Safety In Human Subjects Research Articles

Usefulness of Natural Phenolic Compounds in the Fight against Esophageal Cancer: A Systematic Review

Esophageal cancer (EC) is a very common form of cancer in developing countries, and its exponential progression is a cause for concern. Available treatments face the phenomenon of multi-drug resistance, as well as multiple disabling side effects. The number of deaths is expected to double by 2030 if nothing is done. Due to their high representativeness in plants, phenolic compounds are a potential alternative for halting the spread of this disease, which bereaves many thousands of families every year. This study aims to identify phenolic compounds with activity against esophageal cancer, assess their toxicological profiles, and explore future perspectives. To achieve this, the literature search was meticulously carried out in the Google Scholar, Scopus, Web of Sciences, and Pub-Med/Medline databases, in accordance with the PRISMA 2020 guidelines. The results show that proanthocyanidin and curcumin represent promising therapeutic options, given their significant in vitro and in vivo activity, and their safety in human subjects in clinical trials. Moscatilin, Genistein, and pristimerin have anticancer activities (≤10 µM) very close to those of doxorubicin and 5-FU, although their safety has not yet been fully established. The compounds identified in vivo exhibit highly significant activities compared with the results obtained in vitro, and are sometimes more effective than the molecules conventionally used to treat EC. Generally, with the exceptions of plumbagin, lapachol, and β-lapachone, all other molecules are relatively non-toxic to normal human cells and represent a therapeutic avenue to be explored by pharmaceutical companies in the fight against esophageal cancer. However, more detailed toxicological studies of certain molecules remain a priority.

Preclinical assessment of a noncooled MR thermometry-based neurosurgical laser therapy system.

MRI-guided laser interstitial thermal therapy (MRgLITT) has recently gained interest as an ablative stereotactic procedure for intractable epilepsy, movement disorders, and brain tumors. Conventionally, a LITT system consists of a laser generator and cooled laser applicator, which is a fiber optic core surrounded by a sheath through which cooled fluid is pumped. However, this footprint can make the system bulky and nonmobile, limit the maximum depth of targeting, and increase the chances of breakdown. Herein, the authors conduct a preclinical assessment of a noncooled MRgLITT system in a porcine model. Three-tesla MRI was used to guide the in vivo placement of noncooled laser applicators in the porcine brain. The study consisted of a survival arm and terminal arm. The laser was activated at a power of 4-7 W for ≤ 180 seconds. Temperature changes were monitored using the MR thermometry software ThermoGuide in the survival arm (n = 5) or both ThermoGuide software and adjacently inserted thermal probes in the terminal arm (n = 3). Thermal damage was determined by the software using the temperature-time relationship of cumulative equivalent minutes at 43°C (CEM43). Temperatures calculated by the software were compared with those recorded by the temperature probes. The dimensions of thermal damage thresholds (TDTs; 2-9, 10-59, 60-239, ≥ 240 CEM43 isolines) given by MR thermometry were compared with the dimensions of irreversible damage on histopathological analysis. There was a strong correlation between temperature recordings by ThermoGuide and those by thermal probes at both 4 mm (r = 0.96) and 8 mm (r = 0.80), with a mean absolute error of 0.76°C ± 2.13°C and 0.17°C ± 1.65°C at 4 and 8 mm, respectively. The area of 2-9 CEM43 was larger than the area of irreversible damage seen on histopathological analysis. The dimensions of the 10 and 60 CEM43 correlated well with dimensions of the lesion on histopathological analysis. A well-defined border (≤ 1 mm) was observed between the area of irreversible damage and healthy brain tissue. This preclinical assessment showed that the noncooled LITT system was able to precisely reach the target and create well-defined lesions within a margin of safety, without any adverse effects. MR thermometry software provided an accurate near-real-time temperature of the brain tissue, and dimensions of the lesion as visualized by the software correlated well with histopathological findings. Further studies to test the system's efficacy and safety in human subjects are in progress.

Pharmacological Effects of Urolithin A and Its Role in Muscle Health and Performance: Current Knowledge and Prospects.

Urolithin A (UA) is a naturally occurring compound derived from the metabolism of gut microbiota, which has attracted considerable research attention due to its pharmacological effects and potential implications in muscle health and performance. Recent studies have demonstrated that Urolithin A exhibits diverse biological activities, encompassing anti-inflammatory, antioxidant, anti-tumor, and anti-aging properties. In terms of muscle health, accumulating evidence suggests that Urolithin A may promote muscle protein synthesis and muscle growth through various pathways, offering promise in mitigating muscle atrophy. Moreover, Urolithin A exhibits the potential to enhance muscle health and performance by improving mitochondrial function and regulating autophagy. Nonetheless, further comprehensive investigations are still warranted to elucidate the underlying mechanisms of Urolithin A and to assess its feasibility and safety in human subjects, thereby advancing its potential applications in the realms of muscle health and performance.

Remote Monitoring In Clinical Trial – A Guide for Healthcare Professionals

Remote monitoring is a key step in clinical research that produces reliable, high-quality, and scientifically sound data from clinical studies. According to ICH-GCP, the sponsor has the responsibility for preserving the monitoring of data for the continuing trials. Due to the development of remote monitoring, the monitoring of the trials has become fairly simple for the CRA (a person assigned by the sponsor to monitor the ongoing trials). The primary benefit of remote monitoring is that it speeds up the on-time completion of work by reducing the time required for final trial reports output. It significantly lowers the sponsor's travel costs. Reducing the time between site monitoring enhances the accuracy and timeliness of study data and increases the safety of human subjects participating in a clinical trial. By using the secure off-site electronic health records access is currently utilized for clinical care, and also used to validate the source documentation. This article provides an overview of the offsite monitoring processes involved and standards adopted in remote monitoring.

Practice and consideration of master protocol in clinical trials

There is considerable interest in expediting late-stage therapy development by efficiently conducting trial designs that encompass multiple therapies or multiple subpopulations simultaneously within a unified protocol. Such trial designs are referred to as master protocols, with specific designs characterized by the terms umbrella, basket, or platform. These designs, in contrast to the traditional trial designs, are full of complexity. What factors should be considered in designing a trial ensuring the safety of human subjects and demonstrating the efficacy of new therapy? This paper overviews the master protocol framework, comprehensively unifies the definitions, and illustrates essential design elements of representative example trials conducted in drugs and medical devices. Besides, to understand the master protocols deeply, it is also a need to summarize the commonly-used types of master protocols in various disease and treatment fields, along with the reasons for these phenomena by analyzing the characteristics of the diseases, the mechanism of therapeutic products, and the principles of various types of master protocols. Finally, we also propose practical considerations, including the design, ethical, statistics, and funding considerations that arise from implementing complex master protocols. This information serves to guide practitioners in designing more effective trials and identifying potentially valuable therapies.

A Systematic Review of the Randomized Controlled Trials of Gemcabene and Its Therapeutic Uses.

Statins are the most widely used drugs for reducing lipid and cholesterol levels in the blood. However, statins have shown some adverse effects and less acceptance among patients; hence, new drugs have been promoted in the market. Furthermore, gemcabenes were discovered in 1995 and are now in phase II and III clinical trials. Gemcabene acts by inhibiting incorporation of 14C-acetate into hepatocytes and stops the mechanism of fatty acids and cholesterol synthesis. In this review the six randomized controlled trials (RCTs) were scrutinized from the two databases by using keywords "Gemcabene" AND "Randomized Controlled Trial." The trials were mainly on animal models, and two studies were found to be associated with human subjects. The study concluded that gemcabene was effective as an anti-inflammatory agent and reduced lipid levels and the progression of fibrosis. Hence, further controlled trials are needed to determine its efficacy and safety in human subjects, along with the identification of adverse effects.

Ethics Committees: Structure, Roles, and Issues.

An Ethics Committee (EC) is an independent body composed of members with expertise in both scientific and nonscientific arenas which functions to ensure the protection of human rights and the well-being of research subjects based on six basic principles of autonomy, justice, beneficence, nonmaleficence, confidentiality, and honesty. MEDLINE, Scopus, and Directory of Open Access Journals were searched for studies relevant to this topic. This review is focused on the types of research articles that need EC approval, the submission process, and exemptions. It further highlights the constitution of ECs, their duties, the review process, and the assessment of the risk-benefit of the proposed research including privacy issues. It's pertinent for academicians and researchers to abide by the rules and regulations put forth by ECs for upholding of human rights and protecting research subjects primarily, as well as avoiding other issues like retraction of publications. Despite various issues of cost, backlogs, lack of expertise, lesser representation of laypersons, need for multiple approvals for multisite projects, conflicts of interest, and monitoring of ongoing research for the continued safety of participants, the ECs form the central force in regulating research and participant safety. Data safety and monitoring boards complement the ECs for carrying out continuous monitoring for better protection of research subjects. The establishment of ECs has ensured safe study designs, the safety of human subjects along with the protection of researchers from before the initiation until the completion of a study.

Responsible conduct of research: Preparedness for times of crisis

A live, virtual conference, "Driving Responsible Conduct of Research during a Pandemic," was held in April 2021, 13 months after the COVID-19 pandemic fundamentally altered the conduct of clinical research across the USA. New York was an early epicenter of the US pandemic, highlighting preexisting problems in clinical research and allowing us to assess lessons learned and to identify best practices for the future. Risks and opportunities were categorized broadly into three areas, protecting the welfare and safety of human subjects, ensuring trust in science and medicine, and implementing efficient, ethical, and compliant clinical research. Analysis of conference proceedings, and recent publications, shows a need for preparedness that is more effective, robust partnerships, and organizational systems and standards to strengthen the ethical and responsible conduct of research.

Conducting Research with Marginalized Populations: Methodological, Ethical, and IRB Considerations

Marginalized populations, such as people experiencing homelessness and immigrants, are seen as among the most challenging populations to study, both methodologically and ethically. Although there are basic guidelines on how to conduct research with majority populations, the relative lack of published guidelines on how to conduct ethical and scientifically rigorous research with marginalized populations can make researchers apprehensive about seemingly unending questions from grant reviewers and institutional review boards (IRBs) concerning research ethics and the safety of human subjects. As a result, there is a persisting gap in research conducting large-scale studies on these populations outside of community organizations and clinical and institutional settings. We emphasize the calls of prior research to streamline IRB processes further to study vulnerable groups. In this paper, we focus on the study of people experiencing homelessness, yet we have used related methods to study immigrants, including those who may be undocumented. We provide guidelines derived from successful social scientific studies on homelessness and immigrants, which can be used to help ease IRB approval for other researchers to gather important data. The benefits of social science research on hard-to-reach populations often outweigh possible risk. By helping to increase research on hidden populations, we can improve the scientific rigor of all research and make important contributions to knowledge.

PERCEPTIONS AND EXPECTATIONS OF NURSING STUDENTS REGARDING DIVERSE TECHNOLOGY BASED NURSING EDUCATION

Purpose: Modern nursing care has been described as a blend of high tech and high touch, a term that describes a nurse's traditional caring and compassion combined with 21st-century health-care technology. Technology can be used in nursing schools to improve learning and student performance. Communication, student participation, and critical thinking are all improved when a technology-infused atmosphere is provided. The study aims to determine the student’s perceptions and expectations regarding technology based nursing education.
 Methodology: Descriptive cross sectional study was conduct. Students who were full-time students in class, had enrolled their subjects, were current students, and had signed consent to participate in this study were included. Students who refused to participate and were absent from class were not included in the report. Using easy sampling, a sample size of n=150 nursing department undergraduate students was taken. A self-administered questionnaire with a 5-point Likert scale was used to collect data. Throughout the study, participants' identities were kept private to ensure human subject safety. Data were analyzed using software SPSS (statistical package for social science studies) version 21.
 Results: Demographic characteristics of participants in which Level of the study and programmed of the study included. Minimum students 24(16.0) of the 4th year and maximum students 53(35.3%) from undergraduate 94(62.7%) and postgraduate 56(37.3%) were participate in this study. Over all perception and expectation of nursing students were 1.52± .489 and3.13± 1.32 respectively.
 Unique contribution to theory, practice and policy: Educators use technology for academic and communication purposes at campuses, according to nursing students in this research and that their teachers helped them to learn using their own technology devices and online platforms. As a result, more effort and special care are needed to improve nursing students' abilities at the entry level so that they can efficiently use technology for educational purposes.

Immunogenicity and Safety of an Inactivated SARS-CoV-2 Vaccine: Preclinical Studies.

Since the emergence of SARS-CoV-2 at the end of 2019, 64 candidate vaccines are in clinical development and 173 are in the pre-clinical phase. Five types of vaccines are currently approved for emergency use in many countries (Inactivated, Sinopharm; Viral-vector, Astrazeneca, and Gamaleya Research Institute; mRNA, Moderna, and BioNTech/Pfizer). The main challenge in this pandemic was the availability to produce an effective vaccine to be distributed to the world’s population in a short time. Herein, we developed a whole virus NRC-VACC-01 inactivated candidate SARS-CoV-2 vaccine and tested its safety and immunogenicity in laboratory animals. In the preclinical studies, we used four experimental animals (mice, rats, guinea pigs, and hamsters). Antibodies were detected as of week three post vaccination and continued up to week ten in the four experimental models. Safety evaluation of NRC-VACC-01 inactivated candidate vaccine in rats revealed that the vaccine was highly tolerable. By studying the effect of booster dose in the immunological profile of vaccinated mice, we observed an increase in neutralizing antibody titers after the booster shot, thus a booster dose was highly recommended after week three or four. Challenge infection of hamsters showed that the vaccinated group had lower morbidity and shedding than the control group. A phase I clinical trial will be performed to assess safety in human subjects.

Characterizing Current Attitudes and Practices for Human Subject Safety in Studies Involving Pupil Dilation.

Standards in pupil dilation practices regarding the safety of human subjects are not present in vision research despite the potential for significant adverse effects. We developed two surveys to examine current practices around pupil dilation among vision researchers and individuals associated with oversight of human subjects research. While both groups note an absence of adverse events associated with pupil dilation, vision researcher practices differed with informed consent use and measures taken to minimize complications. For Institutional Review Boards, general risk assumption associated with dilation was not unanimous and there was a lack of specific guidance available to researchers for minimizing risk. These results uncover the need for standardized practices regarding pupil dilation in human subjects research.

4339 Exploring Physician Investigator Clinical Trials Training and Quality Management Systems and its Implementation in Medical School Curriculums

OBJECTIVES/GOALS: Although many physicians conduct clinical trials as Principle Investigators, a systematic training is often lacking. Instead, most receive on-site training, potentially compromising data quality and human subject safety. This research assesses the landscape for physician training through medical school curriculums. METHODS/STUDY POPULATION: This project explored training programs for physician researchers, specifically in the emerging field of quality management systems (QMS). To understand the scope of academic research available for QMS and Good Clinical Practice (GCP) training and lack of clinical trial training implemented in medical school curricula, a literature review was conducted. Available training for physicians was assessed through existing training programs from the FDA, NIH, DIAMOND, ACRP, and Google for accessibility in terms of costs, completion timelines and certification, format (online vs. in-person), and inclusion of GCP and QMS training in the curriculum RESULTS/ANTICIPATED RESULTS: Literature review revealed that not much is known about physician researcher training beyond the institutional requirement for minimal GCP review. Examination of select medical school curriculum also discovered a lack of clinical trial training for students interested in clinical research. Furthermore, existing training programs and modules available for physicians are limited as their syllabi do not include QMS training. In addition, these programs commonly have inaccessible registration links, are expensive, and have significant time commitments for in-person courses. These findings support the need for more accessible and effective training and certification tools for physician researchers. DISCUSSION/SIGNIFICANCE OF IMPACT : QMS training is not included medical school curricula or programs for physician researchers, potentially compromising data integrity and subject protection. This research supports the development of essential QMS training concepts and practical approaches for physician researcher clinical trials.

Microglia and Autism Spectrum Disorder: Overview of Current Evidence and Novel Immunomodulatory Treatment Options.

Autism spectrum disorder is a rapidly increasing heterogeneous neurodevelopmental syndrome, remarked by persistent deficit in social communication, and restricted, repetitive patterns of behavior and interest. Lately, maternal immune activation and micgroglial dysfunction in the developing brain have been gaining mounting evidence and leading to studies of various novel agents as potential treatment options. A few immunomodulatory treatment options—luteolin, minocycline, suramin, vitamin D, gut microbiota—are discussed in the current article, regarding the current understanding of their mechanisms and evidence for potential clinical use. More studies are warranted to understand their exact mechanisms of action and to verify efficacy and safety in human subjects.

Description of a change in teaching methods and comparison of quizzes versus midterms scores in a research methods course.

We describe a change in teaching method from extended face-to-face instruction to a blended classroom environment in a research methods course and compare student scores following a change in assessment from mid-term examination to weekly quizzes. The course traditionally had been taught using a weekly 2-hour lecture for each academic term. A change in teaching methods was designed to include 20 minutes of lecture followed by 30 minutes of topic-specific in-class group discussions. The students then continued group work for an additional hour at an alternative location of their choice, such as the library, café, student study areas, or at home. Student homework/reading assignments were given as topics for weekly group discussions. In addition, the midterm examinations were replaced with weekly quizzes. Using t-test and analysis of variance, scores for four student cohorts in two successive academic terms were compared using identical multiple-choice questions from the midterms and quizzes for two topics. Student verbal feedback was elicited at the end of each term. Quiz scores showed significant improvement over midterm scores for the more challenging statistics multiple-choice questions ( t[371] = -2.21, p = .03, d = 0.23) with no significant improvement in multiple-choice questions about the safety of human subjects ( t[374] = -.401, p = .69, d = 0.04). Student verbal feedback indicated higher satisfaction with the blended classroom and experiential learning style. Assessment using quizzes in an early and often format, instead of a midterm examination, was associated with higher scores on identical questions. Students preferred the blended classroom environment with experiential learning exercises and weekly quizzes.

Overcoming the Challenges of Experimental Research: Lessons From a Criminal Justice Case Study Involving TASER Exposure.

To provide guidance to criminologists for conducting experiments in light of two common discouraging factors: the belief that they are overly time-consuming and the belief that they can compromise the ethical principles of human subjects' research. A case study approach is used, based on a large-scale randomized controlled trial experiment in which we exposed participants to a 5-s TASER shock, to describe how the authors overcame ethical, methodological, and logistical difficulties. We derive four pieces of advice from our experiences carrying out this experimental trial: (1) know your limitations, (2) employ pilot testing, (3) remain flexible and patient, and (4) "hold the line" to maintain the integrity of the research and the safety of human subjects. Criminologists have an obligation to provide the best possible evidence regarding the impact and consequences of criminal justice practices and programs. Experiments, considered by many to be the gold standard of empirical research methodologies, should be used whenever possible in order to fulfill this obligation.

Bone health-promoting bioactive peptides.

Bioactive peptides, derivatives of proteins, show versatile biological effects and represent potential health-promoting agents as functional food ingredients and/or nutraceuticals. Bone health depends on the balance between bone formation and resorption. When the balance is disrupted, bone diseases such as osteoporosis and fragility fractures may result. Accumulating evidence suggests that peptides derived from endogenous proteins and food proteins enhance bone health. This article reviews the literature on peptides exhibiting bone health-promoting effects. Possible biochemical mechanisms and production of these peptides are briefly discussed. PRACTICAL APPLICATIONS: Bioactive peptides are derived from food proteins via enzymatic hydrolysis, are already commercially available. In vitro and in vivo bone health-promoting effects of bioactive peptides have been shown in several animal models of osteoporosis and fractures. Thus, peptides can be used as functional food ingredients and/or nutraceuticals. However, their exact role and safety in human subjects should be evaluated prior to commercialization.

Betrixaban: A New Oral Factor Xa Inhibitor for Extended Venous Thromboembolism Prophylaxis in High-Risk Hospitalized Patients.

To review the pharmacology, pharmacokinetics, efficacy, and safety of the factor Xa (FXa) inhibitor betrixaban for extended-duration prophylaxis of acute medically ill patients with venous thromboembolism (VTE) risk factors. A MEDLINE/PubMed (January 1990 to October 2017) search was conducted using the following keywords: betrixaban, PRT054021, FXa inhibitor, novel oral anticoagulant, NOAC, direct oral anticoagulant, DOAC, and target specific oral anticoagulant, TSOAC. References of identified articles were searched by hand for additional relevant citations. We included English-language articles evaluating betrixaban pharmacology, pharmacokinetics, efficacy, or safety in human subjects for VTE prophylaxis. Betrixaban is a FXa inhibitor that decreases prothrombinase activity and thrombin generation. Betrixaban efficacy and safety has been compared with that of enoxaparin for prophylaxis of VTE in acutely ill medical patients. In the APEX trial and substudies, extended-duration betrixaban was superior in efficacy to standard-duration enoxaparin in patients at high risk for VTE, including those with elevated D-dimer levels (≥2× upper limit of normal) and of older age (≥75 years). Betrixaban is noninferior to enoxaparin in rates of major bleeding, but the former is associated with more clinically relevant nonmajor bleeding events. Betrixaban is the first oral agent approved for extended-duration VTE prophylaxis in acutely ill hospitalized patients. Extended-duration thromboprophylaxis with betrixaban reduces the risk of VTE compared with standard-duration thromboprophylaxis with enoxaparin but is associated with increased risk of bleeding.

Effects of 4-Week Intervention with Ulmus macrocarpa Hance Extract on Immune Function Biomarkers in Healthy Adults: A Randomized Controlled Trial.

Ulmus macrocarpa extract has been shown to have immune-related effects in animals, but no studies have yet been performed in humans. This randomized, double-blind, placebo-controlled trial was conducted to determine the effect of short-term administration of Ulmus macrocarpa Hance extract (UME) on immune function biomarkers and its safety in human subjects. Fifty-eight subjects were randomly assigned to a UME group or a placebo group. Subjects in the UME group were given 500 mg per day of UME orally for 4 weeks. Mean fluorescence intensity (MFI) of tumor necrotic factor-α increased only in the UME group at 1 week (P = 0.027). The MFI of interleukin-2 decreased less significantly in the UME group than in the placebo group at 1 week (P = 0.028). However, unfortunately, at 4 weeks, no intergroup differences were detected in MFIs of cytokine. In conclusion, administration of UME for 1 week increased serum TNF-α and sustains IL-2 in human, which suggests that UME increases Th1-related immune function in the short term in healthy people. However, additional studies are needed to confirm the results of this first-stage study and further trials are required to decide on optimal dosage and duration of administration. This trial is registered with ClinicalTrials.gov Identifier: NCT02414412.

In Vivo Imaging of Human Cholinergic Nerve Terminals with (–)-5-18F-Fluoroethoxybenzovesamicol: Biodistribution, Dosimetry, and Tracer Kinetic Analyses

(-)-5-(18)F-fluoroethoxybenzovesamicol ((18)F-FEOBV) is a vesamicol derivative that binds selectively to the vesicular acetylcholine transporter (VAChT) and has been used in preclinical studies to quantify presynaptic cholinergic nerve terminals. This study presents, to our knowledge, the first-in-human experience with (18)F-FEOBV, including radiation dosimetry, biodistribution, tolerability and safety in human subjects, and brain kinetics and methods for quantitative analysis of (18)F-FEOBV. Whole-body (18)F-FEOBV scans were obtained in 3 healthy human volunteers. Seven additional subjects underwent dynamic brain imaging 0-120, 150-180, and 210-240 min after bolus injection of (18)F-FEOBV. Arterial blood sampling was performed with chromatographic identification of authentic (18)F-FEOBV to determine the arterial plasma input function. Analysis methods included nonlinear least-squares fitting of a 2-tissue-compartmental model, reference tissue modeling, and late single-scan imaging. No pharmacologic or physiologic changes were observed after intravenous administration of up to 1.3 μg of (18)F-FEOBV. Radiation dosimetry estimates indicate that more than 400 MBq may be administered without exceeding regulatory radiation dose limits. Kinetic analysis showed brain uptake to be relatively high with single-pass extraction of 25%-35%. VAChT binding estimates varied by a factor of greater than 30 between the striatum and cortex. Coefficients of variation in k3 estimates varied from 15% to 30%. Volume of distribution measures yielded a dynamic range of approximately 15 but with little reduction in variability. Reference tissue approaches yielded more stable estimates of the distribution volume ratio (1 + BPND), with coefficients of variation ranging from 20% in the striatum to 6%-12% in cortical regions. The late static distribution of (18)F-FEOBV correlated highly with the distribution volume ratio estimates from reference tissue models (r = 0.993). (18)F-FEOBV PET confirms that the tracer binds to VAChT with the expected in vivo human brain distribution. Both reference tissue modeling and late static scanning approaches provide a robust index of VAChT binding.