Publications

BACKGROUND

Cryptococcal infection occurs in HIV-seropositive patients and is associated with high mortality. However, limited information is available on the prevalence and outcomes of cryptococcal antigenemia among hospitalized HIV-seropositive patients in sub-Saharan Africa.

OBJECTIVES

To determine the prevalence of and risk factors for cryptococcal antigenemia among HIV-seropositive patients presenting to Mulago Hospital (Kampala, Uganda) with unexplained cough ≥2 weeks and suspected tuberculosis (TB) and also to determine if antigenemia is associated with an increased mortality.

METHODS

Between September 2009 and September 2010, we enrolled consecutive HIV-seropositive adults hospitalized at Mulago Hospital with cough ≥2 weeks and suspected TB. Banked serum was tested for cryptococcal antigen. We compared demographic and clinical characteristics, and 2-month mortality in patients with and without cryptococcal antigenemia.

RESULTS

Of 563 HIV-seropositive patients, 32 (5.7%) were cryptococcal antigen (CrAg) positive. None had Cryptococcus neoformans detected on fungal culture of bronchoalveolar lavage fluid (n = 116). CrAg-positive patients had a lower median CD4 count compared with CrAg-negative patients (25 vs. 55 cells/μL, P = 0.02), and a substantial proportion of CrAg-positive patients also had concurrent TB (31%). A positive CrAg test was not associated with increased mortality during the 2-month follow-up period (hazard ratio: 0.99, 95% confidence interval: 0.63 to 1.54, P = 0.95) after adjusting for CD4 count and antiretroviral therapy use at enrollment and/or follow-up.

CONCLUSIONS

Occult cryptococcal antigenemia occurs commonly among hospitalized HIV-seropositive patients with suspected TB. CrAg testing should be considered in hospitalized HIV-seropositive patients with CD4 count <50 cells/μL, coupled with longer follow-up to evaluate the diagnostic value of CrAg and therapeutic interventions in patients with asymptomatic cryptococcal antigenemia.

OBJECTIVE

Clinical trials of therapies for lupus nephritis have used many different primary outcome measures, ranging from complete response to time to end-stage renal disease. The objective of this study was to compare several possible outcome measures, using data from a large, multicenter trial of abatacept in lupus nephritis, to gain insight into which outcome measure, if any, was best able to discern differences among treatment groups.

METHODS

Study patients received either abatacept or placebo, on a background of mycophenolate mofetil and glucocorticoids. Using data from this trial, the following primary outcome measures at 24 and 52 weeks were compared: complete response rate, major clinical response rate, total response rate (complete plus partial response), improvement in proteinuria, improvement in estimated glomerular filtration rate, and frequency of treatment failure. Time to complete response was also evaluated.

RESULTS

Complete response rate, major clinical response rate, and time to complete response were the measures that best discriminated between the abatacept groups and placebo, and the sensitivities of these 3 measures were comparable. For these measures, sample sizes of 50 patients would have been sufficient to demonstrate a statistically significant difference between treatment and control at 52 weeks. Each of the other measures also discriminated between treatment and control, but much larger group sizes would have been required to determine statistical significance.

CONCLUSION

The choice of primary outcome measure can substantially influence the ability to detect therapeutic benefit in lupus nephritis trials. This study suggests that complete response rate, major clinical response rate at 52 weeks, and time to complete response may be the most sensitive outcome measures for detecting differences among therapeutic regimens.

We assessed laboratory monitoring after combination antiretroviral therapy initiation among 3678 patients in a large US multisite clinical cohort, censoring participants at last clinic visit, combination antiretroviral therapy change, or 3 years. Median days (interquartile range) to first hematologic, hepatic, renal, and lipid tests were 30 (18-53), 31 (19-56), 33 (20-59), and 350 (96-1106), respectively. At 1 year, approximately 80% received more than 2 hematologic, hepatic, and renal tests consistent with guidelines. However, only 40% received 1 or more lipid tests. Monitoring was more frequent in specific subgroups, likely reflecting better clinic attendance or clinician perception of higher susceptibility to toxicities.

OBJECTIVE

Studies of the association between transportation barriers and HIV-related health outcomes have shown both positive and negative effects, possibly because a reliable, validated measure of transportation barriers has not been identified.

DESIGN

Prospective cohort study of HIV-infected patients in rural Uganda.

METHODS

Participants were enrolled from the HIV clinic at the regional referral hospital in Mbarara, Uganda as part of the Uganda AIDS Rural Treatment Outcomes (UARTO) Study. We collected the following measures of transportation barriers to HIV clinic: global positioning systems (GPS)-tracked distance measured by driving participants to their homes along their typical route; straight-line GPS distance from clinic to home, calculated with the Great Circle Formula; self-reported travel time; and self-reported travel cost. We assessed inter-measure agreement using linear regression, correlation coefficients and κ statistics (by measure quartile) and validated measures by fitting linear regression models to estimate associations with days late for clinic visits.

RESULTS

One hundred and eighty-eight participants were tracked with GPS. Seventy-six percent were women, with a median age of 40 years and median CD4 cell count of 193 cells/μl. We found a high correlation between GPS-based distance measures (β=0.74, P<0.001, R²=0.92, κ=0.73), but little correlation between GPS-based and self-reported measures (all R²≤0.4). GPS-based measures were associated with days late to clinic (P<0.001); but neither self-reported measure was associated (P>0.85).

CONCLUSION

GPS-measured distance to clinic is associated with HIV clinic absenteeism and should be prioritized over self-reported measures to optimally risk-stratify patients accessing care in rural, resource-limited settings.

BACKGROUND

Indoleamine 2,3-dioxygenase, catalyzing tryptophan (Trp) metabolism through the kynurenine (Kyn) metabolic pathway, plays important roles in immune suppression and the CNS. In this article, we report a simple, rapid and specific LC-MS/MS method for accurate determination of Kyn and Trp concentrations in human plasma from HIV-infected patients.

RESULTS

The human plasma sample (100 µl) was mixed with Kyn-d4 and Trp-d5 internal standards and then precipitated with trifluoroacetic acid. The supernatant was directly analyzed by LC-MS/MS. The assay using surrogate matrix calibrators was validated for precision, accuracy, matrix effect, extraction efficiency and stability. Some assay validation issues for endogenous substance bioanalysis using an LC-MS/MS method are discussed.

CONCLUSION

A simple, specific and reproducible LC-MS/MS method has been developed and validated for measuring Kyn and Trp in human plasma samples.

A considerable number of women with breast cancer are diagnosed during their reproductive years. In the short period of time in which newly diagnosed women will need to make decisions about surgical options and adjuvant therapy, younger women with breast cancer also face the potential impairment or complete loss of their fertility. The preservation of fertility should therefore be an integral consideration in the choice of breast cancer therapy. Preserving ovarian function is particularly challenging for women with estrogen receptor-positive tumors, as the suppression of ovarian function has been shown to be beneficial therapy with regard to breast cancer outcomes. The current emerging recommendations of hormonal therapy extending to a 10-year period will likely further impact the timing of any subsequent pregnancy or require an interruption in hormonal therapy. To optimally counsel patients on how to best weigh the risks and benefits of each intervention, both the care provider and the patient must understand the options and the likelihood of their success. Here we summarize the current challenges and options for women diagnosed with breast cancer who wish to preserve their fertility.

BACKGROUND

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with pulmonary vasculopathy.

OBJECTIVE

The purpose of this study was to determine whether sildenafil improves 6-min walk distance (6MWD) in subjects with IPF and right ventricular dysfunction.

METHODS

The IPFnet, a network of IPF research centers in the United States, conducted a randomized trial examining the effect of sildenafil on 6MWD in patients with advanced IPF, defined by carbon monoxide diffusing capacity < 35% predicted. A substudy examined 119 of 180 randomized subjects where echocardiograms were available for independent review by two cardiologists. Right ventricular (RV) hypertrophy (RVH), right ventricular systolic dysfunction (RVSD), and right ventricular systolic pressure (RVSP) were assessed. Multivariable linear regression models estimated the relationship between RV abnormality, sildenafil treatment, and changes in 6MWD, St. George's Respiratory Questionnaire (SGRQ), the EuroQol instrument, and SF-36 Health Survey (SF-36) from enrollment to 12 weeks.

RESULTS

The prevalence of RVH and RVSD were 12.8% and 18.6%, respectively. RVSP was measurable in 71 of 119 (60%) subjects; mean RVSP was 42.5 mm Hg. In the subgroup of subjects with RVSD, subjects treated with sildenafil experienced less decrement in 6MWD (99.3 m; P = .01) and greater improvement in SGRQ (13.4 points; P = .005) and EuroQol visual analog scores (17.9 points; P = .04) than subjects receiving placebo. In the subgroup with RVH, sildenafil was not associated with change in 6MWD (P = .13), but was associated with greater relative improvement in SGRQ (14.8 points; P = .02) vs subjects receiving placebo. Sildenafil treatment in those with RVSD and RVH was not associated with change in SF-36.

CONCLUSIONS

Sildenafil treatment in IPF with RVSD results in better preservation of exercise capacity as compared with placebo. Sildenafil also improves quality of life in subjects with RVH and RVSD.

OBJECTIVE

Evaluate effect of gender role attitudes on tobacco and alcohol use among Argentinean girls.

METHOD

Cross-sectional survey of 10th grade students attending 27 randomly selected schools in Jujuy, Argentina. Questions about tobacco and alcohol use were adapted from global youth surveys. Five items with 5-point response options of agreement-disagreement assessed attitude towards egalitarian (higher score) gender roles.

RESULTS

2133 girls, aged 13-18 years, 71% Indigenous, 22% mixed Indigenous/European, and 7% European responded. Of these, 60% had ever smoked, 32% were current smokers, 58% ever drinkers, 27% drank in previous month, and 13% had ≥5 drinks on one occasion. Mean response to the gender role scale was 3.49 (95% Confidence Intervals = 3.41-3.57) out of 5 tending toward egalitarian attitudes. Logistic regression models using the gender role scale score as the main predictor and adjusting for demographic and social confounders showed that egalitarian gender role was associated with ever smoking (Odds Ratio = 1.25; 95% Confidence Intervals 1.09-1.44), ever drinking (Odds Ratio = 1.24; 95% Confidence Intervals 1.10-1.40), drinking in prior month (Odds Ratio = 1.21; 95% Confidence Intervals 1.07-1.37) and ≥5 drinks on one occasion (Odds Ratio = 1.15; 95% Confidence Intervals 1.00-1.33), but was not significant for current smoking.

CONCLUSION

Girls in Jujuy who reported more egalitarian gender role attitudes had higher odds of smoking or drinking.