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Abstract Background Most Canadians receive their care in community hospitals, yet most clinical research is conducted in academic hospitals. This study aims to compare patients with community acquired pneumonia (CAP) treated in academic and community hospitals with respect to their demographics, clinical characteristics, treatments and outcomes. Methods This nested observational cohort substudy of the Community Acquired Pneumonia: Toward InnoVAtive Treatment (CAPTIVATE) trial included 1,329 hospitalized adults with CAP recruited between March 1st, 2018 and September 31st, 2023 from 15 Canadian hospitals. Unadjusted and adjusted analyses for age, sex and co-morbidities using logistic, Cox and censored quantile regressions were conducted. Results Patients in community hospitals were older (mean [SD] 75.0 [15.7] years vs. 68.3 [16.2] years; p

Background: Frailty is generally a marker of worse prognosis. The impact of frailty on both in-hospital and long-term outcomes in ST-segment-elevation myocardial infarction (STEMI) patients has not been well described. Given this context, we aimed to determine the prevalence and impact of frailty on in-hospital and 1-year outcomes in STEMI patients undergoing primary percutaneous coronary intervention (pPCI). Methods: This retrospective study reviewed STEMI patients aged ≥ 65 years who underwent pPCI at 1 of the 2 pPCI-capable hospitals at Vancouver Coastal Health. A frailty index (FI) was determined using a deficit-accumulation model, with those with an FI > 0.25 being defined as frail. The primary outcome was 1-year all-cause mortality. The secondary outcomes included in-hospital all-cause mortality, a composite of adverse in-hospital outcomes (all-cause mortality, cardiogenic shock, heart failure, reinfarction, major bleeding, or stroke), and the individual components of the composite. Results: A total of 1579 patients were reviewed, of which 228 (14.4%) were determined to be frail. After multivariable adjustment, greater frailty (ie, increasing FI) was associated with increased in-hospital all-cause mortality (odds ratio [OR], 1.88; 95% confidence interval [CI], 1.50-2.35, P < 0.001), the composite adverse in-hospital outcome (OR, 1.46; 95% CI, 1.27-1.68, P < 0.001), and 1-year all-cause mortality (OR, 1.48; 95% CI, 1.10-2.00, P = 0.011). Conclusions: In a contemporary STEMI cohort of older patients receiving pPCI, 1 in 7 patients were frail, with greater frailty being independently associated with increased in-hospital and long-term adverse outcomes. These findings highlight the need for the early recognition of frailty and implementation of an interdisciplinary approach toward the management of frail STEMI patients. Résumé: Contexte: La fragilité est généralement un marqueur de mauvais pronostic. Les conséquences de la fragilité sur l’état de santé des patients hospitalisés et sur l’évolution de l’état de santé à long terme après un infarctus du myocarde avec élévation du segment ST (STEMI) ne sont pas bien établies. Nous avons donc cherché à déterminer la prévalence et les conséquences de la fragilité durant une hospitalisation et après un an chez des patients ayant eu un STEMI et devant subir une première intervention coronarienne percutanée (ICP). Méthodologie: Cette étude rétrospective visait à évaluer les patients de ≥ 65 ans ayant présenté un STEMI et ayant subi une première ICP dans l’un des deux hôpitaux de Vancouver Coastal Health capables d’effectuer une telle intervention. Un indice de fragilité a été établi à l’aide d’un modèle d’accumulation de déficit, les patients ayant un indice > 0,25 étant définis comme fragiles. Le critère d’évaluation principal était la mortalité toutes causes confondues après un an. Les critères d’évaluation secondaires comprenaient la mortalité toutes causes confondues à l’hôpital, un critère composé regroupant les résultats défavorables obtenus à l’hôpital (mortalité toutes causes confondues, choc cardiogénique, insuffisance cardiaque, nouvel infarctus, hémorragie majeure ou accident vasculaire cérébral) et les composants individuels du critère composé. Résultats: Au total, 1579 patients ont été évalués, dont 228 (14,4 %) ont été jugés fragiles. Après un ajustement à variables multiples, une plus grande fragilité (c.-à-d. une augmentation de l’indice de fragilité) était associée à une augmentation de la mortalité toutes causes confondues à l’hôpital (rapport de cote [RC] : 1,88; intervalle de confiance [IC] à 95 % : 1,50 à 2,35; p < 0,001), à des résultats défavorables obtenus à l’hôpital selon le critère composé (RC : 1,46; IC à 95 % : 1,27 à 1,68; p < 0,001) et à la mortalité toutes causes confondues après un an (RC : 1,48; IC à 95 % : 1,10 à 2,00; p = 0,011). Conclusions: Dans une cohorte contemporaine de patients âgés ayant présenté un STEMI et ayant subi une première ICP, un patient sur sept était fragile, une plus grande fragilité étant associée de manière indépendante à une augmentation des résultats défavorables à l’hôpital et à long terme. Ces résultats soulignent la nécessité de reconnaître rapidement la fragilité et de mettre en œuvre une approche interdisciplinaire pour prendre en charge les patients fragiles présentant un STEMI.

BackgroundChronic or gestational hypertension complicates approximately 7% of pregnancies, half of which reach 37 weeks' gestation. Early term birth (at 37 to 38 weeks) may reduce maternal complications, cesareans, stillbirths, and costs but may increase neonatal morbidity. In the WILL Trial (When to Induce Labour to Limit risk in pregnancy hypertension), we aimed to establish optimal timing of birth for women with chronic or gestational hypertension who reach term and remain well.Methods and findingsThis 50-centre, open-label, randomised trial in the United Kingdom included an economic analysis. WILL randomised women with chronic or gestational hypertension at 36 to 37 weeks and a singleton fetus, and who provided documented informed consent to "Planned early term birth at 38+0-3 weeks" (intervention) or "usual care at term" (control). The coprimary outcomes were "poor maternal outcome" (composite of severe hypertension, maternal death, or maternal morbidity; superiority hypothesis) and "neonatal care unit admission for ≥4 hours" (noninferiority hypothesis). The key secondary was cesarean. Follow-up was to 6 weeks postpartum. The planned sample size was 540/group. Analysis was by intention-to-treat. A total of 403 participants (37.3% of target) were randomised to the intervention (n = 201) or control group (n = 202), from 3 June 2019 to 19 December 2022, when the funder stopped the trial for delayed recruitment. In the intervention (versus control) group, losses to follow-up were 18/201 (9%) versus 15/202 (7%). In each group, maternal age was about 30 years, about one-fifth of women were from ethnic minorities, over half had obesity, approximately half had chronic hypertension, and most were on antihypertensives with normal blood pressure. In the intervention (versus control) group, birth was a median of 0.9 weeks earlier (38.4 [38.3 to 38.6] versus 39.3 [38.7 to 39.9] weeks). There was no evidence of a difference in "poor maternal outcome" (27/201 [13%] versus 24/202 [12%], respectively; adjusted risk ratio [aRR] 1.16, 95% confidence interval [CI] 0.72 to 1.87). For "neonatal care unit admission for ≥4 hours," the intervention was considered noninferior to the control as the adjusted risk difference (aRD) 95% CI upper bound did not cross the 8% prespecified noninferiority margin (14/201 [7%] versus 14/202 [7%], respectively; aRD 0.003, 95% CI -0.05 to +0.06), although event rates were lower-than-estimated. The intervention (versus control) was associated with no difference in cesarean (58/201 [29%] versus 72/202 [36%], respectively; aRR 0.81, 95% CI 0.61 to 1.08. There were no serious adverse events. Limitations include our smaller-than-planned sample size, and lower-than-anticipated event rates, so the findings may not be generalisable to where hypertension is not treated with antihypertensive therapy.ConclusionsIn this study, we observed that most women with chronic or gestational hypertension required labour induction, and planned birth at 38+0-3 weeks (versus usual care) resulted in birth an average of 6 days earlier, and no differences in poor maternal outcome or neonatal morbidity. Our findings provide reassurance about planned birth at 38+0-3 weeks as a clinical option for these women.Trial registrationisrctn.com ISRCTN77258279.

Abstract Background Substantial weight loss in people living with type 2 diabetes (T2D) can reduce the need for glucose-lowering medications while concurrently lowering glycemia below the diagnostic threshold for the disease. Furthermore, weight-loss interventions have also been demonstrated to improve aspects of underlying T2D pathophysiology related to ectopic fat in the liver and pancreatic beta-cell function. As such, the purpose of this secondary analysis was to explore the extent to which a low-carbohydrate and energy-restricted (LCER) diet intervention improves markers of beta-cell stress/function, liver fat accumulation, and metabolic related liver function in people with type 2 diabetes. Methods We conducted secondary analyses of blood samples from a larger pragmatic community-based parallel-group randomized controlled trial involving a 12-week pharmacist implemented LCER diet (Pharm-TCR:

Abstract Few studies have examined preventative behaviour practices with respect to COVID-19 among people living with HIV (human immunodeficiency virus). Using a cross-sectional survey from a Canadian Institutes of Health Research Canadian HIV Trials Network study (CTN 328) of people living with HIV on vaccine immunogenicity, we examined the relationships between participant characteristics and behavioural practices intended to prevent COVID-19 infection. Participants living in four Canadian urban centers were enrolled between April 2021–January 2022, at which time they responded to a questionnaire on preventative behaviour practices. Questionnaire and clinical data were combined to explore relationships between preventive behaviours and (1) known COVID-19 infection pre-enrolment, (2) multimorbidity, (3) developing symptomatic COVID-19 infection, and (4) developing symptomatic COVID-19 infection during the Omicron wave. Among 375 participants, 49 had COVID-19 infection pre-enrolment and 88 post-enrolment. The proportion of participants reporting always engaging in preventative behaviours included 87% masking, 79% physical distancing, 70% limiting social gatherings, 65% limiting contact with at-risk individuals, 33% self-isolating due to symptoms, and 26% self-quarantining after possible exposure. Participants with known COVID-19 infection pre-enrolment were more likely to self-quarantine after possible exposure although asymptomatic (65.0% vs 23.4%, p

Background Long‐term (visit‐to‐visit) blood pressure variability (BPV) and heart rate variability (HRV) outside pregnancy are associated with adverse cardiovascular outcomes. Given the limitations of relying solely on blood pressure level to identify pregnancies at risk, long‐term (visit‐to‐visit) BPV or HRV may provide additional diagnostic/prognostic counsel. To address this, we conducted a systematic review to examine the association between long‐term BPV and HRV in pregnancy and adverse maternal and perinatal outcomes. Methods and Results Databases were searched from inception to May 2023 for studies including pregnant women, with sufficient blood pressure or heart rate measurements to calculate any chosen measure of BPV or HRV. Studies were excluded that reported short‐term, not long‐term, variability. Adjusted odds ratios were extracted. Eight studies (138 949 pregnancies) reporting BPV met our inclusion criteria; no study reported HRV and its association with pregnancy outcomes. BPV appeared to be higher in women with hypertension and preeclampsia specifically, compared with unselected pregnancy cohorts. Greater BPV was associated with significantly more adverse pregnancy outcomes, particularly maternal (gestational hypertension [odds ratio range, 1.40–2.15], severe hypertension [1.40–2.20]), and fetal growth (small‐for‐gestational‐age infants [1.12–1.32] or low birth weight [1.18–1.39]). These associations were independent of mean blood pressure level. In women with hypertension, there were stronger associations with maternal outcomes but no consistent pattern for perinatal outcomes. Conclusions Future work should aim to confirm whether BPV could be useful for risk stratification prospectively in pregnancy, and should determine the optimal management path for those women identified at increased risk of adverse outcomes.

There is limited research on how a cervical cancer diagnosis financially impacts women and their families in Uganda. This analysis aimed to describe the economic impact of cervical cancer treatment, including how it differs by socio-economic status (SES) in Uganda. We conducted a cross-sectional study from September 19, 2022 to January 17, 2023. Women were recruited from the Uganda Cancer Institute and Jinja Regional Referral Hospital, and were eligible if they were ≥ of 18 years and being treated for cervical cancer. Participants completed a survey that included questions about their out-of-pocket costs, unpaid labor, and family's economic situation. A wealth index was constructed to determine their SES. Descriptive statistics were reported. Of the 338 participants, 183 were from the lower SES. Women from the lower SES were significantly more likely to be older, have ≤ primary school education, and have a more advanced stage of cervical cancer. Over 90% of participants in both groups reported paying out-of-pocket for cervical cancer. Only 15 participants stopped treatment because they could not afford it. Women of a lower SES were significantly more likely to report borrowing money (higher SES n = 47, 30.5%; lower SES n = 84, 46.4%; p-value = 0.004) and selling possessions (higher SES n = 47, 30.5%; lower SES n = 90, 49.7%; p-value = 0.006) to pay for care. Both SES groups reported a decrease in the amount of time that they spent caring for their children since their cervical cancer diagnosis (higher SES n = 34, 31.2%; lower SES n = 36, 29.8%). Regardless of their SES, women in Uganda incur out-of-pocket costs related to their cervical cancer treatment. However, there are inequities as women from the lower SES groups were more likely to borrow funds to afford treatment. Alternative payment models and further economic support could help alleviate the financial burden of cervical cancer care in Uganda.

In many low-income countries, over five percent of hospitalized children die following hospital discharge. The lack of available tools to identify those at risk of post-discharge mortality has limited the ability to make progress towards improving outcomes. We aimed to develop algorithms designed to predict post-discharge mortality among children admitted with suspected sepsis. Four prospective cohort studies of children in two age groups (0-6 and 6-60 months) were conducted between 2012-2021 in six Ugandan hospitals. Prediction models were derived for six-months post-discharge mortality, based on candidate predictors collected at admission, each with a maximum of eight variables, and internally validated using 10-fold cross-validation. 8,810 children were enrolled: 470 (5.3%) died in hospital; 257 (7.7%) and 233 (4.8%) post-discharge deaths occurred in the 0-6-month and 6-60-month age groups, respectively. The primary models had an area under the receiver operating characteristic curve (AUROC) of 0.77 (95%CI 0.74-0.80) for 0-6-month-olds and 0.75 (95%CI 0.72-0.79) for 6-60-month-olds; mean AUROCs among the 10 cross-validation folds were 0.75 and 0.73, respectively. Calibration across risk strata was good: Brier scores were 0.07 and 0.04, respectively. The most important variables included anthropometry and oxygen saturation. Additional variables included: illness duration, jaundice-age interaction, and a bulging fontanelle among 0-6-month-olds; and prior admissions, coma score, temperature, age-respiratory rate interaction, and HIV status among 6-60-month-olds. Simple prediction models at admission with suspected sepsis can identify children at risk of post-discharge mortality. Further external validation is recommended for different contexts. Models can be digitally integrated into existing processes to improve peri-discharge care as children transition from the hospital to the community.

Abstract Cystic fibrosis (CF) is a progressive multi-organ disease with significant morbidity placing extensive demands on the healthcare system. Little is known about those individuals with CF who continually incur high costs over multiple years. Understanding their characteristics may help inform opportunities to improve management and care, and potentially reduce costs. The purpose of this study was to identify and understand the clinical and demographic attributes of frequent high-costing CF individuals and characterize their healthcare utilization and costs over time. A longitudinal study of retrospective data was completed in British Columbia, Canada by linking the Canadian CF Registry with provincial healthcare administrative databases for the period between 2009 and 2017. Multivariable Cox regression models were employed to identify baseline factors associated with becoming a frequent high-cost CF user (vs. not a frequent high-cost CF user) in the follow-up period. We found that severe lung impairment (Hazard Ratio [HR]: 3.71, 95% confidence interval [CI], 1.49–9.21), lung transplantation (HR: 4.23, 95% CI, 1.68–10.69), liver cirrhosis with portal hypertension (HR: 10.96, 95% CI: 3.85–31.20) and female sex (HR: 1.97, 95% CI: 1.13–3.44) were associated with becoming a frequent high-cost CF user. Fifty-nine (17% of cohort) frequent high-cost CF users accounted for more than one-third of the overall total healthcare costs, largely due to inpatient hospitalization and outpatient medication costs.

Abstract This study tested progesterone for perimenopausal hot flush ± night sweat (vasomotor symptom, VMS) treatment. It was a double-blind, randomized trial of 300 mg oral micronized progesterone@bedtime versus placebo for 3-months (m) after a 1-m untreated baseline during 2012/1–2017/4. We randomized untreated, non-depressed, screen- and baseline-eligible by VMS, perimenopausal women (with flow within 1-year), ages 35–58 (n = 189). Participants aged 50 (± SD = 4.6) were mostly White, educated, minimally overweight with 63% in late perimenopause; 93% participated remotely. The 1° outcome was 3rd-m VMS Score difference. Participants recorded VMS number and intensity (0–4 scale)/24 h on a VMS Calendar. Randomization required VMS (intensity 2–4/4) of sufficient frequency and/or ≥ 2/week night sweat awakenings. Baseline total VMS Score (SD) was 12.2 (11.3) without assignment difference. Third-m VMS Score did not differ by therapy (Rate Difference − 1.51). However, the 95% CI [− 3.97, 0.95] P = 0.222, did not exclude 3, a minimal clinically important difference. Women perceived progesterone caused decreased night sweats (P = 0.023) and improved sleep quality (P = 0.005); it decreased perimenopause-related life interference (P = 0.017) without increased depression. No serious adverse events occurred. Perimenopausal night sweats ± hot flushes are variable; this RCT was underpowered but could not exclude a minimal clinically important VMS benefit. Perceived night sweats and sleep quality significantly improved.

Background: The Vancouver Coastal Health (VCH) ST-elevation myocardial infarction (STEMI) program aimed to increase access to primary percutaneous coronary intervention (PPCI) and reduce first-medical-contact-to-device times (FMC-DTs). We evaluated the long-term program impact on PPCI access and FMC-DT, and overall and reperfusion-specific in-hospital mortality. Methods: We analyzed all VCH STEMI patients between June 2007 and November 2019. The primary outcome was the proportion of patients receiving PPCI over 4 program implementation phases over 12 years. We also evaluated overall changes in median FMC-DT and the proportion of patients achieving guideline-mandated FMC-DT, in addition to overall and reperfusion-specific in-hospital mortality. Results: A total of 3138 of 4305 VCH STEMI patients were treated with PPCI. PPCI rates increased from 40.2% to 78.7% from 2007 to 2019 (P < 0.001). From phase 1 to 4, median FMC-DT improved from 118 to 93 minutes (percutaneous coronary intervention [PCI]-capable hospitals, P < 0.001) and from 174 to 118 minutes (non-PCI-capable hospitals, P < 0.001), with a concomitant increase in those achieving guideline-mandated FMC-DT (35.5% to 66.1%, P < 0.001). Overall in-hospital mortality was 9.0% (P = 0.20 across phases), with mortality differing significantly by reperfusion strategy (4.0% fibrinolysis, 5.7% PPCI, 30.6% no reperfusion therapy, P < 0.001). Mortality significantly decreased from phase 1 to phase 4 at non-PCI-capable centres (9.6% to 3.9%, P = 0.022) but not at PCI-capable centres (8.7% vs 9.9%, P = 0.27). Conclusions: A regional STEMI program increased the proportion of patients who received PPCI and improved reperfusion times over 12 years. Although no statistically significant decrease occurred in overall regional mortality incidence, mortality incidence was decreased for patients presenting to non-PCI-capable centres. Résumé: Contexte: Le programme sur l’infarctus du myocarde avec élévation du segment ST (STEMI) de la régie régionale de santé Vancouver Coastal Health (VCH) visait à améliorer l’accès à des interventions coronariennes percutanées primaires (ICPP) et à réduire le temps entre le premier contact médical et l’intervention. Nous avons évalué les effets à long terme du programme sur l’accès aux ICPP, sur le temps entre le premier contact médical et l’intervention, ainsi que sur le taux global de mortalité hospitalière et le taux de mortalité hospitalière lié à la reperfusion. Méthodologie: Nous avons analysé les cas de tous les patients admis au programme STEMI de la VCH entre juin 2007 et novembre 2019. Le critère d’évaluation principal était la proportion de patients recevant une ICPP pendant les 4 phases du programme, qui se sont étalées sur 12 ans. Nous avons aussi évalué la variation totale du temps médian entre le premier contact médical et l’intervention, et de la proportion de patients chez qui le temps recommandé entre le premier contact médical et l’intervention a été respecté ainsi que la variation du taux global de mortalité hospitalière et du taux de mortalité hospitalière lié à la reperfusion. Résultats: Au total, 3138 des 4305 patients du programme STEMI de la VCH ont été traités par une ICPP. Les taux d’ICPP sont passés de 40,2 % à 78,7 % entre 2007 et 2019 (p < 0,001). De la phase 1 à la phase 4 du programme, le temps médian entre le premier contact médical et l’intervention s’est amélioré, passant de 118 minutes à 93 minutes (hôpitaux en mesure d’effectuer une intervention coronarienne percutanée [ICP]; p < 0,001) et de 174 à 118 minutes (hôpitaux n’étant pas en mesure d’effectuer une ICP; p < 0,001), avec une augmentation du nombre de personnes pour qui le temps recommandé entre le premier contact médical et l’intervention a été respecté (35,5 % à 66,1 %; p < 0,001). Le taux global de mortalité hospitalière était de 9,0 % (p = 0,20 pour toutes les phases), et le taux de mortalité hospitalière lié à la reperfusion différait de manière significative selon la stratégie adoptée (fibrinolyse : 4,0 %; ICPP : 5,7 %; aucune reperfusion : 30,6 %; p < 0,001). Le taux de mortalité a diminué de manière significative entre la phase 1 et la phase 4 dans les centres qui n’étaient pas en mesure d’effectuer une ICP (9,6 % à 3,9 %; p = 0,022), mais pas dans les centres en mesure d’effectuer une ICP (8,7 % c. 9,9 %; p = 0,27). Conclusions: Le programme STEMI régional a permis d’augmenter la proportion de patients qui ont reçu une ICPP et d'améliorer les temps de reperfusion sur 12 ans. Bien qu’aucune diminution statistiquement significative n’ait été observée quant au taux global de mortalité dans la région, le taux de mortalité a diminué chez les patients se présentant dans un centre qui n’était pas en mesure d’effectuer une ICP.

Abstract Background Clinical trials commonly use multiple endpoints to measure the impact of an intervention. While this improves the comprehensiveness of outcomes, it can make trial results difficult to interpret. We examined the impact of integrating patient weights into a composite endpoint on the interpretation of Control of Hypertension in Pregnancy Study (CHIPS) Trial results. Methods Outcome weights were extracted from a previous patient preferences study in pregnancy hypertension (N = 183 women) which identified (i) seven outcomes most important to women (taking medication, severe hypertension, pre-eclampsia, blood transfusion, Caesarean, delivery < 34 weeks, and baby born smaller-than-expected) and (ii) three preference subgroups: (1) ‘equal prioritizers’, 62%; (2) ‘early delivery avoiders’, 23%; and (3) ‘medication minimizers’, 14%. Outcome weights from the preference subgroups were integrated with CHIPS data for the seven outcomes identified in the preference study. A weighted composite score was derived for each participant by multiplying the preference weight for each outcome by the binary outcome if it occurred. Analyses considered equal weights and those from the preference subgroups. The mean composite scores were compared between trial arms (t-tests). Results Composite scores were similar between trial arms with the use of equal weights or those of subgroup (1) (95% confidence intervals [CIs]: − 0.03, 0.02; p > 0.50 for each). ‘Tight’ control was superior when using subgroup (2) weights (95% CIs: 0.002, 0.07; p = 0.03), and ‘less-tight’ control was superior when using subgroup (3) weights (95% CIs: − 0.11, − 0.04; p < 0.01). Conclusions Evidence-based recommendations for ‘tight’ control are consistent with most women’s preferences, but for a sixth of women, ‘less-tight’ control is more preference consistent. Depending on patient preferences, a single trial may support different interventions. Future trials should specify component weights to improve interpretation. Trial registration ClinicalTrials.gov NCT01192412

Summary: Older individuals and people with HIV (PWH) were prioritized for COVID-19 vaccination, yet comprehensive studies of the immunogenicity of these vaccines and their effects on HIV reservoirs are not available. Our study on 68 PWH and 23 HIV-negative participants aged 55 and older post-three vaccine doses showed equally strong anti-spike IgG responses in serum and saliva through week 48 from baseline, while PWH salivary IgA responses were low. PWH had diminished live-virus neutralization responses after two vaccine doses, which were ‘rescued’ post-booster. Spike-specific T cell immunity was enhanced in PWH with normal CD4+ T cell count, suggesting Th1 imprinting. The frequency of detectable HIV viremia increased post-vaccination, but vaccines did not affect the size of the HIV reservoir in most PWH, except those with low-level viremia. Thus, older PWH require three doses of COVID-19 vaccine for maximum protection, while individuals with unsuppressed viremia should be monitored for adverse reactions from HIV reservoirs.

COVID-19 breakthrough infection (BTI) can occur despite vaccination. Using a multi-centre, prospective, observational Canadian cohort of people with HIV (PWH) receiving ≥2 COVID-19 vaccines, we compared the SARS-CoV-2 spike (S) and receptor-binding domain (RBD)-specific IgG levels 3 and 6 months post second dose, as well as 1 month post third dose, in PWH with and without BTI. BTI was defined as positivity based on self-report measures (data up to last study visit) or IgG data (up to 1 month post dose 3). The self-report measures were based on their symptoms and either a positive PCR or rapid antigen test. The analysis was restricted to persons without previous COVID-19 infection. Persons without BTI remained COVID-19-naïve until ≥3 months following the third dose. Of 289 participants, 92 developed BTI (31.5 infections per 100 person-years). The median days between last vaccination and BTI was 128 (IQR 67, 176), with the most cases occurring between the third and fourth dose (n = 59), corresponding to the Omicron wave. In analyses adjusted for age, sex, race, multimorbidity, hypertension, chronic kidney disease, diabetes and obesity, a lower IgG S/RBD (log10 BAU/mL) at 1 month post dose 3 was significantly associated with BTI, suggesting that a lower IgG level at this time point may predict BTI in this cohort of PWH.

Abstract Objective To identify magnetic resonance imaging (MRI) predictors (cartilage [C], osteophytes [O] and meniscus [M] scores) of prevalent and 3-year incident medial tibiofemoral (MTF) and lateral tibiofemoral (LTF) knee joint tenderness and patellofemoral (PF) grind. Methods Population-based knee pain cohort aged 40–79 was assessed at baseline (N = 255), 3- and 7-year follow-up (N = 108 × 2 = 216). COM scores were measured at 6/8/6 subregions respectively. Age-sex-BMI adjusted logistic models predicted prevalence versus relevant COM predictors (medial, lateral or patellar / trochlear groove scores). Fully adjusted models also included all relevant COM predictors. Binary generalized estimating equations models predicting 3-year incidence were also adjusted for individual follow-up time between cycles. Results Significant predictors of prevalent MTF tenderness: medial femoral cartilage (fully adjusted odds ratio [aOR] 1.84; 95% confidence interval [CI] 1.11, 3.05), female (aOR = 3.05; 1.67, 5.58), BMI (aOR = 1.53 per 5 units BMI; 1.10, 2.11). Predictors of prevalent LTF tenderness: female (aOR = 2.18; 1.22, 3.90). There were no predictors of prevalent PF grind in the fully adjusted model. However, medial patellar osteophytes was predictive in the age-sex-BMI adjusted model. There were no predictors of 3-year incident MTF tenderness. Predictors of 3-year incident LTF tenderness: female (aOR = 3.83; 1.25, 11.77). Predictors of 3-year incident PF grind: lateral patellar osteophytes (aOR = 4.82; 1.69, 13.77). In the age-sex-BMI adjusted model, patellar cartilage was also a predictor. Conclusion We explored potential MRI predictors of prevalent and 3-year incident MTF/LTF knee joint tenderness and PF grind. These findings could guide preemptive strategies aimed at reducing these symptoms in the present and future (3-year incidence).

Abstract Background Targeted exercise training is a promising strategy for promoting cognitive function and preventing dementia in older age. Despite the utility of exercise as an intervention, variation still exists in exercise-induced cognitive gains and questions remain regarding the type of training (i.e., what), as well as moderators (i.e., for whom) and mechanisms (i.e., how) of benefit. Both aerobic training (AT) and resistance training (RT) enhance cognitive function in older adults without cognitive impairment; however, the vast majority of trials have focused exclusively on AT. Thus, more research is needed on RT, as well as on the combination of AT and RT, in older adults with mild cognitive impairment (MCI), a prodromal stage of dementia. Therefore, we aim to conduct a 6-month, 2 × 2 factorial randomized controlled trial in older adults with MCI to assess the individual effects of AT and RT, and the combined effect of AT and RT on cognitive function and to determine the possible underlying biological mechanisms. Methods Two hundred and sixteen community-dwelling adults, aged 65 to 85 years, with MCI from metropolitan Vancouver will be recruited to participate in this study. Randomization will be stratified by biological sex and participants will be randomly allocated to one of the four experimental groups: (1) 4×/week balance and tone (BAT; i.e., active control); (2) combined 2×/week AT + 2×/week RT; (3) 2×/week AT + 2×/week BAT; or (4) 2×/week RT + 2×/week BAT. The primary outcome is cognitive function as measured by the Alzheimer’s Disease Assessment Scale-Cognitive-Plus. Secondary outcomes include cognitive function, health-related quality of life, physical function, actigraphy measures, questionnaires, and falls. Outcomes will be measured at baseline, 6 months (i.e., trial completion), and 18 months (i.e., 12-month follow-up). Discussion Establishing the efficacy of different types and combinations of exercise training to minimize cognitive decline will advance our ability to prescribe exercise as “medicine” to treat MCI and delay the onset and progression of dementia. This trial is extremely timely as cognitive impairment and dementia pose a growing threat to global public health. Trial registration ClinicalTrials.gov NCT02737878 . Registered on April 14, 2016.

There has been an increasing interest in patient-reported outcome (PRO) measures in both the clinical and research settings to improve the quality of life among patients and to identify when clinical intervention may be needed. The primary purpose of this prospective study was to validate an acute breast skin toxicity PRO measure across a broad sample of patient body types undergoing radiation therapy. Between August 2018 and September 2019, 134 women undergoing adjuvant breast radiotherapy (RT) consented to completing serial PRO measures both during and post-RT treatment and to having their skin assessed by trained trial radiation therapists. There was high patient compliance, with 124 patients (92.5%) returning to the clinic post-RT for at least one staff skin assessment. Rates of moist desquamation (MD) in the infra-mammary fold (IMF) by PRO were compared with skin assessments completed by trial radiation therapists. There was high sensitivity (86.5%) and good specificity (79.4%) between PRO and staff-reported presence of MD in the IMF, and there was a moderate correlation between the peak severity of the MD reported by PRO and assessed by staff (rho = 0.61, p < 0.001). This prospective study validates a new PRO measure to monitor the presence of MD in the IMF among women receiving breast RT.

Abstract Background A novel device for supine positioning in breast radiotherapy for patients with large or pendulous breasts has been developed and tested in phase II studies. This trial is designed to assess the efficacy of the device to reduce skin toxicity and unwanted normal tissue dose in comparison to the current clinical standard for supine breast support during breast radiotherapy. Methods Patients at high risk for moist desquamation, having infra-mammary fold or lateral ptosis, will be randomized into two arms. Patients in the control arm will receive breast radiotherapy with supine positioning using current standard of care. Patients in the experimental arm will be positioned supine with the novel device. The primary endpoint is the incidence of moist desquamation in the infra-mammary fold. We hypothesize a 20% reduction (from 50 to 30%) in the rate of moist desquamation in the study arm versus the control arm. For 80% power, two-tailed α = 0.05 and 10% loss to follow up, 110 patients will be assigned to each arm. The proportion of patients experiencing moist desquamation in the two arms will be compared using logistic regression adjusting for brassiere cup size, skin fold size, body mass index, smoking status, and dose fractionation schedule. An unadjusted comparison will also be made using the chi-square test, or Fisher’s exact test, if appropriate. Secondary endpoints include dose-volume statistics for the lung and heart, skin dose and clinical parameters including setup time, reproducibility, and staff experience with setup procedures. Patient-reported pain, skin condition interference with sleep and daily activities, and comfort during treatment are also secondary endpoints. Discussion Based on results from earlier phase II studies, it is expected that the device-enabled elimination of infra-mammary fold should reduce toxicity and improve quality of life for this patient population. Earlier studies showed reduction in dose to organs at risk including lung and heart, indicating potential for other long-term benefits for patients using the device. This study is limited to acute skin toxicity, patient-reported outcomes, and clinical factors to inform integration of the device into standard breast radiotherapy procedures. Trial registration Clinicaltrials.gov identifier: NCT04257396 . Registered February 6 2020.

Background: It was unknown if the effectiveness of COVID-19 vaccines could vary between regions. Objective: To explore key differences in COVID-19 pandemics in British Columbia (BC) and Ontario (ON) and to investigate if the vaccine effectiveness (VE) among maintenance dialysis population could vary between these 2 provinces. Study Design: Retrospective cohort. Setting and Patients: This retrospective cohort study included patients from population-level registry in BC who were on maintenance dialysis from December 14, 2020, to December 31, 2021. The COVID-19 VE among BC patients were compared to the previously published VE among similar patient population in ON. Two-sample t -test for unpaired data were used to investigate if the VE estimates from BC and ON were statistically significantly different. Exposure: Exposure to COVID-19 vaccines (BNT162b2, ChAdOx1nCoV-19, mRNA-1273) was modeled in a time-dependent fashion. Outcome: Reverse transcription polymerase chain reaction (RT-PCR) confirmed COVID-19 infection and related severe outcome defined by hospitalization or death. Analytical Approach: Time-dependent Cox regression analysis. Results: This study using BC data included 4284 patients. Median age was 70 years and 61% was male. Median follow-up time was 382 days. 164 patients developed COVID-19 infection. The ON study by Oliver et al included 13 759 patients with a mean age of 68 years. 61% of the study sample was male. Median follow-up time for patients in the ON study was 102 days. A total of 663 patients developed COVID-19 infection. During the overlapped study periods, BC had 1 pandemic wave compared to 2 in Ontario with substantially higher infection rates. Vaccination timing and roll out among the study population were substantially different. Median time between first and second dose was 77 days (interquartile range [IQR] 66-91) in BC compared to 39 days (IQR = 28-56) in Ontario. Distribution of COVID-19 variants during the study period appeared to be similar. In BC, compared to pre-vaccination person-time, risk of developing COVID-19 infection was 64% (aHR [95% CI] 0.36 [0.21, 0.63]), 80% (0.20 [0.12, 0.35]) and 87% (0.13 [0.06, 0.29]) less when exposed to 1 dose, 2 doses, and 3 doses, respectively. In contrast, risk reduction among Ontario patients was 41% (0.59 [0.46, 0.76]) and 69% (0.31 [0.22, 0.42]) for 1 dose and 2 doses, respectively (patients did not receive the third dose by study end date of June 30, 2021). VE against COVID-19 infection in BC and ON was not statistically significantly different, the P values for exposure to 1 dose and 2 doses comparisons were 0.103 and 0.163, respectively. Similarly, in BC, risk of developing COVID-19-related hospitalization or death were 54% (0.46 [0.24, 0.90]), 75% (0.25 [0.13, 0.48]) and 86% (0.14 [0.06, 0.34]) less for 1 dose, 2 doses, and 3 doses, respectively. Interestingly, exposure to second dose appeared to provide better protection against severe outcomes in Ontario versus BC, risk reduction was 83% (aHR = 0.17, 95% CI [0.10, 0.30]) and 75% (aHR = 0.25, 95% CI [0.13, 0.48]), respectively. However, the adjusted hazard ratios were not statistically significantly different between BC and ON, the P values were 0.676 and 0.369 for exposure to 1 dose and 2 doses, respectively. Limitations: Infection rate, variant distribution, and vaccination strategies were compared using publicly available data. VE estimates were compared from 2 independent cohort studies from 2 provinces without patient-level data sharing. Conclusions: Health Canada approved COVID-19 vaccines were highly effective among patients with maintenance dialysis from BC and ON. Although there appeared to be between province differences in pandemic waves and vaccination strategies, the VE against COVID-19 infection as well as related severe outcome appeared to be not statistically significantly different. A nationally representative VE could be estimated using pooled data from multiple regions.

Background: People living with chronic kidney disease (CKD) have been disproportionately affected by the coronavirus disease 2019 (COVID-19) pandemic, including higher rates of infection, hospitalization, and death. Data on responsiveness to COVID-19 vaccination strategies and immunogenicity are limited, yet required to inform vaccination strategies in this at-risk population. Objective: The objective of this study is to characterize the longitudinal serologic response to COVID-19 vaccination. Design: This is a prospective observational cohort study. Setting: Participating outpatient kidney programs within Ontario and British Columbia. Patients: Up to 2500 participants with CKD G3b-5D receiving COVID-19 vaccination, including participants receiving dialysis and kidney transplant recipients (CKD G1T-5T). Measurements: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG antibodies (anti-spike, anti-receptor binding domain, anti-nucleocapsid) will be detected by ELISA (enzyme-linked immunosorbent assay) from serum or dried blood spot testing. In a subset of participants, neutralizing antibodies against novel variants of concern will be evaluated. Peripheral blood mononuclear cells will be collected for exploratory immune profiling of SARS-CoV-2 specific cellular immunity. Methods: Participants will be recruited prior to or following any COVID-19 vaccine dose and have blood sampled for serological testing at multiple timepoints: 1, 3, 6, 9, and 12 months post vaccination. When possible, samples will be collected prior to a dose or booster. Participants will remain in the study for at least 1 year following their last COVID-19 vaccine dose. Strengths and limitations: The adaptive design of this study allows for planned modification based on emerging evidence or rapid changes in public health policy surrounding vaccination. Limitations include incomplete earlier timepoints for blood collection due to rapid vaccination of the population. Conclusions: This large multicenter serologic study of participants living with kidney disease will generate data on the kinetics of SARS-CoV-2 immune response to vaccination across the spectrum of CKD, providing insights into the amplitude and duration of immunity conferred by COVID-19 vaccination and allowing for characterization of factors associated with immune response. The results of this study may be used to inform immunization guidelines and public health recommendations for the 4 million Canadians living with CKD.

Community pharmacists are accessible healthcare providers with expertise in medication management. Here the authors show that a low-carbohydrate, low-energy diet implemented by community pharmacists reduced diabetes medication use and improved glucose control in people with type 2 diabetes.

Background: Major bleeding (MB) is an independent predictor of mortality among ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (pPCI). Prevention of access-site MB has received significant attention. However, limited data have been obtained on the influence of access-site MB vs non-access-site MB and association with subsequent adverse in-hospital outcomes in the STEMI population undergoing pPCI. Methods: We identified 1494 STEMI patients who underwent pPCI between 2012 and 2018. Unadjusted and adjusted differences among patients with no MB, access-site MB, non-access-site MB, and in-hospital clinical outcomes were assessed. The use of bleeding-avoidance strategies and their effects on MB were also evaluated. Results: MB occurred in 121 (8.1%) patients. Access-site MB occurred in 34 (2.3%) patients, and non-access-site MB occurred in 87 (5.8%). The median reduction in hemoglobin was 31 g/L (interquartile range: 19-43) with access-site MB, and 44 g/L (interquartile range: 29-62) with non-access-site MB. After multivariable adjustment, non-access-site MB was independently associated with in-hospital death (adjusted odds ratio [aOR] 4.21; 95% confidence interval [CI] 2.04-8.68), cardiogenic shock (aOR 10.91; 95% CI 5.67-20.98), and cardiac arrest (aOR 5.63; 95% CI 2.88-11.01). Conversely, access-site MB was not associated with adverse in-hospital outcomes. Bleeding-avoidance strategies were used frequently; however, after multivariable adjustment, no single bleeding-avoidance strategy was significantly associated with reduced MB. Conclusions: In STEMI patients undergoing pPCI, non-access-site MB was independently associated with adverse in-hospital outcomes, whereas access-site MB was not. Additional study of strategies to reduce the incidence and impact of non-access-site MB appears to be warranted. Résumé: Contexte: Le saignement majeur (SM) est un facteur prédictif indépendant de la mortalité chez les patients ayant eu un infarctus du myocarde avec élévation du segment ST (STEMI) qui subissent une intervention coronarienne percutanée primaire (ICPp). La prévention du SM lié à l'accès vasculaire a fait l'objet de nombreuses études. Toutefois, rares sont les données sur l'influence du SM lié à l'accès vasculaire par rapport au SM non lié à cet élément et sur son association avec des résultats indésirables intrahospitaliers subséquents chez des patients ayant subi une ICPp après un STEMI. Méthodologie: Nous avons répertorié 1 494 patients ayant subi une ICPp après un STEMI entre 2012 et 2018. Nous avons évalué les différences non ajustées et ajustées entre les cas sans SM, les cas de SM liés à l'accès vasculaire et les cas de SM non liés à l'accès vasculaire, et les résultats cliniques intrahospitaliers. L'utilisation de stratégies d'évitement des saignements et leurs effets sur le SM ont également été évalués. Résultats: Un SM a été observé chez 121 (8,1 %) patients. Le SM lié à l'accès vasculaire touchait 34 (2,3 %) patients, et le SM non lié à l'accès vasculaire 87 (5,8 %) patients. La réduction médiane du taux d'hémoglobine était de 31 g/L (intervalle interquartile : 19 à 43) dans le cas du SM lié à l'accès vasculaire, et de 44 g/L (intervalle interquartile : 29 à 62) pour le SM non lié à l'accès vasculaire. Après ajustement multivarié, une association indépendante a été observée entre le SM non lié à l'accès vasculaire et le décès (rapport de cotes ajusté [RRa] 4,21; intervalle de confiance [IC] à 95 % : de 2,04 à 8,68), le choc cardiogénique (RRa 10,91; IC à 95 % : de 5,67 à 20,98), et l'arrêt cardiaque (RRa 5,63; IC à 95 % : de 2,88 à 11,01) intrahospitaliers. Inversement, le SM lié à l'accès vasculaire n'était associé à aucun résultat indésirable intrahospitalier. Les stratégies d'évitement des saignements avaient été utilisées fréquemment; toutefois, après ajustement multivarié, aucune stratégie particulière d'évitement des saignements n'était associée de façon significative à une réduction du SM. Conclusions: Chez les patients subissant une ICPp après un STEMI, le SM non lié à l'accès vasculaire était associé de façon indépendante aux résultats indésirables intrahospitaliers, alors que le SM lié à l'accès vasculaire ne l'était pas. La poursuite des recherches sur les stratégies permettant de réduire l'incidence et les conséquences du SM non lié à l'accès vasculaire semble donc justifiée.

Background: Angiotensin receptor blockers (ARBs) and/or angiotensin-converting enzyme (ACE) inhibitors could alter mortality from coronavirus disease 2019 (COVID-19), but existing meta-analyses that combined crude and adjusted results may be confounded by the fact that comorbidities are more common in ARB/ACE inhibitor users. Methods: We searched PubMed/MEDLINE/Embase for cohort studies and meta-analyses reporting mortality by preexisting ARB/ACE inhibitor treatment in hospitalized COVID-19 patients. Random effects meta-regression was used to compute pooled odds ratios for mortality adjusted for imbalance in age, sex, and prevalence of cardiovascular disease, hypertension, diabetes mellitus, and chronic kidney disease between users and nonusers of ARBs/ACE inhibitors at the study level during data synthesis. Results: In 30 included studies of 17,281 patients, 22%, 68%, 25%, and 11% had cardiovascular disease, hypertension, diabetes mellitus, and chronic kidney disease. ARB/ACE inhibitor use was associated with significantly lower mortality after controlling for potential confounding factors (odds ratio 0.77 [95% confidence interval: 0.62, 0.96]). In contrast, meta-analysis of ARB/ACE inhibitor use was not significantly associated with mortality when all studies were combined with no adjustment made for confounders (0.87 [95% confidence interval: 0.71, 1.08]). Conclusions: ARB/ACE inhibitor use was associated with decreased mortality in cohorts of COVID-19 patients after adjusting for age, sex, cardiovascular disease, hypertension, diabetes, and chronic kidney disease. Unadjusted meta-analyses may not be appropriate for determining whether ARBs/ACE inhibitors are associated with mortality from COVID-19 because of indication bias. Résumé: Introduction: Les antagonistes des récepteurs de l'angiotensine (ARA) et/ou les inhibiteurs de l'enzyme de conversion de l'angiotensine (IECA) feraient varier la mortalité liée à la COVID-19, mais il est possible que les méta-analyses actuelles qui combinaient les résultats bruts et ajustés soient invalidées du fait que les comorbidités sont plus fréquentes chez les utilisateurs d'ARA/IECA. Méthodes: Nous avons effectué des recherches dans les bases de données PubMed/MEDLINE/Embase pour trouver des études de cohorte et des méta-analyses qui portent sur la mortalité associée à un traitement préexistant par ARA/IECA chez les patients hospitalisés atteints de la COVID-19. Nous avons utilisé la métarégression à effets aléatoires pour calculer les rapports de cotes regroupés de mortalité ajustés en fonction du déséquilibre de l’âge, du sexe, et de la prévalence des maladies cardiovasculaires, de l'hypertension, du diabète sucré et de l'insuffisance rénale chronique entre les utilisateurs et les non-utilisateurs d'ARA/IECA dans le cadre de l’étude durant la synthèse des données. Résultats: Dans les 30 études portant sur 17 281 patients, 22 %, 68 %, 25 % et 11 % avaient respectivement une maladie cardiovasculaire, de l'hypertension, le diabète sucré et de l'insuffisance rénale chronique. L'utilisation des ARA/IECA a été associée à une mortalité significativement plus faible après avoir tenu compte des facteurs confusionnels potentiels (rapport de cotes 0,77 [intervalle de confiance à 95 % : 0,62, 0,96]). En revanche, la méta-analyse sur l'utilisation des ARA/IECA n'a pas été associée de façon significative à la mortalité lorsque toutes les études ont été combinées sans ajustement sur les facteurs confusionnels (0,87 [intervalle de confiance à 95 % : 0,71, 1,08]). Conclusions: L'utilisation des ARA/IECA a été associée à la diminution de la mortalité au sein des cohortes de patients atteints de la COVID-19 après l'ajustement en fonction de l’âge, du sexe, des maladies cardiovasculaires, de l'hypertension, du diabète et de l'insuffisance rénale chronique. Les méta-analyses non ajustées peuvent ne pas permettre de déterminer si les ARA/IECA sont associés à la mortalité liée à la COVID-19 en raison du biais d'indication.

Chronic HIV infection is characterized by persistent inflammation despite antiretroviral therapy (ART). Cannabinoids may help reduce systemic inflammation in people with HIV (PWH). To assess the effects of oral cannabinoids during HIV, ten PWH on ART were randomized (n = 5/group) to increasing doses of oral Δ9-tetrahydrocannabinol (THC): cannabidiol (CBD) combination (2.5:2.5–15:15 mg/day) capsules or CBD-only (200–800 mg/day) capsules for 12 weeks. Blood specimens were collected prospectively 7–21 days prior to treatment initiation and at weeks 0 to 14. Plasma cytokine levels were determined via Luminex and ELISA. Immune cell subsets were characterized by flow cytometry. HIV DNA/RNA were measured in circulating CD4 T-cells and sperm by ultra-sensitive qPCR. Results from both arms were combined for statistical analysis. Plasma levels of IFN-γ, IL-1β, sTNFRII, and REG-3α were significantly reduced at the end of treatment (p ˂ 0.05). A significant decrease in frequencies of PD1+ memory CD4 T-cells, CD73+ regulatory CD4 T-cells, and M-DC8+ intermediate monocytes was also observed (p ˂ 0.05), along with a transient decrease in CD28–CD57+ senescent CD4 and CD8 T-cells. Ki-67+ CD4 T-cells, CCR2+ non-classical monocytes, and myeloid dendritic cells increased over time (p ˂ 0.05). There were no significant changes in other inflammatory markers or HIV DNA/RNA levels. These findings can guide future large clinical trials investigating cannabinoid anti-inflammatory properties.

Background Cardiac intensive care units were originally created in the prerevascularization era for the early recognition of ventricular arrhythmias following a myocardial infarction. Many patients with stable ST‐segment–elevation myocardial infarction (STEMI) are still routinely triaged to cardiac intensive care units after a primary percutaneous coronary intervention (pPCI), independent of clinical risk or the provision of critical care therapies. The aim of this study was to determine factors associated with in‐hospital adverse events in a hemodynamically stable, postreperfusion population of patients with STEMI. Methods and Results Between April 2012 and November 2019, 2101 consecutive patients with STEMI who received pPCI in the Vancouver Coastal Health Authority were evaluated. Patients were stratified into those with and without subsequent adverse events, which were defined as cardiogenic shock, in‐hospital cardiac arrest, stroke, re‐infarction, and death. Multivariable logistic regression models were used to determine predictors of adverse events. After excluding patients presenting with cardiac arrest, cardiogenic shock, or heart failure, the final analysis cohort comprised 1770 stable patients with STEMI who had received pPCI. A total of 94 (5.3%) patients developed at least one adverse event: cardiogenic shock 55 (3.1%), in‐hospital cardiac arrest 42 (2.4%), death 28 (1.6%), stroke 21 (1.2%), and re‐infarction 5 (0.3%). Univariable predictors of adverse events were older age, female sex, prior stroke, chronic kidney disease, and atrial fibrillation. There was no significant difference in reperfusion times between those with and without adverse events. Following multivariable adjustment, moderate to severe chronic kidney disease (creatinine clearance

Background Background: Tryptophan (Trp) catabolism into immunosuppressive kynurenine (Kyn) is involved in immune dysregulation during HIV infection. Niacin (vitamin B3) could control the excess of tryptophan depletion and represents a potential strategy to improve immune functions and CD4 count recovery in immunological non-responder HIV-infected individuals on antiretroviral therapy (ART). Methods Methods: In the CTN PT006 phase 2 pilot randomized trial, 20 adults on ART with CD4 ≤ 350 cells/µl, despite an undetectable viral load (VL) for at least 3 months, received 2000 mg of extended-release (ER)-niacin orally once daily for 24 weeks. Side effects, VL, CD4/CD8 counts, lipid profile, T-cell activation and senescence, Tregs and Th17 cell frequencies, Kyn/Trp ratio, and levels of IL-6, IP-10, sST2, I-FABP, and LBP were assessed following ER-niacin treatment. Results Results: Thirteen participants completed the study. Treatment was interrupted in 4 patients due to loss of follow-up or personal reasons and 3 patients were discontinued due to comorbidity risks. All participants maintained a VL < 40 copies/ml, while ER-niacin did not affect CD4 and CD8 cell counts. Plasma levels of triglycerides, total, and LDL cholesterol significantly decreased, following ER-niacin treatment. ER-niacin also diminished Kyn plasma levels and slightly decreased CD4 T-cell activation. However, no improvement in CD8 subsets, Kyn/Trp ratio, Th17/Treg balance, and plasma inflammatory markers was observed. Conclusions Conclusions: Although ER-niacin combined with ART was well-tolerated among immune non-responders and decreased plasma lipids, it did not improve systemic inflammation, Kyn/Trp ratio, and CD4 cell recovery. Overall, ER-niacin was not effective to overcome chronic inflammation in PLWH.

Abstract Background To evaluate whether knee osteoarthritis (OA) manifestations predict depression and anxiety using cross-sectional and longitudinal prediction models. Methods A population-based cohort (n = 122) with knee pain, aged 40–79, was evaluated at baseline, 3 and 7 years. Baseline predictors were: age decade; sex; BMI ≥ 25; physical exam knee effusion; crepitus; malalignment; quadriceps atrophy; flexion; flexion contracture; Kellgren-Lawrence (KL) x-ray grade (0/1/2/3+); WOMAC pain ≥25; WOMAC stiffness ≥25; self-reported knee swelling; and knee OA diagnosis (no/probable/definite). Depression and anxiety, cutoffs 5+ and 7+ respectively, were measured via the Hospital Anxiety and Depression Scale. We fit logistic models at each cycle using multivariable models selected via lowest Akaike’s information criterion. Results Baseline depression model: sex (female OR = 0.27; 0.10, 0.76) and KL grade (KL 1 OR = 4.21; 1.31, 13.48). Three-year depression model: KL grade (KL 1 OR = 18.92; 1.73, 206.25). Seven-year depression model: WOMAC stiffness ≥25 (OR = 3.49; 1.02, 11.94) and flexion contracture ≥1 degree (OR = 0.23; 0.07, 0.81). Baseline anxiety model: knee swelling (OR = 4.11; 1.51, 11.13) and age (50–59 vs. 40–49 OR = 0.31 [0.11, 0.85]; 60–69 OR = 0.07 [0.01, 0.42]). Three-year anxiety model: WOMAC stiffness ≥25 (OR = 5.80; 1.23, 27.29) and KL grade (KL 1 OR = 6.25; 1.04, 37.65). Seven-year anxiety model: sex (female OR = 2.71; 0.87, 8.46). Conclusion Specific knee OA-related manifestations predict depression and anxiety cross-sectionally, 3 years in the future, and for depression, 7 years in the future. This information may prove useful to clinicians in helping to identify patients most at risk of present or future depression and anxiety, thus facilitating preemptive discussions that may help counter that risk.

Abstract Background Sickle cell disease (SCD) is a genetic disorder which causes dysfunctional red blood cells (RBC) and is thought to increase requirements for folate, an essential B vitamin, due to increased RBC production and turnover in the disease. High-dose supplementation with 1–5 mg/d folic acid, synthetic folate, has been the standard recommendation for children with SCD. There is concern about whether children with SCD need such high doses of folic acid, following mandatory folic acid fortification of enriched grains in Canada, and advancements in medical therapies which extend the average lifespan of RBCs. In animal and human studies, high folic acid intakes (1 mg/d) have been associated with accelerated growth of some cancers, and the biological effects of circulating unmetabolized folic acid (UMFA), which can occur with doses of folic acid ≥ 0.2 mg/d, are not fully understood. The objective of this study is to determine efficacy of, and alterations in folate metabolism from high-dose folic acid in children with SCD during periods of folic acid supplementation versus no supplementation. Methods In this double-blind randomized controlled cross-over trial, children with SCD (n = 36, aged 2–19 years) will be randomized to either receive 1 mg/d folic acid, the current standard of care, or a placebo for 12 weeks. After a 12-week washout period, treatments will be reversed. Total folate concentrations (serum and RBC), different folate forms (including UMFA), folate-related metabolites, and clinical outcomes will be measured at baseline and after treatment periods. The sum of the values measured in the two periods will be calculated for each subject and compared across the two sequence groups by means of a test for independent samples for the primary (RBC folate concentrations) and secondary (UMFA) outcomes. Dietary intake will be measured at the beginning of each study period. Discussion As the first rigorously designed clinical trial in children with SCD, this trial will inform and assess current clinical practice, with the ultimate goal of improving nutritional status of children with SCD. Trial registration ClinicalTrials.gov NCT04011345 . Registered on July 8, 2019

Background: Patients with ST-elevation myocardial infarction (STEMI) presenting to percutaneous coronary intervention (PCI)-capable hospitals often experience delays for primary PCI (pPCI). We sought to describe the effect of specific delay intervals and patient/system-level factors on STEMI reperfusion times. Methods: We analyzed all consecutive patients with STEMI who presented to 2 PCI-capable hospital emergency departments (EDs) between June 2007 and March 2016 who received successful pPCI. We excluded patients with prehospital cardiac arrest. We compared specific system delay intervals, patient characteristics, and in-hospital outcomes among patients who received timely (first medical contact-device ≤90/≤120 minutes) vs delayed >90/>120 minutes) pPCI. Results: Of 1936 patients with STEMI, 1127 (58%) presented directly to a PCI-capable hospital via emergency health services (EHS), 499 (26%) were transferred from the ED of a non-PCI hospital, and 310 (16%) self-presented to the ED of a pPCI-capable hospital. Guideline-recommended reperfusion times were met in 47% of direct-EHS, 42% of transfers, and 33% of self-presenters. Each time interval from first medical contact to device deployment was significantly prolonged in the delayed vs timely reperfusion cohorts across all 3 groups, excepting vascular access time. ED dwell time contributed the most to the difference in median reperfusion time within each group. Time of presentation, comorbidities, and sex were each significantly associated with delayed reperfusion. Within the EHS-direct group, prolonged reperfusion and ED dwell times were significantly associated with increased mortality, major bleeding, and cardiogenic shock. Conclusion: Ongoing efforts to identify and reduce ED dwell time and other systemic pPCI delays may improve STEMI outcomes, including mortality. Résumé: Contexte: Les patients en infarctus du myocarde avec élévation du segment ST (STEMI) qui se présentent dans un hôpital en mesure d’effectuer une intervention coronarienne percutanée (ICP) doivent souvent attendre pour subir une ICP primaire (ICPP). Nous avons tenté de décrire les effets de différents temps d’attente et facteurs relevant des patients ou du système de santé sur le délai avant la reperfusion lors d’un STEMI. Méthodologie: Nous avons analysé tous les cas consécutifs de patients en STEMI admis entre juin 2007 et mars 2016 au service des urgences de deux hôpitaux en mesure d’effectuer une ICP, et qui ont effectivement subi une ICPP. Les patients qui avaient subi un arrêt cardiaque avant leur arrivée à l’hôpital ont été exclus. Nous avons comparé les temps d’attente à des étapes particulières relevant du système de santé, les caractéristiques des patients et les issues de l’hospitalisation chez les patients qui ont subi une ICPP rapidement (intervalle entre la première prise de contact avec les services médicaux et la pose d’un dispositif ≤ 90/≤ 120 minutes) ou tardivement (intervalle > 90/> 120 minutes). Résultats: Sur les 1 936 patients ayant subi un STEMI, 1 127 (58 %) ont été conduits par l’entremise des services d’urgences de santé (SUS) directement dans un hôpital en mesure d’effectuer une ICP, 499 (26 %) ont été transférés depuis le service des urgences d’un hôpital n’étant pas en mesure d’effectuer une ICP et 310 (16 %) se sont présentés eux-mêmes au service des urgences d’un hôpital en mesure d’effectuer une ICPP. Les délais avant la reperfusion recommandés dans les lignes directrices ont été respectés dans 47 % des cas où le patient a été conduit par l’entremise des SUS, dans 42 % des cas de transfert et dans 33 % des cas où le patient s’est présenté lui-même. À l’exception du temps écoulé entre l’arrivée au laboratoire de cathétérisme et la création d’un accès vasculaire, les temps d’attente à chacune des étapes entre la première prise de contact avec les services médicaux et la pose d’un dispositif étaient significativement plus longs chez les patients ayant subi une reperfusion tardive que chez ceux ayant subi rapidement une ICPP, et ce, dans les trois groupes de patients. C’est le temps d’attente au service des urgences qui a le plus contribué à la différence entre les groupes en ce qui concerne le délai médian avant la reperfusion. L’heure de l’arrivée au service des urgences, la présence d’affections concomitantes et le sexe étaient tous des facteurs associés de manière significative à une reperfusion tardive. Chez les patients conduits par l’entremise des SUS directement dans un hôpital en mesure d’effectuer une ICP, un délai avant la perfusion et un temps d’attente au service des urgences plus longs étaient associés de manière significative à une hausse de la mortalité, des hémorragies majeures et des chocs cardiogéniques. Conclusion: Les efforts actuellement déployés pour reconnaître les sources de retard et réduire les temps d’attente au service des urgences et aux autres étapes avant la réalisation de l’ICPP pourraient permettre d’améliorer l’issue d’un STEMI, y compris la mortalité.

Abstract Study Objectives Timely coronary reperfusion is critical for favorable outcomes after ST‐elevation myocardial infarction (STEMI). A substantial proportion of the total ischemic time is patient related, occurring before first medical contact (FMC). We aimed to expand the limited current understanding of the associations between prehospital intervals and clinical outcomes. Methods We conducted a retrospective analysis of consecutive STEMI patients who underwent primary percutaneous coronary intervention (pPCI) (January 2009–March 2016) and assessed the associations between prehospital intervals and the incidence of new heart failure, cardiogenic shock, and hospital length of stay (LOS), adjusting for important clinical variables. Results A total of 773 patients (77% men, median age 65 years) met eligibility criteria. The median pre‐911 activation interval was 29 minutes (interquartile range: 11, 89); the median 911 call to FMC interval was 12 minutes (interquartile range: 9, 15). In multivariable analysis, there was a V‐shaped relationship between the pre‐911 activation interval and outcomes: a lower likelihood of new heart failure (odds ratio [OR] 0.51; 95% confidence interval [CI]: 0.30, 0.87), cardiogenic shock (OR 0.40; 95% CI: 0.21, 0.75) and prolonged LOS (OR 0.24; 95% CI: 0.14, 0.42) for midrange intervals (11–88 minutes) when compared to the early (

BackgroundLow-carbohydrate ketogenic diets are a viable method to lose weight that have regained popularity in recent years. Technology in the form of mobile health (mHealth) apps allows for scalable and remote delivery of such dietary interventions and are increasingly being used by the general population without direct medical supervision. However, it is currently unknown which factors related to app use and user behavior are associated with successful weight loss. ObjectiveFirst, to describe and characterize user behavior, we aim to examine characteristics and user behaviors over time of participants who were enrolled in a remotely delivered clinical weight loss trial that tested an mHealth ketogenic diet app paired with a breath acetone biofeedback device. Second, to identify variables of importance to weight loss at 12 weeks that may offer insight for future development of dietary mHealth interventions, we aim to explore which app- and adherence-related user behaviors characterized successful weight loss. MethodsWe analyzed app use and self-reported questionnaire data from 75 adults with overweight or obesity who participated in the intervention arm of a previous weight loss study. We examined data patterns over time through linear mixed models and performed correlation, linear regression, and causal mediation analyses to characterize diet-, weight-, and app-related user behavior associated with weight loss. ResultsIn the context of a low-carbohydrate ketogenic diet intervention delivered remotely through an mHealth app paired with a breath acetone biofeedback device, self-reported dietary adherence seemed to be the most important factor to predict weight loss (β=–.31; t54=–2.366; P=.02). Furthermore, self-reported adherence mediated the relationship between greater app engagement (from c=–0.008, 95% CI –0.014 to –0.0019 to c’=–0.0035, 95% CI –0.0094 to 0.0024) or higher breath acetone levels (from c=–1.34, 95% CI –2.28 to –0.40 to c’=–0.40, 95% CI –1.42 to 0.62) and greater weight loss, explaining a total of 27.8% and 28.8% of the variance in weight loss, respectively. User behavior (compliance with weight measurements and app engagement) and adherence-related aspects (breath acetone values and self-reported dietary adherence) over time differed between individuals who achieved a clinically significant weight loss of >5% and those who did not. ConclusionsOur in-depth examination of app- and adherence-related user behaviors offers insight into factors associated with successful weight loss in the context of mHealth interventions. In particular, our finding that self-reported dietary adherence was the most important metric predicting weight loss may aid in the development of future mHealth dietary interventions. Trial RegistrationClinicalTrials.gov NCT04165707; https://clinicaltrials.gov/ct2/show/NCT04165707 International Registered Report Identifier (IRRID)RR2-10.2196/19053

BackgroundAlthough micronutrient and antioxidant supplementation are widely used by persons with human immunodeficiency virus (HIV), a therapeutic role beyond recommended daily allowances (RDA) remains unproven. An oral high-dose micronutrient and antioxidant supplement (Treatment) was compared to an RDA supplement (Control) for time to progressive immunodeficiency or initiation of antiretroviral therapy (ART) in people living with HIV (PLWH).MethodsThis study was a randomized, double-blind, placebo-controlled multicenter clinical trial. PLWH were recruited from Canadian HIV Trials Network sites, and followed quarterly for two years. Eligible participants were asymptomatic, antiretroviral treatment (ART)-naïve, HIV-seropositive adults with a CD4 T lymphocyte count (CD4 count) between 375-750 cells/μL. Participants were randomly allocated 1:1 to receive Treatment or Control supplements. The primary outcome was a composite of time-to-first of confirmed CD4 count below 350 cells/μL, initiation of ART, AIDS-defining illness or death. Primary analysis was by intention-to-treat. Secondary outcomes included CD4 count trajectory from baseline to ART initiation or two years. A Data and Safety Monitoring Board reviewed the study for safety, recruitment and protocol adherence every six months.ResultsOf 171 enrolled participants: 66 (38.6%) experienced a primary outcome: 27 reached a CD4 count below 350 cells/μL, and 57 started ART. There was no significant difference in time-to-first outcome between groups (Hazard Ratio = 1.05; 95%CI: 0.65, 1.70), or in time to any component outcome. Using intent-to-treat censoring, mean annualized rates of CD4 count decline were -42.703 cells/μL and -79.763 cells/μL for Treatment and Control groups, with no statistical difference in the mean change between groups (-37.06 cells/μL/52 weeks, 95%CI: (-93.59, 19.47); p = 0.1993). Accrual was stopped at 171 of the 212 intended participants after an interim analysis for futility, although participant follow-up was completed.ConclusionsIn ART-naïve PLWH, high-dose antioxidant, micronutrient supplementation compared to RDA supplementation had no significant effect on disease progression or ART initiation.Clinical trial registrationClinicalTrials.gov Identifier: NCT00798772.

People living with HIV (PLWH) may be at risk for poor immunogenicity to certain vaccines, including the ability to develop immunological memory. Here, we assessed T-cell immunogenicity following three SARS-CoV-2 vaccine doses in PLWH versus uninfected controls. Blood was collected from 38 PLWH on antiretroviral therapy and 24 age-matched HIV-negative controls, pre-vaccination and after 1st/2nd/3rd dose of SARS-CoV-2 vaccines, without prior SARS-CoV-2 infection. Flow cytometry was used to assess ex vivo T-cell immunophenotypes and intracellular Tumor necrosis factor (TNF)-α/interferon(IFN)-γ/interleukin(IL)-2 following SARS-CoV-2-Spike-peptide stimulation. Comparisons were made using Wilcoxon signed-rank test for paired variables and Mann–Whitney for unpaired. In PLWH, Spike-specific CD4 T-cell frequencies plateaued post-2nd dose, with no significant differences in polyfunctional SARS-CoV-2-specific T-cell proportions between PLWH and uninfected controls post-3rd dose. PLWH had higher frequencies of TNFα+CD4 T-cells and lower frequencies of IFNγ+CD8 T-cells than seronegative participants post-3rd dose. Regardless of HIV status, an increase in naive, regulatory, and PD1+ T-cell frequencies was observed post-3rd dose. In summary, two doses of SARS-CoV-2 vaccine induced a robust T-cell immune response in PLWH, which was maintained after the 3rd dose, with no significant differences in polyfunctional SARS-CoV-2-specific T-cell proportions between PLWH and uninfected controls post-3rd dose.

Introduction Most existing vaccines require higher or additional doses or adjuvants to provide similar protection for people living with HIV (PLWH) compared with HIV-uninfected individuals. Additional research is necessary to inform COVID-19 vaccine use in PLWH.Methods and analysis This multicentred observational Canadian cohort study will enrol 400 PLWH aged >16 years from Montreal, Ottawa, Toronto and Vancouver. Subpopulations of PLWH of interest will include individuals: (1) >55 years of age; (2) with CD4 counts 2 comorbidities) and (4) ‘stable’ or ‘reference’ PLWH (CD4 T cells >350 cells/mm3, suppressed viral load for >6 months and 1 COVID-19 vaccine will attend five visits: prevaccination; 1 month following the first vaccine dose; and at 3, 6 and 12 months following the second vaccine dose. The primary end point will be the percentage of PLWH with COVID-19-specific antibodies at 6 months following the second vaccine dose. Humoral and cell-mediated immune responses, and the interplay between T cell phenotypes and inflammatory markers, will be described. Regression techniques will be used to compare COVID-19-specific immune responses to determine whether there are differences between the ‘unstable’ PLWH group (CD4

Introduction Exercise and physical activity (PA) are fundamental to the treatment of type 2 diabetes. Current exercise and PA strategies for newly diagnosed individuals with type 2 diabetes are either clinically effective but unsuitable in routine practice (supervised exercise) or suitable in routine practice but clinically ineffective (PA advice). Mobile health (mHealth) technologies, offering biometric data to patients and healthcare professionals, may bridge the gap between supervised exercise and PA advice, enabling patients to engage in regular long-term physically active lifestyles. This feasibility randomised controlled trial (RCT) will evaluate the use of mHealth technology when incorporated into a structured home-based exercise and PA intervention, in those recently diagnosed with type 2 diabetes.Methods and analysis This feasibility multicentre, parallel group RCT will recruit 120 individuals with type 2 diabetes (diagnosis within 5–24 months, aged 40–75 years) in the UK (n=60) and Canada (n=60). Participants will undertake a 6-month structured exercise and PA intervention and be supported by an exercise specialist (active control). The intervention group will receive additional support from a smartwatch and phone app, providing real-time feedback and enabling improved communication between the exercise specialist and participant. Primary outcomes are recruitment rate, adherence to exercise and loss to follow-up. Secondary outcomes include a qualitative process evaluation and piloting of potential clinical outcome measures for a future RCT.Ethics and dissemination The trial was approved in the UK by the South East Scotland Research Ethics Committee 01 (20/SS/0101) and in Canada by the Clinical Research Ethics Board of the University of British Columbia (H20-01936), and is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Results will be published in peer-reviewed journals and presented at national and international scientific meetings.Trial registration numbers ISRCTN14335124; ClinicalTrials.gov: NCT04653532.

Abstract Background The current treatment paradigm for type 2 diabetes mellitus (T2D) typically involves use of multiple medications to lower glucose levels in hope of reducing long-term complications. However, such treatment does not necessarily address the underlying pathophysiology of the disease and very few patients achieve partial, complete, or prolonged remission of T2D after diagnosis. The therapeutic potential of nutrition has been highlighted recently based on results of clinical trials reporting remission of T2D with targeted dietary approaches. During the initial phase of such interventions that restrict carbohydrates and/or induce rapid weight loss, hypoglycemia presents a notable risk to patients. We therefore hypothesized that delivering very low-carbohydrate, low-calorie therapeutic nutrition through community pharmacies would be an innovative strategy to facilitate lowering of glycated hemoglobin (A1C) while safely reducing the use of glucose-lowering medications in T2D. Methods A community-based randomized controlled trial that is pragmatic in nature, following a parallel-group design will be conducted (N = 200). Participants will have an equal chance of being randomized to either a pharmacist-led, therapeutic carbohydrate restricted (Pharm-TCR) diet or guideline-based treatment as usual (TAU). Pharm-TCR involves a 12-week very low carbohydrate, calorie-restricted commercial diet plan led by pharmacists and lifestyle coaches with pharmacists responsible for managing medications in collaboration with the participants’ family physicians. Main inclusion criteria are diagnosis of T2D, currently treated with glucose-lowering medications, age 30–75 years, and body mass index ≥ 30. The primary outcome is a binary measure of use of glucose-lowering medication. Secondary outcomes include A1C, anthropometrics and clinical blood markers. Discussion There are inherent risks involved if patients with T2D who take glucose-lowering medications follow very low carbohydrate diets. This randomized controlled trial aims to determine whether engaging community pharmacists is a safe and effective way to deliver therapeutic carbohydrate restriction and reduce/eliminate the need for glucose-lowering medications in people with T2D. Trial registration ClinicalTrials.gov, NCT03181165. Registered on 8 June 2017.

Abstract Background Master protocols, classified as basket trials, umbrella trials, and platform trials, are novel designs that investigate multiple hypotheses through concurrent sub-studies (e.g., multiple treatments or populations or that allow adding/removing arms during the trial), offering enhanced efficiency and a more ethical approach to trial evaluation. Despite the many advantages of these designs, they are infrequently used. Methods We conducted a landscape analysis of master protocols using a systematic literature search to determine what trials have been conducted and proposed for an overall goal of improving the literacy in this emerging concept. On July 8, 2019, English-language studies were identified from MEDLINE, EMBASE, and CENTRAL databases and hand searches of published reviews and registries. Results We identified 83 master protocols (49 basket, 18 umbrella, and 16 platform trials). The number of master protocols has increased rapidly over the last five years. Most have been conducted in the US (n = 44/83) and investigated experimental drugs (n = 82/83) in the field of oncology (n = 76/83). The majority of basket trials were exploratory (i.e., phase I/II; n = 47/49) and not randomized (n = 44/49), and more than half (n = 28/48) investigated only a single intervention. The median sample size of basket trials was 205 participants (interquartile range, Q3-Q1 [IQR]: 500–90 = 410), and the median study duration was 22.3 (IQR: 74.1–42.9 = 31.1) months. Similar to basket trials, most umbrella trials were exploratory (n = 16/18), but the use of randomization was more common (n = 8/18). The median sample size of umbrella trials was 346 participants (IQR: 565–252 = 313), and the median study duration was 60.9 (IQR: 81.3–46.9 = 34.4) months. The median number of interventions investigated in umbrella trials was 5 (IQR: 6–4 = 2). The majority of platform trials were randomized (n = 15/16), and phase III investigation (n = 7/15; one did not report information on phase) was more common in platform trials with four of them using seamless II/III design. The median sample size was 892 (IQR: 1835–255 = 1580), and the median study duration was 58.9 (IQR: 101.3–36.9 = 64.4) months. Conclusions We anticipate that the number of master protocols will continue to increase at a rapid pace over the upcoming decades. More efforts to improve awareness and training are needed to apply these innovative trial design methods to fields outside of oncology.

Background: With anti-inflammatory properties, cannabinoids may be a potential strategy to reduce immune activation in people living with HIV (PLWH) but more information on their safety and tolerability is needed. Methods: We conducted an open-label interventional pilot study at the McGill University Health Centre in Montreal, Canada. PLWH were randomized to oral Δ9-tetrahydrocannabinol (THC): cannabidiol (CBD) combination (THC 2.5 mg/CBD 2.5 mg) or CBD-only capsules (CBD 200 mg). Individuals titrated doses as tolerated to a maximum daily dose THC 15 mg/CBD 15 mg or 800 mg CBD, respectively, for 12 weeks. The primary outcome was the percentage of participants without any significant toxicity based on the WHO toxicity scale (Grades 0–2 scores). Results: Out of ten individuals, eight completed the study. Two from the CBD-only arm were withdrawn for safety concerns: phlebotomy aggravating pre-existing anemia and severe hepatitis on 800 mg CBD with newly discovered pancreatic adenocarcinoma, respectively. Seven did not have any significant toxicity. Cannabinoids did not alter hematology/biochemistry profiles. CD4 count, CD4/CD8 ratio, and HIV suppression remained stable. Most adverse effects were mild-moderate. Conclusions: In PLWH, cannabinoids seem generally safe and well-tolerated, though larger studies are needed. Screening for occult liver pathology should be performed and hepatic enzymes monitored, especially with high CBD doses.

Introduction Women living with HIV (WLWH) experience accelerated ageing and an increased risk of age-associated diseases earlier in life, compared with women without HIV. This is likely due to a combination of viral factors, gender differences, hormonal imbalance and psychosocial and structural conditions. This interdisciplinary cohort study aims to understand how biological, clinical and sociostructural determinants of health interact to modulate healthy ageing in WLWH.Methods and analysis The British Columbia Children and Women: AntiRetroviral therapy and Markers of Aging-Canadian HIV Women’s Sexual and Reproductive Health Cohort Study (CARMA-CHIWOS) Collaboration (BCC3) study will enrol WLWH (n=350) and sociodemographically matched HIV-negative women (n=350) living in British Columbia. A subset of BCC3 participants will be past participants of CARMA, n≥1000 women and children living with and without HIV, 2008–2018 and/or CHIWOS, n=1422 WLWH, 2013–2018. Over two study visits, we will collect biological specimens for virus serologies, hormones and biological markers as well as administer a survey capturing demographic and sociostructural–behavioural factors. Sociodemographics, comorbidities, number and type of chronic/latent viral infections and hormonal irregularities will be compared between the two groups. Their association with biological markers and psychostructural and sociostructural factors will be investigated through multivariable regression and structural equation modelling. Retrospective longitudinal analyses will be conducted on data from past CARMA/CHIWOS participants. As BCC3 aims to follow participants as they age, this protocol will focus on the first study visits.Ethics and dissemination This study has been approved by the University of British Columbia Children’s and Women’s Research Ethics Board (H19-00896). Results will be shared in peer-reviewed journals, conferences and at community events as well as at www.hivhearme.ca and @HIV_HEAR_me. WLWH are involved in study design, survey creation, participant recruitment, data collection and knowledge translation. A Community Advisory Board will advise the research team throughout the study.

Summary: Background: The synchronised monthly disbursement of income assistance, whereby all recipients are paid on the same day, has been associated with increases in illicit drug use and serious associated harms. This phenomenon is often referred to as the cheque effect. Because payment variability can affect consumption patterns, this study aimed to assess whether these harms could be mitigated through a structural intervention that varied income assistance payment timing and frequency. Methods: This randomised, parallel group trial was done in Vancouver, Canada, and enrolled recipients of income assistance whose drug use increased around payment days. The recipients were randomly assigned 1:2:2 to a control group that received monthly synchronised income assistance payments on government payment days, a staggered group in which participants received single desynchronised monthly income assistance payments, or a split and staggered group in which participants received desynchronised income assistance payments split into two instalments per month, 2 weeks apart, for six monthly payment cycles. Desynchronised payments in the intervention groups were made on individual payment days outside the week of the standard government schedules. Randomisation was through a pre-established stratified block procedure. Investigators and statisticians were masked to group allocation, but participants and front-line staff were not. Complete final results are reported after scheduled interim analyses and the resulting early stoppage of recruitment. Under intention-to-treat specifications, generalised linear mixed models were used to analyse the primary outcome, which was escalations in drug use, predefined as a 40% increase in at least one of: use frequency; use quantity; or number of substances used during the 3 days after government payments. Secondary analyses examined analogous drug use outcomes coinciding with individual payments as well as exposure to violence. This trial is registered with ClinicalTrials.gov, NCT02457949. Findings: Between Oct 27, 2015, and Jan 2, 2019, 45 participants were enrolled to the control group, 72 to the staggered group, and 77 to the split and staggered group. Intention-to-treat analyses showed a significantly reduced likelihood of increased drug use coinciding with government payment days, relative to the control group, in the staggered (adjusted odds ratio 0·38, 95% CI 0·20–0·74; p=0·0044) and split and staggered (0·44, 0·23–0·83; p=0·012) groups. Findings were consistent in the secondary analyses of drug use coinciding with individual payment days (staggered group 0·50, 0·27–0·96, p=0·036; split and staggered group 0·49, 0·26–0·94, p=0·030). However, secondary outcome analyses of exposure to violence showed increased harm in the staggered group compared with the control group (2·71, 1·06–6·91, p=0·037). Additionally, 51 individuals had a severe or life-threatening adverse event and there were six deaths, none of which was directly attributed to study participation. Interpretation: Complex results indicate the potential for modified income assistance payment schedules to mitigate escalations in drug use, provided measures to address unintended harms are also undertaken. Additional research is needed to clarify whether desynchronised schedules produce other unanticipated consequences and if additional measures could mitigate these harms. Funding: Canadian Institutes of Health Research, Providence Health Care Research Institute, Peter Wall Institute for Advanced Research, Michael Smith Foundation for Health Research.

ObjectiveTo develop a whole-joint, unidimensional, irreversible, and fine-grained MRI knee osteoarthritis (OA) severity score, based on cartilage, osteophytes and meniscus (OA-COM), and to predict progression across different severity states using OA-COM as outcome and clinical variables as predictors.MethodsPopulation-based knee pain cohort aged 40-79 was assessed at baseline and 7-year follow-up. OA-COM score was defined as the sum of MRI scores for cartilage, osteophytes and menisci, measured at 6, 8 and 6 sites, total score 0-54. To anchor severity levels, we fit cross-sectional logistic models using OA-COM to predict Kellgren-Lawrence (KL) grades in subsets at or one point below each grade. OA-COM threshold scores were selected on sensitivity, specificity, positive and negative predictive value. We developed longitudinal logistic models for OA-COM progression over each threshold over 7 years. Potential predictors included age, sex, BMI, malalignment, physical exam effusion, quadriceps weakness, and crepitus, selected on area under the receiver operating characteristic curve (AUC) and Akaike's Information Criterion (AIC).ResultsOptimal OA-COM thresholds were 12, 18, 24 and 30, for KL grades 1 to 4. Significant predictors of progression (depending on threshold) included physical exam effusion, malalignment and female sex, with other selected predictors age, BMI and crepitus.ConclusionOA-COM (0-54 range) is a whole-joint, unidimensional, irreversible, and fine-grained MRI OA severity score reflecting cartilage, osteophytes and menisci. OA-COM scores 12, 18, 24 and 30 are equivalent to KL grades 1 to 4, while offering fine-grained differentiation of states between KL grades, and within pre-radiographic disease (KL = 0) or late-stage disease (KL = 4). In modeling, several clinical variables predicted progression across different states over 7 years.

Introduction The COVID-19 epidemic grows and there are clinical trials of antivirals. There is an opportunity to complement these trials with investigation of angiotensin II type 1 receptor blockers (ARBs) because an ARB (losartan) was effective in murine influenza pneumonia.Methods and analysis Our innovative design includes: ARBs; alignment with the WHO Ordinal Scale (primary endpoint) to align with other COVID-19 trials; joint longitudinal analysis; and predictive biomarkers (angiotensins I, 1–7, II and ACE1 and ACE2). Our hypothesis is: ARBs decrease the need for hospitalisation, severity (need for ventilation, vasopressors, extracorporeal membrane oxygenation or renal replacement therapy) or mortality of hospitalised COVID-19 infected adults. Our two-pronged multicentre pragmatic observational cohort study examines safety and effectiveness of ARBs in (1) hospitalised adult patients with COVID-19 and (2) out-patients already on or not on ARBs. The primary outcome will be evaluated by ordinal logistic regression and main secondary outcomes by both joint longitudinal modelling analyses. We will compare rates of hospitalisation of ARB-exposed versus not ARB-exposed patients. We will also determine whether continuing ARBs or not decreases the primary outcome. Based on published COVID-19 cohorts, assuming 15% of patients are ARB-exposed, a total sample size of 497 patients can detect a proportional OR of 0.5 (alpha=0.05, 80% power) comparing WHO scale of ARB-exposed versus non-ARB-exposed patients.Ethics and dissemination This study has core institution approval (UBC Providence Healthcare Research Ethics Board) and site institution approvals (Health Research Ethics Board, University of Alberta; Comite d’etique de la recerche, CHU Sainte Justine (for McGill University and University of Sherbrook); Conjoint Health Research Ethics Board, University of Calgary; Queen’s University Health Sciences & Affiliated Hospitals Research Ethics Board; Research Ethics Board, Sunnybrook Health Sciences Centre; Veritas Independent Research Board (for Humber River Hospital); Mount Sinai Hospital Research Ethics Board; Unity Health Toronto Research Ethics Board, St. Michael’s Hospital). Results will be disseminated by peer-review publication and social media releases.Trial registration number NCT04510623

Purpose of program: Traditionally, peer review was a closed process conducted only by individuals working in the research field. To establish a more integrated and patient-centered approach, one of Canada’s largest kidney research networks (Can-SOLVE CKD) has created a Research Operations Committee (ROC) that includes patients as key members. The ROC represents one way for achieving meaningful patient-oriented research (POR). Source of information: Can-SOLVE CKD, a network created as part of the Canadian Institutes of Health Research (CIHR) Strategy for Patient-Oriented Research (SPOR). Methods: The ROC consists of patients, physicians, scientists, Indigenous partners, experts in research methodology, and a member of Can-SOLVE CKD’s operational team. On an annual basis, Can-SOLVE CKD’s research teams provide the ROC with a review package, which incorporates information from patient engagement check-in calls and surveys, the project’s knowledge translation plan and products, and a progress report written by the project team. The ROC evaluates the review package and provides feedback and recommendations accordingly. Key findings: The transparent nature of the process, regular feedback and review, along with an overt accountability and scoring system, has been embraced by both patients and researchers. As a result of the ROC process, the number of patient leads for each project has grown over a 3-year period and more researchers have received POR and cultural sensitivity training. Limitations: While anecdotal evidence suggests this approach is beneficial for achieving POR, formal mechanisms of evaluation are currently lacking. Implications: This ROC framework ensures patients are active contributors throughout the research process and could be adopted by other organizations to achieve a more patient-centered approach to research.

Background: Optimizing linear growth in children during complementary feeding period (CFP) (6-24 months) is critical for their development. Several interventions, such as micronutrient and food supplements, deworming, maternal education, and water, sanitation and hygiene (WASH), could potentially be provided to prevent stunting, but their comparative effectiveness are currently unclear. In this study, we evaluated comparative effectiveness of interventions under these domains on child linear growth outcomes of height-for-age z-score (HAZ) and stunting (HAZ

BackgroundST-segment elevation myocardial infarction (STEMI) outcomes are influenced by the location of the culprit vessel with worse outcomes portended with a left anterior descending (LAD) culprit lesion. However, relatively little is known about the independent association of LAD involvement with clinical outcomes of patients with STEMI with and without out-of-hospital cardiac arrest (OHCA).MethodsWe identified 91 patients with and 929 without a preceding OHCA within the Vancouver Coastal Health Authority who presented with an acute STEMI and underwent primary percutaneous coronary intervention between 26 June 2007 and 31 March 2016.ResultsPatients with STEMI with OHCA had higher rates of in-hospital cardiac arrest (43.3% vs 8.3%, p

Objectives To determine if a Canadian voice center is meeting the recommended time to laryngoscopy for hoarseness per the clinical practice guideline of the American Academy of Otolaryngology–Head and Neck Surgery. Study Design Retrospective chart audit. Setting Tertiary referral Canadian voice center. Participants and Methods A total of 149 adult patients presenting with hoarseness over 6 months were included. Primary outcome measures were the time from onset of symptoms to laryngoscopy and the time from referral to laryngoscopy. Secondary outcome measures included patient- and disease-modifying factors, diagnosis, and clinical management. Analysis was performed to determine what factors were associated with meeting the guideline. Results Patients were evaluated by the laryngologist after 21.9 ± 37.6 months (mean ± SD) of symptoms. One-third (34.2%) of patients were seen within 3 months; 10.7% were seen within 4 weeks. Logistic regression showed that patients with neurologic symptoms (odds ratio, 4.04; 95% CI, 1.31-12.43; P = .015) and endotracheal intubation (odds ratio, 5.94; 95% CI, 2.21-15.95; P < .001) were associated with being seen within 3 months. Patients who had recent intubation (odds ratio, 6.04; 95% CI, 1.99-18.34; P = .002) were associated with being seen within 4 weeks. Conclusion It is an ongoing challenge for our Canadian voice center to meet the American Academy of Otolaryngology–Head and Neck Surgery’s clinical practice guideline for recommended time to laryngoscopy. Patients with more severe pathologies were consistently triaged more urgently. It is debatable whether this 4-week time recommendation is generalizable to a socialized health care system.

Abstract Background Cartilage changes are an important early finding of osteoarthritis (OA), which can exist even before symptoms. Our objective was to determine the prevalence of knee cartilage damage on magnetic resonance imaging (MRI) in an asymptomatic population-based cross-sectional study and to evaluate the association of body mass index (BMI) with cartilage damage. Methods Subjects, aged 40-79 years, without knee pain (n = 73) were recruited as a random population sample and assessed for BMI (kg/m2), including current BMI (measured), past BMI at age 25 (self-reported) and change in BMI. Knee cartilage was scored semi-quantitatively (grades 0-4) on MRI. In primary analysis, cartilage damage was defined as ≥2 (at least moderate) and in a secondary analysis as ≥3 (severe). We also conducted a sensitivity analysis by dichotomizing current BMI as