Monoterpenes are the largest source of summertime organic aerosol in the southeastern United States.

The chemical complexity of atmospheric organic aerosol (OA) has caused substantial uncertainties in understanding its origins and environmental impacts. Here, we provide constraints on OA origins through compositional characterization with molecular-level details. Our results suggest that secondary OA (SOA) from monoterpene oxidation accounts for approximately half of summertime fine OA in Centreville, AL, a forested area in the southeastern United States influenced by anthropogenic pollution. We find that different chemical processes involving nitrogen oxides, during days and nights, play a central role in determining the mass of monoterpene SOA produced. These findings elucidate the strong anthropogenic-biogenic interaction affecting ambient aerosol in the southeastern United States and point out the importance of reducing anthropogenic emissions, especially under a changing climate, where biogenic emissions will likely keep increasing.

Medical Provider Promotion of Oral Health and Women's Receipt of Dental Care During Pregnancy.

Objectives Dental care during pregnancy is important. We examined whether promotion of oral health by medical providers during pregnancy and pregnant women's receipt of dental care improved between 2009 and 2012 in California. Methods We used population-based postpartum survey data collected during 2009 (n = 3105) and 2012 (n = 6810) to compare the prevalence of women's reports that, during pregnancy, (a) their medical providers discussed oral health and/or suggested they see a dentist, and (b) they received dental care. Results Between 2009 and 2012, the proportion of women reporting that their medical providers talked about oral health or referred them to a dentist increased significantly overall (from 36 to 42%, and 21-26%, respectively, p < 0.001). The proportion of women with a dental visit during pregnancy also increased, from 38% in 2009 to 42% in 2012 (p < 0.005). The improvements were largely among women of lower income and education levels, those covered by Medi-Cal, and Latinas. Women whose medical providers promoted oral health care were approximately two times more likely to report having had a dental visit during pregnancy, even after adjusting for several potential confounders. Conclusions for Practice Characteristics of women reporting that their medical providers promoted, and that they received, dental care during pregnancy in 2012 suggests that the increases in promotion and use of oral health care were largely concentrated among Medi-Cal recipients. Further improvement is needed for all populations of pregnant women. Both public and private providers need to incorporate promotion of and referral for dental care into routine prenatal care protocols.

Reassessing the Association between WIC and Birth Outcomes Using a Fetuses-at-Risk Approach.

Objectives Women with longer, healthier pregnancies have more time to enroll in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), biasing associations between WIC and birth outcomes. We examined the association between WIC and preterm birth (PTB), low birth weight (LBW), and perinatal death (PND) using a fetuses-at-risk approach to address this bias, termed gestational age bias. Methods We linked California Medi-Cal recipients with a singleton live birth or fetal death from the 2010 Birth Cohort to WIC participant data (n = 236,564). We implemented a fetuses-at-risk approach using survival analysis, which compared, in each week of gestation, women whose pregnancies reached the same length and who had the same opportunity to utilize WIC. In each gestational week, we assessed WIC enrollment and the number of food packages redeemed thus far and computed hazard ratios (HR) using survival models with time-varying exposures and effects. Results Adjusting for maternal socio-demographic and health characteristics, WIC enrollment was associated with a lower risk of PTB from week 29-36 (HR29 = 0.71; HR36 = 0.52); LBW from week 26-40 (HR26 = 0.77; HR40 = 0.64); and PND from week 29-43 (HR29 = 0.78; HR43 = 0.69) (p < 0.05). The number of food packages redeemed was associated with a lower risk of PTB from week 27-36 (HR27 = 0.90; HR36 = 0.84); LBW from week 25-42 (HR25 = 0.93; HR42 = 0.88); and PND from week 27-46 (HR27 = 0.94; HR46 = 0.91) (p < 0.05). Conclusions for Practice To our knowledge this is the first study to examine the association between WIC and birth outcomes using this approach. We found that beginning from about 29 weeks, WIC enrollment was associated with a reduced risk of PTB by 29-48 %, LBW by 23-36 %, and PND by 22-31 %.

Design and synthesis of sarolaner, a novel, once-a-month, oral isoxazoline for the control of fleas and ticks on dogs.

Over the last decade, the isoxazoline motif has become the intense focus of crop protection and animal health companies in their search for novel pesticides and ectoparasiticides. Herein we report the discovery of sarolaner, a proprietary, optimized-for-animal health use isoxazoline, for once-a-month oral treatment of flea and tick infestation on dogs.

The discovery of isoxazoline oxime ethers as a new class of ectoparasiticides for the control of Haematobia irritans (horn fly) in cattle.

Haematobia irritans (horn fly) infestation in cattle is responsible for over a billion dollars a year in global economic loss due to decreased milk production and lower feed conversion. There is significant need for new insecticidal agents since current treatments such as organophosphates and pyrethroids suffer from field resistance. Isoxazoline oxime ethers represent a new class of γ-aminobutyric acid (GABA) receptor channel blockers which show good activity (LD(90) = 1.0 µg/mL) against horn flies in an in vitro feed assay and have demonstrated efficacy (>90% reduction at 1.0mg/kg) as a topical treatment in a field study.

Discovery of sarolaner: A novel, orally administered, broad-spectrum, isoxazoline ectoparasiticide for dogs.

The novel isoxazoline ectoparasiticide, sarolaner, was identified during a lead optimization program for an orally-active compound with efficacy against fleas and ticks on dogs. The aim of the discovery program was to identify a novel isoxazoline specifically for use in companion animals, beginning with de novo synthesis in the Zoetis research laboratories. The sarolaner molecule has unique structural features important for its potency and pharmacokinetic (PK) properties, including spiroazetidine and sulfone moieties. The flea and tick activity resides in the chirally pure S-enantiomer, which was purified to alleviate potential off-target effects from the inactive enantiomer. The mechanism of action was established in electrophysiology assays using CHO-K1 cell lines stably expressing cat flea (Ctenocephalides felis) RDL (resistance-to-dieldrin) genes for assessment of GABA-gated chloride channel (GABACls) pharmacology. As expected, sarolaner inhibited GABA-elicited currents at both susceptible (CfRDL-A285) and resistant (CfRDL-S285) flea GABACls with similar potency. Initial whole organism screening was conducted in vitro using a blood feeding assay against C. felis. Compounds which demonstrated robust activity in the flea feed assay were subsequently tested in an in vitro ingestion assay against the soft tick, Ornithodoros turicata. Efficacious compounds which were confirmed safe in rodents at doses up to 30mg/kg were progressed to safety, PK and efficacy studies in dogs. In vitro sarolaner demonstrated an LC80 of 0.3µg/mL against C. felis and an LC100 of 0.003µg/mL against O. turicata. In a head-to-head comparative in vitro assay with both afoxolaner and fluralaner, sarolaner demonstrated superior flea and tick potency. In exploratory safety studies in dogs, sarolaner demonstrated safety in dogs≥8 weeks of age upon repeated monthly dosing at up to 20mg/kg. Sarolaner was rapidly and well absorbed following oral dosing. Time to maximum plasma concentration occurred within the first day post-dose. Bioavailability for sarolaner was calculated at >85% and the compound was highly protein bound (>99.9%). The half-life for sarolaner was calculated at 11-12 days. Sarolaner plasma concentrations indicated dose proportionality over the range 1.25-5mg/kg, and these same doses provided robust efficacy (>99%) for ≥35days against both fleas (C. felis) and multiple species of ticks (Rhipicephalus sanguineus, Ixodes ricinus and Dermacentor reticulatus) after oral administration to dogs. As a result of these exploratory investigations, sarolaner was progressed for development as an oral monthly dose for treatment and control of fleas and ticks on dogs.

4-(2-[2-(2(R)-methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl)benzonitrile and related 2-aminoethylbenzofuran H3 receptor antagonists potently enhance cognition and attention.

H(3) receptor antagonists based on a 2-aminoethylbenzofuran skeleton have been discovered, which are potent in vitro at human and rat H(3) receptors, with K(i) values of 0.1-5.8 nM. Analogues were discovered with potent (0.01-1 mg/kg) cognition and attention enhancing properties in animal models. One compound in particular, 4-(2-[2-(2(R)-methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl)benzonitrile (ABT-239), combined potent and selective H(3) receptor antagonism and excellent pharmacokinetic and metabolic properties across species, with full efficacy in two behavioral models: a five-trial inhibitory avoidance acquisition model in rat pups at 0.1 mg/kg and a social recognition memory model in adult rats at 0.01 mg/kg. Furthermore, this compound did not stimulate locomotor activity and showed high selectivity for the induction of behavioral efficacy versus central nervous system based side effects. The potency and selectivity of this compound and of analogues from this class support the potential of H(3) receptor antagonists for the treatment of cognitive dysfunction.

Satisfaction with care among community residential care residents.

Measuring satisfaction with community residential care (CRC) is growing in importance but still in its infancy. The authors conducted interviews with 176 CRC residents and their providers. Logistic regression was used to identify resident and physical characteristics, policies and services, and aggregate resident characteristics associated with satisfaction. Residents had high levels of satisfaction, demonstrating most concern with the facility being able to meet their future needs and food quality. Resident demographics and health status were associated with satisfaction. Contrary to hypotheses, facility type (adult family home and assisted living) was the only facility characteristic strongly associated with satisfaction. Possible explanations include that the relationship between satisfaction and facility characteristics is more complex than expected, as well as significant challenges in measuring satisfaction and facility characteristics. The inconsistent results of previous satisfaction studies do not provide direction for imposition of uniform standards for facility characteristics, if the goal is improved satisfaction.

Infant Mortality: Development of a Proposed Update to the Dollfus Classification of Infant Deaths.

OBJECTIVE: Identifying infant deaths with common underlying causes and potential intervention points is critical to infant mortality surveillance and the development of prevention strategies. We constructed an International Classification of Diseases 10th Revision (ICD-10) parallel to the Dollfus cause-of-death classification scheme first published in 1990, which organized infant deaths by etiology and their amenability to prevention efforts. METHODS: Infant death records for 1996, dual-coded to the ICD Ninth Revision (ICD-9) and ICD-10, were obtained from the CDC public-use multiple-cause-of-death file on comparability between ICD-9 and ICD-10. We used the underlying cause of death to group 27,821 infant deaths into the nine categories of the ICD-9-based update to Dollfus' original coding scheme, published by Sowards in 1999. Comparability ratios were computed to measure concordance between ICD versions. RESULTS: The Dollfus classification system updated with ICD-10 codes had limited agreement with the 1999 modified classification system. Although prematurity, congenital malformations, Sudden Infant Death Syndrome, and obstetric conditions were the first through fourth most common causes of infant death under both systems, most comparability ratios were significantly different from one system to the other. CONCLUSION: The Dollfus classification system can be adapted for use with ICD-10 codes to create a comprehensive, etiology-based profile of infant deaths. The potential benefits of using Dollfus logic to guide perinatal mortality reduction strategies, particularly to maternal and child health programs and other initiatives focused on improving infant health, warrant further examination of this method's use in perinatal mortality surveillance.

Discovery of 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744) as a novel positive allosteric modulator of the alpha7 nicotinic acetylcholine receptor.

The discovery of a series of pyrrole-sulfonamides as positive allosteric modulators (PAM) of alpha7 nAChRs is described. Optimization of this series led to the identification of 19 (A-867744), a novel type II PAM with good potency and selectivity. Compound 19 showed acceptable pharmacokinetic profile across species and brain levels sufficient to modulate alpha7 nAChRs. In a rodent model of sensory gating, 19 normalized gating deficits. These results suggest that 19 represents a novel class of molecules capable of allosteric modulation of the alpha7 nAChRs.

Hospitalization for respiratory syncytial virus among California infants: disparities related to race, insurance, and geography.

OBJECTIVES: To evaluate population-based rates of Respiratory Syncytial Virus (RSV)-associated infant hospitalizations related to race/ethnicity, payer source, and geography in California. STUDY DESIGN: Retrospective analysis of RSV-coded infant hospitalizations were performed using the California patient discharge data for 1999 to 2003. All discharge records for infants younger than 1 year of age with an ICD-9-CM code for any RSV-related illness (466.11, 480.1, or 079.6) among any of the diagnosis fields were selected for analysis (n = 45,330). Rates were expressed as the number of RSV-associated hospitalizations per 1000 live births in the same calendar year. RESULTS: Infants enrolled in MediCal (California's version of the United States' national Medicaid program) had a relative risk of 2.03 (95% CI, 1.99 to 2.06) compared with non-MediCal payers (24.3 vs 12.0/1000 live births, respectively). The 1999 to 2003 rates per 1000 live births of RSV-associated hospitalizations for MediCal payers by race/ethnicity were: non-Hispanic white (34.9), African-American (27.9), Hispanic (21.8), Asian/Pacific Islander (12.5), and American Indian/Alaska Native (12.2). CONCLUSIONS: RSV was the leading cause of infant hospitalizations in California between 1999 and 2003. RSV hospitalization rates were highest among non-Hispanic white MediCal insured infants.

Structure-activity relationships of arylbenzofuran H3 receptor antagonists.

An SAR study of histamine H3 receptor antagonists based on substituted (R)-2-methyl-1-[2-(5-phenyl-benzofuran-2-yl)-ethyl]-pyrrolidines is presented.

Potentially inappropriate medication use in community residential care facilities.

OBJECTIVE: To describe the prevalence of potentially inappropriate medication use in community residential care (CRC) facilities at baseline, describe exposure to potentially inappropriate drugs during the 1-year follow-up, and examine characteristics associated with potentially inappropriate use. DESIGN: A cohort study was conducted using 282 individuals aged >/=65 years entering a CRC facility in a 3-county area in the Puget Sound region of Washington State between April 1998 and December 1998 on Medicaid funding. MAIN OUTCOME MEASURE: Use of potentially inappropriate medications as defined by explicit criteria (e.g., drugs that should generally be avoided in the elderly because potential risks outweigh any potential benefits). RESULTS: Sixty-two (22%) residents took a total of 75 potentially inappropriate medications at baseline. The most common agents used at baseline were oxybutynin (3.5%) and amitriptyline (3.5%). The incidence of new use of potentially inappropriate medications was 0.1/100 person-days during the follow-up period. Potentially inappropriate use was related to self-reported fair or poor health (adjusted OR 1.42; 95% CI 1.05 to 1.92) and number of prescription drugs (adjusted OR 1.12; 95% CI 1.05 to 1.19). In the Cox proportional hazard model, no characteristics predicted new potentially inappropriate medication use during the follow-up. CONCLUSIONS: Potentially inappropriate medication use is common among residents in CRC facilities. A comprehensive periodic review may be beneficial for reducing potentially inappropriate use, especially for patients taking multiple drugs.

D-amino acid homopiperazine amides: discovery of A-320436, a potent and selective non-imidazole histamine H(3)-receptor antagonist.

Structure-activity relationships of homopiperazine-containing alkoxybiaryl nitriles employing various D-amino acid moieties and their N-furanoyl analogues were undertaken. This led to A-320436, a potent and selective non-imidazole H(3)-receptor antagonist possessing balanced affinity for both rat and human H(3)-receptors. This compound was shown to demonstrate in vitro and in vivo functional antagonism and is non-neurotoxic at doses (i.p.) up to 163 mg/kg in a general observation test.