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The efficacy, safety, and tolerability of a moderate dose, 3-drug lipid-lowering regimen were evaluated among 29 male patients with hyperlipidemia and coronary artery disease. In an initial 12-month phase, regular niacin, 500 mg qid, lovastatin, 20 mg bid, and colestipol, 10 g/bid, were given with dose adjustment for lipid targets and side effects. This was followed by 2 random sequence crossover phases (8 months each) alternating regular niacin with a polygel controlled-release formulation of niacin for use in this regimen. Lipid, lipoprotein, apoprotein, and clinical chemistry determinations were obtained at baseline, during the initial phase, at the 2 crossover phases, and at 6 weeks after therapy. A final questionnaire queried specific side effects and overall preferences. Low-/high-density lipoprotein (LDL/HDL) changed from means of 215/46 mg/dl at baseline, to 94/59 mg/dl after run-in, to 85/52 mg/dl after 8 months of controlled-release niacin, and to 98/56 mg/dl after 8 months of regular niacin (regular niacin vs controlled-release niacin, p <0.005/<0.05). The target of LDL < or = 100 mg/dl was achieved at 8 months by 83% of these patients with controlled-release niacin and by 52% with regular niacin (p <0.01). Compliance was 95% with controlled-release niacin versus 85% with regular niacin (p <0.001). The controlled-release niacin and regular niacin regimens did not differ in terms of uric acid, glucose, insulin, or asparate aminotransferase levels. Overall, 21% of patients called the 3 drugs "very easy" and 72% "fairly easy" to take. The controlled-release niacin-containing regimen was preferred by 21 patients and the regular niacin by 4. In conclusion, these regimens achieve striking lipid changes among hyperlipidemic patients. Controlled release is the preferred niacin preparation in terms of LDL reduction, compliance, patient preference, and achieving the National Cholesterol Education Program guideline of LDL < or = 100 mg/dl. The 2 niacin preparations did not differ in evidence of toxicity. [ABSTRACT FROM AUTHOR]

We examined the impact of metabolic syndrome (MS) on coronary stenosis progression and major cardiovascular (CV) events and investigated the mitigating effects of low-density lipoprotein (LDL) cholesterol lowering and LDL cholesterol lowering plus high-density lipoprotein (HDL) cholesterol increasing. This analysis combined individual patient data from 445 subjects who participated in 3 double-blinded, randomized, placebo-controlled trials (FATS, HATS, and AFREGS) comparing intensive lipid therapy to placebos on coronary stenosis progression by quantitative coronary angiography and on major CV events. The primary end points were change in mean proximal coronary diameter stenosis (Delta%S(prox)) over 3 years and the frequency of the predefined composite of coronary artery disease death, nonfatal myocardial infarction, stroke, and revascularization due to worsening ischemia. Patients with MS had 50% more rapid coronary stenosis progression and 64% increased CV event frequency compared to those without. More rapid coronary stenosis progression was significantly and independently associated with a 3.5-fold increased event risk (p <0.001). Combination lipid therapy significantly decreased stenosis progression by 83% (Delta%S(prox) 0.5 vs 2.9, p <0.001) in patients with MS and induced a small net regression in those without (Delta%S(prox) -0.3 vs 2.0, p <0.001). Combination therapy decreased the event rate by 54% (13% vs 28%, p = 0.03) in those with MS and by 82% (3% vs 17%, p = 0.002) without. On average, each 10% decrease in LDL cholesterol or 10% increase in HDL cholesterol was significantly associated with a 0.3 Delta%S(prox) decrease. Each 10% decrease in LDL cholesterol or 10% increase in HDL cholesterol was associated with 11% (p = 0.02) or 22% (p <0.001) event risk decrease. In conclusion, patients with MS have significantly more rapid coronary stenosis progression and a higher frequency of CV events. Greater stenosis progression rate is associated with a higher event rate. LDL cholesterol-lowering and HDL cholesterol-increasing therapies independently and significantly decrease coronary stenosis progression and decrease CV events. [ABSTRACT FROM AUTHOR]

Electronic nicotine delivery systems (ENDS) have the potential to provide nicotine to tobacco consumers while reducing exposure to combustion-related toxicants. Here, we report changes in biomarkers of exposure (BoE) and biomarkers of potential harm (BoPH) in smokers who completely switched to Vuse Vibe and Vuse Ciro ENDS products, or to smoking abstinence in a randomized, controlled clinical study. Thirteen BoE (12 urinary and one blood) that indicate exposure to harmful and potentially harmful toxicants (HPHCs) were evaluated at baseline on day 5. Urinary BoPH linked to oxidative stress, platelet activation, and inflammation were also assessed at baseline, and on day 5 and day 7. Nicotine exposure was lower in Vuse Vibe and Vuse Ciro groups compared to baseline values. Urinary non-nicotine BoE decreased significantly (52.3-96.7%) in the Vuse ENDS groups, and the reductions were similar in magnitude to those observed in the abstinence group. Blood carboxyhemoglobin decreased 52.8-55.0% in all study groups. Decreases (10-50%) in BoPH were observed in all study groups. Thus, smokers who switch exclusively to Vuse Vibe or Vuse Ciro products or completely abstain from smoking are exposed to substantially lower levels of HPHCs, and experience improvements in BoPH of oxidative stress and inflammation pathways.

Biomarkers of exposure (BoE) can help evaluate exposure to combustion-related, tobacco-specific toxicants after smokers switch from cigarettes to potentially less-harmful products like electronic nicotine delivery systems (ENDS). This paper reports data for one (Vuse Solo Original) of three products evaluated in a randomized, controlled, confinement study of BoE in smokers switched to ENDS. Subjects smoked their usual brand cigarette ad libitum for two days, then were randomized to one of three ENDS for a 7-day ad libitum use period, or to smoking abstinence. Thirteen BoE were assessed at baseline and Day 5, and percent change in mean values for each BoE was calculated. Biomarkers of potential harm (BoPH) linked to oxidative stress, platelet activation, and inflammation were also assessed. Levels decreased among subjects randomized to Vuse Solo versus Abstinence, respectively, for the following BoE: 42-96% versus 52-97% (non-nicotine constituents); 51% versus 55% (blood carboxyhemoglobin); and 29% versus 96% (nicotine exposure). Significant decreases were observed in three BoPH: leukotriene E4, 11-dehydro-thromboxane B2, and 2,3-dinor thromboxane B2 on Day 7 in the Vuse Solo and Abstinence groups. These findings show that ENDS use results in substantially reduced exposure to toxicants compared to smoking, which may lead to reduced biological effects., (© 2022. The Author(s).)

The Pharmacogenomics Access & Reimbursement Symposium, a landmark event presented by the Golden Helix Foundation and the Pharmacogenomics Access & Reimbursement Coalition, was a 1-day interactive meeting comprised of plenary keynotes from thought leaders across healthcare that focused on value-based strategies to improve patient access to personalized medicine. Stakeholders including patients, healthcare providers, industry, government agencies, payer organizations, health systems and health policy organizations convened to define opportunities to improve patient access to personalized medicine through best practices, successful reimbursement models, high quality economic evaluations and strategic alignment. Session topics included health technology assessment, health economics, health policy and value-based payment models and innovation.

Background: HIV-related stigma among people living with HIV (PLHIV) is associated with worse health outcomes. We used longitudinal data from a multi-site cohort in South Africa to assess changes over time in stigma after HIV diagnosis and determine whether antiretroviral therapy (ART) initiation is associated with stigma reduction., Methods: We administered the Internalized AIDS-Related Stigma Scale (IARSS, a six-item dichotomous scale questionnaire) at baseline, three months, and six months to newly diagnosed ART-eligible participants between 2014-2015. A confirmatory factor analysis indicated that the IARSS contained a four-item internalized stigma factor (α=0.80) and a two-item disclosure concerns factor (α=0.75). We fitted multiple logistic regression models specifying internalized stigma/disclosure concerns at six months as the outcome and ART initiation as the predictor of interest., Results: Of the 500 participants (187 men and 313 women) enrolled, 308 (62%) initiated ART. Internalized stigma declined among people entering care (mean score, 1.0 to 0.7, p<0.01); however, disclosure concerns remained unchanged (percentage endorsing either disclosure concern item, 78% to 77%, p=0.23). These findings were similar between ART initiators and non-initiators. We estimated a statistically significant positive association between ART initiation and disclosure concerns at six months (OR=1.88; 95% CI, 1.20-2.94) but not between ART initiation and internalized stigma at six months (OR=1.15; 95% CI, 0.75-1.78)., Conclusions: Among ART-eligible South African PLHIV entering into HIV care, internalized stigma modestly declined over time but disclosure concerns persisted. PLHIV who initiated ART were more likely to have persistent disclosure concerns over time as compared with those who did not start ART.

Introduction: Cross-sectional evidence suggests that internalized HIV stigma is associated with lower likelihoods of antiretroviral therapy (ART) initiation and HIV-1 RNA suppression among people living with HIV (PLWH). This study examined these associations with longitudinal data spanning the first nine months following HIV diagnosis and explored whether avoidant coping mediates these associations., Methods: Longitudinal data were collected from 398 South African PLWH recruited from testing centres in 2014 to 2015. Self-report data, including internalized stigma and avoidant coping (denying and distracting oneself from stressors), were collected one week and three months following HIV diagnosis. ART initiation at six months and HIV-1 RNA at nine months were extracted from the South Africa National Health Laboratory Service database. Two path analyses were estimated, one testing associations between internalized stigma, avoidant coping and ART initiation, and the other testing associations between internalized stigma, avoidant coping and HIV-1 RNA suppression., Results: Participants were 36 years old, on average, and 63% identified as female, 18% as Zulu and 65% as Xhosa. The two path models fit the data well (ART initiation outcome: X 2 (7) = 8.14, p = 0.32; root mean square error of approximation (RMSEA) = 0.02; comparative fit index (CFI) = 0.92; HIV-1 RNA suppression outcome: X 2 (7)  = 6.58, p = 0.47; RMSEA = 0.00; CFI = 1.00). In both models, internalized stigma one week after diagnosis was associated with avoidant coping at three months, controlling for avoidant coping at one week. In turn, avoidant coping at three months was associated with lower likelihood of ART initiation at six months in the first model and lower likelihood of HIV-1 RNA suppression at nine months in the second model. Significant indirect effects were observed between internalized stigma with ART non-initiation and unsuppressed HIV-1 RNA via the mediator of avoidant coping., Conclusions: Internalized stigma experienced soon after HIV diagnosis predicted lower likelihood of ART initiation and HIV-1 RNA suppression over the first year following HIV diagnosis. Avoidant coping played a role in these associations, suggesting that PLWH who internalize stigma engage in greater avoidant coping, which in turn worsens medication- and health-related outcomes. Interventions are needed to address internalized stigma and avoidant coping soon after HIV diagnosis to enhance treatment efforts during the first year after HIV diagnosis., (© 2018 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background: Stillbirth is a major cause of perinatal mortality and occurs disproportionately in developing countries including Tanzania. However, there is scant information regarding the predictors of this condition in Tanzania. This study aimed to determine maternal and fetal risk factors for stilbirth in northen Tanzania., Methodology: A retrospective cohort study was performed using maternally-linked data from the Kilimanjaro Christian Medical Centre birth registry. A total of 47681 women who had singleton delivery at KCMC between 2000 and 2014 were analyzed. Women with multiple gestations were excluded. Descriptive statistics were summarized using proportions and frequency. Chi-square test was used to determine risk factors for stillbirth in bivariate analysis. A multivariable regression model was used to estimate adjusted odds ratios (AOR) with 95% confidence intervals for maternal and fetal factors associated with stillbirth. A p-value of less than 0.05 was considered statistically significant., Results: The frequency of stillbirth was 3.5%. Pre-eclampsia (AOR 3.99; 95% CI: 3.31-4.81) and placental abruption (AOR 22.62; 95% CI: 15.41-33.19) were the strongest maternal risk factors associated with still birth. While non-cephalic presentation (AOR 6.05; 95% CI: 4.77-7.66) and low birth weight (AOR 9.66; 95%CI: 8.66-10.77) were the fetal factors with the greatest impact on stillbirth., Conclusion: The rate of stillbirth in our study was consistent with past studies of developing countries. Numerous maternal and fetal factors risk factors were identified. Early identification of at risk pregnancies and appropriate intervention may help to reduce the occurrence of stillbirth.

Background and Objective . Placenta previa (PP) is a potential risk factor for obstetric hemorrhage, which is a major cause of fetomaternal morbidity and mortality in developing countries. This study aimed to determine frequency, risk factors, and adverse fetomaternal outcomes of placenta previa in Northern Tanzania. Methodology . A retrospective cohort study was conducted using maternally-linked data from Kilimanjaro Christian Medical Centre birth registry spanning 2000 to 2015. All women who gave birth to singleton infants were studied. Adjusted odds ratios (ORs) with 95% confidence intervals for risk factors and adverse fetomaternal outcomes associated with PP were estimated in multivariable logistic regression models. Result . A total of 47,686 singleton deliveries were analyzed. Of these, the frequency of PP was 0.6%. Notable significant risk factors for PP included gynecological diseases, alcohol consumption during pregnancy, malpresentation, and gravidity ≥5. Adverse maternal outcomes were postpartum haemorrhage, antepartum haemorrhage, and Caesarean delivery. PP increased odds of fetal Malpresentation and early neonatal death. Conclusion. The prevalence of PP was comparable to that found in past research. Multiple independent risk factors were identified. PP was found to have associations with several adverse fetomaternal outcomes. Early identification of women at risk of PP may help clinicians prevent such complications., Competing Interests: The authors declare that they have no competing interests.

Background: Cardiovascular disease (CVD) begins early in life and is associated with both the number of risk factors present and length of exposure to these risk factors including hyperlipidemia., Objectives: The clinical benefit of intensive lipid therapy over 25 years was investigated in the Familial Atherosclerosis Treatment Study-Observational Study., Methods: Of 175 coronary artery disease subjects with mean low-density lipoprotein cholesterol (LDL-C) of 191 mg/dL and mean age of 50 years, who completed the randomized and placebo-controlled Familial Atherosclerosis Treatment Study, 100 chose receiving lipid management by their physicians (usual care [UC]) and 75 elected to receive an intensive treatment [IT] for lipid management with lovastatin (40 mg/d), niacin (2.5 g/d), and colestipol (20 g/d) from 1989 to 2004, followed by double therapy with simvastatin (40-80 mg/d) and niacin from 2005 to 2006 and by triple therapy of ezetimibe 10 mg and simvastatin 40 to 80 mg/d plus niacin during 2007 to 2012. Deaths from CVD, non-CVD, and any cause were compared between UC and IT using Cox proportional hazards model., Results: UC and IT groups were similar in risk factors with the exception that IT had more severe coronary artery disease. Mean LDL-C levels were 167 mg/dL from 1988 to 2004, 97 from 2005 to 2006, and 96 from 2007 to 2012 in surviving subjects receiving UC. IT lowered LDL-C to 119, 97, and 83 mg/dL in the 3 periods, respectively. Compared with UC, IT significantly reduced total mortality (11.1 vs 26.3 per 1000 person years [PY], hazard ratio [HR] = 0.45, 95% confidence interval [CI]: 0.26-0.77, P = .003) and CVD mortality (10.6 vs 27.7 per 1000 PY, HR = 0.34, 95% CI: 0.15-0.80, P = .009). The non-CVD mortality was also reduced but was not of statistical significance (6.8 vs 12.7 per 1000 PY, HR = 0.55, 95% CI: 0.27-1.14, P = .11)., Conclusions: Long-term intensive lipid therapy significantly reduced total and cardiovascular mortality in Familial Atherosclerosis Treatment Study-Observational Study. These results support the importance of lifetime risk management to improve long-term outcome., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

An age-stratified, cross-sectional study was conducted in the US among healthy adult male cigarette smokers, moist snuff consumers, and non-tobacco consumers to evaluate cardiovascular biomarkers of biological effect (BoBE). Physiological assessments included flow-mediated dilation, ankle-brachial index, carotid intima-media thickness and expired carbon monoxide. Approximately one-half of the measured serum BoBE showed statistically significant differences; IL-12(p70), sICAM-1 and IL-8 were the BoBE that best differentiated among the three groups. A significant difference in ABI was observed between the cigarette smokers and non-tobacco consumer groups. Significant group and age effect differences in select biomarkers were identified.

A study was conducted to evaluate biomarkers of biological effect and physiological assessments related to cardiovascular disease (CVD) among adult male cigarette smokers (SMK), moist snuff consumers (MSC) and non-consumers of tobacco (NTC). Additionally, biomarkers of tobacco and tobacco smoke exposure (BoE) were measured in spot urines and are reported here. Except for the BoE to nicotine and NNK, BoE were generally greater in SMK compared with MSC, and BoE were generally not different in comparisons of MSC and NTC. Results demonstrated that MSC had lower systemic exposures to many harmful and potentially harmful constituents than SMK, which is consistent with epidemiological data that indicate a differential in CVD risk between these groups.

Cardiovascular disease (CVD) biomarkers of biological effect (BoBE), including hematologic biomarkers, serum lipid-related biomarkers, other serum BoBE, and one physiological biomarker, were evaluated in adult cigarette smokers (SMK), smokeless tobacco consumers (STC), and non-consumers of tobacco (NTC). Data from adult males and females in the US National Health and Nutrition Examination Survey and a single site, cross-sectional study of healthy US males were analyzed and compared. Within normal clinical reference ranges, statistically significant differences were observed consistently for fibrinogen, C-reactive protein (CRP), hematocrit, mean cell volume, mean cell hemoglobin, hemoglobin, white blood cells, monocytes, lymphocytes, and neutrophils in comparisons between SMK and NTC; for CRP, white blood cells, monocytes, and lymphocytes in comparisons between SMK and STC; and for folate in comparisons with STC and NTC. Results provide evidence for differences in CVD BoBE associated with the use of different tobacco products, and provide evidence of a risk continuum among tobacco products and support for the concept of tobacco harm reduction.

Background: Studies have documented the short-term vascular benefits of combination lipid therapy., Objective: Our objective was to evaluate the long-term effects of combination lipid therapy on carotid intima-media thickness (CIMT) in patients with coronary artery disease., Methods: We performed a case-control study in patients who had finished the Familial Atherosclerosis Treatment Study (FATS) and returned to usual care with statin therapy alone or had elected to participate in the 20-year FATS-Observational Study (FATS-OS) and received combination therapy with lovastatin (40 mg/day), niacin (2-3 g/day), and colestipol (20 gm/day) for 11 years, then continued with simvastatin (10-80 mg/day) or lovastatin (40-80 mg/day) plus niacin (2-4 g/day). After 17.8 ± 0.8 years with combination therapy and 19.0 ± 0.8 years with usual care, cholesterol levels and CIMT were collected in 43 FATS-OS patients and 26 usual care patients., Results: Combination therapy group had a greater decrease in total cholesterol (-42 ± 14% vs -31 ± 17%, P = .008) and low-density lipoprotein cholesterol (LDL-C) (-57 ± 13% vs -38 ± 25%, P < .001) and greater increase in high-density lipoprotein cholesterol (HDL-C) (38 ± 43% vs 15 ± 23%, P = .02) as compared with usual care. CIMT (0.902 ± 0.164 vs 1.056 ± 0.169 mm, P < .001) on intensive therapy was significantly less compared with usual care. Multivariate regression analysis (coefficient, 95% CI) showed that combination therapy (-0.13; -0.21 to -0.04, P = .003) and on-therapy LDL-C (0.15; 0.02 to 0.28, P = .03) were significant independent predictors of CIMT., Conclusions: Prolonged combination lipid therapy is associated with greater improvements in LDL-C and HDL-C levels and less atherosclerotic burden as compared with statin therapy alone., (Copyright © 2014 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Two large studies in populations selected for cardiovascular disease (CVD) demonstrated that raising high-density lipoprotein (HDL) cholesterol with niacin added to statin therapy did not decrease CVD. We examine the association of lipoprotein subfractions with niacin and changes in coronary stenosis and CVD event risk. One hundred and seven patients from 2 previous studies using niacin in combination with either statin or bile acid-binding resin were selected to evaluate changes in lipoproteins separated by density-gradient ultracentrifugation to progression of coronary artery disease as assessed by quantitative coronary angiography. Improvement in coronary stenosis was significantly associated with the decrease of cholesterol in the dense low-density lipoprotein (LDL) particles and across most of the intermediate density lipoprotein (IDL) and very low density lipoprotein particle density range, but, not with any of the HDL fraction or of the more buoyant LDL fractions. Event-free survival was significantly associated with the decrease of cholesterol in the dense LDL and IDL; there was no association with changes in cholesterol in the HDL and buoyant LDL fractions. Niacin combination therapy raises HDL cholesterol and decreases dense LDL and IDL cholesterol levels. Changes in LDL and IDL are related to improvement in CVD. Lipoprotein subfraction analysis should be performed in larger studies utilizing niacin in combination with statins., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Compare gradient gel electrophoresis (GGE), vertical auto profile ultracentrifugation (VAP-II), nuclear magnetic resonance spectroscopy (NMR), and ion mobility for their ability to relate low- (LDL), intermediate- (IDL), very-low-density (VLDL) and high-density lipoprotein (HDL) subfraction concentrations to atherosclerotic progression., Methods and Results: Regression analyses of 136 patients who received baseline and follow-up coronary angiographies and subfraction measurements by all four methods in the HDL Atherosclerosis Treatment Study. Prior analyses have shown that the intervention primarily affected disease progression in proximal arteries with <30% stenoses at baseline. Three-year increases in percent stenoses were consistently associated with higher on-study plasma concentrations of small, dense LDL as measured by GGE (LDLIIIb, P=10(-6); LDLIVa, P=0.006; LDLIVb, P=0.02), VAP-II (LDL4, P=0.002), NMR (small LDL, P=0.001), and ion mobility (LDL IIb, P=0.04; LDLIIIa, P=0.002; LDLIIIb, P=0.0007; LDLIVa, P=0.05). Adjustment for triglycerides, HDL-cholesterol, and LDL-cholesterol failed to eliminate the statistical significance for on-study GGE estimated LDLIIIb (P=10(-5)) and LDLIVa (P=0.04); NMR-estimated small LDL (P=0.03); or ion mobility estimated large VLDL (P=0.02), LDLIIIa (P=0.04) or LDLIIIb (P=0.02). All methods show that the effects were significantly greater for the on-study than the baseline small, dense LDL concentrations, thus establishing that the values concurrent to the progression of disease were responsible. The rate of disease progression was also related to individual VLDL, IDL, and HDL subclasses to differing extents among the various analytic methods., Conclusion: Four methodologies confirm the association of small, dense LDL with greater coronary atherosclerosis progression, and GGE, NMR, and ion mobility confirm that the associations were independent of standard lipid measurements., Clinical Trial Registration: clinicaltrials.gov/ct2/show/NCT00000553., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

Between 1993 and 1999, an average of 1.7 million violent workplace incidents were recorded per year. Of the nonfatal injuries and lost days due to occupational violence, 32% occur in the health care setting. The annual incidence rate for violence against nurses is 22 incidents per 1,000 nurses. When an occupational health professional analyzes an exposure, engineering controls, administrative controls, and personal protective equipment policies are drafted to ensure the future safety of employees. This literature review identifies best practice controls used to protect health care workers from violence in the workplace., (Copyright 2013, SLACK Incorporated.)

Concurrently high values of the maximum potential wind speed of updrafts ( W max ) and 0-6 km wind shear (Shear) have been found to represent conducive environments for severe weather, which subsequently provides a way to study severe weather in future climates. Here, we employ a model for the product of these variables (WmSh) from the National Center for Atmospheric Research/United States National Center for Environmental Prediction reanalysis over North America conditioned on their having extreme energy in the spatial field in order to project the predominant spatial patterns of WmSh. The approach is based on the Heffernan and Tawn conditional extreme value model. Results suggest that this technique estimates the spatial behavior of WmSh well, which allows for exploring possible changes in the patterns over time. While the model enables a method for inferring the uncertainty in the patterns, such analysis is difficult with the currently available inference approach. A variation of the method is also explored to investigate how this type of model might be used to qualitatively understand how the spatial patterns of WmSh correspond to extreme river flow events. A case study for river flows from three rivers in northwestern Tennessee is studied, and it is found that advection of WmSh from the Gulf of Mexico prevails while elsewhere, WmSh is generally very low during such extreme events. © 2013 The Authors. Environmetrics published by JohnWiley & Sons, Ltd.

Although the effect of niacin on the glucose levels in subjects with diabetes mellitus has been investigated, niacin's effects on the glucose levels and atherosclerosis in subjects with normal glucose levels have not been well established. We examined the effect of niacin on the glucose levels, coronary stenosis progression using quantitative coronary angiography, and clinical events in 407 subjects who had a baseline glucose level <100 mg/dl and were enrolled in the Familial Atherosclerosis Treatment Study (FATS), HDL-Atherosclerosis Treatment Study (HATS), Armed Forces Regression Study (AFREGS), or Carotid Plaque Composition by MRI during lipid-lowering (CPC) study testing active niacin therapy. Although the fasting glucose levels increased significantly within 3 years in both subjects treated with niacin (from 85.6 ± 9.5 to 95.5 ± 19.7 mg/dl, p <0.001) and without niacin (from 85.2 ± 9.6 to 90 ± 17.9 mg/dl, p = 0.009), those treated with niacin had a significantly larger increase in glucose levels than those not taking niacin (9.88 vs 4.05 mg/dl, p = 0.002). Overall, 29% of subjects developed impaired fasting glucose within 3 years. Incident impaired fasting glucose was significantly more likely to be observed in subjects treated with niacin than in those who were not. However, the frequency of new-onset diabetes mellitus did not differ significantly between the 2 groups (5.6% vs 4.8%, p = 0.5). Niacin-treated subjects compared to untreated subjects had significantly less change in mean coronary stenosis (0.1 ± 0.3% vs 2 ± 12%, p <0.0001) and less major cardiovascular events (8% vs 21%, p = 0.001). In conclusion, the use of niacin for 3 years in subjects with normal baseline glucose levels was associated with an increase in blood glucose levels and the risk of developing impaired fasting glucose, but not diabetes mellitus, and was associated with a significantly reduced incidence of coronary stenosis progression and major cardiovascular events., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Test whether angiographically-documented changes in percent stenosis and clinical endpoints (coronary-related deaths, myocardial infarctions, stroke, revascularization for worsening ischemia) in the HDL-Atherosclerosis Treatment Study (HATS) were attributable to specific LDL-subclasses., Methods: Gradient gel electrophoresis of on-study LDL-subclass cholesterol concentrations were measured in 32 placebo, 33 simvastatin-niacin, 38 antioxidant, and 39 simvastatin-niacin & antioxidant treated participants. The prespecified primary end point was the mean change per patient from the initial arteriogram to the final arteriogram in the percent stenosis caused by the most severe lesion in each of the nine proximal coronary segments., Results: The change in the percent stenosis of the most severe proximal lesions increased in association with higher concentrations of the small LDL subfractions LDL-IIIb (24.2-24.6 nm) and LDL-IVa (23.3-24.1 nm) before (both P = 0.002) and after (P = 0.01 and P = 0.03 respectively) adjustment for treatment group and on-study HDL-cholesterol, LDL-cholesterol, and triglyceride concentrations. The associations appeared specific to lesions with <30% baseline stenosis. When adjusted for age, sex, baseline BMI and cigarette use, the odds for primary clinical endpoints (death from coronary causes, nonfatal myocardial infarction, stroke, or revascularization for worsening ischemia) were significantly greater in subjects with higher on-study LDL-IIIb levels both before (P = 0.01) and after (P = 0.03) adjustment for treatment group and the standard lipid values., Conclusions: Plasma LDL-IIIb cholesterol concentrations were related to changes in coronary artery stenosis and cardiovascular events in patients with coronary artery disease and low HDL-cholesterol., Trial Registration: ClinicalTrials.gov NCT00000553.

We examined the association between rate of cholesterol esterification in plasma depleted of apolipoprotein B-containing lipoproteins (FER(HDL)), atherogenic index of plasma (AIP) [(log (TG/HDL-C)], concentrations, and size of lipoproteins and changes in coronary artery stenosis in participants in the HDL-Atherosclerosis Treatment Study. A total of 160 patients was treated with simvastatin (S), niacin (N), antioxidants (A) and placebo (P) in four regimens. FER(HDL) was measured using a radioassay; the size and concentration of lipoprotein subclasses were determined by nuclear magnetic resonance spectroscopy. The S+N and S+N+A therapy decreased AIP and FER(HDL), reduced total VLDL (mostly the large and medium size particles), decreased total LDL particles (mostly the small size), and increased total HDL particles (mostly the large size). FER(HDL) and AIP correlated negatively with particle sizes of HDL and LDL, positively with VLDL particle size, and closely with each other (r = 0.729). Changes in the proportions of small and large lipoprotein particles, which were reflected by FER(HDL) and AIP, corresponded with findings on coronary angiography. Logistic regression analysis of the changes in the coronary stenosis showed that probability of progression was best explained by FER(HDL) (P = 0.005). FER(HDL) and AIP reflect the actual composition of the lipoprotein spectrum and thus predict both the cardiovascular risk and effectiveness of therapy. AIP is already available for use in clinical practice as it can be readily calculated from the routine lipid profile.

The Sacred Mountain Youth Project was conducted to investigate risk and protective factors related to alcohol and drug use among American Indian youth. Findings indicated that stressful life events were positively associated with depressed mood, substance use, and risky behavior; cultural identity had no direct effects, but a secondary model showed that social support and protective family and peer influences were related to cultural identity. These findings suggest that the relationships between stressors and their negative sequelae are complex. Emphasis on protective processes that are culturally specific to American Indian youth may lead to effective alcohol and drug use prevention programs.

A new direct method using liquid chromatography-tandem mass spectrometry has been developed and validated for quantitation of 3-hydroxypropylmercapturic acid (3-HPMA) in urine. The method is fast, simple, and does not require extraction from urine. Analyte was separated on a hydrophilic interaction liquid chromatography column. Severe ion suppression was circumvented by a fast gradient after separation. Assay specificity, linearity, precision, and accuracy met the required FDA/CDER bioanalytical method criteria. Matrix effect and carryover of the assay were assessed. Urine sample storage stability and standard solution stability were also tested. The limit of quantitation was 22.0 ng/mL. The results for 3-HPMA obtained by our method were significantly correlated with results obtained by a contract lab.

Mainstream cigarette smoke (MSS) from 12 US cigarette brands and two reference cigarettes was evaluated to determine concentrations of dioxins (i.e., polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (PCBs)). The study included three 'tar' ranges based on Federal Trade Commission (FTC) determination: Low Yield (LY) < or = 5.5, Medium Yield (MY) 9.6-12.2, and High Yield (HY)> or = 14.5 mg/cig. Of the brands studied, the HY cigarettes yielded the greatest mean concentrations of 2005 World Health Organization Toxic Equivalents (WHO-TEQs) on a per cigarette basis. WHO-TEQ levels in LY cigarettes were significantly lower than for HY cigarettes (p=0.039) on a yield per cigarette basis and WHO-TEQ concentrations correlated with 'tar' yield (r=0.73, p=0.007), as did concentration on a WHO-TEQ per body mass per day basis (r=0.73, p=0.007). However, a statistically significant relationship was not observed between 'tar' yield levels and WHO-TEQ concentrations on a per mg Total Particulate Matter (TPM) basis. Concentrations for all brands tested ranged from 0.44 to 3.88 fg WHO-TEQ/mg TPM. Maximum daily exposure estimates calculated from this range (0.004-0.074 pg WHO-TEQ/kg bw/day) are below the current WHO Tolerable Daily Intake range of 1-5 pg/kg bw/day.

Objectives: This study evaluated the safety and lipid-altering efficacy of ezetimibe/simvastatin (E/S) coadministered with extended-release niacin (N) in patients with type IIa or IIb hyperlipidemia., Background: Current guidelines recommend consideration of combination drug therapy to achieve optimal low-density lipoprotein cholesterol (LDL-C) lowering and broader lipid-altering effects when treating hypercholesterolemic patients at high risk for atherosclerotic cardiovascular events., Methods: In this 24-week multicenter, randomized, double-blind study, 1,220 type IIa or IIb hyperlipidemic patients were randomized to treatment with E/S (10/20 mg/day) + N (titrated to 2 g/day), or N (titrated to 2 g/day), or E/S (10/20 mg/day). Changes from baseline in LDL-C (primary) and other secondary variables were assessed in the completers and modified intent-to-treat populations., Results: Coadministered E/S with N resulted in significantly greater reductions in LDL-C, non-high-density lipoprotein cholesterol, triglycerides, apolipoprotein B, and lipid/lipoprotein ratios, compared with either agent alone (p < 0.001). The combination increased levels of apolipoprotein A-I and high-density lipoprotein cholesterol significantly more than E/S (p < 0.001), and reduced high-sensitivity C-reactive protein levels significantly more than N (p = 0.005). A significantly greater percentage of patients discontinued the study in the N (25.0%) and N + E/S (23.3%) groups, compared with E/S (9.6%, p < 0.001) because of clinical adverse experiences (primarily flushing). Incidences of other clinical and laboratory adverse experiences (liver-, muscle-, and gastrointestinal-related) were similar for all groups., Conclusions: Combination treatment with E/S plus N showed superior lipid-altering efficacy compared with N or E/S in type IIa or IIb hyperlipidemia patients and was generally well tolerated aside from N-associated flushing. This combination offers an effective, broad, lipid-altering therapy with improvements in lipid effects beyond LDL-C in these patients. (To Evaluate Ezetimibe/Simvastatin and Niacin [Extended Release Tablet] in Patients With High Cholesterol.

The current guidelines for the treatment of high risk lipid disorders do not specify a therapeutic target level of high-density lipoprotein (HDL) cholesterol for cardiovascular disease prevention in high-risk populations. However, as described in this report, there is a substantial body of evidence from basic science and epidemiologic studies and from clinical trials providing the strong, consistent message that raising HDL cholesterol by therapeutic means will effectively reduce cardiovascular risk independently of reductions in low-density lipoprotein (LDL) cholesterol. Therapeutic HDL cholesterol raising, most effectively achieved by nicotinic acid (niacin), appears to be at least as effective as comparable percentages of LDL cholesterol lowering for the reduction of atherosclerosis progression or clinical cardiovascular events, over a broad range of risk levels. The widespread adoption of this strategy awaits the results of large, ongoing controlled clinical trials of HDL cholesterol raising.

Objective: To determine the mortality rate and its predictors in patients with a presumptive diagnosis of tuberculous pericarditis in sub-Saharan Africa., Design: Between 1 March 2004 and 31 October 2004, we enrolled 185 consecutive patients with presumed tuberculous pericarditis from 15 referral hospitals in Cameroon, Nigeria and South Africa, and observed them during the 6-month course of antituberculosis treatment for the major outcome of mortality. This was an observational study, with the diagnosis and management of each patient left at the discretion of the attending physician. Using Cox regression, we have assessed the effect of clinical and therapeutic characteristics (recorded at baseline) on mortality during follow-up., Results: We obtained the vital status of 174 (94%) patients (median age 33; range 14 - 87 years). The overall mortality rate was 26%. Mortality was higher in patients who had clinical features of HIV infection than in those who did not (40% v. 17%, p=0.001). Independent predictors of death during followup were: (i) a proven non-tuberculosis final diagnosis (hazard ratio (HR) 5.35, 95% confidence interval (CI) 1.76 - 16.25), (ii) the presence of clinical signs of HIV infection (HR 2.28, CI 1.14 - 4.56), (iii) coexistent pulmonary tuberculosis (HR 2.33, CI 1.20 - 4.54), and (iv) older age (HR 1.02, CI 1.01 - 1.05). There was also a trend towards an increase in death rate in patients with haemodynamic instability (HR 1.80, CI 0.90 - 3.58) and a decrease in those who underwent pericardiocentesis (HR 0.34, CI 0.10 - 1.19)., Conclusion: A presumptive diagnosis of tuberculous pericarditis is associated with a high mortality in sub-Saharan Africa. Attention to rapid aetiological diagnosis of pericardial effusion and treatment of concomitant HIV infection may reduce the high mortality associated with the disease.

BACKGROUND: Metabolic syndrome, insulin resistance and diabetes are associated with an increased risk of cardiovascular disease. Niacin is known to increase insulin resistance, and have adverse effects on blood glucose levels, but to have beneficial effects on plasma lipids and lipoproteins. We therefore aimed to determine whether intensive lipid therapy with a niacin-containing regimen would have a beneficial effect on cardiovascular disease, despite an expected increase in plasma glucose and insulin resistance in subjects with the metabolic syndrome, insulin resistance or abnormal fasting plasma glucose levels. METHODS: The effect of three years' treatment with niacin plus simvastatin (N+S) on both angiographic and clinical outcomes were analyzed in the 160 subjects with coronary artery disease (CAD) and low levels of high density lipoproteins (HDL) from the HDL-Atherosclerosis Treatment Study (HATS). A subgroup analysis was performed on the basis of: (1) the presence or absence of the metabolic syndrome, (2) higher or lower insulin resistance, and (3) the presence or absence of impaired fasting glucose or diabetes (dysglycemia). Individuals classified as having the MS, increased insulin resistance or dysglycemia would be expected to have increased cardiovascular risk. RESULTS: N+S reduced the change in mean proximal percent stenosis (Δ%S) compared to placebo (PL) in subjects with the metabolic syndrome (Δ%Sprox 0.3 vs 3.0, p=0.003) and in the more insulin resistant group of subjects (Δ%Sprox 0.5 vs 2.7, p=0.001), while subjects with dysglycemia (impaired fasting glucose or diabetes) showed a lesser benefit (Δ%Sprox 1 vs 3.2, p=0.13). These changes occurred despite increased in-treatment fasting glucose levels (3%), fasting insulin (19%) and decreased insulin sensitivity (-10%). Overall primary clinical events were reduced by 60% with N+S compared to PL (p=0.02). A similar reduction of the rate of primary events was seen in patients with metabolic syndrome, insulin resistance, and to a lesser extent in patients with dysglycemia in the N+S group compared to PL. CONCLUSIONS: These data indicate that, in CAD patients with low HDL, treating the atherogenic dyslipidemia with a combination of N+S leads to substantial benefits in terms of stenosis progression and clinical events, independently of whether the patient has the metabolic syndrome or is insulin resistant. Over a 3 year period, the beneficial effect of niacin in combination with simvastatin appears to offset the modest adverse effect of niacin on glucose metabolism and insulin resistance in at higher risk patients, as long as careful attention is paid to glycemic control.

Are progressive changes in intravascular ultrasound (IVUS)-derived indexes of plaque size sufficiently predictive of in-trial or future cardiovascular event risk that IVUS can serve as an efficient surrogate for clinical events in coronary disease trials? This question remains unanswered by clinical trials reported to date. Indeed, the answer may well be "yes." Nevertheless, there are enough concerns about the physical limitations, the fundamental assumptions, and the interpretation of the IVUS measurements that the answer cannot be taken for granted. Here, we review the evidence to date, discuss some of the concerns, and compare IVUS results with those of quantitative arteriography.

The current guidelines for treatment of high-risk of lipid disorders do not specify a therapeutic target level of high-density lipoprotein cholesterol (HDL-C) for prevention of vascular disease in high-risk populations. However, there is a substantial body of evidence from basic science and epidemiologic studies and from clinical trials, providing the strong, consistent message that raising HDL-C by therapeutic means will effectively and independently reduce cardiovascular risk. This review summarizes epidemiologic evidence and the results of a meta-analysis of 23 published, prospective, randomized, placebo-controlled clinical trials. It focuses on the effects of lipid therapies on coronary stenosis progression, as measured by quantitative arteriography and/or, on clinical cardiovascular endpoints. Among the seven drug/treatment classes into which individual study results were categorized and averaged, reduction in stenosis progression and reduction in clinical events are both very highly correlated with the composite lipid variable (%ΔHDL-C - %Δ low-density lipoprotein cholesterol [LDL-C]; where %Δ is percent change relative to the placebo group response). This holds true for all lipid drug classes or combinations of lipid drug therapy, with the exception of the unexpectedly anomalous effects of the torcetrapib-atorvastatin combination. There is a strong and consistent body of evidence that therapeutic HDL-C-raising is at least as effective as comparable percentages of LDL-C-lowering for reduction of atherosclerosis progression or clinical cardiovascular events over a broad range of risk levels. Adoption of this strategy into guidelines probably awaits results of at least one large controlled HDL-C-raising clinical trial, of which two are ongoing and one other is planned.

Purpose of Review: Our analysis presents an alternative hypothesis to the prevailing view that low-density lipoprotein-C is the only important target of lipid therapy., Recent Findings: Two recently published studies showed surprising results. In the Armed Forces Regression Study, low-density lipoprotein-C was lowered only 22% with cholystyramine, niacin and gemfibrozil. Coronary stenosis regressed, however, and the primary clinical event rate was reduced by 54%. Conversely, in the FIELD trial, the primary event rate reduction was only 11% (P = NS). These differences appeared to be explained largely by the difference in high-density lipoprotein response to these regimens (38 vs. 3%). This meta-analysis of 23 trials strongly supports the notion that the sum of percent reduction in low-density lipoprotein-C plus percent increase in high-density lipoprotein-C predicts benefits much more effectively than either lipoprotein component., Summary: Epidemiology suggests that the cardiovascular event rate is reduced by nearly 1% for each 1% reduction in low-density lipoprotein-C and by at least 1% for each 1% increase in high-density lipoprotein. These effects are statistically independent; thus, for moderate lipid changes, they are additive. If this simple algorithm is proven accurate, a 30% high-density lipoprotein-C increase and a 40% low-density lipoprotein-C reduction would result in a nearly 70% CHD risk reduction - and a revolution in cardiovascular prevention.

Increased low-density lipoprotein (LDL) and decreased high-density lipoprotein cholesterol (HDL-C) predict premature coronary artery disease, as do elevated levels of apolipoprotein B or reduced levels of apolipoprotein AI. Probands were studied of families with common genetic forms of dyslipidaemia to determine if apo B or apo AI define genetic groups and if apo B or apo AI levels relate to premature coronary artery disease risk. Elevated apo B was characteristic of familial hypercholesterolaemia, familial combined hyperlipidaemia (FCHL), and was seen in individuals with elevated Lp(a). Normal apo B levels were seen in familial hypertriglyceridaemia and in 'coronary artery disease with low-HDL cholesterol'. Apo AI levels tended to be low in FCHL and were decreased in 'coronary disease with low-HDL cholesterol'. In familial hypertriglyceraemia, even though HDL-C levels were low, normal apo AI and apo B levels were seen in the absence of premature coronary artery disease. Therefore, in genetic dyslipidaemias elevated apo B levels and reduced apo AI levels (or increased apo B/AI ratio) differ and predict premature coronary artery disease.

Objective: Lipid-lowering therapy (LL-Rx) reduces coronary artery disease (CAD) but the response varies amongst individuals. We investigated the contribution of three genetic forms of dyslipidaemia characterized by elevated plasma apo B, familial hypercholesterolaemia (FH), familial combined hyperlipidaemia (FCHL), and elevated Lp(a), to the angiographic response with LL-Rx., Methods and Results: Fifty-one men, with premature CAD and elevated plasma apo B, were selected in whom a genetic diagnosis was based on lipid phenotypes in relatives. Subjects received conventional (diet +/- colestipol) or intensive LL-Rx (niacin or lovastatin plus colestipol). Clinical parameters and CAD severity were measured before and after 2 years of treatment. Twenty-seven patients had FCHL, 12 FH and 12 elevated Lp(a). Regression of coronary stenosis was dependent on the effect of therapy (P < 0.001), genetic form of dyslipidaemia (P = 0.004) and the interaction between the two variables (P = 0.02). Significant regression of coronary stenosis occurred only in FCHL and Lp(a) (P = 0.03, vs. control groups); CAD progression was only slowed in FH., Conclusions: Three genetic forms of dyslipidaemia were associated with different angiographic outcomes during intensive LL-Rx. Different forms of dyslipidaemia therefore may require different lipid-lowering strategy. Patients with FH and buoyant LDL require more aggressive reduction of LDL cholesterol whilst those with either FCHL or elevated Lp(a) with dense LDL need LDL cholesterol reduction as well as therapies aimed at reduction of the small, dense LDL particles.

Background: The incidence of tuberculous pericarditis has increased in Africa as a result of the human immunodeficiency virus (HIV) epidemic. However, the effect of HIV co-infection on clinical features and prognosis in tuberculous pericarditis is not well characterised. We have used baseline data of the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry to assess the impact of HIV co-infection on clinical presentation, diagnostic evaluation, and treatment of patients with suspected tuberculous pericarditis in sub-Saharan Africa., Methods: Consecutive adult patients in 15 hospitals in three countries in sub-Saharan Africa were recruited on commencement of treatment for tuberculous pericarditis, following informed consent. We recorded demographic, clinical, diagnostic and therapeutic information at baseline, and have used the chi-square test and analysis of variance to assess probabilities of significant differences (in these variables) between groups defined by HIV status., Results: A total of 185 patients were enrolled from 01 March 2004 to 31 October 2004, 147 (79.5%) of whom had effusive, 28 (15.1%) effusive-constrictive, and 10 (5.4%) constrictive or acute dry pericarditis. Seventy-four (40%) had clinical features of HIV infection. Patients with clinical HIV disease were more likely to present with dyspnoea (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.4 to 7.4, P = 0.005) and electrocardiographic features of myopericarditis (OR 2.8, 95% CI 1.1 to 6.9, P = 0.03). In addition to electrocardiographic features of myopericarditis, a positive HIV serological status was associated with greater cardiomegaly (OR 3.89, 95% CI 1.34 to 11.32, P = 0.01) and haemodynamic instability (OR 9.68, 95% CI 2.09 to 44.80, P = 0.0008). However, stage of pericardial disease at diagnosis and use of diagnostic tests were not related to clinical HIV status. Similar results were obtained for serological HIV status. Most patients were treated on clinical grounds, with microbiological evidence of tuberculosis obtained in only 13 (7.0%) patients. Adjunctive corticosteroids were used in 109 (58.9%) patients, with patients having clinical HIV disease less likely to be put on them (OR 0.37, 95% CI 0.20 to 0.68). Seven patients were on antiretroviral drugs., Conclusion: Patients with suspected tuberculous pericarditis and HIV infection in Africa have greater evidence of myopericarditis, dyspnoea, and haemodynamic instability. These findings, if confirmed in other studies, may suggest more intensive management of the cardiac disease is warranted in patients with HIV-associated pericardial disease.