A Randomized Controlled Trial Evaluating the Effectiveness of Supported Employment Integrated in Primary Care.

OBJECTIVES: Mental health issues can cause serious problems in occupational functioning, including higher rates of unemployment. Individual placement and support (IPS) is an evidence-based supported employment intervention that is typically integrated within a mental health setting; however, many primary care patients view referral to a mental health clinic as stigmatizing. Thus, this study examined whether delivery of IPS in a primary care setting provides an effective treatment option and avoids unnecessary delays in obtaining competitive employment. METHODS: U.S. military veterans (N=119) who had a diagnosis in a broad range of nonpsychotic psychiatric disorders and who were receiving care from Veterans Health Administration (VHA) patient-aligned care teams were prospectively randomly assigned to IPS (N=58) or standard VHA non-IPS vocational rehabilitation (VR) (N=61). The primary outcome was achievement of steady worker status, defined as holding a competitive job for ≥6 months of the 12-month follow-up. RESULTS: As hypothesized, a significantly greater proportion of IPS participants achieved steady worker status (45%), compared with VR participants (25%) (p=0.02; odds ratio=2.49, 95% confidence interval=1.14-5.43). On average, the IPS participants worked significantly more weeks (p=0.003) and earned significantly more income (p=0.033) from competitive jobs, compared with VR participants. CONCLUSIONS: The results provide supporting evidence for offering IPS within primary care with the aim of restoring meaningful and sustained competitive employment for veterans living with a mental disorder. Such modifications could improve veterans' vocational outcomes, moving a significantly greater number of disabled veterans back to full and productive lives in the community.

A Randomized, Placebo-Controlled Trial of Mirtazapine for the Treatment of Posttraumatic Stress Disorder in Veterans.

OBJECTIVE: The aim of this study was to determine the efficacy of mirtazapine, a tetracyclic antidepressant, as monotherapy for the treatment of posttraumatic stress disorder (PTSD). METHODS: This multisite, randomized, double-blind, placebo-controlled trial was conducted between April 2006 and November 2010 at the Tuscaloosa and Birmingham Veterans Affairs Medical Centers in Alabama. US military veterans who met DSM-IV criteria for PTSD were randomly assigned to placebo (n = 39) or mirtazapine (n = 39) titrated up to 45 mg/d for an 8-week double-blind period followed by an 8-week open-label phase of mirtazapine treatment. The primary outcome efficacy measure was the Structured Interview for Posttraumatic Stress Disorder (SIP). Secondary measures included other measures of PTSD, depression, and sleep. Analyses of treatment groups involved mixed-model procedures using a random intercept to test the hypotheses that mirtazapine would be more effective than placebo in reducing symptoms of PTSD and depression and improving quality of sleep. RESULTS: Seventy-eight participants were randomized with 61 completing the 8-week controlled phase and 48 completing the open-label phase. No significant differences were observed between groups on the primary outcome of SIP scores during the controlled phase (P = .418). In secondary outcomes, significant improvements per the Clinical Global Impressions-Improvement scale were found for the mirtazapine group compared to the placebo group (P = .041). The 8-week open-label phase demonstrated significant symptom improvement in SIP total score (P = .0003) and in scores on the SIP re-experiencing (P = .0007), avoidance (P = .0309), and hyperarousal (P = .0014) subscales. There were no significant differences in the occurrence of adverse events between groups. CONCLUSIONS: This study did not show efficacy of mirtazapine monotherapy in the treatment of PTSD. Identification of more effective treatments, either as monotherapy or adjunctive, for PTSD is imperative. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00302107.

The methods and baseline characteristics of a VA randomized controlled study evaluating supported employment provided in primary care patient aligned care teams.

BACKGROUND: This article describes the design and baseline sample of a single-site trial comparing Individual Placement and Support (IPS) supported employment delivered within a Veterans Health Administration (VHA) primary care Patient Aligned Care Team (PACT) to treatment-as-usual vocational rehabilitation (TAU-VR) that includes transitional work. METHODS: Unemployed U.S. military veterans receiving care in a VHA PACT who were seeking competitive work, otherwise eligible for vocational rehabilitation, and diagnosed with a mental health condition other than a psychotic or bipolar I disorder were prospectively randomized to receive either IPS or TAU-VR. Employment outcomes and measures of quality of life, self-esteem, and community reintegration are being collected for 12 months. RESULTS: The participant sample (n = 119) is comprised of 17.6% female, 73.1% African-Americans, and 1.7% Hispanic. Average age is 38.2 (SD ± 8.41) years; 80.7% served in the military since 2001; 78% are receiving or applying for U.S. Department of Veterans Affairs (VA) service-connected disability; 26.9% have not held a competitive job in the past 3 years; and the average length of pre-randomization unemployment is 1.4 (SD ± 2.3) years. CONCLUSIONS: Unique design features include evaluating the efficacy of evidenced-based IPS within the primary care setting, having broad diagnostic eligibility, and defining the primary outcome criterion as "steady employment", i.e. holding a competitive job for ≥26 weeks of the 12-month follow-up period. The findings illustrate the characteristics of a primary care veteran sample in need of employment services. TRIAL REGISTRATION: www.clinicaltrials.gov Identifier: NCT02400736.

An Open Label Pilot Study of Adjunctive Asenapine for the Treatment of Posttraumatic Stress Disorder.

OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) remain the first-line treatment for posttraumatic stress disorder (PTSD). However, adjunctive atypical antipsychotics are often used to target residual or refractory symptoms. Asenapine is a novel atypical antipsychotic that possesses a high serotonin (5-HT2A) to dopamine (D2) affinity ratio and alpha-adrenergic antagonism, which may be advantageous in treating PTSD. This pilot study aimed to identify the therapeutic potential of asenapine as an adjunctive treatment for PTSD. METHOD: Eighteen subjects initiated treatment in this single-site prospective, open-label, 12-week trial of flexibly-dosed asenapine in Veterans with PTSD who had not responded to an adequate course of treatment with an SSRI, venlafaxine, or mirtazapine. Subjects remained on their antidepressant medication and were started on adjunctive asenapine 5 mg sublingual at bedtime, which was gradually titrated to a maximum of 10 mg twice per day, as tolerated. The primary outcome measure was the Clinician Administered PTSD Scale (CAPS) for DSM-IV. RESULTS: Fifteen subjects finished at least 4 weeks and eleven completed the 12 week study. There was a significant and clinically meaningful decrease in CAPS from baseline (77.56 ± 14.48) to week 4 (48.7 ± 30.6), and to week 12 (35.3 ± 19.7). Six participants experienced adverse events possibly related to asenapine; however, only three participants discontinued early due to related adverse events. CONCLUSION: This pilot study demonstrated that adjunctive treatment with asenapine may provide additional benefit to some patients experiencing residual PTSD symptoms in spite of optimal antidepressant therapy. A larger efficacy study may be warranted.

A novel iterative-learner simulation model: fellows as teachers.

BACKGROUND: Simulation is an effective method for teaching clinical skills but has not been widely adopted to educate trainees about how to teach. OBJECTIVE: We evaluated a curriculum for pediatrics fellows by using high-fidelity simulation (mannequin with vital signs) to improve pedagogical skills. INTERVENTION: The intervention included a lecture on adult learning and active-learning techniques, development of a case from the fellows' subspecialties, and teaching the case to residents and medical students. Teaching was observed by an educator using a standardized checklist. Learners evaluated fellows' teaching by using a structured evaluation tool; learner evaluations and the observer checklist formed the basis for written feedback. Changes in fellows' pedagogic knowledge, attitudes, and self-reported skills were analyzed by using Friedman and Wilcoxon rank-sum test at baseline, immediate postintervention, and 6-month follow-up. RESULTS: Forty fellows participated. Fellows' self-ratings significantly improved from baseline to 6-month follow-up for development of learning objectives, effectively reinforcing performance, using teaching techniques to promote critical thinking, providing constructive feedback, and using case studies to teach general rules. Fellows significantly increased agreement with the statement "providing background and context is important" (4.12 to 4.44, P  =  .02). CONCLUSIONS: Simulation was an effective means of educating fellows about teaching, with fellows' attitudes and self-rated confidence improving after participation but returning to baseline at the 6-month assessment. The simulation identified common weaknesses of fellows as teachers, including failure to provide objectives to learners, failure to provide a summary of key learning points, and lack of inclusion of all learners.

HIV and hepatitis B and C incidence rates in US correctional populations and high risk groups: a systematic review and meta-analysis.

BACKGROUND: High Human Immunodeficiency Virus (HIV) prevalence and high risk behaviors have been well documented within United States (US) correctional systems. However, uncertainty remains regarding the extent to which placing people in prison or jail increases their risk of HIV infection, and regarding which inmate populations experience an increased incidence of HIV. Describing these dynamics more clearly is essential to understanding how inmates and former detainees may be a source for further spread of HIV to the general US population. METHODS: The authors conducted a systematic review and meta-analysis of studies describing HIV incidence in US correctional facility residents and, for comparison, in high risk groups for HIV infection, such as non-incarcerated intravenous drug users (IVDU) and men who have sex with men (MSM) in the US. HIV incidence rates were further compared with Hepatitis B and Hepatitis C Virus rates in these same populations. RESULTS: Thirty-six predominantly prospective cohort studies were included. Across all infection outcomes, continuously incarcerated inmates and treatment recruited IVDU showed the lowest incidence, while MSM and street recruited IVDU showed the highest. HIV incidence was highest among inmates released and re-incarcerated. Possible sources of heterogeneity identified among HIV studies were risk population and race. CONCLUSIONS: Although important literature gaps were found, current evidence suggests that policies and interventions for HIV prevention in correctional populations should prioritize curtailing risk of infection during the post-release period. Future research should evaluate HIV incidence rates in inmate populations, accounting for proportion of high risk sub-groups.

Effect of epilepsy magnetic source imaging on intracranial electrode placement.

OBJECTIVE: Intracranial electroencephalography (ICEEG) with chronically implanted electrodes is a costly invasive diagnostic procedure that remains necessary for a large proportion of patients who undergo evaluation for epilepsy surgery. This study was designed to evaluate whether magnetic source imaging (MSI), a noninvasive test based on magnetoencephalography source localization, can supplement ICEEG by affecting electrode placement to improve sampling of the seizure onset zone(s). METHODS: Of 298 consecutive epilepsy surgery candidates (between 2001 and 2006), 160 patients were prospectively enrolled by insufficient localization from seizure monitoring and magnetic resonance imaging results. Before presenting MSI results, decisions were made whether to proceed with ICEEG, and if so, where to place electrodes such that the hypothetical seizure-onset zone would be sampled. MSI results were then provided with allowance of changes to the original plan. RESULTS: MSI indicated additional electrode coverage in 18 of 77 (23%) ICEEG cases. In 39% (95% confidence interval, 16.4-61.4), seizure-onset ICEEG patterns involved the additional electrodes indicated by MSI. Sixty-two patients underwent surgical resection based on ICEEG recording of seizures. Highly localized MSI was significantly associated with seizure-free outcome (mean, 3.4 years; minimum, >1 year) for the entire surgical population (n = 62). INTERPRETATION: MSI spike localization increases the chance that the seizure-onset zone is sampled when patients undergo ICEEG for presurgical epilepsy evaluations. The clinical impact of this effect, improving diagnostic yield of ICEEG, should be considered in surgery candidates who do not have satisfactory indication of epilepsy localization from seizure semiology, electroencephalogram, and magnetic resonance imaging.

An examination of Bayesian statistical approaches to modeling change in cognitive decline in an Alzheimer's disease population.

The mini mental state examination (MMSE) is a common tool for measuring cognitive decline in Alzhiemer's Disease (AD) subjects. Subjects are usually observed for a specified period of time or until death to determine the trajectory of the decline which for the most part appears to be linear. However, it may be noted that the decline may not be modeled by a single linear model over a specified period of time. There may be a point called a change point where the rate or gradient of the decline may change depending on the length of time of observation. A Bayesian approach is used to model the trajectory and determine an appropriate posterior estimate of the change point as well as the predicted model of decline before and after the change point. Estimates of the appropriate parameters as well as their posterior credible regions or regions of interest are established. Coherent prior to posterior analysis using mainly non informative priors for the parameters of interest is provided. This approach is applied to an existing AD database.

Functional imaging: II. Prediction of epilepsy surgery outcome.

OBJECTIVE: To gain information on the value of magnetic source imaging (MSI), 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), and ictal single photon emission computed tomography (SPECT) to predict seizure-free outcome following epilepsy surgery in patients who require intracranial electroencephalography (ICEEG). METHODS: This work was part of a prospective observation study of epilepsy surgery candidates not sufficiently localized with scalp EEG and MRI. Of 160 patients enrolled 62 completed ICEEG and subsequent surgical resection. Sixty-one percent resulted in an Engel I seizure-free outcome at a minimum of one-year follow-up (mean = 3.4 years). Sensitivity, specificity, and predictive values were computed for each modality. Multivariate logistical regression was used to identify prediction of surgical outcome by imaging test. RESULTS: MSI sensitivity for a conclusively localized study was 55% with a positive predictive value of 78%. Eliminating non-diagnostic MSI cases (no spikes captured during recording) yielded a corrected negative predictive value of 64%. With available comparison subgroups FDG-PET and ictal SPECT values were similar to MSI. The OR (adjusted for epilepsy and MRI classification) for MSI prediction of seizure-free outcome was 4.4 (p =0.01). In cases with both PET and MSI, the adjusted OR for PET was 7.1 (p <0.01) and for MSI was 6.4 (p = 0.01). In the cases with all three tests (n = 27), ictal SPECT had the highest OR of 9.1 (p = 0.05). INTERPRETATION: MSI, FDG-PET, and ictal SPECT each have clinical value in predicting seizure-free surgical outcome in epilepsy surgery candidates who typically require ICEEG.

Functional imaging: I. Relative predictive value of intracranial electroencephalography.

OBJECTIVE: To gain information on the predictive and prognostic value of magnetic source imaging (MSI), 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography ((18)FDG-PET), and ictal single-photon emission computed tomography (SPECT) as compared with intracranial electroencephalography (ICEEG) localization in epilepsy surgery. METHODS: This work was part of a cohort study of epilepsy surgery candidates not sufficiently localized with noninvasive studies. Of 160 patients enrolled over 4 years, 77 completed ICEEG seizure monitoring. Sensitivity, specificity, and predictive values relative to ICEEG were computed for each modality. RESULTS: Seizures were not captured in five patients. Of the 72 diagnostic ICEEG studies, seizure localization results were 74% localized, 10% multifocal, and 17% nonlocalized. Sixty-one percent were localized to neocortical regions. Depending on patient subgroup pairs, sensitivity ranged from 58 to 64% (MSI), 22 to 40% (PET), and 39 to 48% (SPECT); specificity ranges were 79 to 88% (MSI), 53 to 63% (PET), and 44 to 50% (SPECT). Gains in diagnostic yield were seen only with the combination of MSI and PET or MSI and ictal SPECT. Localization concordance with ICEEG was greatest with MSI, but a significant difference was demonstrated only between MSI and PET. Moderate redundancy was seen between PET and ictal SPECT (kappa = 0.452; p = 0.011). INTERPRETATION: Conclusively positive MSI has a high predictive value for seizures localized with ICEEG. Diagnostic gain may be achieved with addition of either PET or ictal SPECT to MSI. Diagnostic values for imaging tests are lower than "true values" because of the limitations of ICEEG as a gold standard.

Divalproex in the treatment of posttraumatic stress disorder: a randomized, double-blind, placebo-controlled trial in a veteran population.

OBJECTIVE: To evaluate the efficacy of divalproex for the treatment of posttraumatic stress disorder (PTSD) hyperarousal symptom cluster. METHOD: Under double-blind conditions, 85 US military veterans with PTSD were randomized to treatment with divalproex or placebo for 8 weeks. All patients who received at least 1 dose of medication and 1 postbaseline assessment (n = 82) were included in the efficacy population. The primary outcome measure was the hyperarousal subscale of the Clinician-Administered PTSD Scale. RESULT: There were no significant intergroup differences in primary or secondary end points. The final mean (SD) divalproex dose and serum valproic acid level were 2309 +/- 507 mg/d and 82 +/- 30 mg/L, respectively. CONCLUSIONS: Divalproex monotherapy was not effective in the treatment of chronic PTSD in predominantly older male combat veterans. Further study is needed to determine the efficacy of divalproex in the management of PTSD in women or civilians or in combination with antidepressants.

A pharmacokinetic and clinical evaluation of switching patients with bipolar I disorder from delayed-release to extended-release divalproex.

OBJECTIVE: To determine the optimal strategy for converting stable bipolar patients from twice-daily divalproex delayed release (DR) to once-daily divalproex extended release (ER). METHOD: This prospective, open-label, crossover study compared 4 divalproex regimens in euthymic outpatients with bipolar I disorder (DSM-IV diagnosis confirmed by Mini-International Neuropsychiatric Interview). Serum valproic acid levels were collected 12, 16, 20, and 24 hours after the last bedtime dose of the following regimens: DR twice daily (DR b.i.d.) during week 1; total daily DR dose once daily (DR q.h.s.) during week 2; once-daily ER at equal daily DR dose (ER 1:1) during week 3; and once-daily ER with the dose increased by 500 mg (ER + 500) during week 4. Patients continued on ER + 500 for 4 additional weeks after the pharmacokinetic phase. Side effects and psychiatric symptoms were assessed at weeks 1 through 4, 6, and 8. Twenty-one patients were enrolled from July 2002 to July 2004. RESULTS: Of the regimens tested, DR q.h.s. produced the widest fluctuations in valproic acid levels, with the highest 12-hour (82 mug/mL) and lowest 24-hour (44 mug/mL) levels. The ER + 500 dose was the only regimen that maintained the mean minimum valproic acid concentration above 50 mug/mL. Each regimen was well tolerated, and no significant changes in psychometric indices were observed. CONCLUSIONS: When converting stable bipolar patients from twice-daily divalproex DR to once-daily ER, we recommend increasing the total daily dose by 250 to 500 mg to ensure maintenance of therapeutic valproic acid levels.

Ribavirin reveals a lethal threshold of allowable mutation frequency for Hantaan virus.

The broad spectrum of antiviral activity of ribavirin (RBV) lies in its ability to inhibit IMP dehydrogenase, which lowers cellular GTP. However, RBV can act as a potent mutagen for some RNA viruses. Previously we have shown a lack of correlation between antiviral activity and GTP repression for Hantaan virus (HTNV) and evidence for RBV's ability to promote error-prone replication. To further explore the mechanism of RBV, GTP levels, specific infectivity, and/or mutation frequency was measured in the presence of RBV, mycophenolic acid (MPA), selenazofurin, or tiazofurin. While all four drugs resulted in a decrease in the GTP levels and infectious virus, only RBV increased the mutation frequency of viral RNA (vRNA). MPA, however, could enhance RBV's mutagenic effect, which suggests distinct mechanisms of action for each. Therefore, a simple drop in GTP levels does not drive the observed error-prone replication. To further explore RBV's mechanism of action, we made a comprehensive analysis of the mutation frequency over several RBV concentrations. Of importance, we observed that the viral population reached a threshold after which mutation frequency did not correlate with a dose-dependent decrease in the level of vRNA, PFU, or [RTP]/[GTP] (where RTP is ribavirin-5'-triphosphate) over these same concentrations of RBV. Modeling of the relationship of mutation frequency and drug concentration showed an asymptotic relationship at this point. After this threshold, approximately 57% of the viral cDNA population was identical to the wild type. These studies revealed a lethal threshold, after which we did not observe a complete loss of the quasispecies structure of the wild-type genome, although we observed extinction of HTNV.

Comparison of predicted probabilities of proportional hazards regression and linear discriminant analysis methods using a colorectal cancer molecular biomarker database.

BACKGROUND: Although a majority of studies in cancer biomarker discovery claim to use proportional hazards regression (PHREG) to the study the ability of a biomarker to predict survival, few studies use the predicted probabilities obtained from the model to test the quality of the model. In this paper, we compared the quality of predictions by a PHREG model to that of a linear discriminant analysis (LDA) in both training and test set settings. METHODS: The PHREG and LDA models were built on a 491 colorectal cancer (CRC) patient dataset comprised of demographic and clinicopathologic variables, and phenotypic expression of p53 and Bcl-2. Two variable selection methods, stepwise discriminant analysis and the backward selection, were used to identify the final models. The endpoint of prediction in these models was five-year post-surgery survival. We also used linear regression model to examine the effect of bin size in the training set on the accuracy of prediction in the test set. RESULTS: The two variable selection techniques resulted in different models when stage was included in the list of variables available for selection. However, the proportion of survivors and non-survivors correctly identified was identical in both of these models. When stage was excluded from the variable list, the error rate for the LDA model was 42% as compared to an error rate of 34% for the PHREG model. CONCLUSIONS: This study suggests that a PHREG model can perform as well or better than a traditional classifier such as LDA to classify patients into prognostic classes. Also, this study suggests that in the absence of the tumor stage as a variable, Bcl-2 expression is a strong prognostic molecular marker of CRC.

Divalproex in the treatment of bipolar depression: a placebo-controlled study.

BACKGROUND: The treatment of bipolar disorder in the depressed phase is complicated by a tendency for conventional antidepressant drugs to worsen the course of the illness by precipitating a manic episode or increasing cycle frequency. Thus, the potential antidepressant efficacy of mood stabilizers, such as divalproex, which is an effective treatment for the manic phase of bipolar disorder, is of considerable interest. METHODS: The clinical efficacy of divalproex (valproate, Depakote) was tested in an 8-week, double-blind, placebo-controlled, randomized clinical trial in 25 outpatients with bipolar I depression. The primary outcome measure was the 17-item Hamilton Rating Scale for Depression, and secondary measures included the Hamilton Rating Scale for Anxiety, the Clinician Administered Rating Scale for Mania, and the Clinical Global Impression scale. RESULTS: Using repeated measures ANOVA with last observation carried forward, divalproex was more effective than placebo in improving symptoms of depression (p = 0.0002) and symptoms of anxiety (p = 0.0001) than placebo. LIMITATIONS: The sample size was small, and most patients were male. CONCLUSIONS: These pilot results indicate that divalproex is effective in reducing the symptoms of depression and anxiety in bipolar I, depressed phase. These positive results support the need to perform a larger, multisite study of divalproex treatment for bipolar depression.

Stability of adrenocortical steroidogenesis over time in healthy women and women with polycystic ovary syndrome.

Adrenocortical secretion is up-regulated in women with polycystic ovary syndrome (PCOS), and absolute adrenal androgen (AA) excess is evident in approximately 25% of these patients. We hypothesized that AA biosynthesis is an inherited trait and that, as for other inherited traits, AA biosynthesis remains stable over time. To test this hypothesis, we prospectively studied 23 off-treatment PCOS patients and seven age- and body mass index-matched control women on two separate occasions 3-5 yr apart (45.0 +/- 19.0 months and 47.4 +/- 21.3 months, respectively; P > 0.05). All subjects underwent an acute adrenal stimulation using 0.25 mg ACTH-(1-24), and dehydroepiandrosterone (DHEA), androstenedione, and cortisol (F) were measured 0 and 60 min post ACTH; basal levels of total and free testosterone (T), SHBG, and DHEA sulfate (DHEA-S) were also assessed. Among PCOS patients, the mean DHEA-S levels during the repeat study were significantly lower when compared with the initial assessment (170 +/- 107 microg/dl vs. 134 +/- 79 microg/dl, respectively; P = 0.02). However, only patients with initial DHEA-S levels above the median (high DHEA-S) experienced a net decrease in the levels of this metabolite (252.5 +/- 99.2 microg/dl vs. 174.3 +/- 82.5 microg/dl; P = 0.001) over the time of the study; patients with initial DHEA-S levels in the lower half (low DHEA-S) did not experience a change in DHEA-S (94.6 +/- 28.9 microg/dl vs. 97.7 +/- 56.5 microg/dl; P = 0.85). In patients, the total T levels tended to be higher at the second study, although SHBG levels were also higher, resulting in unchanged free T levels over time. Among controls, no significant changes in basal androgens were observed over the time of the study. There were no significant differences in either the basal or ACTH-stimulated levels of DHEA, androstenedione, or F over the time of the study in either PCOS or control women. We conclude that the adrenocortical secretion of AAs or F in PCOS and control women remains stable over time, supporting the hypothesis that the adrenal response to ACTH may be an inherited trait. Alternatively, a decrease in DHEA-S levels over time was observed but only among PCOS patients whose initial levels of this metabolite were above the group median, suggesting that the activity of sulfotransferase in these patients may be up-regulated by factors other than those affecting adrenocortical biosynthesis and that such regulatory influences attenuate over time.

A placebo-controlled study of nefazodone for the treatment of chronic posttraumatic stress disorder: a preliminary study.

Nefazodone is a unique serotonergic antidepressant that acts as both a presynaptic serotonin reuptake inhibitor and a postsynaptic 5-hydroxytryptamine 2A receptor antagonist. Based on the positive results of open-label trials of nefazodone, including one from our group, we tested nefazodone's efficacy in the treatment of posttraumatic stress disorder (PTSD) under placebo-controlled conditions. Forty-one patients with chronic PTSD, predominantly male combat veterans, were enrolled in a randomized, double-blind, placebo-controlled 12-week trial of nefazodone. The primary outcome measure was the Clinician-Administered PTSD Scale. Fifteen patients were randomized to placebo and 26 were randomized to nefazodone. In a repeated-measures analysis of variance with last observation carried forward, patients on nefazodone showed a significant improvement in the percentage change of Clinician-Administered PTSD Scale Total score from baseline compared with those on placebo (P = 0.04; effect size = 0.6). Sample size was not powered to test group differences in the Clinician-Administered PTSD Scale criterion B, C, or D subscale. However, the criterion D subscale showed significant improvement in patients treated with nefazodone compared with those treated with placebo (P = 0.007). In addition, the Hamilton Rating Scale for Depression showed significant improvement compared with placebo (P = 0.008). The nefazodone group also reported an improvement on the PTSD Checklist (self-report scale; P = 0.08) and the Clinician-Administered Dissociative States Scale (P = 0.06). This pilot study supports the efficacy of nefazodone for the treatment of PTSD. However, larger placebo-controlled studies in more diverse patient population are warranted.

Natural history of carotid artery stenosis contralateral to endarterectomy: results from two randomized prospective trials.

PURPOSE: A few nonrandomized studies have reported the natural history of carotid artery stenosis (CAS) contralateral to carotid endarterectomy (CEA). This study analyzed this condition with data from two randomized prospective trials. METHODS: The contralateral carotid arteries in 534 patients from two randomized trials that compared CEA with primary closure versus patching were followed up clinically and with duplex ultrasound scanning at 1 month and then every 6 months. CAS was classified as less than 50%, 50% to 79%, 80% to 99%, and occlusion. Late contralateral CEA was performed to treat significant CAS. Progression was defined as progress to a higher category of stenosis. Kaplan-Meier life table analysis was used to estimate freedom from progression of CAS. The correlation of risk factors and CAS progression was also analyzed. RESULTS: Of 534 patients, 61 had initial contralateral CEA and 53 had contralateral occlusion. Overall, CAS progressed in 109 of 420 patients (26%) at mean follow-up of 41 months. Progression of CAS was noted in 5 of 162 patients (3%) with baseline normal carotid arteries. CAS progressed in 56 of 157 patients (36%) with less than 50% stenosis versus 45 of 95 patients (47%) with 50% to 79% stenosis (P =.003). Median time to progression was 24 months for less than 50% CAS, and 12 months for 50% to 79% CAS (P =.035). At 1, 2, 3, 4, and 5 years, freedom from disease progression in patients with baseline CAS <50% was 95%, 78%, 69%, 61%, 48%, respectively, and in patients with 50% to 79% CAS was 75%, 61%, 51%, 43%, and 33%, respectively (P =.003). Freedom from progression in patients with baseline normal carotid arteries at 1 through 5 years was 99%, 98%, 96%, 96%, and 94%, respectively. Late neurologic events referable to the CCA were infrequent (28 of 420 [6.7%] in the entire series; 28 of 258 [10.9%] patients with contralateral CAS), and included 10 strokes (2.4%) and 18 transient ischemic attacks (4.3%). However, late contralateral CEA was performed in 62 patients (62 of 420 [15%] in the entire series; 62 of 258 [24%] patients with contralateral CAS). Survival rates were 96%, 92%, 90%, 87%, and 82%, respectively, at 1 through 5 years. CONCLUSIONS: Progression of CCA stenosis was noted in a significant number of patients with baseline contralateral CAS. Serial clinical studies and duplex ultrasound scanning every 6 to 12 months in patients with 50% to 79% CAS, and every 12 to 24 months in patients with 50% or less CAS is adequate.

Preparation and examination of proposed consensus reference standards for fiber-counting.

This study provided standard reference materials for fiber-counting by phase-contrast microscopy (PCM). PCM is subject to many sources of variation, including those dependent on the microscopist, so reference standards cannot be produced that are traceable to national or international standard units. Consensus standards using a "true value" agreed on by a number of laboratories may be acceptable. Reference slides for fiber-counting can be prepared using a proprietary process of grid overlay in which the fields of view defined by the grids are identifiable and relocatable. Multiple microscopists then can examine exactly the same areas of samples, reducing one source of potential variation. Twelve slides prepared from proficiency test samples of the American Industrial Hygiene Association (AIHA) Industrial Hygiene Laboratory Quality Program were used in this study, four each of chrysotile asbestos, amosite asbestos, and man-made mineral fibers. Five microscopists from AIHA-accredited laboratories, plus the inventor of the grid process, examined the slides in a blind study. This group represented commercial analytical companies, in-house corporate laboratories, research institutions, and universities. The six microscopists met to obtain consensus agreement on the fibers in each designated field classified as countable under National Institute for Occupational Safety and Health Method 7400. Slides and documentation were forwarded to AIHA for training or other purposes. Examination of the results by statistical methods showed that some microscopists' results were significantly different from others, even though all analysts would have been considered proficient with respect to the final consensus values. Although the reasons for the outliers are complex, this procedure may have value in selecting reference laboratories in proficiency test schemes, possibly leading to more defensible "true" values and tighter limits of variation.