Optimal Weighting of Preclinical Alzheimer’s Cognitive Composite (PACC) Scales to Improve their Performance as Outcome Measures for Alzheimer’s Disease Clinical Trials

Introduction: Cognitive composite scales constructed by combining existing neuropsychometric tests are seeing wide application as endpoints for clinical trials and cohort studies of Alzheimer’s disease (AD) predementia conditions. Preclinical Alzheimer’s Cognitive Composite (PACC) scales are composite scores calculated as the sum of the component test scores weighted by the reciprocal of their standard deviations at the baseline visit. Reciprocal standard deviation is an arbitrary weighting in this context, and may be an inefficient utilization of the data contained in the component measures. Mathematically derived optimal composite weighting is a promising alternative. Methods: Sample size projections using standard power calculation formulas were used to describe the relative performance of component measures and their composites when used as endpoints for clinical trials. Power calculations were informed by (n=1,333) amnestic mild cognitive impaired participants in the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set. Results: A composite constructed using PACC reciprocal standard deviation weighting was both less sensitive to change than one of its component measures and less sensitive to change than its optimally weighted counterpart. In standard sample size calculations informed by NACC data, a clinical trial using the PACC weighting would require 38% more subjects than a composite calculated using optimal weighting. Discussion: These findings illustrate how reciprocal standard deviation weighting can result in inefficient cognitive composites, and underscore the importance of component weights to the performance of composite scales. In the future, optimal weighting parameters informed by accumulating clinical trial data may improve the efficiency of clinical trials in AD

Biomechanics for inclusive urban design : effects of tactile paving on older adults’ gait when crossing the street

In light of our ageing population it is important that the urban environment is easily accessible and hence supports older adults’ independence. Tactile ‘blister’ paving was originally designed to provide guidance for visually impaired people at pedestrian crossings. However, as research links irregular surfaces to falls in older adults, such paving may have an adverse effect on older people. We investigated the effects of tactile paving on older adults’ gait in a scenario closely resembling “crossing the street”. Gait analysis of 32 healthy older adults showed that tactile, as compared to smooth, paving increases the variability in timing of foot placement by 20%, thereby indicating a disturbance of the rhythmic gait pattern. Moreover, toe-clearance during the swing phase increased by 7% on tactile paving, and the ability to stop upon cue from the traffic light was compromised. These results need to be viewed under consideration of the limitations associated with laboratory studies and real world analysis is needed to fully understand their implications for urban design

Rasagiline Effects on Glucose Metabolism, Cognition, and Tau in Alzheimer’s Dementia

Background: A Phase II proof of concept (POC) randomized clinical trial was conducted to evaluate the effects of rasagiline, a monoamine oxidase B (MAO-B) inhibitor approved for Parkinson disease, in mild to moderate Alzheimer\u27s disease (AD). The primary objective was to determine if 1 mg of rasagiline daily for 24 weeks is associated with improved regional brain metabolism (fluorodeoxyglucose–positron emission tomography [FDG-PET]) compared to placebo. Secondary objectives included measurement of effects on tau PET and evaluation of directional consistency of clinical end points. Methods: This was a double-blind, parallel group, placebo-controlled, community-based, three-site trial of 50 participants randomized 1:1 to receive oral rasagiline or placebo (NCT02359552). FDG-PET was analyzed for the presence of an AD-like pattern as an inclusion criterion and as a longitudinal outcome using prespecified regions of interest and voxel-based analyses. Tau PET was evaluated at baseline and longitudinally. Clinical outcomes were analyzed using an intention-to-treat (ITT) model. Results: Fifty patients were randomized and 43 completed treatment. The study met its primary end point, demonstrating favorable change in FDG-PET differences in rasagiline versus placebo in middle frontal (P \u3c 0.025), anterior cingulate (P \u3c 0.041), and striatal (P \u3c 0.023) regions. Clinical measures showed benefit in quality of life (P \u3c 0.04). Digit Span, verbal fluency, and Neuropsychiatric Inventory (NPI) showed non-significant directional favoring of rasagiline; no effects were observed in Alzheimer\u27s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or activities of daily living. Rasagiline was generally well tolerated with low rates of adverse events and notably fewer neuropsychiatric symptoms in the active treatment group. Discussion: These outcomes illustrate the potential benefits of rasagiline on clinical and neuroimaging measures in patients with mild to moderate AD. Rasagiline appears to affect neuronal activity in frontostriatal pathways, with associated clinical benefit potential warranting a more fully powered trial. This study illustrated the potential benefit of therapeutic repurposing and an experimental medicine proof-of-concept design with biomarkers to characterize patient and detect treatment response

Cumulative Burden of Morbidity Among Testicular Cancer Survivors After Standard Cisplatin-Based Chemotherapy: A Multi-Institutional Study

Purpose In this multicenter study, we evaluated the cumulative burden of morbidity (CBM) among > 1,200 testicular cancer survivors and applied factor analysis to determine the co-occurrence of adverse health outcomes (AHOs). Patients and Methods Participants were ≤ 55 years of age at diagnosis, finished first-line chemotherapy ≥ 1 year previously, completed a comprehensive questionnaire, and underwent physical examination. Treatment data were abstracted from medical records. A CBM score encompassed the number and severity of AHOs, with ordinal logistic regression used to assess associations with exposures. Nonlinear factor analysis and the nonparametric dimensionality evaluation to enumerate contributing traits procedure determined which AHOs co-occurred. Results Among 1,214 participants, approximately 20% had a high (15%) or very high/severe (4.1%) CBM score, whereas approximately 80% scored medium (30%) or low/very low (47%). Increased risks of higher scores were associated with four cycles of either ifosfamide, etoposide, and cisplatin (odds ratio [OR], 1.96; 95% CI, 1.04 to 3.71) or bleomycin, etoposide, and cisplatin (OR, 1.44; 95% CI, 1.04 to 1.98), older attained age (OR, 1.18; 95% CI, 1.10 to 1.26), current disability leave (OR, 3.53; 95% CI, 1.57 to 7.95), less than a college education (OR, 1.44; 95% CI, 1.11 to 1.87), and current or former smoking (OR, 1.28; 95% CI, 1.02 to 1.63). CBM score did not differ after either chemotherapy regimen ( P = .36). Asian race (OR, 0.41; 95% CI, 0.23 to 0.72) and vigorous exercise (OR, 0.68; 95% CI, 0.52 to 0.89) were protective. Variable clustering analyses identified six significant AHO clusters (χ2 P < .001): hearing loss/damage, tinnitus (OR, 16.3); hyperlipidemia, hypertension, diabetes (OR, 9.8); neuropathy, pain, Raynaud phenomenon (OR, 5.5); cardiovascular and related conditions (OR, 5.0); thyroid disease, erectile dysfunction (OR, 4.2); and depression/anxiety, hypogonadism (OR, 2.8). Conclusion Factors associated with higher CBM may identify testicular cancer survivors in need of closer monitoring. If confirmed, identified AHO clusters could guide the development of survivorship care strategies

Sparticle mass spectra from SU(5) SUSY GUT models with b−τb-\tau Yukawa coupling unification

Supersymmetric grand unified models based on the gauge group SU(5) often require in addition to gauge coupling unification, the unification of b-quark and $\tau$-lepton Yukawa couplings. We examine SU(5) SUSY GUT parameter space under the condition of $b-\tau$ Yukawa coupling unification using 2-loop MSSM RGEs including full 1-loop threshold effects. The Yukawa-unified solutions break down into two classes. Solutions with low tan\beta ~3-11 are characterized by gluino mass ~1-4 TeV and squark mass ~1-5 TeV. Many of these solutions would be beyond LHC reach, although they contain a light Higgs scalar with mass <123 GeV and so may be excluded should the LHC Higgs hint persist. The second class of solutions occurs at large tan\beta ~35-60, and are a subset of $t-b-\tau$ unified solutions. Constraining only $b-\tau$ unification to ~5% favors a rather light gluino with mass ~0.5-2 TeV, which should ultimately be accessible to LHC searches. While our $b-\tau$ unified solutions can be consistent with a picture of neutralino-only cold dark matter, invoking additional moduli or Peccei-Quinn superfields can allow for all of our Yukawa-unified solutions to be consistent with the measured dark matter abundance.Comment: 19 pages, 5 figures, 1 table, PDFLate

Testing the gaugino AMSB model at the Tevatron via slepton pair production

Gaugino AMSB models-- wherein scalar and trilinear soft SUSY breaking terms are suppressed at the GUT scale while gaugino masses adopt the AMSB form-- yield a characteristic SUSY particle mass spectrum with light sleptons along with a nearly degenerate wino-like lightest neutralino and quasi-stable chargino. The left- sleptons and sneutrinos can be pair produced at sufficiently high rates to yield observable signals at the Fermilab Tevatron. We calculate the rate for isolated single and dilepton plus missing energy signals, along with the presence of one or two highly ionizing chargino tracks. We find that Tevatron experiments should be able to probe gravitino masses into the ~55 TeV range for inoAMSB models, which corresponds to a reach in gluino mass of over 1100 GeV.Comment: 14 pages including 6 .eps figure

Routine dynamics in action: replication and transformation

Contains an Open Access chapter.This book explores central themes in the enactment and coordination of organizational routines, including replication and transfer, ecologies and interdependence, action and the generation of novelty and technology and sociomateriality.

Response of the solar atmosphere to magnetic field evolution in a coronal hole region

Methods. We study an equatorial CH observed simultaneously by HINODE and STEREO on July 27, 2007. The HINODE/SP maps are adopted to derive the physical parameters of the photosphere and to research the magnetic field evolution and distribution. The G band and Ca II H images with high tempo-spatial resolution from HINODE/BFI and the multi-wavelength data from STEREO/EUVI are utilized to study the corresponding atmospheric response of different overlying layers. Results. We explore an emerging dipole locating at the CH boundary. Mini-scale arch filaments (AFs) accompanying the emerging dipole were observed with the Ca II H line. During the separation of the dipolar footpoints, three AFs appeared and expanded in turn. The first AF divided into two segments in its late stage, while the second and third AFs erupted in their late stages. The lifetimes of these three AFs are 4, 6, 10 minutes, and the two intervals between the three divisions or eruptions are 18 and 12 minutes, respectively. We display an example of mixed-polarity flux emergence of IN fields within the CH and present the corresponding chromospheric response. With the increase of the integrated magnetic flux, the brightness of the Ca II H images exhibits an increasing trend. We also study magnetic flux cancellations of NT fields locating at the CH boundary and present the obvious chromospheric and coronal response. We notice that the brighter regions seen in the 171 A images are relevant to the interacting magnetic elements. By examining the magnetic NT and IN elements and the response of different atmospheric layers, we obtain good positive linear correlations between the NT magnetic flux densities and the brightness of both G band (correlation coefficient 0.85) and Ca II H (correlation coefficient 0.58).Comment: 9 pages, 9 figures. A&A, in pres