Search

The 1983 Orphan Drug Act in the United States (US) changed the landscape for development of therapeutics for rare or orphan diseases, which collectively affect approximately 300 million people worldwide, half of whom are children. The act has undoubtedly accelerated drug development for orphan diseases, with over 6,400 orphan drug applications submitted to the US Food and Drug Administration (FDA) from 1983 to 2023, including 350 drugs approved for over 420 indications. Drug development in this population is a global and collaborative endeavor. This position paper of the International Society for Central Nervous System Clinical Trials and Methodology (ISCTM) describes some potential best practices for the involvement of key stakeholder feedback in the drug development process. Stakeholders include advocacy groups, patients and caregivers with lived experience, public and private research institutions (including academia and pharmaceutical companies), treating clinicians, and funders (including the government and independent foundations). The authors articulate the challenges of drug development in orphan diseases and propose methods to address them. Challenges range from the poor understanding of disease history to development of endpoints, targets, and clinical trials designs, to finding solutions to competing research priorities by involved parties. [ABSTRACT FROM AUTHOR]

Background: Unhealthy diet is a key risk factor for Non-Communicable Diseases (NCDs) that contribute to increased morbidity and premature mortality. With increased computer literacy and mobile phone penetration, there is a high opportunity for mobile application-based interventions. The current study was conducted to develop a mobile application to monitor dietary intake and to assess its acceptability and effectiveness in diet control compared to a similar paper-based intervention. A mobile application was developed based on research evidence and opinions of local experts. The mobile application was introduced to a selected group of office workers who were in preparation, action, and maintenance stages of the Trans Theoretical Model (TTM) and a paper-based intervention was used as the comparator. Socio-demographic data were collected through a self-administered questionnaire. Participants were followed up for three months for adherence. The effectiveness of interventions was assessed at the end of three months by comparing the progressive change in the stage of change and the change from unhealthy to healthy dietary intake between two groups as primary and secondary outcomes respectively. Results: Among 123 office workers who participated in the study, 19.5% preferred the mobile intervention over the paper-based intervention. Younger, unmarried office workers and those who do not have children, had a higher acceptance for the mobile intervention (p < 0.05). There was no difference in adherence (in all three months) or outcomes between the two groups of intervention. Conclusion and recommendations: Mobile application-based interventions are better accepted among the young age group and further studies are recommended to explore their applicability. Trial registration: The study was registered in the Sri Lankan Clinical Trial Registry (Registration No. SLCTR/2020/025; Date 15th December 2020). [ABSTRACT FROM AUTHOR]

Background: Interest in and use of electronic consent (e-consent) in the conduct of academic clinical trials has increased since the COVID-19 pandemic. E-consent offers advantages including increased efficiency and accessibility, and reduced burden on site staff, which can be appealing to academic trialists anticipating challenges in recruitment to complex trial designs or with limited funding. However, there are many options to consider when using e-consent in a study protocol. This paper presents five case studies from Norwich Clinical Trials Unit, demonstrating how e-consent models can be effectively tailored to the needs of different trials. These examples illustrate the options around and benefits of e-consent, the acceptability of e-consent by participants, and the design considerations that were made during the development of the trial protocols. Case studies: Five randomised trials are presented, selected from a range of different trial designs, disease areas, interventions, and patient populations. E-consent was either offered as an alternative to paper consent, according to participant preference, or as the sole method of consent. E-consent was generally used to facilitate remote consent in decentralised trials but was also chosen to increase efficiency and reduce burden in an emergency department setting. The technical implementation of e-consent and detailed participant procedures were tailored to the needs of the trial settings and patient populations. For example, accompanying participant information sheets were provided in paper or electronic form, and electronic signatures could be typed or drawn. Administrative data on uptake of e-consent is presented where available. Conclusion: This paper demonstrates that the operational and technical aspects of implementing e-consent in clinical trials can be influenced by the trial design, the needs and characteristics of the trial population, financial/efficiency considerations, and level of risk. E-consent is not a one-size-fits-all tool for trials, and its use should be carefully considered during the development of the trial protocol, in conjunction with patient and public involvement contributors, site staff and other trial stakeholders. [ABSTRACT FROM AUTHOR]

Emerging evidence has shown that microRNAs play pivotal roles in wound healing. MicroRNA-21 (miR-21) was previously found to upregulate in order to fulfill an anti-inflammation role for wounds. Exosomal miRNAs have been identified and explored as essential markers for diagnostic medicine. However, the role of exosomal miR-21 in wounds has yet to be well studied. In order to facilitate the early management of poorly healing wounds, we developed an easy-to-use, rapid, paper-based microfluidic-exosomal miR-21 extraction device to determine wound prognosis in a timely manner. We isolated and then quantitatively examined exosomal miR-21 in wound fluids from normal tissues and acute and chronic wounds. Eight improving wounds displayed lower levels of exosomal miR-21 expression after wound debridement. However, four instances of increased exosomal miR-21 expression levels were notably associated with patients with poor healing wounds despite aggressive wound debridement, indicating a predictive role of tissue exosomal miR-21 for wound outcome. Paper-based nucleic acid extraction device provides a rapid and user-friendly approach for evaluating exosomal miR-21 in wound fluids as a means of monitoring wounds. Our data suggest that tissue exosomal miR-21 is a reliable marker for determining current wound status. [ABSTRACT FROM AUTHOR]

Background: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach. Objective: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials. Methods: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives' input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory. Results: An extensive inventory of OM was created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages. Conclusion: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges. [ABSTRACT FROM AUTHOR]

The safety and efficacy of pharmacotherapy in children, particularly preterms, neonates and infants, is limited by a paucity of good‐quality data from prospective clinical drug trials. A specific challenge is the establishment of valid biomarkers. OMICs technologies may support these efforts by complementary information about targeted and nontargeted molecules through systematic characterization and quantitation of biological samples. OMICs technologies comprise at least genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiomics in addition to the patient's phenotype. OMICs technologies are in part hypothesis‐generating, allowing an in depth understanding of disease pathophysiology and pharmacological mechanisms. Application of OMICs technologies in paediatrics faces major challenges before routine adoption. First, developmental processes need to be considered, including a subdivision into specific age groups as developmental changes clearly impact OMICs data. Second, compared to the adult population, the number of patients is limited as are the type and amount of necessary biomaterial, especially in neonates and preterms. Thus, advanced trial designs and biostatistical methods, noninvasive biomarkers, innovative biobanking concepts including data and samples from healthy children, as well as analytical approaches (eg liquid biopsies) should be addressed to overcome these obstacles. The ultimate goal is to link OMICs technologies with innovative analysis tools, such as artificial intelligence at an early stage. The use of OMICs data based on a feasible approach will contribute to the identification complex phenotypes and subpopulations of patients to improve the development of medicines for children with potential economic advantages. [ABSTRACT FROM AUTHOR]

Background: There is an often-held assumption that the engagement of clinicians and healthcare organizations in research improves healthcare performance at various levels. Previous reviews found up to 28 studies suggesting a positive association between the engagement of individuals and healthcare organizations in research and improvements in healthcare performance. The current study sought to provide an update. Methods: We updated our existing published systematic review by again addressing the question: Does research engagement (by clinicians and organizations) improve healthcare performance? The search covered the period 1 January 2012 to March 2024, in two phases. First, the formal updated search ran from 1 January 2012 to 31 May 2020, in any healthcare setting or country and focussed on English language publications. In this phase two searches identified 66 901 records. Later, a further check of key journals and citations to identified papers ran from May 2020 to March 2024. In total, 168 papers progressed to full-text appraisal; 62 were identified for inclusion in the update. Then we combined papers from our original and updated reviews. Results: In the combined review, the literature is dominated by papers from the United States (50/95) and mostly drawn from the Global North. Papers cover various clinical fields, with more on cancer than any other field; 86 of the 95 papers report positive results, of which 70 are purely positive and 16 positive/mixed, meaning there are some negative elements (i.e. aspects where there is a lack of healthcare improvement) in their findings. Conclusions: The updated review collates a substantial pool of studies, especially when combined with our original review, which are largely positive in terms of the impact of research engagement on processes of care and patient outcomes. Of the potential engagement mechanisms, the review highlights the important role played by research networks. The review also identifies various papers which consider how far there is a "dose effect" from differing amounts of research engagement. Additional lessons come from analyses of equity issues and negative papers. This review provides further evidence of contributions played by systems level research investments such as research networks on processes of care and patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy for lung cancer has been a hot research area for years. This bibliometric analysis aims to present the research trends on lung cancer immunotherapy. Method: On 1 July, 2022, the authors identified 2,941 papers on lung cancer immunotherapy by the Web of Science and extracted their general information and the total number of citations. A bibliometric analysis was carried out to present the research landscape, demonstrate the research trends, and determine the most cited papers (top papers) as well as major journals on lung cancer immunotherapy. After that, recent research hotspots were analyzed based on the latest publications in major journals. Results: These 2,941 papers were cited a total of 122,467 times. “Nivolumab vs. docetaxel in advanced non–squamous non–small–cell lung cancer” published in 2015 by Borghaei H et al. was the most cited paper (5,854 citations). Among the journals, New England Journal of Medicine was most influential. Corresponding authors represented China took part in most articles (904) and papers with corresponding authors from the USA were most cited (139.46 citations per paper). Since 2015, anti–PD–(L)1 has become the hottest research area. Conclusions: This bibliometric analysis comprehensively and quantitatively presents the research trends and hotspots based on thousands of publications, and further suggests future research directions. Moreover, the results can benefit researchers to select journals and find potential collaborators. This study can help researchers get a comprehensive impression of the research landscape, historical development, and recent hotspots in lung cancer immunotherapy and provide inspiration for further research. [ABSTRACT FROM AUTHOR]

Background: The lack of a clear answer regarding the efficacy of physiotherapy in the treatment of cubital tunnel syndrome (CuTS) has led to attempts to critically assess the scientific studies conducted to date. Materials and Methods: Two databases (MEDLINE via PubMed and PEDro) and Google Scholar were used to search for papers. The inclusion criteria were randomized controlled trials, case series, and case reports that evaluate the effects of physiotherapy in the treatment of patients with CuTS. Results: A total of 18 studies met the eligibility criteria, capturing a total of 425 participants. Seven papers were randomized controlled trials, three more described prospective studies without a control group, and eight papers contained case reports. An analysis of the literature evaluating the effectiveness of various forms of broadly defined physiotherapy indicates that their use can have a beneficial effect in reducing many subjective and objective symptoms and improving function. In the majority of papers included in this review, their authors indicated positive therapeutic effects. Only one randomized controlled trial reported no change following therapy. It can therefore be stated that the results of the research conducted so far are optimistic. However, only 7 of the 18 papers were randomized controlled trials, while 3 were prospective studies, and 8 papers were case studies, in which 23 people with CuTS were studied. Conclusions: The small number of randomized clinical trials and their considerable heterogeneity do not allow firm conclusions to be drawn about the effectiveness of physiotherapy in the conservative treatment of CuTS. [ABSTRACT FROM AUTHOR]

The phenomenon of acute behavioral disturbance is an under-recognized and potentially life-threatening syndrome, and sometimes an emergency in psychiatric settings. Patients presenting to the Italian Emergency Departments (EDs) with acute behavioral disturbances account for approximately 3.2% of all ED visits. The spectrum of behaviors and of the signs overlaps with many clinical diseases. In addition to patients with behavioral problems related to mental disorders or substance abuse and toxicity, there is also a large group whose behavioral emergencies result from a medical illness. The complexity of these patients, as well as the interdisciplinary nature of their care, requires a clear and consensual framework for the appropriate medical management. A network of Italian scientific societies developed ten recommendations for good clinical practice. The main purpose is to draw up a document that presents a standardized method for the organization of the care of patients with acute behavioral disorders in EDs. [ABSTRACT FROM AUTHOR]

Background: Overall survival is the "gold standard" endpoint in cancer clinical trials. It plays a key role in determining the clinical- and cost-effectiveness of a new intervention and whether it is recommended for use in standard of care. The assessment of overall survival usually requires trial participants to be followed up for a long period of time. In this time, they may stop receiving the trial intervention and receive subsequent anti-cancer treatments, which also aim to extend survival, during trial follow-up. This can potentially change the interpretation of overall survival in the context of the clinical trial. This review aimed to determine how overall survival has been assessed in cancer clinical trials and whether subsequent anti-cancer treatments are considered. Methods: Two searches were conducted using MEDLINE within OVID© on the 9th of November 2021. The first sought to identify papers publishing overall survival results from randomised controlled trials in eight reputable journals and the second to identify papers mentioning or considering subsequent treatments. Papers published since 2010 were included if presenting or discussing overall survival in the context of treating cancer. Results: One hundred and thirty-four papers were included. The majority of these were presenting clinical trial results (98, 73%). Of these, 45 (46%) reported overall survival as a (co-) primary endpoint. A lower proportion of papers including overall survival as a (co-) primary endpoint compared to a secondary endpoint were published in recent years. The primary analysis of overall survival varied across the papers. Fifty-nine (60%) mentioned subsequent treatments. Seven papers performed additional analysis, primarily when patients in the control arm received the experimental treatment during trial follow-up (treatment switching). Discussion: Overall survival has steadily moved from being the primary to a secondary endpoint. However, it is still of interest with papers presenting overall survival results with the caveat of subsequent treatments, but little or no investigation into their effect. This review shows that there is a methodological gap for what researchers should do when trial participants receive anti-cancer treatment during trial follow-up. Future research will identify the stakeholder opinions, on how this methodological gap should be addressed. [ABSTRACT FROM AUTHOR]

Background The Patient Cloud ePRO app was adopted by the National Cancer Institute National Clinical Trials Network (NCTN) to facilitate capturing electronic patient-reported (ePRO) outcome data, but use has been low. The study objectives were to test whether a patient-targeted ePRO educational resource (ePRO-E) would increase ePRO intent (number of users) and improve data quality (high quality: ≥80% of the required surveys submitted) within an ongoing NCTN study. Methods The ePRO-E intervention, a patient-targeted educational resource (written material and 6-minute animated YouTube video), was designed to address ePRO barriers. ePRO intent and data quality were compared between 2 groups (N  =   69): a historical control group and a prospectively recruited intervention group exposed to ePRO-E. Covariates included technology attitudes, age, sex, education, socioeconomic status, and comorbidity. Results Intervention group ePRO intent (78.8%) was statistically significantly higher than historical control group intent (47.1%) (P  =  .03). Patients choosing ePRO versus paper surveys had more positive and higher technology attitudes scores (P  =  .03). The odds of choosing ePRO were 4.7 times higher (95% Confidence Interval [CI] = 1.2 to 17.8) (P  =  .02) among intervention group patients and 5.2 times higher (95% CI = 1.3 to 21.6) (P = .02) among patients with high technology attitudes scores, after controlling for covariates. However, the 80% submission rate (percentage submitting ≥80% of required surveys) in the ePRO group (30.6%) was statistically significantly lower than in the paper group (57.9%) (P  =  .05). Conclusions ePRO-E exposure increased ePRO intent. High technology attitudes scores were associated with ePRO selection. Since the ePRO survey submission rate was low, additional strategies are needed to promote high-quality data submission. [ABSTRACT FROM AUTHOR]

Objectives: To compare and evaluate the occlusal variability/discrepancy recorded using qualitative (articulating paper) and quantitative (T-scan) techniques in partially edentulous implant-supported restorations. Materials and Methods: A total of 20 patients in the age group of 25-61 yrs participated in this study. All the patients had more than one tooth replaced with implant-supported prosthesis. After three months of restoration, occlusion reevaluated was carried out using qualitative (articulating paper) and quantitative (T-scan). T-scan data were used to measure implant occlusion time, occlusion time, and the relative occlusal force (ROFs) on implant prosthesis. And the data were statistically evaluated. Results: The T-scan values showed high points on the implants in most of the patients, which could not be evaluated by that of articulating paper outcomes. Conclusion: The occlusal harmony achieved from using qualitative analysis of articulating paper was not supported by the finding of the quantitative analysis (T-scan). Also the T-scan provided the time interval of occlusion of the implant-supported restorations, which would help in better defining the implant-protected occlusal. Clinical Relevance: The T-scan occlusal analysis system provides ROF and time intervals of occlusal contact. This allows accurate occlusal equilibration of implant-supported restoration according to implant protected occlusal concept. [ABSTRACT FROM AUTHOR]

In a large proportion of individuals with fronto-temporal lobar degeneration (FTLD), the underlying pathology is associated with the misfolding and aggregation of the microtubule associated protein tau (FTLD-tau). With disease progression, widespread protein accumulation throughout cortical and subcortical brain regions may be responsible for neurodegeneration. One of the syndromes of FTLD is the behavioral variant of frontotemporal dementia (bvFTD), in which the underlying pathology is heterogenous, with half of the cases being related to FTLD-tau. Currently, there are no approved disease-modifying treatments for FTLD-tau, therefore representing a major unmet therapeutic need. These descriptive, preliminary findings of the phase 1 open-label trial provide data to support the potential of sodium selenate to halt the cognitive and behavioral decline, as well as to reduce tau levels in a small group of participants with bvFTD (N = 11). All participants were treated with sodium selenate over a period of 52 weeks. Cognition was assessed with the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG, total scores), social cognition with the Revised Self-Monitoring Scale (RSMS, total scores), behavior with the Cambridge Behavioral Inventory (CBI), and carer burden with the Caregiver Buden Scale (CBS). Fluid biomarker measures include cerebrospinal fluid of total tau (t-tau), phosphorylated tau (p-tau181), NfL, p-tau181/t-tau, t-tau/Aβ1-42, and p-tau181/Aβ1-42 levels. After treatment at follow-up, cognition and behavior showed further negative change (based on a reliable change criterion cut-off of annual NUCOG decline) in the "progressors," but not in the "non-progressors." "Non-progressors" also showed elevated baseline CSF tau levels and no increase after treatment, indicating underlying tau pathology and a positive response to sodium selenate treatment. Significant changes in MRI were not observed. The findings provide useful information for future clinical trials to systematically assess the disease-modifying treatment effects of sodium selenate in randomized controlled designs for bvFTD and FTLD-tau pathologies. [ABSTRACT FROM AUTHOR]

Background: Following the initial identification of the 2019 coronavirus disease (covid-19), the subsequent months saw substantial increases in published biomedical research. Concerns have been raised in both scientific and lay press around the quality of some of this research. We assessed clinical research from major clinical journals, comparing methodological and reporting quality of covid-19 papers published in the first wave (here defined as December 2019 to May 2020 inclusive) of the viral pandemic with non-covid papers published at the same time. Methods: We reviewed research publications (print and online) from The BMJ, Journal of the American Medical Association (JAMA), The Lancet, and New England Journal of Medicine, from first publication of a covid-19 research paper (February 2020) to May 2020 inclusive. Paired reviewers were randomly allocated to extract data on methodological quality (risk of bias) and reporting quality (adherence to reporting guidance) from each paper using validated assessment tools. A random 10% of papers were assessed by a third, independent rater. Overall methodological quality for each paper was rated high, low or unclear. Reporting quality was described as percentage of total items reported. Results: From 168 research papers, 165 were eligible, including 54 (33%) papers with a covid-19 focus. For methodological quality, 18 (33%) covid-19 papers and 83 (73%) non-covid papers were rated as low risk of bias, OR 6.32 (95%CI 2.85 to 14.00). The difference in quality was maintained after adjusting for publication date, results, funding, study design, journal and raters (OR 6.09 (95%CI 2.09 to 17.72)). For reporting quality, adherence to reporting guidelines was poorer for covid-19 papers, mean percentage of total items reported 72% (95%CI:66 to 77) for covid-19 papers and 84% (95%CI:81 to 87) for non-covid. Conclusions: Across various measures, we have demonstrated that covid-19 research from the first wave of the pandemic was potentially of lower quality than contemporaneous non-covid research. While some differences may be an inevitable consequence of conducting research during a viral pandemic, poor reporting should not be accepted. [ABSTRACT FROM AUTHOR]

Background/aims: The value of using qualitative methods within clinical trials is widely recognised. How qualitative research is integrated within trials units to achieve this is less clear. This paper describes the process through which qualitative research has been integrated within Cardiff University's Centre for Trials Research (CTR) in Wales, UK. We highlight facilitators of, and challenges to, integration. Methods: We held group discussions on the work of the Qualitative Research Group (QRG) within CTR. The content of these discussions, materials for a presentation in CTR, and documents relating to the development of the QRG were interpreted at a workshop attended by group members. Normalisation Process Theory (NPT) was used to structure analysis. A writing group prepared a document for input from members of CTR, forming the basis of this paper. Results: Actions to integrate qualitative research comprised: its inclusion in Centre strategies; formation of a QRG with dedicated funding/roles; embedding of qualitative research within operating systems; capacity building/training; monitoring opportunities to include qualitative methods in studies; maximising the quality of qualitative research and developing methodological innovation. Facilitators of these actions included: the influence of the broader methodological landscape within trial/study design and its promotion of the value of qualitative research; and close physical proximity of CTR qualitative staff/students allowing sharing of methodological approaches. Introduction of innovative qualitative methods generated interest among other staff groups. Challenges included: pressure to under-resource qualitative components of research, preference for a statistical stance historically in some research areas and funding structures, and difficulties faced by qualitative researchers carving out individual academic profiles when working across trials/studies. Conclusions: Given that CTUs are pivotal to the design and conduct of RCTs and related study types across multiple disciplines, integrating qualitative research into trials units is crucial if its contribution is to be fully realised. We have made explicit one trials unit's experience of embedding qualitative research and present this to open dialogue on ways to operationalise and optimise qualitative research in trials. NPT provides a valuable framework with which to theorise these processes, including the importance of sense-making and legitimisation when introducing new practices within organisations. [ABSTRACT FROM AUTHOR]

In this study, a bibliometric analysis was carried out to identify the most influential clinical studies and research trends on anti-programmed cell death 1/programmed cell death 1 ligand 1 (anti-PD1/PDL1) immunotherapy. On January 1, 2022, we used Web of Science to identify the 100 most frequently cited papers on clinical studies investigating anti-PD1/PDL1 immunotherapy, and extracted the following data: publication year, source title, country/region, institution, and the total number of citations. The research design and area were classified independently by the authors. Subsequently, we carried out a bibliometric analysis to determine the trends and identify the major journals on anti-PD1/PDL1 immunotherapy. The authors analyzed the current research hotspots based on papers published in major journals from 2020 to 2021. These 100 papers were cited a total of 138,840 times, and the median number of citations was 899.5 (range: 341–7,983). "Safety, activity, and immune correlates of anti-PD-1 antibody in cancer" by Topalian et al. had the highest number of citations (7,983 times). New England Journal of Medicine had the highest number of top-cited papers (40 papers), average citations per paper (1,558.3 citations), and rate of top-cited papers (65.6%). Authors from the USA contributed most of the papers (76 papers). Lung cancer (30 papers, 46,422 citations) and melanoma (20 papers, 30,881 citations) were the most cited research areas. In summary, anti-PD1/PDL1 has become standard treatment for various cancer, while adjuvant anti-PD1/PDL1 therapy is currently a research hotspot. New England Journal of Medicine was identified as the most influential journal in this area. Non-small cell lung cancer and melanoma are the most well-studied cancers, while nivolumab and pembrolizumab are the most commonly investigated anti-PD1/PDL1 antibodies. Further studies are warranted to identify effective predictive biomarkers or models, clarify the molecular mechanism of combined therapy, and establish optimal therapeutic strategies. This study may assist researchers in obtaining a comprehensive impression of the landscape and current trends in anti-PD1/PDL1 immunotherapy and gain inspiration to conduct further studies. [ABSTRACT FROM AUTHOR]

In silico clinical trials (ISCTs) are an emerging method in modeling and simulation where medical interventions are evaluated using computational models of patients. ISCTs have the potential to provide cost-effective, time-efficient, and ethically favorable alternatives for evaluating the safety and effectiveness of medical devices. However, ensuring the credibility of ISCT results is a significant challenge. This paper aims to identify unique considerations for assessing the credibility of ISCTs and proposes an ISCT credibility assessment workflow based on recently published model assessment frameworks. First, we review various ISCTs described in the literature, carefully selected to showcase the range of methodological options available. These studies cover a wide variety of devices, reasons for conducting ISCTs, patient model generation approaches including subject-specific versus 'synthetic' virtual patients, complexity levels of devices and patient models, incorporation of clinician or clinical outcome models, and methods for integrating ISCT results with real-world clinical trials. We next discuss how verification, validation, and uncertainty quantification apply to ISCTs, considering the range of ISCT approaches identified. Based on our analysis, we then present a hierarchical workflow for assessing ISCT credibility, using a general credibility assessment framework recently published by the FDA's Center for Devices and Radiological Health. Overall, this work aims to promote standardization in ISCTs and contribute to the wider adoption and acceptance of ISCTs as a reliable tool for evaluating medical devices. Author summary: A new method for evaluating a medical device is an in silico clinical trial, where the device performance is tested using computational models representing a cohort of patients. Demonstrating that in silico clinical trials are reliable is clearly of paramount importance. However, little information is available on how to ensure this. In this paper we present a workflow for evaluating an in silico clinical trial. This workflow was developed by considering a wide-ranging sample of previously published in silico clinical trials, together with a detailed assessment of how specific model evaluation activities apply to in silico clinical trials. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis (TB) remains a leading cause of death worldwide, with 98% of cases occurring in low- and middle-income countries (LMICs). The only vaccine licenced for the prevention of TB has limited protection for adolescents, adults and vulnerable populations. A safe and effective vaccine for all populations at risk is imperative to achieve global elimination of TB. We aimed to systematically review the efficacy and safety of TB vaccine candidates in late-phase clinical trials conducted in LMICs. Methods: Medline, Embase, CENTRAL, PubMed, Clinicaltrials.gov and Greylit.org were searched in June 2021 to identify phase 2 or later clinical randomised controlled trials that report the efficacy or safety (adverse events) of TB vaccine candidates with participants of any age living in an LMIC. TB vaccine candidates listed in the 2020 WHO Global TB Report were eligible for inclusion aside from BCG revaccination. Trials were excluded if all participants had active TB at baseline. Two reviewers independently assessed papers for eligibility, and for bias and quality using the Risk of Bias 2 tool and GRADE guidelines, respectively. We report efficacy rates and frequencies of adverse events from each included trial where available and qualitatively synthesise the findings. Results: Thirteen papers representing eleven trials met our inclusion criteria. Seven vaccine candidates were reviewed across seven countries: M72/AS01, RUTI, VPM1002, H56:IC31, MTBVAC, DAR-901 and ID93 + GLA-SE. Two trials reported on efficacy: an efficacy rate of 54% (95% CI 11.5, 76.2) was reported for M72/AS01 in adults with latent TB and 3% (95% CI -13.9, 17.7) for DAR-901 in healthy adolescents. However, the latter trial was underpowered. All vaccine candidates had comparable occurrences of adverse events between treatment arms and demonstrated acceptable safety profiles; though, RUTI resulted in one serious complication in a person living with HIV. M72/AS01 was the only vaccine considered safe across a diverse group of people including people living with HIV or latent TB and healthy infants and adolescents. Conclusion: Further efficacy trials for M72/AS01 are warranted to include additional populations at risk where safety has been demonstrated. Further safety trials are needed for the remaining vaccine candidates to confirm safety in vulnerable populations. [ABSTRACT FROM AUTHOR]

Purpose: Electrotherapy is a common intervention for the rehabilitation of Bell's palsy. Lowlevel Laser Therapy (LLLT) and Electrical Stimulation (ES) are two therapeutic interventions for Bell's palsy that have been proven to be superior to conventional treatments. To date, no clinical trial has compared the effectiveness of these two interventions. This pilot study was done to compare the effectiveness of LLLT and ES in the management of acute Bell's palsy. Methods: This randomized clinical trial was done on 25 participants with acute Bell's palsy who were randomized into two groups with 12 participants that received LLLT and 13 participants that received ES. All participants received 12 treatment sessions over two weeks. Sunnybrook Facial Grading System (SFGS) was used to assess facial symmetry and Facial Disability Index (FDI) for facial function. Outcomes were assessed at baseline and after two weeks. Results: There was a significant improvement in SFGS and FDI scores within both groups (P<0.005). There was no significant difference in SFGS and FDI scores between groups (P=0.164; P=0.423). Conclusion: There is no difference between LLLT and ES in improving facial symmetry and function in acute Bell's palsy. [ABSTRACT FROM AUTHOR]

Thousands of clinical trials are conducted globally each year. Yet, little is known about their environmental impact. This paper presents the results of a high-level literature review of the carbon footprint of clinical trials. Five papers were identified and their contents summarised qualitatively. All papers were authored by UK researchers. Carbon footprint metrics from 14 trials were presented in carbon dioxide equivalents (CO2e). Emissions were broken down by three broadly defined clinical trial activities: operations, travel, and supplies. Recommen - dations for carbon reduction are discussed. The review showed a dearth of publications on greenhouse gas emissions generated by clinical trials. More work in this area is needed to achieve sustainable, low carbon clinical research. [ABSTRACT FROM AUTHOR]

Only two articles explicitly differentiated SAs from NSSIs, and one mentioned NSSI without going into any further details. All evaluated papers stated facts about suicide and/or SA, with an evident underlying assumption of a consensus on the nature and definition of such. The latter was done by searching for the term "self" in available texts - since mention of NSSI/deliberate self-harm (DSH)/self-harm/self-injury or self-injurious behavior would have this term contained within. [Extracted from the article]

Background: Poor representation of pregnant and lactating women and people in clinical trials has marginalised their health concerns and denied the maternal–fetal/infant dyad benefits of innovation in therapeutic research and development. This mixed-methods systematic review synthesised factors affecting the participation of pregnant and lactating women in clinical trials, across all levels of the research ecosystem. Methods and findings: We searched 8 databases from inception to 14 February 2024 to identify qualitative, quantitative, and mixed-methods studies that described factors affecting participation of pregnant and lactating women in vaccine and therapeutic clinical trials in any setting. We used thematic synthesis to analyse the qualitative literature and assessed confidence in each qualitative review finding using the GRADE-CERQual approach. We compared quantitative data against the thematic synthesis findings to assess areas of convergence or divergence. We mapped review findings to the Theoretical Domains Framework (TDF) and Capability, Opportunity, and Motivation Model of Behaviour (COM-B) to inform future development of behaviour change strategies. We included 60 papers from 27 countries. We grouped 24 review findings under 5 overarching themes: (a) interplay between perceived risks and benefits of participation in women's decision-making; (b) engagement between women and the medical and research ecosystems; (c) gender norms and decision-making autonomy; (d) factors affecting clinical trial recruitment; and (e) upstream factors in the research ecosystem. Women's willingness to participate in trials was affected by: perceived risk of the health condition weighed against an intervention's risks and benefits, therapeutic optimism, intervention acceptability, expectations of receiving higher quality care in a trial, altruistic motivations, intimate relationship dynamics, and power and trust in medicine and research. Health workers supported women's participation in trials when they perceived clinical equipoise, had hope for novel therapeutic applications, and were convinced an intervention was safe. For research staff, developing reciprocal relationships with health workers, having access to resources for trial implementation, ensuring the trial was visible to potential participants and health workers, implementing a woman-centred approach when communicating with potential participants, and emotional orientations towards the trial were factors perceived to affect recruitment. For study investigators and ethics committees, the complexities and subjectivities in risk assessments and trial design, and limited funding of such trials contributed to their reluctance in leading and approving such trials. All included studies focused on factors affecting participation of cisgender pregnant women in clinical trials; future research should consider other pregnancy-capable populations, including transgender and nonbinary people. Conclusions: This systematic review highlights diverse factors across multiple levels and stakeholders affecting the participation of pregnant and lactating women in clinical trials. By linking identified factors to frameworks of behaviour change, we have developed theoretically informed strategies that can help optimise pregnant and lactating women's engagement, participation, and trust in such trials. Using a mixed-methods approach, Mridula Shankar and colleagues investigate the reasons why those who are pregnant and breastfeeding are under-represented in clinical trials. Author summary: Why was this study done?: Pregnant and lactating women and people are routinely excluded from participating in drug and vaccine clinical trials, resulting in limited options for prevention and treatment of medical conditions. Challenges to including pregnant and lactating women and people in clinical research have been identified at multiple levels of the research and health systems, but the full range of barriers and facilitators to participation are not well known. What did the researchers do and find?: We conducted a mixed-methods systematic review and identified 60 research articles from 27 countries on the views and experiences of pregnant and lactating women's participation in clinical research, from the perspectives of cisgender women, family and community members, health workers, and people involved in the conduct of clinical research. Using a thematic synthesis approach, we identified barriers affecting participation including women having a limited appetite for risk during pregnancy and lactation, concerns about women's bodily autonomy during pregnancy, and challenges in obtaining ethical approval for clinical research with pregnant women. We also identified facilitators of participation including the potential for personal health benefits, expectations of higher quality care, trust in the medical and research systems, and strong teamwork between researchers and health workers. What do these findings mean?: Our findings demonstrate the need for multipronged strategies to address barriers and reinforce facilitators across the various levels of the research and health systems. The actions that are needed to overcome these barriers and reinforce facilitators must be discussed, prioritised, and adapted to specific contexts. All included studies focused on factors affecting participation of cisgender pregnant women in clinical trials; future research should consider other pregnancy-capable populations, including transgender and nonbinary people. [ABSTRACT FROM AUTHOR]

Background: Use of electronic methods to support informed consent ('eConsent') is increasingly popular in clinical research. This commentary reports the approach taken to implement electronic consent methods and subsequent experiences from a range of studies at the Leeds Clinical Trials Research Unit (CTRU), a large clinical trials unit in the UK. Main text: We implemented a remote eConsent process using the REDCap platform. The process can be used in trials of investigational medicinal products and other intervention types or research designs. Our standard eConsent system focuses on documenting informed consent, with other aspects of consent (e.g. providing information to potential participants and a recruiter discussing the study with each potential participant) occurring outside the system, though trial teams can use electronic methods for these activities where they have ethical approval. Our overall process includes a verbal consent step prior to confidential information being entered onto REDCap and an identity verification step in line with regulator guidance. We considered the regulatory requirements around the system's generation of source documents, how to ensure data protection standards were upheld and how to monitor informed consent within the system. We present four eConsent case studies from the CTRU: two randomised clinical trials and two other health research studies. These illustrate the ways eConsent can be implemented, and lessons learned, including about differences in uptake. Conclusions: We successfully implemented a remote eConsent process at the CTRU across multiple studies. Our case studies highlight benefits of study participants being able to give consent without having to be present at the study site. This may better align with patient preferences and trial site needs and therefore improve recruitment and resilience against external shocks (such as pandemics). Variation in uptake of eConsent may be influenced more by site-level factors than patient preferences, which may not align well with the aspiration towards patient-centred research. Our current process has some limitations, including the provision of all consent-related text in more than one language, and scalability of implementing more than one consent form version at a time. We consider how enhancements in CTRU processes, or external developments, might affect our approach. [ABSTRACT FROM AUTHOR]

Background and Objectives: Chloroquine and its analog hydroxychloroquine are derivatives of 4-aminoquinoline and are regularly used in the treatment of malaria and autoimmune diseases. Among the side effects of these drugs, alterations associated with the auditory system are frequently mentioned. Thus, the aim of this systematic review is to systematically review publications on hearing disorders and chloroquine or hydroxychloroquine use. Materials and Methods: Inclusion criteria were observational or interventional studies on audiological assessment in participants who were using chloroquine or hydroxychloroquine. The methodological quality was independently assessed by two reviewers using the Meta-Analysis of Statistics: assessment and review Instrument. The certainty of the evidence was assessed using the GRADE tool. Results: A total of 1,372 non-duplicate papers were screened, out of which 17 were included in the final qualitative synthesis, and 5 studies in the meta-analysis. The odds ratio for the two subgroups evaluated did not show significance with no heterogeneity between the effects observed between the different diseases (I²=0%) and obtaining the global estimate of 0.76 (95% confidence interval [CI]=0.41-1.39; p>0.05). Despite the inclusion of papers with different disease samples, the heterogeneity observed in the analysis was low (I²= 0%) and prediction interval (95% PI=0.32-1.80; p>0.05) remained close to that estimated by the CI (95% CI=0.41-1.39; p>0.05). The certainty of the evidence assessed by the GRADE tool was considered very low due to the risk of bias, indirect evidence, and imprecision. Conclusions: The findings of this study suggest that the use of chloroquine/hydroxychloroquine is not associated with hearing disorders. [ABSTRACT FROM AUTHOR]

Polypharmacy, the use of multiple and potentially inappropriate medications, is an increasing problem among older adults. The global polypharmacy prevalence is 34.6% in patients with COVID-19, and polypharmacy in COVID-19 increases with age. The present paper proposes that polypharmacy in older adults with COVID-19 and other comorbid conditions is linked to the medication outcome reporting bias of randomized controlled trials. Outcome reporting bias can occur when treatment efficacy is reported as relative risk reductions, which overestimates medication benefits and exaggerates disease/illness risk reductions compared to unreported absolute risk reductions. The comorbidities common in patients with COVID-19 include high blood pressure, cardiovascular disease, dementia or cerebrovascular disease, and diabetes. Accordingly, the present paper reassesses the relative and absolute risk reductions in clinical trials from a small convenience sample of antihypertension, statin, anticoagulant, and antihyperglycemic medications. Examples demonstrate a wide gap between reported relative risk reductions and unreported absolute risk reductions in medication clinical trials. This paper concludes that medication clinical trial outcome reporting bias is an important upstream factor that contributes to biased medication benefits and poor clinical decision making, leading to polypharmacy in older adults with COVID-19 and other comorbid conditions. Public health campaigns are urgently needed to educate the public about the link between polypharmacy and medication outcome reporting bias. [ABSTRACT FROM AUTHOR]

Introduction and aim. Alopecia areata is an autoimmune skin disease. It is characterized by the occurrence of transient or permanent alopecia foci, within which there are no inflammatory changes. About 20% have a positive family history, and symptoms can occur at any time in life. Progression of the disease can lead to complete hair loss of the scalp, eyebrows, eyelashes, pubic hair and other body hair. In the outpatient therapy of alopecia areata minoxidil, cygnoline or corticosteroid are routinely used. Corticosteroids can be used intralesionally, locally or systemically, but studies show that the route of administration does not affect the effectiveness of therapy. Additionally, after finishing the treatment, defluvinium showes again. Material and methods. In order to achieve the aim, the most important Four databases (PubMed, Google Scholar, Sciencedirect, Medscape) were systematically searched for studies published from January 2016 to March 2023 in English.The search terms were "alopecia areata JAK-STAT inhibitors", "baricitinib" "tofacytynib" "laser therapy" in the title or abstract or as keywords. A total of 54 references, excluding duplicates, were identified. Analysis of literature. JAK-2-STAT inhibitors stands as the most extensively researched group of drugs. There have been many clinical studies of JAK inhibitor efficacy in treating AA, most of which used oral medications and a few studies using topical formulations. The oral formulations had dramatic outcomes with hair regrowth in about 67--75% of patients in several. Furthermore, ongoing research is being conducted regarding the potential application of topical acid dibutyl ester, non-ablative fractional laser at a wavelength of 1565nm, and the stimulation of TREg lymphocytes for the management of alopecia areata. Conclusion. Determining the most optimal treatment for alopecia areata (AA) presents a considerable challenge. Among the various categories of drugs extensively investigated for this condition, the JAK-STAT inhibitors have garnered significant attention. [ABSTRACT FROM AUTHOR]

Background and Aims: The COVID‐19 pandemic has changed people's lifestyles as well as the way healthcare services are delivered. Undoubtedly, the difficulties associated with COVID‐19 infection and rehabilitation and those associated with quarantine and viral preventive efforts may exacerbate the need for virtual reality to be used as a part of a complete rehabilitation strategy for these individuals. Thus, the present research aimed to evaluate the potential uses of virtual reality for the rehabilitation of individuals suffering from COVID‐19. Methods: From 2019 to March 1, 2022, a systematic search was conducted in PubMed, Cochran Library, Scopus, Science Direct, ProQuest, and Web of Science databases. The papers were selected based on search terms and those that discussed the use of virtual reality in the rehabilitation of COVID‐19 patients were reviewed. Each step of the study was reviewed by two authors. Results: A total of 699 papers were found during the first search. Three papers were chosen for further investigation after a thorough evaluation of the publications' titles, abstracts, and full texts. Cross‐sectional studies, randomized controlled clinical trials, and case reports comprised 33%, 33%, and 33% of the publications, respectively. Based on the results, people suffering from COVID‐19 were the focus of two papers (66%) that employed immersion virtual reality for cognitive rehabilitation, whereas one study (33%) used non‐immersive virtual reality for physical rehabilitation. In two papers (66%), virtual reality was also offered to patients in the form of a game. Conclusion: According to the results of the present research, virtual reality games may enhance functional and cognitive consequences, contentment levels among patients, and their ability to take charge of their own health care. In light of the obstacles faced by COVID‐19 patients, alterations in the delivery of healthcare, and the significance of rehabilitation in this group during quarantine, new techniques have been considered for these patients to maintain treatment, return to regular life, and enhance their standard of life. [ABSTRACT FROM AUTHOR]

Background: In the U.S. there are significant racial and gender disparities in the uptake of pre-exposure prophylaxis (PrEP). Black Americans represented 14% of PrEP users in 2022, but accounted for 42% of new HIV diagnoses in 2021 and in the South, Black people represented 48% of new HIV diagnoses in 2021 but only 21% of PrEP users in 2022. Women who use drugs may be even less likely than women who do not use drugs have initiated PrEP. Moreover, women involved in community supervision programs (CSP) are less likely to initiate or use PrEP, More PrEP interventions that focus on Black women with recent history of drug use in CSPs are needed to reduce inequities in PrEP uptake. Methods: We conducted a secondary analysis from a randomized clinical trial with a sub-sample (n = 336) of the total (N = 352) participants from the parent study (E-WORTH), who tested HIV negative at baseline were considered PrEP-eligible. Black women were recruited from CSPs in New York City (NYC), with recent substance use. Participants were randomized to either E-WORTH (n = 172) an HIV testing plus, receive a 5-session, culturally-tailored, group-based HIV prevention intervention, versus an HIV testing control group (n = 180). The 5 sessions included an introduction to PrEP and access. This paper reports outcomes on improved awareness of PrEP, willingness to use PrEP, and PrEP uptake over the 12-month follow-up period. HIV outcomes are reported in a previous paper. Results: Compared to control participants, participants in this study assigned to E-WORTH had significantly greater odds of being aware of PrEP as a biomedical HIV prevention strategy (OR = 3.25, 95% CI = 1.64–6.46, p = 0.001), and indicated a greater willingness to use PrEP as an HIV prevention method (b = 0.19, 95% CI = 0.06–0.32, p = 0.004) over the entire 12-month follow-up period. Conclusions: These findings underscore the effectiveness of a culturally-tailored intervention for Black women in CSP settings in increasing awareness, and intention to initiate PrEP. Low uptake of PrEP in both arms highlight the need for providing more robust PrEP-on-demand strategies that are integrated into other services such as substance abuse treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02391233. [ABSTRACT FROM AUTHOR]

Biostatistics plays a pivotal role in developing, interpreting and drawing conclusions from clinical, biological and epidemiological data. However, the improper application of statistical methods can lead to erroneous conclusions and misinterpretations. This paper provides a comprehensive examination of the most frequent mistakes encountered in the biostatistical analysis process. We identified and elucidated 10 common errors in biostatistical analysis. These include using the wrong metric to describe data, misinterpreting P -values, misinterpreting the 95% confidence interval, misinterpreting the hazard ratio as an index of prognostic accuracy, ignoring the sample size calculation, misinterpreting analysis by strata in randomized clinical trials, confusing correlation and causation, misunderstanding confounders and mediators, inadequately codifying variables during the data collection, and bias arising when group membership is attributed on the basis of future exposure in retrospective studies. We discuss the implications of these errors and propose some practical strategies to mitigate their impact. By raising awareness of these pitfalls, this paper aims to enhance the rigor and reproducibility of biostatistical analyses, thereby fostering more robust and reliable biomedical research findings. [ABSTRACT FROM AUTHOR]

Background: In light of the FDA's Project Optimus initiative, there is fresh interest in leveraging Patient-reported Outcome (PRO) data to enhance the assessment of tolerability for investigational therapies within early phase dose-finding oncology trials. Typically, dose escalation in most trial designs is solely reliant on clinician assessed adverse events. Research has shown a disparity between patients and clinicians when assessing whether an investigational therapy is tolerable, leading to the recommendation of potentially intolerable doses for further investigation in subsequent trials. It is also increasingly recognized that patient and public involvement and engagement (PPIE) plays a pivotal role in enriching trial design and conduct. However, to our knowledge, no PPIE has explored the optimal integration of PROs in the development of advanced statistical trial designs within early phase dose-finding oncology trials. Methods: A virtual PPIE session was held with nine participants on 18th October 2023 to discuss the incorporation of PROs within a dose-finding trial design. This cross disciplinary session was developed and led by a team of statisticians, clinical specialists, qualitative experts, and trial methodologists. Following the session, in-depth perspectives were provided by two patient advocates who actively engaged in the PPIE session. We discuss the importance of PPIE in shaping advanced dose-finding trial designs, share insights from patients on integrating PROs to inform treatment tolerability, and present a template for meaningful patient involvement in trial design development. Results: Participants generally supported the introduction of PROs within dose-finding trials but showed some apprehensiveness as to how PROs may reduce the size of the recommended dose (and potentially efficacious effect). Some participants shared that they may be reluctant to record the real severity of their symptoms via PROs if it would mean that they would have to discontinue treatment. They discussed that PROs could be used to assess tolerability rather than toxicity of a dose. Conclusions: Amplifying patient voice in the development of patient-centric dose-finding trial designs is now essential. This paper offers an exemplary illustration of how trialists and methodologists can effectively incorporate patient voice in the future development of advanced dose-finding trial designs. Plain English summary: The aim of dose-finding oncology trials is to make sure a treatment is safe, understand its side effects, and recommend the right dose (or doses) for future clinical trials. Traditionally, a patient's tolerance to treatment is assessed by doctors who evaluate toxicities (side-effects) using established grading guidelines. Research has shown that doctors might not identify all the side effects that patients actually experience during a trial. There is growing interest in the introduction of patient-reported outcomes (PROs) within dose-finding trials. PROs are reports of a patient's health and well-being experiences which come directly from the patient themselves, usually assessed using a questionnaire. In a dose-finding trial, we start with a low dose of a drug and increase it until too many patients have severe side effects. The highest safe dose is then investigated in a later phase trial. We are suggesting a new way to do these trials. We want to look at both what doctors see as severe side effects and what patients say. This enables us to recommend a dose that balances both perspectives. We would also like to ask patients what level of risk they are comfortable with regarding severe side effects. In this paper, we highlight the importance of involving patients in creating advanced dose-finding trial designs, particularly with PROs to help decide whether a dose is tolerable for patients. We also share findings of a patient and public involvement and engagement session and provide a guide for meaningful patient involvement in developing trial designs. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) hold great promise for clinical application as new diagnostic and therapeutic modalities. This paper describes major GMP-based upstream and downstream manufacturing processes for EV large-scale production, also focusing on post-processing technologies such as surface bioengineering and uploading studies to yield novel EV-based diagnostics and advanced therapy medicinal products. This paper also focuses on the quality, safety, and efficacy issues of the bioengineered EV drug candidates before first-in-human studies. Because clinical trials involving extracellular vesicles are on the global rise, this paper encompasses different clinical studies registered on clinical-trial register platforms, with varying levels of advancement, highlighting the growing interest in EV-related clinical programs. Navigating the regulatory affairs of EVs poses real challenges, and obtaining marketing authorization for EV-based medicines remains complex due to the lack of specific regulatory guidelines for such novel products. This paper discusses the state-of-the-art regulatory knowledge to date on EV-based diagnostics and medicinal products, highlighting further research and global regulatory needs for the safe and reliable implementation of bioengineered EVs as diagnostic and therapeutic tools in clinical settings. Post-marketing pharmacovigilance for EV-based medicinal products is also presented, mainly addressing such topics as risk assessment and risk management. [ABSTRACT FROM AUTHOR]

Effective clinical trials are necessary for understanding medical advances but early termination of trials can result in unnecessary waste of resources. Survival models can be used to predict survival probabilities in such trials. However, survival data from clinical trials are sparse, and DeepSurv cannot accurately capture their effective features, making the models weak in generalization and decreasing their prediction accuracy. In this paper, we propose a survival prediction model for clinical trial completion based on the combination of denoising autoencoder (DAE) and DeepSurv models. The DAE is used to obtain a robust representation of features by breaking the loop of raw features after autoencoder training, and then the robust features are provided to DeepSurv as input for training. The clinical trial dataset for training the model was obtained from the ClinicalTrials.gov dataset. A study of clinical trial completion in pregnant women was conducted in response to the fact that many current clinical trials exclude pregnant women. The experimental results showed that the denoising autoencoder and deep survival regression (DAE‐DSR) model was able to extract meaningful and robust features for survival analysis; the C‐index of the training and test datasets were 0.74 and 0.75 respectively. Compared with the Cox proportional hazards model and DeepSurv model, the survival analysis curves obtained by using DAE‐DSR model had more prominent features, and the model was more robust and performed better in actual prediction. [ABSTRACT FROM AUTHOR]

The article presents the discussion on health and social care professionals being able to critically appraise quantitative research. Topics include considering the main elements of critiquing quantitative methodology focussing on elements of randomised controlled trials (RCTs); and determining the size of the sample using for the study as well as the number splitting into the cases and controls.

Background: Severe and enduring anorexia nervosa (SE-AN) is amongst the most impairing of all mental illnesses. Collective uncertainties about SE-AN nosology impacts treatment refinement. Qualitative research, particularly lived experience literature, can contribute to a process of revision and enrichment of understanding the SE-AN experience and further develop treatment interventions. Poor outcomes to date, as evidenced in clinical trials and mortality for people with SE-AN (1 in 20) demonstrate the need for research that informs conceptualisations and novel treatment directions. This interpretative, meta-ethnographic meta-synthesis aimed to bridge this gap. Methods: A systematic search for qualitative studies that explored the AN experiences of people with a duration of greater than 3 years was undertaken. These studies included those that encompassed phenomenology, treatment experiences and recovery. Results: 36 papers, comprising 382 voices of SE-AN experiences informed the meta-ethnographic findings. Four higher order constructs were generated through a synthesis of themes and participant extracts cited in the extracted papers: (1) Vulnerable sense of self (2) Intra-psychic processes (3) Global impoverishment (4) Inter-psychic temporal processes. Running across these meta-themes were three cross cutting themes (i) Treatment: help versus harm, (ii) Shifts in control (iii) Hope versus hopelessness. These meta-themes were integrated into conceptualisations of SE-AN that was experienced as a recursive process of existential self-in-relation to other and the anorexia nervosa trap. Conclusions: The alternative conceptualisation of SE-AN proposed in this paper poses a challenge to current conceptualisations of AN and calls for treatments to engage with the complex intra and inter-psychic processes of the SE-AN, more fully. In doing so, clinicians and researchers are asked to continue to be bold in testing novel ideas that may challenge our own rigidity and attachment to dominant paradigms to best serve the individual person with SE-AN. The 'global impoverishment of self', found in this synthesis of AN experiences, should inform proposed diagnostic criteria for SE-AN. [ABSTRACT FROM AUTHOR]

The Declaration of Helsinki is a set of ethical principles to be followed by scientists involved in medical research with humans or human cells and tissues. This Declaration defines how scientific research should be planned, conducted, documented, analysed, and published. We summarise and discuss some ethical issues related to publishing original articles, including clinical trials, review papers, and case reports based on the seventh revision of the Declaration of Helsinki. The principles of the Declaration of Helsinki refer primarily to the publication of medical research results, in particular clinical trials, as original articles. Such papers are required to meet several ethical requirements, particularly the study protocol transparency and the presentation of the results. In terms of case reports, the bioethical aspects related to their publication are twofold - they need to include informed and voluntary consent and the confidentiality of study participants. The review papers are of the least bioethical concern. However, whether patients' agreements with specific studies are valid if the data are used in meta-analyses is uncertain. Adherence to ethical policies and standards helps to ensure the highest possible quality of scientific publications. Responsibility for compliance with the Declaration of Helsinki lies not only with the authors preparing their manuscripts, but also with the editorial board and reviewers, who must evaluate the ethical soundness of the submitted papers. The additional guidelines for the different types of studies facilitate the implementation of the Declaration principles. [ABSTRACT FROM AUTHOR]

In the article, the authors discuss the evolution of clinical trials from the use of papyrus to technology-driven data collection solutions. Other topics include the need to ensure data quality and integrity (DQI), the need for the pharmaceutical industry and regulators to refrain from using paper-based processes as gold standards, and the claim that the first clinical trial was conducted by King Nebuchadnezzar of Babylon as recorded in the Bible book of Daniel.

Background: The SAVVY project aims to improve the analyses of adverse events (AEs) in clinical trials through the use of survival techniques appropriately dealing with varying follow-up times and competing events (CEs). This paper summarizes key features and conclusions from the various SAVVY papers. Methods: Summarizing several papers reporting theoretical investigations using simulations and an empirical study including randomized clinical trials from several sponsor organizations, biases from ignoring varying follow-up times or CEs are investigated. The bias of commonly used estimators of the absolute (incidence proportion and one minus Kaplan-Meier) and relative (risk and hazard ratio) AE risk is quantified. Furthermore, we provide a cursory assessment of how pertinent guidelines for the analysis of safety data deal with the features of varying follow-up time and CEs. Results: SAVVY finds that for both, avoiding bias and categorization of evidence with respect to treatment effect on AE risk into categories, the choice of the estimator is key and more important than features of the underlying data such as percentage of censoring, CEs, amount of follow-up, or value of the gold-standard. Conclusions: The choice of the estimator of the cumulative AE probability and the definition of CEs are crucial. Whenever varying follow-up times and/or CEs are present in the assessment of AEs, SAVVY recommends using the Aalen-Johansen estimator (AJE) with an appropriate definition of CEs to quantify AE risk. There is an urgent need to improve pertinent clinical trial reporting guidelines for reporting AEs so that incidence proportions or one minus Kaplan-Meier estimators are finally replaced by the AJE with appropriate definition of CEs. [ABSTRACT FROM AUTHOR]

Background: While acupuncture treatment has gained extensive usage in addressing headaches, there remains a notable gap in the literature analysis for this field. Therefore, this study aims to conduct a literature review using Citespace, VOSviewer, and Bibliometrix, aiming to examine the current status, strengths, and potential future directions in the utilization of acupuncture for headache treatment. Methods: Relevant literature on acupuncture treatment for headaches between 2003 and 2023 was retrieved from the Web of Science (WoS) core database. Utilizing CiteSpace 6.1.R6, VOSviewer 1.6.18, and Bibliometrix 4.1.4, we conducted bibliometric analyses across various categories, including countries/regions, institutions, authors, journals, references, and keywords. Results: A total of 808 research reports were included. China and the United States have significantly contributed to this field. Chengdu University of Chinese Medicine holds the record for the highest number of published papers. Liu Lu has the highest publication output, while Linde K has the highest citation rate. MEDICINE leads in publication frequency, while CEPHALALGIA holds the highest citation rate. The Long-term Effect of Acupuncture for Migraine Prophylaxis a Randomized Clinical Trial is the most cited reference. Migraine was the most researched type. Filiform needle acupuncture was the most widely used stimulation method. The safety and efficacy of acupuncture have received significant attention. Modern mechanism research shows that depression, brain functional connectivity, and neuroimaging technology have become research hotspots in the acupuncture treatment of headaches. Conclusion: Acupuncture treatment for headaches has established a stable trend with a promising developmental trajectory. Research in this field mainly focuses on different acupuncture prevention and treatment for various types of headaches, the safety and efficacy of acupuncture, etc. Research on the mechanism of action mainly focuses on interpreting bidirectional and holistic regulation between pain and emotion by acupuncture and the regulation of brain function connection and neuroimaging technology by acupuncture. Future research should expand on the advantages and indications of acupuncture treatment for different headaches and their modern mechanisms. [ABSTRACT FROM AUTHOR]

Simple Summary: Metformin is one of the most widely used drugs in the world, since its first use in the second part of the 1950s in France (Aron, 1957) and in the United Kingdom (Rona, 1958), and is on the World Health Organization's List of Essential Medicines. Traditionally, metformin is used in diabetes mellitus, mainly in overweight and obese subjects, but also in other conditions of impaired glucose metabolism, such as insulin resistance. In recent years, in vitro and in vivo data on this molecule as an antiproliferative modulator have suggested a series of clinical trials in several tumors that—at the moment—have not confirmed the expected positive results. The aim of this paper is to offer a double vision of this molecule, with a very light side about the metabolic aspects and a darker side concerning its antineoplastic activity, focusing on molecular and subcellular pathways involved in both fields and discussing the contrast between preliminary cellular data and real clinical outcomes in different neoplasms. The ancient Roman god Ianus was a mysterious divinity with two opposite faces, one looking at the past and the other looking to the future. Likewise, metformin is an "old" drug, with one side looking at the metabolic role and the other looking at the anti-proliferative mechanism; therefore, it represents a typical and ideal bridge between diabetes and cancer. Metformin (1,1-dimethylbiguanidine hydrochloride) is a drug that has long been in use for the treatment of type 2 diabetes mellitus, but recently evidence is growing about its potential use in other metabolic conditions and in proliferative-associated diseases. The aim of this paper is to retrace, from a historical perspective, the knowledge of this molecule, shedding light on the subcellular mechanisms of action involved in metabolism as well as cellular and tissue growth. The intra-tumoral pharmacodynamic effects of metformin and its possible role in the management of different neoplasms are evaluated and debated. The etymology of the name Ianus is probably from the Latin term ianua, which means door. How many new doors will this old drug be able to open? [ABSTRACT FROM AUTHOR]

According to an article in Pulse International, China is expected to become the world leader in research and clinical trials by 2025. Currently, the United States and China publish the most research papers, but China's progress in various fields, including clinical trials, is rapidly increasing. Other countries such as Japan, South Korea, Brazil, and India are also making significant advancements in clinical trials. The article emphasizes the importance of collaboration between academia and the pharmaceutical industry for successful clinical trials and the need for biotechnology plants in Pakistan. The author also discusses the different phases of clinical trials and the challenges faced in conducting research. The article concludes by highlighting the importance of integrity, ethics, and transparency in research, as well as the potential economic benefits of clinical research organizations. [Extracted from the article]

Purpose: Family-based treatment (FBT) has contributed significantly to the treatment of anorexia nervosa (AN) in young people (YP). However, parents are concerned that FBT and the active role of parents in the task of refeeding may have a negative impact on family relations. The aim of the review is to assess whether families engaged in FBT for AN are more or less impacted in their family wellbeing and caregiver burden, compared to families with a YP diagnosed with AN, who are not undergoing treatment with FBT. Method: Computerized searches across six databases complemented by a manual search resulted in 30 papers being included in the scoping review. Results: The review identified 19 longitudinal studies on change in family wellbeing in families in FBT-like treatments, and 11 longitudinal studies on change in family wellbeing in treatment where parents are not in charge of refeeding. Only three randomized controlled studies directly compare FBT to treatment without parent-led refeeding. Conclusion: The available research suggests no difference between intervention types regarding impact on family wellbeing. Approximately half of the studies find improvements in family wellbeing in both treatment with and without parent-led refeeding, while the same proportion find neither improvement nor deterioration. As parents play a pivotal role in FBT, there is a need for good quality studies to elucidate the impact of FBT on family wellbeing. Level of evidenceLevel V: Opinions of authorities, based on descriptive studies, narrative reviews, clinical experience, or reports of expert committees. [ABSTRACT FROM AUTHOR]

According to Prof. Javed Akram, President of the Pakistan Society of Internal Medicine, China is expected to become the world leader in research and clinical trials by 2025. Currently, the United States and China publish the most research papers, but China's progress in these fields is significant. Other countries, such as Japan, South Korea, Brazil, and India, are also prioritizing clinical trials. Prof. Akram emphasized the importance of collaboration between academia and the pharmaceutical industry for successful clinical trials and research publications. He also discussed various clinical trials conducted in Pakistan, including those related to COVID-19 and the need for biotechnology plants. Prof. Akram highlighted the phases of clinical trials, the challenges faced, and the importance of integrity, ethics, and transparency in research. [Extracted from the article]