Canadian Institutes For Health Research Research Articles

Promoting cross-jurisdictional primary health care research: developing a set of common indicators across 12 community-based primary health care teams in Canada.

AimTo describe the process by which the 12 community-based primary health care (CBPHC) research teams worked together and fostered cross-jurisdictional collaboration, including collection of common indicators with the goal of using the same measures and data sources. BACKGROUND: A pan-Canadian mechanism for common measurement of the impact of primary care innovations across Canada is lacking. The Canadian Institutes for Health Research and its partners funded 12 teams to conduct research and collaborate on development of a set of commonly collected indicators. METHODS: A working group representing the 12 teams was established. They undertook an iterative process to consider existing primary care indicators identified from the literature and by stakeholders. Indicators were agreed upon with the intention of addressing three objectives across the 12 teams: (1) describing the impact of improving access to CBPHC; (2) examining the impact of alternative models of chronic disease prevention and management in CBPHC; and (3) describing the structures and context that influence the implementation, delivery, cost, and potential for scale-up of CBPHC innovations.FindingsNineteen common indicators within the core dimensions of primary care were identified: access, comprehensiveness, coordination, effectiveness, and equity. We also agreed to collect data on health care costs and utilization within each team. Data sources include surveys, health administrative data, interviews, focus groups, and case studies. Collaboration across these teams sets the foundation for a unique opportunity for new knowledge generation, over and above any knowledge developed by any one team. Keys to success are each team's willingness to engage and commitment to working across teams, funding to support this collaboration, and distributed leadership across the working group. Reaching consensus on collection of common indicators is challenging but achievable.

Challenges Associated with Cross-Jurisdictional Analyses using Administrative Health Data and Primary Care Electronic Medical Records in Canada.

Over the last 30 years, public investments in Canada and many other countries have created clinical and administrative health data repositories to support research on health and social services, population health and health policy. However, there is limited capacity to share and use data across jurisdictional boundaries, in part because of inefficient and cumbersome procedures to access these data and gain approval for their use in research. A lack of harmonization among variables and indicators makes it difficult to compare research among jurisdictions. These challenges affect the quality, scope, and impact of work that could be done. The purpose of this paper is to compare and contrast the data access procedures in three Canadian jurisdictions (Manitoba, Alberta and British Columbia), and to describe how we addressed the challenges presented by differences in data governance and architecture in a Canadian cross-jurisdictional research study. We characterize common stages in gaining access to administrative data among jurisdictions, including obtaining ethics approval, applying for data access from data custodians, and ensuring the extracted data is released to accredited individuals in secure data environments. We identify advantages of Manitoba’s flexible ‘stewardship’ model over the more restrictive ‘custodianship’ model in British Columbia, and highlight the importance of communication between analysts in each jurisdiction to compensate for differences in coding variables and poor quality data. Researchers and system planners must have access to and be able to make effective use of administrative health data to ensure that Canadians continue to have access to high-quality health care and benefit from effective health policies. The considerable benefits of collaborative population-based research that spans jurisdictional borders have been recognized by the Canadian Institutes for Health Research in their recent call for the creation of a National Data Platform to resolve many of the issues in harmonization and validation of administrative data elements.

Output from the CIHR Canadian HIV Trials Network international postdoctoral fellowship for capacity building in HIV clinical trials.

As a response to the human immunodeficiency virus (HIV) epidemic and part of Canadian Institutes for Health Research’s mandate to support international health research capacity building, the Canadian Institutes for Health Research Canadian HIV Trial Network (CTN) developed an international postdoctoral fellowship award under the CTN’s Postdoctoral Fellowship Awards Program to support and train young HIV researchers in resource-limited settings. Since 2010, the fellowship has been awarded to eight fellows in Cameroon, China, Lesotho, South Africa, Uganda and Zambia. These fellows have conducted research on a wide variety of topics and have built a strong network of collaboration and scientific productivity, with 40 peer-reviewed publications produced by six fellows during their fellowships. They delivered two workshops at international conferences and have continued to secure funding for their research, using the fellowship as a stepping stone. The CTN has been successful in building local HIV research capacity and forming a strong network of like-minded junior low- and middle-income country researchers with high levels of research productivity. They have developed into mentors, supervisors and faculty members, who, in turn, build local capacity. The sustainability of this international fellowship award relies on the recognition of its strengths and the involvement of other stakeholders for additional resources.

Common Hospital Ingredient Perfusate Equivalent to Standard Krebs–Henseleit Buffer with Serum Albumin Derived Perfusate in Negative Pressure Ventilation Ex Vivo Lung Perfusion

Introduction Normothermic ex-vivo lung perfusion (EVLP) using negative pressure ventilation (NPV) and red blood cell-based perfusate solutions have been shown to decrease edema formation and pro-inflammatory cytokine production compared to positive pressure ventilation (PPV). We sought to develop a common hospital ingredient derived perfusate (CHIP) with equivalent functional and inflammatory characteristics to the standard Krebs–Henseleit buffer with 8% serum albumin derived perfusate (KHB-Alb) in order to improve access and reduce costs of ex vivo organ perfusion. Methods Porcine lungs were perfused using NPV-EVLP for 12 hours in a normothermic state, and were allocated to two groups: KHB-Alb (n=8) vs CHIP (n=4). Physiologic parameters, cytokine profiles, and edema formation were compared between treatment groups. Results Perfused lungs in both groups demonstrated equivalent oxygenation (partial pressure of arterial oxygen/ fraction of inspired oxygen ratio >350 mmHg) and physiologic parameters. There was equivalent generation of tumor necrosis factor-α, irrespective of perfusate solution used, when comparing CHIP vs KHB-Alb. Pig lungs developed equivalent edema formation between groups (CHIP: 15.7 ± 5.8%, STEEN 19.5 ± 4.4%, p>0.05). Conclusion A perfusate derived of common hospital ingredients provides equivalent results to standard Krebs–Henseleit buffer with 8% serum albumin based perfusate in NPV-EVLP. Canadian Institutes for Health Research - Canadian National Transplant Research Program (CIHR-CNTRP). University Hospital Foundation (UHF). Mazankowski Alberta Heart Institute - University Hospital Foundation Gerald Averback Award in Cardiovascular Gene Therapy / Genomics and Vascular Biology.

Combined Topical Growth Factor and Protease Inhibitor in Chronic Wound Healing: Protocol for a Randomized Controlled Proof-of-Concept Study.

BackgroundLeg ulcers due to venous disease are chronic wounds that can take 6 or more months to heal. Growth factors have been used to try and improve this healing; however, many such studies have failed, and that is thought to be due to enzymes in the wound that degrade the growth factors and prevent them from working.ObjectiveThis is a proof-of-concept study that will evaluate the treatment of chronic leg ulcers with topically applied growth factors that are combined with a therapy to prevent their inactivation in the wound. This combined therapy has the potential to speed up the healing of these wounds and thereby improve the quality of life of patients and reduce the costs to the health system.MethodsThis will be a double-blind, placebo-controlled, randomized controlled proof-of-concept study comparing growth factor with protease inhibitor wound dressings to growth factors with standard wound dressings.ResultsThe project was funded by the Canadian Institutes for Health Research and enrollment is expected to be initiated in 2018. It is expected that results will be available in 2021.ConclusionsIt is expected that the results of this trial will inform as to whether modifying the wound environment through the use of protease inhibitors increases the effectiveness of topically applied growth factors in the healing of chronic wounds.Trial RegistrationClinicalTrials.gov NCT02845466; https://clinicaltrials.gov/ct2/show/NCT02845466 (Archived by WebCite at http://www.webcitation.org/6yOPhSBUA)

Identification of FZD5 as Genetic Vulnerability in RNF43 Mutant Cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and novel effective treatments are greatly needed. Recent research revealed that a subset of PDAC cell lines is dependent on the Wnt cell‐signaling pathway for cell proliferation and survival. Wnt‐dependent PDAC all contain mutations in the gene encoding RNF43. RNF43 acts as a negative regulator of the Wnt pathway through ubiquitination and degradation of the Frizzled (FZD) family of Wnt receptors. RNF43 mutation status may therefore serve as a suitable biomarker for targeted therapy against the Wnt pathway in PDAC. In order to find novel genetic vulnerabilities in RNF43 mutant PDAC, we used genome‐wide CRISPR/Cas9 knockout screens in RNF43 mutant and wild‐type PDAC cell lines. Comparison of essential genes between RNF43 mutant and wild‐type groups was used to find context‐dependent essential genes for the RNF43 mutant genotype. This revealed the unexpected unique requirement of FZD5 (one of ten FZD homologs in humans) as a common genetic vulnerability in RNF43 mutant PDAC lines. This finding was validated through cell proliferation assays in vitro in both established cell lines and a primary patient derived cell line containing RNF43 mutation. Monoclonal antibodies derived against FZD5 were found to be remarkably effective as a single agent therapy both in vitro and in vivo, in subcutaneous and orthotopic xenograft models. Anti‐FZD5 biologics represent a novel potential targeted therapy in RNF43 mutant pancreatic cancers.Support or Funding InformationThis work was supported from grants funded by the Canadian Institutes for Health Research to S.A. (CIHR‐273548) and J.M. (CIHR‐342551) and by the Ontario Research Fund to S.S. J.M. holds a Canada Research Chair in Functional Genomics of Cancer and S.A. holds a Canada Research Chair in Functional Architecture of Signal Transduction. Z.S. is supported by a scholarship from the Centre for Pharmaceutical Oncology at the Leslie Dan Faculty of Pharmacy, University of Toronto.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Similarities and Differences in Essential Medicines Lists of 137 Countries: A Quantitative Analysis

Background: Essential medicines lists (EMLs) are intended to include medicines that meet the priority needs of populations and they influence medication access for more than 5 billion people. The World Health Organization (WHO) maintains a Model EML that countries may adapt to their own circumstances. We compared the medicines included in national EMLs with the WHO Model EML, and assessed the extent to which countries' characteristics, such as region, size, and healthcare expenditure accounted for the differences. Methods: In this observational study, we searched the WHO EML repository for national EMLs. The medicines in each national EML were abstracted into an electronic database. We compared each national EML to the WHO Model EML and also to other national EMLs. We used a linear regression model to determine whether the differences were accounted for by geographic region, population size, life expectancy, infant mortality, gross domestic product per capita, and health expenditure per capita. Findings: We identified 137 country EMLs including 2182 medicines at least once. Each national EML contained 44 to 990 medicines (median 310, interquartile range, IQR, 271-426). The number of differences between each country's EML and the WHO Model EML ranged from 63 to 666 (289, 262-369). Linear regression showed that geographical region and health expenditure (140 more differences per $1000 in healthcare expenditure, 95 % CI 51-229) were associated with the number of differences and the adjusted R-squared was 0·33. Most medicines (1363, 62 %) were listed by less than 10 % of countries. Interpretation: The substantial differences between national EMLs are not easily explained by differences in country characteristics and thus may not be related to different priority needs. Most medicines are listed by a small number of countries. This information helps to identify specific opportunities to improve EMLs. Funding Statement: Canadian Institutes of Health Research and Ontario SPOR (Strategy for Patient Oriented Research) Support Unit. Declaration of Interests: NP reports grants from Canadian Institutes for Health Research, the Ontario SPOR Support Unit, and Physicians Services Incorporated during the conduct of the study. JKA has written reviews, commentaries, and medicolegal reports on various aspects of prescribing, and has sometimes received remuneration. AP reports grants from NIHR, grants from NIHR School of Primary Care Research, during the conduct of the study; and occasionally receives expenses for teaching Evidence-Based Medicine. CH has received expenses and fees for his media work. CH has received expenses from the WHO and holds grant funding from the NIHR, the NIHR School of Primary Care Research, The Wellcome Trust and is a NIHR Senior Investigator. CH has received financial remuneration from an asbestos case. CH has also received income from the publication of a series of toolkit books published by Blackwell’s. On occasion, CH receives expenses for teaching EBM and is also paid for his GP work in NHS out of hours. All other authors declare no competing interests. Ethics Approval Statement: No ethics approval was sought for this review of publicly available information.

Effect of air quality alerts on human health: a regression discontinuity analysis in Toronto, Canada

Ambient air pollution is a major health risk globally. To reduce adverse health effects on days when air pollution is high, government agencies worldwide have implemented air quality alert programmes. Despite their widespread use, little is known about whether these programmes produce any observable public-health benefits. We assessed the effectiveness of such programmes using a quasi-experimental approach. We assembled a population-based cohort comprising all individuals who resided in the city of Toronto (Ontario, Canada) from 2003 to 2012 (about 2·6 million people). We ascertained seven health outcomes known to be affected by short-term elevation of air pollution, using provincial health administrative databases. These health outcomes were cardiovascular-related mortality, respiratory-related mortality, and hospital admissions or emergency-department visits for acute myocardial infarction, heart failure, stroke, asthma, and chronic obstructive pulmonary disease (COPD). We applied a regression discontinuity design to assess the effectiveness of an intervention (ie, the air quality alert programme). To quantify the effect of the air quality alert programme, we estimated for each outcome both the absolute rate difference and the rate ratio attributable to programme eligibility (by intention-to-treat analysis) and the alerts themselves (by two-stage regression approach), respectively. Between Jan 1, 2003, and Dec 31, 2012, on average between three and 27 daily cardiovascular or respiratory events were reported in Toronto (depending on the outcome). Alert announcements reduced asthma-related emergency-department visits by 4·73 cases per 1 000 000 people per day (95% CI 0·55-9·38), or in relative terms by 25% (95% CI 1-47). Programme eligibility also led to 2·05 (95% CI 0·07-4·00) fewer daily emergency-department visits for asthma. We did not detect a significant reduction in any other health outcome as a result of alert announcements or programme eligibility. However, a non-significant trend was noted towards decreased asthma-related and COPD-related admissions. In this population-based cohort, the air quality alert programme was related to some reductions in respiratory morbidity, but not any other health outcome examined. This finding suggests that issuing air quality alerts alone has a limited effect on public health and that implementing enforced public actions to reduce air pollution on high pollution days could be warranted. Together with accumulating evidence of substantial burden from long-term air pollution exposure, this study underscores the need for further strengthening of global efforts that can lead to long-term improvement of overall air quality. Public Health Ontario, Canadian Institutes for Health Research.

Red blood cell storage and in-hospital mortality: a secondary analysis of the INFORM randomised controlled trial

No randomised trials have addressed whether exposure to red blood cells (RBCs) stored longer than 35 days is associated with harm in patients. We aimed to assess the risk of in-hospital mortality associated with transfusing blood stored longer than 35 days. We did a secondary analysis of the INforming Fresh versus Old Red cell Management (INFORM) trial, a pragmatic, multicentre, randomised controlled trial of patients (≥18 years) admitted to one of six hospitals in Australia, Canada, Israel, and the USA and expected to need RBC transfusions. Patients were randomly assigned (2:1) to receive blood in inventory stored for the longest time (standard care) or the shortest time, using a random allocation schedule and stratified by centre and patient ABO blood group. The primary objective of the INFORM trial was to assess all-cause in-hospital mortality in patients with blood group A and O who were transfused. For our exploratory secondary analysis, we classified individuals into one of three mutually exclusive exposure categories on the basis of the maximum storage duration of any blood unit patients had received on each day in hospital: exclusively exposed to RBCs stored no longer than 7 days, exposed to at least one unit of RBCs stored 8-35 days, and exposed to least one unit of RBCs stored longer than 35 days. Our primary objective was to determine the effect on risk of in-hospital death of time-dependent exposure to RBCs stored longer than 35 days compared with exclusive exposure to RBCs stored no longer than 7 days, both in patients of blood groups A and O and all patients. The INFORM trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN08118744. Between April 2, 2012, and Oct 21, 2015, 31 497 patients were recruited, and 24 736 patients were eligible for inclusion in this analysis. We excluded nine patients for whom information about the storage duration of transfused blood was missing and one patient whose sex was unknown. 4480 (18%) patients were exposed to RBCs with longest storage, 1392 (6%) patients were exposed exclusively to RBCs with shortest storage, and 18 854 (76%) patients were exposed to RBCs stored 8-35 days. Median follow-up was 11 days (IQR 6-20). Exposure to RBCs stored longer than 35 days was not associated with increased risk of in-hospital death compared with exclusive exposure to the freshest RBC units after adjusting for demographic variables, diagnosis category, and blood product use history (in patients with blood group A or O: hazard ratio 0·94, 95% CI 0·73-1·20, p=0·60; in all patients: 0·91, 0·72-1·14, p=0·40). The risk of in-hospital death also did not differ between patients exposed to blood stored 8-35 days and patients exposed to blood stored 7 days or less (in patients with blood group A or O: 0·92, 0·74-1·15, p=0·48; in all patients: 0·90, 0·73-1·10, p=0·29). These data provide evidence that transfusion of blood stored for longer than 35 days has no effect on in-hospital mortality, which suggests that current approaches to blood storage and inventory management are reasonable. Canadian Institutes for Health Research, Canadian Blood Services, and Health Canada.

Reprogramming and Recapitulating T Cells in the Immature Immune Environment of the Neonate to Induce Transplant Tolerance

Introduction: Semi-allogeneic bone marrow and spleen cells (BMC/SC) induce transplant tolerance in neonatal mice whereas allogeneic BMC/SC cause lethal graft-versus-host disease (GVHD). To prevent aGVHD and induce transplant tolerance with allo-SC/BMC we reprogrammed donor/host CD4 T cells by co-stimulation blockade to preserve regulatory CD4 T cells while recapitulating depleted donor/host CD8 T cells. Methods: C3H (H-2k) neonatal mice were injected iv with total or depleted B6 (H-2b) GFP+ SC/BMC. CD8 T and CD49b NK cells were depleted from donor inocula using StemCell Technologies kits. In vivo neonatal host CD8 T cells were depleted (Mab 53–6.7) and donor/host CD4 T cells reprogrammed (CD154 Mab MR1). Trafficking and interactions of injected cells were monitored by microscopy. Tolerance induction was assessed by transplanting treated mice as adults with donor-type hearts. Results: Neonatal mice injected with GFP+ allo-SC/BMC developed aGVHD, with diarrhea, reduced growth and early death. GFP+ cells proliferated and spread throughout injected mice indicating systemic inflammation. Depletion of donor/host CD8 T cells together with co-stimulation blockade of donor/host CD4 T cells (CD154) resulted in GFP signal being reduced and restricted to lymphoid organs (day 6). High resolution microscopy showed donor T and B cells positioned respectively in PALS and follicular regions of host spleen; lack of Ki67 immunostaining indicated many donor cells were not proliferating. Donor DC were detected in host thymus (day 6) suggesting a possible role in central tolerance. Donor-type B6 hearts transplanted into neonatally-treated adult C3H mice (n=5) (CD8 depleted/CD4 co-stimulation blockade) all continued to beat at 100 days post-transplant, 3 grafts with maximal strength and 2 grafts with diminished strength. In untreated control mice (n=3) donor-type hearts stopped beating by day 10. H&E staining of a strongly beating B6 heart graft at 100 days showed undamaged cardiomyocytes with little if any cellular infiltrate and absence of macrophages and T cells by immunostaining. Conclusion: Reprograming CD4 T cells while depleting/recapitulating CD8 T cells in allo-SC/BMC treated neonates leads to 100% cardiac allograft survival at 100days; low beat scores in 2/5 grafts suggests further optimization is required. These findings provide insight into robust tolerance induction in neonates. This project was supported with funding from the Canadian Institutes for Health Research and the Gordon English family.

1072 SLEEP TRAJECTORIES FROM ADOLESCENCE TO ADULTHOOD AND THEIR RELATIONSHIP WITH HEALTH OUTCOMES

Sleep is linked to physiological and mental health outcomes. However, little is known about sleep trajectories from adolescence to adulthood and their relationship with health outcomes. We examined sleep trajectories and their relationship with cardiometabolic and mental health in a representative sample over 16 years. We tracked participants between 1997 and 2013 from the Panel Study of Income Dynamics study and the Child Development and Transition into Adulthood Supplements (n=3,118; age 10-17y at baseline) who reported their sleep duration up to six times during the study. We used latent class growth modelling to identify distinct sleep trajectories (long sleep (8.7% of the sample), average sleep (72.5%), and short sleep (18.8%)) and assessed their relationship with self-rated health, high blood pressure, obesity, and mental health using logistic and linear regressions controlling for the year of birth. Compared to the average sleep trajectory, both short and long sleep trajectories were associated with higher odds of poor or fair self-rated health (OR (95% CI), p-value): 1.82 (1.16, 2.84), p=0.01 and 1.89 (0.98, 3.63), p=0.06, respectively). Both short and long sleep trajectories also had greater mental health problems in adulthood (OR 1.66 (1.11, 2.49), p=0.01) and 1.99 (1.07, 3.69), p=0.03), respectively). Only the trajectory of short sleep was associated with higher odds of having high blood pressure (OR 1.81 (1.06, 3.12), p=0.03), greater distress (β (95% CI), p-value: 1.51 (0.73, 2.28), p<0.01) and lower mental well-being (β -0.63 (-1.15, -0.10, p=0.02)) compared to average sleep trajectory. We found no significant association between sleep trajectories and obesity. We found evidence that short and long sleep trajectories from adolescence to adulthood are linked to poor physiological and mental health outcomes in adulthood. Individuals that follow a trajectory of short sleep seemed particularly vulnerable to poor mental well-being as young adults. Additional research is needed to extend our understanding of the relationship between sleep trajectories over the lifespan and their effect health outcomes. GG is supported by a postdoctoral fellowship from the Canadian Institutes for Health Research. FJE is supported by a Canada Research Chairs program.

Comparison of the Impact of High‐Dose DHA and EPA Supplementation on the Intravascular Kinetics of Very‐Low Density Lipoprotein Apolipoprotein C‐III

BackgroundApolipoprotein C‐III (apoC‐III) is an emerging risk factor for cardiovascular disease (CVD) and its presence on very‐low density lipoproteins (VLDL) may enhance their atherogenicity, primarily by delaying their rate of catabolism. We have shown in a recent study that high‐dose supplementation with docosahexaenoic acid (DHA) led to more pronounced reductions in TG compared with eicosapentaenoic acid (EPA), but mechanisms remain unclear. The objective of this study was to compare the individual effect of EPA and DHA on VLDL‐apoC‐III metabolism in men and women at risk of CVD.MethodsIn a randomized double‐blind crossover trial, 10 men and 8 women with abdominal obesity and low‐grade inflammation were subjected to three 10‐wk supplementation phases: 1) EPA (2.7 g/d); 2) DHA (2.7 g/d); 3) corn oil (0g DHA, 0g EPA, control), separated by a 9‐wk washout. All supplements were provided as 3×1g capsules for a total of 3g/d. After each dietary intervention, subjects received a primed‐constant infusion of [5,5,5‐D(3)]‐L‐leucine for 12h under constant feeding conditions for the determination of VLDL‐apoC‐III kinetics.ResultsBoth DHA (−11.7%, p=0.01) and EPA (−6.4%, p=0.03) similarly reduced the fractional catabolism rate (FCR) of VLDL‐apoC‐III compared with control (p=0.75 between DHA and EPA). On the other hand, neither DHA nor EPA supplementation had a significant impact on VLDL‐apoC‐III concentrations and production rate (PR). Compared with control, DHA‐ and EPA‐induced reductions in TG were correlated with DHA‐ and EPA‐induced variations in VLDL‐apoC‐III PR (r=0.49, p=0.03 and r=0.48, p=0.05 respectively), but not with changes in VLDL‐apoC‐III FCR.ConclusionsHigh‐dose supplementation with DHA or EPA is associated with reduced clearance of VLDL‐apoC‐III, with no effect, however, on VLDL‐apoC‐III concentrations and production. Although the DHA‐ and EPA‐induced reductions in serum TG may be more sensitive to treatment‐induced variations in VLDL‐apoC‐III production, other mechanisms must be investigated to explain why DHA may reduce serum TG more than EPA.Support or Funding InformationFinancial support for this RCT was provided exclusively by a grant from the Canadian Institutes for Health Research (MOP‐123494). Douglas Laboratories provided the EPA, DHA and placebo capsules used in this study. The funding source was not involved in the study design, conduct of the study, or collection, management, analysis, or interpretation of the data or in the preparation or review of the manuscript and had no right to approve or disapprove of the submitted manuscript. CV is a fellow of the French Foundation for Medical Research (FRM, file code: 40303). JA is a recipient of a PhD Scholarships from the Canadian Institutes for Health Research and the Fonds de recherche du Québec – Santé.

Emergence of drug resistance in patients with tuberculosis cared for by the Indian health-care system: a dynamic modelling study

India has the highest number of patients with tuberculosis and multidrug-resistant tuberculosis in the world. We used a transmission model to project the emergence of drug resistance in India due to incorrect tuberculosis management practices in multiple sectors, including public and private providers, chemists, and non-allopathic practitioners. We constructed a dynamic Markov model to represent India's tuberculosis epidemic, including a probabilistic framework reflecting complex treatment-seeking pathways. Underlying drug resistance and the acquisition of drug resistance during treatment were included. India-specific epidemiological data, including tuberculosis management practices, were obtained from published literature. Outcomes, which included annual risk of infection, incidence of new disease, prevalence of untreated tuberculosis, and tuberculosis-related mortality, were stratified by underlying drug resistance, as well as by health sector to understand how each sector contributes to the emergence of drug resistance. If tuberculosis management practices across sectors in India remain unchanged over the next 20 years, we estimated a 47% increase in the incidence of isoniazid resistance, a 152% increase in multidrug-resistant tuberculosis incidence, a 242% increase in prevalent untreated multidrug-resistant tuberculosis, and a 275% increase in the risk of multidrug-resistant tuberculosis infection. By 2032, an estimated 85% of multidrug-resistant tuberculosis will be primary multidrug-resistant tuberculosis compared with only 15% in 2012. The public sector contributed 87% of acquired multidrug-resistant tuberculosis, related to irregular adherence; the remainder came from the private sector, related to treatment non-completion. Chemists and non-allopathic practitioners do not treat with rifampicin, but because of the high rates of inappropriate isoniazid-containing regimens, and treatment non-adherence, this would generate isoniazid resistance. We predict a gradual transformation from the current epidemic of drug-susceptible tuberculosis to a drug-resistant epidemic. Evidence-based strategies to improve provider practices and patient adherence across health sectors are urgently needed to prevent this. United States Agency for International Development and the Canadian Institutes for Health Research.

Should Canada focus on antimicrobial resistance?

The Canadian Institutes for Health Research’s new global health research guru wants Ottawa to put antimicrobial resistance on its list of foreign-aid research priorities. Speaking in Vancouver on Nov. 15 at Health Systems Research 2016, a biennial conference that attracted 2000 delegates from 101

Acute Blood Pressure Management in Intracerebral Hemorrhage: Equipoise Resists an Attack.

There are 2 competing rationales for acute blood pressure (BP) management in primary intracerebral hemorrhage (ICH). A conservative approach is predicated on the possibility that cerebral blood flow is passively dependent on perfusion pressure, whereas an aggressive approach has been hypothesized to improve outcomes via a reduction in early hematoma expansion. Although the latter is a biologically plausible hypothesis, this relationship has not been consistently demonstrated in retrospective or prospective studies, likely reflecting the fact that hematoma expansion is dependent on multiple factors, in particular the time from symptom onset to diagnostic scan, and baseline volume.1 The most effective way to address this clinical equipoise is, therefore, a randomized controlled trial of the 2 different BP management strategies. In the ATACH-II trial (Antihypertensive Treatment of Acute Cerebral Hemorrhage II), 1000 patients were randomized to a systolic BP (SBP) target of 110 to 139 mm Hg or 140 to 179 mm Hg, after the Data Safety Monitoring Board–recommended trial suspension on the basis of a futility analysis.2 Despite a robust and early difference in achieved BP between the 2 groups, the 90-day mortality and disability rate was unaffected (38.7% versus 37.7%; P =0.84). The reasons for this lack of treatment effect are not clear. There was no effect on the frequency of hematoma expansion, although the trend was in favor …

Live Attenuated Versus Inactivated Influenza Vaccine in Hutterite Children

Whether vaccinating children with intranasal live attenuated influenza vaccine (LAIV) is more effective than inactivated influenza vaccine (IIV) in providing both direct protection in vaccinated persons and herd protection in unvaccinated persons is uncertain. Hutterite colonies, where members live in close-knit, small rural communities in which influenza virus infection regularly occurs, offer an opportunity to address this question. To determine whether vaccinating children and adolescents with LAIV provides better community protection than IIV. A cluster randomized blinded trial conducted between October 2012 and May 2015 over 3 influenza seasons. (ClinicalTrials.gov: NCT01653015). 52 Hutterite colonies in Alberta and Saskatchewan, Canada. 1186 Canadian children and adolescents aged 36 months to 15 years who received the study vaccine and 3425 community members who did not. Children were randomly assigned according to community in a blinded manner to receive standard dosing of either trivalent LAIV or trivalent IIV. The primary outcome was reverse transcriptase polymerase chain reaction-confirmed influenza A or B virus in all participants (vaccinated children and persons who did not receive the study vaccine). Mean vaccine coverage among children in the LAIV group was 76.9% versus 72.3% in the IIV group. Influenza virus infection occurred at a rate of 5.3% (295 of 5560 person-years) in the LAIV group versus 5.2% (304 of 5810 person-years) in the IIV group. The hazard ratio comparing LAIV with IIV for influenza A or B virus was 1.03 (95% CI, 0.85 to 1.24). The study was conducted in Hutterite communities, which may limit generalizability. Immunizing children with LAIV does not provide better community protection against influenza than IIV. The Canadian Institutes for Health Research.

Near real-time monitoring of HIV transmission hotspots from routine HIV genotyping: an implementation case study

BackgroundDue to the rapid evolution of HIV, infections with similar genetic sequences are likely to be related by recent transmission events. Clusters of related infections can represent subpopulations with high rates of HIV transmission. Here we describe the implementation of an automated “near real-time” system using clustering analysis of routinely collected HIV resistance genotypes to monitor and characterize HIV transmission hotspots in British Columbia (BC).MethodsA monitoring system was implemented on the BC Drug Treatment Database, which currently holds over 32000 anonymized HIV genotypes for nearly 9000 residents of BC living with HIV. On average, five to six new HIV genotypes are deposited in the database every day, which triggers an automated re-analysis of the entire database. Clusters of five or more individuals were extracted on the basis of short phylogenetic distances between their respective HIV sequences. Monthly reports on the growth and characteristics of clusters were generated by the system and distributed to public health officers.FindingsIn June 2014, the monitoring system detected the expansion of a cluster by 11 new cases over three months, including eight cases with transmitted drug resistance. This cluster generally comprised young men who have sex with men. The subsequent report precipitated an enhanced public health follow-up to ensure linkage to care and treatment initiation in the affected subpopulation. Of the nine cases associated with this follow-up, all had already been linked to care and five cases had started treatment. Subsequent to the follow-up, three additional cases started treatment and the majority of cases achieved suppressed viral loads. Over the following 12 months, 12 new cases were detected in this cluster with a marked reduction in the onward transmission of drug resistance.InterpretationOur findings demonstrate the first application of an automated phylogenetic system monitoring a clinical database to detect a recent HIV outbreak and support the ensuing public health response. By making secondary use of routinely collected HIV genotypes, this approach is cost-effective, attains near realtime monitoring of new cases, and can be implemented in all settings where HIV genotyping is the standard of care.FundingThis work was supported by the BC Centre for Excellence in HIV/AIDS and by grants from the Canadian Institutes for Health Research (CIHR HOP-111406, HOP-107544), the Genome BC, Genome Canada and CIHR Partnership in Genomics and Personalized Health (Large-Scale Applied Research Project HIV142 contract to PRH, JSGM, and AFYP), and by the US National Institute on Drug Abuse (1-R01-DA036307-01, 5-R01-031055-02, R01-DA021525-06, and R01-DA011591).

Feeding a Maternal Diet Enriched in Docosahexaenoic Acid to Lactating Dams Improves the Ex Vivo Tolerance Response to Egg Protein in Suckled Pups

An important T cell mediated process that occurs early in life is the development of oral tolerance (OT). Food allergies are believed to be the result of a failure to develop OT to a dietary antigen. The objective of this study was to determine the effect of feeding a maternal diet supplemented with docosahexaenoic acid (DHA) while containing adequate amounts of arachidonic acid (AA) during the suckling period on the development of the immune system and OT in offspring.Sprague‐Dawley dams were randomized to one of the two nutritionally adequate experimental diets 24–48h prior to parturition: control diet (N=12, 0.4% AA and 0% DHA of total fatty acids) or high DHA diet (N=8, 0.4% AA and 0.9% DHA of total fatty acids). Diets were fed to dams ad libitum throughout the suckling period (21 days) and matched for macronutrient, micronutrient and fatty acid content differing only in the composition of omega‐3. At 14‐days pups from each dam were randomly assigned to a mucosal OT challenge for 5 days: placebo (sucrose) or ovalbumin (OVA). At 3 weeks, pups were euthanized and immune cell phenotypes and cytokine production by mitogen‐ (Concanavalin A (ConA), lipopolysaccharide (LPS)) or OVA‐stimulated splenocytes were measured by direct immunofluorescence assay and ELISA, respectively.Feeding dams a high DHA diet increased the proportion of DHA and AA found in breast milk vs. the control diet (both P&lt;0.01). Regardless of the OT challenge, feeding a high DHA diet led to a higher production of interferon‐γ by splenocytes stimulated with ConA and a higher production of interleukin (IL)‐6, IL‐10 and tumor necrosis factor‐α after LPS stimulation (all P&lt;0.05). OVA‐stimulated splenocytes from suckled pups fed the high DHA diet produced significantly more IL‐10 and less transforming growth factor‐β compared to the control diet (both P&lt;0.02), suggestive of better OT. The OT challenge with OVA resulted in a lower production of IL‐6 by LPS‐stimulated splenocytes and led to a higher proportion of cytotoxic T cells expressing CD28 and total cells expressing CD27 (all P&lt;0.02) compared to non‐tolerized pups.Our results suggest that feeding a maternal diet enriched in DHA during the suckling period improves the ability of splenocytes to respond ex vivo to mitogens and the tolerance response to a dietary antigen. Irrespective of the suckling diet, pups who had been orally tolerized to OVA had a lower response to a bacterial antigen despite the presence of more activated T cells and memory immune cells.Support or Funding InformationSupported from the Natural Sciences and Engineering Research Council of Canada. CR holds a scholarship from Canadian Institutes for Health Research and Fonds de recherche en santé du Québec.

Transdisciplinary tour-de-force: The Canadian National Transplant Research Program.

The Canadian National Transplant Research Program, launched in 2013 with funding from the Canadian Institutes for Health Research and partners, bridges research in the fields of solid organ transplant, hematopoietic cell transplant, and organ donation. We describe the philosophy, structure, accomplishments, and challenges faced by the Canadian National Transplant Research Program to expand on facilitators and overcome roadblocks to successfully developing a transdisciplinary national research structure.

Microgels as vehicles for effective delivery of hydrophilic drugs to the brain

Event Abstract Back to Event Microgels as vehicles for effective delivery of hydrophilic drugs to the brain Madeline Simpson1, Justin Piazza2, Yogesh K. Katare2, Sharnpreet K. Kooner2, Niels B. Smeets1, Ram K. Mishra2 and Todd Hoare1 1 McMaster University, Department of Chemical Engineering, Canada 2 McMaster University, Department of Psychiatry and Behavioural Neuroscience, Canada Introduction: The treatment of central nervous system (CNS) disorders is challenging due to difficulties in drug transport across the blood-brain barrier (BBB). Nanoparticle-based therapies are of interest as they can be designed for specific targets, to control drug release, and lower the required dosage for therapeutic intervention. Degradable microgels (hydrogel-based nanoparticles) composed of poly(oligoethylene glycol methacrylate) (POEGMA), are promising delivery vehicles which have demonstrated protein-repellent properties[1]. In comparison to “hard” nanoparticles widely cited to cross the BBB with diameters of <150 nm[2], we show that larger elastic microgels can be transported across the BBB, which can improve drug loading and biodistribution of the hydrophilic drug 3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide) (PAOPA). This drug is a positive allosteric modulator that selectively targets the dopamine D2 receptor and has been demonstrated to reduce the negative symptoms of schizophrenia in animal models[3]. Materials and Methods: POEGMA-based microgels were synthesized by precipitation polymerization of diethylene glycol methacrylate, acrylic acid (AA) and 2-hydroxyethyl disulfide dimethacrylate (degradable crosslinker) with various quantities of sodium dodecyl sulfate (SDS). The AA groups were functionalized using carbodiimide chemistry with Solanum tuberosum lectin (STL) which enables binding to the nasal epithelium for intranasal delivery. Microgel characterisation was carried out by light scattering (size), transmission electron microscopy (morphology) and conductometric titration (functional group content). PAOPA was passively loaded, with excess drug removed by centrifugation. The in vitro drug release was assessed using HPLC, and microgel cytotoxicity was determined by an MTT assay using RPMI 2650 nasal septum and SH-SY5Y dopamine 2D receptor-transduced neuronal cells. Rhodamine-labelled microgels were injected into the peritoneum of male Sprague-Dawley rats to assess the in vivo biodistribution of different microgel sizes. Blood and tissues were recovered after one hour and analyzed using fluorescence to quantify microgel biodistribution. Results and Discussion: Microgels with sizes of 99±2 nm, 152±3 nm, and 249±4 nm can be prepared with low polydipsersity (<0.1). PAOPA was loaded with an encapsulation efficiency of 30±2%, independent of size. The diffusion of PAOPA from the two smallest microgels occured over four days, with 50% of the drug still retained after 24 hours (Figure 1) while the largest microgel prolonged release to five days. The biodistribution studies with the rhodamine-labelled microgels demonstrated that the smallest microgels were the most effective at crossing the BBB; however the largest microgels were transported in significant numbers despite their larger size than the 150 nm limit cited while also accumulating less in major non-target organs (Figure 2). In vivo efficacy studies as a function of microgel size in a rat schitzophrenia model will be presented. Conclusion: POEGMA microgels are effective delivery vehicles for the transport of hydrophilic drugs across the BBB. Due to their elastic nature, larger microgels may be advantageous as the compressibility may enable the delivery of bigger, longer circulating, and more highly drug loaded particles across tight biological barriers. Canadian Institutes for Health Research (CIHR); Natural Sciences and Engineering Research Council of Canada (NSERC)