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2.  Brain Arterial Diameters as a Risk Factor for Vascular Events 
Arterial luminal diameters are routinely used to assess for vascular disease. Although small diameters are typically considered pathological, arterial dilatation has also been associated with disease. We hypothesize that extreme arterial diameters are biomarkers of the risk of vascular events.
Methods and Results
Participants in the Northern Manhattan Study who had a time-of-flight magnetic resonance angiography were included in this analysis (N=1034). A global arterial Z-score, called the brain arterial remodeling (BAR) score, was obtained by averaging the measured diameters within each individual. Individuals with a BAR score <−2 SDs were considered to have the smallest diameters, individuals with a BAR score >−2 and <2 SDs had average diameters, and individuals with a BAR score >2 SDs had the largest diameters. All vascular events were recorded prospectively after the brain magnetic resonance imaging. Spline curves and incidence rates were used to test our hypothesis. The association of the BAR score with death (P=0.001), vascular death (P=0.02), any vascular event (P=0.05), and myocardial infarction (P=0.10) was U-shaped except for ischemic stroke (P=0.74). Consequently, incidence rates for death, vascular death, myocardial infarction, and any vascular event were higher in individuals with the largest diameters, whereas individuals with the smallest diameters had a higher incidence of death, vascular death, any vascular event, and ischemic stroke compared with individuals with average diameters.
The risk of death, vascular death, and any vascular event increased at both extremes of brain arterial diameters. The pathophysiology linking brain arterial remodeling to systemic vascular events needs further research.
PMCID: PMC4599479  PMID: 26251284
brain arterial remodeling; stroke; vascular death; vascular disease
3.  Trials of Intervention Principles: Evaluation Methods for Evolving Behavioral Intervention Technologies 
In recent years, there has been increasing discussion of the limitations of traditional randomized controlled trial (RCT) methodologies for the evaluation of eHealth and mHealth interventions, and in particular, the requirement that these interventions be locked down during evaluation. Locking down these interventions locks in defects and eliminates the opportunities for quality improvement and adaptation to the changing technological environment, often leading to validation of tools that are outdated by the time that trial results are published. Furthermore, because behavioral intervention technologies change frequently during real-world deployment, even if a tested intervention were deployed in the real world, its shelf life would be limited. We argue that RCTs will have greater scientific and public health value if they focus on the evaluation of intervention principles (rather than a specific locked-down version of the intervention), allowing for ongoing quality improvement modifications to the behavioral intervention technology based on the core intervention principles, while continuously improving the functionality and maintaining technological currency. This paper is an initial proposal of a framework and methodology for the conduct of trials of intervention principles (TIPs) aimed at minimizing the risks of in-trial changes to intervention technologies and maximizing the potential for knowledge acquisition. The focus on evaluation of intervention principles using clinical and usage outcomes has the potential to provide more generalizable and durable information than trials focused on a single intervention technology.
PMCID: PMC4526981  PMID: 26155878
mHealth; eHealth; clinical trials; methodology
4.  N-of-1 randomized trials for psychological and health behavior outcomes: a systematic review protocol 
Systematic Reviews  2015;4:87.
Randomized controlled trials are the sine qua non of causal inference; however, heterogeneity of treatment effects for many chronic conditions and for many symptoms often limits their utility. Single-patient studies in which patients select a treatment after trying a randomized sequence of treatments (i.e., multiple crossover trials) offer an alternative to traditional randomized controlled trials by providing scientifically valid results in a practical manner that can be used by patients and their providers to decide upon their personally optimal treatment. Although N-of-1 trials have been used in the medical literature, their use for interventions that consist of psychological or health behavior outcomes is unknown. This systematic review thus aims to describe the interventions and outcomes and assess the quality of N-of-1 trials for psychological or health behavior outcomes.
Electronic databases (Ovid MEDLINE, EMBASE, CINAHL, PsycINFO, and the six databases in the Cochrane Library) will be searched using all relevant subject headings and free-text terms to represent N-of-1 trials and psychological or behavioral interventions. Full text review and bibliography searching will be conducted. Unpublished studies will be sought by searching trial registries and contacting authors of included studies. Eligibility criteria are the following: population, all human participants for whom N-of-1 trials with psychological or health behavior outcomes have been conducted; interventions, all interventions for which N-of-1 trials have been conducted; comparison, placebo or active treatment control; and outcome, psychological and health behavior outcomes including self-perceived disease severity and psychological phenomena such as mood and affect. Studies that do not contain sufficient trial detail, describe only design or statistical analytic issues in N-of-1 trials without presentation of an N-of-1 trial itself, and/or are not written in the English language are ineligible. Screening, data extraction, and quality assessment will be conducted by two independent reviewers with disagreements resolved through discussion.
This systematic review will describe the interventions and outcomes and assess the quality of N-of-1 trials for psychological or health behavior outcomes. The results will clarify the use of this research methodology in the health psychology and behavioral medicine literature and may pave the way for additional N-of-1 trials to be conducted.
Systematic review registration
PROSPERO CRD42015017853
Electronic supplementary material
The online version of this article (doi:10.1186/s13643-015-0071-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4471921  PMID: 26081256
N-of-1; Crossover; Within-subject; Health psychology; Behavioral medicine
5.  Mediterranean diet and carotid atherosclerosis in the Northern Manhattan Study 
Atherosclerosis  2014;234(2):303-310.
Adherence to a Mediterranean-style diet (MeDi) may protect against clinical vascular events by reducing atherosclerosis, but data is limited. This is the first observational study of the association between MeDi adherence and carotid plaque thickness and area.
The study included 1374 participants of the population-based Northern Manhattan Study with diet assessed and carotid intima-media thickness (cIMT) and plaque measured using B-mode ultrasound (mean age 66 ± 9 years, 60% female, 60% Hispanic, 18% White, 19% Black). A MeDi adherence score (range = 0–9, 9 representing maximal adherence) was examined continuously and in quintiles (3/4/5/6 –9 vs. 0–2).
Mean cIMT = 0.9 ± 0.1 mm and 57% had plaque (median plaque thickness = 1.5 mm, 75th percentile = 2.2; median plaque area = 4.2 mm2, 75th percentile = 15.8). There was no association between MeDi and cIMT or plaque presence. MeDi adherence was inversely associated with the 75th percentile of plaque thickness and median of plaque area in quantile regression analyses. These associations persisted after controlling for demographics, smoking, physical activity, and total energy consumption (effect of a 1-point increase in MeDi score on the 75th percentile of plaque thickness = −0.049 mm, p = 0.03; median of plaque area = −0.371 mm2, p = 0.03), and when additionally controlling for vascular disease biomarkers, medication use, BMI, and previous cardiac disease. The protective associations appeared strongest for those with a MeDi score of 5 (4th quintile) vs. 0–2 (bottom quintile). Differential effects of a MeDi on plaque thickness and area across race/ethnic groups was suggested.
Moderate and strict adherence to a MeDi may protect against a higher burden of carotid atherosclerotic plaque, which may mediate the protection against clinical vascular events. Efforts to improve adherence to a MeDi are critical to reducing the burden of atherosclerotic disease.
PMCID: PMC4370624  PMID: 24721190
Mediterranean diet; Carotid atherosclerosis; Plaque; Intima-media thickness
6.  Design of Implementation Studies for Quality Improvement Programs: An Effectiveness–Cost-Effectiveness Framework 
American journal of public health  2013;104(1):10.2105/AJPH.2013.301579.
Translational research applies basic science discoveries in clinical and community settings. Implementation research is often limited by tremendous variability among settings; therefore, generalization of findings may be limited. Adoption of a novel procedure in a community practice is usually a local decision guided by setting-specific knowledge. The conventional statistical framework that aims to produce generalizable knowledge is inappropriate for local quality improvement investigations. We propose an analytic framework based on cost-effectiveness of the implementation study design, taking into account prior knowledge from local experts. When prior knowledge does not indicate a clear preference between the new and standard procedures, local investigation should guide the choice. The proposed approach requires substantially smaller sample sizes than the conventional approach. Sample size formulae and general guidance are provided.
PMCID: PMC3880412  PMID: 24228672
7.  Designing Clinical Trials for Dystonia 
Neurotherapeutics  2013;11(1):117-127.
With advances in the understanding of the pathophysiology of dystonia, novel therapeutics are being developed. Such therapies will require clinical investigation ranging from exploratory studies to examine safety, tolerability, dosage selection, and preliminary efficacy to confirmatory studies to evaluate efficacy definitively. As dystonia is a rare and complex disorder with clinical and etiological heterogeneity, clinical trials will require careful consideration of the trial design, including enrollment criteria, concomitant medication use, and outcome measures. Given the complexities of designing and implementing efficient clinical trials, it is important for clinicians and statisticians to collaborate closely throughout the clinical development process and that each has a basic understanding of both the clinical and statistical issues that must be addressed. To facilitate designing appropriate clinical trials in this field, we review important general clinical trial and regulatory principles, and discuss the critical components of trials with an emphasis on considerations specific to dystonia. Additionally, we discuss designs used in early exploratory, late exploratory, and confirmatory phases, including adaptive designs.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-013-0221-6) contains supplementary material, which is available to authorized users.
PMCID: PMC3899487  PMID: 24282121
Dystonia; Clinical trials; Exploratory trials; Confirmatory trials; Adaptive designs
8.  Continuous Evaluation of Evolving Behavioral Intervention Technologies 
American journal of preventive medicine  2013;45(4):10.1016/j.amepre.2013.06.006.
Behavioral intervention technologies (BITs) are web-based and mobile interventions intended to support patients and consumers in changing behaviors related to health, mental health, and well-being. BITs are provided to patients and consumers in clinical care settings and commercial marketplaces, frequently with little or no evaluation. Current evaluation methods, including RCTs and implementation studies, can require years to validate an intervention. This timeline is fundamentally incompatible with the BIT environment, where technology advancement and changes in consumer expectations occur quickly, necessitating rapidly evolving interventions. However, BITs can routinely and iteratively collect data in a planned and strategic manner and generate evidence through systematic prospective analyses, thereby creating a system that can “learn.”
A methodologic framework, Continuous Evaluation of Evolving Behavioral Intervention Technologies (CEEBIT), is proposed that can support the evaluation of multiple BITs or evolving versions, eliminating those that demonstrate poorer outcomes, while allowing new BITs to be entered at any time. CEEBIT could be used to ensure the effectiveness of BITs provided through deployment platforms in clinical care organizations or BIT marketplaces. The features of CEEBIT are described, including criteria for the determination of inferiority, determination of BIT inclusion, methods of assigning consumers to BITs, definition of outcomes, and evaluation of the usefulness of the system. CEEBIT offers the potential to collapse initial evaluation and postmarketing surveillance, providing ongoing assurance of safety and efficacy to patients and consumers, payers, and policymakers.
PMCID: PMC3828034  PMID: 24050429
9.  Population Attributable Risks of Hypertension and Diabetes for Cardiovascular Disease and Stroke in the Northern Manhattan Study 
Understanding the population‐level risk factor contribution to disease incidence is critical for effective allocation of resources for prevention. There are little data on the contribution of cardiovascular disease (CVD) risk factors in multiethnic elderly populations.
Methods and Results
The Northern Manhattan Study (n=3298) is a population‐based prospective cohort study of CVD outcomes in a multiethnic urban population. Multivariable Cox's models were used to calculate hazard ratios, population attributable risk (PAR), and 95% confidence intervals (CIs) for (1) combined vascular event (VE) endpoint of stroke/myocardial infarction/vascular death (n=835) and (2) stroke (n=347). The PAR resulting from hypertension (HTN) was 24.3% (95% CI, 13.2 to 35.4) for VE and 29.9% (95% CI, 12.5 to 47.4) for stroke; PAR resulting from diabetes was 12.7% (95% CI, 8.2 to 17.2) for VE and 19.5% (95% CI, 12.4 to 26.5) for stroke. The PAR resulting from HTN and diabetes for stroke differed by race‐ethnicity and age (P for differences <0.05). PAR for stroke reslting from HTN was greater among Hispanics (50.6%; 95% CI, 29.2 to 71.9) than non‐Hispanic whites (2.6%; 95% CI, −33.2 to 38.6) and in those <80 years of age (35.6%; 95% CI, 18.9 to 52.3) than in those ≥80 (−0.3%; 95% CI, −34.2 to 33.6). Similarly, the PAR for stroke resulting from diabetes was 23.6% among those <80 years of age (95% CI, 15.7 to 31.5) and 2.3% among those ≥80 (95% CI, −8.2 to 12.7; P for difference=0.001). The PAR for VE did not differ by age/sex/race‐ethnicity.
HTN and diabetes have important effects on the burden of stroke, particularly among those younger than age 80 and Hispanics. Public health campaigns targeted at specific risk factors in specific populations can lead to a greater reduction in CVD.
PMCID: PMC4323833  PMID: 25227406
Aging; attributable risk; diabetes; hypertension; stroke; vascular death
10.  The Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART): an adaptive design phase I dose-escalation study of high-dose lovastatin in acute ischemic stroke 
There is growing experimental and clinical evidence that by reducing downstream products of the mevalonate pathway other than cholesterol, HMG-CoA reductase inhibitors (‘statins’) have beneficial effects on endothelial function, coronary and cerebral blood flow, inflammation, and hemostasis. Statins have been shown in rodent models of acute ischemic stroke to reduce neuronal injury and infarct size in a dose-dependent fashion. The objective of this early phase trial will be to determine the maximal-tolerated dose of lovastatin for short-term acute stroke therapy. In this multicenter phase 1B dose-escalation and dose-finding study, 33 patients with acute ischemic stroke will be administered lovastatin in increasing doses from one to 10 mg/kg daily for 3 days beginning within 24 hours after symptom onset. The primary safety outcomewill be occurrence of myotoxicity or hepatotoxicity, defined by clinical and laboratory criteria, and the study is designed to determine the highest dose of lovastatin that can be administered with <10% risk of myotoxicity or hepatotoxicity. The statistical design of the study utilizes an adaptive design, the Continual Reassessment Method, which is novel to stroke trials, to find the optimal dosage. The dose–toxicity model is calibrated such that the method will eventually select a dose that causes 7–13% dose-limiting toxicity (within 3% of target). A sample size of 33 will ensure that estimates of any binary variables will have a 95% confidence interval of width ≤0·34, and enable us to detect any unexpected toxicity that occurs at 5% rate (in a non-dose-dependent fashion) with probability 0·82. The probability of choosing a dose for further trials with 25% or higher likelihood of toxicity is no more than 23%. The presently described trial represents a new approach for treatment of acute ischemic stroke, as well as a novel way of conducting a phase I trial, evaluating safety and determining an optimal dose of a potential neuroprotectant drug.
PMCID: PMC4130457  PMID: 18705902
stroke; neuroprotection; statins; clinical trial
11.  Elevated Homocysteine and Carotid Plaque Area and Densitometry in the Northern Manhattan Study (NOMAS) 
Background and purpose
Studies have linked elevated homocysteine (tHcy) levels to atherosclerotic carotid plaque development, but data are limited to predominantly white populations. We examined the association between tHcy and carotid plaque burden and morphology in a multi-ethnic cohort.
In the Northern Manhattan Study, we conducted a cross–sectional analysis among 1327 stroke-free subjects (mean age 66±9, 41% men, 19% black, 62% Hispanic, 17% white) with serum tHcy and ultrasonographic assessment of plaque morphology measured by Gray-Scale Median (GSM) and total plaque area (TPA). GSM and TPA were examined in 4 categories. High and low GSM categories were considered echodense and echolucent plaque respectively and compared to no plaque. Logistic regression models were used to assess the associations of tHcy with GSM and TPA adjusting for demographics, vascular risk factors, renal insufficiency, and B12 deficiency.
The mean tHcy was 9.4±4.8μmol/L (median=8.6). The prevalence of carotid plaque was 57% (52% among Hispanics, 58% black, 70% white). Among those with plaque, the mean TPA was 20.3±20.6 mm2(median=13.6) and mean GSM 90.9±28.5 (median=93.0). The top two tHcy quartiles (vs. quartile 1) had an elevated risk of having either echolucent plaque (tHcy Q3: OR=1.8 (95%CI 1.2–2.8); tHcy Q4: OR=1.9(95% CI 1.2–3.1)) or echodense plaque (tHcy Q3: OR=1.7 (95%CI 1.1–2.7); tHcy Q4 OR=1.9 (95% CI1.2–3.2)). The top two tHcy quartiles were also more likely to be in the highest TPA category (tHcy Q3: OR=1.8 (95%CI 1.1–3.0); tHcy Q4: OR=2.2 (95%CI 1.3–3.7)).
In this population-based multi-ethnic cohort, elevated tHcy was independently associated with plaque morphology and increased plaque area, subclinical markers of stroke risk.
PMCID: PMC3567916  PMID: 23287787
Atherosclerosis; carotid arteries; ultrasonography; plaque area; Gray Scale Median (GSM); echodense plaque; echolucent plaque; homocysteine
12.  Efficiency perspectives on adaptive designs in stroke clinical trials 
An adaptive design allows the modifications of various features such as sample size and treatment assignments in a clinical study based on the analysis of interim data. The goal is to enhance statistical efficiency by maximizing relevant information obtained from the clinical data. The promise of efficiency, however, comes with a “cost” that is seldom made explicit in the literature. This article reviews some commonly used adaptive strategies in early phase stroke trials and discusses their associated costs. Specifically, we illustrate the tradeoffs in several clinical contexts, including dose finding in the Neuroprotection with Statin Therapy for Acute Recovery Trial, futility analyses and internal pilot in phase 2 proof-of-concept trials, and sample size considerations in an imaging-based dose selection trial. Through these illustrations, we demonstrate the potential tension between the perspectives of an individual investigator and the broader community of stakeholders. This understanding is critical to appreciate the limitations, as well as full promise, of adaptive designs, so that investigators can deploy an appropriate statistical design—be it adaptive or not—in a clinical study.
PMCID: PMC3183258  PMID: 21885845
Continual reassessment method; Futility interim analysis; Internal pilot; Prospective planning
13.  Durable Responses with the Metronomic Regimen RT-PEPC in Elderly Patients with Recurrent Mantle Cell Lymphoma 
Cancer  2010;116(11):2655-2664.
Targeting the tumor microenvironment and angiogenesis is a novel lymphoma therapeutic strategy. We report safety, activity and angiogenic profiling with the RT-PEPC regimen (rituximab with thalidomide, and prednisone, etoposide, procarbazine and cyclophosphamide) in recurrent mantle cell lymphoma (MCL).
RT-PEPC includes induction (months 1–3) of weekly rituximab × 4, daily thalidomide (50 mg) and PEPC, then maintenance thalidomide (100 mg), oral PEPC titrated to neutrophil count, and rituximab every 4 months. Endpoints included safety, efficacy, quality of life (QoL), and translational studies including tumor angiogenic phenotyping, plasma VEGF and circulating endothelial cells.
Twenty-five pts were enrolled (22 evaluable) with median age 68 yrs (range 52–81), 24 (96%) stage III/IV, 18 (72%) IPI 3–5, 20 (80%) high risk MIPI, median 2 prior therapies (range 1–7), and 15 (60%) bortezomib progressors. At a median follow-up of 38 months, ORR was 73% (32% CR/CRu, 41% PR, n=22) and median PFS 10 months. Four CRs are ongoing (6+, 31+, 48+ and 50+ months). Toxicities included grade 1–2 fatigue, rash, neuropathy and cytopenias including grade 1–2 thrombocytopenia (64%) and grade 3–4 neutropenia (64%). Two thromboses and 5 grade 3–4 infections occurred. QoL was maintained or improved. Correlative studies demonstrated tumor autocrine angiogenic loop (expression of VEGFA and VEGFR1) and heightened angiogenesis and lymphangiogenesis in stroma. Plasma VEGF and circulating endothelial cells trended down with treatment.
RT-PEPC has significant and durable activity in MCL, with manageable toxicity and maintained QoL. Novel low-intensity approaches warrant further evaluation, potentially as initial therapy in elderly patients.
PMCID: PMC3004744  PMID: 20235190
14.  Quality assessment of phase I dose-finding cancer trials: proposal of a checklist 
Qualitative checklists for phase III trials have been proposed, to improve the reporting of such trials and to assess the validity of their results.
Our objective was to develop such a scale for phase I cancer trials.
From a review of existing guidelines and checklists for phase III clinical trials, a staff team was responsible for the first selection of items and the construction of the questionnaire. The proposed quality assessment measures were rated by the survey respondents comprised of phase I research clinicians and statisticians on a 4-point Likert scale. Selected items from the quantitative analysis of the questionnaires were reviewed by an expert team who was responsible for providing the final items list. This was then applied to 103 recently published cancer phase I trials.
Of the 48 initial items proposed by the staff team, 17 were selected from the quantitative analysis of the 99 participants’ ratings. After qualitative analysis by the expert team, a 15-item checklist was derived, with 5 items related to trial objective, 5 to design, and 5 to analysis. The application to 103 recent journal articles on phase I cancer trials evaluating cytotoxic drugs showed on average the report of 10 items (range: 6–13) with 4 items reported in more than 95% of papers, while 2 were poorly reported.
The response rate of participants was 20.7%.
A quality assessment checklist was developed for improved critical appraisal of the reporting of cytotoxic, dose-finding phase I oncology trials. This may be a first step toward a minimum standard of quality measures for all phase I clinical trial reports.
PMCID: PMC2819819  PMID: 18827040
15.  High-Dose Lovastatin for Acute Ischemic Stroke: Results of the Phase I Dose Escalation Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART) 
Hydroxymethylglutaryl coenzyme A reductase inhibitors (‘statins’) reduce the neuronal injury in dose-dependent fashion in rodent stroke models. We sought to determine whether lovastatin at doses above those currently approved can be administered safely within 24 h after an acute ischemic stroke.
We conducted a phase 1B dose-finding study using an adaptive design novel to stroke trials, the continual reassessment method, to find the highest tolerated dose of lovastatin. Planned doses were 1, 3, 6, 8 and 10 mg/kg/day for 3 days. The primary safety outcomes were myotoxicity and hepatotoxicity. The model was calibrated to select a dose causing 7–13% toxicity.
We enrolled 33 patients (16 men/17 women, age range 23–82 years). Three patients were treated at 1 mg/kg, 10 at 3 mg/kg, 12 at 6 mg/kg, and 8 at 8 mg/kg. Thirty of the 33 patients (90.9%) completed at least 11 of 12 doses. Two patients at the 6-mg/kg dose level experienced transient mild elevations in transaminases without clinical sequelae. After an initial dose reduction, the dose was re-escalated to 8 mg/kg, and no further patients reached safety outcomes. No clinical liver disease, myopathy, or creatine phosphokinase elevations occurred. The final model-based toxicity at 8 mg/kg was 13%; no patient was treated at 10 mg/kg.
Lovastatin at doses above those currently approved by the Food and Drug Administration is feasible for 3 days after an acute ischemic stroke and the maximum tolerated dose is estimated to be 8 mg/kg/day. Further randomized studies are warranted to confirm its safety and to demonstrate its efficacy in improving functional outcomes after stroke.
PMCID: PMC2814015  PMID: 19609078
Acute ischemic stroke; Statins
16.  Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma 
Journal of Clinical Investigation  2005;115(7):1903-1912.
Immunotherapy for the treatment of metastatic melanoma remains a major clinical challenge. The melanoma microenvironment may lead to local T cell tolerance in part through downregulation of costimulatory molecules, such as B7.1 (CD80). We report the results from the first clinical trial, to our knowledge, using a recombinant vaccinia virus expressing B7.1 (rV-B7.1) for monthly intralesional vaccination of accessible melanoma lesions. A standard 2-dose–escalation phase I clinical trial was conducted with 12 patients. The approach was well tolerated with only low-grade fever, myalgias, and fatigue reported and 2 patients experiencing vitiligo. An objective partial response was observed in 1 patient and disease stabilization in 2 patients, 1 of whom is alive without disease 59 months following vaccination. All patients demonstrated an increase in postvaccination antibody and T cell responses against vaccinia virus. Systemic immunity was tested in HLA-A*0201 patients who demonstrated an increased frequency of gp100 and T cells specific to melanoma antigen recognized by T cells 1 (MART-1), also known as Melan-A, by ELISPOT assay following local rV-B7.1 vaccination. Local immunity was evaluated by quantitative real-time RT-PCR, which suggested that tumor regression was associated with increased expression of CD8 and IFN-γ. The local delivery of vaccinia virus expressing B7.1 was well tolerated and represents an innovative strategy for altering the local tumor microenvironment in patients with melanoma.
PMCID: PMC1142116  PMID: 15937544

Results 1-16 (16)