The Benefits and Risks of Receiving Investigational Solid Tumor Drugs in Randomized Trials : A Systematic Review and Meta-analysis.

BACKGROUND: Many patients participate in cancer trials to access new therapies. The extent to which new treatments produce clinical benefit for trial participants is unclear. PURPOSE: To estimate the progression-free survival (PFS) and overall survival (OS) advantage of assignment to experimental groups in randomized trials for 6 solid tumors. DATA SOURCES: ClinicalTrials.gov was searched for trials of investigational drugs with results posted between 2017 and 2021. STUDY SELECTION: Investigational drugs were defined as those not yet having full approval from the U.S. Food and Drug Administration for the study indication. Trials were included if they were randomized and tested drugs or biologics. DATA EXTRACTION: Data extraction was completed by 2 independent reviewers. Data were pooled using a random-effects model. DATA SYNTHESIS: The sample included 128 trials comprising 141 comparisons of a new drug and a comparator. These comparisons included 47 050 patients. The pooled hazard ratio for PFS was 0.80 (95% CI, 0.75 to 0.85), indicating statistically significant benefit for patients in experimental groups. This corresponded to a median PFS advantage of 1.25 months (CI, 0.80 to 1.68 months). The pooled hazard ratio for OS was 0.92 (CI, 0.88 to 0.95), corresponding to a survival gain of 1.18 months (CI, 0.72 to 1.71 months). The absolute risk for a serious adverse event for comparator group patients was 29.56% (CI, 26.64% to 32.65%), with an increase in risk of 7.40% (CI, 5.66% to 9.14%) for patients in experimental groups. LIMITATIONS: Trials in this sample were heterogeneous. Comparator group interventions were assumed to reflect standard of care. CONCLUSION: Assignment to experimental groups produces statistically significant survival gains. However, the absolute survival gain is small, and toxicity is statistically significantly greater. The findings of this review provide reassuring evidence that patients are not meaningfully disadvantaged by assignment to comparator groups. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

Nutritional supplementation to prevent tuberculosis incidence in household contacts of patients with pulmonary tuberculosis in India (RATIONS): a field-based, open-label, cluster-randomised, controlled trial.

BACKGROUND: In India, tuberculosis and undernutrition are syndemics with a high burden of tuberculosis coexisting with a high burden of undernutrition in patients and in the population. The aim of this study was to determine the effect of nutritional supplementation on tuberculosis incidence in household contacts of adults with microbiologically confirmed pulmonary tuberculosis. METHODS: In this field-based, open-label, cluster-randomised controlled trial, we enrolled household contacts of 2800 patients with microbiologically confirmed pulmonary tuberculosis across 28 tuberculosis units of the National Tuberculosis Elimination Programme in four districts of Jharkhand, India. The tuberculosis units were randomly allocated 1:1 by block randomisation to the control group or the intervention group, by a statistician using computer-generated random numbers. Although microbiologically confirmed pulmonary tuberculosis patients in both groups received food rations (1200 kcal, 52 grams of protein per day with micronutrients) for 6 months, only household contacts in the intervention group received monthly food rations and micronutrients (750 kcal, 23 grams of protein per day with micronutrients). After screening all household contacts for co-prevalent tuberculosis at baseline, all participants were followed up actively until July 31, 2022, for the primary outcome of incident tuberculosis (all forms). The ascertainment of the outcome was by independent medical staff in health services. We used Cox proportional hazards model and Poisson regression via the generalised estimating equation approach to estimate unadjusted hazard ratios, adjusted hazard ratios (aHRs), and incidence rate ratios (IRRs). This study is registered with CTRI-India, CTRI/2019/08/020490. FINDINGS: Between Aug 16, 2019, and Jan 31, 2021, there were 10 345 household contacts, of whom 5328 (94·8%) of 5621 household contacts in the intervention group and 4283 (90·7%) of 4724 household contacts in the control group completed the primary outcome assessment. Almost two-thirds of the population belonged to Indigenous communities (eg, Santhals, Ho, Munda, Oraon, and Bhumij) and 34% (3543 of 10 345) had undernutrition. We detected 31 (0·3%) of 10 345 household contact patients with co-prevalent tuberculosis disease in both groups at baseline and 218 (2·1%) people were diagnosed with incident tuberculosis (all forms) over 21 869 person-years of follow-up, with 122 of 218 incident cases in the control group (2·6% [122 of 4712 contacts at risk], 95% CI 2·2-3·1; incidence rate 1·27 per 100 person-years) and 96 incident cases in the intervention group (1·7% [96 of 5602], 1·4-2·1; 0·78 per 100 person-years), of whom 152 (69·7%) of 218 were patients with microbiologically confirmed pulmonary tuberculosis. Tuberculosis incidence (all forms) in the intervention group had an adjusted IRR of 0·61 (95% CI 0·43-0·85; aHR 0·59 [0·42-0·83]), with an even greater decline in incidence of microbiologically confirmed pulmonary tuberculosis (0·52 [0·35-0·79]; 0·51 [0·34-0·78]). This translates into a relative reduction of tuberculosis incidence of 39% (all forms) to 48% (microbiologically confirmed pulmonary tuberculosis) in the intervention group. An estimated 30 households (111 household contacts) would need to be provided nutritional supplementation to prevent one incident tuberculosis. INTERPRETATION: To our knowledge, this is the first randomised trial looking at the effect of nutritional support on tuberculosis incidence in household contacts, whereby the nutritional intervention was associated with substantial (39-48%) reduction in tuberculosis incidence in the household during 2 years of follow-up. This biosocial intervention can accelerate reduction in tuberculosis incidence in countries or communities with a tuberculosis and undernutrition syndemic. FUNDING: Indian Council of Medical Research-India TB Research Consortium.

Role of Physical Activity and Sedentary Behaviors on Vascular and Myocardial Structure and Function in Type 1 Diabetes.

OBJECTIVE: To estimate associations between physical activity and sedentary behaviors and early markers of cardiovascular diseases in adolescents with and without type 1 diabetes. STUDY DESIGN: Cross-sectional data stem from the CARdiovascular Disease risk in pEdiatric type 1 diAbetes (CARDEA) study, a study investigating early cardiovascular disease development in 100 adolescents with type 1 diabetes recruited at Sainte-Justine University Hospital Diabetes Clinic and 97 healthy adolescents without diabetes (14-18 years), in Montreal, Canada. Outcomes included arterial stiffness by pulse-wave velocity, endothelial function (velocity time integral) by flow-mediated dilation test, and cardiac magnetic resonance imaging markers. Moderate-to-vigorous physical activity (MVPA) and sedentary time were estimated by accelerometry and leisure screen time by questionnaire. We estimated multivariable linear regression models stratified by group. RESULTS: In adolescents with type 1 diabetes, 10-minutes daily increase in MVPA was associated with 3.69 g/m (95% CI: -1.16; 8.54) higher left ventricular (LV) mass/height and 1-hour increase in device-measured sedentary time with 0.68 mm (0.20; 1.16) higher wall thickness but only in those with glycated hemoglobin ≤7.5%. In healthy adolescents, a 10-minute increase in MVPA was associated with 1.32 g/m (-0.03; 2.66) higher LV mass/height. Every 1-hour increase in sedentary time was associated with -1.82 cm (-3.25; -0.39) lower velocity time integral, -2.99 g/m (-5.03; -0.95) lower LV mass/height, and -0.47 mm (-0.82; -0.12) lower wall thickness. CONCLUSIONS: Being active and limiting sedentary time appears beneficial for cardiac structure and endothelial function in healthy adolescents; however, adequate glycemic control combined with higher levels of MVPA may be required for adolescents with type 1 diabetes to overcome the impact of diabetes.

Factors associated with physical function among people with systemic sclerosis: a SPIN cohort cross-sectional study.

OBJECTIVES: To compare physical function in systemic sclerosis (SSc, scleroderma) to general population normative data and identify associated factors. METHODS: Scleroderma Patient-centered Intervention Network Cohort participants completed the Physical Function domain of the Patient-Reported Outcomes Measurement Information System Version 2 upon enrolment. Multivariable linear regression was used to assess associations of sociodemographic, lifestyle, and disease-related variables. RESULTS: Among 2385 participants, the mean physical function T-score (43.7, SD = 8.9) was ∼2/3 of a standard deviation (SD) below the US general population (mean = 50, SD = 10). Factors associated in the multivariable analysis included older age (-0.74 points per SD years, 95% CI -0.78 to -1.08), female sex (-1.35, -2.37 to -0.34), fewer years of education (-0.41 points per SD in years, -0.75 to -0.07), being single, divorced, or widowed (-0.76, -1.48 to -0.03), smoking (-3.14, -4.42 to -1.85), alcohol consumption (0.79 points per SD drinks per week, 0.45-1.14), BMI (-1.41 points per SD, -1.75 to -1.07), diffuse subtype (-1.43, -2.23 to -0.62), gastrointestinal involvement (-2.58, -3.53 to -1.62), digital ulcers (-1.96, -2.94 to -0.98), moderate (-1.94, -2.94 to -0.93) and severe (-1.76, -3.24 to -0.28) small joint contractures, moderate (-2.10, -3.44 to -0.76) and severe (-2.54, -4.64 to -0.44) large joint contractures, interstitial lung disease (-1.52, -2.27 to -0.77), pulmonary arterial hypertension (-3.72, -4.91 to -2.52), rheumatoid arthritis (-2.10, -3.64 to -0.56) and idiopathic inflammatory myositis (-2.10, -3.63 to -0.56). CONCLUSION: Physical function is impaired for many individuals with SSc and is associated with multiple disease factors.

Fatigue levels and associated factors in systemic sclerosis: a cross-sectional study of 2,385 SPIN Cohort participants.

OBJECTIVES: To compare fatigue in a large multinational systemic sclerosis (SSc) cohort to general population data and identify associated sociodemographic, lifestyle and SSc disease factors. METHODS: Scleroderma Patient-centered Intervention Network Cohort participants completed the Patient-Reported Outcomes Measurement Information System-29 v2.0 fatigue domain. T-scores were compared with the USA general population (mean = 50; SD = 10). Multivariable linear regression was used to assess associations with sociodemographic, lifestyle, and disease-related variables. RESULTS: Among 2,385 participants (mean age 54.9 (SD = 12.6) years, 87% female, 38% diffuse SSc), mean fatigue T-score was 54.6 (SD = 11.0); 438 (18%) reported mild fatigue, 641 (27%) moderate, and 180 (8%) severe fatigue. Fatigue was independently associated with sociodemographic factors age (-0.10 points per year, [95% CI -0.14;-0.07]), male sex (-1.67 points, [-2.96;-0.37]), non-married status (0.97 points [0.04; 1.89]), and country (reference USA; France -2.35 points [-3.48;-1.21] and UK 2.38 points [0.80; 3.97]), and lifestyle factors smoking (4.16 points [2.52; 5.80]), alcohol consumption (-0.18 points per drink per week [-0.28;-0.07]), and body-mass index (0.34 points per unit [0.27; 0.42]). Fatigue was associated with disease-related factors gastrointestinal involvement (4.21 points [2.99; 5.43]), digital ulcers (1.51 points, [0.25; 2.77]), moderate small joints contractures (1.41 points [0.13; 2.69]), rheumatoid arthritis (4.34 points [2.37-6.31]) and Sjögren's syndrome (1.89 points [0.23; 3.55]). When pain was included in the model, its association was large (2.19 points [2.03; 2.34]) and interstitial lung disease was also associated (1.21 points [0.42; 2.00]). CONCLUSIONS: In people with SSc, fatigue scores were substantially higher than the general population and associated with multiple disease factors including gastrointestinal involvement, several painful disease manifestations, and lung involvement.

Two-stage targeted maximum likelihood estimation for mixed aggregate and individual participant data analysis with an application to multidrug resistant tuberculosis.

In this study, we develop a new method for the meta-analysis of mixed aggregate data (AD) and individual participant data (IPD). The method is an adaptation of inverse probability weighted targeted maximum likelihood estimation (IPW-TMLE), which was initially proposed for two-stage sampled data. Our methods are motivated by a systematic review investigating treatment effectiveness for multidrug resistant tuberculosis (MDR-TB) where the available data include IPD from some studies but only AD from others. One complication in this application is that participants with MDR-TB are typically treated with multiple antimicrobial agents where many such medications were not observed in all studies considered in the meta-analysis. We focus here on the estimation of the expected potential outcome while intervening on a specific medication but not intervening on any others. Our method involves the implementation of a TMLE that transports the estimation from studies where the treatment is observed to the full target population. A second weighting component adjusts for the studies with missing (inaccessible) IPD. We demonstrate the properties of the proposed method and contrast it with alternative approaches in a simulation study. We finally apply this method to estimate treatment effectiveness in the MDR-TB case study.

Association between Bacillus Calmette-Guérin (BCG) vaccination and inflammatory bowel disease: A two-stage sampling design within the Quebec Birth Cohort on Immunity and Health (CO·MMUNITY).

BACKGROUND: Bacillus Calmette-Guérin (BCG) vaccination, primarily administered to prevent tuberculosis, exhibits nonspecific immune effects and could play a role in inflammatory bowel disease prevention. We investigated the associations of BCG with Crohn's disease and ulcerative colitis, and assessed sex-differences. METHODS: This two-stage study included 365,206 Canadians from the Quebec Birth Cohort on Immunity and Health (1970-2014; stage 1). Vaccination status was registry-based and inflammatory bowel disease cases were identified from health services with validated algorithms. We documented additional factors among 2644 participants in a nested case-control study in 2021 (stage 2). A two-stage logistic regression analysis was applied to estimate the odds ratios (OR), corrected for sampling fractions and adjusted for confounding factors. We used interaction terms to assess sex-differences on the multiplicative scale. RESULTS: In the stage 1 sample, 2419 cases of Crohn's disease and 1079 of ulcerative colitis were included. Forty-six percent of non-cases received the BCG vaccine as compared to 47% for Crohn's disease and 49% for ulcerative colitis. Associations differed by sex. BCG vaccination was not associated with Crohn's disease among men (OR = 0.91; 95% CI: 0.79-1.04) but was related to an increased risk among women (OR = 1.13; 95% CI: 1.00-1.28, P interaction: 0.001). For ulcerative colitis, there was a tendency toward a slightly elevated risk among men (OR = 1.09; 95%CI: 0.90-1.32), whereas the risk was more substantial for women (OR = 1.17; 95% CI:0.99-1.39, P interaction: <0.001). CONCLUSION: BCG vaccination does not play a preventive role in inflammatory bowel disease. Our results point to distinct associations between men and women.

Nunavimmi puvakkut kaggutimik aanniaqarniq: Qanuilirqitaa? Lung cancer in Nunavik: How are we doing? A retrospective matched cohort study.

BACKGROUND: Whether Inuit in Canada experience disparities in lung cancer survival remains unknown. When requiring investigation and treatment for lung cancer, all residents of Nunavik, the Inuit homeland in Quebec, are sent to the McGill University Health Centre (MUHC), in Montréal. We sought to compare survival among patients with lung cancer at the MUHC, who were residents of Nunavik and Montréal, Quebec, respectively. METHODS: We conducted a retrospective cohort study. Using lung cancer registry data, we identified Nunavik residents with histologically confirmed lung cancer diagnosed between 2005 and 2017. We aimed to match 2 Montréal residents to each Nunavik resident on sex, age, calendar year of diagnosis, and histology (non-small cell lung cancer v. small cell lung cancer). We reviewed medical records for data on additional patient characteristics and treatment, and obtained vital status from a provincial registry. We compared survival using Kaplan-Meier analysis and Cox proportional hazards regression. RESULTS: We included 95 residents of Nunavik and 185 residents of Montréal. For non-small cell lung cancer, median survival times were 321 (95% confidence interval [CI] 184-626) days for Nunavik (n = 71) and 720 (95% CI 536-1208) days for Montréal residents (n = 141). For small cell lung cancer, median survival times were 190 (95% CI 159-308) days for Nunavik (n = 24) and 270 (95% CI 194-766) days for Montréal residents (n = 44). Adjusting for matching variables, stage, performance status, and comorbidity, Nunavik residents had a higher hazard of death (hazard ratio 1.68, 95% CI 1.17-2.41). INTERPRETATION: Nunavik residents experience disparities in survival after lung cancer diagnosis. Although studies in other Inuit Nunangat regions are needed, our findings point to an urgent need to ensure that interventions aimed at improving lung cancer survival, including lung cancer screening, are accessible to Inuit Nunangat residents.

An empirical comparison of statistical methods for multiple cut-off diagnostic test accuracy meta-analysis of the Edinburgh postnatal depression scale (EPDS) depression screening tool using published results vs individual participant data.

BACKGROUND: Selective reporting of results from only well-performing cut-offs leads to biased estimates of accuracy in primary studies of questionnaire-based screening tools and in meta-analyses that synthesize results. Individual participant data meta-analysis (IPDMA) of sensitivity and specificity at each cut-off via bivariate random-effects models (BREMs) can overcome this problem. However, IPDMA is laborious and depends on the ability to successfully obtain primary datasets, and BREMs ignore the correlation between cut-offs within primary studies. METHODS: We compared the performance of three recent multiple cut-off models developed by Steinhauser et al., Jones et al., and Hoyer and Kuss, that account for missing cut-offs when meta-analyzing diagnostic accuracy studies with multiple cut-offs, to BREMs fitted at each cut-off. We used data from 22 studies of the accuracy of the Edinburgh Postnatal Depression Scale (EPDS; 4475 participants, 758 major depression cases). We fitted each of the three multiple cut-off models and BREMs to a dataset with results from only published cut-offs from each study (published data) and an IPD dataset with results for all cut-offs (full IPD data). We estimated pooled sensitivity and specificity with 95% confidence intervals (CIs) for each cut-off and the area under the curve. RESULTS: Compared to the BREMs fitted to the full IPD data, the Steinhauser et al., Jones et al., and Hoyer and Kuss models fitted to the published data produced similar receiver operating characteristic curves; though, the Hoyer and Kuss model had lower area under the curve, mainly due to estimating slightly lower sensitivity at lower cut-offs. When fitting the three multiple cut-off models to the full IPD data, a similar pattern of results was observed. Importantly, all models had similar 95% CIs for sensitivity and specificity, and the CI width increased with cut-off levels for sensitivity and decreased with an increasing cut-off for specificity, even the BREMs which treat each cut-off separately. CONCLUSIONS: Multiple cut-off models appear to be the favorable methods when only published data are available. While collecting IPD is expensive and time consuming, IPD can facilitate subgroup analyses that cannot be conducted with published data only.

Use of a decision support tool and quick start onboarding tool in individuals with type 1 diabetes using advanced automated insulin delivery: a single-arm multi-phase intervention study.

BACKGROUND: Multiple clinician adjustable parameters impact upon glycemia in people with type 1 diabetes (T1D) using Medtronic Mini Med 780G (MM780G) AHCL. These include glucose targets, carbohydrate ratios (CR), and active insulin time (AIT). Algorithm-based decision support advising upon potential settings adjustments may enhance clinical decision-making. METHODS: Single-arm, two-phase exploratory study developing decision support to commence and sustain AHCL. Participants commenced investigational MM780G, then 8 weeks Phase 1-initial optimization tool evaluation, involving algorithm-based decision support with weekly AIT and CR recommendations. Clinicians approved or rejected CR and AIT recommendations based on perceived safety per protocol. Co-design resulted in a refined algorithm evaluated in a further identically configured Phase 2. Phase 2 participants also transitioned to commercial MM780G following "Quick Start" (algorithm-derived tool determining initial AHCL settings using daily insulin dose and weight). We assessed efficacy, safety, and acceptability of decision support using glycemic metrics, and the proportion of accepted CR and AIT settings per phase. RESULTS: Fifty three participants commenced Phase 1 (mean age 24.4; Hba1c 61.5mmol/7.7%). The proportion of CR and AIT accepted by clinicians increased between Phases 1 and 2 respectively: CR 89.2% vs. 98.6%, p < 0.01; AIT 95.2% vs. 99.3%, p < 0.01. Between Phases, mean glucose percentage time < 3.9mmol (< 70mg/dl) reduced (2.1% vs. 1.4%, p = 0.04); change in mean TIR 3.9-10mmol/L (70-180mg/dl) was not statistically significant: 72.9% ± 7.8 and 73.5% ± 8.6. Quick start resulted in stable TIR, and glycemic metrics compared to international guidelines. CONCLUSION: The co-designed decision support tools were able to deliver safe and effective therapy. They can potentially reduce the burden of diabetes management related decision making for both health care practitioners and patients. TRIAL REGISTRATION: Prospectively registered with Australia/New Zealand Clinical Trials Registry(ANZCTR) on 30th March 2021 as study ACTRN12621000360819.

Comparison of Sleep Apnea Questionnaires and Reported Diagnosis in Neurological Disorders of Aging.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with worse outcomes in stroke, Alzheimer's disease (AD) and Parkinson's disease (PD), but diagnosis is challenging in these groups. We aimed to compare the prevalence of high risk of OSA based on commonly used questionnaires and self-reported OSA diagnosis: 1. within groups with stroke, AD, PD and the general population (GP); 2. Between neurological groups and GP. METHODS: Individuals with stroke, PD and AD were identified in the Canadian Longitudinal Study of Aging (CLSA) by survey. STOP, STOP-BAG, STOP-B28 and GOAL screening tools and OSA self-report were compared by the Chi-squared test. Logistic regression was used to compare high risk/self-report of OSA, in neurological conditions vs. GP, adjusted for confounders. RESULTS: We studied 30,097 participants with mean age of 62.3 years (SD 10.3) (stroke n = 1791; PD n = 175; AD n = 125). In all groups, a positive GOAL was the most prevalent, while positive STOP was least prevalent among questionnaires. Significant variations in high-risk OSA were observed between different questionnaires across all groups. Under 1.5% of individuals self-reported OSA. While all questionnaires suggested a higher prevalence of OSA in stroke than the GP, for PD and AD, there was heterogeneity depending on questionnaire. CONCLUSIONS: The wide range of prevalences of high risk of OSA resulting from commonly used screening tools underscores the importance of validating them in older adults with neurological disorders. OSA was self-reported in disproportionately small numbers across groups, suggesting that OSA is underdiagnosed in older adults or underreported by patients, which is concerning given its increasingly recognized impact on brain health.

Impact of the COVID-19 pandemic on quality of tuberculosis care in private facilities in Bandung, Indonesia: a repeated cross-sectional standardized patients study.

BACKGROUND: Indonesia has the second highest incidence of tuberculosis in the world. While 74% of people with tuberculosis in Indonesia first accessed the private health sector when seeking care for their symptoms, only 18% of tuberculosis notifications originate in the private sector. Little is known about the impact of the COVID-19 pandemic on the private sector. Using unannounced standardized patient visits to private providers, we aimed to measure quality of tuberculosis care during the COVID-19 pandemic. METHODS: A cross-sectional study was conducted using standardized patients in Bandung City, West Java, Indonesia. Ten standardized patients completed 292 visits with private providers between 9 July 2021 and 21 January 2022, wherein standardized patients presented a presumptive tuberculosis case. Results were compared to standardized patients surveys conducted in the same geographical area before the onset of COVID-19. RESULTS: Overall, 35% (95% confidence interval (CI): 29.2-40.4%) of visits were managed correctly according to national tuberculosis guidelines. There were no significant differences in the clinical management of presumptive tuberculosis patients before and during the COVID-19 pandemic, apart from an increase in temperature checks (adjusted odds ratio (aOR): 8.05, 95% CI: 2.96-21.9, p < 0.001) and a decrease in throat examinations (aOR 0.16, 95% CI: 0.06-0.41, p = 0.002) conducted during the pandemic. CONCLUSIONS: Results indicate that providers successfully identify tuberculosis in their patients yet do not manage them according to national guidelines. There were no major changes found in quality of tuberculosis care due to the COVID-19 pandemic. As tuberculosis notifications have declined in Indonesia due to the COVID-19 pandemic, there remains an urgent need to increase private provider engagement in Indonesia and improve quality of care.

Moderators of Loneliness Trajectories in People with Systemic Sclerosis During the COVID-19 Pandemic: A SPIN COVID-19 Cohort Longitudinal Study.

BACKGROUND: Many individuals with systemic sclerosis (SSc) are at heightened risk for COVID-19 related morbidity and isolation due to interstitial lung disease, frailty, and immunosuppressant use. Minimal research has explored loneliness predictors in individuals with chronic illnesses during COVID-19. This study evaluated moderators of loneliness trajectories in individuals with SSc during COVID-19. METHODS: Longitudinal data were analyzed across 30 timepoints from April 2020 to May 2022 from 775 adults in the Scleroderma Patient-centered Intervention Network (SPIN) COVID-19 Cohort. Hierarchical linear modeling evaluated cross-level moderators of loneliness trajectories, including marital status, baseline number of household members, number of virtual or telephone one-on-one or virtual group conversations, number of hours spent enjoying in-person household conversations or activities, and satisfaction with quality of in-person household conversations (all in the past week). Level-1 moderation analyses assessed effects of conversation, activity, and satisfaction means and slopes over time. RESULTS: Baseline values were not statistically significant moderators of loneliness trajectories. Higher mean (averaged over time) virtual or telephone one-on-one and in-person household conversations, in-person household activity, and in-person household conversation satisfaction were associated with lower loneliness trajectories (ps < .05). The relationship between in-person household conversation satisfaction and loneliness trajectory was statistically significantly but minimally attenuated over time (p < .001). CONCLUSIONS: For people with SSc, higher mean conversation, activity, and satisfaction variables were associated with lower levels of loneliness during the pandemic, but changes in these social variables were generally not predictive of changes in loneliness.

Neighbourhood social deprivation and risk of prostate cancer.

BACKGROUND: Striking geographic variations in prostate cancer incidence suggest an aetiological role for spatially-distributed factors. We assessed whether neighbourhood social deprivation, which can reflect limited social contacts, unfavourable lifestyle and environmental exposures, is associated with prostate cancer risk. METHODS: In 2005-2012, we recruited 1931 incident prostate cancer cases and 1994 controls in a case-control study in Montreal, Canada. Lifetime residential addresses were linked to an area-based social deprivation index around recruitment (2006) and about 10 years earlier (1996). Logistic regression estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Men residing in areas characterised by greater social deprivation had elevated prostate cancer risks (ORs of 1.54 and 1.60 for recent and past exposures, respectively; highest vs lowest quintiles), independently from area- and individual-level confounders and screening patterns. The increase in risk with recent high social deprivation was particularly elevated for high-grade prostate cancer at diagnosis (OR 1.87, 95% CI 1.32-2.64). Associations were more pronounced for neighbourhoods with higher proportions of separated/divorced or widowed individuals in the past, and with higher percentages of residents living alone recently. CONCLUSIONS: These novel findings, suggesting that neighbourhood-level social deprivation increases the risk of prostate cancer, point out to potential targeted public health interventions.

Short-term air pollution exposure and exacerbation events in mild to moderate COPD: a case-crossover study within the CanCOLD cohort.

BACKGROUND: Infections are considered as leading causes of acute exacerbations of chronic obstructive pulmonary disease (COPD). Non-infectious risk factors such as short-term air pollution exposure may play a clinically important role. We sought to estimate the relationship between short-term air pollutant exposure and exacerbations in Canadian adults living with mild to moderate COPD. METHODS: In this case-crossover study, exacerbations ('symptom based': ≥48 hours of dyspnoea/sputum volume/purulence; 'event based': 'symptom based' plus requiring antibiotics/corticosteroids or healthcare use) were collected prospectively from 449 participants with spirometry-confirmed COPD within the Canadian Cohort Obstructive Lung Disease. Daily nitrogen dioxide (NO2), fine particulate matter (PM2.5), ground-level ozone (O3), composite of NO2 and O3 (Ox), mean temperature and relative humidity estimates were obtained from national databases. Time-stratified sampling of hazard and control periods on day '0' (day-of-event) and Lags ('-1' to '-6') were compared by fitting generalised estimating equation models. All data were dichotomised into 'warm' (May-October) and 'cool' (November-April) seasons. ORs and 95% CIs were estimated per IQR increase in pollutant concentrations. RESULTS: Increased warm season ambient concentration of NO2 was associated with symptom-based exacerbations on Lag-3 (1.14 (1.01 to 1.29), per IQR), and increased cool season ambient PM2.5 was associated with symptom-based exacerbations on Lag-1 (1.11 (1.03 to 1.20), per IQR). There was a negative association between warm season ambient O3 and symptom-based events on Lag-3 (0.73 (0.52 to 1.00), per IQR). CONCLUSIONS: Short-term ambient NO2 and PM2.5 exposure were associated with increased odds of exacerbations in Canadians with mild to moderate COPD, further heightening the awareness of non-infectious triggers of COPD exacerbations.

A population-based study of reported hepatitis C diagnoses from 1998 to 2018 in immigrants and nonimmigrants in Quebec, Canada.

Immigrants living in low hepatitis C (HCV) prevalence countries bear a disproportionate HCV burden, but there are limited HCV population-based studies focussed on this population. We estimated rates and trends of reported HCV diagnoses over a 20-year period in Quebec, Canada, to investigate subgroups with the highest rates and changes over time. A population-based cohort of all reported HCV diagnoses in Quebec (1998-2018) linked to health administrative and immigration databases. HCV rates, rate ratios (RR) and trends overall and stratified by immigrant status and country of birth were estimated using Poisson regression. Among 38,348 HCV diagnoses, 14% occurred in immigrants, a median of 7.5 years after arrival. The average annual HCV rate/100,000 decreased for immigrants and nonimmigrants, but the risk (RR) among immigrants increased over the study period [35.7 vs. 34.5 (RR = 1.03) and 18.4 vs. 12.7 (1.45) between 1998-2008 and 2009-2018]. Immigrants from middle-income Europe & Central Asia [55.8 (RR = 4.39)], sub-Saharan Africa [51.7 (RR = 4.06)] and South Asia [32.8 (RR = 2.58)] had the highest rates between 2009 and 2018. Annual HCV rates decreased more slowly among immigrants vs. nonimmigrants (-5.9% vs. -8.9%, p < 0.001), resulting in a 2.5-fold (9%-21%) increase in the proportion of HCV diagnoses among immigrants (1998-2018). The slower decline in HCV rates among immigrants over the study period highlights the need for targeted screening for this population, particularly those from sub-Saharan Africa, Asia and middle-income Europe. These data can inform micro-elimination efforts in Canada and other low-HCV-prevalence countries.

Ascertaining asthma status in epidemiologic studies: a comparison between administrative health data and self-report.

BACKGROUND: Studies have suggested that agreement between administrative health data and self-report for asthma status ranges from fair to good, but few studies benefited from administrative health data over a long period. We aimed to (1) evaluate agreement between asthma status ascertained in administrative health data covering a period of 30 years and from self-report, and (2) identify determinants of agreement between the two sources. METHODS: We used administrative health data (1983-2012) from the Quebec Birth Cohort on Immunity and Health, which included 81,496 individuals born in the province of Quebec, Canada, in 1974. Additional information, including self-reported asthma, was collected by telephone interview with 1643 participants in 2012. By design, half of them had childhood asthma based on health services utilization. Results were weighted according to the inverse of the sampling probabilities. Five algorithms were applied to administrative health data (having ≥ 2 physician claims over a 1-, 2-, 3-, 5-, or 30-year interval or ≥ 1 hospitalization), to enable comparisons with previous studies. We estimated the proportion of overall agreement and Kappa, between asthma status derived from algorithms and self-reports. We used logistic regression to identify factors associated with agreement. RESULTS: Applying the five algorithms, the prevalence of asthma ranged from 49 to 55% among the 1643 participants. At interview (mean age = 37 years), 49% and 47% of participants respectively reported ever having asthma and asthma diagnosed by a physician. Proportions of agreement between administrative health data and self-report ranged from 88 to 91%, with Kappas ranging from 0.57 (95% CI: 0.52-0.63) to 0.67 (95% CI: 0.62-0.72); the highest values were obtained with the [≥ 2 physician claims over a 30-year interval or ≥ 1 hospitalization] algorithm. Having sought health services for allergic diseases other than asthma was related to lower agreement (Odds ratio = 0.41; 95% CI: 0.25-0.65 comparing ≥ 1 health services to none). CONCLUSIONS: These findings indicate good agreement between asthma status defined from administrative health data and self-report. Agreement was higher than previously observed, which may be due to the 30-year lookback window in administrative data. Our findings support using both administrative health data and self-report in population-based epidemiological studies.

Mental health symptoms in scleroderma during COVID-19: a Scleroderma Patient-centred Intervention Network (SPIN) cohort longitudinal study.

OBJECTIVES: People with systemic sclerosis (SSc) are vulnerable in COVID-19 and face challenges related to shifting COVID-19 risk and protective restrictions. We evaluated mental health symptom trajectories in people with SSc through March 2022. METHODS: The longitudinal Scleroderma Patient-centred Intervention Network (SPIN) COVID-19 cohort was launched in April 2020 and included participants from the ongoing SPIN Cohort and external enrolees. Analyses included estimated means with 95% CIs for anxiety and depression symptoms pre-COVID-19 for ongoing SPIN Cohort participants and anxiety, depression, loneliness, and fear of COVID-19 for all participants across 28 COVID-19 assessments up to March 2022. We conducted sensitivity analyse including estimating trajectories using only responses from participants who completed >90% of items for ≥21 of 28 possible assessments ("completers") and stratified analyses for all outcomes by sex, age, country, and SSc subtype. RESULTS: Anxiety symptoms increased in early 2020 but returned to pre-COVID-19 levels by mid-2020 and remained stable through March 2022. Depression symptoms did not initially change but were slightly lower by mid-2020 compared to pre-COVID-19 and were stable through March 2022. COVID-19 fear started high and decreased. Loneliness did not change across the pandemic. Results were similar for completers and for all subgroups. CONCLUSIONS: People with SSc continue to face COVID-19 challenges related to ongoing risk, the opening of societies, and removal of protective restrictions. People with SSc, in aggregate, appear to be weathering the pandemic well, but health care providers should be mindful that some individuals may benefit from mental health support.

External validation of a shortened screening tool using individual participant data meta-analysis: A case study of the Patient Health Questionnaire-Dep-4.

Shortened versions of self-reported questionnaires may be used to reduce respondent burden. When shortened screening tools are used, it is desirable to maintain equivalent diagnostic accuracy to full-length forms. This manuscript presents a case study that illustrates how external data and individual participant data meta-analysis can be used to assess the equivalence in diagnostic accuracy between a shortened and full-length form. This case study compares the Patient Health Questionnaire-9 (PHQ-9) and a 4-item shortened version (PHQ-Dep-4) that was previously developed using optimal test assembly methods. Using a large database of 75 primary studies (34,698 participants, 3,392 major depression cases), we evaluated whether the PHQ-Dep-4 cutoff of ≥ 4 maintained equivalent diagnostic accuracy to a PHQ-9 cutoff of ≥ 10. Using this external validation dataset, a PHQ-Dep-4 cutoff of ≥ 4 maximized the sum of sensitivity and specificity, with a sensitivity of 0.88 (95% CI 0.81, 0.93), 0.68 (95% CI 0.56, 0.78), and 0.80 (95% CI 0.73, 0.85) for the semi-structured, fully structured, and MINI reference standard categories, respectively, and a specificity of 0.79 (95% CI 0.74, 0.83), 0.85 (95% CI 0.78, 0.90), and 0.83 (95% CI 0.80, 0.86) for the semi-structured, fully structured, and MINI reference standard categories, respectively. While equivalence with a PHQ-9 cutoff of ≥ 10 was not established, we found the sensitivity of the PHQ-Dep-4 to be non-inferior to that of the PHQ-9, and the specificity of the PHQ-Dep-4 to be marginally smaller than the PHQ-9.

Ambient Air Pollution and Dysanapsis: Associations with Lung Function and Chronic Obstructive Pulmonary Disease in the Canadian Cohort Obstructive Lung Disease Study.

Rationale: Outdoor air pollution is a potential risk factor for lower lung function and chronic obstructive pulmonary disease (COPD). Little is known about how airway abnormalities and lung growth might modify this relationship. Objectives: To evaluate the associations of ambient air pollution exposure with lung function and COPD and examine possible interactions with dysanapsis. Methods: We made use of cross-sectional postbronchodilator spirometry data from 1,452 individuals enrolled in the CanCOLD (Canadian Cohort Obstructive Lung Disease) study with linked ambient fine particulate matter (PM2.5) and nitrogen dioxide (NO2) air pollution estimates. Dysanapsis, or the ratio of the airway-to-lung volume calculated from thoracic computed tomography images, was used to examine possible interactions. Measurements and Main Results: In adjusted models, 101.7 ml (95% confidence interval [CI], -166.2 to -37.2) and 115.0 ml (95% CI, -196.5 to -33.4) lower FEV1 were demonstrated per increase of 2.4 ug/m3 PM2.5 and 9.2 ppb NO2, respectively. Interaction between air pollution and dysanapsis was not statistically significant when modeling the airway-to-lung ratio as a continuous variable. However, a 109.8 ml (95% CI, -209.0 to -10.5] lower FEV1 and an 87% (95% CI, 12% to 213%) higher odds of COPD were observed among individuals in the lowest, relative to highest, airway-to-lung ratio, per 2.4 µg/m3 increment of PM2.5. Conclusions: Ambient air pollution exposure was associated with lower lung function, even at relatively low concentrations. Individuals with dysanaptic lung growth might be particularly susceptible to inhaled ambient air pollutants, especially those at the extremes of dysanapsis.