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The balance between exploration and exploitation is essential for decision-making. The present study investigated the role of ventromedial orbitofrontal cortex (vmOFC) glutamate neurons in mediating value-based decision-making by first using optogenetics to manipulate vmOFC glutamate activity in rats during a probabilistic reversal learning (PRL) task. Rats that received vmOFC activation during informative feedback completed fewer reversals and exhibited reduced reward sensitivity relative to rats. Analysis with a Q-learning computational model revealed that increased vmOFC activity did not affect the learning rate but instead promoted maladaptive exploration. By contrast, vmOFC inhibition increased the number of completed reversals and increased exploitative behavior. In a separate group of animals, calcium activity of vmOFC glutamate neurons was recorded using fiber photometry. Complementing our results above, we found that suppression of vmOFC activity during the latter part of rewarded trials was associated with improved PRL performance, greater win-stay responding and selecting the correct choice on the next trial. These data demonstrate that excessive vmOFC activity during reward feedback disrupted value-based decision-making by increasing the maladaptive exploration of lower-valued options. Our findings support the premise that pharmacological interventions that normalize aberrant vmOFC glutamate activity during reward feedback processing may attenuate deficits in value-based decision-making.

There is an increasing number of culturally diverse individuals, particularly Asians, identified with autism spectrum disorder (ASD) in the United States. Nevertheless, research on culturally diverse caregivers, especially fathers, of children with ASD is scarce. Thus, this phenomenological study explored the essence of shared experiences of Korean fathers of children with ASD in the United States. Five fathers who have a child with ASD participated in a semistructured interview with a Korean-English bilingual researcher. Follow-up interviews and field notes were used for triangulation as a part of data analysis. The fathers' narratives regarding family characteristics, interactions, and functioning are discussed in alignment with the family systems theory. The findings provide recommendations for future practice and research.

In his Scroogenomics, Joel Waldfogel argues that gifting creates enormous deadweight loss, as individuals give one another gifts that they do not want or cannot use. He views efficiency as static, calculating the gains from trade (or gifting) at the moment of transaction. A puzzle arises, however, when one realizes that gifting has been a nearly ubiquitous institution throughout history. If gifting wastes valuable resources, why does it persist? We argue that gift giving is dynamically efficient despite the possibility of generating short-term deadweight loss. A well-functioning market economy requires expanded social networks and trustworthiness among anonymous and quasi-anonymous exchange partners. Gifting allows individuals to signal trustworthiness by offering ‘burnt sacrifices’. Gifting practices that include a willingness to sacrifice via reciprocity norms, public visibility and ritual will tend to promote generalized trust. We consider these four elements – sacrifice, reciprocity, publicness, and ritual – to be critical institutional design principles for fostering dynamic efficiency. Our essay contributes to the literature on institutional economics by prompting scholars to think about the long-term (dynamic) efficiencies generated by cultural practices that appear inexplicably inefficient.

Book synopsis: This book is a definitive reference source for the growing, increasingly more important, and interdisciplinary field of computational cognitive modeling, that is, computational psychology. It combines breadth of coverage with definitive statements by leading scientists in this field. Research in computational cognitive modeling explores the essence of cognition through developing detailed, process-based understanding by specifying computational mechanisms, structures, and processes. Computational models provide both conceptual clarity and precision at the same time. This book substantiates this approach through overviews and many examples.

Myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are bone marrow disorders characterized by cytopenias and progression to acute myeloid leukemia. Hypomethylating agents (HMAs) are Food and Drug Administration-approved therapies for MDS and MDS/MPN patients. HMAs have improved patients' survival and quality of life when compared with other therapies. Although HMAs are effective in MDS and MDS/MPN patients, they are associated with significant toxicities that place a large burden on patients. Our goal is to develop a safer and more effective HMA from natural products. We previously reported that black raspberries (BRBs) have hypomethylating effects in the colon, blood, spleen, and bone marrow of mice. In addition, BRBs exert hypomethylating effects in patients with colorectal cancer and familial adenomatous polyposis. In the current study, we conducted a pilot clinical trial to evaluate the hypomethylating effects of BRBs in patients with low-risk MDS or MDS/MPN. Peripheral blood mononuclear cells (PBMCs) were isolated before and after three months of BRB intervention. CD45

Clinicians caring for persons with mental illness should be aware of increased mortality, physical problems, and health disparities in this population. This article provides a brief overview of physical health problems in the context of mental illness as well as those related to psychotropic medications, and discusses strategies to manage treatment effectively.

ObjectiveThe goal of this study was to examine if mental health and psychosocial well-being differed between middle-aged (MA; 40-59 years), younger-old (YO; 60-79 years), and older-old (OO; 80+ years) adults with respect to their trends, heterogeneity, and correlates.MethodsEighteen mental health and psychosocial well-being instruments were administered to 590 adults over age 40. Cross-sectional data also included self-report-based measures of sociodemographics, cognitive functioning, physical health and activity, and body mass index.ResultsAge trends across instruments varied in magnitude and shape, but generally supported an inverted U-shaped trend in mental health and psychosocial well-being, with small increases from MA to YO age (d = 0.29) and smaller declines from YO to OO age (d = -0.17). A U-shaped association between age and mental health heterogeneity was also observed. The strongest correlates of mental health and psychosocial well-being differed by age (MA: perceived stress; YO: successful aging; OO: compassion toward others), as did the associations of a flourishing versus languishing mental health and well-being profile.ConclusionsOur findings support the "paradox of aging," whereby declines in physical and cognitive health co-occur with relatively preserved mental health and well-being. Our findings indicate that variance in mental and psychosocial health does not increase linearly with age and support careful consideration of heterogeneity in mental health and aging research. Our findings also suggest that mental health and psychosocial well-being decouple from stress-related dimensions in MA and become increasingly associated with positive, other-oriented emotions in OO, broadly supporting socioemotional theories of aging.

Background and Aims Social determinants of health (SDoHs) impact the development and course of schizophrenia-spectrum psychotic disorders (SSPDs). Yet, we found no published scholarly reviews of psychometric properties and pragmatic utility of SDoH assessments among people with SSPDs. We aim to review those aspects of SDoH assessments. Study Design PsychInfo, PubMed, and Google Scholar databases were examined to obtain data on reliability, validity, administration process, strengths, and limitations of the measures for SDoHs identified in a paired scoping review. Study Results SDoHs were assessed using different approaches including self-reports, interviews, rating scales, and review of public databases. Of the major SDoHs, early-life adversities, social disconnection, racism, social fragmentation, and food insecurity had measures with satisfactory psychometric properties. Internal consistency reliabilities—evaluated in the general population for 13 measures of early-life adversities, social disconnection, racism, social fragmentation, and food insecurity—ranged from poor to excellent (0.68–0.96). The number of items varied from 1 to more than 100 and administration time ranged from less than 5 minutes to over an hour. Measures of urbanicity, low socioeconomic status, immigration status, homelessness/housing instability, and incarceration were based on public records or targeted sampling. Conclusions Although the reported assessments of SDoHs show promise, there is a need to develop and test brief but validated screening measures suitable for clinical application. Novel assessment tools, including objective assessments at individual and community levels utilizing new technology, and sophisticated psychometric evaluations for reliability, validity, and sensitivity to change with effective interventions are recommended, and suggestions for training curricula are offered.

MLN4924 is an investigational small-molecule inhibitor of the Nedd8-activating enzyme currently in phase I clinical trials. MLN4924 induces DNA damage via rereplication in most cell lines. This distinct mechanism of DNA damage may affect its ability to combine with standard-of-care agents and may affect the clinical development of MLN4924. As such, we studied its interaction with other DNA-damaging agents. Mitomycin C, cisplatin, cytarabine, UV radiation, SN-38, and gemcitabine demonstrated synergy in combination with MLN4924 in vitro. The combination of mitomycin C and MLN4924 was shown to be synergistic in a mouse xenograft model. Importantly, depletion of genes within the ataxia telangiectasia and Rad3 related (ATR) and BRCA1/BRCA2 pathways, chromatin modification, and transcription-coupled repair reduced the synergy between mitomycin C and MLN4924. In addition, comet assay demonstrated increased DNA strand breaks with the combination of MLN4924 and mitomycin C. Our data suggest that mitomycin C causes stalled replication forks, which when combined with rereplication induced by MLN4924 results in frequent replication fork collisions, leading to cell death. This study provides a straightforward approach to understand the mechanism of synergy, which may provide useful information for the clinical development of these combinations. Mol Cancer Ther; 13(6); 1625–35. ©2014 AACR.

PDF file - 145KB, Comparison of the Degree of Interaction between MLN4924 and 14 Different Agents as Measured by Nonlinear Blending Values.

PDF file - 1215KB, Full Length Western Blots.

PDF file - 664KB, Sensitivity of Cancer Cell Lines to DNA Damaging Agents.

PDF file - 68KB

PDF file - 159KB, The Combination of MLN4924 and Mitomycin C Results in a BRCA1-dependent Activation of ATR following Induction of DNA Strand Breaks.

PDF file - 339KB, Comparison of Isobolograms Calculated for Drug Response Surface Plots for 10 Different Agents.

PDF file - 402KB, The Combination of MLN4924 and Mitomycin C Leads to Increased DNA Strand Breaks.

XLS file - 1161KB, Data Supporting Figures within Paper.

Supplementary Table 1 from Identification of Small Molecules that Sensitize Resistant Tumor Cells to Tumor Necrosis Factor-Family Death Receptors

Supplementary Figure 1 from Identification of Small Molecules that Sensitize Resistant Tumor Cells to Tumor Necrosis Factor-Family Death Receptors

Two major pathways for apoptosis have been identified, involving either mitochondria (intrinsic) or tumor necrosis factor (TNF)-family death receptors (extrinsic) as initiators of caspase protease activation and cell death. Because tumor resistance to TNF-family death receptor ligands is a common problem, helping malignant cells evade host immune defenses, we sought to identify compounds that selectively sensitize resistant tumor cells to death receptor ligands. We screened a 50,000-compound library for agents that enhanced anti-FAS antibody–mediated killing of FAS-resistant PPC-1 prostate cancer cell, then did additional analysis of the resulting hits to arrive at eight compounds that selectively sensitized PPC-1 cells to anti-FAS antibody (extrinsic pathway agonist) without altering sensitivity to staurosporine and etoposide (VP-16; intrinsic pathway agonists). These eight compounds did not increase Fas surface levels and also sensitized PPC-1 cells to apoptosis induced by TNF-family member TNF-related apoptosis-inducing ligand, consistent with a post-receptor mechanism. Of these, two reduced expression of c-FLIP, an intracellular antagonist of the extrinsic pathway. Characterization of the effects of the eight compounds on a panel of 10 solid tumor cell lines revealed two structurally distinct compounds that frequently sensitize to extrinsic pathway agonists. Structure-activity relation studies of one of these compounds revealed a pharmacophore from which it should be possible to generate analogues with improved potency. Altogether, these findings show the feasibility of identifying compounds that selectively enhance apoptosis via the extrinsic pathway, thus providing research tools for uncovering resistance mechanisms and a starting point for novel therapeutics aimed at restoring sensitivity of tumor cells to immune effector mechanisms. (Cancer Res 2006; 66(4): 2367-75)

Little is known about the distribution and ecology of juvenile green sturgeon throughout their range and specifically within California’s Central Valley and the San Francisco Bay Estuary. The objective of our study was to identify rearing movement patterns of juvenile green sturgeon and their interaction with Delta and Bay habitats. Acoustic biotelemetry was used to record juvenile movements and residence within different regions of this highly modified watershed. We document a diversity of movements exhibited by 31 acoustically tagged juvenile green sturgeon monitored over a 9-month period. The juvenile sturgeon either (1) remained in the Delta or moved (2) into the Carquinez Straits, (3) into San Pablo Bay, (4) into San Pablo Bay but returned to Delta, (5) through the estuary and likely left through the mouth of the bay, (6) or left the estuary only to return later. Spatiotemporal habitat quality varies within and between Delta and Bay habitats. Variation in water year and hydrologic connectivity are likely to influence habitat quality and quantity, and behaviors may be differentially optimized for fitness in response to environmental variation. Our results provide initial evidence supporting multiple behavioral movement patterns and a broad use of regional habitats for green sturgeon in the California Central Valley. This apparent behavioral diversity observed through movement patterns may ensure long-term success of all population segments over time in an extremely variable environment, ultimately supporting overall population stability (i.e., the portfolio effect). Enhanced conservation efforts may be needed to protect juvenile green sturgeon and the habitats they rely upon.

Background The novel vaginal pH modulator (VPM; Phexxi) is a non-hormonal, woman-controlled, on-demand, water-based, surfactant-free contraceptive vaginal gel; VPM has also been cleared by the Food and Drug Administration for use as a personal lubricant. Aim The aim of this study is to report on sexual satisfaction results from the phase 3 AMPOWER study. Methods AMPOWER was a single-arm, open-label, multicenter study to assess the safety and efficacy of VPM in preventing pregnancy. Women were enrolled who were healthy, age 18-35 years, and sexually active with regular cyclic menses. Outcomes Women’s satisfaction (including sexual satisfaction) was an exploratory endpoint measured at Baseline and Visits 3-5; sexual satisfaction-related patient reported outcomes (PROs) were assessed via 3 different questions: (i) a question related to the impact on a woman’s sex life; (ii) a question from the Sexual Function Questionnaire (SFQ) related to the frequency of ten sexual problems; and (iii) a question from the Female Sexual Function Index (FSFI) related to lubrication. Results For sexual satisfaction-related PRO measures with baseline assessments, the majority of women reported the same or improved scores at Visit 5 (ranging from 85.8% to 98.4%). The percentage of women who reported that their sex life was improved and/or maintained was higher in Visit 3, 4, and 5 (95.4%, 95.1%, and 93.6%, respectively) compared to Baseline (87.6%). The mean impact on sex life score significantly improved at Visit 5 compared to Baseline (P < .001). In the SFQ, the mean score significantly improved (P < .005) at Visit 5 vs Baseline in 7 of the 10 variables measured (vaginal dryness, lack of sexual interest and/or desire, vaginal tightness, pain, anxiety, unable to orgasm, and vaginal bleeding or irritation). In women who reported sexual activity in the last 4 weeks, the mean FSFI score also significantly improved from Baseline to Visit 5 (P = .037). Clinical Implications In this post-hoc analysis of the phase 3 AMPOWER study, the PRO results demonstrate a high level of sexual satisfaction with VPM. Strengths and Limitations The primary strength of this analysis was the large study size of 1,330 women. Limitations included the non-randomized study design, the post-hoc nature of the analysis, and the fact that sexual satisfaction was an exploratory endpoint. Conclusion As a non-hormonal, woman-controlled, on-demand, lubricating contraceptive gel, VPM offers women a unique set of benefits with positive impacts on their sexual health.

Objective: To describe performance, anxiety, confidence, and time effects across multiple individual simulation experiences in an acute care environment among volunteer Pharm.D. students. Methods: This pilot study used five different cases spanning five weeks. Participants were not aware of case content until each simulation began but topics had been taught in the curriculum. Performance on a SOAP note, self-reported anxiety and confidence, and time to complete each activity were measured. A focus group provided qualitative feedback. Results: Fifteen participants completed the study. Mean performance scores across all cases were variable without a predictable pattern. Global measures of anxiety and confidence numerically improved. The average time to complete simulation activities was similar across the first three cases but decreased for the remaining two cases. Participant comments supported the overall design as meaningful and encouraged self-directed learning. Conclusion: The design of repeated individual simulation experiences improves anxiety and confidence scores and promotes self-directed learning.

Background: There is a critical need to develop effective interventions for cognitive impairments associated with dementia-related disorders (i.e., Alzheimer’s disease, frontotemporal dementia, mild cognitive impairment). Prospective memory (PM), or the ability to create and carry out future intentions, is one cognitive domain that is impaired in individuals with dementia-related disorders. Effective treatment of PM could significantly improve daily functioning, level of independence, and quality of life. Objective: To date, there have been a number of studies investigating potential interventions, but these interventions have not been comprehensively reviewed and compared across the stages of dementia-related disorders, as is the aim of the current review. Methods: This review examined 21 studies on the success of intervention strategies for prospective memory in patients with dementia-related disorders. Results: All the studies demonstrated positive effects of intervention on PM abilities, but there are questions concerning ecological validity, length of positive effects on PM, and a lack of diversity of interventions across the different stages of dementia-related disorders. Conclusion: Future research should address these issues by incorporating daily functioning activities and caregiver support into the intervention process, as well as investigating these interventions at more severe stages of dementia-related disorders.

African American men are at a greater risk for contracting HIV infection, and geography may play an important role in the spread of the virus. This study aimed to quantitatively assess the readiness of rural African American men to participate in a barbershop-based HIV prevention program. A paper-and-pencil survey was administered to rural African American male barbershop attendees to assess their readiness for barbershop-based HIV prevention programs. The results suggested that participants were amenable to this form of programming in the barbershop setting. There was no significance detected by demographic variables in readiness for barbershop-based HIV prevention programs. The results of the study give health education specialists and other public health practitioners insight into ways to effectively research, communicate to, and develop culturally appropriate programming for this priority population in a setting in which they are more likely to frequent.

Atypical antipsychotics are used in cardiac intensive care units (CICU) to treat delirium despite limited data on safety in patients with acute cardiovascular conditions. Patients treated with these agents may be at higher risk for adverse events such as QTc prolongation and arrhythmias. We performed a retrospective cohort study of 144 adult patients who were not receiving antipsychotics before admission and received olanzapine (n = 50) or quetiapine (n = 94) in the Michigan Medicine CICU. Data on baseline characteristics, antipsychotic dose and duration, length of stay, and adverse events were collected. Adverse events included ventricular tachycardia (sustained ventricular tachycardia attributed to the medication), hypotension (systolic blood pressure90 mm Hg attributed to the medication), and QTc prolongation (QTc increase by ≥60 ms or to an interval ≥500 ms). Twenty-six patients (18%) experienced an adverse event. Of those adverse events, 20 patients (14%) experienced QTc prolongation, 3 patients (2%) had ventricular tachycardia, and 3 patients (2%) had hypotension. Patients who received quetiapine had a higher rate of adverse events (25% vs 6%, p = 0.01) including QTc prolongation (18% vs 6%, p = 0.046). Intensive care unit length of stay was shorter in patients who received olanzapine (6.5 vs 9.5 days, p = 0.047). Eighteen patients (13%) had their antipsychotic continued at discharge from the hospital. In conclusion, QTc prolongation was more common in patients treated with quetiapine versus olanzapine although the number of events was relatively low with both agents in a CICU cohort.

Although microbial genomes harbor an abundance of biosynthetic gene clusters, there remain substantial technological gaps that impair the direct correlation of newly discovered gene clusters and their corresponding secondary metabolite products. As an example of one approach designed to minimize or bridge such gaps, we employed hierarchical clustering analysis and principal component analysis (

Millennial caregivers, born between 1981 and 1996, are an understudied caregiver group. They experience stress-related consequences of caregiving and are unique in their developmental stage and generational norms. The purpose of this study was to understand the context of caregiving and stressors for these caregivers. In total, 42 caregivers were recruited through Research Match and social media platforms. Caregivers completed online surveys with open-ended response questions and 15 caregivers completed semistructured interviews. Data were analyzed deductively and inductively using the Stress Process Model as a framework. Millennial caregivers described uncertainty and disruption as overarching experiences. Stressors related to balancing caregiving, work, and family responsibilities were most prominent. Caregivers reported needing support from friends/family, health care team members, community, and work/governmental policy. Mental health treatment was identified as most helpful for managing stress. Millennial caregivers have distinctive contexts that impact their caregiving needs. Caregiving interventions must take these needs into consideration.

Objective Negative symptoms and cognitive impairment in schizophrenia (SZ) remain unmet treatment needs as they are highly prevalent, associated with poor functional outcomes, and resistant to pharmacologic treatment. The current pilot randomized controlled trial examined the efficacy of an integrated Cognitive-Behavioral Social Skills Training and Compensatory Cognitive Training (CBSST-CCT) intervention compared to Goal-focused Supportive Contact (SC) on negative symptoms and cognitive performance. Methods Fifty-five adults with SZ or schizoaffective disorder with moderate-to-severe negative symptoms were randomized to receive 25 twice-weekly, 1-h manualized group sessions (12.5 weeks total duration) of either CBSST-CCT or SC delivered by master’s level clinicians in five community settings. Assessments of negative symptom severity (primary outcomes) and neuropsychological performance, functional capacity, social skills performance, and self-reported functional ability/everyday functioning, psychiatric symptom severity, and motivation (secondary outcomes) were administered at baseline, mid-treatment, post-treatment, and 6-month follow-up. Results Mixed-effects models using baseline, mid-treatment, and post-treatment data demonstrated significant CBSST-CCT-associated effects on negative symptom severity, as assessed by the Scale for the Assessment of Negative Symptoms (p = .049, r = 0.22), with improvements in diminished motivation driving this effect (p = .037, r = 0.24). The CBSST-CCT group also demonstrated improved verbal learning compared to SC participants (p = .026, r = 0.36). The effects of CBSST-CCT appeared to be durable at 6-month follow-up. Conclusions CBSST-CCT improved negative symptom severity and verbal learning in high-negative-symptom individuals relative to SC. CBSST-CCT warrants larger investigations to examine its efficacy in treating negative symptoms, along with other symptoms, cognition, and, ultimately, real-world functional outcomes. Clinical Trial registration number NCT02170051.

Neuromyths are commonly held misconceptions about the brain believed by both the general public and educators. While much research has investigated the prevalence of myths about the typically developing brain, less attention has been devoted to the pervasiveness of neuromyths about neurodevelopmental disorders, which have the potential to exacerbate stigma. This preregistered study investigated to what extent neuromyths about neurodevelopmental disorders (namely dyslexia, attention deficit hyperactivity disorder, autism spectrum disorders, and syndrome) are endorsed by two groups: the general public and those working in education. In an online survey, 366 members of the general public and 203 individuals working in education rated similar numbers of myths to be true, but more about neurodevelopmental disorders than general neuromyths. As the frequency of access to brain information emerged as a protective factor against endorsing myths in both populations, we argue that this problem may be addressed via provision of neuroeducational resources.