Time courses of improvement and symptom remission in children treated with atomoxetine for attention-deficit/hyperactivity disorder: analysis of Canadian open-label studies

<p>Abstract</p> <p>Background</p> <p>The relatively short durations of the initial pivotal randomized placebo-controlled trials involving atomoxetine HCl for the treatment of attention-deficit/hyperactivity disorder (ADHD) provided limited insight into the time courses of ADHD core symptom responses to this nonstimulant, selective norepinephrine reuptake inhibitor. The aim of this analysis was to evaluate time courses of treatment responses or remission, as assessed by attainment of prespecified scores on the ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-PI) and the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) scales, during up to 1 year of atomoxetine treatment in children with ADHD.</p> <p>Methods</p> <p>Using pooled data from three Canadian open-label studies involving 338 children ages 6-11 years with ADHD who were treated with atomoxetine for 3, 6 and 12 months, and survival analysis methods for interval-censored data, we estimated the time to: 1) improvement and robust improvement defined by ≥25% and ≥40% reductions from baseline ADHDRS-IV-PI total scores, respectively; and 2) remission using two definitions: a final score of ADHDRS-IV-PI ≤18 or a final score of CGI-ADHD-S ≤2.</p> <p>Results</p> <p>The median time to improvement was 3.7 weeks (~1 month), but remission of symptoms did not occur until a median of 14.3 weeks (~3.5 months) using the most stringent CGI-ADHD-S threshold. Probabilities of robust improvement were 47% at or before 4 weeks of treatment; 76% at 12 weeks; 85% at 26 weeks; and 96% at 52 weeks. Probabilities of remission at these corresponding time points were 30%, 59%, 77%, and 85% (using the ADHDRS-IV scale) and 8%, 47%, 67%, and 75% (using the CGI-ADHD-S scale). The change from atomoxetine treatment month 5 to month 12 of -1.01 (1.03) was not statistically significant (<it>p </it>= .33).</p> <p>Conclusions</p> <p>Reductions in core ADHD symptoms during atomoxetine treatment are gradual. Although approximately one-half of study participants showed improvement at 1 month of atomoxetine treatment, remission criteria were not met until about 3 months. Understanding the time course of children's responses to atomoxetine treatment may inform clinical decision making and also influence the durations of trials comparing the effects of this medication with other ADHD treatments.</p> <p>Trial Registrations</p> <p>clinicaltrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00191633">NCT00191633</a>, <a href="http://www.clinicaltrials.gov/ct2/show/NCT00216918">NCT00216918</a>, <a href="http://www.clinicaltrials.gov/ct2/show/NCT00191880">NCT00191880</a>.</p

Challenges and opportunities in rapid disaster research: lessons from the field in New Mexico and Vanuatu

Rapid research is essential to assess impacts in communities affected by disasters, particularly those communities made “hard-to-reach” due to their active marginalization across history and in contemporary practices. In this article, we describe two rapid research projects developed to assess needs for and experiences of communities hard-hit by disasters. The first is a project on the COVID-19 pandemic in southern New Mexico (USA) that was developed to provide information to local agencies that are deploying programs to rebuild and revitalize marginalized communities. The second is a project on population displacement due to a volcanic eruption in Vanuatu, a lower-middle income country in the South Pacific, with mental and physical health outcomes data shared with the Vanuatu Ministry of Health. We describe the similar and unique challenges that arose doing rapid research in these two different contexts, the potential broader impacts of the research, and a synthesis of lessons learned. We discuss the challenges of rapidly changing rules and regulations, lack of baseline data, lack of survey instruments validated for specific populations and in local languages, limited availability of community partners, finding funding for rapid deployment of projects, rapidly training and working with research assistants, health and safety concerns of researchers and participants, and communicating with local and international partners. We also specifically discuss how we addressed our own personal challenges while also conducting time-intensive rapid research. In both studies, researchers shared results with governmental and non-governmental partners who may use the data to inform the design of their own relief programs. While different in context, type of disaster, and research strategy, our discussion of these projects provides insights into common lessons learned for working with communities at elevated risk for the worst outcomes during disasters, such as the need for flexibility, compromise, and good working relationships with community partners

A randomized controlled trial investigation of a non-stimulant in attention deficit hyperactivity disorder (ACTION): Rationale and design

<p>Abstract</p> <p>Background</p> <p>The ACTION study (<it>Attention deficit hyperactivity disorder Controlled Trial Investigation Of a Non-stimulant) </it>is a multi-center, double-blind, randomized cross-over trial of the non-stimulant medication, Atomoxetine, in children and adolescents with attention deficit hyperactivity disorder (ADHD). The primary aims are to examine the efficacy of atomoxetine for improving cognition and emotional function in ADHD and whether any improvements in these outcomes are more pronounced in participants with comorbid anxiety; and to determine if changes in these outcomes after atomoxetine are more reliable than changes in diagnostic symptoms of ADHD. This manuscript will describe the methodology and rationale for the ACTION study.</p> <p>Methods</p> <p>Children and adolescents aged 6 - 17 y with ADHD will be enrolled. Clinical interview and validated scales will be used to confirm diagnosis and screen for exclusion criteria, which include concurrent stimulant use, and comorbid psychiatric or neurological conditions other than anxiety. Three assessment sessions will be conducted over the 13-week study period: Session 1 (Baseline, pre-treatment), Session 2 (six weeks, atomoxetine or placebo), and Session 3 (13 weeks, cross-over after one-week washout period). The standardized touch-screen battery, "IntegNeuro™", will be used to assess cognitive and emotional function. The primary measure of response will be symptom ratings, while quality of life will be a secondary outcome. Logistic regression will be used to determine predictors of treatment response, while repeated measures of analysis will determine any differences in effect of atomoxetine and placebo.</p> <p>Results</p> <p>The methodology for the ACTION study has been detailed.</p> <p>Conclusions</p> <p>The ACTION study is the first controlled trial to investigate the efficacy of atomoxetine using objective cognitive and emotional function markers, and whether these objective measures predict outcomes with atomoxetine in ADHD with and without comorbid anxiety. First enrollment was in March 2008. The outcomes of this study will be a significant step towards a 'personalized medicine' (and therefore a more efficient) approach to ADHD treatment.</p> <p>Trial registration</p> <p>Australian and New Zealand Clinical Trials Registry <a href="http://www.anzctr.org.au/ANZCTRN12607000535471.aspx">ANZCTRN12607000535471</a>.</p

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Sources of Carbon to Suspended Particulate Organic Matter in the Northern Gulf of Mexico

Suspended particulate organic carbon (POCsusp) in the Gulf of Mexico is unique compared to other seas and oceans. In addition to surface primary production, isotopic analysis indicates that microbial cycling of oil and riverine inputs are primary sources of carbon to POCsusp in the Gulf. To characterize POCsusp from seep sites and non-seep north central Gulf (NCG) sites potentially affected by the Deepwater Horizon (DWH) spill, we analyzed 277 and 123 samples for δ13C and Δ14C signatures, respectively. Depth, partitioned into euphotic ( \u3c 300 m) and deep ( \u3e 300 m), was the main driver of spatial δ13C differences, with deep depths exhibiting 13C depletion. Both deep depths and proximity to sources of natural seepage resulted in 14C depletion. A two-endmember mixing model based on Δ14C indicated that sources to POCsusp were 14–29% fossil carbon at NCG sites and 19–57% at seep sites, with the balance being modern surface production. A six-component Bayesian mixing model MixSIAR, using both 13C and 14C, suggested that riverine inputs were an important carbon source to POCsusp contributing 34–46%. The influence of seeps was localized. Below the euphotic zone at seep sites, 46 ± 5% (n = 9) of the carbon in POCsusp was derived from environmentally degraded, transformed oil; away from seeps, transformed oil contributed 15 ± 4% (n = 39). We hypothesized that, at NCG sites removed from hydrocarbon seep sources, isotopic signatures would be depleted following the spill and then shift towards background-like enriched values over time. At deep depths we observed decreasing Δ14C signatures in POCsusp from 2010 to 2012, followed by isotopic enrichment from 2012 to 2014 and a subsequent recovery rate of 159‰ per year, consistent with this hypothesis and with biodegraded material from DWH hydrocarbons contributing to POCsusp

Genetic and Small-Molecule Modulation of Stat3 in a Mouse Model of Crohn’s Disease

Crohn’s disease (CD), is an inflammatory bowel disease that can affect any part of the gastro-intestinal tract (GI) and is associated with an increased risk of gastro-intestinal cancer. In the current study, we determined the role of genetic and small-molecule modulation of STAT3 in a mouse model of CD. STAT3 has 2 isoforms (α, β) which are expressed in most cells in a 4:1 ratio (α: β). STAT3α has pro-inflammatory and anti-apoptotic functions, while STAT3β has contrasting roles. We used an animal model of CD consisting of intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid and examined the severity of CD in transgenic-mice that express only STAT3α (∆β/∆β), as well as in wild-type (WT) mice administered TTI-101 (formerly C188-9), a small molecule STAT3 inhibitor. We determined that clinical manifestations of CD, such as mortality, rectal-bleeding, colonic bleeding, diarrhea, and colon shortening, were exacerbated in ∆β/∆β transgenic versus cage-control WT mice, while they were markedly decreased by TTI-101 treatment of WT mice. TTI-101 treatment also increased apoptosis of pathogenic CD4+ T cells and reduced colon levels of IL-17-positive cells. Our results indicate that STAT3 contributes to CD and that targeting of STAT3 with TTI-101 may be a useful approach to treating CD

Petrocarbon Evolution: Ramped Pyrolysis/Oxidation and Isotopic Studies of Contaminated Oil Sediments from the Deepwater Horizon Oil Spill in the Gulf of Mexico

Hydrocarbons released during the Deepwater Horizon (DWH) oil spill weathered due to exposure to oxygen, light, and microbes. During weathering, the hydrocarbons’ reactivity and lability was altered, but it remained identifiable as “petrocarbon” due to its retention of the distinctive isotope signatures (14C and 13C) of petroleum. Relative to the initial estimates of the quantity of oil-residue deposited in Gulf sediments based on 2010–2011 data, the overall coverage and quantity of the fossil carbon on the seafloor has been attenuated. To analyze recovery of oil contaminated deep-sea sediments in the northern Gulf of Mexico we tracked the carbon isotopic composition (13C and 14C, radiocarbon) of bulk sedimentary organic carbon through time at 4 sites. Using ramped pyrolysis/oxidation, we determined the thermochemical stability of sediment organic matter at 5 sites, two of these in time series. There were clear differences between crude oil (which decomposed at a lower temperature during ramped oxidation), natural hydrocarbon seep sediment (decomposing at a higher temperature; Δ14C = -912‰) and our control site (decomposing at a moderate temperature; Δ14C = -189‰), in both the stability (ability to withstand ramped temperatures in oxic conditions) and carbon isotope signatures. We observed recovery toward our control site bulk Δ14C composition at sites further from the wellhead in ~4 years, whereas sites in closer proximity had longer recovery times. The thermographs also indicated temporal changes in the composition of contaminated sediment, with shifts towards higher temperature CO2 evolution over time at a site near the wellhead, and loss of higher temperature CO2 peaks at a more distant site

Petrocarbon Evolution: Ramped Pyrolysis/Oxidation and Isotopic Studies of Contaminated Oil Sediments from the Deepwater Horizon Oil Spill in the Gulf of Mexico

Hydrocarbons released during the Deepwater Horizon (DWH) oil spill weathered due to exposure to oxygen, light, and microbes. During weathering, the hydrocarbons’ reactivity and lability was altered, but it remained identifiable as “petrocarbon” due to its retention of the distinctive isotope signatures (14C and 13C) of petroleum. Relative to the initial estimates of the quantity of oil-residue deposited in Gulf sediments based on 2010–2011 data, the overall coverage and quantity of the fossil carbon on the seafloor has been attenuated. To analyze recovery of oil contaminated deep-sea sediments in the northern Gulf of Mexico we tracked the carbon isotopic composition (13C and 14C, radiocarbon) of bulk sedimentary organic carbon through time at 4 sites. Using ramped pyrolysis/oxidation, we determined the thermochemical stability of sediment organic matter at 5 sites, two of these in time series. There were clear differences between crude oil (which decomposed at a lower temperature during ramped oxidation), natural hydrocarbon seep sediment (decomposing at a higher temperature; Δ14C = -912‰) and our control site (decomposing at a moderate temperature; Δ14C = -189‰), in both the stability (ability to withstand ramped temperatures in oxic conditions) and carbon isotope signatures. We observed recovery toward our control site bulk Δ14C composition at sites further from the wellhead in ~4 years, whereas sites in closer proximity had longer recovery times. The thermographs also indicated temporal changes in the composition of contaminated sediment, with shifts towards higher temperature CO2 evolution over time at a site near the wellhead, and loss of higher temperature CO2 peaks at a more distant site