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Background and Aims: During the COVID‐19 pandemic, US Food and Drug Administration (FDA) permitted emergency use authorizations (EUAs) for vaccines/treatments with promising data. Eight treatments were issued EUAs by May 31, 2021; one of these was approved (Remdesivir for certain populations) and two were revoked (chloroquine phosphate/hydroxychloroquine and bamlanivimab) by September 30, 2021. The aim of this study is to find out what evidence the EUAs were based on and how many studies were published while they remained active (up to September 30, 2021). Methods: A review of published clinical studies for the 6 months before each EUA was issued, and the time after (until September 30, 2021, or until revoked). PubMed and the identified systematic reviews were the sources for identifying published literature. Results: The number of clinical studies published pre‐EUA varied from a single case study (for chloroquine phosphate/hydroxychloroquine) to numerous studies of multiple types (for convalescent plasma). Four treatments had a single randomized controlled trial (RCT) as evidence (bamlanivimab monotherapy, REGN‐COV, bamlanivimab + etesevimab, sotrovimab) and two also had other study types (remdesivir and baricitinib). The number of clinical studies published post‐EUA (for those active on September 30, 2021) was widely varied. Eighteen RCTs were published for Convalescent plasma, while Remdesivir had eight. Baricitinib, REGN‐COV, and bamlanivimab + etesevimab all had one, but none were published for sotrovimab. Conclusion: The number of trials for treatments with EUAs was limited in all cases before the EUA was issued, and in most cases for those with EUAs ongoing at the end of September 2021. The presence of EUAs may discourage participation in relevant clinical trials, which delays the widespread implementation of evidenced‐based therapies. Large, robust RCTs should be completed, such as the RECOVERY trial in the United Kingdom, to quickly find the answers desperately required during a pandemic. [ABSTRACT FROM AUTHOR]

Background: Triple negative breast cancer (TNBC) is the subset of breast cancer associated with the poorest outcome, and currently lacks targeted treatments. Standard of care (SoC) chemotherapy often consists of DNA damaging chemotherapies ± taxanes, with a range of responses observed. However, we currently lack biomarkers to predict this response and lack alternate treatment options. Methods: Pin1 expression was modulated in vitro and proliferation and treatment response was studied. Pin1 expression was analysed in patient samples and correlated with clinical outcome. Results: In this study, we have shown that the prolyl isomerase, Pin1, which is highly expressed in TNBC, plays a key role in pathogenesis of the disease. Knockdown of Pin1 in TNBC resulted in cell death while the opposite is seen in normal cells. We revealed for the first time that loss of Pin1 leads to increased sensitivity to Taxol but only in the absence of functional BRCA1. Conversely, loss of Pin1 results in decreased sensitivity to DNA-damaging agents independent of BRCA1 status. Analysis of Pin1 gene or IHC-based expression in over 200 TNBC patient samples revealed a novel role for Pin1 as a TNBC-specific biomarker, with high expression associated with improved outcome in the context of SoC chemotherapy. Preliminary data indicated this may be extended to other treatment options (e.g. Cisplatin/Parp Inhibitors) that are gaining traction for the treatment of TNBC. Conclusions: This study highlights the important role played by Pin1 in TNBC and highlights the context-dependent functions in modulating cell growth and response to treatment. [ABSTRACT FROM AUTHOR]

BACKGROUND Treatments for Dupuytren's contracture include limited fasciectomy and collagenase injection. Comparisons of the effectiveness of these treatments have been limited. METHODS We performed an unblinded, multicenter, pragmatic, two-group, randomized, controlled noninferiority trial comparing collagenase injection with limited fasciectomy in persons with moderate Dupuytren's contracture. The primary outcome was the score on the Patient Evaluation Measure-Hand Health Profile (PEM), questionnaire for assessing hand health as reported by the patient, at 1 year after treatment. Scores on the PEI\4 range from 0 to 100, with higher scores indicating worse outcomes. The prespecified noninferiority margin was 6 points. RESULTS A total of 672 persons (336 per group) were assigned to receive collagenase injection or to undergo limited fasciectomy. The primary analysis included 599 persons: 314 in the collagenase group and 285 in the limited-fasciectomy group. The mean score on the PEM at lyear was 17.8 among the 284 patients with available data the collagenase group and 11.9 among the 250 patients with available data in the limited-fasciectomy group (estimated difference, 5.9 points; 95°/o confidence interval ICI], 3.l to 8.8; one-sided P=0.49 for noninferiority). Among the patients with available data (229 patients in the collagenase group and 197 patients in the limited-fasciectomy group), the estimated difference in the mean score on the PEM at 2 years was 7. 2 points (95% CI, 4.2 to 10.9). Moderate or severe complications of treatment occurred in 1.8% of the patients in the collagenase group and in 5.1° of those in the limited-fasciectomy group; recurrent contracture resulted in reintervention in 14.6% and 3.4%, respectively. CONCLUSIONS Collagenase injection was not noninferior to limited fasciectomy with respect the score on the PEM at 1 year after treatment. [ABSTRACT FROM AUTHOR]

Background: RCTs often face issues such as slow recruitment, poor intervention adherence and high attrition, however the 2020/2021 COVID-19 pandemic intensified these challenges. Strategies employed by the DISC trial to overcome pandemic-related barriers to recruitment, treatment delivery and retention may be useful to help overcome routine problems., Methods: A structured survey and teleconference with sites was undertaken. Key performance indicators in relation to recruitment, treatment delivery and retention were compared descriptively before and after the pandemic started. This was situated also in relation to qualitative opinions of research staff., Results: Prior to the pandemic, retention was 93.6%. Increased support from the central trial management team and remote data collection methods kept retention rates high at 81.2% in the first 6 months of the pandemic, rising to 89.8% in the subsequent 6 months. Advertising the study to patients resulted in 12.8 patients/month enquiring about participation, however only six were referred to recruiting sites. Sites reported increased support from junior doctors resolved research nurse capacity issues. One site avoided long delays by using theatre space in a private hospital., Conclusions: Recruitment post-pandemic could be improved by identification of barriers, increased support from junior doctors through the NIHR associate PI scheme and advertising. Remote back-up options for data collection can keep retention high while reducing patient and site burden. To future proof studies against similar disruptions and provide more flexibility for participants, we recommend that RCTs have a back-up option of remote recruitment, a back-up location for surgeries and flexible approaches to collecting data., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Early large treatment effects can arise in small studies, which lessen as more data accumulate. This study aimed to retrospectively examine whether early treatment effects occurred for two multicentre orthopaedic randomized controlled trials (RCTs) and explore biases related to this. Included RCTs were ProFHER (PROximal Fracture of the Humerus: Evaluation by Randomisation), a two-arm study of surgery versus non-surgical treatment for proximal humerus fractures, and UK FROST (United Kingdom Frozen Shoulder Trial), a three-arm study of two surgical and one non-surgical treatment for frozen shoulder. To determine whether early treatment effects were present, the primary outcome of Oxford Shoulder Score (OSS) was compared on forest plots for: the chief investigator's (CI) site to the remaining sites, the first five sites opened to the other sites, and patients grouped in quintiles by randomization date. Potential for bias was assessed by comparing mean age and proportion of patients with indicators of poor outcome between included and excluded/non-consenting participants. No bias in treatment effect was observed overall for the CI site, or the first five sites, compared with the remaining sites in either trial. An early treatment effect on the OSS was observed for the first quintile of participants recruited to ProFHER only (clinically relevant difference of seven points). Selection bias for age was observed in the ProFHER trial only, with slightly younger patients being recruited into the study. Both trials showed some selection bias for markers of poor prognosis, although these did not appear to change over time. No bias in treatment effects overall were found at the CI or early sites set-up. An early treatment effect was found in one of the two trials, which was likely a chance effect as this did not continue during the study. Selection bias was observed in both RCTs, however this was minimal and did not impact on outcome., Competing Interests: A. Rangan reports grants from NIHR, AOUK, CIHR, DePuy Johnson & Johnson, and Wishbone Trust, NZ; and speaker payments and expenses from DePuy Johnson & Johnson, unrelated to this study. A. Rangan is also a trustee of the British Orthopaedic Association and the British Elbow & Shoulder Society, and a surgeon member of the NJR Steering Committee., (© 2023 Author(s) et al.)

The RECOVERY trial is a large multi-armed, adaptive randomised controlled trial of treatments for Covid-19.  It has rapidly recruited and demonstrated that hydroxychloroquine is ineffective in reducing mortality for hospitalised patients, whilst dexamethasone significantly reduces mortality among those patients using supplemental oxygen or on a ventilator.  We estimate that the speed of recruitment and dissemination has probably decreased mortality in the UK by at least 200 hospitalised patients in the first month since the British Prime Minister announced the results.  Despite its impressive speed, the trial only recruited about 10-15% of eligible patients, with recruitment rates ranging between 3% to 80% at participating hospitals.  Had the trial recruited 50% of the eligible patients then our analysis suggests that more than 2,000 additional lives could have been saved.  In a pandemic, rapid recruitment with high centre recruitment is absolutely essential to reduce deaths.  Methods of improving site specific recruitment rates need investigating urgently., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Knowlson C and Torgerson DJ.)