A Derivative of the D5 Monoclonal Antibody That Targets the gp41 N-Heptad Repeat of HIV-1 with Broad Tier-2-Neutralizing Activity.

HIV-1 infection is initiated by the viral glycoprotein Env, which, after interaction with cellular coreceptors, adopts a transient conformation known as the prehairpin intermediate (PHI). The N-heptad repeat (NHR) is a highly conserved region of gp41 exposed in the PHI; it is the target of the FDA-approved drug enfuvirtide and of neutralizing monoclonal antibodies (mAbs). However, to date, these mAbs have only been weakly effective against tier-1 HIV-1 strains, which are most sensitive to neutralizing antibodies. Here, we engineered and tested 11 IgG variants of D5, an anti-NHR mAb, by recombining previously described mutations in four of D5's six antibody complementarity-determining regions. One variant, D5_AR, demonstrated 6-fold enhancement in the 50% inhibitory dose (ID50) against lentivirus pseudotyped with HXB2 Env. D5_AR exhibited weak cross-clade neutralizing activity against a diverse set of tier-2 HIV-1 viruses, which are less sensitive to neutralizing antibodies than tier-1 viruses and are the target of current antibody-based vaccine efforts. In addition, the neutralization potency of D5_AR IgG was greatly enhanced in target cells expressing FcγRI, with ID50 values of <0.1 µg/ml; this immunoglobulin receptor is expressed on macrophages and dendritic cells, which are implicated in the early stages of HIV-1 infection of mucosal surfaces. D5 and D5_AR have equivalent neutralization potency in IgG, Fab, and single-chain variable-fragment (scFv) formats, indicating that neutralization is not impacted by steric hindrance. Taken together, these results provide support for vaccine strategies that target the PHI by eliciting antibodies against the gp41 NHR and support investigation of anti-NHR mAbs in nonhuman primate passive immunization studies. IMPORTANCE Despite advances in antiretroviral therapy, HIV remains a global epidemic and has claimed more than 32 million lives. Accordingly, developing an effective HIV vaccine remains an urgent public health need. The gp41 N-heptad repeat (NHR) of the HIV-1 prehairpin intermediate (PHI) is highly conserved (>90%) and is inhibited by the FDA-approved drug enfuvirtide, making it an attractive vaccine target. However, to date, anti-NHR antibodies have not been potent. Here, we engineered D5_AR, a more potent variant of the anti-NHR antibody D5, and established its ability to inhibit HIV-1 strains that are more difficult to neutralize and are more representative of circulating strains (tier-2 strains). The neutralizing activity of D5_AR was greatly potentiated in cells expressing FcγRI; FcγRI is expressed on cells that are implicated at the earliest stages of sexual HIV-1 transmission. Taken together, these results bolster efforts to target the gp41 NHR and the PHI for vaccine development.

A randomized, double-blind, placebo-controlled, pharmacogenetic study of ondansetron for treating alcohol use disorder.

BACKGROUND: In a previous study, ondansetron, a serotonin 5-HT3 receptor antagonist, reduced drinking intensity (drinks/drinking day [DPDD]) among European-ancestry (EA) participants with moderate-to-severe alcohol use disorder (AUD) and variants in genes encoding the serotonin transporter (SLC6A4) and 5-HT3A (HTR3A), and 5-HT3B (HTR3B) receptors. We tested whether (1) ondansetron reduces DPDD among individuals of either European or African ancestry (AA), and (2) that reductions in DPDD are greatest among ondansetron-treated individuals with population-specific combinations of genotypes at SLC6A4, HTR3A, and HTR3B. METHODS: In this 16-week, double-blind, placebo-controlled, parallel-group clinical trial, adults with AUD were randomized to receive low-dose oral ondansetron (0.33 mg twice daily) or placebo stratified by "responsive" versus "nonresponsive" genotype defined using population-specific genotypes at the three genetic loci. Generalized estimating equation regression models and a modified intent-to-treat analysis were used to compare the treatment groups on the primary outcome-DPDD-and two secondary outcomes-heavy drinking days per week [HDD] and drinks per day [DPD] across the 16 weeks of treatment. RESULTS: Of 296 prospective participants screened, 95 (58 EA and 37 AA) were randomized and received at least one dose of study medication. In the modified intent-to-treat analysis, the ondansetron group averaged 0.40 more DPDD (p = 0.51), 1.35 times as many HDD (p = 0.16), and 1.06 times as many DPD (p = 0.59) as the placebo group. There were no significant interactions with genotype. There were no study-related serious adverse events (AEs) and similar proportions of participants in the two treatment groups experienced AEs across organ systems. CONCLUSIONS: We found no evidence that low-dose oral ondansetron is beneficial in the treatment of AUD, irrespective of genotype, thus failing to confirm prior study findings. However, the study was underpowered to identify medication by genotype interactions.

A Multicenter Evaluation of Probiotic Use for the Primary Prevention of Clostridioides difficile Infection.

BACKGROUND: Primary prevention of Clostridioides difficile infection (CDI) is a priority for hospitals. Probiotics have the potential to interfere with colonization and CDI. In this study, we evaluated the impact of a computerized clinical decision support (CCDS) tool to prescribe probiotics for primary prevention of CDI among adult hospitalized patients. METHODS: A CCDS tool was implemented into the electronic medical record at 4 hospitals to prompt prescription of a probiotic preparation at the time of antibiotic prescription in high-risk patients in May 2019. Interrupted time series using segmented regression analysis was conducted to evaluate hospital-wide CDI incidence for the year pre- and post-CCDS implementation. In addition, multivariable logistic regression was used to evaluate CDI incidence in patients who qualified for probiotics in the pre- vs post-intervention periods, adjusting for potential confounders. To adjust for potential differences in patients who received probiotics in the post-intervention period, propensity score-matched pairs were developed to evaluate CDI risk by receipt of probiotics. RESULTS: Quarterly CDI incidence increased over time post-intervention relative to baseline trends (slope change, 1.4; 95% confidence interval [CI], .9-1.9). The odds ratio (OR) of CDI was 1.41 in eligible patients post-intervention compared with pre-intervention (adjusted OR, 1.41; 95% CI, 1.11-1.79). Propensity score-matched analysis showed that patients who received probiotics did not have lower rates of CDI compared with those who did not receive probiotics (OR, 1.46; 95% CI, .87-2.45). CONCLUSIONS: Use of probiotics for primary prevention of CDI among adult inpatients receiving antibiotics is not supported.

The Ending Self-Stigma for Posttraumatic Stress Disorder (ESS-P) Program: Results of a Pilot Randomized Trial.

Experiences of and concerns about encountering stigma are common among veterans with posttraumatic stress disorder (PTSD). One common and serious consequence is self-stigma, which is when an individual comes to believe that common negative stereotypes and assumptions about PTSD are true of oneself. The current study was a pilot randomized trial that evaluated the feasibility, acceptability, and preliminary outcomes of the Ending Self-Stigma for PTSD (ESS-P) program, a nine-session group intervention that aims to assist veterans with PTSD learn tools and strategies to address stigma and self-stigma. Veterans (N = 57) with a diagnosis of PTSD who were receiving treatment in U.S. Veterans Health Administration outpatient mental health programs were recruited. Participants were randomized to either ESS-P or minimally enhanced treatment as usual and assessed at baseline and after treatment on clinical symptoms, self-stigma, self-efficacy, recovery, and sense of belonging. Information on mental health treatment utilization for the 3 months before and after group treatment was also collected. Compared to controls, there was a significant decrease in self-stigma, d = -0.77, and symptoms of depression, d = -0.76, along with significant increases in general and social self-efficacy, ds = 0.73 and 0.60, respectively, and psychological experience of belonging, d = 0.46, among ESS-P participants. There were no differences regarding recovery status or changes in treatment utilization. The results of the pilot study suggest that participation in ESS-P may help reduce self-stigma and improve self-efficacy and a sense of belonging in veterans with PTSD.

Lipophilic vs. hydrophilic statins and psychiatric hospitalizations and emergency room visits in US Veterans with schizophrenia and bipolar disorder.

OBJECTIVE ­: Psychiatric hospitalizations and emergency department (ED) visits are costly, stigmatizing, and often ineffective. Given the immune and kynurenine activation in bipolar disorder (BD) and schizophrenia, as well as the immune-modulatory effects of statins, we aimed to compare the relative risk (RRs) of psychiatric hospitalizations and ED visits between individuals prescribed lipophilic vs. hydrophilic statins vs. no statins. We hypothesized (a) reduced rates of hospitalization and ER utilization with statins versus no statins and (b) differences in outcomes between statins, as lipophilia increases the capability to penetrate the blood-brain barrier with potentially beneficial neuroimmune, antioxidant, neuroprotective, neurotrophic, and endothelial stabilizing effects, and, in contrast, potentially detrimental decreases in brain cholesterol concentrations leading to serotoninergic dysfunction, changes in membrane lipid composition, thus affecting ion channels and receptors. METHODS ­: We used VA service utilization data from October 1, 2010 to September 30, 2015. The RRs for psychiatric hospitalization and ED visits, were estimated using robust Poisson regression analyses. The number of individuals analyzed was 683,129. RESULTS ­: Individuals with schizophrenia and BD who received prescriptions for either lipophilic or hydrophilic statins had a lower RR of psychiatric hospitalization or ED visits relative to nonstatin controls. Hydrophilic statins were significantly associated with lower RRs of psychiatric hospitalization but not of ED visits, compared to lipophilic statins. CONCLUSION ­: The reduction in psychiatric hospitalizations in statin users (vs. nonusers) should be interpreted cautiously, as it carries a high risk of confounding by indication. While the lower RR of psychiatric hospitalizations in hydrophilic statins relative to the lipophilic statins is relatively bias free, the finding bears replication in a specifically designed study. If replicated, important clinical implications for personalizing statin treatment in patients with mental illness, investigating add-on statins for improved therapeutic control, and mechanistic exploration for identifying new treatment targets are natural next steps.

Quality of life outcomes of web-based and in-person weight management for adults with serious mental illness.

Adults with serious mental illness have high rates of obesity, with associated negative impacts on health-related quality of life. The present study utilized data from a randomized controlled trial (N = 276) to examine the effectiveness of in-person and online-delivered weight management interventions, compared to usual care, for improving health-related quality of life in this population. Participants completed quality of life assessments at baseline, 3 months, and 6 months. Mixed effects models examined group by time interactions. Compared to usual care, in-person MOVE was associated with improvements in loneliness (t = - 2.76, p = .006) and mental health related quality of life (t = 1.99, p = 0.048) at 6 months, and webMOVE was associated with improvements in weight-related self-esteem at 6 months (t = 2.23, p = .026) and mental health-related quality of life at 3 months (t = 2.17, p = 0.031) and 6 months (t = 2.38, p = .018). Web-based and in-person weight management led to improvements in health-related quality of life for adults with serious mental illness.ClinicalTrials.gov Identifier: NCT00983476.

Surveillance results and bone effects in the Gulf War depleted uranium-exposed cohort.

A small group of Gulf War I veterans wounded in depleted uranium (DU) friendly-fire incidents have been monitored in a clinical surveillance program since 1993. During the spring of 2017, 42 members of the cohort were evaluated with a protocol which includes exposure monitoring for total and isotopic uranium concentrations in urine and a comprehensive assessment of health outcomes including measures of bone metabolism, and for participants >50 years, bone mineral density (BMD) determination. Elevated urine U concentrations were observed in cohort members with retained DU shrapnel fragments. Only the mean serum estradiol concentration, a marker of bone metabolism, was found to be significantly different for lower-vs- higher urine U (uU) cohort sub-groups. For the first time, a significant deficit in BMD was observed in the over age 50, high uU sub-group. After more than 25 years since first exposure to DU, an aging cohort of military veterans continues to exhibit few U-related adverse health effects in known target organs of U toxicity. The new finding of reduced BMD in older cohort members, while biologically plausible, was not suggested by other measures of bone metabolism in the full (all ages) cohort, as these were predominantly within normal limits over time. Only estradiol was recently found to display a difference as a function of uU grouping. As BMD is further impacted by aging and the U-burden from fragment absorption accrues in this cohort, a U effect may be clarified in future surveillance visits.

Impulse oscillometry measurement of distal airways obstruction in depleted uranium-exposed Gulf War veterans.

INTRODUCTION: A cohort of Gulf War I veterans who sustained exposure to depleted uranium undergoes biennial surveillance for potential uranium-related health effects. We performed impulse oscillometry and hypothesized that veterans with higher uranium body burdens would have more obstructive abnormalities than those with lower burdens. METHODS: We compared pulmonary function of veterans in high versus low urine uranium groups by evaluating spirometry and oscillometry values. RESULTS: Overall mean spirometry and oscillometry resistance values fell within the normal ranges. There were no significant differences between the high and low uranium groups for any parameters. However, more veterans were classified as having obstruction by oscillometry (42%) than spirometry (8%). CONCLUSIONS: While oscillometry identified more veterans as obstructed, obstruction was not uranium-related. However, the added sensitivity of this method implies a benefit in wider surveillance of exposed cohorts and holds promise in identifying abnormalities in areas of the lung historically described as silent.

Consumer satisfaction with antipsychotic medication-monitoring appointments: the role of consumer-prescriber communication patterns.

OBJECTIVE: The study was designed to explore patterns of prescriber communication behaviors as they relate to consumer satisfaction among a serious mental illness sample. METHODS: Recordings from 175 antipsychotic medication-monitoring appointments between veterans with psychiatric disorders and their prescribers were coded using the Roter Interaction Analysis System (RIAS) for communication behavioral patterns. RESULTS: The frequency of prescriber communication behaviors (i.e., facilitation, rapport, procedural, psychosocial, biomedical, and total utterances) did not reliably predict consumer satisfaction. The ratio of prescriber to consumer utterances did predict consumer satisfaction. CONCLUSIONS: Consistent with client-centered care theory, antipsychotic medication consumers were more satisfied with their encounters when their prescriber did not dominate the conversation. PRACTICE IMPLICATIONS: Therefore, one potential recommendation from these findings could be for medication prescribers to spend more of their time listening to, rather than speaking with, their SMI consumers.

Pilot Feasibility Study of Therapeutic Hypothermia for Moderate to Severe Acute Respiratory Distress Syndrome.

OBJECTIVES: Prior studies suggest hypothermia may be beneficial in acute respiratory distress syndrome, but cooling causes shivering and increases metabolism. The objective of this study was to assess the feasibility of performing a randomized clinical trial of hypothermia in patients with acute respiratory distress syndrome receiving treatment with neuromuscular blockade because they cannot shiver. DESIGN: Retrospective study and pilot, prospective, open-label, feasibility study. SETTING: Medical ICU. PATIENTS: Retrospective review of 58 patients with acute respiratory distress syndrome based on Berlin criteria and PaO2/FIO2 less than 150 who received neuromuscular blockade. Prospective hypothermia treatment in eight acute respiratory distress syndrome patients with PaO2/FIO2 less than 150 receiving neuromuscular blockade. INTERVENTION: Cooling to 34-36°C for 48 hours. MEASUREMENTS AND MAIN RESULTS: Core temperature, hemodynamics, serum glucose and electrolytes, and P/F were sequentially measured, and medians (interquartile ranges) presented, 28-day ventilator-free days, and hospital mortality were calculated in historical controls and eight cooled patients. Average patient core temperature was 36.7°C (36-37.3°C), and fever occurred during neuromuscular blockade in 30 of 58 retrospective patients. In the prospectively cooled patients, core temperature reached target range less than or equal to 4 hours of initiating cooling, remained less than 36°C for 92% of the 48 hours cooling period without adverse events, and was lower than the controls (34.35°C [34-34.8°C]; p < 0.0001). Compared with historical controls, the cooled patients tended to have lower hospital mortality (75% vs 53.4%; p = 0.26), more ventilator-free days (9 [0-21.5] vs 0 [0-12]; p = 0.16), and higher day 3 P/F (255 [160-270] vs 171 [120-214]; p = 0.024). CONCLUSIONS: Neuromuscular blockade alone does not cause hypothermia but allowed acute respiratory distress syndrome patients to be effectively cooled. Results support conducting a randomized clinical trial of hypothermia in acute respiratory distress syndrome and the feasibility of studying acute respiratory distress syndrome patients receiving neuromuscular blockade.

Pilot feasibility study of Heart2HAART: a smartphone application to assist with adherence among substance users living with HIV.

BACKGROUND: Smartphones with programmable apps may offer innovative interactive interventions for improving adherence among people living with HIV with substance use problems. METHODS: This pilot randomized controlled trial sought to primarily determine the usability and feasibility of using a smartphone-based intervention called Heart2HAART as an adjunct to directly observed treatment with adherence counseling compared to directly observed treatment with adherence counseling alone among those with HIV and a history of substance use over a three-month time frame. Participants in the Heart2HAART condition completed an additional survey on usability and acceptability. Adherence was measured using unannounced pill counts assessed via a phone call. RESULTS: Twenty-eight participants were randomized to receive Heart2HAART (n = 19) or control (n = 9). All were receiving either weekly (n = 9) or daily (n = 19) observed treatment. Among those randomized to Heart2HAART, 63.2% reported no difficulty using the Heart2HAART smartphone application and 94.7% responded that the medication reminders did not interfere negatively with their activities. On average participants used Heart2HAART application 56.8 times over the three-month trial. In analyses adjusting for age, there was no difference in adherence to HAART medication between the Heart2HAART and control group as evaluated by the random pill count assessment (P = .29). CONCLUSIONS: Heart2HAART was feasible to use during a three-month pilot trial. Future studies may evaluate a more tailored approach, with more robust contingency management.

The Moderated Mediating Effect of Self-Efficacy on Exercise Among Older Adults in an Online Bone Health Intervention Study: A Parallel Process Latent Growth Curve Model.

This secondary data analyses of a longitudinal study assessed whether self-efficacy for exercise (SEE) mediated online intervention effects on exercise among older adults and whether age (50-64 vs. ≥65 years) moderated the mediation. Data were from an online bone health intervention study. Eight hundred sixty-six older adults (≥50 years) were randomized to three arms: Bone Power (n = 301), Bone Power Plus (n = 302), or Control (n = 263). Parallel process latent growth curve modeling (LGCM) was used to jointly model growths in SEE and in exercise and to assess the mediating effect of SEE on the effect of intervention on exercise. SEE was a significant mediator in 50- to 64-year-old adults (0.061, 95 BCI: 0.011, 0.163) but not in the ≥65 age group (-0.004, 95% BCI: -0.047, 0.025). Promotion of SEE is critical to improve exercise among 50- to 64-year-olds.

A Randomized Controlled Trial of a Patient-Centered Approach to Improve Screening for the Metabolic Side Effects of Antipsychotic Medications.

Adherence to recommendations for monitoring of metabolic side effects of antipsychotic medications has been historically low. This randomized controlled trial tested whether a computerized, patient-centered intervention that educated Veterans with serious mental illness about these side effects and encouraged them to advocate for receipt of monitoring would increase rates of monitoring compared to enhanced treatment as usual. The mean proportion of days adherent to monitoring guidelines over the 1-year study was similarly high and did not differ between the intervention (range 0.81-0.98) and comparison (range 0.76-0.96) groups. Many individuals in both groups had persistent abnormal metabolic parameter values despite high rates of monitoring, contact with medical providers, and receipt of cardiometabolic medications. Participants exposed to the intervention were interested in receiving personalized information about their cardiometabolic status, demonstrating the preliminary feasibility of brief interventions for enhancing involvement of individuals with serious mental illness in health care decision making.

Mechanistic and Evolutionary Insights from Comparative Enzymology of Phosphomonoesterases and Phosphodiesterases across the Alkaline Phosphatase Superfamily.

Naively one might have expected an early division between phosphate monoesterases and diesterases of the alkaline phosphatase (AP) superfamily. On the contrary, prior results and our structural and biochemical analyses of phosphate monoesterase PafA, from Chryseobacterium meningosepticum, indicate similarities to a superfamily phosphate diesterase [Xanthomonas citri nucleotide pyrophosphatase/phosphodiesterase (NPP)] and distinct differences from the three metal ion AP superfamily monoesterase, from Escherichia coli AP (EcAP). We carried out a series of experiments to map out and learn from the differences and similarities between these enzymes. First, we asked why there would be independent instances of monoesterases in the AP superfamily? PafA has a much weaker product inhibition and slightly higher activity relative to EcAP, suggesting that different metabolic evolutionary pressures favored distinct active-site architectures. Next, we addressed the preferential phosphate monoester and diester catalysis of PafA and NPP, respectively. We asked whether the >80% sequence differences throughout these scaffolds provide functional specialization for each enzyme's cognate reaction. In contrast to expectations from this model, PafA and NPP mutants with the common subset of active-site groups embedded in each native scaffold had the same monoesterase:diesterase specificities; thus, the >107-fold difference in native specificities appears to arise from distinct interactions at a single phosphoryl substituent. We also uncovered striking mechanistic similarities between the PafA and EcAP monoesterases, including evidence for ground-state destabilization and functional active-site networks that involve different active-site groups but may play analogous catalytic roles. Discovering common network functions may reveal active-site architectural connections that are critical for function, and identifying regions of functional modularity may facilitate the design of new enzymes from existing promiscuous templates. More generally, comparative enzymology and analysis of catalytic promiscuity can provide mechanistic and evolutionary insights.

Recurrence of cervical intraepithelial lesions after thermo-coagulation in HIV-positive and HIV-negative Nigerian women.

BACKGROUND: The burden of cervical cancer remains huge globally, more so in sub-Saharan Africa. Effectiveness of screening, rates of recurrence following treatment and factors driving these in Africans have not been sufficiently studied. The purpose of this study therefore was to investigate factors associated with recurrence of cervical intraepithelial lesions following thermo-coagulation in HIV-positive and HIV-negative Nigerian women using Visual Inspection with Acetic Acid (VIA) or Lugol's Iodine (VILI) for diagnosis. METHODS: A retrospective cohort study was conducted, recruiting participants from the cervical cancer "see and treat" program of IHVN. Data from 6 sites collected over a 4-year period was used. Inclusion criteria were: age ≥18 years, baseline HIV status known, VIA or VILI positive and thermo-coagulation done. Logistic regression was performed to examine the proportion of women with recurrence and to examine factors associated with recurrence. RESULTS: Out of 177 women included in study, 67.8 % (120/177) were HIV-positive and 32.2 % (57/177) were HIV-negative. Recurrence occurred in 16.4 % (29/177) of participants; this was 18.3 % (22/120) in HIV-positive women compared to 12.3 % (7/57) in HIV-negative women but this difference was not statistically significant (p-value 0.31). Women aged ≥30 years were much less likely to develop recurrence, adjusted OR = 0.34 (95 % CI = 0.13, 0.92). Among HIV-positive women, CD4 count <200cells/mm(3) was associated with recurrence, adjusted OR = 5.47 (95 % CI = 1.24, 24.18). CONCLUSION: Recurrence of VIA or VILI positive lesions after thermo-coagulation occurs in a significant proportion of women. HIV-positive women with low CD4 counts are at increased risk of recurrent lesions and may be related to immunosuppression.

Access to and Use of the Internet by Veterans with Serious Mental Illness.

This study evaluated internet use among 239 veterans with serious mental illness who completed questionnaires assessing demographics and internet use in 2010-2011. The majority of individuals (70 %) reported having accessed the internet and among those, 79 % had accessed it within the previous 30 days. Those who were younger and more educated were more likely to have accessed the internet, as were those with a schizophrenia spectrum disorder, bipolar disorder, or major depressive disorder, compared to individuals with PTSD. Veterans with serious mental illness commonly use the internet, including to obtain health information, though use varies across demographic characteristics and clinical diagnosis.

Risky decision-making and ventral striatal dopamine responses to amphetamine: a positron emission tomography [(11)C]raclopride study in healthy adults.

Recent functional magnetic resonance imaging (fMRI) studies have provided compelling evidence that corticolimbic brain regions are integrally involved in human decision-making. Although much less is known about molecular mechanisms, there is growing evidence that the mesolimbic dopamine (DA) neurotransmitter system may be an important neural substrate. Thus far, direct examination of DA signaling in human risk-taking has centered on gambling disorder. Findings from several positron emission tomography (PET) studies suggest that dysfunctions in mesolimbic DA circuits may play an important role in gambling behavior. Nevertheless, interpretation of these findings is currently hampered by a need for better understanding of how individual differences in regional DA function influence normative decision-making in humans. To further our understanding of these processes, we used [(11)C]raclopride PET to examine associations between ventral striatal (VS) DA responses to amphetamine (AMPH) and risky decision-making in a sample of healthy young adults with no history of psychiatric disorder, Forty-five male and female subjects, ages 18-29 years, completed a computerized version of the Iowa Gambling Task. Participants then underwent two 90-minute PET studies with high specific activity [(11)C]raclopride. The first scan was preceded by intravenous saline; the second, by intravenous AMPH (0.3mg/kg). Findings of primary analyses showed that less advantageous decision-making was associated with greater right VS DA release; the relationship did not differ as a function of gender. No associations were observed between risk-taking and left VS DA release or baseline D2/D3 receptor availability in either hemisphere. Overall, the results support notions that variability in striatal DA function may mediate inter-individual differences in risky decision-making in healthy adults, further suggesting that hypersensitive DA circuits may represent a risk pathway in this population.

Smoking Cessation in Individuals With Serious Mental Illness: A Randomized Controlled Trial of Two Psychosocial Interventions.

OBJECTIVE: Smoking among individuals with serious mental illness is a critical public health problem. Although guidelines recommend bupropion for these smokers, many do not want to use medications for smoking cessation, express ambivalence about identifying a "quit date," and do not have access to behavioral smoking cessation services integrated with mental health care. METHODS: Individuals with serious mental illness who smoked 10 or more cigarettes per day (N = 178) were randomized to either a multifaceted behavioral group intervention or a supportive group intervention, both of which were integrated within outpatient mental health services at three VA medical centers. Participants attended twice-weekly meetings for 12 weeks, provided information on their smoking at each meeting, and completed baseline and post-treatment assessments conducted by an assessor who was blind to condition. Primary outcomes collected at post-treatment included 1-week abstinence, number of cigarettes smoked per day during the last week, and number of quit attempts during the treatment period. Outcomes examined for a subset of participants who attended at least one intervention meeting (n = 152) included smoking abstinence for 1-, 2-, and 4-week blocks during the treatment period. Analyses conducted on those participants who attended three or more intervention meetings (n = 127) included time to 50% reduction in the number of cigarettes smoked and time to first quit attempt. RESULTS: Sixteen participants achieved abstinence (11.8%), smoking quantity was significantly reduced (baseline M = 15.2, SD = 9.8 to post-treatment M = 7.5, SD = 7.7, p <.0001), and most reported making a quit attempt (n = 88, 72.7%). There were no differences by study condition on any abstinence or reduction outcomes. Significant reductions in number of cigarettes smoked generally took place within the first two weeks; however, these reductions did not often translate into abstinence. CONCLUSIONS: Many participants reduced their smoking and sampled quitting during the study. Implementing smoking cessation services in mental health treatment settings is feasible and, if delivered in line with best practices, either a behavioral or a supportive approach can be helpful. Future research should examine ways to facilitate the transition from reduction to abstinence. This study was part of a clinical trial registered as NCT #00960375 at www.clinicaltrials.gov.

Factors influencing implementation of smoking cessation treatment within community mental health centers.

OBJECTIVE: Consumers with serious mental illness smoke more and are at higher risk for smoking-related illness. We examined provider and consumer factors influencing the implementation of the evidence-based "5 A's" (ask, advise, assess, assist, arrange) in six community mental health centers in greater Baltimore. METHODS: Data collected as part of a larger study examining the effectiveness of delivery of the 5 A's at patient visits. First, we examined responses to a survey administered to 49 clinicians on barriers and attitudes toward delivering the 5 A's. Second, we used multilevel models to examine variance between patients (n = 228), patient factors, and variance between their psychiatrists (n = 28) in the delivery of the 5 A's (and first 3 A's). RESULTS: The most strongly endorsed barrier was perceived lack of patient interest in smoking cessation. Psychiatrists and patients both accounted for significant variance in the delivery of the 5 A's and 3 A's. Patient "readiness to change" predicted delivery of the full 5 A's, while smoking severity predicted delivery of the first 3 A's. CONCLUSIONS: There is a critical need for creative and collaborative solutions, policies, and clinician training to address actual and perceived obstacles to the delivery of evidence-based smoking cessation treatment in the mental health care setting.

Antiparkinson drug adherence and its association with health care utilization and economic outcomes in a Medicare Part D population.

OBJECTIVES: We examine the associations of adherence to antiparkinson drugs (APDs) with health care utilization and economic outcomes among patients with Parkinson's disease (PD). METHODS: By using 2006-2007 Medicare administrative data, we examined 7583 beneficiaries with PD who filled two or more APD prescriptions during 19 months (June 1, 2006, to December 31, 2007) in the Part D program. Two adherence measures--duration of therapy (DOT) and medication possession ratio (MPR)--were assessed. Negative binomial and gamma generalized linear models were used to estimate the rate ratios (RRs) of all-cause health care utilization and expenditures, respectively, conditional upon adherence, adjusting for survival risk, sample selection, and health-seeking behavior. RESULTS: Approximately one-fourth of patients with PD had low adherence (MPR < 0.80, 28.7%) or had a short DOT (≤ 400 days, 23.9%). Increasing adherence to APD therapy was associated with decreased health care utilization and expenditures. For example, compared with patients with low adherence, those with high adherence (MPR = 0.90-1.00) had significantly lower rates of hospitalization (RR = 0.86), emergency room visits (RR = 0.91), skilled nursing facility episodes (RR = 0.67), home health agency episodes (RR = 0.83), physician visits (RR = 0.93), as well as lower total health care expenditures (-$2242), measured over 19 months. Similarly, lower total expenditure (-$6308) was observed in patients with a long DOT versus those with a short DOT. CONCLUSIONS: In this nationally representative sample, higher adherence to APDs and longer duration of use of APDs were associated with lower all-cause health care utilization and total health care expenditures. Our findings suggest the need for improving medication-taking behaviors among patients with PD to reduce the use of and expenditures for medical resources.