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Contains fulltext : 235396.pdf (Publisher’s version ) (Open Access) In the last decade there has been a revolution in terms of genetic findings in neurodevelopmental disorders (NDDs), with many discoveries critical for understanding their aetiology and pathophysiology. Clinical trials in single-gene disorders such as fragile X syndrome highlight the challenges of investigating new drug targets in NDDs. Incorporating a developmental perspective into the process of drug development for NDDs could help to overcome some of the current difficulties in identifying and testing new treatments. This paper provides a summary of the proceedings of the 'New Frontiers Meeting' on neurodevelopmental disorders organised by the European College of Neuropsychopharmacology in conjunction with the Innovative Medicines Initiative-sponsored AIMS-2-TRIALS consortium. It brought together experts in developmental genetics, autism, NDDs, and clinical trials from academia and industry, regulators, patient and family associations, and other stakeholders. The meeting sought to provide a platform for focused communication on scientific insights, challenges, and methodologies that might be applicable to the development of CNS treatments from a neurodevelopmental perspective. Multidisciplinary translational consortia to develop basic and clinical research in parallel could be pivotal to advance knowledge in the field. Although implementation of clinical trials for NDDs in paediatric populations is widely acknowledged as essential, safety concerns should guide each aspect of their design. Industry and academia should join forces to improve knowledge of the biology of brain development, identify the optimal timing of interventions, and translate these findings into new drugs, allowing for the needs of users and families, with support from regulatory agencies.

Author(s): Anker, Stefan D; Butler, Javed; Khan, Muhammad Shahzeb; Abraham, William T; Bauersachs, Johann; Bocchi, Edimar; Bozkurt, Biykem; Braunwald, Eugene; Chopra, Vijay K; Cleland, John G; Ezekowitz, Justin; Filippatos, Gerasimos; Friede, Tim; Hernandez, Adrian F; Lam, Carolyn SP; Lindenfeld, JoAnn; McMurray, John JV; Mehra, Mandeep; Metra, Marco; Packer, Milton; Pieske, Burkert; Pocock, Stuart J; Ponikowski, Piotr; Rosano, Giuseppe MC; Teerlink, John R; Tsutsui, Hiroyuki; Van Veldhuisen, Dirk J; Verma, Subodh; Voors, Adriaan A; Wittes, Janet; Zannad, Faiez; Zhang, Jian; Seferovic, Petar; Coats, Andrew JS | Abstract: The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has important implications for the safety of participants in clinical trials and the research staff caring for them and, consequently, for the trials themselves. Patients with heart failure may be at greater risk of infection with COVID-19 and the consequences might also be more serious, but they are also at risk of adverse outcomes if their clinical care is compromised. As physicians and clinical trialists, it is our responsibility to ensure safe and effective care is delivered to trial participants without affecting the integrity of the trial. The social contract with our patients demands no less. Many regulatory authorities from different world regions have issued guidance statements regarding the conduct of clinical trials during this COVID-19 crisis. However, international trials may benefit from expert guidance from a global panel of experts to supplement local advice and regulations, thereby enhancing the safety of participants and the integrity of the trial. Accordingly, the Heart Failure Association of the European Society of Cardiology on 21 and 22 March 2020 conducted web-based meetings with expert clinical trialists in Europe, North America, South America, Australia, and Asia. The main objectives of this Expert Position Paper are to highlight the challenges that this pandemic poses for the conduct of clinical trials in heart failure and to offer advice on how they might be overcome, with some practical examples. While this panel of experts are focused on heart failure clinical trials, these discussions and recommendations may apply to clinical trials in other therapeutic areas.

This paper will discuss the integration of electronic Case Report Forms (e-CRFs) into an already existing Android-based Audio Computer-Assisted Self-Interview (ACASI) software solution that was developed for a public health project in Kampala, Uganda, the technical outcome results, and lessons learned that may be useful to other projects requiring or considering such a technology solution. The developed product can function without a connection to the Internet and allows for synchronizing collected data once connectivity is possible. Previously, only paper-based CRFs were utilized at the Uganda project site. A subset or select group of CRFs were targeted for integration with ACASI in order to test feasibility and success. Survey volume, error rate, and acceptance of the system, as well as the operational and technical design of the solution, will be discussed.

BACKGROUND AND OBJECTIVES: There is considerable actual and potential waste in research. The aim of this article is to describe how using an evidence-based research approach before conducting a study helps to ensure that the new study truly adds value.STUDY DESIGN AND SETTING: Evidence-based research is the use of prior research in a systematic and transparent way to inform a new study so that it is answering questions that matter in a valid, efficient, and accessible manner. In this second article of the evidence-based research series, we describe how to apply an evidence-based research approach before starting a new study.RESULTS: Before a new study is performed, researchers need to provide a solid justification for it using the available scientific knowledge as well as the perspectives of end users. The key method for both is to conduct a systematic review of earlier relevant studies.CONCLUSION: Describing the ideal process illuminates the challenges and opportunities offered through the suggested evidence-based research approach. A systematic and transparent approach is needed to provide justification for and to optimally design a relevant and necessary new study.

Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed.

The Fourth Universal Definition of Myocardial Infarction (FUDMI) focuses on the distinction between nonischemic myocardial injury and myocardial infarction (MI), along with the role of cardiovascular magnetic resonance, in order to define the etiology of myocardial injury. As a consequence, there is less emphasis on updating the parts of the definition concerning the electrocardiographic (ECG) changes related to MI. Evidence of myocardial ischemia is a prerequisite for the diagnosis of MI, and the ECG is the main available tool for (a) detecting acute ischemia, (b) triage, and (c) risk stratification upon presentation. This review focuses on multiple aspects of ECG interpretation that we firmly believe should be considered for incorporation in any future update to the Universal Definition of MI.

The inclusion of pharmacists in the healthcare system of a developing country like Pakistan has always been a subject of debate among the healthcare professionals (HCPs), especially physicians, who have long ruled the healthcare system alone and who have had a long-held position of supremacy. The common argument against the inclusion of pharmacists is the dynamics of the healthcare system, and patients being physician oriented, hence, consider the inclusion of pharmacists as no good. Although the trend of defiance is changing, it is worthwhile mentioning here that the concept of the inclusion of pharmacist was implemented in developed countries by an evidence-based approach, i.e., to actually involve pharmacists in the disease state management of a patient and conducting a trial. This opinion calls for the same to be implemented in a developing country like Pakistan to evaluate its significance.

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

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

Background Person-centred care (PCC) has been suggested as a potential means to improve the care of patients with chronic and long-term disorders. In this regard, a model for PCC was developed by the University of Gothenburg Centre for Person-Centred Care (GPCC). Objective The present study aimed to explore the theoretical frameworks, designs, contexts and intervention characteristics in the first 27 interventional studies conducted based on the ethics for person-centredness provided by the GPCC. Design Cross-sectional study. Setting and participants A questionnaire to the principal investigators of the 27 intervention studies financed by the GPCC and conducted between 2010 and 2016. Main outcome measures Theoretical frameworks, contexts of studies, person-centred ethic, and outcome measures. Results Most of the interventions were based on the same ethical assumptions for person-centredness but theories and models in applying the interventions differed. All studies were controlled; 12 randomized and 15 quasi-experimental. Hospital in- and outpatient and primary care settings were represented and the outcome measures were related to the specific theories used. A complexity in designing, introducing and evaluating PCC interventions was evident. Conclusion The frameworks, designs and interventions in the studies were in line with the established ethical basis of PCC, whereas outcome measures varied widely. Consensus discussions among researchers in the field are needed to make comparisons between studies feasible. Patient or public contributions Patients or the public made no direct contributions, although most of the studied projects included such initiatives.

Background: There is a lack of evidence to guide treatment of comorbid depression and anxiety. Preliminary evidence suggests mirtazapine may be effective in treating patients with both depression and anxiety symptoms. Methods: We undertook a secondary analysis of mirtazapine (MIR): a placebo-controlled trial of the addition of mirtazapine to a selective serotonin reuptake inhibitor or serotonin–norepinephrine reuptake inhibitor in treatment-resistant depression (TRD) in primary care. We subdivided participants into three groups by baseline generalized anxiety disorder score (GAD-7): severe (GAD-7 ⩾ 16), moderate (GAD-7 = 11–15), no/mild (GAD-7 ⩽ 10). We used linear regression including likelihood-ratio testing of interaction terms to assess how baseline anxiety altered the response of participants to mirtazapine as measured by 12-week GAD-7 and Beck Depression Inventory II (BDI-II) scores. Results: Baseline generalized anxiety moderated mirtazapine’s effect as measured by GAD-7 ( p = 0.041) and BDI-II ( p = 0.088) at 12 weeks. Participants with severe generalized anxiety receiving mirtazapine had lower 12-week GAD-7 score (adjusted difference between means (ADM) −2.82, 95% confidence interval (CI) −0.69 to −4.95) and larger decreases in BDI-II score (ADM −6.36, 95% CI −1.60 to −10.84) than placebo. Conversely, there was no anxiolytic benefit (ADM 0.28, 95% CI −1.05 to 1.60) or antidepressant benefit (ADM −0.17, 95% CI −3.02 to 2.68) compared with placebo in those with no/mild generalized anxiety. Conclusions: These findings extend the evidence for the effectiveness of mirtazapine to reduce generalized anxiety in TRD in primary care. These results may inform targeted prescribing in depression based on concurrent anxiety symptoms, although these conclusions are constrained by the post-hoc nature of this analysis.

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

In studies with recurrent event endpoints, misspecified assumptions of event rates or dispersion can lead to underpowered trials or overexposure of patients. Specification of overdispersion is often a particular problem as it is usually not reported in clinical trial publications. Changing event rates over the years have been described for some diseases, adding to the uncertainty in planning. To mitigate the risks of inadequate sample sizes, internal pilot study designs have been proposed with a preference for blinded sample size reestimation procedures, as they generally do not affect the type I error rate and maintain trial integrity. Blinded sample size reestimation procedures are available for trials with recurrent events as endpoints. However, the variance in the reestimated sample size can be considerable in particular with early sample size reviews. Motivated by a randomized controlled trial in paediatric multiple sclerosis, a rare neurological condition in children, we apply the concept of blinded continuous monitoring of information, which is known to reduce the variance in the resulting sample size. Assuming negative binomial distributions for the counts of recurrent relapses, we derive information criteria and propose blinded continuous monitoring procedures. The operating characteristics of these are assessed in Monte Carlo trial simulations demonstrating favourable properties with regard to type I error rate, power, and stopping time, ie, sample size.

ABTL0812 is a first-in-class small molecule with anti-cancer activity, which is currently in clinical evaluation in a phase 2 trial in patients with advanced endometrial and squamous non-small cell lung carcinoma (NCT03366480). Previously, we showed that ABTL0812 induces TRIB3 pseudokinase expression, resulting in the inhibition of the AKT-MTORC1 axis and macroautophagy/autophagy-mediated cancer cell death. However, the precise molecular determinants involved in the cytotoxic autophagy caused by ABTL0812 remained unclear. Using a wide range of biochemical and lipidomic analyses, we demonstrated that ABTL0812 increases cellular long-chain dihydroceramides by impairing DEGS1 (delta 4-desaturase, sphingolipid 1) activity, which resulted in sustained ER stress and activated unfolded protein response (UPR) via ATF4-DDIT3-TRIB3 that ultimately promotes cytotoxic autophagy in cancer cells. Accordingly, pharmacological manipulation to increase cellular dihydroceramides or incubation with exogenous dihydroceramides resulted in ER stress, UPR and autophagy-mediated cancer cell death. Importantly, we have optimized a method to quantify mRNAs in blood samples from patients enrolled in the ongoing clinical trial, who showed significant increased DDIT3 and TRIB3 mRNAs. This is the first time that UPR markers are reported to change in human blood in response to any drug treatment, supporting their use as pharmacodynamic biomarkers for compounds that activate ER stress in humans. Finally, we found that MTORC1 inhibition and dihydroceramide accumulation synergized to induce autophagy and cytotoxicity, phenocopying the effect of ABTL0812. Given the fact that ABTL0812 is under clinical development, our findings support the hypothesis that manipulation of dihydroceramide levels might represents a new therapeutic strategy to target cancer., This work was supported by the Centre for Industrial Technological Development [CDTI,INNOGLOBAL/20171061]; European Regional Development Fund [PI18/00442 and PI15/00339]; European Regional Development Fund [INNPACTO/IPT-2012-0614-010000, RETOS RTC-2017-6261-1, SAF2015-64237-R]; Fundació la Marató de TV3 [20134031]; H2020 Marie Skłodowska-Curie Actions [TRAIN GA721532]; Instituto de Salud Carlos III [PI15/00339]; Instituto de Salud Carlos III [PI18/00442]; Ministerio de Ciencia, Innovación y Universidades [CTQ2017- 85378-R]; Ministerio de Economía y Competitividad [RTC-2015-3821-1]; Ministerio de Economía y Competitividad [RTC-2017-6261-1]; Ministerio de Economía y Competitividad [EMP-TU-2015-4576]; Ministerio de Economía y Competitividad [RETOS RTC-2017-6261-1]; Ministerio de Economía y Competitividad [BFU2016-78154-R]; Ministerio de Economía y Competitividad [INNPACTO/IPT-2012-0614-010000]; Ministerio de Economía y Competitividad [SAF2015-64237-R]; Ministerio de Economía y Competitividad [RTC-2014-1532-1].

Purpose The purpose of this review is to quantify the landscape of current clinical trials ongoing for therapies in the treatment of COVID-19. A secondary purpose is to examine the relationship between public and scientific interests in potential therapies for COVID-19. Methods A systematic search of clinicaltrials.gov was undertaken on April 22, 2020, to identify all currently registered clinical trials investigating potential therapies for patients with COVID-19. Public interest in the various therapies was quantified utilizing Google Trends. Public interest in hydroxychloroquine and chloroquine was plotted against the cumulative number of active clinical trials evaluating antimalarials as potential COVID-19 therapies over time. Results There were 341 interventional studies and 208 different therapies actively registered on clinicaltrials.gov whose primary aim is the treatment of COVID-19. The median sample size was 120 patients (range 4–6000) with 154 (45%) trials reporting a planned sample size of 100 patients or less. There was a strong positive correlation (r = 0.76, p = 0.01) between the number of registered clinical trials and the public interest in the top ten proposed therapies. Following the spike in public interest, the average number of new trials increased tenfold with respect to antimalarial therapies. Conclusions The relatively small sample sizes and the number of independent trials investigating similar therapies are concerning. Resources may not be being allocated based on scientific merit and may be driven by public consciousness and speculation. Moving forward, a concerted effort focused on implementing large, well-coordinated and carefully designed multi-armed clinical trials will help to ensure that the most promising therapeutic options are rigorously studied and clinically meaningful results produced.

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

Clinical trials are a fundamental tool used to evaluate the efficacy and safety of new drugs and medical devices and other health system interventions. The traditional clinical trials system acts as a quality funnel for the development and implementation of new drugs, devices and health system interventions. The concept of a “digital clinical trial” involves leveraging digital technology to improve participant access, engagement, trial-related measurements, and/or interventions, enable concealed randomized intervention allocation, and has the potential to transform clinical trials and to lower their cost. In April 2019, the US National Institutes of Health (NIH) and the National Science Foundation (NSF) held a workshop bringing together experts in clinical trials, digital technology, and digital analytics to discuss strategies to implement the use of digital technologies in clinical trials while considering potential challenges. This position paper builds on this workshop to describe the current state of the art for digital clinical trials including (1) defining and outlining the composition and elements of digital trials; (2) describing recruitment and retention using digital technology; (3) outlining data collection elements including mobile health, wearable technologies, application programming interfaces (APIs), digital transmission of data, and consideration of regulatory oversight and guidance for data security, privacy, and remotely provided informed consent; (4) elucidating digital analytics and data science approaches leveraging artificial intelligence and machine learning algorithms; and (5) setting future priorities and strategies that should be addressed to successfully harness digital methods and the myriad benefits of such technologies for clinical research.

Background We conducted a first-in-human dose-escalation study with the oral FASN inhibitor TVB-2640 to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), as monotherapy and with a taxane. Methods This completed open-label outpatient study was conducted at 11 sites in the United States and United Kingdom. Patients with previously-treated advanced metastatic solid tumors and adequate performance status and organ function were eligible. TVB-2640 was administered orally daily until PD. Dose escalation initially followed an accelerated titration design that switched to a standard 3 + 3 design after Grade 2 toxicity occurred. Disease-specific cohorts were enrolled at the MTD. Statistical analyses were primarily descriptive. Safety analyses were performed on patients who received at least 1 dose of study drug. (Clinicaltrials.gov identifier NCT02223247) Findings The study was conducted from 21 November 2013 to 07 February 2017. Overall, 136 patients received TVB-2640, 76 as monotherapy (weight-based doses of 60 mg/m2 to 240 mg/m2 and flat doses of 200 and 250 mg) and 60 in combination, (weight-based doses of 60 mg/m2 to 100 mg/m2 and flat dose of 200 mg) (55 paclitaxel, 5 docetaxel). DLTs with TVB-2640 were reversible skin and ocular effects. The MTD/RP2D was 100 mg/m2. The most common TEAEs (n,%) with TVB-2640 monotherapy were alopecia (46; 61%), PPE syndrome (35; 46%), fatigue (28; 37%), decreased appetite (20; 26%), and dry skin (17; 22%), and with TVB-2640+paclitaxel were fatigue (29 ; 53%), alopecia (25; 46%), PPE syndrome (25; 46%), nausea (22; 40%), and peripheral neuropathy (20; 36%). One fatal case of drug-related pneumonitis occurred with TVB-2640+paclitaxel; no other treatment-related deaths occurred. Target engagement (FASN inhibition) and inhibition of lipogenesis were demonstrated with TVB-2640. The disease control rate (DCR) with TVB-2640 monotherapy was 42%; no patient treated with monotherapy had a complete or partial response (CR or PR). In combination with paclitaxel, the PR rate was 11% and the DCR was 70%. Responses were seen across multiple tumor types, including in patients with KRASMUT NSCLC, ovarian, and breast cancer. Interpretation TVB-2640 demonstrated potent FASN inhibition and a predictable and manageable safety profile, primarily characterized by non-serious, reversible adverse events affecting skin and eyes. Further investigation of TVB-2640 in patients with solid tumors, particularly in KRASMUT lung, ovarian, and breast cancer, is warranted. Funding This trial was funded by 3-V Biosciences, Inc. (now known as Sagimet Biosciences Inc.).

There is growing interest in integrated Phase I/II oncology clinical trials involving molecularly targeted agents (MTA). One of the main challenges of these trials are nontrivial dose–efficacy relationships and administration of MTAs in combination with other agents. While some designs were recently proposed for such Phase I/II trials, the majority of them consider the case of binary toxicity and efficacy endpoints only. At the same time, a continuous efficacy endpoint can carry more information about the agent's mechanism of action, but corresponding designs have received very limited attention in the literature. In this work, an extension of a recently developed information‐theoretic design for the case of a continuous efficacy endpoint is proposed. The design transforms the continuous outcome using the logistic transformation and uses an information–theoretic argument to govern selection during the trial. The performance of the design is investigated in settings of single‐agent and dual‐agent trials. It is found that the novel design leads to substantial improvements in operating characteristics compared to a model‐based alternative under scenarios with nonmonotonic dose/combination–efficacy relationships. The robustness of the design to missing/delayed efficacy responses and to the correlation in toxicity and efficacy endpoints is also investigated.

Background Researchers face challenges in patient recruitment, especially for rare, fatal diseases such as amyotrophic lateral sclerosis (ALS). These challenges include obtaining sufficient statistical power as well as meeting eligibility requirements such as age, sex, and study proximity. Similarly, persons with ALS (PALS) face difficulty finding and enrolling in research studies for which they are eligible. Objective The aim of this study was to describe how the federal Agency for Toxic Substances and Disease Registry’s (ATSDR) National ALS Registry is linking PALS to scientists who are conducting research, clinical trials, and epidemiological studies. Methods Through the Registry’s online research notification mechanism (RNM), PALS can elect to be notified about new research opportunities. This mechanism allows researchers to upload a standardized application outlining their study design and objectives, and proof of Institutional Review Board approval. If the application is approved, ATSDR queries the Registry for PALS meeting the study’s specific eligibility criteria, and then distributes the researcher’s study material and contact information to PALS via email. PALS then need to contact the researcher directly to take part in any research. Such an approach allows ATSDR to protect the confidentiality of Registry enrollees. Results From 2013 to 2019, a total of 46 institutions around the United States and abroad have leveraged this tool and over 600,000 emails have been sent, resulting in over 2000 patients conservatively recruited for clinical trials and epidemiological studies. Patients between the ages of 60 and 69 had the highest level of participation, whereas those between the ages of 18 and 39 and aged over 80 had the lowest. More males participated (4170/7030, 59.32%) than females (2860/7030, 40.68%). Conclusions The National ALS Registry’s RNM benefits PALS by connecting them to appropriate ALS research. Simultaneously, the system benefits researchers by expediting recruitment, increasing sample size, and efficiently identifying PALS meeting specific eligibility requirements. As more researchers learn about and use this mechanism, both PALS and researchers can hasten research and expand trial options for PALS.

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

Response-adaptive randomisation (RAR) can considerably improve the chances of a successful treatment outcome for patients in a clinical trial by skewing the allocation probability towards better performing treatments as data accumulates. There is considerable interest in using RAR designs in drug development for rare diseases, where traditional designs are not either feasible or ethically questionable. In this paper, we discuss and address a major criticism levelled at RAR: namely, type I error inflation due to an unknown time trend over the course of the trial. The most common cause of this phenomenon is changes in the characteristics of recruited patients—referred to as patient drift. This is a realistic concern for clinical trials in rare diseases due to their lengthly accrual rate. We compute the type I error inflation as a function of the time trend magnitude to determine in which contexts the problem is most exacerbated. We then assess the ability of different correction methods to preserve type I error in these contexts and their performance in terms of other operating characteristics, including patient benefit and power. We make recommendations as to which correction methods are most suitable in the rare disease context for several RAR rules, differentiating between the 2-armed and the multi-armed case. We further propose a RAR design for multi-armed clinical trials, which is computationally efficient and robust to several time trends considered.

Background In April 2020, two independent clinical trials to assess SARS-CoV-2 prophylaxis strategies among health care workers were initiated at our hospital: MeCOVID (melatonin vs placebo) and EPICOS (tenofovir disoproxil/emtricitabine vs hydroxychloroquine vs combination therapy vs placebo). Objective This study aimed to evaluate the reasons why health care workers chose to participate in the MeCOVID and EPICOS trials, as well as why they chose one over the other. Methods Both trials were offered to health care workers through an internal news bulletin. After an initial screening visit, all subjects were asked to respond to a web-based survey. Results In the first month, 206 health care workers were screened and 160 were randomized. The survey participation was high at 73.3%. Health care workers cited “to contribute to scientific knowledge” (n=80, 53.0%), followed by “to avoid SARS-CoV-2 infection” (n=33, 21.9%) and “the interest to be tested for SARS-CoV-2” (n=28, 18.5%), as their primary reasons to participate in the trials. We observed significant differences in the expected personal benefits across physicians and nurses (P=.01). The vast majority of volunteers (n=202, 98.0%) selected the MeCOVID trial, their primary reason being their concern regarding adverse reactions to treatments in the EPICOS trial (n=102, 69.4%). Conclusions Health care workers’ reasons to participate in prophylaxis trials in an acute pandemic context appear to be driven largely by their desire to contribute to science and to gain health benefits. Safety outweighed efficacy when choosing between the two clinical trials.

There is a need for measures to track symptom change in autism spectrum disorder (ASD). We conducted a validation study on a revised version of the Autism Behavior Inventory (ABI), and a short form (ABI-S). Caregivers of individuals (6–54 years) with confirmed diagnoses of ASD (N = 144) completed the ABI and other rating scales at 4 time points. Scale consistency for each domain, 3–5 day test–retest reliability, and construct validity, determined by comparison to pre-specified scales, were all good. Change in the ABI was congruent with changes in other instruments. Collectively, results suggest incipient suitability of the ABI as a measure of changes in core and associated symptoms of ASD. Trial Registration NCT02299700. Electronic supplementary material The online version of this article (10.1007/s10803-019-03965-7) contains supplementary material, which is available to authorized users.

Background Clinical trial registries increase transparency in medical research by making information and results of planned, ongoing, and completed studies publicly available. However, the registration of clinical trials remains a time-consuming manual task complicated by the fact that the same studies often need to be registered in different registries with different data entry requirements and interfaces. Objective This study investigates how Health Level 7 (HL7) Fast Healthcare Interoperability Resources (FHIR) may be used as a standardized format for exchanging and storing clinical trial records. Methods We designed and prototypically implemented an open-source central trial registry containing records from university hospitals, which are automatically exported and updated by local study management systems. Results We provided an architecture and implementation of a multisite clinical trials registry based on HL7 FHIR as a data storage and exchange format. Conclusions The results show that FHIR resources establish a harmonized view of study information from heterogeneous sources by enabling automated data exchange between trial centers and central study registries.

Summary Background Certolizumab pegol (CZP) is an Fc‐free, PEGylated anti‐tumour necrosis factor biologic. Objectives To report the 3‐year efficacy of CZP in plaque psoriasis, pooled from the CIMPASI‐1 (NCT02326298) and CIMPASI‐2 (NCT02326272) phase III trials. Methods Adults with moderate‐to‐severe psoriasis for ≥ 6 months were randomized 2 : 2 : 1 to CZP 200 mg, CZP 400 mg or placebo, every 2 weeks (Q2W) for up to 48 weeks. Patients entering the open‐label period (weeks 48–144) from double‐blinded CZP initially received CZP 200 mg Q2W. Patients not achieving ≥ 50% improvement in Psoriasis Area and Severity Index (PASI 50) at week 16 entered an open‐label CZP 400 mg Q2W escape arm (weeks 16–144). Dose adjustments based on PASI response were permitted during open‐label treatment. Outcomes included PASI 75, PASI 90 and Physician’s Global Assessment (PGA) 0/1 responder rates, based on a logistic regression model (missing data imputed using Markov Chain Monte Carlo methodology). Results In total, 186 patients were randomized to CZP 200 mg Q2W and 175 to CZP 400 mg Q2W. At week 48, PASI 75/90 was achieved by 72·7%/51·3% of patients randomized to CZP 200 mg and 84·4%/62·7% randomized to CZP 400 mg. Patients entering the open‐label period at week 48, from blinded treatment, received CZP 200 mg Q2W. At week 144, PASI 75/90 was achieved by 70·6%/48·7% patients randomized to CZP 200 mg and 72·9%/42·7% randomized to CZP 400 mg. At week 16, 72 placebo‐randomized patients entered the CZP 400 mg Q2W escape arm; 75.7%/58.5% achieved PASI 75/90 at week 144. Conclusions Both CZP 200 mg and 400 mg Q2W demonstrated sustained, durable efficacy, with numerically higher responses for some outcomes with 400 mg Q2W., What is already known about this topic? Certolizumab pegol is an Fc‐free, PEGylated, anti‐tumour necrosis factor biologic approved for adults with moderate‐to‐severe plaque psoriasis.Efficacy data from the first 48 weeks of phase III trials have shown significant improvements in the signs and symptoms of psoriasis with certolizumab pegol dosed at either 400 mg or 200 mg every 2 weeks.Numerically greater improvements were observed for patients treated with the higher dose. What does this study add? Plaque psoriasis is a chronic, systemic disease that requires long‐term management and sustained efficacy of therapies.Three‐year efficacy data pooled from the CIMPASI‐1 and CIMPASI‐2 phase III trials demonstrate a sustained and durable response to certolizumab pegol dosed at either 400 mg or 200 mg every 2 weeks.Additional long‐term clinical benefits may be obtained from the higher dose. Linked Comment: Johnson et al. Br J Dermatol 2021; 184:588–589.

Background Population surveillance sites generate many datasets relevant to disease surveillance. However, there is a risk that these data are underutilized because of the volumes of data gathered and the lack of means to quickly disseminate analysis. Data visualization offers a means to quickly disseminate, understand, and interpret datasets, facilitating evidence-driven decision making through increased access to information. Objectives This paper describes the development and evaluation of a framework for data dashboard design, to visualize datasets produced at a demographic health surveillance site. The aim of this research was to produce a comprehensive, reusable, and scalable dashboard design framework to fit the unique requirements of the context. Methods The framework was developed and implemented at a demographic surveillance platform at the Africa Health Research Institute, in KwaZulu-Natal, South Africa. This context represents an exemplar implementation for the use of data dashboards within a population health-monitoring setting. Before the full launch, an evaluation study was undertaken to assess the effectiveness of the dashboard framework as a data communication and decision-making tool. The evaluation included a quantitative task evaluation to assess usability and a qualitative questionnaire exploring the attitudes to the use of dashboards. Results The evaluation participants were drawn from a diverse group of users working at the site (n=20), comprising of community members, nurses, scientific and operational staff. Evaluation demonstrated high usability for the dashboard across user groups, with scientific and operational staff having minimal issues in completing tasks. There were notable differences in the efficiency of task completion among user groups, indicating varying familiarity with data visualization. The majority of users felt that the dashboards provided a clear understanding of the datasets presented and had a positive attitude to their increased use. Conclusions Overall, this exploratory study indicates the viability of the data dashboard framework in communicating data trends within population surveillance setting. The usability differences among the user groups discovered during the evaluation demonstrate the need for the user-led design of dashboards in this context, addressing heterogeneous computer and visualization literacy present among the diverse potential users present in such settings. The questionnaire highlighted the enthusiasm for increased access to datasets from all stakeholders highlighting the potential of dashboards in this context.

Background Novel wearable biosensors, ubiquitous smartphone ownership, and telemedicine are converging to enable new paradigms of clinical research. A new generation of continuous glucose monitoring (CGM) devices provides access to clinical-grade measurement of interstitial glucose levels. Adoption of these sensors has become widespread for the management of type 1 diabetes and is accelerating in type 2 diabetes. In parallel, individuals are adopting health-related smartphone-based apps to monitor and manage care. Objective We conducted a proof-of-concept study to investigate the potential of collecting robust, annotated, real-time clinical study measures of glucose levels without clinic visits. Methods Self-administered meal-tolerance tests were conducted to assess the impact of a proprietary synbiotic medical food on glucose control in a 6-week, double-blind, placebo-controlled, 2×2 cross-over pilot study (n=6). The primary endpoint was incremental glucose measured using Abbott Freestyle Libre CGM devices associated with a smartphone app that provided a visual diet log. Results All subjects completed the study and mastered CGM device usage. Over 40 days, 3000 data points on average per subject were collected across three sensors. No adverse events were recorded, and subjects reported general satisfaction with sensor management, the study product, and the smartphone app, with an average self-reported satisfaction score of 8.25/10. Despite a lack of sufficient power to achieve statistical significance, we demonstrated that we can detect meaningful changes in the postprandial glucose response in real-world settings, pointing to the merits of larger studies in the future. Conclusions We have shown that CGM devices can provide a comprehensive picture of glucose control without clinic visits. CGM device usage in conjunction with our custom smartphone app can lower the participation burden for subjects while reducing study costs, and allows for robust integration of multiple valuable data types with glucose levels remotely. Trial Registration ClinicalTrials.gov NCT04424888; http://clinicaltrials.gov/ct2/show/NCT04424888.

Background To depict a comprehensive changing landscape of anti-lymphoma drug clinical trials in mainland China from 2005 to 2020. Methods A systematic review was conducted on the China National Medical Products Administration Center for Drug Evaluation platform, the Chinese Clinical Trial Registry and ClinicalTrials.gov websites. Findings A total of 797 anti-lymphoma drug clinical trials registered from Jan 1st, 2005 to Aug 1st, 2020 were identified. The number of trials increased gradually over time, and a notable increase was observed in 2016, with the number growing from 29 in 2015 to 72 in 2016. Trials in phase I (26•1%) and phase II (26•6%) represented the majority, followed by phase III (12•5%) and phase IV (7•4%). Regarding sponsorship, industry-sponsored trials (53•2%) accounted for a slightly larger proportion than investigator-initiated trials (IITs) (46•8%). A dramatic growth for IITs was seen during 2017–2020, with the number increasing from 36 in 2017 to 96 in 2020. Additionally, the proportion of trials involving targeted agents (50•2%) accounted for the largest, followed by trials involving immunotherapy agents (41•0%), and cytotoxic agents (8•0%). Besides, a sustainable growth was observed in the number of leading anti-lymphoma drug clinical trial units in mainland China over the past 15 years. The majority of leading principal units (60•8%) were from Beijing, Shanghai, Guangdong and Jiangsu. Interpretation In the past 15 years, the research and development of drugs and clinical trials for lymphoma in mainland China has achieved much progression. Future efforts are needed for improving innovation and sustainability of pharmaceutical research and development. Funding China National Major Project for New Drug Innovation (2017ZX09304015); Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-001).

Approximately one-quarter of human papillomavirus (HPV) infections are acquired by adolescents, with a higher burden among racial/ethnic minorities. However, racial/ethnic minorities have been underrepresented in previous HPV vaccine trials. Ongoing and future HPV vaccine optimization trials would benefit from racially- and ethnically-diverse sample of adolescent trial participants. This study examined factors influencing parental willingness to consent to their adolescents’ participation in HPV vaccine clinical trials and tested for possible racial differences. A convenience sample of parents of adolescents (N = 256) completed a cross-sectional survey. Chi square analyses were used to assess racial differences in parental HPV vaccine awareness and intentions and willingness to consent to their child participating in an HPV vaccine clinical trial. Ordinal logistic regression was used to identify factors associated with willingness. Approximately 47% of parents were willing to allow their adolescent to participate in HPV vaccine clinical trials (30.7% African American and 48.3% Caucasian, p = .081). African Americans had lower HPV vaccine awareness (p = .006) but not lower intentions to vaccinate (p = .086). Parental willingness was positively associated with the following variables: Child’s age (p

One of the aims of the World Health Organisation (WHO) Millennium Development Goals (MDG) is to reduce the number of cases of tuberculosis (TB) infection by the year 2015. However, 9 million new cases were reported in 2013, with an estimated 480,000 new cases of multi-drug resistant tuberculosis (MDR-TB) globally. Bacille Calmette-Guérin (BCG) is the most available and currently used candidate vaccine against tuberculosis; it prevents childhood TB, but its effectiveness against pulmonary TB in adults and adolescents is disputed. To achieve the goal of the WHO MDG, the need for a new improved vaccine is of primary importance. This review highlights several articles that have reported vaccine development. There are about 16 TB vaccines in different phases of clinical trials at the time of writing, which include recombinant peptide/protein, live-attenuated and recombinant live-attenuated, protein/adjuvant, viral-vectored, and immunotherapeutic vaccine. Further studies in reverse vaccinology and massive campaigns on vaccination are needed in order to achieve the target for TB eradication by 2050.

Vaccine clinical trials in low-resource settings have unique challenges due to structural and financial inequities. Specifically, protecting participant and caregiver autonomy to participate in the research study can be a major challenge, so understanding the setting and contextual factors which influence the decision process is necessary. This study investigates the experience of caregivers consenting on behalf of paediatric participants in a malaria vaccine clinical trial where participation enables access to free, high-quality medical care.We interviewed a total of 78 caregivers of paediatric participants previously enrolled in a phase II or III malaria vaccine clinical trial in Uganda, Tanzania and Kenya. Interviews were qualitative and analysed using a thematic framework analysis focusing on the embodied caregiver in the political, economic and social reality.Caregivers of participants in this study made the decision to enrol their child based on economic, social and political factors that extended beyond the trial into the community and the home. The provision of health care was the dominant reason for participation. Respondents reported how social networks, rumours, hierarchal structures, financial constraints and family dynamics affected their experience with research.The provision of medical care was a powerful motivator for participation. Caregiver choice was limited by structural constraints and scarce financial resources. The decision to participate in research extended beyond individual consent and was embedded in community and domestic hierarchies. Future research should assess other contexts to determine how the choice to participate in research is affected when free medical care is offered.Les essais cliniques de vaccins dans les régions à faibles ressources présentent des défis uniques en raison d'iniquités structurelles et financières. En particulier, la protection de l'autonomie des participants et des soignants dans la participation à l’étude de recherche peut être un défi majeur. Il est donc nécessaire de comprendre le contexte et les facteurs contextuels qui influencent le processus de décision. Cette étude examine l'expérience de soignants consentants au nom de participants pédiatriques à un essai clinique de vaccin antipaludique où la participation permet l'accès à des soins médicaux gratuits et de haute qualité. MÉTHODES: Nous avons interviewé un total de 78 soignants de participants pédiatriques qui avaient participé à un essai clinique de vaccin antipaludique de phase II ou III en Ouganda, en Tanzanie et au Kenya. Les entretiens ont été qualitatifs et analysés à l'aide d'une analyse de cadre thématique centrée sur le soignant, en tenant compte de la réalité politique, économique et sociale. RÉSULTATS: Les soignants des participants à cette étude ont pris la décision d'inscrire leur enfant sur base de facteurs économiques, sociaux et politiques qui s’étendaient au-delà de l'essai dans la communauté et à la maison. La fourniture de soins de santé était la principale raison de la participation. Les répondants ont rapporté comment les réseaux sociaux, les rumeurs, les structures hiérarchiques, les contraintes financières et la dynamique familiale ont affecté leur expérience avec la recherche.La fourniture de soins médicaux était un puissant facteur de motivation pour la participation. Le choix du soignant était limité par des contraintes structurelles et les ressources financières limitées. La décision de participer à la recherche allait au-delà du consentement individuel et s'inscrivait dans les hiérarchies communautaires et domestiques. Les recherches futures devraient évaluer d'autres contextes afin de déterminer comment le choix de participer à la recherche est affecté par la gratuité des soins médicaux.

Background This study aims to evaluate the quality of preclinical data, determine the effect sizes, and identify experimental measures that inform efficacy using mesenchymal stromal (or stem) cells (MSC) therapy in animal models of rheumatoid arthritis (RA). Methods Literature searches were performed on MSC preclinical studies to treat RA. MSC treatment effect sizes were determined by the most commonly used outcome measures, including paw thickness, clinical score, and histological score. Findings A total of 48 studies and 94 treatment arms were included, among which 42 studies and 79 treatment arms reported that MSC improved outcomes. The effect sizes of RA treatments using MSC, when compared to the controls, were: paw thickness was ameliorated by 53.6% (95% confidence interval (CI): 26.7% −80.4%), histological score was decreased by 44.9% (95% CI: 33.3% −56.6%), and clinical score was decreased by 29.9% (95% CI: 16.7% −43.0%). Specifically, our results indicated that human umbilical cord derived MSC led to large improvements of the clinical score (−42.1%) and histological score (−51.4%). Interpretation To the best of our knowledge, this meta-analysis is to quantitatively answer whether MSC represent a robust RA treatment in animal models. It suggests that in preclinical studies, MSC have consistently exhibited therapeutic benefits. The findings demonstrate a need for considering variations in different animal models and treatment protocols in future studies using MSC to treat RA in humans to maximise the therapeutic gains in the era of precision medicine. Funds NIH [1DP2CA195763], Baylx Inc.: BI-206512, NINDS/NIH Training Grant [Award# NS082174].

Background Active participant monitoring of adverse events following immunization (AEFI) is a recent development to improve the speed and transparency of vaccine safety postmarketing. Vaxtracker, an online tool used to monitor vaccine safety, has successfully demonstrated its usefulness in postmarketing surveillance of newly introduced childhood vaccines. However, its use in older participants, or for monitoring patients participating in large clinical trials, has not been evaluated. Objective The objective of this study was to monitor AEFIs in older participants enrolled in the Australian Study for the Prevention through the Immunisation of Cardiovascular Events (AUSPICE) trial, and to evaluate the usefulness and effectiveness of Vaxtracker in this research setting. Methods AUSPICE is a multicenter, randomized, placebo-controlled, double-blinded trial in which participants aged 55 to 61 years were given either the pneumococcal polysaccharide vaccine (23vPPV) or 0.9% saline placebo. Vaxtracker was used to monitor AEFIs in participants in either treatment arm through the administration of two online questionnaires. A link to each questionnaire was sent to participants via email or short message service (SMS) text message 7 and 28 days following vaccination. Data were collated and analyzed in near-real time to identify any possible safety signals indicating problems with the vaccine or placebo. Results All 4725 AUSPICE participants were enrolled in Vaxtracker. Participant response rates for the first and final survey were 96.47% (n=4558) and 96.65% (n=4525), respectively. The online survey was completed by 90.23% (4083/4525) of Vaxtracker participants within 3 days of receiving the link. AEFIs were reported by 34.40% (805/2340) of 23vPPV recipients and 10.29% (240/2332) of placebo recipients in the 7 days following vaccination. Dominant symptoms for vaccine and placebo recipients were pain at the injection site (587/2340, 25.09%) and fatigue (103/2332, 4.42%), respectively. Females were more likely to report symptoms following vaccination with 23vPPV compared with males (433/1138, 38.05% versus 372/1202, 30.95%; P Conclusions Vaxtracker is an effective tool for monitoring AEFIs in the 55 to 61 years age group. Participant response rates were high for both surveys, in both treatment arms and for each method of sending the survey. This study indicates that administration of 23vPPV was well-tolerated in this cohort. Vaxtracker has successfully demonstrated its application in the monitoring of adverse events in near-real time following vaccination in people participating in a national clinical trial. Trial Registration Australian New Zealand Trial Registry Number (ACTRN) 12615000536561; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368506

Dysregulated activation of the cyclin-dependent kinases (CDKs) 4/6, leading to uncontrolled cell division, is hallmark of cancers. Further study of the cell cycle will advance the cancer treatment. As powerful and effective drugs, inhibitors of CDK 4/6 have been widely used in clinical practice for several malignancies, particularly against breast cancers driven by the estrogen receptor (ER). Three CDK4/6 inhibitors, including palbociclib (PD0332991), ribociclib (LEE011) and abemaciclib (LY2835219), have been approved by the US Food and Drug Administration (FDA) for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer. However, CDK4/6 inhibitors act downstream of many mitogenic signaling pathways, and this has implications for resistance. It is worth to note that the mechanisms of resistance are not very clear. Up to now, a small number of preclinical and clinical studies have explored potential mechanisms of CDK4/6 inhibitors resistance in breast cancer. On this basis, rational and effective combination therapy is under development. Here we review the current knowledge about the mechanisms and efficacy of CDK4/6 inhibitors, and summarize data on resistance mechanisms to make future combination therapies more accurate and reasonable.

Background Despite increasing international interest, there is a lack of evidence about the most efficient, effective and acceptable ways to implement patient and public involvement (PPI) in clinical trials. Objective To identify the priorities of UK PPI stakeholders for methodological research to help resolve uncertainties about PPI in clinical trials. Design A modified Delphi process including a two round online survey and a stakeholder consensus meeting. Participants In total, 237 people registered of whom 219 (92%) completed the first round. One hundred and eighty‐seven of 219 (85%) completed the second; 25 stakeholders attended the consensus meeting. Results Round 1 of the survey comprised 36 topics; 42 topics were considered in round 2 and at the consensus meeting. Approximately 96% of meeting participants rated the top three topics as equally important. These were as follows: developing strong and productive working relationships between researchers and PPI contributors; exploring PPI practices in selecting trial outcomes of importance to patients; and a systematic review of PPI activity to improve the accessibility and usefulness of trial information (eg participant information sheets) for participants. Conclusions The prioritized methodological research topics indicate important areas of uncertainty about PPI in trials. Addressing these uncertainties will be critical to enhancing PPI. Our findings should be used in the planning and funding of PPI in clinical trials to help focus research efforts and minimize waste.

The challenges faced in improving the prevention and management of rheumatic and musculoskeletal diseases (RMDs) across the globe are addressed in the inaugural White Paper from the World Forum on Rheumatic amd Musculoskeletal Diseases (WFRMD) published in this issue [1]. The WFRMD, convened by Dr Mustafa Al Maini, brings together leaders from the international rheumatological community who are committed to promoting collaborative strategies to deal with this burden and work with major organisations such as ILAR, ACR, EULAR, PANLAR and AFLAR and policy makers such as theWorld Health Organisation (WHO). It is an important and timely initiaitive to increase awareness of the major burden that rheumatic and musculoskeletal diseases have on individuals and society and to explore opportunities to address these challenges on a local and global scale. This is the mission of WFRMD (www.wfrmd.org). It fits within the context of the Global Alliance for Musculoskeletal Health which the Bone and Joint Decade has brought together to call for action by policy makers to deal with the burden of RMDs (http://bjdonline.org). Musculoskeletal health is essential to independent living and self-sustainability as well as enabling people to keep physically active and reduce the risk of non-communicable diseases. It is threatened by a wide range of RMDs at all stages of life. Other risks such as obesity, injuries related to occupation and sports and more serious trauma such as falls and road injuries can often result in musculoskeletal disability. These RMDs are often long term and are an important comorbidity amongst the chronic diseases we accumulate as we age. An RMD as a comorbidity magnifies the physical disability that people suffer [2]. All these factors affecting musculoskeletal health along with the ageing of populations result in the great and growing prevalence and disability across the globe [3]. Further, exacerbating these trends is the growing need for people, as they age, to be able to continue to contribute economically to society with delayed retirement ages becoming commonplace inmany countries around the world. Health and social care systems are struggling to cope with ageing populations and their multimorbidity. For these reasons, there is an urgency to deal with the challenges of rheumatic and musculoskeletal diseases, challenges which are not currently being addressed by policies and priorities of health systems around the globe [4]. Indeed, RMDs are not considered a major noncommunicable disease by the WHO [5] or UN [6]. As a consequence, there is great and growing avoidable disability. The Bone and Joint Decade has responded by bringing together all stakeholders—professional, scientific and patient organisations as a Global Alliance for Musculoskeletal Health calling for action by decision makers to implement policies to deal with this burden (http://bjdonline.org/call-for-action/). The specific challenges and opportunities for the rheumatology community have been considered by the inaugural meeting of the World Forum on Rheumatic and Musculoskeletal Diseases on the 26th of September in Abu Dhabi and are reported in this issue [1]. Subsequent papers are planned to address issues raised in the White Paper. This is much needed as the expert community must propose solutions for the decision makers to deal with these challenges. The burden of RMDs on individuals and societies is now well documented [3, 7–15], and there are many evidenceA. D. Woolf (*) Global Alliance for Musculoskeletal Health of the Bone and Joint Decade, University of Plymouth Peninsula College of Medicine and Dentistry, Plymouth, England, UK e-mail: anthony.woolf@btopenworld.com

Resveratrol (3,5,4-trihydroxystilbene) belongs to a family of polyphenolic compounds known as stilbenes, particularly concentrated in grape and red wine. The aim of our review was to critically review the available evidence of resveratrol effects on brain function and its potential impact on therapy. In preclinical models of cognitive decline, resveratrol displays potent antioxidant activity by scavenging free radicals, reducing quinone reductase 2 activity and upregulating endogenous enzymes. Resveratrol also inhibits pro-inflammatory enzyme expression, reduces nuclear factor-B activation and cytokine release. Treatment with resveratrol can affect multiple signaling pathway effectors involved in cell survival, programmed cell death and synaptic plasticity. Direct and/or indirect activation of the deacetylase sirtuins by resveratrol has also been suggested. In humans, clinical evidence derived from randomized clinical trials suggests that resveratrol is able to improve cerebral blood flow, cerebral vasodilator responsiveness to hypercapnia, some cognitive tests, perceived performances, and the A40 plasma and cerebrospinal fluid level.

There is a need for an effective and safe emetic agent that dog owners could easily administer to their dogs following veterinary advice in cases of potential poisoning. As a response to this need, a randomised, double-blind, multi-site, clinical field study was performed to assess the efficacy, safety and usability of ropinirole eye drops to induce vomiting in dogs. Ropinirole (target dose 3.75 mg/m2) was applied to eyes of 100 dogs, and 32 dogs received placebo. The drug was administered by the dog owner at a veterinary clinic under the supervision of a veterinarian and led to vomition in 95% of the ropinirole-treated dogs within 30 min. The median time to first vomit was 10 min (range: 3–37 min). None of the dogs receiving placebo vomited in this time period. All owners were able to administer the product and 96% of them assessed the administration to be very easy or easy, which was confirmed by the observing veterinarian. Some ocular signs were seen both with ropinirole and placebo, hyperaemia being the most common. All observed signs were transient and in most cases mild. Ropinirole eye drops provided an effective, safe and reliable means to induce emesis in dogs.

Background: Amiselimod, an oral selective sphingosine-1-phosphate 1 receptor modulator, suppressed disease activity dose-dependently without clinically relevant bradyarrhythmia in a 24-week phase 2, placebo-controlled study in relapsing-remitting multiple sclerosis. Objective: To assess safety and efficacy of amiselimod over 96 weeks. Methods: After completing the core study, patients on amiselimod continued at the same dose, whereas those on placebo were randomised 1:1:1 to amiselimod 0.1, 0.2 or 0.4 mg for another 72 weeks. Most patients receiving 0.1 mg were re-randomised to 0.2 or 0.4 mg upon availability of the core study results. Results: Of 415 patients randomised in the core study, 367 (88.4%) entered and 322 (77.6%) completed the extension. One or more adverse events were reported in 303 (82.6%) of 367 patients: ‘headache’, ‘lymphocyte count decreased’, ‘nasopharyngitis’ and ‘MS relapse’ were most common (14.7%–16.9%). No serious opportunistic infection, macular oedema or malignancy was reported and no bradyarrhythmia of clinical concern was observed by Holter or 12-lead electrocardiogram. The dose-dependent effect of amiselimod on clinical and magnetic resonance imaging-related outcomes from the core study was sustained in those continuing on amiselimod and similarly observed after switching to active drug. Conclusion: For up to 2 years of treatment, amiselimod was well tolerated and dose-dependently effective in controlling disease activity.

Recent discoveries have led to the testing of novel targeted therapies for the treatment of acute myeloid leukemia (AML). To better inform the results of clinical trials, there is a need to identify and systematically assess biomarkers of response and pharmacodynamic markers of successful target engagement. Spleen tyrosine kinase (SYK) is a candidate therapeutic target in AML. Small-molecule inhibitors of SYK induce AML differentiation and impair leukemia progression in preclinical studies. However, tools to predict response to SYK inhibition and to routinely evaluate SYK activation in primary patient samples have been lacking. In this study we quantified phosphorylated SYK (P-SYK) in AML cell lines and establish that increasing levels of baseline P-SYK are correlated with an increasing sensitivity to small-molecule inhibitors targeting SYK. In addition, we found that pharmacological inhibition of SYK activity extinguishes P-SYK expression as detected by an immunohistochemical (IHC) test. Quantitative analysis of P-SYK expression by the IHC test in a series of 70 primary bone marrow biopsy specimens revealed a spectrum of P-SYK expression across AML cases and that high P-SYK expression is associated with unfavourable outcome independent of age, cytogenetics, and white blood cell count. This study thus establishes P-SYK as a critical biomarker in AML that identifies tumors sensitive to SYK inhibition, identifies an at-risk patient population, and allows for the monitoring of target inhibition during treatment.

More than 1100 patients with neuropathic pain were examined using quantitative sensory testing. Independent of the etiology, 3 subtypes with distinct sensory profiles were identified and replicated., Patients with neuropathic pain are heterogeneous in etiology, pathophysiology, and clinical appearance. They exhibit a variety of pain-related sensory symptoms and signs (sensory profile). Different sensory profiles might indicate different classes of neurobiological mechanisms, and hence subgroups with different sensory profiles might respond differently to treatment. The aim of the investigation was to identify subgroups in a large sample of patients with neuropathic pain using hypothesis-free statistical methods on the database of 3 large multinational research networks (German Research Network on Neuropathic Pain (DFNS), IMI-Europain, and Neuropain). Standardized quantitative sensory testing was used in 902 (test cohort) and 233 (validation cohort) patients with peripheral neuropathic pain of different etiologies. For subgrouping, we performed a cluster analysis using 13 quantitative sensory testing parameters. Three distinct subgroups with characteristic sensory profiles were identified and replicated. Cluster 1 (sensory loss, 42%) showed a loss of small and large fiber function in combination with paradoxical heat sensations. Cluster 2 (thermal hyperalgesia, 33%) was characterized by preserved sensory functions in combination with heat and cold hyperalgesia and mild dynamic mechanical allodynia. Cluster 3 (mechanical hyperalgesia, 24%) was characterized by a loss of small fiber function in combination with pinprick hyperalgesia and dynamic mechanical allodynia. All clusters occurred across etiologies but frequencies differed. We present a new approach of subgrouping patients with peripheral neuropathic pain of different etiologies according to intrinsic sensory profiles. These 3 profiles may be related to pathophysiological mechanisms and may be useful in clinical trial design to enrich the study population for treatment responders.

// J. Andrew Livingston 1 , Kenneth R. Hess 2 , Aung Naing 3 , David S. Hong 3 , Shreyaskumar Patel 4 , Robert S. Benjamin 4 , Joseph A. Ludwig 4 , Anthony Conley 4 , Cynthia E. Herzog 5 , Pete Anderson 6 Funda Meric-Bernstam 3 , Razelle Kurzrock 7 and Vivek Subbiah 3 1 Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 2 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 4 Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 5 Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 6 Pediatric Hematology Oncology, The Cleveland Clinic, Cleveland, Ohio, USA 7 Experimental Therapeutics Program, University of California – San Diego, San Diego, California, USA Correspondence to: Vivek Subbiah, email: // Keywords : bone sarcoma; phase 1 trials; prognosis scores; Ewing sarcoma; osteosarcoma Received : June 13, 2016 Accepted : June 26, 2016 Published : July 28, 2016 Abstract Background: We sought to validate the Royal Marsden Hospital (RMH) and MD Anderson Cancer Center (MDACC) prognostic scoring systems for the selection of bone sarcoma patients for phase I clinical trials and to identify additional risk factors related to survival. Patients and Methods: We retrospectively reviewed the baseline characteristics and outcomes of 92 bone sarcoma patients who were referred to MDACC’s Phase I Clinical Trials Program. Results: Ninety-two patients with Ewing sarcoma ( N = 47), osteosarcoma ( N = 22), chondrosarcoma ( N = 16), and other tumors ( N = 7) were evaluated; 78 were enrolled in at least 1 of 43 different phase I trials. The median overall survival (OS) was 8.8 months (95% confidence interval [CI] = 6.8–13.7 months). Independent factors that predicted shorter survival were male sex, >2 metastatic sites, >3 previous therapies, hemoglobin level 200 x10 3 /L, creatinine level ≥1.3 mg/dL, and lactate dehydrogenase level >ULN. Patients with good RMH scores (0-1) had longer OS than patients with poor RMH scores (2-3) (HR = 5.8, 95% CI = 2.9–11.0; P < 0.0001), as did patients with low MDACC scores (0-1) as compared to patients with higher MDACC scores (2–4) (HR = 3.2, 95% CI = 1.9–5.6; P < 0.0001). Conclusion: The RMH prognostic score can be used to predict the OS of bone cancer patients referred for phase I trials. The MDACC score added no value to the RMH score and therefore does not have a role in assessment of patients with bone tumors. Patients with advanced bone sarcomas should be considered for phase I trials.

Background: Work-related stress is widespread among employees and associated with high costs for German society. Internet-based stress management interventions (iSMIs) are effective in reducing such stress. However, evidence for their cost-effectiveness is scant.Objective: The aim of this study was to assess the cost-effectiveness of a guided iSMI for employees.Methods: A sample of 264 employees with elevated symptoms of perceived stress (Perceived Stress Scale≥22) was assigned to either the iSMI or a waitlist control condition (WLC) with unrestricted access to treatment as usual. Participants were recruited in Germany in 2013 and followed through 2014, and data were analyzed in 2017. The iSMI consisted of 7 sessions plus 1 booster session. It was based on problem-solving therapy and emotion regulation techniques. Costs were measured from the societal perspective, including all direct and indirect medical costs. We performed a cost-effectiveness analysis and a cost-utility analysis relating costs to a symptom-free person and quality-adjusted life years (QALYs) gained, respectively. Sampling uncertainty was handled using nonparametric bootstrapping (N=5000).Results: When the society is not willing to pay anything to get an additional symptom-free person (eg, willingness-to-pay [WTP]=€0), there was a 70% probability that the intervention is more cost-effective than WLC. This probability rose to 85% and 93% when the society is willing to pay €1000 and €2000, respectively, for achieving an additional symptom-free person. The cost-utility analysis yielded a 76% probability that the intervention is more cost-effective than WLC at a conservative WTP threshold of €20,000 (US $25,800) per QALY gained.Conclusions: Offering an iSMI to stressed employees has an acceptable likelihood of being cost-effective compared with WLC. Background: Work-related stress is widespread among employees and associated with high costs for German society. Internet-based stress management interventions (iSMIs) are effective in reducing such stress. However, evidence for their cost-effectiveness is scant.Objective: The aim of this study was to assess the cost-effectiveness of a guided iSMI for employees.Methods: A sample of 264 employees with elevated symptoms of perceived stress (Perceived Stress Scale≥22) was assigned to either the iSMI or a waitlist control condition (WLC) with unrestricted access to treatment as usual. Participants were recruited in Germany in 2013 and followed through 2014, and data were analyzed in 2017. The iSMI consisted of 7 sessions plus 1 booster session. It was based on problem-solving therapy and emotion regulation techniques. Costs were measured from the societal perspective, including all direct and indirect medical costs. We performed a cost-effectiveness analysis and a cost-utility analysis relating costs to a symptom-free person and quality-adjusted life years (QALYs) gained, respectively. Sampling uncertainty was handled using nonparametric bootstrapping (N=5000).Results: When the society is not willing to pay anything to get an additional symptom-free person (eg, willingness-to-pay [WTP]=€0), there was a 70% probability that the intervention is more cost-effective than WLC. This probability rose to 85% and 93% when the society is willing to pay €1000 and €2000, respectively, for achieving an additional symptom-free person. The cost-utility analysis yielded a 76% probability that the intervention is more cost-effective than WLC at a conservative WTP threshold of €20,000 (US $25,800) per QALY gained.Conclusions: Offering an iSMI to stressed employees has an acceptable likelihood of being cost-effective compared with WLC.Trial Registration: German Clinical Trials Register DRKS00004749; https://www.drks.de/DRKS00004749International Registered Report Identifier (IRRID): RR2-10.1186/1471-2458-13-655

More efficacious treatment regimens are needed for tuberculosis, however, drug development is impeded by a lack of reliable biomarkers of disease severity and of treatment effect. We conducted a directed screen of host biomarkers in participants enrolled in a tuberculosis clinical trial to address this need. Serum samples from 319 protocol-correct, culture-confirmed pulmonary tuberculosis patients treated under direct observation as part of an international, phase 2 trial were screened for 70 markers of infection, inflammation, and metabolism. Biomarker assays were specifically developed for this study and quantified using a novel, multiplexed electrochemiluminescence assay. We evaluated the association of biomarkers with baseline characteristics, as well as with detailed microbiologic data, using Bonferroni-adjusted, linear regression models. Across numerous analyses, seven proteins, SAA1, PCT, IL-1β, IL-6, CRP, PTX-3 and MMP-8, showed recurring strong associations with markers of baseline disease severity, smear grade and cavitation; were strongly modulated by tuberculosis treatment; and had responses that were greater for patients who culture-converted at 8 weeks. With treatment, all proteins decreased, except for osteocalcin, MCP-1 and MCP-4, which significantly increased. Several previously reported putative tuberculosis-associated biomarkers (HOMX1, neopterin, and cathelicidin) were not significantly associated with treatment response. In conclusion, across a geographically diverse and large population of tuberculosis patients enrolled in a clinical trial, several previously reported putative biomarkers were not significantly associated with treatment response, however, seven proteins had recurring strong associations with baseline radiographic and microbiologic measures of disease severity, as well as with early treatment response, deserving additional study., Highlights • Seven proteins, SAA1, PCT, IL-1β, IL-6, CRP, PTX-3 and MMP-8, show recurring strong associations with markers of baseline tuberculosis disease severity, smear grade and cavitation • These same proteins were strongly modulated by tuberculosis treatment; and had responses that were greater for patients who culture-converted at 8 weeks. • Several previously reported putative tuberculosis-associated biomarkers (HOMX1, neopterin, and cathelicidin) were not significantly associated with treatment response in our clinical trial cohort. The identification of improved biomarkers of tuberculosis treatment effect has been recognized as a key research area by the WHO International Roadmap for Tuberculosis Research because it would accelerate the development of new drugs and regimens, and potentially improve approaches to patient monitoring. Our findings within a rigorously conducted phase 2 clinical trial are that across numerous analyses, seven proteins recur with strong associations with both baseline disease severity and treatment effect. The consistency with which these markers are identified provides impetus for their further study as well as the future pursuit of blood-based treatment monitoring assay development.

Tumor sequencing has revolutionized oncology, allowing for detailed interrogation of the molecular underpinnings of cancer at an individual level. With this additional insight, it is increasingly apparent that not only do tumors vary within a sample (tumor heterogeneity), but also that each patient's individual tumor is a constellation of unique molecular aberrations that will require an equally unique personalized therapeutic regimen. We report here the results of 439 patients who underwent Clinical Laboratory Improvement Amendment (CLIA)-certified next generation sequencing (NGS) across histologies. Among these patients, 98.4% had a unique molecular profile, and aside from three primary brain tumor patients with a single genetic lesion (IDH1 R132H), no two patients within a given histology were molecularly identical. Additionally, two sets of patients had identical profiles consisting of two mutations in common and no other anomalies. However, these profiles did not segregate by histology (lung adenocarcinoma-appendiceal cancer (KRAS G12D and GNAS R201C), and lung adenocarcinoma-liposarcoma (CDK4 and MDM2 amplification pairs)). These findings suggest that most advanced tumors are molecular singletons within and between histologies, and that tumors that differ in histology may still nonetheless exhibit identical molecular portraits, albeit rarely.

// Ishwaria M. Subbiah 1 , Gerald S. Falchook 2 , Ahmed O. Kaseb 3 , Kenneth R. Hess 4 , Apostolia M. Tsimberidou 2 , Siqing Fu 2 , Vivek Subbiah 2 , David S. Hong 2 , Aung Naing 2 , Sarina A. Piha-Paul 2 , Owais Akmal 3 , Filip Janku 2 and Razelle Kurzrock 5 1 Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Moores Cancer Center, University of California San Diego, San Diego, CA, USA Correspondence to: Ishwaria M. Subbiah, email: // Keywords : targeted agents, novel therapeutics, management, systemic therapy, clinical trials Received : June 01, 2015 Accepted : June 11, 2015 Published : June 23, 2015 Abstract PURPOSE: Patients with advanced hepatocellular carcinoma (HCC) have limited effective therapeutic options. Given the rapid advanced in drug development and emergence of novel agents, we analyzed the characteristics and outcomes of HCC patients treated on early phase trials with an emphasis on targeted therapies. METHODS: We reviewed the records of consecutive HCC patients evaluated in the Phase I Clinical Trials Program at MD Anderson from March 2004. RESULTS: Thirty-nine patients were not treated due to poor performance status ( n = 22, 56%) and decision to pursue alternate therapies ( n = 10, 27%). Of 61 treated patients (median age, 60 years; median prior therapies, 3), eight patients (13%) attained stable disease lasting ≥6 months; four (7%) had a partial response, mainly with anti-angiogenic or multikinase inhibitors. Median Phase I progression-free survival (PFS) was 2.6 months versus 4.4 months ( p 0.019) and 4.1 months ( p 0.27) for their first-, and second-line FDA-approved therapy. Molecular analysis showed frequent PTEN loss (10/19 patients, 53%) and P53 mutation (4/4 patients tested). On multivariate analysis, independent factors predicting shorter survival were white ethnicity/race (p 0.031), cirrhosis ( p 0.016), and serum sodium ( p 0.0013). CONCLUSIONS: In our heavily-pretreated HCC patients, the phase I PFS was comparable to that of 2 nd -line therapy, highlighting a potential role for clinical trials after progression on first-line therapy. The response rate (SD>6 months/PR) of 20% was observed with early signals of activity in regimens combining inhibitors of angiogenesis, multiple kinases and mTOR with preliminary molecular analysis revealing prevalence of PTEN loss.

Background: There is interest from authors and publishers in sharing the results of their studies over the Internet in order to increase their readership. In this way, articles tend to be discussed and the impact of these articles tends to be increased. In order to measure this type of impact, a new score (named Altmetric) was created. Altmetric aims to understand the individual impact of each article through the attention attracted online. Objective: The primary objective of this study was to analyze potential factors related with the publishing journal and the publishing trial that could be associated with Altmetric scores on a random sample of low back pain randomized controlled trials (RCTs). The secondary objective of this study was to describe the characteristics of these trials and their Altmetric scores. Methods: We searched for all low back pain RCTs indexed on the Physiotherapy Evidence Database (PEDro; www.pedro.org.au) published between 2010 and 2015. A total of 200 articles were randomly selected, and we extracted data related to the publishing trial, the publishing journal, methodological quality of the trials (measured by the 0-10 item PEDro scale), and total and individual scores of Altmetric mentioned and Altmetric reader. The study was a cross-sectional study, and multivariate regression models and descriptive statistics were used. Results: A total of four variables were associated with Altmetric mentioned score: impact factor (β-coefficient=3.4 points), number of years since publication (β-coefficient=–4.9 points), number of citations divided by years since publication (β-coefficient=5.2 points), and descriptive title (β-coefficient=–29.4 points). Only one independent variable was associated with Altmetric reader score: number of citations divided by years since publication (β-coefficient=10.1 points, 95% CI 7.74-12.46). We also found that the majority of articles were published in English, with a descriptive title, and published in open access journals endorsing the Consolidated Standards of Reporting Trials (CONSORT) statement. Conclusions: Researchers should preferably select high impact factor journals for submission and use declarative or interrogative titles, as these factors are likely to increase the visibility of their studies in social media.

Increasing attention has focused on efforts to promote the biological activities of high-density lipoproteins (HDL) in order to reduce cardiovascular risk. Targeting apolipoprotein A-I (apoA-I), the major protein carried on HDL particles, represents an attractive approach to promoting HDL by virtue of its ability to increase endogenous synthesis of functional HDL particles. A number of pharmacological strategies that target apoA-I, including upregulation of its production with the bromodomain and extraterminal (BET) protein inhibitor RVX-208, development of short peptide sequences that mimic its action, and administration as a component of reconstituted HDL particles, have undergone clinical development. The impact of these approaches on cardiovascular biomarkers will be reviewed.

Supplemental Digital Content is Available in the Text. Fewer than half of registered complex regional pain syndrome, post-stroke pain, and analgesic device trials have available results. No single study characteristic predicts unavailability. Practical remedies are available., Evidence-based medicine rests on the assumption that treatment recommendations are robust, free from bias, and include results of all randomized clinical trials. The Repository of Registered Analgesic Clinical Trials search and analysis methodology was applied to create databases of complex regional pain syndrome (CRPS) and central post-stroke pain (CPSP) trials and adapted to create the Repository of Registered Analgesic Device Studies databases for trials of spinal cord stimulation (SCS), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS). We identified 34 CRPS trials, 18 CPSP trials, 72 trials of SCS, and 92 trials of rTMS/tDCS. Irrespective of time since study completion, 45% of eligible CRPS and CPSP trials and 46% of eligible SCS and rTMS/tDCS trials had available results (peer-reviewed literature, results entered on registry, or gray literature); peer-reviewed publications could be found for 38% and 39%, respectively. Examining almost 1000 trials across a spectrum of painful disorders (fibromyalgia, diabetic painful neuropathy, post-herpetic neuralgia, migraine, CRPS, CPSP) and types of treatment, no single study characteristic consistently predicts unavailability of results. Results availability is higher 12 months after study completion but remains below 60% for peer-reviewed publications. Recommendations to increase results availability include supporting organizations advocating for transparency, enforcing existing results reporting regulations, enabling all primary registries to post results, stating trial registration numbers in all publication abstracts, and reducing barriers to publishing “negative” trials. For all diseases and treatment modalities, evidence-based medicine must rigorously adjust for the sheer magnitude of missing results in formulating treatment recommendations.