Chlorthalidone vs. Hydrochlorothiazide for Hypertension-Cardiovascular Events.

BACKGROUND: Whether chlorthalidone is superior to hydrochlorothiazide for preventing major adverse cardiovascular events in patients with hypertension is unclear. METHODS: 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. RESULTS: 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%, P<0.001). CONCLUSIONS: 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.).

Therapies for active rheumatoid arthritis after methotrexate failure.

BACKGROUND: Few blinded trials have compared conventional therapy consisting of a combination of disease-modifying antirheumatic drugs with biologic agents in patients with rheumatoid arthritis who have active disease despite treatment with methotrexate--a common scenario in the management of rheumatoid arthritis. METHODS: We conducted a 48-week, double-blind, noninferiority trial in which we randomly assigned 353 participants with rheumatoid arthritis who had active disease despite methotrexate therapy to a triple regimen of disease-modifying antirheumatic drugs (methotrexate, sulfasalazine, and hydroxychloroquine) or etanercept plus methotrexate. Patients who did not have an improvement at 24 weeks according to a prespecified threshold were switched in a blinded fashion to the other therapy. The primary outcome was improvement in the Disease Activity Score for 28-joint counts (DAS28, with scores ranging from 2 to 10 and higher scores indicating more disease activity) at week 48. RESULTS: Both groups had significant improvement over the course of the first 24 weeks (P=0.001 for the comparison with baseline). A total of 27% of participants in each group required a switch in treatment at 24 weeks. Participants in both groups who switched therapies had improvement after switching (P<0.001), and the response after switching did not differ significantly between the two groups (P=0.08). The change between baseline and 48 weeks in the DAS28 was similar in the two groups (-2.1 with triple therapy and -2.3 with etanercept and methotrexate, P=0.26); triple therapy was noninferior to etanercept and methotrexate, since the 95% upper confidence limit of 0.41 for the difference in change in DAS28 was below the margin for noninferiority of 0.6 (P=0.002). There were no significant between-group differences in secondary outcomes, including radiographic progression, pain, and health-related quality of life, or in major adverse events associated with the medications. CONCLUSIONS: With respect to clinical benefit, triple therapy, with sulfasalazine and hydroxychloroquine added to methotrexate, was noninferior to etanercept plus methotrexate in patients with rheumatoid arthritis who had active disease despite methotrexate therapy. (Funded by the Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, and others; CSP 551 RACAT ClinicalTrials.gov number, NCT00405275.)

Differences in treatment effect among clinical subgroups in a randomized clinical trial of long-acting injectable risperidone and oral antipsychotics in unstable chronic schizophrenia.

A long-term randomized trial of unstable patients with schizophrenia found no benefit of long-acting injectable (LAI) risperidone over oral treatment in preventing or delaying time to psychiatric hospitalizations or on clinical outcomes. The initial analyses did not examine whether benefits of LAI emerged in selected subgroups.Patients with schizophrenia or schizoaffective disorder who had been hospitalized within the past 2 years or judged to be at risk for hospitalization because of increasing psychiatric service use were randomly assigned to LAI risperidone 12.5 to 50 mg per injection biweekly or to the psychiatrist's choice of oral antipsychotics and followed for up to 2 years. The primary endpoint was psychiatric rehospitalization. Symptoms, quality of life, and global functioning were assessed through blinded videoconference interviews. Cox's regression and mixed effects models were used to assess difference in treatment effect within 12 subgroups defined by hospitalization at study entry, substance abuse, race, symptom severity, quality of life, body mass index, age, race or sex, or reported medication compliance.Mixed models and Cox's regression using up to 24 months of follow-up data showed no significant differences in treatment effect in 10 of 12 subgroups on psychiatric symptoms, quality of life, or time to hospitalization. With adjustment for multiple comparisons, treatment effect differed by race on substance use outcomes, with white participants showing more benefit from LAI than other groups.LAI risperidone showed no superiority to psychiatrist's choice of oral treatment in most clinically defined subgroups, although the white patients benefited more than the other groups on substance abuse outcomes.

Chlorthalidone vs Hydrochlorothiazide for Hypertension Treatment After Myocardial Infarction or Stroke: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Patients with prior myocardial infarction (MI) or stroke have a greater risk of recurrent cardiovascular (CV) events. Objective: To evaluate the association of chlorthalidone (CTD) vs hydrochlorothiazide (HCTZ) with CV outcomes and noncancer deaths in participants with and without prior MI or stroke. Design, Setting, and Participants: This was a prespecified secondary analysis of the Diuretic Comparison Project (DCP), a pragmatic randomized clinical trial conducted within 72 participating Veterans Affairs health care systems from June 2016 to June 2021, in which patients aged 65 years or older with hypertension taking HCTZ at baseline were randomized to continue HCTZ or switch to CTD at pharmacologically comparable doses. This secondary analysis was performed from January 3, 2023, to February 29, 2024. Exposures: Pharmacologically comparable daily dose of HCTZ or CTD and history of MI or stroke. Main Outcomes and Measures: Outcome ascertainment was performed from randomization to the end of the study. The primary outcome consisted of a composite of stroke, MI, urgent coronary revascularization because of unstable angina, acute heart failure hospitalization, or noncancer death. Additional outcomes included achieved blood pressure and hypokalemia (potassium level <3.1 mEq/L; to convert to mmol/L, multiply by 1.0). Results: The DCP randomized 13 523 participants to CTD or HCTZ, with a mean (SD) study duration of 2.4 (1.4) years. At baseline, median age was 72 years (IQR, 69-75 years), and 96.8% were male. Treatment effect was evaluated in subgroups of participants with (n = 1455) and without (n = 12 068) prior MI or stroke at baseline. There was a significant adjusted interaction between treatment group and history of MI or stroke. Participants with prior MI or stroke randomized to CTD had a lower risk of the primary outcome than those receiving HCTZ (105 of 733 [14.3%] vs 140 of 722 [19.4%]; hazard ratio [HR], 0.73; 95% CI, 0.57-0.94; P = .01) compared with participants without prior MI or stroke, among whom incidence of the primary outcome was slightly higher in the CTD arm compared with the HCTZ arm (597 of 6023 [9.9%] vs 535 of 6045 [8.9%]; HR, 1.12; 95% CI, 1.00-1.26; P = .054) (P = .01 for interaction). The incidence of a nadir potassium level less than 3.1 mEq/L and hospitalization for hypokalemia differed among those with and without prior MI or stroke when comparing those randomized to CTD vs HCTZ, with a difference only among those without prior MI or stroke (potassium level <3.1 mEq/L: prior MI or stroke, 43 of 733 [5.9%] vs 37 of 722 [5.1%] [P = .57]; no prior MI or stroke, 292 of 6023 [4.9%] vs 206 of 6045 [3.4%] [P < .001]; hospitalization for hypokalemia: prior MI or stroke, 14 of 733 [1.9%] vs 16 of 722 [2.2%] [P = .72]; no prior MI or stroke: 84 of 6023 [1.4%] vs 57 of 6045 [0.9%] [P = .02]). Conclusions and Relevance: Results of this secondary analysis of the DCP trial suggest that CTD may be associated with reduced major adverse CV events and noncancer deaths in patients with prior MI or stroke compared with HCTZ. Trial Registration: ClinicalTrials.gov Identifier: NCT02185417.

Pilot Study of Low-dose Naltrexone for the Treatment of Chronic Pain Due to Arthritis: A Randomized, Double-blind, Placebo-controlled, Crossover Clinical Trial.

PURPOSE: Low-dose naltrexone (LDN) is commonly used to control pain and other symptoms, especially in patients with autoimmune diseases, but with limited evidence. This study tests the efficacy of LDN in reducing chronic pain in patients with osteoarthritis (OA) and inflammatory arthritis (IA), where existing approaches often fail to adequately control pain. METHODS: In this randomized, double-blind, placebo-controlled, crossover clinical trial, each patient received 4.5 mg LDN for 8 weeks and placebo for 8 weeks. Outcome measures were patient reported, using validated questionnaires. The primary outcome was differences in pain interference during the LDN and placebo periods, using the Brief Pain Inventory (scale, 0-70). Secondary outcomes included changes in mean pain severity, fatigue, depression, and multiple domains of health-related quality of life. The painDETECT questionnaire classified pain as nociceptive, neuropathic, or mixed. Data were analyzed using mixed-effects models. FINDINGS: Seventeen patients with OA and 6 with IA completed the pilot study. Most patients described their pain as nociceptive (n = 9) or mixed (n = 8) rather than neuropathic (n = 3). There was no difference in change in pain interference after treatment with LDN (mean [SD], -23 [19.4]) versus placebo (mean [SD], -22 [19.2]; P = 0.90). No significant differences were seen in pain severity, fatigue, depression, or health-related quality of life. IMPLICATIONS: In this small pilot study, findings do not support LDN being efficacious in reducing nociceptive pain due to arthritis. Too few patients were enrolled to rule out modest benefit or to assess inflammatory or neuropathic pain. CLINICALTRIALS: gov identifier: NCT03008590.

Integrating Intimate Partner Violence Screening Programs in Primary Care: Results from a Hybrid-II Implementation-Effectiveness RCT.

INTRODUCTION: The Veterans Health Administration initiated implementation facilitation to integrate intimate partner screening programs in primary care. This study investigates implementation facilitation's impact on implementation and clinical effectiveness outcomes. STUDY DESIGN: A cluster randomized, stepped-wedge, hybrid-II implementation-effectiveness trial (January 2021-April 2022) was conducted amidst the COVID-19 pandemic. SETTING/PARTICIPANTS: Implementation facilitation was applied at 9 Veterans Health Administration facilities, staged across 2 waves. Participants were all women receiving care at participating primary care clinics 3 months before (pre-implementation facilitation n=2,272) and 9 months after initiation of implementation facilitation (implementation facilitation n=5,149). INTERVENTION: Implementation facilitation included an operations-funded external facilitator working for 6 months with a facility-funded internal facilitator from participating clinics. The pre-implementation facilitation period comprised implementation as usual in the Veterans Health Administration. MAIN OUTCOME MEASURES: Primary outcomes were changes in (1) reach of intimate partner violence (IPV) screening programs among eligible women (i.e., those seen within participating clinics during the assessment period; implementation outcome) and (2) disclosure rates among screened women (effectiveness outcome). Secondary outcomes included disclosure rates among all eligible women and post-screening psychosocial service use. Administrative data were analyzed. RESULTS: For primary outcomes, women seen during the implementation facilitation period were nearly 3 times more likely to be screened for IPV than women seen during the pre-implementation facilitation period (OR=2.70, 95% CI=2.46, 2.97). Women screened during the implementation facilitation period were not more likely to disclose IPV than those screened during the pre-implementation facilitation period (OR=1.14, 95% CI=0.86, 1.51). For secondary outcomes, owing to increased reach of screening during implementation facilitation, women seen during the implementation facilitation period were more likely to disclose IPV than those seen during the pre-implementation facilitation period (OR=2.09, 95% CI=1.52, 2.86). Women screened during implementation facilitation were more likely to use post-screening psychosocial services than those screened during pre-implementation facilitation (OR=1.29, 95% CI=1.06, 1.57). CONCLUSIONS: Findings indicate that implementation facilitation may be a promising strategy for increasing the reach of IPV screening programs in primary care, thereby increasing IPV detection and strengthening connections to support services among the patient population. TRIAL REGISTRATION: This study is registered at www. CLINICALTRIALS: gov NCT04106193.

Using the Matrixed Multiple Case Study approach to identify factors affecting the uptake of IPV screening programs following the use of implementation facilitation.

BACKGROUND: Intimate partner violence (IPV) is a prevalent social determinant of health. The US Preventive Services Task Force recommends routine IPV screening of women, but uptake remains variable. The Veterans Health Administration (VHA) initiated implementation facilitation (IF) to support integration of IPV screening programs into primary care clinics. An evaluation of IF efforts showed variability in IPV screening rates across sites. The follow-up study presented here used a Matrixed Multiple Case Study (MMCS) approach to examine the multilevel factors impacting IPV screening program implementation across sites with varying levels of implementation success. METHODS: This mixed methods study is part of a larger cluster randomized stepped wedge Hybrid-II program evaluation. In the larger trial, participating sites received 6 months of IF consisting of an external facilitator from VHA's Office of Women's Health working closely with an internal facilitator and key site personnel. Recognizing the heterogeneity in implementation outcomes across sites, the MMCS approach was used to enable interpretation of qualitative and quantitative data within and across sites to help contextualize the primary findings from the larger study. Qualitative data collection was guided by the integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) framework and included interviews with key informants involved in IPV screening implementation at eight sites. Quantitative data on IPV screening uptake was derived from medical records and surveys completed by key personnel at the same eight sites to understand implementation facilitation activities. RESULTS: Fifteen factors influencing IPV screening implementation spanning all four i-PARIHS domains were identified and categorized into three distinct categories: (1) factors with enabling influence across all sites, (2) factors deemed important to implementation success, and (3) factors differentiating sites with high/medium versus low implementation success. CONCLUSIONS: Understanding the influencing factors across multi-level domains contributing to variable success of IPV screening implementation can inform the tailoring of IF efforts to promote spread and quality of screening. Implementation of IPV screening programs in primary care with IF should consider consistent engagement of internal facilitators with clinic staff involved in implementation, the resourcefulness of external facilitators, and appending resources to IPV screening tools to help key personnel address positive screens. TRIAL REGISTRATION: ClinicalTrials.gov NCT04106193. Registered on September 26, 2019.

Design of a pragmatic clinical trial embedded in the Electronic Health Record: The VA's Diuretic Comparison Project.

BACKGROUND: 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. METHODS: 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%. RESULTS: 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. CONCLUSIONS: DCP should provide much needed evidence as to whether CTD is superior to HCTZ in preventing cardiovascular events in hypertensive patients. CLINICAL TRIAL REGISTRATION: NCT02185417 [https://clinicaltrials.gov/ct2/show/NCT02185417].

A point-of-care clinical trial comparing insulin administered using a sliding scale versus a weight-based regimen.

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.

Assessing the Veterans Health Administration's response to intimate partner violence among women: protocol for a randomized hybrid type 2 implementation-effectiveness trial.

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.

A method to reduce imbalance for site-level randomized stepped wedge implementation trial designs.

BACKGROUND: Controlled implementation trials often randomize the intervention at the site level, enrolling relatively few sites (e.g., 6-20) compared to trials that randomize by subject. Trials with few sites carry a substantial risk of an imbalance between intervened (cases) and non-intervened (control) sites in important site characteristics, thereby threatening the internal validity of the primary comparison. A stepped wedge design (SWD) staggers the intervention at sites over a sequence of times or time waves until all sites eventually receive the intervention. We propose a new randomization method, sequential balance, to control time trend in site allocation by minimizing sequential imbalance across multiple characteristics. We illustrate the new method by applying it to a SWD implementation trial. METHODS: The trial investigated the impact of blended internal-external facilitation on the establishment of evidence-based teams in general mental health clinics in nine US Department of Veterans Affairs medical centers. Prior to randomization to start time, an expert panel of implementation researchers and health system program leaders identified by consensus a series of eight facility-level characteristics judged relevant to the success of implementation. We characterized each of the nine sites according to these consensus features. Using a weighted sum of these characteristics, we calculated imbalance scores for each of 1680 possible site assignments to identify the most sequentially balanced assignment schemes. RESULTS: From 1680 possible site assignments, we identified 34 assignments with minimal imbalance scores, and then randomly selected one assignment by which to randomize start time. Initially, the mean imbalance score was 3.10, but restricted to the 34 assignments, it declined to 0.99. CONCLUSIONS: Sequential balancing of site characteristics across groups of sites in the time waves of a SWD strengthens the internal validity of study conclusions by minimizing potential confounding. TRIAL REGISTRATION: Registered at ClinicalTrials.gov as clinical trials # NCT02543840 ; entered 9/4/2015.

Chemoprevention of Basal and Squamous Cell Carcinoma With a Single Course of Fluorouracil, 5%, Cream: A Randomized Clinical Trial.

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.

Medical hyperspectral imaging to facilitate residual tumor identification during surgery.

INTRODUCTION: Adequate evaluation of breast tumor resection at surgery continues to be an important issue in surgical care, as over 30% of postoperative tumors recur locally unless radiation is used to destroy remaining tumor cells in the field. Medical Hyperspectral Imaging (MHSI) delivers near-real time images of biomarkers in tissue, providing an assessment of pathophysiology and the potential to distinguish different tissues based on spectral characteristics. METHODS: We have used an experimental DMBA-induced rat breast tumor model to examine the intraoperative utility of MHSI, in distinguishing tumor from normal breast and other tissues. Rats bearing tumors underwent surgical exposure and MHSI imaging, followed by partial resection of the tumors, then MHSI imaging of the resection bed, and finally total resection of tumors and of grossly normal-appearing glands. Resected tissue underwent gross examination, MHSI imaging, and histopathological evaluation. RESULTS: An algorithm based on spectral characteristics of tissue types was developed to distinguish between tumor and normal tissues. Tissues including tumor, blood vessels, muscle, and connective tissue were clearly identified and differentiated by MHSI. Fragments of residual tumor 0.5-1 mm in size intentionally left in the operative bed were readily identified. MHSI demonstrated a sensitivity of 89% and a specificity of 94% for detection of residual tumor, comparable to that of histopathological examination of the tumor bed (85% and 92%, respectively). CONCLUSION: We conclude that MHSI may be useful in identifying small residual tumor in a tumor resection bed and for indicating areas requiring more extensive resection and more effective biopsy locations to the surgeon.

Using antineutrophil cytoplasmic antibody testing to diagnose vasculitis: can test-ordering guidelines improve diagnostic accuracy?

BACKGROUND: Antineutrophil cytoplasmic antibodies (ANCAs) are strongly associated with Wegener granulomatosis, Churg-Strauss angiitis, microscopic polyangiitis, and pauci-immune glomerulonephritis, referred to collectively as ANCA-associated vasculitis (AAVs). It is unclear how accurate ANCA measurement is for diagnosing AAV in diverse populations or whether proposed ANCA test-ordering guidelines improve test performance. METHODS: We assembled a retrospective case series of hospitalized and ambulatory patients from 2 academic medical centers to assess the diagnostic accuracy of ANCA measurement by enzyme-linked immunosorbent assay in identifying cases of AAV. In addition, we assessed the effect of applying proposed ANCA test-ordering guidelines on test performance. RESULTS: For ANCA testing, sensitivity was 81%; specificity, 98%; positive predictive value, 54%; and negative predictive value, 99%. There were no significant changes in operating characteristics after applying the guideline criteria. Using guidelines would have decreased ANCA test ordering by 23% and would have decreased the false-positive rate by 27%. No cases of AAV would have been missed if only patients fulfilling the guidelines were ANCA tested. CONCLUSION: A positive result on an enzyme-linked immunosorbent assay ANCA test, as it is currently ordered, is not a definitive diagnostic indicator of AAV. Compliance with guidelines for ANCA testing would decrease the number of false-positive results and has the potential to reduce total test expenditures.

Statistical considerations for stopping systemic lupus erythematosus clinical trials earlier.

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.

Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial.

Specific receptors for vitamin D have been identified in human muscle tissue. Cross-sectional studies show that elderly persons with higher vitamin D serum levels have increased muscle strength and a lower number of falls. We hypothesized that vitamin D and calcium supplementation would improve musculoskeletal function and decrease falls. In a double-blind randomized controlled trial, we studied 122 elderly women (mean age, 85.3 years; range, 63-99 years) in long-stay geriatric care. Participants received 1200 mg calcium plus 800 IU cholecalciferol (Cal+D-group; n = 62) or 1200 mg calcium (Cal-group; n = 60) per day over a 12-week treatment period. The number of falls per person (0, 1, 2-5, 6-7, >7 falls) was compared between the treatment groups. In an intention to treat analysis, a Poisson regression model was used to compare falls after controlling for age, number of falls in a 6-week pretreatment period, and baseline 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D serum concentrations. Among fallers in the treatment period, crude excessive fall rate (treatment - pretreatment falls) was compared between treatment groups. Change in musculoskeletal function (summed score of knee flexor and extensor strength, grip strength, and the timed up&go test) was measured as a secondary outcome. Among subjects in the Cal+D-group, there were significant increases in median serum 25-hydroxyvitamin D (+71%) and 1,25-dihydroxyvitamin D (+8%). Before treatment, mean observed number of falls per person per week was 0.059 in the Cal+D-group and 0.056 in the Cal-group. In the 12-week treatment period, mean number of falls per person per week was 0.034 in the Cal+D-group and 0.076 in the Cal-group. After adjustment, Cal+D-treatment accounted for a 49% reduction of falls (95% CI, 14-71%; p < 0.01) based on the fall categories stated above. Among fallers of the treatment period, the crude average number of excessive falls was significantly higher in the Cal-group (p = 0.045). Musculoskeletal function improved significantly in the Cal+D-group (p = 0.0094). A single intervention with vitamin D plus calcium over a 3-month period reduced the risk of falling by 49% compared with calcium alone. Over this short-term intervention, recurrent fallers seem to benefit most by the treatment. The impact of vitamin D on falls might be explained by the observed improvement in musculoskeletal function.

Evaluation of methods for improving precision of blood pressure measurements in phase I clinical trials.

Small sample sizes are typically incorporated in early Phase I clinical studies, which may lead to insignificant changes in safety parameters such as blood pressure. Therefore, it is paramount to identify an optimal, noninvasive method of accurately measuring blood pressure and an appropriate analysis strategy yielding the smallest variability. The goals of this study were (1) to compare the variability between automated and manual blood pressure measurements, (2) to determine whether triplicate blood pressure measurements were independent of one another, and (3) to assess how the number of blood pressure readings affects variability and study sample size. Twenty healthy volunteers were enrolled in this randomized, two-way crossover study. Each subject received three incremental infusions of phenylephrine or normal saline on separate days to simulate blood pressure variability. The mean systolic blood pressure readings with the automated device were consistently higher than the manual device by 3 to 5 mmHg. Conversely, the mean diastolic blood pressure readings with the automated device were consistently 3 to 5 mmHg lower than the manual device. However, the variability and absolute change in blood pressure were essentially identical with manual and automated methods. No systematic order effects such as the first blood pressure reading always being higher were detected, suggesting that the triplicate readings were independent of one another and that an interval of 2 minutes between readings is adequate. Compared to a single measurement, collecting blood pressure in triplicate results in a 40% lower sample size needed to detect a 5-mmHg difference in systolic blood pressure.

Sun protection policies and environmental features in US elementary schools.

OBJECTIVE: To assess current sun protection policies and the receptiveness to new policies at elementary schools in the United States. DESIGN: A cross-sectional telephone survey. SETTING: General educational community. PATIENTS OR OTHER PARTICIPANTS: In 1998, a random sample of 1000 public elementary schools in the United States was selected (proportional to population size) from 27 metropolitan areas chosen from the 58 US cities regularly reporting the UV index in 1997. A final sample of principals from 412 elementary schools completed the survey. INTERVENTION: None. MAIN OUTCOME MEASURES: Only 3.4% of schools had a sun protection policy. The most common reasons for not having a policy included the principal's lack of awareness (n = 113) or organizational barriers in the school districts (n = 77). Most principals (84.2%) said that students were outdoors during midday hours. Many principals (48.3%) were willing to adopt a sun protection policy. Most schools (72.8%) had shade structures but the majority (67.3%) reportedly covered less than one fifth of the grounds. Most principals (76.4%) were willing to increase the amount of shade structures. CONCLUSIONS: The low frequency of sun protection policies and shade structures calls for national efforts to change policies and environments to increase sun protection at US schools. Research is needed to demonstrate the efficacy of these changes.

Rates and outcomes of primary and revision total hip replacement in the United States medicare population.

BACKGROUND: Information on the epidemiology of primary total hip replacement is limited, and we are not aware of any reports on the epidemiology of revision total hip replacement. The objective of this study was to characterize the rates and immediate postoperative outcomes of primary and revision total hip replacement in persons sixty-five years of age and older residing in the United States. METHODS: We used Medicare claims submitted by hospitals, physicians, and outpatient facilities between July 1, 1995, and June 30, 1996, to identify individuals who had undergone elective primary total hip replacement for a reason other than a fracture (61,568 patients) or had had revision total hip replacement (13,483 patients). Annual incidence rates of primary and revision total hip replacement were calculated, and multivariate modeling was used to evaluate the association between patient characteristics and surgical rates. The rates of occurrence of five complications within ninety days postoperatively were also evaluated, and relationships between those outcomes and patient characteristics were assessed with use of multivariate models adjusted for hospital and surgeon volume. RESULTS: The rates of primary total hip replacement were three to six times higher than the rates of revision total hip replacement. Women had higher rates than men, and whites had higher rates than blacks. The rates of primary and revision total hip replacement increased with age until the age of seventy-five to seventy-nine years and then declined. The rates of complications occurring within ninety days after primary total hip replacement were 1.0% for mortality, 0.9% for pulmonary embolus, 0.2% for wound infection, 4.6% for hospital readmission, and 3.1% for hip dislocation. The rates after revision total hip replacement were 2.6%, 0.8%, 0.95%, 10.0%, and 8.4%, respectively. Factors associated with an increased risk of an adverse outcome included increased age, gender (men were at higher risk than women), race (blacks were at higher risk than whites), a medical comorbidity, and a low income. CONCLUSIONS: Analysis of United States Medicare population data showed that the rates of total hip replacement increased with age up to the age of seventy-five to seventy-nine years and that blacks had a significantly lower rate of total hip replacement than whites. The overall rates of adverse outcomes were relatively low, but they were significantly higher after revision than after primary total hip replacement. LEVEL OF EVIDENCE: Prognostic study, Level II-1 (retrospective study). See p. 2 for complete description of levels of evidence.