Ethical Issues in the Development of Readiness Cohorts in Alzheimer's Disease Research.

There is growing interest in the development of novel approaches to secondary prevention trials in Alzheimer's disease to facilitate screening and recruitment of research participants and to reduce the time and costs associated with clinical trials. Several international research collaborations are setting up research infrastructures that link existing research cohorts, studies or patient registries to establish 'trial-ready' or 'readiness' cohorts. From these cohorts, individuals are recruited into clinical trial platforms. In setting up such research infrastructures, researchers must make ethically challenging design decisions in at least three areas: re-contacting participants in existing research studies, obtaining informed consent for participation in a readiness cohort, and disclosure of Alzheimer's disease-related biomarkers. These ethical considerations have been examined by a dedicated workgroup within the European Prevention of Alzheimer's Dementia (EPAD) project, a trans-European longitudinal cohort and adaptive proof-of-concept clinical trial platform. This paper offers recommendations for the ethical management of re-contact, informed consent and risk disclosure which may be of value to other research collaborations in the process of developing readiness cohorts for prevention trials in Alzheimer's disease and other disease areas.This work was funded through the Ethical Legal and Social Implications work package of the European Prevention of Alzheimer’s Dementia (EPAD) study EPAD receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115736, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. RM was also funded through the UK National Institute of Health Research grant to the Cambridge Biomedical Research Centre

An analysis of passive earth pressure modification due to seepage flow effects

Using an assumed vertical retaining wall with a drainage system along the soil-structure interface, this paper analyses the effect of anisotropic seepage flow on the development of passive earth pressure. Extremely unfavourable seepage flow inside the backfill, perhaps due to heavy rainfall, will dramatically increase the active earth pressure while reducing the passive earth pressure; thus increasing the probability of instability of the retaining structure. In this paper, a trial and error analysis based on limit equilibrium is applied to identify the optimum failure surface. The flow field is computed using Fourier series expansion, and the effective reaction force along the curved failure surface is obtained by solving a modified Kötter equation considering the effect of seepage flow. This approach correlates well with other existing results. For small values of both the internal friction angle and the interface friction angle, the failure surface can be appropriately simplified with a planar approximation. A parametric study indicates that the degree of anisotropic seepage flow affects the resulting passive earth pressure. In addition, incremental increases in the effective friction angle and interface friction both lead to an increase in the passive earth pressure.National Key Basic Research Program of China (No. 2015CB057801), the National Key R & D program of China (No. 2016YFC0800204), and Natural Science Foundation of China (Nos. 51578499 & 51761130078)

Psychological, behavioral and social effects of disclosing Alzheimer's disease biomarkers to research participants

BACKGROUND: Current Alzheimer's disease (AD) research initiatives focus on cognitively healthy individuals with biomarkers that are associated with the development of AD. It is unclear whether biomarker results should be returned to research participants and what the psychological, behavioral and social effects of disclosure are. This systematic review therefore examines the psychological, behavioral and social effects of disclosing genetic and nongenetic AD-related biomarkers to cognitively healthy research participants. METHODS: We performed a systematic literature search in eight scientific databases. Three independent reviewers screened the identified records and selected relevant articles. Results extracted from the included articles were aggregated and presented per effect group. RESULTS: Fourteen studies met the inclusion criteria and were included in the data synthesis. None of the identified studies examined the effects of disclosing nongenetic biomarkers. All studies but one concerned the disclosure of APOE genotype and were conducted in the USA. Study populations consisted largely of cognitively healthy first-degree relatives of AD patients. In this group, disclosure of an increased risk was not associated with anxiety, depression or changes in perceived risk in relation to family history. Disclosure of an increased risk did lead to an increase in specific test-related distress levels, health-related behavior changes and long-term care insurance uptake and possibly diminished memory functioning. CONCLUSION: In cognitively healthy research participants with a first-degree relative with AD, disclosure of APOE ε4-positivity does not lead to elevated anxiety and depression levels, but does increase test-related distress and results in behavior changes concerning insurance and health. We did not find studies reporting the effects of disclosing nongenetic biomarkers and only one study included people without a family history of AD. Empirical studies on the effects of disclosing nongenetic biomarkers and of disclosure to persons without a family history of AD are urgently needed. TRIAL REGISTRATION: PROSPERO international prospective register for systematic reviews CRD42016035388 . Registered 19 February 2016

Sitting Behaviors and Mental Health among Workers and Nonworkers: The Role of Weight Status

Objective. To explore the associations between sitting time in various domains and mental health for workers and nonworkers and the role of weight status. Design. Cross-sectional analyses were performed for 1064 respondents (47% men, mean age 59 years) from the Doetinchem Cohort Study 2008-2009. Sedentary behavior was measured by self-reported time spent sitting during transport, leisure time, and at work. Mental health was assessed by the Mental Health Inventory (MHI-5). BMI was calculated based on measured body height and weight. Results. Neither sitting time during transport nor at work was associated with mental health. In the working population, sitting during leisure time, and particularly TV viewing, was associated with poorer mental health. BMI was an effect modifier in this association with significant positive associations for healthy-weight non-workers and obese workers. Conclusion. Both BMI and working status were effect modifiers in the relation between TV viewing and mental health. More longitudinal research is needed to confirm the results and to gain insight into the causality and the underlying mechanisms for the complex relationships among sedentary behaviors, BMI, working status, and mental health

Crossing barriers:a multidisciplinary approach to children and adults with young-onset movement disorders

Abstract Background Diagnosis of less common young-onset movement disorders is often challenging, requiring a broad spectrum of skills of clinicians regarding phenotyping, normal and abnormal development and the wide range of possible acquired and genetic etiologies. This complexity often leads to considerable diagnostic delays, paralleled by uncertainty for patients and their families. Therefore, we hypothesized that these patients might benefit from a multidisciplinary approach. We report on the first 100 young-onset movement disorders patients who visited our multidisciplinary outpatient clinic. Methods Clinical data were obtained from the medical records of patients with disease-onset before age 18 years. We investigated whether the multidisciplinary team, consisting of a movement disorder specialist, pediatric neurologist, pediatrician for inborn errors of metabolism and clinical geneticist, revised the movement disorder classification, etiological diagnosis, and/or treatment. Results The 100 referred patients (56 males) had a mean age of 12.5 ± 6.3 years and mean disease duration of 9.2 ± 6.3 years. Movement disorder classification was revised in 58/100 patients. Particularly dystonia and myoclonus were recognized frequently and supported by neurophysiological testing in 24/29 patients. Etiological diagnoses were made in 24/71 (34%) formerly undiagnosed patients, predominantly in the genetic domain. Treatment strategy was adjusted in 60 patients, of whom 43 (72%) reported a subjective positive effect. Conclusions This exploratory study demonstrates that a dedicated tertiary multidisciplinary approach to complex young-onset movement disorders may facilitate phenotyping and improve recognition of rare disorders, with a high diagnostic yield and minimal diagnostic delay. Future studies are needed to investigate the cost-benefit ratio of a multidisciplinary approach in comparison to regular subspecialty care

SAFEGUI: resampling-based tests of categorical significance in gene expression data made easy

Summary: A large number of websites and applications perform significance testing for gene categories/pathways in microarray data. Many of these packages fail to account for expression correlation between transcripts, with a resultant inflation in Type I error. Array permutation and other resampling-based approaches have been proposed as solutions to this problem. SAFEGUI provides a user-friendly graphical interface for the assessment of categorical significance in microarray studies, while properly accounting for the effects of correlations among genes. SAFEGUI incorporates both permutation and more recently proposed bootstrap algorithms that are demonstrated to be more powerful in detecting differential expression across categories of genes

Manifolds with small Dirac eigenvalues are nilmanifolds

Consider the class of n-dimensional Riemannian spin manifolds with bounded sectional curvatures and diameter, and almost non-negative scalar curvature. Let r=1 if n=2,3 and r=2^{[n/2]-1}+1 if n\geq 4. We show that if the square of the Dirac operator on such a manifold has $r$ small eigenvalues, then the manifold is diffeomorphic to a nilmanifold and has trivial spin structure. Equivalently, if M is not a nilmanifold or if M is a nilmanifold with a non-trivial spin structure, then there exists a uniform lower bound on the r-th eigenvalue of the square of the Dirac operator. If a manifold with almost nonnegative scalar curvature has one small Dirac eigenvalue, and if the volume is not too small, then we show that the metric is close to a Ricci-flat metric on M with a parallel spinor. In dimension 4 this implies that M is either a torus or a K3-surface

Легочная гипертензия при диастолической дисфункции левого желудочка у больных с ишемической кардиомиопатией

На основании данных эхокардиографического исследования выявлена взаимосвязь между степенью легочной гипертензии и тяжестью диастолической дисфункции левого желудочка у больных с ишемической кардиомиопатией. Показано, что рестриктиное наполнение левого желудочка наблюдается в основном при выраженной легочной гипертензии.The findings of echocardiography were used to reveal interrelation between the degree of pulmonary hypertension and severity of diastolic dysfunction of the left ventricle in patients with ischemic cardiomyopathy. Restrictive filling of the left ventricle is shown to be observed in marked pulmonary hypertension