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Background: Cardiovascular disease (CVD) and heart failure (HF) are disproportionately high in people living with HIV and differ by sex. Few CVD-related studies focus on drug use, yet it is common in low-income women living with HIV (WLWH) and increases cardiac dysfunction.Setting: We recruited unsheltered and unstably housed WLWH from San Francisco community venues to participate in a six-month cohort study investigating linkages between drug use, inflammation, and cardiac dysfunction.Methods: Adjusting for CVD risk factors, co-infections, medications, and menopause, we examined the effects of toxicology-confirmed drug use and inflammation (C-reactive protein, sCD14, sCD163 and sTNFR2) on levels of NT-proBNP, a biomarker of cardiac stretch and HF.Results: Among 74 WLWH, the median age was 53 years and 45 % were Black. At baseline, 72 % of participants had hypertension. Substances used included tobacco (65 %), cannabis (53 %), cocaine (49 %), methamphetamine (31 %), alcohol (28 %), and opioids (20 %). Factors significantly associated with NT-proBNP included cannabis use (Adjusted Relative Effect [ARE]: -39.6 %) and sTNFR2 (ARE: 65.5 %). Adjusting for heart failure and restricting analyses to virally suppressed persons did not diminish effects appreciably. Cannabis use was not significantly associated with sTNFR2 and did not change the association between sTNFR2 and NT-proBNP.Conclusions: Among polysubstance-using WLWH, NT-proBNP levels signaling cardiac stretch were positively associated with sTNFR2, but 40 % lower in people who used cannabis. Whether results suggest that cardiovascular pathways associated with cannabis use mitigate cardiac stress and dysfunction independent of inflammation in WLWH who use multiple substances merits further investigation. [ABSTRACT FROM AUTHOR]

Introduction: Warfarin doses vary greatly among patients and warfarin administration is accompanied by risk of bleeding. Genes responsible for its metabolism (CYP2C9) and effect on clotting (VKORC1) have been identified. It has been suggested that genotyping for variants in these genes can improve warfarin dosing and decrease bleeding complications. We evaluated performance of pharmacogenetic-based warfarin dosing estimation algorithms in old and very old patients. Methods: Cross-sectional study of stable patients older than 65 years receiving warfarin with therapeutic International Normalized Ratio (INR) anticoagulation. Medical and laboratory data were reviewed and genotyping for CYP2C9 and VKORC1 performed. Warfarin dose estimates with and without genotype information were compared to clinically established therapeutic doses. Results: Sixty-nine patients (32 men, 37 women; 41 nursing home residents; 28 senior care community residents) aged 81.4 ± 8.3 (mean ± S.D) years; ethnicity: Caucasian in 53, Asian in 10, Hispanic in 4, and African American in 2, received 3.3 ± 1.7 mg/d (range 0.7–9) warfarin achieving target INRs of 2.5 ± 0.2. Pharmacogenetic-based dose estimates (in combination with age, weight, height, smoking history, ethnicity/race, history of liver disease, selected co-medications such as amiodarone and enzyme inducers, baseline INR, clinical indication, and target INR), explained 50% of variability (P < .0001) compared with 12% without genetic data (P = .003). However, doses were overestimated in 15 of 16 patients requiring less than 2 mg/d (2.6 ± 0.9 mg/d compared with observed 1.5 ± 0.3 mg/d, P = .0001). Renal disease was a potential variable contributing to low warfarin requirements. Discussion: The role of pharmacogenetic testing in the management of warfarin administration in patients is undergoing evaluation. Currently available pharmacogenetic- based warfarin dose estimation algorithms reduce variability in estimates for groups of older patients but consistently overestimate doses for older patients requiring the lowest doses of warfarin. Conclusions: Pharmacogenetic data add to our understanding of variability in warfarin dosing requirements but do not accurately identify older patients requiring the lowest warfarin doses. Therefore, the most prudent approach to warfarin therapy in older patients should include low initial doses in the absence of genotype variants associated with very low warfarin sensitivity and careful monitoring of INR responses. [Copyright &y& Elsevier]

Objectives: The aim of this study was to determine the prognostic utility of midregion proadrenomedullin (MR-proADM) in all patients, cardiac and noncardiac, presenting with acute shortness of breath. Background: The recently published BACH (Biomarkers in Acute Heart Failure) study demonstrated that MR-proADM had superior accuracy for predicting 90-day mortality compared with B-type natriuretic peptide (area under the curve: 0.674 vs. 0.606, respectively, p < 0.001) in acute heart failure. Methods: The BACH trial was a prospective, 15-center, international study of 1,641 patients presenting to the emergency department with dyspnea. Using this dataset, the prognostic accuracy of MR-proADM was evaluated in all patients enrolled for predicting 90-day mortality with respect to other biomarkers, the added value in addition to clinical variables, as well as the added value of additional measurements during hospital admission. Results: Compared with B-type natriuretic peptide or troponin, MR-proADM was superior for predicting 90-day all-cause mortality in patients presenting with acute dyspnea (c index = 0.755, p < 0.0001). Furthermore, MR-proADM added significantly to all clinical variables (all adjusted hazard ratios: >3.28), and it was also superior to all other biomarkers. MR-proADM added significantly to the best clinical model (bootstrap-corrected c index increase: 0.775 to 0.807; adjusted standardized hazard ratio: 2.59; 95% confidence interval: 1.91 to 3.50; p < 0.0001). Within the model, MR-proADM was the biggest contributor to the predictive performance, with a net reclassification improvement of 8.9%. Serial evaluation of MR-proADM performed in patients admitted provided a significant added value compared with a model with admission values only (p = 0.0005). More than one-third of patients originally at high risk could be identified by the biomarker evaluation at discharge as low-risk patients. Conclusions: MR-proADM identifies patients with high 90-day mortality and adds prognostic value to natriuretic peptides in patients presenting with acute shortness of breath. Serial measurement of this biomarker may also prove useful for monitoring, although further studies will be required. (Biomarkers in Acute Heart Failure [BACH]; NCT00537628) [Copyright &y& Elsevier]

Abstract: Background: Binding of a ligand to the epidermal growth factor receptor (EGFR) stimulates various intracellular signaling pathways resulting in cell cycle progression, proliferation, angiogenesis and apoptosis inhibition. KRAS is involved in signaling pathways including RAF/MAPK and PI3K and mutations in this gene result in constitutive activation of these pathways, independent of EGFR activation. Seven mutations in codons 12 and 13 of KRAS comprise around 95% of the observed human mutations, rendering monoclonal antibodies against EGFR (e.g. cetuximab and panitumumab) useless in treatment of colorectal cancer. Methods: KRAS mutation testing by two different methodologies was compared; Sanger sequencing and AutoGenomics INFINITI® assay, on DNA extracted from colorectal cancers. Results: Out of 29 colorectal tumor samples tested, 28 were concordant between the two methodologies for the KRAS mutations that were detected in both assays with the INFINITI® assay detecting a mutation in one sample that was indeterminate by Sanger sequencing and a third methodology; single nucleotide primer extension. Conclusions: This study indicates the utility of the AutoGenomics INFINITI® methodology in a clinical laboratory setting where technical expertise or access to equipment for DNA sequencing does not exist. [Copyright &y& Elsevier]

Abstract: Background: Vitamin D is an essential nutrient, and there is a growing appreciation of its clinical significance. In addition, there has recently been a discussion as to the best method of measuring this analyte in serum: immunoassay, HPLC or LC–MS/MS. Due to the increased interest in vitamin D, there has been an exponential increase in the number of clinicians testing their patients and therefore also in the volume of this test run in clinical laboratories. Methods: Vitamin D levels were determined by chemiluminescence immunoassay in a reference laboratory and a subset by LC–MS/MS at San Francisco General Hospital. Results: We developed a robust and rapid LC–MS/MS assay to detect 25-hydroxyvitamin D3 and D2 in serum for use in the routine clinical laboratory. Additionally, we determined that 71% of patients served by San Francisco General Hospital have insufficient serum vitamin D levels (≤29ng/ml) and that these levels are significantly associated with parathyroid hormone levels, total calcium concentration, age and ethnicity. Conclusions: The high degree of vitamin D insufficiency at San Francisco General Hospital may be reflective of the status of the patients served by this county hospital; largely an underserved, multi-ethnic urban population. [Copyright &y& Elsevier]

Abstract: Background: Liquid chromatography-mass spectrometry (LC-MS) and tandem LC-MS (LC-MS/MS) are increasingly used in toxicology laboratories as a complementary method to gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-ultraviolet detection (LC-UV) for comprehensive drug screening (CDS). This study was designed to characterize the sensitivity and specificity of three LC-MS(/MS) vendor-supplied methods for targeted CDS and identify the current limitations associated with the use of these technologies. Methods: Five methods for broad spectrum CDS, including LC-UV (REMEDi), full scan GC-MS, LC-MS (ZQ™-Mass Detector with MassLynx™-software), LC-QTRAP-MS/MS (3200-QTRAP® with Cliquid®-software) and LC-LIT-MS/MS (LXQ™ Linear Ion Trap with ToxID™-software) were evaluated based on their ability to detect drugs in 48 patient urine samples. Results: The tandem MS methods identified 15% more drugs than the single stage MS or LC-UV methods. Use of two broad spectrum screening methods identified more drugs than any single system alone. False negatives and false positives generated by the LC-MS(/MS) software programs were identified upon manual review of the raw data. Conclusions: The LC-MS/MS methods detected a broader menu of drugs; however, it is essential to establish manual data review criteria for all LC-MS(/MS) drug screening methods. Use of an EI-GC-MS and ESI-LC-MS/MS combination for targeted CDS may be optimal due to the complementary nature of the chromatographic and ionization techniques. [Copyright &y& Elsevier]

Abstract: Whilst it is formally stated that cardiac troponin is only released when cardiac myocytes undergo necrosis, there are a number of clinical situations where troponin is present in the circulation, without any apparent cardiac injury. In these cases, troponin half-life in the circulation is usually substantially shorter than that seen when troponin is released following myocardial infarction with frank necrosis. A mechanism has been described in liver, where large cytoplasmic molecules can pass from the intra- to extra-cellular space without cellular necrosis occurring. This occurs by the formation of membranous blebs which bud off from the plasma membrane of the cell. Blebs develop during cellular ischemia. If the ischemia is limited and re-oxygenation occurs, the blebs may be released into the circulation without rupture of the plasma membrane, resulting in a one-off release of cytoplasmic contents including macromolecules. Evidence from cardiac studies is presented supporting the presence of membranous blebs in cardiac myocytes, enabling troponin to be released from cardiac cells due to ischemia alone, without necrosis. [Copyright &y& Elsevier]

Hypertension may affect the diagnostic performance of B-type natriuretic peptide (BNP). The objective of the present study was to assess the impact of a history of hypertension or blood pressure elevation on admission on the diagnostic performance of BNP in the diagnosis of heart failure (HF) in patients with acute dyspnea. BNP levels were measured using a rapid point-of-care device in 1,586 patients with acute dyspnea. In patients with HF, BNP levels did not differ between those with and without histories of hypertension. Conversely, in patients without HF, a history of hypertension was associated with higher median BNP levels (38 pg/ml [interquartile range 13 to 119] vs 21 pg/ml [interquartile range 7 to 64], p <0.001). The areas under the receiver-operating characteristic curves were 0.88 and 0.93 for those with and without histories of hypertension, respectively (p <0.001). Blood pressure elevation on admission did not affect the diagnostic accuracy of BNP (areas under the curve 0.90 in the 2 groups). In conclusion, although a history of hypertension is associated with higher BNP levels in patients with acute dyspnea without HF, the impact on the overall diagnostic performance of BNP is modest. Accordingly, BNP performs well as an indicator of HF in patients presenting in emergency departments regardless of a history of hypertension or elevated blood pressure on admission. [Copyright &y& Elsevier]

Background: Cardiac troponin provides diagnostic and prognostic information in acute coronary syndromes, but its role in acute decompensated heart failure is unclear. The purpose of our study was to describe the association between elevated cardiac troponin levels and adverse events in hospitalized patients with acute decompensated heart failure. Methods: We analyzed hospitalizations for acute decompensated heart failure between October 2001 and January 2004 that were recorded in the Acute Decompensated Heart Failure National Registry (ADHERE). Entry criteria included a troponin level that was obtained at the time of hospitalization in patients with a serum creatinine level of less than 2.0 mg per deciliter (177 μmol per liter). A positive troponin test was defined as a cardiac troponin I level of 1.0 μg per liter or higher or a cardiac troponin T level of 0.1 μg per liter or higher. Results: Troponin was measured at the time of admission in 84,872 of 105,388 patients (80.5%) who were hospitalized for acute decompensated heart failure. Of these patients, 67,924 had a creatinine level of less than 2.0 mg per deciliter. Cardiac troponin I was measured in 61,379 patients, and cardiac troponin T in 7880 patients (both proteins were measured in 1335 patients). Overall, 4240 patients (6.2%) were positive for troponin. Patients who were positive for troponin had lower systolic blood pressure on admission, a lower ejection fraction, and higher in-hospital mortality (8.0% vs. 2.7%, P<0.001) than those who were negative for troponin. The adjusted odds ratio for death in the group of patients with a positive troponin test was 2.55 (95% confidence interval, 2.24 to 2.89; P<0.001 by the Wald test). Conclusions: In patients with acute decompensated heart failure, a positive cardiac troponin test is associated with higher in-hospital mortality, independently of other predictive variables. (ClinicalTrials.gov number, NCT00366639.) N Engl J Med 2008;358:2117-26. [ABSTRACT FROM AUTHOR]

Abstract: Background: NT-proBNP measurements aid in the evaluation of patients with suspected heart failure (HF) and may facilitate risk stratification in patients with HF and acute coronary syndrome (ACS). Point-of-care (POC) assays may provide more timely results and potentially improve patient outcomes. Methods: We evaluated the analytical performance of the Response Biomedical Corporation whole blood RAMP amino-terminal pro-B type natriuretic peptide (NT-proBNP) POC assay compared to the Roche Elecsys proBNP (NT-proBNP) assay. Results: Intra-day and total imprecision (% CV) ranged from 5.5% to 10.3% at 140, 449 and 1675 ng/L. The lowest concentration that yields a 20% CV was 57 ng/L. The lower limit of detection was 18 ng/L. The upper limit of linearity was validated to 23,428 ng/L with an average recovery of 95%. Correlation by Passing and Bablok regression yielded RAMP=1.01 Elecsys+14.6, r =0.98 (n =540; range of Elecsys values <5 to >35,000). Concordance of RAMP versus Elecsys using cut-offs of 125 ng/L for subjects <75 years and 450 ng/L for subjects ≥75 was 92% (95% CI 89–94%) for a group consisting of 127 apparently healthy individuals and 208 non-healthy subjects without HF, and 99% (95% CI 97–100%) for patients with HF, using the New York Heart Association (NYHA) functional classification. Overall, 80%, 87%, 97% and 100% of the RAMP results and 77%, 85%, 96% and 100% of the Elecsys results were greater than the age appropriate cut-off for NYHA I, II, III or IV groups. For both the RAMP and Elecsys results, the median NT-proBNP value was statistically correlated (increasing) with NYHA I, II, III or IV groups, respectively (p <0.0001), with no significant difference between the two methods. Conclusions: The POC Response Biomedical RAMP NT-proBNP assay provides comparable results that measured on the FDA cleared Roche Elecsys central laboratory platform. [Copyright &y& Elsevier]

Objectives: The aim of this study was to examine the value of measurement of the interleukin-1 receptor family member ST2 in patients with dyspnea. Background: Concentrations of ST2 have been reported to be elevated in patients with heart failure (HF). Methods: Five hundred ninety-three dyspneic patients with and without acute destabilized HF presenting to an urban emergency department were evaluated with measurements of ST2 concentrations. Independent predictors of death at 1 year were identified. Results: Concentrations of ST2 were higher among those with acute HF compared with those without (0.50 vs. 0.15 ng/ml; p < 0.001), although amino-terminal pro-brain natriuretic peptide (NT-proBNP) was superior to ST2 for diagnosis of acute HF. Median concentrations of ST2 at presentation to the emergency department were higher among decedents than survivors at 1 year (1.08 vs. 0.18 ng/ml; p < 0.001), and in multivariable analyses, an ST2 concentration ≥0.20 ng/ml strongly predicted death at 1 year in dyspneic patients as a whole (HR = 5.6, 95% confidence interval [CI] 2.2 to 14.2; p < 0.001) as well as those with acute HF (hazard ratio [HR] = 9.3, 95% CI 1.3 to 17.8; p = 0.03). This risk associated with an elevated ST2 in dyspneic patients with and without HF appeared early and was sustained at 1 year after presentation (log-rank p value <0.001). A multi-marker approach with both ST2 and NT-proBNP levels identified subjects with the highest risk for death. Conclusions: Among dyspneic patients with and without acute HF, ST2 concentrations are strongly predictive of mortality at 1 year and might be useful for prognostication when used alone or together with NT-proBNP. [Copyright &y& Elsevier]

The article focuses on the use of enzymatic hydrolysis of glucuronide metabolites for an incomplete recovery of prescription opioid in urine. The efficiency of acid versus different enzyme hydrolysis methods in recovering morphine and common semisynthetic opioids from glucuronide standards was compared. The results indicate that the majority of opioids tested were extensively glucuronide-conjugated in urine with the exception of oxydocone.