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Metabolic processes can influence disease risk and provide therapeutic targets. By conducting genome-wide association studies of 1,091 blood metabolites and 309 metabolite ratios, we identified associations with 690 metabolites at 248 loci and associations with 143 metabolite ratios at 69 loci. Integrating metabolite-gene and gene expression information identified 94 effector genes for 109 metabolites and 48 metabolite ratios. Using Mendelian randomization (MR), we identified 22 metabolites and 20 metabolite ratios having estimated causal effect on 12 traits and diseases, including orotate for estimated bone mineral density, α-hydroxyisovalerate for body mass index and ergothioneine for inflammatory bowel disease and asthma. We further measured the orotate level in a separate cohort and demonstrated that, consistent with MR, orotate levels were positively associated with incident hip fractures. This study provides a valuable resource describing the genetic architecture of metabolites and delivers insights into their roles in common diseases, thereby offering opportunities for therapeutic targets. Genome-wide association studies comprising 1,091 metabolites and 309 metabolite ratios in 8,299 individuals from the Canadian Longitudinal Study on Aging provide insights into the genetic architecture of metabolites and their role in human diseases.

Low lung function is associated with high mortality and adverse cardiopulmonary outcomes. Less is known of its association with broader health indices such as self-reported respiratory symptoms, perceived general health, and cognitive and physical performance. The present study seeks to address the association between forced expiratory volume in 1 second (FEV1), an indicator of lung function, with broad markers of general health, relevant to aging trajectory in the general population. From the Canadian general population, 22,822 adults (58% females, mean age 58.8 years [standard deviation (SD) 9.6]) were enrolled from the community between June 2012 and April 2015 from 11 Canadian cities and 7 provinces. Mixed effects regression was used to assess the cross-sectional relationship between FEV1 with self-reported respiratory symptoms, perceived poor general health, and cognitive and physical performance. All associations were adjusted for age, sex, body mass index (BMI), education, smoking status, and self-reported comorbidities and expressed as adjusted odds ratios (aORs). Based on the Global Lung Function Initiative (GLI) reference values, 38% (n = 8,626) had normal FEV1 (z-scores >0), 37% (n = 8,514) mild (z-score 0 to > -1 SD), 19% (n = 4,353) moderate (z-score -1 to > -2 SD), and 6% (n = 1,329) severely low FEV1 (z-score = < -2 SD). There was a graded association between lower FEV1 with higher aOR [95% CI] of self-reported moderate to severe respiratory symptoms (mild FEV1 1.09 [0.99 to 1.20] p = 0.08, moderate 1.45 [1.28 to 1.63] p < 0.001, and severe 2.67 [2.21 to 3.23] p < 0.001]), perceived poor health (mild 1.07 [0.9 to 1.27] p = 0.45, moderate 1.48 [1.24 to 1.78] p = <0.001, and severe 1.82 [1.42 to 2.33] p < 0.001]), and impaired cognitive performance (mild 1.03 [0.95 to 1.12] p = 0.41, moderate 1.16 [1.04 to 1.28] p < 0.001, and severe 1.40 [1.19 to 1.64] p < 0.001]). Similar graded association was observed between lower FEV1 with lower physical performance on gait speed, Timed Up and Go (TUG) test, standing balance, and handgrip strength. These associations were consistent across different strata by age, sex, tobacco smoking, obstructive, and nonobstructive impairment on spirometry. A limitation of the current study is the observational nature of these findings and that causality cannot be inferred. We observed graded associations between lower FEV1 with higher odds of disabling respiratory symptoms, perceived poor general health, and lower cognitive and physical performance. These findings support the broader implications of measured lung function on general health and aging trajectory.

This article is to establish recommendations for conducting quantitative synthesis, or meta-analysis, using study-level data in comparative effectiveness reviews (CERs) for the Evidence-based Practice Center (EPC) program of the Agency for Healthcare Research and Quality. We focused on recurrent issues in the EPC program and the recommendations were developed using group discussion and consensus based on current knowledge in the literature. We first discussed considerations for deciding whether to combine studies, followed by discussions on indirect comparison and incorporation of indirect evidence. Then, we described our recommendations on choosing effect measures and statistical models, giving special attention to combining studies with rare events; and on testing and exploring heterogeneity. Finally, we briefly presented recommendations on combining studies of mixed design and on sensitivity analysis. Quantitative synthesis should be conducted in a transparent and consistent way. Inclusion of multiple alternative interventions in CERs increases the complexity of quantitative synthesis, whereas the basic issues in quantitative synthesis remain crucial considerations in quantitative synthesis for a CER. We will cover more issues in future versions and update and improve recommendations with the accumulation of new research to advance the goal for transparency and consistency.

ObjectiveTo describe the sociodemographic characteristics associated with e-cigarette ever use and to examine the impact of e-cigarette ever use on lung function impairment in an ageing population.DesignA cross-sectional analysis of data from the Canadian Longitudinal Study on Aging.SettingA national stratified sample of 44 817 adults living in Canadian provinces.ParticipantsRespondents included participants aged 45–85 and residing in the community in Canadian provinces.Outcome measuresThe Global Lung Function Initiative normative values for forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), forced expiratory ratio (FEV1/FVC) appropriate for age, sex, height and ethnicity were used to interpret the severity of lung function impairment. Multinomial logistic regression analysis was used to examine the impact of e-cigarette ever use on obstructive and restrictive lung function impairment.ResultsThe prevalence of e-cigarette ever use was 6.5% and varied by sociodemographic factors including higher prevalence among individuals younger than 65 years, those with lower education attainment and those with lower annual household income. E-cigarette ever use was associated with 2.10 (95% CI 1.57 to 2.08) times higher odds of obstructive lung function impairment after adjusting for conventional cigarette smoking and other covariates. Individuals with exposure to e-cigarette ever use and 15 or more pack-years had 7.43 (95% CI 5.30 to 10.38) times higher odds for obstructive lung function impairment when compared with non-smokers and non-e-cigarette users after adjusting for covariates. Smokers with 15 or more pack-years had higher odds of restrictive lung function impairment irrespective of e-cigarette ever use.ConclusionsEver use of e-cigarettes was found to be associated with obstructive lung function impairment after adjusting for covariates, suggesting that e-cigarette use may be adding to the respiratory and other chronic disease burden in the population.

COVID-19 infection can lead to multi-organ dysfunction, which has been shown to contribute to the physical disability seen in people after hospital discharge. We aimed to understand the effects of hospitalization for COVID-19 on mobility, cognition, and daily activities over 24-months of follow up. This was a 24-month extension of the COREG-FR prospective cohort study (NCT04602260). We enrolled consecutive adult patients (≥18 years) with lab confirmed SARS-Cov-2 infection who were admitted to five Ontario, Canada hospitals between August 21, 2020, and December 21, 2021. Patients were excluded if they resided in an institution (e.g., long term care facility), had severe premorbid physical function limitations (e.g., unable to stand independently) or had cognitive impairment which limited their ability to complete follow-up assessment. We assessed mobility and cognitive status using the Activity Measure for Post-Acute Care (AM-PAC) Basic Mobility Domain and Cognitive Domain, respectively. Deficits from premorbid status were determined using the minimal clinically important differences in mobility (≥ 3.3) and cognition (≥ 5.5). We also asked participants how much their COVID-19 recovery affected their daily activities within the preceding week with response options from 'not at all' to 'all the time'. Among the 215 participants who participated 12-months after hospital discharge, 170 (79%) consented to the 24-month follow-up. The mean (standard deviation) age was 61.2 (12.7) years and 54% (n = 91) of participants who were male. Compared to pre-morbid function, mobility and cognitive deficits were present in 57% and 41% of participants, respectively. Furthermore, 59% of participants reported COVID-19 continued to impact their daily activities. At 24-months after hospitalization for COVID-19, many participants experience persistent mobility and cognitive deficits. Future work should aim to develop comprehensive rehabilitation strategies for those recovering from COVID-19 which target mobility and cognitive function.

Background Several conservative (i.e., nonpharmacologic, nonsurgical) treatments exist for secondary lymphedema. The optimal treatment is unknown. We examined the effectiveness of conservative treatments for secondary lymphedema, as well as harms related to these treatments. Methods We searched MEDLINE ® , EMBASE ® , Cochrane Central Register of Controlled Trials ® , AMED, and CINAHL from 1990 to January 19, 2010. We obtained English- and non-English-language randomized controlled trials or observational studies (with comparison groups) that reported primary effectiveness data on conservative treatments for secondary lymphedema. For English-language studies, we extracted data in tabular form and summarized the tables descriptively. For non-English-language studies, we summarized the results descriptively and discussed similarities with the English-language studies. Results Thirty-six English-language and eight non-English-language studies were included in the review. Most of these studies involved upper-limb lymphedema secondary to breast cancer. Despite lymphedema's chronicity, lengths of follow-up in most studies were under 6 months. Many trial reports contained inadequate descriptions of randomization, blinding, and methods to assess harms. Most observational studies did not control for confounding. Many studies showed that active treatments reduced the size of lymphatic limbs, although extensive between-study heterogeneity in areas such as treatment comparisons and protocols, and outcome measures, prevented us from assessing whether any one treatment was superior. This heterogeneity also precluded us from statistically pooling results. Harms were rare (< 1% incidence) and mostly minor (e.g., headache, arm pain). Conclusions The literature contains no evidence to suggest the most effective treatment for secondary lymphedema. Harms are few and unlikely to cause major clinical problems.

ObjectivesTo examine the impact of the COVID-19 pandemic on body mass index (BMI) and obesity status among Canadian residents and explore how this association varied by sociodemographic and health status.DesignProspective cohort study.SettingCanada.Participants41 302 adults, aged 45–85 at baseline, participating in the Canadian Longitudinal Study on Aging.Primary and secondary outcomesBMI and BMI-defined obesity were measured at baseline, follow-up 1 and follow-up 2 (FUP2), with 33% of FUP2 data (n=13 444) gathered after 16 March 2020, when COVID-19 restrictions began. Correction factors were applied for self-reported BMI and weighted generalised estimating equations assessed BMI changes before and during the pandemic.ResultsWe found a significant interaction between follow-up time and timing of FUP2 data collection (before or during the pandemic). Participants measured during the pandemic had an excess BMI increase of 0.21 kg/m² (95% CI 0.15 to 0.28) and 1.06 times higher odds of obesity (95% CI 1.03 to 1.09) compared with prepandemic trends. Increases were more pronounced among females, middle-aged adults and those without diabetes.ConclusionsThe COVID-19 pandemic was associated with a modest increase in BMI and obesity among Canadian adults. Ongoing research is needed to assess long-term trends.

It is unknown if the relationship between multimorbidity and disability differs by combinations of chronic conditions. The objective of our study was to elucidate how joint effect of different combinations of chronic conditions impact the five year risk of functional disability at the population level. Participants ≥65 years from the Canadian Study of Health and Aging were assessed for functional disability measured using activities of daily living (ADL) and instrumental ADL (IADL), and the presence of conditions in five disease domains; cardiometabolic, neurological, sensory, musculoskeletal, and respiratory. Logistic regression was used to assess the relationship between each disease domain and incident ADL and IADL measured at five years of follow up and population attributable risk (PAR) was modeled for diseases domains that were significantly associated with disability. Results were stratified by sex and age (65-74 years, ≥75 years). There were 6272 participants free of ADL disability and 4571 participants free from IADL disability at baseline. For incident ADL, the greatest PAR values were 21.3 (9.8-32.8) for the cardiometabolic domain in males 65-74 years, 22.7 (4.7-40.8) for the musculoskeletal domain for females aged 65-74 years, and 11.2 (2.8-19.7) for the musculoskeletal domain in males ≥75 years. The PAR for the musculoskeletal, sensory, and neurological domains were similar in females ≥75 years(9.3-9.9). PAR values were lower but followed similar patterns for IADL disability. The chronic disease domains which most strongly predicted incident ADLs and IADLs did not account for the greatest amount of disability at the population level.

Background Monitoring and improving physical activity levels is essential for promoting healthy aging. The objective of this study was to create age-specific normative values for the Physical Activity Scale for the Elderly (PASE) among community-dwelling women and men aged 45–85 years old. Methods 36,701 participants (47% female) aged 45–85 years old, free of any mobility limitation or activities of daily living disability from the Canadian Longitudinal Study on Aging (CLSA) were included. Best fitting models were identified using Generalized Akaike Information Criteria values and cross-validation. Seasonal differences for males and females were also explored. Results Separate models for males and females are presented, providing a range of percentile values (5–95%) in charts and tables. Total PASE scores were highest in 45-year-olds and decreased with age. Seasonal differences were not substantial or consistent at the population level. Conclusions The age- and sex- specific normative values provided can improve the interpretability of PASE scores among middle-aged and older adults. In addition to PA guideline cut-offs, normative values provide further information for monitoring physical activity by allowing for more personalized observations that account for healthy variation.