Efficacy and Safety of Mifepristone in the Treatment of Male US Veterans With Posttraumatic Stress Disorder: A Phase 2a Randomized Clinical Trial.

Importance: To date, no psychopharmacologic treatment has been found to be uniformly effective in veterans with posttraumatic stress disorder (PTSD); novel targets and approaches are needed to treat this disabling disorder. Objective: To examine whether treatment with the glucocorticoid receptor antagonist mifepristone yields a signal for clinical efficacy in male veterans with PTSD. Design, Setting, and Participants: This phase 2a, double-blind, parallel-group randomized clinical trial was conducted from November 19, 2012 (accrual started), through November 16, 2016 (final follow-up), within the US Department of Veterans Affairs. Participants were male veterans with chronic PTSD and a screening Clinician-Administered PTSD Scale score of 50 or higher. A total of 181 veterans consented to participation. Statistical analysis was conducted between August 2014 and May 2017. Interventions: Participants were randomized in a 1:1 ratio to mifepristone (600 mg) or matched placebo taken orally for 7 days. Main Outcomes and Measures: The clinical outcome was whether a veteran achieved a clinical response status (a reduction of ≥30% of total Clinician-Administered PTSD Scale score from baseline) at 4- and 12-week follow-up. On the basis of a binary statistical selection rule, a difference in the proportion of treatment vs control group responders of 15% would be a clinically relevant difference. Self-report measures of PTSD and associated symptoms were also obtained. Neuroendocrine outcomes and plasma levels of mifepristone were measured. Safety was assessed throughout the study. The primary analysis was based on a multiple imputation technique to address missing outcome data; thus, some participant numbers may not appear as whole numbers. Results: A total of 81 veterans were enrolled and randomized. Excluding 1 participant randomized in error, 80 were included in the modified intention-to-treat analysis (41 randomized to mifepristone and 39 to placebo). The mean (SD) age was 43.1 (13.7) years. A total of 15.6 (38.1%) in the mifepristone group and 12.1 (31.1%) in the placebo group were clinical responders at 4 weeks in the analysis using the multiple imputation technique. The group difference in the proportion of clinical responders (7.0%) was less than the predefined margin of 15% indicating signal for clinical efficacy. In an exploratory analysis, the difference in response to mifepristone vs placebo in the subgroup with no lifetime history of traumatic brain injury (TBI) (7.0 [50.0%] vs 3.0 [27.3%]; difference, 22.7%) exceeded the efficacy margin at 4 weeks and was sustained at 12 weeks. In contrast, in veterans with PTSD and lifetime TBI, the response rate to mifepristone was lower than placebo at 12 weeks (7.4 [27.4%] vs 13.5 [48.3%]; difference, -20.9%). Conclusions and Relevance: This study did not detect a signal for efficacy for mifepristone at 600 mg/d for 1 week in male veterans with chronic PTSD. Thus, this study does not support a phase 3 trial in this population. Future studies of mifepristone for the treatment of PTSD may be of interest in those without a history of TBI or in samples with a low base rate of lifetime head trauma. Trial Registration: ClinicalTrials.gov Identifier: NCT01946685.

Development of a new adapted QuinteT Recruitment Intervention (QRI-Two) for rapid application to RCTs underway with enrolment shortfalls-to identify previously hidden barriers and improve recruitment.

BACKGROUND: Many randomised controlled trials (RCTs) struggle to recruit, despite valiant efforts. The QRI (QuinteT Recruitment Intervention) uses innovative research methods to optimise recruitment by revealing previously hidden barriers related to the perceptions and experiences of recruiters and patients, and targeting remedial actions. It was designed to be integrated with RCTs anticipating difficulties at the outset. A new version of the intervention (QRI-Two) was developed for RCTs already underway with enrolment shortfalls. METHODS: QRIs in 12 RCTs with enrolment shortfalls during 2007-2017 were reviewed to document which of the research methods used could be rapidly applied to successfully identify recruitment barriers. These methods were then included in the new streamlined QRI-Two intervention which was applied in 20 RCTs in the USA and Europe during 2018-2019. The feasibility of the QRI-Two was investigated, recruitment barriers and proposed remedial actions were documented, and the QRI-Two protocol was finalised. RESULTS: The review of QRIs from 2007 to 2017 showed that previously unrecognised recruitment barriers could be identified but data collection for the full QRI required time and resources usually unavailable to ongoing RCTs. The streamlined QRI-Two focussed on analysis of screening/accrual data and RCT documents (protocol, patient-information), with discussion of newly diagnosed barriers and potential remedial actions in a workshop with the RCT team. Four RCTs confirmed the feasibility of the rapid application of the QRI-Two. When the QRI-Two was applied to 14 RCTs underway with enrolment shortfalls, an array of previously unknown/underestimated recruitment barriers related to issues such as equipoise, intervention preferences, or study presentation was identified, with new insights into losses of eligible patients along the recruitment pathway. The QRI-Two workshop enabled discussion of the newly diagnosed barriers and potential remedial actions to improve recruitment in collaboration with the RCT team. As expected, the QRI-Two performed less well in six RCTs at the start-up stage before commencing enrolment. CONCLUSIONS: The QRI-Two can be applied rapidly, diagnose previously unrecognised recruitment barriers, and suggest remedial actions in RCTs underway with enrolment shortfalls, providing opportunities for RCT teams to develop targeted actions to improve recruitment. The effectiveness of the QRI-Two in improving recruitment requires further evaluation.

Defining optimal treatment for recurrent Clostridioides difficile infection (OpTION study): A randomized, double-blind comparison of three antibiotic regimens for patients with a first or second recurrence.

BACKGROUND: Although many large, randomized controlled trials (RCT) have been conducted on antibiotic therapy for patients with primary C. difficile infections (CDI), few RCTs have been performed for patients with recurrent CDI (rCDI). In addition, fecal microbial transplant (FMT) is neither FDA-approved or guideline-recommended for patients with pauci-rCDI (first or second recurrences). Therefore, a rigorous RCT of sufficient size was designed to determine the optimal treatment among three antibiotic regimens in current practice for treatment of pauci-rCDI. METHODS: VA Cooperative Studies Program (CSP) #596 is a prospective, double-blind, multi-center clinical trial of veteran patients with pauci-rCDI comparing fidaxomicin (FDX) 200 mg twice daily for 10 days and vancomycin (VAN) 125 mg four times daily for 10 days followed by a 3-week vancomycin taper and pulse (VAN-T/P) regimen to a standard course of VAN 125 mg four times daily for 10 days. The primary endpoint is sustained clinical response at day 59, with sustained response measured as a diarrhea composite outcome (D-COM) that includes symptom resolution during treatment (before day 10) without recurrence of diarrhea or other clinically important outcomes through day 59. DISCUSSION: CSP study 596 is designed to compare three current antibiotic treatments for recurrent CDI that are in clinical practice, but which lack high-quality evidence to support strong guideline recommendations. The design of the study which included a pilot phase initiated at six sites with expansion to 24 sites is described along with protocol modifications based on early trial experience and clinical realities including the COVID-19 pandemic. TRIAL REGISTRATION: This study is registered with clinicaltrials.gov (Identifier: NCT02667418).

Effect of Pulsed Low-Intensity Ultrasonography on Symptom Relief and Tibiofemoral Articular Cartilage Thickness Among Veterans Affairs Enrollees With Knee Osteoarthritis: A Randomized Clinical Trial.

Importance: Osteoarthritis (OA) is a major cause of disability in the US, with no approved treatments to slow progression, but animal models suggest that pulsed low-intensity ultrasonography (PLIUS) may promote cartilage growth. Objective: To evaluate the efficacy of PLIUS in providing symptom reduction and decreased loss of tibiofemoral cartilage thickness in patients with knee OA. Design, Setting, and Participants: A phase 2A, sham-controlled, parallel, double-blind randomized clinical trial was conducted at 2 Veterans Affairs hospitals in Salt Lake City, Utah, and San Diego, California, from May 22, 2015, to January 31, 2019. Data were analyzed from June 27, 2020, to October 20, 2020. Participants recruited through the US Department of Veterans Affairs (N = 132) with clinical and radiographic evidence of early knee OA were randomly assigned to receive PLIUS or a sham device, self-administered for 20 minutes daily over the medial compartment of the knee. All enrollees participated in a 4-week prerandomization sham run-in period, followed by a 48-week treatment period. Randomization was stratified by study site and Kellgren-Lawrence grades 1 (n = 15), 2 (n = 51), and 3 (n = 66). Intervention: Participants either received 48 weeks of PLIUS or sham ultrasonography. Main Outcomes and Measures: The trial incorporated 2 coprimary outcomes: symptomatic improvement assessed by Outcome Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society International Responder Criteria (ie, met if either >50% improvement in pain and function with at least a 20% absolute improvement of at least 2 of the following 3 factors: improvement by at least 20% [pain, function, and patient global assessment] with at least a 10-mm absolute improvement), and cartilage preservation assessed as change in central medial femoral condyle cartilage thickness by magnetic resonance imaging. Intention-to-treat analysis was used. Results: The mean (SD) participant age was 63.6 (10.7) years and 119 were men (90.2%). The mean (SD) duration of OA symptoms was 13.4 (12.3) years. In the PLIUS group, 70.4% (95% CI, 58.2%-82.6%) of the participants experienced symptomatic improvement, compared with 67.3% (95% CI, 54.9%-79.7%) of participants in the sham group (P = .84); there was no statistically significant difference in response rates between the treatment groups, and the between-group rate difference of 3.1% (95% CI, -14.3% to 20.5%) did not meet the predefined 10% threshold for clinically significant symptomatic improvement from application of PLIUS. At 48 weeks of treatment, central medial femoral condyle cartilage thickness decreased by a mean (SD) of 73.8 (168.1) µm in the PLIUS group and by 42.2 (297.0) µm in the sham group. This 48-week mean change between the 2 groups did not reach statistical significance (P = .44), and the between-group 48-week difference of -31.7 µm (95% CI, -129.0 µm to 65.7 µm) did not meet the predefined threshold. There were 99 nonserious adverse events in the PLIUS group and 89 in the sham group during the trial. No serious adverse events were deemed related to the study device. Conclusions and Relevance: PLIUS, as implemented in this study, demonstrated neither symptomatic benefit nor a decrease in loss of tibiofemoral cartilage thickness in knee OA. Trial Registration: ClinicalTrials.gov Identifier: NCT02034409.

Predictors of multi-domain cognitive decline following DBS for treatment of Parkinson's disease.

BACKGROUND: Statistically and clinically significant cognitive declines are observed in a small subset of individuals with Parkinson's Disease (PD) following treatment with Deep Brain Stimulation (DBS). OBJECTIVES: We examine the association between multi-domain cognitive decline (MCD) and demographic and baseline clinical variables and the incidence of serious adverse events (SAE) arising within a six-month interval following DBS for PD. METHOD: Study participants with PD who displayed MCD at 6-month follow-up evaluation after DBS (n = 18) were contrasted with individuals with PD from the same study who did not show cognitive decline after DBS (n = 146). Logistic regression analyses were employed to assess relationship between predictors, including age (>70 years old), pre-DBS cognitive screening test performance, SAE, and MCD. MCD+ and MCD-groups were also compared on other baseline clinical and demographic variables. RESULTS: MCD showed modest association with older age and lower baseline neurocognitive screening performance, whereas the groups did not differ on most other baseline clinical and demographic variables. SAEs during the study interval were the most robust predictor of MCD in the DBS group. A variety of SAEs were documented in study participants experiencing MCD after DBS surgery, including, but not limited to, infections and small intracranial hemorrhages. CONCLUSIONS: Older age and lower baseline cognition measured prior to treatment are associated with MCD measured at six-months after DBS. SAE occurring following DBS surgery are also predictive of MCD. These predictors may reflect aspects of "frailty" in advanced PD. Risk factors for SAE warrant careful consideration in clinical trials.

Generalizability of heterogeneous treatment effects based on causal forests applied to two randomized clinical trials of intensive glycemic control.

Purpose Machine learning is an attractive tool for identifying heterogeneous treatment effects (HTE) of interventions but generalizability of machine learning derived HTE remains unclear. We examined generalizability of HTE detected using causal forests in two similarly designed randomized trials in type II diabetes patients. Methods We evaluated published HTE of intensive versus standard glycemic control on all-cause mortality from the Action to Control Cardiovascular Risk in Diabetes study (ACCORD) in a second trial, the Veterans Affairs Diabetes Trial (VADT). We then applied causal forests to VADT, ACCORD, and pooled data from both studies and compared variable importance and subgroup effects across samples. Results HTE in ACCORD did not replicate in similar subgroups in VADT, but variable importance was correlated between VADT and ACCORD (Kendall's tau-b 0.75). Applying causal forests to pooled individual-level data yielded seven subgroups with similar HTE across both studies, ranging from risk difference of all-cause mortality of -3.9% (95% CI -7.0, -0.8) to 4.7% (95% CI 1.8, 7.5). Conclusions Machine learning detection of HTE subgroups from randomized trials may not generalize across study samples even when variable importance is correlated. Pooling individual-level data may overcome differences in study populations and/or differences in interventions that limit HTE generalizability.

A cohort study of neuropsychological functioning in spouses of U.S. Gulf War veterans.

AIMS: Veterans of the 1991 Gulf War reported symptoms in their spouses that mirrored veterans' symptoms following their return from the war, including problems with attention and memory. Neuropsychological functioning in these spouses has not been examined with objective tests. This study sought to determine if these spouses exhibited deficits in neuropsychological functioning. MAIN METHODS: Spouses of a national cohort of 1991 Gulf War deployed (n = 470) and non-deployed veterans (n = 524) were examined with neuropsychological tests in 1999-2001. KEY FINDINGS: Neuropsychological tests were factor analyzed yielding five factors: verbal memory, visual memory, attention/working memory, visual organization, and motor speed. Spouses of deployed and nondeployed veterans did not differ on mean factor scores, percentage of impaired factors, or individual test scores. Spouse attention/working memory was related to their having diagnoses of PTSD or anxiety disorders, or self-reported symptoms of current anxiety. Spouse visual memory was related to a diagnosis of current depression. Spouse motor speed was related to their own status of having chronic multisymptom illness (CMI). SIGNIFICANCE: Spouses of Gulf War deployed and nondeployed veterans demonstrated similar neuropsychological functioning, although spouses with psychiatric diagnoses and symptoms, or CMI demonstrated neuropsychological impairments characteristic of those conditions, suggesting that monitoring spouses for these conditions and impairments may be warranted. This pattern of relative weaknesses mirrors some of the previously reported findings for Gulf War veterans, although the veterans displayed neuropsychological impairments beyond what was accounted for by these conditions.

Pentoxifylline in diabetic kidney disease (VA PTXRx): protocol for a pragmatic randomised controlled trial.

INTRODUCTION: Diabetic kidney disease (DKD) is the most frequent cause of end-stage renal disease (ESRD) in the USA and worldwide. Recent experimental and clinical data suggest that the non-specific phosphodiesterase inhibitor pentoxifylline (PTX) may decrease progression of chronic kidney disease. However, a large-scale randomised clinical trial is needed to determine whether PTX can reduce ESRD and death in DKD. METHODS AND ANALYSIS: Veterans Affairs (VA) PTXRx is a pragmatic, randomised, placebo-controlled multicentre VA Cooperative Study to test the hypothesis that PTX, when added to usual care, leads to a reduction in the time to ESRD or death in patients with type 2 diabetes with DKD when compared with usual care plus placebo. The study aims to enrol 2510 patients over a 4-year period with an additional up to 5-year follow-up to generate a total of 646 primary events. The primary objective of this study is to compare the time until ESRD or death (all-cause mortality) between participants randomised to PTX or placebo. Secondary endpoints will be: (1) health-related quality of life, (2) time to doubling of serum creatinine, (3) incidence of hospitalisations for congestive heart failure, (4) incidence of a three-point major adverse cardiovascular events composite (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), (5) incidence of peripheral vascular disease, (6) change in urinary albumin-to-creatinine ratio from baseline to 6 months and (7) rate of annual change in estimated glomerular filtration rate (eGFR) during the study period. ETHICS AND DISSEMINATION: This study was approved by the VA Central Institutional Review Board (cIRB/18-36) and will be conducted in compliance with the Declaration of Helsinki and the Guidelines for Good Clinical Practice. The Hines Cooperative Studies Programme will finalise the study results, which will be published in accordance with the Consolidated Standards of Reporting Trials statement in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: NCT03625648.

Eye Outcomes in Veteran Affairs Diabetes Trial (VADT) After 17 Years.

OBJECTIVE: The objective of this study was to assess the long-term role of intensive glycemic control (INT) compared with standard glycemic control in accumulated eye procedures in patients with advanced diabetes. RESEARCH DESIGN AND METHODS: We compared the effect of treatment assignment on the accumulated number of eye procedures during the intervention period of the Veteran Affairs Diabetes Trial (VADT) (2000-2008) (median follow-up 5.6 years), the interim VADT follow-up study (2000-2013), and the full 17 years of VADT follow-up (2000-2017). We further analyzed data using various cardiovascular markers in two models. Model I included total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, systolic and diastolic blood pressure, and BMI. Model II included these covariates plus age and diabetic retinopathy (DR) severity score at baseline of the original trial. RESULTS: The final analysis of the data showed a mild but nonsignificant increase in number of procedures and in retinal or retinal plus cataract surgery during the three periods of the study. CONCLUSIONS: We found no significant benefit of INT during the original trial period in eye-related procedures, such as various procedures for DR, or during the 17 years of follow-up in cataract surgery. However, after adjusting data for some known vascular markers, the increase in the number of eye procedures with INT becomes more prevalent. This finding indicates that INT might not have a protective role in events requiring surgery in individuals with advanced diabetes.

Generalized confidence interval for an agreement between raters.

Estimation and inference are two key components toward the solution of any statistical problem; however, the inferential issues of statistical assessment of agreement among two or more raters have not been well developed as compared to the development of estimation procedures in this area. The fundamental reason for this gap is the complex expression of the concordance correlation coefficient (CCC) that is frequently used in assessing agreement among raters. Large sample-based statistical tests for CCC often fail to produce desired results for small samples. Hence, inferential procedures for small samples are urgently needed to evaluate agreement between raters. We argue that hypothesis testing of CCC has little value in practice due to the absence of a gold standard of agreement. In this article, we construct the generalized confidence interval (GCI) for CCC utilizing a bivariate normal distribution of measurements, and also develop a large sample-based confidence interval (LSCI). We establish satisfactory performance of GCI by providing the desired coverage probability (CP) via simulation. Results of GCI and LSCI are illustrated and compared with a data set of a recent study performed at U.S. Department of Veterans Affairs, Hines.

Rivastigmine Transdermal Patch Treatment for Moderate to Severe Cognitive Impairment in Veterans with Traumatic Brain Injury (RiVET Study): A Randomized Clinical Trial.

Cognitive impairment is common in veterans with histories of traumatic brain injury (TBI). Cholinergic deficits have been hypothesized as contributors to this impairment. We report the effects of cholinesterase inhibitor rivastigmine transdermal patch treatment in veterans with TBI and post-traumatic memory impairment. Our objective was to evaluate the efficacy and safety of a 9.5 mg/24 h (10 cm2) rivastigmine patch in veterans of military conflicts with persistent moderate to severe memory impairment at least 12 weeks after TBI. This randomized, outpatient, double-blind, placebo-controlled 12-week trial with an exploratory double-blind phase of an additional 14 weeks was conducted at 5 VA Medical Centers, among veterans with closed, non-penetrating TBI who met or exceeded modified American Congress of Rehabilitation Medicine criteria for mild TBI with verbal memory deficits, as assessed by the Hopkins Verbal Learning Test, Revised (HVLT-R). Patients were randomized 1:1 to rivastigmine or matching placebo patches after a 1-week single-blind, placebo run-in phase. At randomization, patients received 4.6 mg/24 h rivastigmine patches or matching placebo increased to a 9.5 mg/24 h patch after 4 weeks. The primary efficacy outcome measure was the proportion of participants who had at least a five-word improvement on the HVLT-R Total Recall Index (Trials 1-3). A total of 3671 participants were pre-screened, of whom 257 (7.0%) were screened; 96 (37%) randomized, and 94 included in study analyses. Responder rates were 40.8% (20 of 49) and 51.1% (23 of 45) in the rivastigmine and placebo groups, respectively (p = 0.41). A mixed-effect model including treatment, time, and treatment-by-time interaction indicated no significant difference in treatment effect over time between the groups (p = 0.24). Overall, there were no significant differences in changes for all secondary outcomes between the rivastigmine and placebo groups. The most commonly observed adverse events were application site reactions. This trial provides the largest sample to date of veterans with TBI and post-traumatic memory deficits enrolled in a pharmacological trial. Trial Registration: clinicaltrials.gov Identifier: NCT01670526.

Plaque Regression and Endothelial Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER).

BACKGROUND: Low-density lipoproteins (LDLs) are removed by extracorporeal filtration during LDL apheresis. It is mainly used in familial hyperlipidemia. The PREMIER trial (Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen) evaluated LDL apheresis in nonfamilial hyperlipidemia acute coronary syndrome patients treated with percutaneous coronary intervention. METHODS: We randomized 160 acute coronary syndrome patients at 4 Veterans Affairs centers within 72 hours of percutaneous coronary intervention to intensive lipid-lowering therapy (ILLT) comprising single LDL apheresis and statins versus standard medical therapy (SMT) with no LDL apheresis and statin therapy alone. Trial objectives constituted primary safety and primary efficacy end points and endothelial progenitor cell colony-forming unit mobilization in peripheral blood. RESULTS: Mean LDL reduction at discharge was 53% in ILLT and 17% in SMT groups (P<0.0001) from baseline levels of 116.3±34.3 and 110.7±32 mg/dL (P=0.2979), respectively. The incidence of the primary safety end point of major peri-percutaneous coronary intervention adverse events was similar in both groups (ILLT, 3; SMT, 0). The primary efficacy end point, percentage change in total plaque volume at 90 days by intravascular ultrasound, on average decreased by 4.81% in the ILLT group and increased by 2.31% in the SMT group (difference of means, -7.13 [95% CI, -14.59 to 0.34]; P=0.0611). The raw change in total plaque volume on average decreased more in the ILLT group than in the SMT group (-6.01 versus -0.95 mm3; difference of means, -5.06 [95% CI, -11.61 to 1.48]; P=0.1286). Similar results were obtained after adjusting for participating sites, age, preexisting coronary artery disease, diabetes mellitus, baseline LDL levels, and baseline plaque burden. There was robust endothelial progenitor cell colony-forming unit mobilization from baseline to 90 days in the ILLT group (P=0.0015) but not in SMT (P=0.0844). CONCLUSIONS: PREMIER is the first randomized clinical trial to demonstrate safety and a trend for early coronary plaque regression with LDL apheresis in nonfamilial hyperlipidemia acute coronary syndrome patients treated with percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01004406 and NCT02347098.

Intensive Glucose Control in Patients with Type 2 Diabetes - 15-Year Follow-up.

BACKGROUND: We previously reported that a median of 5.6 years of intensive as compared with standard glucose lowering in 1791 military veterans with type 2 diabetes resulted in a risk of major cardiovascular events that was significantly lower (by 17%) after a total of 10 years of combined intervention and observational follow-up. We now report the full 15-year follow-up. METHODS: We observationally followed enrolled participants (complete cohort) after the conclusion of the original clinical trial by using central databases to identify cardiovascular events, hospitalizations, and deaths. Participants were asked whether they would be willing to provide additional data by means of surveys and chart reviews (survey cohort). The prespecified primary outcome was a composite of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, and death from cardiovascular causes. Death from any cause was a prespecified secondary outcome. RESULTS: There were 1655 participants in the complete cohort and 1391 in the survey cohort. During the trial (which originally enrolled 1791 participants), the separation of the glycated hemoglobin curves between the intensive-therapy group (892 participants) and the standard-therapy group (899 participants) averaged 1.5 percentage points, and this difference declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a period of 15 years of follow-up (active treatment plus post-trial observation), the risks of major cardiovascular events or death were not lower in the intensive-therapy group than in the standard-therapy group (hazard ratio for primary outcome, 0.91; 95% confidence interval [CI], 0.78 to 1.06; P = 0.23; hazard ratio for death, 1.02; 95% CI, 0.88 to 1.18). The risk of major cardiovascular disease outcomes was reduced, however, during an extended interval of separation of the glycated hemoglobin curves (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but this benefit did not continue after equalization of the glycated hemoglobin levels (hazard ratio, 1.26; 95% CI, 0.90 to 1.75). CONCLUSIONS: Participants with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had a lower risk of cardiovascular events than those who received standard therapy only during the prolonged period in which the glycated hemoglobin curves were separated. There was no evidence of a legacy effect or a mortality benefit with intensive glucose control. (Funded by the VA Cooperative Studies Program; VADT ClinicalTrials.gov number, NCT00032487.).

Mental health in spouses of U.S. Gulf War veterans.

Veterans' spouses are at risk for mental distress and substance use. We examined long term psychological functioning in spouses from a national cohort of 1991 Gulf War era veterans. From clinical interviews, spouses of deployed veterans (n = 488) did not have a greater prevalence of post-war mental disorders compared to spouses of non-deployed veterans (n = 536); however, in couples that were living together since the war, there was an increased risk of anxiety disorders or any one disorder. On questionnaires, the impact varied but was most consistently observed in more severe depression and greater functional impairment in spouses of deployed compared to non-deployed veterans. If a veteran developed post-war anxious/depressive disorders or any one mental disorder, the matched spouse was more likely to develop post-war anxious/depressive disorders or any one mental disorder, respectively. Veteran combat exposure did not similarly increase the risk of spouse post-war mental disorders. Greater spouse self-reported symptomatology was observed in spouses of veterans with anxious/depressive disorders even when controlling for deployment. In summary, the war conferred greater risk for spouse mental disorders and distress for spouses of veterans with mental health disorders, with some increased risk for spouses of deployed veterans, especially in couples together since the war.

Comparing two randomized deep brain stimulation trials for Parkinson's disease.

OBJECTIVE: Several randomized studies have compared the effect of deep brain stimulation (DBS) of the subthalamic nucleus with the best medical treatment in large groups of patients. Important outcome measures differ between studies. Two such major studies, the life-quality study of the German Competence Network for Parkinson's disease (LQ study) and the US Veterans Affairs/National Institute of Neurological Disorders and Stroke trial (VA/NINDS trial), were compared here in order to understand their differences in outcomes. METHODS: Unless otherwise noted, analyses were based on those subjects in each study who received a DBS implant (LQ study 76 patients, VA/NINDS trial 140 patients) and who had data for the measurement under consideration (i.e., no imputations for missing data), referred to hereafter as the "as-treated completers" (LQ 69 patients, VA/NINDS 125 patients). Data were prepared and analyzed by biostatisticians at the US Department of Veterans Affairs Cooperative Studies Program Coordinating Center, the Coordinating Center for Clinical Trials Marburg, and Medtronic, under the direction of two authors (G.D. and K.A.F.). Data were extracted from the respective databases into SAS data sets and analyzed using SAS software. Analyses were based on the 6-month follow-up data from both studies because this was the endpoint for the LQ study. RESULTS: Pre-DBS baseline demographics differed significantly between the studies, including greater levodopa responsiveness (LDR) in the LQ study population than in the VA/NINDS group. After DBS, LQ subjects demonstrated greater improvement in motor function (Unified Parkinson's Disease Rating Scale, Motor Examination [UPDRS-III]), activities of daily living (ADLs), and complications of therapy. Medication reduction and improvements in life quality other than ADLs were not significantly different between LQ and VA/NINDS subjects. When the two populations were compared according to pre-DBS LDR, the "full responders" to levodopa (≥ 50% improvement on UPDRS-III with medication) in the two studies showed no significant difference in motor improvement with DBS (LQ 18.5 ± 12.0-point improvement on UPDRS-III vs VA/NINDS 17.7 ± 15.6-point improvement, p = 0.755). Among levodopa full responders, ADLs improved slightly more in the LQ group, but scores on other UPDRS subscales and the Parkinson's Disease Questionnaire-39 were not significantly different between the two studies. CONCLUSIONS: This comparison suggests that patient selection criteria, especially preoperative LDR, are the most important source of differences in motor outcomes and quality of life between the two studies.

The Effect of Breathing Retraining Using Metronome-Based Acoustic Feedback on Exercise Endurance in COPD: A Randomized Trial.

BACKGROUND: During exercise-training patients with chronic obstructive pulmonary disease (COPD) can entrain their breathing pattern to visual-feedback cues as to achieve a slower respiratory rate and prolong exhalation. The result is an improvement in exercise tolerance and a reduction in dynamic hyperinflation. Acoustic stimuli, including metronome-generated acoustic stimuli, can entrain human movements. Accordingly, we hypothesized that exercise duration and dynamic hyperinflation would be less after exercise-training plus breathing-retraining using a metronome-based acoustic-feedback system than after exercise-training alone. METHODS: Of 205 patients with COPD [FEV1 = 44 ± 16% predicted (± SD)] recruited, 119 were randomly assigned to exercise-training plus breathing-retraining using acoustic feedback (n = 58) or exercise-training alone (n = 61). Patients exercised on a treadmill thrice-weekly for 12 weeks. Before and at completion of training, patients underwent constant-load treadmill testing with inspiratory capacity measures every 2 min. RESULTS: At completion of training, improvements in exercise duration in the breathing-retraining plus exercise-training and exercise-training alone groups were similar (p = 0.35). At isotime, inspiratory capacity increased (less exercise-induced dynamic hyperinflation) by 3% (p = 0.001) in the breathing-retraining plus exercise-training group and remained unchanged in the exercise-alone group. The between-group change in inspiratory capacity, however, was not significant (p = 0.08). CONCLUSIONS: In patients with COPD, breathing-retraining using a metronome-based acoustic feedback did not result in improved exercise endurance or decreased dynamic hyperinflation when compared to exercise-training alone. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT NCT01009099; URL: http://www.clinicaltrials.gov.

Effects of Severe Hypoglycemia on Cardiovascular Outcomes and Death in the Veterans Affairs Diabetes Trial.

OBJECTIVE: To determine the risk factors for severe hypoglycemia and the association between severe hypoglycemia and serious cardiovascular adverse events and cardiovascular and all-cause mortality in the Veterans Affairs Diabetes Trial (VADT). RESEARCH DESIGN AND METHODS: This post hoc analysis of data from the VADT included 1,791 military veterans (age 60.5 ± 9.0 years) with suboptimally controlled type 2 diabetes (HbA1c 9.4 ± 2.0%) of 11.5 ± 7.5 years disease duration with or without known cardiovascular disease and additional cardiovascular risk factors. Participants were randomized to intensive (HbA1c <7.0%) versus standard (HbA1c <8.5%) glucose control. RESULTS: The rate of severe hypoglycemia in the intensive treatment group was 10.3 per 100 patient-years compared with 3.7 per 100 patient-years in the standard treatment group (P < 0.001). In multivariable analysis, insulin use at baseline (P = 0.02), proteinuria (P = 0.009), and autonomic neuropathy (P = 0.01) were independent risk factors for severe hypoglycemia, and higher BMI was protective (P = 0.017). Severe hypoglycemia within the past 3 months was associated with an increased risk of serious cardiovascular events (P = 0.032), cardiovascular mortality (P = 0.012), and total mortality (P = 0.024). However, there was a relatively greater increased risk for total mortality in the standard group compared with the intensive group (P = 0.019). The association between severe hypoglycemia and cardiovascular events increased significantly as overall cardiovascular risk increased (P = 0.012). CONCLUSIONS: Severe hypoglycemic episodes within the previous 3 months were associated with increased risk for major cardiovascular events and cardiovascular and all-cause mortality regardless of glycemic treatment group assignment. Standard therapy further increased the risk for all-cause mortality after severe hypoglycemia.

Birth Defects Among 788 Children Born to Gulf War Veterans Based on Physical Examination.

OBJECTIVE: The aim of the study was to examine the prevalence of birth defects among children born to Gulf War veterans. METHODS: Seven hundred eighty-eight singleton children born after the war to 522 veterans (262 Gulf War-deployed, DV; 260 non-deployed, NDV) underwent physical examinations focusing on major and minor birth defects and other findings. RESULTS: We found no differences between children of DV and NDV in the prevalence of major birth defects or other findings. However, children of DV women were more likely to have minor birth defects compared with children of NDV women (DV 22% NDV 4.8%, odds ratio: 5.47, confidence interval: 2.06, 14.55), mainly due to increased incidence of minor eye and musculoskeletal birth defects. CONCLUSIONS: Our data show that deployment of women to the Persian Gulf arena was associated with increased risk of minor birth defects in their offspring.

Medical Correlates of Chronic Multisymptom Illness in Gulf War Veterans.

BACKGROUND: Chronic multisymptom illness (CMI) is more prevalent among deployed than nondeployed veterans from the first Gulf War. Objective physiologic markers of CMI are lacking. The purpose of this study is to determine whether measurable abnormalities in the autonomic nervous system or hypothalamic-pituitary adrenal axis would distinguish CMI cases (CMI+) from controls (CMI-) among deployed veterans of the 1990-1991 Gulf War. METHODS: This is a cross-sectional case-control cohort study that examined deployed veterans who participated in the Phase III study: National Health Survey of Gulf War Veterans and Their Families. Autonomic nervous system and hypothalamic-pituitary adrenal axis function-related measures included: 24-hour heart-rate variability, urinary catecholamines and cortisol, hypertension, insulin sensitivity, dyslipidemia, body fat, bone mineral density, and ultrasensitive C-reactive protein. RESULTS: Veterans of the first Gulf War with CMI (n = 73) and without the condition (n = 111) were studied. Sociodemographic characteristics were similar. Veterans with CMI reported poorer mental and physical functioning, greater use of prescription medications, and more nonroutine clinic visits. These veterans were also more likely to have fibromyalgia syndrome, irritable bowel syndrome, metabolic syndrome, and among males, a larger waist-to-hip ratio. Lower values for a nonlinear heart-rate-variability parameter-the short-term fractal scaling exponent (DFA1), reflecting an increased randomness of beat-to-beat changes in heart rate-were observed in veterans with CMI than those veterans without it (1.28±0.16vs 1.35±0.15; p=0.005). Hypothalamic-pituitary-adrenal axis function measures were similar between the two groups. CONCLUSION: In this cohort of deployed veterans from the first Gulf War, we identified abnormal heart-rate variability in veterans with CMI compared to veterans without the condition, which suggests abnormal functioning of the autonomic nervous system and possible long-term cardiovascular effects.