Differential Expression of Genes for Ubiquitin Ligases in Medulloblastoma Subtypes.

Using publically available datasets on gene expression in medulloblastoma (MB) subtypes, we selected genes for ubiquitin ligases and identified statistically those that best predicted each of the four major MB subgroups as separate disease entities. We identify a gene coding for an ubiquitin ligase, ZNRF3, whose overexpression alone can predict the WNT subgroup for 100% in the Pfister dataset. For the SHH subgroup, we identify a gene for a regulatory subunit of the protein phosphatase 2A (PP2A), PPP2R2C, as the major predictor among the E3 ligases genes. The ubiquitin and ubiquitin-like conjugation database (UUCD) lists PPP2R2C as coding for a Cullin Ring ubiquitin ligase adaptor. For group 3 MBs, the best ubiquitin ligase predictor was PPP2R2B, a gene which codes for another regulatory subunit of the PP2A holoenzyme. For group 4, the best E3 gene predictors were MID2, ZBTB18, and PPP2R2A, which codes for a third PP2A regulatory subunit. Heatmap analysis of the E3 gene data shows that expression of ten genes for ubiquitin ligases can be used to classify MBs into the four major consensus subgroups. This was illustrated by analysis of gene expression of ubiquitin ligases of the Pfister dataset and confirmed in the dataset of Cavalli. We conclude that genes for ubiquitin ligases can be used as genetic markers for MB subtypes and that the proteins coded for by these genes should be investigated as subtype specific therapeutic targets for MB.

Construct Validation of Three Nutrition Questions Using Health and Diet Ratings in Older Canadian Males Living in the Community.

Brief nutrition screening tools are desired for research and practice. Seniors in the Community: Risk Evaluation for Eating and Nutrition (SCREEN-II, 14 items) and the abbreviated version SCREEN-II-AB (8 items) are valid and reliable nutrition screening tools for older adults. This exploratory study used a retrospective cross-sectional design to determine the construct validity of a subset of 3 items (weight loss, appetite, and swallowing difficulty) currently on the SCREEN-II and SCREEN-II-AB tools. Secondary data on community-dwelling senior males (n = 522, mean ± SD age = 86.7 ± 3.0 years) in the Manitoba Follow-up Study (MFUS) study were available for analysis. Participants completed the mailed MFUS Nutrition Survey that included SCREEN-II items and questions pertaining to self-rated health, diet healthiness, and rating of the importance of nutrition towards successful aging as the constructs for comparison. Self-perceived health status (F = 14.7, P < 0.001), diet healthiness (ρ = 0.17, P = 0.002) and the rating of nutrition's importance to aging (ρ = 0.10, P = 0.03) were correlated with the 3-item score. Inferences were consistent with associations between these construct variables and the full SCREEN-II. Three items from SCREEN-II and SCREEN-II-AB demonstrate initial construct validity with self-perceived health status and diet healthiness ratings by older males; further exploration for criterion and predictive validity in more diverse samples is needed.

Nutritional risk in community-dwelling older men: the Manitoba follow-up study.

PURPOSE: The role of nutrition in older men's health and successful aging has been inadequately studied. We examined the relationships among nutritional risk, self-rated health, and successful aging in community-dwelling Canadian older men. METHODS: The surviving cohort of the Manitoba Follow-up Study (n=690, mean age = 86.8 years) were sent a self-administered nutrition survey in December 2007. The survey consisted of the Seniors in the Community: Risk Evaluation for Eating and Nutrition, version II (SCREEN II), a validated tool for assessing nutritional risk of cognitively intact community-living older adults, and questions about successful aging and health. RESULTS: Of the 553 surveys returned (80% response), 522 with complete SCREEN II data were included in the analysis. Forty-four percent of respondents were at high nutritional risk, 24% were at moderate risk, and 32% were at low risk. Significant relationships were found between nutritional risk and self-rated health (P<0.0001) and successful aging (P=0.008), with greater nutritional risk associated with lower self-ratings of health and successful aging. Higher use of prescription medication was related to greater nutritional risk (P=0.004). CONCLUSIONS: Nutritional screening programs for community-dwelling older men are warranted as two-thirds of the study participants were at nutritional risk. Identifying older men at nutritional risk is a critical step in the process of nutritional assessment, and subsequent nutrition interventions and follow-up are required to prevent further health decline.

Life Course Predictors of Young Men Surviving to Age 90 in a Cohort Study: The Manitoba Follow-up Study.

The purpose of this study was to identify factors at various time points in life that are associated with surviving to age 90. Data from men enrolled in a cohort study since 1948 were considered in 12-year intervals. Logistic regression models were constructed with the outcome of surviving to age 90. Factors were: childhood illness, blood pressure (BP), body mass index (BMI), chronic diseases, and electrocardiogram (ECG) findings. After 1996, the Short Form-36 was added. A total of 3,976 men were born in 1928 or earlier, and hence by the end of our study window in 2018, each had the opportunity of surviving to age 90. Of these, 721 did live to beyond his 90th birthday.The factors in 1948 which predicted surviving were: lower diastolic BP, lower BMI, and not smoking. In 1960, these factors were: lower BP, lower BMI, not smoking, and no major ECG changes. In 1972, these factors were lower BP, not smoking, and fewer disease states. In 1984, these factors were lower systolic BP, not smoking, ECG changes, and fewer disease states. In 1996, the factors were fewer disease states and higher physical and mental health functioning. In 2008, only higher physical functioning predicted survival to the age of 90. In young adulthood, risk factors are important predictors of surviving to age 90; in mid-life, chronic illnesses emerge, and in later life, functional status becomes predominant.

A population-based study of the epidemiology of hepatitis C in a North American population.

BACKGROUND & AIMS: Chronic hepatitis C virus (HCV) infection is a major public health problem with approximately 3% of the world's population thought to be chronically infected. However, population-based data regarding HCV incidence rates, prevalence, residence, age, and gender distributions within North America are limited. We aimed at providing a detailed descriptive epidemiology of HCV infection in a North American population with a focus on time trends in incidence rates and prevalence of newly diagnosed HCV infection since 1991, the time when laboratory testing for HCV infections became first available. METHODS: A Research Database was developed linking records from multiple administrative sources. HCV positive residents of the Canadian province of Manitoba were identified during a twelve-year period (1991-2002). The cumulative and annual incidence rates and the prevalence of newly diagnosed HCV infection in Manitoba were examined and compared between different demographic groups and urban vs. rural residents. RESULTS: A total of 5018 HCV positive cases were identified over a 12-year period. The annual number of newly diagnosed HCV infections peaked in 1998 (59.2/100,000). On the other hand, the known prevalence of HCV continued to increase (4.6-fold during the 12-year study period) among both men and women reflecting the chronic nature of the disease. Males were 1.7 times more often infected than females. HCV infections were more common in urban centers. CONCLUSIONS: Between 1995 and 2002, there was a fairly constant trend for newly diagnosed HCV infection, ranging from approximately 500 to 600 new cases annually. Hence, with a stable population size, and a low case fatality rate, the prevalence of HCV infected persons in our population has been steadily rising. There is no evidence to suggest that the incidence of HCV infection will raise, however, the burden of chronic HCV infection will continue to increase, particularly amongst older males and those residing in urban centers.

Rural practice and the personal and educational characteristics of medical students: survey of 1269 graduates of the University of Manitoba.

OBJECTIVE: To describe the relationships between rural practice and the personal and medical education characteristics of medical students and residents. DESIGN: Cross-sectional, mailed survey. SETTING: Manitoba. PARTICIPANTS: Of 2578 physician graduates of the University of Manitoba from 1965 to 2000 who were surveyed, 1269 (49%) responded. MAIN OUTCOME MEASURES: Whether physicians had ever practised in rural settings, and their demographic characteristics and adolescent, medical school, and residency training experiences. Multivariate logistic regression models were used to determine variables jointly and independently associated with rural practice. RESULTS: Of 1269 respondents, 39% had practised in rural settings, including 58% of the 362 respondents who identified family practice as their primary career activity, and 32% of the 907 respondents whose primary activities were other than family practice. For all graduates, being male (P = .0289), having lived in a rural community (P < .0001), having attended a rural high school (P < .0001), and having rural educational experiences during medical school (P = .0068) or during postgraduate training (P < .0001) were significantly related to a greater likelihood of rural practice. In the final multivariate model, graduates of rural high schools, compared with those from urban public schools, were 1.57 times (95% CI 1.09 to 2.26) more likely to have practised in rural settings. Graduates who undertook part of their undergraduate training in rural settings were 1.34 times (95% CI 1.09 to 1.75) more likely to practise in rural locations. For both undergraduates and residents, the distance of their rural education experiences from Winnipeg and the likelihood of rural practice were directly related. For both FPs and non-FPs, being male and undertaking rural education during residency training were associated with a greater likelihood of rural practice, as was the distance of the training experience from the urban setting. For non-FPs a similar association was observed with undergraduate rural experiences. CONCLUSION: This large survey of graduates from a Canadian medical school demonstrated that attending a rural high school (P < .0001) and having rural educational exposure during medical school and residency training (P = .0068) were significantly associated with a physician practising in a rural location. That is, rural educational experiences on the continuum from high school through residency training appeared to be associated with rural practice.

Patterns of Functional Impairment over Time Amongst Older Men-the Manitoba Follow-up Study.

BACKGROUND: To determine the incidence and prevalence patterns of activity of daily living (ADL) impairments in ageing men. METHODS: 3,983 men were enrolled in the Manitoba Follow-up Study (MFUS) cohort study in 1948. From 1996 onwards, functional status was measured. We classified basic (BADL) and instrumental (IADL) into mutually exclusive categories as a time dependant factor after the second survey wave as: First survey response; no limitation; incident (first episode of disability); persistent (limitation which was seen on all questionnaires after the incident episode); resilient (noted in previous surveys but not present); and recurrent (noted in present survey, and limitations noted as present and absent in previous surveys). RESULTS: There were 1,745 participants in 1996 at a mean age of 76 years. Incident BADL limitations increased substantially with age: from 1% at age 75 to 15% at age 95. Similarly, persistent limitations increased with age: from 0.4% at age 75 to 18% at age 95. However, BADL function was fluid, with many individuals grouped within the resilient and recurrent patterns. Similar age effects and variability were noted in IADLs. CONCLUSION: New and persistent disabilities are highly associated with age. However, there is considerable change in functional status over time.

Associations between concussion and risk of diagnosis of psychological and neurological disorders: a retrospective population-based cohort study.

OBJECTIVE: To investigate associations between concussion and the risk of follow-up diagnoses of attention-deficit hyperactivity disorder (ADHD), mood and anxiety disorders (MADs), dementia and Parkinson's disease. DESIGN: A retrospective population-based cohort study. SETTING: Administrative health data for the Province of Manitoba between 1990-1991 and 2014-2015. PARTICIPANTS: A total of 47 483 individuals were diagnosed with a concussion using International Classification of Diseases (ICD) codes (ICD-9-CM: 850; ICD-10-CA: S06.0). All concussed subjects were matched with healthy controls at a 3:1 ratio based on age, sex and geographical location. Associations between concussion and conditions of interest diagnosed later in life were assessed using a stratified Cox proportional hazards regression model, with adjustments for socioeconomic status and pre-existing medical conditions. RESULTS: 28 021 men (mean age ±SD, 25±18 years) and 19 462 women (30±21 years) were included in the concussion group, while 81 871 men (25±18 years) and 57 159 women (30±21 years) were included in the matched control group. Concussion was associated with adjusted hazard ratios of 1.39 (95% CI 1.32 to 1.46, p<0.001) for ADHD, 1.72 (95% CI 1.69 to 1.76; p<0.001) for MADs, 1.72 (95% CI 1.61 to 1.84; p<0.001) for dementia and 1.57 (95% CI 1.41 to 1.75; p<0.001) for Parkinson's disease. CONCLUSION: Concussion was associated with an increased risk of diagnosis for all four conditions of interest later in life.

QT dispersion and heart rate predict the risk of sudden unexpected cardiac death in men: the Manitoba Follow-Up Study.

As many as half of all sudden cardiac deaths are unexpected, with no preceding symptoms or signs of cardiac problems. Since 1948, the Manitoba Follow-up Study has prospectively recorded routine medical information and resting electrocardiographic (ECG) findings from a cohort of 3983 men. During 58 years of follow-up, 180 men experienced sudden unexpected cardiac death (SUCD). Heart rate, the longest QT interval, the shortest QT interval, and their difference and QT dispersion (QTD) on ECGs recorded prior to SUCD and 5 years and 10 years earlier were compared with QT intervals on ECGs of age-matched controls. QTD and heart rate each were significantly (P < .01) and independently associated with increased risk for SUCD. Only primary prevention can reduce the risk for SUCD. Hence, this relationship between QTD and heart rate and SUCD emphasizes the importance of longitudinal noninvasive QT measurements on routine ECGs in healthy men.

Determinants of self-care behaviors in community-dwelling patients with heart failure.

BACKGROUND AND RESEARCH OBJECTIVE: As the population ages, chronic conditions such as heart failure are becoming more prevalent. An important goal is to understand how patients with heart failure learn to manage the often debilitating disease symptoms. The research objective was to examine the determinants of general and therapeutic self-care behaviors among community-dwelling heart failure patients. Guided by Connelly's Model of Self-care in Chronic Illness, enabling and predisposing factors were evaluated using sociodemographic characteristics, functional ability, and psychological status. Self-care maintenance, self-efficacy, and self-care management characteristics were also evaluated. PARTICIPANTS AND METHODS: Using a cross-sectional design, a convenience sample of 65 ambulatory care patients were recruited. Data were collected through chart reviews and questionnaires. RESULTS AND CONCLUSIONS: Common self-care maintenance behaviors included taking medication as prescribed (95%), seeking physician guidance (80%), and following sodium dietary restrictions (70%). These behaviors were influenced by enabling characteristics such as psychological status (P = .030), ethnicity (P = .048), and comorbidity (P = .023). A unique finding was that self-care maintenance behaviors were significantly lower in aboriginal participants. The predisposing characteristic of self-efficacy influenced self-maintenance behaviors (P = .0002), overall self-care (P = .04) and number of hospital admissions (P < .0001). Higher overall self-care scores, measured by the summative Self-care Heart Failure Index score was correlated with fewer hospital admissions (P = .019).

The relationships between food group consumption, self-rated health, and life satisfaction of community-dwelling canadian older men: the manitoba follow-up study.

We conducted a cross-sectional evaluation nested within a long-term cohort study that was designed to examine the relationship between frequency of food group consumption (FGC), self-rated health, and life satisfaction of community-dwelling older men in the Manitoba Follow-up Study. Questionnaires returned from 1,211 Canadian male participants contained frequency of FGC (daily, most days, or rarely), self-reported nutrition, and health-related perceptions. Men consuming vegetables/fruit (V&F) daily versus rarely were four times more likely to report better self-rated health OR = 4.00 (95%CI = 1.31, 12.3) and three times more likely to rate greater life satisfaction OR = 3.08 (95%CI = 1.00, 9.45). Our findings indicate that frequent consumption of V&F is associated with the perception of better health and greater life satisfaction.

The consistency of definitions of successful aging provided by older men: the Manitoba follow-up study.

ABSTRACTIn the absence of a universally agreed-upon definition of successful aging, researchers increasingly look to older adults for layperson views of aging and definitions of successful aging. To use lay definitions in studies of aging, however, researchers must address the definitions' consistency. In 2004, surviving members of the Manitoba Follow-up Study male cohort (mean age: 83 years) were asked twice for their definition of successful aging. A consistency category was assigned based on the similarity of themes in each of 654 pairs of definitions. At least half of the main themes were similar in 70 per cent of the definition pairs; 80 per cent of respondents repeated at least one theme. Positive or negative health events in the four-week interval between definitions and specific respondents' characteristics did not vary across consistency categories. This evidence for consistency supports our continued reliance on lay definitions of successful aging.

Self-Rated Health Predicts Mortality in Very Old Men-the Manitoba Follow-Up Study.

BACKGROUND: Self-rated health (SRH) predicts death, but there are few studies over long-time horizons that are able to explore the effect age may have on the relationship between SRH and mortality. OBJECTIVES: 1. To determine how SRH evolves over 20 years; and 2. To determine if SRH predicts death in very old men. METHODS: We analyzed a prospective cohort study of men who were fit for air crew training in the Second World War. In 1996, a regular questionnaire was administered to the 1,779 surviving participants. SRH was elicited with a 5-point Likert Scale with the categories: excellent, very good, good, fair and poor/bad. We examined the age-specific distribution of SRH in these categories from the age of 75 to 95 years, to the end of the follow-up period in 2018. We constructed age-specific Cox proportional hazard models with an outcome of time to death. RESULTS: SRH declined with age. The gradient in risk of death persisted across all ages; those with poor/fair/bad SRH had consistently higher mortality rates. However, the discrimination between good and excellent was less in those aged 85+. CONCLUSIONS: SRH declines with advancing age, but continues to predict death in older men.

Older Men's Definitions of Frailty - The Manitoba Follow-up Study.

ABSTRACTBackground: There is little empirical research into lay definitions of frailty. OBJECTIVES: (1) To explore the definitions of frailty among older men, and (2) to explore if these definitions match commonly used clinical definitions of frailty. METHODS: Analysis of open-ended questions to survey data from a prospective cohort study of older airmen. The definitions of frailty were elicited, and grouped according to themes. RESULTS: 147 men responded (mean age: 93). There was considerable heterogeneity in older men's' definitions of frailty, and no theme of frailty was predominant. The most common theme was impairment in activities of daily living. Older men's' definition of frailty was not consistent with any commonly used medical theory of frailty. CONCLUSIONS: Most older men think frailty is important, but their definitions are not consistent. Frailty may be a heterogeneous experience, which different people experience differently.

Ability and accuracy of long-term weight recall by elderly males: the Manitoba follow-up study.

PURPOSE: To assess the ability and accuracy of elderly men to recall their weights and determine what characteristics might predict recall ability and accuracy. METHODS: Eight hundred sixty-nine elderly men (mean age, 84 years), participants of the Manitoba Follow-up Study (MFUS), responded to a questionnaire asking them to recall their weights at ages 20, 30, 50, and 65 years. Recalled weights were compared with measured weights collected since MFUS began in 1948. Logistic regression was used to predict ability and accuracy of weight recall. RESULTS: Only 75% of respondents attempted to recall their weights at all 4 ages. Among men recalling 4 weights, fewer than half were accurate within +/- 10%, just 7% were within +/- 5% of their measured weights. Accuracy of recall was significantly and independently associated with body mass index during middle age (5 kg/m(2)) (odds ratio 0.83, 95% confidence interval: 0.76, 0.90) and weight change. Unmarried men were less likely than married men to attempt recalling all 4 weights. Men overweight at middle age were more likely to underestimate their recalled weights. CONCLUSIONS: Studies relating weight in early adulthood or middle age with outcomes in later life should not rely on elderly male participants recalling those weights.

Quality of Life Trajectories Predict Mortality in Older Men: The Manitoba Follow-Up Study.

OBJECTIVE: To describe quality of life trajectories of older men over a 10-year time frame in mental and physical health domains, and to determine if these trajectories predict death over a subsequent 9-year period. METHOD: A cohort study of Royal Canadian Air Force aircrew veterans. We used Short Form-36 (SF-36) measures of mental and physical functioning collected prospectively at six time points between 1996 to 2006 (734 men with a mean age of 85.5 [ SD 3.0] years in 2006) to determine trajectories. Continued contact with the cohort from 2006 to 2015 determined subsequent mortality. RESULTS: Men were more likely to maintain high levels of mental functioning than physical functioning. Thirty-seven percent of participants maintained a high level of both mental and physical functioning. Declining function in either mental or physical function was associated with lower survival. CONCLUSION: Men who maintain physical and mental functioning have a lower mortality rate.

Lifetime Pattern of Atrial Fibrillation and the Risks of Stroke and Death in a Population-based Cohort of Men (from The Manitoba Follow-Up Study).

Atrial fibrillation (AF) is associated with stroke and mortality. The arrhythmia can be sustained or intermittent. Previous studies that have used fixed covariates and short-time horizons to examine the relation between the pattern of AF and the occurrence of events have produced conflicting results. The Manitoba Follow-Up Study includes 3,983 originally healthy men who have been followed with routine examinations since 1948. AF status during each visit was classified into the following patterns: free of AF, newly diagnosed; intermittent AF-in sinus;intermittent AF-in AF; sustained AF. We created adjusted Cox proportional hazards models with time-dependent covariates to estimate risks for stroke and death according to AF pattern. After 167,982 person-years of follow-up and 66,297 electrocardiograms (ECGs), 548 men had at least 1 ECG documenting AF, 799 had a stroke, and 3173 died. Relative to men free of AF, sustained and newly diagnosed AF were associated with stroke (hazard ratio [HR] 1.85, 95% confidence interval [CI] 1.33 to 2.59 and HR 1.71, 95% CI 1.10 to 2.66, respectively) and death (HR 2.48, 95% CI 2.11 to 2.92 and HR 2.03, 95% CI 1.64 to 2.52, respectively). Intermittent AF was associated with death (HR 2.41 95% CI 1.58 to 3.68 in AF and HR 1.71 95% CI 1.44 to 2.03 in sinus), but not with stroke (HR 0.68, 95% CI 0.22 to 2.13 in AF and HR 1.02 95% CI 0.72 to 1.45 in sinus). Antithrombotic therapy was associated with a reduced risk of the outcomes. In conclusion, longitudinal analysis of patterns of AF evolving over time provided evidence that the associated risks of stroke and death vary considerably with rhythm classification on serial ECGs.

Variation in site of death among nursing home residents in British Columbia, Canada.

OBJECTIVE: To assess the proportion of in-hospital versus in-nursing home deaths among a population of decedent nursing home residents in British Columbia, Canada, and to identify facility and individual characteristics associated with in-hospital death. METHODS: We examined nursing home (ownership/organization, size) and individual (age, level of care, sex, previous hospitalization within 30 days) characteristics of all decedent residents of British Columbia's freestanding publicly funded nursing homes. Secondary administrative data from the Ministry of Health, supplemented with facility data were analyzed. The study population included those aged 65 years and older who died between April 1, 1996 and August 1, 1999 (n = 14,413). Mixed models were used to estimate unadjusted and adjusted odds ratios (AOR; 95% confidence intervals [CI]) for factors associated with in-hospital death. RESULTS: Almost one quarter (24.6%) of deaths occurred in hospital. In-hospital death was more frequent in nonprofit (NP) single-site facilities compared to NP facilities owned and/or operated by a health authority (AOR = 1.37, 95% CI: 1.15, 1.64). Smaller nursing home size (AOR = 1.25, 95% CI: 1.05, 1.50) and male gender (AOR = 1.17, 95% CI: 1.07, 1.27) were also associated with a greater odds of in-hospital death. Progressively lower odds ratios of in-hospital death were observed for each category of increasing age and declining function, respectively. CONCLUSIONS: While individual characteristics play a significant role in explaining variation in site of death, residence in a NP single-site and smaller-sized facility was also associated with a greater frequency of in-hospital death.

Estimating the incidence of dementia: the impact of adjusting for subject attrition using health care utilization data.

PURPOSE: To estimate incidence rates for dementia and the impact of subject attrition on these rates. METHODS: Crude, age- and gender-specific incidence rates of dementia and Alzheimer's disease were calculated using person-years analysis and Cox proportional hazard models in a population-based cohort study of 1952 adults aged 65+ years in Manitoba, Canada. Rates were standardized to the nondemented population using the direct method. Ratios of incidence rates comparing completers to subjects who had died, refused, or were unavailable for follow up were based on health care utilization data (available for all subject groups) and used to adjust rates for attrition. RESULTS: Decedents had a significantly higher incidence of dementia than did subjects who completed the follow-up assessment. The incidence in subjects who refused or were unavailable at follow up was intermediate between decedents and completers. Adjusted for attrition, the standardized dementia incidence rate for community and institutional subjects was 25.3/1000 person-years, significantly higher than that based on follow-up assessments only (17.8/1000 person-years; 95% confidence interval: 14.3-21.4). CONCLUSIONS: The impact of loss to follow up on incidence rates varies depending on the reason for subject attrition. Incidence studies of dementia should develop strategies to characterize and address subject attrition to avoid underestimating disease incidence.