Julie Curtin

Cost-utility analysis of Canadian tailored prophylaxis, primary prophylaxis and on-demand therapy in young children with severe haemophilia A

Summary. Primary prophylaxis is the emerging standard treatment for boys with severe haemophilia. Tailored (escalating‐dose) prophylaxis (EscDose), beginning at a low frequency and escalating with repeated bleeding may prevent arthropathy at a lower cost than standard prophylaxis (SP). From a societal perspective, we compared the incremental cost per joint‐haemorrhage that is avoided and quality‐adjusted‐life‐year (QALY) gained of SP and EscDose to on‐demand (Demand) therapy in severe haemophilia A boys treated to age 6 using a decision analytic model. Costs included factor VIII (FVIII), professional visits and tests, central venous placement/complications, hospitalization, home programmes and parents’ lost work‐days. Resource utilization was estimated by surveying 17 Canadian clinics. The natural history of bleeding and other probabilities were determined from a longitudinal chart review (n = 24) and published literature. EscDose costs an additional

Association Between Physical Activity and Risk of Bleeding in Children With Hemophilia

3192 per joint‐haemorrhage that was avoided compared with Demand whereas SP costs an additional

Extended spectrum of human glucose-6-phosphatase catalytic subunit 3 deficiency: Novel genotypes and phenotypic variability in severe congenital neutropenia

9046 per joint‐haemorrhage that was avoided compared with EscDose. Clinic costs and lost wages were reduced by 60–80% for EscDose and SP compared with Demand. EscDose attained more QALYs than SP and Demand on account of less bleeding than Demand and lower need for ports than SP. The incremental cost per QALY for EscDose vs. Demand was

Bidirectional promoter interference between two widely used internal heterologous promoters in a late-generation lentiviral construct

542 938. EscDose was less expensive with similar QALYs compared to SP. Sensitivity analysis was performed on all probability‐ and cost‐estimates, and showed the model was sensitive to the cost of FVIII and the SP and target joint utilities. In conclusion, prophylaxis will substantially improve clinical outcomes and quality of life compared to Demand treatment, but with substantial cost.

Heterozygous loss of platelet glycoprotein (GP) Ib-V-IX variably affects platelet function in velocardiofacial syndrome (VCFS) patients

CONTEXT Vigorous physical activity is thought to increase risk of bleeds in children with hemophilia, but the magnitude of the risk is unknown. OBJECTIVE To quantify the transient increase in risk of bleeds associated with physical activity in children with hemophilia. DESIGN, SETTING, AND PARTICIPANTS A case-crossover study nested within a prospective cohort study was conducted at 3 pediatric hemophilia centers in Australia between July 2008 and October 2010. A total of 104 children and adolescent boys aged 4 through 18 years with moderate or severe hemophilia A or B were monitored for bleeds for up to 1 year. Following each bleed, the child or parent was interviewed to ascertain exposures to physical activity preceding the bleed. Physical activity was categorized according to expected frequency and severity of collisions. The risk of bleeds associated with physical activity was estimated by contrasting exposure to physical activity in the 8 hours before the bleed with exposures in two 8-hour control windows, controlling for levels of clotting factor in the blood. MAIN OUTCOME MEASURES Association of physical activity and factor level with risk of bleeding. RESULTS The participants were observed for 4839 person-weeks during which time 436 bleeds occurred. Of these, 336 bleeds occurred more than 2 weeks after the preceding bleed and were used in the primary analysis of risk. Compared with inactivity and category 1 activities (eg, swimming), category 2 activities (eg, basketball) were associated with a transient increase in the risk of bleeding (30.6% of bleed windows vs 24.8% of first control windows; odds ratio, 2.7; 95% CI, 1.7-4.8, P < .001). Category 3 activities (eg, wrestling) were associated with a greater transient increase in risk (7.0% of bleed windows vs 3.4% of first control windows; odds ratio, 3.7; 95% CI, 2.3-7.3, P < .001). To illustrate absolute risk increase, for a child who bleeds 5 times annually and is exposed on average to category 2 activities twice weekly and to category 3 activities once weekly, exposure to these activities was associated with only 1 of the 5 annual bleeds. For every 1% increase in clotting factor level, bleeding incidence was lower by 2% (95% CI, 1%-3%; P = .004). CONCLUSIONS In children and adolescents with hemophilia, vigorous physical activity was transiently associated with a moderate relative increase in risk of bleeding. Because the increased relative risk is transient, the absolute increase in risk of bleeds associated with physical activity is likely to be small.

Allogeneic bone marrow transplantation: cure for familial Mediterranean fever

OBJECTIVE To delineate the phenotypic and molecular spectrum of patients with a syndromic variant of severe congenital neutropenia (SCN) due to mutations in the gene encoding glucose-6-phosphatase catalytic subunit 3 (G6PC3). STUDY DESIGN Patients with syndromic SCN were characterized for associated malformations and referred to us for G6PC3 mutational analysis. RESULTS In a cohort of 31 patients with syndromic SCN, we identified 16 patients with G6PC3 deficiency including 11 patients with novel biallelic mutations. We show that nonhematologic features of G6PC3 deficiency are good predictive indicators for mutations in G6PC3. Additionally, we demonstrate genetic variability in this disease and define novel features such as growth hormone deficiency, genital malformations, disrupted bone remodeling, and abnormalities of the integument. G6PC3 mutations may be associated with hydronephrosis or facial dysmorphism. The risk of transition to myelodysplastic syndrome/acute myeloid leukemia may be lower than in other genetically defined SCN subgroups. CONCLUSIONS The phenotypic and molecular spectrum in G6PC3 deficiency is wider than previously appreciated. The risk of transition to myelodysplastic syndrome or acute myeloid leukemia may be lower in G6PC3 deficiency compared with other subgroups of SCN.

Role of hydrochloric acid in the treatment of central venous catheter infections in children with cancer.

Gene transfer vectors encoding two or more genes are potentially powerful research tools and are poised to play an increasingly important role in gene therapy applications. Common strategies employed to express more than one transgene per vector include the use of multiple promoters, internal ribosome entry site (IRES) elements, splicing signals and fusion proteins. Of these, the IRES elements and multiple promoters have been most widely used. The use of multiple promoters, however, may be compromised by interference between promoters, promoter silencing and vector rearrangements or deletions. In this study, we demonstrate promoter interference between two internal heterologous promoters in the context of a late-generation lentiviral vector. The interference, involving the human cytomegalovirus-immediate-early promoter and human elongation-factor-1α promoter, occurred bidirectionally with both promoters markedly impairing expression of the adjacent transcription unit. The data presented not only highlight the potential for interference between these widely-used promoters, but also the value of a sequential approach to vector construction that allows such effects to be recognized.

Pulmonary Embolism in Children

Velocardiofacial syndrome (VCFS) is a common, phenotypically heterogeneous developmental disorder caused by an interstitial microdeletion within human chromosome 22q11. The deleted chromosomal region in >90% of VCFS patients includes the GPIb beta gene, encoding for one subunit of the platelet GPIb-V-IX receptor, which is critical for platelet adhesion under shear, and important in aggregation and thrombin-mediated activation. Complete loss of GPIb-V-IX due to autosomal recessive inheritance of two GPIb alpha, Ib beta or GP9 gene mutations, results in a severe bleeding disorder, Bernard-Soulier syndrome (BSS). In this study, twenty-one confirmedVCFS patients were analyzed for platelet morphological and functional alterations, resulting from the heterozygous loss of one GPIb beta gene allele. Compared to unaffected family members, VCFS patients showed a significant decrease in platelet count; VCFS platelet size and mean platelet volume were increased, but not as markedly as in BSS. As expected from obligatory heterozygotes for GPIb beta deficiency, VCFS patients showed reduced platelet GPIb-V-IX surface expression and total GPIb content, but with considerable variation between cases. Platelet function tested using the PFA-100 trade mark analyzer was impaired in 70% of patients. Platelet aggregation was reduced in response to a GPIb-dependent agonist, ristocetin, in 50% of VCFS patients, with 35% showing a reduced response to thrombin receptor activating peptide. Genomic screening was performed to exclude mutations of the subunit genes, indicating that these platelet abnormalities were due to GPIb beta heterozygosity and not spontaneous BSS. In conclusion, many VCFS patients have in-vitro defects in platelet function that may increase their risk of bleeding during surgery.

Fitness and quality of life in children with haemophilia

We describe data on a 7-year-old girl with congenital dyserythropoietic anemia (CDA), who also had familial Mediterranean fever (FMF). Repeated transfusions required since the age of 6 months to treat her CDA led to iron overload and a persistently high ferritin level. Her relapsing FMF made effective iron chelation therapy very difficult. Consequently, at the age of 4 years, she underwent allogeneic, sibling bone marrow transplantation (BMT). During conditioning for her BMT, symptoms of FMF, including splenomegaly, arthritis, and recurrent abdominal pain, began to resolve and she was gradually weaned off colchicine. Now, 2 years after the transplantation, she remains free from FMF symptomatology and is off all immunosuppressants. This case demonstrates that symptoms of FMF can be alleviated by the therapy used during allogeneic BMT. In this patient it is likely that the missing factor in FMF is now being provided by granulocytes derived from the stem cells within transplanted bone marrow.

Reliability and reproducibility of classification of children as "bleeders" versus "non-bleeders" using a questionnaire for significant mucocutaneous bleeding.

The use of central venous catheters (CVCs) in pediatric cancer patients is associated with substantial risk of producing sepsis. The treatment of catheter‐related infections has generally consisted of antibiotic administration with or without catheter removal. The authors report the first published experience using intraluminal hydrochloric acid (HCl) instillation as an adjunct to systemic antimicrobials in the management of catheter‐related infections in children with cancer.