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Background: Chimeric antigen receptor T cell therapy (CAR-T) represents a promising and exciting new therapy for hematologic malignancies, where prognosis for relapsed/refractory patients remains poor. Encouraging results from clinical trials have often been tempered by heterogeneity in response to treatment among patients, as well as safety concerns including cytokine release syndrome. The identification of specific patient or treatment-specific factors underlying this heterogeneity may provide the key to the long-term sustainability of this complex and expensive therapy. An individual patient data meta-analysis (IPMDA) may provide potential explanations for the high degree of heterogeneity. Therefore, our objective is to perform a systematic review and IPDMA of CAR-T cell therapy in patients with hematologic malignancies to explore potential effect modifiers of CAR-T cell therapy. Methods and analysis: We will search MEDLINE, Embase, and the Cochrane Central Register of Controlled Clinical Trials. Studies will be screened in duplicate at the abstract level, then at the full-text level by two independent reviewers. We will include any prospective clinical trial of CAR-T cell therapy in patients with hematologic malignancies. Our primary outcome is complete response, while secondary outcomes of interest include overall response, progression-free survival, overall survival, and safety. IPD will be collected from each included trial and, in the case of missing data, corresponding authors/study sponsors will be contacted. Standard aggregate meta-analyses will be performed, followed by the IPD meta-analysis using a one-stage approach. A modified Institute of Health Economics tool will be used to evaluate the risk of bias of included studies. Ethics and dissemination: Identifying characteristics that may act as modifiers of CAR-T cell efficacy is of paramount importance and can help shape future clinical trials in the field. Results from this study will be submitted for publication in a peer-reviewed scientific journal, presented at relevant conferences and shared with relevant stakeholders. [ABSTRACT FROM AUTHOR]

Use of rigorous study design methods and transparent reporting in publications are 2 key strategies proposed to improve the reproducibility of preclinical research. Despite promotion of these practices by funders and journals, assessments suggest uptake is low in preclinical research. Thirty preclinical scientists were interviewed to better understand barriers and enablers to rigorous design and reporting. The interview guide was informed by the Theoretical Domains Framework, which is a framework used to understand determinants of current and desired behavior. Four global themes were identified; 2 reflecting enablers and 2 reflecting barriers. We found that basic scientists are highly motivated to apply the methods of rigorous design and reporting and perceive a number of benefits to their adoption (e.g., improved quality and reliability). However, there was varied awareness of the guidelines and in implementation of these practices. Researchers also noted that these guidelines can result in disadvantages, such as increased sample sizes, expenses, time, and can require several personnel to operationalize. Most researchers expressed additional resources such as personnel and education/training would better enable the application of some methods. Using existing guidance (Behaviour Change Wheel (BCW); Expert Recommendations for Implementing Change (ERIC) project implementation strategies), we mapped and coded our interview findings to identify potential interventions, policies, and implementation strategies to improve routine use of the guidelines by preclinical scientists. These findings will help inform specific strategies that may guide the development of programs and resources to improve experimental design and transparent reporting in preclinical research. [ABSTRACT FROM AUTHOR]

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. 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). 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. 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. PROSPERO (CRD42023439896). [ABSTRACT FROM AUTHOR]

Background: Adverse outcomes and resource use rates are high after hip fracture surgery. Peripheral nerve blocks could improve outcomes through enhanced analgesia and decreased opioid related adverse events. We hypothesized that these benefits would translate into decreased resource use (length of stay [primary outcome] and costs), and better clinical outcomes (pneumonia and mortality).Methods: The authors conducted a retrospective cohort study of hip fracture surgery patients in Ontario, Canada (2011 to 2015) using linked health administrative data. Multilevel regression, instrumental variable, and propensity scores were used to determine the association of nerve blocks with resource use and outcomes.Results: The authors identified 65,271 hip fracture surgery patients; 10,030 (15.4%) received a block. With a block, the median hospital stay was 7 (interquartile range, 4 to 13) days versus 8 (interquartile range, 5 to 14) days without. Following adjustment, nerve blocks were associated with a 0.6-day decrease in length of stay (95% CI, 0.5 to 0.8). This small difference was consistent with instrumental variable (1.1 days; 95% CI, 0.9 to 1.2) and propensity score (0.2 days; 95% CI, 0.2 to 0.3) analyses. Costs were lower with a nerve block (adjusted difference, -$1,421; 95% CI, -$1,579 to -$1,289 [Canadian dollars]), but no difference in mortality (adjusted odds ratio, 0.99; 95% CI, 0.89 to 1.11) or pneumonia (adjusted odds ratio, 1.01; 95% CI, 0.88 to 1.16) was observed.Conclusions: Receipt of nerve blocks for hip fracture surgery is associated with decreased length of stay and health system costs, although small effect sizes may not reflect clinical significance for length of stay. [ABSTRACT FROM AUTHOR]

The insertion of a subclavian central venous catheter is generally associated with a high rate of success and a favorable risk profile. The use of ultrasound for procedural guidance has been demonstrated to further increase the rate of success and reduce the risk of specific mechanical complications, especially in patients with difficult surface anatomy. Many individual ultrasound techniques have been described in the literature; this article presents a systematic approach for incorporating these tools into bedside practice and includes a series of illustrative figures and narrated video presentations to demonstrate the techniques described. [ABSTRACT FROM AUTHOR]

See article on page 2250–2259, in this issue [ABSTRACT FROM AUTHOR]

Background: Despite advances in treatment, acute myocardial infarction (MI) is still associated with significant morbidity and mortality, especially in patients with extensive damage and scar formation. Based on some promising preclinical studies, there is interest in the use of mesenchymal stromal cells (MSCs) to promote cardiac repair after acute MI. However, there is a need for a systematic review of this evidence to summarize the efficacy and safety of MSCs in preclinical models of MI. This will better inform the translation of MSC therapy for acute MI and guide the design of a future clinical trial. Methods/design: A systematic literature search of MEDLINE, Embase, and BIOSIS Previews will be conducted. We will identify comparative preclinical studies (randomized and non-randomized) of myocardial infarction that include animals given MSC therapy versus a vehicle/placebo. The primary outcome will be left ventricular ejection fraction. Secondary and tertiary outcomes will include death, infarct size, measures of cardiac function, biochemical outcomes, and MSC retention and differentiation. Risk of bias will be assessed using the Cochrane Risk of Bias Tool. Subgroup analyses will be performed to measure how various sources of preclinical study heterogeneity affect the direction and magnitude of the primary outcome. We will meta-analyze data using inverse variance random effects modeling. Discussion: This systematic review of preclinical evidence will provide a summary of the efficacy and safety of MSCs in animal models of MI. The results will help determine whether sufficient evidence exists to conduct a clinical trial in humans and inform its design. [ABSTRACT FROM AUTHOR]

Objective: Although ultrasound guidance for subclavian vein catheterization has been well described, evidence for its use has not been comprehensively appraised. Thus, we conducted a systematic review and meta-analysis to determine whether ultrasound guidance of subclavian vein catheterization reduces catheterization failures and adverse events compared to the traditional "blind" landmark method. All forms of ultrasound were included (dynamic 2D ultrasound, static 2D ultrasound, and Doppler). Data Sources: Medline, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL (from inception to September 2014).Study Selection: Randomized controlled trials of ultrasound compared to landmark technique for subclavian catheterization in adult populations were considered. Outcomes of interest included safety and failure of catheterization. Data Extraction: Adverse event data were analyzed according to Peto's method and expressed as odd ratios and 95% CIs. Failure of catheterization was analyzed with inverse variance random effects modeling and expressed as risk ratios and 95% CI. Data Synthesis: Six hundred and one studies were reviewed and 10 met inclusion criteria (n = 2,168 participants). Six used dynamic 2D ultrasound (n = 719), one used static 2D ultrasound (n = 821), and three used Doppler-guided insertion techniques (n = 628). Overall complication rates were reduced with ultrasound use compared to the landmark group (odd ratio, 0.53; 95% CI, 0.41-0.69). Subgroup analysis demonstrated that dynamic 2D ultrasound reduced inadvertent arterial puncture, pneumothorax, and hematoma formation. No difference in failure of catheterization was noted between the ultrasound group and the landmark method (risk ratio, 0.85; 95% CI, 0.48-1.51). Subgroup analysis of dynamic 2D ultrasound demonstrated a significant decrease in failed catheterization (risk ratio, 0.24; 95% CI, 0.06-0.92). Conclusions: Ultrasound-guided subclavian catheterization reduced the frequency of adverse events compared with the landmark technique. Our findings support the use of dynamic 2D ultrasound for subclavian catheterization to reduce adverse events and failed catheterization. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stromal cells (MSCs, "adult stem cells") have been widely used experimentally in a variety of clinical contexts. There is interest in using these cells in critical illness, however, the safety profile of these cells is not well known. We thus conducted a systematic review of clinical trials that examined the use MSCs to evaluate their safety. Methods and Findings: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (to June 2011), were searched. Prospective clinical trials that used intravascular delivery of MSCs (intravenously or intra-arterially) in adult populations or mixed adult and pediatric populations were identified. Studies using differentiated MSCs or additional cell types were excluded. The primary outcome adverse events were grouped according to immediate events (acute infusional toxicity, fever), organ system complications, infection, and longer term adverse events (death, malignancy). 2347 citations were reviewed and 36 studies met inclusion criteria. A total of 1012 participants with clinical conditions of ischemic stroke, Crohn's disease, cardiomyopathy, myocardial infarction, graft versus host disease, and healthy volunteers were included. Eight studies were randomized control trials (RCTs) and enrolled 321 participants. Meta-analysis of the RCTs did not detect an association between acute infusional toxicity, organ system complications, infection, death or malignancy. There was a significant association between MSCs and transient fever. Conclusions: Based on the current clinical trials, MSC therapy appears safe. However, further larger scale controlled clinical trials with rigorous reporting of adverse events are required to further define the safety profile of MSCs. [ABSTRACT FROM AUTHOR]

Hypothesis: Increased peroxynitrite formation in endothelial cells incubated with plasma from women with preeclampsia alters the expression of specific endothelial proteins. Methods: We used a proteomic approach to examine the effect of a peroxynitrite scavenger (FeTPPS, 5 μmol/L) on the expression of endothelial proteins in response to plasma from women with preeclampsia. After treatment, cells were subjected to two-dimensional gel electrophoresis and proteins were identified using mass spectrometry. Results: Peroxynitrite scavenging decreased the expression of structural proteins, cytokeratin, actin-γ-1, and moesin, and the calcium-binding protein, calumenin. Conclusions: This study has identified novel proteins that are regulated by peroxynitrite in response to plasma from women with preeclampsia. [ABSTRACT FROM AUTHOR]

Persistent arterial hypotension is a hallmark of sepsis and is believed to be caused, at least in part, by excess nitric oxide (NO). NO can combine with superoxide to produce peroxynitrite, which activates matrix metalloproteinases (MMP5). Whether MMP inhibition in vivo protects against vascular hyporeactivity induced by endotoxemia is unknown. Male Sprague-Dawley rats were administered either bacterial lipopolysaccharide (LPS, 4 mg/kg ip) or vehicle (pyrogen-free water). Later (30 mm), animals received the MMP inhibitor doxycydine (4 mg/kg ip) or vehicle (pyrogen-free water). After LPS injection (6 h), animals were killed, and aortas were excised. Aortic rings were mounted in organ baths, and contractile responses to phenylephrine or KCI were measured. Aortas and plasma were examined for MMP activity by gelatin zymography. Aortic MMP and inducible nitric oxide synthase (iNOS) were examined by immunoblot and/or immunohistochemistry. Doxycycline prevented the LPS-induced development of ex vivo vascular hyporeactivity to phenylephrine and KCI. iNOS protein was significantly upregulated in aortic homogenates from endotoxemic rats; doxycycline did not alter its level. MMP-9 activity was undetectable in aortic homogenates from LPS-treated rats but significantly upregulated in the plasma; this was attenuated by doxycycline. Plasma MMP-2 activities were unchanged by LPS. Specific MMP-2 activity was increased in aortas from LPS-treated rats. This study demonstrates the in vivo protective effect of the MMP inhibitor doxycycline against the development of vascular hyporeactivity in endotoxemic rats. [ABSTRACT FROM AUTHOR]

Publication in scientific journals remains the primary method to disseminate research findings; however, the landscape of scientific publication is rapidly changing. For instance, although open access publication has led to unprecedented opportunities to share information with the global scientific community, it has also contributed to the rise of "predatory journals." These journals accept fees to publish articles without promised quality checks (e.g. peer review). In order to better understand current publication practices and the threat predatory journals pose, this session will: 1) Briefly summarize the history of scientific publication and how the current model of peer-reviewed publication developed. 2) Define predatory journals and review components of the international consensus definition (false or misleading information, deviation from best editorial and publication practices, lack of transparency, aggressive/indiscriminate solicitation; Nature doi. org/10.1038/d41586-019-03759-y). 3) Summarize empirical studies that have assessed the current burden of predatory journals. A broad group of stakeholders are affected by these journals, including researchers and the public. 4) Provide a practical approach for audience members to distinguish between predatory and legitimate journals. 5) Highlight some key developments that will lead to new publication models in the future. [ABSTRACT FROM AUTHOR]

Abstract: Septic shock remains the leading cause of death in intensive care units in North America. Recent evidence implicates matrix metalloproteinases (MMP) in the pathogenesis of sepsis. MMP activity is upregulated in blood vessels exposed to bacterial lipopolysaccharide (LPS) or pro-inflammatory cytokines and contributes to vascular hyporeactivity to vasoconstrictors. The exact mechanism of MMP-mediated vascular hyporeactivity is unknown. We investigated the contribution of the endothelium in the MMP response to LPS-mediated vascular hyporeactivity in vitro. Tone induced by phenylephrine in isolated rat aortic rings with either intact or denuded endothelium was measured in the presence of LPS for 6 h. These rings were incubated with the nitric oxide (NO) synthase inhibitor, N G-nitro-l-arginine methyl ester (l-NAME), to determine whether NO synthase was involved in the response, or the MMP inhibitors, doxycycline or GM6001. MMP activity was measured after 6 h. LPS caused a greater reduction of phenylephrine-induced tone in endothelium-intact rings versus endothelium-denuded rings, indicating both endothelium-independent and -dependent mechanisms for LPS-induced vascular hyporeactivity. l-NAME abolished the response to LPS in both endothelium-intact and endothelium-denuded rings. MMP inhibitors prevented the LPS-induced loss of tone in endothelium-intact but not endothelium-denuded rings. LPS caused significantly greater MMP-2 activity in endothelium-intact aortae which was attenuated by doxycycline. MMP-2 activity in endothelium-denuded aortae was unchanged by LPS. The vascular endothelium contributes to MMP-mediated vascular dysfunction induced by LPS. The protective effect of MMP inhibition is endothelium-dependent and is a novel mechanism by which MMPs contribute to vascular dysfunction. [Copyright &y& Elsevier]

Objective: To investigate whether myocardial and plasma matrix metalloproteinase (MMP) activities are altered during endotoxemia.Design: Prospective randomized, animal study.Setting: University research laboratory.Subjects: Male Sprague-Dawley rats, 250-300 g.Interventions: Rats were administered either bacterial lipopolysaccharide (LPS) or vehicle (pyrogen-free water). Groups of LPS-administered animals were killed at 0.5, 1, 3, 6, 12, and 24 hrs postinjection. Vehicle injected animals were killed at 6 hrs. Blood pressure was recorded before kill. Heart and plasma samples were analyzed by gelatin zymography and immunoblot.Measurements and Main Results: Blood pressure was significantly depressed at 3-24 hrs post-LPS injection; however, overt symptoms of endotoxemia and reduction in blood pressure were most significant 6-12 hrs post-LPS. Heart samples from control rats revealed MMP-2 activity but no MMP-9 activity. MMP-2 activity was significantly depressed when overt symptoms of endotoxemia peaked at 6-12 hrs. Plasma MMP-2 activity significantly decreased 3-12 hrs after LPS injection. This loss of activity was associated with a loss of MMP-2 protein. In contrast, plasma MMP-9 activities were rapidly elevated following LPS injection, peaking between 1 and 12 hrs. MMP-9 activity correlated inversely with blood pressure.Conclusions: Endotoxemia induced rapid changes in MMP activity in both the myocardium and plasma. An increase in circulating MMP-9 activity may contribute to endotoxemic cardiovascular dysfunction. [ABSTRACT FROM AUTHOR]

Release and activation of matrix metalloproteinases (MMPs) significantly contribute to myocardial stunning injury immediately after ischemia and reperfusion, however, their role in preconditioning remains unknown. We therefore examined the effects of preconditioning and subsequent ischemia/reperfusion on MMP activity in isolated rat hearts. Hearts were subjected to a preconditioning protocol (three consecutive 5-min periods of global ischemia interspersed with 5 min of reperfusion) followed by 30 min ischemia and 5 min reperfusion. To measure MMP release, coronary effluent was collected: (a) during aerobic perfusion, (b) in reperfusion following each preconditioning ischemia, and (c) during the final reperfusion following test ischemia. MMP-2 activities could be detected by gelatin zymography in the ventricles and coronary effluent samples from the perfused hearts. The levels of MMP-2 activity in the effluent were markedly increased in effluent following test ischemia from control hearts without preconditioning. This was accompanied by a decrease in corresponding tissue MMP activities. Preconditioning significantly decreased the MMP-2 activity in the coronary effluent following test ischemia/reperfusion and preserved the MMP-2 protein content and activity in the myocardium. Our results demonstrate that classic preconditioning inhibits ischemia/reperfusion induced release and activation of MMP-2. These results suggest that preconditioning may exert part of its cardioprotective effects through the reduction of MMP-2 release. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Older people (≥65 yr) are at increased risk of morbidity and mortality after emergency general surgery. Risk prediction models are needed to guide decision making in this high-risk population. Existing models have substantial limitations and lack external validation, potentially limiting their applicability in clinical use. We aimed to derive and validate, both internally and externally, a multivariable model to predict 30-day mortality risk in older patients undergoing emergency general surgery.Methods: After protocol publication, we used the National Surgical Quality Improvement Program (NSQIP) database (2012-6; estimated to contain 90% data from the USA and 10% from Canada) to derive and internally validate a model to predict 30-day mortality for older people having emergency general surgery using logistic regression with elastic net regularisation. Internal validation was done with 10-fold cross-validation. External validation was done using a temporally separate health administrative database exclusively from Ontario, Canada.Results: Overall, 6012 (12.0%) of the 50 221 patients died within 30 days. The model demonstrated strong discrimination (area under the curve [AUC]=0.871) and calibration across the spectrum of observed and predicted risks. Ten-fold internal cross-validation demonstrated minimal optimism (AUC=0.851, optimism 0.019 [standard deviation=0.06]) with excellent calibration. External validation demonstrated lower discrimination (AUC=0.700) and degraded calibration.Conclusion: A multivariable mortality risk prediction model was strongly discriminative and well calibrated internally. However, poor external validation suggests the model may not be generalisable to non-NSQIP data and hospitals. The findings highlight the importance of external validation before clinical application of risk models. [ABSTRACT FROM AUTHOR]

The authors discuss a study which analyzed the role of mesenchymal stromal cells (MCS) in critical illness, by Chien and colleagues, published within the issue. The study demonstrated the beneficial effects of cytokines or cellular mediators, as shown in MSC therapy in acute lung injury or septic shock. The authors also highlight concerns over MSC therapy for critical illness.

Introduction: Despite older adults being more vulnerable to sepsis, most preclinical research on sepsis has been conducted using young animals. This results in decreased scientific validity since age is an independent predictor of poor outcome. In this study, we explored the impact of aging on the host response to sepsis using the fecal-induced peritonitis (FIP) model developed by the National Preclinical Sepsis Platform (NPSP). Methods: C57BL/6 mice (3 or 12 months old) were injected intraperitoneally with rat fecal slurry (0.75 mg/g) or a control vehicle. To investigate the early stage of sepsis, mice were culled at 4 h, 8 h, or 12 h to investigate disease severity, immunothrombosis biomarkers, and organ injury. Mice received buprenorphine at 4 h post-FIP. A separate cohort of FIP mice were studied for 72 h (with buprenorphine given at 4 h, 12 h, and then every 12 h post-FIP and antibiotics/fluids starting at 12 h post-FIP). Organs were harvested, plasma levels of Interleukin (IL)-6, IL-10, monocyte chemoattract protein (MCP-1)/CCL2, thrombin-antithrombin (TAT) complexes, cell-free DNA (CFDNA), and ADAMTS13 activity were quantified, and bacterial loads were measured. Results: In the 12 h time course study, aged FIP mice demonstrated increased inflammation and injury to the lungs compared to young FIP mice. In the 72 h study, aged FIP mice exhibited a higher mortality rate (89%) compared to young FIP mice (42%) (p < 0.001). Aged FIP non-survivors also exhibited a trend towards elevated IL-6, TAT, CFDNA, CCL2, and decreased IL-10, and impaired bacterial clearance compared to young FIP non-survivors. Conclusion: To our knowledge, this is the first study to investigate the impact of age on survival using the FIP model of sepsis. Our model includes clinically-relevant supportive therapies and inclusion of both sexes. The higher mortality rate in aged mice may reflect increased inflammation and worsened organ injury in the early stage of sepsis. We also observed trends in impaired bacterial clearance, increase in IL-6, TAT, CFDNA, CCL2, and decreased IL-10 and ADAMTS13 activity in aged septic non-survivors compared to young septic non-survivors. Our aging model may help to increase the scientific validity of preclinical research and may be useful for identifying mechanisms of age-related susceptibility to sepsis as well as age-specific treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Anemia is common in neurocritically ill patients. Considering the limited clinical evidence in this population, preclinical data may provide some understanding of the potential impact of anemia and of red blood cell transfusion in these patients. We aim to estimate the association between different transfusion strategies and neurobehavioral outcome in animal models. Methods: We will conduct a systematic review of comparative studies of red blood cell transfusion strategies using animal models of traumatic brain injury, ischemic stroke or cerebral hemorrhage. We will search MEDLINE, EMBASE, and Web of Science databases for eligible studies from inception onwards. Two independent reviewers will perform study selection and data extraction. We will report our results in a descriptive synthesis focusing on characteristics of included studies, reported outcomes, risk of bias, and construct validity. Our primary outcome is the neurological function (neurobehavioral performance) and our secondary outcomes include mortality, infarct size, intracranial pressure, cerebral perfusion pressure, cerebral blood flow, and brain tissue oxygen tension. If appropriate, we will also perform a quantitative synthesis and pool results using random-effect models. Heterogeneity will be expressed with I2 statistics. Subgroup analyses are planned according to animal model characteristics, co-interventions, and risks of bias. Discussion: Our study is aligned with the efforts to better understand the level of evidence on the impact of red blood cell transfusion strategies from preclinical studies in animal models of acute brain injury and the potential translation of information from the preclinical to the clinical research field. Systematic review registration: PROSPERO CRD42018086662. [ABSTRACT FROM AUTHOR]

Background: The consumption of resistant starches is a promising adjuvant therapy for patients with inflammatory bowel disease. Rigorous evaluation of resistant starches in this setting depends on the intervention being delivered, received, and enacted as intended, that is, with fidelity. As part of a planned pilot trial, participants will be randomized to ingest resistant starches or a placebo. They will also be asked to collect stool samples and keep symptom and dose diaries to inform trial outcomes. We aim to identify potential factors impacting fidelity to the receipt and enactment of trial intervention and data collection activities from the perspective of patients and caregivers in the trial. Identifying fidelity barriers and enablers at the pilot trial phase of a clinical intervention may help to determine optimization processes when expanding to multiple sites in future trials. Methods: We will conduct 15-30 semi-structured interviews with pilot trial participants (aged 8-17) and their caregivers. Trial participants will be approached for interviews approximately 6 months after the start of their trial participation. Personal projects analysis, a tool for understanding how individuals manage competing demands in their daily lives, will guide an in-depth exploration of how trial participants engage in activities related to intervention and data collection fidelity (ingesting resistant starches or placebo, collecting stool samples, keeping a symptom and dose diary) amidst the complexities of daily living. Discussion: The present study will seek to explore and demonstrate how theory-informed fidelity assessments can be conducted alongside pilot trials to inform future multisite trials. Study results will clarify what factors may affect fidelity to trial intervention and data collection activities. Results may suggest what to modify to optimize the design and conduct, and ensure the integrity, of future multisite trials. Conducting process evaluations alongside clinical trials has the potential to improve our understanding of trial participant experiences. Results will provide a better understanding of how trial participants manage to engage in necessary trial activities along with other priorities. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A response from the author of the article related to ultrasound-guided subclavian vein catheterization in the previous issue is presented.

Background: When a journal receives a duplicate publication, the ability to identify the submitted work as previously published, and reject it, is an assay to publication ethics best practices. The aim of this study was to evaluate how three different types of journals, namely open access (OA) journals, subscription-based journals, and presumed predatory journals, responded to receiving a previously published manuscript for review.Methods: We performed a quasi-experimental study in which we submitted a previously published article to a random sample of 602 biomedical journals, roughly 200 journals from each journal type sampled: OA journals, subscription-based journals, and presumed predatory journals. Three hundred and three journals received a Word version in manuscript format, while 299 journals received the formatted publisher's PDF version of the published article. We then recorded responses to the submission received after approximately 1 month. Responses were reviewed, extracted, and coded in duplicate. Our primary outcome was the rate of rejection of the two types of submitted articles (PDF vs Word) within our three journal types.Results: We received correspondence back from 308 (51.1%) journals within our study timeline (32 days); (N = 46 predatory journals, N = 127 OA journals, N = 135 subscription-based journals). Of the journals that responded, 153 received the Word version of the paper, while 155 received the PDF version. Four journals (1.3%) accepted our paper, 291 (94.5%) journals rejected the paper, and 13 (4.2%) requested a revision. A chi-square test looking at journal type, and submission type, was significant (χ2 (4) = 23.50, p < 0.001). All four responses to accept our article came from presumed predatory journals, 3 of which received the Word format and 1 that received the PDF format. Less than half of journals that rejected our submissions did so because they identified ethical issues such as plagiarism with the manuscript (133 (45.7%)).Conclusion: Few journals accepted our submitted paper. However, our findings suggest that all three types of journals may not have adequate safeguards in place to recognize and act on plagiarism or duplicate submissions. [ABSTRACT FROM AUTHOR]

Surgical volumes and use of preoperative anaesthesia consultations are increasing. However, contemporary data estimating the association between preoperative anaesthesia consultation and patient (days alive and at home [DAH 30 ], mortality) and system (costs, length of stay, and readmissions) outcomes are not available. We conducted a population-based comparative effectiveness study using linked health administrative data among patients aged ≥40 yr who underwent intermediate-risk to high-risk elective, inpatient, noncardiac surgery in Ontario, Canada (2009–17). Our primary outcome was DAH 30. Secondary outcomes included DAH 90 , 30-day and 1-yr mortality, 30-day health system costs, length of index admission, and 30-day readmissions. Propensity score overlap weights were used to adjust for confounders. Prespecified effect modifier analyses focused on high-risk subgroups. Among 364 149 patients, 274 365 (75.3%) received a preoperative anaesthesia consultation. No adjusted association was found (22.5 days vs 22.5 days; adjusted ratio of means 1.00, 95% CI 1.00–1.00) between consultation and DAH 30 in the full population. We identified significant effect modification (significantly more DAH 30) among patients with ischaemic heart disease, ASA physical status ≥4, frailty index score ≥0.21, and who underwent vascular surgery. Secondary outcomes were associated with preoperative consultation, including greater DAH 90 , decreased length of stay, lower 30-day and 1-yr mortality, and reduced 30-day costs. Preoperative anaesthesia consultation was not associated with greater DAH 30 across the overall study population. However, important potential benefits were observed among high-risk subgroups. Research is needed to identify optimal patient populations and consultation processes. [ABSTRACT FROM AUTHOR]

Protocol registration is required in clinical trials. Registration of animal studies could improve research transparency and reduce redundancy, yet uptake has been minimal. Integrating study registration into institutional approval of animal use protocols is a promising approach to increase uptake. Prospective registration of animal studies could improve research transparency and reduce redundancy. In this Perspective, the authors argue that integrating registration as part of animal ethics review could increase uptake of this practice. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are a promising cell-free therapy for acute lung injury (ALI). To date, no studies have investigated their biodistribution in ALI or discerned the timing of administration for maximal lung targeting, which are crucial considerations for clinical translation. Our study aimed to characterize a mouse model of ALI and establish the distribution kinetics and optimal timing of MSC-EV delivery during lung injury. Methods: MSC-EVs were isolated by ultracentrifugation alone (U/C) or tangential flow filtration with ultracentrifugation (TFF-U/C) and characterized by nanoparticle tracking analysis and western blot. A lipopolysaccharide (LPS)-induced mouse model of ALI was established to study the inflammatory response over 72 h. ALI was assessed by histological lung injury score, bronchoalveolar lavage fluid cell count and inflammatory cytokines. For biodistribution studies, ALI mice were intravenously administered fluorescently labeled MSC-EVs to determine the optimal timing of administration and organ-specific biodistribution. Live in vivo and ex vivo fluorescence imaging was conducted at various timepoints post-EV injection. Results: EVs isolated by either ultracentrifugation alone or TFF-U/C displayed comparable size distribution (~ 50–350 nm) and EV marker expression (CD63/81). TFF-U/C generated a 5.4-fold higher particle concentration and 3.9-fold higher total protein when compared to ultracentrifugation alone. From the inflammatory time-course study, cell count and IL-1β peaked in bronchoalveolar lavage fluid at 24 h after ALI induction. MSC-EVs delivered at 24 h (as opposed to 0.5 h, 5 h or 10 h) after disease induction resulted in a 2.7–4.4-fold higher lung uptake of EVs. Biodistribution studies comparing organ-specific MSC-EV uptake showed progressive lung accumulation up to 48 h post-delivery (threefold higher than the spleen/liver), with a decline at 72 h. Importantly, lung EV fluorescence at 48 h in ALI mice was significantly elevated as compared to control mice. The lung tropism of MSC-EVs was further validated as therapeutically inert EVs derived from HEK293T cells accumulated mainly to the spleen and liver with a 5.5-fold lower distribution to the lungs as compared to MSC-EVs. Conclusion: MSC-EVs exhibit maximal lung accumulation when administered during heightened inflammation at 24 h after ALI induction. This lung tropism suggests that MSC-EVs may serve as a practical rescue treatment for acute inflammatory respiratory conditions. [ABSTRACT FROM AUTHOR]

The author comments on a study by Evandro M. Neto-Neves and colleagues within the issue of "Critical Care Medicine," which investigated the role of matrix metalloproteinases (MMP) in an animal model. The animals have been pre-treated with either doxycycline or saline vehicle. The hemodynamics after embolism have been improved by MMP inhibition and may result to reduced cardiomyocyte and diminished inflammatory response.

The rapidly growing field of mesenchymal stromal cell (MSC) basic and translational research requires standardization of terminology and functional characterization. The International Standards Organization's (ISO) Technical Committee (TC) on Biotechnology, working with extensive input from the International Society for Cells and Gene Therapy (ISCT), has recently published ISO standardization documents that are focused on biobanking of MSCs from two tissue sources, Wharton's Jelly, MSC(WJ) and Bone Marrow, MSC(M)), for research and development purposes and development. This manuscript explains the path towards the consensus on the following two documents: the Technical Standard ISO/TS 22859 for MSC(WJ) and the full ISO Standard 24651 for MSC(M) biobanking. The ISO standardization documents are aligned with ISCT's MSC committee position and recommendations on nomenclature because there was active input and incorporation of ISCT MSC committee recommendations in the development of these standards. The ISO standardization documents contain both requirements and recommendations for functional characterization of MSC(WJ) and MSC(M) using a matrix of assays. Importantly, the ISO standardization documents have a carefully defined scope and are meant for research use of culture expanded MSC(WJ) and MSC(M). The ISO standardization documents can be updated in a revision process and will be systematically reviewed after 3–5 years as scientific insights grow. They represent international consensus on MSC identity, definition, and characterization; are rigorous in detailing multivariate characterization of MSCs and represent an evolving-but-important first step in standardization of MSC biobanking and characterization for research use and development. [ABSTRACT FROM AUTHOR]

Background: Reproducibility is a central tenant of research. We aimed to synthesize the literature on reproducibility and describe its epidemiological characteristics, including how reproducibility is defined and assessed. We also aimed to determine and compare estimates for reproducibility across different fields. Methods: We conducted a scoping review to identify English language replication studies published between 2018 and 2019 in economics, education, psychology, health sciences, and biomedicine. We searched Medline, Embase, PsycINFO, Cumulative Index of Nursing and Allied Health Literature - CINAHL, Education Source via EBSCOHost, ERIC, EconPapers, International Bibliography of the Social Sciences (IBSS), and EconLit. Documents retrieved were screened in duplicate against our inclusion criteria. We extracted year of publication, number of authors, country of affiliation of the corresponding author, and whether the study was funded. For the individual replication studies, we recorded whether a registered protocol for the replication study was used, whether there was contact between the reproducing team and the original authors, what study design was used, and what the primary outcome was. Finally, we recorded how reproducibilty was defined by the authors, and whether the assessed study(ies) successfully reproduced based on this definition. Extraction was done by a single reviewer and quality controlled by a second reviewer. Results: Our search identified 11,224 unique documents, of which 47 were included in this review. Most studies were related to either psychology (48.6%) or health sciences (23.7%). Among these 47 documents, 36 described a single reproducibility study while the remaining 11 reported at least two reproducibility studies in the same paper. Less than the half of the studies referred to a registered protocol. There was variability in the definitions of reproduciblity success. In total, across the 47 documents 177 studies were reported. Based on the definition used by the author of each study, 95 of 177 (53.7%) studies reproduced. Conclusions: This study gives an overview of research across five disciplines that explicitly set out to reproduce previous research. Such reproducibility studies are extremely scarce, the definition of a successfully reproduced study is ambiguous, and the reproducibility rate is overall modest. Funding: No external funding was received for this work. [ABSTRACT FROM AUTHOR]

Keywords: acute lung injury; acute respiratory distress syndrome; exosomes; extracellular vesicles; mesenchymal stem cell; microRNA-27a-3p EN acute lung injury acute respiratory distress syndrome exosomes extracellular vesicles mesenchymal stem cell microRNA-27a-3p 1095 1097 3 06/24/20 20200701 NES 200701 The first clinical trial involving mesenchymal stem cells (MSCs) was conducted in 1995 to investigate their feasibility of administration and safety profile. In preclinical animal models, MSC-EVs have been shown to polarize macrophages from the M1 pro-inflammatory to M2 anti-inflammatory phenotype, improve histological lung injury, reduce alveolar-capillary barrier permeability, and attenuate lung inflammation. In turn, EV therapies may overcome challenges that hamper the successful translation of live cell treatments including tumorigenesis, immunoreactivity, limited shelf-life, and batch-to-batch variability in cell viability and/or efficacy. [Extracted from the article]

Background: Multicentric approaches are widely used in clinical trials to assess the generalizability of findings, however, they are novel in laboratory-based experimentation. It is unclear how multilaboratory studies may differ in conduct and results from single lab studies. Here, we synthesized the characteristics of these studies and quantitatively compared their outcomes to those generated by single laboratory studies. Methods: MEDLINE and Embase were systematically searched. Screening and data extractions were completed in duplicate by independent reviewers. Multilaboratory studies investigating interventions using in vivo animal models were included. Study characteristics were extracted. Systematic searches were then performed to identify single lab studies matched by intervention and disease. Difference in standardized mean differences (DSMD) was then calculated across studies to assess differences in effect estimates based on study design (>0 indicates larger effects in single lab studies). Results: Sixteen multilaboratory studies met inclusion criteria and were matched to 100 single lab studies. The multicenter study design was applied across a diverse range of diseases, including stroke, traumatic brain injury, myocardial infarction, and diabetes. The median number of centers was four (range 2-6) and the median sample size was 111 (range 23-384) with rodents most frequently used. Multilaboratory studies adhered to practices that reduce the risk of bias significantly more often than single lab studies. Multilaboratory studies also demonstrated significantly smaller effect sizes than single lab studies (DSMD 0.72 [95% confidence interval 0.43-1]). Conclusions: Multilaboratory studies demonstrate trends that have been well recognized in clinical research (i.e. smaller treatment effects with multicentric evaluation and greater rigor in study design). This approach may provide a method to robustly assess interventions and the generaliz-ability of findings between laboratories. Funding: uOttawa Junior Clinical Research Chair; The Ottawa Hospital Anesthesia Alternate Funds Association; Canadian Anesthesia Research Foundation; Government of Ontario Queen Elizabeth II Graduate Scholarship in Science and Technology [ABSTRACT FROM AUTHOR]

Background: The importance of investigating sex- and gender-dependent differences has been recently emphasized by major funding agencies. Notably, the influence of biological sex on clinical outcomes in sepsis is unclear, and observational studies suffer from the effect of confounding factors. The controlled experimental environment afforded by preclinical studies allows for clarification and mechanistic evaluation of sex-dependent differences. We propose a systematic review to assess the impact of biological sex on baseline responses to disease induction as well as treatment responses in animal models of sepsis. Given the lack of guidance surrounding sex-based analyses in preclinical systematic reviews, careful consideration of various factors is needed to understand how best to conduct analyses and communicate findings. Methods: MEDLINE and Embase will be searched (2011-present) to identify preclinical studies of sepsis in which any intervention was administered and sex-stratified data reported. The primary outcome will be mortality. Secondary outcomes will include organ dysfunction, bacterial load, and IL-6 levels. Study selection will be conducted independently and in duplicate by two reviewers. Data extraction will be conducted by one reviewer and audited by a second independent reviewer. Data extracted from included studies will be pooled, and meta-analysis will be conducted using random effects modeling. Primary analyses will be stratified by animal age and will assess the impact of sex at the following time points: pre-intervention, in response to treatment, and post-intervention. Risk of bias will be assessed using the SYRCLE's risk-of-bias tool. Illustrative examples of potential methods to analyze sex-based differences are provided in this protocol. Discussion: Our systematic review will summarize the current state of knowledge on sex-dependent differences in sepsis. This will identify current knowledge gaps that future studies can address. Finally, this review will provide a framework for sex-based analysis in future preclinical systematic reviews. Systematic review registration: PROSPERO CRD42022367726. [ABSTRACT FROM AUTHOR]

Evidence regarding the extent that mesenchymal stromal cells (MSCs) may improve clinical outcomes in patients with coronavirus disease 2019 (COVID-19) has been limited by marked inter-study heterogeneity, inconsistent product characterization and appreciable risk of bias (RoB). Given the evolution of treatment options and trajectory of the pandemic, an updated analysis of high-quality evidence from randomized controlled trials is needed for a timely and conclusive understanding of the effectiveness of MSCs. A systematic literature search through March 30, 2022, identified all English language, full-text randomized controlled trials examining the use of MSCs in the treatment of COVID-19. Eight studies were identified (316 patients, 165 administered MSCs and 151 controls). Controls evolved significantly over time with a broad range of comparison treatments. All studies reported mortality at study endpoint. Random effects meta-analysis revealed that MSCs decreased relative risk of death (risk ratio, 0.63, 95% confidence interval, 0.42–0.94, P = 0.02, I2 = 14%) with no significant difference in absolute risk of death. MSCs decreased length of hospital stay and C-reactive protein levels and increased odds of clinical improvement at study endpoint compared with controls. Rates of adverse events and severe adverse events were similar between MSC and control groups. Only two (25%) studies reported all four International Society for Cell & Gene Therapy criteria for MSC characterization. Included studies had low (n = 7) or some (n = 1) concerns regarding RoB. MSCs may reduce risk of death in patients with severe or critical COVID-19 and improve secondary clinical outcomes. Variable outcome reporting, inconsistent product characterization and variable control group treatments remain barriers to higher-quality evidence and may constrain clinical usage. A master protocol is proposed and appears necessary for accelerated translation of higher-quality evidence for future applications of MSC therapy. Forest plot demonstrating significantly decreased relative risk of death at study endpoint in patients administered MSCs (experimental) compared with patients not administered MSCs (control). Control groups received standard of care for COVID-19 at the time of hospital admission, which varied depending on the institution. [Display omitted] [ABSTRACT FROM AUTHOR]

Perioperative frailty is prevalent and requires complex management, which could be guided by clinical practice guidelines (CPGs). The objective of this systematic review was to identify and synthesise CPGs that provide perioperative recommendations specific to older adults living with frailty. After protocol registration, we performed a systematic review of CPGs. MEDLINE, Embase, CINAHL, and 14 grey literature databases were searched (January 1, 2000 until December 22, 2021). We included all CPGs that contained at least one frailty-specific recommendation related to any phase of the perioperative period. We compiled all relevant recommendations, extracted underlying strength of evidence, and categorised them by perioperative phase of care. Within each phase, recommendations were synthesised inductively into themes. Quality of CPGs was assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. From 4707 citations, 13 guidelines were included; 8/13 were focused on the perioperative care of older surgical patients in general. Among 110 recommendations extracted, 37 themes were generated, with the majority pertaining to preoperative care. Four themes were supported by strong evidence: performing preoperative frailty assessments, using multidimensional frailty instruments, reducing urinary catheter use, and following multidisciplinary care and communication throughout the perioperative period. Per AGREE II, most guidelines (8/13; 62%) were recommended for use with modifications. Despite increasing numbers of patients living with frailty, few guidelines exist that address frailty-specific perioperative care. Given the lack of strong evidence-based recommendations, particularly outside the preoperative period, high-quality primary research is required to underpin future guidelines and better inform the care of older surgical patients with frailty. PROSPERO CRD42022320149. [ABSTRACT FROM AUTHOR]

We conducted a systematic review and meta-analysis of randomized control trials to formally assess the safety and efficacy of autologous whole cell vaccines as immunotherapies for solid tumors. Our primary safety outcome was number, and grade of adverse events. Our primary efficacy outcome was clinical responses. Secondary outcomes included survival metrics and correlative immune assays. We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for studies published between 1946 and August 2020 using any autologous whole cell product in the treatment of any solid tumor. The Cochrane Randomized Controlled Trial risk of bias tool was used to assess risk of bias. Eighteen manuscripts were identified with a total of 714 patients enrolled in control and 808 in vaccine arms. In 698 patients receiving at least one dose of vaccine, treatment was well tolerated with a total of 5 grade III or higher adverse events. Clinical response was reported in a minority (n = 2, 14%) of studies. Autologous cell vaccines were associated with improved overall (HR 1.28, 95% CI 1.01–1.63) and disease-free survival (HR 1.33, 95% CI 1.05–1.67) over thirteen and ten trials respectively. Where reported, immune assays correlated well with clinical outcomes. Our results suggest that autologous whole cell vaccination is safe and efficacious in increasing survival in patients undergoing treatment for solid tumors. Registration: PROSPERO CRD42019140187. [ABSTRACT FROM AUTHOR]

Background: Traditionally, economic evaluations have engaged clinicians and policymakers; however, patients and their caregivers have insight that can ensure that the economic evaluation process appropriately reflects disease consequences and adequately addresses their priorities related to treatment.Objective: We aimed to identify patient priorities to inform an early economic evaluation of chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukemia.Methods: We conducted two online group discussions of four participants each, involving patients with experience of hematological cancer and a caregiver. We used an adapted version of the nominal group technique, a consensus-building discussion approach, to generate focused qualitative data.Results: Patients and a caregiver acknowledged both the costs directly related to clinical care, such as the out-of-pocket cost of drugs, and the indirect treatment costs, such as the cost of transport, accommodation, and food. The emotional and physical toll of treatment and the influence of treatment on employment and education were additional costs emphasized by participants. Treatment benefits prioritized by participants included the efficacy of treatment, manageable side effects, improved quality of life, accessibility of treatment, and short treatment duration.Conclusions: Engaging patients and caregivers in an early economic evaluation could help identify additional costs and benefits of therapies that are not typically recognized in economic evaluations but have the potential to increase the commercial viability of novel therapies. This research also demonstrates how patients and caregivers can be engaged at different levels in the development of early economic evaluation models. [ABSTRACT FROM AUTHOR]

Background: Preoperative frailty is associated with increased risk of postoperative mortality and complications. Routine preoperative frailty assessment is underperformed. Automation of preoperative frailty assessment using electronic health data could improve adherence to guideline-based care if an accurate instrument is identified.Methods: We conducted a retrospective cohort study of adults >65 yr undergoing elective noncardiac surgery between 2012 and 2018. Four frailty instruments were compared: Frailty Index, Hospital Frailty Risk Score, Risk Analysis Index-Administrative, and Adjusted Clinical Groups frailty-defining diagnoses indicator. We compared the predictive performance of each instrument added to a baseline model (age, sex, ASA physical status, and procedural risk) using discrimination, calibration, explained variance, net reclassification, and Brier score (binary outcomes); and explained variance, root mean squared error, and mean absolute prediction error (continuous outcomes). Primary outcome was 30-day mortality. Secondary outcomes included 365-day mortality, length of stay, non-home discharge, days alive at home, and 365-day costs.Results: For this study, 171 576 patients met the inclusion criteria; 1370 (0.8%) died within 30 days. Compared with the baseline model predicting 30-day mortality (area under the curve [AUC] 0.85; R2 0.08), the addition of Hospital Frailty Risk Score led to the greatest improvement in discrimination (AUC 0.87), explained variance (R2 0.09), and net reclassification (Net Reclassification Index 0.65). Brier and calibration scores were comparable.Conclusions: All four frailty instruments significantly improved discrimination and risk reclassification when added to typically assessed preoperative risk factors. Accurate identification of the presence or absence of preoperative frailty using electronic frailty instruments may improve perioperative risk stratification. Future research should evaluate the impact of automated frailty assessment in guiding surgical planning and patient-centred optimisation amongst older surgical patients. [ABSTRACT FROM AUTHOR]

Background: Pulmonary arterial hypertension (PAH) is a rare disease (15 cases per million) that is characterized by widespread loss of the pulmonary microcirculation and elevated pulmonary vascular resistance leading to pathological right ventricular remodeling and ultimately right heart failure. Regenerative cell therapies (i.e., therapies involving cells with stem or progenitor-like properties) could potentially restore the effective lung microcirculation and provide a curative therapy for PAH. Preclinical evidence suggests that regenerative cell therapy using endothelial progenitor cells or mesenchymal stem cells may be beneficial in the treatment of PAH. These findings have led to the completion of a small number of human clinical trials, albeit with modest effect compared to animal studies. The objective of this systematic review is to compare the efficacy and safety of regenerative cell therapies in preclinical models of PAH as well as assess study quality to inform future clinical studies. Methods: We will include preclinical studies of PAH in which a regenerative cell type was administered and outcomes compared to a disease control. The primary outcome will be pulmonary hemodynamics as assessed by measurement of right ventricular systolic pressure and/or mean pulmonary arterial pressure. Secondary outcomes will include mortality, survival, right ventricular remodeling, pulmonary vascular resistance, cardiac output, cardiac index, pulmonary acceleration time, tricuspid annular systolic excursion, and right ventricular wall thickness. Electronic searches of MEDLINE and EMBASE databases will be constructed and reviewed by the Peer Review of Electronic Search Strategies (PRESS) process. Search results will be screened independently in duplicate. Data from eligible studies will be extracted, pooled, and analyzed using random effects models. Risk of bias will be assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk of bias tool, and individual study reporting will be assessed according to an itemized checklist based on the Animal Research: Reporting of In vivo Experiments (ARRIVE) guidelines. Discussion: This systematic review will examine the efficacy and safety of regenerative cell therapy in preclinical models of PAH. As well, the literature will be assessed for study quality and risk of bias. The results will guide the design of future clinical trials and preclinical animal studies. Systematic review registration: CAMARADES (http://www.dcn.ed.ac.uk/camarades/SyRF/Protocols.htm). [ABSTRACT FROM AUTHOR]

Introduction: Medical advancements are slow to reach the patient bedside due to issues with knowledge translation from preclinical studies. Multi-laboratory preclinical studies are a promising strategy for addressing the methodological deficiencies that weaken the translational impact of single laboratory findings. However, multi-laboratory preclinical studies are rare and difficult, requiring strong collaboration to plan and execute a shared protocol. In multiteam systems such as these, collaboration is enhanced when members have cohesive ways of thinking about their goals and how to achieve them–that is, when they have "shared mental models". In this research project, we will examine how members of Canada's first multi-laboratory preclinical study build shared mental models and collaborate in the execution of their study. Methods: Six independent labs in Canada will conduct a preclinical study using a common protocol. To investigate mental models and collaboration in this multiteam system we will conduct a longitudinal qualitative study involving interviews at four time points, team observation, and document analysis. We will analyze interview transcripts using deductive coding to produce a matrix analysis of mental model content over time and inductive coding to produce a thematic analysis of members' experiences of collaboration over time. We will also triangulate data sources to "tell the story" of teamwork, capturing events and contextual information that explain changes in mental models and collaboration over time. Discussion: This study will be one of the most comprehensive longitudinal analyses of a real-world multiteam system, and the first within a preclinical laboratory setting. The results will contribute to our understanding of collaboration in multiteam systems, an organizational form increasingly used to tackle complex scientific and social problems. The results will also inform the implementation of future multi-laboratory preclinical studies, enhancing the likelihood of effective collaboration and improved 'bench to bedside' translation. [ABSTRACT FROM AUTHOR]

Mesenchymal stem/stromal cells (MSCs) and their secreted products are a promising therapy for COVID-19 given their immunomodulatory and tissue repair capabilities. Many small studies were launched at the onset of the pandemic, and repeated meta-analysis is critical to obtain timely and sufficient statistical power to determine efficacy. All English-language published studies identified in our systematic search (up to February 3, 2021) examining the use of MSC-derived products to treat patients with COVID-19 were identified. Risk of bias (RoB) was assessed for all studies. Nine studies were identified (189 patients), four of which were controlled (93 patients). Three of the controlled studies reported on mortality (primary analysis) and were pooled through random-effects meta-analysis. MSCs decreased the risk of death at study endpoint compared with controls (risk ratio, 0.18; 95% confidence interval [CI], 0.04 to 0.74; P =.02; I 2 = 0%), although follow-up differed. Among secondary outcomes, interleukin-6 levels were most commonly reported and were decreased compared with controls (standardized mean difference, –0.69; 95% CI, –1.15 to –0.22; P =.004; I 2 = 0%) (n = 3 studies). Other outcomes were not reported consistently, and pooled estimates of effect were not performed. Substantial heterogeneity was observed between studies in terms of study design. Adherence to published ISCT criteria for MSC characterization was low. In two of nine studies, RoB analysis revealed a low to moderate risk of bias in controlled studies, and uncontrolled case series were of good (3 studies) or fair (2 studies) quality. Use of MSCs to treat COVID-19 appears promising; however, few studies were identified, and potential risk of bias was detected in all studies. More controlled studies that report uniform clinical outcomes and use MSC products that meet standard ISCT criteria should be performed. Future iterations of our systematic search should refine estimates of efficacy and clarify potential adverse effects. [ABSTRACT FROM AUTHOR]

Early-phase cell therapy clinical trials depend on patient and physician involvement, yet barriers can impede their participation. To optimize engagement for a planned cell therapy trial to prevent perioperative cardiac complications, the authors conducted semi-structured interviews with at-risk patients and physicians who could potentially be involved in the study. The authors used the theoretical domains framework to systematically identify potential barriers and enablers. Forty-one interviews were conducted to reach data saturation, and four overall potential barriers to participation (themes) were identified. Theme 1 emphasizes that patients and physicians need accessible information to better understand the benefits and risks of the novel therapy and trial procedures and to address misconceptions. Theme 2 underscores the need for clarity on whether the trial's primary purpose is safety or efficacy, as this may influence patient and physician decisions. Theme 3 recognizes the resource and logistic realities for patients (e.g., convenient follow-up appointments) and physicians (e.g., personnel to assist in trial procedures, competing priorities). Theme 4 describes the importance of social influences (e.g., physicians and family, peers/colleagues) that may affect decisions to participate and the importance of patient preferences (e.g., availability of physicians to discuss the trial, including caregivers in discussions). Prospectively addressing these issues may help optimize feasibility prior to conducting an expensive, resource-intensive trial. [ABSTRACT FROM AUTHOR]

Background and Objective: Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are a promising treatment for bone injuries, although studies remain preclinical. A systematic review and meta-analysis can assess the efficacy of MSC-EVs and identify treatment aspects associated with enhanced bone repair. Methods: English language, preclinical, controlled, in vivo studies identified in our systematic search (up to May 8, 2020) examining the use of MSC-EVs in bone healing were included. Risk of bias (ROB) was assessed using the SYRCLE tool. Aggregate Data Meta-Analysis was performed to determine the effect of MSC-EVs on Bone Volume/Total Volume (BV/TV) and New Bone Formation (NBF). Results: Thirteen studies were included. Twelve reported either BV/TV or NBF and were included in meta-analysis. ROB was unclear in all studies. Overall, MSC-EVs displayed benefit in terms of bone healing for both BV/TV (22.2% mean difference (MD); 95% CI: 15.8–28.5%, p < 0.001) and NBF (26.1% MD; 10.3–41.8%, p = 0.001) versus controls. Substantial heterogeneity, however, was observed between studies. MSC-EVs were reported to activate multiple signaling pathways including mTOR/AKT, AMPK and BMP2. Subgroup analysis indicated no significant difference in the improvement of BV/TV when using modified EVs isolated after gene transfection, preconditioning (p = 0.61), or using EVs in combination with a tissue scaffold and/or hydrogel versus other delivery methods (p = 0.20). Conclusion: Use of MSC-EVs to promote healing of bone injury appears promising, however, heterogeneity between studies and the potential for reporting bias limits confidence in the extent of benefit. Reducing bias between studies and addressing aspects of potential reporting bias should augment confidence in future meta-analyses and propel the field towards clinical studies. Forest Plot analysis assessing the percentage change in bone volume (BV) / total volume (TV) in the presence (experimental) or absence (control) of MSC-EVs. [ABSTRACT FROM AUTHOR]

Introduction: Extracellular vesicles from mesenchymal stromal cells (MSC-EVs) have shown promise in wound healing. Their use in diabetic wounds specifically, however, remains pre-clinical and their efficacy remains uncertain less clear. A systematic review of preclinical studies is needed to determine the efficacy of MSC-EVs in the treatment of diabetic wounds to accelerate the clinical translation of this cell-based therapy. Methods: PubMed and Embase were searched (to June 23, 2020). All English-language, full-text, controlled interventional studies comparing MSC-EVs to placebo or a "no treatment" arm in animal models of diabetic wounds were included. Study outcomes, including wound closure (primary outcome), scar width, blood vessel number and density, and re-epithelialisation were pooled using a random effects meta-analysis. Risk of bias (ROB) was assessed using the SYRCLE tool for pre-clinical animal studies. Results: A total of 313 unique records were identified from our search, with 10 full text articles satisfying inclusion criteria (n = 136 animals). The administration of MSC-EVs improved closure of diabetic wounds compared to controls with a large observed effect (Standardized Mean Difference (SMD) 5.48, 95% Confidence Interval (CI) 3.55–8.13). Healing was further enhanced using MSC-EVs enriched in non-coding RNAs or microRNAs compared to controls (SMD 9.89, 95%CI 7.32–12.46). Other outcomes, such as blood vessel density and number, scar width, and re-epithelialisation were improved with the administration of MSC-EVs, with a large effect. ROB across studies was unclear. Conclusion: MSC-EVs, particularly following enrichment for specific RNAs, are a promising treatment for diabetic wounds in pre-clinical studies and translation to the clinical domain appears warranted. Registration: PROSPERO #CRD42020199327 [248]. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stromal cell derived extracellular vesicles (MSC-EVs) have been implicated in the regulation of tumor growth. Studies remain preclinical with effects ranging from inhibition of tumor growth to cancer progression. A systematic review and meta-analysis is needed to clarify the effect of MSC-EVs on tumor growth to facilitate potential translation to clinical trials. Methods: A systematic search of the literature (MEDLINE, Embase, and BIOSIS databases to June 1, 2019) identified all pre-clinical controlled studies investigating the effect of MSC-EVs on tumor growth. Study selection and data extraction were performed in duplicate. Potential risk of bias was assessed using the SYRCLE tool. A random effects meta-analysis of reduction in tumor weight/volume (primary outcome) was performed. Results: We identified 29 articles and 22 reported data on tumor responses that were included for meta-analysis. Studies were associated with unclear risk of bias in a large proportion of domains in accordance with the SYRCLE tool for determining risk of bias in preclinical studies. A high risk of bias was not identified in any study. MSC-EVs had a mixed response on tumor progression with some studies reporting inhibition of tumor growth and others reporting tumor progression. Overall, MSC-EVs exerted a non-significant reduction in tumor growth compared to controls (standardized mean difference (SMD) -0.80, 95 % CI -1.64 to 0.03, p = 0.06, I2 = 87 %). Some studies reported increased tumor growth which aligned with their stated hypothesis and some interrogated mechanisms in cancer biology. EVs isolated from MSCs that overexpressed anti-tumor RNAs were associated with significant tumor reduction in meta-analysis (SMD − 2.40, 95 % CI -3.36 to -1.44, p < 0.001). Heterogeneity between studies was observed and included aspects of study design such as enrichment of MSC-EVs with specific anti-tumor molecules, tissue source of MSCs, method of EV isolation, characterization of MSCs and EVs, dosage and administration schedules, and tissue type and source of tumor cells studied. Conclusions: MSC-EVs are associated with mixed effects on tumor growth in animal models of cancer. In studies where anti-tumor RNAs are packaged in EVs, a significant reduction in tumor growth was observed. Reducing heterogeneity in study design may accelerate our understanding of the potential effects of MSC-EVs on cancer. [274 words] Forest plot of MSC-EV effect on tumor growth accordinggenetic modification of EVs in animal studies identified from a systematicreview of the literature. All cohorts from studies with multiple interventiongroups are presented separately with control groups divided equally among thegroups. M, modified; H, hypoxia [ABSTRACT FROM AUTHOR]

Background: Frailty is associated with poor postoperative outcomes, but existing data do not describe frailty's interaction with tumour characteristics at the time of cancer surgery. Our objective was to estimate the association between frailty and long-term survival, and to explore any interaction with tumour stage and grade.Methods: This was a population-based cohort study conducted using linked provincial health administrative data in Ontario, Canada (2009-20). Using a cancer registry, we identified adults having elective cancer surgery. Frailty was measured using a validated index (range 0-1; higher score=greater frailty). Associations between frailty and long-term postoperative survival (primary outcome) were estimated using proportional hazards regression. Secondary outcomes were length of stay, discharge destination, days alive at home, and healthcare costs.Results: We identified and included 52 012 patients. Mean frailty score was 0.13 (standard deviation 0.07). During follow-up, 19 378 (37.3%) patients died. After adjustment for risk factors, each 10% increase in frailty was associated with a 1.60-fold relative decrease in survival (95% confidence interval: 1.56-1.64). The frailty-survival association was strongest for patients with lower stage and grade cancers. Increased frailty was associated with longer hospital stays (3 days), fewer days alive and at home (42 days yr-1), more frequent discharge to a nursing facility (2.38-fold), and increased healthcare costs ($6048).Conclusions: Patient frailty is associated with decreased long-term survival after cancer surgery. The association is stronger for early-stage and -grade cancers, which would otherwise have a better survival prognosis. [ABSTRACT FROM AUTHOR]

Introduction Frailty is a robust predictor of adverse outcomes in older people. Practice guidelines recommend routine screening for frailty; however, this does not occur regularly. The Clinical Frailty Scale (CFS) is a validated, feasible instrument that can be used in a variety of clinical settings and is associated with many adverse outcomes. Our objective was to develop and evaluate an online training module to guide frailty assessment using the CFS. Methods A multidisciplinary team of clinical experts developed an evidence-based, theory-grounded online training module for users who wished to perform frailty assessment using the CFS. The module was prospectively evaluated for user satisfaction, effectiveness and feasibility using a standardised questionnaire. Qualitative feedback was analysed with thematic analysis. Results Version 1 of the CFS module was used 627 times from 21 October 2019 to 24 March 2020. Satisfaction, effectiveness and feasibility of the module were positively rated (≥4/5 on a 5-point Likert scale n  = 582 [93%], n  = 507, [81%], n  = 575, [91%], respectively). Qualitative feedback highlighted ease of use, likelihood of users to share the module with others and opportunities to increase multimedia content. Conclusion An online tutorial, designed using evidence and theory to guide frailty assessment using the CFS, was positively rated by users. The module's content and structure was rated effective and feasible, and users were satisfied with, and likely to share, the module. Research evaluating the module's impact on the accuracy of frailty assessment is required. [ABSTRACT FROM AUTHOR]