Publications by authors named "Mei-Chiung Shih"

55 Publications

Prevalence of predicted gene-drug interactions for antidepressants in the treatment of major depressive disorder in the Precision Medicine in Mental Health Care Study.

J Affect Disord 2021 03 14;282:1272-1277. Epub 2021 Jan 14.

Veterans Integrated Service Network 4 Mental Illness Research, Education, and Clinical Center (MIRECC), Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background: Pharmacogenetic (PGx) testing is a potentially important, but understudied approach to precision medicine that could improve prescribing practices for antidepressants (ADs) in patients with Major Depressive Disorder (MDD). Thus, it is important to understand the scope of its potential impact and to identify patients who may benefit most from PGx-guided care.

Methods: Participants were treatment-seeking US veterans (N=1149) with MDD enrolled in the Precision Medicine in Mental Health Care study, a pragmatic multi-site, randomized, controlled trial that examines the utility of PGx testing in the context of pharmacotherapy for MDD. We report the prevalence of ADs with predicted moderate and clinically significant gene-drug interaction potential based on next-intended treatment. We also examined demographic and treatment history characteristics as predictors of the gene-drug interaction potential of participants' next-intended treatment.

Results: Prevalence of the next-intended AD with moderate or clinically significant gene-drug interaction was 45.1% and19.3%. Previous treatment with an AD in the past two years was associated with a 1.59 increased likelihood of having a next-intended AD treatment with predicted clinically significant gene-drug interaction (95% CI: 1.08-2.35).

Limitations: The gene-drug interaction potential of ADs is specific to the PGx test panel used in this study and may not generalize to other PGx test panels.

Conclusions: PGx testing could benefit one in five patients prescribed ADs with clinically significant gene-drug interaction potential. Patients with prior AD treatment are more likely to have an AD with significant gene-drug interaction potential as their next-intended treatment and therefore may benefit most from PGx testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jad.2021.01.034DOI Listing
March 2021

Treatment Preferences for Chronic Low Back Pain: Views of Veterans and Their Providers.

J Pain Res 2021 27;14:161-171. Epub 2021 Jan 27.

VA HSR&D Center for Health Information and Communication, Roudebush VA Medical Center, Indianapolis, IN, USA.

Purpose: This study was conducted to characterize chronic low back pain (cLBP) and to identify treatment histories and preferences for cLBP management among Veterans and primary care providers within the Veterans Affairs (VA) healthcare system.

Participants And Methods: Veterans with cLBP from five geographically diverse VA medical centers were identified using International Classification of Diseases (ICD) 9 and 10 codes from VA administrative data as were primary care providers at these same sites. From these data, Veterans (200/per site) and providers (160/per site) were selected and mailed surveys. Open-ended interview data were collected from a subset of Veterans and providers.

Results: In total, 235 Veterans and 67 providers returned completed surveys. More than 80% of the Veteran respondents had daily back pain for more than 1 year. Most Veterans had tried several treatments for their pain with medications and physical therapy being the most commonly used. Veterans and providers had similar attitudes towards many cLBP treatments with the exception of psychological therapies that were more favored by providers. Open-ended interview data showed that Veterans and providers emphasized the need for multi-component approaches to treatment.

Conclusion: Among Veterans, cLBP is typically of sustained duration, is relatively severe, and also interferes significantly with normal functioning. Veterans are experienced with respect to treatments and had similar attitudes towards many cLBP treatments as their providers, especially tailored approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/JPR.S290400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850463PMC
January 2021

Study design and implementation of the PRecision Medicine In MEntal health Care (PRIME Care) Trial.

Contemp Clin Trials 2021 Feb 11;101:106247. Epub 2020 Dec 11.

VA Center for Integrated Healthcare, VAWNYHS (116N), Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 3495 Bailey Avenue, Buffalo, NY 14215, USA. Electronic address:

Genomic testing has the potential to improve patient outcomes and reduce patient care costs by personalizing medication selection. Commercial pharmacogenetic (PGx) testing for psychotropic and other medications is widely available and promoted as a means to implement "precision medicine." Despite evidence that genetic variation affects the metabolism of psychotropic medications, the clinical utility of these test results has not been established. Moreover, implementing such testing in routine clinical care is complex, requiring informatics support and a systematic approach to patient and provider education. The PRIME Care program is designed to bridge this gap, applying both clinical trials and implementation science methods to conduct a program of research. It is centered on a large, pragmatic randomized clinical trial (RCT) in which 2000 Veterans with a major depressive disorder (MDD) and their health care providers are randomized together to receive PGx test results at the beginning of an episode of care or 6 months later. We hypothesize that providers who receive the PGx test results will prescribe an antidepressant guided by the PGx findings and Veterans whose care is guided by PGx testing will experience higher rates of remission from MDD. If the results of the trial replicate those of prior PGx studies, which provided preliminary evidence of the utility of PGx guided prescribing, it would strongly support using a precision medicine approach to treat MDD. This program of research is also evaluating dissemination influencers, other biomarkers (e.g., genetic variation associated with depression response), and the health care cost implications of PGx testing. ClinicalTrials.gov Identifier: NCT03170362.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cct.2020.106247DOI Listing
February 2021

Stent-Only Versus Adjunctive Balloon Angioplasty Approach for Saphenous Vein Graft Percutaneous Coronary Intervention: Insights From DIVA Trial.

Circ Cardiovasc Interv 2020 02 5;13(2):e008494. Epub 2020 Feb 5.

Minneapolis Heart Institute Foundation, MN (B.V.R., E.S.B.).

Background: Direct stenting without pre-dilation or post-dilation has been advocated for saphenous vein graft percutaneous coronary intervention to decrease the incidence of distal embolization, periprocedural myocardial infarction, and target lesion revascularization.

Methods: We performed a post hoc analysis of patients enrolled in the DIVA (Drug-Eluting Stents Versus Bare Metal Stents in Saphenous Vein Graft Angioplasty; NCT01121224) prospective, double-blind, randomized controlled trial. Patients were stratified into stent-only and balloon-stent groups. Primary end point was 12-month incidence of target vessel failure (defined as the composite of cardiac death, target vessel myocardial infarction, or target vessel revascularization). Secondary end points included all-cause death, stent thrombosis, myocardial infarction, and target lesion revascularization during follow-up.

Results: Of the 575 patients included in this substudy, 185 (32%) patients underwent stent-only percutaneous coronary intervention. Patients in the stent-only versus balloon-stent group had similar baseline characteristics and similar incidence of target vessel failure at 12-months (15% versus 19%; hazard ratio, 1.34 [95% CI, 0.86-2.08]; =0.19). During long-term follow-up (median of 2.7 years), the incidence of definite stent thrombosis (1% versus 5%; hazard ratio, 9.20 [95% CI, 1.23-68.92]; =0.0085), the composite of definite or probable stent thrombosis (5% versus 11%; hazard ratio, 2.52 [95% CI, 1.23-5.18]; =0.009), and target vessel myocardial infarction (8% versus 14%; hazard ratio, 1.92 [95% CI, 1.08-3.40]; =0.023) was lower in the stent-only group. Multivariable analysis showed that a higher number of years since coronary artery bypass grafting and >1 target saphenous vein graft lesions were associated with increased target vessel failure during entire follow-up, while preintervention Thrombolysis in Myocardial Infarction-3 flow was protective.

Conclusions: In patients undergoing percutaneous coronary intervention of de novo saphenous vein graft lesions, there was no difference in target vessel failure at 12 months and long-term follow-up in the stent-only versus the balloon-stent group; however, the incidence of stent thrombosis was lower in the stent-only group, as was target vessel myocardial infarction. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01121224.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCINTERVENTIONS.119.008494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053803PMC
February 2020

Veterans Affairs Cooperative Studies Program Study #553: Chemotherapy After Prostatectomy for High-risk Prostate Carcinoma: A Phase III Randomized Study.

Eur Urol 2020 05 8;77(5):563-572. Epub 2020 Jan 8.

VA Puget Sound Health Care System, Seattle, WA, USA.

Background: The Veterans Affairs Cooperative Studies Program study #553 was designed to evaluate the efficacy of adjuvant chemotherapy added to the standard of care (SOC) for patients who are at high risk for relapse after prostatectomy.

Objective: To test whether addition of chemotherapy to surgery for high-risk prostate cancer improves progression-free survival (PFS).

Design, Setting, And Participants: Eligible patients after prostatectomy were randomized to the SOC group with observation or to the chemotherapy group with docetaxel and prednisone administered every 3 wk for six cycles. Randomization was stratified for prostate-specific antigen, Gleason, tumor stage, and surgical margin status.

Outcome Measurements And Statistical Analysis: The primary endpoint was PFS. Secondary endpoints included overall, prostate cancer-specific, and metastasis-free survival, and time to androgen deprivation therapy.

Results And Limitations: A total of 298 of the planned 636 patients were randomized. The median follow-up was 59.1 mo (0.2-103.7 mo). For the primary endpoint, the two groups did not statistically differ in PFS (median 55.5 mo in the chemotherapy group and 42.2 mo in the SOC group; test adjusted for site via gamma frailty p=0.21; adjusted hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.58-1.11; p=0.18). Prespecified subgroup analyses showed benefit in PFS for patients with tumor stage ≥T3b (HR 0.54, 95% CI 0.32-0.92; p=0.022) and patients with Gleason score ≤7 (HR 0.65, 95% CI 0.43-0.99; p=0.046). Secondary endpoint analyses are hampered by low event rates. The most common adverse events (≥grade 3 related or possibly related to chemotherapy) included neutropenia (43%), hyperglycemia (20%), and fatigue (5%), with febrile neutropenia in 2%.

Conclusions: Adjuvant chemotherapy in high-risk prostate cancer using docetaxel and prednisone did not lead to statistically significant improvement in PFS for the intention-to-treat population as a whole. The analysis was challenged by lower power due to accrual limitation. Subgroup analyses suggest potential benefit for patients with Gleason grade ≤7 and stage≥pT3b (ClinicalTrials.gov number NCT00132301).

Patient Summary: In this randomized trial, we tested whether addition of chemotherapy to surgery for high-risk prostate cancer decreased the risk of prostate-specific antigen rise after surgery. We found no benefit from docetaxel given after radical prostatectomy, although some subgroups of patients may benefit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eururo.2019.12.020DOI Listing
May 2020

Corrigendum to "Design of VA Cooperative Study #591: CERV-PTSD, Comparative Effectiveness Research in Veterans with PTSD" [Contemp. Clin. Trials 41 (2015) 75-84].

Contemp Clin Trials 2019 May 5;80:61. Epub 2019 Apr 5.

VA Cooperative Studies Program Coordinating Center, Palo Alto, CA, USA; Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cct.2019.04.003DOI Listing
May 2019

Drug-eluting stents versus bare-metal stents in saphenous vein grafts: a double-blind, randomised trial.

Lancet 2018 05 11;391(10134):1997-2007. Epub 2018 May 11.

VA North Texas Health Care System, Dallas, TX, USA; University of Texas Southwestern Medical School, Dallas, TX, USA.

Background: Few studies have examined the efficacy of drug-eluting stents (DES) for reducing aortocoronary saphenous vein bypass graft (SVG) failure compared with bare-metal stents (BMS) in patients undergoing stenting of de-novo SVG lesions. We assessed the risks and benefits of the use of DES versus BMS in de-novo SVG lesions.

Methods: Patients were recruited to our double-blind, randomised controlled trial from 25 US Department of Veterans Affairs centres. Eligible participants were aged at least 18 years and had at least one significant de-novo SVG lesion (50-99% stenosis of a 2·25-4·5 mm diameter SVG) requiring percutaneous coronary intervention with intent to use embolic protection devices. Enrolled patients were randomly assigned, in a 1:1 ratio, by phone randomisation system to receive a DES or BMS. Randomisation was stratified by presence or absence of diabetes and number of target SVG lesions requiring percutaneous coronary intervention (one or two or more) within each participating site by use of an adaptive scheme intended to balance the two stent type groups on marginal totals for the stratification factors. Patients, referring physicians, study coordinators, and outcome assessors were masked to group allocation. The primary endpoint was the 12-month incidence of target vessel failure, defined as the composite of cardiac death, target vessel myocardial infarction, or target vessel revascularisation. The DIVA trial is registered with ClinicalTrials.gov, number NCT01121224.

Findings: Between Jan 1, 2012, and Dec 31, 2015, 599 patients were randomly assigned to the stent groups, and the data for 597 patients were used. The patients' mean age was 68·6 (SD 7·6) years, and 595 (>99%) patients were men. The two stent groups were similar for most baseline characteristics. At 12 months, the incidence of target vessel failure was 17% (51 of 292) in the DES group versus 19% (58 of 305) in the BMS group (adjusted hazard ratio 0·92, 95% CI 0·63-1·34, p=0·70). Between-group differences in the components of the primary endpoint, serious adverse events, or stent thrombosis were not significant. Enrolment was stopped before the revised target sample size of 762 patients was reached.

Interpretation: In patients undergoing stenting of de-novo SVG lesions, no significant differences in outcomes between those receiving DES and BMS during 12 months of follow-up were found. The study results have important economic implications in countries with high DES prices such as the USA, because they suggest that the lower-cost BMS can be used in SVG lesions without compromising either safety or efficacy.

Funding: US Department of Veterans Affairs Cooperative Studies Program.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(18)30801-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402785PMC
May 2018

Trial of Prazosin for Post-Traumatic Stress Disorder in Military Veterans.

N Engl J Med 2018 02;378(6):507-517

From the Veterans Affairs (VA) Northwest Network Mental Illness Research, Education, and Clinical Center (M.A.R., E.R.P., H.A.H., K.L.H., M.M.) and the Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine (M.A.R., E.R.P., M.M.), Seattle; VA Cooperative Studies Program Coordinating Center, Palo Alto (B.C., M.-C.S., Y.L.), VA Long Beach Healthcare System, Department of Human Behavior, University of California, Irvine (C.R.), the Department of Health Research and Policy, Stanford University School of Medicine, Stanford (M.-C.S., Y.L.), and the VA San Diego Healthcare System (M.B.S.) and the Departments of Psychiatry and Family Medicine and Public Health, University of California at San Diego (M.B.S.), San Diego - all in California; VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, NM (C.H., A.D.-K.); the Department of Psychiatry, Howard University (T.A.M.), and the Cooperative Studies Program Central Office (G.D.H.), Department of Veterans Affairs, Office of Research and Development (T.G.), Washington, DC; VA Salt Lake City, Salt Lake City (J.R.); VA Northeast Program Evaluation Center, West Haven, and the Departments of Psychiatry and Public Health, Yale School of Medicine, New Haven - both in Connecticut (R.R.); and Providence VA Medical Center and the Department of Psychiatry and Human Behavior, Brown Alpert Medical School, Providence, RI (R.S.).

Background: In randomized trials, prazosin, an α-adrenoreceptor antagonist, has been effective in alleviating nightmares associated with post-traumatic stress disorder (PTSD) in military veterans.

Methods: We recruited veterans from 13 Department of Veterans Affairs medical centers who had chronic PTSD and reported frequent nightmares. Participants were randomly assigned to receive prazosin or placebo for 26 weeks; the drug or placebo was administered in escalating divided doses over the course of 5 weeks to a daily maximum of 20 mg in men and 12 mg in women. After week 10, participants continued to receive prazosin or placebo in a double-blind fashion for an additional 16 weeks. The three primary outcome measures were the change in score from baseline to 10 weeks on the Clinician-Administered PTSD Scale (CAPS) item B2 ("recurrent distressing dreams"; scores range from 0 to 8, with higher scores indicating more frequent and more distressing dreams); the change in score from baseline to 10 weeks on the Pittsburgh Sleep Quality Index (PSQI; scores range from 0 to 21, with higher scores indicating worse sleep quality); and the Clinical Global Impression of Change (CGIC) score at 10 weeks (scores range from 1 to 7, with lower scores indicating greater improvement and a score of 4 indicating no change).

Results: A total of 304 participants underwent randomization; 152 were assigned to prazosin, and 152 to placebo. At 10 weeks, there were no significant differences between the prazosin group and the placebo group in the mean change from baseline in the CAPS item B2 score (between-group difference, 0.2; 95% confidence interval [CI], -0.3 to 0.8; P=0.38), in the mean change in PSQI score (between-group difference, 0.1; 95% CI, -0.9 to 1.1; P=0.80), or in the CGIC score (between-group difference, 0; 95% CI, -0.3 to 0.3; P=0.96). There were no significant differences in these measures at 26 weeks (a secondary outcome) or in other secondary outcomes. At 10 weeks, the mean difference between the prazosin group and the placebo group in the change from baseline in supine systolic blood pressure was a decrease of 6.7 mm Hg. The adverse event of new or worsening suicidal ideation occurred in 8% of the participants assigned to prazosin versus 15% of those assigned to placebo.

Conclusions: In this trial involving military veterans who had chronic PTSD, prazosin did not alleviate distressing dreams or improve sleep quality. (Funded by the Department of Veterans Affairs Cooperative Studies Program; PACT ClinicalTrials.gov number, NCT00532493 .).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1507598DOI Listing
February 2018

Rationale and design of the Drug-Eluting Stents vs Bare-Metal Stents in Saphenous Vein Graft Angioplasty (DIVA) Trial.

Clin Cardiol 2017 Nov 25;40(11):946-954. Epub 2017 Aug 25.

VA Cooperative Studies Program Coordinating Center, Mountain View, California.

VA Cooperative Studies Program #571 (DIVA) was designed to evaluate the efficacy of drug-eluting stents (DES) for reducing aortocoronary saphenous vein bypass graft (SVG) failure when compared with bare-metal stents (BMS) in participants undergoing stenting of de novo SVG lesions. Participants undergoing clinically indicated stenting of de novo SVG lesions were randomized in a 1:1 ratio to DES or BMS. Randomization was stratified by presence/absence of diabetes mellitus and the number of target SVG lesions (1 vs ≥2) within each participating site. At sites that did not routinely administer 12-months of dual antiplatelet therapy after SVG stenting participants without acute coronary syndromes received 1 month of open-label clopidogrel, followed by 11 months of clopidogrel for those assigned to DES and 11 months of placebo for those assigned to BMS. The primary endpoint was the 12-month incidence of target-vessel failure (defined as the composite of cardiac death, target-vessel myocardial infarction, or target-vessel revascularization). Secondary endpoints included the incidence of other clinical endpoints and the incremental cost-effectiveness of DES relative to BMS. Due to lower-than-anticipated target-vessel failure rates, target enrollment was increased from 519 to 762. The study had randomized 599 participants when recruitment ended in December 2015. The DIVA trial will provide clarity on the appropriate stent type for de novo SVG lesions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/clc.22763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490623PMC
November 2017

Does distance modify the effect of self-testing in oral anticoagulation?

Am J Manag Care 2016 Jan;22(1):65-71

Bedford VA Medical Center, 200 Springs Rd, Bedford, MA 01730. E-mail:

Objectives: Patient self-testing (PST) improves anticoagulation control and patient satisfaction. It is unknown whether these effects are more pronounced when the patient lives farther from the anticoagulation clinic (ACC). If the benefits of PST are limited to a subset of patients (those living farther from care), selectively providing PST to that subset could enhance cost-effectiveness.

Study Design: This is a secondary analysis of a randomized trial of PST versus usual ACC care, which involved 2922 patients of the Veterans Health Administration (VHA).

Methods: Our 3 outcomes were the primary composite clinical end point (stroke, major hemorrhage, or death), anticoagulation control (percent time in therapeutic range), and satisfaction with anticoagulation care. We measured the driving distance between the patient's residence and the nearest VHA facility. We divided patients into quartiles by distance and looked for evidence of an interaction between distance and the effect of the intervention on the 3 outcomes.

Results: The median driving distance was 12 miles (interquartile range = 6-21). Patients living in the farthest quartile had higher rates of the primary composite clinical end point in both groups compared with patients living in the nearest quartile. For PST, the hazard ratio (HR) was 1.77 (95% CI, 1.18-2.64), and for usual care, the HR was 1.81 (95% CI, 1.19-2.75). Interaction terms did not suggest that distance to care modified the effect of the intervention on any outcome.

Conclusions: The benefits of PST were not enhanced among patients living farther from care. Restricting PST to patients living more than a certain distance from the ACC is not likely to improve its cost-effectiveness.
View Article and Find Full Text PDF

Download full-text PDF

Source
January 2016

Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature.

Intensive Care Med 2016 May 27;42(5):829-840. Epub 2015 Oct 27.

Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.

Purpose: To investigate the effect of prolonged glucocorticoid treatment for patients with acute respiratory distress syndrome (ARDS).

Methods: We conducted two sets of intention-to-treat analyses: (1) a primary analysis of individual patients' data (IPD) of four randomized controlled trials (RCTs) which investigated methylprednisolone treatment (n = 322) and (2) a trial-level meta-analysis incorporating four additional RCTs which investigated hydrocortisone treatment in early ARDS (n = 297). We standardized definitions to derive outcomes in all datasets. The primary outcome for the IPD analysis was time to achieving unassisted breathing (UAB) by study day 28. Secondary outcomes included mechanical ventilation (MV) and intensive care unit (ICU)-free days, hospital mortality, and time to hospital mortality by day 28.

Results: By study day 28, compared to the placebo group, the methylprednisolone group had fewer patients who died before achieving UAB (12 vs. 29 %; p < 0.001) and more patients who achieved UAB (80 vs. 50 %; p < 0.001). In the methylprednisolone group, time to achieving UAB was shorter [hazard ratio 2.59, 95 % confidence interval (CI) 1.95-3.43; p < 0.001], and hospital mortality was decreased (20 vs. 33 %; p = 0.006), leading to increased MV (13.3 ± 11.8 vs. 7.6 ± 5.7; p < 0.001) and ICU-free days (10.8 ± 0.71 vs. 6.4 ± 0.85; p < 0.001). In those patients randomized before day 14 of ARDS onset, the trial-level meta-analysis indicated decreased hospital mortality (36 vs. 49 %; risk ratio 0.76, 95 % CI 0.59-0.98, I (2) = 17 %, p = 0.035; moderate certainty). Treatment was not associated with increased risk for infections (risk ratio 0.77, 95 % CI 0.56-1.08, I (2) = 26 %; p = 0.13; moderate certainty).

Conclusions: Prolonged methylprednisolone treatment accelerates the resolution of ARDS, improving a broad spectrum of interrelated clinical outcomes and decreasing hospital mortality and healthcare utilization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00134-015-4095-4DOI Listing
May 2016

Innovative designs of point-of-care comparative effectiveness trials.

Contemp Clin Trials 2015 Nov 19;45(Pt A):61-8. Epub 2015 Jun 19.

Department of Statistics, Stanford University, Stanford, CA, USA; Department of Health Research and Policy, Stanford University, Stanford, CA, USA.

One of the provisions of the health care reform legislation in 2010 was for funding pragmatic clinical trials or large observational studies for comparing the effectiveness of different approved medical treatments, involving broadly representative patient populations. After reviewing pragmatic clinical trials and the issues and challenges that have made them just a small fraction of comparative effectiveness research (CER), we focus on a recent development that uses point-of-care (POC) clinical trials to address the issue of "knowledge-action gap" in pragmatic CER trials. We give illustrative examples of POC-CER trials and describe a trial that we are currently planning to compare the effectiveness of newly approved oral anticoagulants. We also develop novel stage-wise designs of information-rich POC-CER trials under competitive budget constraints, by using recent advances in adaptive designs and other statistical methodologies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cct.2015.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639459PMC
November 2015

Design of VA Cooperative Study #591: CERV-PTSD, comparative effectiveness research in veterans with PTSD.

Contemp Clin Trials 2015 Mar 29;41:75-84. Epub 2014 Nov 29.

VA Cooperative Studies Program Coordinating Center, Palo Alto, CA, USA; Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA.

CERV-PTSD is a randomized controlled trial of two of the most effective treatments for PTSD, Prolonged Exposure (PE) and Cognitive Processing Therapy (CPT). Despite solid evidence that both treatments are effective, there is limited evidence about their effectiveness relative to one another. The primary objective is to compare the effectiveness of PE and CPT for reducing PTSD symptom severity in a healthcare system that offers both treatments. The secondary objective is to compare the effectiveness of PE and CPT for reducing the severity of comorbid mental health problems and service utilization as well as improving functioning and quality of life. The tertiary objective is to examine whether discrepancy between patient preferences and treatment assignment reduces the effectiveness of each treatment. Exploratory analyses will examine whether demographic and clinical characteristics predict differential response to PE and CPT. The study is designed to randomize 900 male and female veterans with PTSD due to any traumatic military event to receive PE or CPT. The standard dose of treatment is 12 weekly sessions but veterans who improve more rapidly may finish in fewer sessions and veterans who improve more slowly may have additional sessions. The primary outcome is improvement in PTSD symptoms, measured during and after treatment and then 3 and 6 months later. As a large multi-site trial with men and women, CERV-PTSD is designed to advance the delivery of care for PTSD by providing conclusive information about whether one treatment is better than the other, overall, and for different types of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cct.2014.11.017DOI Listing
March 2015

The gender gap in academic medicine: comparing results from a multifaceted intervention for stanford faculty to peer and national cohorts.

Acad Med 2014 Jun;89(6):904-11

Dr. Valantine is professor of medicine and senior associate dean for diversity and leadership, Stanford University School of Medicine, Stanford, California. Dr. Grewal is associate director, Office of Diversity and Leadership, Stanford University School of Medicine, Stanford, California. Dr. Ku is program director and senior research scientist, Office of Diversity and Leadership, Stanford University School of Medicine, Stanford, California. Dr. Moseley is director of organizational effectiveness, Office of Diversity and Leadership, Stanford University School of Medicine, Stanford, California. Dr. Shih is assistant professor of biostatistics, Stanford University School of Medicine, Stanford, California. Dr. Stevenson is vice dean and senior associate dean for academic affairs, Harold K. Faber Professor of Pediatrics, and professor, by courtesy, of obstetrics and gynecology, Stanford University School of Medicine, Stanford, California. Dr. Pizzo is David and Susan Heckerman Professor of Pediatrics and of Microbiology and Immunology and former dean of the School of Medicine, Stanford University, Stanford, California.

Purpose: To assess whether the proportion of women faculty, especially at the full professor rank, increased from 2004 to 2010 at Stanford University School of Medicine after a multifaceted intervention.

Method: The authors surveyed gender composition and faculty satisfaction five to seven years after initiating a multifaceted intervention to expand recruitment and development of women faculty. The authors assessed pre/post relative change and rates of increase in women faculty at each rank, and faculty satisfaction; and differences in pre/post change and estimated rate of increase between Stanford and comparator cohorts (nationally and at peer institutions).

Results: Post intervention, women faculty increased by 74% (234 to 408), with assistant, associate, and full professors increasing by 66% (108 to 179), 87% (74 to 138), and 75% (52 to 91), respectively. Nationally and at peer institutions, women faculty increased by about 30% (30,230 to 39,200 and 4,370 to 5,754, respectively), with lower percentages at each rank compared with Stanford. Estimated difference (95% CI) in annual rate of increase was larger for Stanford versus the national cohort: combined ranks 0.36 (0.17 to 0.56), P = .001; full professor 0.40 (0.18 to 0.62), P = .001; and versus the peer cohort: combined ranks 0.29 (0.07 to 0.51), P = .02; full professor 0.37 (0.14 to 0.60), P = .003. Stanford women faculty satisfaction increased from 48% (2003) to 71% (2008).

Conclusions: Increased satisfaction and proportion of women faculty, especially full professors, suggest that the intervention may ameliorate the gender gap in academic medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/ACM.0000000000000245DOI Listing
June 2014

Sequential design of phase II-III cancer trials.

Stat Med 2012 Aug 16;31(18):1944-60. Epub 2012 Mar 16.

Department of Statistics, Stanford University, Stanford, CA 94305, U.S.A.

Although traditional phase II cancer trials are usually single arm, with tumor response as endpoint, and phase III trials are randomized and incorporate interim analyses with progression-free survival or other failure time as endpoint, this paper proposes a new approach that seamlessly expands a randomized phase II study of response rate into a randomized phase III study of time to failure. This approach is based on advances in group sequential designs and joint modeling of the response rate and time to event. The joint modeling is reflected in the primary and secondary objectives of the trial, and the sequential design allows the trial to adapt to increase in information on response and survival patterns during the course of the trial and to stop early either for conclusive evidence on efficacy of the experimental treatment or for the futility in continuing the trial to demonstrate it, on the basis of the data collected so far.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/sim.5346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532356PMC
August 2012

Clinical trial designs for testing biomarker-based personalized therapies.

Clin Trials 2012 Apr 7;9(2):141-54. Epub 2012 Mar 7.

Department of Statistics, Stanford University, Stanford, CA 94305, USA.

Background: Advances in molecular therapeutics in the past decade have opened up new possibilities for treating cancer patients with personalized therapies, using biomarkers to determine which treatments are most likely to benefit them, but there are difficulties and unresolved issues in the development and validation of biomarker-based personalized therapies. We develop a new clinical trial design to address some of these issues. The goal is to capture the strengths of the frequentist and Bayesian approaches to address this problem in the recent literature and to circumvent their limitations.

Methods: We use generalized likelihood ratio tests of the intersection null and enriched strategy null hypotheses to derive a novel clinical trial design for the problem of advancing promising biomarker-guided strategies toward eventual validation. We also investigate the usefulness of adaptive randomization (AR) and futility stopping proposed in the recent literature.

Results: Simulation studies demonstrate the advantages of testing both the narrowly focused enriched strategy null hypothesis related to validating a proposed strategy and the intersection null hypothesis that can accommodate to a potentially successful strategy. AR and early termination of ineffective treatments offer increased probability of receiving the preferred treatment and better response rates for patients in the trial, at the expense of more complicated inference under small-to-moderate total sample sizes and some reduction in power.

Limitations: The binary response used in the development phase may not be a reliable indicator of treatment benefit on long-term clinical outcomes. In the proposed design, the biomarker-guided strategy (BGS) is not compared to 'standard of care', such as physician's choice that may be informed by patient characteristics. Therefore, a positive result does not imply superiority of the BGS to 'standard of care'. The proposed design and tests are valid asymptotically. Simulations are used to examine small-to-moderate sample properties.

Conclusion: Innovative clinical trial designs are needed to address the difficulties and issues in the development and validation of biomarker-based personalized therapies. The article shows the advantages of using likelihood inference and interim analysis to meet the challenges in the sample size needed and in the constantly evolving biomarker landscape and genomic and proteomic technologies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1740774512437252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296980PMC
April 2012

Adaptive trial designs.

Annu Rev Pharmacol Toxicol 2012 11;52:101-10. Epub 2011 Aug 11.

Department of Statistics, Stanford University, Stanford, California 94305, USA.

We review adaptive designs for clinical trials, giving special attention to the control of the Type I error in late-phase confirmatory trials, when the trial planner wishes to adjust the final sample size of the study in response to an unblinded analysis of interim estimates of treatment effects. We point out that there is considerable inefficiency in using the adaptive designs that employ conditional power calculations to reestimate the sample size and that maintain the Type I error by using certain weighted test statistics. Although these adaptive designs have little advantage over familiar group-sequential designs, our review also describes recent developments in adaptive designs that are both flexible and efficient. We also discuss the use of Bayesian designs, when the context of use demands control over operating characteristics (Type I and II errors) and correction of the bias of estimated treatment effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1146/annurev-pharmtox-010611-134504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296970PMC
May 2012

Radial artery grafts vs saphenous vein grafts in coronary artery bypass surgery: a randomized trial.

JAMA 2011 Jan;305(2):167-74

Cardiology Section (1-111C), Southern Arizona VA Health Care System, 3601 S Sixth Ave, Tucson, AZ 85723, USA.

Context: Arterial grafts are thought to be better conduits than saphenous vein grafts for coronary artery bypass grafting (CABG) based on experience with using the left internal mammary artery to bypass the left anterior descending coronary artery. The efficacy of the radial artery graft is less clear.

Objective: To compare 1-year angiographic patency of radial artery grafts vs saphenous vein grafts in patients undergoing elective CABG.

Design, Setting, And Participants: Multicenter, randomized controlled trial conducted from February 2003 to February 2009 at 11 Veterans Affairs medical centers among 757 participants (99% men) undergoing first-time elective CABG.

Interventions: The left internal mammary artery was used to preferentially graft the left anterior descending coronary artery whenever possible; the best remaining recipient vessel was randomized to radial artery vs saphenous vein graft.

Main Outcome Measures: The primary end point was angiographic graft patency at 1 year after CABG. Secondary end points included angiographic graft patency at 1 week after CABG, myocardial infarction, stroke, repeat revascularization, and death.

Results: Analysis included 733 patients (366 in the radial artery group, 367 in the saphenous vein group). There was no significant difference in study graft patency at 1 year after CABG (radial artery, 238/266; 89%; 95% confidence interval [CI], 86%-93%; saphenous vein, 239/269; 89%; 95% CI, 85%-93%; adjusted OR, 0.99; 95% CI, 0.56-1.74; P = .98). There were no significant differences in the secondary end points.

Conclusion: Among Veterans Affairs patients undergoing first-time elective CABG, the use of a radial artery graft compared with saphenous vein graft did not result in greater 1-year patency.

Trial Registration: clinicaltrials.gov Identifier: NCT00054847.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2010.1976DOI Listing
January 2011

Integrating tobacco cessation into mental health care for posttraumatic stress disorder: a randomized controlled trial.

JAMA 2010 Dec;304(22):2485-93

Veterans Affairs Puget Sound Health Care System, 1660 S Columbian Way, S-116 MHC, Seattle, WA 98108, USA.

Context: Most smokers with mental illness do not receive tobacco cessation treatment.

Objective: To determine whether integrating smoking cessation treatment into mental health care for veterans with posttraumatic stress disorder (PTSD) improves long-term smoking abstinence rates.

Design, Setting, And Patients: A randomized controlled trial of 943 smokers with military-related PTSD who were recruited from outpatient PTSD clinics at 10 Veterans Affairs medical centers and followed up for 18 to 48 months between November 2004 and July 2009.

Intervention: Smoking cessation treatment integrated within mental health care for PTSD delivered by mental health clinicians (integrated care [IC]) vs referral to Veterans Affairs smoking cessation clinics (SCC). Patients received smoking cessation treatment within 3 months of study enrollment.

Main Outcome Measures: Smoking outcomes included 12-month bioverified prolonged abstinence (primary outcome) and 7- and 30-day point prevalence abstinence assessed at 3-month intervals. Amount of smoking cessation medications and counseling sessions delivered were tested as mediators of outcome. Posttraumatic stress disorder and depression were repeatedly assessed using the PTSD Checklist and Patient Health Questionnaire 9, respectively, to determine if IC participation or quitting smoking worsened psychiatric status.

Results: Integrated care was better than SCC on prolonged abstinence (8.9% vs 4.5%; adjusted odds ratio, 2.26; 95% confidence interval [CI], 1.30-3.91; P = .004). Differences between IC vs SCC were largest at 6 months for 7-day point prevalence abstinence (78/472 [16.5%] vs 34/471 [7.2%], P < .001) and remained significant at 18 months (86/472 [18.2%] vs 51/471 [10.8%], P < .001). Number of counseling sessions received and days of cessation medication used explained 39.1% of the treatment effect. Between baseline and 18 months, psychiatric status did not differ between treatment conditions. Posttraumatic stress disorder symptoms for quitters and nonquitters improved. Nonquitters worsened slightly on the Patient Health Questionnaire 9 relative to quitters (differences ranged between 0.4 and 2.1, P = .03), whose scores did not change over time.

Conclusion: Among smokers with military-related PTSD, integrating smoking cessation treatment into mental health care compared with referral to specialized cessation treatment resulted in greater prolonged abstinence.

Trial Registration: clinicaltrials.gov Identifier: NCT00118534.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2010.1769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4218733PMC
December 2010

A biosensor platform for rapid antimicrobial susceptibility testing directly from clinical samples.

J Urol 2011 Jan 12;185(1):148-53. Epub 2010 Nov 12.

Department of Urology, Stanford University School of Medicine, Stanford, California, USA.

Purpose: A significant barrier to efficient antibiotic management of infection is that the standard diagnostic methodologies do not provide results at the point of care. The delays between sample collection and bacterial culture and antibiotic susceptibility reporting have led to empirical use of antibiotics, contributing to the emergence of drug resistant pathogens. As a key step toward the development of a point of care device for determining the antibiotic susceptibility of urinary tract pathogens, we report on a biosensor based antimicrobial susceptibility test.

Materials And Methods: For assay development bacteria were cultured with or without antibiotics, and growth was quantitated by determining viable counts and electrochemical biosensor measurement of bacterial 16S rRNA. To determine antibiotic susceptibility directly from patient samples, urine was cultured on antibiotic plates for 2.5 hours and growth was determined by electrochemical measurement of bacterial 16S rRNA. For assay validation 252 urine samples were collected from patients at the Spinal Cord Injury Service at Veterans Affairs Palo Alto Health Care System. The biosensor based antimicrobial susceptibility test was completed for samples containing gram-negative organisms. Pathogen identification and antibiotic susceptibility results were compared between our assay and standard microbiological analysis.

Results: A direct biosensor quantitation of bacterial 16S rRNA can be used to monitor bacterial growth for a biosensor based antimicrobial susceptibility test. Clinical validation of a biosensor based antimicrobial susceptibility test with patient urine samples demonstrated that this test was 94% accurate in 368 pathogen-antibiotic tests compared to standard microbiological analysis.

Conclusions: This biosensor based antimicrobial susceptibility test, in concert with our previously described pathogen identification assay, can provide culture and susceptibility information directly from a urine sample within 3.5 hours.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.juro.2010.09.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051414PMC
January 2011

Effect of home testing of international normalized ratio on clinical events.

N Engl J Med 2010 Oct;363(17):1608-20

Health Services Research Field Program, Veterans Affairs Medical Center, Durham, NC, USA.

Background: Warfarin anticoagulation reduces thromboembolic complications in patients with atrial fibrillation or mechanical heart valves, but effective management is complex, and the international normalized ratio (INR) is often outside the target range. As compared with venous plasma testing, point-of-care INR measuring devices allow greater testing frequency and patient involvement and may improve clinical outcomes.

Methods: We randomly assigned 2922 patients who were taking warfarin because of mechanical heart valves or atrial fibrillation and who were competent in the use of point-of-care INR devices to either weekly self-testing at home or monthly high-quality testing in a clinic. The primary end point was the time to a first major event (stroke, major bleeding episode, or death).

Results: The patients were followed for 2.0 to 4.75 years, for a total of 8730 patient-years of follow-up. The time to the first primary event was not significantly longer in the self-testing group than in the clinic-testing group (hazard ratio, 0.88; 95% confidence interval, 0.75 to 1.04; P=0.14). The two groups had similar rates of clinical outcomes except that the self-testing group reported more minor bleeding episodes. Over the entire follow-up period, the self-testing group had a small but significant improvement in the percentage of time during which the INR was within the target range (absolute difference between groups, 3.8 percentage points; P<0.001). At 2 years of follow-up, the self-testing group also had a small but significant improvement in patient satisfaction with anticoagulation therapy (P=0.002) and quality of life (P<0.001).

Conclusions: As compared with monthly high-quality clinic testing, weekly self-testing did not delay the time to a first stroke, major bleeding episode, or death to the extent suggested by prior studies. These results do not support the superiority of self-testing over clinic testing in reducing the risk of stroke, major bleeding episode, and death among patients taking warfarin therapy. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT00032591.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1002617DOI Listing
October 2010

Sequential generalized likelihood ratio tests for vaccine safety evaluation.

Stat Med 2010 Nov;29(26):2698-708

VA Palo Alto Cooperative Studies Program Coordinating Center, Mountain View, CA 94043, USA.

The evaluation of vaccine safety involves pre-clinical animal studies, pre-licensure randomized clinical trials, and post-licensure safety studies. Sequential design and analysis are of particular interest because they allow early termination of the trial or quick detection that the vaccine exceeds a prescribed bound on the adverse event rate. After a review of the recent developments in this area, we propose a new class of sequential generalized likelihood ratio tests for evaluating adverse event rates in two-armed pre-licensure clinical trials and single-armed post-licensure studies. The proposed approach is illustrated using data from the Rotavirus Efficacy and Safety Trial. Simulation studies of the performance of the proposed approach and other methods are also given.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/sim.4036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2975406PMC
November 2010

Electrochemical immunosensor detection of urinary lactoferrin in clinical samples for urinary tract infection diagnosis.

Biosens Bioelectron 2010 Oct 8;26(2):649-54. Epub 2010 Jul 8.

Department of Urology, Stanford University, Stanford, CA 94305-5118, USA.

Urine is the most abundant and easily accessible of all body fluids and provides an ideal route for non-invasive diagnosis of human diseases, particularly of the urinary tract. Electrochemical biosensors are well suited for urinary diagnostics due to their excellent sensitivity, low-cost, and ability to detect a wide variety of target molecules including nucleic acids and protein biomarkers. We report the development of an electrochemical immunosensor for direct detection of the urinary tract infection (UTI) biomarker lactoferrin from infected clinical samples. An electrochemical biosensor array with alkanethiolate self-assembled monolayer (SAM) was used. Electrochemical impedance spectroscopy was used to characterize the mixed SAM, consisted of 11-mercaptoundecanoic acid and 6-mercapto-1-hexanol. A sandwich amperometric immunoassay was developed for detection of lactoferrin from urine, with a detection limit of 145 pg/ml. We validated lactoferrin as a biomarker of pyuria (presence of white blood cells in urine), an important hallmark of UTI, in 111 patient-derived urine samples. Finally, we demonstrated multiplex detection of urinary pathogens and lactoferrin through simultaneous detection of bacterial nucleic acid (16S rRNA) and host immune response protein (lactoferrin) on a single sensor array. Our results represent first integrated sensor platform capable of quantitative pathogen identification and measurement of host immune response, potentially providing clinical diagnosis that is not only more expeditious but also more informative than the current standard.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bios.2010.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946447PMC
October 2010

An evaluation of patient self-testing competency of prothrombin time for managing anticoagulation: pre-randomization results of VA Cooperative Study #481--The Home INR Study (THINRS).

J Thromb Thrombolysis 2010 Oct;30(3):263-75

Center for Health Services Research in Primary Care, VA Medical Center, Durham, NC, USA.

Prior studies suggest patient self-testing (PST) of prothrombin time (PT) can improve the quality of anticoagulation (AC) and reduce complications (e.g., bleeding and thromboembolic events). "The Home INR Study" (THINRS) compared AC management with frequent PST using a home monitoring device to high-quality AC management (HQACM) with clinic-based monitoring on major health outcomes. A key clinical and policy question is whether and which patients can successfully use such devices. We report the results of Part 1 of THINRS in which patients and caregivers were evaluated for their ability to perform PST. Study-eligible patients (n = 3643) were trained to use the home monitoring device and evaluated after 2-4 weeks for PST competency. Information about demographics, medical history, warfarin use, medications, plus measures of numeracy, literacy, cognition, dexterity, and satisfaction with AC were collected. Approximately 80% (2931 of 3643) of patients trained on PST demonstrated competency; of these, 8% (238) required caregiver assistance. Testers who were not competent to perform PST had higher numbers of practice attempts, higher cuvette wastage, and were less able to perform a fingerstick or obtain blood for the cuvette in a timely fashion. Factors associated with failure to pass PST training included increased age, previous stroke history, poor cognition, and poor manual dexterity. A majority of patients were able to perform PST. Successful home monitoring of PT with a PST device required adequate levels of cognition and manual dexterity. Training a caregiver modestly increased the proportion of patients who can perform PST.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11239-010-0499-8DOI Listing
October 2010

Effects of the thyromimetic agent diiodothyropropionic acid on body weight, body mass index, and serum lipoproteins: a pilot prospective, randomized, controlled study.

J Clin Endocrinol Metab 2010 Mar 15;95(3):1349-54. Epub 2010 Jan 15.

Department of Endocrinology and Metabolism, John Hopkins University, 1830 East Monument Street, Suite 333, Baltimore, Maryland 21287-0003, USA.

Context: Widespread thyroid hormone actions offer the possibility of developing selective thyromimetic analogs with salutary metabolic properties. Consequently, effects of diiodothyropropionic acid (DITPA) on body weight, serum lipoproteins, and bone metabolism markers were studied in a prospective, controlled, double-blind 24-wk trial, which was primarily designed to assess treatment of stable chronic heart failure.

Design: Eighty-six patients (aged 66 +/- 11 yr, mean +/- sd) were randomized (1:2) to placebo or an escalating DITPA dose (90 to 180, 270, and 360 mg/d) over 8 wk until serum TSH was less than 0.02 mU/liter. Patients were studied at 2, 4, 6, 8, 16, and 24 wk and after 4 wk off study drug. Only 21 DITPA-treated and 27 placebo patients completed the full 24 wk of therapy.

Results: DITPA therapy lowered serum TSH levels and, to a lesser extent, serum T(3) and T(4), but there were no differences in clinical manifestations of thyrotoxicosis or hypothyroidism. Serum total and low-density lipoprotein cholesterol levels both decreased on DITPA; there was a transient decrease in triglycerides and no change in high-density lipoprotein cholesterol. DITPA therapy was associated with significant reduction in body weight, 12.5 lb at 24 wk. Increases in serum osteocalcin, N-telopeptide, and deoxypyridinoline levels were consistent with increased bone turnover on DITPA.

Conclusion: This investigation of DITPA actions demonstrated its efficacy in reducing body weight and lowering total and low-density lipoprotein cholesterol levels. However, DITPA's adverse effects at doses used resulted in a high dropout rate and potentially dangerous skeletal actions were observed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2009-1209DOI Listing
March 2010

Multiplex pathogen identification for polymicrobial urinary tract infections using biosensor technology: a prospective clinical study.

J Urol 2009 Dec 17;182(6):2735-41. Epub 2009 Oct 17.

Department of Urology, Stanford University School of Medicine, Stanford, California 94305-5118, USA.

Purpose: Rapid diagnosis of urinary tract infection would have a significant beneficial impact on clinical management, particularly in patients with structural or functional urinary tract abnormalities who are highly susceptible to recurrent polymicrobial infections. We examined the analytical validity of an electrochemical biosensor array for rapid molecular diagnosis of urinary tract infection in a prospective clinical study in patients with neurogenic bladder.

Materials And Methods: The electrochemical biosensor array was functionalized with DNA probes against 16S rRNA of the most common uropathogens. Spinal cord injured patients at a Veterans Affairs hospital were recruited into the study. Urine samples were generally tested on the biosensor within 1 to 2 hours of collection. Biosensor results were compared with those obtained using standard clinical microbiology laboratory methods.

Results: We successfully developed a 1-hour biosensor assay for multiplex identification of pathogens. From July 2007 to December 2008 we recruited 116 patients, yielding a total of 109 urine samples suitable for analysis and comparison between biosensor assay and standard urine culture. Of the samples 74% were positive, of which 42% were polymicrobial. We identified 20 organisms, of which Escherichia coli, Pseudomonas aeruginosa and Enterococcus species were the most common. Biosensor assay specificity and positive predictive value were 100%. Pathogen detection sensitivity was 89%, yielding a 76% negative predictive value.

Conclusions: To our knowledge we report the first prospective clinical study to successfully identify pathogens within a point of care time frame using an electrochemical biosensor platform. Additional efforts to improve the limit of detection and probe design are needed to further enhance assay sensitivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.juro.2009.08.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035241PMC
December 2009

Defining acute lung disease in children with the oxygenation saturation index.

Pediatr Crit Care Med 2010 Jan;11(1):12-7

Department of Pediatrics and Public Health Sciences, Penn State Center for Host defense, Inflammation, and Lung Disease Research, Penn State Hershey Children's Hospital and Pennsylvania State University College of Medicine, Hershey, PA, USA.

Objective: To evaluate whether a formula could be derived using oxygen saturation (Spo2) to replace Pao2 that would allow identification of children with acute lung injury and acute respiratory distress syndrome. Definitions of acute lung injury and acute respiratory distress syndrome require arterial blood gases to determine the Pao2/Fio2 ratio of 300 (acute lung injury) and 200 (acute respiratory distress syndrome).

Design: Post hoc data analysis of measurements abstracted from two prospective databases of randomized controlled trials.

Setting: Academic pediatric intensive care units.

Patients: A total of 255 children enrolled in two large prospective trials of therapeutic intervention for acute lung disease: calfactant and prone positioning.

Interventions: Data were abstracted including Pao2, Paco2, pH, Fio2, and mean airway pressure. Repeated-measures analyses, using linear mixed-effects models, were used to build separate prediction equations for the Spo2/Fio2 ratio, oxygenation index [(Fio2 x Mean Airway Pressure)/Pao2], and oxygen saturation index [(Fio2 x Mean Airway Pressure)/Spo2 ]. A generalization of R was used to measure goodness-of-fit. Generalized estimating equations with a logit link were used to calculate the sensitivity and specificity for the cutoffs of Pao2/Fio2 ratio of 200 and 300 and equivalent values of Spo2/Fio2 ratio, oxygenation index, and oxygen saturation index.

Measurements And Main Results: An Spo2/Fio2 ratio of 253 and 212 would equal criteria for acute lung injury and acute respiratory distress syndrome, respectively. An oxygenation index of 5.3 would equal acute lung injury criteria, and an oxygenation index of 8.1 would qualify for acute respiratory distress syndrome. An oxygen saturation index, which includes the mean airway pressure and the noninvasive measure of oxygenation, of 6.5 would be equivalent to the acute lung injury criteria, and an oxygen saturation index of 7.8 would equal acute respiratory distress syndrome criteria.

Conclusions: Noninvasive methods of assessing oxygenation may be utilized with reasonable sensitivity and specificity to define acute lung injury and acute respiratory distress syndrome, and, with prospective validation, have the potential to increase the number of children enrolled into clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PCC.0b013e3181b0653dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936504PMC
January 2010

DITPA (3,5-Diiodothyropropionic Acid), a thyroid hormone analog to treat heart failure: phase II trial veterans affairs cooperative study.

Circulation 2009 Jun 8;119(24):3093-100. Epub 2009 Jun 8.

Cardiology Section (1-111C), Southern Arizona VA Health Care System, 3601 S 6th Ave, Tucson, AZ 85723, USA.

Background: In animal studies and a pilot trial in patients with congestive heart failure, the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA) had beneficial hemodynamic effects.

Methods And Results: This was a phase II multicenter, randomized, placebo-controlled, double-blind trial of New York Heart Association class II to IV congestive heart failure patients randomized (2:1) to DITPA or placebo and treated for 6 months. The study enrolled 86 patients (n=57 to DITPA, n=29 to placebo). The primary objective was to assess the effect of DITPA on a composite congestive heart failure end point that classifies patients as improved, worsened, or unchanged based on symptom changes and morbidity/mortality. DITPA was poorly tolerated, which obscured the interpretation of congestive heart failure-specific effects. Fatigue and gastrointestinal complaints, in particular, were more frequent in the DITPA group. DITPA increased cardiac index (by 18%) and decreased systemic vascular resistance (by 11%), serum cholesterol (-20%), low-density lipoprotein cholesterol (-30%), and body weight (-11 lb). Thyroid-stimulating hormone was suppressed in patients given DITPA, which reflects its thyromimetic effect; however, no symptoms or signs of potential hypothyroidism or thyrotoxicosis were seen.

Conclusions: DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.108.834424DOI Listing
June 2009