Sarah E. Wilson

Impaired Elastogenesis in Hurler Disease: Dermatan Sulfate Accumulation Linked to Deficiency in Elastin-Binding Protein and Elastic Fiber Assembly

Hurler disease resulting from a deficiency in alpha-L-iduronidase, which causes an accumulation of dermatan sulfate and heparan sulfate glycosaminoglycans, is characterized by connective tissue and skeletal deformations, cardiomyopathy, cardiac valve defects, and progressive coronary artery stenosis. In this report, we present evidence that accumulation of dermatan sulfate but not heparan sulfate moieties is linked to impaired elastic fiber assembly that, in turn, contributes substantially to the development of the clinical phenotype in Hurler disease. Our data suggest that dermatan sulfate-bearing moieties bind to and cause functional inactivation of the 67-kd elastin-binding protein, a molecular chaperone for tropoelastin, which normally facilitates its secretion and assembly into elastic fibers. We demonstrate that, in contrast to normal skin fibroblasts and cells from Sanfilippo disease, which accumulate heparan sulfate, Hurler fibroblasts show reduced expression of elastin-binding protein and do not assemble elastic fibers, despite an adequate synthesis of tropoelastin and sufficient production of a microfibrillar scaffold of elastic fibers. Because cultured Hurler fibroblasts proliferate more quickly than their normal counterparts and the addition of exogenous insoluble elastin reduces their proliferation, we suggest that cell contacts with insoluble elastin play an important role in controlling their proliferation.

Low-Intensity Warfarin Is Ineffective for the Prevention of PTFE Graft Failure in Patients on Hemodialysis: A Randomized Controlled Trial

Polytetrafluoroethylene (PTFE) dialysis grafts in patients with end-stage renal disease (ESRD) are prone to thrombotic failure. The objective of this multicenter, randomized, double-blind, placebo-controlled clinical trial was to determine if warfarin reduces the risk of failure of PTFE dialysis grafts. Patients with ESRD and newly placed PTFE grafts were studied at community and academic dialysis centers in Southwestern Ontario. Patients were allocated to receive warfarin or matching placebo, with the warfarin administered to achieve a target INR of 1.4 to 1.9. Time to graft failure was the main outcome measure. A total of 107 patients (56 allocated to warfarin) were randomized. The time-to-event analysis revealed no significant difference in the likelihood of graft survival between the two groups (odds ratio, 1.76 in favor of placebo; 95% confidence interval, 0.72 to 4.34). Six major bleeds occurred in five patients allocated to warfarin compared with none in the patients who received placebo (P = 0.03). In conclusion, low-dose warfarin was associated with an excess of clinically important major bleeding in patients with ESRD enrolled in this study. Furthermore, low-intensity, monitored-dose warfarin does not appear to prolong PTFE graft survival.

Epidemiology of serogroup B invasive meningococcal disease in Ontario, Canada, 2000 to 2010

BackgroundInvasive meningococcal disease (IMD) caused by serogroup B is the last major serogroup in Canada to become vaccine-preventable. The anticipated availability of vaccines targeting this serogroup prompted an assessment of the epidemiology of serogroup B disease in Ontario, Canada.MethodsWe retrieved information on confirmed IMD cases reported to Ontario’s reportable disease database between January 1, 2000 and December 31, 2010 and probabilistically-linked these cases to Public Health Ontario Laboratory records. Rates were calculated with denominator data obtained from Statistics Canada. We calculated a crude number needed to vaccinate using the inverse of the infant (<1 year) age-specific incidence multiplied by expected vaccine efficacies between 70% and 80%, and assuming only direct protection (no herd effects).ResultsA total of 259 serogroup B IMD cases were identified in Ontario over the 11-year period. Serogroup B was the most common cause of IMD. Incidence ranged from 0.11 to 0.27/100,000/year, and fluctuated over time. Cases ranged in age from 13 days to 101 years; 21.4% occurred in infants, of which 72.7% were <6 months. Infants had the highest incidence (3.70/100,000). Case-fatality ratio was 10.7% overall. If we assume that all infant cases would be preventable by vaccination, we would need to vaccinate between 33,784 and 38,610 infants to prevent one case of disease.ConclusionsAlthough rare, the proportion of IMD caused by serogroup B has increased and currently causes most IMD in Ontario, with infants having the highest risk of disease. Although serogroup B meningococcal vaccines are highly anticipated, our findings suggest that decisions regarding publicly funding serogroup B meningococcal vaccines will be difficult and may not be based on disease burden alone.

Low-dose oral vitamin K therapy for the management of asymptomatic patients with elevated international normalized ratios: a brief review

ASYMPTOMATIC ELEVATION OF THE INTERNATIONAL normalized ratio (INR) is a common problem associated with hemorrhage. Evidence from randomized controlled trials supports the use of low-dose oral vitamin K therapy as a treatment that promptly reduces the INR. Vitamin K given orally is more effective than subcutaneous vitamin K injection, and as effective as intravenous administration when INR values are compared 24 hours after administration. A 1.0-mg vitamin K dose is likely most appropriate for patients with INR values between 4.5 and 10. The fear of over-correction of the INR has limited the widespread use of vitamin K; however, our review suggests that this occurs infrequently when small doses are administered orally.

Vaccination attitudes and mobile readiness: A survey of expectant and new mothers

Sub-optimal vaccination coverage and recent outbreaks of vaccine-preventable diseases serve as a reminder that vaccine hesitancy remains a concern. ImmunizeCA, a new smartphone app to help track immunizations, may address several reasons for not vaccinating. We conducted a study to describe demographic variables, attitudes, beliefs and information sources regarding pediatric vaccination in a sample of childbearing women who were willing to download an immunization app. We also sought to measure their current mobile usage behaviors and determine if there is an association between participant demographics, attitudes, beliefs and information sources regarding pediatric vaccination and mobile usage. We recruited participants using a combination of passive and active methods at a tertiary care hospital in Ottawa, Canada. We used surveys to collect demographic information, examine attitudes, behavior, and information sources regarding immunization and self-reported mobile phone usage. A total of 54 women participated. The majority had positive attitudes toward vaccination (96%) and intended to vaccinate their children (98%). Participants were interested in information on pediatric vaccination (94%), and found information from public health the most reliable and accessible (78%). Participants also trusted immunization information from their doctor or nurse and public health (83%) more than other sources. There was variability in participant use of mobile apps for other purposes. The median participant mobile readiness score was 3.2. We found no significant associations between participant age, behavior and attitudes regarding vaccination and mobile readiness scores. This is the first evaluation of mobile readiness for a smartphone app to track immunizations. Our findings suggest that there exists an opportunity to provide reliable information on vaccination through mobile devices to better inform the public, however predictors of individual engagement with these technologies merits further study.

Understanding Public Perceptions of the HPV Vaccination Based on Online Comments to Canadian News Articles

Background Given the variation in human papillomavirus (HPV) vaccine coverage across Canada, and debate regarding delivery of HPV vaccines in Catholic schools, we studied online comments on Canadian news websites to understand public perceptions of HPV and HPV vaccine. Methods We searched English- and French-language Canadian news websites for 2012 articles that contained the terms “HPV” or “human papillomavirus.” Articles about HPV vaccinations that contained at least one comment were included. Two researchers independently coded comments, analyzing them for emerging themes. Results We identified 3073 comments from 1198 individuals in response to 71 news articles; 630 (52.6%) individuals expressed positive sentiments about HPV vaccination (2.5 comments/individual), 404 (33.7%) were negative (3.0 comments/individual), 34 (2.8%) were mixed (1.5 comments/individual) and 130 (10.8%) were neutral (1.6 comments/individual). Vaccine-supportive commenters believed the vaccine is safe and effective. Common themes in negative comments included concerns regarding HPV vaccine safety and efficacy, distrust of pharmaceutical companies and government, and belief that school-age children are too young for HPV vaccine. Many comments focused on whether the Catholic Church has the right to inform health policy for students, and discussion often evolved into debates regarding HPV and sexual behaviour. We noted that many individuals doubted the credibility of vaccine safety information. Conclusion The majority of commenters do not appear to be against HPV vaccination, but public health messaging that focuses on both the vaccine’s safety profile, and its use as a means to prevent cancer rather than sexually transmitted HPV infection may facilitate its acceptance.

The role of seroepidemiology in the comprehensive surveillance of vaccine-preventable diseases

Serological surveillance (serosurveillance) provides estimates of population-level immunity against vaccine-preventable diseases using cross-sectional studies of antibody prevalence. Seroepidemiology is important for evaluating the impact of vaccination programs, as these programs change the

Melville and the Architecture of Antebellum Masculinity

The sphere of Herman Melville’s work has, not unreasonably, been understood as masculine. I use sphere advisedly here, for it alludes to the doctrine of separate spheres that so permeated nineteenth-century American thought about gender while insisting on the physical spaces through which this conception of gender was devised, implemented, and maintained. Critics have not yet recognized the degree to which Melville understood gender as produced by lived spaces. Throughout Melville’s writings, gender appears as a performance mounted in consultation with the built environments experienced by characters. In fact, Melville’s oeuvre reveals a consistent fascination with the gender identifications enabled and thwarted by physical spaces. Becoming alert to the dynamic interactions of gender and interior space not only allows a more nuanced understanding of Melville’s approach to questions of identity but also suggests a new basis for asserting continuities between the earlier seafaring work and the later ‘‘lee-shore’’ fiction. In each of these settings, Melville’s male characters need access to domestic space in order to form viable identities. In his attention to the influence of space on identity, Melville was a man of his time. Early-nineteenth-century discussions of domesticity increasingly attributed to houses the ability to shape their inhabitants’ identities. In Rural Architecture (1852), one of a host of popular and influential mid-nineteenth-century Americanwritings on home design, Lewis Allen asserts: ‘‘As the man himself—no matter what his occupation—be lodged and fed, so influenced, in a degree, will be his practice in the daily duties of his life.’’ In the antebellum United

Population-Level Impact of Ontario’s Infant Rotavirus Immunization Program: Evidence of Direct and Indirect Effects

Objective To evaluate the direct and indirect population impact of rotavirus (RV) immunization on hospitalizations and emergency department (ED) visits for acute gastroenteritis (AGE) in Ontario before and after the publicly-funded RV immunization program. Methods Administrative data was used to identify ED visits and hospitalizations for all Ontarians using ICD-10 codes. We used two outcome definitions: RV-specific AGE (RV-AGE) and codes representing RV-, other viral and cause unspecified AGE (“overall AGE”). The pre-program and public program periods were August 1, 2005 to July 31, 2011; and August 1, 2011 to March 31, 2013, respectively. A negative binominal regression model that included the effect of time was used to calculate rates and rate ratios (RRs) and 95% confidence intervals (CIs) for RV-AGE and overall AGE between periods, after adjusting for age, seasonality and secular trends. Analyses were conducted for all ages combined and age stratified. Results Relative to the pre-program period, the adjusted RRs for RV-AGE and overall AGE hospitalizations in the public program period were 0.29 (95%CI: 0.22–0.39) and 0.68 (95%CI: 0.62–0.75), respectively. Significant reductions in RV-AGE hospitalizations were noted overall and for the following age bands: < 12 months, 12–23 months, 24–35 months, 3–4 years, and 5–19 years. Significant declines in overall AGE hospitalizations were observed across all age bands, including older adults > = 65 years (RR 0.80, 95%CI: 0.72–0.90). The program was associated with adjusted RRs of 0.32 (95% CI: 0.20–0.52) for RV-AGE ED visits and 0.90 (95% CI: 0.85–0.96) for overall AGE ED visits. Conclusions This large, population-based study provides evidence of the impact of RV vaccine in preventing hospitalizations and ED visits for RV-AGE and overall AGE, including herd effects.

Estimates and determinants of HPV non-vaccination and vaccine refusal in girls 12 to 14 y of age in Canada: Results from the Childhood National Immunization Coverage Survey, 2013.

ABSTRACT Since the introduction of HPV vaccination programs in Canada in 2007, coverage has been below public health goals in many provinces and territories. This analysis investigated the determinants of HPV non-vaccination and vaccine refusal. Data from the Childhood National Immunization Coverage Survey (CNICS) 2013 were used to estimate the prevalence of HPV non-vaccination and parental vaccine refusal in girls aged 12–14 years, for Canada and the provinces and territories. Multivariate logistic regression was used to examine factors associated with non-vaccination and vaccine refusal, after adjusting for potential confounders. An estimated 27.7% of 12–14 y old girls had not been vaccinated against HPV, and 14.4% of parents reported refusing the vaccine. The magnitude of non-vaccination and vaccine refusal varied by province or territory and also by responding parents country of birth. In addition, higher education was associated with a higher risk of refusal of the HPV vaccine. Rates of HPV non-vaccination and of refusal of the HPV vaccine differ and are influenced by different variables. These findings warrant further investigation.