Sioux Falls VA Health Care System

RATIONALE: The effect of disease management for chronic obstructive pulmonary disease (COPD) is not well established. OBJECTIVES: To determine whether a simplified disease management program reduces hospital admissions and emergency department (ED) visits due to COPD. METHODS: We performed a randomized, adjudicator-blinded, controlled, 1-year trial at five Veterans Affairs medical centers of 743 patients with severe COPD and one or more of the following during the previous year: hospital admission or ED visit for COPD, chronic home oxygen use, or course of systemic corticosteroids for COPD. Control group patients received usual care. Intervention group patients received a single 1- to 1.5-hour education session, an action plan for self-treatment of exacerbations, and monthly follow-up calls from a case manager. MEASUREMENTS AND MAIN RESULTS: We determined the combined number of COPD-related hospitalizations and ED visits per patient. Secondary outcomes included hospitalizations and ED visits for all causes, respiratory medication use, mortality, and change in Saint George's Respiratory Questionnaire. After 1 year, the mean cumulative frequency of COPD-related hospitalizations and ED visits was 0.82 per patient in usual care and 0.48 per patient in disease management (difference, 0.34; 95% confidence interval, 0.15-0.52; P < 0.001). Disease management reduced hospitalizations for cardiac or pulmonary conditions other than COPD by 49%, hospitalizations for all causes by 28%, and ED visits for all causes by 27% (P < 0.05 for all). CONCLUSIONS: A relatively simple disease management program reduced hospitalizations and ED visits for COPD. Clinical trial registered with www.clinicaltrials.gov (NCT00126776).

Cognitive dysfunction is prevalent in psychiatric disorders. Deficits are observed in multiple domains, including working memory, executive function, attention, and information processing. Disability caused by cognitive dysfunction is frequently as debilitating as the prominent emotional disturbances. Interactions between the hippocampus and the prefrontal cortex are increasingly appreciated as an important link between cognition and emotion. Recent developments in optogenetics, imaging, and connectomics can enable the investigation of this circuit in a manner that is relevant to disease pathophysiology. The goal of this review is to shed light on the contributions of this circuit to cognitive dysfunction in neuropsychiatric disorders, focusing on Alzheimer's disease and depression.

Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.

The goal of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Stroke Recovery working group is to understand brain and behavior relationships using well-powered meta- and mega-analytic approaches. ENIGMA Stroke Recovery has data from over 2,100 stroke patients collected across 39 research studies and 10 countries around the world, comprising the largest multisite retrospective stroke data collaboration to date. This article outlines the efforts taken by the ENIGMA Stroke Recovery working group to develop neuroinformatics protocols and methods to manage multisite stroke brain magnetic resonance imaging, behavioral and demographics data. Specifically, the processes for scalable data intake and preprocessing, multisite data harmonization, and large-scale stroke lesion analysis are described, and challenges unique to this type of big data collaboration in stroke research are discussed. Finally, future directions and limitations, as well as recommendations for improved data harmonization through prospective data collection and data management, are provided.

While many studies ask participants to disclose sensitive information or to participate in emotionally arousing tasks, little is known about participants' subjective experiences of discomfort and benefit. Ethics review committees, therefore, have little information about participant experiences to guide their informed decision-making. We asked undergraduate females about their experiences in a study that included an experimental session, interviews, and self-report measures on sensitive topics. We examined results overall, and compared the responses of individuals with and without childhood abuse experiences. Participants who had experienced child abuse were more likely to report distress due to remembering the past, but also more likely to report that participation was helpful. Implications for future research, and recommendations for review boards, are discussed.

PURPOSE: To examine the effectiveness of videoconferencing technology for delivering comprehensive weight management treatment. METHODS: This retrospective cohort study was conducted by extraction of data from medical records for the years 2008-2010. The treatment included a series of 12 weekly MOVE!® classes delivered using videoconferencing. Data were extracted from the time of baseline weight to 1 year after baseline weight for the MOVE! participants (n = 60) and from a concurrent control group (n = 60) that did not participate in MOVE! treatment. FINDINGS: Results indicated that the MOVE! group lost weight while the control group gained weight, resulting in a mean difference between the groups of -5.5 ± 2.7 kg (95% CI = -8.0 to -3.0; P < .0001). CONCLUSIONS: These results indicate that videoconferencing is an effective method to provide the MOVE! Weight Management Program to veterans. Weight loss was maintained for one year after baseline in the MOVE! group. This is very promising as weight re-gain is a common issue and these results support using videoconferencing for a long-term weight management treatment option.

Posttraumatic stress disorder (PTSD) represents a debilitating psychiatric condition that is affecting the lives of many returning veterans. PTSD and alcohol use and dependence are highly comorbid. The purpose of this study was to understand the functional mechanisms between PTSD and alcohol use and problems. Specifically, the role of negative urgency and emotional intelligence were investigated as vulnerability and resiliency factors, respectively. This study utilized experience sampling to test associations between PTSD symptoms and alcohol use and related problems in a sample of 90 OIF/OEF veterans. Participants completed 8 brief questionnaires daily for 2 weeks on palmtop computers. Elevations in PTSD symptoms during the day were associated with subsequent increases in alcohol use and associated problems that night. PTSD symptoms were associated with greater problems above and beyond the effect of drinking level at both the within- and between- person level. Emotional intelligence was associated with lower negative urgency, fewer PTSD symptoms, and less alcohol use and associated problems. The effects of emotional intelligence were primarily indirect via negative urgency and the effects of negative urgency on alcohol use and problems were indirect via its positive association with PTSD symptoms. Hypothesized cross-level effects of emotional intelligence and negative urgency were not supported. The findings suggest a functional association between PTSD symptoms and alcohol consumption. The association between PTSD symptoms and alcohol consumption is consistent with a self-medication model. However, the significant associations between PTSD symptoms and alcohol problems, after controlling for use level, suggest a broader role of dysregulation.

Knockdown of orexin/hypocretin 2 receptor (Orx2) in the basolateral amygdala (BLA) affects anxious and depressive behavior. We use a new behavioral paradigm, the Stress-Alternatives Model (SAM), designed to improve translational impact. The SAM induces social stress in adult male mice by aggression from larger mice, allowing for adaptive decision-making regarding escape. In this model mice remain (Stay) in the oval SAM arena or escape from social aggression (Escape) via routes only large enough for the smaller mouse. We hypothesized intracerebroventricular (icv) stimulation of Orx2 receptors would be anxiolytic and antidepressive in SAM-related social behavior and the social interaction/preference (SIP) test. Conversely, we predicted that icv antagonism of Orx2 receptors would promote anxious and depressive behavior in these same tests. Anxious behaviors such as freezing (both cued and conflict) and startle are exhibited more often in Stay compared with Escape phenotype mice. Time spent attentive to the escape route is more frequent in Escape mice. In Stay mice, stimulation of Orx2 receptors reduces fear conditioning, conflict freezing and startle, and promotes greater attention to the escape hole. This anxiolysis was accompanied by activation of a cluster of inhibitory neurons in the amygdala. A small percentage of those Stay mice also begin escaping; whereas Escape is reversed by the Orx2 antagonist. Escape mice were also Resilient, and Stay mice Susceptible to stress (SIP), with both conditions reversed by Orx2 antagonism or stimulation respectively. Together these results suggest that the Orx2 receptor may be a useful potential target for anxiolytic or antidepressive therapeutics.

Hypothalmic orexin/hypocretin (Orx) neurons in the lateral and dorsomedial perifornical region (LH-DMH/PeF) innervate broadly throughout the brain, and receive similar inputs. This wide distribution, as well as two Orx peptides (OrxA and OrxB) and two Orx receptors (Orx1 and Orx2) allow for functionally related but distinctive behavioral outcomes, that include arousal, sleep-wake regulation, food seeking, metabolism, feeding, reward, addiction, and learning. These are all motivational functions, and tie the orexin systems to anxiety and depression as well. We present evidence, that for affective behavior, Orx1 and Orx2 receptors appear to have opposing functions. The majority of research on anxiety- and depression-related outcomes has focused on Orx1 receptors, which appear to have primarily anxiogenic and pro-depressive actions. Although there is significant research suggesting contrary findings, the primary potential for pharmacotherapies linked to the Orx1 receptor is via antagonists to block anxious and depressive behavior. Dual orexin receptor antagonists have been approved for treatment of sleep disorders, and are likely candidates for adaptation for affect disorder treatments. However, we present evidence here that demonstrates the Orx2 receptors are anxiolytic and antidepressive. Using a new experimental pre-clinical model of anxious and depressive behavior stimulated by social stress and decision-making that produces two stable behavioral phenotypes, Escape/Resilient and Stay/Susceptible, we tested the effects of intracerebroventricular injections of Orx2 agonist and antagonist drugs. Over ten behavioral measures, we have demonstrated that Orx2 agonists promote resilience, as well as anxiolytic and antidepressive behavior. In contrast, Orx2 antagonists or knockdown kindle anxious and pro-depressive behavior plus increase susceptibility. The results suggest that the Orx2 receptor may be a useful target for pharmacotherapies to treat anxiety and depression.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD. METHOD: Adult subjects (N = 2229; 56.2% male) aged 18-69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA-PGC PTSD sites underwent T1-weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel-wise (brainageR) and region-of-interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age - chronological age) controlling for chronological age, sex, and scan site. RESULTS: BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three-way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages. DISCUSSION: Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age-related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan.

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants’ demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2–81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3–85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

loss have not sorted out biomarkers useful for the purpose. One of the most important clinical questions is how to use a CDK4/6 inhibitor with other targeted therapies. Here we provide a rationale that oncologists can use to sequence the CDK4/6 inhibitors along with the PI3K-AKT-mTOR pathway-specific inhibitor(s); future data will better guide this approach. In this review we have tried to (a) describe the specific cellular signals initiated following alterations in the cell cycle pathway genes and the PI3K pathway genes, (b) interrogate how these alterations/co-alterations influence the action of PI3K and cell cycle pathway-targeted drugs in different clinical trials and (c) understand the role of co-alterations towards the development of cell cycle inhibitors induced drug-resistance in ER+ breast cancers.

In a newly developed conceptual model of stressful social decision-making, the Stress-Alternatives Model (SAM; used for the 1st time in mice) elicits two types of response: escape or remain submissively. Daily (4d) aggressive social interaction in a neutral arena between a C57BL6/N test mouse and a larger, novel aggressive CD1 mouse, begin after an audible tone (conditioned stimulus; CS). Although escape holes (only large enough for smaller test animals) are available, and the aggressor is unremittingly antagonistic, only half of the mice tested utilize the possibility of escape. During training, for mice that choose to leave the arena and social interaction, latency to escape dramatically decreases over time; this is also true for control C57BL6/N mice which experienced no aggression. Therefore, the open field of the SAM apparatus is intrinsically anxiogenic. It also means that submission to the aggressor is chosen despite this anxiety and the high intensity of the aggressive attacks and defeat. While both groups that received aggression displayed stress responsiveness, corticosterone levels were significantly higher in animals that chose submissive coexistence. Although both escaping and non-escaping groups of animals experienced aggression and defeat, submissive animals also exhibited classic fear conditioning, freezing in response to the CS alone, while escaping animals did not. In the basolateral amygdala (BLA), gene expression of brain-derived neurotrophic factor (BDNF) was diminished, at the same time neuropeptide S (NPS) expression was significantly elevated, but only in submissive animals. This increase in submission-evoked NPS mRNA expression was greatest in the central amygdala (CeA), which coincided with decreased BDNF expression. Reduced expression of BDNF was only found in submissive animals that also exhibit elevated NPS expression, despite elevated corticosterone in all socially interacting animals. The results suggest an interwoven relationship, linked by social context, between amygdalar BDNF, NPS and plasma corticosterone.

We recently reported reduced activity of the cholinergic marker enzyme cholineacetyltransferase (ChAT) in several brain regions of patients with dominantly inherited olivopontocerebellar atrophy (OPCA). To document the regional extent of these changes we performed a comprehensive examination of the behavior of ChAT throughout both cerebral cortical and subcortical brain areas in 5 patients from one large OPCA pedigree. As compared with the controls, mean ChAT activities in OPCA were reduced by 39 to 72% in all (n = 27) cerebral cortical areas examined and in several thalamic subdivisions, caudate head, globus pallidus, red nucleus, and medial olfactory area. In contradistinction to findings in Alzheimer's disease (AD), mean ChAT levels in OPCA amygdala and hippocampal subdivisions were either normal or only mildly reduced. The lack of severe disabling dementia in our OPCA patients compared with AD patients having a similar cortical cholinergic reduction could be explained by an absence of either a marked cholinergic loss in amygdala or hippocampus or significant loss of noncholinergic cerebral cortical and limbic neurons as occurs in AD brain. We suggest that this and other OPCA pedigrees having a cortical cholinergic reduction represent a unique model for the study of behavioral consequences of a more selective cerebral cortical cholinergic lesion rather than a limbic cholinergic lesion.

Corticotropin releasing factor (CRF) is a primary mediator of endocrine, autonomic and behavioral stress responses. Studies in both humans and animal models have implicated CRF in a wide-variety of psychiatric conditions including anxiety disorders such as post-traumatic stress disorder (PTSD), depression, sleep disorders and addiction among others. The central nucleus of the amygdala (CeA), a key limbic structure with one of the highest concentrations of CRF-producing cells outside of the hypothalamus, has been implicated in anxiety-like behavior and a number of stress-induced disorders. This study investigated the specific role of CRF in the CeA on both endocrine and behavioral responses to stress. We used RNA Interference (RNAi) techniques to locally and specifically knockdown CRF expression in CeA. Behavior was assessed using the elevated plus maze (EPM) and open field test (OF). Knocking down CRF expression in the CeA had no significant effect on measures of anxiety-like behavior in these tests. However, it did have an effect on grooming behavior, a CRF-induced behavior. Prior exposure to a stressor sensitized an amygdalar CRF effect on stress-induced HPA activation. In these stress-challenged animals silencing CRF in the CeA significantly attenuated corticosterone responses to a subsequent behavioral stressor. Thus, it appears that while CRF projecting from the CeA does not play a significant role in the expression stress-induced anxiety-like behaviors on the EPM and OF it does play a critical role in stress-induced HPA activation.

Posttraumatic stress disorder (PTSD) is associated with elevated risk of both alcohol use disorder (AUD) and related conduct problems, which are associated with behavioral and emotional dysregulation. We conducted an intensive longitudinal burst design study with 10 weeks of experience sampling over the course of 1.5 years with 250 veterans of recent conflicts. We tested time-series models of daily associations between posttraumatic stress symptoms (PTSS), alcohol dependence syndrome, and conduct problems. Exacerbations of PTSS predicted higher dependence syndrome and conduct problems the next day. This effect was significant after controlling for both concurrent (i.e., same-day) associations between drinking and the outcomes as well as the strength of associations between the outcomes from one day to the next (i.e., autoregression). Affect lability and disinhibition were hypothesized vulnerability factors increasing the strength of within-person predictors of dependence syndrome and conduct problems. Lability and disinhibition were associated with greater dependence syndrome symptoms and conduct problems over the follow-up period. Consistent with expectation, lability rather than disinhibition increased the association between drinking and dependence syndrome as well as the strength of association between dependence syndrome symptoms from one day to the next. Moderating effects of disinhibition in the conduct problems model were not significant. Importantly, results indicated reciprocal associations over time. Lability potentiated the association between dependence syndrome symptoms and next day PTSS, whereas disinhibition potentiated the association between conduct problems and next day PTSS. Results demonstrate complex dynamic associations between PTSS, AUD symptoms, and conduct problems over time indicative of broad regulatory impairments. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Cognitive deficits are widespread in psychiatric disorders and frequently as debilitating as the affective component. Widely prescribed antidepressants for treating depressive disorders have limited efficacy in normalizing cognitive function. Erythropoietin (Epo) has been shown to improve cognitive function in schizophrenia and treatment resistant depressed patients. However, the potent elevation of red blood cell counts by Epo can cause hematological complications in non-anemic patients. We investigated a chemically engineered, posttranslational modification of Epo, carbamoylation, which renders it non-erythropoietic. We conducted mass-spectrometry-based peptide mapping of carbamoylated Epo (Cepo) and tested its ability to improve cognitive function after social defeat stress. Gene expression analysis in discrete brain regions was performed to obtain mechanistic insight of Cepo action. Cepo reversed stress-induced spatial working memory deficits while affecting long-term (24 h) novel object recognition in these rats. Contextual fear conditioning following defeat was enhanced by Cepo, but attenuated in controls. However, Cepo improved fear extinction in all rats compared to vehicle treatment. Cepo induced differential gene expression of BDNF, VGF, Arc, TH. and neuritin in the mPFC and discrete hippocampal subfields, with strongest induction in the dorsal hippocampus. Analysis of gene-brain region-behavior interactions showed that Cepo-induced neurotrophic mechanisms influence cognitive function. Carbamoylated erythropoietin can be developed as a therapeutic neurotrophic agent to treat cognitive dysfunction in neuropsychiatric diseases. Due to its distinct mechanism of action, it is unlikely to cross react with the activity of currently prescribed small molecule drugs and can be used as an add-on biologic drug.

Social rank functions to facilitate coping responses to socially stressful situations and conditions. The evolution of social status appears to be inseparably connected to the evolution of stress. Stress, aggression, reward, and decision-making neurocircuitries overlap and interact to produce status-linked relationships, which are common among both male and female populations. Behavioral consequences stemming from social status and rank relationships are molded by aggressive interactions, which are inherently stressful. It seems likely that the balance of regulatory elements in pro- and anti-stress neurocircuitries results in rapid but brief stress responses that are advantageous to social dominance. These systems further produce, in coordination with reward and aggression circuitries, rapid adaptive responding during opportunities that arise to acquire food, mates, perch sites, territorial space, shelter and other resources. Rapid acquisition of resources and aggressive postures produces dominant individuals, who temporarily have distinct fitness advantages. For these reasons also, change in social status can occur rapidly. Social subordination results in slower and more chronic neural and endocrine reactions, a suite of unique defensive behaviors, and an increased propensity for anxious and depressive behavior and affect. These two behavioral phenotypes are but distinct ends of a spectrum, however, they may give us insights into the troubling mechanisms underlying the myriad of stress-related disorders to which they appear to be evolutionarily linked.

Abstract Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p -FDR &lt; 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

The objective of this study was to estimate a network model of risk and resilience factors of suicidal ideation among veterans. Two network models of suicidal ideation among Operation Iraqi Freedom/Operation Enduring Freedom/Operation New Dawn veterans (N = 276) incorporated key disorders, traumatic stress, and resilience constructs to contextualize suicidal ideation. Childhood trauma was positively connected with suicidal ideation and harassment and inversely connected with social support and distress tolerance. This exemplifies long-lasting associations between childhood trauma and re-victimization, emotion regulation, and ability to form supportive social relationships. A subsequent model including lower-order facets indicated that combat trauma was predominantly associated with posttraumatic stress disorder-intrusion symptoms. This study highlights the importance of addressing both risk and resilience to reduce suicide risk among veterans and increases understanding of factors that contribute to suicidal ideation.