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Use of patient-reported outcomes (PROs) and patient and public engagement are critical ingredients of pragmatic trials, which are intended to be patient centered. Engagement of patients and members of the public in selecting the primary trial outcome and determining the target difference can better ensure that the trial is designed to inform the decisions of those who ultimately stand to benefit. However, to the best of our knowledge, the use and reporting of PROs and patient and public engagement in pragmatic trials have not been described. The objectives of this study were to review a sample of pragmatic trials to describe (1) the prevalence of reporting patient and public engagement; (2) the prevalence and types of PROs used; (3) how its use varies across trial characteristics; and (4) how sample sizes and target differences are determined for trials with primary PROs. This was a methodological review of primary reports of pragmatic trials. We used a published electronic search filter in MEDLINE to identify pragmatic trials, published in English between January 1, 2014 and April 3, 2019; we identified the subset that were registered in ClinicalTrials.gov and explicitly labeled as pragmatic. Trial descriptors were downloaded from ClinicalTrials.gov; information about PROs and sample size calculations were extracted from the manuscript. Chi-squared, Cochran-Armitage, and Wilcoxon rank sum tests were used to examine associations between trial characteristics and use of PROs. Among 4,337 identified primary trial reports, 1,988 were registered in CT.gov, of which 415 were explicitly labeled as pragmatic. Use of patient and public engagement was identified in 39 (9.4%). PROs were measured in 235 (56.6%): 144 (34.7%) used PROs as primary outcomes and 91 (21.9%) as only secondary outcomes. Primary PROs were symptoms (64; 44%), health behaviors (36; 25.0%), quality of life (17; 11.8%), functional status (16; 11.1%), and patient experience (10; 6.9%). Trial characteristics with lower prevalence of use of PROs included being conducted exclusively in children or adults over age 65 years, cluster randomization, recruitment in low- and middle-income countries, and primary purpose of prevention; trials conducted in Europe had the highest prevalence of PROs. For the 144 trials with a primary PRO, 117 (81.3%) reported a sample size calculation for that outcome; of these, 71 (60.7%) justified the choice of target difference, most commonly, using estimates from pilot studies (31; 26.5%), standardized effect sizes (20; 17.1%), or evidence reviews (16; 13.7%); patient or stakeholder opinions were used to justify the target difference in 8 (6.8%). Limitations of this study are the need for trials to be registered in ClinicalTrials.gov, which may have reduced generalizability, and extracting information only from the primary trial report. In this study, we observed that pragmatic trials rarely report patient and public engagement and do not commonly use PROs as primary outcomes. When provided, target differences are often not justified and rarely informed by patients and stakeholders. Research funders, scientific journals, and institutions should support trialists to incorporate patient engagement to fulfill the mandate of pragmatic trials to be patient centered.

In a trial involving more than 2400 critically ill patients, 90-day mortality was similar among patients receiving blood donated on average 6 days earlier and those receiving blood donated 22 days earlier. The age of the transfused blood did not influence outcomes. Blood transfusions are administered frequently and may have unintended consequences in critically ill patients. 1 – 4 Current regulations permit the storage of red cells for up to 42 days, but prolonged storage has been associated with changes that may render red cells ineffective as oxygen carriers and that lead to the accumulation of substances that have untoward biologic effects. 5 – 8 A systematic review of 18 observational studies involving a total of 409,840 patients and three randomized, controlled trials involving a total of 126 patients suggested that the transfusion of older red cells, as compared with newer red cells, was associated with . . .

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.

In septic animal models mesenchymal stem (stromal) cells (MSCs) modulate inflammation, enhance tissue repair and pathogen clearance, and reduce death. To conduct a phase I dose escalation trial of MSCs in septic shock with the primary objective of examining the safety and tolerability of MSCs. We enrolled nine participants within 24 hours of admission to the ICU. A control cohort of 21 participants was enrolled before starting the MSC interventional cohort to characterize expected adverse events (AEs) and to serve as a comparator for the intervention cohort. Three separate MSC dose cohorts, with three participants per cohort, received a single intravenous dose of 0.3, 1.0, and 3.0 × 10 cells/kg. A prespecified safety plan monitored participants for the occurrence of AEs; cytokines were collected at prespecified time points. Ages of participants in the interventional versus observational cohorts were median of 71 (range, 38-91) and 61 (range, 23-95). Acute Physiology and Chronic Health Evaluation scores were median of 25 (range, 11-28) and 26 (range, 17-32). MSC doses ranged from 19 to 250 million cells. There were no prespecified MSC infusion-associated or serious unexpected AEs, nor any safety or efficacy signals for the expected AEs or the measured cytokines between the interventional and observational cohorts. The infusion of freshly cultured allogenic bone marrow-derived MSCs, up to a dose of 3 million cells/kg (250 million cells), into participants with septic shock seems safe. Clinical trial registered with www.clinicaltrials.gov (NCT02421484).

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. 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. 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. 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. 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.

The state of open science needs to be monitored to track changes over time and identify areas to create interventions to drive improvements. In order to monitor open science practices, they first need to be well defined and operationalized. To reach consensus on what open science practices to monitor at biomedical research institutions, we conducted a modified 3-round Delphi study. Participants were research administrators, researchers, specialists in dedicated open science roles, and librarians. In rounds 1 and 2, participants completed an online survey evaluating a set of potential open science practices, and for round 3, we hosted two half-day virtual meetings to discuss and vote on items that had not reached consensus. Ultimately, participants reached consensus on 19 open science practices. This core set of open science practices will form the foundation for institutional dashboards and may also be of value for the development of policy, education, and interventions.

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality. CAP can trigger acute cardiac events. We sought to determine the incidence of major cardiac complications in CAP patients to characterize the magnitude of this problem. Two investigators searched MEDLINE, Scopus, and EMBASE for observational studies of immunocompetent adults with clinical and radiological evidence of CAP that reported any of the following: overall cardiac complications, incident heart failure, acute coronary syndromes (ACS), or incident cardiac arrhythmias occurring within 30 days of CAP diagnosis. At a minimum, studies had to establish enrolment procedures and inclusion and exclusion criteria, enroll their patients sequentially, and report the incidence of cardiac complications as a function of their entire cohorts. Studies with focus on nosocomial or health care-associated pneumonia were not included. Review of 2,176 citations yielded 25 articles that met eligibility and minimum quality criteria. Seventeen articles (68%) reported cohorts of CAP inpatients. In this group, the pooled incidence rates for overall cardiac complications (six cohorts, 2,119 patients), incident heart failure (eight cohorts, 4,215 patients), acute coronary syndromes (six cohorts, 2,657 patients), and incident cardiac arrhythmias (six cohorts, 2,596 patients), were 17.7% (confidence interval [CI] 13.9-22.2), 14.1% (9.3-20.6), 5.3% (3.2-8.6), and 4.7% (2.4-8.9), respectively. One article reported cardiac complications in CAP outpatients, four in low-risk (not severely ill) inpatients, and three in high-risk inpatients. The incidences for all outcomes except overall cardiac complications were lower in the two former groups and higher in the latter. One additional study reported on CAP outpatients and low-risk inpatients without discriminating between these groups. Twelve studies (48%) asserted the evaluation of cardiac complications in their methods but only six (24%) provided a definition for them. Only three studies, all examining ACS, carried out risk factor analysis for these events. No study analyzed the association between cardiac complications and other medical complications or their impact on other CAP outcomes. Major cardiac complications occur in a substantial proportion of patients with CAP. Physicians and patients need to appreciate the significance of this association for timely recognition and management of these events. Strategies aimed at preventing pneumonia (i.e., influenza and pneumococcal vaccination) in high-risk populations need to be optimized. Further research is needed to understand the mechanisms underlying this association, measure the impact of cardiac complications on other CAP outcomes, identify those patients with CAP at high risk of developing cardiac complications, and design strategies to prevent their occurrence in this population.

Background Method comparison studies are conducted to examine the level of agreement between two instruments measuring physiological continuous parameters. The inclusion of repeated measurements in such studies poses additional challenges. The Bland & Altman limits of agreement (LOA) approach has been adapted to account for the correlation between repeated measurements and is widely used in method comparison studies. Alternate statistical methods are not always appropriate for the analysis of such data, and there is a paucity of evidence and guidelines pertaining to statistical methods that inform the analysis of method comparison studies that include repeated measurements. This scoping review aimed to identify methodological publications that propose statistical methods to inform the analysis of method comparison studies that include repeated measurements of continuous clinical data and that may be compared with the LOA method. Methods Six online databases were searched from inception to November 2022 using a peer-reviewed search strategy. Searching of grey literature and books, as well as backward citation searching were performed to identify additional sources of evidence. Screening and data abstraction were done by two independent reviewers. Results were synthesized narratively. Results Twenty-nine publications were included in this review. Thirty-two independent statistical methods were identified from the included publications, including variants of the LOA method. Four included publications compared findings from different versions of the LOA method. Four different approaches to handling repeated measurements in the context of method comparison studies were identified and were used to group findings from the included publications. Reported strengths and limitations of the LOA method were summarized. Conclusion This scoping review provides a synthesis of existing statistical approaches to inform the analysis of method comparison studies with repeated measurements of clinical data, as well as how the various statistical methods perform when compared with various version of the LOA method. Based on the findings, it is generally advisable to consider using adjusted LOAs or modified mixed-effect LOAs in analyzing method comparison studies with repeated measurements. Trial registration The protocol was registered on Open Science Framework ( https://osf.io/4p8ut ).

Background Regulatory applications for cell therapy face more objections compared to conventional small molecule or biological drugs, leading to delays in market approval and clinical adoption. Increased regulatory objections frequently relate to issues regarding preclinical evidence, such as experimental design of animal studies, selection of animal models, endpoints, and determination of mechanism of action. Synthesis and clarification of the preclinical evidence necessary to demonstrate treatment efficacy and advance into early-phase clinical trials is needed to help researchers avoid regulatory objections. Methods We conducted a scoping review in which we searched repositories of the International Council for Harmonisation and all national member organizations ( N  = 38) for documents related to preclinical studies of cell therapies. Active guidance documents related to cell therapy were included, with no restrictions based on the year or language of publication. Data extraction was conducted in duplicate with conflicts resolved through consensus discussion. Results From 1215 identified documents, a total of 182 were included and analyzed, with 71% originating from ten major regulatory agencies. The most prevalent preclinical item addressed was the mechanism of action ( n  = 161, 88% of documents), underscoring its importance in bridging preclinical findings to clinical application. Most documents ( n  = 140, 77%) emphasized the importance of using clinically relevant preclinical models, though specific recommendations on models of disease were less common ( n  = 81, 45%). Selection of clinically relevant intervention parameters ( n  = 136, 75%) and outcome measures ( n  = 121, 66%) were also frequently recommended, but selection of relevant comparator groups appeared less frequently ( n  = 35, 19%). Furthermore, robust study design elements such as randomization and blinding were less frequently recommended, appearing in 31% of documents ( n  = 57). Comparison with clinical trial guidance revealed a significant gap in the rigor of study design recommendations for preclinical research. Conclusions Regulatory guidance for preclinical efficacy studies often recommends a strong emphasis on the clinical relevance of animal models, intervention parameters, outcomes, and mechanism of action. Incorporating these recommendations into early preclinical studies should improve the acceptability of preclinical evidence for approval by the relevant national regulators and can be used as a guide to ensure that all evidence that regulators say they expect is efficiently assembled into new clinical trial applications.

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.