Recent Trends in Sepsis Mortality, Associations between Initial Source of Sepsis and Hospital Mortality, and Predictors of Sepsis Readmission in Sepsis Survivors
Background: Sepsis, a leading cause of US deaths, is associated with high mortality, although advances in early recognition and treatment have increased survivorship. Many aspects of sepsis pathophysiology and epidemiology have not been fully elucidated; the heterogeneous nature of infections that lead to sepsis has made fully characterizing the underlying epidemiology challenging.
Methods: The University HealthSystem Consortium (UHC) from 2011-2014 and the Cerner HealthFacts® database from 2008-2014 were used. We examined associations between infection source and in-hospital mortality in the UHC dataset, stratified by age and presenting sepsis stage. We examined recent temporal trends in present-on-admission (POA) sepsis diagnoses and mortality and predictors of 30-day sepsis readmissions following sepsis hospitalizations using the HealthFacts® dataset.
Results: Patients with sepsis due to genitourinary or skin, soft tissue, or bone sources had lower mortality than patients with sepsis due to respiratory sources regardless of age or presenting sepsis stage. Overall diagnoses of sepsis increased from 2008-2014; however, POA diagnoses and case fatality rates decreased. Factors that predicted re-hospitalization for sepsis included discharge to hospice, admission from or discharge to a skilled nursing facility, and abdominal infection.
Conclusion: Further investigation will reveal more detail to explain the impact of infection source on in-hospital sepsis mortality for all age groups and sepsis stages. Decreasing mortality rates for all POA sepsis stages and all age groups suggest current approaches to sepsis management are having broad impact. Sepsis survivors are at significant risk for re-hospitalization; further studies are needed to understand the post discharge risks and needs of survivors.
A Synthetic Genetic System to Investigate Brain Connectivity and Genetically Manipulate Interacting Cells
The underlying goal of neuroscience research is to understand how the nervous system functions to bring about behavior. A detailed map of neural circuits is required for scientists to tackle this question. To this purpose, we developed a synthetic and genetically-encoded system, TRanscellular ACtivation of Transcription (TRACT) to monitor cell-cell contact. Upon ligand-receptor interaction at sites of cell-cell contact, the transmembrane domain of an engineered Notch receptor is cleaved by intramembrane proteolysis and releases a fragment that regulates transcription in the receptor-expressing cell. We demonstrate that in cultured cells, the synthetic receptor can be activated to drive reporter gene expression by co-incubation with ligand-expressing cell or by growth on ligand-coated surfaces. We further show that TRACT can detect interactions between neurons and glia in the Drosophila brain; expressing the ligand in spatially-restricted subsets of neurons leads to transcription of a reporter in the glial cells that interact with those neurons. To optimize TRACT for neural tracing, we attempted to target the synthetic receptor to post-synaptic sites by fusion with the intracellular domain of Drosophila neuroligin2. However, this modification only facilitate the receptor to be localized homogeneously throughout the neurites. The induction data of the modified receptor shows that the new receptor has better sensitivity compared to the original receptor, but the ligand-receptor interaction still happened at non-synaptic sites of membrane contact. To further target the ligand to pre-synaptic sites, we fused the ligand to different pre-synaptic markers. We found the one fused with synaptobrevin is likely located at axon terminals, but only able to trigger moderate induction. Therefore, more examinations are required to further characterize the capability of this ligand. In summary, TRACT is useful for monitoring cell-cell interactions in animals and could also be used to genetically manipulate cells based on contact. Moreover, we believe that proper targeting of the ligand to synaptic sites will improve the specificity of TRACT for synaptic connections in the future.
Intensity of Offending Following State Prison Release Among Persons Treated for Mental Health Problems While Incarcerated
OBJECTIVE: This study examined a range of demographic, clinical, and criminal history factors as they relate to the intensity of offending for up to two years postrelease.
METHODS: This study drew on data from 1,438 individuals released from Massachusetts state prisons between 2007 and 2009 who, while incarcerated, received treatment from the prisons' mental health services and were followed for 24 months postrelease. These data were used to explore predictive factors related to the intensity of criminal justice involvement, defined as number of arrests in the two-year follow-up period.
RESULTS: Predictors of subsequent arrests included number of previous incarcerations and black race. Protective factors included older age, supervision by parole, and a drug-related or person-related governing offense on previous arrest. Clinical symptoms were not related to incidence of postrelease arrests.
CONCLUSIONS: This study identified factors related to criminal history, such as type of charge, that were associated with the intensity of subsequent criminal justice involvement. These findings have not been reported in previous studies, perhaps because intensity of offending as opposed to a different dependent variable was used to measure criminal justice involvement. Further investigation should focus on whether the type of previous offense is related to postrelease risk factors for recidivism.
The Neuroimaging Informatics Tools and Resources Clearinghouse (NITRC - www.nitrc.org) suite of services include a resources registry, image repository and a cloud computational environment to meet the needs of the neuroimaging researcher. NITRC provides image-sharing functionality through both the NITRC Resource Registry (NITRC-R), where bulk data files can be released through the file release system (FRS), and the NITRC Image Repository (NITRC-IR), a XNAT-based image data management system. Currently hosting 14 projects, 6845 subjects, and 8285 MRI imaging sessions, NITRC-IR provides a large array of structural, diffusion and resting state MRI data. Designed to be flexible about management of data access policy, NITRC provides a simple, free, NIH-funded service to support resource sharing in general, and image sharing in particular.
Criteria A2, experience of helplessness, fear, or horror at the time of the traumatic event, was removed from the posttraumatic stress disorder diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. We argue that there is empirical support for retention of A2, a criterion that has clinical value and may improve diagnostic accuracy. Specifically, we demonstrate that A2 has high negative predictive power, aids in the prediction of symptom severity, and can be indispensible to detecting the disorder in children. We examine how augmenting A2 with other peritramautic emotions could improve clinical and diagnostic utility. In our opinion, rather than being eliminated, A2 needs to be reconstructed and included as one criterion of PTSD.
What is the experience of psychiatry residents learning to prescribe? A qualitative research inquiry
BACKGROUND: Understanding how psychiatry residents learn to prescribe is important for the future of psychiatry. Prescribing is a complicated act that involves much more than signing a prescription. During residency, psychiatrists develop seminal attitudes and habits about prescribing. There have been no published studies focusing on psychiatry residents' experience when learning to prescribe.
AIMS: Qualitative methodology lends itself to a deep exploration of the process of learning how to prescribe. We undertook a qualitative study questioning psychiatry residents about their prescribing.
METHODS: Psychiatry residents were recruited from three residency programs and focus groups were conducted at each program. The focus groups were audiotaped and transcribed by a professional service. Thematic analysis was used to analyze the data and triangulation to increase the rigor of the study.
RESULTS: A total of 12 residents participated. Three themes were identified concerning identity development as a psychiatrist, uncertainty and fear about prescribing, and the centrality of collaborating with the patient during the prescribing process.
CONCLUSION: Psychiatry residents struggle with significant anxiety and frustration in their experience of learning to prescribe, suggesting a place for mentors and supervisors to focus.
Videogames for health (G4H) offer exciting, innovative, potentially highly effective methods for increasing knowledge, delivering persuasive messages, changing behaviors, and influencing health outcomes. Although early outcome results are promising, additional research is needed to determine the game design and behavior change procedures that best promote G4H effectiveness and to identify and minimize possible adverse effects. Guidelines for ideal use of different types of G4H by children and adolescents should be elucidated to enhance effectiveness and minimize adverse effects. G4H stakeholders include organizational implementers, policy makers, players and their families, researchers, designers, retailers, and publishers. All stakeholders should be involved in G4H development and have a voice in setting goals to capitalize on their insights to enhance effectiveness and use of the game. In the future, multiple targeted G4H should be available to meet a population's diverse health needs in developmentally appropriate ways. Substantial, consistent, and sophisticated research with appropriate levels of funding is needed to realize the benefits of G4H.
Receipt of pharmacotherapy for opioid use disorder by justice-involved U.S. Veterans Health Administration patients
BACKGROUND: Pharmacotherapy - methadone, buprenorphine, or naltrexone - is an evidence-based treatment for opioid use disorder, but little is known about receipt of these medications among veterans involved in the justice system. The current study examines receipt of pharmacotherapy for opioid use disorder among veterans with a history of justice involvement at U.S. Veterans Health Administration (VHA) facilities compared to veterans with no justice involvement.
METHODS: Using national VHA clinical and pharmacy records, we conducted a retrospective cohort study of veterans with an opioid use disorder diagnosis in fiscal year 2012. Using a mixed-effects logistic regression model, we examined receipt of pharmacotherapy in the 1-year period following diagnosis as a function of justice involvement, adjusting for patient and facility characteristics.
RESULTS: The 1-year rate of receipt for pharmacotherapy for opioid use disorder was 27% for prison-involved veterans, 34% for jail/court-involved veterans, and 33% for veterans not justice-involved. Compared to veterans not justice-involved, those prison-involved had 0.75 lower adjusted odds (95% confidence interval [CI]: 0.65-0.87) of receiving pharmacotherapy whereas jail/court-involved veterans did not have significantly different adjusted odds.
CONCLUSIONS: Targeted efforts to improve receipt of pharmacotherapy for opioid use disorder among veterans exiting prison is needed as they have lower odds of receiving these medications.
microRNA-34a-Mediated Down-Regulation of the Microglial-Enriched Triggering Receptor and Phagocytosis-Sensor TREM2 in Age-Related Macular Degeneration
The aggregation of Abeta42-peptides and the formation of drusen in age-related macular degeneration (AMD) are due in part to the inability of homeostatic phagocytic mechanisms to clear self-aggregating Abeta42-peptides from the extracellular space. The triggering receptor expressed in myeloid/microglial cells-2 (TREM2), a trans-membrane-spanning, sensor-receptor of the immune-globulin/lectin-like gene superfamily is a critical component of Abeta42-peptide clearance. Here we report a significant deficit in TREM2 in AMD retina and in cytokine- or oxidatively-stressed microglial (MG) cells. RT-PCR, miRNA-array, LED-Northern and Western blot studies indicated up-regulation of a microglial-enriched NF-small ka, CyrillicB-sensitive miRNA-34a coupled to a down-regulation of TREM2 in the same samples. Bioinformatics/transfection-luciferase reporter assays indicated that miRNA-34a targets the 299 nucleotide TREM2-mRNA-3'UTR, resulting in TREM2 down-regulation. C8B4-microglial cells challenged with Abeta42 were able to phagocytose these peptides, while miRNA-34a down-regulated both TREM2 and the ability of microglial-cells to phagocytose. Treatment of TNFalpha-stressed MG cells with phenyl-butyl nitrone (PBN), caffeic-acid phenethyl ester (CAPE), the NF-kB - [corrected] inhibitor/resveratrol analog CAY10512 or curcumin abrogated these responses. Incubation of anti-miRNA-34a (AM-34a) normalized miRNA-34a abundance and restored TREM2 back to homeostatic levels. These data support five novel observations: (i) that a ROS- and NF-kB - [corrected] sensitive, miRNA-34a-mediated modulation of TREM2 may in part regulate the phagocytic response; (ii) that gene products encoded on two different chromosomes (miRNA-34a at chr1q36.22 and TREM2 at chr6p21.1) orchestrate a phagocytic-Abeta42-peptide clearance-system; (iii) that this NF-kB-mediated-miRNA-34a-TREM2 mechanism is inducible from outside of the cell; (iv) that when operating normally, this pathway can clear Abeta42 peptide monomers from the extracellular medium; and (v) that anti-NF-kB and/or anti-miRNA (AM)-based therapeutic strategies may be useful against deficits in TREM-2 receptor-based-sensing and -phagocytic signaling that promote pathogenic amyloidogenesis.
Abnormal white matter microstructure in drug-naive first episode schizophrenia patients before and after eight weeks of antipsychotic treatment
BACKGROUND: Abnormal white matter integrity has been reported among first episode schizophrenia patients. However, findings on whether it can be reversed by short-term antipsychotic medications are inconsistent.
METHOD: Diffusion tensor imaging (DTI) was obtained from 55 drug-naive first episode schizophrenia patients and 61 healthy controls, and was repeated among 25 patients and 31 controls after 8 weeks during which patients were medicated with antipsychotics. White matter integrity is measured using fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). These measures showing a group difference by Tract-based spatial statistics (TBSS) at baseline were extracted for longitudinal comparisons.
RESULTS: At baseline, patients exhibited lower FA, higher MD and higher RD versus controls in forceps, left superior longitudinal fasciculus, inferior fronto-occipital fasciculus, left corticospinal tract, left uncinate fasciculus, left anterior thalamic radiation, and bilateral inferior longitudinal fasciculi. FA values of schizophrenia patients correlated with their negative symptoms (r=-0.412, P=0.002), working memory (r=0.377, P=0.005) and visual learning (r=0.281, P=0.038). The longitudinal changes in DTI indices in these tracts did not differ between patients and controls. However, among the patients the longitudinal changes in FA values in left superior longitudinal fasciculus correlated with the change of positive symptoms (r=-0.560, p=0.004), and the change of processing speed (r=0.469, p=0.018).
CONCLUSIONS: White matter deficits were validated in the present study by a relatively large sample of medication naive and first episode schizophrenia patients. They could be associated with negative symptoms and cognitive impairment, whereas improvement in white matter integrity of left superior longitudinal fasciculus correlated with improvement in psychosis and processing speed. Further examination of treatment-related changes in white matter integrity may provide clues to the mechanism of antipsychotic response and provide a biomarker for clinical studies.
Cocaine addiction and depression are comorbid disorders. Although it is well recognized that 5-hydroxytryptamine (5-HT; serotonin) plays a central role in depression, our understanding of its role in addiction is notably lacking. The 5-HT system in the brain is carefully controlled by a combined process of regulating 5-HT neuron firing through 5-HT autoreceptors, neurotransmitter release, enzymatic degradation, and reuptake by transporters. This study tests the hypothesis that activation of 5-HT1A autoreceptors, which would lessen 5-HT neuron firing, contributes to cocaine-seeking behaviors. Using 5-HT neuron-specific reduction of 5-HT1A autoreceptor gene expression in mice, we demonstrate that 5-HT1A autoreceptors are necessary for cocaine conditioned place preference. In addition, using designer receptors exclusively activated by designer drugs (DREADDs) technology, we found that stimulation of the serotonergic dorsal raphe nucleus (DRN) afferents to the nucleus accumbens (NAc) abolishes cocaine reward and promotes antidepressive-like behaviors. Finally, using a rat model of compulsive-like cocaine self-administration, we found that inhibition of dorsal raphe 5-HT1A autoreceptors attenuates cocaine self-administration in rats with 6 h extended access, but not 1 h access to the drug. Therefore, our findings suggest an important role for 5-HT1A autoreceptors, and thus DRNshort right arrowNAc 5-HT neuronal activity, in the etiology and vulnerability to cocaine reward and addiction. Moreover, our findings support a strategy for antagonizing 5-HT1A autoreceptors for treating cocaine addiction.
BACKGROUND: Up to 55% of patients who are administered ketamine experience an emergence phenomena (EP) that closely mimics schizophrenia and increases their risk of injury; however, to date, no studies have investigated genetic association of ketamine-induced EP in healthy patients.
OBJECTIVES: The aim of the study was to investigate the feasibility and sample sizes required to explore the relationship between CYP2B6*6 and GRIN2B single-nucleotide polymorphisms and ketamine-induced EP.
METHODS: This cross-sectional, pharmacogenetic candidate, gene pilot study recruited 75 patients having minor elective outpatient surgeries. EP was measured with the Clinician Administered Dissociative State Scale. Genetic association of CYP2B6*6 and GRIN2B (rs1019385 and rs1806191) single-nucleotide polymorphisms and ketamine-induced EP occurrence and severity were tested using logistic and linear regression.
RESULTS: Forty-seven patients (63%) received ketamine and were genotyped, and 40% of them experienced EP. Occurrence and severity of EP were not associated with CYP2B6*6 or GRIN2B (p > .10). Exploratory analysis of nongenotype models containing age, ketamine dose, duration of anesthesia, and time from ketamine administration to assessment for EP significantly predicted EP occurrence (p = .001) and severity (p = .007). This pilot study demonstrates feasibility for implementing a pharmacogenetic study in a clinical setting, and we estimate that between 380 and 570 cases will be needed to adequately power future genetic association studies.
DISCUSSION: Younger age, higher dose, and longer duration of anesthesia significantly predicted EP occurrence and severity among our pilot sample. Although the small sample size limited our ability to demonstrate significant genotype differences, we generated effect sizes, sample size estimates, and nongenetic covariates information in order to support future pharmacogenetic study design for evaluating this adverse event.
The increasing number of senior physicians and calls for increased accountability of the medical profession by the public have led regulators and policymakers to consider implementing age-based competency screening. Some hospitals and health systems have initiated age-based screening, but there is no agreed upon assessment process. Licensing and certifying organizations generally do not require that senior physicians pass additional assessments of health, competency, or quality performance. Studies suggest that physician performance, on average, declines with increasing years in medical practice, but the effect of age on an individual physician's competence is highly variable. Many senior physicians practice effectively and should be allowed to remain in practice as long as quality and safety are not endangered. Stakeholders in the medical profession should consider the need to develop guidelines and methods for monitoring and/or screening to ensure that senior physicians provide safe and effective care for patients. Any screening process needs to achieve a balance between protecting patients from harm due to substandard practice, while at the same time ensuring fairness to physicians and avoiding unnecessary reductions in workforce.
So, besides this amusing parallel between data and children, what have we learned? We are reminded to get identifiers for our data, encourage our data to socialize with other data, and plan in advance for the long-term archival of our data. If we can do this in a well-controlled environment, the benefits, individually and as a community, in terms credit, value and reproducibility, are substantial.
In short, if you love your data, set it free, and watch what happens! Its social life may surprise you.
Integrating Permanent Supportive Housing and Co-Occurring Disorders Treatment for Individuals Who Are Homeless
OBJECTIVES: While permanent housing, addictions, and mental health treatment are often critical needs to achieve housing stability and community reintegration, few studies have systematically integrated them into a single comprehensive approach for people experiencing chronic homelessness. This pilot study examined the feasibility and preliminary outcomes of systematically integrating permanent supportive housing and an evidence-based co-occurring disorders intervention called Maintaining Independence and Sobriety Through Systems Integration, Outreach, and Networking (MISSION).
METHODS: This single-group open pilot enrolled 107 people with co-occurring disorders experiencing chronic homelessness from two Massachusetts inner-city and rural areas. Enrolled subjects were interested in receiving permanent supportive housing along with 1 year of MISSION services. Data were collected through baseline and 6- and 12-month follow-up assessments.
RESULTS: Participants (Mage = 49.52 years, SD = 10.61) were mostly male (76.6%), Caucasian (52.3%), and unemployed (86.0%), with an average of 8.34 years (SD = 8.01) of homelessness. Self-reported lifetime problems with anxiety (75.7%) and depression (76.6%) were common, as was use of alcohol (30.8%), cannabis (31.8%), and cocaine (15.9%). Almost all participants (95.3%) were placed into permanent housing, which took on average 42.6 days from enrollment (SD = 50.09). Among those placed, nearly 80% of the clients were able to retain housing through the end of the study. Overall retention was high, with 86.0% remaining in MISSION treatment until the end of the study. While there were no significant changes in rehospitalization, service utilization, or substance use, there were modest significant mental health symptom improvements from baseline to program completion.
CONCLUSIONS: This pilot study suggests that co-occurring disorder interventions like MISSION are feasible to integrate with permanent supportive housing despite the somewhat differing philosophies, and preliminary data suggested substantial improvements in housing and modest improvements in mental health symptoms. While caution is warranted given the lack of a comparison group, these findings are consistent with other rigorous studies using MISSION among homeless individuals who did not receive permanent supportive housing.
Whole-genome sequencing identifies a novel ABCB7 gene mutation for X-linked congenital cerebellar ataxia in a large family of Mongolian ancestry
X-linked congenital cerebellar ataxia is a heterogeneous nonprogressive neurodevelopmental disorder with onset in early childhood. We searched for a genetic cause of this condition, previously reported in a Buryat pedigree of Mongolian ancestry from southeastern Russia. Using whole-genome sequencing on Illumina HiSeq 2000 platform, we found a missense mutation in the ABCB7 (ABC-binding cassette transporter B7) gene, encoding a mitochondrial transporter, involved in heme synthesis and previously associated with sideroblastic anemia and ataxia. The mutation resulting in a substitution of a highly conserved glycine to serine in position 682 is apparently a major causative factor of the cerebellar hypoplasia/atrophy found in affected individuals of a Buryat family who had no evidence of sideroblastic anemia. Moreover, in these affected men we also found the genetic defects in two other genes closely linked to ABCB7 on chromosome X: a deletion of a genomic region harboring the second exon of copper-transporter gene (ATP7A) and a complete deletion of PGAM4 (phosphoglycerate mutase family member 4) retrogene located in the intronic region of the ATP7A gene. Despite the deletion, eliminating the first of six metal-binding domains in ATP7A, no signs for Menkes disease or occipital horn syndrome associated with ATP7A mutations were found in male carriers. The role of the PGAM4 gene has been previously implicated in human reproduction, but our data indicate that its complete loss does not disrupt male fertility. Our finding links cerebellar pathology to the genetic defect in ABCB7 and ATP7A structural variant inherited as X-linked trait, and further reveals the genetic heterogeneity of X-linked cerebellar disorders.
Telephone Smoking-Cessation Counseling for Smokers in Mental Health Clinics: A Patient-Randomized Controlled Trial
INTRODUCTION: People with a mental health diagnosis have high rates of tobacco use and encounter limited availability of tobacco treatment targeted to their needs. This study compared the effectiveness of a specialized telephone smoking-cessation intervention developed for mental health patients with standard state quit-line counseling. DESIGN: RCT. SETTING/PARTICIPANTS: The study was conducted at six Veterans Health Administration facilities in the Northeast U.S. Participants were 577 mental health clinic patients referred by their providers for smoking-cessation treatment. INTERVENTION: From 2010 to 2012, the study implemented a telephone program that included patient referral from a mental health provider, mailed cessation medications, and telephone counseling. Participants were randomized to receive a specialized multisession telephone counseling protocol (n=270) or transfer to their state's quit-line for counseling (n=307). MAIN OUTCOME MEASURES: Participants completed telephone surveys at baseline, 2 months, and 6 months. The study's primary outcome was self-reported 30-day abstinence at 6 months. Secondary outcomes were self-reported 30-day abstinence, counseling satisfaction and counseling content at 2 months, and self-reported use of cessation treatment and quit attempts at 6 months. Logistic regression was used to compare treatment groups on outcomes, controlling for baseline cigarettes per day and site. Inverse probability weighting and multiple imputation were used to handle missing abstinence outcomes. Data were analyzed in 2014-2015. RESULTS: At 6 months, participants in the specialized counseling arm were more likely to report 30-day abstinence (26% vs 18%, OR=1.62, 95% CI=1.24, 2.11). There was no significant group difference in abstinence at 2 months (18% vs 14%, OR=1.31, 95% CI=0.49, 3.49). Participants in the specialized arm were more likely to be assisted with developing a quit plan; receive follow-up calls after quitting; and receive counseling on several domains, including motivation, confidence, smoking triggers, coping with urges, and mental health symptoms (all p<0.05). Specialized counseling participants were more satisfied with treatment and more likely to find the counseling useful (p<0.05). CONCLUSIONS: The specialized counseling intervention was more effective at helping patients quit than transfer to a state quit-line. Patients were more satisfied with the specialized counseling program. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov NCT00724308.
Women's Behavioral Responses to the Threat of a Hypothetical Date Rape Stimulus: A Qualitative Analysis
One in four college women experience sexual assault on campus; yet, campuses rarely provide the in-depth self-defense programs needed to reduce sexual assault risk. Further, little is known about the range of possible behaviors elicited by sexual assault threat stimuli besides assertion. To fill this gap, the aim of the current study was to explore qualitative themes in women's intended behavioral responses to a hypothetical sexual assault threat, date rape, by using a laboratory-controlled threat. College women (N = 139) were randomly assigned to one of four different levels of sexual assault threat presented via an audio-recorded vignette. Participants articulated how they would hypothetically respond to the experimentally assigned threat. Responses were blinded and analyzed using Consensual Qualitative Research methodology. Six major themes emerged: assertion, compliance/acceptance, conditional decision making, avoidance, expressions of discomfort, and allusion to future contact. Although almost all participants described assertion, a number of non-assertive responses were described that are not currently recognized in the literature. These non-assertive responses, including compliance/acceptance, conditional decision making, and avoidance, may represent unique behavioral response styles and likely reflect the complex psychological process of behavioral response to threat. The variety of themes found illustrates the great range of behavioral responses to threat. This broad range is not currently well represented or measured in the literature and better understanding of these responses can inform future interventions, advocacy efforts, and policies focused on sexual assault.
Trajectories of drinking urges and the initiation of abstinence during cognitive-behavioral alcohol treatment
BACKGROUND AND AIMS: Drinking urges during treatment for alcohol use disorders (AUDs) are common, can cause distress and predict relapse. Clients may have little awareness of how their drinking urges might be expected to change during AUD treatment in general and in response to initiating abstinence. The aim of the present study was to test whether drinking urges change on a daily level during treatment and after initiating abstinence.
DESIGN: Secondary data analysis was performed using daily drinking urge ratings from two randomized clinical trials.
SETTING AND PARTICIPANTS: Women (n = 98) and men (n = 79) with AUDs in separate clinical trials of out-patient AUD-focused cognitive-behavioral therapy.
MEASUREMENTS: Daily dichotomous indicators of any drinking urges or acute escalations in urges (i.e. at least two more urges compared with the previous day) were examined using generalized linear mixed growth-curve modeling.
FINDINGS: Participants who initiated abstinence reported reductions in urges immediately thereafter (log odds ratios: women B = -0.701, P < 0.001; men B = -0.628, P = 0.018), followed by additional, gradual reductions over time (women B = -0.118, P < 0.001; men B = -0.141, P < 0.001). Participants who entered treatment abstaining from alcohol also reported significant reductions in urges over time (women B = -0.147, P < 0.001; men B = -0.142, P < 0.001). Participants who drank throughout treatment had smaller (women B = -0.042, P = 0.012) or no reductions in urges (men B = 0.015, P = 0.545). There was no evidence that urges increased systematically in response to initiating abstinence.
CONCLUSIONS: Drinking urges during out-patient behavioral treatment for alcohol use disorders may be maintained in part by alcohol consumption. Initiating abstinence is associated with reductions in drinking urges immediately and then more gradually over time.
rAAV Gene Therapy in a Canavan's Disease Mouse Model Reveals Immune Impairments and an Extended Pathology Beyond the Central Nervous System
Aspartoacylase (AspA) gene mutations cause the pediatric lethal neurodegenerative Canavan disease (CD). There is emerging promise of successful gene therapy for CD using recombinant adeno-associated viruses (rAAVs). Here, we report an intracerebroventricularly delivered AspA gene therapy regime using three serotypes of rAAVs at a 20-fold reduced dose than previously described in AspA(-/-) mice, a bona-fide mouse model of CD. Interestingly, central nervous system (CNS)-restricted therapy prolonged survival over systemic therapy in CD mice but failed to sustain motor functions seen in systemically treated mice. Importantly, we reveal through histological and functional examination of untreated CD mice that AspA deficiency in peripheral tissues causes morphological and functional abnormalities in this heretofore CNS-defined disorder. We demonstrate for the first time that AspA deficiency, possibly through excessive N-acetyl aspartic acid accumulation, elicits both a peripheral and CNS immune response in CD mice. Our data establish a role for peripheral tissues in CD pathology and serve to aid the development of more efficacious and sustained gene therapy for this disease.