Erik D. Skarsgard

Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector.

Pre-clinical studies in mice and haemophilic dogs have shown that introduction of an adeno-associated viral (AAV) vector encoding blood coagulation factor IX (F.IX) into skeletal muscle results in sustained expression of F.IX at levels sufficient to correct the haemophilic phenotype. On the basis of these data and additional pre-clinical studies demonstrating an absence of vector-related toxicity, we initiated a clinical study of intramuscular injection of an AAV vector expressing human F.IX in adults with severe haemophilia B. The study has a dose-escalation design, and all patients have now been enrolled in the initial dose cohort (2×1011 vg/kg). Assessment in the first three patients of safety and gene transfer and expression show no evidence of germline transmission of vector sequences or formation of inhibitory antibodies against F.IX. We found that the vector sequences are present in muscle by PCR and Southern-blot analyses of muscle biopsies and we demonstrated expression of F.IX by immunohistochemistry. We observed modest changes in clinical endpoints including circulating levels of F.IX and frequency of F.IX protein infusion. The evidence of gene expression at low doses of vector suggests that dose calculations based on animal data may have overestimated the amount of vector required to achieve therapeutic levels in humans, and that the approach offers the possibility of converting severe haemophilia B to a milder form of the disease.

The OOPS procedure (Operation on Placental Support): In utero airway management of the fetus with prenatally diagnosed tracheal obstruction

Tracheal obstruction of the newborn caused by cervical masses such as teratomas and cystic hygromas can result in a profound hypoxic insult and even death, owing to an inability to establish an adequate airway after birth. Prenatal sonographic diagnosis of these congenital anomalies permits (1) anticipation of an airway problem at the time of delivery and (2) formulation of an algorithm for airway management while oxygen delivery to the baby is maintained through the placental circulation. This is the report of a fetus in whom a large anterior cervical cystic hygroma was detected by prenatal ultrasonography. A multidisciplinary management team was assembled, and an algorithm for airway management was developed. Elective cesarean delivery of the fetal head and thorax, under conditions of uterine tocolysis, permitted a controlled evaluation of the airway and endotracheal intubation while oxygen supply to the infant was maintained through the placenta. The baby remained intubated, and 2 days later underwent subtotal excision of the cervical cystic hygroma. Pharmacological maintenance of the feto-placental circulation after hysterotomy is an invaluable adjunct to airway management of the neonate with prenatally diagnosed tracheal obstruction.

Canadian Pediatric Surgical Network: a population-based pediatric surgery network and database for analyzing surgical birth defects. The first 100 cases of gastroschisis

PURPOSE Outcomes studies for gastroschisis are constrained by small numbers, prolonged accrual, and nonstandardized data collection. The aim of this study is to create a national pediatric surgical network and database for gastroschisis (GS) that tracks cases from diagnosis to hospital discharge. METHODS The 16-center network serves a population of 32 million. Gastroschisis cases are ascertained at prenatal diagnosis. Perinatal data include maternal risk and fetal ultrasound variables, delivery plan and outcome, a postnatal bowel injury score, intended and actual surgical treatment, and neonatal outcomes. Institutional review board-approved data collection conforms to regional privacy legislation. Deidentified data are centralized and accessible for research through the network steering committee. RESULTS To date, 114 cases of pre- and/or postnatal gastroschisis have been uploaded. Of 106 live-born infants (40 [38%] by cesarean delivery), 100 had complete records, and overall survival to discharge was 96%, with a mean survivor length of stay (LOS) of 46 days. Infants treated with attempted urgent closure (61%) had significantly shorter LOS (42 vs 57 days; P = .048) but comparable LOS compared with those treated with silos and delayed closure. Fetal bowel dilation 18 mm or greater did not predict a difference in outcome. CONCLUSION Population-based databases allow rapid case accrual and enable studies that should aid in the identification of optimal perinatal treatment.

Function and quality of life results after ileal pouch surgery for chronic ulcerative colitis and familial polyposis

The aim of this study was to assess gastrointestinal function and quality of life, including occupational, social, and sexual function, in 75 patients who underwent pelvic pouch construction between November 1984 and May 1988 at our institution. Complications occurred in 45 percent of patients after pouch construction and in 17 percent after ileostomy closure. One patient died from sepsis caused by an anastomotic leak after ileostomy closure. The most common complication was a pouch-anal anastomotic stricture (22 percent), and the complication with the greatest potential morbidity was pouch-anal dehiscence (8 percent), which was highly predictive of pouch failure. Functional results were assessed by questionnaire during the 3-month period after ileostomy closure in all 58 patients who successfully attained intestinal continuity. A second assessment was performed at 15 +/- 11 months after ileostomy closure in 52 patients whose continuity had been restored for longer than 3 months. In an overall assessment, 94 percent of all patients with restored intestinal continuity (73 percent of entire patient group) rated the pouch as being superior to a permanent ileostomy and 92 percent (71 percent of entire group) would go through another pouch procedure. These results support the continued recommendation of this procedure as an acceptable alternative to proctocolectomy and permanent ileostomy in patients with ulcerative colitis or familial polyposis.

Effect of hospital case volume on outcome in congenital diaphragmatic hernia: the experience of the Canadian Pediatric Surgery Network

PURPOSE Despite advances in neonatal care of congenital diaphragmatic hernia (CDH), a significant variation exists in the mortality rates reported by individual centers. Center experience (reflected by case volume) may contribute to this variation in outcome. The aim of the study was to determine whether CDH mortality is affected by hospital case volume. METHODS The CDH cases were abstracted from a disease-specific, 16-hospital, national network. Thirteen hospitals participated in this study. Anonymized hospitals were categorized as either high (>6 cases) or low-volume (<or=6 cases) centers (HVC, n = 6; LVC, n = 7) according to the median case number per center. Risk-adjusted (Score for Neonatal Acute Physiology, version II [SNAP-II] score) mortality rates were compared between HVC and LVC. RESULTS One hundred twenty-one CDH cases were identified. Overall in-hospital survival was 81%. No significant difference in SNAP-II score was observed between HVC and LVC. Of 97 (15%) infants treated in 6 HVC, 15 (15%) died compared to 8 (33%) of 24 in 7 LVC (P < .05). CONCLUSION Hospital case volume may be partially responsible for mortality rate variation in CDH. This result requires careful analysis, as case volume may merely be a surrogate for other predictive variables.

Single-lung Ventilation in Pediatric Patients

Single-lung Ventilation in Pediatric Patients Gregory Hammer;Steven Manos;Baird Smith;Erik Skarsgard;Jay Brodsky; Anesthesiology

Thrombosis of the portal venous system after splenectomy for pediatric hematologic disease

Splenic, portal, or mesenteric venous thrombosis after splenectomy for hematologic disease has not been reported in the pediatric literature. It is a rare complication associated with significant morbidity and mortality in adult reports. Between 1981 and 1991, 3 patients (13-year-old boy with hereditary elliptocytosis [HE], 13-year-old boy with thalassemia intermedia [TI], and 18-year-old girl with idiopathic thrombocytopenic purpura [ITP]) presented with abdominal pain, nausea, with or without fever, at 4, 11, and 13 days postsplenectomy, respectively. Abdominal Doppler ultrasound (US) and/or computed tomography (CT) showed: (1) an intraluminal filling defect with partial obstruction to flow in the right branch of the portal vein with the remaining vessels patent (HE); (2) splenic vein thrombosis with complete occlusion of the main portal vein and proximal superior mesenteric vein (TI); and (3) complete thrombosis of the splenic vein, proximal superior mesenteric vein and portal vein (including central radicles), with retrogastric collateralization (ITP). Subsequent imaging showed either complete resolution of vascular obstruction on no treatment (patient 1), or portal venous cavernomatous transformation with hepatofugal flow after 6 months of systemic anticoagulation (patients 2 and 3), and all 3 patients are currently asymptomatic. Postoperative sonographic evaluation of a consecutive series of pediatric splenectomies for hematologic disease (n = 16), was performed at a median of 51 days (range, 3 to 124). This demonstrated one case of asymptomatic left portal venous thrombosis with subsequent recanalization in the absence of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

SNAP-II predicts mortality among infants with congenital diaphragmatic hernia.

OBJECTIVE:Outcomes analysis in congenital diaphragmatic hernia (CDH) requires a validated risk-adjustment tool. The purpose of this study was to use the Canadian Neonatal Network (CNN) database to validate the Score for Neonatal Acute Physiology, Version II (SNAP-II) for prediction of mortality among CDH infants admitted to a neonatal intensive care unit (NICU), and to compare this to the predictive equation recently developed by the Congenital Diaphragmatic Hernia Study Group (CDHSG).STUDY DESIGN:Infants with CDH in the CNN database were identified. Bivariate and multivariable logistic regression models were used to identify risk factors predictive of mortality. Model predictive performance and calibration were assessed using the area under the receiver operator characteristic curve and the technique of Hosmer-Lemeshow, respectively, and compared with the CDHSG predictive equation.RESULTS:There were 88 patients with CDH among 19,507 admissions to CNN hospitals. The mortality rate among CDH patients surviving to NICU admission was 17%, and 12.5% received extracorporeal membrane oxygenation therapy. Gestational age and admission SNAP-II score predicted mortality. Model predictive performance and calibration were optimized with these variables combined. The CDHSG equation was equally predictive of mortality, but was only marginally calibrated.CONCLUSIONS:SNAP-II is highly predictive of mortality among patients with CDH, and can be used to risk-adjust these patients.

Evolutionary concepts in biobanking - the BC BioLibrary

BackgroundMedical research to improve health care faces a major problem in the relatively limited availability of adequately annotated and collected biospecimens. This limitation is creating a growing gap between the pace of scientific advances and successful exploitation of this knowledge. Biobanks are an important conduit for transfer of biospecimens (tissues, blood, body fluids) and related health data to research. They have evolved outside of the historical source of tissue biospecimens, clinical pathology archives. Research biobanks have developed advanced standards, protocols, databases, and mechanisms to interface with researchers seeking biospecimens. However, biobanks are often limited in their capacity and ability to ensure quality in the face of increasing demand. Our strategy to enhance both capacity and quality in research biobanking is to create a new framework that repatriates the activity of biospecimen accrual for biobanks to clinical pathology.MethodsThe British Columbia (BC) BioLibrary is a framework to maximize the accrual of high-quality, annotated biospecimens into biobanks. The BC BioLibrary design primarily encompasses: 1) specialized biospecimen collection units embedded within clinical pathology and linked to a biospecimen distribution system that serves biobanks; 2) a systematic process to connect potential donors with biobanks, and to connect biobanks with consented biospecimens; and 3) interdisciplinary governance and oversight informed by public opinion.ResultsThe BC BioLibrary has been embraced by biobanking leaders and translational researchers throughout BC, across multiple health authorities, institutions, and disciplines. An initial pilot network of three Biospecimen Collection Units has been successfully established. In addition, two public deliberation events have been held to obtain input from the public on the BioLibrary and on issues including consent, collection of biospecimens and governance.ConclusionThe BC BioLibrary framework addresses common issues for clinical pathology, biobanking, and translational research across multiple institutions and clinical and research domains. We anticipate that our framework will lead to enhanced biospecimen accrual capacity and quality, reduced competition between biobanks, and a transparent process for donors that enhances public trust in biobanking.

Institutional practice and outcome variation in the management of congenital diaphragmatic hernia and gastroschisis in Canada: a report from the Canadian Pediatric Surgery Network

BACKGROUND Perinatal management of congenital diaphragmatic hernia (CDH) and gastroschisis (GS) remains nonstandardized and institution specific. This analysis describes practice and outcome variation across a national network. METHODS A national, prospective, disease-specific database for CDH and GS was evaluated over 4 years. Centers were evaluated individually and defined as low (low-volume center [LVC]) or high (high-volume center [HVC]) volume based on case mean. RESULTS Congenital diaphragmatic hernia. Two hundred fifteen liveborn cases were studied (mean, 14.3 cases/center) across 15 centers (8 LVCs and 7 HVCs). Significant interinstitutional practice variation was noted in rates of termination (0%-40%) and cesarean delivery (0%-61%). Centers demonstrated marked variation in ventilation strategies, vasodilator and paralytic use, timing of surgery, and rates of primary closure. Overall survival was 81.4% (LVC, 76.9%; HVC, 82.4%; P = .43). Gastroschisis. Four hundred sixteen cases were investigated (mean, 26 cases/center; range, 6-72) across 16 centers (10 LVCs and 6 HVCs). Cesarean delivery rates varied widely between centers (0%-86%) as did timing of closure (early vs delayed, 1%-100%). There was no difference in length of stay, days on total parenteral nutrition, and overall survival (94.3% vs 97.2%; P = .17) between LVCs and HVCs. CONCLUSIONS The existence of perinatal practice and outcome variation for GS and CDH suggests targets for improved delivery of care and justifies efforts to standardize treatment on a national basis.