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This study investigated the latent factor structure of the NIH Toolbox Cognition Battery (NIHTB-CB) and its measurement invariance across clinical diagnosis and key demographic variables including sex, race/ethnicity, age, and education for a typical Alzheimer’s disease (AD) research sample.
The NIHTB-CB iPad English version, consisting of 7 tests, was administered to 411 participants aged 45–94 with clinical diagnosis of cognitively unimpaired, dementia, mild cognitive impairment (MCI), or impaired not MCI. The factor structure of the whole sample was first examined with exploratory factor analysis (EFA) and further refined using confirmatory factor analysis (CFA). Two groups were classified for each variable (diagnosis or demographic factors). The confirmed factor model was next tested for each group with CFA. If the factor structure was the same between the groups, measurement invariance was then tested using a hierarchical series of nested two-group CFA models.
A two-factor model capturing fluid cognition (executive function, processing speed, and memory) versus crystalized cognition (language) fit well for the whole sample and each group except for those with age < 65. This model generally had measurement invariance across sex, race/ethnicity, and education, and partial invariance across diagnosis. For individuals with age < 65, the language factor remained intact while the fluid cognition was separated into two factors: (1) executive function/processing speed and (2) memory.
The findings mostly supported the utility of the battery in AD research, yet revealed challenges in measuring memory for AD participants and longitudinal change in fluid cognition.
Cognitive behavior therapy (CBT) is effective for most patients with a social anxiety disorder (SAD) but a substantial proportion fails to remit. Experimental and clinical research suggests that enhancing CBT using imagery-based techniques could improve outcomes. It was hypothesized that imagery-enhanced CBT (IE-CBT) would be superior to verbally-based CBT (VB-CBT) on pre-registered outcomes.
A randomized controlled trial of IE-CBT v. VB-CBT for social anxiety was completed in a community mental health clinic setting. Participants were randomized to IE (n = 53) or VB (n = 54) CBT, with 1-month (primary end point) and 6-month follow-up assessments. Participants completed 12, 2-hour, weekly sessions of IE-CBT or VB-CBT plus 1-month follow-up.
Intention to treat analyses showed very large within-treatment effect sizes on the social interaction anxiety at all time points (ds = 2.09–2.62), with no between-treatment differences on this outcome or clinician-rated severity [1-month OR = 1.45 (0.45, 4.62), p = 0.53; 6-month OR = 1.31 (0.42, 4.08), p = 0.65], SAD remission (1-month: IE = 61.04%, VB = 55.09%, p = 0.59); 6-month: IE = 58.73%, VB = 61.89%, p = 0.77), or secondary outcomes. Three adverse events were noted (substance abuse, n = 1 in IE-CBT; temporary increase in suicide risk, n = 1 in each condition, with one being withdrawn at 1-month follow-up).
Group IE-CBT and VB-CBT were safe and there were no significant differences in outcomes. Both treatments were associated with very large within-group effect sizes and the majority of patients remitted following treatment.
Seismic-reflection surveys of the Isle Royale sub-basin, central Lake Superior, reveal two large end moraines and associated glacial sediments deposited during the last cycle of the Laurentide Ice Sheet in the basin. The Isle Royale moraines directly overlie bedrock and are cored with dense, acoustically massive till intercalated down-ice with acoustically stratified outwash. Till and outwash are overlain by glacial varves, a lower red unit and an upper gray unit.
The maximum extent of late Younger Dryas-age readvance into the western Lake Superior basin is uncertain, but it was probably controlled by both ice dynamics and climate. Our data indicate that during retreat from the maximum, the ice paused just long enough to construct the outer of the two moraines, >100 m high, and then retreated to the inner moraine, during which time most of the lower glacial-lacustrine sequence (red varves) was deposited. Retreat from the inner moraine coincided with a marked flux of icebergs at the calving margin and a change to gray varves. Rapid retreat may be related to both an influx of meltwater from Glacial Lake Agassiz about 10,500 cal yr BP and retreat of the calving margin down an adverse slope into the Isle Royale sub-basin.
OBJECTIVES/GOALS: 1. Understand the association between patient perceptions of care measured by the Interpersonal Processes of Care (IPC) Survey and glycemic control, appointment no-shows/cancellations and medication adherence in patients with type II diabetes. 2. Determine how these relationships differ by race for non-Hispanic White and Black patients. METHODS/STUDY POPULATION: This is a cross-sectional study of a random sample of 100 White and 100 Black Type II diabetic patients followed in Duke primary care clinics and prescribed antihyperglycemic medication. We will recruit through email and phone calls. Enrolled patients will complete the Interpersonal Processes of Care Short Form and Extent of Medication Adherence survey to measure patient perceptions of care (predictor) and medication adherence (secondary outcome). No show appointments and cancellations (secondary outcomes) and most recent hemoglobin A1c (primary outcome) will be collected from the Electronic Medical Record. We will also collect basic demographic information, insurance status, financial security, significant co-morbidities, and number and type (subcutaneous vs oral) of antihyperglycemic medications. RESULTS/ANTICIPATED RESULTS: -The study is powered to detect a 0.6% difference in HbA1c, our primary outcome, between high and low scorers on the Interpersonal Processes of Care subdomains. -We expect that higher patient scores in the positive domains of the IPC survey and lower DISCUSSION/SIGNIFICANCE OF IMPACT: This study will provide information to develop and implement targeted interventions to reduce racial and ethnic disparities in patients with Type II diabetes. We hope to gain information on potentially modifiable factors in patient-provider interactions that can be intervened upon to improve prevention and long-term outcomes in these populations.
Optimal management of schizophrenia in adolescents is limited by the lack of available therapies. The efficacy and tolerability of aripiprazole was investigated in this patient population.
This 6-week, randomized, double-blind, placebo controlled trial was conducted at 101 international centers, with a safety monitoring board. 13-17 year-olds with a DSM-IV diagnosis of schizophrenia were randomized to placebo, or a fixed dose of aripiprazole 10 mg or 30 mg reached after a 5 or 11 day titration, respectively. The primary endpoint was mean change from baseline on the PANSS Total score at week 6. Secondary endpoints included the PANSS Positive and Negative subscales, and CGI Improvement score. Tolerabilility assessements included frequency and severity of adverse events, as well as blood chemistries, metabolic parameters and weight gain.
Over 85% of 302 patients completed this study. Both 10 mg and 30 mg doses were superior to placebo on the primary endpoint (PANSS total), with significant differences observed as early as Week 1 (30mg). Both doses showed significant improvement on the PANSS Positive and CGI-I scales; and the 10 mg dose group was superior on PANSS Negative score. Approximately 5% of aripiprazole patients discontinued due to AEs. Weight gain and changes in prolactin were minimal.
10mg and 30mg doses of aripiprazole were superior to placebo in the treatment of adolescents with schizophrenia. Aripiprazole was well tolerated, in general, with few discontinuations due to AEs. EPS was the most common AE. Change in body weight was similar to placebo.
There is limited published data from long-term pediatric bipolar clinical trials with which to guide appropriate treatment decisions. Long-term efficacy and safety of aripiprazole was investigated in this patient population.
296 youths, ages 10-17 year-old with a DSM-IV diagnosis of bipolar I disorder were randomized to receive either placebo or aripiprazole (10mg or 30mg) in a 4-week double-blind trial. Completers continued assigned treatments for an additional 26 weeks (double-blind). Efficacy endpoints included mean change from baseline to week 4 and week 30 on the Young Mania Rating Scale; Children's Global Assessment Scale, Clinical Global Impressions-Bipolar version severity scale, General Behavior Inventory, Attention Deficit Hyperactivity Disorders Rating Scale, and time to discontinuation. Tolerability/safety assessments included incidence and severity of AEs, blood chemistries and metabolic parameters.
Over the 30-week course of double-blind treatment, aripiprazole (10 mg and 30 mg) was superior to placebo as early as week 1 (p< 0.002) and at all scheduled visits from week 2 through week 30 on mean change from baseline in the Y-MRS total score (p<.0001; all visits). Significant improvements were observed on multiple endpoints including the CGAS, GBI, CGI-BP, ADHD-RS-IV total score, time to discontinuation, and response and remission rates. The 3 most common AEs were somnolence, extrapyramidal disorder, and fatigue. Mean change in body weight z-scores over 30 weeks was not clinically significant.
Over 30-weeks of treatment, both doses of aripiprazole were superior to placebo in the long term treatment of pediatric bipolar patients. Aripiprazole was generally well tolerated.
Lisdexamfetamine dimesylate (LDX) is a long-acting prodrug stimulant for treatment of attention-deficit/hyperactivity disorder (ADHD).
Review efficacy and safety data from two double-blind, randomized trials (SPD489-325 and SPD489-326) in patients with ADHD aged 6–17 years.
In SPD489-325, patients received placebo or optimized doses of LDX or the reference treatment, osmotic-release oral system methylphenidate (OROS-MPH) for ≤7 weeks. The primary efficacy measure was ADHD Rating Scale IV (ADHD-RS-IV) total score. Statistical comparison of LDX versus OROS-MPH was not pre-specified. In SPD489-326, a ≥26-week open-label LDX period preceded a 6-week, placebo-controlled, randomized-withdrawal period (RWP). The primary endpoint was treatment failure (50% increase in ADHD-RS-IV total score and ≥2-point increase in Clinical Global Impressions-Severity score from RWP baseline). Efficacy was assessed in the full analysis sets.
In SPD489-325 (N=317), placebo-adjusted least-squares-mean changes in ADHD-RS-IV total score from baseline to endpoint were: LDX, –18.6 (95% confidence interval [CI]: –21.5, –15.7; p<0.001; effect size 1.80) and OROS MPH, –13.0 (–15.9, –10.2; p<0.001; 1.26). In SPD489-326 (N=262, open-label period; N=153, RWP), 15.8% and 67.5% of patients receiving LDX and placebo, respectively, met treatment failure criteria at RWP endpoint (differen –51.7%; 95% CI: –65.0%, –38.5%; p<0.001). The most common treatment-emergent adverse events in LDX-treated patients were decreased appetite, headache and decreased weight.
Short-term LDX treatment improved symptoms of ADHD in children and adolescents. Continued LDX treatment was associated with maintenance of efficacy compared with placebo. The safety profile of LDX was generally consistent with that of stimulant therapy.
In a European, phase 3 study (SPD489-325), lisdexamfetamine dimesylate (LDX) and osmotic-release oral system methylphenidate (OROS-MPH) were more effective than placebo in improving core symptoms in children and adolescents with attention-deficit/hyperactivity disorder (ADHD).
Objectives and aims
To compare post hoc the efficacy of LDX and OROS-MPH in study SPD489-325.
This 7-week, randomized, double-blind, parallel-group, dose-optimized, placebo-controlled trial enrolled patients aged 6-17 years with ADHD of at least moderate severity. Patients were randomized (1:1:1) to receive a once-daily dose of LDX (30, 50, 70 mg/day), OROS-MPH (18, 36, 54 mg/day) or placebo. Efficacy was assessed using the ADHD Rating Scale version IV (ADHD-RS-IV) and the Clinical Global Impression-Improvement (CGI-I) scale. Endpoint was defined as the last ontherapy treatment visit with a valid assessment.
The full analysis set comprised 317 patients (LDX, n=104; placebo, n=106; OROS-MPH, n=107). The difference between LDX and OROS-MPH in least squares mean change (95% confidence interval [CI]) in ADHD-RS-IV total score from baseline to endpoint was statistically significant in favour of LDX (-5.6 [-8.4, -2.7]; p < 0.001; effect size, 0.541). The difference (LDX minus OROS-MPH) in the percentage of patients (95% CI) with an improved CGI-I score at endpoint was also statistically significant in favour of LDX (17.4 [5.0, 29.8]; p < 0.05).
This post hoc analysis indicated that LDX is significantly more effective than OROS-MPH in improving core symptoms and global functioning in children and adolescents with ADHD.
The Health Utilities Index-Mark 2 (HUI2), a generic instrument for assessing health status, is an important effectiveness input for pharmacoeconomic modelling. It has not previously been used in patients with attention deficit/hyperactivity disorder (ADHD).
To use HUI2 to assess health utility in patients aged 6–17 years with ADHD receiving the prodrug stimulant lisdexamfetamine dimesylate (LDX).
SPD489-325 was a 7-week, randomized, double-blind, placebo-controlled trial of LDX, with osmotic-release oral system methylphenidate (OROSMPH) as a reference treatment. Patients’ parents or guardians completed HUI2 questionnaires at baseline and weeks 4 and 7. Utilities were estimated for treatment responders and non-responders, with response defined as a Clinical Global Impressions-Improvement (CGI-I) score of 1 or 2, or a ≥25% or ≥30% reduction in ADHD Rating Scale IV (ADHD-RS-IV) total score.
Of 336 patients randomized, 317 were included in the full analysis set (LDX, n=104; OROS-MPH, n=107; placebo, n=106) and 196 completed the study. At endpoint, mean HUI2 utility scores across all treatment groups were higher for responders than non-responders when response was based on CGI-I score (responders: 0.896 [SD, 0.0990]; non-responders: 0.838 [0.1421]), on a ≥25% reduction in ADHD-RS-IV score from baseline (responders, 0.899 [0.0969]; non-responders, 0.809 [0.1474]), or on a ≥30% reduction in ADHD-RS-IV score from baseline (responders, 0.902 [0.0938]; non-responders 0.814 [0.1477]).
The HUI2 instrument is sensitive to treatment response in the child and adolescent ADHD patient population. Health utilities generated using HUI2 are therefore suitable for cost effectiveness evaluations of ADHD medications.
The Weiss Functional Impairment Rating Scale–Parent Report (WFIRS-P) is an ADHD-specific instrument comprising 50 items, grouped into six domains. Parents score each item on a Likert scale (0–3 or not applicable).
To evaluate functional impairment using the WFIRS-P in two phase 3 studies (SPD489-325 and SPD489-326) of lisdexamfetamine dimesylate (LDX) in children and adolescents with ADHD.
Patients’ parents or guardians completed WFIRS-P assessments at baseline, and weeks 4 and 7 of SPD489-325, a 7-week, randomized, placebo controlled trial incorporating a reference treatment (osmotic-release oral system methylphenidate; OROS-MPH). Statistical comparison of LDX versus OROS-MPH was not pre-specified. In SPD489-326, WFIRS-P assessments were performed in the ≥26-week open-label period and the subsequent 6-week randomized-withdrawal period.
In SPD489-325, statistically significant placebo-adjusted effects of LDX were observed in WFIRS-P total score (effect size, 0.924; p<0.001) and in Family, Learning and School, Social Activities and Risky Activities; OROS-MPH effects were significant in total score (effect size 0.772; p<0.001) and in all domains. In SPD489-326, scores were improved or stable in the open-label period. In the randomized-withdrawal period, total score and all domain scores were stable in the LDX group, but worsened in the placebo group. LDX was significantly more effective than placebo in Family, Learning and School, Risky Activities and in total score (effect size, 0.908; p<0.001).
Short-term treatment with LDX or OROS-MPH led to improved functional impairment scores. These benefits were maintained during long-term LDX treatment, and scores declined following treatment withdrawal.
In a European, phase 3 study (SPD489-325), lisdexamfetamine dimesylate (LDX) was more effective than placebo in improving symptoms and global functioning in children and adolescents with attention-deficit/hyperactivity disorder (ADHD).
Objectives and aims
To evaluate the impact of age, sex and baseline disease severity on efficacy outcomes in SPD489- 325.
This 7-week, double-blind, parallel-group, dose-optimized study enrolled patients aged 6-17 years with ADHD. Patients were randomized (1:1:1) to once-daily LDX (30, 50 or 70mg/day), osmotic-release oral system methylphenidate (OROS-MPH; 18, 36 or 54mg/day) or placebo. Efficacy outcomes were analysed in patients dichotomized by age (6-12 years [n=229] or 13-17 years [n=88]), sex (male [n=255] or female [n=62]) and baseline ADHD Rating Scale version IV (ADHD-RSIV) total score (28-41 [n=161] or 42-54 [n=152]). Endpoint was the last on-treatment visit with a valid assessment.
At endpoint, differences (active-placebo) in least-squares mean changes from baseline in ADHD-RS-IV total scores were statistically significant in all age, sex and ADHD-RS-IV total score subgroups for LDX (p< 0.001; effect sizes, 1.68-2.26) and OROS-MPH (p< 0.01; effect sizes, 0.88-1.46). Proportions of patients with a Clinical Global Impressions-Improvement rating of 1 (very much improved) or 2 (much improved) were statistically significantly greater than placebo at endpoint in all subgroups receiving LDX (p< 0.01) and in all subgroups except females receiving OROS-MPH (p< 0.05).
LDX showed greater efficacy than placebo in children and adolescents with ADHD, regardless of their age, sex or baseline disease severity.
Studies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds.
We examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes.
In COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47–0.68%, p = 2.0 × 10−8–1.0 × 10−10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10−8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10−6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10−11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10−7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10−16).
AUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.
Multispectral imaging – the acquisition of spatially contiguous imaging data in a modest number (~3–16) of spectral bandpasses – has proven to be a powerful technique for augmenting panchromatic imaging observations on Mars focused on geologic and/or atmospheric context. Specifically, multispectral imaging using modern digital CCD photodetectors and narrowband filters in the 400–1100 nm wavelength region on the Mars Pathfinder, Mars Exploration Rover, Phoenix, and Mars Science Laboratory missions has provided new information on the composition and mineralogy of fine-grained regolith components (dust, soils, sand, spherules, coatings), rocky surface regions (cobbles, pebbles, boulders, outcrops, and fracture-filling veins), meteorites, and airborne dust and other aerosols. Here we review recent scientific results from Mars surface-based multispectral imaging investigations, including the ways that these observations have been used in concert with other kinds of measurements to enhance the overall scientific return from Mars surface missions.
Moral reasoning and decision making help guide behavior and facilitate interpersonal relationships. Accounts of morality that position commonsense psychology as the foundation of moral development, (i.e., rationalist theories) have dominated research in morality in autism spectrum disorder (ASD). Given the well-documented differences in commonsense psychology among autistic individuals, researchers have investigated whether the development and execution of moral judgement and reasoning differs in this population compared with neurotypical individuals. In light of the diverse findings of investigations of moral development and reasoning in ASD, a summation and critical evaluation of the literature could help make sense of what is known about this important social-cognitive skill in ASD. To that end, we conducted a systematic review of the literature investigating moral decision making among autistic children and adults. Our search identified 29 studies. In this review, we synthesize the research in the area and provide suggestions for future research. Such research could include the application of an alternative theoretical framework to studying morality in autism spectrum disorder that does not assume a deficits-based perspective.
The spread of the Zika virus (ZIKV) in the Americas led to large outbreaks across the region and most of the Southern hemisphere. Of greatest concern were complications following acute infection during pregnancy. At the beginning of the outbreak, the risk to unborn babies and their clinical presentation was unclear. This report describes the methods and results of the UK surveillance response to assess the risk of ZIKV to children born to returning travellers. Established surveillance systems operating within the UK – the paediatric and obstetric surveillance units for rare diseases, and national laboratory monitoring – enabled rapid assessment of this emerging public health threat. A combined total of 11 women experiencing adverse pregnancy outcomes after possible ZIKV exposure were reported by the three surveillance systems; five miscarriages, two intrauterine deaths and four children with clinical presentations potentially associated with ZIKV infection. Sixteen women were diagnosed with ZIKV during pregnancy in the UK. Amongst the offspring of these women, there was unequivocal laboratory evidence of infection in only one child. In the UK, the number and risk of congenital ZIKV infection for travellers returning from ZIKV-affected countries is very small.
The rocky shores of the north-east Atlantic have been long studied. Our focus is from Gibraltar to Norway plus the Azores and Iceland. Phylogeographic processes shape biogeographic patterns of biodiversity. Long-term and broadscale studies have shown the responses of biota to past climate fluctuations and more recent anthropogenic climate change. Inter- and intra-specific species interactions along sharp local environmental gradients shape distributions and community structure and hence ecosystem functioning. Shifts in domination by fucoids in shelter to barnacles/mussels in exposure are mediated by grazing by patellid limpets. Further south fucoids become increasingly rare, with species disappearing or restricted to estuarine refuges, caused by greater desiccation and grazing pressure. Mesoscale processes influence bottom-up nutrient forcing and larval supply, hence affecting species abundance and distribution, and can be proximate factors setting range edges (e.g., the English Channel, the Iberian Peninsula). Impacts of invasive non-native species are reviewed. Knowledge gaps such as the work on rockpools and host–parasite dynamics are also outlined.
Dense granular flows can spontaneously self-channelise by forming a pair of parallel-sided static levees on either side of a central flowing channel. This process prevents lateral spreading and maintains the flow thickness, and hence mobility, enabling the grains to run out considerably further than a spreading flow on shallow slopes. Since levees commonly form in hazardous geophysical mass flows, such as snow avalanches, debris flows, lahars and pyroclastic flows, this has important implications for risk management in mountainous and volcanic regions. In this paper an avalanche model that incorporates frictional hysteresis, as well as depth-averaged viscous terms derived from the
-rheology, is used to quantitatively model self-channelisation and levee formation. The viscous terms are crucial for determining a smoothly varying steady-state velocity profile across the flowing channel, which has the important property that it does not exert any shear stresses at the levee–channel interfaces. For a fixed mass flux, the resulting boundary value problem for the velocity profile also uniquely determines the width and height of the channel, and the predictions are in very good agreement with existing experimental data for both spherical and angular particles. It is also shown that in the absence of viscous (second-order gradient) terms, the problem degenerates, to produce plug flow in the channel with two frictionless contact discontinuities at the levee–channel margins. Such solutions are not observed in experiments. Moreover, the steady-state inviscid problem lacks a thickness or width selection mechanism and consequently there is no unique solution. The viscous theory is therefore a significant step forward. Fully time-dependent numerical simulations to the viscous model are able to quantitatively capture the process in which the flow self-channelises and show how the levees are initially emplaced behind the flow head. Both experiments and numerical simulations show that the height and width of the channel are not necessarily fixed by these initial values, but respond to changes in the supplied mass flux, allowing narrowing and widening of the channel long after the initial front has passed by. In addition, below a critical mass flux the steady-state solutions become unstable and time-dependent numerical simulations are able to capture the transition to periodic erosion–deposition waves observed in experiments.