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NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

Tue, 08/02/2016 - 11:29am

To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.

A New MI-Based Visualization Aided Validation Index for Mining Big Longitudinal Web Trial Data

Mon, 08/01/2016 - 4:34pm

Web-delivered clinical trials generate big complex data. To help untangle the heterogeneity of treatment effects, unsupervised learning methods have been widely applied. However, identifying valid patterns is a priority but challenging issue for these methods. This paper, built upon our previous research on multiple imputation (MI)-based fuzzy clustering and validation, proposes a new MI-based Visualization-aided validation index (MIVOOS) to determine the optimal number of clusters for big incomplete longitudinal Web-trial data with inflated zeros. Different from a recently developed fuzzy clustering validation index, MIVOOS uses a more suitable overlap and separation measures for Web-trial data but does not depend on the choice of fuzzifiers as the widely used Xie and Beni (XB) index. Through optimizing the view angles of 3-D projections using Sammon mapping, the optimal 2-D projection-guided MIVOOS is obtained to better visualize and verify the patterns in conjunction with trajectory patterns. Compared with XB and VOS, our newly proposed MIVOOS shows its robustness in validating big Web-trial data under different missing data mechanisms using real and simulated Web-trial data.

Structural organization of the inactive X chromosome in the mouse

Mon, 08/01/2016 - 8:39am

X-chromosome inactivation (XCI) involves major reorganization of the X chromosome as it becomes silent and heterochromatic. During female mammalian development, XCI is triggered by upregulation of the non-coding Xist RNA from one of the two X chromosomes. Xist coats the chromosome in cis and induces silencing of almost all genes via its A-repeat region, although some genes (constitutive escapees) avoid silencing in most cell types, and others (facultative escapees) escape XCI only in specific contexts. A role for Xist in organizing the inactive X (Xi) chromosome has been proposed. Recent chromosome conformation capture approaches have revealed global loss of local structure on the Xi chromosome and formation of large mega-domains, separated by a region containing the DXZ4 macrosatellite. However, the molecular architecture of the Xi chromosome, in both the silent and expressed regions, remains unclear. Here we investigate the structure, chromatin accessibility and expression status of the mouse Xi chromosome in highly polymorphic clonal neural progenitors (NPCs) and embryonic stem cells. We demonstrate a crucial role for Xist and the DXZ4-containing boundary in shaping Xi chromosome structure using allele-specific genome-wide chromosome conformation capture (Hi-C) analysis, an assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq) and RNA sequencing. Deletion of the boundary disrupts mega-domain formation, and induction of Xist RNA initiates formation of the boundary and the loss of DNA accessibility. We also show that in NPCs, the Xi chromosome lacks active/inactive compartments and topologically associating domains (TADs), except around genes that escape XCI. Escapee gene clusters display TAD-like structures and retain DNA accessibility at promoter-proximal and CTCF-binding sites. Furthermore, altered patterns of facultative escape genes in different neural progenitor clones are associated with the presence of different TAD-like structures after XCI. These findings suggest a key role for transcription and CTCF in the formation of TADs in the context of the Xi chromosome in neural progenitors.

Paternal Postpartum Depression

Fri, 07/29/2016 - 5:50pm

While postpartum depression (PPD) has historically been associated primarily with mothers, recently there has been increased awareness of the experience of fathers and strategies to address postpartum depression in men. For fathers willing to seek help, the lack of recognition of paternal PPD results in limited supports and treatments. Given the potential implications of paternal PPD, it is essential for new fathers and their healthcare providers to recognize the prevalence of paternal PPD, the symptoms, and the challenges surrounding this issue for men.

Childhood Maltreatment, Emotional Dysregulation, and Psychiatric Comorbidities (poster)

Mon, 07/25/2016 - 12:32pm

There is a complex and bi-directional relationship between childhood trauma and emotional dysregulation. Childhood trauma is associated with: reduced ability to understand and regulate emotions; mediated by relational/attachment difficulties with caregivers and peers; heightened levels of internalizing and externalizing psychopathology; impaired social functioning beginning in childhood and continuing into adulthood.

Therapeutic Assignments: Structured Framework for Interaction Between Medical Students and Patients on Psychiatry Clerkships

Mon, 07/25/2016 - 12:31pm

Medical students enjoy high level of patient contact on psychiatric clerkships. They have felt that forming a relationship with a patient can have therapeutic effects by imparting hope, decreasing their isolation and providing individualized attention. However students have encountered difficulties forming alliance with their patients, either due to acuity of illness such as psychosis or due to character pathology, addiction etc. They need to feel comfortable dealing with more difficult situations such as extremes of emotion or breaks with reality. Interviewing skills must be continually developed. We hope that Therapeutic Assignments (TA) will: provide a medium for students to improve their interviewing skills; enhance their comfort around communicating with patients about sensitive topics; form a therapeutic alliance with their patients, which will support the growth of empathy and be an important aspect in the patient’s treatment.

Enhancing the Social Networks of People with Mental Illnesses: A Qualitative Study on the Role of Peer-Operated Recovery Learning Communities

Fri, 07/22/2016 - 2:08pm

In 2014, researchers from the UMass Systems and Psychosocial Advances Research Center (SPARC) partnered with the Central Massachusetts Recovery Learning Communities (RLC) to complete a pilot study exploring the relationship between RLC participation and experiences of social integration. Utilizing participatory action research (PAR) principles, investigators from both SPARC and the RLC worked collaboratively to design an exploratory qualitative study, analyze data, and present findings.

Synthesis and Testing of Modular Dual-Modality Nanoparticles for Magnetic Resonance and Multispectral Photoacoustic Imaging

Fri, 07/22/2016 - 1:58pm

Magnetic resonance (MR) and photoacoustic (PA) imaging are currently being investigated as complementing strategies for applications requiring sensitive detection of cells in vivo. While combined MR/PAI detection of cells requires biocompatible cell labeling probes, water-based synthesis of dual-modality MR/PAI probes presents significant technical challenges. Here we describe facile synthesis and characterization of hybrid modular dextran-stabilized gold/iron oxide (Au-IO) multimetallic nanoparticles (NP) enabling multimodal imaging of cells. The stable association between the IO and gold NP was achieved by priming the surface of dextran-coated IO with silver NP resulting from silver(I) reduction by aldehyde groups, which are naturally present within the dextran coating of IO at the level of 19-23 groups/particle. The Au-IO NP formed in the presence of silver-primed Au-IO were stabilized by using partially thiolated MPEG5-gPLL graft copolymer carrying residual amino groups. This stabilizer served as a carrier of near-infrared fluorophores (e.g., IRDye 800RS) for multispectral PA imaging. Dual modality imaging experiments performed in capillary phantoms of purified Au-IO-800RS NPs showed that these NPs were detectible using 3T MRI at a concentration of 25 μM iron. PA imaging achieved approximately 2.5-times higher detection sensitivity due to strong PA signal emissions at 530 and 770 nm, corresponding to gold plasmons and IRDye integrated into the coating of the hybrid NPs, respectively, with no "bleaching" of PA signal. MDA-MB-231 cells prelabeled with Au-IO-800RS retained plasma membrane integrity and were detectable by using both MR and dual-wavelength PA at 49 ± 3 cells/imaging voxel. We believe that modular assembly of multimetallic NPs shows promise for imaging analysis of engineered cells and tissues with high resolution and sensitivity.

Gold nanoparticles stabilized with MPEG-grafted poly(l-lysine): in vitro and in vivo evaluation of a potential theranostic agent

Fri, 07/22/2016 - 1:58pm

As the number of diagnostic and therapeutic applications utilizing gold nanoparticles (AuNPs) increases, so does the need for AuNPs that are stable in vivo, biocompatible, and suitable for bioconjugation. We investigated a strategy for AuNP stabilization that uses methoxypolyethylene glycol-graft-poly(l-lysine) copolymer (MPEG-gPLL) bearing free amino groups as a stabilizing molecule. MPEG-gPLL injected into water solutions of HAuCl4 with or without trisodium citrate resulted in spherical (Zav = 36 nm), monodisperse (PDI = 0.27), weakly positively charged nanoparticles (AuNP3) with electron-dense cores (diameter: 10.4 ± 2.5 nm) and surface amino groups that were amenable to covalent modification. The AuNP3 were stable against aggregation in the presence of phosphate and serum proteins and remained dispersed after their uptake into endosomes. MPEG-gPLL-stabilized AuNP3 exhibited high uptake and very low toxicity in human endothelial cells, but showed a high dose-dependent toxicity in epithelioid cancer cells. Highly stable radioactive labeling of AuNP3 with (99m)Tc allowed imaging of AuNP3 biodistribution and revealed dose-dependent long circulation in the blood. The minor fraction of AuGNP3 was found in major organs and at sites of experimentally induced inflammation. Gold analysis showed evidence of a partial degradation of the MPEG-gPLL layer in AuNP3 particles accumulated in major organs. Radiofrequency-mediated heating of AuNP3 solutions showed that AuNP3 exhibited heating behavior consistent with 10 nm core nanoparticles. We conclude that PEG-pPLL coating of AuNPs confers "stealth" properties that enable these particles to exist in vivo in a nonaggregating, biocompatible state making them suitable for potential use in biomedical applications such as noninvasive radiofrequency cancer therapy.

Substrate-Based Near-Infrared Imaging Sensors Enable Fluorescence Lifetime Contrast via Built-in Dynamic Fluorescence Quenching Elements

Fri, 07/22/2016 - 1:57pm

Enzymatic activity sensing in fluorescence lifetime (FLT) mode with “self-quenched” macromolecular near-infrared (NIR) sensors is a highly promising strategy for in vivo imaging of proteolysis. However, the mechanisms of FLT changes in such substrate-based NIR sensors have not yet been studied. We synthesized two types of sensors by linking the near-infrared fluorophore IRDye 800CW to macromolecular graft copolymers of methoxy polyethylene glycol and polylysine (MPEG-gPLL) with varying degrees of MPEGylation and studied their fragmentation induced by trypsin, elastase, plasmin, and cathepsins (B,S,L,K). We determined that the efficiency of such NIR sensors in FLT mode depends on sensor composition. While MPEG-gPLL with a high degree of MPEGylation showed rapid (τ1/2 = 0.1–0.2 min) FLT increase (Δτ = 0.25 ns) upon model proteinase-mediated hydrolysis in vivo, lower MPEGylation density resulted in no such FLT increase. Temperature-dependence of fluorescence dequenching of NIR sensors pointed to a mixed dynamic/static-quenching mode of MPEG-gPLL-linked fluorophores. We further demonstrated that although the bulk of sensor-linked fluorophores were dequenched due to the elimination of static quenching, proteolysis-mediated deletion of a fraction of short (8–10 kD) negatively charged fragments of highly MPEGylated NIR sensor is the most likely event leading to a rapid FLT increase phenomenon in quenched NIR sensors. Therefore, the optimization of “built-in” dynamic quenching elements of macromolecular NIR sensors is a potential avenue for improving their response in FLT mode.

Tweet, Like, Share: Using Social Media to Connect with the Evaluation World

Fri, 07/22/2016 - 12:23pm

Blog post to AEA365, a blog sponsored by the American Evaluation Association (AEA) dedicated to highlighting Hot Tips, Cool Tricks, Rad Resources, and Lessons Learned for evaluators. The American Evaluation Association is an international professional association of evaluators devoted to the application and exploration of program evaluation, personnel evaluation, technology, and many other forms of evaluation. Evaluation involves assessing the strengths and weaknesses of programs, policies, personnel, products, and organizations to improve their effectiveness.

Searching for Literature Using Google Scholar

Thu, 07/21/2016 - 8:53pm

Blog post to AEA365, a blog sponsored by the American Evaluation Association (AEA) dedicated to highlighting Hot Tips, Cool Tricks, Rad Resources, and Lessons Learned for evaluators. The American Evaluation Association is an international professional association of evaluators devoted to the application and exploration of program evaluation, personnel evaluation, technology, and many other forms of evaluation. Evaluation involves assessing the strengths and weaknesses of programs, policies, personnel, products, and organizations to improve their effectiveness.

Driving Change: Tips for Helping Stakeholders Stay Motivated

Thu, 07/21/2016 - 8:53pm

Blog post to AEA365, a blog sponsored by the American Evaluation Association (AEA) dedicated to highlighting Hot Tips, Cool Tricks, Rad Resources, and Lessons Learned for evaluators. The American Evaluation Association is an international professional association of evaluators devoted to the application and exploration of program evaluation, personnel evaluation, technology, and many other forms of evaluation. Evaluation involves assessing the strengths and weaknesses of programs, policies, personnel, products, and organizations to improve their effectiveness.

The Beauty of Banner Tables

Thu, 07/21/2016 - 8:53pm

Blog post to AEA365, a blog sponsored by the American Evaluation Association (AEA) dedicated to highlighting Hot Tips, Cool Tricks, Rad Resources, and Lessons Learned for evaluators. The American Evaluation Association is an international professional association of evaluators devoted to the application and exploration of program evaluation, personnel evaluation, technology, and many other forms of evaluation. Evaluation involves assessing the strengths and weaknesses of programs, policies, personnel, products, and organizations to improve their effectiveness.

What explains the link between reproductive events and women's longevity

Wed, 07/20/2016 - 9:52am

Introduction: Several investigations have shown a link between older age at last birth and extreme longevity. The latest study in the current issue of Menopause found that women giving birth to their last child beyond age 33 years had twice the odds of being in the top 5% of survival. Consistent with these results, age at final menstrual period (FMP) also has been shown to predict subsequent mortality, with lower mortality in women with older age at FMP. FMP results from a loss of ovarian follicles, which presumably also affects age at last birth. Of the few studies investigating the relationship between age at last birth and age at FMP, several —though not all —have indicated a positive association. Thus, a similar set of factors may explain the link between age at last birth and longevity and the link between age at FMP and subsequent morbidity/mortality.

Evaluation of tobacco use on Chinese population through ATTOC model: a cross-sectional survey on hospitalized psychiatric patients

Wed, 07/20/2016 - 9:51am

OBJECTIVES: To evaluate the feasibility of Addressing Tobaccos through Organizational Change (ATTOC) intervention to Chinese psychiatric patients, and to better address tobacco use through the ATTOC intervention model in the context of China.

METHODS: The study was conducted in Mental Health Center of West China Hospital in 2010. A total of 100 hospitalized psychiatric patients were recruited to carry out ATTOC intervention. Subjects suffers from mental illness were diagnosed by professional psychiatrists according to the International Statistical Classification of Diseases (ICD-10) criteria.

RESULTS: The prevalence of tobacco use in hospitalized psychiatric patients were closely correlated with the type of mental illness, family smoking history, sex, age, marital status, education status, etc. However, most psychiatric patients knew little about these, and tended to ignore the importance of smoking cessation.

CONCLUSIONS: The ATTOC intervention program of the U.S. may be suitable for hospitalized Chinese psychiatric patients, and it could be applied for the tobacco smoking treatment in China. However, the health effects of tobacco use still did not draw amount attentions from both the clinicians and general public. It is urgently needed to raise people's awareness and carry out ATTOC intervention to control tobacco use, and ultimately terminate tobacco use.

Influence of race/ethnicity, body mass index, and proximity of menopause on menstrual cycle patterns in the menopausal transition: the Study of Women's Health Across the Nation

Wed, 07/20/2016 - 9:51am

OBJECTIVE: Few studies have evaluated factors that influence menstrual cycle length (MCL) during the menopausal transition (MT), a life stage during which very long cycles become more likely to occur. The objective of this article was to assess how body mass index and race/ethnicity--factors associated with MCL in young women--influence MCL during the MT.

METHODS: Study of Women's Health Across the Nation menstrual calendar substudy data of African-American, white, Chinese, and Japanese women were available for three sites (southeastern Michigan, Los Angeles, and northern California). Self-recorded monthly menstrual calendars with end-of-the-month questions on hormone therapy use and smoking were collected from 1996 to 2006. Height and weight were measured at annual study visits. We used quantile regression to model MCL at the 25th, 50th, 75th, and 90th percentiles with bootstrap sampling to construct 95% CIs. Models evaluated MCL with time indexed to the start of the MT (n = 963) and to the final menstrual period (n = 431).

RESULTS: During the MT, increases in MCL occurred mostly at the right tail of the distribution, reflecting a lengthening of long menstrual cycles, not of the median MCL. After adjustment for smoking, education, physical activity, and time, Chinese and Japanese women had 1 day to 6 days longer MCLs compared with white women. Obese women had 1 day to 5 days longer MCLs compared with nonobese women.

CONCLUSIONS: As occurs in younger women, menstrual characteristics during the MT are influenced by race/ethnicity and obesity. The long menstrual cycles characteristic of the MT are longer in obese women and in Chinese and Japanese women.

Parent preferences for telephone coaching to prevent and manage childhood obesity

Wed, 07/20/2016 - 9:51am

OBJECTIVE: To assess parent preferences for utilisation of a parent-focused, telephone-based coaching service, or 'FITLINE,' to prevent or manage childhood obesity.

METHODS: A cross-sectional survey of parents of children aged 2-12 years was conducted at a paediatric practice in Greater Boston, Massachusetts, USA, between July 2012 and May 2013. Parents received questionnaires with clinic visit paperwork and opted-in to the study by returning them to clinic staff or by mail. The anonymous pen-to-paper questionnaire assessed parents' potential FITLINE utilisation, preferences regarding educational content and logistics, and parent/child demographics. Simple logistical regression was used to assess associations between parent and child factors and FITLINE interest.

RESULTS: Among n=114 participants, most parents reported being very likely (n=53, 48%) or somewhat likely (n=44, 40%) to use a FITLINE-promoting healthy habits for children if it was made available. Interest in a FITLINE was greatest among overweight or obese parents (OR 3.12, CI 1.17 to 8.30) and those with children aged < 5 years (OR 2.42, CI 1.02 to 5.73). Parents desired to discuss their own health and fitness goals (84%) along with educational topics such as healthy food shopping on a budget (91%) and how to meet children's physical activity needs (81%). Most parents preferred to obtain a FITLINE referral from a paediatrician or nurse (73%), instead of a school nurse (42%) or child-care provider (26%).

CONCLUSIONS: Given strong interest among parents in a FITLINE and the urgency of the youth obesity epidemic, implementation of a pilot phone-based service should be strongly considered.

Duration of menopausal vasomotor symptoms over the menopause transition

Wed, 07/20/2016 - 9:51am

IMPORTANCE: The expected duration of menopausal vasomotor symptoms (VMS) is important to women making decisions about possible treatments.

OBJECTIVES: To determine total duration of frequent VMS ( > /= 6 days in the previous 2 weeks) (hereafter total VMS duration) during the menopausal transition, to quantify how long frequent VMS persist after the final menstrual period (FMP) (hereafter post-FMP persistence), and to identify risk factors for longer total VMS duration and longer post-FMP persistence.

DESIGN, SETTING, AND PARTICIPANTS: The Study of Women's Health Across the Nation (SWAN) is a multiracial/multiethnic observational study of the menopausal transition among 3302 women enrolled at 7 US sites. From February 1996 through April 2013, women completed a median of 13 visits. Analyses included 1449 women with frequent VMS.

MAIN OUTCOMES AND MEASURES: Total VMS duration (in years) (hot flashes or night sweats) and post-FMP persistence (in years) into postmenopause.

RESULTS: The median total VMS duration was 7.4 years. Among 881 women who experienced an observable FMP, the median post-FMP persistence was 4.5 years. Women who were premenopausal or early perimenopausal when they first reported frequent VMS had the longest total VMS duration (median, > 11.8 years) and post-FMP persistence (median, 9.4 years). Women who were postmenopausal at the onset of VMS had the shortest total VMS duration (median, 3.4 years). Compared with women of other racial/ethnic groups, African American women reported the longest total VMS duration (median, 10.1 years). Additional factors related to longer duration of VMS (total VMS duration or post-FMP persistence) were younger age, lower educational level, greater perceived stress and symptom sensitivity, and higher depressive symptoms and anxiety at first report of VMS.

CONCLUSIONS AND RELEVANCE: Frequent VMS lasted more than 7 years during the menopausal transition for more than half of the women and persisted for 4.5 years after the FMP. Individual characteristics (eg, being premenopausal and having greater negative affective factors when first experiencing VMS) were related to longer-lasting VMS. Health care professionals should counsel women to expect that frequent VMS could last more than 7 years, and they may last longer for African American women.