The Full SPECTRUM: Developing a Tripartite Partnership between Community, Government and Academia for Collaborative Social Policy Research

Problem: In Canadian society, public policies guide the development and administration of social services and systems, including the public education system, the justice system, family services, social housing and income support. However, because social services are often planned and implemented in a ‘siloed’ manner, coordination and collaboration across departments, sectors and organisations is sorely lacking. Data and resource constraints may prevent services being evaluated to ensure they meet the needs of the people for whom they are intended. When the needs of individuals are not addressed, the result is poor outcomes and wasted resources across multiple areas.Our Response: In 2018, we formed the SPECTRUM Partnership in response to a recognised need for collaborative cross-sector approaches to strengthening the policies that shape social services and systems in our country. The tripartite SPECTRUM partnership comprises representatives from community organisations, government and academia, and is an entity designed to conduct social policy research and evaluation, incorporating interdisciplinary perspectives and expertise from its members. Guided by community-driven research questions and building on existing data resources, SPECTRUM seeks to address specific knowledge gaps in social programs, services and systems. New research findings are then translated into viable public policy options, in alignment with government priorities, and presented to policy-makers for consideration.Implications: In this practice-based article, we describe the key steps we took to create the SPECTRUM partnership, build our collective capacity for research and evaluation, and transform our research findings into actionable evidence to support sound public policy. We outline four of SPECTRUM’s achievements to date in the hope that the lessons we learned during the development of the partnership may serve as a guide for others aiming to optimise public policy development in a collaborative evidence-based way

Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders

Purpose: Liver transplantation (LTx) is performed in individuals with urea cycle disorders when medical management (MM) insufficiently prevents the occurrence of hyperammonemic events. However, there is a paucity of systematic analyses on the effects of LTx on health-related outcome parameters compared to individuals with comparable severity who are medically managed. Methods: We investigated the effects of LTx and MM on validated health-related outcome parameters, including the metabolic disease course, linear growth, and neurocognitive outcomes. Individuals were stratified into “severe” and “attenuated” categories based on the genotype-specific and validated in vitro enzyme activity. Results: LTx enabled metabolic stability by prevention of further hyperammonemic events after transplantation and was associated with a more favorable growth outcome compared with individuals remaining under MM. However, neurocognitive outcome in individuals with LTx did not differ from the medically managed counterparts as reflected by the frequency of motor abnormality and cognitive standard deviation score at last observation. Conclusion: Whereas LTx enabled metabolic stability without further need of protein restriction or nitrogen-scavenging therapy and was associated with a more favorable growth outcome, LTx—as currently performed—was not associated with improved neurocognitive outcomes compared with long-term MM in the investigated urea cycle disorders.</p

Helicobacter pylori Perturbs Iron Trafficking in the Epithelium to Grow on the Cell Surface

Helicobacter pylori (Hp) injects the CagA effector protein into host epithelial cells and induces growth factor-like signaling, perturbs cell-cell junctions, and alters host cell polarity. This enables Hp to grow as microcolonies adhered to the host cell surface even in conditions that do not support growth of free-swimming bacteria. We hypothesized that CagA alters host cell physiology to allow Hp to obtain specific nutrients from or across the epithelial barrier. Using a polarized epithelium model system, we find that isogenic ΔcagA mutants are defective in cell surface microcolony formation, but exogenous addition of iron to the apical medium partially rescues this defect, suggesting that one of CagA's effects on host cells is to facilitate iron acquisition from the host. Hp adhered to the apical epithelial surface increase basolateral uptake of transferrin and induce its transcytosis in a CagA-dependent manner. Both CagA and VacA contribute to the perturbation of transferrin recycling, since VacA is involved in apical mislocalization of the transferrin receptor to sites of bacterial attachment. To determine if the transferrin recycling pathway is involved in Hp colonization of the cell surface, we silenced transferrin receptor expression during infection. This resulted in a reduced ability of Hp to colonize the polarized epithelium. To test whether CagA is important in promoting iron acquisition in vivo, we compared colonization of Hp in iron-replete vs. iron-deficient Mongolian gerbils. While wild type Hp and ΔcagA mutants colonized iron-replete gerbils at similar levels, ΔcagA mutants are markedly impaired in colonizing iron-deficient gerbils. Our study indicates that CagA and VacA act in concert to usurp the polarized process of host cell iron uptake, allowing Hp to use the cell surface as a replicative niche

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Long-term effects of medical management on growth and weight in individuals with urea cycle disorders

Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs

Correlating Quantitative Fecal Immunochemical Test Results with Neoplastic Findings on Colonoscopy in a Population-Based Colorectal Cancer Screening Program: A Prospective Study

Background and Aims. The Canadian Partnership Against Cancer (CPAC) recommends a fecal immunochemical test- (FIT-) positive predictive value (PPV) for all adenomas of ≥50%. We sought to assess FIT performance among average-risk participants of the British Columbia Colon Screening Program (BCCSP). Methods. From Nov-2013 to Dec-2014 consecutive participants of the BCCSP were assessed. Data was obtained from a prospectively collected database. A single quantitative FIT (NS-Plus, Alfresa Pharma Corporation, Japan) with a cut-off of ≥10 μg/g (≥50 ng/mL) was used. Results. 20,322 FIT-positive participants underwent CSPY. At a FIT cut-off of ≥10 μg/g (≥50 ng/mL) the PPV for all adenomas was 52.0%. Increasing the FIT cut-off to ≥20 μg/g (≥100 ng/mL) would increase the PPV for colorectal cancer (CRC) by 1.5% and for high-risk adenomas (HRAs) by 6.5% at a cost of missing 13.6% of CRCs and 32.4% of HRAs. Conclusions. As the NS-Plus FIT cut-off rises, the PPV for CRC and HRAs increases but at the cost of missed lesions. A cut-off of ≥10 μg/g (≥50 ng/mL) produces a PPV for all adenomas exceeding national recommendations. Health authorities need to take into consideration endoscopic resources when selecting a FIT positivity threshold

Temperament can be an indicator of feedlot performance and carcass merit in beef cattle

Cattle producers historically have selected for docile temperaments simply for management convenience because calmer animals are conducive to safe environments for their peers as well as their handlers. As many producers would acknowledge, however, there seems to be a relationship between temperament and cattle health, and calmer cattle tend to frequent the working chute for treatment of disease less often. Positive correlations have been found in cattle between temperament traits (chute scores, pen scores, and chute exit velocities) and cortisol concentration in the blood, suggesting that more excitable cattle are easily stressed (Curley et al., 2006; Cooke et al., 2009). Curley et al. (2007) also found that easily excitable animals sustain elevated cortisol concentrations for a longer duration and have greater pituitary and adrenal responses following a stressor than calm cattle. Temperamental cattle have significantly higher mean temperament responses at all points (Oliphint, 2006). Higher basal serum cortisol concentrations may suggest that easily excitable cattle are chronically stressed (Curley et al., 2007), possibly resulting in a compromised immune system, illness, and decreased fat and protein deposition. This study was conducted to further investigate the relationships between cattle temperament (measured by chute score and exit velocity), immunological factors, and a range of economically relevant performance traits

Genetic relationships among temperament, immune function, and carcass merit in beef cattle

Cattle producers historically have selected for docile temperaments simply for management convenience because calmer animals are conducive to safe environments for their peers as well as their handlers. As many producers would acknowledge, there seems to be a relationship between temperament and health, and calmer cattle tend to frequent the working chute for treatment of disease less often. Positive correlations have been found in cattle between temperament traits (chute scores, pen scores, and chute exit velocities) and cortisol concentration in the blood, suggesting that more excitable cattle are easily stressed (Curley et al., 2006; Cooke et al., 2009). In addition, Curley et al. (2007) found that easily excitable animals sustain elevated cortisol concentrations for a longer duration and had greater pituitary and adrenal responses following a stressor than calm cattle. Temperamental cattle have significantly higher mean temperament responses at all points (Oliphint, 2006). Higher basal serum cortisol concentrations may suggest that easily excitable cattle are chronically stressed (Curley et al., 2007), possibly resulting in a compromised immune system, illness, and decreased fat and protein deposition. Common measures of cattle temperament are pen scores, chute scores, and exit velocities. Temperament appears to be moderately heritable, with estimates ranging from 0.15 to 0.44 (Burrow and Corbet, 2000; Kadel et al., 2006; Schrode and Hammack, 1971; Stricklin et al., 1980; Fordyce et al., 1988). If genetic correlations are found between temperament and production traits or immunological factors, they may aid cattle breeders in producing profitable cattle. Such relationships have been found between exit velocity and hot carcass weight (r = -0.54), exit velocity and marbling score (r = 0.10), exit velocity and yield grade (r = -0.22) (Nkrumah et al., 2007), and post-weaning weight gain and exit velocity (Weaber et al., 2006). Bovine respiratory disease (BRD) susceptibility has been estimated to be lowly heritable (Muggli-Cockett et al., 1992; Snowder et al., 2005, 2006, 2007; Schneider et al., 2008). This study was conducted to further investigate the genetic relationships between cattle temperament measured by chute score and exit velocity, immunological factors, and a range of economically relevant performance traits

Does Participation in Full-Time Kindergarten Improve Metis Students’ School Outcomes? A Longitudinal Population-Based Study from Manitoba, Canada

As a result of the colonization of Canada, Metis have faced many political and socioeconomic challenges, one of which is the lower educational achievement of Metis students vs other Canadian students. In this study, we examined whether full-time kindergarten (FTK) vs half-time kindergarten (HTK) was associated with improved educational outcomes for Metis students in Manitoba using linked, population-based administrative data from 1998/99-2012/13. The cohort included 271 FTK and 405 HTK Metis students. We used generalized linear models with binomial distribution to calculate predicted probabilities and risk ratios for the outcomes (assessments of numeracy and literacy in Grades 3, 7 and 8; student engagement in Grade 7; high school graduation). However, we observed no significant differences in outcomes between FTK and HTK students, suggesting that FTK is not sufficient to overcome the structural barriers to academic success Metis students may face