Preact to lower the risk of falling by customized rehabilitation across Europe: the feasibility study protocol of the PRECISE project in Italy.

Introduction: Falls are a major worldwide health problem in older people. Several physical rehabilitation programs with home-based technologies, such as the online DigiRehab platform, have been successfully delivered. The PRECISE project combines personalized training delivered through the application with an artificial intelligence-based predictive model (AI-DSS platform) for fall risk assessment. This new system, called DigiRehab, will enable early identification of significant risk factors for falling and propose an individualized physical training plan to attend to these critical areas. Methods: The study will test the usability of the DigiRehab platform in generating personalized physical rehabilitation programs at home. Fifty older adults participants will be involved, 20 of them testing the beta version prototype, and 30 participants testing the updated version afterwards. The inclusion criteria will be age ≥65, independent ambulation, fall risk (Tinetti test), Mini Mental State Examination ≥24, home residents, familiarity with web applications, ability and willingness to sign informed consent. Exclusion criteria will be unstable clinical condition, severe visual and/or hearing impairment, severe impairment in Activities of Daily Living and absence of primary caregiver. Discussion: The first part of the screening consists in a structured questionnaire of 10 questions regarding the user's limitations, including the risk of falling, while the second consists in 10 physical tests to assess the functional status. Based on the results, the program will help define the user's individual profile upon which the DSS platform will rate the risk of falling and design the personalized exercise program to be carried out at home. All measures from the initial screening will be repeated and the results will be used to optimize the predictive algorithms in order to prepare the tool in its final version. For the usability assessment, the System Usability Scale will be administered. The follow-up will take place after the 12-week intervention at home. A semi-structured satisfaction questionnaire will also be administered to verify whether the project will meet the needs of older adults and their family caregiver. Conclusion: We expect that personalized training prescribed by DigiRehab platform could help to reduce the need for care in older adults subjects and the care burden.Clinical trial registration: [https://clinicaltrials.gov/], identifier [NCT05846776].

Protocol for the "magnitude of cigarette substitution after initiation of e-cigarettes and its impact on biomarkers of exposure and potential harm in dual users" (MAGNIFICAT) study.

Introduction: Many smokers who use e-cigarettes (ECs) to quit continue smoking alongside vaping. The impact on health among individuals who simultaneously smoke conventional cigarettes (CCs) and use ECs remains unclear. The varying patterns of dual use present differing levels of overall toxin exposure and relative risks concerning smoking-related diseases. Understanding these complexities is vital to assessing the implications for human health. Objective: Herein we describe a protocol designed to analyze the impact of different level of substituting CCs with ECs on exposure to toxicants. We'll use biomarkers to measure this exposure and assess harm reduction in dual users through clinical endpoints, harm-related biomarkers, and behavioral correlations. We expect to observe progressive changes with varying patterns of dual use. Methods and analyses: For this purpose, we planned to recruit a group of 250 smokers who will be asked to reduce their CC consumption by adopting ECs (intervention group). A separate group of 50 smokers will continue to smoke CC (reference group). Study groups will be followed up for 6 months during which biospecimens will be collected for biomarker analyses, and clinical endpoints will be assessed. The trial is structured to characterize subjects' usage patterns over time using robust biomarkers of exposure and a standardized mobile phone application to facilitate the precise categorization of dual users along the risk continuum based on their usage behaviors. Subject recruitment will start in February 2024 and enrolment is expected to be completed by August 2024. Results will be reported early in 2025. Study findings may provide valuable insights into health benefits or risks associated with varying patterns of dual use. Ethics and dissemination: The study protocol and informed consent forms will be approved by the local Ethical Review Boards. Study results will be disseminated through articles published in reputable, peer-reviewed, open access, scientific journals, presentations at conferences, and the University website.

A maturity model for the scientific review of clinical trial designs and their informativeness.

BACKGROUND: Informativeness, in the context of clinical trials, defines whether a study's results definitively answer its research questions with meaningful next steps. Many clinical trials end uninformatively. Clinical trial protocols are required to go through reviews in regulatory and ethical domains: areas that focus on specifics outside of trial design, biostatistics, and research methods. Private foundations and government funders rarely require focused scientific design reviews for these areas. There are no documented standards and processes, or even best practices, toward a capability for funders to perform scientific design reviews after their peer review process prior to a funding commitment. MAIN BODY: Considering the investment in and standardization of ethical and regulatory reviews, and the prevalence of studies never finishing or failing to provide definitive results, it may be that scientific reviews of trial designs with a focus on informativeness offer the best chance for improved outcomes and return-on-investment in clinical trials. A maturity model is a helpful tool for knowledge transfer to help grow capabilities in a new area or for those looking to perform a self-assessment in an existing area. Such a model is offered for scientific design reviews of clinical trial protocols. This maturity model includes 11 process areas and 5 maturity levels. Each of the 55 process area levels is populated with descriptions on a continuum toward an optimal state to improve trial protocols in the areas of risk of failure or uninformativeness. CONCLUSION: This tool allows for prescriptive guidance on next investments to improve attributes of post-funding reviews of trials, with a focus on informativeness. Traditional pre-funding peer review has limited capacity for trial design review, especially for detailed biostatistical and methodological review. Select non-industry funders have begun to explore or invest in post-funding review programs of grantee protocols, based on exemplars of such programs. Funders with a desire to meet fiduciary responsibilities and mission goals can use the described model to enhance efforts supporting trial participant commitment and faster cures.

Validation of the Onychomycosis Severity Index in a Brazilian population.

Onychomycosis is the most frequent nail disorder, but unfortunately, curative treatment is still a challenge, and commonly the infection recurs. A widely disseminated system to accurately assess and classify the severity of this disease, such as the MASI score for melasma or PASI for psoriasis, is lacking in the literature. In 2011, Carney et al. established and successfully validated the Onychomycosis Severity Index (OSI), proving it to be a simple and reproducible tool. To validate the Onychomycosis Severity Index in a Brazilian population. Four experienced dermatologists were taught how to use the OSI system, and then evaluated photographs of 24 nails. There was no consultation between the dermatologists, and the results were evaluated by an impartial third party. A statistically significant (p<0.001) high degree of agreement was observed between the evaluators and overall OSI score (mild, moderate or severe) as well as its subcategories (area of involvement, proximity to the nail matrix and presence of dermatophytoma or hyperkeratosis). OSI is a very useful tool to improve the clinical assessment of onychomycosis and support clinical trial inclusion criteria (p<0.001). It also provides important prognostic data and allows for a better follow-up of treatment efficacy.

Editorial: Forty Years of Waiting for Prevention and Cure of HIV Infection - Ongoing Challenges and Hopes for Vaccine Development and Overcoming Antiretroviral Drug Resistance.

In April 1984, 40 years ago, the Secretary of the US Department of Health and Human Services announced that Dr. Robert Gallo and his colleagues at the National Cancer Institute (NCI) had confirmed the cause of acquired immunodeficiency syndrome (AIDS) as a retrovirus, which became known as human immunodeficiency virus (HIV) in 1986. For the past 40 years, prevention and cure of HIV infection have been the dual 'holy grail' sought but still not achieved. By the beginning of 2024, the World Health Organization (WHO) estimated that in the past 40 years, between 65.0 million and 113.0 million people have been infected with HIV, and between 32.9 million and 51.3 million people have died from HIV infection. On 29 February 2024, the WHO published an updated report in response to increasing reports of HIV drug resistance (HIVDR). Currently, HIV vaccines in development are in early-stage clinical trials. People with HIV are more likely to develop tuberculosis, with increasing rates of antimicrobial resistance. MTBVAC is the first live attenuated vaccine to prevent Mycobacterium tuberculosis infection, with phase 2a safety and efficacy clinical trial data expected at the end of 2024. This editorial aims to summarize the current challenges and hopes for developing vaccines to prevent HIV infection and approaches to overcome antiretroviral drug resistance as a cure for HIV/AIDS.

Reliability and Validity of Smartphone Cognitive Testing for Frontotemporal Lobar Degeneration.

Importance: Frontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD. Objective: To evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations. Design, Setting, and Participants: In this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)-based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes. Exposure: Participants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests. Main Outcomes and Measures: Internal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy. Results: In the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized ß range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, -2.49 [95% CI, -0.19 to -0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back ß = -0.49 [95% CI, -0.72 to -0.25]; P < .001) but not a composite of traditional neuropsychological measures (ß = -0.14 [95% CI, -0.42 to 0.14]; P = .32). Conclusions and Relevance: The findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.

Vitamin D and Insulin-Dependent Diabetes: A Systematic Review of Clinical Trials.

(1) Background: Vitamin D supplementation after type 1 diabetes mellitus (T1DM) onset has led to conflicting results on beta-cell preservation. Aim: This paper presents a systematic review to verify whether randomized prospective controlled trials (RCTs) demonstrate that improved vitamin D status confers protection on T1DM. (2) Methods: A systematic review was conducted up until 18 January 2024 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching MEDLINE, MEDLINE In-Process, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials, using keywords "vitamin D", "type 1 diabetes", and "children". (3) Results: Following the above-mentioned search process, 408 articles in PubMed and 791 in Embase met inclusion criteria. After removing duplicates, 471 articles remained. After exclusion criteria, 11 RCTs remained. Because of major heterogeneity in design and outcomes, no meta-analyses were conducted, allowing only for qualitative analyses. There was no strong evidence that vitamin D supplementation has lasting effects on beta-cell preservation or glycemic control in new-onset T1DM. (4) Conclusions: More rigorous, larger studies are needed to demonstrate whether vitamin D improves beta-cell preservation or glycemic control in new-onset T1DM. Because T1DM may cause osteopenia, it is advisable that patients with new onset T1DM have adequate vitamin D stores.

A Vision for Democratizing Next-Generation Oncology Clinical Trials.

SUMMARY: Revolutionary advancements in oncology have transformed lives, but the clinical trials ecosystem encounters challenges, including restricted access to innovative therapies and a lack of diversity in participant representation. A vision emerges for democratized, globally accessible oncology trials, necessitating collaboration among researchers, clinicians, patients, and policymakers to shift from converting complex, exclusive trials into a dynamic, inclusive force against cancer.

What Is "Key Information"? Consideration of the Reasons People Do or Do Not Take Part in Research.

We performed a qualitative review of 50 consent forms posted on Clinicaltrials.gov, examining the content of key information sections. We found that key information disclosures are typically focused on procedures, risks, potential benefits, and alternatives. Drawing upon reviews of the large literature examining the reasons people do or do not take part in research, we propose that these disclosures should be based more directly on what we know to be the real reasons why people choose to take part or refuse participation. We propose key information language for consideration by researchers and institutional review boards.

Two-stage stratified designs with survival outcomes and adjustment for misclassification in predictive biomarkers.

Biomarker stratified clinical trial designs are versatile tools to assess biomarker clinical utility and address its relationship with clinical endpoints. Due to imperfect assays and/or classification rules, biomarker status is prone to errors. To account for biomarker misclassification, we consider a two-stage stratified design for survival outcomes with an adjustment for misclassification in predictive biomarkers. Compared to continuous and/or binary outcomes, the test statistics for survival outcomes with an adjustment for biomarker misclassification is much more complicated and needs to take special care. We propose to use the information from the observed biomarker status strata to construct adjusted log-rank statistics for true biomarker status strata. These adjusted log-rank statistics are then used to develop sequential tests for the global (composite) hypothesis and component-wise hypothesis. We discuss the power analysis with the control of the type-I error rate by using the correlations between the adjusted log-rank statistics within and between the design stages. Our method is illustrated with examples of the recent successful development of immunotherapy in nonsmall-cell lung cancer.

An agent-based model on antimicrobial de-escalation in intensive care units: Implications on clinical trial design.

Antimicrobial de-escalation refers to reducing the spectrum of antibiotics used in treating bacterial infections. This strategy is widely recommended in many antimicrobial stewardship programs and is believed to reduce patients' exposure to broad-spectrum antibiotics and prevent resistance. However, the ecological benefits of de-escalation have not been universally observed in clinical studies. This paper conducts computer simulations to assess the ecological effects of de-escalation on the resistance prevalence of Pseudomonas aeruginosa-a frequent pathogen causing nosocomial infections. Synthetic data produced by the models are then used to estimate the sample size and study period needed to observe the predicted effects in clinical trials. Our results show that de-escalation can reduce colonization and infections caused by bacterial strains resistant to the empiric antibiotic, limit the use of broad-spectrum antibiotics, and avoid inappropriate empiric therapies. Further, we show that de-escalation could reduce the overall super-infection incidence, and this benefit becomes more evident under good compliance with hand hygiene protocols among health care workers. Finally, we find that any clinical study aiming to observe the essential effects of de-escalation should involve at least ten arms and last for four years-a size never attained in prior studies. This study explains the controversial findings of de-escalation in previous clinical studies and illustrates how mathematical models can inform outcome expectations and guide the design of clinical studies.

The Question of HIV Vaccine: Why Is a Solution Not Yet Available?

Ever since its discovery, human immunodeficiency virus type 1 (HIV-1) infection has remained a significant public health concern. The number of HIV-1 seropositive individuals currently stands at 40.1 million, yet definitive treatment for the virus is still unavailable on the market. Vaccination has proven to be a potent tool in combating infectious diseases, as evidenced by its success against other pathogens. However, despite ongoing efforts and research, the unique viral characteristics have prevented the development of an effective anti-HIV-1 vaccine. In this review, we aim to provide an historical overview of the various approaches attempted to create an effective anti-HIV-1 vaccine. Our objective is to explore the reasons why specific methods have failed to induce a protective immune response and to analyze the different modalities of immunogen presentation. This trial is registered with NCT05414786, NCT05471076, NCT04224701, and NCT01937455.

Value of Information for Clinical Trial Design: The Importance of Considering All Relevant Comparators.

Value of Information (VOI) analyses calculate the economic value that could be generated by obtaining further information to reduce uncertainty in a health economic decision model. VOI has been suggested as a tool for research prioritisation and trial design as it can highlight economically valuable avenues for future research. Recent methodological advances have made it increasingly feasible to use VOI in practice for research; however, there are critical differences between the VOI approach and the standard methods used to design research studies such as clinical trials. We aimed to highlight key differences between the research design approach based on VOI and standard clinical trial design methods, in particular the importance of considering the full decision context. We present two hypothetical examples to demonstrate that VOI methods are only accurate when (1) all feasible comparators are included in the decision model when designing research, and (2) all comparators are retained in the decision model once the data have been collected and a final treatment recommendation is made. Omitting comparators from either the design or analysis phase of research when using VOI methods can lead to incorrect trial designs and/or treatment recommendations. Overall, we conclude that incorrectly specifying the health economic model by ignoring potential comparators can lead to misleading VOI results and potentially waste scarce research resources.

Exploring the Strategic Use of TikTok for Clinical Trial Recruitment: How audiences' Prior Short-Form Video Usage Influences Persuasive Effects.

Guided by the elaboration likelihood model and framing theory, this study explores the potential of short-form video platforms (e.g. TikTok), for targeted clinical trial recruitment. An online experiment compared doctor vs. peer-led videos addressing logistical or psychological barriers to participation, mimicking common TikTok communication tactics. Results indicate that high (vs. low) TikTok users are more persuaded by recruitment messages, and they exhibit stronger intentions to participate in clinical trials. Although doctor-sourced messages generate greater credibility and a more favorable message attitude, peer-sourced messages may be more effective in increasing participation intention. Lastly, doctor-sourced videos that address logistical barriers and peer-sourced videos that discuss psychological barriers result in higher self-efficacy for clinical trial participation. This study contributes to the growing body of research on new media's role in health communication and provides insights into how to strategically utilize TikTok and other short-form video platforms for clinical trial recruitment.

In-Depth Retinal Sensitivity Assessment With the MP3 Type S Microperimeter: A Methods Study.

Purpose: Retinal sensitivity is frequently listed as an end point in clinical trials, often with long working practices. The purpose of this methods study was to provide a new workflow and reduced test time for in-depth characterization of retinal sensitivity. Methods: A workflow for the MP3-S microperimeter with detailed functional characterization of the retina under photopic, mesopic, and scotopic conditions was evaluated. Grids of 32 and 28 test positions for photopic/mesopic and scotopic, respectively, were tested in 12 healthy individuals and compared with an established 68-point grid for test time, mean sensitivity (MS), and bivariate contour ellipse area (BCEA). Results: The mean test time (range; ±SD) was 10.5 minutes (8.4-14.9; ±2.0) in the 68-point grid and 4.3 minutes (3.8-5.0; ±0.4) in the 32-point grid, which was significantly different (P < 0.0001). The mean of difference in test time (±SD; 95% confidence interval) was 6.1 minutes (±2.0; 4.6-7.6). MS and BCEA were significantly correlated between grids (r = 0.89 and 0.74; P = 0.0005 and 0.014, respectively). Mean test time of subjects who underwent the full protocol (n = 4) was 2.15 hours. Conclusions: The protocol suggested herein appears highly feasible with in-depth characterization of retinal function under different testing conditions and in a short test time. Translational Relevance: The protocol described herein allows for characterization of the retina under different testing conditions and in a short test time, which is relevant due to its potential for patient prognostication and follow-up in clinical settings and also given its increasing role as a clinical trial end point.