Adverse birth outcomes related to concentrations of per- and polyfluoroalkyl substances (PFAS) in maternal blood collected from pregnant women in 1960-1966.

BACKGROUND: Prior animal and epidemiological studies suggest that per- and polyfluoroalkyl substances (PFAS) exposure may be associated with reduced birth weight. However, results from prior studies evaluated a relatively small set of PFAS. OBJECTIVES: Determine associations of gestational PFAS concentrations in maternal serum samples banked for 60 years with birth outcomes. METHODS: We used data from 97 pregnant women from Boston and Providence that enrolled in the Collaborative Perinatal Project (CPP) study (1960-1966). We quantified concentrations of 27 PFAS in maternal serum in pregnancy and measured infant weight, height and ponderal index at birth. Covariate-adjusted associations between 11 PFAS concentrations (>75% detection limits) and birth outcomes were estimated using linear regression methods. RESULTS: Median concentrations of PFOA, PFNA, PFHxS, and PFOS were 6.189, 0.330, 14.432, and 38.170 ng/mL, respectively. We found that elevated PFAS concentrations during pregnancy were significantly associated with lower birth weight and ponderal index at birth, but no significant associations were found with birth length. Specifically, infants born to women with PFAS concentrations ≥ median levels had significantly lower birth weight (PFOS: ß = -0.323, P = 0.006; PFHxS: ß = -0.292, P = 0.015; PFOA: ß = -0.233, P = 0.03; PFHpS: ß = -0.239, P = 0.023; PFNA: ß = -0.239, P = 0.017). Similarly, women with PFAS concentrations ≥ median levels had significantly lower ponderal index (PFHxS: ß = -0.168, P = 0.020; PFHxA: ß = -0.148, P = 0.018). CONCLUSIONS: Using data from this US-based cohort study, we found that 1) maternal PFAS levels from the 1960s exceeded values in contemporaneous populations and 2) that gestational concentrations of certain PFAS were associated with lower birth weight and infant ponderal index. Additional studies with larger sample size are needed to further examine the associations of gestational exposure to individual PFAS and their mixtures with adverse birth outcomes.

FTO predicts weight regain in the Look AHEAD clinical trial.

BACKGROUND: Genome-wide association studies have provided new insights into the genetic factors that contribute to the development of obesity. We hypothesized that these genetic markers would also predict magnitude of weight loss and weight regain after initial weight loss. METHODS: Established obesity risk alleles available on the Illumina CARe iSelect (IBC) chip were characterized in 3899 overweight or obese participants with type 2 diabetes from the Look AHEAD (Action for Health in Diabetes), a randomized trial to determine the effects of intensive lifestyle intervention (ILI) and diabetes support and education (DSE) on cardiovascular morbidity and mortality. Primary analyses examined the interaction between 13 obesity risk polymorphisms in eight genes and randomized treatment arm in predicting weight change at year 1, and weight regain at year 4 among individuals who lost 3% or more of their baseline weight by year 1. RESULTS: No single-nucleotide polymorphisms (SNPs) were significantly associated with magnitude of weight loss or interacted with treatment arm at year 1. However, fat mass and obesity associated gene (FTO) rs3751812 predicted weight regain within DSE (1.56 kg per risk allele, P=0.005), but not ILI (P=0.761), resulting in SNP × treatment arm interaction (P=0.009). In a partial replication of prior research, the obesity risk (G) allele at BDNF rs6265 was associated with greater weight regain across treatment arms (0.773 kg per risk allele), although results were of borderline statistical significance (P=0.051). CONCLUSIONS: Variations in the FTO and BDNF loci may contribute risk of weight regain after weight loss.

Decreased serum BDNF levels in patients with epileptic and psychogenic nonepileptic seizures.

OBJECTIVE: Neurotrophins promote neurogenesis and help regulate synaptic reorganization. Their dysregulation has been implicated in a number of neurologic and psychiatric disorders. Previous studies have shown decreased levels of brain-derived neurotrophic factor (BDNF) in the serum of patients with psychiatric disorders such as major depressive disorder (MDD) and conversion disorder (CD). In human patients with temporal lobe epilepsy, there is an increase in both BDNF mRNA and protein levels in surgically resected hippocampi compared to controls. One study of children with epilepsy has found normal to increased serum BDNF levels compared to controls. Plasma [corrected] BDNF levels have not been investigated in adult patients with epileptic seizures (ES). We hypothesized that BDNF would differentiate between ES and psychogenic nonepileptic seizures (PNES). METHODS: We assessed plasma [corrected] BDNF immunoreactivity in 15 patients with ES, 12 patients with PNES, and 17 healthy volunteers. Plasma [corrected] BDNF levels were measured using an enzyme-linked immunoassay. RESULTS: Healthy controls showed higher BDNF levels (4,289 ± 1,810 pg/mL) compared to patients with PNES (1,033 ± 435 pg/mL) (p < 0.001). However, unexpectedly, healthy controls also showed higher levels of BDNF compared to patients with ES without comorbid MDD (977 ± 565 pg/mL) (p < 0.001). CONCLUSIONS: Unlike children, adults with epilepsy appear to have decreased levels of plasma [corrected] BDNF. Reduced plasma [corrected] BDNF levels can be used to differentiate adult patients with ES or PNES from healthy controls. Further human studies are needed to better understand the pathophysiology explaining the decreased plasma [corrected] BDNF levels found in epilepsy and in PNES.

Pilot pharmacologic randomized controlled trial for psychogenic nonepileptic seizures.

OBJECTIVE: There have been few treatment trials for psychogenic nonepileptic seizures (PNES). Some psychotherapies have been shown to improve PNES and comorbid symptom outcomes. We evaluated a pharmacologic intervention to test the hypothesis that sertraline would reduce PNES. METHODS: We conducted a pilot, double-blind, randomized, placebo-controlled trial in an academic medical hospital with epilepsy center outpatients. Subjects aged 18 to 65 years diagnosed with video-EEG-confirmed PNES were treated with flexible-dose sertraline or placebo over 12 weeks. Seizure calendars and symptom scales were charted prospectively. Secondary outcome measures included psychiatric symptom scales and psychosocial variables. RESULTS: Thirty-eight subjects enrolled, and 26 (68%) completed the trial. Thirty-three subjects with nonzero nonepileptic seizure rates at baseline were included in intent-to-treat analysis of the primary outcome. Subjects assigned to the sertraline arm experienced a 45% reduction in seizure rates from baseline to final visit (p = 0.03) vs an 8% increase in placebo (p = 0.78). Secondary outcome scales revealed no significant between-group differences in change scores from baseline to final visit, after adjustment for differences at baseline. CONCLUSIONS: PNES were reduced in patients treated with a serotonin selective reuptake inhibitor, whereas those treated with placebo slightly increased. This study provides feasibility data for a larger-scale study. LEVEL OF EVIDENCE: This study provides Class II evidence that flexible-dose sertraline up to a maximum dose of 200 mg is associated with a nonsignificant reduction in PNES rate compared with a placebo control arm (risk ratio 0.51, 95% confidence interval 0.25-1.05, p = 0.29), adjusting for differences at baseline.

Interrater reliability of EEG-video monitoring.

OBJECTIVE: The diagnosis of psychogenic nonepileptic seizures (PNES) can be challenging. In the absence of a gold standard to verify the reliability of the diagnosis by EEG-video, we sought to assess the interrater reliability of the diagnosis using EEG-video recordings. METHODS: Patient samples consisted of 22 unselected consecutive patients who underwent EEG-video monitoring and had at least an episode recorded. Other test results and histories were not provided because the goal was to assess the reliability of the EEG-video. Data were sent to 22 reviewers, who were board-certified neurologists and practicing epileptologists at epilepsy centers. Choices were 1) PNES, 2) epilepsy, and 3) nonepileptic but not psychogenic ("physiologic") events. Interrater agreement was measured using a kappa coefficient for each diagnostic category. We used generalized kappa coefficients, which measure the overall level of between-method agreement beyond that which can be ascribed to chance. We also report category-specific kappa values. RESULTS: For the diagnosis of PNES, there was moderate agreement (kappa = 0.57, 95% confidence interval [CI] 0.39-0.76). For the diagnosis of epilepsy, there was substantial agreement (kappa = 0.69, 95% CI 0.51-0.86). For physiologic nonepileptic episodes, the agreement was low (kappa = 0.09, 95% CI 0.02-0.27). The overall kappa statistic across all 3 diagnostic categories was moderate at 0.56 (95% CI 0.41-0.73). CONCLUSIONS: Interrater reliability for the diagnosis of psychogenic nonepileptic seizures by EEG-video monitoring was only moderate. Although this may be related to limitations of the study (diagnosis based on EEG-video alone, artificial nature of the forced choice paradigm, single episode), it highlights the difficulties and subjective components inherent to this diagnosis.

Lifetime characteristics of participants and non-participants in a smoking cessation trial: implications for external validity and public health impact.

BACKGROUND: Detailed information about the characteristics of smokers who do and do not participate in smoking cessation treatment is needed to improve efforts to reach, motivate, and treat smokers. PURPOSE: The aim of this study is to explore a broad range of characteristics related to participation in a smoking cessation trial. METHODS: Eligible smokers were recruited from a longitudinal birth cohort. Participants and non-participants were compared on a broad range of sociodemographics, smoking, psychiatric and substance abuse disorders, personality, and prospective measures from early childhood. Eligible smokers were compared to a matched regional subsample of the Behavioral Risk Factor Surveillance System (BRFSS). RESULTS: Few differences were observed, most of which were statistically significant but not clinically meaningful. Compared to non-participants, participants were more likely to be single, have lower income, be more nicotine-dependent, be more motivated to quit, and have higher levels of depressed mood and stress even after covariance of gender, income, and marital status. Sociodemographic differences between participants and the BRFSS sample reflect the skew toward lower socioeconomic status in the original birth cohort. CONCLUSIONS: The encouraging conclusion is that smokers who enroll in cessation trials may not differ much from non-participants. Information about treatment participants can inform the development of recruitment strategies, improve the tailoring of treatment to individual smoker profiles, help to estimate potential selection bias, and improve estimates of population impact.

A longitudinal study of drivers with Alzheimer disease.

OBJECTIVE: The goal of this study was to define the natural progression of driving impairment in persons who initially have very mild to mild dementia. METHODS: We studied 128 older drivers, including 84 with early Alzheimer disease (AD) and 44 age-matched control subjects without cognitive impairment. Subjects underwent repeated assessments of their cognitive, neurologic, visual, and physical function over 3 years. Self-reports of driving accidents and traffic violations were supplemented by reports from family informants and state records. Within 2 weeks of the office evaluation, subjects were examined by a professional driving instructor on a standardized road test. RESULTS: At baseline, subjects with AD had experienced more accidents and performed more poorly on the road test, compared to controls. Over time, both groups declined in driving performance on the road test, with subjects with AD declining more than controls. Survival analysis indicated that while the majority of subjects with AD passed the examination at baseline, greater severity of dementia, increased age, and lower education were associated with higher rates of failure and marginal performance. CONCLUSIONS: This study confirms previous reports of potentially hazardous driving in persons with early Alzheimer disease, but also indicates that some individuals with very mild dementia can continue to drive safely for extended periods of time. Regular follow-up assessments, however, are warranted in those individuals.

Educational attainment, smoking initiation and lifetime nicotine dependence among male Vietnam-era twins.

BACKGROUND: Smoking initiation and persistence are clearly associated with factors commonly thought to be environmental in origin, including socio-economic status. However, twin models that incorporate gene-environment correlation and gene x environment interaction have not been applied to elucidate the genetic or environmental role that socio-economic status plays in smoking initiation and nicotine dependence. METHOD: Twin structural equation modelling was used to examine gene-environment correlation and gene x environment interaction of one index of socio-economic status, educational attainment, with smoking initiation and nicotine dependence among 5119 monozygotic and 4295 dizygotic male-male Vietnam-era twins from the Vietnam Era Twin Registry, a national registry of twin pairs who served in the military during the Vietnam era. RESULTS: Educational attainment correlated significantly with smoking initiation (r=-0.27, p<0.001). Additive genetic (p=0.011), shared environment (p=0.002) and unique environment (p=0.027) components contributed to the correlation between educational attainment and smoking initiation. Educational attainment also significantly moderated the variance in smoking initiation (p<0.001), suggestive of gene x environment interaction, although the interaction with the additive genetic, shared environmental and unique environmental components could not be resolved due to multi-collinearity. In contrast, educational attainment neither correlated with nor moderated nicotine dependence, once smokers had initiated. CONCLUSIONS: Our study suggests that educational attainment is associated with smoking initiation, in part due to gene-environment correlation and gene x environment interaction. However, once smoking initiation is taken into account, there are no effects--be they gene-environment correlation or gene x environmental interaction--of educational attainment on nicotine dependence.

Dissemination of the AHCPR clinical practice guideline in community health centres.

OBJECTIVE: To evaluate dissemination of the Agency for Health Care Policy and Research (AHCPR) Smoking cessation clinical practice guideline in community health centres. DESIGN: Pre- and post-trial. SETTING: Fourteen community health centres in Rhode Island. SUBJECTS: Provider performance was assessed with 1798 and 1591 patient contacts, in pre-post cross sectional consecutive samples, respectively, and 891 contacts at one year follow up. INTERVENTIONS: Three, one hour on-site provider training sessions, on review of effective tobacco interventions, use of office systems, and tobacco counselling skill building. OUTCOME MEASURES: Chart documentation of four A's (Ask, Advise, Assist, and Arrange follow up) at most recent primary care visit. RESULTS: While average performance rates increased for Ask and Advise (from 30% to 44%, and 19% to 26%, pre-post, respectively), significant increases were found only for some visit types, with further differences by patient sex. There were significant increases for Ask for all except obstetric/gynaecological (ob/gyn) visit types. Patients at yearly physicals and first visits were more likely to be asked at all time points, while males were more likely to be asked at acute visits than were females. There were no significant increases for Advise, Assist, and Arrange across time, although female patients showed a differential increase in Advise post-training. Advise was significantly more likely in yearly physicals and first visits, and less likely in ob/gyn visits, at all time points. CONCLUSIONS: This guideline dissemination effort resulted in quite different provider counselling rates across patient sexes, and visit types. Guideline implementation may require more sustained efforts, with multiple strategies, which are reinforced at higher policy levels, to more fully integrate tobacco interventions into routine primary care practice with all patients who smoke.

Smoking-cessation counseling in the home. Attitudes, beliefs, and behaviors of home healthcare nurses.

BACKGROUND: Despite advances in smoking treatment, cessation rates remain stagnant, possibly a function of the lack of new channels to reach heavily addicted smokers. This cross-sectional study examined home care nurses' attitudes, beliefs, and counseling behaviors regarding counseling their home care patients who smoke. METHODS: Home healthcare nurses (N=98) from the Visiting Nurse Association of Rhode Island were randomly selected to participate in a study helping home-bound medically ill smokers to quit. At baseline, nurses completed a questionnaire that assessed a constellation of cognitive factors (self-efficacy, outcome expectations, perceived effectiveness, risk perception, motivation, and perceived patient adherence) as correlates of self-reported nurse counseling behaviors. RESULTS: Nurses with higher outcome expectations spent more time counseling their patients about quitting (p<0.04). Nurses' self-efficacy was the only variable associated with consistent counseling (p<0.05). While the majority of nurses "asked and advised" their patients, a minority of nurses "assisted or arranged" follow-up. Perceived importance of counseling was associated with a greater likelihood of asking, advising and assisting (p<0.05). None of the nurses who currently smoked (n=13) provided follow-up to their patients. Nurses who reported higher levels of both risk perception (regarding the harmful effects of smoking) and perceived effectiveness were more likely to recommend the nicotine patch. CONCLUSIONS: Attitudes and beliefs about smoking are significantly associated with nurse counseling behaviors. Helping nurses to overcome their barriers to smoking counseling may open up new channels for smoking intervention.

Influences of gender and weight gain on short-term relapse to smoking in a cessation trial.

Few researchers have studied whether weight gain has an impact on short-term relapse to smoking. The authors of this study investigated predictors of relapse among 989 participants (60% women) in a randomized, double-blind, 10-week multicenter trial to determine the effect of fluoxetine (30 or 60 mg) versus placebo in combination with behavioral counseling for smoking cessation. Medication compliance and smoking status were biochemically verified. At Visit 2, participants were asked to set a quit date within the subsequent 2 visits. A proportional hazards regression model was used to predict risk of relapse within the first 3 months of quitting. Weight gain predicted relapse, but for men only. Female gender also predicted relapse. The results led the authors to question whether postcessation weight gain interventions should be restricted to women smokers.

Influence of antidepressant pharmacotherapy on behavioral treatment adherence and smoking cessation outcome in a combined treatment involving fluoxetine.

The authors examined whether serum fluoxetine levels influence behavioral treatment adherence and smoking cessation outcome. Nondepressed smokers (N = 989) from 16 centers were randomized on a double-blind basis to receive either fluoxetine (30 or 60 mg) or placebo plus 9 sessions of behavioral smoking cessation treatment. Fluoxetine and norfluoxetine blood levels were assayed 1 week after the quit date. Logistic regression was used to predict treatment completion and cessation outcome, controlling for gender, age, treatment site, and degree of nicotine dependence. Higher steady-state fluoxetine blood levels (fluoxetine + norfluoxetine) predicted less likelihood of dropping out, chi2(1, N = 820) = 3.9, p < .05, and more likelihood of being abstinent, chi2(1, N = 513) = 18.1, p < .001. Attaining a higher fluoxetine blood level improved the likelihood of completing behavioral treatment and increased the probability of achieving abstinence.

Ewing's sarcoma of the pelvis. Long-term survival and functional outcome.

Fifty patients with Ewing's sarcoma of the pelvis were treated using a multidisciplinary approach; followup of surviving patients averaged 137 months (range, 40-276 months). The addition of surgical resection to the multidisciplinary treatment for all patients was associated with improved survival compared with survival of patients treated with chemotherapy and radiation therapy alone; the addition of surgery to the treatment regimen of 37 patients without metastases also was associated with improved survival. There were no significant differences between the surgical and nonsurgical groups in terms of tumor size, stage of disease, patient age, duration of symptoms before diagnosis, or anatomic site. Surgery was used more often in recently treated patients, but the year of diagnosis and treatment did not significantly affect overall survival, secondary to large confidence intervals. The Short Form-36 and the Musculoskeletal Tumor Society functional evaluation instruments showed a superior level of function in the nonsurgical group, but this difference was not statistically significant. There have been many advances in the treatment of patients with Ewing's sarcoma during the past 3 decades, resulting in improved survival for patients with Ewing's sarcoma of the pelvis. The addition of surgery significantly improved survival and did not show a significant difference in functional outcome.

Prevention of disseminated Mycobacterium avium complex infection with reduced dose clarithromycin in patients with advanced HIV disease.

OBJECTIVE: To evaluate the ability of once daily reduced dose clarithromycin to prevent disseminated Mycobacterium avium complex (dMAC) infection in patients with advanced HIV disease. DESIGN: Non-randomized, retrospective study. SETTING: Outpatient clinic of an urban university-affiliated municipal hospital. PATIENTS: A group of 192 HIV-infected patients with a CD4 count < 100 x 10(6) cells/l who were followed for at least 90 days during a 6-year period (1991-1996) before the use of protease inhibitors. INTERVENTIONS: Clarithromycin 500 mg orally once daily (n = 84), rifabutin 300 mg orally once daily (n = 47) or no prophylaxis (n = 61). MAIN OUTCOME MEASURES: Positive blood culture for M. avium complex (MAC), time to development of dMAC, and time to death. RESULTS: When compared with no prophylaxis or rifabutin, the incidence of dMAC and time to development of dMAC were improved among those patients receiving clarithromycin (P < 0.001). Prolonged survival was associated with both clarithromycin and rifabutin use when compared with no prophylaxis (P < 0.002). In patients who failed prophylaxis, resistance to clarithromycin and rifabutin was observed. CONCLUSIONS: In the era prior to protease inhibitor use, once daily clarithromycin at a dose of 500 mg was associated with a reduction in the incidence of dMAC, appeared to be superior to rifabutin, and was associated with prolonged survival in patients with advanced HIV disease.

Effect of maternal diabetes on the fetal exocrine pancreas.

To test the hypothesis that fetal pancreatic exocrine and endocrine function are stimulated in parallel in the diabetic pregnancy, 68 mothers with gestational and pregestational diabetes who underwent amniocenteses after 34 weeks' for the evaluation of fetal lung maturity were enrolled. Amniotic fluid specimens were analyzed for C-peptide and trypsin content. Amniotic fluid specimens were obtained from 92 non-diabetic women undergoing amniocenteses for lung maturity, preterm labor, or premature rupture of membranes. Groups were compared using the Wilcoxon rank-sum test, Kruskal Wallis rank sum test, and Spearman's rank correlation test. C-peptide amniotic fluid concentrations were significantly greater in diabetics (median 0.6 ng/ml) than non-diabetics (median 0.4 ng/ml, P= 0.0001), in pregestational (median 0.6 ng/ml) vs. gestational diabetics (median 0.4 ng/ml, P = 0.006), and greater in proportion to severity of disease according to diabetic class (A1 = 0.4 ng/ml, A2 = 0.55 ng/ml, B = 0.6 ng/ml, C = 0.7 ng/ml, D = 0.85 ng/ml, P = 0.04). No significant differences were detected in amniotic fluid trypsin between the diabetic and non-diabetic or the gestational and non-gestational diabetic groups. There was no correlation between C-peptide and trypsin within the diabetic groups. Stimulation of the exocrine and endocrine pancreas does not occur in parallel in the fetus of the diabetic mother. Although originating as a single organ, pancreatic exocrine and endocrine functions are distinct in both physiologic and pathologic conditions.

Associations between oral conditions and respiratory disease in a national sample survey population.

Respiratory infectious diseases such as bacterial pneumonia and bronchitis are common and costly, especially in institutionalized and elderly inpatients. Respiratory infection is thought to rely in part on the aspiration of oropharyngeal flora into the lower respiratory tract and failure of host defense mechanisms to eliminate the contaminating bacteria, which then multiply to cause infection. It has been suggested that dental plaque may act as a reservoir of respiratory pathogens, especially in patients with periodontal disease. However, the impact of poor oral health on oral respiratory pathogen colonization and lung infection is uncertain, especially in ambulatory, non-institutionalized populations. To begin to assess potential associations between respiratory diseases and oral health, data from the National Health and Nutrition Examination Survey I (NHANES I) were analyzed. This database contains information on the general health status of 23,808 individual Of these, 386 individuals reported a suspected respiratory condition that was further assessed by a physician. These subjects were categorized as having a confirmed chronic respiratory disease (chronic bronchitis or emphysema) or an acute respiratory disease (influenza, pneumonia, acute bronchitis). They were compared to those not having a respiratory disease. Initial non-parametric analysis noted that individuals with a confirmed chronic respiratory disease (n = 41) had significantly greater oral hygiene index scores than subjects without respiratory disease (n = 193; P = 0.0441). Logistic regression analysis of data from these subjects, which considered age, race, gender, smoking status, and simplified oral hygiene index (OHI), suggested that subjects having the median OHI value were 1.3 times more likely to have a chronic respiratory disease relative to those with and OHI of O. Similarly, subjects with the maximum OHI value were 4.5 times more likely to have a chronic respiratory disease than those with an OHI of O. No evidence was found to support an association between the periodontal index and any respiratory disease. These results suggest OHI to have a residual effect on chronic respiratory disease of both practical and statistical significance.

Ecological momentary assessment in a behavioral drinking moderation training program.

We assessed predictors of self-reported excessive drinking (> 5 drinks) in a sample of heavy drinkers. Participants were randomly assigned to moderation training or a waiting-list control condition. They were trained in ecological momentary assessment (EMA) involving self-monitoring of drinking and other variables on a small hand-held computer, the electronic diary (ED). During the 8-week study, participants were compliant in their use of the ED for both random prompts and the entry of data related to specific drinking episodes. Generalized estimating equations were used to fit models involving predictors related to past history of drinking, aspects of the training program, drinking restraint, and episode-specific mood. The models indicated robust predictors of decreased and increased drinking. Our results suggest that EMA is a useful methodology for assessing drinking and related behaviors.