Examining animal testing for risk assessment: A WC-12 workshop report.

In toxicology and regulatory testing, the use of animal methods has been both a cornerstone and a subject of intense debate. To continue this discourse a panel and audience representing scientists from various sectors and countries convened at a workshop held during the 12th World Congress on Alternatives and Animal Use in the Life Sciences (WC-12). The ensuing discussion focused on the scientific and ethical considerations surrounding the necessity and responsibility of defending the creation of new animal data in regulatory testing. The primary aim was to foster an open dialogue between the panel members and the audience while encouraging diverse perspectives on the responsibilities and obligations of various stakeholders (including industry, regulatory bodies, technology developers, research scientists, and animal welfare NGOs) in defending the development and subsequent utilization of new animal data. This workshop summary report captures the key elements from this critical dialogue and collective introspection. It describes the intersection of scientific progress and ethical responsibility as all sectors seek to accelerate the pace of 21st century predictive toxicology and new approach methodologies (NAMs) for the protection of human health and the environment.

Niche construction and the environmental term of the price equation: How natural selection changes when organisms alter their environments.

Organisms construct their own environments and phenotypes through the adaptive processes of habitat choice, habitat construction, and phenotypic plasticity. We examine how these processes affect the dynamics of mean fitness change through the environmental change term of the Price Equation. This tends to be ignored in evolutionary theory, owing to the emphasis on the first term describing the effect of natural selection on mean fitness (the additive genetic variance for fitness of Fisher's Fundamental Theorem). Using population genetic models and the Price Equation, we show how adaptive niche constructing traits favorably alter the distribution of environments that organisms encounter and thereby increase population mean fitness. Because niche-constructing traits increase the frequency of higher-fitness environments, selection favors their evolution. Furthermore, their alteration of the actual or experienced environmental distribution creates selective feedback between niche constructing traits and other traits, especially those with genotype-by-environment interaction for fitness. By altering the distribution of experienced environments, niche constructing traits can increase the additive genetic variance for such traits. This effect accelerates the process of overall adaption to the niche-constructed environmental distribution and can contribute to the rapid refinement of alternative phenotypic adaptations to different environments. Our findings suggest that evolutionary biologists revisit and reevaluate the environmental term of the Price Equation: owing to adaptive niche construction, it contributes directly to positive change in mean fitness; its magnitude can be comparable to that of natural selection; and, when there is fitness G × E, it increases the additive genetic variance for fitness, the much-celebrated first term.

Host-parasite coevolution: Partitioning the effects of natural selection and environmental change using coupled Price equations.

George Price showed how the effects of natural selection and environmental change could be mathematically partitioned. This partitioning may be especially useful for understanding host-parasite coevolution, where each species represents the environment for the other species. Here, we use coupled Price equations to study this kind of antagonistic coevolution. We made the common assumption that parasites must genetically match their host's genotype to avoid detection by the host's self/nonself recognition system, but we allowed for the possibility that non-matching parasites have some fitness. Our results show how natural selection on one species results in environmental change for the other species. Numerical iterations of the model show that these environmental changes can periodically exceed the changes in mean fitness due to natural selection, as suggested by R.A. Fisher. Taken together, the results give an algebraic dissection of the eco-evolutionary feedbacks created during host-parasite coevolution.

Web-Based Problem-solving Training With and Without Peer Support in Veterans With Unmet Mental Health Needs: Pilot Study of Feasibility, User Acceptability, and Participant Engagement.

BACKGROUND: eHealth tools have the potential to meet the mental health needs of individuals who experience barriers to accessing in-person treatment. However, most users have less than optimal engagement with eHealth tools. Coaching from peer specialists may increase their engagement with eHealth. OBJECTIVE: This pilot study aims to test the feasibility and acceptability of a novel, completely automated web-based system to recruit, screen, enroll, assess, randomize, and then deliver an intervention to a national sample of military veterans with unmet mental health needs; investigate whether phone-based peer support increases the use of web-based problem-solving training compared with self-directed use; and generate hypotheses about potential mechanisms of action for problem-solving and peer support for future full-scale research. METHODS: Veterans (N=81) with unmet mental health needs were recruited via social media advertising and enrolled and randomized to the self-directed use of a web-based problem-solving training called Moving Forward (28/81, 35%), peer-supported Moving Forward (27/81, 33%), or waitlist control (26/81, 32%). The objective use of Moving Forward was measured with the number of log-ins. Participants completed pre- and poststudy measures of mental health symptoms and problem-solving confidence. Satisfaction was also assessed post treatment. RESULTS: Automated recruitment, enrollment, and initial assessment methods were feasible and resulted in a diverse sample of veterans with unmet mental health needs from 38 states. Automated follow-up methods resulted in 46% (37/81) of participants completing follow-up assessments. Peer support was delivered with high fidelity and was associated with favorable participant satisfaction. Participants randomized to receive peer support had significantly more Moving Forward log-ins than those of self-directed Moving Forward participants, and those who received peer support had a greater decrease in depression. Problem-solving confidence was associated with greater Moving Forward use and improvements in mental health symptoms among participants both with and without peer support. CONCLUSIONS: Enrolling and assessing individuals in eHealth studies without human contact is feasible; however, different methods or designs are necessary to achieve acceptable participant engagement and follow-up rates. Peer support shows potential for increasing engagement in web-based interventions and reducing symptoms. Future research should investigate when and for whom peer support for eHealth is helpful. Problem-solving confidence should be further investigated as a mechanism of action for web-based problem-solving training. TRIAL REGISTRATION: ClinicalTrials.gov NCT03555435; http://clinicaltrials.gov/ct2/show/NCT03555435.

Improving Readiness and Reducing Costs: An Analysis of Factors That Influence Site Selection for Army Outpatient Surgical Services.

EXECUTIVE SUMMARY: The variable costs of providing surgical procedures for military beneficiaries are greater when care is rendered in the civilian purchased care network than when provided at a direct care military treatment facility (MTF). To reduce healthcare-related costs, retaining surgical services is a priority at MTFs across the U.S. Army Medical Command. This study is the first to identify factors significantly associated with outpatient surgical service site selection in the military health system (MHS). We analyzed 1,000,305 patient encounters in fiscal year 2014, of which 970,367 were direct care encounters and 29,938 were purchased care encounters. We used multiple binomial logistic regression to assess and compare the odds of site selection at a purchased care facility and an MTF. We found that an increase in provider administrative time (OR = 1.024, p < .001) and an increase in case complexity (OR = 1.334, p < .001) were associated with increased odds that an outpatient surgical service was provided in a purchased care setting. The increased odds that highly complex cases were seen in purchased care has the potential to affect the medical readiness of military providers and the efficacy of graduate medical education programs. Healthcare administrators can use the results of this study to develop and implement MTF level policies to enhance outpatient surgical service practices in the Army medical system. These efforts may reduce costs and increase military provider medical readiness.

Recommended approaches in the application of toxicogenomics to derive points of departure for chemical risk assessment.

There is increasing interest in the use of quantitative transcriptomic data to determine benchmark dose (BMD) and estimate a point of departure (POD) for human health risk assessment. Although studies have shown that transcriptional PODs correlate with those derived from apical endpoint changes, there is no consensus on the process used to derive a transcriptional POD. Specifically, the subsets of informative genes that produce BMDs that best approximate the doses at which adverse apical effects occur have not been defined. To determine the best way to select predictive groups of genes, we used published microarray data from dose-response studies on six chemicals in rats exposed orally for 5, 14, 28, and 90 days. We evaluated eight approaches for selecting genes for POD derivation and three previously proposed approaches (the lowest pathway BMD, and the mean and median BMD of all genes). The relationship between transcriptional BMDs derived using these 11 approaches and PODs derived from apical data that might be used in chemical risk assessment was examined. Transcriptional BMD values for all 11 approaches were remarkably aligned with corresponding apical PODs, with the vast majority of toxicogenomics PODs being within tenfold of those derived from apical endpoints. We identified at least four approaches that produce BMDs that are effective estimates of apical PODs across multiple sampling time points. Our results support that a variety of approaches can be used to derive reproducible transcriptional PODs that are consistent with PODs produced from traditional methods for chemical risk assessment.

Prescription Drug Promotion from 2001-2014: Data from the U.S. Food and Drug Administration.

The volume of prescription drug promotion over time is often measured by assessing changes in ad spending. However, this method obscures the fact that some types of advertising are more expensive than others. Another way to measure the changes in prescription drug promotion over time is to assess the number of promotional pieces submitted to the U.S. Food and Drug Administration (FDA). Form FDA 2253 collects information such as the date submitted and the type of material submitted. We analyzed data from Forms FDA 2253 received from 2001-2014. We examined the frequency of submissions by audience (consumer and healthcare professional) and type of promotional material. There was a noted increase in prescription drug promotion submissions across all media in the early 2000s. Although non-Internet promotion submissions have since plateaued, Internet promotion continued to increase. These results can help public health advocates and regulators focus attention and resources.

Toxicogenomic assessment of liver responses following subchronic exposure to furan in Fischer F344 rats.

Furan is a widely used industrial chemical and a contaminant in heated foods. Chronic furan exposure causes cholangiocarcinoma and hepatocellular tumors in rats at doses of 2 mg/kg bw/day or greater, with gender differences in frequency and severity. The hepatic transcriptional alterations induced by low doses of furan (doses below those previously tested for induction of liver tumors) and the potential mechanisms underlying gender differences are largely unexplored. We used DNA microarrays to examine the global hepatic mRNA and microRNA transcriptional profiles of male and female rats exposed to 0, 0.03, 0.12, 0.5 or 2 mg/kg bw/day furan over 90 days. Marked gender differences in gene expression responses to furan were observed, with many more altered genes in exposed males than females, confirming the increased sensitivity of males even at the low doses. Pathway analysis supported that key events in furan-induced liver tumors in males include gene expression changes related to oxidative stress, apoptosis and inflammatory response, while pathway changes in females were consistent with primarily adaptive responses. Pathway benchmark doses (BMDs) were estimated and compared to relevant apical endpoints. Transcriptional pathway BMDs could only be examined in males. These median BMDs ranged from 0.08 to 1.43 mg/kg bw/day and approximated those derived from traditional histopathology. MiR-34a (a P53 target) was the only microRNA significantly increased at the 2 mg/kg bw/day, providing evidence to support the importance of apoptosis and cell proliferation in furan hepatotoxicity. Overall, this study demonstrates the use of transcriptional profiling to discern mode of action and mechanisms involved in gender differences.

Awareness of treatment needs and length of stay amongst psychiatric inpatients.

INTRODUCTION: Inpatient psychiatric units experience significant pressure from third party payers to keep length of stay (LOS) to a minimum despite having to treat more severely ill patients. However, there is a paucity of empiric data for guiding treatment decisions that maximize therapeutic outcome while minimizing LOS. We therefore endeavored to begin utilizing a newly created psychometric instrument that assesses patient psychological factors, which we propose will allow for LOS prediction and individualization of therapeutic outcome. MATERIALS AND METHODS: The Goals Questionnaire (GQ), created to determine awareness of treatment needs, was administered to newly admitted patients. Linear regression analyses were conducted to ascertain the relationship between the GQ score and LOS, as well as the effects of confounding factors. RESULTS: A significant and inverse relationship was found between the GQ score and LOS (ß=-4.4; p=0.007) that was dependent upon (i.e., had a significant interaction with) age and substance use disorders. There was minimal confounding from common administrative, legal, and clinical factors. CONCLUSIONS: The GQ may have utility for inpatient treatment teams, providing information that can be used to maximize and individualize therapeutic outcome while minimizing LOS.

Ecological momentary assessment of PTSD symptoms and alcohol use in combat veterans.

Despite high rates of comorbid hazardous alcohol use and posttraumatic stress disorder (PTSD), the nature of the functional relationship between these problems is not fully understood. Insufficient evidence exists to fully support models commonly used to explain the relationship between hazardous alcohol use and PTSD including the self-medication hypothesis and the mutual maintenance model. Ecological momentary assessment (EMA) can monitor within-day fluctuations of symptoms and drinking to provide novel information regarding potential functional relationships and symptom interactions. This study aimed to model the daily course of alcohol use and PTSD symptoms and to test theory-based moderators, including avoidance coping and self-efficacy to resist drinking. A total of 143 recent combat veterans with PTSD symptoms and hazardous drinking completed brief assessments of alcohol use, PTSD symptoms, mood, coping, and self-efficacy 4 times daily for 28 days. Our results support the finding that increases in PTSD are associated with more drinking within the same 3-hr time block, but not more drinking within the following time block. Support for moderators was found: Avoidance coping strengthened the relationship between PTSD and later drinking, while self-efficacy to resist drinking weakened the relationship between PTSD and later drinking. An exploratory analysis revealed support for self-medication occurring in certain times of the day: Increased PTSD severity in the evening predicted more drinking overnight. Overall, our results provide mixed support for the self-medication hypothesis. Also, interventions that seek to reduce avoidance coping and increase patient self-efficacy may help veterans with PTSD decrease drinking.

Clinical course of alcohol use in veterans following an AUDIT-C Positive Screen.

There is little known regarding the typical trajectory of alcohol use following a positive screen for hazardous alcohol use. This information would help primary care providers as they attempt to determine the best use of patient visits that might include brief alcohol interventions versus other competing medical demands. This longitudinal observational study included 98 Veterans who screened positive on the Alcohol Use Disorders Identification Test-Consumption (>3) and were asked to report on their alcohol use every 3 months for 1 year. Using latent class growth modeling, we identified the best fitting latent class structure for each outcome of high-risk and heavy drinking, respectively. There was a class of participants with increased probability of having a high-risk week or episode of heavy drinking as well as a group of participants who appeared to maintain their current drinking pattern. Although the latent class growth modeling suggested that none of the groups of participants reduced the likelihood of occurrence of heavy drinking days, two groups did significantly reduce the probability of having a hazardous alcohol use week. These results suggest that there are specific classes of patients who are less likely to change their alcohol use following a positive screen, especially those patients who report engaging in heavy drinking.

The relationships among premilitary vocational aptitude assessment, traumatic brain injury, and postdeployment cognitive functioning in combat veterans.

Traumatic brain injury (TBI) in Iraq and Afghanistan war veterans is frequently associated with a variety of complaints, including cognitive problems and posttraumatic stress disorder. In this study, the authors explored the predictive impact of premilitary cognitive abilities on postdeployment cognitive functioning, as mitigated by posttraumatic stress symptoms in a sample of veterans with and without history of TBI. Measures included clinical interview, neuropsychological tests, the PTSD Checklist-Military Version, and the Armed Services Vocational Aptitude Battery. In contrast to history of TBI, premilitary abilities and posttraumatic stress symptoms emerged as significant predictors of postdeployment cognitive deficits.

Toward a population genetic framework of developmental evolution: the costs, limits, and consequences of phenotypic plasticity.

Adaptive phenotypic plasticity allows organisms to cope with environmental variability, and yet, despite its adaptive significance, phenotypic plasticity is neither ubiquitous nor infinite. In this review, we merge developmental and population genetic perspectives to explore costs and limits on the evolution of plasticity. Specifically, we focus on the role of modularity in developmental genetic networks as a mechanism underlying phenotypic plasticity, and apply to it lessons learned from population genetic theory on the interplay between relaxed selection and mutation accumulation. We argue that the environmental specificity of gene expression and the associated reduction in pleiotropic constraints drive a fundamental tradeoff between the range of plasticity that can be accommodated and mutation accumulation in alternative developmental networks. This tradeoff has broad implications for understanding the origin and maintenance of plasticity and may contribute to a better understanding of the role of plasticity in the origin, diversification, and loss of phenotypic diversity.

Longitudinal assessment of BMI in relation to ADT use among early stage prostate cancer survivors.

INTRODUCTION: The use of androgen deprivation therapy (ADT) for prostate cancer is on the rise, but its adverse side effects may include increased fat mass and decreased lean muscle mass. The net effect of ADT on BMI is unknown. METHODS: Primary, incident cases of early stage prostate cancer (n = 473) were identified from the Buffalo VA Medical Center tumor registry and matched to body size, demographic, comorbidity, and treatment exposure data from veteran medical records. Multilevel modeling was used to assess the association between ADT and changes in BMI. RESULTS: On average, survivors were overweight at diagnosis and showed small, non-significant changes in BMI over time. However, among those survivors with a history of ADT, a significant decrease of 0.05 BMI units per year was associated with each additional dose of ADT (p < 0.001). When the association between BMI rate of change and ADT was allowed to vary with respect to age, additional doses of ADT predicted stronger decreases in BMI for younger survivors as compared to older survivors (p < 0.05). Neither a history of surgery nor radiation influenced the association between ADT use and BMI. CONCLUSIONS: Declines in BMI in relation to ADT exposure may be reflective of unfavorable changes in body composition, especially decreased muscle mass, that is most pronounced in younger survivors. IMPLICATIONS FOR CANCER SURVIVORS: Survivors on ADT may benefit from close monitoring of physical functioning and referral for exercise interventions to preserve muscle mass and improve health related quality of life.