Edwin van Wijngaarden

Cumulative Antibiotic Exposures Over Time and the Risk of Clostridium difficile Infection

BACKGROUND Clostridium difficile infection (CDI) is a major cause of hospital-acquired diarrhea and is most commonly associated with changes in normal intestinal flora caused by administration of antibiotics. Few studies have examined the risk of CDI associated with total dose, duration, or number of antibiotics while taking into account the complex changes in exposures over time. METHODS A retrospective cohort study conducted from 1 January to 31 December 2005 among hospitalized patients 18 years or older receiving 2 or more days of antibiotics. RESULTS The study identified 10,154 hospitalizations for 7,792 unique patients and 241 cases of CDI, defined as the detection of C. difficile toxin in a diarrheal stool sample within 60 days of discharge. We observed dose-dependent increases in the risk of CDI associated with increasing cumulative dose, number of antibiotics, and days of antibiotic exposure. Compared to patients who received only 1 antibiotic, the adjusted hazard ratios (HRs) for those who received 2, 3 or 4, or 5 or more antibiotics were 2.5 (95% confidence interval [CI] 1.6-4.0), 3.3 (CI 2.2-5.2), and 9.6 (CI 6.1-15.1), respectively. The receipt of fluoroquinolones was associated with an increased risk of CDI, while metronidazole was associated with reduced risk. CONCLUSIONS Cumulative antibiotic exposures appear to be associated with the risk of CDI. Antimicrobial stewardship programs that focus on the overall reduction of total dose as well as number and days of antibiotic exposure and the substitution of high-risk antibiotic classes for lower-risk alternatives may reduce the incidence of hospital-acquired CDI.

Brain cancer mortality and potential occupational exposure to lead: findings from the National Longitudinal Mortality Study, 1979-1989.

We evaluated the association between potential occupational lead exposure and the risk of brain cancer mortality in the National Longitudinal Mortality Study (NLMS), which is a prospective census‐based cohort study of mortality among the noninstitutionalized United States population (1979–1989). The present study was limited to individuals for whom occupation and industry were available (n = 317,968). Estimates of probability and intensity of lead exposure were assigned using a job‐exposure matrix (JEM). Risk estimates for the impact of lead on brain cancer mortality were computed using standardized mortality ratio (SMR) and proportional hazards and Poisson regression techniques, adjusting for the effects of age, gender and several other covariates. Brain cancer mortality rates were greater among individuals in jobs potentially involving lead exposure as compared to those unexposed (age‐ and gender‐adjusted hazard ratio (HR) = 1.5; 95% confidence interval (CI) = 0.9–2.3) with indications of an exposure–response trend (probability: low HR = 0.7 (95% CI = 0.2–2.2), medium HR = 1.4 (95% CI = 0.8–2.5), high HR = 2.2 (95% CI = 1.2–4.0); intensity: low HR = 1.2 (95% CI = 0.7–2.1), medium/high HR = 1.9 (95% CI = 1.0–3.4)). Brain cancer risk was greatest among individuals with the highest levels of probability and intensity (HR = 2.3; 95% CI = 1.3–4.2). These findings provide further support for an association between occupational lead exposure and brain cancer mortality, but need to be interpreted cautiously due to the consideration of brain cancer as one disease entity and the absence of biological measures of lead exposure.

Fish consumption, mercury exposure, and their associations with scholastic achievement in the Seychelles Child Development Study §

Studies of neurodevelopmental outcomes in offspring exposed to MeHg from maternal consumption of fish have primarily measured cognitive abilities. Reported associations have been subtle and in both adverse and beneficial directions. Changes in functional outcomes such as school achievement and behavior in exposed children and adolescents have not been examined. We undertook an assessment of school success of children in the Seychelles Child Development Study (SCDS) main cohort to determine if there were any associations with either prenatal or recent postnatal MeHg exposure. The primary endpoints were Seychelles nationally standardized end-of-year examinations given when the cohort children were 9 and 17 years of age. A subgroup (n=215) from the main cohort was also examined at 9 years of age using a regional achievement test called SACMEQ. Prenatal MeHg exposure was 6.8 ppm in maternal hair; recent postnatal exposure was 6.09 ppm at 9 years and 8.0 ppm at 17 years, measured in child hair. Multiple linear regression analyses showed no pattern of associations between prenatal or postnatal exposure, and either the 9- or 17-year end-of-year examination scores. For the subgroup of 215 subjects who participated in the SACMEQ test, there were significant adverse associations between examination scores and postnatal exposure, but only for males. The average postnatal exposure level in child hair for this subgroup was significantly higher than for the overall cohort. These results are consistent with our earlier studies and support the interpretation that prenatal MeHg exposure at dosages achieved by mothers consuming a diet high in fish are not associated with adverse educational measures of scholastic achievement. The adverse association of educational measures with postnatal exposure in males is intriguing, but will need to be confirmed by further studies examining factors that influence scholastic achievement.

Timing of Delivery and Survival Rates for Infants With Prenatal Diagnoses of Congenital Diaphragmatic Hernia

OBJECTIVES. The goal of the study was to test the hypothesis that infants with known congenital diaphragmatic hernias born at early term gestation (37–38 weeks) rather than later (39–41 weeks) had greater survival rates and less extracorporeal membrane oxygenation use. Primary outcomes were survival to hospital discharge or transfer and extracorporeal membrane oxygenation use. METHODS. A retrospective cohort study of term infants with prenatal diagnoses of congenital diaphragmatic hernia was performed with the Congenital Diaphragmatic Hernia Study Group Registry of patients with congenital diaphragmatic hernias who were treated between January 1995 and December 2006. RESULTS. Among 628 term infants at 37 to 41 weeks of gestation who had prenatal diagnoses of congenital diaphragmatic hernia and were free of major associated anomalies, early term birth (37 vs 39–41 weeks) and greater birth weight were associated independently with survival, whereas black race was related inversely to survival. Infants born at early term with birth weights at or above the group mean (3.1 kg) had the greatest survival rate (80%). Among infants born through elective cesarean delivery, infants born at 37 to 38 weeks of gestation, compared with 39 to 41 weeks, had less use of extracorporeal membrane oxygenation (22.0% vs 35.5%) and a trend toward a greater survival rate (75.0% vs 65.8%). CONCLUSIONS. The timing of delivery is an independent, potentially important factor in the consideration of elective delivery for infants diagnosed prenatally as having congenital diaphragmatic hernias. Among fetuses with prenatally diagnosed congenital diaphragmatic hernias and without major associated anomalies, early term delivery may confer advantage.

Parental exposure to pesticides and childhood brain cancer: U.S. Atlantic Coast childhood brain cancer study.

Background The etiology of childhood brain cancer remains largely unknown. However, previous studies have yielded suggestive associations with parental pesticide use. Objectives We aimed to evaluate parental exposure to pesticides at home and on the job in relation to the occurrence of brain cancer in children. Methods We included 526 one-to-one–matched case–control pairs. Brain cancer cases were diagnosed at < 10 years of age, and were identified from statewide cancer registries of four U.S. Atlantic Coast states. We selected controls by random digit dialing. We conducted computer-assisted telephone interviews with mothers. Using information on residential pesticide use and jobs held by fathers during the 2-year period before the child’s birth, we assessed potential exposure to insecticides, herbicides, and fungicides. For each job, two raters independently classified the probability and intensity of exposure; 421 pairs were available for final analysis. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression, after adjustment for maternal education. Results A significant risk of astrocytoma was associated with exposures to herbicides from residential use (OR = 1.9; 95% CI, 1.2–3.0). Combining parental exposures to herbicides from both residential and occupational sources, the elevated risk remained significant (OR = 1.8; 95% CI, 1.1–3.1). We observed little association with primitive neuroectodermal tumors (PNET) for any of the pesticide classes or exposure sources considered. Conclusions Our observation is consistent with a previous literature reporting suggestive associations between parental exposure to pesticides and risk of astrocytoma in offspring but not PNET. However, these findings should be viewed in light of limitations in exposure assessment and effective sample size.

Case-cohort analysis of brain cancer and leukemia in electric utility workers using a refined magnetic field job-exposure matrix

BACKGROUND The potential association between occupational electric and magnetic field exposure and cancer is well documented in the literature, but there is uncertainty regarding a causal relation. METHODS Using data from a completed cohort study, we sought to refine the job-exposure matrix in a case-cohort analysis by regrouping jobs into more homogeneous groups, but without making additional measurements. From the original cohort, we selected the 164 men who died of leukemia, 145 men who died of brain cancer, and a random subcohort of 800 men (0.6% of the cohort). Erroneous job assignments were corrected and job groups were subdivided based on differences in work environments or tasks performed. RESULTS Magnetic field exposure remained unrelated to leukemia mortality and positively associated with brain cancer mortality based on both cumulative and average magnetic field indices. Although not monotonic across the middle intervals, increased risk of brain cancer was found in relation to career exposure, with risk ratios of 1.8 (95% CI = 0.7-4.7) and 2.5 (95% CI = 1.0-6.3) in the uppermost categories for cumulative and average exposure, stronger for exposure 2-10 years past. CONCLUSIONS Improvements in exposure assignment based only on reassignment of job titles to occupational categories had little impact on the measured associations of magnetic fields with leukemia or brain cancer.

Sleep-Disordered Breathing and Behaviors of Inner-City Children With Asthma

OBJECTIVE: To explore the relationship between sleep-disordered breathing (SDB) and behavioral problems among inner-city children with asthma. METHODS: We examined data for 194 children (aged 4–10 years) who were enrolled in a school-based asthma intervention program (response rate: 72%). SDB was assessed by using the Sleep-Related Breathing Disorder Questionnaire that contains 3 subscales: snoring, sleepiness, and attention/hyperactivity. For the current study, we modified the Sleep-Related Breathing Disorder Questionnaire by removing the 6 attention/hyperactivity items. A sleep score of >0.33 was considered indicative of SDB. To assess behavior, caregivers completed the Behavior Problem Index (BPI), which includes 8 behavioral subdomains. We conducted bivariate analyses and multiple linear regression to determine the association of SDB with BPI scores. RESULTS: The majority of children (mean age: 8.2 years) were male (56%), black (66%), and insured by Medicaid (73%). Overall, 33% of the children experienced SDB. In bivariate analyses, children with SDB had significantly higher (worse) behavior scores compared with children without SDB on total BPI (13.7 vs 8.8) and the subdomains externalizing (9.4 vs 6.3), internalizing (4.4 vs 2.5), anxious/depressed (2.4 vs 1.3), headstrong (3.2 vs 2.1), antisocial (2.3 vs 1.7), hyperactive (3.0 vs 1.8), peer conflict (0.74 vs 0.43), and immature (2.0 vs 1.5). In multiple regression models adjusting for several important covariates, SDB remained significantly associated with total BPI scores and externalizing, internalizing, anxious/depressed, headstrong, and hyperactive behaviors. Results were consistent across SDB subscales (snoring, sleepiness). CONCLUSIONS: We found that poor sleep was independently associated with behavior problems in a large proportion of urban children with asthma. Systematic screening for SDB in this high-risk population might help to identify children who would benefit from additional intervention.

Prenatal exposure to methyl mercury from fish consumption and polyunsaturated fatty acids: associations with child development at 20 mo of age in an observational study in the Republic of Seychelles

BACKGROUND Fish is a rich source of n-3 polyunsaturated fatty acids (PUFAs) but also contains the neurotoxicant methyl mercury (MeHg). PUFAs may modify the relation between prenatal MeHg exposure and child development either directly by enhancing neurodevelopment or indirectly through the inflammatory milieu. OBJECTIVE The objective was to investigate the associations of prenatal MeHg exposure and maternal PUFA status with child development at 20 mo of age. DESIGN The Seychelles Child Development Study Nutrition Cohort 2 is an observational study in the Republic of Seychelles, a high-fish-eating population. Mothers were enrolled during pregnancy and their children evaluated at 20 mo of age by using the Bayley Scales of Infant Development II (BSID-II), the MacArthur Bates Communicative Development Inventories (CDI), and the Infant Behavior Questionnaire-Revised. There were 1265 mother-child pairs with complete data. RESULTS Prenatal MeHg exposure had no direct associations with neurodevelopmental outcomes. Significant interactions were found between MeHg and PUFAs on the Psychomotor Developmental Index (PDI) of the BSID-II. Increasing MeHg was associated with lower PDI but only in children of mothers with higher n-6/n-3. Among mothers with higher n-3 PUFAs, increasing MeHg was associated with improved PDI. Higher maternal docosahexaenoic acid (DHA) was associated with improved CDI total gestures (language development) but was significantly adversely associated with the Mental Development Index (MDI), both with and without MeHg adjustment. Higher n-6:n-3 ratios were associated with poorer scores on all 3 CDI outcomes. CONCLUSIONS We found no overall adverse association between prenatal MeHg exposure and neurodevelopmental outcomes. However, maternal PUFA status as a putative marker of the inflammatory milieu appeared to modify the associations of prenatal MeHg exposure with the PDI. Increasing DHA status was positively associated with language development yet negatively associated with the MDI. These findings may indicate the existence of an optimal DHA balance with respect to arachidonic acid for different aspects of neurodevelopment.

An exploratory investigation of suicide and occupational exposure

This exploratory study evaluated the association between suicide and occupational exposure to electromagnetic fields, pesticides, and hydrocarbon solvents. The study population comprised 11,707 suicide deaths and 132,771 eligible controls identified from United States death certificate files for the years 1991 and 1992. Exposure assignment was based on job title reported on the death certificates. Exposure to electromagnetic fields and pesticides was weakly associated with suicide risk, while little evidence for an increased risk was seen for hydrocarbon solvents. The association for electromagnetic field exposure was highest for suicide between the ages 20 and 35 (odds ratio; OR = 1.5), while the highest risk of suicide for pesticide exposure was seen between the ages of 35 and 49 years (OR = 1.5). Further investigation to replicate these findings seems warranted, using higher quality occupational data.

Neoadjuvant gemcitabine and cisplatin chemotherapy for locally advanced urothelial cancer of the bladder

The purpose of this study was to investigate the effect of neoadjuvant chemotherapy with gemcitabine and cisplatin (GC) on pathologic down‐staging of patients with locally advanced urothelial cancer (UC) of the bladder.