Showing papers by "David J. Margolis published in 2011"
TL;DR: An overview of the ethical foundations of trial design, trial oversight, and the process of obtaining approval of a therapeutic, from its pre-clinical phase to post-marketing surveillance is provided.
Abstract: The recent focus of federal funding on comparative effectiveness research underscores the importance of clinical trials in the practice of evidence-based medicine and health care reform. The impact of clinical trials not only extends to the individual patient by establishing a broader selection of effective therapies, but also to society as a whole by enhancing the value of health care provided. However, clinical trials also have the potential to pose unknown risks to their participants, and biased knowledge extracted from flawed clinical trials may lead to the inadvertent harm of patients. Although conducting a well-designed clinical trial may appear straightforward, it is founded on rigorous methodology and oversight governed by key ethical principles. In this review, we provide an overview of the ethical foundations of trial design, trial oversight, and the process of obtaining approval of a therapeutic, from its pre-clinical phase to post-marketing surveillance. This narrative review is based on a course in clinical trials developed by one of the authors (DJM), and is supplemented by a PubMed search predating January 2011 using the keywords "randomized controlled trial," "patient/clinical research," "ethics," "phase IV," "data and safety monitoring board," and "surrogate endpoint." With an understanding of the key principles in designing and implementing clinical trials, health care providers can partner with the pharmaceutical industry and regulatory bodies to effectively compare medical therapies and thereby meet one of the essential goals of health care reform.
209 citations
TL;DR: The results suggest that glycemia, as assessed by HbA1c, may be an important biomarker in predicting wound healing rate in diabetic patients.
157 citations
TL;DR: There is profound “region-correlated” variation in the rate of LEA among Medicare beneficiaries with diabetes and location matters and whereas the likelihood of an amputation varies dramatically across the U.S. overall, neighboring locations have unexpectedly similar amputation rates.
Abstract: OBJECTIVE Lower-extremity amputation (LEA) is common among persons with diabetes. The goal of this study was to identify geographic variation and the influence of location on the incidence of LEA among U.S. Medicare beneficiaries with diabetes. RESEARCH DESIGN AND METHODS We conducted a cohort study of beneficiaries of Medicare. The geographic unit of analysis was hospital referral regions (HRRs). Tests of spatial autocorrelation and geographically weighted regression were used to evaluate the incidence of LEA by HRRs as a function of geographic location in the U.S. Evaluated covariates covered sociodemographic factors, risk factors for LEA, diabetes severity, provider access, and cost of care. RESULTS Among persons with diabetes, the annual incidence per 1,000 of LEA was 5.0 in 2006, 4.6 in 2007, and 4.5 in 2008 and varied by the HRR. The incidence of LEA was highly concentrated in neighboring HRRs. High rates of LEA clustered in contiguous portions of Texas, Oklahoma, Louisiana, Arkansas, and Mississippi. Accounting for geographic location greatly improved our ability to understand the variability in LEA. Additionally, covariates associated with LEA per HRR included socioeconomic status, prevalence of African Americans, age, diabetes, and mortality rate associated with having a foot ulcer. CONCLUSIONS There is profound “region-correlated” variation in the rate of LEA among Medicare beneficiaries with diabetes. In other words, location matters and whereas the likelihood of an amputation varies dramatically across the U.S. overall, neighboring locations have unexpectedly similar amputation rates, some being uniformly high and others uniformly low.
139 citations
TL;DR: This study aims to establish the validity of psoriasis information in The Health Improvement Network (THIN) by conducting a large-scale study of Psoriasis patients enrolled in the THIN database.
Abstract: Background
Psoriasis is a common disease frequently studied in large databases. To date the validity of psoriasis information has not been established in The Health Improvement Network (THIN).
110 citations
17 Feb 2011
TL;DR: The annual mortality rate for Medicare Parts A and B fee-for-service beneficiaries with diabetes who have an incident diabetic foot ulcer is about 11%; for those with an incident lower extremity amputation, about 22%.
Abstract: The annual mortality rate for Medicare Parts A and B fee-for-service beneficiaries with diabetes who have an incident diabetic foot ulcer is about 11%; for those with an incident lower extremity amputation, about 22%. Diabetes mellitus, a metabolic disorder characterized by elevated blood glucose, is a serious and growing problem. More than 23 million people in the United States (U.S.) are believed to have diabetes. It is estimated that by 2025, 300 million people worldwide will have diabetes and by 2030, 360 million people. Thus, by 2030, worldwide prevalence will approach 5 percent.1-4
94 citations
17 Feb 2011
77 citations
TL;DR: HBO2T stimulates vasculogenic stem cell mobilization from bone marrow of diabetics and more cells are recruited to skin wounds and nitric oxide synthase activity is acutely increased in patients' platelets following HBO2T and remains elevated for at least 20 hours.
Abstract: Diabetic patients undergoing hyperbaric oxygen therapies (HBO(2)T) for refractory lower extremity neuropathic ulcers exhibit more than a twofold elevation (p=0.004) in circulating stem cells after treatments and the post-HBO(2)T CD34(+) cell population contains two- to threefold higher levels of hypoxia inducible factors-1, -2, and -3, as well as thioredoxin-1 (p<0.003), than cells present in blood before HBO(2)T. Skin margins obtained from 2-day-old abdominal wounds exhibit higher expression of CD133, CD34, hypoxia inducible factor-1, and Trx-1 vs. margins from refractory lower extremity wounds and expression of these proteins in all wounds is increased due to HBO(2)T (p<0.003). HBO(2)T is known to mobilize bone marrow stem cells by stimulating nitric oxide synthase. We found that nitric oxide synthase activity is acutely increased in patients' platelets following HBO(2)T and remains elevated for at least 20 hours. We conclude that HBO(2) T stimulates vasculogenic stem cell mobilization from bone marrow of diabetics and more cells are recruited to skin wounds.
73 citations
TL;DR: Patch-clamp recordings from identified types of ON and OFF retinal ganglion cells in the adult rd1 mouse show that the ongoing oscillatory spike activity in both cell types is driven by strong rhythmic synaptic input from presynaptic neurons that is blocked by CNQX.
Abstract: Here we review evidence that loss of photoreceptors due to degenerative retinal disease causes an increase in the rate of spontaneous ganglion spike discharge. Information about persistent spike activity is important since it is expected to add noise to the communication between the eye and the brain and thus impact the design and effective use of retinal prosthetics for restoring visual function in patients blinded by disease. Patch-clamp recordings from identified types of ON and OFF retinal ganglion cells in the adult (36–210 d old) rd1 mouse show that the ongoing oscillatory spike activity in both cell types is driven by strong rhythmic synaptic input from presynaptic neurons that is blocked by CNQX. The recurrent synaptic activity may arise in a negative feedback loop between a bipolar cell and an amacrine cell that exhibits resonant behavior and oscillations in membrane potential when the normal balance between excitation and inhibition is disrupted by the absence of photoreceptor input.
71 citations
TL;DR: Denial is the most common patient-specific factor accounting for delayed presentation for NMSC diagnosis and treatment, and patients younger than 65 years, with a skin cancer history, with major life problems, and with a history of any cancer were most likely to wait to see a doctor.
Abstract: Background Patients may delay treatment for skin cancer for various reasons. Prior research on treatment delay has focused on melanoma rather than nonmelanoma skin cancer (NMSC), which is much more common. Objective We sought to clarify the reasons for delay in the presentation for diagnosis and treatment of NMSC. Methods This was a prospective cohort study in a Mohs micrographic surgery private practice in an urban setting. Eligible subjects were 982 consecutive patients presenting for Mohs micrographic surgery for NMSC between March and December 2005. No enrolled subjects were withdrawn for adverse effects. The survey was a 4-page written self-administered questionnaire, eliciting patient medical history, skin cancer history, demographic information, initial and subsequent lesion size, and reasons for delay in presentation for evaluation and management. Outcome analyses addressed the: (1) frequency of specific reasons for delayed presentation, as provided by self-report; (2) association between reasons for delay with demographic or other patient-specific factors; and (3) change in lesion diameter from the time of detection by the patient to the time of presentation to the doctor. Results Among the reasons for waiting, denial (including: thought it would go away, thought it wasn't important, too busy, thought they could self-treat, afraid it might be something dangerous) was the most frequent, accounting for 71% of cases; difficulty scheduling was associated with 10% of the instances of delay. Older patients (age >64 years) were more likely to wait to seek care than younger patients (odd ratio [OR] = 0.5; 95% confidence interval [CI] 0.4-0.7). Patients with a prior skin cancer were more likely to wait (OR = 1.4; 95% CI 1.1-2.0), as were patients with major life problems (OR = 2.6; 95% CI 1.6-4.3) and patients with a history of any cancer (OR = 1.8; 95% CI 1.3-2.4). Weighted kappa analysis comparing tumor size at the two time points yielded a kappa of 0.72 (SE = .02; 95% CI 0.68-0.77). When the data were separated into two groups, one including those tumors that had decreased in size or remained the same (698 patients), and those that had increased in size (120 patients), the median delay-to-presentation intervals associated with these two groups (2.5 vs 6.0 months, respectively) were found to be significantly different ( P Limitations This study may have limited generalizability to the extent that it reflects the characteristics only of the subpopulation of patients with skin cancer who eventually received treatment at a referral-based, urban, dermatology private practice. Overall, these patients may have been better insured and be more affluent than the general population. Conclusions Denial is the most common patient-specific factor accounting for delayed presentation for NMSC diagnosis and treatment. Patients younger than 65 years, with a skin cancer history, with major life problems, and with a history of any cancer were most likely to wait to see a doctor. There was a significant increase in tumor size from the time when tumors were noticed by patients to the time when patients presented to a physician. Increased delay was associated with increased tumor growth.
66 citations
04 Nov 2011
TL;DR: The prevalence rates for foot ulcer and lower extremity amputation among diabetic Medicare beneficiaries vary dramatically by geographic region and are thought to underestimate the true prevalence by one-third.
Abstract: The prevalence of diabetes in the Medicare population may be one-third higher than previously estimated.Overall, approximately 8% of diabetic Medicare beneficiaries have a foot ulcer and 1.8% have an amputation. These prevalence rates are further elevated for the subset of beneficiaries with lower extremity peripheral artery disease.The prevalence rates for foot ulcer and lower extremity amputation among diabetic Medicare beneficiaries vary dramatically by geographic region.
64 citations
08 Mar 2011
TL;DR: Beneficiaries with a lower extremity amputation are seen by their outpatient health care provider about 12 times per year and are hospitalized about 2 timesper year, and the cost of care for these beneficiaries is substantial, at about $52,000 for total reimbursement of all Medicare services per year.
Abstract: Beneficiaries with a lower extremity amputation are seen by their outpatient health care provider about 12 times per year and are hospitalized about 2 times per year. The cost of care for these beneficiaries is substantial, at about $52,000 for total reimbursement of all Medicare services per year. Diabetes mellitus is a significant illness, both from an individual point of view and a societal perspective. According to the Centers for Disease Control and Prevention in 2007, the number of people in the United States (U.S.) with diabetes mellitus reached 24 million, with another 57 million people estimated to have prediabetes.1 From 1980 to 2008, the number of diabetic Medicare beneficiaries aged 65 or older increased from 2.3 million to 7.4 million.2 In a population of beneficiaries with at least 12 months of continuous enrollment in Medicare Parts A and B fee-for-service (FFS) in 2008, 8.9 million all-age Medicare beneficiaries had diabetes mellitus, or nearly 28 percent of this cohort.3 The actual national cost burden of diabetes is thought to exceed $174 billion, including the social cost of intangibles such as pain and suffering, care provided by nonpaid caregivers, medical costs associated with undiagnosed diabetes, and diabetes-attributed costs.4 On average, medical expenditures are thought to be 2.3 times higher in people with diabetes as compared to those without diabetes.4 Many of these expenditures are likely related to comorbidities associated with diabetes like diabetic foot ulcer (DFU) and lower extremity amputation (LEA).
TL;DR: No association was found between frequent repositioning of bed‐bound patients and lower pressure ulcer incidence, calling into question the allocation of resources for repositioner, according to a 2004–2007 cohort study in nine Maryland and Pennsylvania hospitals.
Abstract: Frequent manual repositioning is an established part of pressure ulcer prevention, but there is little evidence for its effectiveness. This study examined the association between repositioning and pressure ulcer incidence among bed-bound elderly hip fracture patients, using data from a 2004-2007 cohort study in nine Maryland and Pennsylvania hospitals. Eligible patients (n=269) were age ≥ 65 years, underwent hip fracture surgery, and were bed-bound at index study visits (during the first 5 days of hospitalization). Information about repositioning on the days of index visits was collected from patient charts; study nurses assessed presence of stage 2+ pressure ulcers 2 days later. The association between frequent manual repositioning and pressure ulcer incidence was estimated, adjusting for pressure ulcer risk factors using generalized estimating equations and weighted estimating equations. Patients were frequently repositioned (at least every 2 hours) on only 53% (187/354) of index visit days. New pressure ulcers developed at 12% of visits following frequent repositioning vs. 10% following less frequent repositioning; the incidence rate of pressure ulcers per person-day did not differ between the two groups (incidence rate ratio 1.1, 95% confidence interval 0.5-2.4). No association was found between frequent repositioning of bed-bound patients and lower pressure ulcer incidence, calling into question the allocation of resources for repositioning.
TL;DR: Compared with current dogma about the long-term use of antimicrobial agents, the prolonged use of tetracycline antibiotics commonly used to treat acne lowered the prevalence of colonization by S aureus and did not increase resistance to the tetradecidine antibiotics.
Abstract: Objectives To determine the frequency of Staphylococcus aureus colonization among patients with acne and to compare the susceptibility patterns between the patients who are using antibiotics and those who are not using antibiotics. Design Survey (cross-sectional) study of patients treated for acne. Setting Dermatology outpatient office practice Participants The study included 83 patients who were undergoing treatment and evaluation for acne. Main Outcome Measure Colonization of the nose or throat with S aureus. Results A total of 36 of the 83 participants (43%) were colonized with S aureus. Two of the 36 patients (6%) had methicillin-resistant S aureus ; 20 (56%) had S aureus solely in their throat; 9 (25%) had S aureus solely in their nose; and 7 (19%) had S aureus in both their nose and their throat. When patients with acne who were antibiotic users were compared with nonusers, the prevalence odds ratio for the colonization of S aureus was 0.16 (95% confidence interval [CI], 0.08-1.37) after 1 to 2 months of exposure and increased to 0.52 (95% CI, 0.12-2.17) after 2 months of exposure (P = .31). Many of the S aureus isolates were resistant to treatment with clindamycin and erythromycin (40% and 44%, respectively), particularly the nasal isolates. Very few showed resistance rates ( Conclusion Unlike current dogma about the long-term use of antimicrobial agents, the prolonged use of tetracycline antibiotics commonly used to treat acne lowered the prevalence of colonization by S aureus and did not increase resistance to the tetracycline antibiotics.
TL;DR: Many theories have been proposed to address the profound inflammatory dysregulation, with the majority focusing on fibrin trap, inflammatory trap, cytokines, growth factors, and matrix metalloproteinases.
Journal Article•
TL;DR: The Body Image Disturbance Questionnaire appears to be an accurate instrument that can assess appearance-related concern and impairment in patients with acne vulgaris and correlated with Skindex-16 scores, confirming that quality of life and body image are related psychosocial constructs.
Abstract: Psychosocial outcome measures, which attempt to examine acne from the patient's perspective, have become increasingly important in dermatology research. One such measure is the Body Image Disturbance Questionnaire. The authors' primary aim was to determine the validity and internal consistency of the Body Image Disturbance Questionnaire in patients with acne vulgaris. The secondary aim was to investigate the relationship between body image disturbance and quality of life. This cross-sectional investigation included 52 consecutive acne patients presenting to an outpatient dermatology clinic. Subjects completed the Body Image Disturbance Questionnaire, Skindex-16, and other body image and psychosocial functioning measures. An objective assessment of acne was performed. The Body Image Disturbance Questionnaire was internally consistent and converged with other known body image indices. Body Image Disturbance Questionnaire scores also correlated with Skindex-16 scores, confirming that quality of life and body image are related psychosocial constructs. The Body Image Disturbance Questionnaire appears to be an accurate instrument that can assess appearance-related concern and impairment in patients with acne vulgaris. Limitations include a small sample size and the cross-sectional design.
01 Jan 2011
TL;DR: In this article, the annual mortality rate for Medicare Parts A and B fee-for-service beneficiaries with diabetes who have an incident diabetic foot ulcer is about 11%; for those with an incident lower extremity amputation, about 22%.
Abstract: In Medicare Parts A and B fee-for-service beneficiaries with diabetes, the incidence of diabetic foot ulcer is about 6.0% and lower extremity amputation about 0.5%.Among Medicare Parts A and B fee-for-service beneficiaries with diabetes and foot ulcer, the prevalence of microvascular and macrovascular complications is about 46% and 65%, respectively. Further, among those with a lower extremity amputation, the prevalence of microvascular and macrovascular complications is about 46% and 76%, respectively.The annual mortality rate for Medicare Parts A and B fee-for-service beneficiaries with diabetes who have an incident diabetic foot ulcer is about 11%; for those with an incident lower extremity amputation, about 22%.
TL;DR: Evaluation of the association between pressure‐redistributing support surface (PRSS) use and incident pressure ulcers in older adults with hip fracture finds no link between PRSS use and injury.
Abstract: OBJECTIVES: To evaluate the association between pressure-redistributing support surface (PRSS) use and incident pressure ulcers in older adults with hip fracture.
DESIGN: Secondary analysis of data from prospective cohort with assessments performed as soon as possible after hospital admission and on alternating days for 21 days.
SETTING: Nine hospitals in the Baltimore Hip Studies network and 105 postacute facilities to which participants were discharged.
PARTICIPANTS: Six hundred fifty-eight people aged 65 and older who underwent surgery for hip fracture.
MEASUREMENTS: Full-body examination for pressure ulcers; bedbound status; and PRSS use, recorded as none, powered (alternating pressure mattresses, low-air-loss mattresses, and alternating pressure overlays), or nonpowered (high-density foam, static air, or gel-filled mattresses or pressure-redistributing overlays except for alternating pressure overlays).
RESULTS: Incident pressure ulcers (IPUs), Stage 2 or higher, were observed at 4.2% (195/4,638) of visits after no PRSS use, 4.5% (28/623) of visits after powered PRSS use, and 3.6% (54/1,496) of visits after nonpowered PRSS use. The rate of IPU per person-day of follow-up did not differ significantly between participants using powered PRSSs and those not using PRSSs. The rate also did not differ significantly between participants using nonpowered PRSSs and those not using PRSSs, except in the subset of bedbound participants (incidence rate ratio=0.3, 95% confidence interval=0.1\u20130.7).
CONCLUSION: PRSS use was not associated with a lower IPU rate. Clinical guidelines may need revision for the limited effect of PRSS use, and it may be appropriate to target PRSS use to bedbound patients at risk of pressure ulcers.
01 Jan 2011
TL;DR: In this paper, the authors report that patients with a lower extremity amputation are seen by their outpatient health care provider about 12 times per year and are hospitalized about 2.5 times each year, and the cost of care for these patients is substantial at about $33,000 for total reimbursement of all Medicare services per year.
Abstract: Beneficiaries with a diabetic foot ulcer are seen by their outpatient health care provider about 14 times per year and are hospitalized about 1.5 times per year. The cost of care for these beneficiaries is substantial, at about $33,000 for total reimbursement of all Medicare services per year.Beneficiaries with a lower extremity amputation are seen by their outpatient health care provider about 12 times per year and are hospitalized about 2 times per year. The cost of care for these beneficiaries is substantial, at about $52,000 for total reimbursement of all Medicare services per year.
TL;DR: The feasibility of obtaining DNA from a large national community-based population of children who have AD is demonstrated and the effectiveness of using a pre-notification letter and the use of monetary incentives to improve participation rates for obtaining buccal-DNA through the mail is assessed.
TL;DR: The comment on information bias is interesting: is there a possibility that patients treated with isotretinoin would be more likely to have their suicidal behaviour recorded, and assuming a higher propensity to admit a patient who has made a suicide attempt because of isot retinoin treatment may seem a bit farfetched.
Abstract: The comment on information bias is interesting: is there a possibility that patients treated with isotretinoin would be more likely to have their suicidal behaviour recorded? This may be the case today, but during the 1980s the suspicion of an association between isotretinoin and psychiatric sideeffects was not widespread, and maybe even less so among psychiatrists. More importantly, the suicide attempts included in this study all led to hospitalization; assuming a higher propensity to admit a patient who has made a suicide attempt because of isotretinoin treatment may seem a bit farfetched.
TL;DR: The majority of evidence suggests that an association exists between having moderate to severe psoriasis and an increased risk of CAD, but neither of these new studies help us understand if Psoriasis is a modifiable risk factor for CAD.
Abstract: Worldwide psoriasis is a common systemic inflammatory illness. The majority of recent studies have shown an association between psoriasis and coronary artery disease (CAD). It has been hypothesized that the association between psoriasis and CAD is due to chronic systemic inflammation. As a risk factor for CAD, psoriasis represents a disease that could potentially be modified, thereby decreasing the risk of morbidity and mortality due to CAD, a very important public health concern. In fact, this should be a directly testable hypothesis, which as a question is ‘Does the aggressive treatment of psoriasis prevent CAD?’. The study by Abuabara et al. attempted to answer this question. This well-conducted study published in this issue of the BJD evaluated more than 25 000 individuals with psoriasis who are at highest risk for CAD – those with severe to moderate disease. They conducted this study using administrative claims data from a very large healthcare insurance programme. They basically compared two broad classes of therapy: those receiving light therapy and those receiving systemic agents such as ‘biologics’, methotrexate and ciclosporin. They assumed that the systemic therapies would have a greater effect on the systemic inflammatory components of psoriasis. While it is up to the reader to review this study comprehensively, overall they did not find a decreased risk of myocardial infarction in those treated with systemic agents compared with those who received light therapy. A more nuanced view might be that there was a trend toward an overall 30% increase among systemic therapy users and about a 30% decrease in a subset of those at highest risk of CAD, those aged < 50 years. Interestingly, a very recent meta-analysis of randomized clinical trials (RCT) appeared in JAMA on this same topic. This meta-analysis of available RCTs evaluated a newer class of biologic, antagonistic monoclonal antibodies to interleukin (IL)-12 and IL-23. The results were somewhat similar. No significant difference in the rate of a composite cardiovascular disease endpoint was noted in those treated with these newer biologics compared with those treated with standard care or placebo therapies. The authors of this study noted that they did not have access to all studies that have been conducted and opined in their comment section that studies for one of these agents (briakinumab) had been discontinued due to concerns about a potential association with cardiovascular disease. So what should a careful clinician conclude from these studies? First and foremost, at this time, the majority of evidence suggests that an association exists between having moderate to severe psoriasis and an increased risk of CAD. Unfortunately, neither of these new studies help us understand if psoriasis is a modifiable risk factor for CAD. Both of these studies fail to demonstrate that successful treatment of psoriasis (i.e. a risk factor for CAD) diminishes the risk of developing CAD. The studies might even raise a concern about an increased risk of CAD after treatment with some of the systemic agents. There are, however, many reasons why CAD risk reduction has not been noted. It is possible that some treatments for psoriasis increase the risk of CAD. It is possible that both psoriasis and CAD are physiologically unrelated outcomes of another process. For example, obesity, which has been associated with both disease processes, may cause both diseases but treating one does not affect the prognosis of the other. Attempts to control statistically for obesity have not shown this to be true but these attempts may have been insufficient. It could also be possible that the genetic tendency to develop psoriasis and CAD are linked (found close together on a common chromosome), such that one is not really on the causal pathway for the other but that they occur in genetically similar people. There could be many other explanations including the most common concern of nearly every study that the study was not designed well enough to test the study question properly. We really will not know the answer to this fascinating and important question until more investigations are complete.