Policy Implications of Genetic Information on Regulation under the Clean Air Act: The Case of Particulate Matter and Asthmatics

The U.S. Clean Air Act (CAA) explicitly guarantees the protection of sensitive human subpopulations from adverse health effects associated with air pollution exposure. Identified subpopulations, such as asthmatics, may carry multiple genetic susceptibilities to disease onset and progression and thus qualify for special protection under the CAA. Scientific advances accelerated as a result of the ground-breaking Human Genome Project enable the quantification of genetic information that underlies such human variability in susceptibility and the cellular mechanisms of disease. In epidemiology and regulatory toxicology, genetic information can more clearly elucidate human susceptibility essential to risk assessment, such as in support of air quality regulation. In an effort to encourage the incorporation of genomic information in regulation, the U.S. Environmental Protection Agency (EPA) has issued an Interim Policy on Genomics. Additional research strategy and policy documents from the National Academy of Science, the U.S. EPA, and the U.S. Department of Health and Human Services further promote the expansion of asthma genetics research for human health risk assessment. Through a review of these government documents, we find opportunities for the inclusion of genetic information in the regulation of air pollutants. In addition, we identify sources of information in recent scientific research on asthma genetics relevant to regulatory standard setting. We conclude with recommendations on how to integrate these approaches for the improvement of regulatory health science and the prerequisites for inclusion of genetic information in decision making

Perceptions of Midwestern Crop Advisors and Growers on Foliar Fungicide Adoption and Use in Maize

Foliar fungicide use in hybrid maize in the United States was rare before 2000. The decade from 2000 to 2010 saw foliar fungicides increasingly applied to maize in the absence of appreciable disease pressure, a practice seemingly at odds with integrated pest management philosophy. Yet, it is commonly believed that growers do not employ management strategies unless there are perceived benefits. Maize (corn) growers (CGs) and certified crop advisors (CCAs) across four Midwestern states (Iowa, Illinois, Ohio, and Wisconsin) were surveyed to better understand their practices, values and perceptions concerning the use of foliar fungicides during 2005 to 2009. The survey results demonstrated the rapid rise in maize foliar fungicide applications from 2000 through 2008, with 84% of CGs who sprayed having used a foliar fungicide in maize production for the very first time during 2005 to 2009. During 2005 to 2009, 73% of CCAs had recommended using a foliar fungicide, but only 35% of CGs sprayed. Perceived yield gains, conditional on having sprayed, were above the break-even point on average. However, negative yield responses were also observed by almost half of CCAs and a quarter of CGs. Hybrid disease resistance was a more important factor to economically successful maize production than foliar fungicides. Diseases as a yield-limiting factor were more important to CGs than CCAs. As a group, CGs were not as embracing of foliar fungicide as were CCAs, and remained more conservative about the perceived benefits to yield

Luminous Infrared Galaxies with the Submillimeter Array: I. Survey Overview and the Central Gas to Dust Ratio

We present new data obtained with the Submillimeter Array for a sample of fourteen nearby luminous and ultraluminous infrared galaxies. The galaxies were selected to have luminosity distances D < 200 Mpc and far-infrared luminosities log(L_FIR) > 11.4. The galaxies were observed with spatial resolutions of order 1 kpc in the CO J=3-2, CO J=2-1, 13CO J=2-1, and HCO+ J=4-3 lines as well as the continuum at 880 microns and 1.3 mm. We have combined our CO and continuum data to measure an average gas-to-dust mass ratio of 120 +/- 28 (rms deviation 109) in the central regions of these galaxies, very similar to the value of 150 determined for the Milky Way. This similarity is interesting given the more intense heating from the starburst and possibly accretion activity in the luminous infrared galaxies compared to the Milky Way. We find that the peak H_2 surface density correlates with the far-infrared luminosity, which suggests that galaxies with higher gas surface densities inside the central kiloparsec have a higher star formation rate. The lack of a significant correlation between total H_2 mass and far-infrared luminosity in our sample suggests that the increased star formation rate is due to the increased availability of molecular gas as fuel for star formation in the central regions. In contrast to previous analyses by other authors, we do not find a significant correlation between central gas surface density and the star formation efficiency, as trace by the ratio of far-infrared luminosity to nuclear gas mass. Our data show that it is the star formation rate, not the star formation efficiency, that increases with increasing central gas surface density in these galaxies.Comment: 66 pages, 39 figures, aastex preprint format; to be published in ApJ Supplements. Version of paper with full resolution figures available at http://www.physics.mcmaster.ca/~wilson/www_xfer/ULIRGS_publi

The prevalence and incidence of mental ill-health in adults with autism and intellectual disabilities

The prevalence, and incidence, of mental ill-health in adults with intellectual disabilities and autism were compared with the whole population with intellectual disabilities, and with controls, matched individually for age, gender, ability-level, and Down syndrome. Although the adults with autism had a higher point prevalence of problem behaviours compared with the whole adult population with intellectual disabilities, compared with individually matched controls there was no difference in prevalence, or incidence of either problem behaviours or other mental ill-health. Adults with autism who had problem behaviours were less likely to recover over a two-year period than were their matched controls. Apparent differences in rates of mental ill-health are accounted for by factors other than autism, including Down syndrome and ability level

A Comprehensive Resource for Induced Pluripotent Stem Cells from Patients with Primary Tauopathies.

Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies

Genome sequencing of the extinct Eurasian wild aurochs, Bos primigenius, illuminates the phylogeography and evolution of cattle

Background Domestication of the now-extinct wild aurochs, Bos primigenius, gave rise to the two major domestic extant cattle taxa, B. taurus and B. indicus. While previous genetic studies have shed some light on the evolutionary relationships between European aurochs and modern cattle, important questions remain unanswered, including the phylogenetic status of aurochs, whether gene flow from aurochs into early domestic populations occurred, and which genomic regions were subject to selection processes during and after domestication. Here, we address these questions using whole-genome sequencing data generated from an approximately 6,750-year-old British aurochs bone and genome sequence data from 81 additional cattle plus genome-wide single nucleotide polymorphism data from a diverse panel of 1,225 modern animals. Results Phylogenomic analyses place the aurochs as a distinct outgroup to the domestic B. taurus lineage, supporting the predominant Near Eastern origin of European cattle. Conversely, traditional British and Irish breeds share more genetic variants with this aurochs specimen than other European populations, supporting localized gene flow from aurochs into the ancestors of modern British and Irish cattle, perhaps through purposeful restocking by early herders in Britain. Finally, the functions of genes showing evidence for positive selection in B. taurus are enriched for neurobiology, growth, metabolism and immunobiology, suggesting that these biological processes have been important in the domestication of cattle. Conclusions This work provides important new information regarding the origins and functional evolution of modern cattle, revealing that the interface between early European domestic populations and wild aurochs was significantly more complex than previously thought

Using genetic information from candidate gene and genome-wide association studies in risk prediction for alcohol dependence

Family-based and genome-wide association studies (GWAS) of alcohol dependence (AD) have reported numerous associated variants. The clinical validity of these variants for predicting AD compared with family history information has not been reported. Using the Collaborative Study on the Genetics of Alcoholism (COGA) and the Study of Addiction: Genes and Environment (SAGE) GWAS samples, we examined the aggregate impact of multiple single nucleotide polymorphisms (SNPs) on risk prediction. We created genetic sum scores by adding risk alleles associated in discovery samples, and then tested the scores for their ability to discriminate between cases and controls in validation samples. Genetic sum scores were assessed separately for SNPs associated with AD in candidate gene studies and SNPs from GWAS analyses that met varying P-value thresholds. Candidate gene sum scores did not exhibit significant predictive accuracy. Family history was a better classifier of case-control status, with a significant area under the receiver operating characteristic curve (AUC) of 0.686 in COGA and 0.614 in SAGE. SNPs that met less stringent P-value thresholds of 0.01-0.50 in GWAS analyses yielded significant AUC estimates, ranging from mean estimates of 0.549 for SNPs with P < 0.01 to 0.565 for SNPs with P < 0.50. This study suggests that SNPs currently have limited clinical utility, but there is potential for enhanced predictive ability with better understanding of the large number of variants that might contribute to risk

Meta-analysis of yield response of foliar fungicide-treated hybrid corn in the United States and Ontario, Canada

Background Foliar fungicide applications to corn (Zea mays L.) occur at one or more application timings ranging from early vegetative growth stages to mid-reproductive stages. Previous studies indicated that fungicide applications are profitable under high disease pressure when applied during the tasseling to silking growth stages. Few comprehensive studies in corn have examined the impact of fungicide applications at an early vegetative growth stage (V6) compared to late application timings (VT) for yield response and return on fungicide investment (ROI) across multiple locations. Objective Compare yield response of fungicide application timing across multiple fungicide classes and calculate the probability of positive ROI. Methods Data were collected specifically for this analysis using a uniform protocol conducted in 13 states in the United States and one province in Canada from 2014–2015. Data were subjected to a primary mixed-model analysis of variance. Subsequent univariate meta-analyses, with and without moderator variables, were performed using standard meta-analytic procedures. Follow-up power and prediction analyses were performed to aid interpretation and development of management recommendations. Results Fungicide application resulted in a range of yield responses from -2,683.0 to 3,230.9 kg/ha relative to the non-treated control, with 68.2% of these responses being positive. Evidence suggests that all three moderator variables tested (application timing, fungicide class, and disease base level), had some effect (α = 0.05) on the absolute difference in yield between fungicide treated and non-treated plots (). Application timing influenced , with V6 + VT and the VT application timings resulting in greater yield responses than the V6 application timing alone. Fungicide formulations that combined demethylation inhibitor and quinone outside inhibitor fungicides significantly increased yield response. Conclusion Foliar fungicide applications can increase corn grain yield. To ensure the likelihood of a positive ROI, farmers should focus on applications at VT and use fungicides that include a mix of demethylation inhibitor and quinone outside inhibitor active ingredients

Randomised trials comparing different healthcare settings : an exploratory review of the impact of pre-trial preferences on participation, and discussion of other methodological challenges

BACKGROUND: We recently published a systematic review of different healthcare settings (such as outpatient, community or home) for administering intravenous chemotherapy, and concluded that performing conventionally designed randomised trials was difficult. The main problems were achieving adequate trial accrual rates and recruiting a study population which adequately represented the target population of interest. These issues stemmed from the fact that potential participants may have had pre-trial perceptions about the trial settings they may be allocated; such preferences will sometimes be strong enough for patients to decline an invitation to participate in a trial. A patient preference trial design (in which patients can choose, or be randomised to, an intervention) may have obviated these recruitment issues, although none of the trials used such a design. METHODS: In order to gain a better understanding of the broader prevalence and extent of these preference issues (and any other methodological challenges), we undertook an exploratory review of settings trials in any area of healthcare treatment research. We searched The Cochrane Library and Google Scholar and used snowballing methods to identify trials comparing different healthcare settings. RESULTS: Trial accrual was affected by patient preferences for a setting in 15 of the 16 identified studies; birth setting trials were the most markedly affected, with between 68 % and 85 % of eligible women declining to participate specifically because of preference for a particular healthcare setting. Recruitment into substance abuse and chemotherapy setting studies was also notably affected by preferences. Only four trials used a preference design: the proportion of eligible patients choosing to participate via a preference group ranged from between 33 % and 67 %. CONCLUSIONS: In trials of healthcare settings, accrual may be seriously affected by patient preferences. The use of trial designs which incorporate a preference component should therefore strongly be considered. When designing such trials, investigators should consider settings to be complex interventions, which are likely to have linked components which may be difficult to control for. Careful thought is also needed regarding the choice of comparator settings and the most appropriate outcome measures to be used

In Vitro and In Vivo Characterization of the Alkaloid Nuciferine

RationaleThe sacred lotus (Nelumbo nucifera) contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes nuciferine using in vitro and in vivo pharmacological assays.MethodsNuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms.ResultsNuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT2A, 5-HT2C, and 5-HT2B, an inverse agonist at 5-HT7, a partial agonist at D2, D5 and 5-HT6, an agonist at 5-HT1A and D4 receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP)-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy.ConclusionsThe molecular profile of nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that nuciferine has atypical antipsychotic-like actions