Publications
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2017
Associations of Body Mass Index With Laboratory and Biomarkers in Patients With Acute Heart Failure.
2017
2017
BACKGROUND
Decreased kidney function and greater albuminuria are associated with increased incidence and extent of coronary artery calcium (CAC). We investigated whether the associations between kidney function and urine protein-to-creatinine ratio (UPCR) with CAC differ by HIV serostatus.
METHODS
Using data from the Multicenter AIDS Cohort Study, a prospective multicenter US study of men who have sex with men, we carried out a cross-sectional study comprised of 592 HIV-infected (HIV+) and 378 uninfected (HIV-) men who underwent noncontrast computed tomography to measure CAC. Logistic and linear regression models were used to determine whether HIV infection modified associations of estimated glomerular filtration rate and UPCR with the presence and extent of CAC, adjusting for age, race, and cardiovascular risk factors.
RESULTS
Every 10 U decrease in estimated glomerular filtration rate below 90 ml/min/1.73 m was significantly associated with 1.3-fold [95% confidence interval (CI): 1.06-1.51] higher odds of CAC presence and was similar by HIV serostatus (Pinteraction=0.37). Greater UPCR was associated with more extensive CAC, with a change in log CAC score of 0.32 (95% CI: 0.10-0.55) per 1% increase in UPCR. There was a strong trend for effect modification by HIV serostatus for this association [HIV-: 0.75 (95% CI: 0.26-1.25); HIV+: 0.22 (95% CI: -0.03 to 0.47), Pinteraction=0.06].
CONCLUSION
Greater CAC burden is apparent among individuals with early kidney disease, irrespective of HIV serostatus. Increased UPCR is associated with a greater extent of CAC with a trend for differences by HIV serostatus; a clearer proteinuria/CAC extent relationship was apparent among HIV- patients.
View on PubMed2016
Background
Risk factors may differentially influence development of estrogen receptor (ER)-positive vs -negative breast cancer. We examined associations with strong, prevalent risk factors by ER subtype.
Methods
Of 1 279 443 women age 35 to 74 years participating in the Breast Cancer Surveillance Consortium, 14 969 developed ER-positive and 3617 developed ER-negative invasive breast cancer. We calculated hazard ratios (HRs) using Cox regression and compared ER subtype hazard ratios at representative ages or by menopausal status using Wald tests. All statistical tests were two-sided.
Results
For women age 40 years, compared with no prior biopsy, ER-positive vs ER-negative HRs were 1.53 (95% CI = 1.30 to 1.81) vs 1.26 (95% CI = 0.90 to 1.76) for nonproliferative disease, 1.63 (95% CI = 1.23 to 2.17) vs 1.41 (95% CI = 0.78 to 2.57) for proliferative disease without atypia, and 4.47 (95% CI = 2.88 to 6.96) vs 0.20 (95% CI = 0.02 to 2.51) for proliferative disease with atypia. Benign disease proliferation risk was stronger for ER-positive than ER-negative cancer for women age 35 years (Wald P = .04), age 40 years (Wald P = .04), and age 50 years (Wald P = .06). Among pre/perimenopausal women, body mass index (BMI) had a stronger association with ER-negative than ER-positive cancer (obese II/III vs. normal weight: HR = 1.52, 95% CI = 1.19 to 1.94; vs 1.21, 95% CI = 1.08 to 1.36). Increasing BMI similarly increased ER-positive and ER-negative cancer risk among postmenopausal hormone users (Wald P = .15) and nonusers (Wald P = .08). Associations with ER subtype varied by race/ethnicity across all ages (P < .001) and by family history of breast cancer and breast density for specific ages.
Conclusions
Strength of risk factor associations differed by ER subtype. Separate risk models for ER subtypes may improve identification of women for targeted prevention strategies.
View on PubMed2016
2016
PURPOSE
Clinically relevant pharmacokinetic interactions exist between gastric acid-reducing agents and certain weakly basic drugs that rely on acidic environments for optimal oral absorption. In this study, we examine whether the administration of betaine hydrochloride under fed conditions can enhance the absorption of atazanavir, an HIV-1 protease inhibitor, during pharmacologically-induced hypochlorhydria.
METHODS
In this randomized, single-dose, 3 period, crossover study healthy volunteers received ritonavir-boosted atazanavir (atazanavir/ritonavir 300/100 mg) alone, following pretreatment with the proton pump inhibitor rabeprazole (20 mg twice daily), and with 1500 mg of betaine HCl after rabeprazole pretreatment. Atazanavir was administered with a light meal and gastric pH was monitored using the Heidelberg Capsule.
RESULTS
Pretreatment with rabeprazole resulted in significant reductions in atazanavir C (p < 0.01) and AUC (p < 0.001) (71 and 70%, respectively), and modest decreases in ritonavir C and AUC (p < 0.01) (40% and 41%, respectively). The addition of betaine HCl restored 13% of ATV C and 12% of AUC lost due to rabeprazole.
CONCLUSIONS
The co-administration of rabeprazole with atazanavir resulted in significant decreases in atazanavir exposure. The addition of betaine HCl did not sufficiently mitigate the loss of ATV exposure observed during RAB-induced hypochlorhydria. Meal effects lead to a marked difference in the outcome of betaine HCl on atazanavir exposure than we previously reported for dasatanib under fasting conditions.
View on PubMed2016
2016
BACKGROUND & AIMS
Many cancers in the proximal colon develop via from sessile serrated adenomas (SSAs), which have flat, subtle features that are difficult to detect with conventional white-light colonoscopy. Many SSA cells have the V600E mutation in BRAF. We investigated whether this feature could be used with imaging methods to detect SSAs in patients.
METHODS
We used phage display to identify a peptide that binds specifically to SSAs, using subtractive hybridization with HT29 colorectal cancer cells containing the V600E mutation in BRAF and Hs738.St/Int cells as a control. Binding of fluorescently labeled peptide to colorectal cancer cells was evaluated with confocal fluorescence microscopy. Rats received intra-colonic 0.0086 mg/kg, 0.026 mg/kg, or 0.86 mg/kg peptide or vehicle and morbidity, mortality, and injury were monitored twice daily to assess toxicity. In the clinical safety study, fluorescently labeled peptide was topically administered, using a spray catheter, to the proximal colon of 25 subjects undergoing routine outpatient colonoscopies (3 subjects were given 2.25 μmol/L and 22 patients were given 76.4 μmol/L). We performed blood cell count, chemistry, liver function, and urine analyses approximately 24 hours after peptide administration. In the clinical imaging study, 38 subjects undergoing routine outpatient colonoscopies, at high risk for colorectal cancer, or with a suspected unresected proximal colonic polyp, were first evaluated by white-light endoscopy to identify suspicious regions. The fluorescently labeled peptide (76.4 μmol/L) was administered topically to proximal colon, unbound peptide was washed away, and white-light, reflectance, and fluorescence videos were recorded digitally. Fluorescence intensities of SSAs were compared with those of normal colonic mucosa. Endoscopists resected identified lesions, which were analyzed histologically by gastrointestinal pathologists (reference standard). We also analyzed the ability of the peptide to identify SSAs vs adenomas, hyperplastic polyps, and normal colonic mucosa in specimens obtained from the tissue bank at the University of Michigan.
RESULTS
We identified the peptide sequence KCCFPAQ and measured an apparent dissociation constant of K = 72 nM and an apparent association time constant of K = 0.174 min (5.76 minutes). During fluorescence imaging of patients during endoscopy, regions of SSA had 2.43-fold higher mean fluorescence intensity than that for normal colonic mucosa. Fluorescence labeling distinguished SSAs from normal colonic mucosa with 89% sensitivity and 92% specificity. The peptide had no observed toxic effects in animals or patients. In the analysis of ex vivo specimens, peptide bound to SSAs had significantly higher mean fluorescence intensity than to hyperplastic polyps.
CONCLUSIONS
We have identified a fluorescently labeled peptide that has no observed toxic effects in animals or humans and can be used for wide-field imaging of lesions in the proximal colon. It distinguishes SSAs from normal colonic mucosa with 89% sensitivity and 92% specificity. This targeted imaging method might be used in early detection of premalignant serrated lesions during routine colonoscopies. ClinicalTrials.gov ID: NCT02156557.
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