Search

Purpose To compare the effects of prevention interventions on delirium occurrence in critically ill adults. Methods MEDLINE, Embase, PsychINFO, CINAHL, Web of Science, Cochrane Library, Prospero, and WHO international clinical trial registry were searched from inception to April 8, 2021. Randomized controlled trials of pharmacological, sedation, non-pharmacological, and multi-component interventions enrolling adult critically ill patients were included. We performed conventional pairwise meta-analyses, NMA within Bayesian random effects modeling, and determined surface under the cumulative ranking curve values and mean rank. Reviewer pairs independently extracted data, assessed bias using Cochrane Risk of Bias tool and evidence certainty with GRADE. The primary outcome was delirium occurrence; secondary outcomes were durations of delirium and mechanical ventilation, length of stay, mortality, and adverse effects. Results Eighty trials met eligibility criteria: 67.5% pharmacological, 31.3% non-pharmacological and 1.2% mixed pharmacological and non-pharmacological interventions. For delirium occurrence, 11 pharmacological interventions (38 trials, N = 11,993) connected to the evidence network. Compared to placebo, only dexmedetomidine (21/22 alpha2 agonist trials were dexmedetomidine) probably reduces delirium occurrence (odds ratio (OR) 0.43, 95% Credible Interval (CrI) 0.21–0.85; moderate certainty). Compared to benzodiazepines, dexmedetomidine (OR 0.21, 95% CrI 0.08–0.51; low certainty), sedation interruption (OR 0.21, 95% CrI 0.06–0.69; very low certainty), opioid plus benzodiazepine (OR 0.27, 95% CrI 0.10–0.76; very low certainty), and protocolized sedation (OR 0.27, 95% CrI 0.09–0.80; very low certainty) may reduce delirium occurrence but the evidence is very uncertain. Dexmedetomidine probably reduces ICU length of stay compared to placebo (Ratio of Means (RoM) 0.78, CrI 0.64–0.95; moderate certainty) and compared to antipsychotics (RoM 0.76, CrI 0.61–0.98; low certainty). Sedative interruption, protocolized sedation and opioids may reduce hospital length of stay compared to placebo, but the evidence is very uncertain. No intervention influenced mechanical ventilation duration, mortality, or arrhythmia. Single and multi-component non-pharmacological interventions did not connect to any evidence networks to allow for ranking and comparisons as planned; pairwise comparisons did not detect differences compared to standard care. Conclusion Compared to placebo and benzodiazepines, we found dexmedetomidine likely reduced the occurrence of delirium in critically ill adults. Compared to benzodiazepines, sedation-minimization strategies may also reduce delirium occurrence, but the evidence is uncertain. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06490-3.

Background Primary febrile neutropenia (FN) prophylaxis with ciprofloxacin or granulocyte-colony stimulating factors (G-CSF) is recommended with docetaxel-cyclophosphamide (TC) chemotherapy for early-stage breast cancer (EBC). A pragmatic randomised trial compared the superiority of G-CSF to ciprofloxacin and a cost-utility analysis were conducted. Methods EBC patients receiving TC chemotherapy were randomised to ciprofloxacin or G-CSF. The primary outcome was a composite of FN and non-FN treatment-related hospitalisation. Secondary outcomes included; rates of FN, non-FN treatment-related hospitalisation, chemotherapy dose reductions/delays/discontinuations. Primary analysis was performed with the intention to treat population. Cost-utility analyses were conducted from the Canadian public payer perspective. Results 458 eligible patients were randomised: 228 to ciprofloxacin and 230 to G-CSF. For the primary endpoint there was non-statistically significant difference (Risk difference = −6.7%, 95%CI = −13.5%–0.1%, p = 0.061) between ciprofloxacin patients (46,20.2%) and G-CSF (31,13.5%). Patients receiving ciprofloxacin were more likely to experience FN (36/228, 15.8% vs 13/230, 5.7%) than patients receiving G-CSF (p, Highlights • Primary febrile neutropenia (FN) prophylaxis is indicated for docetaxel-cyclophosphamide (TC) chemotherapy. • In this multicentre trial 458 breast cancer patients receiving TC chemotherapy were randomised to ciprofloxacin or to G-CSF. • For the primary endpoint of FN and non-FN treatment-related hospitalizations, G-CSF was not superior over ciprofloxacin. • While there were reduced FN rates with G-CSF, the incremental cost-effectiveness ratio was C$1,760,796 per one QALYWALY gained.

Background: Non-compliance and non-persistence with endocrine therapy for breast cancer is common and usually related to treatment-induced side effects. There are anecdotal reports that simply changing the time of day when taking endocrine therapy (i.e., changing morning dosing to evening dosing or vice versa) can reduce side effects. Literature review: We conducted a literature review to evaluate whether changing the timing of tamoxifen and/or aromatase inhibitor administration impacted patient outcomes. No randomized control trials or prospective cohort studies that looked at time of day of endocrine therapy were identified through our review of literature from 1947 until August 2020. Conclusions: Given the rates of endocrine therapy non-compliance and non-persistence reported in the literature, ranging from 41–72% and 31–73%, respectively, simply changing the time of day when medications are taken could be an important strategy. We could identify no trials evaluating the effect of changes in timing of administration of endocrine therapy on breast cancer patient outcomes. Randomized control trials are clearly indicated for this simple and cost-effective intervention.

To provide a contemporary global prevalence of mental health issues among the general population amid the coronavirus disease-2019 (COVID-19) pandemic. We searched electronic databases, preprint databases, grey literature, and unpublished studies from January 1, 2020, to June 16, 2020 (updated on July 11, 2020), with no language restrictions. Observational studies using validated measurement tools and reporting data on mental health issues among the general population were screened to identify all relevant studies. We have included information from 32 different countries and 398,771 participants. The pooled prevalence of mental health issues amid the COVID-19 pandemic varied widely across countries and regions and was higher than previous reports before the COVID-19 outbreak began. The global prevalence estimate was 28.0% for depression; 26.9% for anxiety; 24.1% for post-traumatic stress symptoms; 36.5% for stress; 50.0% for psychological distress; and 27.6% for sleep problems. Data are limited for other aspects of mental health issues. Our findings highlight the disparities between countries in terms of the poverty impacts of COVID-19, preparedness of countries to respond, and economic vulnerabilities that impact the prevalence of mental health problems. Research on the social and economic burden is needed to better manage mental health problems during and after epidemics or pandemics. Systematic review registration: PROSPERO CRD 42020177120.

Background Optimal use of bone-modifying agent (BMA) therapy in patients with bone metastases from breast and castrate-resistant prostate cancer (CRPC) is evolving. Methods Patients receiving BMA for bone metastases from breast or CRPC were surveyed. Information was collected on patient and disease characteristics, BMA treatments and perceptions regarding BMA benefits and side effects. Interest in participation in trials of de-escalated BMA therapy was also gauged. Results Of 220 patients contacted, 172 eligible patients responded (response rate 78%). Median age was 67 (range: 21–91); 137 (80%) had breast cancer and 35 (20%) CRPC. Symptomatic skeletal events (SSEs) occurred prior to starting BMAs in 61% (84/137) of breast and 48% (17/35) of CRPC patients. Among breast cancer patients, 47, 33 and 13% received zoledronate, pamidronate and denosumab, respectively. Eighty-five percent (30/35) of CRPC patients received denosumab. De-escalation of therapy was more common among breast cancer patients. Although most patients correctly reported the goals of BMA therapy were to “help stop fractures” (62%) and “[improve] quality of life” (63%), 46.5% felt it prolonged survival and 54% felt it reduced bone progression. Most respondents (102/129, 79%) were comfortable with de-escalating to 6-monthly treatment after 2 years of BMA therapy. Patients considered the most important endpoints of de-escalation studies to be “stability of bone metastases” (45%), “quality of life” (22%) and “SSE rates” (14%). Conclusion Twelve weekly BMA was more common in breast than in prostate cancer. There remain misconceptions about the benefits of BMAs, highlighting potential gaps in patient education. Patients were interested in further BMA de-escalation after 2 years of prior BMA and provided study endpoints that were most important to them. Supplementary Information The online version contains supplementary material available at 10.1007/s00520-021-06238-1.

Taxane-associated pain syndrome (TAPS) is common with docetaxel and is characterised by myalgias and arthralgias starting 2–3 days after treatment and can last for up to 7 days. Anecdotal evidence suggests that corticosteroids can reduce TAPS. This multicentre, randomized trial evaluated the effect of additional tapering dexamethasone on TAPS. 130 breast cancer patients commencing docetaxel were randomized to dexamethasone premedication (8 mg/twice daily for 3 days) or dexamethasone premedication followed by tapering dexamethasone (4 mg/daily for 2 days followed by 2 mg/daily for 2 days). The primary endpoint was absolute change in FACT-Taxane questionnaire during the first chemotherapy cycle. Secondary endpoints: proportion of patients with clinically significant TAPS, QoL, pain and toxicity. 110/130 patients had complete data included in the primary analysis. The fall in FACT-Taxane scores was lower in the experimental group on day 5 (p = 0.05), but not on day 7 (p = 0.21). There was no difference in FACT-Taxane scores over the entire study duration (p = 0.59). Fewer patients in the experimental arm reported TAPS on day 5 (30 vs. 47%). There was a borderline significant attenuation of impairment of QoL with experimental treatment on day 5 (p = 0.06), but not day 7 (p = 0.53). Tapered schedule was associated with more dyspepsia and insomnia. A tapering schedule of dexamethasone was associated with a brief reduction in docetaxel-associated symptoms which was observed only during dexamethasone exposure and did not persist after discontinuation of the drug. ClinicalTrials.gov NCT03348696

Cell‐based therapies hold promise to substantially curb complications from extreme preterm birth, the main cause of death in children below the age of 5 years. Exciting preclinical studies in experimental neonatal lung injury have provided the impetus for the initiation of early phase clinical trials in extreme preterm infants at risk of developing bronchopulmonary dysplasia. Clinical translation of promising therapies, however, is slow and often fails. In the adult population, results of clinical trials so far have not matched the enticing preclinical data. The neonatal field has experienced many hard‐earned lessons with the implementation of oxygen therapy or postnatal steroids. Here we briefly summarize the preclinical data that have permitted the initiation of early phase clinical trials of cell‐based therapies in extreme preterm infants and describe the INCuBAToR concept (Innovative Neonatal Cellular Therapy for Bronchopulmonary Dysplasia: Accelerating Translation of Research), an evidence‐based approach to mitigate the risk of translating advanced therapies into this vulnerable patient population. The INCuBAToR addresses several of the shortcomings at the preclinical and the clinical stage that usually contribute to the failure of clinical translation through (a) systematic reviews of preclinical and clinical studies, (b) integrated knowledge transfer through engaging important stakeholders early on, (c) early economic evaluation to determine if a novel therapy is viable, and (d) retrospective and prospective studies to define and test ideal eligibility criteria to optimize clinical trial design. The INCuBAToR concept can be applied to any novel therapy in order to enhance the likelihood of success of clinical translation in a timely, transparent, rigorous, and evidence‐based fashion., The INCuBAToR is a framework built into the classical clinical translation pathway from laboratory discovery to human trials. It is designed to mitigate the risk of translating cell therapies into the clinic by providing an evidence‐based approach. Systematic reviews, integrated knowledge translation, early economic evaluation, and retro‐ and prospective observational cohort studies can substantially enhance success of the clinical translation.

Background Major depressive disorder is common, debilitating, and affects feelings, thoughts, mood, and behaviors. Childhood and adolescence are critical periods for the development of depression and adolescence is marked by an increased incidence of mental health disorders. This protocol outlines the planned scope and methods for a systematic review update that will evaluate the benefits and harms of screening for depression in children and adolescents. Methods This review will update a previously published systematic review by Roseman and colleagues. Eligible studies are randomized controlled trials (RCTs) assessing formal screening in primary care to identify children or adolescents not already self-reporting symptoms of, diagnosed with, or treated for depression. If no or only a single RCT is available, we will consider controlled studies without random assignment. Studies of participants with characteristics associated with an elevated risk of depression will be analyzed separately. Outcomes of interest are symptoms of depression, classification of major depressive disorder based on a validated diagnostic interview, suicidality, health-related quality of life, social function, impact on lifestyle behavior (e.g., substance use, school performance, lost time at work, or school), false-positive results, overdiagnosis, overtreatment, labeling, and other harms such as those arising from treatment. We will search MEDLINE, Embase, PsycINFO, CINAHL, the Cochrane Library, and grey literature sources. Two reviewers will independently screen the titles and abstracts using the liberal accelerated method. Full-text screening will be performed independently by two reviewers using pre-specified eligibility criteria. Data extraction and risk of bias assessments will be performed independently by two reviewers. Pre-planned analyses, including subgroup and sensitivity analyses, are detailed within this protocol. Two independent reviewers will assess and finalize through consensus the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, and prepare GRADE evidence profiles and summary of findings tables for each outcome of interest. Discussion The systematic review will provide a current state of the evidence of benefits and harms of depression screening in children and adolescents. These findings will be used by the Canadian Task Force on Preventive Health Care to inform the development of recommendations on depression screening. Systematic review registration PROSPERO CRD42020150373

Background: The effectiveness of different acellular dermal matrices (ADM) used for implant-based reconstruction immediately following mastectomy is an important clinical question. A prospective randomized clinical trial was performed to evaluate the superiority of DermACELL over Alloderm-RTU in reducing drain duration. Methods: Patients undergoing mastectomy with subpectoral immediate and permanent implant-based breast reconstruction were randomized to Alloderm-RTU or DermACELL. The primary outcome was seroma formation, measured by the duration of postoperative drain placement. Secondary outcomes included: post drain removal seroma aspiration, infection, redbreast syndrome, wound dehiscence, loss of the implant, and unplanned return to the operating room. Results: 62 patients were randomized for 81 mastectomies (41 Alloderm-RTU, 40 DermACELL). Baseline characteristics were similar. There was no statistically significant difference in mean drain duration (p = 0.16), with a trend towards longer duration in the Alloderm-RTU group (1.6 days, 95%CI, 0.7 to 3.9). The overall rate of minor and major complications were statistically similar between the two groups, although patients with Alloderm-RTU had 3 times as many infections requiring antibiotics (7.9% vs. 2.5%) with a risk difference of 5.4 (95%CI &minus, 4.5 to 15.2), and twice as many unplanned returns to the operating room (15.8% vs. 7.5%) with a risk difference of 8.3 (95% CI &minus, 5.9 to 22.5) as DermACELL. Conclusion: This is the first prospective randomized clinical trial comparing the two most commonly used human-derived ADMs. There was no statistically significant difference in drain duration, minor, or major complications between DermACELL over Alloderm-RTU in immediate subpectoral permanent implant-based breast reconstruction post-mastectomy.

Choosing Wisely (CW)® was created by the American Board of Internal Medicine (ABIM) to promote patient–physician conversations about unnecessary medical interventions. Similarly, other countries created their own panels of experts called “CW® campaigns” which review recommendations submitted by that country’s oncology societies. We performed a scoping review to consolidate CW® recommendations from different groups with respect to breast cancer care. A systematic search of Medline and Embase was designed by an information specialist for publications presenting CW® recommendations for breast cancer care practices from 2011–2020. We also reviewed the websites of all CW® campaigns and reference sections of each CW® recommendation. Two reviewers independently screened studies for inclusion and performed data extraction. Findings were summarized narratively. Review of ABIM CW® recommendations showed 19 breast cancer-related recommendations pertaining to; screening (n = 4), radiological staging (n = 2), treatment (n = 10), surveillance (n = 2), and miscellaneous (genetic testing; n = 1). Of 22 countries with CW® campaigns, 10 published recommendations for breast cancer. Over half (57%) of recommendations were supported by more than one country. No recommendations were refuted between campaigns. Two campaigns developed 3 novel recommendations on new topics, including chemotherapy in ductal carcinoma in situ (Italy) and comparison of screening imaging modalities (Portugal). CW® recommendations focus on reducing overutilization of investigations and treatments. There was a high rate of consensus between different CW® campaigns. As health care systems globally move attention to reduce low-value care, further studies are required to address adherence to these current recommendations and develop new recommendations.

Prior to docetaxel chemotherapy, incomplete dosing of steroid premedication is common. The lack of standardized steroid replacement strategies can lead to variability in care and delays in starting docetaxel. This randomized trial compared physician-directed with fixed-dose dexamethasone. Patients who had missed at least one dose of steroid premedication were randomized to physician-directed replacement (any choice of steroid, dose or route) or to dexamethasone 8 mg oral before starting docetaxel. The primary outcome was time from randomization to starting docetaxel. Secondary outcomes included rates of acute and delayed hypersensitivity reactions, fluid retention and skin toxicity. Of 60 eligible patients, 30 (50%) and 30 (50%) were randomized to physician-directed and fixed-dose arms, respectively. Overall tumour types: breast (42 [70%]), gastrointestinal (7 [12%]), prostate (7 [12%]) and lung (3 [7%]). Dexamethasone was most commonly incompletely taken with cycles 1 (28 [48%]) and 2 (13 [22%]) of docetaxel. Seven different replacement strategies were used in the physician-choice arm. Patients in the fixed-dose arm received docetaxel a mean of 21.2 (95% CI for the difference is 2.1 to 44.6) minutes earlier than the physician-choice arm (p = 0.033 Wilcoxon rank sum test or p = 0.073 two-sample t test). Median time to docetaxel was 47.5 vs 61 min (mean 62.2 vs 83.4 min) by arm, respectively. No significant difference in toxicity rates was observed. While not meeting our predefined criteria of improving the time from randomization to starting docetaxel by 30 min, the fixed-dose replacement strategy reduced both the time to starting docetaxel and treatment variability. Fixed dosing with oral dexamethasone 8 mg should be the preferred standard of care. www.clinicaltrials.gov NCT02815319 June 28, 2016

PET with (18)F-FDG has been increasingly applied, predominantly in the research setting, to study drug effects and pulmonary biology and to monitor disease progression and treatment outcomes in lung diseases that interfere with gas exchange through alterations of the pulmonary parenchyma, airways, or vasculature. To date, however, there are no widely accepted standard acquisition protocols or imaging data analysis methods for pulmonary (18)F-FDG PET/CT in these diseases, resulting in disparate approaches. Hence, comparison of data across the literature is challenging. To help harmonize the acquisition and analysis and promote reproducibility, we collated details of acquisition protocols and analysis methods from 7 PET centers. From this information and our discussions, we reached the consensus recommendations given here on patient preparation, choice of dynamic versus static imaging, image reconstruction, and image analysis reporting.

Positron emission tomography/computed tomography (PET/CT) lung imaging is highly sensitive to motion. Although several techniques exist to diminish motion artifacts, a few accounts for both tissue displacement and changes in density due to the compression and dilation of the lungs, which cause quantification errors. This article presents an experimental framework for joint activity image reconstruction and motion estimation in PET/CT, where the PET image and the motion are directly estimated from the raw data. Direct motion estimation methods for motion-compensated PET/CT are preferable as they require a single attenuation map only and result in optimal signal-to-noise ratio (SNR). Previous implementations, however, failed to address changes in density during respiration. We propose to account for such changes using the Jacobian determinant of the deformation fields. In a feasibility study, we demonstrate on a modified extended cardiac-torso (XCAT) phantom with breathing motion—where the lung density and activity vary—that our approach achieved better quantification in the lungs than conventional PET/CT joint activity image reconstruction and motion estimation that does not account for density changes. The proposed method resulted in lower bias and variance in the activity images, reduced mean relative activity error in the lung at the reference gate (−4.84% to −3.22%) and more realistic Jacobian determinant values.

Background The optimal duration of filgrastim as primary febrile neutropenia (FN) prophylaxis in early breast cancer patients is unknown, with 5, 7 or 10 days being commonly prescribed. This trial evaluates whether 5 days of filgrastim was non-inferior to 7/10 days. Patients and methods In this randomised, open-label trial, early breast cancer patients who were to receive filgrastim as primary FN prophylaxis were randomly allocated to 5 versus 7 versus 10 days of filgrastim for all chemotherapy cycles. A protocol amendment in November 2017 allowed subsequent patients (N = 324) to be randomised to either 5 or 7/10 days. The primary outcome was a composite of either FN or treatment-related hospitalisations. Secondary outcomes included chemotherapy dose reductions, delays and discontinuations. Analyses were carried out by per protocol (primary) and intention-to-treat, and the non-inferiority margin was set at 3% for the risk of having FN and/or hospitalisation per cycle of chemotherapy. Results Patients (N = 466) were randomised to receive 5 (184, 39.5%), or 7/10 (282, 60.5%) days of filgrastim. In our primary analysis, the difference in risk of either FN or treatment-related hospitalisation per cycle was −1.52% [95% confidence interval (CI): −3.22% to 0.19%] suggesting non-inferiority of a 5-day filgrastim schedule compared with 7/10-days. The difference in events per cycle for FN was 0.11% (95% CI: −1.05 to 1.27) while for treatment-related hospitalisations it was −1.68% (95% CI: −2.73% to −0.63%). The overall proportions of patients having at least one occurrence of either FN or treatment-related hospitalisation were 11.8% and 14.96% for the 5- and 7/10-day groups, respectively (risk difference: −3.17%, 95% CI: −9.51% to 3.18%). Conclusion Five days of filgrastim was non-inferior to 7/10 days. Given the cost and toxicity of this agent, 5 days should be considered standard of care. ClinicalTrials.gov registration NCT02428114 and NCT02816164.

Bone-modifying agents (BMAs) for bone metastases are commonly prescribed for many years even though randomized clinical trials are only 1–2 years in duration. A systematic review on the risk-benefit of BMA use for > 2 years in breast cancer or castrate-resistant prostate cancer was conducted. MEDLINE, Embase, and Cochrane databases were searched (1970–February 2019) for randomized and observational studies, and case series reporting on BMA efficacy (skeletal-related events and quality of life) and toxicity (osteonecrosis of the jaw, renal impairment, hypocalcemia, and atypical femoral fractures) beyond 2 years. Of 2107 citations, 64 studies were identified. Three prospective and 9 retrospective studies were eligible. Data beyond 2 years was limited to subgroup analyses in all studies. Only one study (n = 181) reported skeletal-related event rates based on bisphosphonate exposure, with decreased rates from 27.6% (0–24 months) to 15.5% (> 24 months). None reported on quality of life. All 12 studies (denosumab (n = 948), zoledronate (n = 1036), pamidronate (n = 163), pamidronate-zoledronate (n = 522), ibandronate (n = 118)) reported ≥ 1 toxicity outcome. Seven bisphosphonate studies (n = 1077) and one denosumab study (n = 948) reported on osteonecrosis of the jaw. Across three studies (n = 1236), osteonecrosis of the jaw incidence ranged from 1 to 4% in the first 2 years to 3.8–18% after 2 years. Clinically significant hypocalcemia ranged from 1 to 2%. Severe renal function decline was ≤ 3%. Atypical femoral fractures were rare. Evidence informing the use of BMA beyond 2 years is heterogeneous and based on retrospective analysis. Prospective randomized studies with greater emphasis on quality of life are needed. CRD42019126813

Background: There is increasing evidence that premature newborns and infants with low birth weight can benefit substantially from an exclusive human milk-based diet (EHMD), consisting of human milk...

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.

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).

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.

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

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.

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.

[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.

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.

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.

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%).

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.

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.

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

Background Methamphetamine use and harms are rising rapidly. Management of patients with methamphetamine use disorder (MUD) and problematic methamphetamine use (PMU) is challenging, with no clearly established best approach; both psychosocial and pharmacologic interventions have been described. Furthermore, given the diversity of individuals that use methamphetamines, there is a need to assess evidence for treatments for subgroups including youths; gay, bisexual, and other men who have sex with men; individuals with mental health comorbidities; and individuals in correction services. Establishing awareness of the messages regarding treatment from recent clinical practice guidelines (CPG) in the field is also of value. The first study objective will be to establish a greater understanding of the methods, populations, and findings of controlled studies for psychosocial and pharmacologic treatments for MUD and PMU. Investigation of this information can help establish the potential for advanced syntheses of the evidence (such as network meta-analysis) to compare therapies for this condition and to identify gaps related to key populations where more primary research is needed. Summarizing the recommendations regarding treatment of MUD/PMU from recent CPGs and systematic reviews will be an important secondary objective. Methods A scoping review will be performed. Using the OVID platform, MEDLINE, Embase, PsycINFO, and relevant Cochrane databases from EBM Reviews will be searched (from databases’ inception onwards). Eligibility criteria will include individuals described as having MUD or PMU, with designs of interest including randomized trials, non-randomized trials, and controlled cohort studies with three or more months of follow-up; systematic reviews and CPGs will also be sought. Two reviewers (with support from automation tools) will independently screen all citations, full-text articles, and chart data. Different approaches to handling and summarizing the data will be implemented for each type of study design. Tables and graphics will be used to map evidence sources and identify evidence gaps. Discussion This research will enhance awareness of evidence addressing the effects of psychosocial and pharmacologic interventions for MUD/PMU overall and in sub-populations, both in terms of recent CPGs/reviews and primary studies; inspection of the latter will also help establish the feasibility of future syntheses to compare treatments, such as network meta-analysis. Systematic review protocol registration Open Science Framework (https://osf.io/9wy8p)

Background Systematic reviews often require substantial resources, partially due to the large number of records identified during searching. Although artificial intelligence may not be ready to fully replace human reviewers, it may accelerate and reduce the screening burden. Using DistillerSR (May 2020 release), we evaluated the performance of the prioritization simulation tool to determine the reduction in screening burden and time savings. Methods Using a true recall @ 95%, response sets from 10 completed systematic reviews were used to evaluate: (i) the reduction of screening burden; (ii) the accuracy of the prioritization algorithm; and (iii) the hours saved when a modified screening approach was implemented. To account for variation in the simulations, and to introduce randomness (through shuffling the references), 10 simulations were run for each review. Means, standard deviations, medians and interquartile ranges (IQR) are presented. Results Among the 10 systematic reviews, using true recall @ 95% there was a median reduction in screening burden of 47.1% (IQR: 37.5 to 58.0%). A median of 41.2% (IQR: 33.4 to 46.9%) of the excluded records needed to be screened to achieve true recall @ 95%. The median title/abstract screening hours saved using a modified screening approach at a true recall @ 95% was 29.8 h (IQR: 28.1 to 74.7 h). This was increased to a median of 36 h (IQR: 32.2 to 79.7 h) when considering the time saved not retrieving and screening full texts of the remaining 5% of records not yet identified as included at title/abstract. Among the 100 simulations (10 simulations per review), none of these 5% of records were a final included study in the systematic review. The reduction in screening burden to achieve true recall @ 95% compared to @ 100% resulted in a reduced screening burden median of 40.6% (IQR: 38.3 to 54.2%). Conclusions The prioritization tool in DistillerSR can reduce screening burden. A modified or stop screening approach once a true recall @ 95% is achieved appears to be a valid method for rapid reviews, and perhaps systematic reviews. This needs to be further evaluated in prospective reviews using the estimated recall.

Background Mental health (MH) problems are among the most important causes of morbidity and mortality for children and youth. Problems of lack of equity in child and youth MH services (CYMHS)—including, but not limited to, problems in inaccessibility and quality of services—are widespread. Characterizing the nature of equity in CYMHS is an ongoing challenge because the field lacks a consistent approach to conceptualizing equity. We will conduct a scoping review of how equity in MH services for children and youth has been defined, operationalized, and measured. Our objectives are to discover: (1) What conceptual definitions of equity are used by observational studies of CYMHS?; (2) What service characteristics of CYMHS care do indices of equity cover?; (3) What population dimensions have been used to operationalize equity?; (4) What statistical constructs have been used in indices that measure CYMHS equity?; and (5) What were the numerical values of those indices? Methods The following databases will be searched: Medline, Embase, PsycINFO, Cochrane Controlled Register of Trials, CINAHL, EconLit, and Sociological Abstracts. Searches will be conducted from the date of inception to the end of the last full calendar year (December 2019). Studies will be included if they include an evaluation of a mental health service for children or youth (defined as those under 19 years of age) and which quantify variation in some aspect of child or youth mental health services (e.g., accessibility, volume, duration, or quality) as a function of socio-demographic and/or geographic variables. Study selection will occur over two stages. Stage one will select articles based on title and abstract using the liberal-accelerated method. Stage two will review the full texts of selected titles. Two reviewers will work independently on full-text reviewing, with each study screened twice using pre-specified eligibility criteria. One reviewer will chart study characteristics and indices to be verified by a second reviewer. Reviewers will resolve full-text screening and data extraction disagreements through discussion. Synthesis of the collected data will focus on compiling and mapping the types and characteristics of the indices used to evaluate MH services equity. Discussion The planned, systematic scoping review will survey the literature regarding how equity in MH services for children and youth has been operationalized and help inform future studies of equity in CYMHS. Systematic review registration Open Science Foundation ID SYSR-D-19-00371, https://osf.io/58srv/.

Highlights • Questions around optimal use of bone-modifying agents (BMAs) still exist. • Most physicians are de-escalating BMAs in patients with metastatic breast cancer. • Practice varies according to patient insurance coverage. • There is interest performing further trials of de-escalation especially after 2 years of treatment., Background There remain questions around the optimal use of bone-modifying agents (BMAs) in patients with bone metastases from breast and castration-resistant prostate cancer (CRPC). A physician survey was performed to identify current practices, as well as perceptions around long-term BMA use, BMA de-escalation, and further BMA de-escalation after 2 years of use. Methods Canadian oncologists treating breast cancer or CRPC were surveyed via an anonymized online survey. The survey collected physician demographics, current practice patterns, perception on risk of symptomatic skeletal events (SSE) and BMA-associated toxicities, and attitudes towards further de-escalation of BMAs after 2 years of treatment. Results A total of 334 physicians in Canada were contacted, of which 295 were eligible on initial screening, and 65 completed the survey (response rate 22%): 35 treated breast cancer, 25 treated prostate cancer and 5 treated both. The most common BMA regimens in patients with no limitation in drug coverage were denosumab q4wks for 3–4 months followed by a de-escalation to q12wks (breast cancer) and denosumab q4wks (prostate cancer). In patients with provincial health coverage only the common choices were zoledronate q4wks for 3–4 months followed by de-escalation to q12wks (breast cancer) and denosumab q4wks (prostate cancer). There was equipoise regarding the benefit of continuing BMA beyond 2 years and interest in further trials of de-escalation of BMA in both breast and prostate cancer. The most favored alternative primary study endpoints to SSE were BMA toxicity (67.2%), pain (46.9%), and physical function (48.4%). Conclusion Despite their extensive use and costs, questions around optimal use of BMAs still exist. Practice varies according to patient insurance coverage. However, most physicians are de-escalating BMAs. There is interest amongst clinicians in performing trials of de-escalation, especially after 2 years of treatment.

For systematic reviews of interventions, replication is defined as the reproduction of findings of previous systematic reviews looking at the same effectiveness question either by: purposefully repeating the same methods to verify one or more empirical findings; or purposefully extending or narrowing the systematic review to a broader or more focused question (eg, across broader or more focused populations, intervention types, settings, outcomes, or study designs) Although systematic reviews are often used as the basis for informing policy and practice decisions, little evidence has been published so far on whether replication of systematic reviews is worthwhile Replication of existing systematic reviews cannot be done for all topics; any unnecessary or poorly conducted replication contributes to research waste The decision to replicate a systematic review should be based on the priority of the research question; the likelihood that a replication will resolve uncertainties, controversies, or the need for additional evidence; the magnitude of the benefit or harm of implementing findings of a replication; and the opportunity cost of the replication Systematic review authors, commissioners, funders, and other users (including clinicians, patients, and representatives from policy making organisations) can use the guidance and checklist proposed here to assess the need for a replication