Publications

OBJECTIVE

To determine the association of inflammatory markers, fibrinogen, and C-reactive protein (CRP), with 5-year mortality risk.

METHODS

Vital status was ascertained in 922 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV infection. Multivariable logistic regression estimated odds ratios after adjustment for demographic, cardiovascular, and HIV-related factors.

RESULTS

Over a 5-year period, HIV-infected participants with fibrinogen levels in the highest tertile (>406 mg/dL) had 2.6-fold higher adjusted odds of death than those with fibrinogen in the lowest tertile (<319 mg/dL). Those with high CRP (>3 mg/L) had 2.7-fold higher adjusted odds of death than those with CRP <1 mg/L. When stratified by CD4 count category, fibrinogen (as a linear variable) remained independently associated [odds ratio (95% confidence intervals)] per 100 mg/dL increase in fibrinogen: 1.93 (1.57 to 2.37); 1.43 (1.14 to 1.79); 1.43 (1.14 to 1.81); and 1.30 (1.04 to 1.63) for CD4 <200, 200-350, >350 to 500, and >500 cells per microliter, respectively. Higher CRP also remained associated with higher odds of death overall and within each CD4 subgroup.

CONCLUSIONS

Fibrinogen and CRP are strong and independent predictors of mortality in HIV-infected adults. Our findings suggest that even in those with relatively preserved CD4 counts >500 cells per microliter, inflammation remains an important risk factor for mortality. Further investigation should determine whether interventions to reduce inflammation might decrease mortality risk in HIV-infected individuals.

The carbohydrate-binding region of the bacterial adhesin GspB from Streptococcus gordonii strain M99 (GspB(BR)) was expressed in Escherichia coli and purified using affinity and size-exclusion chromatography. Separate sparse-matrix screening of GspB(BR) buffered in either 20 mM Tris pH 7.4 or 20 mM HEPES pH 7.5 resulted in different crystallographic behavior such that different precipitants, salts and additives supported crystallization of GspB(BR) in each buffer. While both sets of conditions supported crystal growth in space group P2(1)2(1)2(1), the crystals had distinct unit-cell parameters of a = 33.3, b = 86.7, c = 117.9 Å for crystal form 1 and a = 34.6, b = 98.3, c = 99.0 Å for crystal form 2. Additive screening improved the crystals grown in both conditions such that diffraction extended to beyond 2 Å resolution. A complete data set has been collected to 1.3 Å resolution with an overall R(merge) value of 0.04 and an R(merge) value of 0.33 in the highest resolution shell.

Coronary artery ectasia (CAE) is generally diagnosed in patients undergoing arteriography for presumptive atherosclerotic coronary artery disease. CAE is commonly considered as a variant of atherosclerotic disease; however, recent studies suggest that CAE is the result of a systemic vascular disorder. There is increasing evidence that aneurysmal vascular disease is a systemic disorder characterized by enhanced expression of pro-inflammatory cytokines and increased synthesis of enzymes capable of degrading elastin and other components of the vascular wall. Matrix metalloproteinase-2 degrades a number of extracellular substrates, including elastin and has been shown to play a critical role in the development of abdominal aortic aneurysms. This study characterizes the development of CAE in a unique murine transgenic model with cardiac-specific expression of active MMP-2. Transgenic mice were engineered to express an active form of MMP-2 under control of the α-myosin heavy chain promoter. Coronary artery diameters were quantified, along with studies of arterial structure, elastin integrity and vascular expression of the MMP-2 transgene. Latex casts quantified total coronary artery volumes and arterial branching. Mid-ventricular coronary luminal areas were increased in the MMP-2 transgenics, coupled with foci of aneurysmal dilation, ectasia and perivascular fibrosis. There was no evidence for atherogenesis. Coronary vascular elastin integrity was compromised and coupled with inflammatory cell infiltration. Latex casts of the coronary arteries displayed ectasia with fusiform dilatation. The MMP-2 transgenic closely replicates human CAE and supports a critical and initiating role for this enzyme in the pathogenesis of this disorder.

OBJECTIVES

To conduct an evidence-based review of the common medication toxicities and strategies and utility of drug toxicity monitoring among patients with systemic lupus erythematosus (SLE).

METHODS

PubMed and other databases were searched for articles published between the years 1960 and 2010 for keywords referring to medication toxicity or monitoring strategies for 7 drugs commonly used in SLE. All relevant English-language articles were reviewed. Most of the evidence we reviewed comprised studies that addressed the incidence of toxicity-randomized trials that compare different monitoring strategies for these drugs do not exist.

RESULTS

Data to describe the frequency of adverse events and appropriate strategies for screening for these events are scarce. Toxicities do not appear to be substantially more common among patients with SLE compared to other conditions for which these drugs are used.

CONCLUSIONS

Our review demonstrates that the scientific basis for many aspects of drug toxicity monitoring is weak and that most current recommendations are based largely on expert consensus. We present a future research agenda to address these gaps.

BACKGROUND

Several strategies have been proposed to reform physician reimbursement while improving quality of care. Despite much debate, physicians' opinions regarding reimbursement reform proposals have not been objectively assessed.

METHODS

We conducted a national survey of randomly selected physicians between June 25 and October 31, 2009. Physicians rated their support for several reimbursement reform proposals: rewarding quality with financial incentives, bundling payments for episodes of care, shifting payments from procedures to management and counseling services, increasing pay to generalists, and offsetting increased pay to generalists with a reduction in pay for other specialties. Support for the different reform options was compared with physician practice characteristics.

RESULTS

The response rate was 48.5% (n = 1222). Four of 5 physicians (78.4%) indicated that under Medicare, some procedures are compensated too highly and others are compensated at rates insufficient to cover costs. Incentives were the most frequently supported reform option (49.1%), followed by shifting payments (41.6%) and bundling (17.2%). Shifting payments and bundling were more commonly supported by generalists than by other specialists. There was broad support for increasing pay for generalists (79.8%), but a proposal to offset the increase with a 3% reduction in specialist reimbursement was supported by only 39.1% of physicians.

CONCLUSIONS

Physicians are dissatisfied with Medicare reimbursement and show little consensus for major proposals to reform reimbursement. The successful adoption of payment reform proposals may require a better understanding of physicians' concerns and their willingness to make tradeoffs.

OBJECTIVE

To determine whether raltegravir-containing antiretroviral therapy (ART) intensification reduces HIV levels in the gut.

DESIGN

Open-label study in HIV-positive adults on ART with plasma HIV RNA below 40 copies/ml.

METHODS

Seven HIV-positive adults received 12 weeks of ART intensification with raltegravir alone or in combination with efavirenz or darunavir. Gut cells were obtained by upper and lower endoscopy with biopsies from duodenum, ileum, colon, and rectum at baseline and 12 weeks. Study outcomes included plasma HIV RNA, HIV DNA and RNA from peripheral blood mononuclear cells (PBMC) and four gut sites, T-cell subsets, and activation markers.

RESULTS

Intensification produced no consistent decrease in HIV RNA in the plasma, PBMC, duodenum, colon, or rectum. However, five of seven participants had a decrease in unspliced HIV RNA per 10 CD4(+) T cells in the ileum. There was a trend towards decreased T-cell activation in all sites, which was greatest for CD8(+) T cells in the ileum and PBMC, and a trend towards increased CD4(+) T cells in the ileum.

CONCLUSION

Most HIV RNA and DNA in the blood and gut is not the result of ongoing replication that can be impacted by short-term intensification with raltegravir. However, the ileum may support ongoing productive infection in some patients on ART, even if the contribution to plasma RNA is not discernible.