Showing papers by "Research Triangle Park published in 2014"

An Integrated Risk Function for Estimating the Global Burden of Disease Attributable to Ambient Fine Particulate Matter Exposure

Abstract: Background: Estimating the burden of disease attributable to long-term exposure to fine particulate matter (PM2.5) in ambient air requires knowledge of both the shape and magnitude of the relative ...

QSAR Modeling: Where have you been? Where are you going to?

Abstract: Quantitative structure–activity relationship modeling is one of the major computational tools employed in medicinal chemistry. However, throughout its entire history it has drawn both praise and criticism concerning its reliability, limitations, successes, and failures. In this paper, we discuss (i) the development and evolution of QSAR; (ii) the current trends, unsolved problems, and pressing challenges; and (iii) several novel and emerging applications of QSAR modeling. Throughout this discussion, we provide guidelines for QSAR development, validation, and application, which are summarized in best practices for building rigorously validated and externally predictive QSAR models. We hope that this Perspective will help communications between computational and experimental chemists toward collaborative development and use of QSAR models. We also believe that the guidelines presented here will help journal editors and reviewers apply more stringent scientific standards to manuscripts reporting new QSAR stu...

Oral Glucocorticoid-Sparing Effect of Mepolizumab in Eosinophilic Asthma

Abstract: Background Many patients with severe asthma require regular treatment with oral glucocorticoids despite the use of high-dose inhaled therapy. However, the regular use of systemic glucocorticoids can result in serious and often irreversible adverse effects. Mepolizumab, a humanized monoclonal antibody that binds to and inactivates interleukin-5, has been shown to reduce asthma exacerbations in patients with severe eosinophilic asthma. Methods In a randomized, double-blind trial involving 135 patients with severe eosinophilic asthma, we compared the glucocorticoid-sparing effect of mepolizumab (at a dose of 100 mg) with that of placebo administered subcutaneously every 4 weeks for 20 weeks. The primary outcome was the degree of reduction in the glucocorticoid dose (90 to 100% reduction, 75 to less than 90% reduction, 50 to less than 75% reduction, more than 0 to less than 50% reduction, or no decrease in oral glucocorticoid dose, a lack of asthma control during weeks 20 to 24, or withdrawal from treatment)....

Pharmacotherapy for Adults With Alcohol Use Disorders in Outpatient Settings A Systematic Review and Meta-analysis

Abstract: prevent return to any drinking for acamprosate was 12 (95% CI, 8 to 26; risk difference [RD], −0.09; 95% CI, −0.14 to −0.04) and was 20 (95% CI, 11 to 500; RD, −0.05; 95% CI, −0.10 to −0.002) for oral naltrexone (50 mg/d). The NNT to prevent return to heavy drinking was 12 (95% CI, 8 to 26; RD −0.09; 95% CI, −0.13 to −0.04) for oral naltrexone (50 mg/d). Meta-analyses of trials comparing acamprosate to naltrexone found no statistically significant difference between them for return to any drinking (RD, 0.02; 95% CI, −0.03 to 0.08) or heavy drinking (RD, 0.01; 95% CI, −0.05 to 0.06). For injectable naltrexone, meta-analyses found no association with return to any drinking (RD, −0.04; 95% CI, −0.10 to 0.03) or heavy drinking (RD, −0.01; 95% CI, −0.14 to 0.13) but found an association with reduction in heavy drinking days (weighted mean difference [WMD], −4.6%; 95% CI, −8.5% to −0.56%). Among medications used off-label, moderate evidence supports an association with improvement in some consumption outcomes for nalmefene (heavy drinking days per month: WMD, −2.0; 95% CI, −3.0 to −1.0; drinks per drinking day: WMD, −1.02; 95% CI, −1.77 to −0.28) and topiramate (% heavy drinking days: WMD, −9.0%; 95% CI, −15.3% to −2.7%; drinks per drinking day: WMD, −1.0; 95% CI, −1.6 to −0.48). For naltrexone and nalmefene, NNHs for withdrawal from trials due to adverse events were 48 (95% CI, 30 to 112) and 12 (95% CI, 7 to 50), respectively; risk was not significantly increased for acamprosate or topiramate. CONCLUSIONS AND RELEVANCE Both acamprosate and oral naltrexone were associated with reduction in return to drinking. When directly compared with one another, no significant differences were found between acamprosate and naltrexone for controlling alcohol consumption. Factors such as dosing frequency, potential adverse events, and availability of treatments may guide medication choice.

Methods for estimating uncertainty in factor analytic solutions

Abstract: . The EPA PMF (Environmental Protection Agency positive matrix factorization) version 5.0 and the underlying multilinear engine-executable ME-2 contain three methods for estimating uncertainty in factor analytic models: classical bootstrap (BS), displacement of factor elements (DISP), and bootstrap enhanced by displacement of factor elements (BS-DISP). The goal of these methods is to capture the uncertainty of PMF analyses due to random errors and rotational ambiguity. It is shown that the three methods complement each other: depending on characteristics of the data set, one method may provide better results than the other two. Results are presented using synthetic data sets, including interpretation of diagnostics, and recommendations are given for parameters to report when documenting uncertainty estimates from EPA PMF or ME-2 applications.

Exploring genetic variation in the tomato (Solanum section Lycopersicon) clade by whole‐genome sequencing

Abstract: We explored genetic variation by sequencing a selection of 84 tomato accessions and related wild species representative of the Lycopersicon, Arcanum, Eriopersicon and Neolycopersicon groups, which has yielded a huge amount of precious data on sequence diversity in the tomato clade. Three new reference genomes were reconstructed to support our comparative genome analyses. Comparative sequence alignment revealed group-, species- and accession-specific polymorphisms, explaining characteristic fruit traits and growth habits in the various cultivars. Using gene models from the annotated Heinz 1706 reference genome, we observed differences in the ratio between non-synonymous and synonymous SNPs (dN/dS) in fruit diversification and plant growth genes compared to a random set of genes, indicating positive selection and differences in selection pressure between crop accessions and wild species. In wild species, the number of single-nucleotide polymorphisms (SNPs) exceeds 10 million, i.e. 20-fold higher than found in most of the crop accessions, indicating dramatic genetic erosion of crop and heirloom tomatoes. In addition, the highest levels of heterozygosity were found for allogamous self-incompatible wild species, while facultative and autogamous self-compatible species display a lower heterozygosity level. Using whole-genome SNP information for maximum-likelihood analysis, we achieved complete tree resolution, whereas maximum-likelihood trees based on SNPs from ten fruit and growth genes show incomplete resolution for the crop accessions, partly due to the effect of heterozygous SNPs. Finally, results suggest that phylogenetic relationships are correlated with habitat, indicating the occurrence of geographical races within these groups, which is of practical importance for Solanum genome evolution studies.

Ammonia Emissions in the United States, European Union, and China Derived by High-Resolution Inversion of Ammonium Wet Deposition Data: Interpretation with a New Agricultural Emissions Inventory (MASAGE_NH3)

Abstract: We use the adjoint of a global 3-D chemical transport model (GEOS-Chem) to optimize ammonia (NH3) emissions in the U.S., European Union, and China by inversion of 2005–2008 network data for NH4+ wet deposition fluxes. Optimized emissions are derived on a 2° × 2.5° grid for individual months and years. Error characterization in the optimization includes model errors in precipitation. Annual optimized emissions are 2.8 Tg NH3−N a−1 for the contiguous U.S., 3.1 Tg NH3−N a−1 for the European Union, and 8.4 Tg NH3−N a−1 for China. Comparisons to previous inventories for the U.S. and European Union show consistency (∼±15%) in annual totals but some large spatial and seasonal differences. We develop a new global bottom-up inventory of NH3 emissions (Magnitude And Seasonality of Agricultural Emissions model for NH3 (MASAGE_NH3)) to interpret the results of the adjoint optimization. MASAGE_NH3 provides information on the magnitude and seasonality of NH3 emissions from individual crop and livestock sources on a 0.5° × 0.5° grid. We find that U.S. emissions peak in the spring in the Midwest due to corn fertilization and in the summer elsewhere due to manure. The seasonality of European emissions is more homogeneous with a well-defined maximum in spring associated with manure and mineral fertilizer application. There is some evidence for the effect of European regulations of NH3 emissions, notably a large fall decrease in northern Europe. Emissions in China peak in summer because of the summertime application of fertilizer for double cropping.

Health Literacy Measurement: An Inventory and Descriptive Summary of 51 Instruments

Abstract: This article aimed to provide a descriptive review of the psychometric properties and conceptual dimensions of published health literacy measurement tools. PsycINFO and PubMed search from 1999 through 2013, review of the grey literature, and an environmental scan was conducted to identify health literacy measurement tools. For each tool, we evaluated the conceptual dimensions assessed, test parameters, and psychometric properties. Of the 51 tools identified, 26 measured general health literacy, and 15 were disease or content specific, and 10 aimed at specific populations. Most tools are performance based, require in-person administration, and are exclusively available in a pencil and paper testing mode. The tools assess 0 (proxy measure) to 9 of the 11 defined dimensions of health literacy. Reported administration times vary, from less than 1 to 60 minutes. Validation procedures for most of the tools are limited by inadequate power to ensure reliability across subgroups (i.e., race, age, ethnicity, and gender). The health literacy measurement tools currently available generally represent a narrow set of conceptual dimensions with limited modes of administration. Most of the tools lack information on key psychometric properties. Significant work is needed to establish important aspects of the construct, convergent, and predictive validity for many tools. As researchers develop new measures, inclusion of a full range of conceptual dimensions of health literacy, more representative sampling for testing, and additional modes of administration will allow a more refined and flexible approach to research in this field.

HIBAG—HLA genotype imputation with attribute bagging

Abstract: Genotyping of classical human leukocyte antigen (HLA) alleles is an essential tool in the analysis of diseases and adverse drug reactions with associations mapping to the major histocompatibility complex (MHC). However, deriving high-resolution HLA types subsequent to whole-genome single-nucleotide polymorphism (SNP) typing or sequencing is often cost prohibitive for large samples. An alternative approach takes advantage of the extended haplotype structure within the MHC to predict HLA alleles using dense SNP genotypes, such as those available from genome-wide SNP panels. Current methods for HLA imputation are difficult to apply or may require the user to have access to large training data sets with SNP and HLA types. We propose HIBAG, HLA Imputation using attribute BAGging, that makes predictions by averaging HLA-type posterior probabilities over an ensemble of classifiers built on bootstrap samples. We assess the performance of HIBAG using our study data (n=2668 subjects of European ancestry) as a training set and HLA data from the British 1958 birth cohort study (n≈1000 subjects) as independent validation samples. Prediction accuracies for HLA-A, B, C, DRB1 and DQB1 range from 92.2% to 98.1% using a set of SNP markers common to the Illumina 1M Duo, OmniQuad, OmniExpress, 660K and 550K platforms. HIBAG performed well compared with the other two leading methods, HLA*IMP and BEAGLE. This method is implemented in a freely available HIBAG R package that includes pre-fit classifiers for European, Asian, Hispanic and African ancestries, providing a readily available imputation approach without the need to have access to large training data sets.

Comparison of 2 transvaginal surgical approaches and perioperative behavioral therapy for apical vaginal prolapse: The OPTIMAL randomized trial

Abstract: Importance More than 300 000 surgeries are performed annually in the United States for pelvic organ prolapse. Sacrospinous ligament fixation (SSLF) and uterosacral ligament suspension (ULS) are commonly performed transvaginal surgeries to correct apical prolapse. Little is known about their comparative efficacy and safety, and it is unknown whether perioperative behavioral therapy with pelvic floor muscle training (BPMT) improves outcomes of prolapse surgery. Objective To compare outcomes between (1) SSLF and ULS and (2) perioperative BPMT and usual care in women undergoing surgery for vaginal prolapse and stress urinary incontinence. Design, Setting, and Participants Multicenter, 2 × 2 factorial, randomized trial of 374 women undergoing surgery to treat both apical vaginal prolapse and stress urinary incontinence was conducted between 2008 and 2013 at 9 US medical centers. Two-year follow-up rate was 84.5%. Interventions The surgical intervention was transvaginal surgery including midurethral sling with randomization to SSLF (n = 186) or ULS (n = 188); the behavioral intervention was randomization to receive perioperative BPMT (n = 186) or usual care (n = 188). Main Outcomes and Measures The primary outcome for the surgical intervention (surgical success) was defined as (1) no apical descent greater than one-third into vaginal canaloranterior or posterior vaginal wall beyond the hymen (anatomic success), (2) no bothersome vaginal bulge symptoms, and (3) no re-treatment for prolapse at 2 years. For the behavioral intervention, primary outcome at 6 months was urinary symptom scores (Urinary Distress Inventory; range 0-300, higher scores worse), and primary outcomes at 2 years were prolapse symptom scores (Pelvic Organ Prolapse Distress Inventory; range 0-300, higher scores worse) and anatomic success. Results At 2 years, surgical group was not significantly associated with surgical success rates (ULS, 64.5% [100/155] vs SSLF, 63.1% [94/149]; unadjusted difference, 1.4%; 95% CI, −9.4% to 12.2%; adjusted odds ratio [OR], 1.1; 95% CI, 0.7 to 1.7) or serious adverse event rates (ULS, 16.5% [31/188] vs SSLF, 16.7% [31/186]; unadjusted difference, −0.2%; 95% CI, −7.7% to 7.4%; adjusted OR, 0.9; 95% CI, 0.5 to 1.6). Perioperative BPMT was not associated with greater improvements in urinary scores at 6 months (adjusted treatment difference, −6.7; 95% CI, −19.7 to 6.2), prolapse scores at 24 months (adjusted treatment difference, −8.0; 95% CI, −22.1 to 6.1), or anatomic success at 24 months. Conclusions and Relevance Two years after vaginal surgery for prolapse and stress urinary incontinence, neither ULS nor SSLF was significantly superior to the other for anatomic, functional, or adverse event outcomes. Perioperative BPMT did not improve urinary symptoms at 6 months or prolapse outcomes at 2 years. Trial Registration clinicaltrials.gov Identifier:NCT00597935

Quality assessment of observational studies in a drug-safety systematic review, comparison of two tools: the Newcastle–Ottawa Scale and the RTI item bank

Abstract: Background The study objective was to compare the Newcastle–Ottawa Scale (NOS) and the RTI item bank (RTI-IB) and estimate interrater agreement using the RTI-IB within a systematic review on the cardiovascular safety of glucose-lowering drugs.

Dolutegravir in Antiretroviral-Experienced Patients With Raltegravir- and/or Elvitegravir-Resistant HIV-1: 24-Week Results of the Phase III VIKING-3 Study

Abstract: Background. The pilot phase IIb VIKING study suggested that dolutegravir (DTG), a human immunodeficiency virus (HIV) integrase inhibitor (INI), would be efficacious in INI-resistant patients at the 50 mg twice daily (BID) dose. Methods. VIKING-3 is a single-arm, open-label phase III study in which therapy-experienced adults with INIresistant virus received DTG 50 mg BID while continuing their failing regimen (without raltegravir or elvitegravir) through day 7, after which the regimen was optimized with ≥1 fully active drug and DTG continued. The primary efficacy endpoints were the mean change from baseline in plasma HIV-1 RNA at day 8 and the proportion of subjects with HIV-1 RNA <50 c/mL at week 24. Results. Mean change in HIV-1 RNA at day 8 was −1.43 log10 c/mL, and 69% of subjects achieved <50 c/mL at week 24. Multivariate analyses demonstrated a strong association between baseline DTG susceptibility and response. Response was most reduced in subjects with Q148+ ≥2 resistance-associated mutations. DTG 50 mg BID had a low (3%) discontinuation rate due to adverse events, similar to INI-naive subjects receiving DTG 50 mg once daily. Conclusions. DTG 50 mg BID–based therapy was effective in this highly treatment-experienced population with INI-resistant virus. Clinical Trials Registration. www.clinicaltrials.gov (NCT01328041) and http://www.gsk-clinicalstudywww.gskclinicalstudyregister.com (112574).

Exposure to Electronic Cigarette Television Advertisements Among Youth and Young Adults

Abstract: BACKGROUND AND OBJECTIVE: Currently, the US Food and Drug Administration does not regulate electronic cigarette (e-cigarette) marketing unless it is advertised as a smoking cessation aid. To date, the extent to which youth and young adults are exposed to e-cigarette television advertisements is unknown. The objective of this study was to analyze trends in youth and young adult exposure to e-cigarette television advertisements in the United States. METHODS: Nielsen data on television household audiences’ exposure to e-cigarette advertising across US markets were examined by calendar quarter, year, and sponsor. RESULTS: Youth exposure to television e-cigarette advertisements, measured by target rating points, increased 256% from 2011 to 2013. Young adult exposure increased 321% over the same period. More than 76% of all youth e-cigarette advertising exposure occurred on cable networks and was driven primarily by an advertising campaign for 1 e-cigarette brand. CONCLUSIONS: E-cigarette companies currently advertise their products to a broad audience that includes 24 million youth. The dramatic increase in youth and young adult television exposure between 2011 and 2013 was driven primarily by a large advertising campaign on national cable networks. In the absence of evidence-based public health messaging, the current e-cigarette television advertising may be promoting beliefs and behaviors that pose harm to the public health. If current trends in e-cigarette television advertising continue, awareness and use of e-cigarettes are likely to increase among youth and young adults.

Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial

Abstract: Summary Background In preclinical studies, davunetide promoted microtubule stability and reduced tau phosphorylation. Because progressive supranuclear palsy (PSP) is linked to tau pathology, davunetide could be a treatment for PSP. We assessed the safety and efficacy of davunetide in patients with PSP. Methods In a double-blind, parallel group, phase 2/3 trial, participants were randomly assigned with permuted blocks in a 1:1 ratio to davunetide (30 mg twice daily, intranasally) or placebo for 52 weeks at 48 centres in Australia, Canada, France, Germany, the UK, and the USA. Participants met the modified Neuroprotection and Natural History in Parkinson Plus Syndrome study criteria for PSP. Primary endpoints were the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England Activities of Daily Living (SEADL) scale at up to 52 weeks. All participants and study personnel were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with Clinicaltrials.gov, number NCT01110720. Findings 313 participants were randomly assigned to davunetide (n=157) or to placebo (n=156), and 241 (77%) completed the study (118 and 156 in the davunetide and placebo groups, respectively). There were no differences in the davunetide and placebo groups in the baseline PSPRS and SEADL. The davunetide and placebo groups did not differ in the change from baseline in PSPRS (median 11·8 [95% CI 10·5 to 13·0] vs 11·8 [10·5 to 13·0], respectively, p=0·41) or SEADL (−0·20 [−0·20 to −0·17] vs −0·20 [−0·22 to −0·17], respectively, p=0·92). 54 serious adverse events were reported in each of the treatment groups, including 11 deaths in the davunetide group and ten in the placebo group. The frequency of nasal adverse events was greater in the davunetide group than in the placebo group (epistaxis 18 [12%] of 156 vs 13 [8%] of 156, rhinorrhoea 15 [10%] vs eight [5%], and nasal discomfort 15 [10%] vs one [ Interpretation Davunetide is not an effective treatment for PSP. Clinical trials of disease-modifying treatment are feasible in patients with PSP and should be pursued with other promising tau-directed treatments. Funding Allon Therapeutics.

Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: A phase 2 study

Abstract: Objectives: We present the first study to explore safety and efficacy of the human CD20 monoclonal antibody ofatumumab in relapsing-remitting multiple sclerosis (RRMS). Methods: In this randomized, double-blind, placebo-controlled study, patients received 2 ofatumumab infusions (100 mg, 300 mg, or 700 mg) or placebo 2 weeks apart. At week 24, patients received alternate treatment. Safety and efficacy were assessed. Results: Thirty-eight patients were randomized (ofatumumab/placebo, n = 26; placebo/ofatumumab, n = 12) and analyzed; 36 completed the study. Two patients in the 300-mg group withdrew from the study because of adverse events. No unexpected safety signals emerged. Infusion-related reactions were common on the first infusion day but not observed on the second infusion day. None of the patients developed human anti-human antibodies. Ofatumumab was associated with profound selective reduction of B cells as measured by CD19 + expression. New brain MRI lesion activity was suppressed (>99%) in the first 24 weeks after ofatumumab administration (all doses), with statistically significant reductions ( p Conclusions: Ofatumumab (up to 700 mg) given 2 weeks apart was not associated with any unexpected safety concerns and was well tolerated in patients with RRMS. MRI data suggest a clinically meaningful effect of ofatumumab for all doses studied. Results warrant further exploration of ofatumumab in RRMS. Classification of evidence: This study provides Class II evidence that in patients with RRMS, ofatumumab compared with placebo does not increase the number of serious adverse events and decreases the number of new MRI lesions.

Women's experiences with oral and vaginal pre-exposure prophylaxis: the VOICE-C qualitative study in Johannesburg, South Africa.

Abstract: Background: In VOICE, a multisite HIV pre-exposure prophylaxis (PrEP) trial, plasma drug levels pointed to widespread product nonuse, despite high adherence estimated by self-reports and clinic product counts. Using a socio-ecological framework (SEF), we explored socio-cultural and contextual factors that influenced participants’ experience of daily vaginal gel and oral tablet regimens in VOICE. Methods: In Johannesburg, a qualitative ancillary study was concurrently conducted among randomly selected VOICE participants assigned to in-depth interviews (n=41), serial ethnographic interviews (n=21), or focus group discussions (n=40). Audiotaped interviews were transcribed, translated, and coded thematically for analysis. Results: Of the 102 participants, the mean age was 27 years, and 96% had a primary sex partner with whom 43% cohabitated. Few women reported lasting nonuse, which they typically attributed to missed visits, lack of product replenishments, and family-related travel or work. Women acknowledged occasionally skipping or mistiming doses because they forgot, were busy, felt lazy or bored, feared or experienced side effects. However, nearly all knew or heard of other study participants who did not use products daily. Three overarching themes emerged from further analyses: ambivalence toward research, preserving a healthy status, and managing social relationships. These themes highlighted the profound and complex meanings associated with participating in a blinded HIV PrEP trial and taking antiretroviral-based products. The unknown efficacy of products, their connection with HIV infection, challenges with daily regimen given social risks, lack of support–from partners and significant others–and the relationship tradeoffs entailed by using the products appear to discourage adequate product use. Conclusions: Personal acknowledgment of product nonuse was challenging. This qualitative inquiry highlighted key influences at all SEF levels that shaped women’s perceptions of trial participation and experiences with investigational products. Whether these impacted women’s behaviors and may have contributed to ineffective trial results warrants further investigation.

Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus.

Abstract: Metformin, a biguanide derivate, has pleiotropic effects beyond glucose reduction, including improvement of lipid profiles and lowering microvascular and macrovascular complications associated with type 2 diabetes mellitus (T2DM). These effects have been ascribed to adenosine monophosphate-activated protein kinase (AMPK) activation in the liver and skeletal muscle. However, metformin effects are not attenuated when AMPK is knocked out and intravenous metformin is less effective than oral medication, raising the possibility of important gut pharmacology. We hypothesized that the pharmacology of metformin includes alteration of bile acid recirculation and gut microbiota resulting in enhanced enteroendocrine hormone secretion. In this study we evaluated T2DM subjects on and off metformin monotherapy to characterize the gut-based mechanisms of metformin. Subjects were studied at 4 time points: (i) at baseline on metformin, (ii) 7 days after stopping metformin, (iii) when fasting blood glucose (FBG) had risen by 25% after stopping metformin, and (iv) when FBG returned to baseline levels after restarting the metformin. At these timepoints we profiled glucose, insulin, gut hormones (glucagon-like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY) and glucose-dependent insulinotropic peptide (GIP) and bile acids in blood, as well as duodenal and faecal bile acids and gut microbiota. We found that metformin withdrawal was associated with a reduction of active and total GLP-1 and elevation of serum bile acids, especially cholic acid and its conjugates. These effects reversed when metformin was restarted. Effects on circulating PYY were more modest, while GIP changes were negligible. Microbiota abundance of the phylum Firmicutes was positively correlated with changes in cholic acid and conjugates, while Bacteroidetes abundance was negatively correlated. Firmicutes and Bacteroidetes representation were also correlated with levels of serum PYY. Our study suggests that metformin has complex effects due to gut-based pharmacology which might provide insights into novel therapeutic approaches to treat T2DM and associated metabolic diseases.

Microbial terroir for wine grapes

Abstract: The viticulture industry has been selectively growing vine cultivars with different traits (grape size, shape, color, flavor, yield of fruit, and so forth) for millennia, and small variations in soil composition, water management, climate, and the aspect of vineyards have long been associated with shifts in these traits. As such, many different clonal varieties of vines exist, even within given grape varieties, such as merlot, pinot noir, and chardonnay. The commensal microbial flora that coexists with the plant may be one of the key factors that influence these traits. To date, the role of microbes has been largely ignored, outside of microbial pathogens, mainly because the technologies did not exist to allow us to look in any real depth or breadth at the community structure of the multitudes of bacterial and fungal species associated with each plant. In PNAS, Bokulich et al. (1) used next-generation sequencing of 16S rRNA and internal transcribed spacer ribosomal sequence to determine the relative abundances of bacteria and fungi, respectively, from grape must (freshly pressed grape juice, containing the skins and seeds) from plants in eight vineyards representing four of the major wine growing regions in California. The authors show that the microbiomes (bacterial and fungal taxonomic structure) associated with this early fermentation stage show defined biogeography, illustrating that different wine-growing regions maintain different microbial communities, with some influences from the grape variety and the year of production.

HARMONY 3: 104-week randomized, double-blind, placebo- and active-controlled trial assessing the efficacy and safety of albiglutide compared with placebo, sitagliptin, and glimepiride in patients with type 2 diabetes taking metformin.

Abstract: OBJECTIVE To compare the efficacy and safety of weekly albiglutide with daily sitagliptin, daily glimepiride, and placebo. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes receiving metformin were randomized to albiglutide (30 mg), sitagliptin (100 mg), glimepiride (2 mg), or placebo. Blinded dose titration for albiglutide (to 50 mg) and glimepiride (to 4 mg) was based on predefined hyperglycemia criteria. The primary end point was change in HbA 1c from baseline at week 104. Secondary end points included fasting plasma glucose (FPG), weight, and time to hyperglycemic rescue. RESULTS Baseline characteristics were similar among the albiglutide ( n = 302), glimepiride ( n = 307), sitagliptin ( n = 302), and placebo ( n = 101) groups. Baseline HbA 1c was 8.1% (65.0 mmol/mol); mean age was 54.5 years. The mean doses for albiglutide and glimepiride at week 104 were 40.5 and 3.1 mg, respectively. At week 104, albiglutide significantly reduced HbA 1c compared with placebo (−0.9% [−9.8 mmol/mol]; P P = 0.0001), and glimepiride (−0.3% [−3.3 mmol/mol]; P = 0.0033). Outcomes for FPG and HbA 1c were similar. Weight change from baseline for each were as follows: albiglutide −1.21 kg (95% CI −1.68 to −0.74), placebo −1.00 kg (95% CI −1.81 to −0.20), sitagliptin −0.86 kg (95% CI −1.32 to −0.39), glimepiride 1.17 kg (95% CI 0.70–1.63). The difference between albiglutide and glimepiride was statistically significant ( P P P = 0.0118), and 32.7% ( P = 0.1504) for placebo, sitagliptin, and glimepiride, respectively. Rates of serious adverse events in the albiglutide group were similar to comparison groups. Diarrhea (albiglutide 12.9%, other groups 8.6–10.9%) and nausea (albiglutide 10.3%, other groups 6.2–10.9%) were generally the most frequently reported gastrointestinal events. CONCLUSION Added to metformin, albiglutide was well-tolerated; produced superior reductions in HbA 1c and FPG at week 104 compared with placebo, sitagliptin, and glimepiride; and resulted in weight loss compared with glimepiride.

Perfluoroalkyl acid distribution in various plant compartments of edible crops grown in biosolids-amended soils.

Abstract: Crop uptake of perfluoroalkyl acids (PFAAs) from biosolids-amended soil has been identified as a potential pathway for PFAA entry into the terrestrial food chain. This study compared the uptake of PFAAs in greenhouse-grown radish (Raphanus sativus), celery (Apium graveolens var. dulce), tomato (Lycopersicon lycopersicum), and sugar snap pea (Pisum sativum var. macrocarpon) from an industrially impacted biosolids-amended soil, a municipal biosolids-amended soil, and a control soil. Individual concentrations of PFAAs, on a dry weight basis, in mature, edible portions of crops grown in soil amended with PFAA industrially impacted biosolids were highest for perfluorooctanoate (PFOA; 67 ng/g) in radish root, perfluorobutanoate (PFBA; 232 ng/g) in celery shoot, and PFBA (150 ng/g) in pea fruit. Comparatively, PFAA concentrations in edible compartments of crops grown in the municipal biosolids-amended soil and in the control soil were less than 25 ng/g. Bioaccumulation factors (BAFs) were calculated for the root, shoot, and fruit compartments (as applicable) of all crops grown in the industrially impacted soil. BAFs were highest for PFBA in the shoots of all crops, as well as in the fruit compartment of pea. Root-soil concentration factors (RCFs) for tomato and pea were independent of PFAA chain length, while radish and celery RCFs showed a slight decrease with increasing chain length. Shoot-soil concentration factors (SCFs) for all crops showed a decrease with increasing chain length (0.11 to 0.36 log decrease per CF2 group). The biggest decrease (0.54-0.58 log decrease per CF2 group) was seen in fruit-soil concentration factors (FCFs). Crop anatomy and PFAA properties were utilized to explain data trends. In general, fruit crops were found to accumulate fewer long-chain PFAAs than shoot or root crops presumably due to an increasing number of biological barriers as the contaminant is transported throughout the plant (roots to shoots to fruits). These data were incorporated into a preliminary conceptual framework for PFAA accumulation in edible crops. In addition, these data suggest that edible crops grown in soils conventionally amended for nutrients with biosolids (that are not impacted by PFAA industries) are unlikely a significant source of long-chain PFAA exposure to humans.

Implementing and evaluating shared decision making in oncology practice.

Abstract: Engaging individuals with cancer in decision making about their treatments has received increased attention; shared decision making (SDM) has become a hallmark of patient-centered care. Although physicians indicate substantial interest in SDM, implementing SDM in cancer care is often complex; high levels of uncertainty may exist, and health care providers must help patients understand the potential risks versus benefits of different treatment options. However, patients who are more engaged in their health care decision making are more likely to experience confidence in and satisfaction with treatment decisions and increased trust in their providers. To implement SDM in oncology practice, physicians and other health care providers need to understand the components of SDM and the approaches to supporting and facilitating this process as part of cancer care. This review summarizes recent information regarding patient and physician factors that influence SDM for cancer care, outcomes resulting from successful SDM, and strategies for implementing SDM in oncology practice. We present a conceptual model illustrating the components of SDM in cancer care and provide recommendations for facilitating SDM in oncology practice.

U.S. national PM2.5 Chemical Speciation Monitoring Networks-CSN and IMPROVE: description of networks.

Abstract: The US. EnvironmentalProtection Agency (EPA) initiated the national PM2.5 Chemical Speciation Monitoring Network (CSN) in 2000 to support evaluation of long-term trends and to better quantify the impact of sources on particulate matter (PM) concentrations in the size range below 2.5 μm aerodynamic diameter (PM2.5; fine particles). The network peaked at more than 260 sites in 2005. In response to the 1999 Regional Haze Rule and the need to better understand the regional transport of PM, EPA also augmented the long-existing Interagency Monitoring of Protected Visual Environments (IMPROVE) visibility monitoring network in 2000, adding nearly 100 additional IMPROVE sites in rural Class 1 Areas across the country. Both networks measure the major chemical components of PM2.5 using historically accepted filter-based methods. Components measured by both networks include major anions, carbonaceous material, and a series of trace elements. CSN also measures ammonium and other cations directly, whereas IMPROVE estimates ammonium assuming complete neutralization of the measured sulfate and nitrate. IMPROVE also measures chloride and nitrite. In general, the field and laboratory approaches used in the two networks are similar; however, there are numerous, often subtle differences in sampling and chemical analysis methods, shipping, and quality control practices. These could potentially affect merging the two data sets when used to understand better the impact of sources on PM concentrations and the regional nature and long-range transport of PM2zs. This paper describes, for the first time in the peer-reviewed literature, these networks as they have existed since 2000, outlines differences infield and laboratory approaches, provides a summary of the analytical parameters that address data uncertainty, and summarizes major network changes since the inception of CSN. Implications: Two long-term chemical speciation particle monitoring networks have operated simultaneously in the United States since 2001, when the EPA began regular operations of its PM2.5 Chemical Speciation Monitoring Network (IMPROVE began in 1988). These networks use similar field sampling and analytical methods, but there are numerous, often subtle differences in equipment and methodologies that can affect the results. This paper describes these networks since 20000 (inception of CSN) and their differences, and summarizes the analytical parameters that address data uncertainty, providing researches and policymakers with background information they may need (e.g., for 2018 PM2.5 designation and State Implementation Plan process; McCarthy, 2013) to assess results from each network and decide how these data sets can be mutually employed for enhanced analyses. Changes in CSN and IMPROVE that have occurred over the years also are described.

Advancing Basal Insulin Replacement in Type 2 Diabetes Inadequately Controlled With Insulin Glargine Plus Oral Agents: A Comparison of Adding Albiglutide, a Weekly GLP-1 Receptor Agonist, Versus Thrice-Daily Prandial Insulin Lispro

Abstract: OBJECTIVE GLP-1 receptor agonists may provide an alternative to prandial insulin for advancing basal insulin therapy. Harmony 6 was a randomized, open-label, active-controlled trial testing once-weekly albiglutide vs thrice-daily prandial insulin lispro as an add-on to titrated once-daily insulin glargine. RESEARCH DESIGN AND METHODS Patients taking basal insulin (with or without oral agents) with HbA 1c 7–10.5% (53–91 mmol/mol) entered a glargine standardization period, followed by randomization to albiglutide, 30 mg weekly ( n = 282), subsequently uptitrated to 50 mg, if necessary, or thrice-daily prandial lispro ( n = 281) while continuing metformin and/or pioglitazone. Glargine was titrated to fasting plasma glucose of 1c change from baseline at week 26. RESULTS At week 26, HbA 1c decreased from baseline by −0.82 ± SE 0.06% (9.0 mmol/mol) with albiglutide and −0.66 ± 0.06% (7.2 mmol/mol) with lispro; treatment difference, −0.16% (95% CI −0.32 to 0.00; 1.8 mmol/mol; P CONCLUSIONS Weekly albiglutide is a simpler therapeutic option than thrice-daily lispro for advancing basal insulin glargine therapy, resulting in comparable HbA 1c reduction with weight loss and lower hypoglycemia risk.

Brief Intervention for Problem Drug Use in Safety-Net Primary Care Settings: A Randomized Clinical Trial

Abstract: Importance Although brief intervention is effective for reducing problem alcohol use, few data exist on its effectiveness for reducing problem drug use, a common issue in disadvantaged populations seeking care in safety-net medical settings (hospitals and community health clinics serving low-income patients with limited or no insurance). Objective To determine whether brief intervention improves drug use outcomes compared with enhanced care as usual. Design, Setting, and Participants A randomized clinical trial with blinded assessments at baseline and at 3, 6, 9, and 12 months conducted in 7 safety-net primary care clinics in Washington State. Of 1621 eligible patients reporting any problem drug use in the past 90 days, 868 consented and were randomized between April 2009 and September 2012. Follow-up participation was more than 87% at all points. Interventions Participants received a single brief intervention using motivational interviewing, a handout and list of substance abuse resources, and an attempted 10-minute telephone booster within 2 weeks (n = 435) or enhanced care as usual, which included a handout and list of substance abuse resources (n = 433). Main Outcomes and Measures The primary outcomes were self-reported days of problem drug use in the past 30 days and Addiction Severity Index–Lite (ASI) Drug Use composite score. Secondary outcomes were admission to substance abuse treatment; ASI composite scores for medical, psychiatric, social, and legal domains; emergency department and inpatient hospital admissions, arrests, mortality, and human immunodeficiency virus risk behavior. Results Mean days used of the most common problem drug at baseline were 14.40 (SD, 11.29) (brief intervention) and 13.25 (SD, 10.69) (enhanced care as usual); at 3 months postintervention, means were 11.87 (SD, 12.13) (brief intervention) and 9.84 (SD, 10.64) (enhanced care as usual) and not significantly different (difference in differences, β = 0.89 [95% CI, −0.49 to 2.26]). Mean ASI Drug Use composite score at baseline was 0.11 (SD, 0.10) (brief intervention) and 0.11 (SD, 0.10) (enhanced care as usual) and at 3 months was 0.10 (SD, 0.09) (brief intervention) and 0.09 (SD, 0.09) (enhanced care as usual) and not significantly different (difference in differences, β = 0.008 [95% CI, −0.006 to 0.021]). During the 12 months following intervention, no significant treatment differences were found for either variable. No significant differences were found for secondary outcomes. Conclusions and Relevance A one-time brief intervention with attempted telephone booster had no effect on drug use in patients seen in safety-net primary care settings. This finding suggests a need for caution in promoting widespread adoption of this intervention for drug use in primary care. Trial Registration clinicaltrials.gov Identifier:NCT00877331