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Whether chlorthalidone is superior to hydrochlorothiazide for preventing major adverse cardiovascular events in patients with hypertension is unclear.In a pragmatic trial, we randomly assigned adults 65 years of age or older who were patients in the Department of Veterans Affairs health system and had been receiving hydrochlorothiazide at a daily dose of 25 or 50 mg to continue therapy with hydrochlorothiazide or to switch to chlorthalidone at a daily dose of 12.5 or 25 mg. The primary outcome was a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death. Safety was also assessed.A total of 13,523 patients underwent randomization. The mean age was 72 years. At baseline, hydrochlorothiazide at a dose of 25 mg per day had been prescribed in 12,781 patients (94.5%). The mean baseline systolic blood pressure in each group was 139 mm Hg. At a median follow-up of 2.4 years, there was little difference in the occurrence of primary-outcome events between the chlorthalidone group (702 patients [10.4%]) and the hydrochlorothiazide group (675 patients [10.0%]) (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.16; P = 0.45). There were no between-group differences in the occurrence of any of the components of the primary outcome. The incidence of hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide group (6.0% vs. 4.4%, P0.001).In this large pragmatic trial of thiazide diuretics at doses commonly used in clinical practice, patients who received chlorthalidone did not have a lower occurrence of major cardiovascular outcome events or non-cancer-related deaths than patients who received hydrochlorothiazide. (Funded by the Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT02185417.).

Objective Improved biomarkers of current disease activity and prediction of relapse are needed in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). For clinical relevance, biomarkers must perform well longitudinally in patients on treatment and in patients with nonsevere flares. Methods Twenty-two proteins were measured in 347 serum samples from 74 patients with AAV enrolled in a clinical trial. Samples were collected at Month 6 after remission induction, then every 3 months until Month 18, or at the time of flare. Associations of protein concentrations with concurrent disease activity and with future flare were analyzed using mixed-effects models, Cox proportional hazards models, and conditional logistic regression. Results Forty-two patients had flares during the 12-month follow-up period, and 32 remained in remission. Twenty-two patients had severe flares. Six experimental markers (CXCL13, IL-6, IL-8, IL-15, IL-18BP, and matrix metalloproteinase-3 [MMP-3]) and ESR were associated with disease activity using all three methods (P < 0.05, with P < 0.01 in at least one method). A rise in IL-8, IL-15, or IL-18BP was associated temporally with flare. Combining C-reactive protein (CRP), IL-18BP, neutrophil gelatinase-associated lipocalin (NGAL), and sIL-2R alpha improved association with active AAV. CXCL13 and MMP-3 were increased during treatment with prednisone, independent of disease activity. Marker concentrations during remission were not predictive of future flare. Conclusion Serum biomarkers of inflammation and tissue damage and repair have been previously shown to be strongly associated with severe active AAV were less strongly associated with active AAV in a longitudinal study that included mild flares and varying treatment. Markers rising contemporaneously with flare or with an improved association in combination merit further study.

Recent US guidelines recommend chlorthalidone over other thiazide-type diuretics for the treatment of hypertension based on its long half-life and proven ability to reduce CVD events. Despite recommendations most clinicians prescribe hydrochlorothiazide (HCTZ) over chlorthalidone (CTD). No randomized controlled data exist comparing these two diuretics on cardiovascular outcomes.The Diuretic Comparison Project (DCP) is a multicenter, two-arm, parallel, Prospective Randomized Open, Blinded End-point (PROBE) trial testing the primary hypothesis that CTD is superior to HCTZ in the prevention of non-fatal CVD events and non-cancer death. Patients with hypertension taking HCTZ 25 or 50 mg were randomly assigned to either continue their current HCTZ or switch to an equipotent dose of CTD. The primary outcome is time to the first occurrence of a composite outcome consisting of a non-fatal CVD event (stroke, myocardial infarction, urgent coronary revascularization because of unstable angina, or hospitalization for acute heart failure) or non-cancer death. The trial randomized 13,523 patients at 72 VA medical centers. The study is conducted by a centralized research team with site procedures embedded in the electronic health record and all data collected through administrative claims data, with no study related visits for participants. The trial will have 90% power to detect an absolute reduction in the composite event rate of 2.4%.Enrollment ended in November 2021. There are 4128 participting primary care providers and 16,595 patients individually consented to participate, 13,523 of whom were randomized.DCP should provide much needed evidence as to whether CTD is superior to HCTZ in preventing cardiovascular events in hypertensive patients.NCT02185417 [https://clinicaltrials.gov/ct2/show/NCT02185417].

Collaborative chronic care models (CCMs) were established with implementation support in nine mental health clinics. This study sought to determine whether their clinical impact was maintained after implementation support ceased.Posttrial data were analyzed from a randomized stepped-wedge CCM implementation trial in general mental health clinics in nine Department of Veterans Affairs medical centers. Sites received 1 year of implementation support, which was associated with reduced mental health hospitalization rates compared with non-CCM clinics in the same medical centers. Hospitalization rates for the year after implementation support were analyzed by using repeated measures logistic regression comparing the same clinics.Hospitalization rates for the postsupport year did not differ from comparison clinics either in the population that initially showed the difference or the population active in the clinics at the end of the year of implementation support.Clinical effects of the CCM may wane after cessation of active implementation support.

Introduction: Approximately 25–30% of veterans deployed to Kuwait, 1990-91, report persistent multi-symptom Gulf War Illness (GWI) likely from neurotoxicant exposures. Photobiomodulation (PBM) in red/near-infrared (NIR) wavelengths is a safe, non-invasive modality shown to help repair hypoxic/stressed cells. Red/NIR wavelengths are absorbed by cytochrome C oxidase in mitochondria, releasing nitric oxide (increasing local vasodilation), and increasing adenosine tri-phosphate production. We investigated whether PBM applied transcranially could improve cognition, and health symptoms in GWI.Materials and Methods: Forty-eight (40 M) participants completed this blinded, randomized, sham-controlled trial using Sham or Real, red/NIR light-emitting diodes (LED) applied transcranially. Fifteen, half-hour transcranial LED (tLED) treatments were twice a week (7.5 weeks, in-office). Goggles worn by participant and assistant maintained blinding for visible red. Pre-/Post- testing was at Entry, 1 week and 1 month post- 15th treatment. Primary outcome measures were neuropsychological (NP) tests; secondary outcomes, Psychosocial Questionnaires, including PTSD.Results: Primary Analyses (all participants), showed improvement for Real vs. Sham, for Digit Span Forwards (p < 0.01); and a trend for Trails 4, Number/Letter Sequencing (p < 0.10). For secondary outcomes, Real group reported more improvement on the SF-36V Plus, Physical Component Score (p < 0.08). Secondary Analyses included only subjects scoring below norm (50%ile) at Entry, on specific NP test/s. Real and Sham improved at 1 week after 15th treatment; however, at 1 month, only those receiving Real improved further: Digit Span Total, Forwards and Backwards; Trails 4, Number/Letter Sequencing; California Verbal Learning Test-II, long delay free recall; Continuous Performance Test-II, False Alarm Rate; and Color-Word Interference, Stroop, Trial 3, Inhibition; Sham group worsened, toward Entry values. Only those with more post-traumatic stress disorder (PTSD) symptomatology at Entry, receiving Real, continued to have additional PTSD reduction at 1 month; Sham regressed.Conclusion: This study was underpowered (n = 48), with large heterogeneity at Entry. This likely contributed to significance or trend to significance, for only two of the NP tests (Digit Span Forwards; Trails 4, Number/Letter Sequencing) and only one general health measure, the SF-36V Plus, Physical Component Score. More subjects receiving Real, self-reported increased concentration, relaxation and sleep. Controlled studies with newer, transcranial LED home treatment devices are warranted; this is expected to increase enrollment.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT01782378.

Background Intervention trials with nested designs seek to balance sites randomized regarding key site characteristics. Among the goals of such site-level balancing is to accrue patient-level equivalence among treatment arms. We investigated patient-level equivalence in a cluster randomized controlled trial, which balanced study waves on site-level characteristics.MethodsThe Behavioral Health Interdisciplinary Program - Collaborative Chronic Care Model project utilized a stepped wedge design to stagger implementation of an evidence-based team-oriented mental health patient management system at 9 Veteran Affairs Medical Centers. Study sites were balanced on eight site-level characteristics over time (3 balanced waves [consecutive time periods] with 3 sites per wave) to minimize trend. Sites were balanced on selected site-level characteristics but not on patient-level variables. We explored internal differences in patient demographics across the three study waves. Eligible patients had at least two visits to a participating mental health clinic in the prior year and did not have a diagnosis of dementia (n=5,596).ResultsWe found modest but statistically significant inter-site differences in age, marital status, ethnicity, service-related disability, mental health hospitalizations, and selected diagnoses by study wave. Although many of the differences in patient demographics by study wave were statistically significant, only a few results were practically meaningful as measured by effect size. A bipolar diagnosis (49.0%, 21.0%, 17.0% in waves 1-3, respectively; Cramer’s V=.3124) and Hispanic ethnicity (2.9%, 29.6%, 2.0% in waves 1-3, respectively; Cramer’s V=.3949) resulted in differences that were considered a ‘moderate’ effect size. The number of patient characteristics that were both statistically and meaningfully different by study wave among all possible site assignments was comparable to the 34 most balanced site assignments identified in our balancing algorithm.ConclusionsUsing a balancing algorithm to reduce imbalance among site characteristics across time periods did not appear to negatively affect the balance of patient characteristics across sites over time. A site-level balancing algorithm that includes characteristics with a direct relationship to relevant patient-level factors may improve the overall balance across key elements of the study, and aide in the interpretation of results. Trial registration: Hybrid Collaborative Care Randomized Program Evaluation (BHIP-CCM) NCT02543840 (September 7, 2015)

Importance Suicide and suicide attempts are persistent and increasing public health problems. Observational studies and meta-analyses of randomized clinical trials have suggested that lithium may prevent suicide in patients with bipolar disorder or depression. Objective To assess whether lithium augmentation of usual care reduces the rate of repeated episodes of suicide-related events (repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event. Design, Setting, and Participants This double-blind, placebo-controlled randomized clinical trial assessed lithium vs placebo augmentation of usual care in veterans with bipolar disorder or depression who had survived a recent suicide-related event. Veterans at 29 VA medical centers who had an episode of suicidal behavior or an inpatient admission to prevent suicide within 6 months were screened between July 1, 2015, and March 31, 2019. Interventions Participants were randomized to receive extended-release lithium carbonate beginning at 600 mg/d or placebo. Main Outcomes and Measures Time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide. Results The trial was stopped for futility after 519 veterans (mean [SD] age, 42.8 [12.4] years; 437 [84.2%] male) were randomized: 255 to lithium and 264 to placebo. Mean lithium concentrations at 3 months were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depressive disorder. No overall difference in repeated suicide-related events between treatments was found (hazard ratio, 1.10; 95% CI, 0.77-1.55). No unanticipated safety concerns were observed. A total of 127 participants (24.5%) had suicide-related outcomes: 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and 3 in the placebo group. Conclusions and Relevance In this randomized clinical trial, the addition of lithium to usual Veterans Affairs mental health care did not reduce the incidence of suicide-related events in veterans with major depression or bipolar disorders who experienced a recent suicide event. Therefore, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events in patients who are actively being treated for mood disorders and substantial comorbidities. Trial Registration ClinicalTrials.gov Identifier:NCT01928446

In clinical trials, placebo response can affect the inference about efficacy of the studied treatment. It is important to have a robust way to classify trial subjects with respect to their response to placebo. Simple, criterion-based classification may lead to classification error and bias the inference. The uncertainty about placebo response characteristic has to be factored into the treatment effect estimation. We propose a novel approach that views the placebo response as a latent characteristic and the study sample as an unlabeled mixture of “placebo responders” and “placebo nonresponders.” The likelihood-based methodology is used to estimate the treatment effect corrected for placebo response as defined within sequential parallel comparison design.

Background Intimate partner violence (IPV) against women in the United States (US) remains a complex public health crisis. Women who experience IPV are among the most vulnerable patients seen in primary care. Screening increases the detection of IPV and, when paired with appropriate response interventions, can mitigate the health effects of IPV. The Department of Veterans Affairs (VA) has encouraged evidence-based IPV screening programs since 2014, yet adoption is modest and questions remain regarding the optimal ways to implement these practices, which are not yet available within the majority of VA primary care clinics. Methods/design This paper describes the planned evaluation of VA’s nationwide implementation of IPV screening programs in primary care clinics through a randomized implementation-effectiveness hybrid type 2 trial. With the support of our VA operational partners, we propose a stepped wedge design to compare the impact of two implementation strategies of differing intensities (toolkit + implementation as usual vs. toolkit + implementation facilitation) and investigate the clinical effectiveness of IPV screening programs. Using balanced randomization, 16–20 VA Medical Centers will be assigned to receive implementation facilitation in one of three waves, with implementation support lasting 6 months. Implementation facilitation in this effort consists of the coordinated efforts of the two types of facilitators, external and internal. Implementation facilitation is compared to dissemination of a toolkit plus implementation as usual. We propose a mixed methods approach to collect quantitative (clinical records data) and qualitative (key informant interviews) implementation outcomes, as well as quantitative (clinical records data) clinical effectiveness outcomes. We will supplement these data collection methods with provider surveys to assess discrete implementation strategies used before, during, and following implementation facilitation. The integrated-Promoting Action on Research Implementation in Health Services (i-PARIHS) framework will guide the qualitative data collection and analysis. Summative data will be analyzed using the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) framework. Discussion This research will advance national VHA efforts by identifying the practices and strategies useful for enhancing the implementation of IPV screening programs, thereby ultimately improving services for and health of women seen in primary care. Trial registration NCT04106193. Registered on 23 September 2019.

SummaryBackground Topical 5-fluorouracil (5-FU) is commonly used for high-risk patients with keratinocyte carcinoma (KC). Skindex and Skin Cancer Index (SCI) are validated instruments to measure quality of life (QoL) of patients with KC and those who have had surgical treatment of KCs. Aim To validate Skindex and SCI for topical 5-fluorouracil (5-FU) application and to compare the two QoL instruments. Methods We randomized 932 veterans at high risk for developing a KC to either topical 5-FU or vehicle control cream applied to the face and ears for up to 1 month. We collected their Skindex-29 and SCI scores at baseline and follow-up visits. Results Compared with controls, 5-FU reduced QoL, measured by the Skindex symptom, Skindex function and SCI social subscales (P

We propose a joint hypothesis test for simultaneous confirmatory inference in the overall population and a pre-defined marker-positive subgroup under the assumption that the treatment effect in the marker-positive subgroup is larger than that in the overall population. The proposed confirmatory overall-subgroup simultaneous test (COSST) is based on partitioning the sample space of the test statistics in the marker-positive and marker-negative subgroups. We define two rejection regions in the joint sample space of the two test statistics: (1) efficacy in the marker-positive subgroup only; (2) efficacy in the overall population. COSST achieves higher statistical power to detect the overall and subgroup efficacy than most sequential procedures while controlling the family-wise type I error rate. COSST also takes into account the potentially harmful effect in the subgroups in the decision. The optimal rejection regions depend on the specific alternative hypothesis and the sample size. COSST can be useful for Phase III clinical trials with tailoring objectives.

Background: Extensive evidence indicates that Collaborative Chronic Care Models (CCMs) improve outcome in chronic medical conditions and depression treated in primary care. Beginning with an evidence synthesis which indicated that CCMs are also effective for multiple mental health conditions, we describe a multistage process that translated this knowledge into evidence-based health system change in the US Department of Veterans Affairs (VA). Evidence Synthesis: In 2010, recognizing that there had been numerous CCM trials for a wide variety of mental health conditions, we conducted an evidence synthesis compiling randomized controlled trials of CCMs for any mental health condition. The systematic review demonstrated CCM effectiveness across mental health conditions and treatment venues. Cumulative meta-analysis and meta-regression further informed our approach to subsequent CCM implementation. Policy Impact: In 2015, based on the evidence synthesis, VA Office of Mental Health and Suicide Prevention (OMHSP) adopted the CCM as the model for their outpatient mental health teams. Randomized Implementation Trial: In 2015–2018 we partnered with OMHSP to conduct a 9-site stepped wedge implementation trial, guided by insights from the evidence synthesis. Scale-Up and Spread: In 2017 OMHSP launched an effort to scale-up and spread the CCM to additional VA medical centers. Seventeen facilitators were trained and 28 facilities engaged in facilitation. Discussion: Evidence synthesis provided leverage for evidence-based policy change. This formed the foundation for a health care leadership/researcher partnership, which conducted an implementation trial and subsequent scale-up and spread effort to enhance adoption of the CCM, as informed by the evidence synthesis.

Background: An objective tool quantifying the toxicity of 5-fluorouracil (5-FU) from photographs was recently reported, and its reliability was confirmed. Objective: The aim of this study was to validate the photograph-based toxicity score. Methods: Photograph-based toxicity scores of participants assigned to the 5-FU arm of a randomized placebo-controlled trial were tested for correlations with their patient-reported symptom scores and baseline characteristics. Results: Each pair of individual and overall scores of patient-reported symptoms and photograph-based toxicity was correlated at 2 and 4 weeks (correlation coefficient range, 0.34-0.95; P < .001 for all). Older age, more actinic keratoses, previous topical 5-FU use, and more keratinocyte carcinomas on the face and ears in the previous 5 years were correlated with increased 5-FU toxicity at 2 weeks ( P < .05). An increase in the total number of 5-FU applications during the trial was correlated with less severe toxicity at 2 weeks ( P < .001), but with increased toxicity at 4 weeks ( P < .001). Conclusion: This study provides evidence for construct validity of the photograph-based 5-FU toxicity score. The tool can be used to objectively measure 5-FU toxicity in clinical or research setting, and it can be a prototype for toxicity measurements of other topical medications.

Importance Keratinocyte carcinoma (ie, cutaneous basal and squamous cell carcinoma) is the most common cancer in the United States. Objective To determine whether topical fluorouracil could prevent surgically treated keratinocyte carcinoma. Design, Setting, and Participants The Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial was a randomized, double-blind, placebo-controlled trial of topical fluorouracil for chemoprevention of keratinocyte carcinoma. Participants were recruited from May 2009 to September 2011 from 12 Veterans Affairs medical centers and followed until June 30, 2013. Participants were veterans (n = 932) with a history of at least 2 keratinocyte carcinomas in the past 5 years; almost all were white males and the median age was 70 years. Interventions Application of fluorouracil, 5%, (n = 468) or vehicle control cream (n = 464) to the face and ears twice daily for 2 to 4 weeks upon randomization. Main Outcomes and Measures Surgically treated keratinocyte, basal cell, and squamous cell carcinoma risk on the face and ears in the first year after enrollment; and time to first surgically treated keratinocyte, basal cell, and squamous cell carcinoma. The a priori hypothesis was that fluorouracil would be effective in preventing these cancers. Results Of 932 participants (916 men [98%]; 926 white [99%]; median age, 70 years), 299 developed a basal cell carcinoma end point (95 in year 1) and 108 developed a squamous cell carcinoma end point (25 in year 1) over 4 years (median follow-up, 2.8 years). Over the entire study, there was no difference between treatment groups in time to first keratinocyte, basal cell, or squamous cell carcinoma. During the first year, however, 5 participants (1%) in the fluorouracil group developed a squamous cell carcinoma vs 20 (4%) in the control group, a 75% (95% CI, 35%-91%) risk reduction (P = .002). The 11% reduction in basal cell carcinoma risk during year 1 (45 [10%] in the fluorouracil group vs 50 [11%] in the control group) was not statistically significant (95% CI, 39% reduction to 31% increase), nor was there a significant effect on keratinocyte carcinoma risk. However, a reduction in keratinocyte carcinomas treated with Mohs surgery was observed. Conclusions and Relevance A conventional course of fluorouracil to the face and ears substantially reduces surgery for squamous cell carcinoma for 1 year without significantly affecting the corresponding risk for basal cell carcinoma. Trial Registration clinicaltrials.gov Identifier:NCT00847912

Importance Collaborative chronic care models (CCMs) have extensive randomized clinical trial evidence for effectiveness in serious mental illnesses, but little evidence exists regarding their feasibility or effect in typical practice conditions. Objective To determine the effectiveness of implementation facilitation in establishing the CCM in mental health teams and the impact on health outcomes of team-treated individuals. Design, Setting, and Participants This quasi-experimental, randomized stepped-wedge implementation trial was conducted from February 2016 through February 2018, in partnership with the US Department of Veterans Affairs (VA) Office of Mental Health and Suicide Prevention. Nine facilities were enrolled from all VA facilities in the United States to receive CCM implementation support. All veterans (n = 5596) treated by designated outpatient general mental health teams were included for hospitalization analyses, and a randomly selected sample (n = 1050) was identified for health status interviews. Individuals with dementia were excluded. Clinicians (n = 62) at the facilities were surveyed, and site process summaries were rated for concordance with the CCM process. The CCM implementation start time was randomly assigned across 3 waves. Data analysis of this evaluable population was performed from June to September 2018. Interventions Internal-external facilitation, combining a study-funded external facilitator and a facility-funded internal facilitator working with a designated team for 1 year. Main Outcomes and Measures Facilitation was hypothesized to be associated with improvements in both implementation and intervention outcomes (hybrid type II trial). Implementation outcomes included the clinician Team Development Measure (TDM) and proportion of CCM-concordant team care processes. The study was powered for the primary health outcome, mental component score (MCS). Hospitalization rate was derived from administrative data. Results The veteran population (n = 5596) included 881 women (15.7%), and the mean (SD) age was 52.2 (14.5) years. The interviewed sample (n = 1050) was similar but was oversampled for women (n = 210 [20.0%]). Facilitation was associated with improvements in TDM subscales for role clarity (53.4%-68.6%; δ = 15.3; 95% CI, 4.4-26.2;P = .01) and team primacy (50.0%-68.6%; δ = 18.6; 95% CI, 8.3-28.9;P = .001). The percentage of CCM-concordant processes achieved varied, ranging from 44% to 89%. No improvement was seen in veteran self-ratings, including the primary outcome. In post hoc analyses, MCS improved in veterans with 3 or more treated mental health diagnoses compared with others (β = 5.03; 95% CI, 2.24-7.82;P Conclusions and Relevance Implementation facilitation that engages clinicians under typical practice conditions can enhance evidence-based team processes; its effect on self-reported overall population health status was negligible, although health status improved for individuals with complex conditions and hospitalization rate declined. Trial Registration ClinicalTrials.gov Identifier:NCT02543840

Actinic keratoses (AK) are common, costly, and may evolve to keratinocyte carcinoma (KC): basal cell (BCC) and squamous cell carcinoma (SCC) of the skin. Time to malignant transformation is controversial. We used data from the placebo arm (n=166) of a randomized trial of veterans with multiple prior KCs. Study dermatologists examined participants’ faces/ears at enrollment and semiannual visits. Clinically diagnosed AKs were marked, photographed, and treated with cryotherapy (starting at 6 months). Lesions suspicious for KC were marked, photographed, and biopsied. AKs were tracked using these photographs. For each AK that progressed to KC (n=23), the time between the first appearance of the AK and the biopsy resulting in a KC diagnosis was measured. Among all 4,231 tracked AKs, the difference in time to progression of AKs that progressed to BCC (12/4,231) vs. SCC (11/4,231) was not statistically detectable (Cox proportional hazards analysis). However, among the 23 AKs that progressed to KC, AKs progressed more quickly to SCC compared to BCC (two-sided Wilcoxon test; p=0.01) with respective mean progression times of 13 and 25 months. This may be due to clinical misdiagnosis of early BCCs as AKs, as BCCs are known to grow slowly; or perhaps SCCs become more rapidly clinically distinguishable. Differences in progression could also indicate differences in sensitivity to cryotherapy, as lesions progressed despite this treatment. Alternatively, if these were true AKs, then certain events—with different likelihoods and timing—may be needed for AKs to progress to BCC vs. SCC.

Group sequential designs are used to potentially shorten randomized clinical trials and thereby reduce subject burden, improve safety, and save time and resources. Clinical trials comparing treatments for systemic lupus erythematosus (SLE) might adopt such designs if the ordinal outcome scales for SLE, such as the Systemic Lupus Activity Measure and Systemic Lupus Erythematosus Disease Activity Index, were more like continuous outcome scales with interval properties. After describing the basic features of sequential trials and highlighting some major issues in their design, we propose approaches that mitigate these issues. In particular, high-speed computing has accelerated advances in sequential design, making available a variety of designs that can be implemented with minimal technical support. The challenge now is to understand the concepts behind such flexible designs and then to apply them to improve studies of SLE.

Outcome for mental health conditions is suboptimal, and care is fragmented. Evidence from controlled trials indicates that collaborative chronic care models (CCMs) can improve outcomes in a broad array of mental health conditions. US Department of Veterans Affairs leadership launched a nationwide initiative to establish multidisciplinary teams in general mental health clinics in all medical centers. As part of this effort, leadership partnered with implementation researchers to develop a program evaluation protocol to provide rigorous scientific data to address two implementation questions: (1) Can evidence-based CCMs be successfully implemented using existing staff in general mental health clinics supported by internal and external implementation facilitation? (2) What is the impact of CCM implementation efforts on patient health status and perceptions of care? Health system operation leaders and researchers partnered in an iterative process to design a protocol that balances operational priorities, scientific rigor, and feasibility. Joint design decisions addressed identification of study sites, patient population of interest, intervention design, and outcome assessment and analysis. Nine sites have been enrolled in the intervention-implementation hybrid type III stepped-wedge design. Using balanced randomization, sites have been assigned to receive implementation support in one of three waves beginning at 4-month intervals, with support lasting 12 months. Implementation support consists of US Center for Disease Control’s Replicating Effective Programs strategy supplemented by external and internal implementation facilitation support and is compared to dissemination of materials plus technical assistance conference calls. Formative evaluation focuses on the recipients, context, innovation, and facilitation process. Summative evaluation combines quantitative and qualitative outcomes. Quantitative CCM fidelity measures (at the site level) plus health outcome measures (at the patient level; n = 765) are collected in a repeated measures design and analyzed with general linear modeling. Qualitative data from provider interviews at baseline and 1 year elaborate CCM fidelity data and provide insights into barriers and facilitators of implementation. Conducting a jointly designed, highly controlled protocol in the context of health system operational priorities increases the likelihood that time-sensitive questions of operational importance will be answered rigorously and that the outcomes will result in sustainable change in the health-care system. NCT02543840 ( https://www.clinicaltrials.gov/ct2/show/NCT02543840 ).

Background Clinical trials are widely considered the gold standard in comparative effectiveness research (CER) but the high cost and complexity of traditional trials and concerns about generalizability to broad patient populations and general clinical practice limit their appeal. Unsuccessful implementation of CER results limits the value of even the highest quality trials. Planning for a trial comparing two standard strategies of insulin administration for hospitalized patients led us to develop a new method for a clinical trial designed to be embedded directly into the clinical care setting thereby lowering the cost, increasing the pragmatic nature of the overall trial, strengthening implementation, and creating an integrated environment of research-based care. Purpose We describe a novel randomized clinical trial that uses the informatics and statistics infrastructure of the Veterans Affairs Healthcare System (VA) to illustrate one key component (called the point-of-care clinical trial – POC-CT) of a ‘learning healthcare system,’ and settles a clinical question of interest to the VA. Methods This study is an open-label, randomized trial comparing sliding scale regular insulin to a weight-based regimen for control of hyperglycemia, using the primary outcome length of stay, in non-ICU inpatients within the northeast region of the VA. All non-ICU patients who require in-hospital insulin therapy are eligible for the trial, and the VA’s automated systems will be used to assess eligibility and present the possibility of randomization to the clinician at the point of care. Clinicians will indicate their approval for informed consent to be obtained by study staff. Adaptive randomization will assign up to 3000 patients, preferentially to the currently ‘winning’ strategy, and all care will proceed according to usual practices. Based on a Bayesian stopping rule, the study has acceptable frequentist operating characteristics (Type I error 6%, power 86%) against a 12% reduction of median length of stay from 5 to 4.4 days. The adaptive stopping rule promotes implementation of a successful treatment strategy. Limitations Despite clinical equipoise, individual healthcare providers may have strong treatment preferences that jeopardize the success and implementation of the trial design, leading to low rates of randomization. Unblinded treatment assignment may bias results. In addition, generalization of clinical results to other healthcare systems may be limited by differences in patient population. Generalizability of the POC-CT method depends on the level of informatics and statistics infrastructure available to a healthcare system. Conclusions The methods proposed will demonstrate outcome-based evaluation of control of hyperglycemia in hospitalized veterans. By institutionalizing a process of statistically sound and efficient learning, and by integrating that learning with automatic implementation of best practice, the participating VA Healthcare Systems will accelerate improvements in the effectiveness of care.

Comparative effectiveness research (CER) may be defined informally as an assessment of available options for treating specific medical conditions in selected groups of patients. In this context, the most prominent features of CER are the various patient populations, medical ailments, and treatment options involved in any particular project. Yet, each research investigation also has a corresponding study design or "architecture," and in patient-oriented research a common distinction used to describe such designs are randomized controlled trials (RCTs) versus observational studies. The purposes of this overview, with regard to CER, are to (1) understand how observational studies can provide accurate results, comparable to RCTs; (2) recognize strategies used in selected newer methods for conducting observational studies; (3) review selected observational studies from the Veterans Health Administration; and (4) appreciate the importance of fundamental methodological principles when conducting or evaluating individual studies.

Although estrogen receptor (ER) content and its clinical significance have been extensively evaluated in invasive breast cancer, ER expression in carcinoma in situ (CIS) of the breast and its correlates are less well understood. Thus, using an indirect immunoperoxidase technique and paraffin-embedded tissue, the authors studied ER expression in 100 breast tumors containing CIS with or without invasive carcinoma. The percentages of positive and of strongly positive nuclei were compared among histologic categories of CIS and between CIS and invasive carcinoma. The relationships between histologic features of CIS (cell size, nuclear pleomorphism, necrosis, extent of CIS) the patient's age, and the ER status of CIS also were evaluated. ER expression in pure CIS was compared with that of CIS with adjacent invasive carcinoma. Significant differences were observed between comedo CIS, which was frequently ER negative, and non-comedo and lobular CIS, which usually were positive. A predominance of large cells, independently from other features, was the best morphologic predictor of ER negative status in CIS. ER in CIS correlated with ER in invasive carcinoma in 98% of cases (r2 = 0.677). CIS without invasive carcinoma was more frequently ER weak or negative than CIS associated with invasive carcinoma. There was no difference in the overall percentage of nuclear staining in CIS of women of premenopausal versus postmenopausal age; however, a higher proportion of strongly positive cells occurred in the postmenopausal group. The authors conclude that the ER expression in CIS correlates with pathologic features of differentiation and is similar to that of invasive carcinoma.

Problem statement: Reliability studies are concerned with the study o f "consistency" or "repeatability" of measurements. Often times (but n ot always) the reliability coefficients are Intra-c lass Correlation Coefficients (ICC). Depending on the de sign or the conceptual intent of the study there ar e three types of intra-class correlation coefficients , termed intra-class correlation coefficients Case 1, 2 and 3, for measuring the reliability of a single in terval measure. While methods for sample size calculations for intra-class correlation coefficien ts in Case 1 are available and implemented in Power Analysis and Sample Size System (PASS); to our knowledge, no methods based on intra-class correlation coefficients in Case 2 and 3 are availa ble. Objective: Develop a method for calculating the size of a reliability study based on intra-class co rrelation coefficients Case 1 and 2. Approach: A practical method for computing sample size using si mulations was proposed. We proposed to compute sample size based on the expected width of the conf idence interval. For a given target value of the intra-class correlation coefficient, the proposed m ethod chooses the design assures a 95% confidence interval with average length shorter than a pre-spe cified value. The applicability of the proposed method in practice for intra-class coefficients Cas e 2 was supported by demonstrating three invariance properties of the proposed confidence intervals. Results: Tables with sample size requirements were derived and displayed. A program for carrying out t he calculations was developed in R. The method was used to size a trial aimed to study the reliabi lity of a scale that measures the cleanness of the colon at the time of colonoscopy. Conclusion: A simple method for sample size calculation for int ra-class correlation coefficient Case 1 and 2 based on the a verage length of confidence intervals was proposed. The proposed was implemented by the authors in R (freely available software). Three invariance properties of the confidence intervals for the intr a-class correlation coefficients Case 2 were studie d by simulations. These properties are an important tool when considering the design of this type of studie s.

The clustered permutation test is a nonparametric method of significance testing for correlated data. It is often used in cluster randomized trials where groups of patients rather than individuals are randomized to either a treatment or control intervention. We describe a flexible and efficient SAS macro that implements the 2-sample clustered permutation test. We discuss the theory and applications behind this test as well as details of the SAS code.

Background and Purpose— We hypothesized that transcranial laser therapy (TLT) can use near-infrared laser technology to treat acute ischemic stroke. The NeuroThera Effectiveness and Safety Trial–2 (NEST-2) tested the safety and efficacy of TLT in acute ischemic stroke. Methods— This double-blind, randomized study compared TLT treatment to sham control. Patients receiving tissue plasminogen activator and patients with evidence of hemorrhagic infarct were excluded. The primary efficacy end point was a favorable 90-day score of 0 to 2 assessed by the modified Rankin Scale. Other 90-day end points included the overall shift in modified Rankin Scale and assessments of change in the National Institutes of Health Stroke Scale score. Results— We randomized 660 patients: 331 received TLT and 327 received sham; 120 (36.3%) in the TLT group achieved favorable outcome versus 101 (30.9%), in the sham group ( P =0.094), odds ratio 1.38 (95% CI, 0.95 to 2.00). Comparable results were seen for the other outcome measures. Although no prespecified test achieved significance, a post hoc analysis of patients with a baseline National Institutes of Health Stroke Scale score of P Conclusions— TLT within 24 hours from stroke onset demonstrated safety but did not meet formal statistical significance for efficacy. However, all predefined analyses showed a favorable trend, consistent with the previous clinical trial (NEST-1). Both studies indicate that mortality and adverse event rates were not adversely affected by TLT. A definitive trial with refined baseline National Institutes of Health Stroke Scale exclusion criteria is planned.

Wearable sensors have been developed and used in nondisabled adults. Little is known about their accuracy in patients with chronic disease. We tested the ActiHealth accelerometer, which measures step counts, in subjects with chronic obstructive pulmonary disease (COPD). We determined the intra- and interdevice coefficients of variation (CVs). We assessed the accuracy of the device in 15 nondisabled males and 46 subjects with COPD. Accuracy was defined as percent step capture, (device step count divided by manual step count) times 100. Predictors of percent step capture were identified using linear regression methods. The accelerometer has an intradevice CV ranging from 0.008 to 0.025 and an interdevice CV of 0.64. In nondisabled males, median percent step capture was 96% (interquartile range 81%-98%). In subjects with COPD, median percent step capture was 86% (interquartile range 72%-96%). Usual walking speed was the most important predictor of percent step capture (p = 0.004). The ActiHealth accelerometer has acceptable intra- and interdevice CVs. It is highly accurate in nondisabled subjects. The accuracy declines in subjects with COPD based on walking speed. Prior to using the ActiHealth accelerometer, researchers and clinicians should assess walking speed and percent step capture in each subject.

Health care quality improvement interventions are often evaluated in randomized trials in which individual physicians serve as the unit of randomization. These cluster randomized trials present a unique data structure that consists of many clusters of highly variable size. The appropriate method of analysis for these trials is unknown. We conducted a simulation study to compare several methods for analyzing data which were generated to replicate the structure of our motivating example. We varied the treatment effect size and the distributional assumptions about the random effect. Simulation was used to estimate power, coverage, bias, and mean squared error of full maximum likelihood estimation (MLE), approximate MLE using penalized quasi-likelihood (PQL), generalized estimating equations (GEE), group-bootstrapped logistic regression, and a clustered permutation test. Across all conditions tested, GEE and full MLE performed comparably. Bootstrapped methods were less powerful and had higher mean squared error under conditions of variable cluster size. PQL yielded biased results. The permutation test preserved Type I error rates, but had less power than the other methods considered.

Background: Meta-analyses of trials of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors or statins for cardiovascular disease prevention have failed to show any statistically significant benefit of statins for cancer prevention. However, these trials included relatively young participants, who develop few cancers, and their follow-up periods may have been too short to detect an association between statin use and cancer incidence. We investigated this association in a population of veterans. Methods: We identified patients using antihypertensive medications but no cholesterol-lowering medications (n = 25,594) and patients using statins (n = 37,248) who were enrolled in the Veterans Affairs New England Healthcare System between January 1, 1997, and December 31, 2005. Age- and multivariable-adjusted Cox proportional hazards models were used to calculate the hazard ratio (HR) and its 95% confidence interval (CI) for cancer incidence, excluding nonmelanoma skin cancer, among patients taking statins compared with patients taking antihypertensive medications and among patients grouped by statin dose (as equivalent simvastatin dose). All statistical tests were two-sided. Results: The absolute incidence of total cancers was 9.4% among statin users and 13.2% among nonusers (difference = 3.8%, 95% CI = 3.3% to 4.3%, P(difference) < .001). Statin users had a statistically significant lower risk for total cancer than nonusers after adjustment for age (HR = 0.76, 95% CI = 0.73 to 0.80) and multiple potential confounders (HR = 0.74, 95% CI = 0.70 to 0.78). After multivariable adjustment, a statistically significantly decreased risk of all cancers was also associated with increasing statin use (P(trend) < .001). Conclusions: Patients using statins may be at lower risk for developing cancer. Additional observational studies and randomized trials of statins for cancer prevention are warranted.

Background and Purpose— The SAINT I trial that showed a significant benefit of the neuroprotectant NXY-059 used a novel outcome for acute ischemic stroke trials: a shift toward good functional outcome on the 7-category modified Rankin scale (mRS). Methods— We used the Cochran-Mantel-Haenszel shift test to analyze the distribution of the 90-day mRS outcomes in the NINDS and ECASS-II databases and compared the results with a dichotomized mRS outcome by logistic regression (0 to 2 vs 3 to 6, or 0 to 1 vs 2 to 6). We also stratified each dataset based on National Institutes of Health Stroke Scale baseline severity. Results— Each dataset showed a statistically significant shift in the 90-day mRS distributions favoring tissue plasminogen activator (odds ratio, 1.6 for NINDS, 1.3 for ECASS-II). For ECASS-II, larger shift effects appeared in National Institutes of Health Stroke Scale 0 to 6 and 16 to 40 strata. Similarly, the mRS 0 to 2 analysis but not mRS 0 to 1 found similar treatment effects in both datasets (odds ratio, 1.6 for NINDS, 1.5 for ECASS-II) and similar variations in the low and high strata in the ECASS-II trial. NINDS found no significant treatment effects across the strata. After removing the strata at the fringes, the shift test lost significance in both datasets. Conclusions— Tissue plasminogen activator causes a beneficial shift toward wellness on the mRS in both the NINDS and ECASS-II trials, and ECASS-II would have been a positive trial according to the shift approach. However, the shift effect is not global for all treated patients and does not outperform the dichotomized 0 to 2 outcome. Patients with mild and severe deficits also shifted favorably on the mRS in the ECASS-II trial.

Erectile dysfunction (ED) is a prevalent condition and a predictor of future cardiovascular events. Screening and treatment of ED may improve management of cardiovascular risk factors. We evaluated the potential beneficial effect of newly treating ED on the management of hypertension in men in the New England Veteran Affairs Healthcare System. We conducted a retrospective cohort study using medical record data to identify patients diagnosed with and treated at any time for hypertension who received a prescription for a phosphodiesterase type 5 inhibitor (PDE5i) before February 1, 2003. Fifty percent of 6,768 men (mean +/- SD 61.6 +/- 9.9 years of age) had a systolic blood pressure (BP) > or =140 mm Hg before PDE5i administration. Overall, there was a decrease in systolic BP by 1.43 mm Hg (95% confidence interval -1.69 to -1.18) after initiation of PDE5i. The decrease in systolic BP was most pronounced in men with a systolic BP > or =160 mm Hg at baseline (-17.8 mm Hg, 95% confidence interval -18.8 to -16.8). After initiating therapy with PDE5i, patients were more likely to start an antihypertensive medication (17.3%) versus stop therapy (2.3%) and add additional antihypertensive medication to their existing therapy (42.2%) versus decrease the number of medications (17.3%). Surveillance also increased with total number of systolic BP measurements increasing by 42%. In conclusion, men with high systolic BP who initiated ED therapy had improvements in systolic BP control that may be related to clinically relevant behaviors, such as more aggressive monitoring and treatment with antihypertensive medications.

Background and Purpose— The NeuroThera Effectiveness and Safety Trial-1 (NEST-1) study evaluated the safety and preliminary effectiveness of the NeuroThera Laser System in the ability to improve 90-day outcomes in ischemic stroke patients treated within 24 hours from stroke onset. The NeuroThera Laser System therapeutic approach involves use of infrared laser technology and has shown significant and sustained beneficial effects in animal models of ischemic stroke. Methods— This was a prospective, intention-to-treat, multicenter, international, double-blind, trial involving 120 ischemic stroke patients treated, randomized 2:1 ratio, with 79 patients in the active treatment group and 41 in the sham (placebo) control group. Only patients with baseline stroke severity measured by National Institutes of Health Stroke Scale (NIHSS) scores of 7 to 22 were included. Patients who received tissue plasminogen activator were excluded. Outcome measures were the patients’ scores on the NIHSS, modified Rankin Scale (mRS), Barthel Index, and Glasgow Outcome Scale at 90 days after treatment. The primary outcome measure, prospectively identified, was successful treatment, documented by NIHSS. This was defined as a complete recovery at day 90 (NIHSS 0 to 1), or a decrease in NIHSS score of at least 9 points (day 90 versus baseline), and was tested as a binary measure (bNIH). Secondary outcome measures included mRS, Barthel Index, and Glasgow Outcome Scale. Primary statistical analyses were performed with the Cochran-Mantel-Haenszel rank test, stratified by baseline NIHSS score or by time to treatment for the bNIH and mRS. Logistic regression analyses were conducted to confirm the results. Results— Mean time to treatment was >16 hours (median time to treatment 18 hours for active and 17 hours for control). Time to treatment ranged from 2 to 24 hours. More patients (70%) in the active treatment group had successful outcomes than did controls (51%), as measured prospectively on the bNIH ( P =0.035 stratified by severity and time to treatment; P =0.048 stratified only by severity). Similarly, more patients (59%) had successful outcomes than did controls (44%) as measured at 90 days as a binary mRS score of 0 to 2 ( P =0.034 stratified by severity and time to treatment; P =0.043 stratified only by severity). Also, more patients in the active treatment group had successful outcomes than controls as measured by the change in mean NIHSS score from baseline to 90 days ( P =0.021 stratified by time to treatment) and the full mRS (“shift in Rankin”) score ( P =0.020 stratified by severity and time to treatment; P =0.026 stratified only by severity). The prevalence odds ratio for bNIH was 1.40 (95% CI, 1.01 to 1.93) and for binary mRS was 1.38 (95% CI, 1.03 to 1.83), controlling for baseline severity. Similar results held for the Barthel Index and Glasgow Outcome Scale. Mortality rates and serious adverse events (SAEs) did not differ significantly (8.9% and 25.3% for active 9.8% and 36.6% for control, respectively, for mortality and SAEs). Conclusion— The NEST-1 study indicates that infrared laser therapy has shown initial safety and effectiveness for the treatment of ischemic stroke in humans when initiated within 24 hours of stroke onset. A larger confirmatory trial to demonstrate safety and effectiveness is warranted.

OBJECTIVE—Foot ulceration is a serious complication of diabetes, and new techniques that can predict wound healing may prove very helpful. We tested the ability of medical hyperspectral technology (HT), a novel diagnostic scanning technique that can quantify tissue oxy- and deoxyhemoglobin to predict diabetic foot ulcer healing. RESEARCH DESIGN AND METHODS—Ten type 1 diabetic patients with 21 foot ulcer sites, 13 type 1 diabetic patients without ulcers, and 14 nondiabetic control subjects were seen up to 4 times over a 6-month period. HT measurements of oxyhemoglobin (HT-oxy) and deoxyhemoglobin (HT-deoxy) were performed at or near the ulcer area and on the upper and lower extremity distant from the ulcer. An HT healing index for each site was calculated from the HT-oxy and -deoxy values. RESULTS—Hyperspectral tissue oxygenation measurements observed changes in tissue immediately surrounding the ulcer when comparing ulcers that heal and ulcers that do not heal (P < 0.001). The sensitivity, specificity, and positive and negative predictive values of the HT index for predicting healing were 93, 86, 93, and 86%, respectively, when evaluated on images taken at the first visit. Changes in HT-oxy among the three risk groups were noted for the metatarsal area of the foot (P < 0.05) and the palm (P < 0.01). Changes in HT-deoxy and the HT healing index were noted for the palm only (P < 0.05 and P < 0.01, respectively). CONCLUSIONS—HT has the capability to identify microvascular abnormalities and tissue oxygenation in the diabetic foot and predict ulcer healing. HT can assist in the management of foot ulceration.

This study was designed to determine whether there is a lateralized pattern of cognitive dysfunction in patients with systemic lupus erythematosus (SLE). Fifty right-handed patients with SLE, but no history of cerebrovascular disease participated in the study. Thirty right-handed healthy subjects matched for age and education served as controls. SLE and healthy control subjects underwent a three-hour neuropsychological evaluation designed to measure attention, memory, visual spatial skills, verbal skills reasoning, psychomotor speed, and motor function. A cognitive disability index was created to identify cognitive impairment. Percentile tables based on the performance of all subjects were constructed for 20 component scores. Any subject with five or more component scores below the 25th percentile was designated impaired. Using this criterion, cognitive impairment was identified in 50% of patients with SLE and 20% of healthy controls. Patients with SLE were impaired on measures of psychomotor speed/fluency, verbal speed/fluency and verbal memory. This pattern of performance on neuropsycholgical testing was consistent with left hemisphere brain dysfunction. The observed deficits were not clearly attributable to vascular lesions and suggest immune-mediated effects on specific brain regions in a subgroup of patients with SLE.

Dehydroepiandrosterone (DHEA) may be beneficial in cardiovascular health, but mechanisms of DHEA action in the cardiovascular system are unclear. We have therefore 1) determined DHEA effects on the proliferation of cultured endothelial cells (EC), 2) compared effects of DHEA with estradiol (E) and testosterone (T), and 3) examined DHEA effects on subcellular messengers. We have in addition examined effects of DHEA (100 mg/d, 3 months) in 36 healthy postmenopausal women on blood pressure, lipids, and endothelial function, assessed noninvasively in large vessels by flow-mediated dilation of the brachial artery during reactive hyperemia, and in small vessels by laser Doppler velocimetry with iontophoresis of acetylcholine. DHEA, E, and T all increased EC proliferation; the effect of E was abolished by the estrogen receptor antagonist ICI 182,780, and that of T was abolished by the androgen receptor antagonist flutamide; neither blocked the effect of DHEA. In vitro, DHEA increased EC expression of endothelial nitric oxide synthase and activity of extracellular signal-regulated kinase 1/2. In vivo, DHEA increased flow-mediated dilation and laser Doppler velocimetry and reduced total plasma cholesterol. Thus, DHEA increases EC proliferation in vitro by mechanism(s) independently of either androgen receptor or estrogen receptor and in vivo enhances large and small vessel EC function in postmenopausal women.

Clinical decision-making in managing the patient with peripheral vascular disease is dependent upon patient history, physical examination, and noninvasive and invasive testing. Noninvasive testing currently includes the ankle-brachial index, pulse volume recordings, and transcutaneous oximetry. Each test yields information regarding perfusion and tissue oxygenation, but has limitations. The ankle-brachial index compares lower extremity blood pressure with the upper extremity, but it must be interpreted with caution in a patient with calcified atherosclerotic vessels, as is seen with diabetic patients, which can lead to an overestimation of actual pressure. Pulse volume recordings are mainly a qualitative estimation of distal perfusion and are highly dependent on the operator, which introduces both intraobserver and interobserver variability. Duplex ultrasound evaluation looses sensitivity in the small vessels of the limb and can be limited by instrument and operator. Transcutaneous oximetry is a quantitative measure of skin (end organ) oxygenation, but is limited by only evaluating one small area of the foot at a given time. Hyperspectral imaging was developed to possibly provide quantitative information regarding the spatial tissue oxygen saturation in patients with peripheral vascular disease.