Reformulating provider profiling by grouping providers treating similar patients prior to evaluating performance.

Standard approaches to comparing health providers' performance rely on hierarchical logistic regression models that adjust for patient characteristics at admission. Estimates from these models may be misleading when providers treat different patient populations and the models are misspecified. To address this limitation, we propose a novel profiling approach that identifies groups of providers treating similar populations of patients and then evaluates providers' performance within each group. The groups of providers are identified using a Bayesian multilevel finite mixture of general location models. To compare the performance of our proposed profiling approach to standard methods, we use patient-level data from 119 skilled nursing facilities in Massachusetts. We use simulated and observed outcome data to explore the performance of these profiling methods in different settings. In simulations, our proposed method classifies providers to groups with similar patients' admission characteristics. In addition, in the presence of limited overlap in patient characteristics across providers and misspecifications of the outcome model, the provider-level estimates obtained using our approach identified providers that under- and overperformed compared to the standard regression-based approaches more accurately.

Bichectomy Surgery and EMG Masticatory Muscles Function in Adult Women: A Longitudinal Study.

AIM: This longitudinal study aimed to evaluate the electromyographic activity of the masseter and temporal muscles in adult women who underwent buccal fat removal. MATERIALS AND METHODS: The sample consisted of 20 healthy adult women with no temporomandibular dysfunction and normal occlusion, who were assessed before, 30, and 60 days after the surgery. The electromyographic signal of the masseter and temporal muscles was captured through mandibular tasks including rest, protrusion, right and left laterality, and maximum voluntary contraction with and without parafilm. The results obtained were tabulated and the Shapiro-Wilk normality test was performed, which indicated a normal distribution. Statistical analysis was performed using the repeated measures test (p < 0.05). RESULTS: Significant differences were observed between time periods in maximum voluntary contraction for the left masseter muscle (p = 0.006) and in maximum voluntary contraction with parafilm for the right temporal (p = 0.03) and left temporal (p = 0.03) muscles. CONCLUSION: Bichectomy surgery did not modify the electromyographic activity of the masseter and temporal muscles during the rest task but may have influenced variations in the electromyographic signal during different mandibular tasks after 60 days of surgery, suggesting compensatory adaptations and functional recovery. CLINICAL SIGNIFICANCE: Understanding the impact of buccal fat removal surgery on the stomatognathic system function provides insights into postoperative functional recovery and potential compensatory adaptations, guiding clinical management and rehabilitation strategies for patients undergoing such procedures. How to cite this article: Cardoso AHDLS, Palinkas M, Bettiol NB, et al. Bichectomy Surgery and EMG Masticatory Muscles Function in Adult Women: A Longitudinal Study. J Contemp Dent Pract 2024;25(3):207-212.

Variation in trauma-related behavioral effects using a preclinical rat model of three predator exposure stress.

The underlying mechanisms of trauma-related disorders are challenging to discover and the disorders are difficult to treat, in part due to the complex and varied expressions of response to traumatic stress. These challenges will be easier to overcome as more is understood about the variability in response to trauma. Incorporating assessment of variability into animal models of traumatic stress may allow better translation to clinical research and treatment development. In this study, we characterized variability in behavioral responses following traumatic stress exposure using a predator exposure (PE) animal model. Elevated plus maze (EPM) and acoustic startle response (SR) were used to study avoidance and arousal symptoms in male Sprague-Dawley rats. Behavioral data were compared between control (n = 31) and predator-exposed (n = 30) rats. PE behavior was clustered using k-means principal components analysis. Four clusters and three distinct subgroups were identified and were characterized as avoidant (Cluster 4, 30%), moderately avoidant (Clusters 2 and 3, 49%), and unaffected (Cluster 1, 17%). These results demonstrate that rodent responses to PE are varied, similar to human presentations following traumatic stress, suggesting it may be possible to develop treatment strategies for varied symptom presentations using a preclinical animal model.

Multiple imputation procedures for estimating causal effects with multiple treatments with application to the comparison of healthcare providers.

Choosing between multiple healthcare providers requires us to simultaneously compare the expected outcomes under each provider. This comparison is complex because the composition of patients treated by each provider may differ. Similar issues arise when simultaneously comparing the adverse effects of interventions using non-randomized data. To simultaneously estimate the effects of multiple providers/interventions we propose procedures that explicitly impute the set of potential outcomes for each subject. The procedures are based on different specifications of the generalized additive models (GAM) and the Bayesian additive regression trees (BART). We compare the performance of the proposed procedures to previously proposed matching and weighting procedures using an extensive simulation study for continuous outcomes. Our simulations show that when the distributions of the covariates across treatment groups have adequate overlap, the multiple imputation procedures based on separate BART or GAM models in each treatment group are generally superior to weighting based methods and have similar and sometimes better performance than matching on the logit of the generalized propensity score. Another advantage of these multiple imputation procedures is the ability to provide point and interval estimates to a wide range of causal effect estimands. We apply the proposed procedures to comparing multiple nursing homes in Massachusetts for readmission outcomes. The proposed approach can be applied to other causal effects applications with multiple treatments.

MAPPING MENTAL HEALTH INTERVENTIONS DURING THE COVID-19 PANDEMIC. A COMPARISON REVIEW OF CHINA AND WESTERN EUROPE.

OBJECTIVE: The aim: To map and compare mental health interventions during the Covid-19 pandemic in China and Western-Europe. The focus was specifically on the availability, duration, target group, content, setting, and outcomes of the interventions. PATIENTS AND METHODS: Materials and methods: A scoping review was conducted by utilising several scientific databases. A total of 479 articles were found after removing the duplicate records. After screening, 36 articles were included in the study. Relevant intervention characteristics were systematically mapped, and compared within and among countries. CONCLUSION: Conclusions: All interventions had shared aims to improve the psychological resilience and to reduce psychological distress. In particular, anxiety- and depression-related symptoms were commonly addressed. On average, interventions in China were larger scaled, had longer durations, and often used combinations of strategies such as therapies and exercises both in-person and remotely. Interventions in Western-Europe tend to be locally implemented on a smaller scale, and often used a single strategy. Most Chinese interventions targeted adolescents, while all interventions in Western-Europe were meant for adults. Most interventions were assessed using quantitative methods using various mental health scales, showing statistically significant effects in improving mental health.

Racial/Ethnic Differences in 30-Day Mortality for Heart Failure and Pneumonia in the Veterans Health Administration Using Claims-based, Clinical, and Social Risk-adjustment Variables.

BACKGROUND: Prior studies have identified lower mortality in Black Veterans compared with White Veterans after hospitalization for common medical conditions, but these studies adjusted for comorbid conditions identified in administrative claims. OBJECTIVES: The objectives of this study were to compare mortality for non-Hispanic White (hereafter, "White"), non-Hispanic Black (hereafter, "Black"), and Hispanic Veterans hospitalized for heart failure (HF) and pneumonia and determine whether observed mortality differences varied according to whether claims-based comorbid conditions and/or clinical variables were included in risk-adjustment models. RESEARCH DESIGN: This was an observational study. SUBJECTS: The study cohort included 143,520 admissions for HF and 127,782 admissions for pneumonia for Veterans hospitalized in 132 Veterans Health Administration (VA) Medical Centers between January 2009 and September 2015. MEASURES: The primary independent variable was racial/ethnic group (ie, Black, Hispanic, and non-Hispanic White), and the outcome was all-cause mortality 30 days following admission. To compare mortality by race/ethnicity, we used logistic regression models that included different combinations of claims-based, clinical, and sociodemographic variables. For each model, we estimated the average marginal effect (AME) for Black and Hispanic Veterans relative to White Veterans. RESULTS: Among the 143,520 (127,782) hospitalizations for HF (pneumonia), the average patient age was 71.6 (70.9) years and 98.4% (97.1%) were male. The unadjusted 30-day mortality rates for HF (pneumonia) were 7.2% (11.0%) for White, 4.1% (10.4%) for Black and 8.4% (16.9%) for Hispanic Veterans. Relative to White Veterans, when only claims-based variables were used for risk adjustment, the AME (95% confidence interval) for the HF [pneumonia] cohort was -2.17 (-2.45, -1.89) [0.08 (-0.41, 0.58)] for Black Veterans and 1.32 (0.49, 2.15) [4.51 (3.65, 5.38)] for Hispanic Veterans. When clinical variables were incorporated in addition to claims-based ones, the AME, relative to White Veterans, for the HF [pneumonia] cohort was -1.57 (-1.88, -1.27) [-0.83 (-1.31, -0.36)] for Black Veterans and 1.50 (0.71, 2.30) [3.30 (2.49, 4.11)] for Hispanic Veterans. CONCLUSIONS: Compared with White Veterans, Black Veterans had lower mortality, and Hispanic Veterans had higher mortality for HF and pneumonia. The inclusion of clinical variables into risk-adjustment models impacted the magnitude of racial/ethnic differences in mortality following hospitalization. Future studies examining racial/ethnic disparities should consider including clinical variables for risk adjustment.

Emergency CT of abdominal complications of ingested fish bones: what not to miss.

Fish bones are the most commonly ingested structures and the most common cause of foreign body perforation of the gastrointestinal tract (GIT). Clinical presentation of foreign body GIT perforation is nonspecific, in many cases with clinical signs of acute abdomen, which can mimic appendicitis, diverticulitis, ulcer peptic disease, and other common inflammatory conditions. Besides, patients commonly do not refer that a fish bone was swallowed. Since this condition is usually not suspected by referring physicians of the emergency department (ED), radiologists play a key role in this diagnosis; the spectrum of these imaging features must be known in order to be accurately reported in the ED.

Impairment of electrical activation of wrist flexor and extensor muscles during gripping and functional activities in the early stage of hand osteoarthritis: A cross-sectional study.

STUDY DESIGN: This is a cross-sectional study. INTRODUCTION: The wrist extensor muscles have a fundamental role in the stabilization of the wrist while performing manual activities. However, it is unknown if the clinical signs of hand osteoarthritis (HOA) cause impairment in the activation of these muscles PURPOSE OF THE STUDY: The purpose of this study was to investigate whether early-stage HOA affects the magnitude of activation and coactivation between the wrist extensor and flexor muscles METHODS: Thirty-two subjects were divided into two groups: control group (n = 16; 55 ± 7.42 years) and a group with HOA grades 2 or 3 (HOAG; n = 16; 57 ± 7.82 years). Muscle activation was measured in m. flexor digitorum superficialis, m. flexor carpi ulnaris (FCU) and extensors (EXT) during the evaluation of grip strength and three manual activities (write, cut a paper with scissors, and close and open a bottle). The coactivation index was calculated between the electromyography of the flexors (FCU and FSD) and wrist EXT. RESULTS: HOAG presented reduced muscle activation in all tasks, with a statistical difference for the flexor digitorum superficialis and EXT in the scissors activity, and for the FCU in the bottle activity. No differences were found between groups for the coactivation index and grip strength. DISCUSSION: The reduced muscle activity may be due to an inability of the patients of the HOAG to recruit all motor units or to an inhibition related to the presence of pain. CONCLUSION: In the early stages of HOA, there is a functional deficit associated with a reduced muscle activity of the wrist muscles during manual activities.

Evaluation of the masticatory biomechanical function in Down syndrome and its Influence on sleep disorders, body adiposity and salivary parameters.

OBJECTIVE: To evaluate the phenotypic features of the masticatory biomechanics in atypical subjects with Down syndrome (DS). Its influence was analysed on sleep disorders, body adiposity and its risks, and some physicochemical properties of saliva. METHODS: Seventy subjects were enrolled to assess masticatory biomechanical function and divided into two groups: DS and control groups. Electrical activities of the masseter and temporal muscles (at rest and in maximum voluntary clench-MVC), maximum bite force-MBF and maximum mouth opening-MMO were investigated. Among the atypical subjects, just 24 participants underwent the anthropometry, the polysomnography II and the saliva testing (salivary flow rate-SFR, buffer capacity-BC and salivary cortisol levels, morning/SC-AM and night/SC-PM). RESULTS: MVC and MBF values showed high statistical significance in the control group (P < .001) than in the DS group of 35. MMO values were slightly increased in the DS group in relation to the control group. Overweight and obesity were found in both genders. Atypical women showed higher risk to develop cardiovascular-metabolic diseases than in atypical men. OSA severe was 20% for atypical women and 42.8% for atypical men, whereas snoring index was present in all genders. SFR was reduced in 100% of atypical subjects (hyposalivation in 10% women and 28.5% men). Furthermore, 100% BC, 66.6% SC-AM and 91.6% SC-PM showed normal patterns. CONCLUSION: Masseter and temporal muscle hypotonia was found in all atypical subjects with DS. This muscle dysfunction strongly was related to overweight/obesity, risks for development of cardiovascular/metabolic diseases, OSA severity, successive snoring episodes and salivary flow reduction in DS.

Social Motivation Differentiates Social Anxiety and Depression: A Daily Diary Study.

Because social anxiety and depression commonly co-occur, it can be challenging to disentangle the emotional and motivational features of these conditions in everyday life contexts. In this daily diary study, we sought to understand the interplay between daily social anxiety and depression symptoms and emotion and motivation, determining whether daily symptoms are independently linked with positive affect, negative affect, and social motivation (desire to approach or to withdraw from others). Community-dwelling adults (N = 269) with a wide range of social anxiety and depression symptoms completed daily assessments for 14 consecutive days (a total of 2,986 daily surveys). Within-person analyses found that increases in social anxiety and depression symptoms were uniquely associated with elevated negative affect; only increases in depression symptoms were associated with diminished positive affect. Increases in social anxiety symptoms were associated with an elevated desire to approach others but not a desire to withdraw from others. By contrast, increases in depression symptoms were associated with a diminished desire to approach others and an elevated desire to withdraw from others. Desire for social connection may distinguish social anxiety from depression. Examining patterns of daily social motivation may enhance clinicians' ability to differentiate the difficulties that arise from social anxiety from those that arise from depression.

A zinc finger transcription factor enables social behaviors while controlling transposable elements and immune response in prefrontal cortex.

The neurobiological origins of social behaviors are incompletely understood. Here we utilized synthetic biology approaches to reprogram the function of ZFP189, a transcription factor whose expression and function in rodent prefrontal cortex was previously demonstrated to be protective against stress-induced social deficits. We created novel synthetic ZFP189 transcription factors including ZFP189VPR, which activates the transcription of target genes and therefore exerts opposite functional control from the endogenous, transcriptionally repressive ZFP189WT. Following viral delivery of these synthetic ZFP189 transcription factors to mouse prefrontal cortex, we observe that ZFP189-mediated transcriptional control promotes mature dendritic spine morphology on transduced pyramidal neurons. Interestingly, inversion of ZFP189-mediated transcription in this brain area, achieved by viral delivery of synthetic ZFP189VPR, precipitates social behavioral deficits in terms of social interaction, motivation, and the cognition necessary for the maintenance of social hierarchy, without other observable behavioral deficits. RNA sequencing of virally manipulated prefrontal cortex tissues reveals that ZFP189 transcription factors of opposing regulatory function (ZFP189WT versus ZFP189VPR) have opposite influence on the expression of genetic transposable elements as well as genes that participate in adaptive immune functions. Collectively, this work reveals that ZFP189 function in the prefrontal cortex coordinates structural and transcriptional neuroadaptations necessary for complex social behaviors while regulating transposable element-rich regions of DNA and the expression of immune-related genes. Given the evidence for a co-evolution of social behavior and the brain immune response, we posit that ZFP189 may have evolved to augment brain transposon-associated immune function as a way of enhancing an animal's capacity for functioning in social groups.

Histone H1x in mouse ventral hippocampus associates with, but does not cause behavioral adaptations to stress.

Prior research has identified differential protein expression levels of linker histone H1x within the ventral hippocampus (vHipp) of stress-susceptible versus stress-resilient mice. These mice are behaviorally classified based on their divergent responses to chronic social stress. Here, we sought to determine whether elevated vHipp H1x protein levels directly contribute to these diverging behavioral adaptations to stress. First, we demonstrated that stress-susceptible mice uniquely express elevated vHipp H1x protein levels following chronic stress. Given that linker histones coordinate heterochromatin compaction, we hypothesize that elevated levels of H1x in the vHipp may impede pro-resilience transcriptional adaptations and prevent development of the resilient phenotype following social stress. To test this, 8-10-week-old male C57BL/6 J mice were randomly assigned to groups undergoing 10 days of chronic social defeat stress (CSDS) or single housing, respectively. Following CSDS, mice were classified as susceptible versus resilient based on their social interaction behaviors. We synthesized a viral overexpression (OE) vector for H1x and transduced all stressed and single housed mice with either H1x or control GFP within vHipp. Following viral delivery, we conducted social, anxiety-like, and memory-reliant behavior tests on distinct cohorts of mice. We found no behavioral adaptations following H1x OE compared to GFP controls in susceptible, resilient, or single housed mice. In sum, although we confirm elevated vHipp protein levels of H1x associate with susceptibility to social stress, we observe no significant behavioral consequence of H1x OE. Thus, we conclude elevated levels of H1x are associated with, but are not singularly sufficient to drive development of behavioral adaptations to stress.

Transcranial direct current stimulation and cognitive changes in Parkinson's disease, a systematic review with meta-analysis and meta-regression.

Parkinson's disease is the second most common neurodegenerative disease, but therapeutic options such as neuromodulation continue to show variable effects, making clinical management of the disease difficult. This systematic review with meta-analysis and meta-regression aimed to analyze the isolated effect of cortical modulation with transcranial direct current stimulation (tDCS) compared to sham stimulation on cognitive changes in people with Parkinson's disease. The databases used were: Web of Science, Scopus, PsycINFO, PubMed, and Cochrane. The results showed that tDCS can influence the improvement of cognition in PD (Inverse Variance:0.24 [95% Confidence Interval: 0.09 to -0.40], p < 0.00). The meta-analysis showed that active tDCS can influence cognitive function by improving aspects related to memory (Inverse Variance:0.34 [95% Confidence Interval: 0.07 to 0.61], p < 0.01) and reducing reaction time in cognitive tasks (Inverse Variance:0.42 [95% Confidence Interval: 0.07 to 0.76], p < 0.02). Innovative meta-regression analyses showed that variables such as age (Q = 2.54, df = 1, p < 0.11), education level (Q = 2.62, df = 1, p < 0.10), disease duration (Q = 0.01, df = 1, p < 0.92), and Unified PD Rating Scale stage (Q = 0.01, df = 1, p < 0.92) did not influence the results. Thus, tDCS may be a therapeutic option for cognitive changes in people with PD, and we suggest further studies to identify protocols that can be replicated.

Suppression of HIV in the first 12 months of antiretroviral therapy: a comparative analysis of dolutegravir- and efavirenz-based regimens.

OBJECTIVE: To compare viral suppression in treatment-naïve adults starting antiretroviral therapy with dolutegravir (50mg)- and efavirenz (600mg)-based regimens. METHODS: We analyzed secondary data from Brazilian health information systems of people living with human immunodeficiency virus who started antiretroviral therapy between 2015 and 2017 in Minas Gerais, Brazil. The outcome was viral suppression, defined as the achievement of the first viral load <50 copies/mL within 12 months after initiating antiretroviral therapy. This outcome was also compared with viral load <1,000 copies/mL and analyzed in two scenarios: intention-to-treat versus per-protocol. Time to viral suppression and adjusted odds ratio accompanied by 95% confidence intervals were estimated. RESULTS: Of the 2,599 participants enrolled, 77.5% were men, and the median age was 34 years. In the intention-to-treat analysis, viral suppression was 58.1% for efavirenz and 76.7% for dolutegravir. People living with HIV on dolutegravir-based regimen were more likely to achieve viral suppression (aOR: 2.44; 95%CI: 2.01-2.95) and had a shorter median time to viral suppression (p<0.0001). Antiretroviral therapy initiation within <120 days, baseline CD4⁺T-cells ≥200 cells/mm3, and viral load <100,000 copies/mL had higher odds of viral suppression. According to the per-protocol analysis, viral suppression ≥90% was observed by considering viral load <1,000 copies/mL. CONCLUSION: Our study demonstrated that viral suppression improved after introducing dolutegravir, although the proportion of patients with viral load <50 copies/mL was lower than expected. Improved access to routine viral load examinations and continuous surveillance of the effectiveness of antiretroviral therapy should be considered.

Histone H1x in mouse ventral hippocampus correlates with, but does not cause behavioral adaptations to stress.

Prior research has identified differential protein expression levels of linker histone H1x within the ventral hippocampus (vHipp) of stress-susceptible versus stress-resilient mice. These mice are behaviorally classified based on their divergent responses to chronic social stress. Here, we sought to determine whether elevated vHipp H1x protein levels directly contribute to these diverging behavioral adaptations to stress. First, we demonstrate that stress-susceptible mice uniquely express elevated vHipp H1x protein levels following chronic stress. Given that linker histones coordinate heterochromatin compaction, we hypothesize that elevated levels of H1x in the vHipp may impede pro-resilience transcriptional adaptations and prevent development of the resilient phenotype following social stress. To test this, 8-10-week-old male C57BL/6J mice were randomly assigned to stressed and unstressed groups undergoing 10 days of chronic social defeat stress (CSDS) or single housing respectively. Following CSDS, mice were classified as susceptible versus resilient based on their social interaction behaviors. We synthesized a viral overexpression (OE) vector for H1x and transduced experimental mice with either H1x or control GFP within vHipp. Following viral delivery, we conducted social, anxiety-like, and memory-reliant behavior tests on distinct cohorts of mice. We found no behavioral adaptations following H1x OE compared to GFP controls in susceptible, resilient, or unstressed mice. In sum, although we confirm vHipp protein levels of H1x correlate with susceptibility to social stress, we observe no significant behavioral consequence of H1x OE. Thus, we conclude elevated levels of H1x are correlated with, but are not singularly sufficient to drive development of behavioral adaptations to stress.

Magnetic resonance imaging findings in autoimmune hepatitis: how frequent and reproducible are they?

Objective: To determine the frequency and interobserver reproducibility of the magnetic resonance imaging (MRI) features considered diagnostic for autoimmune hepatitis. Materials and Methods: Two abdominal radiologists, blinded to pathology data, reviewed the MRI examinations of 20 patients with autoimmune hepatitis, looking for liver enhancement, lymphadenopathy, portal hypertension, and chronic liver disease. The pattern of liver fibrosis was categorized as reticular, confluent, or mixed. Interobserver agreement was assessed by calculating intraclass correlation coefficients and kappa statistics. Results: The most common abnormal finding on MRI was surface nodularity (in 85%), followed by liver fibrosis with a reticular pattern (in 80%)-categorized as mild (in 25.0%), moderate (in 43.8%), or severe (in 31.2%)-; heterogeneous liver enhancement (in 65%); splenomegaly (in 60%); caudate lobe enlargement (in 50%); and lymphadenopathy (in 40%). The interobserver agreement was almost perfect for surface nodularity (0.83), ascites (0.89), and liver volume (0.95), whereas it was just slight and fair for the degree of fibrosis and for heterogeneous liver enhancement (0.12 and 0.25, respectively). It was also slight and fair for expanded gallbladder fossa and enlarged preportal space (0.14 and 0.36, respectively), both of which are indicative of chronic liver disease. Conclusion: The interobserver agreement was satisfactory for surface nodularity (the most prevalent abnormal MRI finding), ascites, liver volume, and splenomegaly. Conversely, it was only slight or fair for common but less objective criteria.

Objetivo: Determinar a frequência e reprodutibilidade interobservador das características de imagem por ressonância magnética na hepatite autoimune. Materiais e Métodos: Dois radiologistas abdominais, cegos para dados patológicos, revisaram ressonâncias magnéticas de 20 pacientes com hepatite autoimune quanto ao realce hepático, linfadenopatia, hipertensão portal e doença hepática crônica. A fibrose foi classificada como reticular, confluente ou ambas. A concordância interobservador foi avaliada por coeficientes de correlação intraclasse e estatística kappa. Resultados: O achado anormal mais comum foi nodularidade superficial (85%), seguido de fibrose reticular hepática (80%) ­ leve (25%), moderada (43,8%), grave (31,2%) ­, realce heterogêneo (65%), esplenomegalia (60%), aumento do lobo caudado (50%) e linfadenopatia (40%). A concordância interobservador foi quase perfeita para nodularidade superficial (0,83), ascite (0,89) e volume hepático (0,95); entretanto, foi apenas leve (0,12) e razoável (0,25) para grau de fibrose e realce heterogêneo, respectivamente. Também foi leve (0,14) ou regular (0,36) para achados de doença hepática crônica, como fossa da vesícula biliar expandida e espaço pré-portal alargado, respectivamente. Conclusão: A concordância geral foi satisfatória para nodularidade superficial (achado anormal mais prevalente), ascite, volume hepático e esplenomegalia. Critérios frequentes, porém menos objetivos, tiveram apenas concordância leve a razoável.

Development of an Animal Model of Military-Relevant Traumatic Stress.

INTRODUCTION: Acute Stress Reactions (ASRs) affect a subgroup of individuals who experience traumatic stress. In the context of military operations, such reactions are often termed Combat and Operational Stress Reactions (COSRs). COSRs not only encompass all symptoms of ASRs but also include additional symptoms related to military combat and may develop at a rate higher than the general public experiences ASRs. Despite an obvious need, there are currently no approved pharmacologic treatments or guidelines for ASR and/or COSR. Preclinical rodent stress models and behavioral assessments are used to evaluate pharmacotherapies and elucidate underlying mechanisms. Here, we combined established traumatic stress models to develop a model of traumatic stress relevant to military trauma exposure and measured behavioral outcomes that reflect outcomes observed in ASRs and COSRs. MATERIALS AND METHODS: Adult male rats underwent exposure to either a combination of two or three traumatic stress exposures (e.g., predator exposure, underwater trauma (UWT), and/or inescapable shock) or control procedures. Behavioral performance on the open field, elevated plus maze, and acoustic startle response (SR) was then assessed 24- and 48-hours following stress/control procedures. RESULTS: In Experiment 1, rats were exposed to a two-stressor model, where predator exposure was coupled with UWT. Minor behavioral deficits were observed in SR for stress-exposed rats as compared to controls. In Experiment 2, inescapable shock was added to predator exposure and UWT. Behavioral performance deficits were observed across all behavioral tests. In Experiment 3, procedures from Experiment 2 were repeated with the only major modification being a shortened predator exposure duration, which resulted in performance deficits in SR only. CONCLUSIONS: We found that the three-stressor model of Experiment 2 resulted in the greatest overall behavioral disturbance (both in the number of variables and magnitude of stress effects). Interestingly, behavioral deficits elicited from the shorter predator exposure were distinct from those observed with longer predator exposure times. Together, these results generally suggest that combined preclinical stressors with military-relevant elements result in behavioral performance deficits reflective of post-trauma phenotypes in Soldiers. The present findings support the use of both physical and psychological stressors to model operationally relevant traumatic stress exposure.

A zinc finger transcription factor tunes social behaviors by controlling transposable elements and immune response in prefrontal cortex.

The neurobiological origins of social behaviors are incompletely understood. Here we utilized synthetic biology approaches to reprogram the function of ZFP189, a transcription factor whose expression and function in the rodent prefrontal cortex was previously determined to be protective against stress-induced social deficits. We created novel synthetic ZFP189 transcription factors including ZFP189VPR, which activates the transcription of target genes and therefore exerts opposite functional control from the endogenous, transcriptionally repressive ZFP189WT. Upon viral delivery of these synthetic ZFP189 transcription factors to mouse prefrontal cortex, we observe that ZFP189-mediated transcriptional control promotes mature dendritic spine morphology on transduced pyramidal neurons. Interestingly, dysregulation of ZFP189-mediated transcription in this brain area, achieved by delivery of synthetic ZFP189VPR, precipitates social behavioral deficits in terms of social interaction, motivation, and the cognition necessary for the maintenance of social hierarchy, without other observable behavioral deficits. By performing RNA sequencing in virally manipulated prefrontal cortex tissues, we discover that ZFP189 transcription factors of opposing regulatory function have opposite influence on the expression of genetic transposable elements as well as genes that participate in immune functions. Collectively, this work reveals that ZFP189 function in the prefrontal cortex coordinates structural and transcriptional neuroadaptations necessary for social behaviors by binding transposable element-rich regions of DNA to regulate immune-related genes. Given the evidence for a co-evolution of social behavior and the brain immune response, we posit that ZFP189 may have evolved to augment brain transposon-associated immune function as a way of enhancing an animal's capacity for functioning in social groups.

CREB Binding at the Zfp189 Promoter Within Medium Spiny Neuron Subtypes Differentially Regulates Behavioral and Physiological Adaptations Over the Course of Cocaine Use.

BACKGROUND: Over the course of chronic drug use, brain transcriptional neuroadaptation is thought to contribute to a change in drug use behavior over time. The function of the transcription factor CREB (cAMP response element binding protein) within the nucleus accumbens (NAc) has been well documented in opposing the rewarding properties of many classes of drugs, yet the gene targets through which CREB causally manifests these lasting neuroadaptations remain unknown. Here, we identify zinc finger protein 189 (Zfp189) as a CREB target gene that is transcriptionally responsive to acute and chronic cocaine use within the NAc of mice. METHODS: To investigate the role of the CREB-Zfp189 interaction in cocaine use, we virally delivered modified clustered regularly interspaced short palindromic repeats (CRISPR)/dCas9 constructs capable of selectively localizing CREB to the Zfp189 gene promoter in the NAc of mice. RESULTS: We observed that CREB binding to the Zfp189 promoter increased Zfp189 expression and diminished the reinforcing responses to cocaine. Furthermore, we showed that NAc Zfp189 expression increased within D1 medium spiny neurons in response to acute cocaine but increased in both D1- and D2-expressing medium spiny neurons in response to chronic cocaine. CREB-mediated induction of Zfp189 potentiated electrophysiological activity of D1- and D2-expressing medium spiny neurons, recapitulating the known effect of CREB on these neurons. Finally, targeting CREB to the Zfp189 promoter within NAc Drd2-expressing neurons, but not Drd1-expressing neurons, was sufficient to diminish cocaine-conditioned behaviors. CONCLUSIONS: Together, these findings point to the CREB-Zfp189 interaction within the NAc Drd2+ neurons as a molecular signature of chronic cocaine use that is causal in counteracting the reinforcing effects of cocaine.