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Background and Purpose— Interventional Management of Stroke (IMS) III is a randomized, parallel arm trial comparing the approach of intravenous tissue-type plasminogen activator followed by endovascular treatment with intravenous tissue-type plasminogen activator alone in patients with acute ischemic stroke presenting Methods— Conditional power was defined as the likelihood of finding statistical significance at the end of the study, given the accumulated data to date and with the assumption that a minimum hypothesized difference of 10% truly exists between the 2 groups. The evolution of study data leading to futility determination is described, including the interaction between the unblinded study statisticians and the Data and Safety Monitoring Board in the complex deliberation of analysis results. Results— The futility boundary was crossed at the trial’s fourth interim analysis. At this point, based on the conditional power criteria, the Data and Safety Monitoring Board recommended termination of the trial. Conclusions— Even in spite of prespecified interim analysis boundaries, interim looks at data pose challenges in interpretation and decision making, underscoring the importance of objective stopping criteria. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00359424.

Mixed-effects regression models have extraordinary capacity to capture the essence of complex longitudinal data. In this paper we present analyses from a longitudinal study on 157 patients with osteoarthritis (OA) where real-time momentary self-reported pain and physical activity level were collected. We illustrate the application of heterogeneous mixed effect (HME) models to examine the effect of time-varying activity level assessments (sedentary vs. moderate/vigorous) during the 30 min prior to the pain recording on mean pain levels and variability. We also examine the variation in pain associated with activity level and the degree that participant characteristics (weight-bearing vs. non-weight bearing joint w/OA, body mass index, white vs. non-white race, gender) and psychosocial factors (mood, tension, pain catastrophizing) influence pain variation. We fit separate HME models for each characteristic or factor. These HME models are fit with standard statistical software, but there are challenges to fitting and interpreting these models. Once fit the models provide a powerful tool to help guide researchers in understanding highly individualized pain trajectories.

Missing data, e.g. patient attrition, are endemic in sleep disorder clinical trials. Common approaches for dealing with this situation include complete-case analysis (CCA) and last observation carried forward (LOCF). Although these methods are simple to implement, they are deeply flawed in that they may introduce bias and underestimate uncertainty, leading to erroneous conclusions. There are alternative principled approaches, however, that are available in statistical software namely mixed-effects models and multiple imputation. In this paper we introduce terminology used to describe different assumptions about missing data. We emphasize that understanding reasons for missingness is a critical step in the analysis process. We describe and implement both linear mixed-effects models and an inclusive multiple imputation strategy for handling missing data in a randomized trial examining sleep outcomes. These principled strategies are compared with "complete-case analysis" and LOCF. These analyses illustrate that methodologies for accommodating missing data can produce different results in both direction and strength of treatment effects. Our goal is for this paper to serve as a guide to sleep disorder clinical trial researchers on how to utilize principled methods for incomplete data in their trial analyses.

Background and Purpose: Ischemic stroke lesion volumes have proven difficult to analyze due to the extremely skewed shape of their underlying distribution. We introduce an extension of generalized linear models, beta regression, as a possible method of modeling extremely skewed distributions as evidenced in ischemic stroke lesion volumes. Methods: The NINDS rt-PA clinical trials measured ischemic stroke lesion volume as a secondary trial outcome. Three-month lesion volumes from these trials were analyzed using beta regression. A multi-variable regression model associating explanatory variables with ischemic stroke lesion volumes was constructed using accepted model building strategies and compared with the previously published volumetric analysis. Results: Beta regression produced a similar model when compared to the previous analysis published by the study group. All previously identified variables of importance were detected in the model building process. The age by treatment interaction described in previous studies was also found in this analysis, confirming the strong effect age has on stroke outcomes. Further, a treatment effect was elicited in terms of odds ratios, yielding a previously unknown quantification of the effect of rt-PA on lesion volumes. Conclusions: Beta regression proved adept in modeling ischemic stroke lesions and offered the interpretation of covariates in terms of odds ratios. Beta regression is seen as a legitimate alternative to analyze ischemic stroke volumes.

"Loss to follow-up" can be substantial in substance abuse clinical trials. When extensive losses to follow-up occur, one must cautiously analyze and interpret the findings of a research study. Aims of this project were to introduce the types of missing data mechanisms and describe several methods for analyzing data with loss to follow-up. Furthermore, a simulation study compared Type I error and power of several methods when missing data amount and mechanism varies. Methods compared were the following: Last observation carried forward (LOCF), multiple imputation (MI), modified stratified summary statistics (SSS), and mixed effects models. Results demonstrated nominal Type I error for all methods; power was high for all methods except LOCF. Mixed effect model, modified SSS, and MI are generally recommended for use; however, many methods require that the data are missing at random or missing completely at random (i.e., "ignorable"). If the missing data are presumed to be nonignorable, a sensitivity analysis is recommended.

PURPOSE Recent evidence supports a signifi cant association between the intake of dietary fi ber and levels of infl ammatory markers. The objective of this study was to determine whether daily fi ber supplementation would reduce levels of infl ammatory markers. METHODS This study was a prospective randomized controlled trial at a single university medical center. Participants were overweight or obese adults with no history of heart disease. The intervention was psyllium supplementation at either 7 or 14 g/d for 3 months compared with no supplements in a control group. The main outcome measure was change in level of high-sensitivity C-reactive protein (hsCRP) concentration; secondary outcomes included changes in interleukin-6 (IL- 6) levels, fi brinogen levels, and white blood cell (WBC) count. Protocol completers attended at least 2 visits and took more than 75% of the prescribed fi ber dose. RESULTS In this intent-to-treat analysis (n = 158), there were no signifi cant dif- ferences between either of the 2 treatment groups and the control group in the amount of change in CRP, fi brinogen, or IL-6 levels or in WBC count (P >.05). In the analysis of protocol completers (n = 132), there also were no signifi cant dif- ferences between the groups except for a small decrease in fi brinogen level in the high-fi ber group (-6 mg/dL (-0.18 μmol/L) compared with 13 mg/dL (0.38 μmol/L) in the control group, P

We analyzed cardiovascular disease mortality risks associated with obesity using participant-level meta-analysis of data from the Black Pooling Project for Black and White individuals. The adjusted relative risks (ARRs) were stronger among White participants than among Black participants for coronary heart disease AAR=1.21 (95% confidence interval [CI]=1.07, 1.36) versus 0.87 (95% CI=0.69, 1.09), respectively, and cardiovascular disease ARR=1.18 (95% CI=1.07, 1.29) versus 0.91 (95% CI=0.77, 1.05), repectively. The results suggest that obesity is an independent risk factor in White people, and additional study of body size and disease progression is necessary in the assessment of racial disparities.

Our study sought to 1) determine if deployment status is associated with chronic widespread pain (CWP), and 2) evaluate whether veterans with CWP have greater psychiatric comorbidity, higher health care utilization, and poorer health status than veterans without CWP. Five years after the conclu- sion of the first Gulf War (August 1990 to June 1991), we conducted a cross-sectional study of veterans who listed Iowa as the home of record using a stratified sampling design to determine their health status. We compared the prevalence of CWP between deployed and nondeployed veterans. Logistic and multiple linear regression models were constructed to test whether CWP was associated with comorbidities and health-related outcomes of interest. Five hundred ninety of 3695 veterans interviewed (16%) had CWP. Gulf deployment was associated with higher prevalence of CWP than deployment elsewhere (OR 2.03, 95%CI 1.60-2.58), after adjustment. Both deployed and nondeployed veterans with CWP reported more health care utilization and comorbidities and lower health-related quality of life scores than veterans without CWP. Deployed veterans were more likely to have CWP than nondeployed veterans, and CWP was associated with poor health outcomes. Military and medical personnel should be aware that efforts to prevent, identify, and treat CWP in veterans returning from the current war may be needed. Perspective: This article indicates that deployed veterans may have an increased risk for develop- ment of CWP, which is associated with greater healthcare utilization and comorbidity and lower quality of life. The risk of poor health outcomes suggests that veterans returning from the present conflict should be screened for CWP on their return. © 2007 by the American Pain Society

Background. Nephrogenic systemic fibrosis is a debilitating disease occurring exclusively in patients with renal failure. The aetiology of nephrogenic systemic fibrosis is unclear, but recent reports suggest that exposure to gadolinium for enhancement of magnetic resonance imaging may play a role. In the present study, we assessed the association of exposure to gadolinium with the development of nephrogenic systemic fibrosis in patients with various stages of chronic kidney disease. Methods. We analysed the exposure to gadolinium and development of nephrogenic systemic fibrosis in 849 patients on renal replacement therapy over 5 years. We also performed inquiry of development of the nephrogenic systemic fibrosis in 592 patients exposed to gadolinium and estimated to be in stages 3 and 4 of chronic kidney disease. Results. In 849 patients undergoing chronic dialysis from 2001 through 2006 time period, four of the 261 who had received gadolinium (1.5%) and none of the 588 not exposed to gadolinium developed clinically apparent disease. The odds ratio for developing nephrogenic systemic fibrosis was 6.671 [95% confidence interval (CI) 1.537–53.97] in patients with a single gadolinium exposure compared to patients without gadolinium exposure. This ratio increased to 44.5 (95% CI 2.362–2913) in patients with multiple gadolinium exposures compared to patients not receiving gadolinium. None of the 592 patients estimated to be in stage 3 or 4 of chronic kidney disease developed nephrogenic systemic fibrosis after exposure to gadolinium. Conclusion. Gadolinium exposure is associated with nephrogenic systemic fibrosis in patients on chronic renal replacement therapy at a low rate. This association appears to increase with repeated exposure to gadolinium. Since nephrogenic systemic fibrosis may be clinically occult, its prevalence may be higher than reported. Despite this association, it is unclear if gadolinium is the sole or most important factor in the pathogenesis of the disease.

Purpose: To examine the patterns of coexisting (comorbid) mental disorders and whether comorbidity influences quality of life ratings in a sample of U.S. veterans. Patients and Methods: The Iowa Gulf War Study Case Validation study evaluated 602 military personnel, two-thirds of whom had symptoms of depression, cognitive dysfunction, or chronic widespread pain, who were activated or on active duty sometime during the first Gulf War (GW). Mental health disorders were defined using the SCID-IV, and the Health Utilities Index Mark 3 (HUI3) was used to measure health-related quality of life (HRQoL). Comorbidity was defined as having two or more mental disorders that spanned across at least two separate categories (e.g., depressive disorders and anxiety disorders). Results: Over 35% of veterans with a current mental disorder had at least one other comorbid mental disorder. Those with mental disorder comorbidity had lower HUI scores than veterans with only one or less mental disorders (mean 0.41 ± 0.30 vs. 0.72 ± 0.25, p < 0.0001). Conclusion: The co-occurrence of mental disorders that span at least two mental disorder categories is associated with impaired HRQoL in this veteran population. Early identification of mental health comorbidity may lead to interventions to enhance HRQoL among military personnel.

Background and Purpose— Most large, randomized phase III efficacy trials of therapeutic agents in ischemic stroke have failed to find treatment benefit. We determined whether some phase III studies could have been avoided if preceded by smaller single-arm phase II studies to evaluate the futility of proceeding to phase III. Methods— To provide examples of the application of phase II methodology, we obtained primary outcome data for the active treatment group of 6 phase III ischemic stroke therapy trials. For each study, we estimated the sample size number required for a multistage single-arm study using parameters specified in the original study. We evaluated outcome data for the first number of subjects in the phase III study treatment arm ordered by enrollment dates. We compared the proportion of favorable outcomes to prespecified stopping criteria derived from a single-arm phase II futility design. If the observed proportion of favorable outcomes was less than the stopping criterion, we declared the treatment not sufficiently effective to warrant further evaluation in phase III. Results— We identified 3 trials as futile in phase II; none of 3 showed treatment efficacy in phase III. In the 3 remaining phase II trials in which we did not show futility, one showed efficacy in phase III. Conclusion— Single-arm phase II futility studies have been underused in stroke research, but provide a strategy for discarding treatments likely to be ineffective in phase III trials.

Preclinical models of cocaine dependence have shown favorable reductions in cocaine use using dihydropyridine calcium channel antagonists. This is one of the first reports testing the efficacy of the long-acting calcium channel antagonist, amlodipine, for the treatment of cocaine dependence. This was a 12-week, double-blind, randomized, placebo-controlled, parallel patient group trial of amlodipine vs. placebo for the treatment of cocaine dependence. One hundred and sixteen subjects participated in a 12-week medication trial in which 60 subjects received medication and 56 received placebo. Subjects in both groups received up to 12 standard manual-driven cognitive behavioral therapy sessions. Overall, drop-out rate for both groups was high, with only about 20% of subjects completing all 12 weeks of treatment. Both groups showed comparable levels of medication compliance and therapy attendance. In the end, amlodipine was no more effective than placebo in reducing craving or measured levels of cocaine use.

To delineate the frequency, course, risk factors, and neuroanatomy of hemispatial neglect in a large stroke cohort.One thousand two hundred eighty-one patients with acute stroke were enrolled in a multicenter trial of an anticoagulant. Presence and severity of neglect were assessed with the NIH Stroke Scale (NIHSS) neglect item, assessing tactile extinction and visuospatial neglect at entry, daily for 1 week, and at 3 months. Head CT scans were obtained on day 7, and infarct location and size were characterized.Neglect was common at presentation, occurring in 43% of right brain-lesioned (RBL) patients and 20% of left brain-lesioned (LBL) patients (p0.001). At 3 months, neglect was present in 17% of RBL patients and in 5% of LBL patients (p0.001). In RBL patients, neglect was most frequently associated with lesions involving the (in descending order) temporal, parietal, frontal, occipital lobes, basal ganglia, and thalamus. Neglect was more common and persistent with cortical than with subcortical lesions. Increasing age was associated with increased risk of neglect in RBL patients, whereas gender and handedness did not significantly affect neglect frequency.This series confirms that hemispatial neglect may occur with damage to several supratentorial structures but is most common and persistent with lesions of the right temporoparietal cortex. Increasing age is associated with neglect, particularly after right brain lesions. Gender and handedness do not exert a marked effect on the likelihood of the occurrence of neglect.

Depression is a common mental disorder associated with poor health outcomes. The purpose of this study is to examine the prevalence of depression, mental health comorbidity, illness variables, and quality of life in a sample of military veterans serving during the first Gulf War. The Iowa Gulf War Case Validation Study involved face-to-face evaluations in 1999--2002 of 602 military personnel--either deployed ("deployed veterans") or eligible but not deployed ("non-deployed veterans") to the Gulf. Subjects were sampled by conducting a series of case-control studies nested within a population-based survey of 4,886 military personnel. All subjects were interviewed using the Structured Clinical Interview for DSM-IV (SCID-IV), and a series of semi-structured interviews and validated questionnaires. Best estimate psychiatric diagnoses were assigned based on all available data. One-hundred-ninety-two (32%) of the 602 surveyed veterans met criteria for a current or lifetime depressive disorder (major depression, dysthymia, depressive disorder--not otherwise specified). Depressed non-deployed veterans were more likely to be female and to have served in the Air Force than depressed deployed veterans. There were few significant differences between the depressed deployed veterans and the depressed non-deployed veterans. Depressed deployed veterans had significantly higher lifetime rates of comorbid cognitive dysfunction (55% vs. 35%), and anxiety disorders (59% vs. 33%)--mainly accounted for by specific phobias (12% vs. 2%) and posttraumatic stress disorder (33% vs. 10%)--than did depressed non-deployed veterans. Lifetime substance use disorders were significantly more frequent in deployed veterans than non-deployed veterans (70% vs. 52%), particularly alcohol disorders (68% vs. 52%). There were no differences in rates of personality characteristics, family psychiatric history, stressors, hypochondriasis, and level of functioning between the two study groups showed no significant differences. Depressive illness is frequent in military samples, as it is in the general population. The prevalence, pattern of comorbidity, and illness features were similar in deployed veterans and non-deployed veterans, suggesting that the depression suffered by both groups of veterans is qualitatively comparable. The main difference between study, groups was that depressed deployed veterans had higher rates than depressed non-deployed veterans of comorbid anxiety disorders, hypothesized to be part of the stress-related syndromes seen in those who experience combat.

To identify consistent provision of clinical preventive services, we sought to benchmark all acute care Veterans Affairs Medical Centers (VAMCs) against each other nationally on the basis of multiple evidence-based, performance measures to identify facilities performing consistently higher and lower than expected.The 1998 Veterans Health Survey assessed the self-reported delivery of evidence-based clinical preventive services in a stratified national sample of 450 ambulatory care patients seen at each VAMC. Proportions appropriately receiving each service within the recommended time interval were calculated for 138 VAMCs. Percentile ranks for each outcome were assigned. Two approaches were used for benchmarking performance. First, a scaled score for each facility was calculated across the set of 12 measures. Second, facilities were ranked based on the sum of the percentile ranks over a range of specific high cutoffs (eg, 70-80%) and above a range of lower cutoffs (eg, 40-50%). Ranking was validated by comparing with deciles of ranks on chart audit (External Peer Review Program, EPRP) data using Kendall's tau-b and chi2 quality-of-fit test. Differences between consistently high adherence (CHA) and low adherence (CLA) facilities were compared using the Wilcoxon rank sum test on 14 VHS and 11 EPRP outcomes.Data from 39,939 patients (67% response rate) were examined. In combination, cutoffs of greater than 50th percentile and greater than 75th percentile rank yielded 12 of 14 VHS and 6 of 11 EPRP measures different between CHA and CLA facilities. The scaled-score approach resulted in 20 CHA and 14 CLA facilities. The sum of outcomes ranked above 50th percentile and over 75th percentile for CHA facilities (n = 17) was 15 or more. The sum of outcomes ranked above the same cutoffs for CLA facilities (n = 16) was 3 or less. EPRP and 1998 VHS data demonstrated that the survey measures and benchmarking approaches were both reliable and valid. Both approaches resulted in multiple differences between CHA and CLA facilities; differences were greater using the percentile rank approach.The VA has successfully encouraged adoption of evidence-based clinical preventive services throughout its health care system. However, facilities show wide variation in their levels of delivery and can be distinguished on the basis of their consistently high or low levels of adherence. Examining service delivery across multiple performance indicators allows identification of opportunities to improve clinical practice guideline implementation and the delivery of preventive services. This approach identifies model institutions where focused investigation of factors associated with consistent performance may be particularly fruitful.

The objective of this study was to investigate the relation between posttraumatic stress disorder (PTSD) and perceived physical health. Participants included 3,682 Gulf War veterans and control subjects of the same era who completed a telephone survey about their health status. PTSD was assessed using the PTSD Checklist-Military Version. Veterans screening positive for PTSD reported significantly more physical health symptoms and medical conditions than did veterans without PTSD. They were also more likely to rate their health status as fair or poor and to report lower levels of health-related quality of life. The results of this study are consistent with studies of other combat veterans and provide further support for an association between PTSD and adverse physical health outcomes. Stressful or traumatic life events, such as those encountered during a rapid military deployment and conflict, are associated with a variety of adverse health effects. These health effects may manifest themselves in both psychological and physical outcomes. Health care providers must be attentive to recognize and evaluate both of these dimensions.

Background and Purpose — Although the efficacy of aspirin in reducing stroke incidence is clear, its role in reducing stroke severity is disputed. This study compares stroke severity between patients who did or did not take aspirin in the week before stroke and enrollment in the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Methods — Of 1275 patients randomized, 509 reported aspirin use in the week before stroke; 766 did not. Clinical stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS) and the Supplementary Motor Examination (SME) at trial entry and at 3 months. Using these scales, we compared the categorization of stroke severity (mild, moderate, and severe) and mean scores between aspirin users and nonusers. Results — The difference in distribution of baseline NIHSS scores was statistically significant between aspirin users and nonusers ( P =0.006), with a greater percentage of milder strokes among aspirin users. The difference in mean baseline NIHSS scores was also significantly lower in aspirin users (8.2) and nonusers (9.3) ( P =0.003). The distribution of baseline SME scores and mean SME scores also showed lower stroke severity in aspirin users than in nonusers ( P =0.048 and P =0.004, respectively). At 3 months, differences in stroke severity measured by the SME but not the NIHSS remained statistically significant. Seven-day and 3-month mortality did not differ significantly. Conclusions — In this study aspirin use is associated with milder clinical deficits at stroke onset. These deficits may affect prognosis and influence response to treatment. Future clinical trials should ensure that prestroke aspirin use is comparable in study groups.

Purpose To provide ophthalmologists and pathologists with expanded criteria for separating patients at high risk of metastatic melanoma from those at low risk on the basis of microcirculation patterns in choroidal and ciliary body melanomas. Design Tissue culture studies and observational case series. Participants The pattern-forming ability of four uveal melanoma cell lines of varying degrees of aggressive behavior was studied in vitro. Histologic sections of 234 eyes removed for choroidal or ciliary body melanoma were studied for the presence of microcirculation patterns. Methods The study was divided into two phases: the study of histologic sections of eyes removed for choroidal and ciliary body melanomas and observations on the in vitro behavior of cultured melanoma cells of varying degrees of invasive behavior. The presence or absence of each of nine microcirculation patterns was recorded from tissue sections, and interrelationships between different patterns were explored statistically. In vitro reconstitution of patterns and a study of the interrelationships of patterns in histologic sections was carried out. In the in vitro studies, uveal melanoma cell lines of varying degrees of aggressive potential were cultured to observe the development of architectural patterns other than loops and networks. Main outcome measures In histologic studies, the outcome measure was the conditional probability of detecting loops or networks given the presence or absence of other patterns positive for periodic acid–Schiff. For tissue culture studies, the outcome measure was either the development or lack of development of patterns of different shapes in vitro. Results Histologic studies disclosed that given the presence of arcs without or with branching in a tissue section, it is likely that loops or networks will be detected in the same section plane, suggesting that the production of these patterns by aggressive tumor cells reflects a spectrum of architectural potential. In vitro studies confirmed this hypothesis by revealing that highly aggressive and metastatic uveal melanoma cell lines, but not poorly aggressive tumor cell lines, generated parallel channels with and without crosslinking and arcs with and without branching as well as loops and networks. Conclusions The criteria for separating patients into low- and high-risk categories for metastasis from uveal melanoma should be expanded to include patterns other than loops or networks. In both the pathology laboratory as well as in a clinical setting, the detection of arcs or arcs with branching and parallel channels should prompt a careful search for loops and networks and for crosslinking parallel channels, respectively.

Objective:To describe hospital practices and policies relating to bloodborne pathogens and current rates of occupational exposure among healthcare workers.Participants and Methods:Hospitals in Iowa and Virginia were surveyed in 1996 and 1997 about Standard Precautions training programs and compliance. The primary outcome measures were rates of percutaneous injuries and mucocutaneous exposures.Results:153 (64%) of 240 hospitals responded. New employee training was offered no more than twice per year by nearly one third. Most (79%-80%) facilities monitored compliance of nurses, housekeepers, and laboratory technicians; physicians rarely were trained or monitored. Implementation of needlestick prevention devices was the most common action taken to decrease sharps injuries. Over one half of hospitals used needleless intravenous systems; larger hospitals used these significantly more often. Protected devices for phlebotomy or intravenous placement were purchased by only one third. Most (89% of large and 80% of small) hospitals met the recommended infection control personnel-to-bed ratio of 1:250. Eleven percent did not have access to postexposure care during all working hours. Percutaneous injury surveillance relied on incident reports (99% of facilities) and employee health records (61%). The annual reported percutaneous injury incidence rate from 106 hospitals was 5.3 injuries per 100 personnel. Compared to single tertiary-referral institution rates determined more than 5 years previously, current injury rates remain elevated in community hospitals.Conclusions:Healthcare institutions need to commit sufficient resources to Standard Precautions training and monitoring and to infection control programs to meet the needs of all workers, including physicians. Healthcare workers clearly remain at risk for injury. Further effective interventions are needed for employee training, improving adherence, and providing needlestick prevention devices.

Background and Purpose: Clinicians have tended to view anterior circulation (AC) and posterior circulation (PC) strokes as separate entities, with different underlying pathogenesis, natural histories, and potential responsiveness to interventions such as anticoagulation. We sought to explore differences between AC and PC stroke in the Trial of ORG 10172 in Acute Stroke Treatment (TOAST). Methods: For patients enrolled in TOAST, prospective clinical information was collected including outcome at 3 months. Data on vascular distribution were obtained from the clinical impression of the investigators. Group comparisons for categorical data were performed using Fisher’s exact test. Independent sample t tests and analysis of covariance were used for all continuous data. Results: The analysis included 1,039 patients with AC stroke and 180 patients with PC stroke. There were fewer women in the PC than in the AC groups, but otherwise there were no differences in demographics, risk factors or stroke subtypes between the two groups. Headache (AC 8.7%, PC 15%, p = 0.013) and vomiting (AC 3.5%, PC 17.8%, p < 0.001) were more common among PC patients. Mean baseline National Institutes of Health Stroke Scale (NIHSS) score was lower (less severe) among PC (6.1) than AC patients (9.5; p < 0.001). On univariate analysis, favorable outcome at 3 months was more common for PC patients in both the placebo group (PC 82%, AC 71%, p = 0.04) and heparinoid group (PC 87%, AC 73%, p = 0.005). However, multivariate analysis, controlling for gender, history of previous stroke and baseline NIHSS score, showed no difference in outcome between PC and AC stroke. For favorable outcome, there was no interaction between vascular distribution and treatment category, suggesting that the effect of heparinoid did not differ between PC and AC strokes. Conclusion: Patients with PC stroke seem to have a better long-term outcome than do AC patients, but this difference is no longer apparent when controlling for important prognostic variables. PC patients did not show any particular benefit from anticoagulation, and the efficacy of heparinoid did not vary between AC and PC stroke. While AC and PC patients do differ in some respects, it may be inappropriate to single out PC patients for anticoagulant treatment.

PURPOSE: Concerns have been raised about whether veterans of the Gulf War have a medical illness of uncertain etiology. We surveyed veterans to look for evidence of an illness that was unique to those deployed to the Persian Gulf and was not seen in comparable military controls. SUBJECTS AND METHODS: A population-based sample of veterans (n = 1,896 from 889 units) deployed to the Persian Gulf and other Gulf War–era controls (n = 1799 from 893 units) who did not serve in the Gulf were surveyed in 1995–1996. Seventy-six percent of eligible subjects, including 91% of located subjects, answered questions about commonly reported and potentially important symptoms. We used factor analysis, a statistical technique that can identify patterns of related responses, on a random subset of the deployed veterans to identify latent patterns of symptoms. The results from this derivation sample were compared with those obtained from a separate validation sample of deployed veterans, as well as the nondeployed controls, to determine whether the results were replicable and unique. RESULTS: One half (50%) of the deployed veterans and 14% of the nondeployed controls reported health problems that they attributed to military service during 1990–1991. Compared with the nondeployed controls, the deployed veterans had significantly greater prevalences of 123 of 137 (90%) symptoms; none was significantly lower. Factor analysis identified three replicable symptom factors (or patterns) in the deployed veterans (convergent correlations ≥0.85). However, these patterns were also highly replicable in the nondeployed controls (convergent correlations of 0.95 to 0.98). The three factors also accounted for similar proportions of the common variance among the deployed veterans (35%) and nondeployed controls (30%). CONCLUSIONS: The increased prevalence of nearly every symptom assessed from all bodily organ systems among the Gulf War veterans is difficult to explain pathophysiologically as a single condition. Identification of the same patterns of symptoms among the deployed veterans and nondeployed controls suggests that the health complaints of Gulf War veterans are similar to those of the general military population and are not consistent with the existence of a unique Gulf War syndrome.

On 12 June 1991, Mt Pinatubo in the Philippines erupted in what was the largest volcanic disaster of this century. Three hundred and fifty-one tribal and nontribal disaster victims were interviewed 6 years after they were displaced following the eruption. The acute and chronic effects of the eruption and the populations affected by Mt Pinatubo are described. The culturally and ecologically diverse population imposed logistical and methodological challenges that were expressed in ways not ordinarily encountered when conducting a community survey. Translating and administering survey instruments involved modifications of traditional methods to minimize item, method, construct and selection bias. Investigators conducting cross-cultural field studies in developing countries must strive to maintain high standards of scientific rigor, yet remain flexible, efficient and culturally sensitive.

This report presents the initial results of a mental health survey of 351 tribal and non-tribal Mount Pinatubo disaster victims 6 years after they were displaced following the volcanic eruption in the Philippines on June 12, 1991. Mental illness prevalence rates in both Filipino ethnic groups were comparable to those found in a U.S. study using the same assessment instrument. Post-traumatic stress disorder (PTSD; 27.6%) and major depression (14.0%) were the two most frequent diagnoses. Diagnostic test-retest interviewer agreement was good for probable alcohol abuse (kappa = .65, agreement = 97%) and any mood disorder (kappa = .53, agreement = 91%) but was reduced for any anxiety disorder (kappa = .15, agreement = 81%) and separately evaluated PTSD (kappa = .18, agreement = 69%). Diagnostic test-retest agreement was good among typical Filipinos (mean kappa = .66, mean agreement = 93%) but was reduced among tribal aborigines (mean = .30, mean agreement = 86%). Internal consistency of the PTSD rating scale was high within and across both ethnic groups, including total scale (alpha = .91) and DSM-IV Criteria B, C, and D sub-scales (alpha = .80, 81, and .78, respectively). With the exception of probable alcohol abuse, construct and criterion validity was demonstrated among both tribal and non-tribal Filipinos for all classes of psychiatric disorders by comparing diagnostic results with respondents' views of their physical and mental health and level of functional impairment. Overall, DSM-IV mood, anxiety, alcohol use, and PTSDs with adequate reliability and construct and criterion validity were made in this culturally diverse, non-Western, disaster victim population. However, test-retest diagnostic agreement was reduced for anxiety disorders and among aboriginal respondents, and validity was not demonstrated for probable alcohol abuse.

Background and Purpose —While previous studies suggest that the peak time period for the occurrence of ischemic stroke is in the mid- to late-morning hours, detailed information pertaining to circadian variations among the various stroke subtypes has been limited. The purpose of our study was to define the circadian patterns of symptom onset in an acute stroke trial with an established system for stroke subtype classification. Methods —An analysis was conducted on 1272 patients enrolled in the Trial of Org 10172 in Acute Stroke Treatment (TOAST) study. All patients had a documented time of stroke symptom onset, and all stroke subtype determinations were made by a single rater. Results —The greatest portion of atherothrombotic strokes (25.7%), cardioembolic strokes (30.5%), and strokes of other/unknown mechanism (27.1%) occurred between 6:01 am and 12:00 noon. The greatest portion of lacunar strokes (31.6%) were present on awakening. More than one half of the infarcts in this series were either present on awakening or occurred in the mid- to late-morning hours. The correlation between stroke subtype and time of symptom onset did not reach statistical significance ( P =0.07, Pearson’s χ 2 method). Conclusions —Although there is a trend for clustering of ischemic stroke in the morning hours, there is insufficient specificity to predict with any reasonable likelihood the stroke subtype according to the circadian pattern of symptom onset.

We previously demonstrated that whole blood contains significantly more hepatitis C virus (HCV) RNA than plasma. To validate the whole-blood-based HCV RNA detection method, a prospective comparison of HCV RNA detection in whole blood and plasma from 50 patients with chronic liver disease was undertaken. Whole-blood and plasma aliquots were independently tested for HCV RNA by reverse transcriptase (RT) PCR assay, and plasma was tested by the Roche Amplicor assay. HCV RNA was detected in 35 of 50 (70%) whole-blood samples by RT-PCR but in only 26 of 50 (52%) plasma samples tested by the Amplicor assay ( P < 0.01). HCV RNA was detected in 85% of HCV antibody-positive patients by the whole-blood method compared with 74% of plasma samples by the Amplicor method. The five HCV antibody-positive subjects who were negative by whole-blood-based RT-PCR assay were all receiving interferon therapy and had normal transaminases at the time of testing. HCV RNA was detected in 38% of HCV antibody-negative subjects by the whole-blood-based RT-PCR assay compared with 6.25% of these patients by the Amplicor assay ( P < 0.05). There were nine samples in which HCV RNA was detected in whole blood but the Amplicor test was negative. Eight of the nine RNAs prepared from these whole-blood samples tested positive in the Amplicor assay, thus confirming the specificity of our results. This study demonstrates that whole-blood-based HCV RNA detection is more sensitive than currently available commercial tests and that whole-blood RNA is suitable for use in commercial assays.

TOAST is a multicenter, randomized, placebo-controlled clinical trial testing the usefulness of a new antithrombotic drug in improving the outcome of persons with acute ischemic stroke. Until recently, no clinical trial testing a treatment for ischemic stroke had demonstrated efficacy in outcome. Design problems of previously conducted trials with inconclusive results may partly explain their failures. During the design of TOAST, the investigators addressed several issues so the trial could test the treatment accurately. We report the strategies used in designing, implementing, and coordinating the trial.

The microcirculation of choroidal and ciliary body melanomas is remodeled into architecturally distinctive patterns. The presence of two histologic microvascular patterns, networks and parallel vessels with cross-linking, is strongly associated with metastasis. This study was designed to test the hypothesis that networks and parallel vessels with cross-linking patterns are not distributed evenly throughout the tumor. From a set of 234 eyes removed for ciliary body or choroidal melanoma, 152 tumors contained at least one focus of either vascular networks or parallel vessels with crosslinking. Histological cross-sections were digitized and foci of tumor containing these patterns were pseudocolorized so that their location within the periphery or central tumor zone could be mapped. Ciliary body and choroidal melanomas vary widely in size and shape and it is not appropriate to describe the periphery of a tumor as a fixed value because in a small tumor, the periphery thus defined would occupy a larger percent area than in a larger tumor. In this study, the peripheral and central zones of each tumor were described by a function that was constant from tumor to tumor, allowing the width of the peripheral and central zones to vary proportionally with tumor size. Observed counts of vascular patterns per zone were compared statistically with expected counts based upon the percent area occupied by the peripheral and central zones. Discrete foci of networks and parallel with cross-linking vessels are over-represented in the tumor periphery (p < 0.0001).

A 1-year, double-blind, placebo-controlled, randomized, parallel-group study compared the efficacy and safety of acetyl-L-carnitine hydrochloride (ALCAR) with placebo in patients with probable Alzheimer's disease (AD). Subjects with mild to moderate probable AD, aged 50 or older, were treated with 3 g/day of ALCAR or placebo (1 g tid) for 12 months. Four hundred thirty-one patients entered the study, and 83% completed 1 year of treatment.The Alzheimer's Disease Assessment Scale cognitive component and the Clinical Dementia Rating Scale were the primary outcome measures.Overall, both ALCAR- and placebo-treated patients declined at the same rate on all primary and most secondary measures during the trial. In a subanalysis by age that compared early-onset patients (aged 65 years or younger at study entry) with late-onset patients (older than 66 at study entry), we found a trend for early-onset patients on ALCAR to decline more slowly than early-onset AD patients on placebo on both primary endpoints. In addition, early-onset patients tended to decline more rapidly than older patients in the placebo groups. Conversely, late-onset AD patients on ALCAR tended to progress more rapidly than similarly treated early-onset patients. The drug was very well tolerated during the trial.The study suggests that a subgroup of AD patients aged 65 or younger may benefit from treatment with ALCAR whereas older individuals might do more poorly.However, these preliminary findings are based on post hoc analyses. A prospective trial of ALCAR in younger patients is underway to test the hypothesis that young, rapidly progressing subjects will benefit from ALCAR treatment.NEUROLOGY 1996;47: 705-711

Purpose: To study the relation between vascular patterns and the biologically aggressive behavior of Ciliary body melanomas. Methods: The authors compared the frequency distribution of vascular patterns by location for 234 uveal melanomas (54 tumors involving the Ciliary body, and 180 without Ciliary body involvement). Stepwise Cox regressions (for the endpoint of timeto-death due to melanoma), performed separately for melanomas with and without Ciliary body involvement, included the following variables: size, vascular patterns, cell type, mean of the largest nucleoli, mitoses, tumor infiltrating lymphocytes, age, and sex. A separate Cox regression procedure included the variable of tumor location. Kaplan-Meier survival curves were generated for time to melanoma death with Ciliary body involvement and melanomas without Ciliary body involvement for tumors containing or lacking vascular networks. Results: These vascular patterns appear more often in the Ciliary body than in the choroid: parallel vessels ( P = 0.022), arcs ( P = 0.003), and parallel with cross-linking, arcs with branching, and loops and networks (all P = 0.0001). Stepwise regression for tumors confined to the choroid indicated that the presence of networks was the most significant variable ( P = 0.0001); stepwise regression for tumors with Ciliary body involvement suggested that only one variable, networks, was significant ( P = 0.0066). Kaplan-Meier survival estimates indicated that the survival of patients with tumors containing networks in the Ciliary body was comparable to those containing networks in the choroid. Conclusion: Regardless of location, Ciliary body or choroid, the presence of vascular networks shortens survival. The tumor location does not enter a stepwise Cox regression model when vascular patterns are included as variables. Therefore, the aggressive behavior of Ciliary body melanomas appears to be related to the tendency for vascular networks to develop in this location. Ophthalmology 1995;102:844-851

Purpose: This study was designed to (1) describe the vascular patterns of ciliary body and choroidal nevi by light microscopy, (2) compare the vascular ultrastructure of nevi with vessels of the normal uvea and uveal melanomas, and (3) compare the behavior of ciliochoroidal melanomas with and without a nevus-like vascular architecture. Methods: After delineating the vascular patterns of 23 choroidal and ciliary body nevi by light microscopy, the authors identified 49 melanomas that had the same vascular patterns as nevi from a previously published series of 234 uveal melanomas. The survival of these 49 patients who had melanomas with a nevus-like vascular architecture was compared with the 185 patients who had melanomas that lacked this vascular profile. Results: By light microscopy, the only vascular patterns identified in nevi are “normal” vessels, zones of avascularity (“silent” pattern), straight, and parallel vessels; closed vascular loops and networks were not detected in nevi. By transmission electron microscopy, the vascular basement membrane of malignant melanomas was multilaminar, fragmented, and significantly thicker than in normal eyes or nevi. None of the patients with nevi died of metastatic disease. Fourteen percent of patients whose melanomas had the same vascular profile as nevi died of metastatic disease, whereas 32% of patients whose melanomas had vascular patterns other than those seen in nevi died of metastatic melanoma ( P = 0.012). Conclusions: The microcirculation architecture marks tumor progression in uveal melanocytic lesions by light and electron microscopy. In the spectrum of these lesions, nevi are benign, melanomas that have the same vascular profile as nevi have an intermediate biologic behavior, and melanomas with vascular networks are strongly associated with death due to metastatic disease.

An ecological study of lung cancer, cigarette smoking, and radon exposure was conducted in 20 Iowa counties. County-based lung cancer incidence data for white female residents of Iowa were stratified according to radon level and smoking status. Cancer incidence data for the period 1973-1990 were obtained from the State Health Registry of Iowa. Smoking level was determined from a randomly mailed survey. Radon level was determined according to an EPA supported charcoal canister survey. Within low smoking counties, rates for all lung cancer and small cell carcinoma were significantly lower (p0.05) in the high radon counties relative to the medium and low radon counties. However, within high smoking counties, rates for all lung cancer, adenocarcinoma, and small cell carcinoma were significantly higher (p0.05) in the high radon counties relative to the low radon counties. Variations in socioeconomic data for these counties, available through the 1980 and 1990 census, did not explain these results. Lung cancer rates also were significantly increased in urban counties even after holding smoking status constant. Multivariate analyses revealed significant interactions between smoking, urbanization, radon levels, and lung cancer. The results of this hypothesis generating study will be tested in a case/control study now ongoing in Iowa. Analysis will need to include separate evaluations by smoking status, radon level, and residence in urban or rural areas for the major morphologic types of lung cancer.

Background: It is possible to identify at least nine vascular patterns in melanomas of the ciliary body and choroid from histologic sections. An association between the presence of at least one closed vascular loop and death from metastases was shown in a matched-pair, case-control study of 40 patients whose eyes were removed for ciliary body or choroidal melanomas. Methods: Two independent observers who were masked to the follow-up of patients examined histologic preparations of 234 eyes removed for ciliary body or choroidal melanomas for the presence of each of the tumor vascular patterns. Statistical analyses included tests for interobserver reliability, Kaplan-Meier survival curves, and the fitting of Cox regression models. Results: The detection of each of the nine vascular patterns is highly reproducible. The Cox model indicates that the presence of vascular networks, defined as at least three back-to-back closed vascular loops, is the feature most strongly associated with death from metastatic melanoma. Other significant factors in the Cox model include (in descending order of importance) largest tumor dimension, mitoses, the parallel with cross-linking vascular pattern, age, the presence of tumor-infiltrating lymphocytes, and male gender. Conclusions: The presence of vascular networks provides the most significant association with death from metastatic melanoma of all variables tested. The presence of this pattern should be recorded on pathology reports. If it becomes possible to detect this vascular pattern clinically using a noninvasive imaging technique, then ophthalmologists may be able to determine the likely biologic behavior of a melanoma before resorting to the removal of tissue.

The objective of this study was to test the hypothesis that diverse risk variables including infections during the index pregnancy independently increase the risk of preterm premature rupture of amniotic membranes (PROM) and preterm delivery without PROM. A case-control design was used to study women 15-45 years old who had preterm PROM, full-term PROM or preterm without PROM and were singly matched by age race and parity to controls who delivered full-term infants. The odds for preterm PROM was 6.0 times that of controls among women with intra-amniotic infection, 3.7 times among those with urinary tract and 7.6 times among women with gonorrhoea infections after controlling for the effects of exposure to cigarette smoke, having previous preterm and full-term PROM deliveries and antepartum bleeding that independently increased the odds. The odds for preterm births without PROM was 4.8 times that of controls among women with a previous preterm PROM birth, was significantly increased among those exposed to cigarette smoke or having antepartum bleeding, but not among those exposed to chlamydia infection. Even after adjusting for concomitant risk factors, women with preterm PROM births were more likely than their matched controls to have had infections.

Premature rupture of amniotic membranes (PROM) is associated with perinatal morbidity and mortality. A matched case-control study was undertaken to determine whether adequacy of prenatal care was associated with increased risk for PROM. Three study groups were defined, consisting of women delivering pre term with PROM, full term with PROM, and pre term without PROM. Cases were singly matched by race, age, and parity with women having full term deliveries without PROM. Data were collected by face-to-face structured interviews with eligible subjects and by medical records abstraction. Conditional multiple logistic regression indicated that among women with inadequate levels of prenatal care during pregnancy the risk for pre term PROM was 3.11 (CI = 1.10-8.78) and for pre term without PROM 2.18 (CI = 1.05-4.53) times higher than for their matched controls, even when adjusted for other sociodemographic, behavioral, index pregnancy, and medical history factors. We conclude that inadequate prenatal care may be a marker for less healthy behaviors, lifestyles, and environmental factors among women at increased risk for pre term delivery.

Geographic variation in hypertension is hypothesized as contributing to the stroke belt, an area in the southeastern United States with high stroke mortality. No study has examined hypertension by lifetime exposure to the stroke belt. This association was studied in 19,385 participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study, a national population-based cohort. Prevalent hypertension was defined as systolic blood pressure ≥140, diastolic blood pressure ≥90, or use of antihypertensive medications. Stroke belt exposure was assessed by residence at birth, currently, early childhood, adolescence, early adulthood, mid-adulthood, and recently. After adjustment for age, race, sex, physical activity level, body mass index, smoking, alcohol, education, and income, the prevalence of hypertension was significantly more strongly related (P < .0001) with lifetime exposure, adolescence, or early adulthood exposure than exposures at other times. Birthplace and current residence were independently associated with hypertension; however, lifetime, adolescence, or early adulthood exposures were more predictive than joint model with both birthplace and current residence. That adolescence and early adulthood periods are more predictive than residence in the stroke belt for most recent 20-year period suggests community and environmental strategies to prevent hypertension need to start earlier in life.

Nine morphologic patterns of tumor vessels were identified in eyes removed for ciliary body or choroidal melanoma by the examination of tissue sections stained with fluorescein-conjugated Ulex europaeus I using laser scanning confocal microscopy. This technique also highlights intravascular tumor invasion. Each of these nine morphologic patterns of tumor vessels also may be demonstrated by a modification of the periodic acid-Schiff reaction, viewed with a green narrow band pass filter, but this modified histochemical technique does not accurately identify intravascular tumor invasion. Most tumors have a heterogeneous distribution of vascular patterns. Melanomas in two groups of 20 tumors each were matched by tumor size and location (one group of tumors from patients who survived at least 15 years free of metastatic melanoma after enucleation and one group of tumors from patients who died of metastatic melanoma). A matched case-control analysis indicates that the presence of at least one closed vascular loop in a uveal melanoma is the most significant vascular pattern associated with death from metastatic melanoma after enucleation. Closed loops are associated with other histologic features that are predictive of an unfavorable outcome after enucleation: epithelioid cells and mitotic figures. In this preliminary study the formation of closed vascular loops is a marker of tumor progression in ciliary body and choroidal melanomas.

Premature rupture of amniotic sac membranes (PROM) is associated with perinatal morbidity and mortality. A matched case-control study was undertaken to determine whether dietary habits, prepregnancy weight, and weight gain during pregnancy were associated with increased risks for PROM.Three study groups were defined, consisting of women delivering pre term with PROM (PP), full term with PROM (FP), and pre term without PROM (PWP). Cases were singly matched by race, age, and parity with women having full term deliveries without PROM. Data were collected by face-to-face structured interviews with eligible subjects and by medical records abstraction.Conditional multiple logistic regression indicated that during pregnancy, PP cases were significantly more likely to have gained less than 21 pounds (9.5 kg) (OR = 2.7, CI = 1.14-6.36) and were only half as likely as controls to have improved their diet (OR = 0.43, CI = 0.18-0.99) while controlling for cigarette smoking, urinary tract infection, chorioamnionitis, chlamydia, and a history of previous PROM. FP cases were significantly less likely than controls to have gained 31-40 pounds (14-18 kg) while pregnant (OR = 0.56, CI = 0.33-0.94) and were significantly more likely than controls to have a somewhat inadequate pregnancy diet (OR = 2.05, CI = 1.11-3.77) while controlling for a history of previous PROM. PWP cases were significantly less likely to have gained 31-40 pounds (14-18 kg) (OR = 0.42, CI = 0.21-0.84) or greater than 40 pounds (18 kg) (OR = 0.37, CI = 0.17-0.80) while pregnant or to have had adequate dairy products intake (OR = 0.60, CI = 0.36-0.99) while controlling for cigarette usage.Maternal dietary habits, weight gain during pregnancy, and supplement intake are associated with the occurrence of both pre term and full term PROM and pre term delivery without PROM.

Parkinson's disease (PD) impairments are multidimensional, making it difficult to choose a single primary outcome when evaluating treatments to stop or lessen the long-term decline in PD. We review commonly used multivariate statistical methods for assessing a treatment's global impact, and we highlight the novel Global Statistical Test (GST) methodology. We compare the GST to other multivariate approaches using data from two PD trials. In one trial where the treatment showed consistent improvement on all primary and secondary outcomes, the GST was more powerful than other methods in demonstrating significant improvement. In the trial where treatment induced both improvement and deterioration in key outcomes, the GST failed to demonstrate statistical evidence even though other techniques showed significant improvement. Based on the statistical properties of the GST and its relevance to overall treatment benefit, the GST appears particularly well suited for a disease like PD where disability and impairment reflect dysfunction of diverse brain systems and where both disease and treatment side effects impact quality of life. In future long term trials, use of GST for primary statistical analysis would allow the assessment of clinically relevant outcomes rather than the artificial selection of a single primary outcome.

Membrane complement inhibitors (CD46, CD55 and CD59) are upregulated in some human cancers indicating that they play a role in immune evasion. We investigated complement inhibitor expression in bladder cancer and examined the hypothesis that selective pressure of an antibody response (anti-MUC1) results in the upregulated expression of complement inhibitors on tumor cells. Paired samples of tumor and normal tissue from 22 bladder cancer patients were analyzed for expression of MUC1, CD46, CD55 and CD59, and matched serum samples analyzed for anti-MUC1 IgM and IgG levels. Relationships between anti-MUC1 antibody levels and complement inhibitor expression were investigated. MUC1 mRNA was upregulated in 86% of tumor samples. CD46 was upregulated in 77%, CD55 in 55% and CD59 in 59% of tumors. Low titer anti-MUC1 IgM was detected in normal human sera, but was elevated in 41% of the bladder cancer patients. Anti-MUC1 IgG was virtually absent from normal sera, but present in 32% of the cancer patients. There was a direct relationship between anti-MUC1 antibody titer and expression level of complement inhibitors. Analysis of the correlation of each antibody with the expression of each complement inhibitor by Spearman's rank test revealed a strong correlation between both anti-MUC1 IgM and IgG levels and increased expression of CD46 and CD55, and combined anti-MUC1 IgM/IgG levels correlated with increased expression of all 3 complement inhibitors. In conclusion, the data demonstrate upregulated complement inhibitor expression and the presence of an anti-MUC1 antibody response in bladder cancer patients and support the hypothesis of antibody-mediated immune selection.

Background Missing data due to attrition are rampant in substance abuse clinical trials. However, missing data are often ignored in the presentation of substance abuse clinical trials. This paper demonstrates missing data methods which may be used for hypothesis testing. Methods Methods involving stratifying and weighting individuals based on missing data pattern are shown to produce tests that are robust to missing data mechanisms in terms of Type I error and power. In this article, we describe several methods of combining data that may be used for testing hypotheses of the treatment effect. Furthermore, illustrations of each test's Type I error and power under different missing data percentages and mechanisms are quantified using a Monte-Carlo simulation study. Results Type I error rates were similar for each method, while powers depended on missing data assumptions. Specifically, power was greatest for the weighted, compared to un-weighted methods, especially for greater missing data percentages. Conclusion Results of this study as well as extant literature demonstrate the need for standards of design and analysis specific to substance abuse clinical trials. Given the known substantial attrition rates and concern for the missing data mechanism in substance abuse clinical trials, investigators need to incorporate missing data methods a priori. That is, missing data methods should be specified at the outset of the study and not after the data have been collected.

Objectives. In previous studies, we have shown that obesity is associated with increased cardiovascular disease (CVD) mortality in white women but not in black women. Earlier research suggests that body mass index (BMI) has a greater effect on CVD mortality in younger white females than older white females, whereas this relationship in black women is not as clear. This study examines the effect of age on the association of BMI to CVD in black and white women. Methods. The Black Pooling Project includes data on 2,843 black women with 50,464 person-years of follow-up, and 12,739 white women with 214,606 person-years of follow-up. A Cox proportional hazards model was used to examine the association between BMI and CVD mortality for specific age/race groups. The younger group was 60 years of age. Results. In younger white women, the relative risk (95% confidence interval [CI]) for CVD mortality was significant in obese women (BMI >30 kg/m2) vs. women of normal weight (BMI 18.5–24.9 kg/m2) (1.59 [CI 1.20, 2.09]). Similarly, in older white women, the relative risk for CVD mortality in obese women vs. women of normal weight was significant (1.21 [CI 1.04, 1.41]). There were no such associations for black women. Overweight (BMI 25–29.9 kg/m2) was not associated with increased risk in black or white women. Conclusion. These findings indicate that obesity is associated with a significantly greater risk of CVD mortality among white women, with the strongest association among white women

Persons with persistent mental illness are at risk for failure to receive medical services. In order to deliver appropriate preventive and primary care for this population, it is important to determine which chronic medical conditions are most common.We examined chronic medical comorbidity in persons with schizophrenia using validated methodologies.Retrospective analysis of longitudinal administrative claims data from Wellmark Blue Cross/Blue Shield of Iowa.Subjects with schizophrenia or schizoaffective disorder (N=1,074), and controls (N=726,262) who filed at least 1 claim for medical services, 1996 to 2001.Case subjects had schizophrenia as the most clinically predominant psychotic disorder, based on psychiatric hospitalization, psychiatrist diagnoses, and outpatient care. Controls had no claims for any psychiatric comorbidity. Using a modified version of the Elixhauser Comorbidity Index, inpatient and outpatient claims were used to determine the prevalence of 46 common medical conditions. Odds ratios (ORs) were adjusted for age, gender, residence, and nonmental health care utilization using logistic regression.Subjects with schizophrenia were significantly more likely to have 1 or more chronic conditions compared with controls. Adjusted OR (95% confidence interval [CI]) were 2.62 (2.09 to 3.28) for hypothyroidism, 1.88 (1.51 to 2.32) for chronic obstructive pulmonary disease, 2.11 (1.36 to 3.28) for diabetes with complications, 7.54 (3.55 to 15.99) for hepatitis C, 4.21 (3.25 to 5.44) for fluid/electrolyte disorders, and 2.77 (2.23 to 3.44) for nicotine abuse/dependence.Schizophrenia is associated with substantial chronic medical burden. Familiarity with conditions affecting persons with schizophrenia may assist programs aimed at providing medical care for the mentally ill.

BackgroundA well designedrandomizedclinical trial rates as the highest level of evidence for a particular intervention's efficacy. Randomization, a fundamental feature of clinical trials design, is a process invoking the use of probability to assign treatment interventions to patients. In general, randomization techniques pursue the goal of providing objectivity to the assignment of treatments, while at the same time balancing for treatment assignment totals and covariate distributions. Numerous randomization techniques, each with varying properties of randomness and balance, are suggested in the statistical literature. This paper reviews common randomization techniques often used in substance abuse research and an application from a National Institute on Drug Abuse (NIDA)-funded clinical trial in substance abuse is used to illustrate several choices an investigator faces when designing a clinical trial.ResultsComparisons and contrasts of randomization schemes are provided with respect to deterministic and balancing properties. Specifically, Monte Carlo simulation is used to explore the balancing nature of randomization techniques for moderately sized clinical trials. Results demonstrate large treatment imbalance for complete randomization with less imbalance for the urn or adaptive scheme. The urn and adaptive randomization methods display smaller treatment imbalance as demonstrated by the low variability of treatment allocation imbalance. For all randomization schemes, covariate imbalance between treatment arms was small with little variation between adaptive schemes, stratified schemes and unstratified schemes given that sample sizes were moderate to large.ConclusionWe develop this paper with the goal of reminding substance abuse researchers of the broad array of randomization options available for clinical trial designs. There may be too quick a tendency for substance abuse researchers to implement the fashionable urn randomization schemes and other highly adaptive designs. In many instances, simple or blocked randomization with stratification on a major covariate or two will accomplish the same objectives as an urn or adaptive design, and it can do so with more simply implemented schedules and without the dangers of overmatching. Furthermore, the proper analysis, fully accounting for the stratified design, can be conducted.

Background Cardiac surgical procedures can be associated with significant morbidity and mortality. Recently, it has been recognized that statins might induce multiple biologic effects independent of lipid lowering that could potentially ameliorate adverse surgical outcomes. Accordingly, this study tested the central hypothesis that pretreatment with statins before cardiac surgery would reduce adverse postoperative surgical outcomes. Methods Demographic and outcomes data were collected retrospectively for 3829 patients admitted for planned cardiac surgery between February 1994 and December 2002. Statin pretreatment occurred in 1044 patients who were comparable with non–statin-pretreated (n = 2785) patients with regard to sex, race, and age. Primary outcomes examined included postoperative mortality (30-day) and a composite morbidity variable. Results The odds of experiencing 30-day mortality and morbidity were significantly less in the statin-pretreated group, with unadjusted odds ratios of 0.43 (95% confidence interval [CI], 0.28-0.66) and 0.72 (95% CI, 0.61-0.86), respectively. Risk-adjusted odds ratios for mortality and morbidity were 0.55 (95% CI, 0.32-0.93) and 0.76 (95% CI, 0.62-0.94), respectively, by using a logistic regression model and 0.51 (95% CI, 0.27-0.94) and 0.71 (95% CI, 0.55-0.92), respectively, in the propensity-matched model, demonstrating significant reductions in 30-day morbidity and mortality. In a subsample of patients undergoing valve-only surgery (n = 716), fewer valve-only patients treated with statins experienced mortality, although these results were not statistically significant (1.96% vs 7.5%). Conclusions These findings indicate that statin pretreatment before cardiac surgery confers a protective effect with respect to postoperative outcomes.

Elevated levels of C-reactive protein (CRP) have been associated with increased risk of cardiovascular disease among the general population (1–6). People with diabetes (7), hypertension (8), and obesity (9) have CRP levels that are higher than those in people without these conditions in the general population. Previous studies indicate an inverse association between dietary fiber intake and levels of inflammatory biomarkers (10,11). Acknowledging that individuals with certain conditions (e.g., diabetes) are at higher risk for elevated CRP, it is unclear whether intake of dietary fiber may have more impact on inflammatory markers among such people. To investigate the relationship between dietary fiber and inflammatory markers in people with diabetes, hypertension, and obesity, we conducted a study using the nationally representative 1999–2002 National Health and Nutrition Examination Survey (NHANES). We conducted an analysis of the 1999–2002 NHANES (http://www.cdc.gov/nchs/nhanes.htm). Our sample was limited to participants ≥20 years of age who had valid high-sensitivity CRP measurements and dietary information (unweighted n = 7,891). The study was approved by the institutional review board at the Medical University of South Carolina. Individuals were considered to have a previous diagnosis of diabetes or hypertension based on questions asking whether the individual had ever been told by a doctor that he or she had the condition. People with …

Background & Aims: Alpha1-antitrypsin deficiency (AAT) is an autosomal recessive disease that affects 1 in 2500 persons and might lead to cirrhosis. Our study aim was to characterize the liver disease in AAT and identify factors associated with advanced liver disease. Methods: A cohort of the Alpha-1 Foundation Registry who reported liver disease was surveyed with a liver disease questionnaire to obtain information related to liver disease, liver transplantation, and AAT phenotype. Results: One hundred sixty-five of the 2175 participants in the registry reported a history of jaundice or liver disease, and 139 (84.2%) completed the questionnaire. Of these, 71.3% were PiZZ, 18.0% were PiMZ, and 5.7% did not know their phenotype. Analysis of 104 participants with a known age of diagnosis included 30 participants diagnosed with liver disease before 18 years, of whom 15 had advanced liver disease defined as liver transplantation or listed for liver transplantation. No differences in age, age at diagnosis, gender, race, phenotype, or infant jaundice were identified. Seventy-four participants were diagnosed after age 18 years, of whom 25 had advanced liver disease. In this group, advanced liver disease was associated with male gender (P = .006) and a greater mean body mass index (P = .01), but not with race, Pi phenotype, infant jaundice, diabetes, or hypercholesterolemia. Viral hepatitis was more frequently reported in the nontransplant group (34.7% vs 8.0%, P = .01), and the mean daily alcohol use was significantly greater in this group (P = .04). Conclusions: Our results suggest that male gender and obesity but not alcohol or viral hepatitis predispose to advanced liver disease in adults with AAT.

Few studies of preeclampsia have assessed physical activity level, yet recent evidence suggests that the pathologic mechanisms in preeclampsia are similar to those in cardiovascular disease, for which physical activity is shown to be protective. The authors assessed the independent and combined effects of work and regular leisure-time physical activity (LTPA) during early pregnancy on risk of de novo preeclampsia (n = 44) and gestational hypertension (n = 172) among women recruited from 13 obstetric practices in the New Haven, Connecticut, area between 1988 and 1991. Control subjects were normotensive throughout pregnancy (n = 2,422). Information on time at work spent sitting, standing, and walking and on LTPA before and during pregnancy was collected via face-to-face interviews. Logistic regression analyses suggested that women who engaged in any regular LTPA regardless of caloric expenditure (adjusted odds ratio (aOR) = 0.66, 95% confidence interval (CI): 0.35, 1.22), were unemployed (aOR = 0.64, 95% CI: 0.21, 2.00), or had nonsedentary jobs (aOR = 0.71, 95% CI: 0.37, 1.36) were at decreased risk of preeclampsia. Analyses of gestational hypertension showed no indication of a protective effect of workplace activity, LTPA, or unemployment. Consistent with other studies, these data suggest that regular physical activity during pregnancy may reduce preeclampsia risk.

Objective: The objective of this research is to determine whether people with mental disorders are at increased risk for the subsequent development of malignancies compared with people without mental disorders. Methods: This is a retrospective cohort study of administrative claims data. The study population included 722,139 adults who filed at least one medical claim from 1989 to 1993. The mental disorder cohort included people with a) one psychiatric hospitalization, b) one outpatient psychiatrist visit, or c) two outpatient mental health claims occurring at least 6 months before a cancer claim. The controls were subjects filing claims for medical services who had no mental health visits. We calculated age-stratified odds ratios (ORs) for development of malignancy. Results: People with mental disorders were no more or less likely to develop a malignancy than those without after adjusting for age (women: OR, 1.03; 95% confidence interval [CI], 0.95–1.12; men: OR, 1.10; 95% CI, 0.97–1.24). People with mental disorders, however, developed cancer at younger ages and had increased odds of primary central nervous system tumors (women: OR, 2.12; 95% CI, 1.40–3.21; men: OR, 2.09; 95% CI, 1.22–3.59) and respiratory system cancers (women: OR, 1.57; 95% CI, 1.13–2.19; men: OR, 1.52; 95% CI, 1.09–2.12). Conclusions: Insured people with mental disorder claims had an increased risk of certain malignancies and developed malignancies at younger ages. The increased odds of respiratory tumors are likely secondary to increased rates of smoking among people with mental disorders and support use of smoking cessation interventions in this population. The increased odds for brain tumors may reflect only the early presence of mental symptoms, or a true association between the two conditions. Further study of these findings is mandated.

Background Veterans of the first Gulf War have higher rates of medical and psychiatric symptoms than nondeployed military personnel. Methods To assess the prevalence of and risk factors for current anxiety disorders in Gulf War veterans, we administered a structured telephone interview to a population-based sample of 4886 military personnel from Iowa at enlistment. Participants were randomly drawn from Gulf War regular military, Gulf War National Guard/ Reserve, non-Gulf War regular military, and non-Gulf War National Guard/Reserve. Medical and psychiatric conditions were assessed through standardized interviews and questionnaires in 3695 subjects (76% participation). Risk factors were assessed using multivariate logistic regression models. Results Veterans of the first Gulf War reported a markedly higher prevalence of current anxiety disorders than nondeployed military personnel (5.9% vs. 2.8%; odds ratio = 2.1; 95% confidence interval = 1.3-3.1), and their anxiety disorders are associated with co-occurring psychiatric disorders. Posttraumatic stress disorder, panic disorder, and generalized anxiety disorder were each present at rates nearly twice expected. In our multivariate model, predeployment psychiatric treatment and predeployment diagnoses (posttraumatic stress disorder, depression, or anxiety) were independently associated with current anxiety disorder. Participation in Gulf War combat was independently associated with current posttraumatic stress disorder, panic disorder, and generalized anxiety disorder. Conclusions Current anxiety disorders are relatively frequent in a military population and are more common among Gulf War veterans than nondeployed military personnel. Predeployment psychiatric difficulties are robustly associated with the development of anxiety. Healthcare providers and policymakers need to consider panic disorder and generalized anxiety disorder, in addition to posttraumatic stress disorder, to ensure their proper assessment, treatment, and prevention in veteran populations.

Background: The prevention of early recurrent stroke, which worsens outcomes after a cerebral infarction, is a major objective for acute stroke therapy. The ability to predict which patients are at risk for early recurrence would be useful for both the management and design of clinical trials. Methods: Using the prospective database with the 1,266 stroke patients admitted in the TOAST study, we analyzed all the patients who had suffered either a transient ischemic attack (TIA) or a recurrent stroke within 3 months after stroke, and their possible association with 20 selected clinical variables. Both univariate and stepwise regression analyses were performed. Results: Sixty-two patients (4.9%) had a second stroke, and 47 patients (3.7%) had at least one TIA. No particular high-risk period was observed. Early recurrent stroke was associated with the large artery atherosclerosis subtype. A prior history of TIA increased the odds for recurrent stroke (OR = 2.52; 1.16–5.46) or poststroke TIA (OR = 3.46; 1.59–7.48). In addition, patients who had a TIA after the stroke had a 17% chance of having an early recurrent stroke, as compared with 4.4% among those that did not (p = 0.001). Conclusion: Our present ability to identify patients at risk for early recurrence based on baseline clinical features remains limited. While the presence of TIA before or after the stroke denotes a subgroup of acute stroke patients at higher risk for early recurrence in the first 3 months, no other factors reliably identify high-risk patients.