Search

Canada is a low-incidence country for tuberculosis (TB). The BC Public Health Laboratory diagnostic algorithm for pulmonary TB includes acid fast bacilli (AFB) smear and mycobacterial culture of all submitted sputa. TB nucleic acid amplification testing (NAT) is routinely performed on AFB-smear-positive (AFB+) sputa only. We assessed the laboratory-associated costs of implementing the international recommendations for TB NAT on AFB-smear-negative (AFB-) sputa.Two data sets were obtained: (1) all AFB- samples for a 3-year period (October 1, 2014-September 30, 2017) and (2) all AFB-, TB-culture-positive samples for the same period. One AFB- sample/patient from each defined diagnostic set of sputa was deemed eligible for TB NAT. To stratify patients by ordering location, a 1-year subset of data (October 1, 2016-September 30, 2017) was examined.In the 3-year period, 0.7% of all diagnostic sets were AFB- and culture-positive. In the 1-year period, the provincial TB Services clinics submitted 26% of all AFB- samples received, but these constituted 78% of AFB-, culture-positive samples.The annual cost of TB NAT on one AFB- sputum sample from each eligible diagnostic set would total approximately $247,000. Targeting only TB Services clinic patients would reduce this cost to approximately $64,000/year while capturing more than 75% of AFB-, culture-positive patients. On the basis of our provincial positivity rate, it would cost approximately $6,000 to provide an early TB diagnosis for an AFB-, culture-positive patient. The cost-effectiveness to public health of this approach in a TB low-incidence setting needs to be carefully evaluated.Le Canada est un pays à faible incidence de tuberculose. L’algorithme diagnostique de tuberculose pulmonaire duLes chercheurs ont obtenu deux groupes de données : 1) tous les échantillons BAAR– sur une période de trois ans (du 1Pendant la période de trois ans, 0,7 % de tous les groupes diagnostiques étaient BAAR– et positifs à la culture. Pendant la période d’un an, les cliniques provinciales de services pour la tuberculose ont soumis 26 % de tous les échantillons BAAR– reçus, mais ils représentaient 78 % des échantillons BAAR– positifs aux cultures.Le coût annuel du TAN TB sur un échantillon d’expectoration BAAR– de chaque groupe diagnostique admissible totaliserait environ 247 000 $. Si on ciblait seulement les patients ayant consulté des services pour la tuberculose, ce coût fléchirait à environ 64 000 $ par année, mais saisirait plus de 75 % des patients BAAR– dont la culture est positive. D’après le taux de positivité provinciale, un diagnostic précoce de tuberculose chez un patient BAAR– positif à la culture coûterait environ 6 000 $. Le rapport coût-efficacité de cette approche pour la santé publique dans les milieux à faible incidence de tuberculose devra faire l’objet d’une évaluation attentive.

Aim To investigate the role of the gut microbiome in regulating key insulin homeostasis traits (insulin sensitivity, insulin secretion and insulin clearance) whose dysfunction leads to type 2 diabetes (T2D). Materials and methods The Microbiome and Insulin Longitudinal Evaluation Study (MILES) focuses on African American and non-Hispanic white participants aged 40-80 years without diabetes. Three study visits are planned (at baseline, 15 and 30 months). Baseline measurements include assessment of the stool microbiome and administration of an oral glucose tolerance test, which will yield indexes of insulin sensitivity, insulin secretion and insulin clearance. The gut microbiome profile (composition and function) will be determined using whole metagenome shotgun sequencing along with analyses of plasma short chain fatty acids. Additional data collected include dietary history, sociodemographic factors, health habits, anthropometry, medical history, medications and family history. Most assessments are repeated 15 and 30 months following baseline. Results After screening 875 individuals, 129 African American and 224 non-Hispanic white participants were enrolled. At baseline, African American participants have higher blood pressure, weight, body mass index, waist and hip circumferences but similar waist-hip ratio compared with the non-Hispanic white participants. On average, African American participants are less insulin-sensitive and have higher acute insulin secretion and lower insulin clearance. Conclusions The longitudinal design and robust characterization of potential mediators will allow for the assessment of glucose and insulin homeostasis and gut microbiota as they change over time, improving our ability to discern causal relationships between the microbiome and the insulin homeostasis traits whose deterioration determines T2D, setting the stage for future microbiome-directed therapies to prevent and treat T2D.

Insulin resistance and insufficient insulin secretion lead to type 2 diabetes. A role of reduced insulin clearance has been suggested, but few studies have investigated the contribution of insulin clearance while simultaneously examining insulin sensitivity and secretion. The goal of this study was to conduct such an investigation in 224 non-Hispanic White and 129 African Americans individuals from MILES (mean age 59, 62% female). Participants underwent oral glucose tolerance tests from which insulin sensitivity, insulin secretion, insulin clearance, and disposition index were calculated. Logistic regression models (controlling for age, sex, race, and BMI) examined the individual contributions of these traits separately, as well as the joint contribution of insulin sensitivity, clearance, and secretion, to early dysglycemia (prediabetes plus newly diagnosed diabetes; 46% of cohort). Models used standardized predictors such that odds ratios (OR) represent the change in odds of dysglycemia per standard deviation change. Model performance was assessed via Akaike’s Information Criterion (AIC) and area under the receiver operator characteristic curves (AUROC). In separate models, dysglycemia was associated with insulin sensitivity (OR 0.2; 0.14-0.30; P Disclosure A. Wood: None. E. T. Jensen: None. G. Ramesh: None. Z. Arzumanyan: None. K. Lam: None. A. Bertoni: None. J. I. Rotter: None. Y. Chen: None. M. O. Goodarzi: None. Funding National Institutes of Health (R01DK109588)

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite notable anthropometric variability with ancestry proportions, and a high burden of growth stunting and overweight/obesity in Hispanic/Latino populations. This address this knowledge gap, we analyzed densely-imputed genetic data in a sample of Hispanic/Latino adults, to identify and fine-map common genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (Stage 1, n=59,769) and validated our findings in 9 additional studies (HISLA Stage 2, n=9,336). We conducted a trans-ethnic GWAS with summary statistics from HISLA Stage 1 and existing consortia of European and African ancestries. In our HISLA Stage 1+2 analyses, we discovered one novel BMI locus, as well two novel BMI signals and another novel height signal, each within established anthropometric loci. In our trans-ethnic meta- analysis, we identified three additional novel BMI loci, one novel height locus, and one novel WHRadjBMI locus. We also identified three secondary signals for BMI, 28 for height, and two for WHRadjBMI. We replicated >60 established anthropometric loci in Hispanic/Latino populations at genome-wide significance—representing up to 30% of previously-reported index SNP anthropometric associations. Trans-ethnic meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our novel findings demonstrate that future studies may also benefit from leveraging differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

Glycaemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycaemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated haemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase understanding of diabetes pathophysiology by use of trans-ancestry studies for improved power and resolution.

Background Although propofol is widely used for sedation in intensive care units around Australia, evaluation of bedside nursing practices of the administration of propofol have been limited. We investigated whether there was a discrepancy between the amount of propofol delivered by the infusion pump and that recorded electronically and consequently patient exposure to avoidable harms. Aims The aim of this research was to compare the total amount of propofol administered to intensive care patients via a programmable infusion pump with that documented in the electronic medical record (EMR). Secondary objectives were to ascertain the percentage of 1) patients exposed to a propofol dose greater than recommended and 2) daily energy requirements administered as propofol infusion. Methods This was a prospective, observational study of total propofol delivered to 50 patients in a 14-bed metropolitan, Australian intensive care unit. Infusion pump data and entries from the EMR were collated. Results Propofol sedation was administered for a median 18 (interquartile range: 14–47) hours with median total propofol 3025 mg (interquartile range: 1840–7755 mg) by pump and 3250 mg (interquartile range: 1915–6960 mg) by EMR, i.e. 1.9 (interquartile range: 1.3–2.3) mg/kg/hour by pump (correlation coefficient = 0.99). The total bolus propofol documented in the EMR was a median 330 mg (interquartile range: −838 to −124) less than the pump amount. Nineteen (38%) patients had no EMR-documented propofol boluses yet had received at least one bolus via the pump. In two of 50 (4%) patients, the pump propofol infusion dose was above the recommended maximum safe dose of 4 mg/kg/h. Conclusion In this cohort of patients, the bolus administration of propofol was frequently not documented, potentially placing some patients at risk of drug-related toxicity. Further research to develop and implement strategies to improve the documentation of propofol administration is indicated.

Objective: Little is known about mental health service use among Canadian children and youth. Our objective was to examine temporal trends in mental health service use across different sectors of the health care system among children and youth living in Ontario. Methods: We conducted a population-based, repeated annual cross-sectional study of mental health service use, including mental health- and addictions-related emergency department (ED) visits, psychiatric hospitalizations, and mental health-related outpatient physician visits using linked health administrative databases. Subjects included Ontario residents between 10 and 24 years of age. We tested temporal trends between 2006 and 2011 using linear regression models. Results: Between 2006 and 2011, the relative increase in rates of mental health-related ED visits and hospitalizations were 32.5% and 53.7%, respectively. The absolute increase in anxiety disorders, the most common reason for ED visits, was 2.2 per 1000 population ( P < 0.001) while mood and affective disorders, the most common reason for hospitalizations, showed an increase of 0.6 per 1000 population ( P < 0.01). The overall relative increase in rates of outpatient visits was 15.8%, with the largest absolute increase found among family physician visits (28.7 per 1000 population, P = 0.01). Conclusions: Mental health care use for children and youth is increasing over time in all sectors, but appears to be increasing at a greater rate in the acute care sector. Further research is required to understand whether the observed differences reflect difficulty with access to outpatient care.

OBJECTIVES: To identify factors associated with repeat emergency department (ED) presentations for suicide-related behaviors (SRB) - hereafter referred to as repetition - among children/youth to aid secondary prevention initiatives. To compare rates of repetition in children/youth with substantiated maltreatment requiring removal from their parental home with their peers in the general population. METHODS: A population-based (retrospective) cohort study was established for children/youth with a first ED SRB presentation at risk for repetition in the Province of Ontario, Canada between 1 January 2004 and 31 December 2008. Children/youth legally removed from their parental home because of substantiated maltreatment (n=179) and their population-based peers (n=6,305) were individually linked to administrative health care records over time to ascertain social, demographic and clinical information and subsequent ED presentations for SRB during follow-up. These children/youth were described and their repetition-free probabilities over time compared. To identify factors associated with repetition we fit multivariable, recurrent event survival analysis models stratified by repetition and present unadjusted and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Children/youth with substantiated maltreatment (as noted) were two times more likely to have repetition than their peers after adjustments for social, demographic and clinical factors (conditional on prior ED SRB presentations). A number of these factors were independently associated with repetition. No one factor distinguished between having a first and second repetition nor was more strongly associated with repetition than another. CONCLUSIONS: The risk of repetition is higher in children with substantiated maltreatment (as noted) than their peers. No one factor stood out as predictive of repetition. Implications for secondary prevention initiatives include a non-selective approach, sensitive to family difficulties and the need to better contextualize repetition and harness data linkages. Language: en

OBJECTIVES: To describe the relationship of primary care physician (PCP) supply for children and measures of health care access, use, and outcomes. METHODS: We conducted a population-based, cross-sectional study of all Ontario children from 2003 to 2005. We used health administrative data to calculate county-level supply (full-time equivalents [FTEs]) of PCPs. We modeled the relationship of supply to (1) recommended primary care visits, (2) emergency department (ED) use, and (3) ambulatory care–sensitive condition admissions and adjusted for neighborhood income. We used population-based surveys to describe access. RESULTS: The county-level PCP supply ranged from 1720 to 4720 children per FTE. Of the children, 45.4% live in the highest-supply areas (3000 children per FTE). Compared with high-supply counties, the lowest had significantly lower rates of primary care visits (2716 vs 7490 per 1000) and higher proportions of newborns without early follow-care (58.2% vs 14.5%). Low-supply areas had higher rates of ED visits (440 vs 179 per 1000) and admissions. A stepwise gradient existed for every decrease in supply for most measures. Self-reported access barriers were most evident in areas with >3500 children per FTE (32.8% without a physician). CONCLUSIONS: Under universal insurance there are differences in access to, and outcomes of, primary care related to local physician supply after controlling for neighborhood income. The most pronounced effect is on primary and ED care use, but there are implications for acute and chronic disease control. Physician distribution is a critical issue to address in policies to improve access to care.

Guttmann A, Nakhla M, Henderson M, To T, Daneman D, Cauch-Dudek K, Wang X, Lam K, Hux J. Validation of a health administrative data algorithm for assessing the epidemiology of diabetes in Canadian children. Objective: To validate a case definition of pediatric diabetes using administrative health data and describe trends in incidence and prevalence over time in Ontario, Canada. Methods: We sampled hospital records of 700 children from 1994 to 2003 with a prior history of at least one outpatient or hospital record for diabetes mellitus and 300 randomly selected children with no diabetes records. We defined patients as having diabetes based on diagnoses and drug utilization from chart abstraction and compared sensitivity and specificity of a number of combinations of overall health care use using administrative data to develop a highly specific definition. We used Poisson regression to test changes in incidence over time (1994–2003). Results: Use of four physician claims and no hospital records over a 2-yr period yielded the most specific definition (83% sensitivity, 99% specificity). Using this definition overall age/sex standardized incidence per 100 000 was 32.3 [95% confidence intervals (CI) 30.4, 34.4] and prevalence 241.5 per 100 000 (95% CI 236.2–249.9) in 2003/2004. Overall incidence differs by age, (peaking in 10–14 yr olds) but not significantly by sex. The overall incidence has increased on average by 3.1% per year since 1994 (95% CI 1.02–1.04), with no difference in the rate of increase by age. Conclusions: Population-based surveillance of diabetes in children is possible using administrative data. This will facilitate further study of trends in incidence but also in use of health services and outcomes. Further work to differentiate type 1 and 2 diabetes will be important.

Purpose: Patients with advanced cancer are referred to our Rapid Response Radiotherapy Program for quick access to palliative radiotherapy. The primary objective of this prospective study was to determine the physician expectations of the treatment outcomes for patients with brain metastases referred for whole brain radiotherapy (WBRT). The secondary objectives were to determine the factors influencing the expectations and to examine the accuracy of the physician-estimated patient survival. Methods and Materials: Patients were identified during a 17-month period. The referring physicians were sent a survey by facsimile to be completed and returned before the patient consultation. Information was sought on the patient's disease status, the physician's expectations of WBRT, the estimated patient survival and performance status, and physician demographic data. Results: A total of 137 surveys were sent out, and the overall response rate was 57.7%. The median patient age was 66 years (range, 35-87), 78.5% had multiple brain metastases, 42.3% had a controlled primary tumor, and 62.3% had extracranial disease. WBRT was thought to stabilize neurologic symptoms, improve quality of life, and allow for a Decadron (dexamethasone) taper by >=94.9% of the referring physicians; 87.0% thought WBRT would improve performance status; 77.9% thought it would improve neurologic symptoms; andmore » 40.8% thought it would improve survival. The referring physicians estimated patient survival as a median of 6.0 months; however, the actual survival was a median of 2.5 months, for a median individual difference of 1.9 months (p < .0001). Conclusion: Physicians referring patients with brain metastases for consideration of WBRT are often overly optimistic when estimating the clinical benefit of the treatment and overestimate patient survival. These findings highlight the need for education and additional research in this field.« less

Objectif: La pseudoprogression (psPD), qui survient apres le traitement par radiotherapie associee a l'administration de temozolomide (RT/TMZ) pour traiter le glioblastome multiforme (GBM), est maintenant bien connue. Le but de cette etude etait de determiner l'incidence de la psPD apres le traitement par la RT/TMZ et ses consequences sur le pronostic. Materiel et methodes: Tous les patients traites par RT/TMZ pour un GBM nouvellement diagnostique ont ete identifies dans une banque de donnees prospective. Les donnees cliniques et radiologiques ont ete revisees retrospectivement. Une progression precoce etait definie comme une progression radiologique (criteres RECIST) pendant ou au cours des 8 semaines suivant la fin du traitement par RT/TMZ. La pseudoprogression etait definie comme la progression precoce suivie d'une stabilisation de la maladie, sans traitement de rattrapage pendant au moins 6 mois apres la fin du traitement par RT/TMZ. L'issue primaire etait la survie (Kaplan-Meier) et les groupes ont ete compares au moyen du test du logrank. Resultats: Nous avons pu evaluer la reponse radiologique chez 104 des 111 patients etudies. L'âge median etait de 58 ans et le suivi median de 55 semaines. Une progression precoce a ete confirmee chez 26% des patients et de ce groupe, 32% avaient eu une psPD. La survie mediane de la cohorte entiere etait de 56,7 semaines (IC a 95% de 51,0 a 71,3). La survie mediane chez les patients qui avaient presente une psPD etait significativement plus elevee que celle des patients qui avaient eu une veritable progression precoce (124,9 semaines versus 36,0 semaines, p = 0,0286). Conclusions: Environ un tiers des patients qui ont presente une progression precoce avaient presente une psPD associee a un pronostic favorable. Le traitement d'entretien par la TMZ ne devrait pas etre abandonne a cause d'une imagerie dont l'aspect semble decourageant dans les trois premiers mois apres la RT/TMZ.

Transition to adult care occurs at age 18 during a vulnerable adolescent period for pediatric renal transplant (RTx) patients.We examined renal allograft loss and hospitalization for RTx biopsy or rejection before and after transition to adult care using clinical and administrative health records of children who underwent RTx (1992-2002) in Ontario, Canada. Life-table analyses examined event rates/100 person years according to age at first RTx.A total of 115 patients were included (57% men; mean age at first transplant 13.9+/-3.7 years). Allograft loss rates were similar across ages 14.0 to 23.9 years. No increase in allograft loss was observed during transition period (ages 18.0-19.9 years). Hospitalizations for RTx rejection or biopsy were much lower after age 18.Our findings do not support an increased risk of allograft loss after transition to adult care, although there is less hospital use for rejection or biopsy suggesting that differences exist in use of care before complete allograft loss after transition to adult care.

Stepwise differentiation from embryonic stem cells (ESCs) to functional insulin-secreting beta cells will identify key steps in beta-cell development and may yet prove useful for transplantation therapy for diabetics. An essential step in this schema is the generation of pancreatic progenitors--cells that express Pdx1 and produce all the cell types of the pancreas. High-content chemical screening identified a small molecule, (-)-indolactam V, that induces differentiation of a substantial number of Pdx1-expressing cells from human ESCs. The Pdx1-expressing cells express other pancreatic markers and contribute to endocrine, exocrine and duct cells, in vitro and in vivo. Further analyses showed that (-)-indolactam V works specifically at one stage of pancreatic development, inducing pancreatic progenitors from definitive endoderm. This study describes a chemical screening platform to investigate human ESC differentiation and demonstrates the generation of a cell population that is a key milepost on the path to making beta cells.

Purpose It is important for cancer patients to maintain continuity of care with their family physician (FP) while being followed at the cancer center. The primary objective of this study was to determine the perception of patients seen in the palliative Rapid Response Radiotherapy Program (RRRP) on FP involvement in their cancer care. Secondary objectives were to identify factors predicting for perceived FP involvement in patient cancer care. Patients and Methods Consecutive patients were approached for study enrollment at the time of RRRP visit and asked to complete a 15-item survey. Results Three hundred sixty-five patients were accrued over 15 months. Ninety-eight percent had an FP, and 43% felt their FP was involved in their cancer care. Eighty percent of patients were satisfied with the overall medical care provided by their FP, and 71% had been with their FP for ≥ 5 years. The most common reason patients gave for perceiving limited FP involvement was the medical oncologist looking after all of their cancer needs. Multivariate analysis found that satisfaction with overall medical care provided by the FP, shorter time since last FP visit, seeing the FP since cancer diagnosis, and FP providing on-call service for after-hour emergencies all significantly predicted for patients perceiving FP involvement in their cancer care. Conclusion Less than half of patients surveyed perceived their FP as involved in their cancer care. Encouraging continuity of care between patients and FPs may allow for easier transition of care back to the FP once palliative treatment at the cancer center has finished and help facilitate end-of-life planning.

The primary objective of this study was to assess whether there was an improvement in quality of life for patients with brain metastases as measured 1 and 2 months after a course of whole-brain radiotherapy. The secondary objective was to assess the level of agreement between patient and proxy quality of life scores.Sixty patients with brain metastases and their proxy completed the Functional Assessment of Cancer Therapy-Brain (FACT-BR) questionnaire independently. Proxies were given instructions to answer from the patient's perspective. Quality-of-life assessments were conducted at baseline, 1 month, and 2 months after completion of whole-brain radiotherapy. Paired t tests with Bonferroni adjustment for multiple comparisons were calculated to detect significant differences in global quality-of-life scores. Lin's concordance correlation coefficient measured agreement between patient and proxy quality-of-life ratings.No significant difference was detected in overall quality of life after whole-brain radiotherapy. At 2 months after whole-brain radiotherapy, there was a trend toward worsening general and brain specific quality-of-life scores. There was poor concordance between patients and their proxies for all quality-of-life domains at baseline.At 2 months after whole-brain radiotherapy, there was a trend toward worsening general and brain specific quality-of-life scores. Proxy rating of patients' quality of life showed poor concordance at baseline.

OBJECTIVES. We studied the association between immunization coverage for a cohort of 2-year-old children covered by a universal health insurance plan and pediatric provider and other health services characteristics.METHODS. We assembled a cohort of 101570 infants born in urban areas in Ontario, Canada, between July 1, 1997, and June 31, 1998. Children were considered to have up-to-date (UTD) immunization coverage if they had ≥5 immunizations by 2 years of age, ie, the recommended 3 doses and 1 booster of diphtheria-polio-tetanus-pertussis/Haemophilus influenzae type b vaccine and 1 dose of measles-mumps-rubella vaccine. Provider practice characteristics were derived from outpatient billing records, and 1996 census data were used to derive neighborhood income quintiles. The association between UTD immunization status and provider characteristics was assessed with multilevel regression models, controlling for patient characteristics.RESULTS. Overall, the rate of complete UTD immunization coverage was low (66.3%) despite a large number of primary care visits (median: 19 visits). Children whose usual provider had a low volume of pediatric primary care were less than one half as likely to be UTD. Other factors associated with not being UTD included very low continuity of care, low continuity of care, and usual provider in practice for CONCLUSIONS. Despite universal access to primary care services, rates of complete immunization coverage among 2-year-old children in Ontario are low. Because visit rates are high, primary care reform should include interventions directed at provider immunization practices to reduce missed opportunities.

Nicotinamide (2) is a potent and selective inhibitor of the PDE4D isozyme and as a chemical tool selectively blocks eosinophil mediator release and chemotaxis thus linking the role of PDE4D to eosinophil function.

The Greater Toronto Area (GTA) was considered a "hot zone" for severe acute respiratory syndrome (SARS) in 2003. In accordance with mandated city-wide infection control measures, the Hospital for Sick Children (HSC) drastically reduced all services while maintaining a fully operational emergency department. Because of the GTA health service suspensions and the overlap of SARS-like symptoms with many common childhood illnesses, this introduced the potential for a change in the volumes of patients visiting the emergency department of the only regional tertiary care children's hospital.We compared HSC emergency department patient volumes, admission rates and length of stay in the emergency department in the baseline years of 2000-2002 (non-SARS years) with those in 2003 (SARS year). The data from the prior years were modeled as a time series. Using an interrupted time series analysis, we compared the 2003 data for the periods before, during and after the SARS periods with the modeled data for significant differences in the 3 aforementioned outcomes of interest.Compared with the 2000-2002 data, we found no differences in visits, admission rates or length of stay in the pre-SARS period in 2003. There were significant decreases in visits and length of stay (p0.001) and increases in admission rates (p0.001) during the periods in 2003 when there were new and active cases of SARS in the GTA. All 3 outcomes returned to expected estimates coincident with the absence of SARS cases from September to December 2003.During the SARS outbreak in the GTA, the HSC emergency department experienced significantly reduced volumes of patients with low-acuity complaints. This gives insight into utilization rates of a pediatric emergency department during a time when there was additional perceived risk in using emergency department services and provides a foundation for emergency department preparedness policies for SARS-like public health emergencies.

Hedgehog (Hh) signaling promotes tumorigenesis. The accumulation of the membrane protein Smoothened (Smo) within the primary cilium (PC) is a key event in Hh signal transduction, and many pharmacological inhibitors identified to date target Smo's actions. Smo ciliary translocation is inhibited by some pathway antagonists, while others promote ciliary accumulation, an outcome that can lead to a hypersensitive state on renewal of Hh signaling. To identify novel inhibitory compounds acting on the critical mechanistic transition of Smo accumulation, we established a high content screen to directly analyze Smo ciliary translocation. Screening thousands of compounds from annotated libraries of approved drugs and other agents, we identified several new classes of compounds that block Sonic hedgehog-driven Smo localization within the PC. Selective analysis was conducted on two classes of Smo antagonists. One of these, DY131, appears to inhibit Smo signaling through a common binding site shared by previously reported Smo agonists and antagonists. Antagonism by this class of compound is competed by high doses of Smo-binding agonists such as SAG and impaired by a mutation that generates a ligand-independent, oncogenic form of Smo (SmoM2). In contrast, a second antagonist of Smo accumulation within the PC, SMANT, was less sensitive to SAG-mediated competition and inhibited SmoM2 at concentrations similar to those that inhibit wild-type Smo. Our observations identify important differences among Hh antagonists and the potential for development of novel therapeutic approaches against mutant forms of Smo that are resistant to current therapeutic strategies.

Diabetes is a pathological condition characterized by relative insulin deficiency, persistent hyperglycemia, and, consequently, diffuse micro- and macrovascular disease. One therapeutic strategy is to amplify insulin-secretion capacity by increasing the number of the insulin-producing β cells without triggering a generalized proliferative response. Here, we present the development of a small-molecule screening platform for the identification of molecules that increase β-cell replication. Using this platform, we identify a class of compounds [adenosine kinase inhibitors (ADK-Is)] that promote replication of primary β cells in three species (mouse, rat, and pig). Furthermore, the replication effect of ADK-Is is cell type-selective: treatment of islet cell cultures with ADK-Is increases replication of β cells but not that of α cells, PP cells, or fibroblasts. Short-term in vivo treatment with an ADK-I also increases β-cell replication but not exocrine cell or hepatocyte replication. Therefore, we propose ADK inhibition as a strategy for the treatment of diabetes.

OBJECTIVES: To determine whether the rates of a first presentation to the emergency department (ED) for suicide-related behavior (SRB) are higher among children/youth permanently removed from their parental home because of substantiated maltreatment than their peers. To describe the health care settings accessed by these children/youth before a first SRB presentation to help design preventive interventions. METHODS: A population-based (retrospective) cohort of 12-17-year-olds in Ontario, Canada was established. Children/youth removed from their parental home because of the above noted maltreatment (n=4683) and their population-based peers (n=1,034,546) were individually linked to administrative health care records over time to ascertain health service use and subsequent ED presentations for SRB during follow-up. Person-time incidence rates were calculated and Cox regression models used to estimate adjusted hazard ratios (HR) and corresponding 95% confidence intervals (CI). RESULTS: After controlling for demographic characteristics and prior health service use, maltreated children/youth were about five times more likely to have a first ED presentation for SRB compared to their peers, in both boys (HR: 5.13, 95% CI: 3.94, 6.68) and girls (HR: 5.36, 95% CI: 4.40, 6.54). CONCLUSIONS: Children/youth permanently removed from their parental home because of substantiated child maltreatment are at an increased risk of a first presentation to the ED for SRB. The prevention of child maltreatment and its recurrence and the promotion of resilience after maltreatment has occurred are important avenues to study toward preventing ED SRB presentations in children/youth. Provider and system level linkages between care sectors may prevent the need for such presentations by providing ongoing environmental support. Language: en

The motor neuron disease spinal muscular atrophy (SMA) results from mutations that lead to low levels of the ubiquitously expressed protein survival of motor neuron (SMN). An ever-increasing collection of data suggests that therapeutics that elevate SMN may be effective in treating SMA. We executed an image-based screen of annotated chemical libraries and discovered several classes of compounds that were able to increase cellular SMN. Among the most important was the RTK-PI3K-AKT-GSK-3 signaling cascade. Chemical inhibitors of glycogen synthase kinase 3 (GSK-3) and short hairpin RNAs (shRNAs) directed against this target elevated SMN levels primarily by stabilizing the protein. It was particularly notable that GSK-3 chemical inhibitors were also effective in motor neurons, not only in elevating SMN levels, but also in blocking the death that was produced when SMN was acutely reduced by an SMN-specific shRNA. Thus, we have established a screen capable of detecting drug-like compounds that correct the main phenotypic change underlying SMA.

Background:It is controversial if distant recurrence of glioblastoma is more common after temozolomide (TMZ) concurrent with radiotherapy (RT). Optimal therapy for patients with recurrent disease after RT/TMZ is unclear. Our purpose was to evaluate recurrence patterns in glioblastoma and the effect of treatment at recurrence upon survival.Methods:We performed a retrospective review of 67 patients with newly diagnosed glioblastoma treated with RT/TMZ between 2003-2007. Statistical analyses included Kaplan-Meier method for survival, and multivariate Cox proportional hazards model for the effect of salvage treatment on survival.Results:58 patients (86.6%) recurred locally; 9 patients (13.4%) had a distant non-contiguous focus of new disease. Median survival(MS) was 17 months; median time-to-progression(TTP) 6.8 months. The local and distant groups had comparable prognostic factors. There was no difference in MS(p=0.35) or TTP(p=0.95) by location of recurrence. At relapse, 26 patients(38.8%) received continuous, dose-intense TMZ, 24(35.8%) other therapy(4.5% RT; 20.9% lomustine+/-procarbazine; 4.5% etoposide; 1.5% conventional TMZ; 4.5% TMZ then lomustine), and 17(25.4%) were untreated. Dose-intense TMZ was associated with prolonged MS compared to all other patients(21.5 months vs. 12.4 months, p=0.019, HR=3.86, 95%CI: 1.81-8.22) and similar to MS with other chemotherapy regimens(18.8 months, p=0.40, HR=1.30, 95% CI: 0.65-2.61).Conclusion:The pattern of recurrence of glioblastoma treated with RT/TMZ was predominantly local. Second-line treatment with continuous dose-intense TMZ may prolong survival in patients with recurrent glioblastoma. Overall survival is similar to other conventional salvage regimens; however TMZ may be better tolerated. This study is limited by its retrospective nature and potential selection bias. Prospective controlled studies are needed.

Behavioral Profiling The complexity of the brain makes it difficult to predict how a drug will affect behavior without direct testing in live animals. Rihel et al. (p. 348 ) developed a high-throughput assay to assess the effects of thousands of drugs on sleep/wake behaviors of zebrafish larvae. The data set reveals a broad conservation of zebrafish and mammalian sleep/wake pharmacology and identifies pathways that regulate sleep. Moreover, the biological targets of poorly characterized small molecules can be predicted by matching their behavioral profiles to those of well-known drugs. Thus, behavioral profiling in zebrafish offers a cost-effective way to characterize neuroactive drugs and to predict biological targets of novel compounds.

Many women have significant sleep complaints during pregnancy. One of the more frequent complaints is that of restless legs. Ekbom in 1945 was the first person to describe this in detail, labeled it as a ‘‘restless leg’’ condition and identified pregnancy as a common cause (1, 2). Further study of patients with complaints of restless legs revealed there were patients who had limb (both legs and arms) movements during wakefulness and sleep that was disruptive. In 1980, Coleman characterized these limb movements based on the periodicity, duration, and persistence of the movements during sleep (3). His work and others lead to a separate diagnostic condition referred to as Periodic Limb Movement Disorder (PLMD) (4). Pregnancy is a risk factor for developing both Restless Legs Syndrome (RLS) and PLMD. Most of the available scientific literature focuses on RLS and its association with pregnancy. PLMD has an 80–90% association withRLS; however, PLMD is a distinct condition that has been associated not only with RLS but also with narcolepsy and Parkinson’s disease. Unfortunately, there is very little data on PLMD in pregnancy. In this chapter, we will discuss in detail RLS during pregnancy and briefly discuss PLMD in pregnancy.

OBJECTIVES. The goals were to examine bicycle-related mortality rates in Ontario, Canada, from 1991 to 2002 among bicyclists 1 to 15 years of age and 16 years of age through adulthood and to determine the effect of legislation (introduced in October 1995 for bicyclists METHODS. The average numbers of deaths per year and mortality rates per 100000 person-years for the prelegislation and postlegislation periods, and the percentage changes, were calculated for each of the 2 age groups (1–15 years and ≥16 years). Differences before and after legislation in the 2 age groups were modeled in a time series analysis.RESULTS. There were 362 bicycle-related deaths in the 12-year period (1–15 years: 107 deaths; ≥16 years: 255 deaths). For bicyclists 1 to 15 years of age, the average number of deaths per year decreased 52%, the mortality rate per 100000 person-years decreased 55%, and the time series analysis demonstrated a significant reduction in deaths after legislation. The estimated change in the number of deaths per month was −0.59 deaths per month. For bicyclists ≥16 years of age, there were only slight changes in the average number of deaths per year and the mortality rate per 100000 person-years, and the time series analysis demonstrated no significant change in deaths after legislation.CONCLUSIONS. The bicycle-related mortality rate in children 1 to 15 years of age has decreased significantly, which may be attributable in part to helmet legislation. A similar reduction for bicyclists 16 years of age through adulthood was not identified. These findings support promotion of helmet use, enforcement of the existing law, and extension of the law to adult bicyclists.

The RNA polymerase holoenzyme (RNAP) of Enterobacter cloacae was purified by gel filtration and heparin affinity chromatography and shown to consist of four subunits (beta', beta, alpha and sigma) of 156, 151, 45 and 82 kDa, as measured by SDS-PAGE. The 82 kDa protein was shown to be related to the Escherichia coli primary sigma factor by western blot analysis with polyclonal antisera raised against purified E. coli sigma 70. Functional reconstitution of E. cloacae core enzyme with purified E. coli sigma 70 showed that E. cloacae and E. coli sigma factors are closely related. The RNAP of E. cloacae initiated transcription from the tac promoter with an efficiency similar to that of E. coli. Measuring promoter-specific transcription, the dependence of holoenzyme activity on salt, divalent cation and temperature was also similar to that of the E. coli RNAP. We also showed that the transcriptional inhibitor, rifampicin, inhibits the enzyme activity of the purified RNAP of E. cloacae and E. coli at similar concentrations. We conclude, based on these data, that the RNAP of E. cloacae and E. coli, both enterobacteria, are closely related.

Introduction Care giving for children with chronic diseases can lead to financial strain and compromised family well being. Little is known about whether these stresses lead to changes in residential movement patterns as they relate to income adequacy and proximity to care. Methods We compared the residential movement patterns and associated changes in neighbourhood income of children with mild to severe chronic diseases compared with those that are healthy. A cohort of infants born from 2002–2007 in Ontario, Canada was followed for 5 years and divided into those with single- or multiple- body system complex chronic conditions (CCCs); low birth weight (LBW); asthma/recurrent wheeze (A/RW) and the control group of otherwise healthy children. Results Of 598,716 children studied, 15,207 had a single CCC, 3,600 multiple CCCs, 33,206 LBW, 57,137 A/RW and 489,566 were healthy. Lowest income quintile children were most likely to move residence. Compared with healthy controls, chronic disease cohorts, apart from those with asthma, were more likely to be born in the lowest income quintile neighbourhood and to move. Among children who moved, all chronic disease cohorts were significantly more likely to move to a low income quintile neighborhood (adjusted odds ratios for all chronic disease cohorts of 1.1-1.2). There were no differences across cohorts in residential movement close to a children’s hospital. Conclusions Young children with chronic conditions, particularly those born in low income neighbourhoods, are more likely to move residence than other healthy young children. However, it does not seem that proximity to specialized care is driving this movement. Further research is required to determine if these movement patterns impact the ability of children with chronic conditions to secure health services.

Vascular endothelial growth factor (VEGF) is potent mitogen for endothelial cells that signals through VEGF Receptor-type2 (VEGFR-2)/Flk-1/KDR. Binding of VEGF to VEGFR-2, a membrane bound receptor tyrosine kinase of the VEGF-receptor family, leads to receptor dimerization, protein kinase activation, trans-autophosphorylation, and initiation of signaling pathways stimulating angiogenesis. In adults, angiogenesis normally occurs during wound healing to restore blood flow post injury and during menstruation and pregnancy. Angiogenesis is also involved in several pathological disease states such as rheumatoid arthritis, psoriasis, diabetic retinopathy and cancer. While physiological angiogenesis involves interplay between pro- and anti-angiogenic factors, the ability to inhibit pathological angiogenesis has therapeutic potential. Inhibitors of VEGFR-2 provide targeted treatments for tumor growth as well as abnormal neovascularization related diseases. The caveat of traditional biochemical VEGFR-2 assays is that only the catalytic domain of the receptor is used to identify hits. One strategy to identify true novel inhibitors against membrane associated proteins is to screen these targets in a more physiological environment, where lipid-protein and protein-protein interactions are included in the assay. We achieved this goal by docking the entire cytoplasmic domain of the receptor on a liposome. Template Directed Assembly (TDA) is a screening technology designed to accomplish this objective. TDA technology utilizes recombinant VEGFR-2 cytoplasmic domain tagged with polyhistidine at the juxtamembrane position and docked to the liposome via the nickel residues. The lipids in TDA are able to diffuse within the surface of the liposome and, therefore, proteins can diffuse to form oligomeric complexes such as homo- or hetero-dimers formation. To compliment the TDA biochemical screen, we are implementing an image based high content screen (HCS) utilizing human umbilical vein endothelial cells (HUVECs) that express native VEGFR-2. The HCS screen is designed to identify potent and specific inhibitors of VEGFR-2 as assessed by a reduction in the proliferation marker Ki67. We are currently (1) validating the TDA assay with known VEGFR-2 inhibitors (2) screening a focus small molecule library to identify novel hits (3) testing the primary hits against a kinase selectivity panel and (4) designing and developing a VEGFR2 cell-based HCS assay to confirm the primary hits. The hit to lead program will be guided by using both physiologically relevant biochemical-based and cell-based assays. The combination of our novel TDA screening platform and the HCS assay technology permits us to identify unique VEGFR-2 inhibitors. Citation Format: Kelvin Lam, Edward Esposito, Deanna Navaroli, Ryan Clinton, Kerrin Beovich, Norman Garceau. Novel TDA technology and high content imaging as complementary assay platforms to identify VEGFR-2 inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4544. doi:10.1158/1538-7445.AM2013-4544

A 60-year old female presented with a 6 month history of dizziness, poor balance and reduced visual acuity in the left eye. Neurological examination revealed a left 3rd nerve palsy. CT scans and MRI demonstrated a well-defined mass arising from the left sphenoid wing and cavernous sinus, extending into the pituitary fossa and left orbital apex. The mass demonstrated a high signal on T2-weighted MRI compared with cerebral parenchyma (Fig. 1A). The lesion initially enhanced peripherally on coronal post-contrast T1-weighted MRI (Fig. 1B) and then filled in on 4-minute delayed axial T1-weighted MRI (Fig. 1C).

Germ-line mutations in the p53 tumor suppressor gene have been observed in patients with Li-Fraumeni syndrome, brain tumors, second malignancies, and breast cancers. It is unclear whether all of these mutations have inactivated p53 and thereby provide an increased risk for cancer. Therefore, it is necessary to establish the biological significance of these germ-line mutations by the functional and structural analysis of the resulting mutant p53 proteins. We analyzed the ability of seven germ-line mutant proteins observed in patients with Li-Fraumeni syndrome, second primary neoplasms, or familial breast cancer to block the growth of malignant cells and compared the structural properties of the mutant proteins to that of the wild-type protein. Six of seven missense mutations disrupted the growth inhibitory properties and structure of the wild-type protein. One germ-line mutation retained the features of the wild-type p53. Genetic analysis of the breast cancer family in which this mutation was observed indicated that this germ-line mutation was not associated with the development of cancer. These results demonstrate that germ-line p53 mutations observed in patients with Li-Fraumeni syndrome and with second malignancies have inactivated the p53 tumor suppressor gene. The inability of the germ-line p53 mutants to block the growth of malignant cells can explain why patients with these germ-line mutations have an increased risk for cancer. The observation of a functionally silent germ-line mutation indicates that, before associating a germ-line tumor suppressor gene mutation with cancer risk, it is prudent to consider its functional significance.

Antipsychotic drugs are widely used to manage behavioral and psychological symptoms in dementia despite concerns about their safety.To examine the association between treatment with antipsychotics (both conventional and atypical) and all-cause mortality.Population-based, retrospective cohort study.Ontario, Canada.Older adults with dementia who were followed between 1 April 1997 and 31 March 2003.The risk for death was determined at 30, 60, 120, and 180 days after the initial dispensing of antipsychotic medication. Two pairwise comparisons were made: atypical versus no antipsychotic use and conventional versus atypical antipsychotic use. Groups were stratified by place of residence (community or long-term care). Propensity score matching was used to adjust for differences in baseline health status.A total of 27,259 matched pairs were identified. New use of atypical antipsychotics was associated with a statistically significant increase in the risk for death at 30 days compared with nonuse in both the community-dwelling cohort (adjusted hazard ratio, 1.31 [95% CI, 1.02 to 1.70]; absolute risk difference, 0.2 percentage point) and the long-term care cohort (adjusted hazard ratio, 1.55 [CI, 1.15 to 2.07]; absolute risk difference, 1.2 percentage points). Excess risk seemed to persist to 180 days, but unequal rates of censoring over time may have affected these results. Relative to atypical antipsychotic use, conventional antipsychotic use was associated with a higher risk for death at all time points. Sensitivity analysis revealed that unmeasured confounders that increase the risk for death could diminish or eliminate the observed associations.Information on causes of death was not available. Many patients did not continue their initial treatments after 1 month of therapy. Unmeasured confounders could affect associations.Atypical antipsychotic use is associated with an increased risk for death compared with nonuse among older adults with dementia. The risk for death may be greater with conventional antipsychotics than with atypical antipsychotics.

Background Ontario, the most populous province in Canada, has a universal healthcare system that routinely collects health administrative data on its 13 million legal residents that is used for health research. Record linkage has become a vital tool for this research by enriching this data with the Immigration, Refugees and Citizenship Canada Permanent Resident (IRCC-PR) database and the Office of the Registrar General’s Vital Statistics-Death (ORG-VSD) registry. Our objectives were to estimate linkage rates and compare characteristics of individuals in the linked versus unlinked files. Methods We used both deterministic and probabilistic linkage methods to link the IRCC-PR database (1985–2012) and ORG-VSD registry (1990–2012) to the Ontario’s Registered Persons Database. Linkage rates were estimated and standardized differences were used to assess differences in socio-demographic and other characteristics between the linked and unlinked records. Results The overall linkage rates for the IRCC-PR database and ORG-VSD registry were 86.4 and 96.2 %, respectively. The majority (68.2 %) of the record linkages in IRCC-PR were achieved after three deterministic passes, 18.2 % were linked probabilistically, and 13.6 % were unlinked. Similarly the majority (79.8 %) of the record linkages in the ORG-VSD were linked using deterministic record linkage, 16.3 % were linked after probabilistic and manual review, and 3.9 % were unlinked. Unlinked and linked files were similar for most characteristics, such as age and marital status for IRCC-PR and sex and most causes of death for ORG-VSD. However, lower linkage rates were observed among people born in East Asia (78 %) in the IRCC-PR database and certain causes of death in the ORG-VSD registry, namely perinatal conditions (61.3 %) and congenital anomalies (81.3 %). Conclusions The linkages of immigration and vital statistics data to existing population-based healthcare data in Ontario, Canada will enable many novel cross-sectional and longitudinal studies to be conducted. Analytic techniques to account for sub-optimal linkage rates may be required in studies of certain ethnic groups or certain causes of death among children and infants. Electronic supplementary material The online version of this article (doi:10.1186/s12911-016-0375-3) contains supplementary material, which is available to authorized users.