Feasibility and Safety of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia (SANE-01): A Randomized, Double-blind, Placebo-controlled Phase Ib Clinical Trial.

OBJECTIVE: To test feasibility and safety of administering sildenafil in neonates with neonatal encephalopathy (NE), developing brain injury despite therapeutic hypothermia (TH). STUDY DESIGN: We performed a randomized, double-blind, placebo-controlled phase Ib clinical trial between 2016 and 2019 in neonates with moderate or severe NE, displaying brain injury on day-2 magnetic resonance imaging (MRI) despite TH. Neonates were randomized (2:1) to 7-day sildenafil or placebo (2 mg/kg/dose enterally every 12 hours, 14 doses). Outcomes included feasibility and safety (primary outcomes), pharmacokinetics (secondary), and day-30 neuroimaging and 18-month neurodevelopment assessments (exploratory). RESULTS: Of the 24 enrolled neonates, 8 were randomized to sildenafil and 3 to placebo. A mild decrease in blood pressure was reported in 2 of the 8 neonates after initial dose, but not with subsequent doses. Sildenafil plasma steady-state concentration was rapidly reached, but decreased after TH discontinuation. Twelve percent of neonates (1/8) neonates died in the sildenafil group and 0% (0/3) in the placebo group. Among surviving neonates, partial recovery of injury, fewer cystic lesions, and less brain volume loss on day-30 magnetic resonance imaging were noted in 71% (5/7) of the sildenafil group and in 0% (0/3) of the placebo group. The rate of death or survival to 18 months with severe neurodevelopmental impairment was 57% (4/7) in the sildenafil group and 100% (3/3) in the placebo group. CONCLUSIONS: Sildenafil was safe and well-absorbed in neonates with NE treated with TH. Optimal dosing needs to be established. Evaluation of a larger number of neonates through subsequent phases II and III trials is required to establish efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT02812433.

Measuring positive mental health in Canada: construct validation of the Mental Health Continuum-Short Form. / Mesurer la santé mentale positive au Canada : validation des concepts du Continuum de santé mentale ­ Questionnaire abrégé.

INTRODUCTION: Positive mental health is increasingly recognized as an important focus for public health policies and programs. In Canada, the Mental Health Continuum-Short Form (MHC-SF) was identified as a promising measure to include on population surveys to measure positive mental health. It proposes to measure a three-factor model of positive mental health including emotional, social and psychological well-being. The purpose of this study was to examine whether the MHC-SF is an adequate measure of positive mental health for Canadian adults. METHODS: We conducted confirmatory factor analysis (CFA) using data from the 2012 Canadian Community Health Survey (CCHS)-Mental Health Component (CCHS-MH), and cross-validated the model using data from the CCHS 2011-2012 annual cycle. We examined criterion-related validity through correlations of MHC-SF subscale scores with positively and negatively associated concepts (e.g. life satisfaction and psychological distress, respectively). RESULTS: We confirmed the validity of the three-factor model of emotional, social and psychological well-being through CFA on two independent samples, once four correlated errors between items on the social well-being scale were added. We observed significant correlations in the anticipated direction between emotional, psychological and social well-being scores and related concepts. Cronbach's alpha for both emotional and psychological well-being subscales was 0.82; for social well-being it was 0.77. CONCLUSION: Our study suggests that the MHC-SF measures a three-factor model of positive mental health in the Canadian population. However, caution is warranted when using the social well-being scale, which did not function as well as the other factors, as evidenced by the need to add several correlated error terms to obtain adequate model fit, a higher level of missing data on these questions and weaker correlations with related constructs. Social well-being is important in a comprehensive measure of positive mental health, and further research is recommended.

INTRODUCTION: La santé mentale positive est de plus en plus reconnue comme un élément central des politiques et des programmes en matière de santé publique. On a déterminé au Canada que le Continuum de santé mentale ­ Questionnaire abrégé (CSM-QA) constituait un outil de mesure prometteur qu'il fallait intégrer aux enquêtes d'évaluation de la santé mentale positive de la population. Ce questionnaire vise à évaluer un modèle à trois facteurs de santé mentale positive : le bien-être émotionnel, le bien-être social et le bienêtre psychologique. Cette étude a pour but de déterminer si le CSM-QA offre une mesure adéquate de la santé mentale positive des Canadiens adultes. MÉTHODOLOGIE: Nous avons réalisé une analyse factorielle confirmatoire (AFC) à l'aide des données de l'Enquête sur la santé dans les collectivités canadiennes ­ Santé mentale de 2012 (ESCC-SM). Nous avons également effectué une validation croisée du modèle à l'aide des données de l'Enquête sur la santé dans les collectivités canadiennes ­ Composante annuelle (ESCC ­ Composante annuelle) de 2011-2012. Nous avons examiné la validité reliée à un critère dans le cadre d'analyses de corrélation entre les scores des sous-échelles du CSM-QA et les concepts positifs (comme la satisfaction à l'égard de la vie) et négatifs (comme la détresse psychologique) associés. RÉSULTATS: Nous avons confirmé la validité du modèle à trois facteurs du bien-être émotionnel, social et psychologique dans le cadre d'une AFC de deux échantillons distincts, et ce, après avoir intégré les quatre erreurs corrélées entre les questions relatives à l'échelle du bien-être social. Nous avons observé, comme prévu, des corrélations significatives entre le bien-être émotionnel, psychologique et social et les concepts associés. Le coefficient alpha de Cronbach était de 0,82 pour les sous-échelles du bien-être émotionnel et du bien-être psychologique et de 0,77 pour le bien-être social. CONCLUSION: Notre étude suggère que le CSM-QA permet de rendre compte du modèle à trois facteurs de la santé mentale positive de la population canadienne. Toutefois, la prudence est de mise lorsque l'on utilise l'échelle du bien-être social, qui ne s'est pas avérée aussi efficace que les autres facteurs, comme l'ont mis en évidence la nécessité d'ajouter plusieurs termes d'erreur corrélés afin d'obtenir un ajustement adéquat du modèle, le pourcentage plus élevé de données manquantes pour ces questions et les corrélations plus faibles avec les concepts connexes. Comme le bien-être social constitue un élément important d'une évaluation exhaustive de la santé mentale positive, la tenue d'autres recherches est recommandée.

Periprosthetic Infection following Primary Hip and Knee Arthroplasty: The Impact of Limiting the Postoperative Surveillance Period.

BACKGROUND Hip and knee arthroplasty infections are associated with considerable healthcare costs. The merits of reducing the postoperative surveillance period from 1 year to 90 days have been debated. OBJECTIVES To report the first pan-Canadian hip and knee periprosthetic joint infection (PJI) rates and to describe the implications of a shorter (90-day) postoperative surveillance period. METHODS Prospective surveillance for infection following hip and knee arthroplasty was conducted by hospitals participating in the Canadian Nosocomial Infection Surveillance Program (CNISP) using standard surveillance definitions. RESULTS Overall hip and knee PJI rates were 1.64 and 1.52 per 100 procedures, respectively. Deep incisional and organ-space hip and knee PJI rates were 0.96 and 0.71, respectively. In total, 93% of hip PJIs and 92% of knee PJIs were identified within 90 days, with a median time to detection of 21 days. However, 11%-16% of deep incisional and organ-space infections were not detected within 90 days. This rate was reduced to 3%-4% at 180 days post procedure. Anaerobic and polymicrobial infections had the shortest median time from procedure to detection (17 and 18 days, respectively) compared with infections due to other microorganisms, including Staphylococcus aureus. CONCLUSIONS PJI rates were similar to those reported elsewhere, although differences in national surveillance systems limit direct comparisons. Our results suggest that a postoperative surveillance period of 90 days will detect the majority of PJIs; however, up to 16% of deep incisional and organ-space infections may be missed. Extending the surveillance period to 180 days could allow for a better estimate of disease burden. Infect Control Hosp Epidemiol 2017;38:147-153.

Results from the Canadian Nosocomial Infection Surveillance Program on Carbapenemase-Producing Enterobacteriaceae, 2010 to 2014.

Carbapenemase-producing Enterobacteriaceae (CPE) are increasing globally; here we report on the investigation of CPE in Canada over a 5-year period. Participating acute care facilities across Canada submitted carbapenem-nonsusceptible Enterobacteriaceae from 1 January 2010 to 31 December 2014 to the National Microbiology Laboratory. All CPE were characterized by antimicrobial susceptibilities, pulsed-field gel electrophoresis, multilocus sequence typing, and plasmid restriction fragment length polymorphism analysis and had patient data collected using a standard questionnaire. The 5-year incidence rate of CPE was 0.09 per 10,000 patient days and 0.07 per 1,000 admissions. There were a total of 261 CPE isolated from 238 patients in 58 hospitals during the study period. blaKPC-3 (64.8%) and blaNDM-1 (17.6%) represented the highest proportion of carbapenemase genes detected in Canadian isolates. Patients who had a history of medical attention during international travel accounted for 21% of CPE cases. The hospital 30-day all-cause mortality rate for the 5-year surveillance period was 17.1 per 100 CPE cases. No significant increase in the occurrence of CPE was observed from 2010 to 2014. Nosocomial transmission of CPE, as well as international health care, is driving its persistence within Canada.

Risk factors for severe outcomes following 2009 influenza A (H1N1) infection: a global pooled analysis.

BACKGROUND: Since the start of the 2009 influenza A pandemic (H1N1pdm), the World Health Organization and its member states have gathered information to characterize the clinical severity of H1N1pdm infection and to assist policy makers to determine risk groups for targeted control measures. METHODS AND FINDINGS: Data were collected on approximately 70,000 laboratory-confirmed hospitalized H1N1pdm patients, 9,700 patients admitted to intensive care units (ICUs), and 2,500 deaths reported between 1 April 2009 and 1 January 2010 from 19 countries or administrative regions--Argentina, Australia, Canada, Chile, China, France, Germany, Hong Kong SAR, Japan, Madagascar, Mexico, The Netherlands, New Zealand, Singapore, South Africa, Spain, Thailand, the United States, and the United Kingdom--to characterize and compare the distribution of risk factors among H1N1pdm patients at three levels of severity: hospitalizations, ICU admissions, and deaths. The median age of patients increased with severity of disease. The highest per capita risk of hospitalization was among patients <5 y and 5-14 y (relative risk [RR] = 3.3 and 3.2, respectively, compared to the general population), whereas the highest risk of death per capita was in the age groups 50-64 y and ≥65 y (RR = 1.5 and 1.6, respectively, compared to the general population). Similarly, the ratio of H1N1pdm deaths to hospitalizations increased with age and was the highest in the ≥65-y-old age group, indicating that while infection rates have been observed to be very low in the oldest age group, risk of death in those over the age of 64 y who became infected was higher than in younger groups. The proportion of H1N1pdm patients with one or more reported chronic conditions increased with severity (median = 31.1%, 52.3%, and 61.8% of hospitalized, ICU-admitted, and fatal H1N1pdm cases, respectively). With the exception of the risk factors asthma, pregnancy, and obesity, the proportion of patients with each risk factor increased with severity level. For all levels of severity, pregnant women in their third trimester consistently accounted for the majority of the total of pregnant women. Our findings suggest that morbid obesity might be a risk factor for ICU admission and fatal outcome (RR = 36.3). CONCLUSIONS: Our results demonstrate that risk factors for severe H1N1pdm infection are similar to those for seasonal influenza, with some notable differences, such as younger age groups and obesity, and reinforce the need to identify and protect groups at highest risk of severe outcomes. Please see later in the article for the Editors' Summary.

Age-specific differences in influenza A epidemic curves: do children drive the spread of influenza epidemics?

There is accumulating evidence suggesting that children may drive the spread of influenza epidemics. The objective of this study was to quantify the lead time by age using laboratory-confirmed cases of influenza A for the 1995/1996-2005/2006 seasons from Canadian communities and laboratory-confirmed hospital admissions for the H1N1/2009 pandemic strain. With alignment of the epidemic curves locally before aggregation of cases, slight age-specific differences in the timing of infection became apparent. For seasonal influenza, both the 10-19- and 20-29-year age groups peaked 1 week earlier than other age groups, while during the fall wave of the 2009 pandemic, infections peaked earlier among only the 10-19-year age group. In the H3N2 seasons, infections occurred an average of 3.9 (95% confidence interval: 1.7, 6.1) days earlier in the 20-29-year age group than for youth aged 10-19 years, while during the fall pandemic wave, the 10-19-year age group had a statistically significant lead of 3 days compared with both younger children aged 4-9 years and adults aged 20-29 years (P < 0.0001). This analysis casts doubt on the hypothesis that younger school-age children actually lead influenza epidemic waves.

Incidence of hospital admissions and severe outcomes during the first and second waves of pandemic (H1N1) 2009.

BACKGROUND: Canada experienced two distinct waves of pandemic (H1N1) influenza during the 2009 pandemic, one in the spring and the second in early fall 2009. We compared the incidence of hospital admissions and severe outcomes (admission to intensive care unit [ICU] and death) during the two waves. METHODS: We reviewed data on all laboratory-confirmed cases of pandemic (H1N1) influenza that resulted in hospital admission, ICU admission or death reported to the Public Health Agency of Canada by all provinces and territories from Apr. 18, 2009, to Apr. 3, 2010. RESULTS: A total of 8678 hospital admissions (including 1473 ICU admissions) and 428 deaths related to pandemic (H1N1) influenza were reported during the pandemic and post-peak period. There were 4.8 times more hospital admissions, 4.0 times more ICU admissions and 4.6 times more deaths in the second pandemic wave than in the first wave. ICU admissions and deaths as a proportion of hospital admissions declined in the second wave; there was a 16% proportional decline in ICU admissions and a 6% proportional decline in deaths compared with the first wave. Compared with patients admitted to hospital in the first wave, those admitted in the second wave were older (median age 30 v. 23 years) and more had underlying conditions (59.7% v. 47.5%). Pregnant women and Aboriginal people accounted for proportionally fewer patients who were admitted to hospital or who died in the second wave than in the first. INTERPRETATION: The epidemiologic features of the first and second waves of the 2009 pandemic differed. The second wave was substantially larger and, although the patients admitted to hospital were older and more of them had underlying conditions, a smaller proportion had a severe outcome.

Risk of severe outcomes among patients admitted to hospital with pandemic (H1N1) influenza.

BACKGROUND: We describe the disease characteristics and outcomes, including risk factors for admission to intensive care unit (ICU) and death, of all patients in Canada admitted to hospital with pandemic (H1N1) influenza during the first five months of the pandemic. METHODS: We obtained data for all patients admitted to hospital with laboratory-confirmed pandemic (H1N1) influenza reported to the Public Health Agency of Canada from Apr. 26 to Sept. 26, 2009. We compared inpatients who had nonsevere disease with those who had severe disease, as indicated by admission to ICU or death. RESULTS: A total of 1479 patients were admitted to hospital with confirmed pandemic (H1N1) influenza during the study period. Of these, 1171 (79.2%) did not have a severe outcome, 236 (16.0%) were admitted to ICU and survived, and 72 (4.9%) died. The median age was 23 years for all of the patients, 18 years for those with a nonsevere outcome, 34 years for those admitted to ICU who survived and 51 years for those who died. The risk of a severe outcome was elevated among those who had an underlying medical condition and those 20 years of age and older. A delay of one day in the median time between the onset of symptoms and admission to hospital increased the risk of death by 5.5%. The risk of a severe outcome remained relatively constant over the five-month period. INTERPRETATION: The population-based incidence of admission to hospital with laboratory-confirmed pandemic (H1N1) influenza was low in the first five months of the pandemic in Canada. The risk of a severe outcome was associated with the presence of one or more underlying medical conditions, age of 20 years or more and a delay in hospital admission.

Temporal references in dreams and autobiographical memory.

In an attempt to determine whether temporal references identified in dreams follow the same temporal distributions as those documented for autobiographical memories, 28 younger women (18-35 years of age) and 30 older women (60-77 years of age) kept a home dream diary for 1 week and then slept 1 night in the laboratory for rapid eye movement sleep dream collection. The following morning, they identified temporal references in their dreams and produced a sample of autobiographical memories using the semantic cuing method. For both groups, there was a linear decrease in temporal references identified in dreams and autobiographical memories with increased remoteness for the last 30 years. As predicted, for the older group, there were similar cubic trends reflecting a disproportionately higher number of both temporal references identified in dreams and autobiographical memories from adolescence/early adulthood compared with adulthood and childhood. The results support the notion of continuity between waking and dreaming memory processes.

Adolescent gambling: relationships with parent gambling and parenting practices.

This study explored the possible links between family risk factors (i.e., parent gambling and parenting practices) and adolescent gambling. A community sample of 938 adolescents (496 females and 442 males) completed the South Oaks Gambling Screen Revised for Adolescents (SOGS-RA; K. C. Winters, R. Stinchfield, & J. Fulkerson, 1993b) along with a questionnaire assessing parenting practices. Both parents completed the SOGS (H. R. Lesieur & S. B. Blume, 1987). Results showed that adolescent gambling frequency was related to both parents' gambling frequency and problems. However, adolescent gambling problems were linked only to fathers' severity of gambling problems. Low levels of parental monitoring enhanced adolescents' risk of getting involved in gambling activities and developing related problems. A higher level of inadequate disciplinary practices was also related to greater gambling problems in youth. These links were significant after controlling for socioeconomic status, gender, and impulsivity-hyperactivity problems.