Rapid normalization of vitamin D deficiency in PICU (VITdALIZE-KIDS): study protocol for a phase III, multicenter randomized controlled trial.

BACKGROUND: The rate of vitamin D deficiency (VDD) in critically ill children worldwide has been estimated at 50%. These children are at risk of multiple organ dysfunction, chronic morbidity, and decreased health related quality of life (HRQL). Pediatric and adult ICU clinical trials suggest that VDD is associated with worse clinical outcomes, although data from supplementation trials are limited and inconclusive. Our group's phase II multicenter dose evaluation pilot study established the efficacy and safety of an enteral weight-based cholecalciferol loading dose to rapidly restore vitamin D levels in critically ill children. METHODS: Our aim is to evaluate the impact of this dosing regimen on clinical outcomes. VITdALIZE-KIDS is a pragmatic, phase III, multicenter, double-blind RCT aiming to randomize 766 critically ill children from Canadian PICUs. Participants are randomized using a 1:1 scheme to receive a single dose at enrollment of enteral cholecalciferol (10,000 IU/kg, max 400,000 IU) or placebo. Eligibility criteria include critically ill children aged newborn (> 37 weeks corrected gestational age) to < 18 years who have blood total 25-hydroxyvitamin D < 50 nmol/L. The primary objective is to determine if rapid normalization of vitamin D status improves HRQL at 28 days following enrollment. The secondary objective is to evaluate the impact of rapid normalization of vitamin D status on multiple organ dysfunction. The study includes additional tertiary outcomes including functional status, HRQL and mortality at hospital discharge and 90 days, PICU and hospital length of stay, and adverse events related to vitamin D toxicity. Additionally, we are performing comprehensive vitamin D speciation and non-targeted metabolite profiling as part of a sub-study for the first 100 participants from whom an enrollment and at least one post-intervention blood and urine sample were obtained. DISCUSSION: The VITdALIZE-KIDS trial is the first phase III, multicenter trial to evaluate whether rapid normalization of vitamin D status could represent a simple, inexpensive, and safe means of improving outcomes following pediatric critical illness. Recruitment was initiated in June 2019 and is expected to continue to March 2026. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03742505. Study first submitted on November 12, 2018 https://clinicaltrials.gov/study/NCT03742505.

Planning for implementation success: insights from conducting an implementation needs assessment.

AIM: The aim of this paper is to provide insights into conducting an implementation needs assessment using a case example in a less-research-intensive setting. DESIGN AND METHODS: In the case example, an implementation needs assessment was conducted, including1 an environmental scan of the organization's website and preliminary discussions with key informants to learn about the implementation context, and2 a formal analysis of the evidence-practice gap (use of sedation interruptions) deploying a chart audit methodology using legal electronic reports. RESULTS: Our needs assessment was conducted over 5 months and demonstrated how environmental scans reveal valuable information that can inform the evidence-practice gap analysis. A well-designed gap analysis, using suitable indicators of best practice, can reveal compliance rates with local protocol recommendations, even with a small sample size. In our case, compliance with the prescribed practices for sedation interruptions ranged from 65% (n=53) to as high as 84% (n=69). CONCLUSIONS: Implementation needs assessments provide valuable information that can inform implementation planning. Such assessments should include an environmental scan to understand the local context and identify both current recommended best practices and local best practices for the intervention of interest. When addressing an evidence-practice gap, analyses should quantify the difference between local practice and desired best practice. IMPACT: The insights gained from the case example presented in this paper are likely transferrable to implementation research or studies conducted in similar, less-research-intensive settings. SPANISH ABSTRACT: http://links.lww.com/IJEBH/A257.

Barriers, Solutions, and Opportunities for Adapting Critical Care Clinical Trials in the COVID-19 Pandemic.

Importance: The COVID-19 pandemic created unprecedented challenges for clinical trials worldwide, threatening premature closure and trial integrity. Every phase of research operations was affected, often requiring modifications to protocol design and implementation. Objectives: To identify the barriers, solutions, and opportunities associated with continuing critical care trials that were interrupted during the pandemic, and to generate suggestions for future trials. Design, Setting, and Participants: This mixed-methods study performed an explanatory sequential analysis involving a self-administered electronic survey and focus groups of principal investigators (PIs) and project coordinators (PCs) conducting adult and pediatric individual-patient randomized trials of the Canadian Critical Care Trials Group during the COVID-19 pandemic. Eligible trials were actively enrolling patients on March 11, 2020. Data were analyzed between September 2023 and January 2024. Main Outcomes and Measures: Importance ratings of barriers to trial conduct and completion, solutions employed, opportunities arising, and suggested strategies for future trials. Quantitative data examining barriers were analyzed using descriptive statistics. Data addressing solutions, opportunities, and suggestions were analyzed by qualitative content analysis. Integration involved triangulation of data sources and perspectives about 13 trials, synthesized by an interprofessional team incorporating reflexivity and member-checking. Results: A total of 13 trials run by 29 PIs and PCs (100% participation rate) were included. The highest-rated barriers (on a 5-point scale) to ongoing conduct during the pandemic were decisions to pause all clinical research (mean [SD] score, 4.7 [0.8]), focus on COVID-19 studies (mean [SD] score, 4.6 [0.8]), and restricted family presence in hospitals (mean [SD] score, 4.1 [0.8]). Suggestions to enable trial progress and completion included providing scientific leadership, implementing technology for communication and data management, facilitating the informed consent process, adapting the protocol as necessary, fostering site engagement, initiating new sites, streamlining ethics and contract review, and designing nested studies. The pandemic necessitated new funding opportunities to sustain trial enrollment. It increased public awareness of critical illness and the importance of randomized trial evidence. Conclusions and Relevance: While underscoring the vital role of research in society and drawing the scientific community together with a common purpose, the pandemic signaled the need for innovation to ensure the rigor and completion of ongoing trials. Lessons learned to optimize research procedures will help to ensure a vibrant clinical trials enterprise in the future.

What to Measure in Aneurysmal Subarachnoid Haemorrhage Research-An International Delphi Survey.

Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating condition with high mortality and morbidity. The outcome measures used in aSAH clinical research vary making it challenging to compare and combine different studies. Additionally, there may be a mismatch between the outcomes prioritized by patients, caregivers, and health care providers and those selected by researchers. We conducted an international, online, multiple round Delphi study to develop consensus on domains (where a domain is a health concept or aspect) prioritized by key stakeholders including those with lived experience of aSAH, health care providers, and researchers, funders, or industry professionals. One hundred seventy-five people participated in the survey, 59% of whom had lived experience of aSAH. Over three rounds, 32 domains reached the consensus threshold pre-defined as 70% of participants rating the domain as being critically important. During the fourth round, participants ranked the importance of each of these 32 domains. The top ten domains ranked highest to lowest were (1) Cognition and executive function, (2) Aneurysm obliteration, (3) Cerebral infarction, (4) Functional outcomes including ability to walk, (5) Delayed cerebral ischemia, (6) The overall quality of life as reported by the SAH survivor, (7) Changes to emotions or mood (including depression), (8) The basic activities of daily living, (9) Vasospasm, and (10) ICU complications. Our findings confirm that there is a mismatch between domains prioritized by stakeholders and outcomes used in clinical research. Our future work aims to address this mismatch through the development of a core outcome set in aSAH research.

A randomised trial comparing 6-monthly adjuvant zoledronate with a single one-time dose in patients with early breast cancer.

PURPOSE: While adjuvant bisphosphonate use in early breast cancer (EBC) is associated with improvements in breast cancer-specific outcomes, questions remain around optimal bisphosphonate type, dose and scheduling. We evaluated a single zoledronate infusion in a prospective randomised trial. METHODS: Postmenopausal patients with EBC were randomised to receive a single infusion of zoledronate (4 mg IV) or 6-monthly treatment for 3 years. Outcomes measured were; Quality of Life (QoL; EQ-5D-5L), bisphosphonate-related toxicities, including acute phase reactions (APRs), recurrence-free survival (RFS), bone metastasis-free survival (BMFS) and overall survival (OS). RESULTS: 211 patients were randomized to either a single infusion (n = 107) or six-monthly treatment (n = 104). After 3 years of follow up there were no significant differences between the arms for QoL and most toxicity endpoints. APRs following zoledronate occurred in 81% (171/211) of patients (77.6% in single infusion arm and 84.6% in the 6-monthly group). While the frequency of APRs decreased over 3 years in the 6-monthly arm, they still remain common. Of 34/104 (32.7%) patients who discontinued zoledronate early in the 6-monthly treatment group, the most common reason was APRs (16/34, 47%). At the 3 year follow up, there were no differences between arms for RFS, BMFS or OS. CONCLUSION: A single infusion of zoledronate was associated with increased patient convenience, less toxicity, and lower rates of treatment discontinuation. Despite the common clinical impression that APRs decrease with time, this was not observed when patients were specifically questioned. While the study is not powered for non-inferiority, longer-term follow-up for confirmation of RFS and OS rates is ongoing.

A qualitative evaluation of treatment fidelity alongside a pilot trial of a novel therapy for pediatric Inflammatory Bowel Disease.

BACKGROUND: Process evaluations conducted alongside clinical trials can improve understanding of treatment fidelity and provide contextual knowledge to aide interpretations of trial outcomes. We adopted a multiple-goals perspective to investigate treatment fidelity in two related pilot clinical trials of an adjuvant treatment for pediatric-onset Inflammatory Bowel Disease. This included a focus on barriers and enablers of performing trial-specific activities and of integrating those activities into daily life. METHODS: We conducted one-time semi-structured interviews with a sub-sample of participants of the Resistant Starch in Pediatric Inflammatory Bowel Disease (NCT04522271) and Optimized Resistant Starch in Inflammatory Bowel Disease pilot trials (NCT04520594) and their caregivers (N = 42). The trials examined the effects of personalized food-derived resistant starches as an adjuvant therapy on intestinal microbiome functioning. Interviews were conducted within 3-months of participants completing or withdrawing from the trials. Interview guides with age-appropriate language were developed and pilot tested. Codes were identified inductively though conventional content analysis and then mapped to personal projects analysis, to explore how participants navigated between activities. RESULTS: Three themes were identified. The first described the potential impact of living with inflammatory bowel disease and taking prescribed medications. The second described characteristics of trial-specific activities that might impact on their enactment, including perceived difficulty, and challenges following procedures or using trial materials. The third described the integration of trial-specific activities with school, work, household demands, and social, and extracurricular activities. CONCLUSIONS: Adjusting to living with inflammatory bowel disease and managing its treatment can impact trial participation. Integrating trial-related activities into daily life can be challenging, which could heighten perceptions of goal conflict. Findings can inform interpretations of trial outcomes and development of strategies for trial optimization and implementation of the adjuvant therapy into clinical practice.

Perioperative Transfusion Practices in Adults Having Noncardiac Surgery.

Surgical patients are often transfused to manage bleeding and anemia. Best practices for red blood cell (RBC) transfusion administration in patient having noncardiac surgery remains controversial and a robust evaluation and description of perioperative transfusion practices is lacking. We characterized perioperative hemoglobin concentrations and transfusion practices from the prospective VISION cohort which included 39,222 patients aged ≥45 years who had inpatient noncardiac surgery. Variations in transfusion practices were analyzed using hierarchical mixed models, and associations with mortality and complications were evaluated using a nested frailty survival model. Within the cohort, 16.1% (n = 6296) were given perioperative RBC transfusions, with the fraction declining from 20% to 13% over the 6-year study period. The proportion of patients transfused varied by surgery type from 6.4% for low-risk operations (i.e., minor surgery) to 31.5% for orthopedic surgeries. Variations were largely associated with patient hemoglobin concentrations, but also with center (range: 3.7%-27.3%) and country (0.4%-25.3%). Even after adjusting for baseline hemoglobin, comorbidities and type of surgery, both center and country were significant sources of variation in transfusion practices. Among transfused participants, 60.4% (n = 3728/6170) had at least 1 hemoglobin concentration ≤80g/L and 86.0% (n = 5305/6170) had at least 1 hemoglobin concentration ≤90g/L, suggesting that relatively restrictive transfusion strategies were used in most. The proportion of patients receiving at least 1 RBC transfusion declined from 20% to 13% over 6 years. However, there was considerable unexplained variation in transfusion practices.

The effects of estrogens on spatial learning and memory in female rodents - A systematic review and meta-analysis.

Estrogens have inconsistent effects on learning and memory in both the clinical and preclinical literature. Preclinical literature has the advantage of investigating an array of potentially important factors contributing to the varied effects of estrogens on learning and memory, with stringently controlled studies. This study set out to identify specific factors in the animal literature that influence the effects of estrogens on cognition, for possible translation back to clinical practice. The literature was screened and studies meeting strict inclusion criteria were included in the analysis. Eligible studies included female ovariectomized rodents with an adequate vehicle for the estrogen treatment, with an outcome of spatial learning and memory in the Morris water maze. Training days of the Morris water maze were used to assess acquisition of spatial learning, and the probe trial was used to evaluate spatial memory recall. Continuous outcomes were pooled using a random effects inverse variance method and reported as standardized mean differences with 95 % confidence intervals. Subgroup analyses were developed a priori to assess important factors. The overall analysis favoured treatment for the later stages of training and for the probe trial. Factors including the type of estrogen, route, schedule of administration, age of animals, timing relative to ovariectomy, and duration of treatment were all found to be important. The subgroup analyses showed that chronic treatment with 17ß-estradiol, either cyclically or continuously, to young animals improved spatial recall. These results, observed in animals, can inform and guide further clinical research on hormone replacement therapy for cognitive benefits.

Effectiveness of dexmedetomidine on patient-centred outcomes in surgical patients: a systematic review and Bayesian meta-analysis.

BACKGROUND: Dexmedetomidine is increasingly used for surgical patients requiring general anaesthesia. However, its effectiveness on patient-centred outcomes remains uncertain. Our main objective was to evaluate the patient-centred effectiveness of intraoperative dexmedetomidine for adult patients requiring surgery under general anaesthesia. METHODS: We conducted a systematic search of MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL from inception to October 2023. Randomised controlled trials (RCTs) comparing intraoperative use of dexmedetomidine with placebo, opioid, or usual care in adult patients requiring surgery under general anaesthesia were included. Study selection, data extraction, and risk of bias assessment were performed by two reviewers independently. We synthesised data using a random-effects Bayesian regression framework to derive effect estimates and the probability of a clinically important effect. For continuous outcomes, we pooled instruments with similar constructs using standardised mean differences (SMDs) and converted SMDs and credible intervals (CrIs) to their original scale when appropriate. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Our primary outcome was quality of recovery after surgery. To guide interpretation on the original scale, the Quality of Recovery-15 (QoR-15) instrument was used (range 0-150 points, minimally important difference [MID] of 6 points). RESULTS: We identified 49,069 citations, from which 44 RCTs involving 5904 participants were eligible. Intraoperative dexmedetomidine administration was associated with improvement in postoperative QoR-15 (mean difference 9, 95% CrI 4-14, n=21 RCTs, moderate certainty of evidence). We found 99% probability of any benefit and 88% probability of achieving the MID. There was a reduction in chronic pain incidence (odds ratio [OR] 0.42, 95% CrI 0.19-0.79, n=7 RCTs, low certainty of evidence). There was also increased risk of clinically significant hypotension (OR 1.98, 95% CrI 0.84-3.92, posterior probability of harm 94%, n=8 RCTs) and clinically significant bradycardia (OR 1.74, 95% CrI 0.93-3.34, posterior probability of harm 95%, n=10 RCTs), with very low certainty of evidence for both. There was limited evidence to inform other secondary patient-centred outcomes. CONCLUSIONS: Compared with placebo or standard of care, intraoperative dexmedetomidine likely results in meaningful improvement in the quality of recovery and chronic pain after surgery. However, it might increase clinically important bradycardia and hypotension. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42023439896).

Chronic obstructive pulmonary disease exacerbation purulence status and its association with pulmonary embolism: protocol for a systematic review with meta-analysis.

INTRODUCTION: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) increases the risk of pulmonary embolism (PE). AECOPD and PE have similar symptoms which results in a high proportion of patients with AECOPD undergoing imaging to rule out PE. Finding predictors and explanatory factors of PE in AECOPD, such as purulence status, could help reduce the need for imaging. This systematic review with meta-analysis aims to evaluate if there is an association between purulence status in AECOPD and PE diagnosis. METHODS AND ANALYSIS: MEDLINE, EMBASE and CENTRAL will be searched from database inception to April 2024. Randomised trials, cohort studies and cross-sectional studies on the prevalence of PE in patients with AECOPD will be included if the prevalence of PE based on the AECOPD purulence status is available. There will be no restriction on language. The primary outcome will be PE at the initial assessment and secondary outcomes will be all venous thromboembolism (deep venous thrombosis (DVT) and PE) and DVT, respectively, diagnosed at the initial assessment. Relative risks with their 95% CI will be calculated by using a Mantel-Haenszel random-effect model to compare the association between the risk of PE and the AECOPD purulence status (purulent vs non-purulent/unknown). Subgroup analyses will be performed based on the type of study, systematic search of PE versus no systematic search of PE and localisation of PE. Risk of bias will be evaluated by the ROBINS-E tool, publication bias will be evaluated with the funnel plot. The manuscript will be drafted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement. ETHICS AND DISSEMINATION: This study does not require ethics approval. This work will be submitted for presentation at an international conference and for publication in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42023459429.

What guidance exists to support patient partner compensation practices? A scoping review of available policies and guidelines.

BACKGROUND: An integral aspect of patient engagement in research, also known as patient and public involvement, is appropriately recognising patient partners for their contributions through compensation (e.g., coauthorship, honoraria). Despite known benefits to compensating patient partners, our previous work suggested compensation is rarely reported and researchers perceive a lack of guidance on this issue. To address this gap, we identified and summarised available guidance and policy documents for patient partner compensation. METHODS: We conducted this scoping review in accordance with methods suggested by the JBI. We searched the grey literature (Google, Google Scholar) in March 2022 and Overton (an international database of policy documents) in April 2022. We included articles, guidance or policy documents regarding the compensation of patient partners for their research contributions. Two reviewers independently extracted and synthesised document characteristics and recommendations. RESULTS: We identified 65 guidance or policy documents. Most documents were published in Canada (57%, n = 37) or the United Kingdom (26%, n = 17). The most common recommended methods of nonfinancial compensation were offering training opportunities to patient partners (40%, n = 26) and facilitating patient partner attendance at conferences (38%, n = 25). The majority of guidance documents (95%) suggested financially compensating (i.e., offering something of monetary value) patient partners for their research contributions. Across guidance documents, the recommended monetary value of financial compensation was relatively consistent and associated with the role played by patient partners and/or specific engagement activities. For instance, the median monetary value for obtaining patient partner feedback (i.e., consultation) was $19/h (USD) (range of $12-$50/h). We identified several documents that guide the compensation of specific populations, including youth and Indigenous peoples. CONCLUSION: Multiple publicly available resources exist to guide researchers, patient partners and institutions in developing tailored patient partner compensation strategies. Our findings challenge the perception that a lack of guidance hinders patient partner financial compensation. Future efforts should prioritise the effective implementation of these compensation strategies to ensure that patient partners are appropriately recognised. PATIENT OR PUBLIC CONTRIBUTIONS: The patient partner coauthor informed protocol development, identified data items, and interpreted findings.

Hospital policy of tranexamic acid to reduce transfusion in major non-cardiac surgery (TRACTION): protocol for a phase IV randomised controlled trial.

INTRODUCTION: Tranexamic acid (TXA) is an inexpensive and widely available medication that reduces blood loss and red blood cell (RBC) transfusion in cardiac and orthopaedic surgeries. While the use of TXA in these surgeries is routine, its efficacy and safety in other surgeries, including oncologic surgeries, with comparable rates of transfusion are uncertain. Our primary objective is to evaluate whether a hospital-level policy implementation of routine TXA use in patients undergoing major non-cardiac surgery reduces RBC transfusion without increasing thrombotic risk. METHODS AND ANALYSIS: A pragmatic, registry-based, blinded, cluster-crossover randomised controlled trial at 10 Canadian sites, enrolling patients undergoing non-cardiac surgeries at high risk for RBC transfusion. Sites are randomised in 4-week intervals to a hospital policy of intraoperative TXA or matching placebo. TXA is administered as 1 g at skin incision, followed by an additional 1 g prior to skin closure. Coprimary outcomes are (1) effectiveness, evaluated as the proportion of patients transfused RBCs during hospital admission and (2) safety, evaluated as the proportion of patients diagnosed with venous thromboembolism within 90 days. Secondary outcomes include: (1) transfusion: number of RBC units transfused (both at a hospital and patient level); (2) safety: in-hospital diagnoses of myocardial infarction, stroke, deep vein thrombosis or pulmonary embolism; (3) clinical: hospital length of stay, intensive care unit admission, hospital survival, 90-day survival and the number of days alive and out of hospital to day 30; and (4) compliance: the proportion of enrolled patients who receive a minimum of one dose of the study intervention. ETHICS AND DISSEMINATION: Institutional research ethics board approval has been obtained at all sites. At the completion of the trial, a plain language summary of the results will be posted on the trial website and distributed in the lay press. Our trial results will be published in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: NCT04803747.

Liberal or Restrictive Transfusion Strategy in Patients with Traumatic Brain Injury.

BACKGROUND: The effect of a liberal transfusion strategy as compared with a restrictive strategy on outcomes in critically ill patients with traumatic brain injury is unclear. METHODS: We randomly assigned adults with moderate or severe traumatic brain injury and anemia to receive transfusion of red cells according to a liberal strategy (transfusions initiated at a hemoglobin level of ≤10 g per deciliter) or a restrictive strategy (transfusions initiated at ≤7 g per deciliter). The primary outcome was an unfavorable outcome as assessed by the score on the Glasgow Outcome Scale-Extended at 6 months, which we categorized with the use of a sliding dichotomy that was based on the prognosis of each patient at baseline. Secondary outcomes included mortality, functional independence, quality of life, and depression at 6 months. RESULTS: A total of 742 patients underwent randomization, with 371 assigned to each group. The analysis of the primary outcome included 722 patients. The median hemoglobin level in the intensive care unit was 10.8 g per deciliter in the group assigned to the liberal strategy and 8.8 g per deciliter in the group assigned to the restrictive strategy. An unfavorable outcome occurred in 249 of 364 patients (68.4%) in the liberal-strategy group and in 263 of 358 (73.5%) in the restrictive-strategy group (adjusted absolute difference, restrictive strategy vs. liberal strategy, 5.4 percentage points; 95% confidence interval, -2.9 to 13.7). Among survivors, a liberal strategy was associated with higher scores on some but not all the scales assessing functional independence and quality of life. No association was observed between the transfusion strategy and mortality or depression. Venous thromboembolic events occurred in 8.4% of the patients in each group, and acute respiratory distress syndrome occurred in 3.3% and 0.8% of patients in the liberal-strategy and restrictive-strategy groups, respectively. CONCLUSIONS: In critically ill patients with traumatic brain injury and anemia, a liberal transfusion strategy did not reduce the risk of an unfavorable neurologic outcome at 6 months. (Funded by the Canadian Institutes of Health Research and others; HEMOTION ClinicalTrials.gov number, NCT03260478.).

Restrictive versus liberal red blood cell transfusion strategies for people with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without haematopoietic stem cell support.

BACKGROUND: An estimated one-quarter to one-half of people diagnosed with haematological malignancies experience anaemia. There are different strategies for red blood cell (RBC) transfusions to treat anaemia. A restrictive transfusion strategy permits a lower haemoglobin (Hb) level whereas a liberal transfusion strategy aims to maintain a higher Hb. The most effective and safest strategy is unknown. OBJECTIVES: To determine the efficacy and safety of restrictive versus liberal RBC transfusion strategies for people diagnosed with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without a haematopoietic stem cell transplant (HSCT). SEARCH METHODS: We searched for randomised controlled trials (RCTs) and non-randomised studies (NRS) in MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1982), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2023, Issue 2), and eight other databases (including three trial registries) to 21 March 2023. We also searched grey literature and contacted experts in transfusion for additional trials. There were no language, date or publication status restrictions. SELECTION CRITERIA: We included RCTs and prospective NRS that evaluated restrictive versus liberal RBC transfusion strategies in children or adults with malignant haematological disorders receiving intensive chemotherapy or radiotherapy, or both, with or without HSCT. DATA COLLECTION AND ANALYSIS: Two authors independently screened references, full-text reports of potentially relevant studies, extracted data from the studies, and assessed the risk of bias. Any disagreement was discussed and resolved with a third review author. Dichotomous outcomes were presented as a risk ratio (RR) with a 95% confidence interval (CI). Narrative syntheses were used for heterogeneous outcome measures. Review Manager Web was used to meta-analyse the data. Main outcomes of interest included: all-cause mortality at 31 to 100 days, quality of life, number of participants with any bleeding, number of participants with clinically significant bleeding, serious infections, length of hospital admission (days) and hospital readmission at 0 to 3 months. The certainty of the evidence was assessed using GRADE. MAIN RESULTS: Nine studies met eligibility; eight RCTs and one NRS. Six hundred and forty-four participants were included from six completed RCTs (n = 560) and one completed NRS (n = 84), with two ongoing RCTs consisting of 294 participants (260 adult and 34 paediatric) pending inclusion. Only one completed RCT included children receiving HSCT (n = 6); the other five RCTs only included adults: 239 with acute leukaemia receiving chemotherapy and 315 receiving HSCT (166 allogeneic and 149 autologous). The transfusion threshold ranged from 70 g/L to 80 g/L for restrictive and from 80 g/L to 120 g/L for liberal strategies. Effects were reported in the summary of findings tables only for the trials that included adults to reduce indirectness due to the limited evidence contributed by the prematurely terminated paediatric trial. Evidence from RCTs Overall, there may be little to no difference in the number of participants who die within 31 to 100 days using a restrictive compared to a liberal transfusion strategy, but the evidence is very uncertain (three studies; 451 participants; RR 1.00, 95% CI 0.27 to 3.70, P=0.99; very low-certainty evidence). There may be little to no difference in quality of life at 0 to 3 months using a restrictive compared to a liberal transfusion strategy, but the evidence is very uncertain (three studies; 431 participants; analysis unable to be completed due to heterogeneity; very low-certainty evidence). There may be little to no difference in the number of participants who suffer from any bleeding at 0 to 3 months using a restrictive compared to a liberal transfusion strategy (three studies; 448 participants; RR 0.91, 95% CI 0.78 to 1.06, P = 0.22; low-certainty evidence). There may be little to no difference in the number of participants who suffer from clinically significant bleeding at 0 to 3 months using a restrictive compared to a liberal transfusion strategy (four studies; 511 participants; RR: 0.94, 95% CI 0.74 to 1.19, P = 0.60; low-certainty evidence). There may be little to no difference in the number of participants who experience serious infections at 0 to 3 months using a restrictive compared to a liberal transfusion strategy (three studies, 451 participants; RR: 1.20, 95% CI 0.93 to 1.55, P = 0.17; low-certainty evidence). A restrictive transfusion strategy likely results in little to no difference in the length of hospital admission at 0 to 3 months compared to a liberal strategy (two studies; 388 participants; analysis unable to be completed due to heterogeneity in reporting; moderate-certainty evidence). There may be little to no difference between hospital readmission using a restrictive transfusion strategy compared to a liberal transfusion strategy (one study, 299 participants; RR: 0.89, 95% CI 0.52 to 1.50; P = 0.65; low-certainty evidence). Evidence from NRS The evidence is very uncertain whether a restrictive RBC transfusion strategy: reduces the risk of death within 100 days (one study, 84 participants, restrictive 1 death; liberal 1 death; very low-certainty evidence); or decreases the risk of clinically significant bleeding (one study, 84 participants, restrictive 3; liberal 8; very low-certainty evidence). No NRS reported on the other eligible outcomes. AUTHORS' CONCLUSIONS: Findings from this review were based on seven studies and 644 participants. Definite conclusions are challenging given the relatively few included studies, low number of included participants, heterogeneity of intervention and outcome reporting, and overall certainty of evidence. To increase the certainty of the true effect of a restrictive RBC transfusion strategy on clinical outcomes, there is a need for rigorously designed and executed studies. The evidence is largely based on two populations: adults with acute leukaemia receiving intensive chemotherapy and adults with haematologic malignancy requiring HSCT. Despite the addition of 405 participants from three RCTs to the previous review's results, there is still insufficient evidence to answer this review's primary outcome. If we assume a mortality rate of 3% within 100 days, we would need a total of 1492 participants to have an 80% chance of detecting, at a 5% level of significance, an increase in all-cause mortality from 3% to 6%. Further RCTs are needed overall, particularly in children.

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

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

Economic Evaluations of Chimeric Antigen Receptor T-Cell Therapies for Hematologic and Solid Malignancies: A Systematic Review.

OBJECTIVES: This study aimed to systematically review evidence on the cost-effectiveness of chimeric antigen receptor T-cell (CAR-T) therapies for patients with cancer. METHODS: Electronic databases were searched in October 2022 and updated in September 2023. Systematic reviews, health technology assessments, and economic evaluations that compared costs and effects of CAR-T therapy in patients with cancer were included. Two reviewers independently screened studies, extracted data, synthesized results, and critically appraised studies using the Philips checklist. Cost data were presented in 2022 US dollars. RESULTS: Our search yielded 1809 records, 47 of which were included. Most of included studies were cost-utility analysis, published between 2018 and 2023, and conducted in the United States. Tisagenlecleucel, axicabtagene ciloleucel, idecabtagene vicleucel, ciltacabtagene autoleucel, lisocabtagene maraleucel, brexucabtagene autoleucel, and relmacabtagene autoleucel were compared with various standard of care chemotherapies. The incremental cost-effectiveness ratio (ICER) for CAR-T therapies ranged from $9424 to $4 124 105 per quality-adjusted life-year (QALY) in adults and from $20 784 to $243 177 per QALY in pediatric patients. Incremental cost-effectiveness ratios were found to improve over longer time horizons or when an earlier cure point was assumed. Most studies failed to meet the Philips checklist due to a lack of head-to-head comparisons and uncertainty surrounding CAR-T costs and curative effects. CONCLUSIONS: CAR-T therapies were more expensive and generated more QALYs than comparators, but their cost-effectiveness was uncertain and dependent on patient population, cancer type, and model assumptions. This highlights the need for more nuanced economic evaluations and continued research to better understand the value of CAR-T therapies in diverse patient populations.

Describing the content of trial recruitment interventions using the TIDieR reporting checklist: a systematic methodology review.

BACKGROUND: Recruiting participants to clinical trials is an ongoing challenge, and relatively little is known about what recruitment strategies lead to better recruitment. Recruitment interventions can be considered complex interventions, often involving multiple components, targeting a variety of groups, and tailoring to different groups. We used the Template for Intervention Description and Replication (TIDieR) reporting checklist (which comprises 12 items recommended for reporting complex interventions) to guide the assessment of how recruitment interventions are described. We aimed to (1) examine to what extent we could identify information about each TIDieR item within recruitment intervention studies, and (2) observe additional detail for each item to describe useful variation among these studies. METHODS: We identified randomized, nested recruitment intervention studies providing recruitment or willingness to participate rates from two sources: a Cochrane review of trials evaluating strategies to improve recruitment to randomized trials, and the Online Resource for Research in Clinical triAls database. First, we assessed to what extent authors reported information about each TIDieR item. Second, we developed descriptive categorical variables for 7 TIDieR items and extracting relevant quotes for the other 5 items. RESULTS: We assessed 122 recruitment intervention studies. We were able to extract information relevant to most TIDieR items (e.g., brief rationale, materials, procedure) with the exception of a few items that were only rarely reported (e.g., tailoring, modifications, planned/actual fidelity). The descriptive variables provided a useful overview of study characteristics, with most studies using various forms of informational interventions (55%) delivered at a single time point (90%), often by a member of the research team (59%) in a clinical care setting (41%). CONCLUSIONS: Our TIDieR-based variables provide a useful description of the core elements of complex trial recruitment interventions. Recruitment intervention studies report core elements of complex interventions variably; some process elements (e.g., mode of delivery, location) are almost always described, while others (e.g., duration, fidelity) are reported infrequently, with little indication of a reason for their absence. Future research should explore whether these TIDieR-based variables can form the basis of an approach to better reporting of elements of successful recruitment interventions.

Population Survival Kinetics Derived from Clinical Trials of Potentially Curable Lung Cancers.

Using digitized data from progression-free survival (PFS) and overall survival Kaplan-Meier curves, one can assess population survival kinetics through exponential decay nonlinear regression analyses. To demonstrate their utility, we analyzed PFS curves from published curative-intent trials of non-small cell lung cancer (NSCLC) adjuvant chemotherapy, adjuvant osimertinib in resected EGFR-mutant NSCLC (ADAURA trial), chemoradiotherapy for inoperable NSCLC, and limited small cell lung cancer (SCLC). These analyses permit assessment of log-linear curve shape and estimation of the proportion of patients cured, PFS half-lives for subpopulations destined to eventually relapse, and probability of eventual relapse in patients remaining progression-free at different time points. The proportion of patients potentially cured was 41% for adjuvant controls, 58% with adjuvant chemotherapy, 17% for ADAURA controls, not assessable with adjuvant osimertinib, 15% with chemoradiotherapy, and 12% for SCLC. Median PFS half-life for relapsing subpopulations was 11.9 months for adjuvant controls, 17.4 months with adjuvant chemotherapy, 24.4 months for ADAURA controls, not assessable with osimertinib, 9.3 months with chemoradiotherapy, and 10.7 months for SCLC. For those remaining relapse-free at 2 and 5 years, the cure probability was 74%/96% for adjuvant controls, 77%/93% with adjuvant chemotherapy, 51%/94% with chemoradiation, and 39%/87% with limited SCLC. Relatively easy population kinetic analyses add useful information.

Nonclinical factors affecting intraoperative red blood cell transfusion: a systematic review.

PURPOSE: There is significant variability in intraoperative red blood cell (RBC) transfusion practice. We aimed to use the theoretical domains framework (TDF) to categorize nonclinical and behavioural factors driving intraoperative RBC transfusion practice in a systematic review of the literature. SOURCE: We searched electronic databases from inception until August 2021 to identify studies evaluating nonclinical factors affecting intraoperative RBC transfusion. Using the Mixed Methods Appraisal Tool, we assessed the quality of included studies and identified relevant nonclinical factors, which were coded into TDF domains by two independent reviewers using NVivo (Lumivero, QSR International, Burlington, MA, USA). We identified common themes within domains and sorted domains based on the frequency of reported factors. PRINCIPAL FINDINGS: Our systematic review identified 18 studies: nine retrospective cohort studies, six cross-sectional surveys, and three before-and-after studies. Factors related to the social influences, behavioural regulation, environmental context/resources, and beliefs about consequences domains of the TDF were the most reported factors. Key factors underlying the observed variability in transfusion practice included the social effects of peers, patients, and institutional culture on decision-making (social influences), and characteristics of the practice environment including case volume, geographic location, and case start time (environmental context/resources). Studies reported variable beliefs about the consequences of both intraoperative transfusion and anemia (beliefs about consequences). Provider- and institutional-level audits, educational sessions, and increased communication between surgeons/anesthesiologists were identified as strategies to optimize intraoperative transfusion decision-making (behavioural regulation). CONCLUSION: Our systematic review has synthesized the literature on nonclinical and behavioural factors impacting intraoperative transfusion decision-making, categorized using the TDF. These findings can inform evidence-based interventions to reduce intraoperative RBC transfusion variability. STUDY REGISTRATION: Open Science Framework ( https://osf.io/pm8zs/?view_only=166299ed28964804b9360c429b1218c1 ; first posted, 3 August 2022).

RéSUMé: OBJECTIF: Il existe une variabilité importante dans les pratiques de transfusion peropératoire de culots sanguins. Nous avons cherché à utiliser le cadre des domaines théoriques (TDF, pour theoretical domains framework) pour catégoriser les facteurs non cliniques et comportementaux motivant les pratiques de transfusion peropératoire de culots sanguins dans une revue systématique de la littérature. SOURCES: Nous avons réalisé des recherches dans les bases de données électroniques de leur création jusqu'en août 2021 pour identifier les études évaluant les facteurs non cliniques affectant la transfusion peropératoire de culots sanguins. À l'aide de l'outil d'évaluation des méthodes mixtes, nous avons évalué la qualité des études incluses et identifié les facteurs non cliniques pertinents, qui ont été codés dans les domaines TDF par deux personnes les révisant de manière indépendante utilisant NVivo (Lumivero, QSR International, Burlington, MA, États-Unis). Nous avons identifié des thèmes communs au sein des domaines et trié les domaines en fonction de la fréquence des facteurs signalés. CONSTATATIONS PRINCIPALES: Notre revue systématique a identifié 18 études : neuf études de cohorte rétrospectives, six sondages transversaux et trois études avant-après. Les facteurs liés aux influences sociales, à la régulation comportementale, au contexte et aux ressources environnementaux et les croyances concernant les domaines de conséquences du TDF étaient les facteurs les plus rapportés. Les principaux facteurs sous-jacents à la variabilité observée dans la pratique transfusionnelle comprenaient les effets sociaux des pairs, de la patientèle et de la culture de l'établissement sur la prise de décision (influences sociales) et les caractéristiques de l'environnement de pratique, y compris le volume de cas, l'emplacement géographique et l'heure de début des cas (contexte/ressources environnementaux). Des études ont fait état de croyances variables sur les conséquences de la transfusion peropératoire et de l'anémie (croyances sur les conséquences). Des vérifications au niveau des prestataires et des établissements, des séances de formation et une communication accrue entre les chirurgien·nes et les anesthésiologistes ont été identifiées comme des stratégies pouvant optimiser la prise de décision transfusionnelle peropératoire (régulation comportementale). CONCLUSION: Notre revue systématique a synthétisé la littérature sur les facteurs non cliniques et comportementaux ayant une incidence sur la prise de décision transfusionnelle peropératoire, classés à l'aide du TDF. Ces résultats peuvent éclairer les interventions fondées sur des données probantes pour réduire la variabilité de transfusion peropératoire de culots sanguins. ENREGISTREMENT DE L'éTUDE: Open Science Framework ( https://osf.io/pm8zs/?view_only=166299ed28964804b9360c429b1218c1 ; soumis pour la première fois, 3 août 2022).