Paige L. Williams

Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors

Abstract Objective: To summarise quantitatively the association between moderate alcohol intake and biological markers of risk of coronary heart disease and to predict how these changes would lower the risk. Design: Meta-analysis of all experimental studies that assessed the effects of moderate alcohol intake on concentrations of high density lipoprotein cholesterol, apolipoprotein A I, fibrinogen, triglycerides, and other biological markers previously found to be associated with risk of coronary heart disease. Participants: Men and women free of previous chronic disease and who were not dependent on alcohol Studies were included in which biomarkers were assessed before and after participants consumed up to 100 g of alcohol a day. Interventions: Alcohol as ethanol, beer, wine, or spirits. Main outcome measures: Changes in concentrations of high density lipoprotein cholesterol, apolipoprotein A I, Lp(a) lipoprotein, triglycerides, tissue type plasminogen activator activity, tissue type plasminogen activator antigen, insulin, and glucose after consuming an experimental dose of alcohol for 1 to 9 weeks; a shorter period was accepted for studies of change in concentrations of fibrinogen, factor VII, von Willebrand factor, tissue type plasminogen activator activity, and tissue type plasminogen activator antigen. Results: 61 data records were abstracted from 42 eligible studies with information on change in biological markers of risk of coronary heart disease. An experimental dose of 30 g of ethanol a day increased concentrations of high density lipoprotein cholesterol by 3.99 mg/dl (95% confidence interval 3.25 to 4.73), apolipoprotein A I by 8.82 mg/dl (7.79 to 9.86), and triglyceride by 5.69 mg/dl (2.49 to 8.89). Several haemostatic factors related to a thrombolytic profile were modestly affected by alcohol On the basis of published associations between these biomarkers and risk of coronary heart disease 30 g of alcohol a day would cause an estimated reduction of 24.7% in risk of coronary heart disease. Conclusions: Alcohol intake is causally related to lower risk of coronary heart disease through changes in lipids and haemostatic factors. Key messages Results from observational studies provide strong evidence that moderate alcohol intake lowers risk of coronary heart disease Short term trials of alcohol intake show significant changes in concentrations of lipids and clotting factors The changes in concentrations of high density lipoprotein cholesterol, fibrinogen, and triglycerides associated with an intake of 30 g of alcohol a day should reduce risk of coronary disease by 24.7% Alcohol intake may be causally related to lower risk of coronary heart disease through changes in lipids and haemostatic factors

Clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion.

Objective:Clinical predictors for acute respiratory distress syndrome (ARDS) have been studied in few prospective studies. Although transfusions are common in the intensive care unit, the role of submassive transfusion in non-trauma-related ARDS has not been studied. We describe here the clinical predictors of ARDS risk and mortality including the role of red cell transfusion. Design:Observational prospective cohort. Setting:Intensive care unit of Massachusetts General Hospital. Patients:We studied 688 patients with sepsis, trauma, aspiration, and hypertransfusion. Interventions:None. Measurements and Main Results:Two hundred twenty-one (32%) subjects developed ARDS with a 60-day mortality rate of 46%. Significant predictors for ARDS on multivariate analyses included trauma (adjusted odds ratio [ORadj] 0.22, 95% confidence interval [CI] 0.09–0.53), diabetes (ORadj 0.58, 95% CI 0.36–0.92), direct pulmonary injury (ORadj 3.78, 95% CI 2.45–5.81), hematologic failure (ORadj 1.84, 95% CI 1.05–3.21), transfer from another hospital (ORadj 2.08, 95% CI 1.33–3.25), respiratory rate >33 breaths/min (ORadj 2.39, 95% CI 1.51–3.78), hematocrit >37.5% (ORadj 1.77, 95% CI 1.14–2.77), arterial pH <7.33 (ORadj 2.00, 95% CI 1.31–3.05), and albumin ≤2.3 g/dL (ORadj 1.80, 95% CI 1.18–2.73). Packed red blood cell transfusion was associated with ARDS (ORadj 1.52, 95% CI 1.00–2.31, p = .05). Significant predictors for mortality in ARDS included age (ORadj 1.96, 95% CI 1.50–2.53), Acute Physiology and Chronic Health Evaluation III score (ORadj 1.78, 95% CI 1.16–2.73), trauma (ORadj 0.075, 95% CI 0.006–0.96), corticosteroids before ARDS (ORadj 4.65, 95% CI 1.47–14.7), and arterial pH <7.22 (ORadj 2.32, 95% CI 1.02–5.25). Packed red blood cell transfusions were associated with increased mortality in ARDS (ORadj 1.10 per unit transfused; 95% CI 1.04–1.17) with a significant dose-dependent response (p = .02). Conclusions:Important predictors for the development of and mortality in ARDS were identified. Packed red blood cell transfusion was associated with an increased development of and increased mortality in ARDS.

Characterization of Phthalate Exposure among Pregnant Women Assessed by Repeat Air and Urine Samples

Background Although urinary concentrations of phthalate metabolites are frequently used as biomarkers in epidemiologic studies, variability during pregnancy has not been characterized. Methods We measured phthalate metabolite concentrations in spot urine samples collected from 246 pregnant Dominican and African-American women. Twenty-eight women had repeat urine samples collected over a 6-week period. We also analyzed 48-hr personal air samples (n = 96 women) and repeated indoor air samples (n = 32 homes) for five phthalate diesters. Mixed-effects models were fit to evaluate reproducibility via intraclass correlation coefficients (ICC). We evaluated the sensitivity and specificity of using a single specimen versus repeat samples to classify a woman’s exposure in the low or high category. Results Phthalates were detected in 85–100% of air and urine samples. ICCs for the unadjusted urinary metabolite concentrations ranged from 0.30 for mono-ethyl phthalate to 0.66 for monobenzyl phthalate. For indoor air, ICCs ranged from 0.48 [di-2-ethylhexyl phthalate (DEHP)] to 0.83 [butylbenzyl phthalate (BBzP)]. Air levels of phthalate diesters correlated with their respective urinary metabolite concentrations for BBzP (r = 0.71), di-isobutyl phthalate (r = 0.44), and diethyl phthalate (DEP; r = 0.39). In women sampled late in pregnancy, specific gravity appeared to be more effective than creatinine in adjusting for urine dilution. Conclusions Urinary concentrations of DEP and DEHP metabolites in pregnant women showed lower reproducibility than metabolites for di-n-butyl phthalate and BBzP. A single indoor air sample may be sufficient to characterize phthalate exposure in the home, whereas urinary phthalate biomarkers should be sampled longitudinally during pregnancy to minimize exposure misclassification.

Predictors of Adherence to Antiretroviral Medications in Children and Adolescents With HIV Infection

BACKGROUND. Most evaluations of adherence to antiretroviral therapy in children with HIV infection have focused on validation of adherence measures via their association with virological outcomes. However, few studies have fully explored associations with other factors to guide development of adherence interventions. METHODS. In this study, we examined the relationship of self-reported medication adherence to health, demographic, and psychosocial characteristics of children and their caregivers, using data from an ongoing multicenter prospective observational study of long-term outcomes of HIV infection conducted by the Pediatric AIDS Clinical Trials Group. Child and caregiver characteristics were evaluated for association with adherence via univariate and multiple logistic regression models. RESULTS. Of the 2088 children and adolescents, 84% reported complete adherence to antiretroviral therapy medications over the past 3 days. The median viral load was ∼10 times higher among nonadherent than adherent children, and the strength of this association increased with age. Factors associated with at least marginally significant increases in nonadherence in a multiple logistic regression model included increasing age in years, female gender, detectable HIV viral load, occurrence of recent stressful life events, repeating a grade in school, self-assessment of adherence by the subject, and diagnosis of depression or anxiety. Having an adult other than the biological parent as the primary caregiver, using a buddy system to remember to take antiretroviral therapy medications, higher caregiver education level, previous adherence assessments, and taking antipsychotic medications were each associated with improved adherence. After controlling for these characteristics, there was no significant association of adherence with race, knowledge of HIV status, medication burden, CD4 percentage, or current antiretroviral therapy. CONCLUSIONS. Rates of self-reported adherence were relatively high and were influenced by multiple child and family characteristics. These findings identify targets for adherence interventions and highlight the importance of evaluating and supporting the family environment to optimize adherence.

Declines in mortality rates and changes in causes of death in HIV-1-infected children during the HAART era.

Context:Introduction of highly active antiretroviral therapy has significantly decreased mortality in HIV-1-infected adults and children. Although an increase in non-HIV-related mortality has been noted in adults, data in children are limited. Objectives:To evaluate changes in causes and risk factors for death among HIV-1-infected children in Pediatric AIDS Clinical Trials Group 219/219C. Design, Setting, and Participants:Multicenter, prospective cohort study designed to evaluate long-term outcomes in HIV-1-exposed and infected US children. There were 3553 HIV-1-infected children enrolled and followed up between April 1993 and December 2006, with primary cause of mortality identified in the 298 observed deaths. Main Outcome Measures:Mortality rates per 100 child-years overall and by demographic factors; survival estimates by birth cohort; and hazard ratios for mortality by various demographic, health, and antiretroviral treatment factors were determined. Results:Among 3553 HIV-1-infected children followed up for a median of 5.3 years, 298 deaths occurred. Death rates significantly decreased between 1994 and 2000, from 7.2 to 0.8 per 100 person-years, and remained relatively stable through 2006. After adjustment for other covariates, increased risk of death was identified for those with low CD4 and AIDS-defining illness at entry. Decreased risks of mortality were identified for later birth cohorts, and for time-dependent initiation of highly active antiretroviral therapy (hazard ratio 0.54, P < 0.001). The most common causes of death were “End-stage AIDS” (N = 48, 16%) and pneumonia (N = 41, 14%). The proportion of deaths due to opportunistic infections (OIs) declined from 37% in 1994-1996 to 24% after 2000. All OI mortality declined during the study period. However, a greater decline was noted for deaths due to Mycobacterium avium complex and cryptosporidium. Deaths from “End-stage AIDS,” sepsis and renal failure increased. Conclusions:Overall death rates declined from 1993 to 2000 but have since stabilized at rates about 30 times higher than for the general US pediatric population. Deaths due to OIs have declined, but non-AIDS-defining infections and multiorgan failure remain major causes of mortality in HIV-1-infected children.

Variability of Urinary Phthalate Metabolite and Bisphenol A Concentrations before and during Pregnancy

Background: Gestational phthalate and bisphenol A (BPA) exposure may increase the risk of adverse maternal/child health outcomes, but there are few data on the variability of urinary biomarkers before and during pregnancy. Objective: We characterized the variability of urinary phthalate metabolite and BPA concentrations before and during pregnancy and the ability of a single spot urine sample to classify average gestational exposure. Methods: We collected 1,001 urine samples before and during pregnancy from 137 women who were partners in couples attending a Boston fertility clinic and who had a live birth. Women provided spot urine samples before (n ≥ 2) and during (n ≥ 2) pregnancy. We measured urinary concentrations of monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), mono-iso-butyl phthalate, monobenzyl phthalate (MBzP), four metabolites of di-(2-ethylhexyl) phthalate (DEHP), and BPA. After adjusting for specific gravity, we characterized biomarker variability using intraclass correlation coefficients (ICCs) and conducted several surrogate category analyses to determine whether a single spot urine sample could adequately classify average gestational exposure. Results: Absolute concentrations of phthalate metabolites and BPA were similar before and during pregnancy. Variability was higher during pregnancy than before pregnancy for BPA and MBzP, but similar during and before pregnancy for MBP, MEP, and ΣDEHP. During pregnancy, MEP (ICC = 0.50) and MBP (ICC = 0.45) were less variable than BPA (ICC = 0.12), MBzP (ICC = 0.25), and ΣDEHP metabolites (ICC = 0.08). Surrogate analyses suggested that a single spot urine sample may reasonably classify MEP and MBP concentrations during pregnancy, but more than one sample may be necessary for MBzP, DEHP, and BPA. Conclusions: Urinary phthalate metabolites and BPA concentrations were variable before and during pregnancy, but the magnitude of variability was biomarker specific. A single spot urine sample adequately classified MBP and MEP concentrations during pregnancy. The present results may be related to unique features of the women studied, and replication in other pregnancy cohorts is recommended.

Long-Term Effectiveness of Highly Active Antiretroviral Therapy on the Survival of Children and Adolescents with HIV Infection: A 10-Year Follow-Up Study

BACKGROUND Previous observational studies found highly active antiretroviral therapy (HAART) to be associated with improved survival among human immunodeficiency virus (HIV)-infected children and adolescents. However, these studies had limited follow-up of HIV-infected children undergoing HAART. Given that HIV infection is chronic and that exposure to HAART is likely to be life-long, there is a need to evaluate the long-term effect of HAART on survival in this population. METHODS The study included 1236 children and adolescents who were perinatally infected with HIV, who were on study or enrolled after January 1996 in a United States-based multicenter prospective cohort study (Pediatric AIDS Clinical Trials Group 219/219C), and who were not receiving HAART at baseline; subjects were observed for a maximum of 10 years through June 2006. A weighted Cox regression model was used to estimate the effect of HAART on survival, appropriately adjusted for time-varying confounding by severity. RESULTS At the end of the 10-year follow-up period (median duration of follow-up, 6.3 years; interquartile range, 4.3-9.8 years), 70% of participants had initiated HAART. Lower CD4 cell percentages, total lymphocyte counts, and albumin levels were associated with an increased probability of initiating HAART. Eighty-five deaths were observed, and the mortality hazard ratio associated with HAART, compared with non-HAART regimens, was 0.24 after adjusting for measured confounding by severity (95% confidence interval, 0.11-0.51). CONCLUSIONS The use of HAART was highly effective in reducing mortality during the period 1996-2006 among children and adolescents infected with HIV. With improved long-term survival, continued follow-up is necessary to evaluate the effects of prolonged use of HAART on potential adverse events, immune function, growth, sexual maturation, and quality of life in this population.

Urinary bisphenol A concentrations and ovarian response among women undergoing IVF

Bisphenol A (BPA) is a synthetic chemical used in the manufacture of materials present in many common consumer products. In experimental animals, BPA caused oocyte aneuploidy and reduced production of oestradiol. In a prospective cohort study, we investigated the association between urinary BPA concentrations and ovarian response among women undergoing in vitro fertilization (IVF) at the Massachusetts General Hospital (MGH) Fertility Center. The geometric mean of two specific-gravity (SG) adjusted urinary BPA concentrations collected during each IVF cycle was used as the cycle-specific BPA exposure level. BPA concentrations were measured using online solid phase extraction coupled to isotope dilution-high-performance liquid chromatography-tandem mass spectrometry. Peak serum oestradiol was measured using the Elecsys Estradiol II immunoassay kit. Multivariable mixed effect models and Poisson regression models adjusting for correlation between multiple IVF cycles in the same woman were used to evaluate the association between urinary BPA concentrations and ovarian response, adjusting for age, BMI and day 3 follicle stimulating hormone (FSH) levels, a clinical measure of ovarian reserve. Urinary BPA concentrations were measured in 84 women (mean age 35.6 years) undergoing 112 IVF cycles; 23 women (27%) contributed more than one IVF cycle. BPA concentrations ranged from <0.4 to 25.5 microg/L (geometric mean 2.52 +/- SD 3.2); 15% of urine samples had concentrations <0.4 microg/L. Peak serum oestradiol levels correlated with the total number of oocytes retrieved per cycle (r = 0.65, p < 0.001). For each log unit increase in SG-BPA, there was an average decrease of 12% (95% CI: 4, 23%; p = 0.007) in the number of oocytes retrieved and an average decrease of 213 pg/ml (95% CI: -407, -20; p = 0.03) in peak oestradiol. BPA was detected in the urine of the majority of women undergoing IVF, and was inversely associated with number of oocytes retrieved and peak oestradiol levels.

Evidence of Interaction between Polychlorinated Biphenyls and Phthalates in Relation to Human Sperm Motility

Previously, we reported evidence of inverse associations between exposure to some polychlorinated biphenyls (PCBs) and some phthalate monoesters in relation to semen parameters, specifically sperm motility. Because humans are exposed to both phthalates and PCBs and because experimental studies suggest that PCBs may interact with glucuronidative enzymes that are responsible for phthalate metabolism, we explored the potential interaction between phthalates and PCBs in relation to human semen quality. We studied 303 men who were partners in subfertile couples seeking infertility diagnosis from the andrology laboratory at Massachusetts General Hospital. Semen parameters were dichotomized based on World Health Organization reference values, and phthalate and PCB levels were dichotomized at their respective medians. After adjusting for age and abstinence time, for below reference sperm motility there was a greater than additive interaction between monobenzyl phthalate and PCB-153 [relative excess risk due to interaction (RERI) = 1.40; 95% confidence interval (CI), 0.41–3.22], sum of PCBs (RERI = 1.24; 95% CI, 0.15–2.94), and cytochrome P450 (CYP450)-inducing PCBs (RERI = 1.30; 95% CI, 0.21–3.06). For below-reference sperm motility, there was also a greater than additive interaction between monobutyl phthalate (MBP) and PCB-153 (RERI = 1.42; 95% CI, 0.09–3.76) and CYP450-inducing PCBs (RERI = 1.87; 95% CI, 0.56–4.52) and a suggestive interaction between MBP and sum of PCBs (RERI = 1.35; 95% CI, −0.11 to 3.48). In conclusion, because there are important risk assessment and public health implications of interactions between these two ubiquitous classes of compounds, further studies need to be conducted to confirm these results and identify potential mechanisms of interactions.

Gender differences in health-related quality of life in patients with HIV/AIDS

Background: In studies evaluating the general US population, patients in primary care, and patients with chronic conditions, women consistently report poorer health-related quality of life (HRQoL) than men; however, studies evaluating HRQoL in patients with HIV/AIDS have not completely corroborated those findings. The objective of this study was to evaluate gender differences in HRQoL for participants in a large randomized trial comparing antiretroviral regimens. Methods: AIDS Clinical Trials Group (ACTG) 320 was a randomized, blinded, placebo-controlled trial comparing the 3-drug regimen of indinavir + zidovudine (or stavudine) + lamivudine with the 2-drug combination of zidovudine (or stavudine) + lamivudine in subjects with CD4 cell counts less than 200 cells/μl and no prior treatment with protease inhibitors. Nine quality of life domains scored on 0–100 scales were assessed using the ACTG QOL 601-602 Health Survey at 3 points in the trial: baseline, 24 weeks and 40 weeks. Differences between men and women in HRQoL scores were assessed using the Wilcoxon rank-sum test and generalized estimating equation (GEE) models. Results: Overall, 202 females and 976 males were randomized to one of two treatment arms. Female participants were more likely to be black or Hispanic and tended to be younger. At baseline, females reported lower HRQoL scores than males in all of the domains except social functioning, and at week 40, women scored lower in all of the domains except overall health. In repeated measures models, women were found to score lower in all HRQoL domains except overall health, with significant differences of 3.5–6.7 points in 3 of the 9 quality of life domains: physical functioning, pain, and energy/fatigue. HRQoL scores improved for participants in the study over time and in response to potent treatment, and the improvements were similar for men and women. Conclusions: Women with HIV/AIDS report substantially poorer HRQoL than men with HIV/AIDS in several HRQoL domains. However, changes in domain scores over time and in response to treatment do not differ significantly by gender, implying that changes in domain scores may be better HRQoL outcomes to compare between HIV-infected men and women in clinical trials than mean domain scores.