Evidence-Based Medicine: Acknowledging the Role for Physical Activity

Modern technology and lifestyles have created an environment that predisposes our population to inactivity, resulting in fewer people meeting the Canadian Physical Activity Guidelines. There is a clear link between inactivity and the risk of developing chronic health conditions including hypertension, type 2 diabetes, and cancer; however, exercise prescription and counselling by physicians is lacking. This may in part be attributed to inadequate training of physicians during medical school. In this commentary, we outline the demand for awareness and training of physicians to prepare them to prescribe physical activity, and propose steps to increase exercise prescrip­tion for improved population health.   La technologie moderne ainsi que nos habitudes de vie actuelles nous prédisposent à l’inactivité ce qui mène moins de personnes à respecter les directives canadiennes en matière d’activité physique. Un lien direct existe entre l’inactivité et le risque de développer des problèmes de santé chroniques incluant l’hypertension, le diabète de type 2, et le cancer. Toutefois, l’exercice et le counseling pre­scrits par les médecins sont peu pratiqués par les patients qui pourraient en bénéficier. Dans cet article, nous soulignerons le besoin de formation des médecins afin de mieux les préparer à prescrire de l’activité physique à leur patients et leur proposer des étapes pour améliorer la santé physique de la population

Use of tocilizumab and sarilumab alone or in combination with corticosteroids for covid-19: systematic review and network meta-analysis

Objective: To compare the effects of interleukin 6 receptor blockers, tocilizumab and sarilumab, with or without corticosteroids, on mortality in patients with covid-19. Design: Systematic review and network meta-analysis. Data sources: World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature, and two prospective meta-analyses (up to 9 June 2021). Review methods: Trials in which people with suspected, probable, or confirmed covid-19 were randomised to interleukin 6 receptor blockers (with or without corticosteroids), corticosteroids, placebo, or standard care. The analysis used a bayesian framework and assessed the certainty of evidence using the GRADE approach. Results from the fixed effect meta-analysis were used for the primary analysis. Results: Of 45 eligible trials (20 650 patients) identified, 36 (19 350 patients) could be included in the network meta-analysis. Of 36 trials, 27 were at high risk of bias, primarily due to lack of blinding. Tocilizumab, in combination with corticosteroids, suggested a reduction in the risk of death compared with corticosteroids alone (odds ratio 0.79, 95% credible interval 0.70 to 0.88; 35 fewer deaths per 1000 people, 95% credible interval 52 fewer to 18 fewer per 1000; moderate certainty of evidence), as did sarilumab in combination with corticosteroids, compared with corticosteroids alone (0.73, 0.58 to 0.92; 43 fewer per 1000, 73 fewer to 12 fewer; low certainty). Tocilizumab and sarilumab, each in combination with corticosteroids, appeared to have similar effects on mortality when compared with each other (1.07, 0.86 to 1.34; eight more per 1000, 20 fewer to 35 more; low certainty). The effects of tocilizumab (1.12, 0.91 to 1.38; 20 more per 1000, 16 fewer to 59 more; low certainty) and sarilumab (1.07, 0.81 to 1.40; 11 more per 1000, 38 fewer to 55 more; low certainty), when used alone, suggested an increase in the risk of death. Conclusion: These findings suggest that in patients with severe or critical covid-19, tocilizumab, in combination with corticosteroids, probably reduces mortality, and that sarilumab, in combination with corticosteroids, might also reduce mortality. Tocilizumab and sarilumab, in combination with corticosteroids, could have similar effectiveness. Tocilizumab and sarilumab, when used alone, might not be beneficial.This project is supported by two Canadian Institutes of Health Research grants (VR4-172738; MM1-174897). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.publishedVersio

Impact of Value Frameworks on the Magnitude of Clinical Benefit: Evaluating a Decade of Randomized Trials for Systemic Therapy in Solid Malignancies

In the era of rapid development of new, expensive cancer therapies, value frameworks have been developed to quantify clinical benefit (CB). We assessed the evolution of CB since the 2015 introduction of The American Society of Clinical Oncology and The European Society of Medical Oncology value frameworks. Randomized clinical trials (RCTs) assessing systemic therapies for solid malignancies from 2010 to 2020 were evaluated and CB (Δ) in 2010–2014 (pre-value frameworks (PRE)) were compared to 2015–2020 (POST) for overall survival (OS), progression-free survival (PFS), response rate (RR), and quality of life (QoL). In the 485 studies analyzed (12% PRE and 88% POST), the most common primary endpoint was PFS (49%), followed by OS (20%), RR (12%), and QoL (6%), with a significant increase in OS and decrease in RR as primary endpoints in the POST era (p = 0.011). Multivariable analyses revealed significant improvement in ΔOS POST (OR 2.86, 95% CI 0.46 to 5.26, p = 0.02) while controlling for other variables. After the development of value frameworks, median ΔOS improved minimally. The impact of value frameworks has yet to be fully realized in RCTs. Efforts to include endpoints shown to impact value, such as QoL, into clinical trials are warranted

The Utility of Penile Bulb Contouring to Localise the Prostate Apex as Compared to Urethrography

Purpose: High-precision radiotherapy relies on accurate anatomic localisation. Urethrography is often used to localise the prostatic apex. However, urethrography is an invasive localisation procedure and may introduce a systemic error. The penile bulb (PB) is contoured to minimise the risk of erectile dysfunction. The purpose of this study is to assess the value of using the PB, as an alternative to urethrography, to localise the prostate. Methods and Materials: The PB was localised on 10 patients treated with simplified intensity-modulated arc radiotherapy at computed tomography simulation during treatment weeks 1 and 7. All patients underwent placement of fiducial markers. Urethrography was used only at simulation. Distances from the superior PB contour to the inferior prostate contour, the apex fiducial marker, and to the inferior prostate contour were obtained as well. The PB was contoured by two observers independently. Agreement coefficients and analysis of variance were used to assess reliability between rates and consistency of measurements over time. Results: The PB-apex distance was greater than or equal to the urethrogram-apex distance in 24/30 (80%) measurements, and the median difference was 3 mm and was consistent between raters. The greatest variation in PB-IM distance between weeks was 6 mm, the median was 3 mm, and the agreements of measurements between weeks for raters 1 and 2 were 0.79 and 0.69, respectively. These differences were not statistically different and were consistent with the computed tomography slice thickness. Conclusions: The PB can be used to identify the prostate apex and can be reliably contoured between observers. Measurements are consistent between patients and through the duration of treatment. The PB distance measurements support studies indicating that urethrography causes a shift of the prostate superiorly. The distance from the PB to prostate apex remains stable during treatment for individual patients but varies between patients

Immediate-term cognitive impairment following intravenous (IV) chemotherapy: a prospective pre-post design study

Abstract Background Cognitive impairment is commonly reported in patients receiving chemotherapy, but the acuity of onset is not known. This study utilized the psychomotor vigilance test (PVT) and trail-making test B (TMT-B) to assess cognitive impairment immediately post-chemotherapy. Methods Patients aged 18–80 years receiving first-line intravenous chemotherapy for any stage of breast or colorectal cancer were eligible. Patient symptoms, peripheral neuropathy and Stanford Sleepiness Scale were assessed. A five-minute PVT and TMT-B were completed on a tablet computer pre-chemotherapy and immediately post-chemotherapy. Using a mixed linear regression model, changes in reciprocal transformed PVT reaction time (mean 1/RT) were assessed. A priori, an increase in median PVT reaction times by > 20 ms (approximating PVT changes with blood alcohol concentrations of 0.04–0.05 g%) was considered clinically relevant. Results One hundred forty-two cancer patients (73 breast, 69 colorectal, median age 55.5 years) were tested. Post-chemotherapy, mean 1/RT values were significantly slowed compared to pre-chemotherapy baseline (p = 0.01). This corresponded to a median PVT reaction time slowed by an average of 12.4 ms. Changes in PVT reaction times were not correlated with age, sex, cancer type, treatment setting, or use of supportive medications. Median post-chemotherapy PVT reaction time slowed by an average of 22.5 ms in breast cancer patients and by 1.6 ms in colorectal cancer patients. Post-chemotherapy median PVT times slowed by > 20 ms in 57 patients (40.1%). Exploratory analyses found no statistically significant association between the primary outcome and self-reported anxiety, fatigue or depression. TMT-B completion speed improved significantly post-chemotherapy (p = 0.03), likely due to test-retest phenomenon. Conclusions PVT reaction time slowed significantly immediately post-chemotherapy compared to a pre-chemotherapy baseline, and levels of impairment similar to effects of alcohol consumption in other studies was seen in 40% of patients. Further studies assessing functional impact of cognitive impairment on patients immediately after chemotherapy are warranted

Identification of outcomes in clinical studies of interventions for venous thromboembolism in non-pregnant adults: A scoping review.

INTRODUCTION The development of a core outcome set (COS), defined as an agreed minimum set of outcome domains that should be measured and reported in all trials of a specific disease, aims to increase the relevance of study findings to stakeholder groups and improve standardization. OBJECTIVES As the first step in developing a COS for venous thromboembolism (VTE) treatment studies, we aimed to generate an inclusive list of unique outcomes reported in previous VTE treatment studies and classify them into domains and core areas. METHODS MEDLINE, Embase and CENTRAL were searched for prospective studies reporting on interventions for VTE in non-pregnant adults. Study selection and data extraction were performed in blocks based on publication date, starting with 2015-2020 and subsequent 1-year periods, until no new outcome was identified. Outcomes were classified into domains, which are groups of closely related outcomes, and domains into four core areas including death, pathophysiological manifestations/abnormalities, life impact, and resource use. RESULTS Of 7100 records identified, we included 240 publications, representing 165 distinct studies. We identified 205 unique outcomes that were grouped into 48 domains. A total of 30 (13%) studies covered ≥3 core areas; death was included in 102 (43%), pathophysiological manifestations/abnormalities in 218 (91%), life impact in 41 (17%), and resource use in 25 (10%) studies. CONCLUSION Most VTE treatment studies evaluated pathophysiological features of VTE, but few studies reported outcomes that measured life impact or resource use. Our findings will inform next steps in the development of a COS for VTE treatment studies

Antibody and cellular therapies for treatment of covid-19 : a living systematic review and network meta-analysis

OBJECTIVE To evaluate the efficacy and safety of antiviral antibody therapies and blood products for the treatment of novel coronavirus disease 2019 (covid-19). DESIGN Living systematic review and network meta-analysis, with pairwise meta-analysis for outcomes with insufficient data. DATA SOURCES WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, and six Chinese databases (up to 21 July 2021). STUDY SELECTION Trials randomising people with suspected, probable, or confirmed covid-19 to antiviral antibody therapies, blood products, or standard care or placebo. Paired reviewers determined eligibility of trials independently and in duplicate. METHODS After duplicate data abstraction, we performed random effects bayesian meta-analysis, including network meta-analysis for outcomes with sufficient data. We assessed risk of bias using a modification of the Cochrane risk of bias 2.0 tool. The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We meta-analysed interventions with ≥100 patients randomised or ≥20 events per treatment arm. RESULTS As of 21 July 2021, we identified 47 trials evaluating convalescent plasma (21 trials), intravenous immunoglobulin (IVIg) (5 trials), umbilical cord mesenchymal stem cells (5 trials), bamlanivimab (4 trials), casirivimab-imdevimab (4 trials), bamlanivimab-etesevimab (2 trials), control plasma (2 trials), peripheral blood non-haematopoietic enriched stem cells (2 trials), sotrovimab (1 trial), anti-SARS-CoV-2 IVIg (1 trial), therapeutic plasma exchange (1 trial), XAV-19 polyclonal antibody (1 trial), CT-P59 monoclonal antibody (1 trial) and INM005 polyclonal antibody (1 trial) for the treatment of covid-19. Patients with non-severe disease randomised to antiviral monoclonal antibodies had lower risk of hospitalisation than those who received placebo: casirivimab-imdevimab (odds ratio (OR) 0.29 (95% CI 0.17 to 0.47); risk difference (RD) −4.2%; moderate certainty), bamlanivimab (OR 0.24 (0.06 to 0.86); RD −4.1%; low certainty), bamlanivimab-etesevimab (OR 0.31 (0.11 to 0.81); RD −3.8%; low certainty), and sotrovimab (OR 0.17 (0.04 to 0.57); RD −4.8%; low certainty). They did not have an important impact on any other outcome. There was no notable difference between monoclonal antibodies. No other intervention had any meaningful effect on any outcome in patients with non-severe covid-19. No intervention, including antiviral antibodies, had an important impact on any outcome in patients with severe or critical covid-19, except casirivimab-imdevimab, which may reduce mortality in patients who are seronegative. CONCLUSION In patients with non-severe covid-19, casirivimab-imdevimab probably reduces hospitalisation; bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalisation. Convalescent plasma, IVIg, and other antibody and cellular interventions may not confer any meaningful benefit. SYSTEMATIC REVIEW REGISTRATION This review was not registered. The protocol established a priori is included as a data supplement. FUNDING This study was supported by the Canadian Institutes of Health Research (grant CIHR- IRSC:0579001321). READERS’ NOTE This article is a living systematic review that will be updated to reflect emerging evidence. Interim updates and additional study data will be posted on our website (www.covid19lnma.com).Medicine, Faculty ofNon UBCPediatrics, Department ofReviewedFacultyResearcherPostdoctoralGraduateOthe