Showing papers by "Research Triangle Park published in 2013"
TL;DR: The SPIRIT 2013 Explanation and Elaboration paper provides important information to promote full understanding of the checklist recommendations and strongly recommends that this explanatory paper be used in conjunction with the SPIRit Statement.
Abstract: High quality protocols facilitate proper conduct, reporting, and external review
of clinical trials. However, the completeness of trial protocols is often
inadequate. To help improve the content and quality of protocols, an
international group of stakeholders developed the SPIRIT 2013 Statement
(Standard Protocol Items: Recommendations for Interventional Trials). The SPIRIT
Statement provides guidance in the form of a checklist of recommended items to
include in a clinical trial protocol. This SPIRIT 2013 Explanation and Elaboration paper provides important
information to promote full understanding of the checklist recommendations. For
each checklist item, we provide a rationale and detailed description; a model
example from an actual protocol; and relevant references supporting its
importance. We strongly recommend that this explanatory paper be used in
conjunction with the SPIRIT Statement. A website of resources is also available
(www.spirit-statement.org). The SPIRIT 2013 Explanation and Elaboration paper, together with the Statement,
should help with the drafting of trial protocols. Complete documentation of key
trial elements can facilitate transparency and protocol review for the benefit
of all stakeholders.
3,108 citations
University of Ottawa1, Health Science University2, University of York3, University of Warwick4, Abu Dhabi Indian School5, Ottawa Hospital Research Institute6, Ben-Gurion University of the Negev7, Tufts Medical Center8, University of Buenos Aires9, University of Glasgow10, Research Triangle Park11, Brigham and Women's Hospital12
TL;DR: The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement is an attempt to consolidate and update previous health economic evaluation guidelines into one current, useful reporting guidance and it is hoped that this guidance will lead to more consistent and transparent reporting, and ultimately, better health decisions.
1,563 citations
TL;DR: The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement as mentioned in this paper is an attempt to consolidate and update previous health economic evaluation guidelines efforts into one current, useful reporting guidance.
Abstract: Economic evaluations of health interventions pose a particular challenge for reporting. There is also a need to consolidate and update existing guidelines and promote their use in a user friendly manner. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement is an attempt to consolidate and update previous health economic evaluation guidelines efforts into one current, useful reporting guidance. The primary audiences for the CHEERS statement are researchers reporting economic evaluations and the editors and peer reviewers assessing them for publication. The need for new reporting guidance was identified by a survey of medical editors. A list of possible items based on a systematic review was created. A two round, modified Delphi panel consisting of representatives from academia, clinical practice, industry, government, and the editorial community was conducted. Out of 44 candidate items, 24 items and accompanying recommendations were developed. The recommendations are contained in a user friendly, 24 item checklist. A copy of the statement, accompanying checklist, and this report can be found on the ISPOR Health Economic Evaluations Publication Guidelines Task Force website (www.ispor.org/TaskForces/ EconomicPubGuidelines.asp). We hope CHEERS will lead to better reporting, and ultimately, better health decisions. To facilitate dissemination and uptake, the CHEERS statement is being co-published across 10 health economics and medical journals. We encourage other journals and groups, to endorse CHEERS. The author team plans to review the checklist for an update in five years.
1,454 citations
TL;DR: This report provides an overview of the role of experimental designs for the successful implementation of the DCE approach in health care studies and provides researchers with an introduction to constructing experimental designs on the basis of study objectives and the statistical model researchers have selected for the study.
1,042 citations
Health Science University1, University of Ottawa2, University of York3, University of Warwick4, Abu Dhabi Indian School5, Ottawa Hospital Research Institute6, Ben-Gurion University of the Negev7, Tufts Medical Center8, University of Buenos Aires9, University of Glasgow10, Research Triangle Park11, Brigham and Women's Hospital12
TL;DR: The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement is an attempt to consolidate and update previous health economic evaluation guidelines efforts into one current, useful reporting guidance.
Abstract: Economic evaluations of health interventions pose a particular challenge for reporting. There is also a need to consolidate and update existing guidelines and promote their use in a user friendly manner. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement is an attempt to consolidate and update previous health economic evaluation guidelines efforts into one current, useful reporting guidance. The primary audiences for the CHEERS statement are researchers reporting economic evaluations and the editors and peer reviewers assessing them for publication. The need for new reporting guidance was identified by a survey of medical editors. A list of possible items based on a systematic review was created. A two round, modified Delphi panel consisting of representatives from academia, clinical practice, industry, government, and the editorial community was conducted. Out of 44 candidate items, 24 items and accompanying recommendations were developed. The recommendations are contained in a user friendly, 24 item checklist. A copy of the statement, accompanying checklist, and this report can be found on the ISPOR Health Economic Evaluations Publication Guidelines Task Force website (
www.ispor.org/TaskForces/EconomicPubGuidelines.asp
). We hope CHEERS will lead to better reporting, and ultimately, better health decisions. To facilitate dissemination and uptake, the CHEERS statement is being co-published across 10 health economics and medical journals. We encourage other journals and groups, to endorse CHEERS. The author team plans to review the checklist for an update in five years.
697 citations
TL;DR: Air pollution monitoring paradigm is rapidly changing due to recent advances in the development of portable, lower-cost air pollution sensors reporting data in near-real time at a high-time resolution, increased computational and visualization capabilities, and wireless communication/infrastructure.
Abstract: The air pollution monitoring paradigm is rapidly changing due to recent advances in (1) the development of portable, lower-cost air pollution sensors reporting data in near-real time at a high-time...
653 citations
TL;DR: If approved, combination treatment with once-daily dolutegravir and fixed-dose nucleoside reverse transcriptase inhibitors would be an effective new option for treatment of HIV-1 in treatment-naive patients.
467 citations
TL;DR: Once-daily dolutegravir, in combination with up to two other antiretroviral drugs, is well tolerated with greater virological effect compared with twice-daily raltegravIR in this treatment-experienced patient group.
449 citations
TL;DR: The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement is an attempt to consolidate and update previous health economic evaluation guidelines efforts into one current, useful reporting guidance.
Abstract: Economic evaluations of health interventions pose a particular challenge for reporting. There is also a need to consolidate and update existing guidelines and promote their use in a user friendly manner. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement is an attempt to consolidate and update previous health economic evaluation guidelines efforts into one current, useful reporting guidance. The primary audiences for the CHEERS statement are researchers reporting economic evaluations and the editors and peer reviewers assessing them for publication. The need for new reporting guidance was identified by a survey of medical editors. A list of possible items based on a systematic review was created. A two round, modified Delphi panel consisting of representatives from academia, clinical practice, industry, government, and the editorial community was conducted. Out of 44 candidate items, 24 items and accompanying recommendations were developed. The recommendations are contained in a user friendly, 24 item checklist. A copy of the statement, accompanying checklist, and this report can be found on the ISPOR Health Economic Evaluations Publication Guidelines Task Force website (
http://www.ispor.org/TaskForces/EconomicPubGuidelines.asp
). We hope CHEERS will lead to better reporting, and ultimately, better health decisions. To facilitate dissemination and uptake, the CHEERS statement is being co-published across 10 health economics and medical journals. We encourage other journals and groups, to endorse CHEERS. The author team plans to review the checklist for an update in five years.
435 citations
TL;DR: Various traditional and novel in vitro liver models are described and a perspective on the challenges and opportunities afforded by each individual test system is provided.
Abstract: Over the years, various liver-derived in vitro model systems have been developed to enable investigation of the potential adverse effects of chemicals and drugs. Liver tissue slices, isolated microsomes, perfused liver, immortalized cell lines, and primary hepatocytes have been used extensively. Immortalized cell lines and primary isolated liver cells are currently the most widely used in vitro models for liver toxicity testing. Limited throughput, loss of viability, and decreases in liver-specific functionality and gene expression are common shortcomings of these models. Recent developments in the field of in vitro hepatotoxicity include three-dimensional tissue constructs and bioartificial livers, co-cultures of various cell types with hepatocytes, and differentiation of stem cells into hepatic lineage-like cells. In an attempt to provide a more physiological environment for cultured liver cells, some of the novel cell culture systems incorporate fluid flow, micro-circulation, and other forms of organotypic microenvironments. Co-cultures aim to preserve liver-specific morphology and functionality beyond those provided by cultures of pure parenchymal cells. Stem cells, both embryonic- and adult tissue-derived, may provide a limitless supply of hepatocytes from multiple individuals to improve reproducibility and enable testing of the individual-specific toxicity. This review describes various traditional and novel in vitro liver models and provides a perspective on the challenges and opportunities afforded by each individual test system.
405 citations
TL;DR: It is suggested that loss of trees to the emerald ash borer increased mortality related to cardiovascular and lower-respiratory-tract illness, adding to the growing evidence that the natural environment provides major public health benefits.
TL;DR: This review has been split and updated as two reviews: Rubinstein SM, van Middelkoop M, Assendelft WJJ, de Boer MR, van Tulder MW, Spinal manipulative therapy for chronic low-back pain.
Abstract: Reason for withdrawal from publication
This review has been split and updated as two reviews:
Rubinstein SM, van Middelkoop M, Assendelft WJJ, de Boer MR, van Tulder MW. Spinal manipulative therapy for chronic low-back pain. Cochrane Database of Systematic Reviews 2011, Issue 2. Art. No.: CD008112. DOI: 10.1002/14651858.CD008112.pub2.
Rubinstein SM, Terwee CB, Assendelft WJJ, de Boer MR, van Tulder MW. Spinal manipulative therapy for acute low-back pain. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD008880. DOI: 10.1002/14651858.CD008880.pub2.
TL;DR: Once-daily dosing without requirement for a pharmacokinetic booster makes dolutegravir-based therapy an attractive treatment option for HIV-1-infected treatment-naive patients.
Abstract: Summary Background In the primary analysis of SPRING-2 at week 48, dolutegravir showed non-inferior efficacy to and similar tolerability to raltegravir in adults infected with HIV-1 and naive for antiretroviral treatment. We present the 96 week results. Methods SPRING-2 is an ongoing phase 3, randomised, double-blind, active-controlled, non-inferiority study in treatment-naive adults infected with HIV-1 that started in Oct 19, 2010. We present results for the safety cutoff date of Jan 30, 2013. Patients had to be aged 18 years or older and have HIV-1 RNA concentrations of 1000 copies per mL or more. Patients were randomly assigned (1:1) to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily), plus investigator-selected tenofovir–emtricitabine or abacavir–lamivudine. Prespecified 96 week secondary endpoints included proportion of patients with HIV-1 RNA less than 50 copies per mL, CD4 cell count changes from baseline, safety, tolerability, and genotypic or phenotypic resistance. We used an intention-to-treat exposed population (received at least one dose of study drug) for the analyses. Sponsor staff were masked to treatment assignment until primary analysis at week 48; investigators, site staff, and patients were masked until week 96. This study is registered with ClinicalTrials.gov, NCT01227824. Findings Of 1035 patients screened, 827 were randomly assigned to study group, and 822 received at least one dose of the study drug (411 patients in each group). At week 96, 332 (81%) of 411 patients in the dolutegravir group and 314 (76%) of 411 patients in the raltegravir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 4·5%, 95% CI −1·1% to 10·0%) confirming non-inferiority. Secondary analyses of efficacy such as per protocol (HIV RNA vs 43 [10%] patients for raltegravir). Median increases in CD4 cell count from baseline were similar between groups (276 cells per μL for dolutegravir and 264 cells per μL for raltegravir). Ten patients (2%) in each group discontinued because of adverse events, with few such events between weeks 48 and 96 (zero in the dolutegravir group and one in the raltegravir group). No study-related serious adverse events occurred between week 48 and week 96. At virological failure, no additional resistance to integrase inhibitors or nucleotide reverse transcriptase inhibitors was detected since week 48 or in any patient receiving dolutegravir. Interpretation At week 96, once-daily dolutegravir was non-inferior to twice-daily raltegravir in treatment-naive, patients with HIV-1. Once-daily dosing without requirement for a pharmacokinetic booster makes dolutegravir-based therapy an attractive treatment option for HIV-1-infected treatment-naive patients. Funding ViiV Healthcare.
TL;DR: The NLCD 2006 dataset as discussed by the authors provides the first wall-to-wall land-cover change database for the conterminous United States from Landsat Thematic Mapper (TM) data.
University of Edinburgh1, Research Triangle Park2, University of Barcelona3, University of Bergen4, Brigham and Women's Hospital5, University of British Columbia6, University of Cambridge7, GlaxoSmithKline8, University of Nebraska Medical Center9, University of Southern Denmark10, Manchester Academic Health Science Centre11, Maastricht University Medical Centre12
TL;DR: COPD and cardiovascular disease was associated with poorer quality of life, higher MRC dyspnea scores, reduced 6MWD, higher BODE index scores, and the comorbidities of heart disease, hypertension and diabetes are associated with increased systemic inflammation.
TL;DR: Computational techniques for systematic analysis of transcriptomics, side effects, and genetics data to generate new hypotheses for additional indications and data domains such as electronic health records (EHRs) and phenotypic screening that are considered promising for novel computational repositioning methods are discussed.
Abstract: Traditionally, most drugs have been discovered using phenotypic or target-based screens. Subsequently, their indications are often expanded on the basis of clinical observations, providing additional benefit to patients. This review highlights computational techniques for systematic analysis of transcriptomics (Connectivity Map, CMap), side effects, and genetics (genome-wide association study, GWAS) data to generate new hypotheses for additional indications. We also discuss data domains such as electronic health records (EHRs) and phenotypic screening that we consider promising for novel computational repositioning methods.
TL;DR: A collection of 400 chemotypes, selected based on their drug-like properties and the others as molecular probes, are assembled, termed the Malaria Box, and can now be requested as a pharmacological test set by malaria biologists, but importantly by groups working on related parasites.
Abstract: Historically, one of the key problems in neglected disease drug discovery has been identifying new and interesting chemotypes. Phenotypic screening of the malaria parasite, Plasmodium falciparum has yielded almost 30,000 submicromolar hits in recent years. To make this collection more accessible, a collection of 400 chemotypes has been assembled, termed the Malaria Box. Half of these compounds were selected based on their drug-like properties and the others as molecular probes. These can now be requested as a pharmacological test set by malaria biologists, but importantly by groups working on related parasites, as part of a program to make both data and compounds readily available. In this paper, the analysis and selection methodology and characteristics of the compounds are described.
TL;DR: Few studies were identified that compared consumers' ability to select healthier products using nutrient-specific FOP nutrition labels that incorporate text and color codes with multiple-level summary icons, and more research is needed to assess the influence of nutrient- specific labels on consumers' purchases.
Abstract: As standards are considered for nutrition front-of-package (FOP) and shelf-labeling systems in the United States, it is important to know what types of systems are most effective in conveying scientifically accurate and useful information to consumers. A systematic literature review identified 38 empirical studies on consumer response to FOP nutrition labeling and shelf labeling. Studies indicate that consumers can more easily interpret and select healthier products with nutrient-specific FOP nutrition labels that incorporate text and symbolic color to indicate nutrient levels rather than nutrient-specific labels that only emphasize numeric information, such as Guideline Daily Amounts expressed as percentages and/or grams. Summary systems may influence consumers to purchase healthier products. However, more research is needed to assess the influence of nutrient-specific labels on consumers’ purchases. This review identified few studies that compared consumers’ ability to select healthier products using nutrient-specific systems that incorporate text and color codes with multiple-level summary icons. More research is needed to determine the effects of FOP nutrition labeling on consumers’ actual shopping behaviors and dietary intakes.
University of Alabama at Birmingham1, McGill University2, St George's, University of London3, Baylor College of Medicine4, Dartmouth College5, University of Manchester6, University of Southern Denmark7, Odense University Hospital8, University of Michigan9, Research Triangle Park10, GlaxoSmithKline11, University of Liverpool12
TL;DR: Addition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD in patients with a history of exacerbation, but was also associated with an increased pneumonia risk.
TL;DR: Around the world, hypertension and obesity, separately or together, are common comorbidities in adults with T2DM.
Abstract: Background
Hypertension and obesity are known to contribute, directly or indirectly, to the development of long-term complications of type 2 diabetes mellitus (T2DM). Knowing the prevalence of these comorbidities is important for determining the size of the population that may benefit from strategies that reduce blood pressure and weight while controlling blood glucose.
TL;DR: The discovery of inhibitors that fill this void with an unprecedented metal-binding group, trifluoromethyloxadiazole (TFMO), which circumvents the selectivity and pharmacologic liabilities of hydroxamates is reported.
Abstract: In contrast to studies on class I histone deacetylase (HDAC) inhibitors, the elucidation of the molecular mechanisms and therapeutic potential of class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) is impaired by the lack of potent and selective chemical probes. Here we report the discovery of inhibitors that fill this void with an unprecedented metal-binding group, trifluoromethyloxadiazole (TFMO), which circumvents the selectivity and pharmacologic liabilities of hydroxamates. We confirm direct metal binding of the TFMO through crystallographic approaches and use chemoproteomics to demonstrate the superior selectivity of the TFMO series relative to a hydroxamate-substituted analog. We further apply these tool compounds to reveal gene regulation dependent on the catalytic active site of class IIa HDACs. The discovery of these inhibitors challenges the design process for targeting metalloenzymes through a chelating metal-binding group and suggests therapeutic potential for class IIa HDAC enzyme blockers distinct in mechanism and application compared to current HDAC inhibitors.
TL;DR: Pulmonary arterial hypertension (PAH) is a progressive, fatal disease with no cure as mentioned in this paper, and it is the most common cause of death in people with lung cancer. Parenteral and inhaled prostacyclin analogue therapies are effective for the treatment of PAH.
Abstract: Background—Pulmonary arterial hypertension (PAH) is a progressive, fatal disease with no cure. Parenteral and inhaled prostacyclin analogue therapies are effective for the treatment of PAH, but com...
TL;DR: These data are the first clinical demonstration of the activity of any integrase inhibitor in subjects with HIV-1 resistant to RAL, and dolutegravir 50 mg twice daily with an optimized background provided greater and more durable benefit than the once-daily regimen.
Abstract: Integrase inhibitors (INIs) represent a class of drugs for the treatment of human immunodeficiency virus (HIV)–infected individuals, blocking HIV genome integration into the host cell DNA [1]. They have been shown to be highly effective for the treatment of antiretroviral-naive and antiretroviral-experienced subjects, as demonstrated first with raltegravir (RAL) and more recently with elvitegravir (EVG) [2–6]. However, these first-generation INIs share common resistance pathways. In clinical studies of RAL, subjects with virologic failure and reduced RAL susceptibility typically harbored virus with 1 of 3 signature mutational pathways (ie, N155H, Q148H/K/R, or Y143C/H/R) in the integrase gene [7]. Continuing RAL treatment in these circumstances may lead to the addition of secondary mutations or pathway evolution; N155H may evolve to Y143 or Q148 pathways [4]. In addition, EVG does not appear to have activity against RAL-resistant isolates, and RAL does not appear to have activity against EVG-resistant isolates [8–10]. Therefore, there is a need for an INI with a high barrier to resistance and activity in subjects with human immunodeficiency virus type 1 (HIV-1) resistant to EVG and RAL.
Dolutegravir (DTG) is a new HIV-1 INI that has demonstrated good efficacy and safety in treatment-naive, HIV-infected individuals [11]. In vitro studies demonstrate limited cross-resistance between DTG and RAL or EVG, with no or minimal impact on DTG fold-change against Q148 single mutants or against viruses with Y143 or N155 signature mutations regardless of RAL-associated secondary mutations [12, 13]. However, the DTG fold-change increased for Q148H/K/R as secondary RAL resistance–associated mutations increased. On the basis of these in vitro findings, this phase IIb pilot study was conducted to assess and demonstrate the activity of DTG in HIV-1–infected individuals with RAL-resistant viral isolates.
TL;DR: Once-daily UMEC/VI 62.5/25 mcg was well tolerated and provided clinically-significant improvements in lung function and symptoms in patients with COPD.
University of Colorado Boulder1, National Oceanic and Atmospheric Administration2, University of California, Davis3, Peking University4, University of Houston5, University of Manchester6, Georgia Institute of Technology7, University of California, San Diego8, University of California, Berkeley9, University of North Carolina at Chapel Hill10, Research Triangle Park11, university of lille12, Indiana University13
TL;DR: In this paper, five organic aerosols (OA) components are identified using positive matrix factorization including hydrocarbon-like OA (HOA) and two types of oxygenated OA(OOA) components, and the Pasadena OA elemental composition when plotted as H:C versus O:C follows a line less steep than that observed for Riverside, CA.
Abstract: [1] Organic aerosols (OA) in Pasadena are characterized using multiple measurements from the California Research at the Nexus of Air Quality and Climate Change (CalNex) campaign. Five OA components are identified using positive matrix factorization including hydrocarbon-like OA (HOA) and two types of oxygenated OA (OOA). The Pasadena OA elemental composition when plotted as H : C versus O : C follows a line less steep than that observed for Riverside, CA. The OOA components from both locations follow a common line, however, indicating similar secondary organic aerosol (SOA) oxidation chemistry at the two sites such as fragmentation reactions leading to acid formation. In addition to the similar evolution of elemental composition, the dependence of SOA concentration on photochemical age displays quantitatively the same trends across several North American urban sites. First, the OA/ΔCO values for Pasadena increase with photochemical age exhibiting a slope identical to or slightly higher than those for Mexico City and the northeastern United States. Second, the ratios of OOA to odd-oxygen (a photochemical oxidation marker) for Pasadena, Mexico City, and Riverside are similar, suggesting a proportional relationship between SOA and odd-oxygen formation rates. Weekly cycles of the OA components are examined as well. HOA exhibits lower concentrations on Sundays versus weekdays, and the decrease in HOA matches that predicted for primary vehicle emissions using fuel sales data, traffic counts, and vehicle emission ratios. OOA does not display a weekly cycle—after accounting for differences in photochemical aging —which suggests the dominance of gasoline emissions in SOA formation under the assumption that most urban SOA precursors are from motor vehicles.
TL;DR: This work sought to identify research priorities for exposure assessment that will more accurately and precisely define exposure–response relationships of household air pollution necessary to inform future cleaner-burning cookstove dissemination programs.
Abstract: Background: Nearly 3 billion people worldwide rely on solid fuel combustion to meet basic household energy needs. The resulting exposure to air pollution causes an estimated 4.5% of the global burd...
University of British Columbia1, University of Copenhagen2, Research Triangle Park3, University of Barcelona4, University of Bergen5, University of Liverpool6, Brigham and Women's Hospital7, University of Cambridge8, University of Edinburgh9, GlaxoSmithKline10, University of Nebraska Medical Center11, Maastricht University12, University of Manchester13, University of Southern Denmark14
TL;DR: This study shows that decline in lung density in COPD can be measured, that it is variable, and related to smoking and gender.
TL;DR: It is suggested that NOX contributes to persistent microglial activation, ROS production, and dopaminergic neurodegeneration that persist and continue to increase with age.
Abstract: Parkinson's disease is characterized by a progressive degeneration of substantia nigra (SN) dopaminergic neurons with age. We previously found that a single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) injection caused a slow progressive loss of tyrosine hydroxylase immunoreactive (TH+IR) neurons in SN associated with increasing motor dysfunction. In this study, we investigated the role of NADPH oxidase (NOX) in inflammation-mediated SN neurotoxicity. A comparison of control (NOX2(+/+) ) mice with NOX subunit gp91(phox) -deficient (NOX2(-/-) ) mice 10 months after LPS administration (5 mg/kg, i.p.) resulted in a 39% (P < 0.01) loss of TH+IR neurons in NOX2(+/+) mice, whereas NOX2(-/-) mice did not show a significant decrease. Microglia (Iba1+IR) showed morphological activation in NOX2(+/+) mice, but not in NOX2(-/-) mice at 1 hr. Treatment of NOX2(+/+) mice with LPS resulted in a 12-fold increase in NOX2 mRNA in midbrain and 5.5-6.5-fold increases in NOX2 protein (+IR) in SN compared with the saline controls. Brain reactive oxygen species (ROS), determined using diphenyliodonium histochemistry, was increased by LPS in SN between 1 hr and 20 months. Diphenyliodonium (DPI), an NOX inhibitor, blocked LPS-induced activation of microglia and production of ROS, TNFα, IL-1β, and MCP-1. Although LPS increased microglial activation and ROS at all ages studied, saline control NOX2(+/+) mice showed age-related increases in microglial activation, NOX, and ROS levels at 12 and 22 months of age. Together, these results suggest that NOX contributes to persistent microglial activation, ROS production, and dopaminergic neurodegeneration that persist and continue to increase with age.
TL;DR: The intent was to determine the effectiveness of ancillary counseling techniques to improve adherence to, and continuation of, hormonal methods of contraception.
Abstract: Background Worldwide, hormonal contraceptives are among the most popular reversible contraceptives. Despite their high theoretical effectiveness, typical use results in much lower effectiveness. In large part, this disparity reflects difficulties in adherence to the contraceptive regimen and low rates for long-term continuation. Objectives The intent was to determine the effectiveness of ancillary counseling techniques to improve adherence to, and continuation of, hormonal methods of contraception. Search methods Through August 2013, we searched computerized databases for randomized controlled trials (RCTs) comparing client-provider interventions with standard family planning counseling. Sources included CENTRAL, MEDLINE, EMBASE, POPLINE, ClinicalTrials.gov and ICTRP. Earlier searches also included LILACS, PsycINFO, Dissertation Abstracts, African Index Medicus, and IMEMR. Selection criteria We included RCTs of an intensive counseling technique or other client-provider intervention compared to routine family planning counseling. Interventions included group motivation; structured, peer, or multi-component counseling; and intensive reminders of appointments or next dosing. Outcome measures were discontinuation, reasons for discontinuation, number of missed pills or on-time injections, and pregnancy. Data collection and analysis One author evaluated the titles and abstracts from the searches to determine eligibility. Two authors extracted data from the included studies. We calculated the Mantel-Haenszel odds ratio (OR) for dichotomous outcomes. For continuous variables, the mean difference (MD) was computed; RevMan uses the inverse variance approach. For all analyses, 95% confidence intervals (CI) were also computed. Since the studies identified differed in both interventions and outcome measures, we did not conduct a meta-analysis. Main results Nine RCTs met our inclusion criteria. Five involved direct counseling; of those, two also provided multiple contacts by telephone. Four other trials provided intensive reminders, two of which also provided health education information. Three trials showed some benefit of the experimental intervention. In a counseling intervention, women who received repeated structured information about the injectable depot medroxyprogesterone acetate (DMPA) were less likely to discontinue the method by 12 months (OR 0.27; 95% CI 0.16 to 0.44) than women who had routine counseling. The intervention group was also less likely to discontinue due to menstrual disturbances (OR 0.20; 95% CI 0.11 to 0.37). Another trial showed a group with special counseling plus phone calls was more likely than the special-counseling group to report consistent use of oral contraceptives (OC) at 3 months (OR 1.41; 95% CI 1.06 to 1.87), though not at 12 months. The group with only special counseling did not differ significantly from those with standard care for any outcome. The third trial compared daily text-message reminders about OCs plus health information versus standard care. Women in the text-message group were more likely than the standard-care group to continue OC use by six months (OR 1.54; 95% CI 1.14 to 2.10). The text-message group was also more likely to avoid an interruption in OC use longer than seven days (OR 1.53; 95% CI 1.13 to 2.07). Authors' conclusions Only three trials showed some benefit of strategies to improve adherence and continuation. However, several had small sample sizes and six had high losses to follow up. The overall quality of evidence was considered moderate. The intervention type and intensity varied greatly across the studies. A combination of intensive counseling and multiple contacts and reminders may be needed to improve adherence and acceptability of contraceptive use. High-quality RCTs with adequate power and well-designed interventions could help identify ways to improve adherence to, and continuation of, hormonal contraceptive methods.
TL;DR: In vitro studies demonstrate a low propensity for DTG to be a perpetrator of clinical drug interactions and provide a basis for predicting when other drugs could result in a drug interaction with DTG.
Abstract: Dolutegravir (DTG; S/GSK1349572) is a potent HIV-1 integrase inhibitor with a distinct resistance profile and a once-daily dose regimen that does not require pharmacokinetic boosting. This work investigated the in vitro drug transport and metabolism of DTG and assessed the potential for clinical drug-drug interactions. DTG is a substrate for the efflux transporters P-glycoprotein (Pgp) and human breast cancer resistance protein (BCRP). Its high intrinsic membrane permeability limits the impact these transporters have on DTG's intestinal absorption. UDP-glucuronosyltransferase (UGT) 1A1 is the main enzyme responsible for the metabolism of DTG in vivo, with cytochrome P450 (P450) 3A4 being a notable pathway and UGT1A3 and UGT1A9 being only minor pathways. DTG demonstrated little or no inhibition (IC(50) values > 30 μM) in vitro of the transporters Pgp, BCRP, multidrug resistance protein 2, organic anion transporting polypeptide 1B1/3, organic cation transporter (OCT) 1, or the drug metabolizing enzymes CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, UGT1A1, or 2B7. Further, DTG did not induce CYP1A2, 2B6, or 3A4 mRNA in vitro using human hepatocytes. DTG does inhibit the renal OCT2 (IC(50) = 1.9 μM) transporter, which provides a mechanistic basis for the mild increases in serum creatinine observed in clinical studies. These in vitro studies demonstrate a low propensity for DTG to be a perpetrator of clinical drug interactions and provide a basis for predicting when other drugs could result in a drug interaction with DTG.