Publications

In 2011, an expert panel from the National Heart, Lung, and Blood Institute released recommendations for universal lipid screening and treatment of high cholesterol in children. There is no evidence that universal screening will help children lead longer, healthier lives. These recommendations will, however, fuel the epidemic of overtreatment that is currently threatening our healthcare system and our patients.

Gender-specific data focused on cardiovascular disease (CVD) are becoming increasingly available. This is of great importance, given that CVD has become the number 1 killer of women, and unlike for men, mortality rates do not seem to be declining. Many factors are cited as the causes of sex-based differences, including delays in recognizing symptoms, underutilization of diagnostic tests and treatments, as well as anatomic, physiological, and genetic factors. Evidence of fundamental biological differences in vascular function and the underlying pathologic processes is only beginning to elucidated, motivated by growing evidence of differences in clinical presentations and outcomes between men and women. The good news is that we are starting to see improvements in outcomes for women, such as after coronary revascularization; decrease in complication rates with the advent of new techniques, such as radial access for cardiac catheterizations; as well as increased participation of women in clinical trials. The underlying mechanisms of ischemic heart disease remain to be elucidated, and will help guide therapy and ultimately may explain the higher prevalence of : subendocardial myocardial infarctions, spontaneous arterial dissections, plaque erosion, increased vasospastic disorders, such as coronary microvascular disease, and pulmonary hypertension in women compared with men. We have made great progress in understanding gender-related differences in CVDs, but much remains to be done to optimize the prevention of CVD for both men and women.

The yeast Candida albicans transitions between distinct lifestyles as a normal component of the human gastrointestinal microbiome and the most common agent of disseminated fungal disease. We previously identified Sef1 as a novel Cys(6)Zn(2) DNA binding protein that plays an essential role in C. albicans virulence by activating the transcription of iron uptake genes in iron-poor environments such as the host bloodstream and internal organs. Conversely, in the iron-replete gastrointestinal tract, persistence as a commensal requires the transcriptional repressor Sfu1, which represses SEF1 and genes for iron uptake. Here, we describe an unexpected, transcription-independent role for Sfu1 in the direct inhibition of Sef1 function through protein complex formation and localization in the cytoplasm, where Sef1 is destabilized. Under iron-limiting conditions, Sef1 forms an alternative complex with the putative kinase, Ssn3, resulting in its phosphorylation, nuclear localization, and transcriptional activity. Analysis of sfu1 and ssn3 mutants in a mammalian model of disseminated candidiasis indicates that these post-transcriptional regulatory mechanisms serve as a means for precise titration of C. albicans virulence.

BACKGROUND

The antiretroviral drug efavirenz (EFV) and the antimalarial artemisinin-based combination therapy artemether-lumefantrine (AL) are commonly co-administered to treat HIV and malaria. EFV is a known inducer of cytochrome P450 3A4, which converts artemether to dihydroartemisinin (DHA) that is also active and metabolizes longer acting lumefantrine (LR). A study in healthy volunteers was completed to address the concern that EFV impacts AL pharmacokinetics (PKs).

METHODS

Adults received AL (80/480 mg twice daily) for 3-days before and during EFV co-administration (600 mg daily for 26 days) with intensive PK for artemether, DHA, and LR conducted after the last AL dose for each period. EFV PK was evaluated with and without AL. PK parameters were estimated using noncompartmental methods.

RESULTS

Twelve subjects completed the 2-period study. PK exposure for artemether, DHA, and LR [as estimated by the area under the concentration time curve (AUClast)] decreased or trended toward decrease with EFV, compared with when administered alone [-51% (P = 0.084), -46% (P = 0.005), and -21% (P = 0.102), respectively]. Day-7 LR levels, previously deemed predictive of treatment success, were 46% lower (P = 0.002) with EFV, but the LR half-life was unchanged. EFV PK exposure was minimally altered after AL co-administration [AUC0-24 hrs decreased by 17% (P = 0.034)].

CONCLUSIONS

Exposure to DHA, but not LR, was significantly lower during EFV-AL co-administration compared with that during administration of AL alone. These findings may have implications for the treatment efficacy of AL, particularly in children. However, the observed modest changes probably do not warrant dosage adjustment during co-administration of AL with EFV.

The American Association of Occupational Health Nurses, Inc. (AAOHN) conducted a web-based membership survey of 2123 members (41% response rate) in May and June 2012. This column presents educational, certification, and selected industry data for registered nurse and advanced practice nurse AAOHN members. Members are highly experienced, with 57% reporting more than 16 years of experience. Sixty-eight percent of AAOHN members are educated at or above the baccalaureate level. An additional 8.4% are currently enrolled in an educational program. Seventy-six percent are nationally certified as occupational health nurses or occupational health nurse specialists (COHN/COHN-S), case managers, safety professionals, ergonomists, or nurse practitioners. The majority (89%) work full-time as employees of their facility (85%), with manufacturing (34%), hospital/health care (26%), and government/military (10%) being the top three industry sectors. Ten percent work for small employers (fewer than 500 employees), whereas 12% work with more than 50,000 employees. Thirteen percent of AAOHN members work globally. Future columns will present additional 2012 AAOHN member survey data.

Household air pollution (HAP) from biomass fuels, coal, and kerosene burned in open fires, primitive stoves, and lamps causes at least 2 million deaths per year. Many of these deaths occur in children <5 years of age with pneumonia and in women with COPD, lung cancer, and cardiovascular disease. HAP is inextricably linked to poverty, with activities to obtain fuel consuming a large proportion of the time and financial resources of poor households. Thus, fewer resources used in this way means less is available for basic needs like food, education, and health care. The burden of work and the exposure to smoke, particularly during cooking, are predominantly borne by women and children. Although historically HAP has not received sufficient attention from the scientific, medical, public health, development, and policy-making communities, the tide has clearly changed with the broad-based support and launch of the Global Alliance for Clean Cookstoves in 2010. There is now considerable reason for optimism that this substantial cause of cardiorespiratory morbidity and mortality will be addressed comprehensively and definitively. Drawing on our experience from four continents, we provide background information on the problem of HAP, health impacts of HAP, opportunities for research, and the current best solutions.

OBJECTIVES

To determine whether intensification with raltegravir improves endothelial function in antiretroviral-treated HIV-infected individuals.

DESIGN

: Randomized, double-blinded, placebo-controlled study.

METHODS

Fifty-six subjects with treatment-mediated viral suppression for at least 1 year were randomized to add 400 mg of raltegravir twice daily or matching placebo for 24 weeks. The primary endpoint was the difference in rate of change in endothelial function [as assessed by flow-mediated vasodilation (FMD) of the brachial artery] from baseline to week 24 between the raltegravir and placebo groups. Linear mixed models were used to evaluate the association of treatment group with changes in FMD, immune activation, and measures of viral persistence.

RESULTS

At baseline, the median CD4 T-cell count was 498 cells/mm, nadir CD4 T-cell count was 191 cells/mm, duration of HIV infection was 18 years, FMD was 3.3%, and hyperemic velocity (a marker of microvascular function) was 68.3 cm. There were no significant differences between treatment groups in rate of change in FMD (raltegravir group: +0.032% per week, placebo group: +0.023% per week; P = 0.60). There were also no differences between treatment groups in rate of change in hyperemic velocity, immune activation, or viral persistence. In multivariable analysis, older age, longer duration of HIV infection, and current abacavir use were associated with lower FMD. Lower CD4 T-cell count and current abacavir use were associated with lower hyperemic velocity.

CONCLUSIONS

The addition of raltegravir to suppressive antiretroviral therapy did not have a significant impact on cardiovascular risk, as assessed by endothelial function (ClinicalTrials.gov NCT00843713).

OBJECTIVE

Recent clinical trials in lupus nephritis have all used different criteria to assess complete response. The objective of this analysis was to compare several previously proposed criteria, using the same data set from a large trial of abatacept in lupus nephritis (IM101075). In so doing, we sought to determine which criteria are most sensitive to differences among treatment groups and to further examine the potential of abatacept in lupus nephritis.

METHODS

Patients in the IM101075 trial received abatacept at 1 of 2 different dose regimens or placebo, both on a background of mycophenolate mofetil and corticosteroids. Using data from this trial, we assessed rates of complete response at 12 months according to 5 sets of criteria, from 1) the trial protocol, 2) the Aspreva Lupus Management Study (ALMS) trial of mycophenolate mofetil, 3) the Lupus Nephritis Assessment with Rituximab (LUNAR) trial of rituximab, 4) an ongoing National Institutes of Health trial of abatacept (Abatacept and Cyclophosphamide Combination: Efficacy and Safety Study [ACCESS]), and 5) published recommendations of the American College of Rheumatology.

RESULTS

According to the complete response definition from the IM101075 study protocol, there was no difference among treatment groups in the IM101075 study. In contrast, according to the ALMS, LUNAR, and ACCESS criteria, rates of complete response among patients in the IM101075 study were higher in both treatment groups relative to control. The largest differences were obtained with use of the LUNAR criteria (complete response rate of 6% in the control group, compared to 22% and 24% in the 2 abatacept groups).

CONCLUSION

The choice of definition of complete response can determine whether a lupus nephritis trial is interpreted as a success or a failure. The results of this analysis provide an evidence-based rationale for choosing among alternative definitions and offer a strong rationale for conducting further studies of abatacept in lupus nephritis.