Activity, Cry, and Consolability (FLACC) scale. A before-and-after retrospective cohort analysis was performed and process control charts were used to examine trends in post-operative opiate use in our pre-intervention (January 2012 to January 2016), roll-out (January 2016 to December 2016), and post-intervention (December 2016 to December 2020) cohorts. RESULTS: A total of 131 infants were included: 56 in the pre-intervention, 17 in the roll-out, and 58 in the post-intervention group. Patient demographics were equivalent. The intervention was associated with a 36-fold reduction in post-operative morphine equivalents (median 0.36 mg/kg in the pre-intervention group versus 0.0 mg/kg in the post-intervention group, P < 0.0001). The median and maximum FLACC pain scores along with clinical safety profiles were statistically equivalent between the groups. The intervention was associated with a 2-d reduction in post-operative length of stay (P < 0.0001). CONCLUSIONS: Standing IV acetaminophen is associated with a reduction of post-operative opioid use in infants being treated on the acute care floor while maintaining equivalent FLACC pain scores. Similar opiate reduction strategies may be of value at other institutions.

Clinical regression of inguinal hernias in premature infants without surgical repair.

BACKGROUND: The incidence of inguinal hernias in premature infants is approximately 30%. Due to concerns about a high risk of incarceration, early repair is commonly performed. We present a series of patients whose families opted to delay repair until after 55 weeks corrected gestational age (GA) and experienced safe clinical regression of their hernias. METHODS: Between June 2015 and July 2020, premature infants (< 37 weeks GA) diagnosed with inguinal hernias on physical examination were identified. Families of eligible infants were offered either immediate or delayed repair after 55 weeks corrected GA. Infants whose families elected to delay were followed until their hernia(s) clinically regressed, or until older than 55 weeks. RESULTS: Families of 68 infants consented to delay repair. 23 infants (33.8%) had hernias that clinically regressed at median follow up from diagnosis of 14.1 weeks. Univariate analysis demonstrated female sex as a significant predictor of hernia clinical regression (OR: 3.08; p = 0.046). Of the 45 infants who underwent repair, 84.4% safely progressed to 55 weeks corrected GA prior to. CONCLUSION: Delaying inguinal hernia repair in this series of premature infants until after 55 weeks corrected GA revealed that one third of hernias, especially in females, safely regressed upon follow-up examination.

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.

Estimates of number of children and adolescents without access to surgical care.

OBJECTIVE: To estimate how many children and adolescent worldwide do not have access to surgical care. METHODS: We estimated the number of children and adolescents younger than 19 years worldwide without access to safe, affordable and timely surgical care, by using population data for 2017 from the United Nations and international data on surgical access in 2015. We categorized countries by World Bank country income group and obtained the proportion of the population with no access to surgical care from a study by the Lancet Commission on Global Surgery. FINDINGS: An estimated 1.7 billion (95% credible interval: 1.6-1.8) children and adolescents worldwide did not have access to surgical care in 2017. Lack of access occurred overwhelmingly in low- and middle-income countries where children and adolescents make up a disproportionately large fraction of the population. Moreover, 453 million children younger than 5 years did not have access to basic life-saving surgical care. According to Lancet Commission on Global Surgery criteria, less than 3% of the paediatric population in low-income countries and less than 8% in lower-middle-income countries had access to surgical care. CONCLUSION: There were substantial gaps in the availability of surgical services for children worldwide, particularly in low- and middle-income countries. Future research should focus on developing specific measures for assessing paediatric surgical access, delivery and outcomes and on clarifying how limited surgical access in the poorest parts of the world affects child health, especially mortality in children younger than 5 years.

Close to the Bedside: A Systematic Review of Endogenous Retroviruses and Their Impact in Oncology.

BACKGROUND: Human endogenous retroviruses (HERVs) are genetic elements in the human genome, which resulted from ancient retroviral germline infections. HERVs have strong transcriptional promoters and enhancers that affect a cell's transcriptome. They also encode proteins that can exert effects in human cells. This review examines how our increased understanding of HERVs have led to their potential use as biomarkers and immunologic targets. MATERIAL AND METHODS: PubMed/Medline, Embase, Web of Science, and Cochrane databases were used in a systematic search to identify all articles studying the potential impact of HERVs on surgical diseases. The search included studies that involved clinical patient samples in diseases including cancer, inflammatory conditions, and autoimmune disease. Articles focused on conditions not routinely managed by surgeons were excluded. RESULTS: Eighty six articles met inclusion and quality criteria for this review and were included. Breast cancer and melanoma have robust evidence regarding the use of HERVs as potential tumor markers and immunologic targets. Reported evidence of the activity of HERVs in colorectal cancer, pancreatic cancer, hepatocellular cancer, prostate and ovarian cancer, germ cell tumors as well as idiopathic pulmonary hypertension, and the inflammatory response in burns was also reviewed. CONCLUSIONS: Increasingly convincing evidence indicates that HERVs may play a role in solid organ malignancy and present important biomarkers or immunologic targets in multiple cancers. Innovative investigation of HERVs is a valuable focus of translational research and can deepen our understanding of cellular physiology and the effects of endogenous retroviruses on human biology. As strategies for treatment continue to focus on genome-based interventions, understanding the impact of endogenous retroviruses on human disease will be critical.

Gastrostomy tubes appear to be safe following pediatric orthotopic heart transplant.

BACKGROUND: Gastrostomy tube (GT) placement is a common pediatric surgical procedure typically indicated for oral aversion. This may develop in patients with congenital heart disease (CHD) who require an orthotopic heart transplant (OHT). The safety profile of GT placement in OHT patients who are immunosuppressed is unknown. Given the potential increased risk of wound site complications on a patient receiving immunosuppression, we sought to determine the safety profile of GT placement in pediatric patients with OHT. MATERIALS AND METHODS: We performed a retrospective case series of all pediatric OHT recipients who subsequently underwent GT placement from January 1, 2009, to August 1, 2018, at the University of Virginia Children's Hospital. Major GT complications of wound breakdown, wound infection, peristomal GT leakage, ileus, or persistent emesis, and minor GT complication including the presence of granulation tissue are reported. RESULTS: Six patients who had a pediatric OHT subsequently underwent GT placement over the study period. There were no major 30-day or 90-day GT complications. One patient had excessive granulation tissue at their GT site. There were no accounts of acute kidney injury, urinary tract infection, sepsis, or pneumonia. CONCLUSION: Gastrostomy tube (GT) placement appears to be safe in pediatric OHT patients who are on immunosuppressive medications and unable to feed orally. This is the first study documenting the safety profile of GTs in pediatric OHT patients and may aid clinicians to make decisions regarding this intervention.

Unifying Children's Surgery and Anesthesia Stakeholders Across Institutions and Clinical Disciplines: Challenges and Solutions from Uganda.

BACKGROUND: There is a significant unmet need for children's surgical care in low- and middle-income countries (LMICs). Multidisciplinary collaboration is required to advance the surgical and anesthesia care of children's surgical conditions such as congenital conditions, cancer and injuries. Nonetheless, there are limited examples of this process from LMICs. We describe the development and 3-year outcomes following a 2015 stakeholders' meeting in Uganda to catalyze multidisciplinary and multi-institutional collaboration. METHODS: The stakeholders' meeting was a daylong conference held in Kampala with local, regional and international collaborators in attendance. Multiple clinical specialties including surgical subspecialists, pediatric anesthesia, perioperative nursing, pediatric oncology and neonatology were represented. Key thematic areas including infrastructure, training and workforce retention, service delivery, and research and advocacy were addressed, and short-term objectives were agreed upon. We reported the 3-year outcomes following the meeting by thematic area. RESULTS: The Pediatric Surgical Foundation was developed following the meeting to formalize coordination between institutions. Through international collaborations, operating room capacity has increased. A pediatric general surgery fellowship has expanded at Mulago and Mbarara hospitals supplemented by an international fellowship in multiple disciplines. Coordinated outreach camps have continued to assist with training and service delivery in rural regional hospitals. CONCLUSION: Collaborations between disciplines, both within LMICs and with international partners, are required to advance children's surgery. The unification of stakeholders across clinical disciplines and institutional partnerships can facilitate increased children's surgical capacity. Such a process may prove useful in other LMICs with a wide range of children's surgery stakeholders.

Correction to: Epidemiology and mortality of pediatric surgical conditions: insights from a tertiary center in Uganda.

In the original publication, the family name of one of the authors was spelt incorrectly. The correct name should read as Nensi Ruzgar.

Epidemiology and mortality of pediatric surgical conditions: insights from a tertiary center in Uganda.

INTRODUCTION/PURPOSE: The burden of pediatric surgical disease is largely unknown in low- and middle-income countries such as Uganda where access to care is limited. METHODS: Implementation of a locally led database in January 2012 at a Ugandan tertiary referral hospital, and review of 3465 prospectively collected pediatric surgical admissions from January 2012 to August 2016. RESULTS: 2090 children (60.3%) underwent surgery during admission. 59% were male and 41% female. 28.6% of admissions were in neonates and 50.4% were in children less than 1 year old. Congenital anomalies including Hirschsprung's, anorectal malformations, intestinal atresias, omphalocele, and gastroschisis were the most common diagnoses (38.6%) followed by infections (15.0%) and tumors (8.6%). Mortality rates were substantially higher than those of high-income countries; for example, gastroschisis and intussusception had mortality rates of 90.1% and 19.7%, respectively. Post-operative mortality was highest in the congenital anomalies group (15.0%). CONCLUSION: There is a high burden of infant congenital anomalies with higher mortality rates compared to high-income countries. The unit performs primarily specialized procedures appropriate for a tertiary center. We hope that these data will facilitate evaluation of ongoing quality improvement and capacity-building initiatives.

Post-operative Opioid Reduction Protocol Reduces Racial Disparity in Clinical Outcomes in Children.

INTRODUCTION: Racial disparities in health outcomes continue to exist for children requiring surgery. Previous investigations suggest that clinical protocols may reduce racial disparities. A post-operative opioid reduction protocol was implemented in children undergoing abdominal surgery who were less than 1 years old at a tertiary level hospital. The purpose of this investigation was to determine if the clinical protocol was associated with a reduction in racial disparity in post-operative opioid prescribing patterns and associated clinical outcomes. METHODS: A post-operative opioid reduction protocol based on standing intravenous acetaminophen, educational sessions with nursing staff, and standardized post-operative sign-out between the surgical and NICU teams was implemented in children under 1 year old in 2016. A time series and before and after analysis was conducted using a historical pre-intervention cohort (Jan 2011-Dec 2015) and prospectively collected post-intervention cohort (Jan 2016-Jan 2021). Primary outcomes included post-operative opioid use and post-operative pain scores stratified by race. Secondary outcomes included associated clinical outcomes also stratified by race. RESULTS: A total of 249 children were included in the investigation, 117 in the pre-intervention group and 132 in the post intervention group. The majority of patients in both cohorts were either White or Black. The two cohorts were equally matched in terms of pre-operative clinical variables. In the pre-intervention cohort, the median post-operative morphine equivalents in White children was 2.1 mg/kg (IQR 0.2, 11.1) while in Black children it was 13.1 mg/kg (IQR 2.4, 65.3), p-value = 0.0352. In the post-intervention cohort, the median value for White children and Black children was statistically identical (0.05 mg/kg (IQR 0, 0.5) and 0.0 mg/kg (IQR 0, 0.3), respectively, p-value = 0.237). This pattern was also demonstrated in clinical variables including length of stay, intubation length and total parenteral nutrition use. In the pre-intervention cohort, the total length of stay for white children was 16 days while for black children it was 45 days (p = 0.007). In the postintervention cohort the length of stay for both White and Black children were identical at 8 days (p = 0.748). CONCLUSION: The use of a clinical opioid reduction protocol implemented at a tertiary medical center was associated with a reduction in racial disparity in opioid prescribing habits in children. Prior to the protocol, there was a racial disparity in clinical variables associated with prolonged opioid use including length of stay, TPN use, and intubation length. The clinical protocol reduced variability in opioid prescribing patterns in all racial groups which was associated with a reduction in variability in associated clinical variables. LEVEL OF EVIDENCE: Level III.

Reduction of post-operative opioid use in neonates following open congenital diaphragmatic hernia repairs: A quality improvement initiative.

BACKGROUND: A limited number of post-operative opioid reduction strategies have been implemented in the neonatal population. Given the potential neurodevelopment effects of prolonged opioid use, we created a quality improvement initiative to reduce opioids in our NICU and evaluated the intervention in our CDH population. METHODS: Our opioid reduction intervention was based on standing post-operative IV acetaminophen, standardizing post-surgical sign-out between the surgical, anesthesia and NICU teams and a series of education seminars with NICU providers on post-operative pain control management. A historical control was used to perform a retrospective cohort analysis of opioid prescribing patterns in addition to a utilizing process control charts to investigate time trends in prescribing patterns. RESULTS: Forty-five children with CDH underwent an operation were included in our investigation- 18 in our pre-intervention cohort, 6 in a roll-out cohort and 21 in our post-intervention cohort. Each cohort was clinically similar. The intervention reduced total post-operative opioid use (morphine equivalents) from 82.2 (mg/kg) to 2.9 (mg/kg) in our post-intervention group (p < 0.0001). Our maximum Neonatal Pain and Agitation Sedation Score over the first 48 post-operative hours were equivalent (p = 0.827). Safety profiles were statistically equivalent. The opioid reduction intervention reduced post-operative intubation length from 156 to 44 h (p = 0.021). CONCLUSION: A multi-tiered intervention can decrease opioid use in post-surgical neonates with complex surgical pathology including CDH. The intervention proposed in this investigation is safe and does not increase pain or sedation scores in neonates, while lessening post-operative intubation length. EVIDENCE LEVEL: Level II.

Intron retention and its impact on gene expression and protein diversity: A review and a practical guide.

Intron retention (IR) occurs when a complete and unspliced intron remains in mature mRNA. An increasing body of literature has demonstrated a major role for IR in numerous biological functions, including several that impact human health and disease. Although experimental technologies used to study other forms of mRNA splicing can also be used to investigate IR, a specialized downstream computational analysis is optimal for IR discovery and analysis. Here we provide a review of IR and its biological implications, as well as a practical guide for how to detect and analyze it. Several methods, including long read third generation direct RNA sequencing, are described. We have developed an R package, FakIR, to facilitate the execution of the bioinformatic tasks recommended in this review and a tutorial on how to fit them to users aims. Additionally, we provide guidelines and experimental protocols to validate IR discovery and to evaluate the potential impact of IR on gene expression and protein output. This article is categorized under: RNA Evolution and Genomics > Computational Analyses of RNA RNA Processing > Splicing Regulation/Alternative Splicing RNA Methods > RNA Analyses in vitro and In Silico.

A multimodal protocol utilizing liposomal bupivacaine rib blocks leads to opioid reduction in patients undergoing the Nuss procedure.

BACKGROUND: A major challenge associated with the Nuss procedure for pectus excavatum repair is postoperative pain control. Early Recovery Program (ERP) protocols for the Nuss procedure are becoming common, but there is a paucity of experience using liposomal bupivacaine (LB), a long-acting local anesthetic, for rib blocks in this setting. We investigated whether a protocol utilizing LB rib blocks decreased opioid use after the Nuss procedure while achieving equivalent pain control. METHODS: All adolescent patients undergoing the Nuss procedure at our institution between January 2013 and January 2021 were included. Patients were divided into a pre-intervention cohort (n=15), a transition cohort (n=4), and a post-intervention cohort (n=13). Patients in all groups received scheduled acetaminophen and non-steroidals postoperatively. The pre-intervention cohort received an opioid patient-controlled analgesia (PCA) pump postoperatively, with a transition to oral opiates. The transition and post-intervention cohorts received scheduled gabapentin in addition to intraoperative bilateral rib blocks with longer-acting local anesthetic. Rib blocks were performed using 0.25% Bupivacaine in the pre-intervention group. In the transition group, epinephrine (1 mg/kg) was added to 0.25% bupivacaine for the rib block. Following approval in patients aged 13-18 years, 1.3% LB (2.25 mg/kg) was given for a rib block in the post-intervention cohort. RESULTS: Demographic and clinical variables were equivalent in all groups. Post-intervention patients received 90% fewer opioids [median morphine equivalent (MME) mg/kg] compared to the pre-intervention cohort (0.8 vs. 8.2 MME mg/kg, P<0.0001), with no significant difference in pain scores between groups. Hospital length of stay was decreased among the intervention cohort (3 vs. 4 days, P=0.002). CONCLUSIONS: Significant decreases in opioid use and length of stay after the Nuss procedure were achieved by the implementation of a multimodal ERP for pain management, without increase in patient-reported pain scores.

Upregulation of human endogenous retrovirus-K (HML-2) mRNAs in hepatoblastoma: Identification of potential new immunotherapeutic targets and biomarkers.

PURPOSE: Hepatoblastoma is the most common liver malignancy in children. In order to advance therapy against hepatoblastoma, novel immunologic targets and biomarkers are needed. Our purpose in this investigation is to examine hepatoblastoma transcriptomes for the expression of a class of genomic elements known as Human Endogenous Retrovirus (HERVs). HERVs are abundant in the human genome and are biologically active elements that have been associated with multiple malignancies and proposed as immunologic targets in a subset of tumors. A sub-family of HERVs, HERV-K(HML-2) (HERV-K), have been shown to be tightly regulated in fetal development, making investigation of these elements in pediatric tumors paramount. METHODS: We first created a HERVK-FASTA file utilizing 91 previously described HML-2 proviruses. We then concatenated the file onto the GRCh38.95 cDNA library from Ensembl. We used this reference database to evaluate existing RNA-seq data from 10 hepatoblastoma tumors and 3 normal liver controls (GEO accession ID: GSE8977575). Quantification and differential proviral expression analysis between hepatoblastoma and normal liver controls was performed using the pseudo-alignment program Salmon and DESeq2, respectively. RESULTS: HERV-K mRNA was expressed in hepatoblastoma from multiple proviral loci. All expressed HERV-K proviral loci were upregulated in hepatoblastoma compared to normal liver controls. Five HERV-K proviruses (1q21.3, 3q27.2, 7q22.2, 12q24.33 and 17p13.1) were significantly differentially expressed (p-adjusted value <0.05, |log2 fold change| > 1.5) across conditions. The provirus at 17p13.1 had an approximately 300-fold increased expression in hepatoblastoma as compared to normal liver. This was in part due to the near absence of HERV-K mRNA at the 17p13.1 locus in fully differentiated liver samples. CONCLUSIONS: Our investigation demonstrates that HERV-K is expressed from multiple loci in hepatoblastoma and that the expression is increased for several proviruses compared to normal liver controls. Our results suggest that HERV-K mRNA expression may be useful as a biomarker in hepatoblastoma, given the large differential expression profiles in hepatoblastoma, with very low mRNA levels in liver control samples.

Access to pediatric surgery delivered by general surgeons and anesthesia providers in Uganda: Results from 2 rural regional hospitals.

BACKGROUND: Significant limitations in pediatric surgical capacity exist in low- and middle-income countries, especially in rural regions. Recent global children's surgical guidelines suggest training and support of general surgeons in rural regional hospitals as an effective approach to increasing pediatric surgical capacity. METHODS: Two years of a prospective clinical database of children's surgery admissions at 2 regional referral hospitals in Uganda were reviewed. Primary outcomes included case volume and clinical outcomes of children at each hospital. Additionally, the disability-adjusted life-years averted by delivery of pediatric surgical services at these hospitals were calculated. Using a value of statistical life calculation, we also estimated the economic benefit of the pediatric surgical care currently being delivered. RESULTS: From 2016 to 2019, more than 300 surgical procedures were performed at each hospital per year. The majority of cases were standard general surgery cases including hernia repairs and intussusception as well as procedures for surgical infections and trauma. In-hospital mortality was 2.4% in Soroti and 1% in Lacor. Pediatric surgical capacity at these hospitals resulted in over 12,400 disability-adjusted life-years averted/year. This represents an estimated economic benefit of 10.2 million US dollars/year to the Ugandan society. CONCLUSION: This investigation demonstrates that lifesaving pediatric procedures are safely performed by general surgeons in Uganda. General surgeons who perform pediatric surgery significantly increase surgical access to rural regions of the country and add a large economic benefit to Ugandan society. Overall, the results of the study support increasing pediatric surgical capacity in rural areas of low- and middle-income countries through support and training of general surgeons and anesthesia providers.

Burden of emergency pediatric surgical procedures on surgical capacity in Uganda: a new metric for health system performance.

BACKGROUND: The significant burden of emergency operations in low- and middle-income countries can overwhelm surgical capacity leading to a backlog of elective surgical cases. The purpose of this investigation was to determine the burden of emergency procedures on pediatric surgical capacity in Uganda and to determine health metrics that capture surgical backlog and effective coverage of children's surgical disease in low- and middle-income countries. METHODS: We reviewed 2 independent and prospectively collected databases on pediatric surgical admissions at Mulago National Referral Hospital and Mbarara Regional Referral Hospital in Uganda. Pediatric surgical patients admitted at either hospital between October 2015 to June 2017 were included. Our primary outcome was the distribution of surgical acuity and associated mortality. RESULTS: A combined total of 1,930 patients were treated at the two hospitals, and 1,110 surgical procedures were performed. There were 571 emergency cases (51.6%), 108 urgent cases (9.7%), and 429 elective cases (38.6%). Overall mortality correlated with surgical acuity. Emergency intestinal diversions for colorectal congenital malformations (anorectal malformations and Hirschsprung's disease) to elective definitive repair was 3:1. Additionally, 30% of inguinal hernias were incarcerated or strangulated at time of repair. CONCLUSION: Emergency and urgent operations utilize the majority of operative resources for pediatric surgery groups in low- and middle-income countries, leading to a backlog of complex congenital procedures. We propose the ratio of emergency diversion to elective repair of colorectal congenital malformations and the ratio of emergency to elective repair of inguinal hernias as effective health metrics to track this backlog. Surgical capacity for pediatric conditions should be increased in Uganda to prevent a backlog of elective cases.