Publications

Despite advances in medicine, infectious diseases remain major causes of death and disability worldwide. Acute or chronic infectious agents mediate host tissue damage and cause a spectrum of disease as diverse as overwhelming sepsis and shock within hours to persistent tissue inflammation causing organ failure or even cancer over years. Although pathogen exposure can cause disease via host-derived inflammation, pathogens share recognized elements with harmless human commensals. Mouse models and organisms with simpler flora are revealing the dialogue between multicellular hosts and commensal flora. In some instances the persistent inflammation associated with pathogens can be interpreted within a framework of frustrated commensalism in which the host and pathogen cannot complete the requisite dialogue that establishes homeostasis. In contrast, coevolved commensals interact cooperatively with the host immune system, resulting in immunotolerance. Attempts to more thoroughly understand the molecular nature of the dialogue may uncover novel approaches to the control of inflammation and tissue damage.

Use of chemoprevention to prevent development of breast cancer among high-risk women has been limited despite clinical evidence of its benefit. Our goals were to determine whether knowledge of the benefits and risks of tamoxifen affects a woman's willingness to take it to prevent breast cancer, to define factors associated with willingness to take tamoxifen, and to evaluate race/ethnic differences. Women, ages 50-80, who identified as African American, Asian, Latina, or White, and who had at least one visit to a primary care physician in the previous 2 years, were recruited from ambulatory practices. After a screening telephone survey, women completed an in-person interview in their preferred language. Multivariate regression models were constructed to examine the associations of demographic characteristics, numeracy, breast cancer history, and health knowledge with willingness to take tamoxifen. Over 40% of the women reported they would likely take tamoxifen if determined to be at high risk, and 31% would be somewhat likely to do so. Asian women, those with no insurance, and those with less than high school education were significantly more likely to be willing to take tamoxifen. Higher scores on numeracy and on breast cancer knowledge were also associated with willingness to take tamoxifen. A higher tamoxifen knowledge score was inversely related to willingness to take the drug. Factors affecting women's willingness to take breast cancer chemoprevention drugs vary and are not determined solely by knowledge of risk/benefit or risk perception.

Chronic hepatitis C virus (HCV) infection affects approximately 1.3 % of the United States population and 4 % of veterans who use Department of Veterans Affairs medical services. Chronic HCV is the primary cause of cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver disease requiring liver transplantation in the United States. Management of chronic HCV is aimed at halting disease progression, preventing cirrhosis decompensation, reducing the risk of HCC, and treating extrahepatic complications of the infection. As part of a comprehensive HCV management strategy, peginterferon alfa and ribavirin, along with the addition of a hepatitis C protease inhibitor therapy for many genotype 1-infected patients, are the current standard of care. Antiviral therapy should be provided to those individuals who are clinically stable, have moderate liver disease or compensated cirrhosis, and are motivated to pursue therapy. Many patients have comorbid medical and psychiatric conditions, which may affect their adherence to antiviral therapy or worsen while on antiviral therapy. To optimally manage hepatitis C and associated comorbidities, patients benefit from multidisciplinary teams that can provide HCV-specific care and treatment. Sustained virologic response is associated with "cure" of chronic HCV, and results in improved liver disease outcomes and prolonged survival.

A major function of the skin is to provide a barrier to the movement of water and electrolytes, which is required for life in a terrestrial environment. This permeability barrier is localized to the stratum corneum and is mediated by extracellular lipid-enriched lamellar membranes, which are delivered to the extracellular spaces by the secretion of lamellar bodies by stratum granulosum cells. A large number of factors have been shown to regulate the formation of this permeability barrier. Specifically, lamellar body secretion and permeability barrier formation are accelerated by decreases in the calcium content in the stratum granulosum layer of the epidermis. In addition, increased expression of cytokines and growth factors and the activation of nuclear hormone receptors (peroxisome proliferator-activated receptors, liver X receptors, vitamin D receptor) accelerate permeability barrier formation. In contrast, nitric oxide, protease-activated receptor 2 activation, glucocorticoids, and testosterone inhibit permeability barrier formation. The ability of a variety of factors to regulate permeability barrier formation allows for a more precise and nuanced regulation.

Ichthyoses, including inherited disorders of lipid metabolism, display a permeability barrier abnormality in which the severity of the clinical phenotype parallels the prominence of the barrier defect. The pathogenesis of the cutaneous phenotype represents the consequences of the mutation for epidermal function, coupled with a "best attempt" by affected epidermis to generate a competent barrier in a terrestrial environment. A compromised barrier in normal epidermis triggers a vigorous set of metabolic responses that rapidly normalizes function, but ichthyotic epidermis, which is inherently compromised, only partially succeeds in this effort. Unraveling mechanisms that account for barrier dysfunction in the ichthyoses has identified multiple, subcellular, and biochemical processes that contribute to the clinical phenotype. Current treatment of the ichthyoses remains largely symptomatic: directed toward reducing scale or corrective gene therapy. Reducing scale is often minimally effective. Gene therapy is impeded by multiple pitfalls, including difficulties in transcutaneous drug delivery, high costs, and discomfort of injections. We have begun to use information about disease pathogenesis to identify novel, pathogenesis-based therapeutic strategies for the ichthyoses. The clinical phenotype often reflects not only a deficiency of pathway end product due to reduced-function mutations in key synthetic enzymes but often also accumulation of proximal, potentially toxic metabolites. As a result, depending upon the identified pathomechanism(s) for each disorder, the accompanying ichthyosis can be treated by topical provision of pathway product (eg, cholesterol), with or without a proximal enzyme inhibitor (eg, simvastatin), to block metabolite production. Among the disorders of distal cholesterol metabolism, the cutaneous phenotype in Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects (CHILD syndrome) and X-linked ichthyosis reflect metabolite accumulation and deficiency of pathway product (ie, cholesterol). We validated this therapeutic approach in two CHILD syndrome patients who failed to improve with topical cholesterol alone, but cleared with dual treatment with cholesterol plus lovastatin. In theory, the ichthyoses in other inherited lipid metabolic disorders could be treated analogously. This pathogenesis (pathway)-driven approach possesses several inherent advantages: (1) it is mechanism-specific for each disorder; (2) it is inherently safe, because natural lipids and/or approved drugs often are utilized; and (3) it should be inexpensive, and therefore it could be used widely in the developing world.

BACKGROUND

The purpose of this study was to examine the health and social circumstances, knowledge of and access to health and social services, and success at getting work among urban day laborers.

METHODS

We conducted an interview survey of 217 men waiting for work at several sites in San Francisco.

RESULTS

Day laborers were generally unsuccessful at obtaining work and had less than optimal housing, but supported a number of family members. Over half reported fair or poor health, associated with longer time as a day laborer, poor English proficiency, and financially supporting three or more other people. Awareness of health and social services available to them was low.

DISCUSSION

The stress of seeking work daily, separation from family, inadequate housing and lack of health care puts this population at increased risk for disease conditions associated with poor physical and mental health.

OBJECTIVE

Although the systematic measurement of disease activity facilitates clinical decision making in rheumatoid arthritis (RA), no recommendations currently exist on which measures should be applied in clinical practice in the US. The American College of Rheumatology (ACR) convened a Working Group (WG) to comprehensively evaluate the validity, feasibility, and acceptability of available RA disease activity measures and derive recommendations for their use in clinical practice.

METHODS

The Rheumatoid Arthritis Clinical Disease Activity Measures Working Group conducted a systematic review of the literature to identify RA disease activity measures. Using exclusion criteria, input from an Expert Advisory Panel (EAP), and psychometric analysis, a list of potential measures was created. A survey was administered to rheumatologists soliciting input. The WG used these survey results in conjunction with the psychometric analyses to derive final recommendations.

RESULTS

Systematic review of the literature resulted in identification of 63 RA disease activity measures. Application of exclusion criteria and ratings by the EAP narrowed the list to 14 measures for further evaluation. Practicing rheumatologists rated 9 of these 14 measures as most useful and feasible. From these 9 measures, the WG selected 6 with the best psychometric properties for inclusion in the final set of ACR-recommended RA disease activity measures.

CONCLUSION

We recommend the Clinical Disease Activity Index, Disease Activity Score with 28-joint counts (erythrocyte sedimentation rate or C-reactive protein), Patient Activity Scale (PAS), PAS-II, Routine Assessment of Patient Index Data with 3 measures, and Simplified Disease Activity Index because they are accurate reflections of disease activity; are sensitive to change; discriminate well between low, moderate, and high disease activity states; have remission criteria; and are feasible to perform in clinical settings.

PURPOSE

Patients and relatives have varying preferences for genetic testing and interventions related to hereditary cancer syndromes. We examined how the impact of these services on quality of life (QoL) affects the cost-effectiveness of screening for Lynch syndrome among probands newly diagnosed with colorectal cancer and their relatives.

METHODS

We constructed a state-transition model comparing screening strategies (clinical criteria, prediction algorithms, tumor testing, and upfront germline testing) with no screening to identify Lynch syndrome. The model incorporated individuals' health state utilities after screening, germline testing, and risk-reducing surgeries, with utilities persisting for 12 months in the base case. Outcomes consisted of quality-adjusted life-years (QALYs), costs, and cost per QALY gained. Sensitivity analyses assessed how the duration and magnitude of changes in QoL influenced results.

RESULTS

Multiple screening strategies yielded gains in QALYs at acceptable costs compared with no screening. The preferred strategy-immunohistochemistry of tumors followed by BRAF mutation testing (IHC/BRAF)-cost $59,700 per QALY gained in the base case. The duration and magnitude of decreases in QoL after decisions related to germline testing and surgeries were key determinants of the cost-effectiveness of screening. IHC/BRAF cost > $100,000 per QALY gained when decrements to QoL persisted for 21 months.

CONCLUSION

Screening for Lynch syndrome in the population is likely to yield long-term gains in life expectancy that outweigh any short-term decreases in QoL, at acceptable costs. Counseling for individuals should aim to mitigate potential negative impact of genetic testing and risk-reducing interventions on QoL.

BACKGROUND

Performance measures often fail to account for legitimate reasons why patients do not achieve recommended treatment targets.

METHODS

We tested a novel performance measurement system for blood pressure (BP) control that was designed to mimic clinical reasoning. This clinically guided approach focuses on (1) exempting patients for whom tight BP control may not be appropriate or feasible and (2) assessing BP over time. Trained abstractors conducted structured chart reviews of 201 adults with hypertension in 2 VA health care systems. Results were compared with traditional methods of performance measurement.

RESULTS

Among 201 veterans, 183 (91%) were male, and the mean age was 71±11 years. Using the clinically guided approach, 61 patients (30%) were exempted from performance measurement. The most common reasons for exemption were inadequate opportunity to manage BP (35 patients, 17%) and the use of 4 or more antihypertensive medications (19 patients, 9%). Among patients eligible for performance measurement, there was little agreement on the presence of controlled versus uncontrolled BP when comparing the most recent BP (the traditional approach) with an integrated assessment of BP control (κ 0.14). After accounting for clinically guided exemptions and methods of BP assessment, only 15 of 72 patients (21%) whose last BP was ≥140/90 mm Hg were classified as problematic by the clinically guided approach.

CONCLUSIONS

Many patients have legitimate reasons for not achieving tight BP control, and the methods used for BP assessment have marked effects on whether a patient is classified as having adequate or inadequate BP control.