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How healthy are the "Healthy volunteers"? Penetrance of NAFLD in the biomedical research volunteer pool.

ABSTRACT: Healthy volunteers are crucial for biomedical research. Inadvertent inclusion of subjects with nonalcoholic fatty liver disease (NAFLD) as controls can compromise study validity and subject safety. Given the rising prevalence of NAFLD in the general population, we sought to identify its prevalence and potential impact in volunteers for clinical trials. We conducted a cross-sectional study of subjects who were classified as healthy volunteers between 2011 and 2015 and had no known liver disease. Subjects were classified as presumed NAFLD (pNF; alanine aminotransferase [ALT] level???20 for women or???31 for men and body mass index [BMI]?>?25?kg/m2 ), healthy non-NAFLD controls (normal ALT and BMI), or indeterminate. A total of 3160 subjects participated as healthy volunteers in 149 clinical trials (1-29 trials per subject); 1732 of these subjects (55%) had a BMI?>?25?kg/m2 and 1382 (44%) had abnormal ALT. pNF was present in 881 subjects (27.9%), and these subjects were older than healthy control subjects and had higher triglycerides, low-density lipoprotein cholesterol, and HbA1c and lower high-density lipoprotein cholesterol (P?

SUBMITTER: Takyar V

PROVIDER: S-EPMC5570632 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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How healthy are the "Healthy volunteers"? Penetrance of NAFLD in the biomedical research volunteer pool.

Takyar Varun V Nath Anand A Beri Andrea A Gharib Ahmed M AM Rotman Yaron Y

Hepatology (Baltimore, Md.) 20170727 3

Healthy volunteers are crucial for biomedical research. Inadvertent inclusion of subjects with nonalcoholic fatty liver disease (NAFLD) as controls can compromise study validity and subject safety. Given the rising prevalence of NAFLD in the general population, we sought to identify its prevalence and potential impact in volunteers for clinical trials. We conducted a cross-sectional study of subjects who were classified as healthy volunteers between 2011 and 2015 and had no known liver disease. ...[more]

PMID: 28470683

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Project description:Rationale: The acute respiratory distress syndrome is refractory to pharmacological intervention. Inappropriate activation of alveolar neutrophils is believed to underpin this disease’s complex pathophysiology, yet these cells have been little studied. Objectives: To examine the functional and transcriptional profiles of patient blood and alveolar neutrophils compared to healthy volunteer cells, and define their sensitivity to phosphoinositide 3-kinase inhibition. Methods: Twenty three ventilated patients underwent bronchoalveolar lavage. Alveolar and blood neutrophil apoptosis, phagocytosis and adhesion molecules were quantified by flow cytometry, and oxidase responses by chemiluminescence. Cytokine and transcriptional profiling utilized multiplex and GeneChip arrays. Measurements and Main Results: Patient blood and alveolar neutrophils were distinct from healthy circulating cells, with increased CD11b and reduced CD62L expression, delayed apoptosis and constitutively primed oxidase responses. Incubating control cells with disease bronchoalveolar lavage recapitulated the aberrant functional phenotype and this could be reversed by phosphoinositide 3-kinase inhibitors. In contrast, the pro-survival phenotype of patient cells was recalcitrant to phosphoinositide 3-kinase inhibition. RNA transcriptomic analysis revealed modified immune, cytoskeletal and cell death pathways in patient cells, aligning closely to sepsis and burns data sets but not with phosphoinositide 3-kinase signatures. Conclusions: Acute respiratory distress syndrome blood and alveolar neutrophils display a distinct primed, pro-survival profile and transcriptional signature. The enhanced respiratory burst was phosphoinositide 3-kinase-dependent, but delayed apoptosis and the altered transcriptional profile were not. These unexpected findings cast doubt over the utility of phosphoinositide 3-kinase inhibition in acute respiratory distress syndrome and highlight the importance of evaluating novel therapeutic strategies in patient-derived cells.

Project description:Background: Environmental volunteering can increase well-being, but environmental volunteer well-being has rarely been compared to participant well-being associated with other types of volunteering or nature-based activities. This paper aims to use a multidimensional approach to well-being to explore the immediately experienced and later remembered well-being of environmental volunteers and to compare this to the increased well-being of participants in other types of nature-based activities and volunteering. Furthermore, it aims to compare volunteer managers' perceptions of their volunteers' well-being with the self-reported well-being of the volunteers. Methods: Onsite surveys were conducted of practical conservation and biodiversity monitoring volunteers, as well as their control groups (walkers and fieldwork students, respectively), to measure general well-being before their nature-based activity and activity-related well-being immediately after their activity. Online surveys of current, former and potential volunteers and volunteer managers measured remembered volunteering-related well-being and managers' perceptions of their volunteers' well-being. Data were analysed based on Seligman's multidimensional PERMA ('positive emotion', 'engagement', 'positive relationship', 'meaning', 'achievement') model of well-being. Factor analysis recovered three of the five PERMA elements, 'engagement', 'relationship' and 'meaning', as well as 'negative emotion' and 'health' as factors. Results: Environmental volunteering significantly improved positive elements and significantly decreased negative elements of participants' immediate well-being, and it did so more than walking or student fieldwork. Even remembering their volunteering up to six months later, volunteers rated their volunteering-related well-being higher than volunteers rated their well-being generally in life. However, volunteering was not found to have an effect on overall mean well-being generally in life. Volunteer managers did not perceive the significant increase in well-being that volunteers reported. Conclusions: This study showed how environmental volunteering immediately improved participants' well-being, even more than other nature-based activities. It highlights the benefit of regarding well-being as a multidimensional construct to more systematically understand, support and enhance volunteer well-being.

Project description:BACKGROUND:With the exception of genotoxic oncology drugs, first-in-human, Phase 1 clinical studies of investigational drugs have traditionally been conducted in healthy volunteers (HVs). The primary goal of these studies is to investigate the pharmacokinetics and pharmacodynamics of a novel drug candidate, determine appropriate dosing, and document safety and tolerability. MAIN BODY:When tailored to specific study objectives, HV studies are beneficial to manufacturers and patients alike and can be applied to both non-oncology and oncology drug development. Enrollment of HVs not only increases study accrual rates for dose-escalation studies but also alleviates the ethical concern of enrolling patients with disease in a short-term study at subtherapeutic doses when other studies (e.g. Phase 2 or Phase 3 studies) may be more appropriate for the patient. The use of HVs in non-oncology Phase 1 clinical trials is relatively safe but nonetheless poses ethical challenges because of the potential risks to which HVs are exposed. In general, most adverse events associated with non-oncology drugs are mild in severity, and serious adverse events are rare, but examples of severe toxicity have been reported. The use of HVs in the clinical development of oncology drugs is more limited but is nonetheless useful for evaluating clinical pharmacology and establishing an appropriate starting dose for studies in cancer patients. During the development of oncology drugs, clinical pharmacology studies in HVs have been used to assess pharmacokinetics, drug metabolism, food effects, potential drug-drug interactions, effects of hepatic and renal impairment, and other pharmacologic parameters vital for clinical decision-making in oncology. Studies in HVs are also being used to evaluate biosimilars versus established anticancer biologic agents. CONCLUSION:A thorough assessment of toxicity and pharmacology throughout the drug development process is critical to ensure the safety of HVs. With the appropriate safeguards, HVs will continue to play an important role in future drug development.

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How healthy are the "Healthy volunteers"? Penetrance of NAFLD in the biomedical research volunteer pool.

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How healthy are the "Healthy volunteers"? Penetrance of NAFLD in the biomedical research volunteer pool.

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