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Purpose: Journal impact factor (IF) is often used to measure research quality and importance. We assessed trial factors associated with the publication of cancer trials in journals with higher IF and publications receiving higher citations. Materials and Methods: Cancer-specific phase III RCTs were screened through https://clinicaltrials.gov. We identified trials with published primary endpoints, along with their corresponding journal IF and relative citation ratio (RCR). Results: Seven-hundred ninety manuscripts were included in our study. Trials that met their primary endpoint were more commonly published in journals with higher IF (Median IF: positive trials 35.4 vs. negative trials 26.3, P < 0.001). Furthermore, trials that led to subsequent FDA drug approvals were also published in journals with higher IF (Median IF: 59.1 vs. 26.3 in trials not leading to FDA approvals, P < 0.001). When analyzing RCR, trial positivity (meeting primary endpoint) was not associated with increased citations on multivariable analysis (P = 0.56). Lastly, publications of trials leading to FDA approvals (P < 0.001), and publications of trials in journals with higher IF (P < 0.001) were associated with increased RCR. Conclusions: Positive trials are commonly published in journals with high IF, but do not necessarily lead to increased citations. Moreover, trials published in journals with higher IF are more likely to receive increased citations.

Production of recombinant proteins is primarily established in cultures of mammalian, insect and bacterial cells. Concurrently, concept of using plants to produce high-value pharmaceuticals such as vaccines, antibodies, and dietary proteins have received worldwide attention. Newer technologies for plant transformation such as plastid engineering, agroinfiltration, magnifection, and deconstructed viral vectors have been used to enhance the protein production in plants along with the inherent advantage of speed, scale, and cost of production in plant systems. Production of therapeutic proteins in plants has now a more pragmatic approach when several plant-produced vaccines and antibodies successfully completed Phase I clinical trials in humans and were further scheduled for regulatory approvals to manufacture clinical grade products on a large scale which are safe, efficacious, and meet the quality standards. The main thrust of this review is to summarize the data accumulated over the last two decades and recent development and achievements of the plant derived therapeutics. It also attempts to discuss different strategies employed to increase the production so as to make plants more competitive with the established production systems in this industry.

Contains fulltext : 248580.pdf (Publisher’s version ) (Open Access) OBJECTIVE: The aim of this study was to develop an evidence-based framework for evaluation of therapeutic devices, based on ethical principles and clinical evidence considerations. SUMMARY BACKGROUND DATA: Nearly all medical products which do not work solely through chemical action are regulated as medical devices. Their huge range of purposes, mechanisms of action and risks pose challenges for regulation. High-profile implantable device failures have fuelled concerns about the level of clinical evidence needed for market approval. Calls for more rigorous evaluation lack clarity about what kind of evaluation is appropriate, and are commonly interpreted as meaning more randomized controlled trials (RCTs). These are valuable where devices are genuinely new and claim to offer measurable therapeutic benefits. Where this is not the case, RCTs may be inappropriate and wasteful. METHODS: Starting with a set of ethical principles and basic precepts of clinical epidemiology, we developed a sequential decision-making algorithm for identifying when an RCT should be performed to evaluate new therapeutic devices, and when other methods, such as observational study designs and registry-based approaches, are acceptable. RESULTS: The algorithm clearly defines a group of devices where an RCT is deemed necessary, and the associated framework indicates that an IDEAL 2b study should be the default clinical evaluation method where it is not. CONCLUSIONS: The algorithm and recommendations are based on the principles of the IDEAL-D framework for medical device evaluation and appear eminently practicable. Their use would create a safer system for monitoring innovation, and facilitate more rapid detection of potential hazards to patients and the public.

Background Various instruments for patient screening and diagnosis have been developed for and applied in posttraumatic stress disorder (PTSD). Objective This study comprehensively investigates the prevalence and temporal trends of the most widely used instruments in PTSD-related studies. Methods A total of 1345 files of registered clinical trials from ClinicalTrials.gov and 9422 abstracts from the PubMed database from 2005 to 2020 were downloaded for this study. The instruments applied in clinical trials were manually annotated, and instruments in abstracts were recognized using exact string matching. The prevalence score of an instrument in a certain period was calculated as the number of studies divided by the number of instances of the instrument. By calculating the yearly prevalence index of each instrument, we conducted a trends analysis and compared the trends in index change between instruments. Results A total of 4178 instrument synonyms were annotated, which were mapped to 1423 unique instruments. In the 16 years from 2005 to 2020, only 10 instruments were used more than once per year; the 4 most used instruments were the PTSD Checklist, the Clinician-Administered PTSD Disorder Scale, the Patient Health Questionnaire, and the Beck Depression Inventory. There were 18 instruments whose yearly prevalence index score exceeded 0.1 at least once during the 16 years. The changes in trends and time points of partial instruments in clinical trials and PubMed abstracts were highly consistent. The average time duration of a PTSD-related trial was 1495.5 days or approximately 4 years from submission to ClinicalTrial.gov to publication in a journal. Conclusions The application of widely accepted and appropriate instruments can help improve the reliability of research results in PTSD-related clinical studies. With extensive text data obtained from real clinical trials and published articles, we investigated and compared the usage of instruments in the PTSD research community.

Background As the cost of clinical trials continues to rise, novel approaches are required to ensure ethical allocation of resources. Multisite trials have been increasingly utilized in phase 1 trials for rare diseases and in phase 2 and 3 trials to meet accrual needs. The benefits of multisite trials include easier patient recruitment, expanded generalizability, and more robust statistical analyses. However, there are several problems more likely to arise in multisite trials, including accrual inequality, protocol nonadherence, data entry mistakes, and data integration difficulties. Objective The Biostatistics & Data Science department at the University of Kansas Medical Center developed a clinical trial management system (comprehensive research information system [CRIS]) specifically designed to streamline multisite clinical trial management. Methods A National Institute of Child Health and Human Development–funded phase 3 trial, the ADORE (assessment of docosahexaenoic acid [DHA] on reducing early preterm birth) trial fully utilized CRIS to provide automated accrual reports, centralize data capture, automate trial completion reports, and streamline data harmonization. Results Using the ADORE trial as an example, we describe the utility of CRIS in database design, regulatory compliance, training standardization, study management, and automated reporting. Our goal is to continue to build a CRIS through use in subsequent multisite trials. Reports generated to suit the needs of future studies will be available as templates. Conclusions The implementation of similar tools and systems could provide significant cost-saving and operational benefit to multisite trials. Trial Registration ClinicalTrials.gov NCT02626299; https://tinyurl.com/j6erphcj

The aim of the three-report review is the historical development of clinical trials, controlled trials (CT) and randomized controlled trials (RCT), and the inclusion of these approaches in health-related disciplines (Medicine and Epidemiology). Report 2 provides a description of the wellknown James Lind Library (JLL), as well as a formed database of sources on the theme. JLL was internationalized, although most of the papers belong to authors from the UK. Many studies on the history of CT and RCT are reflected in JLL publications, but remain unclaimed without changing on common milestones and priorities. Besides, the formed base of sources included 9 studies not reflected in the JLL, of which three are principled. Six of them are given in Report 2.Half of historical milestones on the theme (168 in total) belong to the United Kingdom, 23% to the United States, and 4% to the Italy. The remaining 19 countries, ancient, medieval and modern, contribute 0.6–4% (Russia – 1.2% by the 20th century). The earliest source on the history of CT is J.P. Bull’s dissertation (1951). The formed database as of July 2020 contained more than 260 publications, and only 9 of them were Russian (2005–2018). The base includes 7 western dissertations on the history of CT.The object of the Report 2 study was CT as such, without any attempts at randomization or even quasi-randomization by alternate allocation. The most comprehensive thematic table on non-randomized CTs has been compiled, including studies from the Chinese emperor Shen Nung (2373 BC) and the prophet Daniel (6th century BC), to BCG vaccination for children of Canadian Indians (1941–1949). PubMed search on ‘non-randomized controlled trial’ was made. For the period of 1990–2020 years, 303 publications were found (up to 32 papers in 2020). Compared to RCT, the number of such studies is small (estimated at 0.08%), but it is important to have an appropriate conjuncture in the modern period. Along with the fact that most of the drugs and therapies currently in use are developed without RCT, the revealed ‘immortality’ of CT, even without quasi-randomization, can have social significance, removing complexes and embarrassment in cases where neither RCT nor even quasi-RCT is possible, but social and public needs require the immediate receipt of at least an approximate answer to hot questions of public health (for example, in 2020).

Perinatal derivatives are drawing growing interest among the scientific community as an unrestricted source of multipotent stromal cells, stem cells, cellular soluble mediators, and biological matrices. They are useful for the treatment of diseases that currently have limited or no effective therapeutic options by means of developing regenerative approaches. In this paper, to generate a complete view of the state of the art, a comprehensive 10-years compilation of clinical-trial data with the common denominator of PnD usage has been discussed, including commercialized products. A set of criteria was delineated to challenge the 10-years compilation of clinical trials data. We focused our attention on several aspects including, but not limited to, treated disorders, minimal or substantial manipulation, route of administration, dosage, and frequency of application. Interestingly, a clear correlation of PnD products was observed within conditions, way of administration or dosage, suggesting there is a consolidated clinical practice approach for the use of PnD in medicine. No regulatory aspects could be read from the database since this information is not mandatory for registration. The database will be publicly available for consultation. In summary, the main aims of this position paper are to show possibilities for clinical application of PnD and propose an approach for clinical trial preparation and registration in a uniform and standardized way. For this purpose, a questionnaire was created compiling different sections that are relevant when starting a new clinical trial using PnD. More importantly, we want to bring the attention of the medical community to the perinatal products as a consolidated and efficient alternative for their use as a new standard of care in the clinical practice.

“Readiness cohorts” are an innovation in clinical trial design to tackle the scarcity of time and people in drug studies. This has emerged in response to the challenges of recruiting the “right” research participants at the “right time” in the context of precision medicine. In this paper, we consider how the achievement of “readiness” aligns temporalities, biologies, and market processes of pharmaceutical innovation: how the promise of “willing bodies” in research emerges in relation to intertwined economic and biological time imperatives. Drawing on long-term engagement with the field of Alzheimer’s disease prevention and interviews with researchers from academia and the pharmaceutical industry, we describe the discursive construction and practical arrangement of readiness. This paper contributes to understandings of temporal specificity, or “timing,” within prevention research and casts critical light on the way this specificity—the threshold for “trial readiness”—relates to an opaque and highly speculative drug development pipeline. Extending the study of biomedical potential, as that which holds promise but may not yet exist, we consider how absences operate in adaptive trials. By highlighting these absences (“ready for what?”), we outline an opportunity for socio-ethical research to intervene in the speculative gaps of drug development.

The present review deals with bioactive glasses (BGs), a class of biomaterials renowned for their osteoinductive and osteoconductive capabilities, and thus widely used in tissue engineering, i.e., for the repair and replacement of damaged or missing bone. In particular, the paper deals with applications in periodontal regeneration, with a special focus on in vitro, in vivo and clinical studies. The study reviewed eligible publications, identified on the basis of inclusion/exclusion criteria, over a ranged time of fifteen years (from 1 January 2006 to 31 March 2021). While there are many papers dealing with in vitro tests, only a few have reported in vivo (in animal) research, or even clinical trials. Regardless, BGs seem to be an adequate choice as grafts in periodontal regeneration.

Background Selection of appropriate trial endpoints and outcome measures is particularly important in rare disease and rapidly progressing disease such as amyotrophic lateral sclerosis (ALS) where the challenges to conducting clinical trials, are substantial: patient and disease heterogeneity, limited understanding of exact disease pathophysiology, and lack of robust and available biomarkers. To address these challenges in ALS, the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised version (ALSFRS-R) was developed and has become a key primary endpoint in ALS clinical trials to assess functional disability and disease progression, often replacing survival as a primary outcome. However, increased understanding of the ALS disease journey and improvements in assistive technology for ALS patients have exposed issues with the ALSFRS-R, including non-linearity, multidimensionality and floor and ceiling effects that could challenge its continued utility as a primary outcome measure in ALS clinical trials. Recently, other qualitative scale measures of functioning disability have been developed to help address these issues. With this in mind, we conducted a literature search aimed at identifying both established and promising new measures for potential use in clinical trials. Methods We searched PubMed, Google, Google Scholar, and the reference sections of key studies to identify papers that discussed qualitative measures of functional status for potential use in ALS studies. We also searched clinicaltrials.gov to identify functional status and health-related quality of life (HRQoL) measures that have been used in ALS interventional studies. Results In addition to the ALSFRS-R, we identified several newer qualitative scales including ALSFRS-EX, ALS-MITOS, CNS-BFS, DALS-15, MND-DS, and ROADS. Strengths and limitations of each measure were identified and discussed, along with their potential to act as a primary or secondary outcome to assess patient functional status in ALS clinical trials. Conclusion This paper serves as a reference guide for researchers deciding which qualitative measures to use as endpoints in their ALS clinical trials to assess functional status. This paper also discusses the importance of including ALS HRQoL and ALS cognitive screens in future clinical trials to assess the value of a new ALS therapy more comprehensively.

Background Patient and Public Involvement and Engagement (PPIE) in research positively affects the relevance, quality, and impact of research. Around 11% of studies published in leading medical journals demonstrate PPIE. The extent of PPIE in nursing research has not been previously studied. Methods A descriptive study of PPIE in clinical trials published in general nursing science journals between 1st January and 31st August 2021. Data were extracted from included studies against the five items of the Guidance for Reporting Involvement of Patients and the Public (GRIPP2) short form reporting checklist. Results We searched 27 journals and identified 89 randomised controlled clinical trials. There was no statement or evidence of PPIE in any of the included trials. Conclusion Nurse researchers need to ensure that they purposefully involve patients in their research and report this in papers describing study findings. Supplementary Information The online version contains supplementary material available at 10.1186/s40900-021-00331-9., Plain English summary Patient involvement in research may improve the quality and relevance of the work. The British Medical Journal—one of the top medical research journals in the world—has developed a patient partnership plan. Part of this plan requires papers sent to the journal for publication to include a statement about how patients were involved in the research. If patients were not involved in the research, this should be stated in the paper. Most papers published in the British Medical Journal now include a statement about patient involvement. We wanted to check if nurses were reporting patient involvement in the research they do. We read 89 randomised controlled trials (RCTs) published in 27 general nursing journals. We focused on RCTs because they are widely considered the gold standard for evaluating interventions and therefore are most likely to impact on patient care. Unlike the British Medical Journal, there was no evidence that nursing journals required authors to say how patients were engaged or involved in the research they published. There was no evidence of patient involvement in any of the nursing research articles that we looked at. The implication of our work is that nurse researchers need to be developing ways for effective engagement of patients in all aspects of their research and explaining how they did this in the papers they publish in nursing journals. Supplementary Information The online version contains supplementary material available at 10.1186/s40900-021-00331-9.

SARS-CoV-2 has spread across the globe in no time. In the beginning, people suffered due to the absence of efficacious drugs required to treat severely ill patients. Nevertheless, still, there are no established therapeutic molecules against the SARS-CoV-2. Therefore, repurposing of the drugs started against SARS-CoV-2, due to which several drugs were approved for the treatment of COVID-19 patients. This paper reviewed the treatment regime for COVID-19 through drug repurposing from December 8, 2019 (the day when WHO recognized COVID-19 as a pandemic) until today. We have reviewed all the clinical trials from RECOVERY trials, ACTT-1 and ACTT-2 study group, and other major clinical trial platforms published in highly reputed journals such as NEJM, Lancet, etc. In addition to single-molecule therapy, several combination therapies were also evaluated to understand the treatment of COVID-19 from these significant clinical trials. To date, several lessons have been learned on the therapeutic outcomes for COVID-19. The paper also outlines the experiences gained during the repurposing of therapeutic molecules (hydroxychloroquine, ritonavir/ lopinavir, favipiravir, remdesivir, ivermectin, dexamethasone, camostatmesylate, and heparin), immunotherapeutic molecules (tocilizumab, mavrilimumab, baricitinib, and interferons), combination therapy, and convalescent plasma therapy to treat COVID-19 patients. We summarized that anti-viral therapeutic (remdesivir) and immunotherapeutic (tocilizumab, dexamethasone, and baricitinib) therapy showed some beneficial outcomes. Until March 2021, 4952 clinical trials have been registered in ClinicalTrials.gov toward the drug and vaccine development for COVID-19. More than 100 countries have participated in contributing to these clinical trials. Other than the registered clinical trials (medium to large-size), several small-size clinical trials have also been conducted from time to time to evaluate the treatment of COVID-19. Four molecules showed beneficial therapeutic to treat COVID-19 patients. The short-term repurposing of the existing drug may provide a successful outcome for COVID-19 patients. Therefore, more clinical trials can be initiated using potential anti-viral molecules by evaluating in different phases of clinical trials.

Background and Objectives: The average treatment effect estimate from a randomized controlled trial (RCT) may not be valid for deciding what treatment is best for individual patients with specific characteristics. Characteristics may include contextual factors related to the person (e.g. age), disease (e.g. disease duration), or environmental (e.g. healthcare system). However, individual RCTs rarely report results stratified by potentially important contextual factors in a consistent manner. In this study we will summarize existing guidance from key organizations and other research initiatives, and subsequently demonstrate how subgroup results from RCTs can be presented in a consistent manner that enables future evidence synthesis. Study Design and Setting: We will use a tutorial-type approach to explain and demonstrate the recommended presentation of subgroup results from RCTs. In part 1, we will systematically review papers and official documents. Relevant guidance will be identified via a broad search strategy, including searching MEDLINE (via PubMed) and Web of Science, reviewing official websites of FDA, EMA, ICH, Equator Network etc., ‘asking around’, and snowball methods. Recommendations will be extracted and summarized. In part 2, we will demonstrate the recommendations in practice. We will use data from four previously published RCTs of rheumatic and musculoskeletal conditions from the Parker Institute, Bispebjerg and Frederiksberg Hospital, Denmark. For each RCT, we will reanalyze the data by stratifying according to proposed potential candidates of effect modifying contextual factors and apply the reporting guidance described in part 1. Dissemination and perspectives: This study will be disseminated in a peer-reviewed publication and conference presentations. It is anticipated that this tutorial can guide researchers in reporting trial results stratified by effect modifying contextual factors in a consistent manner, allowing for investigation of subgroup effects in future meta-analyses, potentially leading to more patient-specific evidence-based management of patients with rheumatic conditions.

COVID-19 led to changes in the way blood samples are collected. As societies were isolated to control viral spread, access to facilities became limited. Remote sample collection with a volumetric microsampling approach, using Mitra® devices based on VAMS® technology, proved to be highly effective. It allowed people to collect high-quality samples at home and post them to a laboratory. This enabled scientists to conduct large serosurveillance studies, with results showing that seroprevalence of COVID-19 was higher than initially expected. Furthermore, remote microsampling studies by several institutions were conducted to measure the relationship between antigen levels and antibody response and duration. VAMS technology was also used in COVID-19 clinical trials. In summary, the independent research reviewed in this paper proved that VAMS is an effective sample collection alternative.

Despite a global and nationwide decrease, Native Americans continue to experience high rates of cancer morbidity and mortality. Vaccination is one approach to decrease cancer incidence such as the case of cervical cancer. However, the availability of vaccines does not guarantee uptake, as evident in the Coronavirus 2019 pandemic. Therefore, as we consider current and future cancer vaccines, there are certain considerations to be mindful of to increase uptake among Native Americans such as the incidence of disease, social determinants of health, vaccine hesitancy, and historical exclusion in clinical trials. This paper primarily focuses on human papillomavirus (HPV) and potential vaccines for Native Americans. However, we also aim to inform researchers on factors that influence Native American choices surrounding vaccination and interventions including cancer therapies. We begin by providing an overview of the historical distrust and trauma Native Americans experience, both past and present. In addition, we offer guidance and considerations when engaging with sovereign Tribal Nations in vaccine development and clinical trials in order to increase trust and encourage vaccine uptake.

Human beings around the globe have been suffering from a devastating novel pandemic and public health emergency, coronavirus disease 2019 (COVID-19), for more than one and a half years due to the deadly and highly pathogenic severe acute respiratory coronavirus 2 (SARS-CoV-2) infection worldwide. Notably, no effective treatment strategy has been approved for the complete recovery of COVID-19 patients, though several vaccines have been rolled out around the world upon emergency use authorization. After the emergence of the COVID-19 outbreak globally, plenty of clinical investigations commenced to screen the safety and efficacy of several previously approved drugs to be repurposed against the SARS-CoV-2 pathogen. This concise review aims at exploring the current status of the clinical efficacy and safety profile of several antiviral medications for the treatment of patients with COVID-19 and other respiratory complications caused by SARS-CoV-2 infection. The paper covers all kinds of human studies (January 2020 to June 2021) except case reports/series to highlight the clear conclusion based on the current clinical evidence. Among the promising repositioned antivirals, remdesivir has been recommended in critical conditions to mitigate the fatality rate and improve clinical conditions. In addition, boosting the immune system is believed to be beneficial in treating COVID-19 patients, so interferon type I might exert immunomodulation through its antiviral effects by stimulating interferon-stimulated gene (ISG). However, more extensive clinical studies covering all ethnic groups globally are warranted based on current data to better understand the clinical efficacy of the currently proposed repurposed drugs against COVID-19.

Background. An active molecule in sulfurous mineral - therapeutic waters and also in sapropelic mud is H2S, a hormetic gaseous molecule that can actively penetrate the skin. While high levels of H2S are extremely toxic, low levels are tolerated and have potential cytoprotective effects, with anti-inflammatory and antioxidant applications. Objective. This systematic review aims to rigorously select related articles and identify within their content the main possible uses of hydrogen sulfide from balneary sources and to explain its physiological mechanisms and therapeutic properties. Methods. To elaborate our systematic review, we have searched for relevant open access articles in 6 international databases: Cochrane , Elsevier , NCBI/PubMed , NCBI/PMC , PEDro , and ISI Web of Knowledge/Science , published from January 2016 until July 2021. The contextually quested keywords combinations/ syntaxes used are specified on this page. The eligible articles were analyzed in detail regarding pathologies addressed by hydrogen sulfide. All articles with any design (reviews, randomized controlled trials, non-randomized controlled trials, case-control studies, cross-sectional studies), if eligible according to the above-mentioned selection methodology, containing in the title the selected combinations, were included in the analysis. Articles were excluded in the second phase if they did not reach the relevance criterion. Results. Our search identified, first, 291 articles. After eliminating the duplicates and non-ISI articles, remained 121 papers. In the second phase, we applied a PEDro selection filter, resulting in 108 articles that passed the relevance criterion and were included in this systematic review. Conclusions. H2S biology and medical relevance are not fully understood and used adequately for sanogenic or medical purposes. More research is needed to fully understand the mechanisms and importance of this therapeutic gase. The link between balneotherapy and medical rehabilitation regarding the usage of hydrogen sulfide emphasises the unity for this medical speciality.

Executive Summary: The present Deliverable ‘D9.1 – Legal and Ethical Inventory’, part of Work Package 9 ‘Ethical and Legal Framework’ of the In Silico World project, provides an overview of the core pieces of legislation and ethical principles that are relevant to the In Silico project, and thus, in silico trials. The analysis finds the following areas of legislation are of relevance: Privacy and Data Protection: The data processed for in silico trials entail the processing of personal data of individuals (notably, patients) in healthcare settings. As a consequence, privacy and data protection legislation becomes relevant. Privacy and data protection are distinct fundamental rights enshrined in the European Union’s (EU) treaties. The core and directly applicable regulation concerning the processing of personal data is the General Data Protection Legislation (GDPR). Other important data protection initiatives are undertaken by the Council of Europe and the Organisation for Economic Co-operation and Development (OECD). Data Governance: In healthcare and in silico trials, the sharing of data across healthcare facilities may be considered a key factor for the development, testing, and validation of in silico models. The European legislator’s and national Member States' growing interest in regulating data sharing has resulted in a new and rapidly evolving framework concerning the governance of data. The current EU legal framework on data governance includes the Open Data Directive, the Free Flow of Non-Personal Data Regulation, and the Data Governance Act. In addition to these, two legislative proposals are expected to radically change data sharing in the healthcare sector: the Data Act and the European Health Data Space. Clinical Trials: The legislation and regulatory documentation concerning clinical trials are relevant to the very essence of in silico trials. One of the main barriers envisaged by the In Silico World project is the lack of clear regulatory pathways for in silico trials. Illustrating the clinical trials' fundamental pieces of legislation in Europe is crucial for the project's objectives. The most relevant items of clinical trials legislation in the EU include the Declaration of Helsinki, the Declaration of Taipei, the Clinical Trials Directive, the Good Clinical Practice Directive, and the Clinical Trials Regulation. Medical Devices and Medicinal Products: From a product regulation perspective, in silico trials encompass medical devices and medicinal products. Concerning the first, the Medical Device Regulation and the In Vitro Medical Device Regulation are of primary importance, unitedly with the EU-level relevant bodies' guidance issued by the Medical Device Coordination Group. Concerning medicinal products, the analysis includes the Community Code for Medicinal Products for Human Use Directive 2009/94, the Advanced Therapeutic Medicinal Product Regulation, and the Health Technology Assessment Regulation. Artificial Intelligence (AI): It is no surprise that a fundamental component of in silico trials is artificial intelligence. The EU legal framework on Artificial Intelligence is in the process of being established. After the White Paper on Artificial Intelligence and the Guidelines on Trustworthy elaborated by the EU High-Level Expert Group on AI, the piece to monitor in the following months is the Artificial Intelligence Act. This proposal, if approved, will apply directly to all the EU Member States, and it will include general provisions of relevance to healthcare (including, for instance, medical devices) and in silico trials. In addition to the above pieces of legislation, the study outlines the framework for forthcoming Ethics guidelines. Based on a principlist approach, these guidelines propose the analysis of four main Biomedical Ethics principles – i.e. autonomy, justice, beneficence, non-maleficence – and the secondary principle of responsibility. These principles will ultimately be beneficial for studying the fundamental ethical principles that may be used as guidance for interpreting the law and supporting stakeholders to ensure the protection and advancement of human values in the context of in silico trials. The deliverable provides a descriptive overview of the above mentioned legal frameworks. It is prodromic to the next phases of the WP9, where the analysis will adopt an evaluative approach on legislation (D9.2, D9.3) to ultimately result in policy recommendations (D9.4).

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network.

My technical work and my STS research are connected primarily through the ways they address the challenges of diversity and accountability within healthcare systems and institutions. However, the two works differ in how they address diversity and accountability, and occur in very different time periods. My technical work focuses on how the current clinical trial standards and guidelines could be changed to incorporate more diversity and accountability, whereas my research explores the implications of the lack of diversity and accountability in medicine. So, while my technical work and STS research address diversity and accountability in healthcare from different angles, the theme of diversity inclusion and accountability as vital instruments to public trust in medical practice and research is consistent across both projects. My technical work explores the current standards and guidelines that shape the conduction of clinical trials. My capstone project required extensive research about the steps required to conduct a clinical trial. Furthermore, additional information was acquired to explore the potential of utilizing new recruitment strategies, such as telehealth and remote trials, to increase the diversity amongst clinical trial participant pools. The goal of this project is to determine whether the inclusion of new recruitment strategies can provide new avenues for increasing diversity and inclusion in the conduction of the clinical trial process, in comparison to the current standards and guidelines that determine the conduction of clinical trials. I hope that this project serves as a foundation to inform policy decisions to adjust healthcare delivery services as needed based on patient demand, as well as improve future patient experiences and outcomes. My STS research examines the ethical concerns of the use of human biospecimens in clinical research, which has brought about concerns about the limits of patient consent and scientific innovation. Specifically, my research explores Henrietta Lacks, an African-American woman, whose cancer cells are the source of the HeLa cell line, the first immortalized human cell line and one of the most important cell lines in medical research. Landon Winner’s theory of technological politics is utilized to illustrate both the technical work and political work of HeLa cells. My claim is that despite the profound impact of HeLa cells on scientific innovation and discovery, the continued commercial use of the cells is rooted with ethical concerns that express and shape power relations in regards to patient consent, confidentiality, exploitation, and racial inequity. My paper illustrates this claim by exploring the numerous contributions of HeLa cells to scientific, as well as explores the mistreatment of Henrietta Lacks, the commercialization of HeLa cells, and the enduring racial inequities that continue to be perpetuated in U.S. healthcare systems and institutions. The combined results of the technical and STS projects will serve to support healthcare systems in the future through the use of technological innovation and inclusion to improve patient outcomes and experience. My technical work gave me a deeper understanding of the standards and guidelines that inform the conduction of clinical trials, which provided me with the foundations that govern accountability and trust within the healthcare community. My research project explored the ways in which the standards that guide the actions of healthcare professionals may not be as trustworthy and ethical as the society believes. By working on both projects simultaneously, I was able to explore the implications of the social and technical dynamics that surround technology, allowing for an exploration of targeted recommendations that will influence and change the way healthcare systems interact with patients.

INTRODUCTION: Decentering describes the ability to voluntarily adopt an objective self-perspective from which to notice internal, typically distressing, stressors (eg, difficult thoughts, memories and feelings). The reinforcement of this skill may be an active ingredient through which different psychological interventions accrue reductions in anxiety and/or depression. However, it is unclear if decentering can be selectively trained at a young age and if this might reduce psychological distress. The aim of the current trial is to address this research gap. METHODS AND ANALYSIS: Adolescents, recruited from schools in the UK and Ireland (n=57 per group, age range=16-19 years), will be randomised to complete 5 weeks of decentering training, or an active control group that will take part in a combination of light physical exercise and cognitive training. The coprimary training outcomes include a self-reported decentering inventory (ie, the Experiences Questionnaire) and the momentary use of decentering in response to psychological stressors, using experience sampling. The secondary mental health outcomes will include self-reported inventories of depression and anxiety symptoms, as well as psychological well-being. Initial statistical analysis will use between-group analysis of covariance to estimate the effect of training condition on self-rated inventories, adjusted for baseline scores. Additionally, experience sampling data will be examined using hierarchical linear models. ETHICS AND DISSEMINATION: This study was approved by the Cambridge Psychology Research Ethics Committee, University of Cambridge (PRE.2019.109). Findings will be disseminated through typical academic routes including poster/paper presentations at (inter)national conferences, academic institutes and through publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN14329613.

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), better known as COVID-19, is a highly contagious virus, transferable via air droplets from close human-human contact. The pandemic has led to over 6.5 million deaths worldwide, making it the largest global health crisis since the influenza pandemic in 1918. SARS-CoV-2 rapidly spread around the world, forcing the World Health Organization (WHO) to deem it a global health pandemic after three months of its initiation. The virus has wreaked havoc on many countries worldwide, overwhelming healthcare systems, hence damaging many economies. Even though research has progressed the understanding of the SARS-CoV-2 virus, the information gathered about the vaccine trials and their findings have been scarcely distributed to the public in a single study. The information available to scientists has therefore given researchers a pathway to building an efficacious vehicle to substantially decrease the spread of the virus. The vaccines formulated had many challenges due to multiple factors such as viral mutations and clinical trial delays. This paper will aim to educate readers on the processes that the vaccine candidates took, and better understand the procedures; additionally, we’ll look at all candidates’ findings that went into clinical trials, assessing, analyzing, and evaluating the 27 vaccine candidates that went into phase III trials and the 13 candidates that went into either phase I/II trials.

Presentation for the EU-PEARL webinar on the use of non-concurrent controls in platform trials (https://eu-pearl.eu/workshops/non-concurrent-controls-in-platform-trials/). This work is based on the paper: "On model-based time trend adjustments in platform trials with non-concurrent controls". (2021). M. Bofill Roig, P. Krotka, CF. Burman, E. Glimm, K. Hess, P. Jacko, F. Koenig, D. Magirr, P. Mesenbrink, K. Viele, and M. Posch. arXiv:2112.06574 [stat.ME] - EU-PEARL (EU Patient-cEntric clinicAl tRial pLatforms) project has received funding from the Innovative Medicines Initiative (IMI) 2 Joint Undertaking (JU) under grant agreement No 853966. This Joint Undertaking receives support from the European Union���s Horizon 2020 research and innovation programme and EFPIA and Children���s Tumor Foundation, Global Alliance for TB Drug Development non-profit organisation, Springworks Therapeutics Inc., {"references":["On model-based time trend adjustments in platform trials with non-concurrent controls. (2021). M. Bofill Roig, P. Krotka, CF. Burman, E. Glimm, K. Hess, P. Jacko, F. Koenig, D. Magirr, P. Mesenbrink, K. Viele, and M. Posch. arXiv:2112.06574 [stat.ME]"]}

Personalized medicine has been emerging to take into account individual variability in genes and environment. In the era of personalized medicine, it is critical to incorporate the patients’ characteristics and improve the clinical benefit for patients. The patients’ characteristics are incorporated in adaptive randomization to identify patients who are expected to get more benefit from the treatment and optimize the treatment allocation. However, it is challenging to control potential selection bias from using observed efficacy data and the effect of prognostic covariates in adaptive randomization. This paper proposes a personalized risk-based screening design using Bayesian covariate-adjusted response-adaptive randomization that compares the experimental screening method to a standard screening method based on indicators of having a disease. Personalized risk-based allocation probability is built for adaptive randomization, and Bayesian adaptive decision rules are calibrated to preserve error rates. A simulation study shows that the proposed design controls error rates and yields a much smaller number of failures and a larger number of patients allocated to a better intervention compared to existing randomized controlled trial designs. Therefore, the proposed design performs well for randomized controlled clinical trials under personalized medicine.

Funder: Wellcome Trust, OBJECTIVES: Chronic rhinosinusitis (CRS) symptoms are experienced by an estimated 11% of UK adults, and symptoms have major impacts on quality of life. Data from UK and elsewhere suggest high economic burden of CRS, but detailed cost information and economic analyses regarding surgical pathway are lacking. This paper estimates healthcare costs for patients receiving surgery for CRS in England. DESIGN: Observational retrospective study examining cost of healthcare of patients receiving CRS surgery. SETTING: Linked electronic health records from the Clinical Practice Research Datalink, Hospital Episode Statistics and Office for National Statistics databases in England. PARTICIPANTS: A phenotyping algorithm using medical ontology terms identified 'definite' CRS cases who received CRS surgery. Patients were registered with a general practice in England. Data covered the period 1997-2016. A cohort of 13 462 patients had received surgery for CRS, with 9056 (67%) having confirmed nasal polyps. OUTCOME MEASURES: Information was extracted on numbers and types of primary care prescriptions and consultations, and inpatient and outpatient hospital investigations and procedures. Resource use was costed using published sources. RESULTS: Total National Health Service costs in CRS surgery patients were £2173 over 1 year including surgery. Total costs per person-quarter were £1983 in the quarter containing surgery, mostly comprising surgical inpatient care costs (£1902), and around £60 per person-quarter in the 2 years before and after surgery, of which half were outpatient costs. Outpatient and primary care costs were low compared with the peak in inpatient costs at surgery. The highest outpatient expenditure was on CT scans, peaking in the quarter preceding surgery. CONCLUSIONS: We present the first study of costs to the English healthcare system for patients receiving surgery for CRS. The total aggregate costs provide a further impetus for trials to evaluate the relative benefit of surgical intervention.

The risk of morbidity and mortality increases exponentially with age. Chronic inflammation, accumulation of DNA damage, dysfunctional mitochondria, and increased senescent cell load are factors contributing to this. Mechanistic investigations have revealed specific pathways and processes which, proposedly, cause age-related phenotypes such as frailty, reduced physical resilience, and multi-morbidity. Among promising treatments alleviating the consequences of aging are caloric restriction and pharmacologically targeting longevity pathways such as the mechanistic target of rapamycin (mTOR), sirtuins, and anti-apoptotic pathways in senescent cells. Regulation of these pathways and processes has revealed significant health- and lifespan extending results in animal models. Nevertheless, it remains unclear if similar results translate to humans. A requirement of translation are the development of age- and morbidity associated biomarkers as longitudinal trials are difficult and not feasible, practical, nor ethical when human life span is the endpoint. Current biomarkers and the results of anti-aging intervention studies in humans will be covered within this paper. The future of clinical trials targeting aging may be phase 2 and 3 studies with larger populations if safety and tolerability of investigated medication continues not to be a hurdle for further investigations.

Introduction Existing randomised controlled trials (RCTs) comparing a freeze-all embryo transfer strategy and a fresh embryo transfer strategy have shown conflicting results. A freeze-all or a fresh transfer policy may be preferable for some couples undergoing in-vitro fertilisation (IVF), but it is unclear which couples would benefit most from each policy, how and under which protocols. Therefore, we plan a systematic review and individual participant data meta-analysis of RCTs comparing a freeze-all and a fresh transfer policy. Methods and analysis We will search electronic databases (Medline, Embase, PsycINFO and CENTRAL) and trial registries (ClinicalTrials.gov and the International Clinical Trials Registry Platform) from their inception to present to identify eligible RCTs. We will also check reference lists of relevant papers. The search was performed on 23 September 2020 and will be updated. We will include RCTs comparing a freeze-all embryo transfer strategy and a fresh embryo transfer strategy in couples undergoing IVF. The primary outcome will be live birth resulting from the first embryo transfer. All outcomes listed in the core outcome set for infertility research will be reported. We will invite the lead investigators of eligible trials to join the Individual participant data meta-analysis of trials comparing frozen versus fresh embryo transfer strategy (INFORM) collaboration and share the deidentified individual participant data (IPD) of their trials. We will harmonise the IPD and perform a two-stage meta-analysis and examine treatment-covariate interactions for important baseline characteristics. Ethics and dissemination The study ethics have been granted by the Monash University Human Research Ethics Committee (Project ID: 30391). The findings will be disseminated via presentations at international conferences and publication in peer-reviewed journals. PROSPERO registration number CRD42021296566.

Background: The aim of the present systematic review was to evaluate the clinical effect of vitamin C on bone healing after bone fracture or bone reconstruction procedures. Material and Methods: In October 2020, Cochrane Library, Scopus and PubMed-Medline databases were searched without restrictions to identify animal and human studies that fulfilled the eligibility criteria. Outcome measures were bone healing time, bone gain (mm), bone density and adverse events. The risk of bias assessment of the selected studies was evaluated by means of Cochrane Collaboration's Tool for randomized clinical trials, while randomized clinical animal trials were assessed according to SYRCLE's tool. Additionally, quality of reporting animal studies were assessed according to ARRIVE guidelines. Results: Out of the 248 articles that yielded the initial search, 11 papers about the effect of ascorbic acid on bone healing were selected. In most of the animal studies, vitamin C seemed to accelerate bone formation owing to an enhanced osteoblastic proliferation and differentiation and its antioxidant function when pro-oxidant substances were added. It was not possible to observe this phenomenon in human studies. Conclusions: Although additional well-performed animal and human studies are required, vitamin C seems to accelerate bone regeneration without adverse events. However, it is not possible to recommend a specific dose or route of administration of vitamin C to improve the bone healing process in humans as there was great heterogeneity among the included studies.

Introduction: Clinical trial protocols are essential documents that serve as a basis for research planning. The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement aimed to increase the transparency and integrity of clinical trial protocols. Objectives: This paper described the main aspects of the SPIRIT, highlighting the importance of using this guideline in Orthodontics. Results: The SPIRIT is composed of 33 items and the diagram, which were presented and explained. Conclusion: The use of the SPIRIT checklist must become essential to increase the transparency and integrity of more reliable and less biased clinical trials in orthodontic research, improving the quality of future publications in this field. RESUMO Introdução: Protocolos de ensaios clínicos são documentos essenciais, que servem como base para o planejamento da pesquisa. As diretrizes do Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) objetivam aumentar a transparência e a integridade dos protocolos de ensaios clínicos. Objetivos: O presente trabalho descreve os principais aspectos do SPIRIT, destacando a importância do uso dessas diretrizes na Ortodontia. Resultados: O SPIRIT é composto por 33 itens e 1 diagrama, que foram aqui apresentados e explicados. Conclusão: O uso do checklist SPIRIT deve se tornar essencial, para aumentar a transparência e a integridade de ensaios clínicos na pesquisa ortodôntica, tornando-os mais confiáveis e menos tendenciosos, melhorando, dessa forma, a qualidade das futuras publicações nessa área.

This review aims to collate the literature about the process, statements, and standards of complaints and correspondence raising post-publication concerns, investigations, corrections, retractions, furture research recommendations, and other related issues about pre-prints and published papers of randomized clinical trials.

The recent National Institute of Health (NIH) INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) initiative has bolstered capacity for the current increase in clinical trials involving individuals with Down syndrome (DS). This new NIH funding mechanism offers new opportunities to expand and develop novel approaches in engaging and effectively enrolling a broader representation of clinical trials participants addressing current medical issues faced by individuals with DS. To address this opportunity, the NIH assembled leading clinicians, scientists, and representatives of advocacy groups to review existing methods and to identify those areas where new approaches are needed to engage and prepare DS populations for participation in clinical trial research. This paper summarizes the results of the Clinical Trial Readiness Working Group that was part of the INCLUDE Project Workshop: Planning a Virtual Down Syndrome Cohort Across the Lifespan Workshop held virtually September 23 and 24, 2019.

Background The COVID-19 pandemic significantly impacted the conduct of clinical trials through delay, interruption or cancellation. Decentralised methods in clinical trials could help to continue trials during a pandemic. This paper presents the results of an exploratory study conducted early in the pandemic to gain insight into and describe the experiences of organisations involved in clinical trials, with regard to the impact of COVID-19 on the conduct of trials, and the adoption of decentralised methods prior to, and as mitigation for the impact, of COVID-19. Methods A survey with 11 open-ended and four multiple choice questions was conducted in June 2020 among member organisations of the public-private “Trials@Home” consortium. The survey investigated (1) the impact and challenges of COVID-19 on the continuation of ongoing clinical trials, (2) the adoption of decentralised methods in clinical trials prior to and as a mitigation strategy for COVID-19, (3) the challenges of conducting clinical trials during COVID-19, (4) the expected permanency of COVID-19-driven changes to the adoption of decentralised methods in clinical trials, and (5) lessons learned from conducting clinical trials during the COVID-19 pandemic. A thematic, inductive analysis of open survey questions was performed, complemented with descriptive statistics (frequencies and distributions). Results The survey had a response rate of 81%. All organisations included in the analysis (n = 18) implemented (some) decentralised methods in their clinical trials prior to COVID-19, and 15 (83%) implemented decentralised methods as mitigation for COVID-19. Decentralised methods for IMP supply, patient-health care provider interaction and communication, clinic visits and source document verification were used more often as mitigation strategies than they were used prior to COVID-19. Many respondents expect to maintain those decentralised methods they implemented during COVID-19 in ongoing trials, as well as implement them in future trials. Conclusions Decentralised methods are a widely implemented mitigation strategy for trial conduct in the face of the COVID-19 pandemic. The results of this survey show that there is an interest to continue the use of decentralised methods in future trials, but important points of attention have been identified that need solutions to help guide the transition from the traditional trial model to a more decentralised trial model.

Best practices for designing, conducting, documenting, and reporting human nutrition randomized controlled trials were developed and published in Advances in Nutrition. Through an example of the randomized clinical trial on blueberries and bone health funded by the National Institutes of Health, this paper will illustrate the elements of those best practices that apply specifically to plant-based intervention clinical trials. Unique study design considerations for human feeding interventions with bioactive plant compounds include the difficulty of blinding the intervention, background nutritional status of participants, carry-over effects of the intervention, benefits of a run-in period, lack of safety/tolerability data, and nutrition-specific regulatory policies. Human nutrition randomized controlled trials are the gold standard for establishing causal relations between an intervention and health outcome measures. Rigorous studies and documentation define the quality of the evidence-base to inform public health guidelines and to establish personalized dietary recommendations for the health-promoting plant components.

Background Ethnobotanical studies investigating a large number of traditional herbs and uses have an important role in the discovery of new drugs. Nowadays, some of these traditional herbs are researched directly in the clinical trials. In this study, it is aimed to evaluate the 19 plant species that have been identified in the clinical trials among 300 plant species belonging to 79 families with traditional use for skin problems in Turkey. Main body Natural sources are very important to treat diseases for thousands of years. The ethnopharmacological research of natural products ranges from the collection of biogenic samples such as plants to preclinical and clinical studies with the aim of developing drug templates or new drugs. In the ethnopharmacological approach, it is aimed to reach the result based on the traditional and modern knowledge about natural resources. The biggest advantage of this approach is synthesizing new and old information. After the plant or natural compound is determined, other processes work similarly with conventional drugs. Methods Ethnobotanical papers, thesis and projects in Istanbul University Faculty of Pharmacy Department of Pharmaceutical Botany and databases (PubMed and Google Scholar) have been sought and results were synthesized. Results Most of the clinical uses of herbs have been seen similar to their traditional uses. On the other hand, there are some plants on which their clinical uses differ from the traditional uses such as Borago officinalis, Calendula officinalis or Euphorbia peplus. When the frequency of traditional uses of herbs are compared, Plantago species, Plantago major and Plantago lanceolata are the most used taxa in Turkey, secondly, Hypericum perforatum comes. However, Plantago species are not of much interest in clinical trials. It is seen that most of the plants in the clinical research are tried for wound healing occuring due to different origins such as cancer, surgery and injury. Side effects were observed only during the application of Allium cepa, Cydonia oblonga and H. perforatum. Conclusions When clinical trials are evaluated in terms of efficacy and overall results, significant differences and effective results are seen in treatment groups given herbs in comparison with placebo or control groups.

BackgroundPneumonia is a leading cause of death among children under 5 specifically in South Asia and sub-Saharan Africa. Hypoxaemia is a life-threatening complication among children under 5 with pneumonia. Hypoxaemia increases risk of mortality by 4.3 times in children with pneumonia than those without hypoxaemia. Prevalence of hypoxaemia varies with geography, altitude and severity (9%–39% Asia, 3%–10% African countries). In this protocol paper, we describe research methods for assessing impact of Lady Health Workers (LHWs) identifying hypoxaemia in children with signs of pneumonia during household visits on acceptance of hospital referral in district Jamshoro, Sindh.Methods and analysisA cluster randomised controlled trial using pulse oximetry as intervention for children with severe pneumonia will be conducted in community settings. Children aged 0–59 months with signs of severe pneumonia will be recruited by LHWs during routine visits in both intervention and control arms after consent. Severe pneumonia will be defined as fast breathing and/or chest in-drawing, and, one or more danger sign and/or hypoxaemia (Sa02 Ethics and disseminationEthical approval was granted by the Ethics Review Committee of the Aga Khan University (4722-Ped-ERC-17), Karachi. Study results will be shared with relevant government and non-governmental organisations, presented at national and international research conferences and published in international peer-reviewed scientific journals.Trial registration numberNCT03588377.

Ever since the emergence of the coronavirus disease 2019 (COVID-19), global public health infrastructures and systems, along with community-wide collaboration and service, have risen to an unprecedented challenge. Vaccine development was immediately propelled to the centre of all our scientific, public health and community efforts. Despite the development of SARS-CoV-2 vaccines arguably being the greatest and most palpable achievements of the past 12 months, they have also been one of the most contentious and debated issues during the pandemic. However, what uniquely differentiates vaccine development is its intimate relationship with the community it seeks to serve; both in its clinical trial testing as an efficacious and safe prophylactic, and its post-developmental ‘roll-out’ success, as an effective public health tool. These relationships have birthed a myriad of complexities, from community-based mistrust, to academically contended ethical dilemmas. Indeed, the accelerated advances in the COVID-19 vaccine race have further exacerbated this phenomenon, bringing with it new ethical dilemmas that need to be examined to ensure the continued clinical success of these therapeutics and a renewed societal trust in clinical medicine.In this paper, we discuss two major ethical dilemmas: (1) the equipoise of continuing new vaccine trials in the advent of successful candidates and (2) the maleficence of blinded placebo arms. Accordingly, we discuss six different potential approaches to these ethical dilemmas: (1) continuing with placebo-controlled trials, (2) transitioning from placebo-controlled to open-label, (3) unblinding at-risk priority groups only, (4) transitioning to a blinded stepped-wedge cross-over design, (5) progressing to a blinded active-controlled stepped-wedge cross-over trial, and (6) conducting randomised stepped-wedge community trials. We also propose a decision-making algorithm for relevant stakeholders in advanced stages of vaccine trials.It is important to remember that the emergent nature of the COVID-19 situation does not justify a compromise on core ethical values. In fact, the discourse surrounding this topic and the decisions made will remain a potent case study and a continuously referenced example for all such future scenarios.

IntroductionPeriprosthetic infection is one of the most severe complications following implant-based breast reconstruction affecting 5%–10% of the women. Currently, many surgeons apply antibiotics locally on the breast implant to reduce the risk of postoperative infection, but no randomised, placebo-controlled trials have tested the treatment’s efficacy.Methods and analysisThe BREAST-AB trial (BREAST-AntiBiotics) is an investigator-initiated, multicentre, randomised, placebo-controlled, double-blind trial of local treatment with gentamicin, vancomycin and cefazolin on breast implants in women undergoing implant-based breast reconstruction. The trial drug consists of 80 mg gentamicin, 1 g vancomycin and 1 g cefazolin dissolved in 500 mL of isotonic saline. The placebo solution consists of 500 mL isotonic saline. The trial drug is used to wash the dissected tissue pocket and the breast implant prior to insertion. The primary outcome is all-cause explantation of the breast implant within 180 days after the breast reconstruction surgery. This excludes cases where the implant is replaced with a new permanent implant, for example, for cosmetic reasons. Key long-term outcomes include capsular contracture and quality of life. The trial started on 26 January 2021 and is currently recruiting.Ethics and disseminationThe trial was approved by the Regional Ethics Committee of the Capital Region (H-20056592) on 1 January 2021 and the Danish Medicines Agency (2020070016) on 2 August 2020. The main paper will include the primary and secondary outcomes and will be submitted to an international peer-reviewed journal.Trial registration numberNCT04731025.

Introduction In June 2021, United Nations (UN) Member States committed to ambitious targets for scaling up community-led responses by 2025 toward meeting the goals of ending the AIDS epidemic by 2030. These targets build on UN Member States 2016 commitments to ensure that 30% of HIV testing and treatment programmes are community-led by 2030. At its current pace, the world is not likely to meet these nor other global HIV targets, as evidenced by current epidemiologic trends. The COVID-19 pandemic threatens to further slow momentum made to date. The purpose of this paper is to review available evidence on the comparative advantages of community-led HIV responses that can better inform policy making towards getting the world back on track. Methods We conducted a scoping review to gather available evidence on peer- and community-led HIV responses. Using UNAIDS’ definition of ‘community-led’ and following PRISMA guidelines, we searched peer-reviewed literature published from January 1982 through September 2020. We limited our search to articles reporting findings from randomized controlled trials as well as from quasi-experimental, prospective, pre/post-test evaluation, and cross-sectional study designs. The overall goals of this scoping review were to gather available evidence on community-led responses and their impact on HIV outcomes, and to identify key concepts that can be used to quickly inform policy, practice, and research. Findings Our initial search yielded 279 records. After screening for relevance and conducting cross-validation, 48 articles were selected. Most studies took place in the global south (n = 27) and a third (n = 17) involved youth. Sixty-five percent of articles (n = 31) described the comparative advantage of peer- and community-led direct services, e.g., prevention and education (n = 23) testing, care, and treatment programs (n = 8). We identified more than 40 beneficial outcomes linked to a range of peer- and community-led HIV activities. They include improved HIV-related knowledge, attitudes, intentions, self-efficacy, risk behaviours, risk appraisals, health literacy, adherence, and viral suppression. Ten studies reported improvements in HIV service access, quality, linkage, utilization, and retention resulting from peer- or community-led programs or initiatives. Three studies reported structural level changes, including positive influences on clinic wait times, treatment stockouts, service coverage, and exclusionary practices. Conclusions and recommendations Findings from our scoping review underscore the comparative advantage of peer- and community-led HIV responses. Specifically, the evidence from the published literature leads us to recommend, where possible, that prevention programs, especially those intended for people living with and disproportionately affected by HIV, be peer- and community-led. In addition, treatment services should strive to integrate specific peer- and community-led components informed by differentiated care models. Future research is needed and should focus on generating additional quantitative evidence on cost effectiveness and on the synergistic effects of bundling two or more peer- and community-led interventions.

Urothelial carcinoma therapy is a rapidly evolving and expanding field. Traditional cytotoxic chemotherapy regimens have not produced optimal long-term outcomes, and many urothelial cancer patients have comorbidities that disqualify them as chemotherapy candidates. In recent years, a plethora of novel therapeutic agents that target diverse molecular pathways has emerged as alternative treatment modalities for not only metastatic urothelial carcinoma, but also for muscle-invasive bladder cancer and non-muscle invasive bladder cancer in adjuvant and definitive settings. This review paper aims to discuss the various categories of therapeutic agents for these different types of urothelial cancer, discussing immunotherapy, antibody-drug conjugates, kinase inhibitors, CAR-T cell therapy, peptide vaccination, and other drugs targeting pathways such as angiogenesis, DNA synthesis, mTOR/PI3K/AKT, and EGFR/HER-2.

ObjectiveTo evaluate systematically the fidelity of a peer-befriending intervention for people with aphasia.DesignSUpporting wellbeing through Peer-befriending (SUPERB) was a feasibility randomised controlled trial comparing usual care to usual care +peer-befriending. This paper reports on the fidelity of all intervention aspects (training and supervision of providers/befrienders; intervention visits) which was evaluated across all areas of the Behaviour Change Consortium framework.SettingCommunity.ParticipantsPeople with aphasia early poststroke and low levels of distress, randomised to the intervention arm of the trial (n=28); 10 peer-befrienders at least 1-year poststroke.InterventionPeer-befrienders were trained (4–6 hours); and received regular supervision (monthly group while actively befriending, and one-to-one as and when needed) in order to provide six 1-hour peer-befriending visits over 3 months.Main measuresMetrics included number and length of training, supervision sessions and visits. All training and supervision sessions and one (of six) visits per pair were rated against fidelity checklists and evaluated for inter-rater and intrarater reliability (Gwets AC1 agreement coefficient). Per-cent adherence to protocol was evaluated.ResultsAll peer-befrienders received 4–6 hours training over 2–3 days as intended. There were 25 group supervision sessions with a median number attended of 14 (IQR=8–18). Twenty-six participants agreed (92.8%) to the intervention and 21 (80.8%) received all six visits (median visit length 60 min). Adherence was high for training (91.7%–100%) and supervision (83%–100%) and moderate-to-high for befriending visits (66.7%–100%). Where calculable, inter-rater and intrarater reliability was high for training and supervision (Gwets AC1 >0.90) and moderate-to-high for intervention visits (Gwets AC1 0.44–1.0).ConclusionPlanning of fidelity processes at the outset of the trial and monitoring throughout was feasible and ensured good-to-high fidelity for this peer-befriending intervention. The results permit confidence in other findings from the SUPERB trial.Trial registration numberNCT02947776.

IntroductionImmune thrombocytopaenia (ITP) is an acquired disorder of low platelets and risk of bleeding. Although many children can be observed until spontaneous remission, others require treatment due to bleeding or impact on health-related quality of life. Standard first-line therapies for those who need intervention include corticosteroids, intravenous immunoglobulin and anti-D globulin, though response to these agents may be only transient. Eltrombopag is an oral thrombopoietin receptor agonist approved for children with chronic ITP who have had an insufficient response to corticosteroids, intravenous immunoglobulin or splenectomy. This protocol paper describes an ongoing open-label, randomised trial comparing eltrombopag to standard first-line management in children with newly diagnosed ITP.Methods and analysisRandomised treatment assignment is 2:1 for eltrombopag versus standard first-line management and is stratified by age and by prior treatment. The primary endpoint of the study is platelet response, defined as ≥3 of 4 weeks with platelets >50×109/L during weeks 6–12 of therapy. Secondary outcomes include number of rescue therapies needed during the first 12 weeks, proportion of patients who do not need ongoing treatment at 12 weeks and 6 months, proportion of patients with a treatment response at 1 year, and number of second-line therapies used in weeks 13–52, as well as changes in regulatory T cells, iron studies, bleeding, health-related quality of life and fatigue. A planned sample size of up to 162 randomised paediatric patients will be enrolled over 2 years at 20 sites.Ethics and disseminationThe study has been approved by the centralised Baylor University Institutional Review Board. The results are expected to be published in 2023.Trial registration numberNCT03939637.

IntroductionObesity is a global health issue that impacts quality of life. A calorie-restricted diet with high-intensity consultation provided via the internet may be an effective way to lose weight. The objective of this study was to assess the effectiveness of a practitioner-guided, mobile internet-based low-energy dietary intervention in overweight and obese populations in China.Methods and analysisThis open-label randomised controlled trial enrolled 220 overweight and obese adults aged 18–70 years who met the inclusion criteria. Participants were assigned to the control group (n=110) or trial group (n=110). The trial group will be enrolled in the MetaWell programme, a weight loss programme using diet replacement products, wireless scales and a mobile phone app. Participants in the control group will receive paper material containing a sample diet for weight loss. The follow-up period will be 1 year, and measurements will occur at 3, 6 and 12 months. Dual-emission X-ray absorptiometry and abdominal quantitative CT will be performed to estimate the percentage of overall body fat and areas of visceral and subcutaneous fat, alongside several cardiometabolic measurements. The primary outcome of this study is the change in body mas index (BMI) at 6 months after enrolment. A mixed-effects model will be used to compare BMI and body fat changes between the two groups.Ethics and disseminationThis study was approved by the ethics committee of the Hospital of Chengdu Office of the People’s Government of the Tibetan Autonomous Region. Advertisements for recruitment will be sent via official accounts using WeChat. The results will be disseminated via publications in academic journals and our clinic. Our study group will maintain contact with the participants to inform them of the study findings.Trial registration numberChiCTR1900021630.

Simple Summary Cell therapy has become a powerful method for regenerative medicine. However, there has not been an ideal cell type and cell source for the treatment of neurological diseases such as Parkinson’s disease and Alzheimer’s disease. This review aims to introduce the potentials of different cells for treating neurological disorders by collecting the results from related clinical trials and recent animal studies. It is an overview of some promising cells that may be clinically used for neurological disorders. The characteristics of each cell type and the main mechanism of function are also described. Abstract Neurological disorders are big public health challenges that are afflicting hundreds of millions of people around the world. Although many conventional pharmacological therapies have been tested in patients, their therapeutic efficacies to alleviate their symptoms and slow down the course of the diseases are usually limited. Cell therapy has attracted the interest of many researchers in the last several decades and has brought new hope for treating neurological disorders. Moreover, numerous studies have shown promising results. However, none of the studies has led to a promising therapy for patients with neurological disorders, despite the ongoing and completed clinical trials. There are many factors that may affect the outcome of cell therapy for neurological disorders due to the complexity of the nervous system, especially cell types for transplantation and the specific disease for treatment. This paper provides a review of the various cell types from humans that may be clinically used for neurological disorders, based on their characteristics and current progress in related studies.

The development of peptide-based vaccines for treating human neurodegenerative diseases has been the eventual aim of many research endeavors, although no active immunotherapies have been approved for clinical use till now. A typical example of such endeavors is the effort to develop vaccines for Alzheimer’s disease based on the beta-amyloid peptide, which continues to be intensively investigated despite previous setbacks. In this paper, recent developments in peptide-based vaccines which target beta-amyloid as well as tau protein and α-synuclein are presented. Particular focus has been directed toward peptide epitopes and formulation systems selected/developed and employed to enhance vaccine efficacy and safety. Results from both, human clinical trials and animal preclinical studies conducted mainly in transgenic mice have been included. Future perspectives on the topic are also briefly discussed.

This paper describes a randomized controlled trial on the Online Life Story Book (OLSB), a digital reminiscence intervention for people with (very) mild dementia living at home. The aim of the study was to investigate the effectiveness of the OLSB on (i) neuropsychiatric symptoms (NPS) in persons with dementia and (ii) the distress and quality of life (QOL) of primary informal caregivers. A randomized controlled trial with individual randomization to one of two conditions was conducted: 1) intervention “Online Life Story Book”; 2) wait list control condition. In the intervention OLSB, a trained volunteer guided the participants through the process of creating an OLSB in approximately 5 meetings within a period of 8–10 weeks. Participants in the control condition received care as usual while they waited for 6 months before starting. Outcomes on NPS and distress and QOL of the informal caregiver were assessed at baseline (baseline, T0), 3 months (T1) and 6 months (T2) post baseline. Of the 42 persons with dementia, 23 were female and 19 were male. They had a mean age of 80 years, ranging from 49 to 95. The total drop-out rate was 14.3 percent. Small but insignificant effects on NPS, caregiver distress and QOL of caregivers were found with the exception of self-rated caregiver distress that reduced significantly during the intervention. One reason to explain the results might be that the included participants were in relatively good health. Practical challenges during the intervention could have affected the results as well. It might also be that the intervention caused effects on other outcomes than NPS and caregiver distress. In future research, it is important to study the effects in persons with more complaints and higher distress and to be careful in the selection of outcome variables in relation to the reminiscence functions served by the intervention.

IntroductionEarly phase cancer clinical trials have become increasingly complicated in terms of patient selection and trial procedures—this is reflected in the increasing length of participant information sheets (PIS). Informed consent for early phase clinical trials has been contentious due to the potential ethical issues associated with performing experimental research on a terminally ill population which has exhausted standard treatment options. Empirical studies have demonstrated significant gaps in patient understanding regarding the nature and intent of these trials. This study aims to test whether enhanced informed consent for patient education can improve patient scores on a validated questionnaire testing clinical trial comprehension.Methods and analysisThis is a randomised controlled trial that will allocate patients who are eligible to participate in one of four investigator-initiated clinical trials at the Royal Marsden Drug Development Unit to either a standard arm or an experimental arm, stratified by age and educational level. The standard arm will involve the full length trial PIS, followed by electronic or paper administration of the Quality of Informed Consent Questionnaire Parts A and B (QuIC-A and QuIC-B). The experimental arm will involve the full length trial PIS, exposure to a two-page study aid and 10 online educational videos, followed by administration of the QuIC-A and QuIC-B. The primary endpoint will be the difference (using a one-sided two-sample t-test) in the QuIC-A score, which measures objective understanding, between the standard and experimental arm. Accrual target is at least 17 patients per arm to detect an 8 point difference (80% power, alpha 0.05).Ethics and disseminationEthics approval was granted by the National Health Service Health Research Authority on 15 June 2020—IRAS Project ID 277065, Protocol Number CCR5165, REC Reference 20/EE/0155. Results will be disseminated via publication in a relevant journal.Trial registration numberNCT04407676; Pre-results.

BackgroundReporting of yoga research often lacks the detail required for clinical application, study replication, summary research and comparative effectiveness studies.MethodsTo improve the transparency of reporting yoga interventions, and building on the development of previous reporting guidelines, a group of international yoga research stakeholders developed the consensus-based CheckList stAndardising the Reporting of Interventions For Yoga (CLARIFY) guidelines.ResultsThe 21-item CLARIFY checklist outlines the minimum details considered necessary for high-quality reporting of yoga research. This paper provides a detailed explanation of each of the 21 items of the CLARIFY checklist, together with model examples of how to integrate each item into publications of yoga research. The CLARIFY guideline serves as an extension for existing research reporting guidelines, and is flexible for use across all study designs.ConclusionWe strongly encourage the uptake of these reporting guidelines by researchers and journals, to facilitate improvements in the transparency and utility of yoga research.