Polymorphisms in HLA Class II Genes Are Associated With Susceptibility to Staphylococcus aureus Infection in a White Population.

BACKGROUND: Staphylococcus aureus can cause life-threatening infections. Human susceptibility to S. aureus infection may be influenced by host genetic variation. METHODS: A genome-wide association study (GWAS) in a large health plan-based cohort included biologic specimens from 4701 culture-confirmed S. aureus cases and 45 344 matched controls; 584 535 single-nucleotide polymorphisms (SNPs) were genotyped on an array specific to individuals of European ancestry. Coverage was increased by imputation of >25 million common SNPs, using the 1000 Genomes Reference panel. In addition, human leukocyte antigen (HLA) serotypes were also imputed. RESULTS: Logistic regression analysis, performed under the assumption of an additive genetic model, revealed several imputed SNPs (eg, rs115231074: odds ratio [OR], 1.22 [P = 1.3 × 10(-10)]; rs35079132: OR, 1.24 [P = 3.8 × 10(-8)]) achieving genome-wide significance on chromosome 6 in the HLA class II region. One adjacent genotyped SNP was nearly genome-wide significant (rs4321864: OR, 1.13; P = 8.8 × 10(-8)). These polymorphisms are located near the genes encoding HLA-DRA and HLA-DRB1. Results of further logistic regression analysis, in which the most significant GWAS SNPs were conditioned on HLA-DRB1*04 serotype, showed additional support for the strength of association between HLA class II genetic variants and S. aureus infection. CONCLUSIONS: Our study results are the first reported evidence of human genetic susceptibility to S. aureus infection.

Racial-ethnic differences in midtrimester maternal serum levels of angiogenic and antiangiogenic factors.

BACKGROUND: Little is known about racial-ethnic differences in the distribution of maternal serum levels of angiogenic and antiangiogenic factors and their associations with early-onset preeclampsia. OBJECTIVE: We sought to investigate the distribution of midtrimester maternal serum levels of placental growth factor, soluble endoglin, and soluble vascular endothelial growth factor receptor 1 and their associations with early-onset preeclampsia in whites, Hispanics, and blacks. STUDY DESIGN: A population-based nested case-control design was used to identify cases and controls of white, Hispanic, and black origin from a 2000 through 2007 live-birth cohort in 5 southern California counties. Cases included 197 women (90 whites, 67 Hispanics, and 40 blacks) with early-onset preeclampsia defined as hypertension and proteinuria with onset <32 weeks according to hospital records. Controls included a random sample of 2363 women without early-onset preeclampsia. Maternal serum specimens collected at 15-20 weeks' gestation as part of routine prenatal screening were tested for placental growth factor, soluble endoglin, and soluble vascular endothelial growth factor receptor 1. Serum levels of the 3 factors were log-normally distributed. Adjusted natural logarithmic means were compared between cases and controls and between racial-ethnic groups. Odds ratios and 95% confidence intervals derived from logistic regression models were calculated to measure the magnitude of the associations. RESULTS: Cases showed lower adjusted logarithmic means of placental growth factor but higher adjusted logarithmic means of soluble endoglin than controls across all 3 groups (P < .05). Cases also had higher adjusted means of soluble vascular endothelial growth factor receptor 1 than controls in whites (7.75 vs 7.52 log pg/mL, P < .05) and Hispanics (7.73 vs 7.40 log pg/mL, P < .05) but not in blacks (7.85 vs 7.69 log pg/mL, P = .47). Blacks were found to have higher levels of placental growth factor in both cases and controls when compared to whites and Hispanics (adjusted means: 4.69 and 5.20 log pg/mL in blacks, 4.08 and 4.78 log pg/mL in whites, and 3.89 and 4.70 log pg/mL in Hispanics, respectively, P < .05). Hispanic cases had the highest adjusted mean of soluble endoglin compared to white and black cases (9.24, 9.05, and 8.93 log pg/mL, respectively, P < .05). The weakest association of early-onset preeclampsia with placental growth factor and soluble endoglin was observed in blacks. The adjusted odds ratio per log pg/mL increase of the 2 analytes were 0.219 (95% confidence interval, 0.124-0.385) and 5.02 (95% confidence interval, 2.56-9.86) in blacks in comparison to 0.048 (95% confidence interval, 0.026-0.088) and 36.87 (95% confidence interval, 17.00-79.96) in whites (P < .05) and 0.028 (95% confidence interval, 0.013-0.060) and 86.68 (95% confidence interval, 31.46-238.81) in Hispanics (P < .05), respectively. As for soluble vascular endothelial growth factor receptor 1, the association was not significantly different among the racial-ethnic groups. CONCLUSION: Racial-ethnic differences were observed in the distribution of midtrimester maternal levels of placental growth factor and soluble endoglin and in the associations with early-onset preeclampsia. These differences should be considered in future studies to improve etiologic and prognostic understanding of early-onset preeclampsia.

Neonatal cytokines and chemokines and risk of Autism Spectrum Disorder: the Early Markers for Autism (EMA) study: a case-control study.

BACKGROUND: Biologic markers of infection and inflammation have been associated with Autism Spectrum Disorders (ASD) but prior studies have largely relied on specimens taken after clinical diagnosis. Research on potential biologic markers early in neurodevelopment is required to evaluate possible causal pathways and screening profiles. OBJECTIVE: To investigate levels of cytokines and chemokines in newborn blood specimens as possible early biologic markers for autism. METHODS: We conducted a population-based case-control study nested within the cohort of infants born from July 2000 to September 2001 to women who participated in the prenatal screening program in Orange County, California, USA. The study population included children ascertained from the California Department of Developmental Services with Autism Spectrum Disorder (ASD, n = 84), or developmental delay but not ASD (DD, n = 49), and general population controls randomly sampled from the birth certificate files and frequency matched to ASD cases on sex, birth month and birth year (GP, n = 159). Cytokine and chemokine concentrations were measured in archived neonatal blood specimens collected for routine newborn screening. RESULTS: Cytokines were not detected in the vast majority of newborn samples regardless of case or control status. However, the chemokine monocyte chemotactic protein-1 (MCP-1) was elevated and the chemokine Regulated upon Activation Normal T-Cell Expressed and Secreted (RANTES) was decreased in ASD cases compared to GP controls. The chemokines macrophage inflammatory protein-1alpha (MIP-1α) and RANTES were decreased in children with DD compared to GP controls. CONCLUSION: Measurement of immune system function in the first few days of life may aid in the early identification of abnormal neurodevelopment and shed light on the biologic mechanisms underlying normal neurodevelopment.

Levels of cotinine in dried blood specimens from newborns as a biomarker of maternal smoking close to the time of delivery.

The precise quantitation of smoking during pregnancy is difficult in retrospective studies. Routinely collected blood specimens from newborns, stored as dried blood spots, may provide a low-cost method to objectively measure maternal smoking close to the time of delivery. This article compares cotinine levels in dried blood spots to those in umbilical cord blood to assess cotinine in dried blood spots as a biomarker of maternal smoking close to the time of delivery. The California Genetic Disease Screening Program provided dried blood spots from 428 newborns delivered in 2001-2003 with known umbilical cord blood cotinine levels. Cotinine in dried blood spots was measured in 6.35--mm punches by using liquid chromatography--tandem mass spectrometry (quantitation limit, 3.1 ng/mL). Repeated measures of cotinine in dried blood spots were highly correlated (R(2) = 0.99, P < 0.001) among 100 dried blood spots with cotinine quantitated in 2 separate punches. Linear regression revealed that cotinine levels in dried blood spots were slightly lower than those in umbilical cord blood and predicted umbilical cord blood cotinine levels well (ß = 0.95, R(2) = 0.80, and P < 0.001 for both cotinine levels in log10 scale). When defining active smoking as a cotinine level of 10 ng/mL or more and using umbilical cord blood cotinine as the criterion standard, we found that measurements of cotinine in dried blood spots had high sensitivity (92.3%) and specificity (99.7%) in the prediction of maternal active smoking. Cotinine levels in dried blood spots are an accurate biomarker of maternal smoking close to the time of delivery.

California Very Preterm Birth Study: design and characteristics of the population- and biospecimen bank-based nested case-control study.

Very preterm birth (VPTB) is a leading cause of infant mortality, morbidity and racial disparity in the US. The underlying causes of VPTB are multiple and poorly understood. The California Very Preterm Birth Study was conducted to discover maternal and infant genetic and environmental factors associated with VPTB. This paper describes the study design, population, data and specimen collection, laboratory methods and characteristics of the study population. Using a large, population-based cohort created through record linkage of livebirths delivered from 2000 to 2007 in five counties of southern California, and existing data and banked specimens from statewide prenatal and newborn screening, 1100 VPTB cases and 796 control mother-infant pairs were selected for study (385/200 White, 385/253 Hispanic and 330/343 Black cases/controls, respectively). Medical record abstraction of cases was conducted at over 50 hospitals to identify spontaneous VPTB, improve accuracy of gestational age, obtain relevant clinical data and exclude cases that did not meet eligibility criteria. VPTB was defined as birth at <32 weeks in Whites and Hispanics and <34 weeks in Blacks. Approximately 55% of all VPTBs were spontaneous and 45% had medical indications or other exclusions. Of the spontaneous VPTBs, approximately 41% were reported to have chorioamnionitis. While the current focus of the California Very Preterm Birth Study is to assess the role of candidate genetic markers on spontaneous VPTB, its design enables the pursuit of other research opportunities to identify social, clinical and biological determinants of different types of VPTB with the ultimate aim of reducing infant mortality, morbidity and racial disparities in these health outcomes in the US and elsewhere.

Excess mortality among HIV-infected patients diagnosed with substance use dependence or abuse receiving care in a fully integrated medical care program.

BACKGROUND: We examined the association between substance use (SU) disorder and mortality among HIV-infected patients in a large, private medical care program. METHODS: In a retrospective cohort design, HIV-infected patients (≥14 years old) from a large health plan (Northern California) were studied to examine mortality associated with diagnosis of SU dependence or abuse over an 11-year period. RESULTS: At study entry or during follow-up, 2,279 (25%) of 9,178 HIV-infected patients had received a diagnosis of SU disorder. Diagnoses were categorized as alcohol dependence/abuse only, illicit drugs only, or both. Cause of death differed by the category of SU diagnosis. Mortality rates ranged from 35.5 deaths per 1,000 person-years in patients with an SU disorder to 17.5 deaths among patients without an SU disorder. Regression results indicated mortality risk was significantly higher in all categories of SU disorder compared to no SU diagnosis (hazard ratios ranging from 1.65 to 1.67) after adjustment for SU treatment and confounders. CONCLUSIONS: A diagnosis of SU dependence/abuse is associated with higher mortality among HIV-infected patients for whom access to medical services is not a significant factor.

Association between second-generation antipsychotics and newly diagnosed treated diabetes mellitus: does the effect differ by dose?

BACKGROUND: The benefits of some second-generation antipsychotics (SGAs) must be weighed against the increased risk for diabetes mellitus. This study examines whether the association between SGAs and diabetes differs by dose. METHODS: Patients were ≥18 years of age from three US healthcare systems and exposed to an SGA for ≥45 days between November 1, 2002 and March 31, 2005. Patients had no evidence of diabetes before index date and no previous antipsychotic prescription filled within 3 months before index date.49,946 patients were exposed to SGAs during the study period. Person-time exposed to antipsychotic dose (categorized by tertiles for each drug) was calculated. Newly treated diabetes was identified using pharmacy data to determine patients exposed to anti-diabetic therapies. Adjusted hazard ratios for diabetes across dose tertiles of SGA were calculated using the lowest dose tertile as reference. RESULTS: Olanzapine exhibited a dose-dependent relationship for risk for diabetes, with elevated and progressive risk across intermediate (diabetes rate per 100 person-years = 1.9; adjusted Hazard Ratio (HR), 1.7, 95% confidence interval (CI), 1.0-3.1) and top tertile doses (diabetes rate per 100 person-years = 2.7; adjusted HR, 2.5, 95% CI, 1.4-4.5). Quetiapine and risperidone exhibited elevated risk at top dose tertile with no evidence of increased risk at intermediate dose tertile. Unlike olanzapine, quetiapine, and risperidone, neither aripiprazole nor ziprasidone were associated with risk of diabetes at any dose tertile. CONCLUSIONS: In this large multi-site epidemiologic study, within each drug-specific stratum, the risk of diabetes for persons exposed to olanzapine, risperidone, and quetiapine was dose-dependent and elevated at therapeutic doses. In contrast, in aripiprazole-specific and ziprasidone-specific stratum, these newer agents were not associated with an increased risk of diabetes and dose-dependent relationships were not apparent. Although, these estimates should be interpreted with caution as they are imprecise due to small numbers.

Daily intake of antioxidants in relation to survival among adult patients diagnosed with malignant glioma.

BACKGROUND: Malignant glioma is a rare cancer with poor survival. The influence of diet and antioxidant intake on glioma survival is not well understood. The current study examines the association between antioxidant intake and survival after glioma diagnosis. METHODS: Adult patients diagnosed with malignant glioma during 1991-1994 and 1997-2001 were enrolled in a population-based study. Diagnosis was confirmed by review of pathology specimens. A modified food-frequency questionnaire interview was completed by each glioma patient or a designated proxy. Intake of each food item was converted to grams consumed/day. From this nutrient database, 16 antioxidants, calcium, a total antioxidant index and 3 macronutrients were available for survival analysis. Cox regression estimated mortality hazard ratios associated with each nutrient and the antioxidant index adjusting for potential confounders. Nutrient values were categorized into tertiles. Models were stratified by histology (Grades II, III, and IV) and conducted for all (including proxy) subjects and for a subset of self-reported subjects. RESULTS: Geometric mean values for 11 fat-soluble and 6 water-soluble individual antioxidants, antioxidant index and 3 macronutrients were virtually the same when comparing all cases (n=748) to self-reported cases only (n=450). For patients diagnosed with Grade II and Grade III histology, moderate (915.8-2118.3 mcg) intake of fat-soluble lycopene was associated with poorer survival when compared to low intake (0.0-914.8 mcg), for self-reported cases only. High intake of vitamin E and moderate/high intake of secoisolariciresinol among Grade III patients indicated greater survival for all cases. In Grade IV patients, moderate/high intake of cryptoxanthin and high intake of secoisolariciresinol were associated with poorer survival among all cases. Among Grade II patients, moderate intake of water-soluble folate was associated with greater survival for all cases; high intake of vitamin C and genistein and the highest level of the antioxidant index were associated with poorer survival for all cases. CONCLUSIONS: The associations observed in our study suggest that the influence of some antioxidants on survival following a diagnosis of malignant glioma are inconsistent and vary by histology group. Further research in a large sample of glioma patients is needed to confirm/refute our results.

Differences in Prenatal Tobacco Exposure Patterns among 13 Race/Ethnic Groups in California.

Prenatal tobacco exposure is a significant, preventable cause of childhood morbidity, yet little is known about exposure risks for many race/ethnic subpopulations. We studied active smoking and environmental tobacco smoke (ETS) exposure in a population-based cohort of 13 racially/ethnically diverse pregnant women: white, African American, Hispanic, Native American, including nine Asian/Pacific Islander subgroups: Chinese, Japanese, Korean, Filipino, Cambodian, Vietnamese, Laotian, Samoan, and Asian Indians (N = 3329). Using the major nicotine metabolite, cotinine, as an objective biomarker, we analyzed mid-pregnancy serum from prenatal screening banked in 1999⁻2002 from Southern California in an effort to understand differences in tobacco exposure patterns by race/ethnicity, as well as provide a baseline for future work to assess secular changes and longer-term health outcomes. Prevalence of active smoking (based on age- and race-specific cotinine cutpoints) was highest among African American, Samoan, Native Americans and whites (6.8⁻14.1%); and lowest among Filipinos, Chinese, Vietnamese and Asian Indians (0.3⁻1.0%). ETS exposure among non-smokers was highest among African Americans and Samoans, followed by Cambodians, Native Americans, Vietnamese and Koreans, and lowest among Filipinos, Japanese, whites, and Chinese. At least 75% of women had detectable cotinine. While for most groups, levels of active smoking corresponded with levels of ETS, divergent patterns were also found. For example, smoking prevalence among white women was among the highest, but the group's ETS exposure was low among non-smokers; while Vietnamese women were unlikely to be active smokers, they experienced relatively high ETS exposure. Knowledge of race/ethnic differences may be useful in assessing disparities in health outcomes and creating successful tobacco interventions.

Older age and the response to and tolerability of antiretroviral therapy.

BACKGROUND: The unique health needs of a growing older adult population infected with human immunodeficiency virus (HIV) require study, especially in terms of the response to and tolerability of highly active antiretroviral therapy (HAART). METHODS: Changes in HIV clinical markers after HAART initiation were compared among 2259 patients aged 18 to 39 years (reference group), 1834 patients aged 40 to 49 years, and 997 patients 50 years or older enrolled in an integrated health care system. RESULTS: Patients 50 years or older were more likely to achieve HIV RNA levels of less than 500 copies/mL within 1 year of HAART initiation (hazard ratio [HR], 1.15; P =.009), but adjustment for adherence attenuated this finding (HR, 1.03; P =.59). Subsequent HIV RNA level rebound (to > or =1000 copies/mL) was less likely among patients aged 40 to 49 years (HR, 0.81; P =.01), which persisted after adjustment for adherence (HR, 0.79; P =.004). In year 1 of HAART, younger patients had larger CD4 T-cell count increases (131.8, 121.3, and 111.8 CD4 T cells/microL per year among patients aged 18-39, 40-49, and > or =50 years, respectively; P =.046). In years 2 through 6, older patients had larger CD4 T-cell count increases (4.5, 11.6, and 9.7 CD4 T cells/microL per year among patients aged 18-39, 40-49, and > or =50 years, respectively; P =.04). After adjustment for adherence, age differences in CD4 T-cell count changes remained in year 1 (P =.02) but not in years 2 through 6 (P =.08). Other factors, including comorbidities, had no effect on study results. Metabolic (glucose and lipids), hematologic (absolute neutrophils and hemoglobin), and renal (creatinine) abnormalities were more likely among older patients. CONCLUSION: Despite a higher risk of adverse events, patients 50 years or older sustained high therapy adherence to maintain improved virological outcomes and to compensate for their early blunted CD4 T-cell count response compared with younger patients.

Cross-genetic determination of maternal and neonatal immune mediators during pregnancy.

BACKGROUND: The immune system plays a fundamental role in development during pregnancy and early life. Alterations in circulating maternal and neonatal immune mediators have been associated with pregnancy complications as well as susceptibility to autoimmune and neurodevelopmental conditions in later life. Evidence suggests that the immune system in adults not only responds to environmental stimulation but is also under strong genetic control. METHODS: This is the first genetic study of > 700 mother-infant pairs to analyse the circulating levels of 22 maternal mid-gestational serum-derived and 42 neonatal bloodspot-derived immune mediators (cytokines/chemokines) in the context of maternal and fetal genotype. We first estimated the maternal and fetal genome-wide SNP-based heritability (h2g) for each immune molecule and then performed genome-wide association studies (GWAS) to identify specific loci contributing to individual immune mediators. Finally, we assessed the relationship between genetic immune determinants and ASD outcome. RESULTS: We show maternal and neonatal cytokines/chemokines displaying genetic regulation using independent methodologies. We demonstrate that novel fetal loci for immune function independently affect the physiological levels of maternal immune mediators and vice versa. The cross-associated loci are in distinct genomic regions compared with individual-specific immune mediator loci. Finally, we observed an interaction between increased IL-8 levels at birth, autism spectrum disorder (ASD) status, and a specific maternal genotype. CONCLUSIONS: Our results suggest that maternal and fetal genetic variation influences the immune system during pregnancy and at birth via distinct mechanisms and that a better understanding of immune factor determinants in early development may shed light on risk factors for developmental disorders.

Prenatal Serum Concentrations of Brominated Flame Retardants and Autism Spectrum Disorder and Intellectual Disability in the Early Markers of Autism Study: A Population-Based Case-Control Study in California.

BACKGROUND: Prior studies suggest neurodevelopmental impacts of polybrominated diphenyl ethers (PBDEs), but few have examined diagnosed developmental disorders. OBJECTIVES: Our aim was to determine whether prenatal exposure to brominated flame retardants (BFRs) is associated with autism spectrum disorder (ASD) or intellectual disability without autism (ID). METHODS: We conducted a population-based case-control study including children with ASD (n=545) and ID (n=181) identified from the California Department of Developmental Services and general population (GP) controls (n=418) from state birth certificates. ASD cases were matched to controls by sex, birth month, and birth year. Concentrations of 10 BFRs were measured in maternal second trimester serum samples stored from routine screening. Logistic regression was used to calculate crude and adjusted odds ratios (AOR) for associations with ASD, and separately for ID, compared with GP controls, by quartiles of analyte concentrations in primary analyses. RESULTS: Geometric mean concentrations of five of the six congeners with ≥55% of samples above the limit of detection were lower in mothers of children with ASD or ID than in controls. In adjusted analyses, inverse associations with several congeners were found for ASD relative to GP (e.g., quartile 4 vs. 1, BDE-153: AOR=0.56, 95% CI: 0.38, 0.84). When stratified by child sex (including 99 females with ASD, 77 with ID, and 73 with GP), estimates were consistent with overall analyses in boys, but in the opposite direction among girls, particularly for BDE-28 and -47 (AOR=2.58, 95% CI: 0.86, 7.79 and AOR=2.64, 95% CI: 0.97, 7.19, respectively). Similar patterns overall and by sex were observed for ID. CONCLUSIONS: Contrary to expectation, higher PBDE concentrations were associated with decreased odds of ASD and ID, though not in girls. These findings require confirmation but suggest potential sexual dimorphism in associations with prenatal exposure to BFRs. https://doi.org/10.1289/EHP1079.

Independent Maternal and Fetal Genetic Effects on Midgestational Circulating Levels of Environmental Pollutants.

Maternal exposure to environmental pollutants could affect fetal brain development and increase autism spectrum disorder (ASD) risk in conjunction with differential genetic susceptibility. Organohalogen congeners measured in maternal midpregnancy blood samples have recently shown significant, but negative associations with offspring ASD outcome. We report the first large-scale maternal and fetal genetic study of the midpregnancy serum levels of a set of 21 organohalogens in a subset of 790 genotyped women and 764 children collected in California by the Early Markers for Autism (EMA) Project. Levels of PCB (polychlorinated biphenyl) and PBDE (polybrominated diphenyl ether) congeners showed high maternal and fetal estimated SNP-based heritability (h2g ) accounting for 39-99% of the total variance. Genome-wide association analyses identified significant maternal loci for p,p'-DDE (P = 7.8 × 10-11) in the CYP2B6 gene and for BDE-28 (P = 3.2 × 10-8) near the SH3GL2 gene, both involved in xenobiotic and lipid metabolism. Fetal genetic loci contributed to the levels of BDE-100 (P = 4.6 × 10-8) and PCB187 (P = 2.8 × 10-8), near the potential metabolic genes LOXHD1 and PTPRD, previously implicated in neurodevelopment. Negative associations were observed for BDE-100, BDE153, and the sum of PBDEs with ASD, partly explained by genome-wide additive genetic effects that predicted PBDE levels. Our results support genetic control of midgestational biomarkers for environmental exposures by nonoverlapping maternal and fetal genetic determinants, suggesting that future studies of environmental risk factors should take genetic variation into consideration. The independent influence of fetal genetics supports previous hypotheses that fetal genotypes expressed in placenta can influence maternal physiology and the transplacental transfer of organohalogens.

Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up.

OBJECTIVE: To determine whether serum titers of anti-Epstein-Barr virus (EBV) antibodies are elevated in blood specimens collected up to 30 years prior to onset of multiple sclerosis (MS). METHODS: Individuals with MS were identified among members of the Kaiser Permanente Northern California health plan who participated in the multiphasic examinations administered between 1965 and 1974. Stored serum samples were used to compare anti-EBV antibody titers in 42 individuals who developed MS with age-matched and sex-matched controls. RESULTS: The geometric mean titers of antibodies to the Epstein-Barr nuclear antigen (EBNA) complex and its component EBNA-1 were significantly higher in the MS cases when compared with matched controls. The relative risk of MS associated with a 4-fold increase in antibody titers was 2.1 (95% confidence interval, 1.1-3.8) for the EBNA complex and 1.8 (95% confidence interval, 1.1-2.9) for EBNA-1. Elevations of antibody titers to the EBNA complex and EBNA-1 among MS cases first occurred between 15 to 20 years before the onset of symptoms and persisted thereafter. CONCLUSION: The elevation of anti-EBV titers is probably an early event in the pathogenesis of MS and is unlikely to be the result of an aspecific immune dysregulation.

Hospital-level rates of fluoroquinolone use and the risk of hospital-acquired infection with ciprofloxacin-nonsusceptible Pseudomonas aeruginosa.

BACKGROUND: In recent years, Pseudomonas aeruginosa has become increasingly resistant to fluoroquinolones, and fluoroquinolone use in the United States has also increased. Our objective was to determine whether higher hospital-level rates of use of ciprofloxacin, levofloxacin, and moxifloxacin antimicrobials were predictors that a higher proportion of P. aeruginosa isolates from hospital-acquired infections (hereafter, "hospital-acquired isolates") would be nonsusceptible to ciprofloxacin. METHODS: We identified all hospital-acquired isolates from 14 hospitals in the Northern California Kaiser Permanente health care delivery system between 1998 and 2003 and determined their susceptibility to ciprofloxacin. For each facility, we determined the number of days of fluoroquinolone use per 1000 patient-days, by calendar quarter. We used a logistic regression model to analyze the data, with susceptibility status as the outcome variable. Hospital-level rates of use of the 3 fluoroquinolones were the predictors of interest; we adjusted for year, for use of nonquinolone antimicrobials, and for patient variables, including the number of days spent in the hospital in the prior year and fluoroquinolone use in the prior year. The model tested whether isolates from those facilities with higher rates of use of antimicrobials were more likely to be nonsusceptible to ciprofloxacin. RESULTS: Of 6099 isolates tested, 15% were not susceptible to ciprofloxacin. The nonsusceptibility rate increased from 9% to 20% between 1998 and 2003. Both the overall rate of use at the hospital and prior patient-specific use of ciprofloxacin, levofloxacin, and moxifloxacin were found to be independent predictors that a subsequent P. aeruginosa isolate would be nonsusceptible to ciprofloxacin. CONCLUSIONS: Higher hospital-level rates of use of ciprofloxacin, levofloxacin, and moxifloxacin are each associated with an increased proportion of hospital-acquired P. aeruginosa isolates being nonsusceptible to ciprofloxacin.

Cost of Care for HIV-Infected Patients with Co-Occurring Substance Use Disorder or Psychiatric Disease: Report from a Large, Integrated Health Plan.

Background. The costs of providing care to HIV-infected (HIV+) patients with co-occurring diagnoses of substance use (SU) disorder or psychiatric disease (PD) are not well documented. It is our objective to evaluate costs in these HIV+ patients receiving care in a large health plan. Methods. We conducted a retrospective cohort study from 1995 to 2010 to compare costs of healthcare in HIV+ patients with and without co-occurring SU disorder and/or PD diagnoses. Estimates of proportional differences in costs (rate ratios) were obtained from repeated measures generalized linear regression. Models were stratified by cost category (e.g., inpatient, outpatient). Results. Mean total healthcare costs per patient per year were higher in HIV+ patients diagnosed with SU disorder or PD compared to HIV+ patients without these comorbid conditions. After controlling for confounders, total mean costs remained significantly higher in patients diagnosed with SU disorder (RR = 1.24, 95% CI = 1.18-1.31) or PD (RR = 1.19, 95% CI = 1.15-1.24). Mean outpatient care costs were significantly greater in patients with both SU disorder and PD (RR = 1.52, 95% CI = 1.41-1.64). Conclusions. Given these higher expenditures in the care of HIV+ patients with comorbid SU disorder and/or PD, greater efforts to facilitate SU disorder or PD treatment initiation and persistence could provide substantial savings.

Factors associated with treatment initiation for psychiatric and substance use disorders among persons with HIV.

OBJECTIVE: Prior studies of individuals with HIV infection have found that accessing psychiatric and substance abuse treatment when needed can improve health and prolong life, yet little is known about factors associated with treatment initiation. METHODS: In a retrospective cohort design including individuals with HIV infection (≥14 years old) in an integrated health care system in Northern California, this study included 822 patients with a major psychiatric diagnosis and 1,624 with a substance use disorder diagnosis. Data were extracted from a regional HIV registry and computerized databases. RESULTS: Twenty-four percent (N=198) of study patients with psychiatric diagnoses and 15% (N=245) with substance abuse or dependence received one or more specialty care visits within 12 months of diagnosis. Among patients with a psychiatric diagnosis, significant predictors of visiting a psychiatry clinic included not having an AIDS diagnosis at baseline or before the study (p=.049), having a diagnosis of major depression (p=.013), having a diagnosis of bipolar disorder (p<.001), and receiving a psychiatric diagnosis in 1996 versus later years of the study (p<.01). Among patients with a substance use disorder, significant predictors of initiating substance abuse treatment included age <30 (p=.015) and being in the HIV transmission risk group of injection drug use (p<.001). CONCLUSIONS: Clinical, diagnostic, and demographic factors were associated with specialty care treatment initiation in this sample of individuals with HIV infection and substance use or psychiatric disorders. Developing strategies to enhance treatment initiation has the potential to improve outcomes for individuals with HIV infection.

A genome-wide survey of transgenerational genetic effects in autism.

Effects of parental genotype or parent-offspring genetic interaction are well established in model organisms for a variety of traits. However, these transgenerational genetic models are rarely studied in humans. We have utilized an autism case-control study with 735 mother-child pairs to perform genome-wide screening for maternal genetic effects and maternal-offspring genetic interaction. We used simple models of single locus parent-child interaction and identified suggestive results (P<10(-4)) that cannot be explained by main effects, but no genome-wide significant signals. Some of these maternal and maternal-child associations were in or adjacent to autism candidate genes including: PCDH9, FOXP1, GABRB3, NRXN1, RELN, MACROD2, FHIT, RORA, CNTN4, CNTNAP2, FAM135B, LAMA1, NFIA, NLGN4X, RAPGEF4, and SDK1. We attempted validation of potential autism association under maternal-specific models using maternal-paternal comparison in family-based GWAS datasets. Our results suggest that further study of parental genetic effects and parent-child interaction in autism is warranted.

Mortality after diagnosis of psychiatric disorders and co-occurring substance use disorders among HIV-infected patients.

We examined the associations between psychiatric diagnoses, substance use disorders, health services, and mortality among 9751 HIV-infected patients (≥14 years old) in a large, private medical care program, in a retrospective cohort design over a 12-year period. All study data were extracted from computerized clinical and administrative databases. Results showed that 25.4% (n = 2472) of the 9751 study subjects had received a psychiatric diagnosis (81.1% had major depression, 17.1% had panic disorder, 14.2% had bipolar disorder, and 8.1% had anorexia/bulimia); and 25.5% (n = 2489) had been diagnosed with substance use disorder; 1180 (12.1%) patients had received both psychiatric and substance diagnoses. In comparison to patients with neither a psychiatric diagnosis nor a SU diagnosis, the highest risk of death was found among patients with dual psychiatric and substance use diagnoses who had no psychiatric treatment visits and no substance treatment (relative hazards [RH] = 4.17, 95% confidence interval [CI] = 2.35 to 7.40). Among dually diagnosed patients, receiving psychiatric and/or substance use disorder treatment somewhat reduced the risk of death compared to patients with neither diagnosis. The lowest risks of death were observed among patients with a single diagnosis who had received corresponding treatment. Our study findings suggest that screening for psychiatric and substance problems at the initiation and during the course of HIV/AIDS treatment and providing psychiatric and substance use disorder treatment may extend life for these vulnerable patients.

Medication error in the care of HIV/AIDS patients: electronic surveillance, confirmation, and adverse events.

BACKGROUND: Medication error occurring during the care of HIV-infected patients may lead to treatment failure, drug toxicity, or even death. OBJECTIVE: The objective of this study was to ascertain and confirm 5 categories of medication error in the care of HIV-infected patients. RESEARCH DESIGN: This study was a retrospective study to describe the occurrence of preventable medication error and to determine if adverse events were associated with confirmed errors. A roster of medications for each category of potential errors was created. Computerized pharmacy records were scanned for all dispensing of these medications. Potential errors were confirmed by medical records abstraction. For the incorrect dosing, coadministration of contraindicated medications, and antiretroviral monotherapy error categories, random samples were chart reviewed for confirmation. For the remaining 2 error categories, all potential errors were chart reviewed. The positive predictive value (PPV) of potential errors, the incidence of confirmed error among all new prescription orders filled and the patient characteristics predicting likelihood of error confirmation were estimated for each error category. SUBJECTS: The study sample involved 5473 HIV-infected patients of the Kaiser Permanente Northern California (KPNC) health plan. RESULTS: Among the 5 error categories, PPVs ranged from a high of 80% for coadministration of contraindicated medications to <1% for antiretroviral monotherapy. Incidence of confirmed errors was 9.80 errors per 1000 new prescriptions dispensed for incorrect dosing, 9.51 errors per 1000 for contraindicated medications, and <1.00 for all other categories. Adverse events associated with confirmed errors were observed only in the contraindicated medications error category. The likelihood of a contraindicated medications error was significantly increased among patients >or=50 years of age and decreased among black patients. CONCLUSIONS: Use of electronic pharmacy records to ascertain true medication errors appears most reliable when conducting surveillance for contraindicated medications errors and less reliable for other error categories. Lack of confirmation is likely the result of patients' lack of adherence to drug regimens or providers' intentional deviation from accepted prescribing guidelines. Only confirmed contraindicated medications errors appear to be linked to adverse events.