Randomized Trial of Medical versus Surgical Treatment for Refractory Heartburn.

BACKGROUND: Heartburn that persists despite proton-pump inhibitor (PPI) treatment is a frequent clinical problem with multiple potential causes. Treatments for PPI-refractory heartburn are of unproven efficacy and focus on controlling gastroesophageal reflux with reflux-reducing medication (e.g., baclofen) or antireflux surgery or on dampening visceral hypersensitivity with neuromodulators (e.g., desipramine). METHODS: Patients who were referred to Veterans Affairs (VA) gastroenterology clinics for PPI-refractory heartburn received 20 mg of omeprazole twice daily for 2 weeks, and those with persistent heartburn underwent endoscopy, esophageal biopsy, esophageal manometry, and multichannel intraluminal impedance-pH monitoring. If patients were found to have reflux-related heartburn, we randomly assigned them to receive surgical treatment (laparoscopic Nissen fundoplication), active medical treatment (omeprazole plus baclofen, with desipramine added depending on symptoms), or control medical treatment (omeprazole plus placebo). The primary outcome was treatment success, defined as a decrease of 50% or more in the Gastroesophageal Reflux Disease (GERD)-Health Related Quality of Life score (range, 0 to 50, with higher scores indicating worse symptoms) at 1 year. RESULTS: A total of 366 patients (mean age, 48.5 years; 280 men) were enrolled. Prerandomization procedures excluded 288 patients: 42 had relief of their heartburn during the 2-week omeprazole trial, 70 did not complete trial procedures, 54 were excluded for other reasons, 23 had non-GERD esophageal disorders, and 99 had functional heartburn (not due to GERD or other histopathologic, motility, or structural abnormality). The remaining 78 patients underwent randomization. The incidence of treatment success with surgery (18 of 27 patients, 67%) was significantly superior to that with active medical treatment (7 of 25 patients, 28%; P = 0.007) or control medical treatment (3 of 26 patients, 12%; P<0.001). The difference in the incidence of treatment success between the active medical group and the control medical group was 16 percentage points (95% confidence interval, -5 to 38; P = 0.17). CONCLUSIONS: Among patients referred to VA gastroenterology clinics for PPI-refractory heartburn, systematic workup revealed truly PPI-refractory and reflux-related heartburn in a minority of patients. For that highly selected subgroup, surgery was superior to medical treatment. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT01265550.).

Follow-up of Prostatectomy versus Observation for Early Prostate Cancer.

BACKGROUND: We previously found no significant differences in mortality between men who underwent surgery for localized prostate cancer and those who were treated with observation only. Uncertainty persists regarding nonfatal health outcomes and long-term mortality. METHODS: From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer to radical prostatectomy or observation. We extended follow-up through August 2014 for our primary outcome, all-cause mortality, and the main secondary outcome, prostate-cancer mortality. We describe disease progression, treatments received, and patient-reported outcomes through January 2010 (original follow-up). RESULTS: During 19.5 years of follow-up (median, 12.7 years), death occurred in 223 of 364 men (61.3%) assigned to surgery and in 245 of 367 (66.8%) assigned to observation (absolute difference in risk, 5.5 percentage points; 95% confidence interval [CI], -1.5 to 12.4; hazard ratio, 0.84; 95% CI, 0.70 to 1.01; P=0.06). Death attributed to prostate cancer or treatment occurred in 27 men (7.4%) assigned to surgery and in 42 men (11.4%) assigned to observation (absolute difference in risk, 4.0 percentage points; 95% CI, -0.2 to 8.3; hazard ratio, 0.63; 95% CI, 0.39 to 1.02; P=0.06). Surgery may have been associated with lower all-cause mortality than observation among men with intermediate-risk disease (absolute difference, 14.5 percentage points; 95% CI, 2.8 to 25.6) but not among those with low-risk disease (absolute difference, 0.7 percentage points; 95% CI, -10.5 to 11.8) or high-risk disease (absolute difference, 2.3 percentage points; 95% CI, -11.5 to 16.1) (P=0.08 for interaction). Treatment for disease progression was less frequent with surgery than with observation (absolute difference, 26.2 percentage points; 95% CI, 19.0 to 32.9); treatment was primarily for asymptomatic, local, or biochemical (prostate-specific antigen) progression. Urinary incontinence and erectile and sexual dysfunction were each greater with surgery than with observation through 10 years. Disease-related or treatment-related limitations in activities of daily living were greater with surgery than with observation through 2 years. CONCLUSIONS: After nearly 20 years of follow-up among men with localized prostate cancer, surgery was not associated with significantly lower all-cause or prostate-cancer mortality than observation. Surgery was associated with a higher frequency of adverse events than observation but a lower frequency of treatment for disease progression, mostly for asymptomatic, local, or biochemical progression. (Funded by the Department of Veterans Affairs and others; PIVOT ClinicalTrials.gov number, NCT00007644 .).

Minimal Clinically Important Differences (MCID) in Assessing Outcomes of Post-Traumatic Stress Disorder.

This study sought to determine the minimal clinically important difference (MCID) for two frequently used measures of symptom severity in Post-Traumatic Stress Disorder: the Clinician Administered PTSD Scale (CAPS) and the PTSD Symptom Checklist (PCL). Data from a randomized clinical trial of antipsychotic medication in military-related treatment-resistant PTSD (N= 267) included assessments 4 times over 26 weeks. Methods for estimating the MCID were based on both the anchor-based approach, using the Clinical Global Impressions (CGI) severity and improvement scales, rated by both clinicians and patients; and the distribution-based approach (based on standardized z-scores). Severity and change scores on the CAPS and PCL were converted to z-scores and compared across CGI levels using analysis of variance. The average difference in CAPS z-scores between each of three CGI levels between "moderate" to "severe" and from "no change" to "much improved" was 0.758 for clinician CGI ratings and 0.525 for patient CGI ratings and were similar for the PCL (0.483 and 0.471) with all differences significant at p<.0001). Clinically meaningful CAPS and PCL severity and change z-scores range between 0.5-0.8 standard deviations. The MCID estimates suggested here provide an empirical basis for determining whether statistically significant changes in CAPS and PCL scores are clinically meaningful.

Radical prostatectomy versus observation for localized prostate cancer.

BACKGROUND: The effectiveness of surgery versus observation for men with localized prostate cancer detected by means of prostate-specific antigen (PSA) testing is not known. METHODS: From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality. RESULTS: During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P=0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P=0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P=0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P=0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death. CONCLUSIONS: Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points. (Funded by the Department of Veterans Affairs Cooperative Studies Program and others; PIVOT ClinicalTrials.gov number, NCT00007644.).

The fluctuation of nocturia in men with lower urinary tract symptoms allocated to placebo during a 12-month randomized, controlled trial.

PURPOSE: We determined the fluctuation of nocturia in a 12-month period in men with lower urinary tract symptoms. MATERIALS AND METHODS: Men with lower urinary tract symptoms were allocated to the placebo arm of the United States Department of Veterans Affairs Cooperative Studies Program Benign Prostatic Hyperplasia Study. Reported nocturia frequency using the American Urological Association Symptom Index was collected at 6 time points (2, 4, 13, 26, 39 and 52 weeks). Repeat measurements of nocturia during a 1-year period were analyzed using a generalized mixed linear model. RESULTS: Of the 305 men allocated to the placebo group 256 participants (84%) gave answers for all 6 time points. In the entire sample the mean nocturia count did not significantly vary from baseline (week 2) after adjusting for covariates (p = 0.542). However, there was considerable fluctuation in nocturia during 1 year. Of the 93 men with 3 or 4 episodes at baseline 47% had improvement and 12% had worsening at 1 year. Of the 184 men who reported 2 or greater nocturia episodes at baseline 15% reported 0 or 1 at 52 weeks. Depending on the case definition during followup the probability of nocturia progression varied between 8% and 54% while nocturia regression varied between 2% and 33%. CONCLUSIONS: Using repeat questionnaire based assessments we observed considerable fluctuation in nocturia. However, overall there was no significant increase in prevalence in a 1-year period. These findings may be reassuring to providers and patients who elect to delay interventions for nocturia.

Characterizing infection prevention programs and urinary tract infection prevention practices in nursing homes: A mixed-methods study.

OBJECTIVE: US policies require robust nursing home (NH) infection prevention and control (IPC) programs to ensure safe care. We assessed IPC resources and practices related to catheter and non-catheter-associated urinary tract infection (CAUTI and UTI) prevention among NHs. METHODS: We conducted a mixed-methods study from April 2018 through November 2019. Quantitative surveys assessed NH IPC program resources, practices, and communication during resident transfer. Semistructured qualitative interviews focused on IPC programs, CAUTI and UTI prevention practices, and resident transfer processes. Using a matrix as an analytic tool, findings from the quantitative survey data were combined with the qualitative data in the form of a joint display. RESULTS: Representatives from 51 NHs completed surveys; interviews were conducted with 13 participants from 7 NHs. Infection preventionists (IPs) had limited experience and/or additional roles, and in 36.7% of NHs, IPs had no specific IPC training. IP turnover was often mentioned during interviews. Most facilities were aware of their CAUTI and UTI rates and reported using prevention practices, such as hydration (85.7%) or nurse-initiated catheter discontinuation (65.3%). Qualitative interviewees confirmed use of these practices and expressed additional concerns about overuse of urine testing and antibiotics. Although transfer sheets were used by 84% to communicate about infections, the information received was described as suboptimal. CONCLUSIONS: NHs identified IP challenges related to turnover, limited education, and serving multiple roles. However, most NHs reported awareness of their CAUTI and UTI rates as well as their use of prevention practices. Importantly, we identified opportunities to enhance communication between NHs and hospitals to improve resident care and safety.

Exoskeletal-Assisted Walking in Veterans With Paralysis: A Randomized Clinical Trial.

Importance: Robotic exoskeletons leverage technology that assists people with spinal cord injury (SCI) to walk. The efficacy of home and community exoskeletal use has not been studied in a randomized clinical trial (RCT). Objective: To examine whether use of a wheelchair plus an exoskeleton compared with use of only a wheelchair led to clinically meaningful net improvements in patient-reported outcomes for mental and physical health. Design, Setting, and Participants: This RCT of veterans with SCI was conducted at 15 Veterans Affairs medical centers in the US from September 6, 2016, to September 27, 2021. Data analysis was performed from March 10, 2022, to June 20, 2024. Interventions: Participants were randomized (1:1) to standard of care (SOC) wheelchair use or SOC plus at-will use of a US Food and Drug Administration (FDA)-cleared exoskeletal-assisted walking (EAW) device for 4 months in the home and community. Main Outcomes and Measures: Two primary outcomes were studied: 4.0-point or greater improvement in the mental component summary score on the Veterans RAND 36-Item Health Survey (MCS/VR-36) and 10% improvement in the total T score of the Spinal Cord Injury-Quality of Life (SCI-QOL) physical and medical health domain and reported as the proportion who achieved clinically meaningful changes. The primary outcomes were measured at baseline, post randomization after advanced EAW training sessions, and at 2 months and 4 months (primary end point) in the intervention period. Device usage, reasons for not using, and adverse events were collected. Results: A total of 161 veterans with SCI were randomized to the EAW (n = 78) or SOC (n = 83) group; 151 (94%) were male, the median age was 47 (IQR, 35-56) years, and median time since SCI was 7.3 (IQR, 0.5 to 46.5) years. The difference in proportion of successes between the EAW and SOC groups on the MCS/VR-36 (12 of 78 [15.4%] vs 14 of 83 [16.9%]; relative risk, 0.91; 95% CI, 0.45-1.85) and SCI-QOL physical and medical health domain (10 of 78 [12.8%] vs 11 of 83 [13.3%]; relative risk, 0.97; 95% CI, 0.44-2.15) was not statistically different. Device use was lower than expected (mean [SD] distance, 1.53 [0.02] miles per month), primarily due to the FDA-mandated companion being unavailable 43.9% of the time (177 of 403 instances). Two EAW-related foot fractures and 9 unrelated fractures (mostly during wheelchair transfers) were reported. Conclusions and Relevance: In this RCT of veterans with SCI, the lack of improved outcomes with EAW device use may have been related to the relatively low device usage. Solutions for companion requirements and user-friendly technological adaptations should be considered for improved personal use of these devices. Trial Registration: ClinicalTrials.gov Identifier: NCT02658656.

Ascertaining cause of death among men in the prostate cancer intervention versus observation trial.

BACKGROUND: The Prostate Cancer Intervention Versus Observation Trial (PIVOT) randomized 731 men with localized prostate cancer to radical prostatectomy or observation. PURPOSE: We describe the methods and results for cause-of-death assignments in PIVOT, and compare them to alternative strategies for ascertaining prostate cancer-specific mortality, as well as to the methods and results in the similar Scandinavian Prostate Cancer Group Study 4 (SPCG-4) trial. METHODS: Three PIVOT Endpoints Committee members, blinded to randomized treatment assignments, reviewed medical records and death certificates when available to assign a cause of death using a primary and a secondary adjudication question. Initial disagreements were resolved through discussion. The level of initial agreement among committee members was examined, as well as guesses at randomized treatment assignments for a convenience sample of cases. Final cause of death determinations were compared to death certificates. RESULTS: Complete agreement on cause of death by all three committee members before any discussion was achieved in 200/354 (56%) cases on the primary and 209/354 (59%) cases on the secondary. However, complete agreement on the primary rose to 306/354 (86%) when 'definite' and 'probably' categories were collapsed, as planned a priori. The three committee members' proportions of correct guesses of randomized treatment assignment were 82/121 (68%), 113/148 (76%), and 99/134 (74%). Using the committee's final adjudications as a gold standard, death certificates had suboptimal sensitivities, specificities, or predictive values depending on how they were used to determine cause of death. LIMITATIONS: There was no separate 'gold standard' by which to judge the accuracy of the final endpoints committee adjudications, and useful death certificates could not be obtained on about a third of PIVOT participants who died. CONCLUSIONS: The low level of initial agreement on cause of death among endpoint committee members and the potential for biased determinations due to partial unblinding to treatment assignment raise methodologic concerns about using prostate cancer mortality as an endpoint in clinical trials like PIVOT.

Association of Exposure to High-risk Antibiotics in Acute Care Hospitals With Multidrug-Resistant Organism Burden in Nursing Homes.

Importance: Little is known about the contribution of hospital antibiotic prescribing to multidrug-resistant organism (MDRO) burden in nursing homes (NHs). Objectives: To characterize antibiotic exposures across the NH patient's health care continuum (preceding health care exposure and NH stay) and to investigate whether recent antibiotic exposure is associated with MDRO colonization and room environment contamination at NH study enrollment. Design, Setting, and Participants: This is a secondary analysis of a prospective cohort study (conducted from 2013-2016) that enrolled NH patients and followed them up for as long as 6 months. The study was conducted in 6 NHs in Michigan among NH patients who were enrolled within 14 days of admission. Clinical metadata abstraction, multi-anatomical site screening, and room environment surveillance for MDROs were conducted at each study visit. Data were analyzed between May 2019 and November 2021. Exposures: Antibiotic data were abstracted from NH electronic medical records by trained research staff and characterized by class, route, indication, location of therapy initiation, risk for Clostridioides difficile infection (C diffogenic agents), and 2019 World Health Organization Access, Watch, and Reserve (AWARE) antibiotic stewardship framework categories. Main Outcomes and Measures: The primary outcomes were MDRO colonization and MDRO room environment contamination at NH study enrollment, measured using standard microbiology methods. Multivariable logistic regression was used to identify whether antibiotic exposure within 60 days was associated with MDRO burden at NH study enrollment. Additionally, antibiotic exposure data were characterized using descriptive statistics. Results: A total of 642 patients were included (mean [SD] age, 74.7 [12.2] years; 369 [57.5%] women; 402 [62.6%] White; median [IQR] NH days to enrollment, 6.0 [3.0-7.0]). Of these, 422 (65.7%) received 1191 antibiotic exposures: 368 (57.3%) received 971 hospital-associated prescriptions, and 119 (18.5%) received 198 NH-associated prescriptions. Overall, 283 patients (44.1%) received at least 1 C diffogenic agent, and 322 (50.2%) received at least 1 high-risk WHO AWARE antibiotic (watch or reserve agent). More than half of NH patients (364 [56.7%]) and room environments (437 [68.1%]) had MDRO-positive results at enrollment. In multivariable analysis, recent antibiotic exposure was positively associated with baseline MDRO colonization (odds ratio [OR], 1.70; 95% CI, 1.22-2.38) and MDRO environmental contamination (OR, 1.67; 95% CI, 1.17-2.39). Exploratory stratification by C diffogenic agent exposure increased the effect size (MDRO colonization: OR, 1.99; 95% CI, 1.33-2.96; MDRO environmental contamination: OR, 1.86; 95% CI, 1.24-2.79). Likewise, exploratory stratification by exposure to high-risk WHO AWARE antibiotics increased the effect size (MDRO colonization: OR, 2.32; 95% CI, 1.61-3.36; MDRO environmental contamination: OR, 1.86; 95% CI, 1.26-2.75). Conclusions and Relevance: The findings of this study suggest that high-risk, hospital-based antibiotics are a potentially high-value target to reduce MDROs in postacute care NHs. This study underscores the potential utility of integrated hospital and NH stewardship programming on regional MDRO epidemiology.

Adjunctive risperidone treatment for antidepressant-resistant symptoms of chronic military service-related PTSD: a randomized trial.

CONTEXT: Serotonin reuptake-inhibiting (SRI) antidepressants are the only FDA-approved pharmacotherapies for the treatment of posttraumatic stress disorder (PTSD). OBJECTIVE: To determine efficacy of the second-generation antipsychotic risperidone as an adjunct to ongoing pharmacologic and psychosocial treatments for veterans with chronic military-related PTSD. DESIGN, SETTING, AND PARTICIPANTS: A 6-month, randomized, double-blind, placebo-controlled multicenter trial conducted between February 2007 and February 2010 at 23 Veterans Administration outpatient medical centers. Of the 367 patients screened, 296 were diagnosed with military-related PTSD and had ongoing symptoms despite at least 2 adequate SRI treatments, and 247 contributed to analysis of the primary outcome measure. INTERVENTION: Risperidone (up to 4 mg once daily) or placebo. MAIN OUTCOME MEASURES: The Clinician-Administered PTSD Scale (CAPS) (range, 0-136). Other measures included the Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Scale (HAMA), Clinical Global Impression scale (CGI), and Veterans RAND 36-Item Health Survey (SF-36V). RESULTS: Change in CAPS scores from baseline to 24 weeks in the risperidone group was -16.3 (95% CI, -19.7 to -12.9) and in the placebo group, -12.5 (95% CI, -15.7 to -9.4); the mean difference was 3.74 (95% CI, -0.86 to 8.35; t = 1.6; P = .11). Mixed model analysis of all time points also showed no significant difference in CAPS score (risperidone: mean, 64.43; 95% CI, 61.98 to 66.89, vs placebo: mean, 67.16; 95% CI, 64.71 to 69.62; mean difference, 2.73; 95% CI, -0.74 to 6.20; P = .12). Risperidone did not reduce symptoms of depression (MADRS mean difference, 1.19; 95% CI, -0.29 to 2.68; P = .11) or anxiety (HAMA mean difference, 1.16; 95% CI, -0.18 to 2.51; P = .09; patient-rated CGI mean difference, 0.20; 95% CI, -0.06 to 0.45; P = .14; observer-rated CGI mean difference, 0.18; 95% CI, 0.01 to 0.34; P = .04), or increase quality of life (SF-36V physical component mean difference, -1.13, 95% CI, -2.58 to 0.32; P = .13; SF-36V mental component mean difference, -0.26; 95% CI, -2.13 to 1.61; P = .79). Adverse events were more common with risperidone vs placebo, including self-reported weight gain (15.3% vs 2.3%), fatigue (13.7% vs 0.0%), somnolence (9.9% vs 1.5%), and hypersalivation (9.9% vs 0.8%), respectively. CONCLUSION: Among patients with military-related PTSD with SRI-resistant symptoms, 6-month treatment with risperidone compared with placebo did not reduce PTSD symptoms. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00099983.

The design of a randomized control trial of exoskeletal-assisted walking in the home and community on quality of life in persons with chronic spinal cord injury.

There are more than 300,000 estimated cases of spinal cord injury (SCI) in the United States, and approximately 27,000 of these are Veterans. Immobilization from SCI results in adverse secondary medical conditions and reduced quality of life. Veterans with SCI who have completed rehabilitation after injury and are unable to ambulate receive a wheelchair as standard of care. Powered exoskeletons are a technology that offers an alternative form of limited mobility by enabling over-ground walking through an external framework for support and computer-controlled motorized hip and knee joints. Few studies have reported the safety and efficacy for use of these devices in the home and community environments, and none evaluated their impact on patient-centered outcomes through a randomized clinical trial (RCT). Absence of reported RCTs for powered exoskeletons may be due to a range of challenges, including designing, statistically powering, and conducting such a trial within an appropriate experimental framework. An RCT for the study of exoskeletal-assisted walking in the home and community environments also requires the need to address key factors such as: avoiding selection bias, participant recruitment and retention, training, and safety concerns, particularly in the home environment. These points are described here in the context of a national, multisite Department of Veterans Affairs Cooperative Studies Program-sponsored trial. The rationale and methods for the study design were focused on providing a template for future studies that use powered exoskeletons or other strategies for walking and mobility in people with immobilization due to SCI.

Neural changes following remediation in adult developmental dyslexia.

Brain imaging studies have explored the neural mechanisms of recovery in adults following acquired disorders and, more recently, childhood developmental disorders. However, the neural systems underlying adult rehabilitation of neurobiologically based learning disabilities remain unexplored, despite their high incidence. Here we characterize the differences in brain activity during a phonological manipulation task before and after a behavioral intervention in adults with developmental dyslexia. Phonologically targeted training resulted in performance improvements in tutored compared to nontutored dyslexics, and these gains were associated with signal increases in bilateral parietal and right perisylvian cortices. Our findings demonstrate that behavioral changes in tutored dyslexic adults are associated with (1) increased activity in those left-hemisphere regions engaged by normal readers and (2) compensatory activity in the right perisylvian cortex. Hence, behavioral plasticity in adult developmental dyslexia involves two distinct neural mechanisms, each of which has previously been observed either for remediation of developmental or acquired reading disorders.

1500 gram suprarenal mass: a case report.

Adrenocortical carcinoma can have a clinical presentation that mimics a primary renal tumor. We describe a case of a 47-year-old male who presented with flank pain, weight loss, and a 14 cm mass arising from the upper pole of the right kidney on imaging. Upon surgical resection he was found to have a 1500 gram stage II adrenocortical carcinoma. The clinical features, pathologic findings, grading criteria, and differential diagnosis of adrenocortical carcinoma are reviewed.

Sleep disturbance in chronic military-related PTSD: clinical impact and response to adjunctive risperidone in the Veterans Affairs cooperative study #504.

OBJECTIVE: Sleep disturbances are common among veterans with chronic military-related posttraumatic stress disorder (PTSD). This article reports the results of a multicenter clinical trial that explored the clinical correlates of reported sleep impairment in these veterans and tested the impact of the second-generation antipsychotic risperidone upon these symptoms. METHOD: This article reports secondary analyses of a 24-week multicenter randomized placebo-controlled trial of adjunctive risperidone in patients with chronic military-related PTSD symptoms (n = 267, 97% male) who were symptomatic despite treatment with antidepressants and other medications. The study was conducted between February 2007 and February 2010. DSM-IV PTSD diagnoses were made by using the Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Nonpatient Edition. Sleep disturbances were assessed principally by using the Pittsburgh Sleep Quality Index (PSQI) (primary outcome measure). Analyses were conducted using bivariate correlations and longitudinal mixed model regressions. RESULTS: Eighty-eight percent of the patients in this study had clinically significantly impaired sleep on the PSQI. Severity of sleep disturbances correlated with PTSD symptom severity as measured by the Clinician-Administered PTSD Scale (CAPS) and reductions in multiple measures of quality of life (Veterans RAND 36-item Health Survey [SF-36 V] subscales, Boston Life Satisfaction Index). Risperidone produced small but statistically significant effects on total PSQI scores (main effect of drug: F1,228 = 4.57, P = .034; drug-by-time interaction: F2,421 = 4.32, P = .014) and severity of nightmares as assessed by the CAPS (main effect of drug: F1,248 = 4.60, P = .033). The improvements in sleep quality produced by risperidone correlated with reductions in PTSD symptom severity and improvement in the mental health subscale of the SF-36 V. CONCLUSIONS: This study highlighted the near universality and significant negative impact of severe disturbances in sleep quality in veterans with chronic military-related PTSD who were partial responders to standard pharmacotherapies. The modest improvements in sleep quality produced by adjunctive risperidone were correlated with limited reductions in PTSD severity and improvements in quality of life. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00099983.

Hypothesis testing for selective, differential, and conjoined brain activation.

Hypothesis testing in functional neuroimaging studies relies heavily on the computation of categorical contrasts in which brain activation associated with one experimental condition is assessed relative to brain activation associated with a different experimental condition. Often, multiple pair-wise contrasts are computed and reported independently. Here we describe an approach to hypothesis testing that logically combines multiple pair-wise contrasts to distinguish among selective, differential and conjoined brain activation patterns. Using a sample dataset in which participants viewed objects, visual noise patterns or a fixation cross, we demonstrate that selective and differential brain activation patterns are often confounded with current approaches to hypothesis testing but that the logical combination approach can distinguish between these two types of data patterns. Specifically, we show that brain regions that respond selectively to an object recognition task relative to viewing visual noise or a fixation cross (selective activation) are mutually exclusive from brain regions that show a graded response to object viewing, noise viewing and visual fixation (differential activation). We thus show that the logical combination approach sufficiently constrains the results of categorical contrasts to reflect only the data pattern that would be predicted from the cognitive processing account under investigation.

The Prostate cancer Intervention Versus Observation Trial:VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): design and baseline results of a randomized controlled trial comparing radical prostatectomy to watchful waiting for men with clinically localized prostate cancer.

BACKGROUND: Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer death in men. Ninety percent of men with prostate cancer are over aged 60 years, diagnosed by early detection with the prostate specific antigen (PSA) blood test and have disease believed confined to the prostate gland (clinically localized). Common treatments for clinically localized prostate cancer include watchful waiting surgery to remove the prostate gland (radical prostatectomy), external beam radiation therapy and interstitial radiation therapy (brachytherapy) and androgen deprivation. Little is known about the relative effectiveness and harms of treatments due to the paucity of randomized controlled trials. The VA/NCI/AHRQ Cooperative Studies Program Study #407: Prostate cancer Intervention Versus Observation Trial (PIVOT), initiated in 1994, is a multicenter randomized controlled trial comparing radical prostatectomy to watchful waiting in men with clinically localized prostate cancer. METHODS: We describe the study rationale, design, recruitment methods and baseline characteristics of PIVOT enrollees. We provide comparisons with eligible men declining enrollment and men participating in another recently reported randomized trial of radical prostatectomy versus watchful waiting conducted in Scandinavia. RESULTS: We screened 13,022 men with prostate cancer at 52 United States medical centers for potential enrollment. From these, 5023 met initial age, comorbidity and disease eligibility criteria and a total of 731 men agreed to participate and were randomized. The mean age of enrollees was 67 years. Nearly one-third were African-American. Approximately 85% reported they were fully active. The median prostate specific antigen (PSA) was 7.8 ng/mL (mean 10.2 ng/mL). In three-fourths of men the primary reason for biopsy leading to a diagnosis of prostate cancer was a PSA elevation or rise. Using previously developed tumor risk categorizations incorporating PSA levels, Gleason histologic grade and tumor stage, approximately 43% had low risk, 36% had medium risk and 20% had high-risk prostate cancer. Comparison to our national sample of eligible men declining PIVOT participation as well as to men enrolled in the Scandinavian trial indicated that PIVOT enrollees are representative of men being diagnosed and treated in the U.S. and quite different from men in the Scandinavian trial. CONCLUSIONS: PIVOT enrolled an ethnically diverse population representative of men diagnosed with prostate cancer in the United States. Results will yield important information regarding the relative effectiveness and harms of surgery compared to watchful waiting for men with predominately PSA detected clinically localized prostate cancer.

Phonological decoding involves left posterior fusiform gyrus.

Aloud reading of novel words is achieved by phonological decoding, a process in which grapheme-to-phoneme conversion rules are applied to "sound out" a word's spoken representation. Numerous brain imaging studies have examined the neural bases of phonological decoding by contrasting pseudoword (pronounceable nonwords) to real word reading. However, only a few investigations have examined pseudoword reading under both aloud and silent conditions, task parameters that are likely to significantly alter the functional anatomy of phonological decoding. Subjects participated in an fMRI study of aloud pseudoword, aloud real word, silent pseudoword, and silent real word reading. Using this two-by-two design, we examined effects of word-type (real words vs. pseudowords) and response-modality (silent vs. aloud) and their interactions. We found 1) four regions to be invariantly active across the four reading conditions: the anterior aspect of the left precentral gyrus (Brodmann's Area (BA) 6), and three areas within the left ventral occipitotemporal cortex; 2) a main effect of word-type (pseudowords > words) in left inferior frontal gyrus and left intraparietal sulcus; 3) a main effect of response-modality (aloud > silent) that included bilateral motor, auditory, and extrastriate cortex; and 4) a single left hemisphere extrastriate region showing a word-type by response-modality interaction effect. This region, within the posterior fusiform cortex at BA 19, was uniquely modulated by varying phonological processing demands. This result suggests that when reading, word forms are subject to phonological analysis at the point they are first recognized as alphabetic stimuli and BA 19 is involved in processing the phonological properties of words.

Meta-analysis of the functional neuroanatomy of single-word reading: method and validation.

Intersubject variability and subtle differences in experimental design can lead to variable results in studies of cognitive processes such as reading. To accurately identify the neural processes associated with cognition and sensorimotor processing, meta-analytic methods capable of identifying areas of consistent activation among studies are useful. This paper describes a novel approach for combining published neuroimaging results from multiple studies, designed to maximize the quantification of interstudy concordance while minimizing the subjective aspects of meta-analysis. In this method, a localization probability distribution was modeled for each activation focus obtained from 11 PET studies of reading single words aloud, and the union of these distributions was taken to yield an activation likelihood estimate map for the brain. Significance was assessed via permutation analysis of randomly generated sets of foci. Regions of significant concordance were identified in bilateral motor and superior temporal cortices, pre-SMA, left fusiform gyrus, and the cerebellum. These meta-analytic results were validated by comparison with new fMRI data on aloud word reading in normal adult subjects. Excellent correspondence between the two statistical maps was observed, with fMRI maxima lying close to all meta-analysis peaks and statistical values at the peaks identified by the two techniques correlating strongly. This close correspondence between PET meta-analysis and fMRI results also demonstrates the validity of using fMRI for the study of language tasks involving overt speech responses. Advantages of this automated meta-analysis technique include quantification of the level of concordance at all brain locations and the provision for use of a threshold for statistical significance of concordance.