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Medications for opioid use disorder (MOUD) increase retention in care and decrease mortality during active treatment; however, information about the comparative effectiveness of different forms of MOUD is sparse. Observational comparative effectiveness studies are subject to many types of bias; a robust framework to minimize bias would improve the quality of comparative effectiveness evidence. This paper discusses the use of target trial emulation as a framework to conduct comparative effectiveness studies of MOUD with administrative data. Using examples from our planned research project comparing buprenorphine‐naloxone and extended‐release naltrexone with respect to the rates of MOUD discontinuation, we provide a primer on the challenges and approaches to employing target trial emulation in the study of MOUD. [ABSTRACT FROM AUTHOR]

Pragmatism in clinical trials is focused on increasing the generalizability of research findings for routine clinical care settings. Hybridism in clinical trials (i.e., assessing both clinical effectiveness and implementation success) is focused on speeding up the process by which evidence-based practices are developed and adopted into routine clinical care. Even though pragmatic trial methodologies and implementation science evolved from very different disciplines, Pragmatic Trials and Hybrid Effectiveness-Implementation Trials share many similar design features. In fact, these types of trials can easily be conflated, creating the potential for investigators to mislabel their trial type or mistakenly use the wrong trial type to answer their research question. Blurred boundaries between trial types can hamper the evaluation of grant applications, the scientific interpretation of findings, and policy-making. Acknowledging that most trials are not pure Pragmatic Trials nor pure Hybrid Effectiveness-Implementation Trials, there are key differences in these trial types and they answer very different research questions. The purpose of this paper is to clarify the similarities and differences of these trial types for funders, researchers, and policy-makers. In addition, recommendations are offered to help investigators choose, label, and operationalize the most appropriate trial type to answer their research question. These recommendations complement existing reporting guidelines for clinical effectiveness trials (TIDieR) and implementation trials (StaRI). [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]

This paper elucidates and rationalizes the ethical governance system for healthcare AI research, as outlined in the 'Research Ethics Guidelines for AI Researchers in Healthcare' published by the South Korean government in August 2023. In developing the guidelines, a four-phase clinical trial process was expanded to six stages for healthcare AI research: preliminary ethics review (stage 1); creating datasets (stage 2); model development (stage 3); training, validation, and evaluation (stage 4); application (stage 5); and post-deployment monitoring (stage 6). Researchers identified similarities between clinical trials and healthcare AI research, particularly in research subjects, management and regulations, and application of research results. In the step-by-step articulation of ethical requirements, this similarity benefits from a reliable and flexible use of existing research ethics governance resources, research management, and regulatory functions. In contrast to clinical trials, this procedural approach to healthcare AI research governance effectively highlights the distinct characteristics of healthcare AI research in research and development process, evaluation of results, and modifiability of findings. The model exhibits limitations, primarily in its reliance on self-regulation and lack of clear delineation of responsibilities. While formulated through multidisciplinary deliberations, its application in the research field remains untested. To overcome the limitations, the researchers' ongoing efforts for educating AI researchers and public and the revision of the guidelines are expected to contribute to establish an ethical research governance framework for healthcare AI research in the South Korean context in the future. [ABSTRACT FROM AUTHOR]

BACKGROUND: Primary liver cancer is a major health issue, so finding the most effective treatment is vital. OBJECTIVE: The present meta-analysis compares high-intensity focused ultrasound (HIFU) to radiofrequency (RF) ablation for primary liver cancer treatment. METHODS: PubMed, MEDLINE, CNKI, VIP, and Wanfang were used to search for English and Chinese papers. After carefully confirming data completeness and applying inclusion and exclusion criteria, RevMan 5.3 was used to evaluate the included literature. Data analysis utilized a fixed-effects model for heterogeneity between 0.1 and 0.5. RESULTS: The meta-analysis included 304 patients: 119 had HIFU and 185 RF ablation. For primary liver cancer, HIFU and RF ablation were equally efficacious (odds ratio 1.02, 95% confidence interval [0.54, 1.92]). Overall survival, disease-free survival, and complications at 1, 2, and 3 years were not significantly different (odds ratio 0.72, 95% confidence range [0.04, 12.79], P = 0.82). CONCLUSION: The meta-analysis shows no significant difference in efficacy, long-term survival rates, or complication rates between HIFU and RF ablation for primary liver cancer, but more large-scale, high-quality randomized clinical trials are needed to prove their equivalence. Both therapy strategies seem promising, but additional information is needed to determine their respective merits. [ABSTRACT FROM AUTHOR]

Interest in applications of protein crystallography to medicine was evident, as the first high-resolution structures emerged in the 50s and 60s. In Cambridge, Max Perutz and John Kendrew sought to understand mutations in sickle cell and other genetic diseases related to hemoglobin, while in Oxford, the group of Dorothy Hodgkin became interested in long-lasting zinc-insulin crystals for treatment of diabetes and later considered insulin redesign, as synthetic insulins became possible. The use of protein crystallography in structure-guided drug discovery emerged as enzyme structures allowed the identification of potential inhibitor-binding sites and optimization of interactions of hits using the structure of the target protein. Early examples of this approach were the use of the structure of renin to design antihypertensives and the structure of HIV protease in design of AIDS antivirals. More recently, use of structure-guided design with fragment-based drug discovery, which reduces the size of screening libraries by decreasing complexity, has improved ligand efficiency in drug design and has been used to progress three oncology drugs through clinical trials to FDA approval. We exemplify current developments in structure-guided target identification and fragment-based lead discovery with efforts to develop new antimicrobials for mycobacterial infections. [ABSTRACT FROM AUTHOR]

Background Allergen immunotherapy ( AIT) is an effective treatment for allergic rhinoconjunctivitis ( AR) with or without asthma. It is important to note that due to the complex interaction between patient, allergy triggers, symptomatology and vaccines used for AIT, some patients do not respond optimally to the treatment. Furthermore, there are no validated or generally accepted candidate biomarkers that are predictive of the clinical response to AIT. Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers. Method The EAACI taskforce reviewed all candidate biomarkers used in clinical trials of AR patients with/without asthma in a literature review. Biomarkers were grouped into seven domains: (i) IgE (total IgE, specific IgE and sIgE/Total IgE ratio), (ii) IgG-subclasses ( sIgG1, sIgG4 including SIgE/IgG4 ratio), (iii) Serum inhibitory activity for IgE (IgE- FAB and IgE- BF), (iv) Basophil activation, (v) Cytokines and Chemokines, (vi) Cellular markers (T regulatory cells, B regulatory cells and dendritic cells) and (vii) In vivo biomarkers (including provocation tests?). Results All biomarkers were reviewed in the light of their potential advantages as well as their respective drawbacks. Unmet needs and specific recommendations on all seven domains were addressed. Conclusions It is recommended to explore the use of allergen-specific IgG4 as a biomarker for compliance. sIgE/ tIgE and IgE-FAB are considered as potential surrogate candidate biomarkers. Cytokine/chemokines and cellular reponses provided insight into the mechanisms of AIT. More studies for confirmation and interpretation of the possible association with the clinical response to AIT are needed. [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]

OBJECTIVE: At present, there are various surgical repair strategies for the lateral stability of chronic ankle instability after the injury of the lateral collateral ligament of the ankle, but the specific repair strategy to maximize the recovery of lateral stability of the ankle still lacks of evidence-based medical evidence. Based on this, for the first time, this paper systematically evaluated the effects of four popular repair strategies to restore the lateral stability of chronic ankle instability using the network meta-analysis method. METHODS: Computer retrieval was conducted on CNKI, WanFang, VIP, PubMed, Embase, Web of Science and Cochrane Library. The retrieval time was from the establishment of each database to December 2022. The randomized controlled trials or clinical controlled trials on different repair strategies to recover chronic ankle instability after injury of the lateral ligament of the ankle were included. The literature was screened and extracted. The literature quality was evaluated and data were analyzed using RevMan 5.4, R4.2 and Stata 14.2 software. RESULTS: Twelve studies (including 10 randomized controlled trials and 2 cohort studies) were included. A total of 673 patients with chronic ankle instability were involved in 4 repair strategies. The observation indicators were: anterior talar translation distance and talar tilt angle of ankle joint stress X-ray film (hereinafter referred to as anterior talar translation distance and talar tilt angle). The results of network meta-analysis showed that: (1) In terms of anterior talar translation distance, the sequence of reticular meta-analysis results from inferior to superior was anatomical repair > anatomical repair + enhancement of inferior extensor retinaculum > internal brake anatomical reconstruction > autologous/allogeneic tendon anatomical reconstruction. (2) In terms of talar tilt angle, the sorting results of reticular meta-analysis from inferior to superior were as follows: anatomical repair > anatomical repair + inferior extensor retinaculum enhancement > internal brace anatomical reconstruction > autologous/allogeneic tendon anatomical reconstruction. CONCLUSION: Anatomical reconstruction strategy of autologous/allogeneic tendon is the first in improving anterior talar translation distance and talar tilt angle, suggesting that this strategy may have the best effect in restoring the stability of chronic joint instability after injury of the lateral ligament of ankle, but more large sample, multicenter, double-blind randomized controlled trials are still needed in the future to further confirm. [ABSTRACT FROM AUTHOR]

An attractive feature of using a Bayesian analysis for a clinical trial is that knowledge and uncertainty about the treatment effect is summarized in a posterior probability distribution. Researchers often find probability statements about treatment effects highly intuitive and the fact that this is not accommodated in frequentist inference is a disadvantage. At the same time, the requirement to specify a prior distribution in order to obtain a posterior distribution is sometimes an artificial process that may introduce subjectivity or complexity into the analysis. This paper considers a compromise involving confidence distributions, which are probability distributions that summarize uncertainty about the treatment effect without the need for a prior distribution and in a way that is fully compatible with frequentist inference. The concept of a confidence distribution provides a posterior–like probability distribution that is distinct from, but exists in tandem with, the relative frequency interpretation of probability used in frequentist inference. Although they have been discussed for decades, confidence distributions are not well known among clinical trial statisticians and the goal of this paper is to discuss their use in analyzing treatment effects from randomized trials. As well as providing an introduction to confidence distributions, some illustrative examples relevant to clinical trials are presented, along with various case studies based on real clinical trials. It is recommended that trial statisticians consider presenting confidence distributions for treatment effects when reporting analyses of clinical trials. [ABSTRACT FROM AUTHOR]

Rotavirus is the leading cause of severe diarrhea in infants and young children. Live attenuated vaccines can lead to horizontal transmission with the risk of vaccine-derived disease in contacts. Transmission of pentavalent human-bovine reassortant rotavirus vaccine (RV5) strains leading to clinical disease was not well evaluated in the pivotal clinical trials, and only a few case reports have been described in the literature. We performed a systematic literature review to investigate secondary transmission of RV5 strains to unvaccinated subjects globally. We searched Embase, Medline for English papers, CNKI, Wan Fang for Chinese papers, and other resources (i.e., conference papers with full text) from January 2005 to June 2021. Eligibility criteria for inclusion were original articles based on non-interventional studies (case-control studies, cohort studies, cross-sectional studies) using RV5 strain transmission as outcomes. Other study or publication types were excluded, such as pre-clinical studies, interventional studies and case reports. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was used, and study quality was assessed using the Newcastle-Ottawa Scale (NOS) for cohort studies and the JBI checklist for cross-sectional studies to assess the risk of bias. The search generated 2,089 articles in total. Seven articles met all inclusion criteria, including six cohort studies and one cross-sectional study. All studies underwent quality assessment and complied with the quality criteria of the NOS or JBI checklist, respectively. Overall, none of the seven studies identified RV5 vaccine-type transmission to an unvaccinated population, in either hospitals or nurseries under a close contact environment. One study reported that 1% of unvaccinated infants had gastrointestinal symptoms, but all symptoms were attributed to other clinical conditions. We found no evidence of horizontal transmission of RV5 strains to unvaccinated infants in a context of a limited amount and the descriptive nature of the identified studies. [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]

The objective of this current opinion paper is to draw global attention to medication adherence, emphasizing its crucial role in drug trials. Frequently, trialists lean on traditional approaches to assess medication adherence, which, while comfortable, may only reveal what trialists desire rather than offering the essential insights needed for informed decision making in drug development. Understanding drug exposure and medication adherence is paramount when evaluating the effectiveness and safety of investigational medications. Without a comprehensive understanding of how patients adhere to their prescribed treatment regimens, the integrity and dependability of clinical trial results can be compromised. This paper emphasizes the need for measures that accurately and reliably assess medication intake behaviors, enabling the differentiation between minor dosing errors and significant deviations that may impact the drug's efficacy and safety. Accurate knowledge of drug exposure empowers researchers to make informed decisions, identify potential confounding factors, and appropriately interpret study outcomes, ultimately ensuring the validity and reliability of the research findings. By prioritizing drug exposure assessment and medication adherence measurement, clinical trials can enhance their scientific rigor, contribute to more accurate evaluations of investigational medications, and ultimately speed up the development process. [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]

Diabetic wounds, a prevalent diabetes complication, pose significant challenges in treatment. MicroRNA-engineered exosomes (miR-exo) are a promising new treatment for diabetic wounds; however, their mechanism remains to be completely understood. Therefore, we aimed to conduct a meta-analysis to evaluate the efficacy of miR-exo treatment in the management of diabetic wounds. To achieve this aim, academic databases, including PubMed, Embase, Web of Science, and the Cochrane Library, were searched for papers published before July 4, 2023. Outcome indicators (e.g., rate of wound healing, neovascular count, rate of re-epithelialization, deposition of collagen, breadth of scar, and inflammatory factors) were assessed. Six studies (total of 72 animals) met inclusion criteria and were analyzed. The amalgamated data revealed that miR-exo treatment exhibited superior results compared to those of control therapy. miR-exo treatment significantly enhanced the rate of wound healing, increased the number of neovascular formations, accelerated the rate of re-epithelialization, increased collagen deposition, reduced scar width, while significantly downregulating the expression of inflammatory factors. Our findings indicate that miR-exo treatment augments overall diabetic wound healing, especially when administered in conjunction with innovative dressings. To ascertain the optimal parameters for miR-exo treatment in managing diabetic wounds, future studies must encompass rigorous, large-scale, double-blinded clinical trials while incorporating long-term follow-up assessments for enhanced reliability and accuracy. [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]

Abstract: Objective: To explore the value of multiple clinical endpoints in the unique setting of ovarian cancer. Methods: A clinical trial workgroup was established by the Society of Gynecologic Oncology to develop a consensus statement via multiple conference calls, meetings and white paper drafts. Results: Clinical trial endpoints have profound effects on late phase clinical trial design, result interpretation, drug development, and regulatory approval of therapeutics. Selection of the optimal clinical trial endpoint is particularly provocative in ovarian cancer where long overall survival (OS) is observed. The lack of new regulatory approvals and the lack of harmony between regulatory bodies globally for ovarian cancer therapeutics are of concern. The advantages and disadvantages of the numerous endpoints available are herein discussed within the unique context of ovarian cancer where both crossover and post-progression therapies potentially uncouple surrogacy between progression-free survival (PFS) and OS, the two most widely supported and utilized endpoints. The roles of patient reported outcomes (PRO) and health related quality of life (HRQoL) are discussed, but even these widely supported parameters are affected by the unique characteristics of ovarian cancer where a significant percentage of patients may be asymptomatic. Original data regarding the endpoint preferences of ovarian cancer advocates is presented. Conclusions: Endpoint selection in ovarian cancer clinical trials should reflect the impact on disease burden and unique characteristics of the treatment cohort while reflecting true patient benefit. Both OS and PFS have led to regulatory approvals and are clinically important. OS remains the most objective and accepted endpoint because it is least vulnerable to bias; however, the feasibility of OS in ovarian cancer is compromised by the requirement for large trial size, prolonged time-line for final analysis, and potential for unintended loss of treatment effect from active post-progression therapies. A large magnitude of effect in PFS improvement should establish benefit, and further communication with regulatory authorities to clarify acceptable endpoints should be undertaken. [Copyright &y& Elsevier]

The U.S. health care system is undergoing a shift from individual clinical practice toward team-based care. This move toward team-based care requires fresh thinking about clinical leadership and responsibilities to ensure that the unique skills of each clinician are used to provide the best care for the patient as the patient's needs dictate, while the team as a whole must work together to ensure that all aspects of a patient's care are coordinated for the benefit of the patient. In this position paper, the American College of Physicians offers principles, definitions, and examples to dissolve barriers that prevent movement toward dynamic clinical care teams. These principles offer a framework for an evolving, updated approach to health care delivery, providing policy guidance that can be useful to clinical teams in organizing the care processes and clinician responsibilities consistent with professionalism. [ABSTRACT FROM AUTHOR]

Rheumatic and musculoskeletal diseases (RMDs) represent a multitude of degenerative, inflammatory and auto-immune conditions affecting millions of people worldwide. Persons with these diseases may potentially experience severe chronic pain, joint damage, increasing disability and even death. With an increasingly ageing population, the prevalence and burden of RMDs are predicted to increase, placing greater demands on the global practice of rheumatology and related healthcare budgets. Effective treatment of RMDs currently faces a number of challenges in both the developed and developing world, and individual countries may face more specific local challenges. However, limited understanding of the burden of RMDs amongst public health professionals and policy-makers means that these diseases are often not considered a public health priority. The objective of this review is to increase awareness of the RMDs and to identify opportunities to address RMD challenges on both a local and global scale. On 26 September 2014, rheumatology experts from five different continents met at the World Forum on Rheumatic and Musculoskeletal Diseases (WFRMD) to discuss and identify some key challenges for the RMDs community today. The outcomes are presented in this review, focusing on access to rheumatology services, diagnostics and therapies, rheumatology education and training and on clinical trials, as well as investigator-initiated and epidemiological research. The long-term vision of the WFRMD is to increase perception of the RMDs as a major burden to society and to explore potential opportunities to improve global and local RMD care. [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]

AbstractIn epidemiological cohort studies, the relative risk is a key measure to gauge the connection between two treatments or exposures. It quantifies the proportional change in the risk of disease due to the application of a specific treatment. However, the conventional methods for calculating relative risk, available in widely-used software, might yield inaccurate results when applied to correlated binary data from studies conducted over time or in clusters. Recently, various techniques have been proposed to estimate the risk ratio for correlated binary data. However, some methods exhibit a tradeoff between maintaining accurate coverage probability (CP) and ensuring an appropriate interval width or location. This paper introduces a new approach to confidently estimating the risk ratio using a hybrid method. This hybrid method combines two distinct confidence intervals (CIs) derived from single risk rates to establish a unified confidence interval for their ratio. Furthermore, we present a methodology to construct a confidence interval for the risk ratio, which builds upon established methods for correlated binary data. This extension incorporates principles such as the design effect and adequate sample sizes commonly used in representative sample surveys. An extensive simulation study is conducted to evaluate the effectiveness of these proposed methods. The performance of the methods is thoroughly examined in various scenarios. Additionally, the practicality of the proposed methods is showcased through three real-life examples. These examples involve comparing the side effects of low-dose tricyclic antidepressants with a placebo, assessing the efficacy of a treatment group in a teratological experiment, and evaluating the efficiency of active drugs in curing infections during clinical trials. [ABSTRACT FROM AUTHOR]

Rationale and Aim Methods Results Conclusion Testing of new drugs through clinical trials is essential in efforts to increase generalizable knowledge. Little is known about the medical students' perception of their participation as research subjects in clinical trials. The aim of this study was to examine the willingness and attitudes of medical students towards participation as volunteer subjects in clinical trials.A cross‐sectional study was conducted among 297 medical students in years 4, 5 and 6 at the University of Belgrade, from October to December 2023. Participants completed a pen‐and‐paper questionnaire including demographic characteristics, opinions on their participation in clinical trials, and attitudes towards clinical trials in general. The validity of the attitude scale was verified.One in five medical students expressed a positive opinion about their participation in clinical trials, with the majority (about one‐half) remaining undecided. General attitudes of students about research and their participation were positive. Students with prior blood donation experience were more willing to participate. Lower socioeconomic status and volunteering experience were also associated with stronger positive attitudes towards clinical trials in general.Most students were undecided about their participation, but their attitudes towards clinical trials in general were positive. Positive attitudes towards clinical trials did not uniformly translate to the willingness for personal participation. Promotion of blood donation and volunteering at universities could help to increase the interest in clinical trials as volunteer subjects. [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]

Neurological disorders (NDs) are diseases that seriously affect the health of individuals worldwide, potentially leading to a significant reduction in the quality of life for patients and their families. Herbal medicines have been widely used in the treatment of NDs due to their multi-target and multi-pathway features. Ginkgo biloba leaves (GBLs), one of the most popular herbal medicines in the world, have been demonstrated to present therapeutic effects on NDs. However, the pharmacological mechanisms of GBLs in the treatment of neurological disorders have not been systematically summarized. This study aimed to summarize the molecular mechanism of GBLs in treating NDs from the cell models, animal models, and clinical trials of studies. Four databases, i.e., PubMed, Google Scholar, CNKI, and Web of Science were searched using the following keywords: "Ginkgo biloba", "Ginkgo biloba extract", "Ginkgo biloba leaves", "Ginkgo biloba leaves extract", "Neurological disorders", "Neurological diseases", and "Neurodegenerative diseases". All items meeting the inclusion criteria on the treatment of NDs with GBLs were extracted and summarized. Additionally, PRISMA 2020 was performed to independently evaluate the screening methods. Out of 1385 records in the database, 52 were screened in relation to the function of GBLs in the treatment of NDs; of these 52 records, 39 were preclinical trials and 13 were clinical studies. Analysis of pharmacological studies revealed that GBLs can improve memory, cognition, behavior, and psychopathology of NDs and that the most frequently associated GBLs are depression, followed by Alzheimer's disease, stroke, Huntington's disease, and Parkinson's disease. Additionally, the clinical studies of depression, AD, and stroke are the most common, and most of the remaining ND data are available from in vitro or in vivo animal studies. Moreover, the possible mechanisms of GBLs in treating NDs are mainly through free radical scavenging, anti-oxidant activity, anti-inflammatory response, mitochondrial protection, neurotransmitter regulation, and antagonism of PAF. This is the first paper to systematically and comprehensively investigate the pharmacological effects and neuroprotective mechanisms of GBLs in the treatment of NDs thus far. All findings contribute to a better understanding of the efficacy and complexity of GBLs in treating NDs, which is of great significance for the further clinical application of this herbal medicine. [ABSTRACT FROM AUTHOR]

Influence from bias is unavoidable in clinical decision-making, and mental health assessment seems particularly vulnerable. Individuals with intellectual disabilities have increased risk of developing co-occurring mental disorder. Due to the inherent difficulties associated with intellectual disabilities, assessment of mental health in this population often relies on a different set of strategies, and it is unclear how these may affect risk of bias. In this theoretical paper, we apply recent conceptualisations of bias in clinical decision-making to the specific challenges and strategies in mental health assessment in intellectual disabilities. We suggest that clinical decision-making in these assessments is particularly vulnerable to bias, including sources of bias present in mental health assessment in the general population, as well as potential sources of bias which may be specific to assessments in this population. It follows that to manage potential bias, triangulating information from multi-informant, multi-method, interdisciplinary assessment strategies is likely to be necessary. [ABSTRACT FROM AUTHOR]

High-grade gliomas (HGGs) constitute the most common malignant primary brain tumor with a poor prognosis despite the standard multimodal therapy. In recent years, immunotherapy has changed the prognosis of many cancers, increasing the hope for HGG therapy. We conducted a comprehensive search on PubMed, Scopus, Embase, and Web of Science databases to include relevant studies. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Fifty-two papers were finally included (44 phase II and eight phase III clinical trials) and further divided into four different subgroups: 14 peptide vaccine trials, 15 dendritic cell vaccination (DCV) trials, six immune checkpoint inhibitor (ICI) trials, and 17 miscellaneous group trials that included both "active" and "passive" immunotherapies. In the last decade, immunotherapy created great hope to increase the survival of patients affected by HGGs; however, it has yielded mostly dismal results in the setting of phase III clinical trials. An in-depth analysis of these clinical results provides clues about common patterns that have led to failures at the clinical level and helps shape the perspective for the next generation of immunotherapies in neuro-oncology. [ABSTRACT FROM AUTHOR]

Background: Vocabulary learning in a second language (L2) encompasses crucial aspects, including single words and collocations. Research indicates that L2 learners can incidentally learn single words from captioned videos, but less is known about the incidental learning outcomes of collocations, let alone the differences in learning gains for single words and collocations under different captioned conditions, as well as individual differences that may account for such differences. Objectives: This study aimed to fill this gap by comparing the learning gains of single words and collocations while investigating the influence of vocabulary knowledge (VK) and working memory (WM) on the learning results within diverse forms of captioning conditions: full captions, keyword captions, and no captions. Methods: The study involved 129 young Chinese ESL learners who completed vocabulary tests assessing their meaning recall before, immediately after, and 2 weeks after the study, as well as tests for VK and WM. Results and Conclusions: The results showed that full captions are the most efficacious condition for enhancing both single word and collocation learning. The depth of VK, as well as phonological and complex WM, were significant factors in the learning of new language items. Takeaways: Different types of captioning (full or keyword) contribute differently to the learning of various language items. Individual differences in WM and depth of VK among learners should be considered when utilizing captioned videos for language learning. Lay Description: What is already known about this topic: The type of captions employed does influence incidental single word learning.Incidental collocation learning from captioned videos is worth to be investigated due to the essential role of collocation knowledge in L2 development and the limited classroom time.The breadth of prior vocabulary knowledge (VK) does impact the incidental learning of single words across different captioned conditions. However, the findings remain inconclusive.Working memory (WM) plays a vital role in single word learning. However, limited emphasis has been placed on the examination of how WM affects the incidental learning of collocations across various captioning conditions. What this paper adds: Different captioned conditions play different roles in the incidental learning of different language units: single word learning benefits most from full captioning, whereas both full and keyword captioning lead to significant improvements in incidental collocation learning.The depth of VK is a key determinant of both single word and collocation learning from captioned videos, but its impact is greater for collocations.The breadth of VK is more relevant to collocation learning than single word learning.Both phonological and complex WM play an important role in learning both single words and collocations, but their contribution is greater for collocations. Implications for practice and/or policy: L2 policymakers can incorporate short storytelling videos into the EFL curriculum to facilitate vocabulary learning among young learners and ultimately enhance their L2 proficiency.Teachers can strategically design and implement various types of captioned videos (full or keyword) as out‐of‐class extensive viewing activities, targeting different language components such as single words and collocations.Teachers should be mindful of individual differences (e.g., VK and WM) among learners when utilizing captioned videos for language learning, particularly when it comes to incidental collocation learning.Parents are encouraged to include short storytelling videos with captions as part of their children's home entertainment activities. [ABSTRACT FROM AUTHOR]

Methods for designing and analyzing multiple arms survival trials that incorporate patient's treatment choice are needed. In these trials, patients are randomized into two groups, random and choice. Participants in the choice group choose their treatment, which is not a current standard practice in randomized clinical trials. In this paper, we propose a new method based on the likelihood function to design and analyze these trials with time to event outcomes in the presence of non-informative right censoring. We use simulations to evaluate the methods for Weibull outcomes, complete and censored. Finally, we provide an illustration for designing a study in which we discuss some design considerations and demonstrate the methods. [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]

Aim: This scoping review aimed to identify and appraise the effectiveness and impact of breastfeeding promotion interventions conducted across Portuguese- speaking sovereign countries. Methods: Using the PRISMA-ScR guidelines, we searched 14 electronic databases for publications published through 31 July 2023. The search terms were designed to find studies promoting breastfeeding or exclusive breastfeeding in pre- defined Portuguese- speaking countries. Results: Of the 5263 papers initially retrieved, 30 interventional studies on breastfeeding met the inclusion criteria across three countries: Brazil (N = 26), Portugal (N = 2) and Guinea Bissau (N = 2). Participants ranged from pregnant women, mothers, mother-infant pairs, healthcare professionals, and school children. Overall, the interventions increased exclusive breastfeeding and better breastfeeding practices, such as a higher duration of breastfeeding. The interventions positively affected maternal breastfeeding self-efficacy, knowledge and perception. Only four studies used a theoretical framework. Conclusion: While the results were often statistically significant, no study had an outcome close to the recommended UNICEF and WHO goal of 70% breastfeeding at six months. The need to determine what works for the recommended six months postpartum period is critical for maximising children's health in Portuguese- speaking countries. [ABSTRACT FROM AUTHOR]

Background: Afferent neuronal hypersensitization via P2X3 receptor signaling has been implicated as a driver of several disorders, including refractory chronic cough, endometriosis, diabetic neuropathic pain, and overactive bladder. Eliapixant, a selective P2X3 receptor antagonist, has been in clinical development for all four disorders. Objective: This paper describes pharmacokinetic (PK) and safety data from two phase I studies of eliapixant in healthy Japanese and Chinese participants and compares those data within the two populations and with previous multiple dose data from Caucasian participants. Methods: Two separate phase I, single-center, randomized, placebo-controlled studies were conducted with healthy male participants. The Japanese study was single-blind and the Chinese study was double-blind. Eliapixant was administered as an oral amorphous solid dispersion immediate-release tablet in strengths of 25 mg, 75 mg, and 150 mg. PK characteristics after a single dose (SD) and at steady state (multiple dose [MD], twice daily), adverse events (AEs), and tolerability were evaluated. A post hoc comparison of PK characteristics after SD of eliapixant in Japanese and Chinese participants, and after MD of eliapixant in Japanese, Chinese, and Caucasian participants, was performed. Results: Overall, 36/39 participants enrolled in the Japanese/Chinese studies, respectively (mean [standard deviation] age 25.4 [6.5] and 26.7 [5.0] years, respectively). After SD administration, maximum plasma concentration (Cmax) was higher among Japanese than Chinese participants in the 25 mg and 75 mg dose groups, but comparable in the 150 mg dose group. The area under the concentration–time curve (AUC) was comparable between Japanese and Chinese participants in the 25 mg and 75 mg dose groups, but lower among Japanese participants in the 150 mg group. Half-lives after SD and MD administration were also comparable in Japanese and Chinese participants. The post hoc analysis included 26 Japanese, 30 Chinese, and 50 Caucasian participants. Comparable exposure (Cmax,md and AUC[0–12]md) was observed after MD administration of eliapixant in Chinese and/or Japanese compared with Caucasian participants (geometric mean inter-ethnic ratios close to 1). The trough plasma concentration after eliapixant 150 mg MD, which was assumed to be relevant to eliapixant efficacy, was comparable across all ethnicity groups. Most AEs reported in the Japanese (eliapixant 75 mg SD, n = 2; eliapixant 150 mg MD, n = 2) and Chinese participants (eliapixant 25 mg SD, n = 7; eliapixant 75 mg SD, n = 6; eliapixant 150 mg SD, n = 7; eliapixant 150 mg MD, n = 9; placebo SD, n = 5; placebo MD, n = 1) were of mild intensity. Higher incidences of AEs in the Chinese population were likely due to differing standards of AE reporting between investigators. Conclusion: Eliapixant was well tolerated by Japanese and Chinese participants. The inter-ethnic evaluation demonstrated similar PK characteristics across Japanese, Chinese, and Caucasian participants. Registration: ClinicalTrials.gov identifier numbers: NCT04265781 and NCT04802343. [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]

In phase 2 clinical trials, we expect to make a right Go or No-Go decision during the interim analysis (IA) and make this decision at the right time. The optimal time for IA is usually determined based on a utility function. In most previous research, utility functions aim to minimize the expected sample size or total cost in confirmatory trials. However, the selected time can vary depending on different alternative hypotheses. This paper proposes a new utility function for Bayesian phase 2 exploratory clinical trials. It evaluates the predictability and robustness of the Go and No-Go decision made during the IA. We can make a robust time selection for the IA based on the function regardless of the treatment effect assumptions. [ABSTRACT FROM AUTHOR]

Selecting a safe and clinically beneficial dose can be difficult in drug development. Dose justification often relies on dose-response modeling where parametric assumptions are made in advance which may not adequately fit the data. This is especially problematic in longitudinal dose-response models, where additional parametric assumptions must be made. This paper proposes a class of longitudinal dose-response models to be used in the Bayesian model averaging paradigm which improve trial operating characteristics while maintaining flexibility a priori. A new longitudinal model for non-monotonic longitudinal profiles is proposed. The benefits and trade-offs of the proposed approach are demonstrated through a case study and simulation. [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]

The objective of this paper is to conduct a systematic thematic review of adverse events, safety, and toxicity of traditional ayahuasca plant preparations and its main psychoactive alkaloids (dimethyltryptamine [DMT], harmine, harmaline, and tetrahydroharmine), including discussing clinical considerations (within clinical trials or approved settings). A systematic literature search of preclinical, clinical, epidemiological, and pharmacovigilance data (as well as pertinent reviews and case studies) was conducted for articles using the electronic databases of PubMed and Web of Science (to 6 July 2023) and PsycINFO, ClinicalTrials.gov, and Embase (to 21 September 2022) and included articles in English in peer-reviewed journals. Additionally, reference lists were searched. Due to the breadth of the area covered, we presented the relevant data in a thematic format. Our searches revealed 78 relevant articles. Data showed that ayahuasca or DMT is generally safe; however, some adverse human events have been reported. Animal models using higher doses of ayahuasca have shown abortifacient and teratogenic effects. Isolated harmala alkaloid studies have also revealed evidence of potential toxicity at higher doses, which may increase with co-administration with certain medications. Harmaline revealed the most issues in preclinical models. Nevertheless, animal models involving higher-dose synthetic isolates may not necessarily be able to be extrapolated to human use of therapeutic doses of plant-based extracts. Serious adverse effects are rarely reported within healthy populations, indicating an acceptable safety profile for the traditional use of ayahuasca and DMT in controlled settings. Further randomized, controlled trials with judicious blinding, larger samples, and longer duration are needed. [ABSTRACT FROM AUTHOR]

In the ongoing, randomised, double-blind phase 3 TOPAZ-1 study, durvalumab, a PD-L1 inhibitor, plus gemcitabine and cisplatin was associated with significant improvements in overall survival compared with placebo, gemcitabine, and cisplatin in people with advanced biliary tract cancer at the pre-planned intermin analysis. In this paper, we present patient-reported outcomes from TOPAZ-1. In TOPAZ-1 (NCT03875235), participants aged 18 years or older with previously untreated, unresectable, locally advanced, or metastatic biliary tract cancer with an Eastern Cooperative Oncology Group performance status of 0 or 1 and one or more measurable lesions per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) were randomly assigned (1:1) to the durvalumab group or the placebo group using a computer-generated randomisation scheme. Participants received 1500 mg durvalumab or matched placebo intravenously every 3 weeks (on day 1 of the cycle) for up to eight cycles in combination with 1000 mg/m2 gemcitabine and 25 mg/m2 cisplatin intravenously on days 1 and 8 every 3 weeks for up to eight cycles. Thereafter, participants received either durvalumab (1500 mg) or placebo monotherapy intravenously every 4 weeks until disease progression or other discontinuation criteria were met. Randomisation was stratified by disease status (initially unresectable vs recurrent) and primary tumour location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer). Patient-reported outcomes were assessed as a secondary outcome in all participants who completed the European Organisation for Research and Treatment of Cancer's 30-item Quality of Life of Cancer Patients questionnaire (QLQ-C30) and the 21-item Cholangiocarcinoma and Gallbladder Cancer Quality of Life Module (QLQ-BIL21). We calculated time to deterioration—ie, time from randomisation to an absolute decrease of at least 10 points in a patient-reported outcome that was confirmed at a subsequent visit or the date of death (by any cause) in the absence of deterioration—and adjusted mean change from baseline in patient-reported outcomes. Between April 16, 2019, and Dec 11, 2020, 685 participants were enrolled and randomly assigned, 341 to the durvalumab group and 344 to the placebo group. Overall, 345 (50%) of participants were male and 340 (50%) were female. Data for the QLQ-C30 were available for 318 participants in the durvalumab group and 328 in the placebo group (median follow-up 9·9 months [IQR 6·7 to 14·1]). Data for the QLQ-BIL21 were available for 305 participants in the durvalumab group and 322 in the placebo group (median follow-up 10·2 months [IQR 6·7 to 14·3]). The proportions of participants in both groups who completed questionnaires were high and baseline scores were mostly similar across treatment groups. For global health status or quality of life, functioning, and symptoms, we noted no difference in time to deterioration or adjusted mean changes from baseline were observed between groups. Median time to deterioration of global health status or quality of life was 7·4 months (95% CI 5·6 to 8·9) in the durvalumab group and 6·7 months (5·6 to 7·9) in the placebo group (hazard ratio 0·87 [95% CI 0·69 to 1·12]). The adjusted mean change from baseline was 1·23 (95% CI –0·71 to 3·16) in the durvalumab group and 0·35 (–1·63 to 2·32) in the placebo group. The addition of durvalumab to gemcitabine and cisplatin did not have a detrimental effect on patient-reported outcomes. These results suggest that durvalumab, gemcitabine, and cisplatin is a tolerable treatment regimen in patients with advanced biliary tract cancer. AstraZeneca. [ABSTRACT FROM AUTHOR]

Immunotherapy has transformed the endometrial cancer treatment landscape, particularly for those exhibiting mismatch repair deficiency [MMRd/microsatellite instability-hypermutated (MSI-H)]. A growing body of evidence supports the integration of immunotherapy with chemotherapy as a first-line treatment strategy. Recently, findings from ongoing trials such as RUBY (NCT03981796), NRG-GY018 (NCT03914612), AtTEnd (NCT03603184), and DUO-E (NCT04269200) have been disclosed. This paper constitutes a review and meta-analysis of phase III trials investigating the role of immunotherapy in the first-line setting for advanced or recurrent endometrial cancer. The pooled data from 2320 patients across these trials substantiate the adoption of chemotherapy alongside immunotherapy, revealing a significant improvement in progression-free survival compared to chemotherapy alone [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.62-0.79] across all patient groups. Progression-free survival benefits are more pronounced in MMRd/MSI-H tumors (n = 563; HR 0.33, 95% CI 0.23-0.43). This benefit, albeit less robust, persists in the MMR-proficient/microsatellite stable group (n = 1757; HR 0.74, 95% CI 0.60-0.91). Pooled data further indicate that chemotherapy plus immunotherapy enhances overall survival compared to chemotherapy alone in all patients (HR 0.75, 95% CI 0.63-0.89). However, overall survival data maturity remains low. The incorporation of immunotherapy into the initial treatment for advanced and metastatic endometrial cancer brings about a substantial improvement in oncologic outcomes, especially within the MMRd/MSI-H subset. This specific subgroup is currently a focal point of investigation for evaluating the potential of chemotherapy-free regimens. Ongoing exploratory analyses aim to identify non-responding patients eligible for inclusion in clinical trials. • Immunotherapy added to chemotherapy improves disease-free and overall survival in advanced and metastatic endometrial cancer. • Endometrial cancer is the malignancy with the highest prevalence of MMRd/MSI-H. • MMRd/MSI-H is an agnostic biomarker suggesting the efficacy of immunotherapy. • Immunotherapy plus chemotherapy improves progression-free survival even in the MMR-proficient population. [ABSTRACT FROM AUTHOR]

Sarcopenia is a prevalent degenerative skeletal muscle condition in the elderly population, posing a tremendous burden on diseased individuals and healthcare systems worldwide. Conventionally, sarcopenia is currently managed through nutritional interventions, physical therapy, and lifestyle modification, with no pharmaceutical agents being approved for specific use in this disease. As the pathogenesis of sarcopenia is still poorly understood and there is no treatment recognized as universally effective, recent research efforts have been directed at better comprehending this illness and diversifying treatment strategies. In this respect, this paper overviews the new advances in sarcopenia treatment in correlation with its underlying mechanisms. Specifically, this review creates an updated framework for sarcopenia, describing its etiology, pathogenesis, risk factors, and conventional treatments, further discussing emerging therapeutic approaches like new drug formulations, drug delivery systems, stem cell therapies, and tissue-engineered scaffolds in more detail. [ABSTRACT FROM AUTHOR]

In recent years, gut microbiome has evolved as a focal point of interest with growing recognition that a well-balanced gut microbiota is highly relevant to an individual's health status. The present review provides a mechanistic insight on the effects of cocoa chemicals on the gut microbiome and further reveals in silico biomarkers, taxonomic and functional features that distinguish gut microbiome of cocoa consumers and controls by using 16S rRNA gene sequencing data. The polyphenols in cocoa can change the gut microbiota either by inhibiting the growth of pathogenic bacteria in the gut such as Clostridium perfringens or by increasing the growth of beneficial microbiota in the gut such as Lactobacillus and Bifidobacterium. This paper demonstrates the holistic effect of gut microbiota on cocoa chemicals and how it impacts human health. We present herein the first comprehensive review and analysis of how raw and roasted cocoa and its products can specifically influence gut homeostasis, and likewise, how microbiota metabolizes cocoa chemicals. In addition to that, our 16S rRNA amplicon sequencing analysis revealed that the flavone and flavonols metabolism, aminobenzoate degradation and fatty acid elongation pathways represent the three most important signatures of microbial functions associated with cocoa consumption. [ABSTRACT FROM AUTHOR]

The aim of this paper was to analyze the acute and chronic effects of physical activity (PA) on cognition, behavior, and motor skill in youth with autism spectrum disorder (ASD), taking into account potential confounders. In addition, it was intended to elaborate a guide of educational applications with strategies for PA use. Studies were identified in four databases from January 2010 to June 2023. A total of 19 interventional studies met the inclusion criteria. PA programs ranged from two weeks to one year in duration, with a frequency of one to five sessions per week. More than 58% of the studies showed positive effects of PA on cognition, and 45.5% on behavior and motor skill. Moderate–vigorous PA for 15–30 min has shown acute effects on cognition, general behavior, and stereotypic/repetitive behaviors in youth with ASD. A total of 9 out of 14 studies showed chronic effects on general behavior and stereotypic behaviors, and only 6 on motor skills. [ABSTRACT FROM AUTHOR]