Study protocol of Phase 2 open-label multicenter randomized controlled trial for granulocyte-colony stimulating factor (GCSF) in post-Kasai Type 3 biliary atresia.

Animal studies support RCT findings of improved liver function and short-term benefits using repurposed Granulocyte Colonic Stimulating Factor GCSF in adults with decompensated cirrhosis. We describe the protocol for phase 2 RCT of sequential Kasai-GCSF under an FDA-approved IND to test that GCSF improves early bile flow and post-Kasai biliary atresia BA clinical outcome. Immediate post-Kasai neonates, age 15-180 days, with biopsy-confirmed type 3 BA, without access to early liver transplantation, will be randomized 1:1 to standard of care SOC + GCSF at 10 ug/kg in 3 daily doses within 4 days of Kasai vs SOC + NO-GCSF (ClinicalTrials.gov NCT0437391). They will be recruited from children's hospitals in Vietnam, Pakistan and one US center. The primary objective is to demonstrate that GCSF decreases the proportion of subjects with a 3-month post-Kasai serum Total Bilirubin ≥ 34 umol/L by 20%, (for a = 0.05, b = 0.80, i.e., calculated sample size of 218 subjects). The secondary objectives are to demonstrate that the frequency of post-Kasai cholangitis at 6-month and 24-month transplant-free survival are improved. The benefits are that GCSF is an affordable BA adjunct therapy, especially in developing countries, to improve biliary complications, enhance quality of liver and survival while diminishing costly liver transplantation.Clinical trial registration: A phase 1 for GCSF dose and safety determination under ClinicalTrials.gov identifier NCT03395028 was completed in 2019. The current Phase 2 trial was registered under NCT04373941.

Determination of reference interval (RI) of spot urinary oxalate to creatinine ratio in children of pakistani origin under six years of age: A cross-sectional study.

BACKGROUND: The gold standard screening method of hyperoxaluria in children is using 24-hour urine collection. Urine collection may be cumbersome and challenging for children. Reference intervals (RI) of oxalate for the Pakistani population are not readily available. Therefore we aimed to determine the oxalate to creatinine ratio (Ox: Cr) for Pakistani children <6 years of age. MATERIALS AND METHODS: A cross-sectional study was conducted at Aga Khan University from June 2018 to October 2019. Random urine samples from apparently healthy children < 6 years were collected and stored at -30°C until analysis after adding 6M HCl. Oxalate was measured on Micro lab 300 using a kit based on oxalate oxidase principle, while creatinine was measured by kinetic Jaffe reaction. Data was analyzed by EP evaluator and SPSS 23. Ox: Cr ratio was calculated and reported with 90% confidence interval (CI) and interquartile range (IQR). RESULTS: The mean age of study subjects (n=120) was 29 ±22.3 months with an M: F ratio of 1:1. Children of various ethnicities were included from all over Karachi. The majority of the subjects were Urdu speaking (37.5%). Median Ox: Cr was 0.13(0.10). No significant difference was noted in the median Ox: Cr ratio between various ethnicities (p>0.05). It was significantly different in group I to V which was 0.25 (IQR: 0.06), 0.19 (IQR: 0.11), 0.15 (IQR: 0.04), 0.11 (IQR: 0.06) and 0.08 (IQR: 0.04) respectively (pvalue <0.001). CONCLUSION: The established RIs of Ox: Cr ratio was 0.05-0.34 (90% CI). Ox: Cr ratio showed a declining trend with age. Large scale reference interval studies are encouraged, taking diet and age into consideration.

Simulation-based training in the Paediatric Surgery population: A review of current trends and future direction.

In recent years, simulation-based training in surgery has emerged as a viable accompaniment to traditional teaching methods. Multiple studies have highlighted the benefits of simulation-based training in both learning and teaching aspects of surgical training, with a particular emphasis on the honing of technical skills. However, multiple issues still exist in widespread implementation of simulation-based training, especially in the developing countries. Furthermore, the existing literature needs to be expanded upon in both quantity and quality domains to ensure a more evidence-based transition to simulation-based training in surgery. The current review article was planned to take a look at the existing literature on the current state of simulation-based training in paediatric surgery, its potential to revolutionise paediatric surgical training, and to propose solutions to the issues that are delaying wider implementation.

Burden of Culture Confirmed Enteric Fever Cases in Karachi, Pakistan: Surveillance For Enteric Fever in Asia Project (SEAP), 2016-2019.

BACKGROUND: The Surveillance for Enteric Fever in Asia Project (SEAP) is a multicenter, multicountry study conducted in Pakistan, Nepal, and Bangladesh. The objectives of the study were to characterize disease incidence among patients with enteric fever. We report the burden of enteric fever at selected sites of Karachi, Pakistan. METHODS: During September 2016 to September 2019, prospective surveillance was conducted at inpatient, outpatient, surgical departments, and laboratory networks of Aga Khan University Hospital, Kharadar General Hospital, and surgery units of National Institute of Child Health and Jinnah Postgraduate Medical Centre. Socio-demographic, clinical, and laboratory data were obtained from all suspected or confirmed enteric fever cases. RESULTS: Overall, 22% (2230/10 094) of patients enrolled were culture-positive for enteric fever. 94% (2093/2230) of isolates were Salmonella Typhi and 6% (137/2230) were S. Paratyphi. 15% of isolates multi-drug resistant (MDR) to first-line antibiotics and 60% were extensively drug-resistant (XDR), resistant to first-line antibiotics, fluoroquinolones and third generation cephalosporin. CONCLUSION: Enteric fever cases have increased during the last 3 years with large proportion of drug resistant S. Typhi cases. However, the burden of paratyphoid is still relatively low. Strengthening the existing surveillance system for enteric fever and antimicrobial resistance at the national level is recommended in Pakistan to inform prevention measures. While typhoid vaccination can significantly decrease the burden of typhoid and may also impact antimicrobial resistance, water, sanitation, and hygiene improvement is highly recommended to prevent the spread of enteric fever.

Challenges to delivering pediatric surgery services in the midst of COVID 19 crisis: experience from a tertiary care hospital of Pakistan.

Covid-19 pandemic has significantly challenged the healthcare delivery across the world. Surgery departments across the country responded to this challenge by halting all non-emergency procedures. This delay in diagnosis and management of surgical disease could result in significant mortality and morbidity among the most vulnerable population-the children. In this manuscript, we discuss the measures adopted as well as the challenges faced by the pediatric surgery department at Aga Khan University Hospital, Karachi (AKUH), Pakistan, which is a private, not-for-profit entity and providing optimum surgical care to the patients. We also underscore the need for global strategies for tackling such crisis.

Laparoscopic total colectomy in an eight-year-old with familial adenomatous polyposis: A case report.

Familial Adenomatous Polyposis accounts for <1% of all the colorectal cancer cases, with progression to colorectal cancer usually at >20 years of age. Endoscopy is essential for the diagnosis with definitive treatment involving prophylactic total colectomy. With current surgical advances, this is routinely being performed with the aid of laparoscopy. Due to resource limitations and non-availability of the screening programs in the developing world, such cases remain under diagnosed. Genetic testing is necessary for prognostication of both the index case and their at-risk family members. Thus, we present a rare case of an eight-year-old female, with an early onset progression to colorectal cancer with Familial Adenomatous Polyposis. We performed a prophylactic laparoscopic total procto-colectomy with ileo-anal anastomosis, which to our knowledge is the first ever-performed procedure in Pakistan. We conclude that progression to colorectal carcinoma in familial adenomatous polyposis can present at an earlier age than that reported in the literature. Laparoscopic total colectomy has similar outcomes than open surgical methods with better cosmetic results.

Infectious Etiologies of Intussusception Among Children <2 Years Old in 4 Asian Countries.

BACKGROUND: The etiology of intussusception, the leading cause of bowel obstruction in infants, is unknown in most cases. Adenovirus has been associated with intussusception and slightly increased risk of intussusception with rotavirus vaccination has been found. We conducted a case-control study among children <2 years old in Bangladesh, Nepal, Pakistan, and Vietnam to evaluate infectious etiologies of intussusception before rotavirus vaccine introduction. METHODS: From 2015 to 2017, we enrolled 1-to-1 matched intussusception cases and hospital controls; 249 pairs were included. Stool specimens were tested for 37 infectious agents using TaqMan Array technology. We used conditional logistic regression to estimate odds ratio (OR) and 95% confidence interval (CI) of each pathogen associated with intussusception in a pooled analysis and quantitative subanalyses. RESULTS: Adenovirus (OR, 2.67; 95% CI, 1.75-4.36) and human herpes virus 6 (OR, 3.50; 95% CI, 1.15-10.63) were detected more frequently in cases than controls. Adenovirus C detection <20 quantification cycles was associated with intussusception (OR, 18.59; 95% CI, 2.45-140.89). Wild-type rotavirus was not associated with intussusception (OR, 1.07; 95% CI, 0.52-2.22). CONCLUSIONS: In this comprehensive evaluation, adenovirus and HHV-6 were associated with intussusception. Future research is needed to better understand mechanisms leading to intussusception, particularly after rotavirus vaccination.

Approaches to the management of pediatric ovarian masses in the 21st century: Systematic review and meta-analysis.

BACKGROUND: Laparoscopy is increasingly being adopted for the treatment of ovarian pathologies in adults. However, its implementation for the management of pediatric ovarian masses varies and the evidence, to date, has not been comprehensively analyzed. This review aims to compare laparoscopic and open surgical management of pediatric ovarian masses. METHODS: We searched PubMed, Cochrane Library and Google Scholar from the year 2000 till April 2017. Studies selected for this included those on epidemiological trends of pediatric ovarian lesions, assessing outcomes of laparoscopic management and comparison of laparoscopic and open surgical techniques for pediatric ovarian masses. A meta-analysis comparing outcomes of both modalities was performed using standard methodology. RESULTS: A total of 44 studies met the inclusion criteria of which 15 were on histological types of ovarian lesions, 24 assessed laparoscopic management only and five compared laparoscopy with open surgery for pediatric ovarian masses. Nonneoplastic lesions were the most common ranging from 36.5% to 73.7%, with cystic lesions being the most prevalent. Neoplastic lesions ranged between 26.3% and 63.5%, with germ cell tumors being the most common, while malignancy ranged between 3.5% and 10.8%. Laparoscopic management was generally advocated for managing benign lesions with a cautious approach for suspicion of malignant lesions. In comparison to open surgery, laparoscopic surgery had shorter operating time (MD = -33.24 min, 95% CI = -34.29 to -32.19, p < 0.0001), less intraop bleeding (MD = - 61.46 ml, 95% CI = -62.69 to -60.24, p < 0.0001), and reduced length of hospital stay (MD = -2.78 days, 95% CI= -2.82 to -2.74, p<0.0001). Complication rates were equivocal between the two approaches. Spillage rates could not be assessed. CONCLUSION: Limited evidence suggests that laparoscopic approach to presumptively benign ovarian masses have better outcomes when compared to open surgery with regards to operating time, blood loss and hospital stay. However, complication rates were similar between the two approaches. Studies with rigorous scientific methods are needed for a definitive recommendation, especially in resource limiting settings. However malignant lesions should still be managed with an open surgical approach to avoid upstaging of disease status. LEVEL OF EVIDENCE: II.

Amoebic liver abscess: Outcomes of percutaneous needle aspiration vs drain placement in paediatric population.

OBJECTIVE: To compare the effectiveness of percutaneous catheter drain placement with percutaneous needle aspiration in terms of hospital stay, time to resolution of symptoms and cost of intervention performed. Methods: The retrospective cohort study was conducted at Aga Khan University Hospital, Karachi, and comprised data of patients with amoebic liver abscess from, January 2006 to December 2016 which was collected using non-probability purposeful sampling. Primary outcome included length of hospital stay, time to resolution of symptoms and cost of intervention. Secondary outcomes included development of complications, need for re-intervention and abscess resolution. SPSS 22 was used for data analysis. . Results: Of the 62 patients, 36(58%) underwent percutaneous needle aspiration Group A, and 26(42%) were treated with percutaneous catheter drain placement Group B. Both groups were malnourished and anaemic at presentation. Overall, 56(90.3%) patients had single abscess and 44(71%) had it in the right lobe. Mean duration of symptoms was less in Group B compared to Group A (11.2±4.5 versus 16.4±3.2 days). Mean abscess size was 6.13cm ± 9.75cm in Group A and 7.40cm ± 8.40cm in Group B. The mean length of hospital stay Group A was shorter than in Group B (p=0.047) with earlier resolution of symptoms (p=0.027). Conclusion: Both methods were found to be effective in treating amoebic liver abscess in children, but percutaneous needle aspiration was more effective.

Global perspective of paediatric surgery in low and middle income countries.

There is huge burden of paediatric surgical diseases in low and middle income countries. Issues behind such a scenario include lack of trained paediatric surgeons, higher mortality due to infections, and poor postoperative care. The possible solution is improvement in the existing structure, which is government hospitals, because they are the most prevalent form of healthcare delivery in such countries. Proper coding system, research and identification of paediatric bellwether procedures can improve the existing health system. Task shifting and sharing can help in many areas. The doctors leaving their countries for better training and employment options should be properly incentivised locally. A lot can be done in terms of providing infrastructure, finances, changing mind-sets, developing expertise, making registry and rehabilitation. By doing so, millions of paediatric mortalities can be prevented in low and middle income countries.

Pediatric laparoscopic surgery; initial experience from Pakistan; first 100 cases in single center.

In a developing country like Pakistan, laparoscopic surgeries are not considered favourable by many, possibly because of high costs or a lack of expertise. It is an established fact that laparoscopic surgery offers better surgical treatments with a shorter hospital stay and fewer complications. The current retrospective study was conducted at a tertiary care hospital in Karachi and comprised of laparoscopy cases performed by a single surgeon from March 2012 to September of 2014. A total of 100laparoscopic surgeries were performed; mostly appendectomies 49(49%) and undescended testes (UDTs) 34(34%). Overall, there were 70(70%) male patients. The mean age of the patients was 7.1 years and standard deviation (SD) of 2. Four (4%) patients had cellulitis. Laparoscopy paediatric surgery offered advantages of fewer wound-associated complications, less incisional pain, a shorter recovery time, and improved cosmesis.

Functional Outcome of Anorectal Malformations and Associated Anomalies in Era of Krickenbeck Classification.

OBJECTIVE: To describe the management and functional outcome of anorectal malformations and associated anomalies according to Krickenbeck classification. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: The Aga Khan University Hospital, Karachi, from January 2002 to December 2012. METHODOLOGY: Anorectal anomalies were classified according to Krickenbeck classification. Data was collected and proforma used regarding the primary disease associated anomalies, its management and functional outcome, according to Krickenbeck classification. Cases included were: all those children with imperforate anus managed during the study period. Qualitative variables like gender and functional outcome were reported as frequencies and percentages. Quantitative variables like age were reported as medians with interquartile ranges. RESULTS: There were 84 children in study group. Most common associated anomaly was cardiac (38%), followed by urological anomaly (33%). All children were treated by Posterior Sagittal Anorectoplasty (PSARP). Fistula was present in 64 out of 84 (76%) cases. The most common fistula was rectourethral (33%), followed by recto vestibular (31%). According to Krickenbeck classification, continence was achieved in 62% children; however 27% children were constipated, followed by 12% children having fecal soiling. CONCLUSION: Functional outcome of anorectal malformation depends upon severity of disease. A thorough evaluation of all infants with ARM should be done with particular focus on cardiovascular (38%) and genitourinary abnormalities (33%).

Posterior mediastinal branchial cleft cyst: an unusual site.

A two and a half year old Kenyan girl presented with recurrent chest infections and difficulty in swallowing. Her clinical and laboratory workup was suggestive of lower respiratory tract infection for which she received a course of antibiotics; however, she remains symptomatic after the management of her suspected diagnosis. Therefore, further radiological workup including a chest CT scan and barium study were performed. This showed a homogeneous mass surrounded by ascending and descending aorta in the posterior mediastinum that was compressing the middle esophagus. She had a posterolateral thoracotomy which revealed a cystic mass with smooth surfaces (5x5 cm) in the posterior mediastinum. Histopathology showed branchial cleft cyst predominately lined by stratified squamous epithelium, with lymphocytes predominance. A final diagnosis of posterior mediastinal branchial cleft cyst was made. She was discharged home and remained well at follow-up.

Isolated splenic abscess in children, role of splenic preservation.

PURPOSE: Splenic abscess (SA) is rare life threatening clinical condition in children. Diagnosis is delayed because of its non-specific clinical presentation. It has a high mortality rate even in the era of antibiotics. This study aim to determine the role of splenic preservation in the management of isolated splenic abscess in children, and to compare different treatment modalities for it. METHODS: A retrospective cross-sectional study of 20 years was conducted including all children <14 years of age with the principal diagnosis of "Splenic abscess". We have excluded all splenic abscesses occurring after penetrating or blunt abdominal trauma. RESULTS: Total of 17 children were managed during the study period. Most of our patients were older than 10 years of age. Majority of patients had a significant delay in presentation. Fever, abdominal pain, and vomiting were the main mode of presentation. Splenomegaly on abdominal examination was present in 12 patients. 15 (88 %) children were managed conservatively; however, 2 children required surgical intervention. CONCLUSION: Splenic abscess in children is a rare disease and its diagnosis is often delayed. Delay in diagnosis of SA in children can lead to life threatening complications. A high index of suspicion is needed to reduce delay in diagnosis. Children presenting with non-specific high grade fever vomiting and abdominal pain should be evaluated for SA. Timely ultrasound and CT scan will lead to earlier diagnosis. A conservative approach with intravenous antibiotics and early percutaneous drainage especially in immunocompetent children can preserve spleen to continue immune function.

Pulmonary agenesis--vascular airway compression and gastroesophageal reflux influence outcome.

Pulmonary agenesis (PA) is a rare malformation that can be isolated or associated with other anomalies. We report 3 cases of left-sided PA having ipsilateral renal agenesis, facial, and radial ray anomalies. Patients presented in infancy with nonspecific respiratory symptoms and were diagnosed to have PA on chest radiograph and computed tomographic scan. Bronchial compression, by dilated pulmonary artery and associated severe gastroesophageal reflux, aggravated respiratory symptoms and required surgical intervention. The relevant literature is briefly reviewed.