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Background Laboratory tests and transfusions are sometimes ordered inappropriately, particularly in the critical care setting, which sees frequent use of both. Audit and Feedback (A&F) is a potentially useful intervention for modifying healthcare provider behaviors, but its application to the complex, team-based environment of critical care is not well understood. We conducted a systematic review of the literature on A&F interventions for improving test or transfusion ordering in the critical care setting. Methods Five databases, two registries, and the bibliographies of relevant articles were searched. We included critical care studies that assessed the use of A&F targeting healthcare provider behaviors, alone or in combination with other interventions to improve test and transfusion ordering, as compared to historical practice, no intervention, or another healthcare behaviour change intervention. Studies were included only if they reported laboratory test or transfusion orders, or the appropriateness of orders, as outcomes. There were no restrictions based on study design, date of publication, or follow-up time. Intervention characteristics and absolute differences in outcomes were summarized. The quality of individual studies was assessed using a modified version of the Effective Practice and Organisation of Care Cochrane Review Group’s criteria. Results We identified 16 studies, including 13 uncontrolled before-after studies, one randomized controlled trial, one controlled before-after study, and one controlled clinical trial (quasi-experimental). These studies described 17 interventions, mostly (88%) multifaceted interventions with an A&F component. Feedback was most often provided in a written format only (41%), more than once (53%), and most often only provided data aggregated to the group-level (41%). Most studies saw a change in the hypothesized direction, but not all studies provided statistical analyses to formally test improvement. Overall study quality was low, with studies often lacking a concurrent control group. Conclusions Our review summarizes characteristics of A&F interventions implemented in the critical care context, points to some mechanisms by which A&F might be made more effective in this setting, and provides an overview of how the appropriateness of orders was reported. Our findings suggest that A&F can be effective in the context of critical care; however, further research is required to characterize approaches that optimize the effectiveness in this setting alongside more rigorous evaluation methods. Trial registration PROSPERO CRD42016051941.

PROBLEM IDENTIFICATION. Hot flashes (HF) are common and bothersome in breast and prostate cancer and can adversely impact patients’ quality of life. The best approach to manage them is unclear. We sought to perform network meta-analyses (NMA) of the available evidence to compare interventions previously studied in the literature. LITERATURE SEARCH. A librarian searched Medline, Embase, and additional databases for randomized controlled trials (RCTs) evaluating the effects of one or more interventions for hot flashes in patients with a history of breast or prostate cancer. DATA EVALUATION. Outcomes of interest included changes in HF severity, HF frequency, quality of life, and harms. Two reviewers were involved in the phases of study selection, data collection and risk of bias appraisal. Pairwise meta-analyses and NMAs were performed where feasible, with narrative synthesis used where required. SYNTHESIS. 40 RCTs studying drugs, psychological interventions, natural health products and exercise were included. Most interventions were assessed in only one trial, typically versus inactive control. The outcomes of interest were not consistently available from the included studies, and NMAs were feasible for HF frequency and HF score. Findings from NMA for HF frequency suggested several therapies may offer benefits compared to no treatment, though little data suggested differences between active therapies. Findings from NMA for HF score were similar. For remaining outcomes including HF severity, QoL measures and harms, studies were summarized narratively due to limited availability of data. Limited evidence of clear benefits was found for the therapies assessed. IMPLICATIONS FOR RESEARCH. While many interventions may offer improvements for HFs versus no treatment, few data suggest important differences between therapies. Future research is needed to enrich available evidence for decision-making. REVIEW REGISTRATION #: CRD42015024286

Background Network meta-analysis (NMA) has rapidly grown in use during the past decade for the comparison of healthcare interventions. While its general use in the comparison of conventional medicines has been studied previously, to our awareness, its use to assess complementary and alternative medicines (CAM) has not been studied. A scoping review of the literature was performed to identify systematic reviews incorporating NMAs involving one or more CAM interventions. Methods An information specialist executed a multi-database search (e.g., MEDLINE, Embase, Cochrane), and two reviewers performed study selection and data collection. Information on publication characteristics, diseases studied, interventions compared, reporting transparency, outcomes assessed, and other parameters were extracted from each review. Results A total of 89 SR/NMAs were included. The largest number of NMAs was conducted in China (39.3%), followed by the United Kingdom (12.4%) and the United States (9.0%). Reviews were published between 2010 and 2018, with the majority published between 2015 and 2018. More than 90 different CAM therapies appeared at least once, and the median number per NMA was 2 (IQR 1–4); 20.2% of reviews consisted of only CAM therapies. Dietary supplements (51.1%) and vitamins and minerals (42.2%) were the most commonly studied therapies, followed by electrical stimulation (31.1%), herbal medicines (24.4%), and acupuncture and related treatments (22.2%). A diverse set of conditions was identified, the most common being various forms of cancer (11.1%), osteoarthritis of the hip/knee (7.8%), and depression (5.9%). Most reviews adequately addressed a majority of the PRISMA NMA extension items; however, there were limitations in indication of an existing review protocol, exploration of network geometry, and exploration of risk of bias across studies, such as publication bias. Conclusion The use of NMA to assess the effectiveness of CAM interventions is growing rapidly. Efforts to identify priority topics for future CAM-related NMAs and to enhance methods for CAM comparisons with conventional medicine are needed. Systematic review registration https://ruor.uottawa.ca/handle/10393/35658

Regenerative stem cell-based therapies for bronchopulmonary dysplasia (BPD), the most common preterm birth complication, demonstrate promise in animals. Failure to objectively appraise available preclinical data and identify knowledge gaps could jeopardize clinical translation. We performed a systematic review and network meta-analysis (NMA) of preclinical studies testing cell-based therapies in experimental neonatal lung injury. Fifty-three studies assessing 15 different cell-based therapies were identified: 35 studied the effects of mesenchymal stromal cells (MSCs) almost exclusively in hyperoxic rodent models of BPD. Exploratory NMAs, for select outcomes, suggest that MSCs are the most effective therapy. Although a broad range of promising cell-based therapies has been assessed, few head-to-head comparisons and unclear risk of bias exists. Successful clinical translation of cell-based therapies demands robust preclinical experimental design with appropriately blinded, randomized, and statistically powered studies, based on biological plausibility for a given cell product, in standardized models and endpoints with transparent reporting. Significance statement Bronchopulmonary dysplasia (BPD), a chronic lung disease that follows ventilator and oxygen therapy for acute respiratory failure after premature birth, is the most frequent complication of extreme prematurity. BPD is associated with long-term respiratory and neurological consequences reaching into adulthood and currently lacks effective therapy. Regenerative cell-based therapy, demonstrating therapeutic benefit in experimental neonatal lung injury, has now spawned clinical trials. Yet there has been no systematic review to assess the extent of current evidence regarding safety and efficacy of cell-based therapies in preclinical BPD and identify gaps that could jeopardize successful clinical translation.

Trastuzumab-based chemotherapy is usually administered through either a peripherally inserted central catheter (PICC) or a totally implanted vascular access device (PORT). As the most effective type of access is unknown, a feasibility trial, prior to conducting a large pragmatic trial, was undertaken. The trial methodology utilized the integrated consent model incorporating oral consent. Patients receiving trastuzumab-based neo/adjuvant chemotherapy for early-stage breast cancer were randomized to a PICC or PORT insertion. Feasibility was reflected through a combination of endpoints; however, the a priori definition of feasibility was > 25% of patients approached agreed to randomization and > 25% of physicians approached patients. Secondary outcomes included rates of line-associated complications such as thrombotic events requiring anticoagulation, line infections or phlebitis. During the study period, 4/15 (26.7%) medical oncologists approached patients about study participation. Of 59 patients approached, 56 (94.9%) agreed to randomization, 29 (51.8%) were randomized to PICC and 27 (48.2%) to PORT access. Overall, 17.2% (5/29) and 14.8% (4/27) of patients had at least one line-associated complication in the PICC and PORT arms respectively. The study was terminated early due to slow accrual. The study met its feasibility endpoints with respect to patient and physician engagement. However, the slow rate of accrual (56 patients in 2 years) means that conducting a large pragmatic trial would require additional strategies to make such a study possible. ClinicalTrials.gov Identifier: NCT02632435

BackgroundThere has been increased interest in the role of cannabis for treating medical conditions. The availability of different cannabis-based products can make the side effects of exposure unpredictable. We sought to conduct a scoping review of systematic reviews assessing benefits and harms of cannabis-based medicines for any condition.MethodsA protocol was followed throughout the conduct of this scoping review. A protocol-guided scoping review conduct. Searches of bibliographic databases (e.g., MEDLINE®, Embase, PsycINFO, the Cochrane Library) and gray literature were performed. Two people selected and charted data from systematic reviews. Categorizations emerged during data synthesis. The reporting of results from systematic reviews was performed at a high level appropriate for a scoping review.ResultsAfter screening 1975 citations, 72 systematic reviews were included. The reviews covered many conditions, the most common being pain management. Several reviews focused on management of pain as a symptom of conditions such as multiple sclerosis (MS), injury, and cancer. After pain, the most common symptoms treated were spasticity in MS, movement disturbances, nausea/vomiting, and mental health symptoms. An assessment of review findings lends to the understanding that, although in a small number of reviews results showed a benefit for reducing pain, the analysis approach and reporting in other reviews was sub-optimal, making it difficult to know how consistent findings are when considering pain in general. Adverse effects were reported in most reviews comparing cannabis with placebo (49/59, 83%) and in 20/24 (83%) of the reviews comparing cannabis to active drugs. Minor adverse effects (e.g., drowsiness, dizziness) were common and reported in over half of the reviews. Serious harms were not as common, but were reported in 21/59 (36%) reviews that reported on adverse effects. Overall, safety data was generally reported study-by-study, with few reviews synthesizing data. Only one review was rated as high quality, while the remaining were rated of moderate (n= 36) or low/critically low (n= 35) quality.ConclusionsResults from the included reviews were mixed, with most reporting an inability to draw conclusions due to inconsistent findings and a lack of rigorous evidence. Mild harms were frequently reported, and it is possible the harms of cannabis-based medicines may outweigh benefits.Systematic review registrationThe protocol for this scoping review was posted in the Open Access (https://ruor.uottawa.ca/handle/10393/37247).

There may be the potential to improve stroke recovery with mesenchymal stem cells (MSCs); however, questions about the efficacy and safety of this treatment remain. To address these issues and inform future studies, we performed a preclinical and clinical systematic review of MSC therapy for subacute and chronic ischemic stroke. MEDLINE, Embase, the Cochrane Register of Controlled Trials, and PubMed were searched. For the clinical review, interventional and observational studies of MSC therapy in ischemic stroke patients were included. For the preclinical review, interventional studies of MSC therapy using in vivo animal models of subacute or chronic stroke were included. Measures of safety and efficacy were assessed. Eleven clinical and 76 preclinical studies were included. Preclinically, MSC therapy was associated with significant benefits for multiple measures of motor and neurological function. Clinically, MSC therapy appeared to be safe, with no increase in adverse events reported (with the exception of self-limited fever immediately following injection). However, the efficacy of treatment was less apparent, with significant heterogeneity in both study design and effect size being observed. Additionally, in the only randomized phase II study to date, efficacy of MSC therapy was not observed. Preclinically, MSC therapy demonstrated considerable efficacy. Although MSC therapy demonstrated safety in the clinical setting, efficacy has yet to be determined. Future studies will need to address the discordance in the continuity of evidence as MSC therapy has been translated from "bench-to-bedside".

Background The optimal duration of anticoagulation after a first unprovoked venous thromboembolism (VTE) remains controversial. Deciding to stop or continue anticoagulant therapy indefinitely after completing 3 to 6 months of initial treatment requires balancing the long-term risk of recurrent VTE if anticoagulation is stopped against the long-term risk of major bleeding if anticoagulation is continued. However, knowledge of the long-term risk for major bleeding events during extended anticoagulation in this patient population is limited. We plan to conduct a systematic review and meta-analysis to quantify the risk for major bleeding events during extended oral anticoagulation in patients with first unprovoked VTE. Methods Electronic databases including MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials will be systematically searched with the assistance of an information specialist (from inception to March 1, 2019) to identify randomized controlled trials and prospective cohort studies reporting major bleeding during extended oral anticoagulation in patients with first unprovoked VTE, who have completed at least 3 months of initial anticoagulant therapy. Study selection, risk of bias assessment, and data extraction will be performed independently by at least two investigators. The number of major bleeding events and person-years of follow-up will be used to calculate the rate (events per 100 person-years) with its 95% confidence interval for each study cohort, during clinically relevant time periods of extended anticoagulant therapy. Results will be pooled using random effect meta-analysis. Discussion The planned systematic review and meta-analysis will provide reliable estimates of the risk for major bleeding events during extended anticoagulation. This information will help inform patient prognosis and assist clinicians with balancing the risks and benefits of treatment to guide management of unprovoked VTE. Systematic review registration PROSPERO CRD42019128597.

Background The long-term risk of major bleeding after discontinuing anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. Objectives To determine the incidence of major bleeding up to 5 years after discontinuing anticoagulation for a first unprovoked VTE. Methods We searched MEDLINE, EMBASE, and Cochrane CENTRAL (from inception to January 2021) to identify relevant randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding after discontinuing anticoagulation in patients with a first unprovoked or weakly provoked VTE who had completed (IMAGE_)3 months of initial treatment. Unpublished data on major bleeding events and person-years were obtained from authors of included studies to calculate study-level incidence rates. Random-effects meta-analysis was used to pool results across studies. Results Of 1,123 records identified by the search, 20 studies (17 RCTs) and 8,740 patients were included in the analysis. During 13,011 person-years of follow-up after discontinuing anticoagulation, the pooled incidence of major bleeding (n = 41) and fatal bleeding (n = 7) per 100 person-years was 0.35 (95% confidence interval [CI]: 0.20–0.54) and 0.09 (95% CI: 0.05–0.15). The 5-year cumulative incidence of major bleeding was of 1.0% (95% CI: 0.4–2.4%). The case-fatality rate of major bleeding after discontinuing anticoagulation was 19.9% (95% CI: 10.6–31.1%). Conclusion The risk of major bleeding once anticoagulants are discontinued in patients with a first unprovoked VTE is not zero. Estimates from this study can help clinicians counsel patients about the incremental risk of major bleeding with extended anticoagulation to guide decision making about treatment duration for unprovoked VTE.

The certainty that prehabilitation improves postoperative outcomes is not clear. The objective of this umbrella review (i.e. systematic review of systematic reviews) was to synthesise and evaluate evidence for prehabilitation in improving health, experience, or cost outcomes.We performed an umbrella review of prehabilitation systematic reviews. MEDLINE, Embase, Cochrane, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Joanna Briggs Institute's database, and Web of Science were searched (inception to October 20, 2020). We included all systematic reviews of elective, adult patients undergoing surgery and exposed to a prehabilitation intervention, where health, experience, or cost outcomes were reported. Evidence certainty was assessed using Grading of Recommendations Assessment, Development and Evaluation. Primary syntheses of any prehabilitation were stratified by surgery type.From 1412 titles, 55 systematic reviews were included. For patients with cancer undergoing surgery who participate in any prehabilitation, moderate certainty evidence supports improvements in functional recovery. Low to very low certainty evidence supports reductions in complications (mixed, cardiovascular, and cancer surgery), non-home discharge (orthopaedic surgery), and length of stay (mixed, cardiovascular, and cancer surgery). There was low to very low certainty evidence that exercise prehabilitation reduces the risk of complications, non-home discharge, and length of stay. There was low to very low certainty evidence that nutritional prehabilitation reduces risk of complications, mortality, and length of stay.Low certainty evidence suggests that prehabilitation may improve postoperative outcomes. Future low risk of bias, randomised trials, synthesised using recommended standards, are required to inform practice. Optimal patient selection, intervention design, and intervention duration must also be determined.

IntroductionPrehabilitation is a high-priority intervention for patients, the public, clinicians and health systems. However, existing knowledge syntheses are generally low quality and do not provide insights regarding the relative efficacy of different prehabilitation components (eg, exercise, nutrition, psychosocial or cognitive interventions). The objective of the planned review is to evaluate the relative efficacy of different prehabilitation components to inform current care, implementation and future research.Methods and analysisWe will perform a systematic review and component network meta-analysis (CNMA). We will use a peer-reviewed search strategy to identify all randomised trials of prehabilitation in adult surgical patients from Ovid Medline, Embase, the CINAHL, PsycINFO, Web of Science and the Cochrane Central Register of Controlled Trials, along with grey literature. All stages of the review and data extraction process will be performed in duplicate, following recommended best practices. To compare the relative efficacy of different prehabilitation components (prespecified as exercise, nutrition, psychosocial or cognitive interventions), we will use CNMA, an extension of network meta-analysis that allows estimation of the contributions to efficacy of each component of a multicomponent intervention through direct and indirect comparisons. We will use additive CNMA models for critical outcomes (postoperative complications, patient-reported recovery, physical recovery and length of stay); standard care will be the common reference condition. Pre-specified sensitivity and subgroup analyses will be conducted.Ethics and disseminationThis review of published data does not require ethical review. Results will be disseminated via scientific conferences, peer-reviewed publications, social and traditional media and via our research network to target partners and organisations.

IntroductionPrior to the COVID-19 pandemic, substance use health services for treatment of alcohol use disorder and problematic alcohol use (AUD/PAU) were fragmented and challenging to access. The pandemic magnified system weaknesses, often resulting in disruptions of treatment as alcohol use during the pandemic rose. When treatment services were available, utilisation was often low for various reasons. Virtual care was implemented to offset the drop in in-person care, however accessibility was not universal. Identification of the characteristics of treatment services for AUD/PAU that impact accessibility, as perceived by the individuals accessing or providing the services, will provide insights to enable improved access. We will perform a scoping review that will identify characteristics of services for treatment of AUD/PAU that have been identified as barriers to or facilitators of service access from the perspectives of these groups.Methods and analysisWe will follow scoping review methodological guidance from the Joanna Briggs Institute. Using the OVID platform, we will search Ovid MEDLINE including Epub Ahead of Print and In-Process and Other Non-Indexed Citations, Embase Classic+Embase, APA PsychInfo, Cochrane Register of Controlled Trials, the Cochrane Database of Systematic Reviews and CINAHL (Ebsco Platform). Multiple reviewers will screen citations. We will seek studies reporting data collected from individuals with AUD/PAU or providers of treatment for AUD/PAU on service-level factors affecting access to care. We will map barriers to and facilitators of access to AUD/PAU treatment services identified in the relevant studies, stratified by service type and key measures of inequity across service users.Ethics and disseminationThis research will enhance awareness of existing evidence regarding barriers to and facilitators of access to services for the treatment of alcohol use disorder and problematic alcohol use. Findings will be disseminated through publications, conference presentations and a stakeholder meeting. As this is a scoping review of published literature, no ethics approval was required.

Background: The long-term risk for recurrent venous thromboembolism (VTE) during extended anticoagulation for a first unprovoked VTE is uncertain. Objectives: To determine the incidence of recurrent VTE during extended anticoagulation of up to 5years in patients with a first unprovoked VTE. Methods: MEDLINE, EMBASE, and the Cochrane CENTRAL were searched to identify randomized trials and prospective cohort studies reporting recurrent VTE among patients with a first unprovoked VTE who were to receive anticoagulation for a minimum of six additional months after completing ≥3months of initial treatment. Unpublished data on number of recurrent VTE and person-years, obtained from authors of included studies, were used to calculate study-level incidence rate, and random-effects meta-analysis was used to pool results. Results: Twenty-six studies and 15603 patients were included in the analysis. During 11631 person-years of follow-up, the incidence of recurrent VTE and fatal pulmonary embolism per 100 person-years was 1.41 (95% CI, 1.03–1.84) and 0.09 (0.04–0.16), with 5-year cumulative incidences of 7.1% (3.0%–13.2%) and 1.2% (0.4%–4.6%), respectively. The incidence of recurrent VTE was 1.08 (95% CI, 0.77–1.44) with direct oral anticoagulants and 1.55 (1.01–2.20) with vitamin K antagonists. The case-fatality rate of recurrent VTE was 4.9% (95% CI, 2.2%–8.7%). Conclusions: In patients with a first unprovoked VTE, the long-term risk of recurrent VTE during extended anticoagulation is low but not negligible. Thus, clinicians and patients should be aware of this risk and take appropriate and timely action in case of suspicion of recurrent VTE. Estimates from this study can be used to advise patients on what to expect while receiving extended anticoagulation, and estimate the net clinical benefit of extended treatment to guide long-term management of unprovoked VTE. © 2021 International Society on Thrombosis and Haemostasis.

Blood-based kinetic analysis of PET data relies on an accurate estimate of the arterial plasma input function (PIF). An alternative to invasive measurements from arterial sampling is an image-derived input function (IDIF). However, an IDIF provides the whole blood radioactivity concentration, rather than the required free tracer radioactivity concentration in plasma. To estimate the tracer PIF, we corrected an IDIF from the carotid artery with estimates of plasma parent fraction (PF) and plasma-to-whole blood (PWB) ratio obtained from five venous samples. We compared the combined IDIF+venous approach to gold standard data from arterial sampling in 10 healthy volunteers undergoing [18F]GE-179 brain PET imaging of the NMDA receptor. Arterial and venous PF and PWB ratio estimates determined from 7 patients with traumatic brain injury (TBI) were also compared to assess the potential effect of medication. There was high agreement between areas under the curves of the estimates of PF (r = 0.99, p

Concerns around pharmacological interaction between tamoxifen and antidepressants have resulted in evidence-base guidelines that recommend avoidance or caution with concurrent use. It remains unclear however whether this interaction is clinically important. A systematic review of studies comparing endocrine therapy (including tamoxifen and aromatase inhibitors) alone or concurrent with antidepressants in breast cancer patients was performed. The literature search sought studies within MEDLINE, EMBASE, and the Cochrane Collaboration Library published from database inception until December 1, 2020. Outcomes of interest included recurrence, breast cancer-specific survival, overall mortality, quality of life, and treatment compliance. Studies were assessed with the Cochrane Risk of Bias tool for randomized controlled trials and the Newcastle Ottawa tool for case-control and cohort studies. From 695 citations, we included 15 studies (2 randomized controlled trials [255 patients], 10 retrospective cohort studies [75,678 patients], and 3 case-control studies [18,836 patients]). While between-study clinical and methodologic differences (including analysis of confounding variables) precluded formal meta-analysis, findings from included studies did not find consistent evidence that concurrent use of antidepressants (including paroxetine) with tamoxifen therapy has negative impacts on the outcomes of interest. In this systematic review, despite data from nearly 100,000 patients, concurrent use of tamoxifen and antidepressants showed no consistent negative effect on clinical outcomes. Given the recognized harm to patients of changing either endocrine therapy or antidepressants to avoid concurrent use, current evidence-based guidelines should be updated accordingly. More rigorously designed pharmacoepidemiologic studies are needed.

IntroductionSystematic reviews with network meta-analysis (NMA; ie, multiple treatment comparisons, indirect comparisons) have gained popularity and grown in number due to their ability to provide comparative effectiveness of multiple treatments for the same condition. The methodological review aims to develop a list of items relating to biases in reviews with NMA. Such a list will inform a new tool to assess the risk of bias in NMAs, and potentially other reporting or quality checklists for NMAs which are being updated.Methods and analysisWe will include articles that present items related to bias, reporting or methodological quality, articles assessing the methodological quality of reviews with NMA, or papers presenting methods for NMAs. We will search Ovid MEDLINE, the Cochrane library and difficult to locate/unpublished literature. Once all items have been extracted, we will combine conceptually similar items, classifying them as referring to bias or to other aspects of quality (eg, reporting). When relevant, reporting items will be reworded into items related to bias in NMA review conclusions, and then reworded as signalling questions.Ethics and disseminationNo ethics approval was required. We plan to publish the full study open access in a peer-reviewed journal, and disseminate the findings via social media (Twitter, Facebook and author affiliated websites). Patients, healthcare providers and policy-makers need the highest quality evidence to make decisions about which treatments should be used in healthcare practice. Being able to critically appraise the findings of systematic reviews that include NMA is central to informed decision-making in patient care.

BACKGROUND Recently, pharmacological treatment options for H1-antihistamine-refractory chronic spontaneous urticaria (CSU) have increased dramatically; however, their effects on patient-reported outcomes (PROs), including health-related quality of life (HRQOL), remain unclear. OBJECTIVE This study was designed to compare the impact of these treatments on HRQOL among H1-antihistamine-refractory CSU patients. METHODS We completed a comprehensive search of the available literature in the electronic databases, grey literature, and preprint reports up to April 19, 2021, with no language restrictions. The primary outcome for evaluation was a change in HRQOL from the baseline and secondary outcomes included patient unacceptability and other PROs. We used a random-effects network meta-analysis and estimated differences in standardized mean differences (SMDs) and odds ratios with 95% confidence intervals. Evidence-based synthesis was based on magnitudes of effect size, evidence certainty, ranking of treatment effects, and clinically meaningful improvement. RESULTS Twelve randomized controlled trials encompassed 1,866 adolescent and adult patients were included. Our evidence synthesis analyses revealed that hydroxychloroquine (SMD, -1.00 [-1.61 to -0.39]), 72 mg ligelizumab (SMD, -0.66 [-0.96 to -0.35]), 240 mg ligelizumab (SMD, -0.67 [-0.98 to -0.37]), and 300 mg omalizumab (SMD, -0.53 [-0.67 to -0.39]) significantly improved HRQOL with a moderate beneficial effect. However, the use of hydroxychloroquine seems to be limited by a higher risk of patient unacceptability of treatment. Other secondary outcomes remain inconclusive based on the available evidence. CONCLUSION Both ligelizumab (72 or 240 mg) and 300 mg omalizumab appeared to be effective treatments for H1-antihistamine-refractory CSU, as they were closely associated with improved HRQOL.

Background The present study evaluated the relative survival benefits associated with enasidenib and current standard of care (SoC) therapies for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and an isocitrate dehydrogenase 2 (IDH2) mutation who are ineligible for hematopoietic stem cell transplantation (HSCT). Methods Propensity score matching (PSM) analysis compared survival outcomes observed with enasidenib 100 mg daily in the phase I/II AG221‐C‐001 trial and SoC outcomes obtained from a real‐world chart review of patients in France. Results Before matching, enasidenib (n = 195) was associated with numerically improved overall survival (OS) relative to SoC (n = 80; hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.61–1.11). After matching and adjusting for covariates (n = 78 per group), mortality risk was significantly lower with enasidenib than with SoC (HR, 0.67; 95% CI, 0.47–0.97). The median OS was 9.26 months for enasidenib (95% CI, 7.72–13.24) and 4.76 months for SoC (95% CI, 3.81–8.21). Results remained robust across all sensitivity analyses conducted. Conclusions PSM analyses indicate that enasidenib significantly prolongs survival relative to SoC among patients with R/R AML and an IDH2 mutation who are ineligible for HSCT. Future prospective studies are needed to validate these findings using other data sources and to assess the comparative efficacy of enasidenib for other treatment outcomes., Overall survival was improved with enasidenib compared with SoC. Enasidenib may be an important advance in treatment for patients with R/R acute myeloid leukemia associated with IDH2 mutations who are ineligible for hematopoietic stem cell transplantation.

[See related article at [www.cmaj.ca/lookup/doi/10.1503/cmaj.191089][2]][2] KEY POINTS Parkinson disease is chronic and progressive in nature, decreasing the quality of life for both patients with the disease and their caregivers and placing an onerous economic burden on society.[1][2] The first

The proportion of breast cancer patients enrolled in clinical trials is falling. The Rethinking Clinical Trials (REaCT) program was developed to challenge some of the contemporary barriers responsible for this fall in accrual. In this article, we review the successes and challenges our program has faced. The REaCT program was created to improve care and outcomes for cancer patients through surveys of patients and healthcare providers, systematic reviews, economic evaluations, and the performance of pragmatic randomized trials with patient-centered outcomes. Likely, the greatest difference to conventional trial methodologies has been our widespread use of the integrated consent model (ICM) incorporating oral consent. Between 2014 and 2018, the program has recruited over 2000 patients to 15 randomized studies at 11 Canadian cancer centers. The REaCT program has completed and published five patient surveys, six healthcare provider surveys, ten systematic reviews, performed four economic evaluations, opened 15 clinical trials comparing standard of care interventions (two surgical, two adjuvant chemotherapy, five adjuvant supportive care, one radiology, two vascular devices, two palliative supportive care, and one molecular diagnostics). Patient surveys have shown high levels of satisfaction with the ICM. The REaCT program was developed to tackle important practice questions that will better guide optimal practice and to increase the availability of pragmatic clinical trials. While many challenges remain, future strategies will involve including more study sites and efforts to integrate novel information technology strategies.

Bone-modifying agents (BMAs) such as bisphosphonates and denosumab are usually administered every 4 weeks (standard) in patients with bone metastases from breast cancer to prevent skeletal-related events (SREs). Recent randomized controlled trials suggest every 12-week (de-escalated) dosing interval may be non-inferior. The objective of this systematic review and meta-analysis was to compare the efficacy and harms of standard with de-escalated administration of BMA’s in patients with bone metastases from breast cancer. We searched Medline, PubMed, and the Cochrane Register of Controlled Trials from 1947 to March 14, 2018 and conference abstracts from (2014–March 14, 2018) for randomized clinical trials comparing every 4-week and every 12-week dosing interval of bone-modifying agents. Using PRISMA guidelines, meta-analyses were performed using random-effects models, with findings reported as risk ratios with 95% confidence intervals (CI). From a total of 1311 citations, we identified 8 full-text articles and 1 abstract comprising data from 5 completed randomized clinical trials (n = 1807). Zoledronate administration every 12 weeks compared to every 4 weeks produced a summary risk ratio of 1.05 (95% CI 0.88–1.25) for patients with ≥ 1 on-study SRE indicating similar efficacy. These results did not differ whether patients had received prior intravenous bisphosphonate. De-escalation was associated with a non-statistically significant lower risk of increased creatinine (summary risk ratio 0.41 [95% CI 0.15–1.16]). Currently, there are insufficient data for pamidronate and denosumab de-escalation. These data are supportive of de-escalation of zoledronate from onset for patients with bone metastases from breast cancer.

Promising efficacy results of chimeric antigen receptor (CAR) T-cell therapy have been tempered by safety considerations. Our objective was to comprehensively summarize the efficacy and safety of CAR-T cell therapy in patients with relapsed or refractory hematologic or solid malignancies. MEDLINE, Embase, and the Cochrane Register of Controlled Trials (inception - November 21, 2017). Interventional studies investigating CAR-T cell therapy in patients with malignancies were included. Our primary outcome of interest was complete response (defined as the absence of detectable cancer). Two independent reviewers extracted relevant data, assessed risk of bias, and graded the quality of evidence using established methods. A total of 42 hematological malignancy studies and 18 solid tumor studies met were included (913 participants). Of 486 evaluable hematologic patients, 54.4% [95% CI, 42.5%-65.9%] experienced complete response in 27 CD19 CAR-T cell therapy studies. Of 65 evaluable hematologic patients, 24.4% [95% CI, 9.4%-50.3%] experienced complete response in seven non-CD19 CAR-T cell therapy studies. Cytokine release syndrome was experienced by 55.3% [95% CI, 40.3%-69.4%] of patients and neurotoxicity 37.2% [95% CI, 28.6%-46.8%] of patients with hematologic malignancies. Of 86 evaluable solid tumor patients, 4.1% [95% CI, 1.6%-10.6%] experienced complete response in eight CAR-T cell therapy studies. Limitations include heterogeneity of study populations, as well as high risk of bias of included studies. There was a strong signal for efficacy of CAR-T cell therapy in patients with CD19+ hematologic malignancies and no overall signal in solid tumor trials published to date. These results will help inform patients, physicians, and other stakeholders of the benefits and risks associated with CAR-T cell therapy.

Systematic reviews are the most common form of knowledge synthesis and remain a cornerstone of the practice of evidence-based medicine. They offer enhanced rigor and validity relative to traditional narrative review articles by reducing bias and increasing objectivity. In answering focused research questions, systematic reviews are directly applicable to clinical practice as well as the development of clinical guidelines and the identification of knowledge gaps, which may drive future primary research directions. Typically, such a rigorous process necessarily requires substantive time to carefully and systematically identify, screen, and synthesize all relevant available primary research on a topic. Further, other knowledge synthesis methods have emerged to address the varying needs of decision makers with respect to condensed timelines and more diverse research questions, as well as to allow incorporation of already synthesized evidence into reviews. These alternative methods include rapid reviews, scoping reviews, and overviews of systematic reviews, which are being used with increasing frequency by clinicians, decision-makers, and researchers. We encourage clinicians and researchers in nuclear medicine and other imaging sciences to acquire a greater familiarity with these methods and to consider them in clinical decision making, the development of clinical guidelines, and the planning of future research activities.

Background Patients can start endocrine therapy before, concurrently with, or sequentially after radiotherapy. The optimal timing of starting adjuvant endocrine therapy is unknown. This survey was performed to evaluate physician recommendations. Methods Canadian oncologists were surveyed to evaluate institutional and personal practices regarding the prescription of adjuvant endocrine therapy and radiotherapy. Perspectives regarding the design of a clinical trial to compare concurrent versus sequential therapy, and the optimum end points for such a trial, were also sought. Results The overall response rate was 30% (65/220), with responses mainly from medical (35/65, 54%) and radiation (28/65, 43%) oncologists. Eighty-four percent of respondents reported an absence of institutional protocols. The majority of physicians (57%, 36/65) identified endocrine therapy provided after radiotherapy as the preferred sequence of treatments. Twenty-two percent (14/65) had no preference, while 21%, (14/65) started endocrine therapy either before or concurrent with radiotherapy. Practice patterns were largely based on the physician’s own clinical experience. Thirty-two percent of physicians (21/65) had concerns regarding concurrent endocrine therapy and radiotherapy, including increased adverse effects with endocrine therapy (13/21, 62%), reduced efficacy of radiotherapy (4/21, 19%), reduced compliance with endocrine therapy (3/21, 14%), and increased radiation toxicity (1/21, 5%). Most thought a pragmatic clinical trial addressing this question would help standardize and improve patient care. Conclusion Decisions around the timing of endocrine therapy and radiotherapy are largely being made on the basis of physicians’ personal choices. In the absence of data to support these decisions, appropriately powered trials are needed.

OBJECTIVE The three Magee Equations provide an estimate of the Oncotype DX recurrence score using commonly available clinicopathologic information (tumour size, grade, oestrogen receptor, progesterone receptor, HER2, and Ki67). We assessed whether integration of Magee Equations into routine clinical practice affected the frequency of Oncotype DX requests. METHODS Patients with newly diagnosed, node negative, hormone receptor positive, and HER2 negative invasive breast cancer were randomized to undergo a Magee calculation or not. At the first clinic assessment, the oncologist was provided with all routinely available clinicopathologic information (including Ki67) either with or without the results of Magee Equations. Primary outcome was frequency of Oncotype DX ordering. Secondary outcomes included frequency of chemotherapy use, time to commencement of radiotherapy, or systemic therapy. Physician comfort with systemic therapy choices and the use of Ki67 and Magee Equations was also assessed. RESULTS Data from 175 randomized patients was available, 84 patients (48%) with and 91 (52%) without calculated Magee Equations. Oncotype DX was ordered in 10 (12.05%) and 13 (14.44%) (RR 0.83, 0.39-1.80; P = 0.64) in the Magee and no Magee groups, respectively. There were no statistically or clinically significant differences between the randomized groups for any of the secondary outcomes. Availability of both Ki67 and Magee Equations was associated with increased physician comfort around systemic treatment decisions. CONCLUSIONS In a practice where Ki67 is routinely available, addition of Magee Equations into routine clinic practice was not associated with a reduction in Oncotype DX use. Availability of both Ki67 and Magee Equations did however increase physician comfort with systemic therapy decisions.

Background: Guselkumab is an interleukin-23 inhibitor indicated for treatment of moderate-to-severe plaque psoriasis. Objective: The objective was to determine the relative efficacy and safety of guselkumab compared to other biologics. Methods: A systematic review was performed to identify randomized controlled trials (RCTs). Bayesian network meta-analyses (NMAs) were conducted using meta-regression analyses that adjusted for cross-trial differences and risk differences. The primary outcome was Psoriasis Area and Severity Index (PASI) 90 response. Other efficacy and safety outcomes were considered. Several meta-regressions were performed to account for variations in patient and study characteristics: baseline risk adjustment (ie, control group response), prior biologic use, duration of psoriasis, weight, age, race, and baseline PASI/dermatology life quality index scores. The best-fitting model using predefined criteria was selected. Results: Forty-five RCTs were identified. Patient and study characteristics differed between RCTs as reflected in variations in control group response. Both the baseline risk-adjusted NMA and the risk-difference NMA fit the data best and suggested guselkumab has one of the highest PASI 90 responses. Pairwise comparisons from the baseline risk-adjusted PASI 90 NMA suggested guselkumab has comparable efficacy with ixekizumab (relative risk [RR]: 0.999, 95% credible intervals [CrIs]: 0.89-1.13) and brodalumab (RR: 1.04, 95% CrIs: 0.91-1.17) and superior efficacy versus all other treatments in the network (RR range, 1.20 to 43.22). Guselkumab was superior or comparable to other therapies for other efficacy outcomes and had a more favorable safety profile than most. Conclusions: Guselkumab has one of the highest PASI 90 responses among psoriasis treatments; similar findings were observed for other efficacy outcomes. Guselkumab has a favorable benefit–risk balance compared to moderate-to-severe psoriasis therapies.

Aim: The importance of adjusting for cross-study heterogeneity when conducting network meta-analyses (NMAs) was demonstrated using a case study of biologic therapies for moderate-to-severe plaque psoriasis. Methods: Bayesian NMAs were conducted for Psoriasis Area and Severity Index 90 response. Several covariates were considered to account for cross-trial differences: baseline risk (i.e., placebo response), prior biologic use, body weight, psoriasis duration, age, race and baseline Psoriasis Area and Severity Index score. Model fit was evaluated. Results: The baseline risk-adjusted NMA, which adjusts for multiple observed and unobserved effect modifiers, was associated with the best model fit. Lack of adjustment for cross-trial differences led to different clinical interpretations of findings. Conclusion: Failure to adjust for cross-trial differences in NMA can have important implications for clinical interpretations when studying the comparative efficacy of healthcare interventions.

Aim Conduct a systematic review of the effectiveness of systemic therapies for adult recurrent glioblastoma (rGBM). Methods We electronically searched for randomized controlled trials from three major databases and four conferences from 2009-Dec 2020. Two independent reviewers conducted screening, data extraction, and quality assessment. Results 48 randomized trials were identified. Outcome reporting was inconsistent: overall survival (OS) in 46 studies, progression free survival in 37 studies, 6-month PFS in 30 studies, objective response rate in 28 studies, and 6-month OS in 7 studies. Network meta-analysis was not feasible due to heterogeneity in outcome reporting and single-study linkages. Most studies compared lomustine (8 studies), bevacizumab (18), or temozolomide (8) with other treatments. The median OS across all studies ranged from 3-17.6 months. Conclusions Based on level one evidence, there is no superior systemic regimen for rGBM. rGBM is a heterogeneous population with no single regimen demonstrating OS benefit. Registration number: CRD42020148512

BACKGROUND Evidence to guide treatment of pediatric medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency and phenylketonuria (PKU) is fragmented because of large variability in outcome selection and measurement. Our goal was to develop core outcome sets (COSs) for these diseases to facilitate meaningful future evidence generation and enhance the capacity to compare and synthesize findings across studies. METHODS Parents and/or caregivers, health professionals, and health policy advisors completed a Delphi survey and participated in a consensus workshop to select core outcomes from candidate lists of outcomes for MCAD deficiency and PKU. Delphi participants rated the importance of outcomes on a nine-point scale (1–3: not important, 4–6: important but not critical, 7–9: critical). Candidate outcomes were progressively narrowed down over 3 survey rounds. At the workshop, participants evaluated the remaining candidate outcomes using an adapted nominal technique, open discussion, and voting. After the workshop, we finalized the COSs and recommended measurement instruments for each outcome. RESULTS There were 85, 61, and 53 participants across 3 Delphi rounds, respectively. The candidate core outcome lists were narrowed down to 20 outcomes per disease to be discussed at the consensus workshop. Voting by 18 workshop participants led to COSs composed of 8 and 9 outcomes for MCAD deficiency and PKU, respectively, with measurement recommendations. CONCLUSIONS These are the first known pediatric COSs for MCAD deficiency and PKU. Adoption in future studies will help to ensure best use of limited research resources to ultimately improve care for children with these rare diseases.

Introduction One of the current challenges in long-term care homes (LTCH) is to identify the optimal model of care, which may include specialty physicians, nursing staff, person support workers, among others. There is currently no consensus on the complement or scope of care delivered by these providers, nor is there a repository of studies that evaluate the various models of care. We conducted a rapid scoping review to identify and map what care provider models and interventions in LTCH have been evaluated to improve quality of life, quality of care, and health outcomes of residents. Methods We conducted this review over 10-weeks of English language, peer-reviewed studies published from 2010 onward. Search strategies for databases (e.g., MEDLINE) were run on July 9, 2020. Studies that evaluated models of provider care (e.g., direct patient care), or interventions delivered to facility, staff, and residents of LTCH were included. Study selection was performed independently, in duplicate. Mapping was performed by two reviewers, and data were extracted by one reviewer, with partial verification by a second reviewer. Results A total of 7,574 citations were screened based on the title/abstract, 836 were reviewed at full text, and 366 studies were included. Studies were classified according to two main categories: healthcare service delivery (n = 92) and implementation strategies (n = 274). The condition/ focus of the intervention was used to further classify the interventions into subcategories. The complex nature of the interventions may have led to a study being classified in more than one category/subcategory. Conclusion Many healthcare service interventions have been evaluated in the literature in the last decade. Well represented interventions (e.g., dementia care, exercise/mobility, optimal/appropriate medication) may present opportunities for future systematic reviews. Areas with less research (e.g., hearing care, vision care, foot care) have the potential to have an impact on balance, falls, subsequent acute care hospitalization.

Introduction: Systematic reviews with network meta-analysis (NMA; i.e., multiple treatment comparisons, indirect comparisons) have gained popularity and grown in number due to their ability to provide comparative effectiveness of multiple treatments for the same condition. The methodological review aims to develop a list of items relating to biases in reviews with NMA. Such a list will inform a new tool to assess the risk of bias in NMAs, and potentially other reporting or quality checklists for NMAs which are being updated.Methods and Analysis: We will include articles that present items related to bias, reporting, or methodological quality, articles assessing the methodological quality of reviews with NMA, or papers presenting methods for NMAs. We will search Ovid MEDLINE, the Cochrane library, and difficult to locate/unpublished literature. Once all items have been extracted, we will combine conceptually similar items, classifying them as referring to bias or to other aspects of quality (e.g. reporting). When relevant, reporting items will be re-worded into items related to bias in NMA review conclusions, and then re-worded as signalling questions. Ethics and Dissemination: No ethics approval was required. Patients, healthcare providers and policy makers need the highest quality evidence to make decisions about which treatments should be used in healthcare practice. Being able to critically appraise the findings of systematic reviews that include NMA is central to informed decision-making in patient care.

Synthesising computed tomography (CT) images from magnetic resonance images (MRI) plays an important role in the field of medical image analysis, both for quantification and diagnostic purposes. Convolutional neural networks (CNNs) have achieved state-of-the-art results in image-to-image translation for brain applications. However, synthesising whole-body images remains largely uncharted territory, involving many challenges, including large image size and limited field of view, complex spatial context, and anatomical differences between images acquired at different times. We propose the use of an uncertainty-aware multi-channel multi-resolution 3D cascade network specifically aiming for whole-body MR to CT synthesis. The Mean Absolute Error on the synthetic CT generated with the MultiResunc network (73.90 HU) is compared to multiple baseline CNNs like 3D U-Net (92.89 HU), HighRes3DNet (89.05 HU) and deep boosted regression (77.58 HU) and shows superior synthesis performance. We ultimately exploit the extrapolation properties of the MultiRes networks on sub-regions of the body.

Purpose Vasomotor symptoms (VMS) such as hot flashes and night sweats are common in breast cancer patients and can affect both quality of life and treatment adherence. However, there is limited practical data to guide clinicians in the optimal selection of therapeutic strategies. A survey of health care providers was performed to better understand perspectives and prescribing practices for managing this problem. Methods Canadian health care providers who treat patients with early stage breast cancer (EBC) participated in an anonymous electronic survey. Participants provided their perspectives on the prevalence and severity of VMS among patients with EBC, outlined their management strategies, and provided feedback on the perceived efficacy of interventions for VMS. Results Responses were received from 65 providers including breast oncologists (36/65, 55%) and nurses with oncology expertise (29/65, 45%). Seventy-seven percent of participants reported regularly asking patients about VMS, and most indicated that bothersome VMS occurred in the majority of patients. Health care providers cited hot flash severity and sleep disruption as the most important issues for patients. The most common first- and second-line interventions recommended were lifestyle modifications (n = 32/65, 49.2%) and pharmacologic strategies (n = 27/65, 41.5%), respectively. Most respondents felt that interventions, including pharmacologic, over-the-counter, and complementary therapies, were only “somewhat effective”. Overall, half of respondents (n = 35/65, 54%) reported being “confident” in managing VMS. Conclusion Given the variability of treatment recommendations, and health care provider uncertainty around the benefits of therapies for VMS, more ‘real-world’ trials are needed to optimize patient care.

Highlights • Adjuvant bisphosphonates are an established standard in postmenopausal breast cancer. • Guidelines note the need to explore different agents, doses, and intervals of bisphosphonates. • Feasibility of randomizing to 6-monthly vs one dose of IV zoledronate was demonstrated., Background Adjuvant zoledronate is widely used in patients with early stage breast cancer (EBC), but its optimal duration and dosing interval is still unknown. While a single-dose of zoledronate can improve bone density for many years, a proper evaluation of its effects on breast cancer-related outcomes would require a large trial. In this pilot study we evaluated the feasibility of performing such a trial. Methods Eligible patients with EBC were randomised to receive either one dose of zoledronate or 7 doses (6-monthly dosing for 3 years). Feasibility was assessed by a combination of primary outcomes including: activation of at least 6 Ontario sites within a year, active participation (i.e. approaching eligible patients for study participation) of at least half of the medical oncologists, and enrolment of at least 100 patients across all sites within 9 months of the sixth site being activated. Results All 6 sites were activated within 1 year and of 47 medical oncologists, 27 (57%) approached patients. Between November 2018 and April 2020, 211 eligible patients were randomised, 106 (50.2%) to a single dose of zoledronate and 105 (49.8%) to 6-monthly dosing. Baseline characteristics of randomised patients included; median age 59 (range 36–88), ER and/or PR positive (85%), Her2 positive (23%), menopausal status (premenopausal [19%], perimenopausal [6.7%] and postmenopausal [74%]) and 74% received neo/adjuvant chemotherapy. Conclusions All study feasibility endpoints were met in this trial comparing alternative schedules for adjuvant zoledronate. We will now seek funding for performing a larger efficacy trial. Trial registration: NCT03664687.

Highlights • Guidelines recommend adjuvant bisphosphonates for postmenopausal higher risk breast cancer patients. • Use of these agents in clinical practice appears low. • We surveyed patients receiving adjuvant bisphosphonate therapy · Results showed that while patients plan to complete all treatment cycles, they are enthusiastic about future trials evaluating de-escalation strategies., Background Despite the increasing use of adjuvant bisphosphonates for early stage breast cancer (EBC), little is known about the patient experience with such treatments. A patient survey was performed to identify current prescribing practices, perceptions around the role of treatment, the impact of treatment on patients’ quality of life, and future trial designs. Methods EBC patients who had either completed or were currently receiving adjuvant bisphosphonates were sent an anonymized survey. The survey collected information on patient and disease characteristics, bisphosphonate scheduling, compliance, and tolerance. Questions also assessed patient interest in trials of de-escalated bisphosphonate therapy. Results A total of 255 patients were contacted, with 164 eligible respondents (eligible response rate 164/255, 64.3%). Median patient age was 52 years (range 28 to 82 years). The majority (111/163, 68.1%) were postmenopausal at the time of diagnosis, 23.3% (38/163) were premenopausal, and 7.4% (12/163) were perimenopausal. Most patients (78%) had received chemotherapy. Zoledronate was the most commonly used bisphosphonate (92%), with the majority receiving treatment every 6 months for 3 years (73%). While 66% (107/161) of respondents had experienced side effects with treatment, most had, or expected to, complete treatment (154/163, 94%). Provided there was no detriment in breast cancer outcomes, there was strong interest in future studies of de-escalating adjuvant bisphosphonate therapy. Conclusion While most patients tolerate their treatment, there is interest in performing trials of de-escalation of these agents.

BACKGROUND The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).

Highlights • CT-based losses neglect the PET data when doing MR to CT synthesis. • MR to CT synthesis networks should account for PET reconstruction error. • Multi-hypothesis uncertainty provides the best approximation of the true PET. • Imitation learning results in a better optima and more generalisable model., Graphical abstract, The assessment of the quality of synthesised/pseudo Computed Tomography (pCT) images is commonly measured by an intensity-wise similarity between the ground truth CT and the pCT. However, when using the pCT as an attenuation map (μ-map) for PET reconstruction in Positron Emission Tomography Magnetic Resonance Imaging (PET/MRI) minimising the error between pCT and CT neglects the main objective of predicting a pCT that when used as μ-map reconstructs a pseudo PET (pPET) which is as similar as possible to the gold standard CT-derived PET reconstruction. This observation motivated us to propose a novel multi-hypothesis deep learning framework explicitly aimed at PET reconstruction application. A convolutional neural network (CNN) synthesises pCTs by minimising a combination of the pixel-wise error between pCT and CT and a novel metric-loss that itself is defined by a CNN and aims to minimise consequent PET residuals. Training is performed on a database of twenty 3D MR/CT/PET brain image pairs. Quantitative results on a fully independent dataset of twenty-three 3D MR/CT/PET image pairs show that the network is able to synthesise more accurate pCTs. The Mean Absolute Error on the pCT (110.98 HU ± 19.22 HU) compared to a baseline CNN (172.12 HU ± 19.61 HU) and a multi-atlas propagation approach (153.40 HU ± 18.68 HU), and subsequently lead to a significant improvement in the PET reconstruction error (4.74% ± 1.52% compared to baseline 13.72% ± 2.48% and multi-atlas propagation 6.68% ± 2.06%).

Olfactory loss has been identified as one of the common symptoms related to COVID-19 infection. Although olfactory loss is recognized, our understanding of both the extent of loss and time to olfactory recovery following infection is less well known. Similarly, knowledge of potential impactful patient factors and therapies that influence olfactory recovery is desirable but is not overtly clear in the literature. Our systematic review sought to fill this knowledge gap. We included studies that: involved either an observational or an interventional design that reported data on patients with olfactory dysfunction due to Reverse Transcription Polymerase Chain Reaction (RT-PCR) diagnosed COVID-19 infection; and reported data regarding olfactory recovery measured by an objective olfactory test, Likert scale and/or visual analog scale (VAS). The study methods were determined a priori and registered in PROSPERO (Registration Number CRD42020204354). An information specialist searched Medline, Embase, LitCovid and the Cochrane Register of Controlled Trials up to March 2021, and two reviewers were involved in all aspects of study selection and data collection. After screening 2788 citations, a total of 44 studies of assorted observational designs were included. Patients had undergone objective COVID-19 testing, and most were adult patients with mild to moderate COVID-19. Olfactory recovery was found to occur as early as 7 days, with most patients recovering olfaction within 30 days. Few studies included prolonged follow-up to 6 months or longer duration. Poor olfaction at initial presentation was associated with poor recovery rates. Only a small number of studies assessed olfactory retraining and steroid therapy. Additional trials are underway.

Background Excess weight has been associated with increased morbidity and a worse prognosis in adult patients with early-stage cancer. The optimal lifestyle interventions to optimize anthropometric measures amongst cancer patients and survivors remain inconsistent. Objective To conduct a systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing the effects of exercise and dietary interventions alone or in combination on anthropometric measures of adult cancer patients and survivors. Methods A systematic search of Medline, Embase and the Cochrane Trials Registry was performed. Outcomes of interest included changes in weight, body mass index (BMI), and waist circumference. Screening and data collection were performed by two reviewers. Bayesian NMAs were performed. Results Overall, 98 RCTs were included; 75 were incorporated in NMAs (n = 12,199). Groups of intervention strategies included: 3 exercise interventions, 8 dietary interventions, 7 combination interventions of diet and exercise and standard care. Median intervention duration was 26 weeks. NMA suggested that diet alone (mean difference [MD] -2.25kg, 95% CrI -3.43 to -0.91kg) and combination strategies (MD -2.52kg, 95% CrI -3.54 to -1.62kg) were associated with more weight loss compared to standard care. All dietary interventions achieved a similar magnitude of weight loss (MD range from -2.03kg to -2.52kg). Both diet alone and combination strategies demonstrated greater BMI reductions versus standard care, and each of diet alone, exercise alone and combination strategies demonstrated greater reductions in waist circumference than standard care. Conclusion Diet and exercise alone or in combination are effective lifestyle interventions to improve anthropometric measures in cancer patients and survivors. All reputable diets appear to be similarly effective to achieve weight loss.

Objective This overview of reviews aims to map and compare of objectives, methods, and findings of existing systematic reviews to develop a greater understanding of the information available about prolonged beta-lactam infusions in hospitalized patients with infection. Design Overview of systematic reviews. Data sources Medline, Embase, PROSPERO and the Cochrane Library were systematically searched from January, 1990 to June, 2019 using a peer reviewed search strategy. Grey literature was also searched for relevant reviews. Eligibility criteria for selecting reviews Systematic reviews were sought that compared two or more infusion strategies for intravenous beta-lactam antimicrobials and report clinical cure or mortality. Populations of included reviews were restricted to hospitalized patients with infection, without restrictions on age, infection type, or disease. Data extraction and analysis Abstract screening, data extraction, quality and risk of bias assessment were conducted by two independent reviewers. Overlap between reviews was assessed using a modified corrected covered area. Overview findings are reported in accordance with Cochrane’s recommendation for overview conduct. Clinical outcomes extracted included survival, clinical cure, treatment failure, microbiological cure, length of stay, adverse events, cost, and emergence of resistance. Results The search strategy identified 3327 unique citations from which 21 eligible reviews were included. Reviews varied by population, intervention and outcomes studied. Between reviews, overlap of primary studies was generally high, methodologic quality generally low and risk of bias variable. Nine of 14 reviews that quantitatively evaluated mortality and clinical cure identified a benefit with prolonged infusions of beta lactams when compared with intermittent infusions. Evidence of mortality and clinical cure benefit was greater among critically ill patients when compared to less sick patients and lower in randomized controlled trials when compared with observational studies. Conclusions Findings from our review demonstrate a consistent and reproducible lack of harm with prolonged infusions of beta-lactam antibiotics with variability in effect size and significance of benefits. Despite 21 systematic reviews addressing prolonged infusions of beta-lactams, this overview supports the continued need for a definitive systematic review given variability in populations, interventions and outcomes in the current systematic reviews. Subsequent systematic reviews should have more rigorous and transparent methods, only include RCTs and evaluate the proposed benefits found in various subgroup-analyses—i.e. high risk of mortality. Trial registration Prospero registry, CRD42019117118.

Single photon emission computed tomography (SPECT) and SPECT-CT are widely used in clinical practice, mostly based on rotation of planar gamma cameras. Tomographic images are reconstructed mainly using iterative algorithms that permit use of flexible geometry and can easily incorporate various corrections. There are several recent advances in instrumentation that include the use of solid state detectors and specialized collimators with improved performance in terms of spatial resolution and/or energy resolution. Compact systems can be constructed that are well suited to organ-specific application with advantages over conventional rotating cameras. With appropriate correction for attenuation and scatter, as well as the effects of motion and limited resolution, absolute quantification of activity concentration is possible. This is particularly important in the increasingly important area of theranostics where radiation dose to target organs or tissues at risk can be estimated.

Purpose Despite the increasing use of adjuvant bone-modifying agents (BMAs) such as zoledronate and clodronate in the treatment of patients with early stage breast cancer (EBC), little is known about real world practice patterns. A physician survey was performed to address this deficit and determine interest in clinical trials of alternative strategies for BMA administration. Methods Canadian oncologists treating patients with EBC were surveyed via an anonymized online survey. The survey collected information on: physician demographics, knowledge and interpretation of adjuvant bisphosphonate guidelines, and real world prescribing practices. Questions also determined thoughts around the design of future adjuvant BMA trials. Results Of 127 surveyed physicians, 53 eligible invitees responded (response rate 42%). The majority of physicians are offering high-risk postmenopausal patients adjuvant BMAs. The most common BMA regimen was adjuvant zoledronate (45/53, 85%) every 6 months for 3 years. Concerns around toxicities and repeated visits to the cancer centre were perceived as the greatest barriers to adjuvant bisphosphonate use. Respondents were interested in future trials of de-escalation of BMAs comparing a single infusion of zoledronate vs. 6-monthly zoledronate for 3 years. The most favoured primary endpoints for such a trial included disease recurrence and fragility fracture rates. Conclusion Questions around optimal use of adjuvant bisphosphonates in patients with EBC still exist. There is interest among physicians in performing trials of de-escalation of these agents. The results of this survey will assist in designing pragmatic clinical trials to address this question. Supplementary Information The online version contains supplementary material available at 10.1007/s10549-021-06147-1.

When used during surgery, antifibrinolytic hemostatic agents such as lysine analogues are effective at reducing blood loss and the need for transfusions. Despite proven efficacy, use of hemostatic agents remains low during some surgeries. Our objective was to explore surgeon opinions about, and use of lysine analogues in, oncologic surgeries at a large tertiary care academic institution. We administered a survey to surgeons who perform high-transfusion-risk oncologic surgeries at a large academic hospital in Ottawa, Ontario. Design and distribution of the survey followed a modified Dillman method. To ensure that the survey questionnaire was relevant, clear, and concise, we performed informant interviews, cognitive interviews, and pilot-testing. The final survey consisted of 19 questions divided into 3 sections: respondent demographics, use of hemostatic agents, and potential clinical trial opinions. Of 28 surgeons, 24 (86%) participated. When asked to indicate the frequency of lysine analogue use, &ldquo, never&rdquo, accounted for 46% of the responses, and &ldquo, rarely&rdquo, (, unfamiliar with benefits&rdquo, and &ldquo, prefer alternatives.&rdquo, Fifteen surgeons (63%) felt that a trial was needed to demonstrate the efficacy and safety of lysine analogues in their cancer field. Our survey found that lysine analogues are infrequently used during oncologic surgeries at our institution. Many surgeons are unfamiliar with the benefits and side effects of lysine analogues and, alternatively, use topical hemostatic agents. Our results demonstrate that future trials exploring the efficacy and safety of lysine analogues in oncologic surgery are needed.

IntroductionVenous thromboembolism (VTE) is a common, potentially fatal yet treatable disease. Several advances in treatment of VTE have been made over the past decades, but definition and reporting of outcomes across those studies are inconsistent. Development of an international core outcome set for clinical studies of interventions for VTE addresses this lack of standardisation. The first step in the development of a core outcome set is to conduct a scoping review which aims to generate an inclusive list of unique outcomes that have been reported in previous studies.Methods and analysisMEDLINE, Embase and the Cochrane Central Register of Controlled Trials will be searched with no language restriction for prospective studies reporting on interventions for treatment of VTE in patients who are adult and non-pregnant. Records will be sorted in reverse chronological order. Study screening and data extraction will be independently performed by two authors in blocks based on date of publication, starting with 2015 to 2020 and subsequent 1-year periods, until no new outcome measures are identified from the set of included studies. After homogenising spelling and combining outcomes with the same meaning, a list of unique outcomes will be determined. Those outcomes will be grouped into outcome domains. Qualitative analysis and descriptive statistics will be used to report results.Ethics and disseminationEthical approval is not required for this study. The results of this scoping review will be presented at scientific conferences, published in a peer-reviewed journal, and they will provide candidate outcome domains to be considered in subsequent steps in the development of a core outcome set for clinical studies of interventions for VTE.Protocol registration detailshttp://hdl.handle.net/10393/40459

Respiratory motion correction is beneficial in positron emission tomography. Different strategies for handling attenuation correction in conjunction with motion correction exist. In clinical practice, usually a single attenuation map is available, derived from computed tomography in one respiratory state. This can introduce an unwanted bias (through misaligned anatomy) into the motion correction algorithm. This paper builds upon previous work which suggested that non-attenuation corrected data was suitable for motion estimation, through the use of motion models, if time-of-flight data are available. Here, the previous work is expanded upon by incorporating attenuation correction in an iterative process. Non-attenuation corrected volumes are reconstructed using ordered subset expectation maximisation and used as input for motion model estimation. A single attenuation map is then warped to the volumes, using the motion model, the volumes are attenuation corrected, after which another motion estimation and correction cycle is performed. For validation, 4-Dimensional Extended Cardiac Torso simulations are used, for one bed position, with a field of view including the base of the lungs and the diaphragm. The output from the proposed method is evaluated against a non-motion corrected reconstruction of the same data visually, using a profile as well as standardised uptake value analysis. Results indicate that motion correction of inter-respiratory cycle motion is possible with this method, while accounting for attenuation deformation.

Several groups have considered the option of using multiple-energy window emission data to improve reconstruction accuracy for PET/MR imaging. However, the feasibility of this approach has only been studied with analytic simulations. To be able to handle realistic measurements a remaining challenge is related to the detection efficiencies (“normalisation”) for the different energy windows, which likely differ for scattered and unscattered events given the heterogeneity of photon energies, angles of incidence, and points of origination. In addition, the lower energy windows will potentially contain events that have been affected by scatter in the detector. This manuscript investigates the problem of estimating the normalisation factors for PET data acquired from multiple energy windows.

Accurate quantification of radiopharmaceutical uptake from lung PET/CT is challenging due to large variations in fractions of tissue, air, blood and water. Air fraction correction (AFC) uses voxel-wise air fractions, which can be determined from the CT acquired for attenuation correction (AC). However, resolution effects can cause artefacts in either of these corrections. In this work, we hypothesise that the resolution of the CT image used for AC should match that of the intrinsic resolution of the PET scanner but should approximate the reconstructed PET image resolution for AFC. Simulations and reconstructions were performed with the Synergistic Image Reconstruction Framework (SIRF) using phantoms with inhomogeneous attenuation (mu) maps, mimicking the densities observed in lung pathologies. Poisson noise was added to the projection data prior to OSEM reconstruction. AC was performed with a smoothed mu-map, the full-width-half-maximum (FWHM) of the 3D Gaussian kernel was varied (0 - 10 mm). Post-filters were applied to the reconstructed AC images (FWHM: 0 - 8 mm). The simulated mu-map was independently convolved with another set of 3D Gaussian kernels, of varying FWHM (0 - 12 mm), for AFC. The coefficient of variation (CV) in the lung region, designed to be homogeneous post-AFC with optimised kernels, and the mean AFC-standardized uptake value (AFC-SUV) in the regions of simulated pathologies were determined. The spatial resolution of each post-filtered image was determined via a point-source insertion-and-subtraction method on noiseless data. Results showed that the CV was minimised when the kernel applied to the mu-map for AC matched that for the simulated PET scanner and the kernel applied to the mu-map for AFC matched the spatial resolution of the reconstructed PET image. This was observed for all post-reconstruction filters and supports the hypothesis. Initial results from Monte Carlo simulations validate these findings.

Penalised PET image reconstruction methods are often accelerated with the use of only a subset of the data at each update. It is known that many subset algorithms, such as Ordered Subset Expectation Maximisation, do not converge to a single solution but to a limit cycle, which can lead to variations between subsequent image estimates. A new class of stochastic variance reduction optimisation algorithms have been recently proposed for general optimisation problems. These methods aim to reduce the subset update variance by incorporating previous subset gradients into the update direction computation. This work applies three of these algorithms to iterative PET penalised reconstruction and exhibits superior performance to standard deterministic reconstruction methods after only a few epochs.

The estimation of the Depth-of-Interaction (DOI) of detected gamma photons is especially challenging for thick scintillators, yet relevant for moderately thin ones (8 mm CsI(Tl) in our case) employed in nuclear imaging. In SPECT, in particular using pinhole or slit-slat collimation, the parallax error produced by photons passing through the collimator holes, with trajectories non orthogonal to the crystal surface, can be reduced by including the DOI information into the tomographic reconstruction. We present an algorithm based on maximum likelihood that classifies into 4 layers the events absorbed in the scintillator. A novel initialization signal (a ring footprint surrounding the channel detecting the highest intensity) is proposed, only requiring a flood field irradiation as training. The algorithm is experimentally validated by means of a tilted collimated beam on a single camera. The DOI information will be applied in a stationary clinical MRI-compatible SPECT insert which is composed of 20 identical modules mounted in a partial ring.

BACKGROUND The COVID-19 pandemic has had a negative impact on both the physical and mental health of individuals worldwide. Evidence regarding the association between mental health problems and information exposure among Thai citizens during the COVID-19 outbreak is limited. OBJECTIVE This study aimed to explore the relationship between information exposure and mental health problems during the COVID-19 pandemic in Thailand. METHODS Between April 21 and May 4, 2020, we conducted a cross-sectional, nationwide online survey of the general population in Thailand. We categorized the duration of exposure to COVID-19-related information as follows: RESULTS Of the 4322 eligible participants, 4004 (92.6%) completed the online survey. Of them, 1481 (37.0%), 1644 (41.1%), and 879 (22.0%) participants were exposed to COVID-19-related information for less than 1 hour per day, 1 to 2 hours per day, or 3 or more hours per day, respectively. The major source of information related to the COVID-19 pandemic was social media (95.3%), followed by traditional media (68.7%) and family members (34.9%). Those exposed to information for 3 or more hours per day had a higher risk of developing symptoms of depression (adjusted odds ratio [OR] 1.35, 95% CI 1.03-1.76; P=.03), anxiety (adjusted OR 1.88, 95% CI 1.43-2.46; PP=.001) than people exposed to information for less than 1 hour per day. Meanwhile, people exposed to information for 1 to 2 hours per day were only at risk of developing symptoms of anxiety (adjusted OR 1.35, 95% CI 1.08-1.69; P=.008). However, no association was found between information exposure and the risk of perceived stress. In the ancillary analysis, a dose-response relationship was observed between information exposure of 3 or more hours per day and the severity of mental health problems. CONCLUSIONS These findings suggest that social media is the main source of COVID-19-related information. Moreover, people who are exposed to information for 3 or more hours per day are more likely to develop psychological problems, including depression, anxiety, and insomnia. Longitudinal studies investigating the long-term effects of COVID-19-related information exposure on mental health are warranted.