Foundation For Clinical Research Research Articles

Cantilever FPDs Have Lower Success Rates Than End Abutted FPDs After 10-Years of Follow-up

Studies were located using a MEDLINE search strategy for English-language articles published from 1966 to 2004. A systematic review of 13 studies of cohort design (no randomized control trials were available) with the majority being retrospective. Seven hundred subjects with an age range of 26 to 84-years with a total of 816 FPDs with cantilever extensions were selected. The mean number of cantilever extensions varied from 1 to 6. Prostheses were of mixed design with 72% gold/acrylic structures. There are no data on the number of abutments compared with pontics or the overall length of the prostheses in this analysis Longitudinal follow-up of cantilever FPDs to failure or complication. All studies were required to have a mean minimum follow-up time of 5 years. Time to survival of the restorations, with secondary outcome measures of proportion of restoration successful at 10 years (success was defined as survival with no biological or mechanical complications) and time to biological (caries, loss of vitality and periodontal disease) and technical (loss of retention, abutment fracture, superstructure fracture) complication. The estimated aggregate proportion of cantilever FPDs surviving at 10 years was 81.8% (95% CI: 78.2-84.9%), with an annualized failure rate of 2 per 100 FPDs (95% CI: 1.63%-2.46%). Failure was not influenced by the number of cantilevered pontics or the material used for bridge construction in these data. The estimated aggregate proportion of cantilever FPDs successful (free of all complications) at 10 years was 63% (95% CI: 54.7%-70.2%). The estimated aggregate proportion with caries at one or more abutment teeth at 10 years was 9.1% (95% CI: 6.3%-13%). The estimated aggregate proportion with loss of vitality of one or more abutment teeth at 10 years was 32.6% (95% CI: 13.9%-64.9%). Rates of loss of vitality were much higher in the studies using extensive (12-unit FPDs supported by 2 cuspids) mandibular prostheses than those with shorter extensions. The estimated aggregate proportion with progression of periodontal disease leading to loss of the FPD at 10 years was 1% (95% CI: 0.3%-3%).The estimated aggregate proportion with loss of retention of the FPD at 10 years was 16.1% (95% CI: 8.8%-28.4%). Rates of loss of retention were much higher in the studies using extensive (12-unit FPDs supported by 2 cuspids) mandibular prostheses than those with shorter extensions. The estimated aggregate proportion with fracture of abutment teeth at 10 years was 2.4% (95% CI: 0.6%-9.8%). The estimated aggregate proportion with framework, veneer, or core fractures at 10 years was 5.9% (95% CI: 3.3%-10.4%). Estimated survival and success rates of cantilever FPDs were lower than previously reported rates for typical end-abutement supported FPDs; a 10-year failure rate of 18.2% had previously been reported for end-abutment supported FPDs for comparison.

PS1-25: Patient Outcomes in Systemic Lupus Erythematosus: A Collaborative Study Fostered by a New CTSA-based Partnership

Introduction: This project catalyzes a strategic partnership between Marshfield Clinic Research Foundation (MCRF) and the University of Wisconsin (UW), supported by an NIH Clinical and Translational Science Award (CTSA), to explore outcomes of systemic lupus erythematosus (SLE) in a community setting. The study pairs pilot funding and study staff from MCRF with a KL2 scholar/rheumatologist from the UW Institute for Clinical and Translational Research (ICTR). The project also uses ICTR-supported core resources at MCRF (Marshfield Epidemiologic Study Area [MESA]) and at UW (biostatistical support). Background: Survival among SLE patients has improved in recent decades, although studies continue to demonstrate excess mortality and cardiovascular disease. Whereas typical SLE studies represent urban tertiary referral populations, this study explores a community base, where the presence and extent of any mortality or cardiovascular excess is not clearly established. A past study described the spectrum of SLE in MESA from 19912001, finding cases were older, were less predominantly female, and had milder disease than in published reports from tertiary referral centers. Methods: Incident cases from 2002–2007 in this rural, population-based cohort are being ascertained and validated using the same American College of Rheumatology diagnostic criteria as the previous study. All incident cases 1991–2007 are being followed longitudinally to examine rates of all-cause and cardiovascular mortality, and of non-fatal cardiovascular events including MI, stroke, or heart failure hospitalization. Outcomes are to be compared with a matched set of MESA cohort members without SLE. Results/Conclusions: Automated data queries identified 167 new potential cases of SLE. After applying proportions of invalidation and non-incidence from the previous study, we estimate there will be an additional 31 incident cases from 2002–2007 to join the 44 cases previously identified. This represents one of only two rural US-based SLE cohorts with reported mortality outcomes. We anticipate that study results will support future funded research opportunities to ultimately inform evidence-based prevention strategies for SLE patients in real-world community practice.

PS1-10: Laboratory Content Area Development Within the Virtual Data Warehouse

Marsha A Raebel, PharmD, Gwyn Saylor, BA, Richard J Krajenta, BS, Jeremy McCauley, MBA, Paul Hitz, BS, Terese A DeFor, MS and Susan Andrade, ScD Marsha A Raebel, PharmD, Kaiser Permanente Colorado Institute for Health Research; Gwyn Saylor, BA, KPCO Institute for Health Research; Richard J Krajenta, BS, Henry Ford Health Systems; Jeremy McCauley, MBA, Marshfield Clinic Research Foundation; Paul Hitz, BS, Marshfield Clinic Research Foundation; Terese A DeFor, MS, HealthPartners Research Foundation; Susan Andrade, ScD, Meyers Primary Care Institute

PS1-30: Research Mentor: A Web-based Reference for Planning and Preparing a Research Proposal

Background: National emphasis on interdisciplinary and translational research as research priorities has created new challenges in grantsmanship. The Office of Scientific Writing and Publication at Marshfield Clinic Research Foundation utilized an informatics approach to create a comprehensive educational resource to assist new and established investigators engaged in research design. An interactive website accessible on the institutional intranet was designed to provide links to information, resources and support personnel to assist with navigating the central and peripheral processes required for successful procurement of institutional and external grants. Methods: Research Mentor was designed to provide comprehensive guidance to research fundamentals in a conveniently accessible interactive, user-friendly, online format. The website included resources and links to guidelines for grant development including feasibility analysis and study design planning, biostatistical considerations, peer review, grantsmanship, intellectual property protection, regulatory policies, computer-based training, institutional and national policies governing research, and access to funding agencies, forms, and appropriate support staff. The website was beta-tested by 25 physicians and scientists with varying degrees of research experience and refined based on user comments before the website was launched in spring of 2008. Results: Research Mentor proved to be an effective orientation tool for researchers by enhancing grantsmanship skills and providing access to research resources. Research Mentor has been effective in linking the researchers with appropriate support personnel who offer further assistance to researchers in producing competitive proposals. Tools custom-designed for Research Mentor to assist in project planning and design have been frequently accessed by investigators and reduce time spent by support staff on assisting with project planning. Conclusions: Informatics venues such as interactive user-friendly online educational websites can offer step-by-step guidance to research design and processes by providing a comprehensive cross-disciplinary research resource that offers value to new and established investigators alike. These tools promote networking with experienced support personnel to facilitate production of competitive grants.

PS2-08: Development and Implementation of a Genetic Fingerprinting Assay for the Personalized Medicine Research Project

Deanna S Cross, PhD, Lynn C Ivacic, Elisha L Stefanski and Catherine McCarty, PhD MPH Deanna S Cross, PhD, Marshfield Clinic Research Foundation; Lynn C Ivacic, , Marshfield Clinic Research Foundation; Elisha L Stefanski, , Marshfield Clinic Research Foundation; Catherine McCarty, PhD MPH, Marshfield Clinic Research Foundation

Mammalian Target of Rapamycin Signaling and Autophagy: Roles in Lymphangioleiomyomatosis Therapy

The pace of progress in lymphangioleiomyomatosis (LAM) is remarkable. In the year 2000, TSC2 gene mutations were found in LAM cells; in 2001 the tuberous sclerosis complex (TSC) genes were discovered to regulate cell size in Drosophila via the kinase TOR (target of rapamycin); and in 2008 the results were published of a clinical trial of rapamycin, a specific inhibitor of TOR, in patients with TSC and LAM with renal angiomyolipomas. This interval of just 8 years between a genetic discovery for which the relevant signaling pathway was as yet unknown, to the initiation, completion, and publication of a clinical trial, is an almost unparalleled accomplishment in modern biomedical research. This robust foundation of basic, translational, and clinical research in TOR, TSC, and LAM is now poised to optimize and validate effective therapeutic strategies for LAM. An immediate challenge is to deduce the mechanisms underlying the partial response of renal angiomyolipomas to rapamycin, and thereby guide the design of combinatorial approaches. TOR complex 1 (TORC1), which is known to be active in LAM cells, is a key inhibitor of autophagy. One hypothesis, which will be explored here, is that low levels of autophagy in TSC2-null LAM cells limits their survival under conditions of bioenergetic stress. A corollary of this hypothesis is that rapamycin, by inducing autophagy, promotes the survival of LAM cells, while simultaneously arresting their growth. If this hypothesis proves to be correct, then combining TORC1 inhibition with autophagy inhibition may represent an effective clinical strategy for LAM.

Dynamic retinal vessel response to flicker in age-related macular degeneration patients before and after vascular endothelial growth factor inhibitor injection

Retinal vessel responses to flickering light are different in various systemic and ocular diseases and can be improved after successful therapy. We investigated retinal vessel response to flickering light in age-related macular degeneration (AMD) patients before and after treatment with a single intravitreal bevacizumab (Avastin(®) ) injection. In 10 patients with exudative AMD [age: median (1.quartile; 3.quartile) 76.0 (73.5; 80.0) years], retinal vessel reactions were examined by Dynamic Vessel Analyser (DVA) before and 3 months after a single intravitreal application of bevacizumab (1.25 mg). A baseline measurement was followed by three consecutive monochromatic flicker stimulations (530-600 nm, 12.5 Hz, 20 seconds). Temporal retinal vessel reaction was analysed and compared with the reaction in healthy controls. Mean arterial dilation at the end of flicker was not different in all groups. For veins this parameter amounted to: pre-treatment, 2.6 (1.7; 3.9)%; post-treatment, 2.9 (2.4; 4.0)%; control, 4.3 (3.2; 5.7)%; significant: pre-treatment - control (Dunnett's procedure, p < 0.05). Maximal dilation occurred in arteries at: pre-treatment, 17.5 (14.8; 32.5) seconds; post-treatment, 18.0 (16.6; 30.6) seconds; control, 14.5 (10.8; 17.3) seconds. Both AMD groups were slower (p < 0.05): in veins at 17.0 (14.5; 20.0) seconds, 12.8 (8.6; 14.8) seconds and 18.5 (17.1; 19.9) seconds, respectively; significant post-treatment - control (p < 0.05). In the post-treatment AMD group arterial constriction after stimulation occurred more slowly compared with the control group (p < 0.05). Dynamic retinal arterial and venous reactions to flickering light are altered in AMD compared with controls. Three months after a single injection of a vascular endothelial growth factor inhibitor, the investigated retinal dynamic vascular parameters were not altered in our study.

Review of: Foundations of Clinical Research Applications to Practice (3rd edition)

Foundations of Clinical Research: Applications to Practice is the third edition written by physical therapy professors at MGH Institute of Health Professions in Boston Massachusetts. The textbook is intended as the primary textbook for educational instruction related to research and critical thinking. The authors intended use of this text by physical therapists, occupational therapists, speech therapists, nursing, medicine, exercise physiologists and other health care related disciplines. This user-friendly textbook can be utilized by anyone interested in step-by-step illustrations for developing, implementing and disseminating research related activities.

Principles and Practice of Therapeutic Exercise for Horses

Physical therapists are an integral component of the medical team in human health care. They are backed by a solid foundation of basic science and clinical research. Veterinarians have only recently begun to incorporate physical therapy into clinical practice, but without formal research that validates therapeutic interventions specific to equine patients. The purpose of this article is to present a series of therapeutic exercises adapted for horses based on knowledge and experience of human physical therapy, equine biomechanics, and the types of movement dysfunction commonly seen in the performance horse. Injuries, lameness and musculoskeletal pain syndromes, frequently encountered in equine practice, are disorders that may be successfully addressed with physical therapy. Incorporating standard therapeutic interventions based on clinical success in humans, basic science research, or expert opinion is possible with the understanding that these techniques will ultimately be accepted or refuted when their success or failure is formally documented. This review is designed to stimulate discussion and encourage research that will add to the knowledge base and lead to effective therapeutic protocols in the equine patient.

Microdialysis: A Technique for Pharmacokinetic-Pharmacodynamic Studies of Oncological Drugs

Solid tumors have several barriers that may limit drug penetration and provide inherent mechanisms of resistance. Therefore, the evaluation of antineoplastic agents should base on tumor drug exposure and antitumor activity. Owing to selective access to the extracellular space of the tumor, which acts as target site for most antineoplastic drugs, monitoring drug disposition and corresponding antitumor activity, microdialysis (MD), a probe-based sampling technique, satisfies regulatory requirements for pharmacokinetic- pharmacodynamic (PK-PD) studies. MD is a powerful tool for PK-PD studies of oncological drugs, which would allow better understanding of exposure-response relationships and contributes to the research and development of oncological drugs. Recent progresses in the development of MD for estimating PK-PD studies of oncological drugs are summarized in this review. Special preclinical application examples of MD for PK-PD studies of oncological drugs organized by types of antineoplastic drugs and informations collected are also described. In conclusion, the role of MD in preclinical PK-PD studies of oncological drugs has been confirmed and it has provided a strong foundation for further clinical research.

Treatment of atherosclerotic intracranial arterial stenosis.

David Pelz MD L. Nelson Hopkins MD Elad Levy MD Section Editors: Atherosclerotic stenosis of the major intracranial arteries (intracranial internal carotid artery, middle cerebral artery, vertebral artery, basilar artery) is probably the most common cause of stroke worldwide.1 Intracranial atherosclerosis causes 30% to 50% of strokes in Asia2 and 8% to 10% of strokes in North America.3 This review focuses on the medical and endovascular treatment of atherosclerotic intracranial arterial stenosis. Initially, a retrospective study suggested that warfarin was superior to aspirin for stroke prevention in patients with symptomatic intracranial arterial stenosis.4 This retrospective data combined with a proposed pathophysiological rationale for anticoagulation5 made warfarin a common treatment choice for symptomatic intracranial stenosis.6 However, the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial showed that aspirin was safer and as effective as warfarin for stroke prevention in patients with symptomatic intracranial stenosis. WASID was stopped early after a mean follow-up of 1.8 years because of higher rates of death and major hemorrhage in the warfarin arm. The primary end point of ischemic stroke, brain hemorrhage or vascular death, occurred in 22.1% of patients assigned aspirin and 21.8% of those in the warfarin group.7 The rates of myocardial infarction or sudden death were also higher in the warfarin arm. Certain high-risk subgroups of patients with intracranial stenosis were previously thought to benefit from anticoagulation, such as those with severe stenosis,4 vertebrobasilar disease,4 and those who have failed antithrombotic therapy.8 In WASID, however, patients with severe stenosis9 or those previously on antithrombotic therapy9,10 did not benefit from warfarin. Patients with basilar artery stenosis in WASID did appear to have a lower rate of the primary end point on warfarin, but there was no difference in the rate of stroke in the …

Web 2.0 rollercoaster. A ride we should all take

Web 2.0 rollercoaster. A ride we should all take

Flu Vaccine Didn't Cut Pneumonia Risk

Fran Lowry is with the Orlando, Fla., bureau of Elsevier Global Medical News. Influenza vaccination was not associated with a significantly reduced risk of community-acquired pneumonia in a large population of people aged 65 and older. In the study of 1,173 cases and 2,346 controls, flu vaccine was associated with an 8% lower risk of community-acquired pneumonia among immunocompetent seniors during influenza season, investigators reported in The Lancet. The finding stands in contrast to a number of observational studies that suggest that vaccination substantially reduces the risk of hospital admission due to pneumonia in elderly adults. But these studies have not differentiated between healthy, mobile, immunocompetent seniors and frail seniors of advanced age or chronic health conditions, who are known to benefit from influenza vaccine. The investigators conducted a nested case-control study of individuals aged 65-94 years who were enrolled in Group Health, a health maintenance organization in Seattle, during 2000, 2001, and 2002. To ensure that they were removing any bias in their results, the researchers looked at both the preinfluenza and influenza periods of each year, reasoning that any benefit from the flu vaccine that was seen in the preinfluenza season could not be due to the protective effects of the vaccine. They found that in the preinfluenza season, there was an apparent strong benefit of the vaccine, with a 40% reduction in the risk of pneumonia. But after controlling for the presence of frail and sick seniors, they found essentially no effect of influenza vaccine during preinfluenza periods, reported the researchers, led by Michael L. Jackson, PhD, of the Group Health Center for Health Studies, Seattle (Lancet 2008;372:398-405). To look at the effect of the flu vaccine during influenza periods, they selected subjects who were immunocompetent and had no serious comorbidities. The age- and sex-adjusted odds ratio for the association between influenza vaccination and risk of community-acquired pneumonia was 1.04, but after adjustment for the confounding factors that were identified in the preinfluenza periods, the influenza season odds ratio was 0.92. In an interview, Dr. Jackson said that the findings are consistent with there being no link between flu vaccine and pneumonia risk in seniors. However, this does not mean that they should forego flu shots. “Randomized trials, which are the gold standard for public health-related evidence, have found that influenza vaccine reduces the risk of influenza infection in young—that is, 75 years and younger—healthy seniors. So they should still get their flu shots,” he said. He added that more work needs to be done to understand how well the vaccine prevents serious complications of the flu, such as pneumonia, in older seniors and those with chronic health problems. In an accompanying commentary, Edward A. Belongia, MD, of the Marshfield (Wis.) Clinic Research Foundation, and David K. Shay, MD, of the influenza division, Centers for Disease Control and Prevention, agreed with the need for additional studies about the causes of pneumonia in elderly adults, particularly in highly vaccinated populations (Lancet 2008;372:352-4). Calling the study by Dr. Jackson and his colleagues “well designed,” they added that standard methods of comparing the effectiveness of flu shots in different seasons and in different populations are also needed. The commentators also suggested that future studies of vaccine effectiveness should include other flu-related acute illnesses besides pneumonia and use sensitive and specific diagnostic tests, such as the polymerase chain reaction, for influenza. Dr. Belongia is director of the Epidemiology Research Center at the Marshfield Clinic Research Foundation. One of the authors of the study disclosed that she is a paid consultant to Sanofi Pasteur and to Novartis, manufacturers of the influenza vaccine. The other authors declared no conflict of interest.

Abstract PS1-20: Fiscal Tracking of Clinical Research: Marshfield Clinic Research Foundation Community Clinical Oncology Program

Kim M. Fuehrer, RN, BSN, MSM and Tarit K. Banerjee, MD, FACP Kim M. Fuehrer, RN, BSN, MSM, Marshfield Clinic Research Foundation; Tarit K. Banerjee, MD, FACP, Marshfield Clinic

Intrathecal corticosteroids might slow Alzheimer&amp;rsquo;s disease progression

Anti-inflammatory drugs for treatment and prevention of Alzheimer's disease have to date proved disappointing, including a large study of low-dose prednisone, but higher dose steroids significantly reduced amyloid secretion in a small series of nondemented patients. In addition, there is a case report of a patient with amyloid angiopathy who had complete remission from two doses of dexamethasone, and very high dose steroids are already used for systemic amyloidosis. This paper presents the hypothesis that pulse-dosed intrathecal methylprednisolone or dexamethasone will produce detectable slowing of Alzheimer's progression, additive to that obtained with cholinesterase inhibitors and memantine. A protocol based on treatment regimens for multiple sclerosis and central nervous system lupus is outlined, to serve as a basis for formulating clinical trials. Ultimately intrathecal corticosteroids might become part of a multi-agent regimen for Alzheimer's disease and also have application for other neurodegenerative disorders.

Uncontrolled Randomized Clinical Trial Demonstrates Similar Long-Term (6 months) Antigingivitis and Antiplaque Efficacy for 2 Mouth Rinses: One that Uses Cetylpyridinium Chloride (CPC) as an Active Agent and the Other that Uses Essential Oils (EO) as an Active Agent

Article Title and Bibliographic Information Comparison of the effects of cetylpyridinium chloride with an essential oil mouth rinse on dental plaque and gingivitis—a six-month randomized controlled clinical trial Albert-Kiszely A, Pjetursson BE, Salvi GE, Witt J, Hamilton A, Persson GR, et al. J Clin Periodontol 2007;34(8):658-67 Level of Evidence 2 Purpose/Question The purpose of this study was to compare the long-term (6 months) clinical and microbiological effects of an experimental CPC mouth rinse with that of a commercially available and widely used EO mouth rinse in an unsupervised, uncontrolled 6-month randomized clinical trial. Source of Funding This study was supported by a grant from the manufacture of the experimental CPC mouth rinse, Procter & Gamble Company (Mason, OH), and by the Clinical Research Foundation (CRF) for the Promotion of Oral Health, University of Berne, Switzerland. Type of Study/Design This is a parallel randomized 2-group study that had no negative control.

How Are Drugs Approved? Part 3. the Stages of Drug Development

The first article of this series on the drug development process described the historical evolution of the U.S. Food and Drug Administration (FDA), and last month's article reviewed the ethical foundations of clinical research. Before a new drug is marketed, a sequence of preclinical investigations and three phases of clinical studies are conducted. This drug development process involves the FDA, pharmaceutical companies (sponsors), clinical investigators, and institutional review boards. This article further describes this aspect of the drug development process.

How Are Drugs Approved? Part 2: Ethical Foundations of Clinical Research

In the United States, the U.S. Food and Drug Administration (FDA) evaluates and approves drugs through a process that includes clinical research. The purpose of clinical research is to diminish uncertainty by acquiring knowledge. For drug development, the goal is to approve drugs that are safe and effective. Because of the uncertainty, however, participation in clinical research entails some degree of risk. Ethical principles provide the framework on which studies can be designed and conducted and which appropriately balance benefits and risks for research participants. As part of a broad overview of the drug development process, this article reviews the ethical foundations of clinical research.

How Are Drugs Approved? Part 1: the Evolution of the Food and Drug Administration

The discovery, development, and marketing of drugs for clinical use is a process that is complex, arduous, expensive, highly regulated, often criticized, and sometimes controversial. In the United States, the Food and Drug Administration (FDA) is the governmental agency responsible for regulating the development and marketing of drugs, medical devices, biologics, foods, cosmetics, radiation-emitting electronic devices, and veterinary products, with the objective of ensuring their safety and efficacy. As part of a broad overview of the drug development process, this article will describe the historical evolution of the FDA. This will provide background for two subsequent articles in this series, which will describe the ethical foundations of clinical research and hethe stages of drug development.

Running an ethical trial 60 years after the Nuremberg Code

The Nuremberg Code has served as a foundation for ethical clinical research since its publication 60 years ago. This landmark document, developed in response to the horrors of human experimentation done by Nazi physicians and investigators, focused crucial attention on the fundamental rights of research participants and on the responsibilities of investigators. Although the Nuremberg Code has provided an important framework for discussions on the requirements of ethical clinical research, and has resulted in the development of other initiatives-eg, the Declaration of Helsinki and the Belmont Report-designed to ensure the rights and safety of human beings taking part in medical research, knowledge of both past events and the current complexity of research suggests further improvements are necessary in the existing approaches to human clinical research.