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.

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

OBJECTIVES: This study aims to systematically review evidence on the cost-effectiveness of chimeric antigen receptor (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 cancer patients 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 1,809 records, 47 of which were included. The majority 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 to various standard-of-care chemotherapies. The incremental cost-effective ratio (ICER) for CAR-T therapies ranged from $9,424 to $4,124,105 per QALY in adults and from $20,784 to $243,177 per QALY in pediatric patients. ICERs 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 were 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.

The prevalence of non-contrast CT imaging abnormalities in reversible cerebral vasoconstriction syndrome: A systematic review and meta-analysis.

BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) is a syndrome of recurrent thunderclap headaches and reversible vasoconstriction of the cerebral arteries on neuroimaging within 3 months of onset. Initial non-contrast computed tomography (CT) can reveal abnormalities such as ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage (SAH) can be present in patients with RCVS and may delay diagnosis. AIMS: We conducted a systematic review and meta-analysis in accordance with the PRISMA guidelines. We aimed to estimate the prevalence of imaging abnormalities on initial non-contrast CT head in adult patients with RCVS. DATA SOURCES & ELIGIBILITY CRITERIA: We searched electronic databases including MEDLINE, EMBASE, and the Cochrane Register of Clinical Trials from inception to August 2, 2022. Eligible studies included articles reporting the prevalence of non-contrast CT abnormalities on initial neuroimaging in patients with RCVS, aged 18 and older. Case series, observational studies and clinical trials were included. Data was extracted directly from included papers using a standardized data charting form. RESULTS: The search yielded 722 titles with duplicates removed. Twenty studies that included 379 patients with RCVS met inclusion criteria. We classified non-contrast CT abnormalities as either ischemic stroke, ICH, or SAH. We pooled prevalence data using a random effects model with the inverse-variance weighted method. The most common imaging finding was SAH with a pooled prevalence of 24% (95% CI:17%-33%), followed by ICH at 14% (95% CI:8%-22%), and ischemic stroke at 10% (95% CI:7%-14%). The pooled prevalence of any of these imaging abnormalities on initial non-contrast CT was 31% (95% CI:23%-40%). Risk of bias was moderate to very-high-risk for case-series and low-risk for observational studies. CONCLUSION: Our review demonstrates that one-third of patients with RCVS will have an abnormality on initial non-contrast CT head, including either an ischemic stroke, ICH, or SAH. These findings highlight the diagnostic challenges of RCVS imaging and contribute to our understanding of this disease.

Evidence for clinician underprescription of and patient non-adherence to guideline-recommended cardiovascular medications among adults with peripheral artery disease: protocol for a systematic review and meta-analysis.

INTRODUCTION: International guidelines recommend that adults with peripheral artery disease (PAD) be prescribed antiplatelet, statin and antihypertensive medications. However, it is unclear how often people with PAD are underprescribed these drugs, which characteristics predict clinician underprescription of and patient non-adherence to guideline-recommended cardiovascular medications, and whether underprescription and non-adherence are associated with adverse health and health system outcomes. METHODS AND ANALYSIS: We will search MEDLINE, EMBASE and Evidence-Based Medicine Reviews from 2006 onwards. Two investigators will independently review abstracts and full-text studies. We will include studies that enrolled adults and reported the incidence and/or prevalence of clinician underprescription of or patient non-adherence to guideline-recommended cardiovascular medications among people with PAD; adjusted risk factors for underprescription of/non-adherence to these medications; and adjusted associations between underprescription/non-adherence to these medications and outcomes. Outcomes will include mortality, major adverse cardiac and limb events (including revascularisation procedures and amputations), other reported morbidities, healthcare resource use and costs. Two investigators will independently extract data and evaluate study risk of bias. We will calculate summary estimates of the incidence and prevalence of clinician underprescription/patient non-adherence across studies. We will also conduct subgroup meta-analyses and meta-regression to determine if estimates vary by country, characteristics of the patients and treating clinicians, population-based versus non-population-based design, and study risks of bias. Finally, we will calculate pooled adjusted risk factors for underprescription/non-adherence and adjusted associations between underprescription/non-adherence and outcomes. We will use Grading of Recommendations, Assessment, Development and Evaluation to determine estimate certainty. ETHICS AND DISSEMINATION: Ethics approval is not required as we are studying published data. This systematic review will synthesise existing evidence regarding clinician underprescription of and patient non-adherence to guideline-recommended cardiovascular medications in adults with PAD. Results will be used to identify evidence-care gaps and inform where interventions may be required to improve clinician prescribing and patient adherence to prescribed medications. PROSPERO REGISTRATION NUMBER: CRD42022362801.

Long-term survival and functional outcomes of critically ill patients with hematologic malignancies: a Canadian multicenter prospective study.

PURPOSE: Patients with hematologic malignancy (HM) commonly develop critical illness. Their long-term survival and functional outcomes have not been well described. METHODS: We conducted a prospective, observational study of HM patients admitted to seven Canadian intensive care units (ICUs) (2018-2020). We followed survivors at 7 days, 6 months and 12 months following ICU discharge. The primary outcome was 12-month survival. We evaluated functional outcomes at 6 and 12 months using the functional independent measure (FIM) and short form (SF)-36 as well as variables associated with 12-month survival. RESULTS: We enrolled 414 patients including 35% women. The median age was 61 (interquartile range, IQR: 52-69), median Sequential Organ Failure Assessment (SOFA) score was 9 (IQR: 6-12), and 22% had moderate-severe frailty (clinical frailty scale [CFS] ≥ 6). 51% had acute leukemia, 38% lymphoma/multiple myeloma, and 40% had received a hematopoietic stem cell transplant (HCT). The most common reasons for ICU admission were acute respiratory failure (50%) and sepsis (40%). Overall, 203 (49%) were alive 7 days post-ICU discharge (ICU survivors). Twelve-month survival of the entire cohort was 21% (43% across ICU survivors). The proportion of survivors with moderate-severe frailty was 42% (at 7 days), 14% (6 months), and 8% (12 months). Median FIM at 7 days was 80 (IQR: 50-109). Physical function, pain, social function, mental health, and emotional well-being were below age- and sex-matched population scores at 6 and 12 months. Frailty, allogeneic HCT, kidney injury, and cardiac complications during ICU were associated with lower 12- month survival. CONCLUSIONS: 49% of all HM patients were alive at 7 days post-ICU discharge, and 21% at 12 months. Survival varied based upon hematologic diagnosis and frailty status. Survivors had important functional disability and impairment in emotional, physical, and general well-being.

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).

Factors influencing nurses' use of sedation interruptions in a critical care unit: a descriptive qualitative study.

INTRODUCTION AND AIMS: This study examined critical care nurses', physicians', and allied health professionals' perceptions of factors that support, inhibit, or limit the use of sedation interruption (SI) to improve the use of this integral component of care for mechanically ventilated patients. METHOD: We conducted a theory-based, descriptive qualitative study using semi-structured interviews with critical care registered nurses, respiratory therapists, a pharmacist, and a physician in a hospital in Ontario, Canada. The interview guide and analysis were informed by the Theoretical Domains Framework and transcripts were analyzed using content analysis. RESULTS: We identified 9 facilitators and 20 barriers to SI use by nurses. Facilitators included the innovation (importance of protocols) and potential adopters (comfort with the skill). The barriers were the potential adopters' (nurses) knowledge gaps regarding the performance and goal of SI and the practice environment (lack of time, availability of extra staff, and lack of multidisciplinary rounds). CONCLUSION: This study identified facilitators and barriers to SI for mechanically ventilated patients. Implementation efforts must address barriers associated with nurses, the environment, and contextual factors. A team-based approach is essential, as the absence of interprofessional rounds is a significant barrier to the appropriate use or non-use of SI. Future research can focus on the indications, contraindications, and goals of SI, emphasizing a shared appreciation for these factors across disciplines. Nursing capacity to manage a patient waking up from sedation is necessary for point-of-care adherence; future research should focus on the best ways to do so. Implementation study designs should use theory and evidence-based determinants of SI to bridge the evidence-to-practice gap. SPANISH ABSTRACT: http://links.lww.com/IJEBH/A178.

Intraoperative pharmacologic opioid minimisation strategies and patient-centred outcomes after surgery: a scoping review.

BACKGROUND: Postoperative patient-centred outcome measures are essential to capture the patient's experience after surgery. Although a large number of pharmacologic opioid minimisation strategies (i.e. opioid alternatives) are used for patients undergoing surgery, it remains unclear which strategies are most promising in terms of patient-centred outcome improvements. This scoping review had two main objectives: (1) to map and describe evidence from clinical trials assessing the patient-centred effectiveness of pharmacologic intraoperative opioid minimisation strategies in adult surgical patients, and (2) to identify promising pharmacologic opioid minimisation strategies. METHODS: We searched MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL databases from inception to February 2023. We included trials investigating the use of opioid minimisation strategies in adult surgical patients and reporting at least one patient-centred outcome. Study screening and data extraction were conducted independently by at least two reviewers. RESULTS: Of 24,842 citations screened for eligibility, 2803 trials assessed the effectiveness of intraoperative opioid minimisation strategies. Of these, 457 trials (67,060 participants) met eligibility criteria, reporting at least one patient-centred outcome. In the 107 trials that included a patient-centred primary outcome, patient wellbeing was the most frequently used domain (55 trials). Based on aggregate findings, dexmedetomidine, systemic lidocaine, and COX-2 inhibitors were promising strategies, while paracetamol, ketamine, and gabapentinoids were less promising. Almost half of the trials (253 trials) did not report a protocol or registration number. CONCLUSIONS: Researchers should prioritise and include patient-centred outcomes in the assessment of opioid minimisation strategy effectiveness. We identified three potentially promising pharmacologic intraoperative opioid minimisation strategies that should be further assessed through systematic reviews and multicentre trials. Findings from our scoping review may be influenced by selective outcome reporting bias. STUDY REGISTRATION: OSF - https://osf.io/7kea3.

Protocol for co-producing a framework and integrated resource platform for engaging patients in laboratory-based research.

BACKGROUND: Patient engagement in research is the meaningful and collaborative interaction between patients and researchers throughout the research process. Patient engagement can help to ensure patient-oriented values and perspectives are incorporated into the development, conduct, and dissemination of research. While patient engagement is increasingly prevalent in clinical research, it remains relatively unrealized in preclinical laboratory research. This may reflect the nature of preclinical research, in which routine interactions or engagement with patients may be less common. Our team of patient partners and researchers has previously identified few published examples of patient engagement in preclinical laboratory research, as well as a paucity of guidance on this topic. Here we propose the development of a process framework to facilitate patient engagement in preclinical laboratory research. METHODS: Our team, inclusive of researchers and patient partners, will develop a comprehensive, empirically-derived, and stakeholder-informed process framework for 'patient engagement in preclinical laboratory research.' First, our team will create a 'deliberative knowledge space' to conduct semi-structured discussions that will inform a draft framework for preclinical patient engagement. Over the course of several sessions, we will identify actions, activities, barriers, and enablers (e.g. considerations and motivations for patient engagement in preclinical laboratory research, define roles of key players). The resulting draft process framework will be further populated with examples and refined through an international consensus-building Delphi survey with patients, researchers, and other collaborator organizations. We will then conduct pilot field tests to evaluate the framework with preclinical laboratory research groups paired with patient partners. These results will be used to create a refined framework enriched with real-world examples and considerations. All resources developed will be made available through an online repository. DISCUSSION: Our proposed process framework will provide guidance, best practices, and standardized procedures to promote patient engagement in preclinical laboratory research. Supporting and facilitating patient engagement in this setting presents an exciting new opportunity to help realize the important impact that patients can make.

Engaging patients as partners or collaborators in clinical research is becoming more common, but it is still new in preclinical research. Preclinical researchers work in laboratories on cell and animal experiments. They traditionally don't have frequent interactions with patients compared to their clinical research colleagues. Integrating patient engagement in preclinical laboratory research may help ensure that patient perspectives and values are considered. To help preclinical laboratory research align with patient-centred priorities we propose the development of a practical framework. This framework will facilitate patient engagement in preclinical laboratory research. To achieve this, we will first hold in-depth discussions with patient partners, researchers, and other collaborators to understand views on patient engagement in preclinical laboratory research. Together, we will identify key considerations to draft a framework, including motivations for patient engagement in preclinical laboratory research, and defining the roles of those who need to be involved. We will refine the framework through an international survey where we will collect feedback from researchers, patient partners, and other collaborators to make further improvements. The framework will then be tested and refined by preclinical laboratory teams inclusive of patient partners. The finalized framework and other resources to facilitate patient engagement in preclinical laboratory research will be hosted in a 'one-stop-shop' of online resources. Ultimately, this framework will enable partnerships between patients and researchers and provide a roadmap for patient engagement in preclinical laboratory research. This presents an exciting new opportunity for patients and researchers to collaborate and potentially improve translation of laboratory-based research.

Efficacy and Safety of Umbilical Cord-Derived Mesenchymal Stromal Cell Therapy in Preclinical Models of Sepsis: A Systematic Review and Meta-analysis.

BACKGROUND: In preclinical studies, mesenchymal stromal cells (MSCs), including umbilical cord-derived MSCs (UC-MSCs), demonstrate the ability to modulate numerous pathophysiological processes related to sepsis; however, a systematic synthesis of the literature is needed to assess the efficacy of UC-MSCs for treating sepsis. OBJECTIVE: To examine the effects of UC-MSCs on overall mortality (primary outcome) as well as on organ dysfunction, coagulopathy, endothelial permeability, pathogen clearance, and systemic inflammation (secondary outcomes) at prespecified time intervals in preclinical models of sepsis. METHODS: A systematic search was conducted on Embase, Ovid MEDLINE, and Web of Science up to June 20, 2023. Preclinical controlled studies using in vivo sepsis models with systemic UC-MSC administration were included. Meta-analyses were conducted and expressed as odds ratios (OR) and ratios of the weighted means with 95% CI for categorical and continuous data, respectively. Risk of bias was assessed with the SYRCLE tool. RESULTS: Twenty-six studies (34 experiments, n = 1258 animals) were included in this review. Overall mortality was significantly reduced with UC-MSC treatment as compared to controls (OR: 0.26, 95% CI: 0.18-0.36). At various prespecified time intervals, UC-MSCs reduced surrogate measures of organ dysfunction related to the kidney, liver, and lung; reduced coagulopathy and endothelial permeability; and enhanced pathogen clearance from multiple sites. UC-MSCs also modulated systemic inflammatory mediators. No studies were rated as low risk across all SYCLE domains. CONCLUSIONS: These results demonstrate the efficacy of UC-MSC treatment in preclinical sepsis models and highlight their potential as a therapeutic intervention for septic shock.

Effectiveness of dexmedetomidine during surgery under general anaesthesia on patient-centred outcomes: a systematic review and Bayesian meta-analysis protocol.

INTRODUCTION: Dexmedetomidine is a promising pharmaceutical strategy to minimise opioid use during surgery. Despite its growing use, it is uncertain whether dexmedetomidine can improve patient-centred outcomes such as quality of recovery and pain. METHODS AND ANALYSIS: We will conduct a systematic review and meta-analysis following the recommendations of the Cochrane Handbook for Systematic Reviews. We will search MEDLINE, Embase, CENTRAL, Web of Science and CINAHL approximately in October 2023. We will include randomised controlled trials evaluating the impact of systemic intraoperative dexmedetomidine on patient-centred outcomes. Patient-centred outcome definition will be based on the consensus definition established by the Standardised Endpoints in Perioperative Medicine initiative (StEP-COMPAC). Our primary outcome will be the quality of recovery after surgery. Our secondary outcomes will be patient well-being, function, health-related quality of life, life impact, multidimensional assessment of postoperative acute pain, chronic pain, persistent postoperative opioid use, opioid-related adverse events, hospital length of stay and adverse events. Two reviewers will independently screen and identify trials and extract data. We will evaluate the risk of bias of trials using the Cochrane Risk of Bias Tool (RoB 2.0). We will synthesise data using a random effects Bayesian model framework, estimating the probability of achieving a benefit and its clinical significance. We will assess statistical heterogeneity with the tau-squared and explore sources of heterogeneity with meta-regression. We have involved patient partners, clinicians, methodologists, and key partner organisations in the development of this protocol, and we plan to continue this collaboration throughout all phases of this systematic review. ETHICS AND DISSEMINATION: Our systematic review does not require research ethics approval. It will help inform current clinical practice guidelines and guide development of future randomised controlled trials. The results will be disseminated in open-access peer-reviewed journals, presented at conferences and shared among collaborators and networks. PROSPERO REGISTRATION NUMBER: CRD42023439896.

A preclinical systematic review and meta-analysis assessing the effect of biological sex in lipopolysaccharide-induced acute lung injury.

It is unclear what effect biological sex has on outcomes of acute lung injury (ALI). Clinical studies are confounded by their observational design. We addressed this knowledge gap with a preclinical systematic review of ALI animal studies. We searched MEDLINE and Embase for studies of intratracheal/intranasal/aerosolized lipopolysaccharide administration (the most common ALI model) that reported sex-stratified data. Screening and data extraction were conducted in duplicate. Our primary outcome was histological tissue injury and secondary outcomes included alveolar-capillary barrier alterations and inflammatory markers. We used a random-effects inverse variance meta-analysis, expressing data as standardized mean difference (SMD) with 95% confidence intervals (CIs). Risk of bias was assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. We identified six studies involving 132 animals across 11 independent experiments. A total of 41 outcomes were extracted, with the direction of effect suggesting greater severity in males than females in 26/41 outcomes (63%). One study reported on lung histology and found that male mice exhibited greater injury than females (SMD: 1.61, 95% CI: 0.53-2.69). Meta-analysis demonstrated significantly elevated albumin levels (SMD: 2.17, 95% CI: 0.63-3.70) and total cell counts (SMD: 0.80, 95% CI: 0.27-1.33) in bronchoalveolar lavage fluid from male mice compared with female mice. Most studies had an "unclear risk of bias." Our findings suggest sex-related differences in ALI severity. However, these conclusions are drawn from a small number of animals and studies. Further research is required to address the fundamental issue of biological sex differences in LPS-induced ALI.

Accuracy of point-of-care testing devices for haemoglobin in the operating room: meta-analysis.

BACKGROUND: Point-of-care tests (POCT) for haemoglobin are increasingly used to guide intraoperative transfusion. However, their accuracy compared to central laboratory tests is unknown. The objective was to perform a systematic review and meta-analysis of method comparison studies assessing the accuracy of POCT versus central laboratory haemoglobin tests in patients undergoing surgery. METHODS: Electronic databases were searched from inception to April 2020 (updated August 2023). Any methodological approach comparing haemoglobin measurements between POCT and central laboratory in patients undergoing surgery under anaesthesia in the operating room were included. Data abstraction was guided by PRISMA and risk of bias was assessed by QUADAS-2. Data were extracted independently and in duplicate by two reviewers. Outcomes included mean differences between POCT and central laboratory haemoglobin with associated standard deviations and 95% limits of agreement (LOA). RESULTS: Of 3057 citations, 34 studies were included (n = 2427, 6857 paired measurements). Several devices were compared (pulse co-oximetry, n = 25; HemoCue, n = 10; iSTAT, n = 6; blood gas analysers, n = 10; haematology analyser, n = 2). Median sample size was 41 patients, and 11 studies were funded by device manufacturers. Fifteen of 34 studies had low risk of bias. Pooled mean differences (95% LOA) were: pulse co-oximeters 2.3 g/l (-25.2-29.8), HemoCue -0.3 g/l (-11.1-10.5), iSTAT -0.3 g/l (-8.4-7.8) and blood gas analysers -2.6 g/l (-17.8-12.7). CONCLUSION: All POCT examining intraoperative haemoglobin measurement yielded pooled mean difference LOAs larger than the allowable limit difference of ±4 g/dl. Intraoperative haemoglobin measured by POCT should not be considered interchangeable with central laboratory values and caution is necessary when using these tests to guide intraoperative transfusion.

Recurrence of cervical artery dissection: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Cervical artery dissection (CAD) involving the carotid or vertebral arteries is an important cause of stroke in younger patients. The purpose of this systematic review is to assess the risk of recurrent CAD. METHODS: A systematic review and meta-analysis was conducted on studies in which patients experienced radiographically confirmed dissections involving an extracranial segment of the carotid or vertebral artery and in whom CAD recurrence rates were reported. RESULTS: Data were extracted from 29 eligible studies (n = 5898 patients). Analysis of outcomes was performed by pooling incidence rates with random effects models weighting by inverse of variance. The incidence of recurrent CAD was 4% overall (95% confidence interval (CI) = 3-7%), 2% at 1 month (95% CI = 1-5%), and 7% at 1 year in studies with sufficient follow-up (95% CI = 4-13%). The incidence of recurrence associated with ischemic events was 2% (95% CI = 1-3%). CONCLUSIONS: We found low rates of recurrent CAD and even lower rates of recurrence associated with ischemia. Further patient-level data and clinical subgroup analyses would improve the ability to provide patient-level risk stratification.

Intraoperative Blood Management Strategies for Patients Undergoing Noncardiac Surgery: The Ottawa Intraoperative Transfusion Consensus.

Importance: There is marked variability in red blood cell (RBC) transfusion during the intraoperative period. The development and implementation of existing clinical practice guidelines have been ineffective in reducing this variability. Objective: To develop an internationally endorsed consensus statement about intraoperative transfusion in major noncardiac surgery. Evidence Review: A Delphi consensus survey technique with an anonymous 3-round iterative rating and feedback process was used. An expert panel of surgeons, anesthesiologists, and transfusion medicine specialists was recruited internationally. Statements were informed by extensive preparatory work, including a systematic reviews of intraoperative RBC guidelines and clinical trials, an interview study with patients to explore their perspectives about intraoperative transfusion, and interviews with physicians to understand the various behaviors that influence intraoperative transfusion decision-making. Thirty-eight statements were developed addressing (1) decision-making (interprofessional communication, clinical factors, procedural considerations, and audits), (2) restrictive transfusion strategies, (3) patient-centred considerations, and (4) research considerations (equipoise, outcomes, and protocol suspension). Panelists were asked to score statements on a 7-point Likert scale. Consensus was established with at least 75% agreement. Findings: The 34-member expert panel (14 of 33 women [42%]) included 16 anesthesiologists, 11 surgeons, and 7 transfusion specialists; panelists had a median of 16 years' experience (range, 2-50 years), mainly in Canada (52% [17 of 33]), the US (27% [9 of 33]), and Europe (15% [5 of 33]). The panel recommended routine preoperative and intraoperative discussion between surgeons and anesthesiologists about intraoperative RBC transfusion as well as postoperative review of intraoperative transfusion events. Point-of-care hemoglobin testing devices were recommended for transfusion guidance, alongside an algorithmic transfusion protocol with a restrictive hemoglobin trigger; however, more research is needed to evaluate the use of restrictive triggers in the operating room. Expert consensus recommended a detailed preoperative consent discussion with patients of the risks and benefits of both anemia and RBC transfusion and routine disclosure of intraoperative transfusion. Postoperative morbidity and mortality were recommended as the most relevant outcomes associated with intraoperative RBC transfusion, and transfusion triggers of 70 and 90 g/L were considered acceptable hemoglobin triggers to evaluate restrictive and liberal transfusion strategies, respectively, in clinical trials. Conclusions and Relevance: This consensus statement offers internationally endorsed expert guidance across several key domains on intraoperative RBC transfusion practice for noncardiac surgical procedures for which patients are at medium or high risk of bleeding. Future work should emphasize knowledge translation strategies to integrate these recommendations into routine clinical practice and transfusion research activities.

Point-of-care haemoglobin accuracy and transfusion outcomes in non-cardiac surgery at a Canadian tertiary academic hospital: protocol for the PREMISE observational study.

INTRODUCTION: Transfusions in surgery can be life-saving interventions, but inappropriate transfusions may lack clinical benefit and cause harm. Transfusion decision-making in surgery is complex and frequently informed by haemoglobin (Hgb) measurement in the operating room. Point-of-care testing for haemoglobin (POCT-Hgb) is increasingly relied on given its simplicity and rapid provision of results. POCT-Hgb devices lack adequate validation in the operative setting, particularly for Hgb values within the transfusion zone (60-100 g/L). This study aims to examine the accuracy of intraoperative POCT-Hgb instruments in non-cardiac surgery, and the association between POCT-Hgb measurements and transfusion decision-making. METHODS AND ANALYSIS: PREMISE is an observational prospective method comparison study. Enrolment will occur when adult patients undergoing major non-cardiac surgery require POCT-Hgb, as determined by the treating team. Three concurrent POCT-Hgb results, considered as index tests, will be compared with a laboratory analysis of Hgb (lab-Hgb), considered the gold standard. Participants may have multiple POCT-Hgb measurements during surgery. The primary outcome is the difference in individual Hgb measurements between POCT-Hgb and lab-Hgb, primarily among measurements that are within the transfusion zone. Secondary outcomes include POCT-Hgb accuracy within the entire cohort, postoperative morbidity, mortality and transfusion rates. The sample size is 1750 POCT-Hgb measurements to obtain a minimum of 652 Hgb measurements <100 g/L, based on an estimated incidence of 38%. The sample size was calculated to fit a logistic regression model to predict instances when POCT-Hgb are inaccurate, using 4 g/L as an acceptable margin of error. ETHICS AND DISSEMINATION: Institutional ethics approval has been obtained by the Ottawa Health Science Network-Research Ethics Board prior to initiating the study. Findings from this study will be published in peer-reviewed journals and presented at relevant scientific conferences. Social media will be leveraged to further disseminate the study results and engage with clinicians.

Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia.

BACKGROUND: A strategy of administering a transfusion only when the hemoglobin level falls below 7 or 8 g per deciliter has been widely adopted. However, patients with acute myocardial infarction may benefit from a higher hemoglobin level. METHODS: In this phase 3, interventional trial, we randomly assigned patients with myocardial infarction and a hemoglobin level of less than 10 g per deciliter to a restrictive transfusion strategy (hemoglobin cutoff for transfusion, 7 or 8 g per deciliter) or a liberal transfusion strategy (hemoglobin cutoff, <10 g per deciliter). The primary outcome was a composite of myocardial infarction or death at 30 days. RESULTS: A total of 3504 patients were included in the primary analysis. The mean (±SD) number of red-cell units that were transfused was 0.7±1.6 in the restrictive-strategy group and 2.5±2.3 in the liberal-strategy group. The mean hemoglobin level was 1.3 to 1.6 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group on days 1 to 3 after randomization. A primary-outcome event occurred in 295 of 1749 patients (16.9%) in the restrictive-strategy group and in 255 of 1755 patients (14.5%) in the liberal-strategy group (risk ratio modeled with multiple imputation for incomplete follow-up, 1.15; 95% confidence interval [CI], 0.99 to 1.34; P = 0.07). Death occurred in 9.9% of the patients with the restrictive strategy and in 8.3% of the patients with the liberal strategy (risk ratio, 1.19; 95% CI, 0.96 to 1.47); myocardial infarction occurred in 8.5% and 7.2% of the patients, respectively (risk ratio, 1.19; 95% CI, 0.94 to 1.49). CONCLUSIONS: In patients with acute myocardial infarction and anemia, a liberal transfusion strategy did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days. However, potential harms of a restrictive transfusion strategy cannot be excluded. (Funded by the National Heart, Lung, and Blood Institute and others; MINT ClinicalTrials.gov number, NCT02981407.).

Metabolomics Analysis of Mesenchymal Stem Cell (MSC) Therapy in a Phase I Clinical Trial of Septic Shock: An Exploratory Study.

Sepsis is the result of an uncontrolled host inflammatory response to infection that may lead to septic shock with multiorgan failure and a high mortality rate. There is an urgent need to improve early diagnosis and to find markers identifying those who will develop septic shock and certainly a need to develop targeted treatments to prevent septic shock and its high mortality. Herein, we explore metabolic alterations due to mesenchymal stromal cell (MSC) treatment of septic shock. The clinical findings for this study were already reported; MSC therapy was well-tolerated and safe in patients in this phase I clinical trial. In this exploratory metabolomics study, 9 out of 30 patients received an escalating dose of MSC treatment, while 21 patients were without MSC treatment. Serum metabolomics profiling was performed to detect and characterize metabolite changes due to MSC treatment and to help determine the sample size needed for a phase II clinical trial and to define a metabolomic response to MSC treatment. Serum metabolites were measured using 1H-NMR and HILIC-MS at times 0, 24 and 72 h after MSC infusion. The results demonstrated the significant impact of MSC treatment on serum metabolic changes in a dose- and time-dependent manner compared to non-MSC-treated septic shock patients. This study suggests that plasma metabolomics can be used to assess the response to MSC therapy and that treatment-related metabolomics effects can be used to help determine the sample size needed in a phase II trial. As this study was not powered to detect outcome, how the treatment-induced metabolomic changes described in this study of MSC-treated septic shock patients are related to outcomes of septic shock in the short and long term will need to be explored in a larger adequately powered phase II clinical trial.

Safety and Efficacy of Adeno-Associated Viral Gene Therapy in Patients With Retinal Degeneration: A Systematic Review and Meta-Analysis.

Purpose: This systematic review evaluates the safety and efficacy of ocular gene therapy using adeno-associated virus (AAV). Methods: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched systematically for controlled or non-controlled interventional gene therapy studies using key words related to retinal diseases, gene therapy, and AAV vectors. The primary outcome measure was safety, based on ocular severe adverse events (SAEs). Secondary outcome measures evaluated efficacy of the therapy based on best corrected visual acuity (BCVA) and improvements in visual sensitivity and systemic involvement following ocular delivery. Pooling was done using a DerSimonian Laird random effects model. Risk of bias was assessed using the Cochrane Risk of Bias Tool, version 1. Results: Our search identified 3548 records. Of these, 80 publications met eligibility criteria, representing 28 registered clinical trials and 5 postmarket surveillance studies involving AAV gene therapy for Leber congenital amaurosis (LCA), choroideremia, Leber hereditary optic neuropathy (LHON), age-related macular degeneration (AMD), retinitis pigmentosa (RP), X-linked retinoschisis, and achromatopsia. Overall, AAV therapy vectors were associated with a cumulative incidence of at least one SAE of 8% (95% confidence intervals [CIs] of 5% to 12%). SAEs were often associated with the surgical procedure rather than the therapeutic vector itself. Poor or inconsistent reporting of adverse events (AEs) were a limitation for the meta-analysis. The proportion of patients with any improvement in BCVA and visual sensitivity was 41% (95% CIs of 31% to 51%) and 51% (95% CIs of 31% to 70%), respectively. Systemic immune involvement was associated with a cumulative incidence of 31% (95% CI = 21% to 42%). Conclusions: AAV gene therapy vectors appear to be safe but the surgical procedure required to deliver them is associated with some risk. The large variability in efficacy can be attributed to the small number of patients treated, the heterogeneity of the population and the variability in dosage, volume, and follow-up. Translational Relevance: This systematic review will help to inform and guide future clinical trials.

Effect of red blood cell storage time in pediatric cardiac surgery patients: A subgroup analysis of a randomized controlled trial.

Objective: This study aimed to determine whether or not transfusion of fresh red blood cells (RBCs) reduced the incidence of new or progressive multiple organ dysfunction syndrome compared with standard-issue RBCs in pediatric patients undergoing cardiac surgery. Methods: Preplanned secondary analysis of the Age of Blood in Children in Pediatric Intensive Care Unit study, an international randomized controlled trial. This study included children enrolled in the Age of Blood in Children in Pediatric Intensive Care Unit trial and admitted to a pediatric intensive care unit after cardiac surgery with cardiopulmonary bypass. Patients were randomized to receive either fresh (stored ≤7 days) or standard-issue RBCs. The primary outcome measure was new or progressive multiple organ dysfunction syndrome, measured up to 28 days postrandomization or at pediatric intensive care unit discharge, or death. Results: One hundred seventy-eight patients (median age, 0.6 years; interquartile range, 0.3-2.6 years) were included with 89 patients randomized to the fresh RBCs group (median length of storage, 5 days; interquartile range, 4-6 days) and 89 to the standard-issue RBCs group (median length of storage, 18 days; interquartile range, 13-22 days). There were no statistically significant differences in new or progressive multiple organ dysfunction syndrome between fresh (43 out of 89 [48.3%]) and standard-issue RBCs groups (38 out of 88 [43.2%]), with a relative risk of 1.12 (95% CI, 0.81 to 1.54; P = .49) and an unadjusted absolute risk difference of 5.1% (95% CI, -9.5% to 19.8%; P = .49). Conclusions: In neonates and children undergoing cardiac surgery with cardiopulmonary bypass, the use of fresh RBCs did not reduce the incidence of new or progressive multiple organ dysfunction syndrome compared with the standard-issue RBCs. A larger trial is needed to confirm these results.