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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]

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]

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]

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]

Introduction: Flexibility is an essential component of muscle function, and insufficient muscle flexibility may lead to muscle injuries. Decreased hamstring flexibility is one of the frequently reported risk factors for a hamstring strain and diminished athletic performance. Stretching is a commonly used intervention for increasing muscle length. There is a lack of evidence concerning the possible effects of hamstring stretching in balance and gait biomechanics. So, this study was designed to investigate the potential effects of static hamstring stretching on the range of motion (ROM), dynamic balance, and biomechanical variables of gait in athletes with hamstring tightness. Materials and Methods: This study is a single-group, pretest-posttest clinical trial performed on semi-professional female athletes. Twelve female athletes aged 20 to 35 years with bilateral hamstring tightness received a single session of unilateral static hamstring stretching on their randomly selected side. All subjects were assessed for straight leg raise, popliteal angle (using standard goniometry), perceived hamstring tightness (using a visual analog scale). They completed single-leg standing and 15-m walking and running tasks before and immediately after the intervention. The biomechanical parameters, including gait-line length, swing duration, and stance duration in walking tasks, maximum total force and mean total force in running task, and center of pressure (COP) displacement and standard deviation during balance task were measured using OpenGo sensor insole system. The pre-post values were compared using the paired sample t-test, and the level of significance was 0.05. Results: The values for straight leg raise and popliteal angle significantly increased (P<0.05) compared with the baseline, while perceived tightness significantly decreased following stretching (P<0.001). The amplitude (P₌0.006) and standard deviation (P₌0.016) of COP displacement in the mediolateral direction during the single leg stance balance task were significantly decreased after the intervention. Stance duration in slow walking (P₌0.004), as well as stance duration (P₌0.012) and swing duration (P<0.001) in fast walking, were significantly decreased (P<0.05) after stretching. No change was observed in gait biomechanical variables during the running test (P>0.05). Conclusion: The results of this study indicate that static hamstring stretching can be a promising intervention not just for increasing hamstring flexibility but also for improving balance ability. [ABSTRACT FROM AUTHOR]

Great expectations have been set around the clinical potential of regenerative and reparative medicine in the treatment of cardiovascular diseases [i.e. in particular, heart failure (HF)]. Initial excitement, spurred by encouraging preclinical data, resulted in a rapid translation into clinical research. The sobering outcome of the resulting clinical trials suggests that preclinical testing may have been insufficient to predict clinical outcome. A number of barriers for clinical translation include the inherent variability of the biological products and difficulties to develop potency and quality assays, insufficient rigour of the preclinical research and reproducibility of the results, manufacturing challenges, and scientific irregularities reported in the last years. The failure to achieve clinical success led to an increased scrutiny and scepticism as to the clinical readiness of stem cells and gene therapy products among clinicians, industry stakeholders, and funding bodies. The present impasse has attracted the attention of some of the most active research groups in the field, which were then summoned to analyse the position of the field and tasked to develop a strategy, to re-visit the undoubtedly promising future of cardiovascular regenerative and reparative medicine, based on lessons learned over the past two decades. During the scientific retreat of the ESC Working Group on Cardiovascular Regenerative and Reparative Medicine (CARE) in November 2018, the most relevant and timely research aspects in regenerative and/or reparative medicine were presented and critically discussed, with the aim to lay out a strategy for the future development of the field. We report herein the main ideas and conclusions of that meeting. [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]

Introduction: Sustained Attention (SA) failure is one of the main characteristics of Specific Learning Disorders (SLD). Recent studies have reported a positive effect of Cognitive Rehabilitation (CR) and Neurofeedback (NFB) on SA in SLD. Thus, the effectiveness of CR and NFB is well understood. This preliminary study aimed to compare the effects of CR and NFB on SA among the elementary school students with SLD, using a randomized controlled clinical trial. Methods: In this preliminary randomized controlled clinical trial, 53 eligible students with SLD (based on DSM-5) within the age range of 7 to 10 years were randomly assigned in the NFB (n=18), CR (n=18), and control group (n=17). All the participants were evaluated for SA using the Continuous Performance Test (CPT), at the time of entry to the study, and one month later. The intervention groups participated in 20 sessions of CR and 20 sessions of NFB, while the control group was evaluated without any intervention. Results: A total number of 24 boys and 36 girls in four groups (n=15) completed the study. The Mean±SD age of the participants in the CR, NFB, and control groups were 8.66±1.48 years, 8.40±1.73 years, and 8.53±1.63 years, respectively. Results showed a significant difference in the variables of the CPT between the study groups (P<0.05). Also, the CPT scores of the CR group were higher than that of the NFB group (P<0.001). Conclusion: This study supports that CR is more effective than NFB on SA in students with SLD. [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]

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]

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]

Summary: After more than 120 hand‐upper extremity and 37 face transplant procedures performed worldwide, vascularized composite allotransplantation (VCA) now falls under the scope of organ transplant legislation in Europe and the United States. While in the USA, VCA has been considered as standard care since 2014, VCA in Europe is still performed through clinical research trials, except in United Kingdom. However, after two decades of favourable experience with upper extremity transplantation (UET), professionals in Europe are proposing hand allotransplantation as "controlled standard" care, as opposed to face transplantation (FT), which is still a challenging activity. The European Committee on Organ Transplantation (CD‐P‐TO) has elaborated a position paper to provide recommendations concerning regulatory aspects for UET and FT. It is aimed at Health Authorities in charge of the oversight – and coordination – of organ donation and transplantation, and at professional groups to help them manage such complex and costly programs dedicated to properly selected patients. [ABSTRACT FROM AUTHOR]

Abstract Background Our current understanding of the pathophysiology and management of sepsis is associated with a lack of progress in clinical trials, which partly reflects insufficient appreciation of the heterogeneity of this syndrome. Consequently, more patient-specific approaches to treatment should be explored. Aims To summarize the current evidence on precision medicine in sepsis, with an emphasis on translation from theory to clinical practice. A secondary objective is to develop a framework enclosing recommendations on management and priorities for further research. Sources A global search strategy was performed in the MEDLINE database through the PubMed search engine (last search December 2017). No restrictions of study design, time, or language were imposed. Content The focus of this Position Paper is on the interplay between therapies, pathogens, and the host. Regarding the pathogen, microbiologic diagnostic approaches (such as blood cultures (BCs) and rapid diagnostic tests (RDTs)) are discussed, as well as targeted antibiotic treatment. Other topics include the disruption of host immune system and the use of biomarkers in sepsis management, patient stratification, and future clinical trial design. Lastly, personalized antibiotic treatment and stewardship are addressed (Fig. 1). Implications A road map provides recommendations and future perspectives. RDTs and identifying drug-response phenotypes are clear challenges. The next step will be the implementation of precision medicine to sepsis management, based on theranostic methodology. This highly individualized approach will be essential for the design of novel clinical trials and improvement of care pathways. [ABSTRACT FROM AUTHOR]

Introduction: The purpose of this study was to investigate the effects of shortened-length versus through-range exercise training on upper quarter posture in primary school students with Forward Head Posture (FHP). Materials and Methods: Sixty pain-free participants with FHP were randomly allocated to one of three groups; shortened-length training (n=20), through-range training (n=20), and notreatment control group (n=20). The shortened-length and through-range groups participated in training programs 3 times per week for 8 weeks. Upper quarter postures, including Craniovertebral Angle (CVA), Shoulder Angle (SA), Cranial Angle (CA), and thoracic kyphosis were measured by photogrammetry before and after the training. The confidence level was set at 95% (P<0.05). Results: After training, both exercise groups showed significant changes in CVA (P=0.001), SA (P=0.001), CA (P=0.001), and thoracic kyphosis (P=0.001) compared to the control group. Besides, CVA changed more in the shortened-length exercise group compared to the throughrange exercise group (P=0.003) (effect size =0.446). Conclusion: Both through-range and shortened-length exercises altered upper quarter alignment. The shortened-length training resulted in a more significant change in CVA. These changes were small, and more studies are needed to investigate the effects of such training programs among people with pain. [ABSTRACT FROM AUTHOR]

Introduction: Lumbar stiffness is a common complaint of patients with low back pain. The Muscle Energy Technique (MET) is a common intervention to treat the spine and sacroiliac joint dysfunctions and their resulting disability in daily activities. This research aimed to evaluate the effects of MET on pain, functional disability, and lumbar stiffness of patients with sacroiliac joint dysfunctions by considering the type of dysfunction and the orientation of the correcting maneuver. Materials and Methods: Fifty women with ant innominate or post innominate dysfunctions were recruited for the research and randomly divided into two groups (n=25). One group received one session of MET, and the other group received the sham position. Visual Analogue Scale (VAS), lumbar Stiffness Disability Index (SDI) and Oswestry Disability Index (ODI) were used for the evaluation of the participants before, 24 hours after and one week after the intervention. Results: According to the results, MET significantly decreased the mean range of VAS and ODI, 24 hours, and a week after the intervention (P<0.01). We did not see any significant difference in SDI values before, 24 hours, and one week after MET in the patients (P>0.01). Conclusion: Applying MET regarding the kind of dysfunction may reduce the patient's pain and disability. [ABSTRACT FROM AUTHOR]

Modulation of vessel growth holds great promise for treatment of cardiovascular disease. Strategies to promote vascularization can potentially restore function in ischaemic tissues. On the other hand, plaque neovascularization has been shown to associate with vulnerable plaque phenotypes and adverse events. The current lack of clinical success in regulating vascularization illustrates the complexity of the vascularization process, which involves a delicate balance between pro- and anti-angiogenic regulators and effectors. This is compounded by limitations in the models used to study vascularization that do not reflect the eventual clinical target population. Nevertheless, there is a large body of evidence that validate the importance of angiogenesis as a therapeutic concept. The overall aim of this Position Paper of the ESC Working Group of Atherosclerosis and Vascular biology is to provide guidance for the next steps to be taken from pre-clinical studies on vascularization towards clinical application. To this end, the current state of knowledge in terms of therapeutic strategies for targeting vascularization in post-ischaemic disease is reviewed and discussed. A consensus statement is provided on how to optimize vascularization studies for the identification of suitable targets, the use of animal models of disease, and the analysis of novel delivery methods. [ABSTRACT FROM AUTHOR]

This is a position paper of the Radiopharmacy Committee of the EANM (European Association of Nuclear Medicine) addressing toxicology studies for application of new diagnostic and therapeutic radiopharmaceuticals (RP) that are not approved (i.e., not having a marketing authorization or a monograph in the European Pharmacopoeia), excluding endogenous and ubiquitous substances in humans. This paper discusses the requirements for clinical trials with radiopharmaceuticals for clinical research applications, not necessarily intended to aim at a marketing authorization. If marketing authorization is intended, scientific advice of the competent authorities is mandatory and cannot be replaced by this position paper. The position paper reflects the view of the Radiopharmacy Committee of the EANM and can be used as a basis for discussions with the responsible authorities. [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]

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]

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/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]

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]

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]

Background Lyme borreliosis (LB) is a tick-borne infection caused by Borrelia burgdorferi sensu lato . The most frequent clinical manifestations are erythema migrans and Lyme neuroborreliosis. Currently, a large volume of diagnostic testing for LB is reported, whereas the incidence of clinically relevant disease manifestations is low. This indicates overuse of diagnostic testing for LB with implications for patient care and cost-effective health management. Aim The recommendations provided in this review are intended to support both the clinical diagnosis and initiatives for a more rational use of laboratory testing in patients with clinically suspected LB. Sources This is a narrative review combining various aspects of the clinical and laboratory diagnosis with an educational purpose. The literature search was based on existing systematic reviews, national and international guidelines and supplemented with specific citations. Implications The main recommendations according to current European case definitions for LB are as follows. Typical erythema migrans should be diagnosed clinically and does not require laboratory testing. The diagnosis of Lyme neuroborreliosis requires laboratory investigation of the spinal fluid including intrathecal antibody production, and the remaining disease manifestations require testing for serum antibodies to B. burgdorferi . Testing individuals with non-specific subjective symptoms is not recommended, because of a low positive predictive value. [ABSTRACT FROM AUTHOR]

Background: Despite Africa's significant infectious disease burden, it is underrepresented in global vaccine clinical trials. While this trend is slowly reversing, it is important to recognize and mitigate the challenges that arise when conducting vaccine clinical trials in this environment. These challenges stem from a variety of factors peculiar to the population and may negatively impact adverse event collection and reporting if not properly addressed. Methods: As a team of clinical researchers working within the MRCG (Medical Research Council Unit The Gambia), we have conducted 12 phase 1 to 3 vaccine trials over the past 10 years. In this article, we discuss the challenges we face and the strategies we have developed to improve the collection and reporting of adverse events in low-income settings. Outcome. Healthcare-seeking behaviors in the Gambia are influenced by spiritual and cultural beliefs as well as barriers to accessing orthodox healthcare; participants in trials may resort to non-orthodox care, reducing the accuracy of reported adverse events. To address this, trial eligibility criteria prohibit self-treatment and herbal product use during trials. Instead, round-the-clock care is provided to trial participants, facilitating safety follow-up. Constraints in the healthcare system in the Gambia such as limitations in diagnostic tools limit the specificity of diagnosis when reporting adverse events. To overcome these challenges, the Medical Research Council Unit maintains a Clinical Services Department, offering medical care and diagnostic services to study participants. Sociocultural factors, including low literacy rates and social influences, impact adverse event collection. Solicited adverse events are collected during home visits on paper-based or electronic report forms. Community engagement meetings are held before each study starts to inform community stakeholders about the study and answer any questions they may have. These meetings ensure that influential members of the community understand the purpose of the study and the risks and benefits of participating in the trial. This understanding makes them more likely to support participation within their communities. Conclusion: Conducting ethical vaccine clinical trials in resource-limited settings requires strategies to accurately collect and report adverse events. Our experiences from the Gambia offer insights into adverse event collection in these settings. [ABSTRACT FROM AUTHOR]

Background: The Stop Cancer PAIN Trial was a phase III pragmatic stepped wedge cluster randomised controlled trial which compared effectiveness of screening and guidelines with or without implementation strategies for improving pain in adults with cancer attending six Australian outpatient comprehensive cancer centres (n = 688). A system for pain screening was introduced before observation of a 'control' phase. Implementation strategies introduced in the 'intervention' phase included: (1) audit of adherence to guideline recommendations, with feedback to clinical teams; (2) health professional education via an email-administered 'spaced education' module; and (3) a patient education booklet and self-management resource. Selection of strategies was informed by the Capability, Opportunity and Motivation Behaviour (COM-B) Model (Michie et al., 2011) and evidence for each strategy's stand-alone effectiveness. A consultant physician at each centre supported the intervention as a 'clinical champion'. However, fidelity to the intervention was limited, and the Trial did not demonstrate effectiveness. This paper reports a sub-study of the Trial which aimed to identify factors inhibiting or enabling fidelity to inform future guideline implementation initiatives. Methods: The qualitative sub-study enabled in-depth exploration of factors from the perspectives of personnel at each centre. Clinical champions, clinicians and clinic receptionists were invited to participate in semi-structured interviews. Analysis used a framework method and a largely deductive approach based on the COM-B Model. Results: Twenty-four people participated, including 15 physicians, 8 nurses and 1 clinic receptionist. Coding against the COM-B Model identified 'capability' to be the most influential component, with 'opportunity' and 'motivation' playing largely subsidiary roles. Findings suggest that fidelity could have been improved by: considering the readiness for change of each clinical setting; better articulating the intervention's value proposition; defining clinician roles and responsibilities, addressing perceptions that pain care falls beyond oncology clinicians' scopes of practice; integrating the intervention within existing systems and processes; promoting patient-clinician partnerships; investing in clinical champions among senior nursing and junior medical personnel, supported by medical leaders; and planning for slow incremental change rather than rapid uptake. Conclusions: Future guideline implementation interventions may require a 'meta-implementation' approach based on complex systems theory to successfully integrate multiple strategies. Trial registration: Registry: Australian New Zealand Clinical Trials Registry; number: ACTRN 12615000064505; data: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspxid=367236&isReview=true. [ABSTRACT FROM AUTHOR]

Despite the introduction of targeted vaccines and screening protocols, locally advanced cervical cancer represents a median proportion of 37% among all cervical carcinomas. Compared to early stages, it presents significantly lower cure rates, with a 5-year disease-free survival rate of 68% and a 5-year overall survival rate of 74%. According to current guidelines, definitive radiotherapy with concomitant chemotherapy represents the gold standard for locally advanced cervical cancer treatment. However, a significant number of patients relapse and die from metastatic disease. The aim of this narrative review is to examine the recent advancements in treating locally advanced cervical cancer, exploring new frontiers in therapeutic approaches. The PubMed database and clinical trial registries were searched to identify relevant articles published on locally advanced cervical cancer treatment up to March 2024, mainly focusing on papers published in the last decade. Abstracts presented at major international congresses that bring relevant evidence were included. Progress achieved in refining radiotherapy techniques, recent evidence regarding neoadjuvant treatment preceding surgery or concurrent chemoradiotherapy, and key findings concerning adjuvant treatment are thoroughly explored. Furthermore, a comprehensive review of prominent phase II and phase III trials examining the integration of immune checkpoint inhibitors is conducted, analyzing the various contexts in which they are applied. In light of the new evidence that has emerged in recent years and is discussed in this article, the appropriate selection of the most suitable therapeutic approach for each patient remains a complex but crucial issue. [ABSTRACT FROM AUTHOR]

Medication-related osteonecrosis of the jaw (MRONJ) is a debilitating adverse effect of bisphosphates, antiresorptive therapy or antiangiogenic agents that can potentially increase oxidative stress, leading to progressive osteonecrosis of the jaws. Despite the large number of published systematic reviews, there is a lack of potential MRONJ treatment protocols utilising photobiomodulation (PBM) as a single or adjunct therapy for preventive or therapeutic oncology or non-oncology cohort. Hence, this systematic review aimed to evaluate PBM laser efficacy and its dosimetry as a monotherapy or combined with the standard treatments for preventive or therapeutic approach in MRONJ management. The objectives of the review were as follows: (1) to establish PBM dosimetry and treatment protocols for preventive, therapeutic or combined approaches in MRONJ management; (2) to highlight and bridge the literature gaps in MRONJ diagnostics and management; and (3) to suggest rationalised consensus recommendations for future randomised controlled trials (RCTs) through the available evidence-based literature. This review was conducted according to the PRISMA guidelines, and the protocol was registered at PROSPERO under the ID CRD42021238175. A multi-database search was performed to identify articles of clinical studies published from their earliest records until 15 December 2023. The data were extracted from the relevant papers and analysed according to the outcomes selected in this review. In total, 12 out of 126 studies met the eligibility criteria. The striking inconsistent conclusions made by the various authors of the included studies were due to the heterogeneity in the methodology, diagnostic criteria and assessment tools, as well as in the reported outcomes, made it impossible to conduct a meta-analysis. PBM as a single or adjunct treatment modality is effective for MRONJ preventive or therapeutic management, but it was inconclusive to establish a standardised and replicable protocol due to the high risk of bias in a majority of the studies, but it was possible to extrapolate the PBM dosimetry of two studies that were close to the WALT recommended parameters. In conclusion, the authors established suggested rationalised consensus recommendations for future well-designed robust RCTs, utilising PBM as a monotherapy or an adjunct in preventive or therapeutic approach of MRONJ in an oncology and non-oncology cohort. This would pave the path for standardised PBM dosimetry and treatment protocols in MRONJ management. [ABSTRACT FROM AUTHOR]

Clinical trials, the empirical discipline of medical experimentation conducted on human subjects, have engendered a paradigm shift in medical research. The need for new clinical studies is paramount in the Middle East and North Africa (MENA) region, with its rising cancer incidence and demand for efficient oncology treatments. This paper comprehensively reviews the challenges, opportunities, and future directions of phase I oncology clinical trials in the MENA region. Early-phase trials are vital in determining drug dosage and assessing toxicity, bridging the gap between preclinical research and clinical practice. Considering the unique landscape of MENA, this review explores regulatory aspects, specific hurdles faced, potential advantages, and areas for improvement in conducting these trials. Various future directions can be pursued to maximize the potential of phase I oncology trials in MENA. While regulatory bodies like the Ministry of Health adhere to the International Conference on Harmonization-Good Clinical Practice guidelines, a unified system meeting high standards would yield better results. Strengthening research infrastructure, establishing research centers, incorporating clinical trial education into the curriculum, and improving access to medical facilities are crucial. Enhancing consumer understanding of research would facilitate increased participation and promote sustainability in trial recruitment. Navigating various funding sources would open the door for more funding opportunities. Collaborations between academia, industry, and regulatory bodies, both international and local, should be fostered to promote knowledge sharing, resource pooling, and harmonization of standards. Such collaborations would contribute to the sustainability of clinical trial activities by leveraging collective expertise, sharing research infrastructure, and distributing the burden of regulatory compliance. By adopting these strategies, the MENA region can advance its capacity to conduct early phases of oncology trials and contribute significantly to the global medical research landscape. [ABSTRACT FROM AUTHOR]

Engineered biomaterials are materials specifically designed to interact with biological systems for biomedical applications. This paper offers the comprehensive analysis of global clinical trial trends involving such materials. We surveyed 834 studies in the ClinicalTrials.gov database and explored biomaterial types, their initiation points, and durations in clinical trials. Predominantly, synthetic and natural polymers, particularly silicone and collagen, are used. Trials, focusing on ophthalmology, dentistry, and vascular medicine, are primarily conducted in the United States, Canada, and Italy. These trials encompass a broad demographic, and trials enrolled fewer than 100 participants. The study duration varied ranging from 0.5 to 4.5 years. These biomaterials are mainly bioresorbable or bioinert, with the integration of cells in biomaterials remaining an underexplored area. Our findings shed light on current practices and future potentials of engineered biomaterials in clinical research, offering insights for advancing this dynamic field globally. [ABSTRACT FROM AUTHOR]

This paper reviews the latest trends and applications of silicone in ophthalmology, especially related to intraocular lenses (IOLs). Silicone, or siloxane elastomer, as a synthetic polymer, has excellent biocompatibility, high chemical inertness, and hydrophobicity, enabling wide biomedical applications. The physicochemical properties of silicone are reviewed. A review of methods for mechanical and in vivo characterization of IOLs is presented as a prospective research area, since there are only a few available technologies, even though these properties are vital to ensure medical safety and suitability for clinical use, especially if long-term function is considered. IOLs represent permanent implants to replace the natural lens or for correcting vision, with the first commercial foldable lens made of silicone. Biological aspects of posterior capsular opacification have been reviewed, including the effects of the implanted silicone IOL. However, certain issues with silicone IOLs are still challenging and some conditions can prevent its application in all patients. The latest trends in nanotechnology solutions have been reviewed. Surface modifications of silicone IOLs are an efficient approach to further improve biocompatibility or to enable drug-eluting function. Different surface modifications, including coatings, can provide long-term treatments for various medical conditions or medical diagnoses through the incorporation of sensory functions. It is essential that IOL optical characteristics remain unchanged in case of drug incorporation and the application of nanoparticles can enable it. However, clinical trials related to these advanced technologies are still missing, thus preventing their clinical applications at this moment. [ABSTRACT FROM AUTHOR]

Focused Very-High Energy Electron (VHEE, 50–300 MeV) and Ultra-High Energy Electron (UHEE, > 300 MeV) beams can accurately target both large and deeply seated human tumors with high sparing properties, while avoiding the spatial requirements and cost of proton and heavy ion facilities. Advanced testing phases are underway at the CLEAR facilities at CERN (Switzerland), NLCTA at Stanford (USA), and SPARC at INFN (Italy), aiming to accelerate the transition to clinical application. Currently, Monte Carlo (MC) transport is the sole paradigm supporting preclinical trials and imminent clinical deployment. In this paper, we propose an alternative: the first extension of the nuclear-reactor deterministic chain Njoy-Dragon for VHEE and UHEE applications. We have extended the Boltzmann-Fokker-Planck (BFP) multigroup formalism and validated it using standard radio-oncology benchmarks, complex assemblies with a wide range of atomic numbers, and comprehensive irradiation of the entire periodic table. We report that 99 % of water voxels exhibit a BFP-MC deviation below 2 % for electron energies under 1.5 GeV . Additionally, we demonstrate that at least 97 % of voxels of bone, lung, adipose tissue, muscle, soft tissue, tumor, steel, and aluminum meet the same criterion between 50 MeV and 1.5 GeV . For water, the thorax, and the breast intra-operative benchmark, typical average BFP-MC deviations of 0.3 % and 0.4 % were observed at 300 MeV and 1 GeV , respectively. By irradiating the entire periodic table, we observed similar performance between lithium ( Z = 3 ) and cerium ( Z = 58 ). Deficiencies observed between praseodymium ( Z = 59 ) and einsteinium ( Z = 99 ) have been reported, analyzed, and quantified, offering critical insights for the ongoing development of the Evaluated Nuclear Data File mode in Njoy. [ABSTRACT FROM AUTHOR]

Severe acute malnutrition (SAM) remains a major global public health problem. SAM cases are treated using ready‐to‐use therapeutic food (RUTF) at a dosage of ∼200 kcal/kg/day per the standard treatment protocol (STD). Emerging evidence on simplifications to the standard protocol, which among other adaptations, includes reducing the daily RUTF dosage, indicates that it is effective and safe for treating children with SAM. In response to a foreseen stock shortage of RUTF, the government of Afghanistan endorsed the temporary use of a modified treatment protocol in which the daily RUTF dosage was prescribed at 1000 kcal/day (irrespective of body weight) until the child achieved moderate acute malnutrition status (weight‐for‐height z‐score ≥ −3 or mid‐upper arm circumference [MUAC] ≥ 115 mm), at which point 500 kcal/day was prescribed until cured (modified treatment protocol [MTP]). In this paper, we report the results of this nonweight‐based daily RUTF dosage experience. Data of 2042 children with SAM, treated using either the STD protocol (n = 269) or the MTP protocol (n = 1773) from August 2019 to March 2021 in five provinces, were analyzed. The per‐protocol analyses confirmed noninferiority of MTP protocol when compared to STD protocol for recovery rate [93.3% vs. 90.2%; ∆ (95% confidence interval, CI) = 3.1 (−0.9; 7.2) %] and length‐of‐stay [82.6 vs. 75.6 days; ∆ (95% CI) = 6.9 (3.3; 10.5) days], considering the margin of noninferiority of −10% and +14 days, respectively. Weight gain velocity was smaller in the MTP protocol group than in the STD protocol group [3.7 (1.7) vs. 5.2 (2.9) g/kg/day; ∆ (95% CI) = −1.5 (−1.8, −1.2); p < 0.001]. The STD group had a significantly higher mean than the MTP group for absolute MUAC gain [∆ (95% CI) = 1.7 (1.0; 2.3) mm; p < 0.001] and the MUAC velocity [∆ (95% CI) = 0.29 (0.20; 0.37) mm/week; p < 0.001]. Our results confirm the noninferiority of a nonweight‐based daily dosage and support the endorsement of this modification as an alternative to the standard protocol in resource‐constrained contexts. Key messages: More evidence supporting the use of the nonweight‐based daily ready‐to‐use therapeutic food (RUTF) dosage for treating uncomplicated severe acute malnutrition (SAM), in specific contexts, is needed.Our real‐world prospective nonrandomized study showed that the fixed nonweight‐based daily RUTF dosage protocol is as effective as the standard weight‐based protocol for treating uncomplicated SAM in children <5 in the Afghanistan context.Our findings support the reflection of a nonweight‐based daily RUTF dosage in resource‐constrained contexts in national and global policies and guidelines to improve coverage of all children in need of treatment. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is common in patients with heart failure (HF) and associated with considerable morbidity and mortality. Significant advances have recently occurred in the treatment of T2DM, with evidence of several new glucose-lowering medications showing either neutral or beneficial cardiovascular effects. However, some of these agents have safety characteristics with strong practical implications in HF [i.e. dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose co-transporter type 2 (SGLT-2) inhibitors]. Regarding safety of DPP-4 inhibitors, saxagliptin is not recommended in HF because of a greater risk of HF hospitalisation. There is no compelling evidence of excess HF risk with the other DPP-4 inhibitors. GLP-1 RAs have an overall neutral effect on HF outcomes. However, a signal of harm suggested in two small trials of liraglutide in patients with reduced ejection fraction indicates that their role remains to be defined in established HF. SGLT-2 inhibitors (empagliflozin, canagliflozin and dapagliflozin) have shown a consistent reduction in the risk of HF hospitalisation regardless of baseline cardiovascular risk or history of HF. Accordingly, SGLT-2 inhibitors could be recommended to prevent HF hospitalisation in patients with T2DM and established cardiovascular disease or with multiple risk factors. The recently completed trial with dapagliflozin has shown a significant reduction in cardiovascular mortality and HF events in patients with HF and reduced ejection fraction, with or without T2DM. Several ongoing trials will assess whether the results observed with dapagliflozin could be extended to other SGLT-2 inhibitors in the treatment of HF, with either preserved or reduced ejection fraction, regardless of the presence of T2DM. This position paper aims to summarise relevant clinical trial evidence concerning the role and safety of new glucose-lowering therapies in patients with HF. [ABSTRACT FROM AUTHOR]

The prevalence of cerebral palsy (CP) varies globally, with higher rates and burden of disease in low- and middle-income countries. CP is a lifelong condition with no cure, presenting diverse challenges such as motor impairment, epilepsy, and mental health disorders. Research progress has been made but more is needed, especially given consumer demands for faster advancements and improvements in the scientific evidence base for interventions. This paper explores three strategies to accelerate CP research: consumer engagement, global clinical trial networks, and adaptive designs. Consumer engagement involving individuals with lived experience enhances research outcomes. Global clinical trial networks provide efficiency through larger and more diverse participant pools. Adaptive designs, unlike traditional randomized controlled trials, allow real-time modifications based on interim analyses, potentially answering complex questions more efficiently. The establishment of a CP Global Clinical Trials Network, integrating consumer engagement, global collaboration, and adaptive designs, marks a paradigm shift. The Network aims to address consumer-set research priorities. While challenges like ethical considerations and capacity building exist, the potential benefits for consumers, clinicians, researchers, and funding bodies are substantial. This paper underscores the urgency of transforming CP research methodologies for quicker translation of novel treatments into clinical practice to improve quality of life for those with CP. [ABSTRACT FROM AUTHOR]

Objective We assessed the measurement equivalence and feasibility of the paper-and-pencil and touchscreen modes of administration of the Taiwan Chinese version of the EORTC QLQ-PR25, a commonly used questionnaire to evaluate the health-related quality of life (HRQOL) in patients with prostate cancer in Taiwan. Methods A cross-over design study was conducted in 99 prostate cancer patients at an urology outpatient clinic. Descriptive exact and global agreement percentages, intraclass correlation, and equivalence test based on minimal clinically important difference (MCID) approach were used to examine the equity of HRQOL scores between these two modes of administration. We also evaluated the feasibility of computerized assessment based on patients' acceptability and preference. Additionally, we used Rasch rating scale model to assess differential item functioning (DIF) between the two modes of administration. Results The percentages of global agreement in all domains were greater than 85% in the EORTC QLQ-PR25. All results from equivalence tests were significant, except for Sexual functioning, indicating good equivalence. Only one item exhibited DIF between the two modes. Although nearly 80% of the study patients had no prior computer-use experience, the overall proportion of acceptance and preference for the touch-screen mode were quite high and there was no significant difference across age groups or between computer-use experience groups. Conclusions The study results showed that the data obtained from the modes of administration were equivalent. The touch-screen mode of administration can be a feasible and suitable alternative to the paper-and-pencil mode for assessment of patient-reported outcomes in patients with prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Sponsors that seek to commercialize new drugs apply to the Food and Drug Administration (FDA) which independently analyzes the raw data and reports the results on its website. Objectives: This study sought to determine if there are differences between the FDA assessments and journal reports on biologic agents developed for the treatment of rheumatoid arthritis. Methods: Available data on FDA-approved drugs were extracted from the website, and a systematic literature search was conducted to identify matching studies in peer-reviewed medical journals. Outcome measures were the American College of Rheumatology response criteria ACR20 (efficacy) and withdrawal due to adverse events (safety). As effect size odds ratios were estimated for each active trial arm vs. control arm (i.e. for both sources: FDA and journal report), followed by calculation of the ratios of the FDA and journal report odds ratios. A ratio of odds ratios not equal to 1 was categorized as a discrepancy. Results: FDA reports were available for 8 of 9 FDA-approved biologic agents for rheumatoid arthritis; all identified trials (34) except one were published in peer-reviewed journals. Overall, discrepancies were noted for 20 of the 33 evaluated trials. Differences in the apparent benefit reporting were found in 39% (24/61) pairwise comparisons and in 11 cases these were statistically significant; the FDA report showed greater benefit than the journal publication in 15 comparisons and lesser benefit in 9. Differences in the reported harms were found in 51% (28/55) pairwise comparisons and were statistically significant in 5. The “signal” in FDA reports showed a less harmful effect than the journal publication in 17 comparisons whereas a more harmful effect in 11. The differences were attributed to differences in analytic approach, patient inclusion, rounding effect, and counting discrepancies. However, no differences were categorized as critical. Conclusion: There was no empirical evidence to suggest biased estimates between the two sources. Increased and detailed transparency in publications would improve the understanding and credibility of published results. Further, the FDA report was found to be a useful source when data are missing in the published report (i.e. reporting bias). [ABSTRACT FROM AUTHOR]

The management and maintenance of paper-based patient record archives involve high running costs. Therefore, many health care providers choose to digitize their paper records subsequently destroying the originals. By now, this is an established procedure for patient records from routine care. However, at present it is unclear under which circumstances the patient records of patients taking part in clinical trials can be destroyed after digitization. Paper-based original records may only be destroyed if their digital copies are recognized as source documents by both sponsors and authorities. The authors believe that this recognition should be possible, as long as the scanned paper-based records fulfill the requirements for certified copies according to the Note for Guidance CPMP/ICH/135/95 (ICH-GCP). This requires that, based on the applied rules, it can be proven at any time that the existing digitization process is clearly regulated, and the resulting quality is regularly controlled and sufficiently high. The objective of this key issues paper is to present the manner in which the existing regulatory guidelines can be implemented to allow the digitized patient records being recognized as source documents. An English version of this article will be published in “Clinical Investigation” (Future Science) [1]. [ABSTRACT FROM AUTHOR]

Purpose: To describe the present status and changing patterns of medical papers related to keywords of vaccine and vaccination published in Korea over the last 50 years, and provide basic data for future studies. Materials and Methods: 185,603 papers are registered in the medical database KoreaMed, which is run by Korean Association of Medical Journal Editors. Among these papers, a search with the keywords vaccine or vaccination revealed a total of 1,089 articles which were published on vaccine and/or vaccination during the period of September 2, 1962 to April 30, 2012. Our study endeavors to analyze these 1,089 articles. Results: Only one article published with the keywords vaccine and/or vaccination was published in the 1960s, and the number of journals steadily increased starting from the 1970s (24 articles) to 2 times, 10 times, 20 times in the 1980s, 1990s, and the 2000s (585 articles), respectively. The articles were classified into reviews (20.2%), original articles with clinical study (40.7%), original articles with experimental study (24.6%), and case reports (8.2%). The review articles mainly dealt with an overview. The original articles with clinical study were on epidemiology, effect and immunogenicity, clinical trial. Original articles with experimental study were mainly comprised of complication and overview. Articles on vaccine, pathogen or disease topics were mostly microorganisms such as bacteria or viruses, and studies on anti-cancer vaccines or vaccines of specific diseases were sparse. Conclusion: The above data reflects the clinical uses of vaccines in Korea and the history of vaccine studies. The number of vaccine-related articles is increasing rapidly since the first article was published in 1962. This implies that with the increase of studies of clinical trials, clinical uses and results and analyses of the results, articles relating to basic studies are also on the rise. We intend these findings to be of use to researchers in this... [ABSTRACT FROM AUTHOR]

While they account for one-fifth of new cancer cases, rare cancers are difficult to study. A higher than average degree of uncertainty should be accommodated for clinical as well as for population-based decision making. Rules of rational decision making in conditions of uncertainty should be rigorously followed and would need widely informative clinical trials. In principle, any piece of new evidence would need to be exploited in rare cancers. Methodologies to explicitly weigh and combine all the available evidence should be refined, and the Bayesian logic can be instrumental to this end. Likewise, Bayesian-design trials may help optimize the low number of patients liable to be enrolled in clinical studies on rare cancers, as well as adaptive trials in general, with their inherent potential of flexibility when properly applied. While clinical studies are the mainstay to test hypotheses, the potential of electronic patient records should be exploited to generate new hypotheses, to create external controls for future studies (when internal controls are unpractical), to study effectiveness of new treatments in real conditions. Framework study protocols in specific rare cancers to sequentially test sets of new agents, as from the early post-phase I development stage, should be encouraged. Also the compassionate and the off-label settings should be exploited to generate new evidence, and flexible regulatory innovations such as adaptive licensing could convey new agents early to rare cancer patients, while generating evidence. Though validation of surrogate end points is problematic in rare cancers, the use of an updated notion of tumor response may be of great value in the single patient to optimize the use of therapies, all the more the new ones. Disease-based communities, involving clinicians and patients, should be regularly consulted by regulatory bodies when setting their policies on drug approval and reimbursement in specific rare cancers. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the tumors with the highest prevalence rate among women in the world, and its BRCA1/2 gene is a common mutation site. Talazoparib, as a targeted PARP inhibitor, can effectively control the occurrence and development of breast cancer with BRCA1/2 gene mutation, and play a therapeutic role. Based on the findings from the Phase III EMBRACE trial (NCT01945775 clinical trial), our analysis reveals that the talazoparib group demonstrated a significant extension in progression-free survival, along with improved response markers and patient-reported outcomes when compared to conventional therapies. This study aims to assess the cost-effectiveness of talazoparib for treating advanced breast cancer with germline BRCA1/2 mutations and HER2 negativity, considering the perspectives of health services in China and the United States. The results obtained will serve as a valuable reference for promoting rational drug utilization and enhancing medical resource efficiency. To evaluate the cost-effectiveness of Talazoparib more scientifically and provide clinicians with chemotherapy options, this paper developed a Markov model based on the EMBRACA clinical trial (clinical Trails.gov No., NCT01945775) to simulate the survival events of breast cancer patients in the Talazoparib group and the standard treatment group. The state transition probability and clinical data of breast cancer patients during treatment were extracted from the phase III EMBRACA clinical trial. The cost data generated during the treatment process comes from local hospital pricing, other references, and expert consultation. This article uses US dollars to calculate the treatment cost and incremental cost-effectiveness ratio. Health outcomes are expressed in Quality Adjusted Life Years (QALYs). In addition, Outcomes were measured in quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio, which robustness was evaluated by deterministic and probabilistic sensitivity analyses. This article establishes a Markov model for single-item sensitivity analysis. The results show that the economic benefits of using Talazoparib as a new treatment strategy in both China and the United States are higher than other drugs, and it is cost-effective. Compared to the control group, the incremental cost incurred by the Talazoparib treatment group in China was $2484.48/QALY, with an incremental QALY of 1.5. However, Talazoparib in the United States holds a dominant position, saving costs of $10,223.43 and increasing QALYs by 1.5. The clinical treatment effect of Talazoparib group in BRCA1/2 mutant advanced breast cancer patients is better than that of the standard treatment group, and the progression free survival period is significantly prolonged. From the perspective of medical and health services in China and the United States, the Talazoparib group is more economical than the standard treatment group in treating patients with BRCA1/2 mutant advanced breast cancer. [ABSTRACT FROM AUTHOR]

Background: Stroke survivors with aphasia want to improve their everyday talking (discourse). In current UK practice, 90% of speech and language therapists believe discourse assessment and treatment is part of their role but are hampered by barriers in resources, time and expertise. There is a clinical need for well-articulated discourse assessment and treatments. LUNA is a multi-level treatment targeting words, sentences and discourse macrostructure in personal stories that addresses this clinical need. Objectives: This study aimed to assess the feasibility and acceptability of LUNA trial procedures in a randomised waitlist-controlled trial; and to evaluate preliminary efficacy. Methods: This paper reports a phase II, waitlist-controlled, proof-of-concept feasibility trial. Participants with chronic aphasia (n = 28) were recruited from the community and randomised to an Immediate (n = 14) or Delayed (n = 14) group. LUNA treatment was delivered twice weekly for 10 weeks via the videoconferencing technology, Zoom. Feasibility was assessed in terms of participant recruitment and retention, adherence, missing data, and treatment fidelity. Preliminary treatment efficacy was assessed in terms of between group differences in outcome measures relating to discourse, language, and psychosocial state. Results: The remote LUNA trial was feasible: 85% of those eligible consented to the trial; trial retention was 86%; 87% of treatment sessions were delivered as scheduled, and 79% of participants completed 80%+ of the treatment programme; data was missing only for participants who withdrew; treatment fidelity was high at 92% adherence; and only one clinical outcome measure demonstrated ceiling effects. ANCOVA analysis of the clinical outcome measures revealed group differences with medium and large effect sizes, indicating, improvements in the production of words, sentences, discourse macrostructure, overall language functioning (WAB-R), and psychosocial state (VAMS) following LUNA treatment. For most outcomes measured, similar treatment benefits were suggested in a secondary, non-parametric analysis. Conclusions: Large-scale evaluation of the clinical efficacy and cost-effectiveness of LUNA is warranted and supported by these findings. Trial registration: Clinical trials registration: NCT05847023 (clinical trials.gov). [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]

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]

Iptacopan, the first orally available small-molecule complement factor B inhibitor, was developed by Novartis AG of Switzerland. Iptacopan for the treatment of PNH was just approved by the FDA in December 2023. Other indications for treatment are still in phase III clinical trials. Iptacopan is a small-molecule inhibitor targeting complement factor B, showing positive therapeutic effects in the treatment of PNH, C3 glomerulonephritis, and other diseases. Although Iptacopan is already on the market, there has been no detailed synthesis process or specific parameter report on the intermediates during the synthesis of its compounds except for the original research patent. In this study, a practical synthesis route for Iptacopan was obtained through incremental improvement while a biosynthesis method for ketoreductase was used for the synthesis of the pivotal intermediate 12. Moreover, by screening the existing enzyme library of our research group on the basis of random as well as site-directed mutagenesis methods, an enzyme (M8) proven to be of high optical purity with a high yield for biocatalectic reduction was obtained. This enzyme was used to prepare the compound benzyl (2S,4S)-4-hydroxy-2-(4-(methoxycarbonyl)-phenyl)-piperidine-1-carboxylate) white powder (36.8 g HPLC purity: 98%, ee value: 99%). In the synthesis of intermediate 15, the reaction was improved from two-step to one-step, which indicated that the risk of chiral allosterism was reduced while the scale was expanded. Finally, Iptacopan was synthesized in a seven-step reaction with a total yield of 29%. Since three chiral intermediate impurities were synthesized directionally, this paper lays a solid foundation for the future of pharmaceutical manufacturing. [ABSTRACT FROM AUTHOR]

Background: The Brief Educational Workshops in Secondary Schools Trial (BESST) is an England-wide school-based cluster randomised controlled trial assessing the clinical and cost-effectiveness of an open-access psychological workshop programme (DISCOVER) for 16–18-year-olds. This baseline paper describes the self-referral and other recruitment processes used in this study and the baseline characteristics of the enrolled schools and participants. Method: We enrolled 900 participants from 57 Secondary schools across England from 4th October 2021 to 10th November 2022. Schools were randomised to receive either the DISCOVER day-long Stress workshop or treatment as usual which included signposting information. Participants will be followed up for 6 months with outcome data collection at baseline, 3-month, and 6-month post randomisation. Results: Schools were recruited from a geographically and ethnically diverse sample across England. To reduce stigma, students were invited to self-refer into the study if they wanted help for stress. Their mean age was 17.2 (SD = 0.6), 641 (71%) were female and 411 (45.6%) were from ethnic minority groups. The general wellbeing of our sample measured using the Mood and Feelings Questionnaire (MFQ) found 314 (35%) of students exhibited symptoms of depression at baseline. Eighty percent of students reported low wellbeing on the Warwick Edinburgh Mental Wellbeing Scale (WEMWBS) suggesting that although the overall sample mean is below the cut-off for depression, the self-referral approach used in this study supports distressed students in coming forward. Conclusion: The BESST study will continue to follow up participants to collect outcome data and results will be analysed once all the data have been collected. Trial registration: ISRCTN registry ISRCTN90912799. Registered on 28 May 2020. [ABSTRACT FROM AUTHOR]

Previous studies suggested effectiveness of psilocybin in the field of mental health. FDA designated psilocybin as a "breakthrough therapy" for the treatment of treatment-resistant depression (TRD) in 2018. This paper provided a review of psilocybin's potential role in treatment of depression by focusing on published clinical trials. Studies showed that psilocybin, an agonist on 5-HT2A receptors, manifests antidepressant and anxiolytic effects by increasing glutamate transmission, reducing brain inflammation, decreasing default mode network activity. In terms of clinical trials, eleven studies (six open-label and five double blinded randomized clinical trials, DB-RCTs) trials exploring psilocybin's impact on depression were found. Among open-label studies, a pilot study on TRD patients demonstrated significant reductions in depressive symptoms after two psilocybin sessions. Psilocybin also improved cognitive bias associated with depression. Extension studies confirmed sustained improvements and high remission rates. Among five DB-RCTs, two showed that psilocybin led to significant reductions in anxiety and depression in cancer patients, and the improvements sustained for over 6 months. In MDD, psilocybin showed rapid reductions in depression, with higher remission rates compared to escitalopram in a DB-RCT. Another DB-RCT showed that psilocybin induced higher decrease in depression around 6 hours after their administrations than placebo. The last DB-RCT showed that in patients with TRD, a single dose of psilocybin 25 mg, but not psilocybin 10 mg, resulted in superior antidepressant effect than psilocybin 1 mg. Overall, psilocybin showed promise in treating depression and anxiety, with notable safety profiles. Further research should explore optimal dosages and long-term effects. [ABSTRACT FROM AUTHOR]

177Lu is a radioisotope that has become increasingly popular as a therapeutic agent for treating various conditions, including neuroendocrine tumors and metastatic prostate cancer. 177Lu-tagged radioligands are molecules precisely designed to target and bind to specific receptors or proteins characteristic of targeted cancer. This review paper will present an overview of the available 177Lu-labelled radioligands currently used to treat patients. Based on recurring, active, and completed clinical trials and other available literature, we evaluate current status, interests, and developments in assessing patient-specific dosimetry, which will define the future of this particular treatment modality. In addition, we will discuss the challenges and opportunities of the existing dosimetry standards to measure and calculate the radiation dose delivered to patients, which is essential for ensuring treatments' safety and efficacy. Finally, this article intends to provide an overview of the current state of 177Lu-tagged radioligand therapy and highlight the areas where further research can improve patient treatment outcomes. [ABSTRACT FROM AUTHOR]