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"What Does Weight Have to Do with It?" Parent Perceptions of Weight and Pain in a Pediatric Chronic Pain Population

Fri, 04/14/2017 - 3:01pm

Tailored pain management strategies are urgently needed for youth with co-occurring chronic pain and obesity; however, prior to developing such strategies, we need to understand parent perspectives on weight in the context of pediatric chronic pain. Participants in this study included 233 parents of patients presenting to a multidisciplinary pediatric chronic pain clinic. Parents completed a brief survey prior to their child's initial appointment; questions addressed parents' perceptions of their child's weight, and their perceptions of multiple aspects of the relationship between their child's weight and chronic pain. The majority (64%) of parents of youth with obesity accurately rated their child's weight; this group of parents was also more concerned (p < 0.05) about their child's weight than parents of youth with a healthy weight. However, the majority of parents of youth with obesity did not think their child's weight contributed to his/her pain, or that weight was relevant to their child's pain or pain treatment. Overall, only half of all parents saw discussions of weight, nutrition, and physical activity as important to treating their child's pain. Results support the need for addressing parents' perceptions of their child's weight status, and educating parents about the relationship between excessive weight and chronic pain.

Smoking Cessation and Electronic Cigarettes in Community Mental Health Centers: Patient and Provider Perspectives

Fri, 04/14/2017 - 3:01pm

Little is known about patients' electronic cigarette use, interest in and use of smoking cessation treatments, and providers' attitude towards such treatment. We assessed patients (N = 231) and providers (45 psychiatrists, 97 case workers) in four Community Mental Health Centers. Interestingly, 50% of smokers reported interest in using electronic cigarettes to quit smoking, and 22% reported current use. While 82% of smokers reported wanting to quit or reduce smoking, 91% of psychiatrists and 84% of case workers reported that patients were not interested in quitting as the lead barrier, limiting the provision of cessation interventions. Providers' assumption of low patient interest in treatment may account for the low rate of smoking cessation treatment. In contrast, patients report interest and active use of electronic cigarettes to quit smoking. This study highlights the need for interventions targeting different phases of smoking cessation in these patients suffering disproportionately from tobacco dependence.

Neuronal Deletion of Kmt2a/Mll1 Histone Methyltransferase in Ventral Striatum is Associated with Defective Spike-Timing-Dependent Striatal Synaptic Plasticity, Altered Response to Dopaminergic Drugs, and Increased Anxiety

Fri, 04/14/2017 - 3:01pm

Lysine (K) methyltransferase 2a (Kmt2a) and other regulators of H3 lysine 4 methylation, a histone modification enriched at promoters and enhancers, are widely expressed throughout the brain, but molecular and cellular phenotypes in subcortical areas remain poorly explored. We report that Kmt2a conditional deletion in postnatal forebrain is associated with excessive nocturnal activity and with absent or blunted responses to stimulant and dopaminergic agonist drugs, in conjunction with near-complete loss of spike-timing-dependent long-term potentiation in medium spiny neurons (MSNs). Selective ablation of Kmt2a, but not the ortholog Kmt2b, in adult ventral striatum/nucleus accumbens neurons markedly increased anxiety scores in multiple behavioral paradigms. Striatal transcriptome sequencing in adult mutants identified 262 Kmt2a-sensitive genes, mostly downregulated in Kmt2a-deficient mice. Transcriptional repression includes the 5-Htr2a serotonin receptor, strongly associated with anxiety- and depression-related disorders in human and animal models. Consistent with the role of Kmt2a in promoting gene expression, the transcriptional regulators Bahcc1, Isl1, and Sp9 were downregulated and affected by H3K4 promoter hypomethylation. Therefore, Kmt2a regulates synaptic plasticity in striatal neurons and provides an epigenetic drug target for anxiety and dopamine-mediated behaviors.

The importance of rare diseases for psychiatry

Fri, 04/14/2017 - 3:01pm

Expanded knowledge of rare diseases is becomingly increasingly important for psychiatric clinical care and research.

Psychiatric hospitalisation among individuals with intellectual disability referred to the START crisis intervention and prevention program

Fri, 04/14/2017 - 3:01pm

BACKGROUND: Little is known about inpatient psychiatric hospitalisation among adults with intellectual disability (ID) in the United States. Greater research is, therefore, required to inform efforts aimed at preventing this costly and restrictive form of care.

METHODS: Data were from 3299 individuals with ID (mean age = 31 years; SD = 14 years) who were referred to START (Systemic, Therapeutic, Assessment, Resources, and Treatment), a community-based crisis intervention and prevention programme. A random effects logistic regression model was used to examine the association between 11 factors and caregiver report of psychiatric hospitalisation in the past 12 months.

RESULTS: Twenty eight percent of the sample had at least one psychiatric inpatient stay in the prior year. Factors associated with an increased likelihood of prior hospitalisation included: younger age, diagnosis of a psychotic disorder, a score of > 30 on the irritability subscale of the Aberrant Behavior Checklist, increasing number of psychiatric diagnoses, less severe ID, Black/AA race and not having a home and community waiver.

CONCLUSIONS: Among this high-risk referred group, more than 1 in 4 individuals were hospitalised in the year prior to referral. While results from the analyses will help profile those at risk for hospitalisation, the findings suggest that interventions at the policy level may play an important role in reducing psychiatric hospitalisation.

Modulation of ethanol reward sensitivity by nicotinic acetylcholine receptors containing the alpha6 subunit

Fri, 04/14/2017 - 3:01pm

The prevalent co-abuse of nicotine and alcohol suggests a common neural mechanism underlying the actions of the two drugs. Nicotine, the addictive component of tobacco, activates nicotinic acetylcholine receptors (nAChRs) containing the alpha6 subunit (alpha6* nAChRs) in dopaminergic (DAergic) neurons of the ventral tegmental area (VTA), a region known to be crucial for drug reward. Recent evidence suggests that ethanol may potentiate ACh activation of these receptors as well, although whether alpha6* nAChR expression is necessary for behavioral effects of acute ethanol exposure is unknown. We compared binge-like ethanol consumption and ethanol reward sensitivity between knockout (KO) mice that do not express chrna6 (the gene encoding the alpha6 nAChR subunit, the alpha6 KO line) and wild-type (WT) littermates using the Drinking-in-the-Dark (DID) and Conditioned Place Preference (CPP) assay, respectively. In the DID assay, alpha6 KO female and male mice consumed ethanol similarly to WT mice at all concentrations tested. In the CPP assay, 2.0-g/kg and 3.0-g/kg, but not 0.5-mg/kg, ethanol conditioned a place preference in WT female and male mice, whereas only 2.0-g/kg ethanol conditioned a place preference in alpha6 KO mice. Acute challenge with ethanol reduced locomotor activity, an effect that developed tolerance with repeated injections, similarly between genotypes in both female and male mice. Together, these data indicate that expression of alpha6* nAChRs is not required for binge-like ethanol consumption and reward, but modulate sensitivity to the rewarding properties of the drug.

Rhythmic Interlimb Coordination Impairments and the Risk for Developing Mobility Limitations

Fri, 04/14/2017 - 3:01pm

BACKGROUND: The identification of novel rehabilitative impairments that are risk factors for mobility limitations may improve their prevention and treatment among older adults. We tested the hypothesis that impaired rhythmic interlimb ankle and shoulder coordination are risk factors for subsequent mobility limitations among older adults.

METHODS: We conducted a 1-year prospective cohort study of community-dwelling older adults (N = 99) aged 67 years and older who did not have mobility limitations (Short Physical Performance Battery score > 9) at baseline. Participants performed antiphase coordination of the right and left ankles or shoulders while paced by an auditory metronome. Using multivariable logistic regression, we determined odds ratios (ORs) for mobility limitations at 1-year follow-up as a function of coordination variability and asymmetry.

RESULTS: After adjusting for age, sex, body mass index, Mini-Mental State Examination score, number of chronic conditions, and baseline Short Physical Performance Battery score, ORs were significant for developing mobility limitations based on a 1 SD difference in the variability of ankle (OR = 1.88; 95% confidence interval [CI]: 1.16-3.05) and shoulder (OR = 1.96; 95% CI: 1.17-3.29) coordination. ORs were significant for asymmetry of shoulder (OR = 2.11; 95% CI: 1.25-3.57), but not ankle (OR = 0.95; 95% CI: 0.59-1.55) coordination. Similar results were found in unadjusted analyses.

CONCLUSIONS: The results support our hypothesis that impaired interlimb ankle and shoulder coordination are risk factors for the development of mobility limitations. Future work is needed to further examine the peripheral and central mechanisms underlying this relationship and to test whether enhancing coordination alters mobility limitations.

BRAF and epithelial-mesenchymal transition in papillary thyroid carcinoma - challenging the roles of Snail and E-Cadherin

Fri, 04/14/2017 - 11:34am

OBJECTIVE: In papillary thyroid carcinoma (PTC), while the role of BRAF is well established, the contribution of BRAF to epithelial-mesenchymal transition is not.

STUDY DESIGN/SETTING: To elucidate the relationship between BRAF, surrogates of epithelial-mesenchymal transition (Snail, E-cadherin) and established histopathologic prognosticators in papillary thyroid carcinoma.

SUBJECTS/METHODS: In this IRB approved cross-sectional study, 50 cases of archived annotated PTC samples were retrieved and immunohistochemically stained for Snail and E-cadherin protein. A semi-quantitative scoring system (incorporating proportion and intensity) was utilized.

RESULTS: Snail and E-cadherin expression were noted in 44% and 84% of BRAF mutant and, in 29% and 95% of BRAFWT samples, respectively. No statistically significant correlations were noted between Snail, E-cadherin and histopathologic prognosticators. However, a trend was noted between Snail expression and tumor size < 5 cm (P=0.07). Statistically significant differences between BRAF mutant and BRAFWT samples were noted in the following groups: conventional (68% vs. 5%) and tall cell (32% vs. 0%) histopathologic variants, extrathyroidal extension (32% vs. 5%), infiltrative growth pattern (80% vs. 48%), presence of desmoplasia (72% vs. 29%), psammona bodies (48% vs. 10%), and cystic change (32% vs. 5%). Among follicular variant of papillary thyroid carcinoma compared to BRAF mutant samples, BRAFWT samples were more commonly of the encapsulated variety (52% vs. 4%), and microcarcinomas (29% vs. 0%) (P < 0.001 and =0.007, respectively).

CONCLUSION: Our findings, supporting the utility of BRAF as a putative therapeutic target in PTC, suggest that the interaction between BRAF and epithelial-mesenchymal transition in papillary thyroid carcinoma is not through induction of the Snail/E-cadherin pathway.

Metabolomic Profiling in Relation to New-Onset Atrial Fibrillation (from the Framingham Heart Study)

Fri, 04/14/2017 - 11:34am

Previous studies have shown several metabolic biomarkers to be associated with prevalent and incident atrial fibrillation (AF), but the results have not been replicated. We investigated metabolite profiles of 2,458 European ancestry participants from the Framingham Heart Study without AF at the index examination and followed them for 10 years for new-onset AF. Amino acids, organic acids, lipids, and other plasma metabolites were profiled by liquid chromatography-tandem mass spectrometry using fasting plasma samples. We conducted Cox proportional hazard analyses for association between metabolites and new-onset AF. We performed hypothesis-generating analysis to identify novel metabolites and hypothesis-testing analysis to confirm the previously reported associations between metabolites and AF. Mean age was 55.1 +/- 9.9 years, and 53% were women. Incident AF developed in 156 participants (6.3%) in 10 years of follow-up. A total of 217 metabolites were examined, consisting of 54 positively charged metabolites, 59 negatively charged metabolites, and 104 lipids. None of the 217 metabolites met our a priori specified Bonferroni corrected level of significance in the multivariate analyses. We were unable to replicate previous results demonstrating associations between metabolites that we had measured and AF. In conclusion, in our metabolomics approach, none of the metabolites we tested were significantly associated with the risk of future AF.

DNA methylation directs genomic localization of Mbd2 and Mbd3 in embryonic stem cells

Fri, 04/14/2017 - 11:34am

Cytosine methylation is an epigenetic and regulatory mark that functions in part through recruitment of chromatin remodeling complexes containing methyl-CpG binding domain (MBD) proteins. Two MBD proteins, Mbd2 and Mbd3, were previously shown to bind methylated or hydroxymethylated DNA, respectively; however, both of these findings have been disputed. Here, we investigated this controversy using experimental approaches and re-analysis of published data and find no evidence for methylation-independent functions of Mbd2 or Mbd3. We show that chromatin localization of Mbd2 and Mbd3 is highly overlapping and, unexpectedly, we find Mbd2 and Mbd3 are interdependent for chromatin association. Further investigation reveals that both proteins are required for normal levels of cytosine methylation and hydroxymethylation in murine embryonic stem cells. Furthermore, Mbd2 and Mbd3 regulate overlapping sets of genes that are also regulated by DNA methylation/hydroxymethylation factors. These findings reveal an interdependent regulatory mechanism mediated by the DNA methylation machinery and its readers.

High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources

Fri, 04/14/2017 - 11:34am

Extracellular vesicles (EVs), including exosomes and microvesicles (MVs), are explored for use in diagnostics, therapeutics and drug delivery. However, little is known about the relationship of protein and lipid composition of EVs and their source cells. Here, we report high-resolution lipidomic and proteomic analyses of exosomes and MVs derived by differential ultracentrifugation from 3 different cell types: U87 glioblastoma cells, Huh7 hepatocellular carcinoma cells and human bone marrow-derived mesenchymal stem cells (MSCs). We identified 3,532 proteins and 1,961 lipid species in the screen. Exosomes differed from MVs in several different areas: (a) The protein patterns of exosomes were more likely different from their cells of origin than were the protein patterns of MVs; (b) The proteomes of U87 and Huh7 exosomes were similar to each other but different from the proteomes of MSC exosomes, whereas the lipidomes of Huh7 and MSC exosomes were similar to each other but different from the lipidomes of U87 exosomes; (c) exosomes exhibited proteins of extracellular matrix, heparin-binding, receptors, immune response and cell adhesion functions, whereas MVs were enriched in endoplasmic reticulum, proteasome and mitochondrial proteins. Exosomes and MVs also differed in their types of lipid contents. Enrichment in glycolipids and free fatty acids characterized exosomes, whereas enrichment in ceramides and sphingomyelins characterized MVs. Furthermore, Huh7 and MSC exosomes were specifically enriched in cardiolipins; U87 exosomes were enriched in sphingomyelins. This study comprehensively analyses the protein and lipid composition of exosomes, MVs and source cells in 3 different cell types.

Radial glia regulate vascular patterning around the developing spinal cord

Fri, 04/14/2017 - 11:33am

Vascular networks surrounding individual organs are important for their development, maintenance, and function; however, how these networks are assembled remains poorly understood. Here we show that CNS progenitors, referred to as radial glia, modulate vascular patterning around the spinal cord by acting as negative regulators. We found that radial glia ablation in zebrafish embryos leads to excessive sprouting of the trunk vessels around the spinal cord, and exclusively those of venous identity. Mechanistically, we determined that radial glia control this process via the Vegf decoy receptor sFlt1: sflt1 mutants exhibit the venous over-sprouting observed in radial glia-ablated larvae, and sFlt1 overexpression rescues it. Genetic mosaic analyses show that sFlt1 function in trunk endothelial cells can limit their over-sprouting. Together, our findings identify CNS-resident progenitors as critical angiogenic regulators that determine the precise patterning of the vasculature around the spinal cord, providing novel insights into vascular network formation around developing organs.

Encouraging Patient Portal Use in the Patient-Centered Medical Home: Three Stakeholder Perspectives

Fri, 04/14/2017 - 11:33am

BACKGROUND: Health care organizations are increasingly offering patients access to their electronic medical record and the ability to communicate with their providers through Web-based patient portals, thus playing a prominent role within the patient-centered medical home (PCMH). However, despite enthusiasm, adoption remains low.

OBJECTIVE: We examined factors in the PCMH context that may affect efforts to improve enrollment in a patient portal.

METHODS: Using a sociotechnical approach, we conducted qualitative, semistructured interviews with patients and providers from 3 primary care clinics and with national leaders from across a large integrated health care system.

RESULTS: We gathered perspectives and analyzed data from 4 patient focus groups and one-on-one interviews with 1 provider from each of 3 primary care clinics and 10 program leaders. We found that leaders were focused on marketing in primary care, whereas patients and providers were often already aware of the portal. In contrast, both patients and providers cited administrative and logistical barriers impeding enrollment. Further, although leadership saw the PCMH as the logical place to focus enrollment efforts, providers and patients were more circumspect and expressed concern about how the patient portal would affect their practice and experience of care. Further, some providers expressed ambivalence about patients using the portal. Despite absence of consensus on how and where to encourage portal adoption, there was wide agreement that promoting enrollment was a worthwhile goal.

CONCLUSIONS: Patients, clinicians, and national leaders agreed that efforts were needed to increase enrollment in the patient portal. Opinions diverged regarding the suitability of the PCMH and, specifically, the primary care clinic for promoting patient portal enrollment. Policymakers should consider diverse stakeholder perspectives in advance of interventions to increase technology adoption.

Older Veteran Digital Disparities: Examining the Potential for Solutions Within Social Networks

Fri, 04/14/2017 - 11:33am

BACKGROUND: Older adults typically have less access to the Internet than other age groups, and older Veterans may use the Internet even less due to economic and geographic reasons.

OBJECTIVE: To explore solutions to this problem, our study examined older Veterans' reported ability to access technology through their close social ties.

METHODS: Data were collected via mail survey from a sample of Veterans aged 65 years and older (N=266).

RESULTS: Nearly half (44.0%, 117/266) of the sample reported having no Internet access. Yet, among those without current access, older Veterans reported having a median of 5 (IQR 7) close social ties with home Internet access. These older Veterans also reported that they would feel comfortable asking a median of 2 (IQR 4) social ties for help to access the Internet, and that a median of 2 (IQR 4) social ties would directly access the Internet for the older Veteran to help with health management.

CONCLUSIONS: Findings suggest that even older Veterans without current Internet access have at least two social ties with home Internet who could be called upon for technology support. Thus, older Veterans may be willing to call upon these "surrogate seekers" for technology assistance and support in health management. This has implications for the digital divide, technology design, and health care policy.

Access to substance use treatment among young adults who use prescription opioids non-medically

Fri, 04/14/2017 - 11:33am

BACKGROUND: Non-medical prescription opioid (NMPO) use is a substantial public health problem in the United States, with 1.5 million new initiates annually. Only 746,000 people received treatment for NMPO use in 2013, demonstrating substantial disparities in access to treatment. This study aimed to assess correlates of accessing substance use treatment among young adult NMPO users in Rhode Island, a state heavily impacted by NMPO use and opioid overdose.

METHODS: This analysis uses data from a study of 200 Rhode Island residents aged 18 to 29 who reported NMPO use in the past 30 days. We compared individuals who had ever successfully enrolled in a substance use treatment program without ever facing barriers, individuals who had ever attempted to enroll but were unable, and individuals who never attempted to enroll. We used multinomial logistic regression to determine the independent correlates of never attempting and unsuccessfully attempting to access substance use treatment.

RESULTS: Among 200 participants, the mean age was 24.5, 65.5% were male, and 61.5% were white. Nearly half (45.5%) had never attempted to enroll in substance use treatment, while 35.0% had successfully enrolled without ever facing barriers and 19.5% were unsuccessful in at least one attempt to enroll. In multivariable models, non-white participants were more likely to never have attempted to enroll compared to white participants. Previous incarceration, experiencing drug-related discrimination by the medical community, and a monthly income of $501 - $1500 were associated with a decreased likelihood of never attempting to enroll. A history of overdose and a monthly income of $501 - $1500 were associated with an increased likelihood of unsuccessfully accessing treatment. The most commonly reported barriers to accessing treatment were waiting lists (n = 23), health insurance not approving enrollment (n = 20), and inability to pay (n = 16).

CONCLUSIONS: This study demonstrates significant disparities in access to treatment among young adults who report NMPO use. A history of overdose was shown to correlate with experiencing barriers to substance use treatment utilization. Interventions are needed to reduce drug-related discrimination in clinical settings and to provide mechanisms that link young adults (particularly with a history of overdose) to evidence-based treatment.

Patient prioritization of comorbid chronic conditions in the Veteran population: Implications for patient-centered care

Fri, 04/14/2017 - 11:33am

OBJECTIVE: Patients with comorbid chronic conditions may prioritize some conditions over others; however, our understanding of factors influencing those prioritizations is limited. In this study, we sought to identify and elaborate a range of factors that influence how and why patients with comorbid chronic conditions prioritize their conditions.

METHODS: We conducted semi-structured, one-on-one interviews with 33 patients with comorbidities recruited from a single Veterans Health Administration Medical Center.

FINDINGS: The diverse factors influencing condition prioritization reflected three overarching themes: (1) the perceived role of a condition in the body, (2) self-management tasks, and (3) pain. In addition to these themes, participants described the rankings that they believed their healthcare providers would assign to their conditions as an influencing factor, although few reported having shared their priorities or explicitly talking with providers about the importance of their conditions.

CONCLUSION: Studies that advance understanding of how and why patients prioritize their various conditions are essential to providing care that is patient-centered, reflecting what matters most to the individual while improving their health. This analysis informs guideline development efforts for the care of patients with comorbid chronic conditions as well as the creation of tools to promote patient-provider communication regarding the importance placed on different conditions.

Engaging Moms on Teen Indoor Tanning Through Social Media: Protocol of a Randomized Controlled Trial

Fri, 04/14/2017 - 11:33am

BACKGROUND: Indoor tanning elevates the risk for melanoma, which is now the most common cancer in US women aged 25-29. Public policies restricting access to indoor tanning by minors to reduce melanoma morbidity and mortality in teens are emerging. In the United States, the most common policy restricting indoor tanning in minors involves parents providing either written or in person consent for the minor to purchase a tanning visit. The effectiveness of this policy relies on parents being properly educated about the harms of indoor tanning to their children.

OBJECTIVE: This randomized controlled trial will test the efficacy of a Facebook-delivered health communication intervention targeting mothers of teenage girls. The intervention will use health communication and behavioral modification strategies to reduce mothers' permissiveness regarding their teenage daughters' use of indoor tanning relative to an attention-control condition with the ultimate goal of reducing indoor tanning in both daughters and mothers.

METHODS: The study is a 12-month randomized controlled trial comparing 2 conditions: an attention control Facebook private group where content will be relevant to teen health with 25% focused on prescription drug abuse, a topic unrelated to tanning; and the intervention condition will enter participants into a Facebook private group where 25% of the teen health content will be focused on indoor tanning. A cohort of 2000 mother-teen daughter dyads will be recruited to participate in this study. Only mothers will participate in the Facebook groups. Both mothers and daughters will complete measures at baseline, end of intervention (1-year) and 6 months post-intervention. Primary outcomes include mothers' permissiveness regarding their teenage daughters' use of indoor tanning, teenage daughters' perception of their mothers' permissiveness, and indoor tanning by both mothers and daughters.

RESULTS: The first dyad was enrolled on March 31, 2016, and we anticipate completing this study by October 2019.

CONCLUSIONS: This trial will deliver social media content grounded in theory and will test it in a randomized design with state-of-the-art measures. This will contribute much needed insights on how to employ social media for health behavior change and disease prevention both for indoor tanning and other health risk behaviors and inform future social media efforts by public health and health care organizations.

CLINICALTRIAL: Clinicaltrials.gov NCT02835807; https://clinicaltrials.gov/ct2/show/NCT02835807 (Archived by WebCite at http://www.webcitation.org/6mDMICcCE).

Finding Important Terms for Patients in Their Electronic Health Records: A Learning-to-Rank Approach Using Expert Annotations

Fri, 04/14/2017 - 11:33am

BACKGROUND: Many health organizations allow patients to access their own electronic health record (EHR) notes through online patient portals as a way to enhance patient-centered care. However, EHR notes are typically long and contain abundant medical jargon that can be difficult for patients to understand. In addition, many medical terms in patients' notes are not directly related to their health care needs. One way to help patients better comprehend their own notes is to reduce information overload and help them focus on medical terms that matter most to them. Interventions can then be developed by giving them targeted education to improve their EHR comprehension and the quality of care.

OBJECTIVE: We aimed to develop a supervised natural language processing (NLP) system called Finding impOrtant medical Concepts most Useful to patientS (FOCUS) that automatically identifies and ranks medical terms in EHR notes based on their importance to the patients.

METHODS: First, we built an expert-annotated corpus. For each EHR note, 2 physicians independently identified medical terms important to the patient. Using the physicians' agreement as the gold standard, we developed and evaluated FOCUS. FOCUS first identifies candidate terms from each EHR note using MetaMap and then ranks the terms using a support vector machine-based learn-to-rank algorithm. We explored rich learning features, including distributed word representation, Unified Medical Language System semantic type, topic features, and features derived from consumer health vocabulary. We compared FOCUS with 2 strong baseline NLP systems.

RESULTS: Physicians annotated 90 EHR notes and identified a mean of 9 (SD 5) important terms per note. The Cohen's kappa annotation agreement was .51. The 10-fold cross-validation results show that FOCUS achieved an area under the receiver operating characteristic curve (AUC-ROC) of 0.940 for ranking candidate terms from EHR notes to identify important terms. When including term identification, the performance of FOCUS for identifying important terms from EHR notes was 0.866 AUC-ROC. Both performance scores significantly exceeded the corresponding baseline system scores (P < .001). Rich learning features contributed to FOCUS's performance substantially.

CONCLUSIONS: FOCUS can automatically rank terms from EHR notes based on their importance to patients. It may help develop future interventions that improve quality of care.

Keeping Weight Off: study protocol of an RCT to investigate brain changes associated with mindfulness-based stress reduction

Fri, 04/14/2017 - 11:33am

INTRODUCTION: Obesity is a growing epidemic fuelled by unhealthy behaviours and associated with significant comorbidities and financial costs. While behavioural interventions produce clinically meaningful weight loss, weight loss maintenance is challenging. This may partially be due to failure to target stress and emotional reactivity. Mindfulness-based stress reduction (MBSR) reduces stress and emotional reactivity and may be a useful tool for behaviour change maintenance. This study seeks to provide a mechanistic understanding for clinical trials of the benefits of MBSR for weight loss maintenance by examining changes in functional connectivity (FC) and the association of these changes with clinical outcomes.

METHODS AND ANALYSIS: Community-dwelling individuals (n=80) who intentionally lost > /=5% of their body weight in the past year will be recruited and randomised to an MBSR programme or educational control. FC using resting-state functional MRI will be measured at baseline and 8 weeks. Psychological factors, health behaviours, body mass index and waist circumference will be measured at baseline, 8 weeks and 6 months post intervention. A 12-month telephone follow-up will assess self-reported weight. Analyses will characterise FC changes in response to MBSR in comparison with a control condition, assess the relationship between baseline FC status and pre-post MBSR changes in FC and investigate the association of FC change with changes in psychological factors and weight loss maintenance.

ETHICS AND DISSEMINATION: The University of Massachusetts Medical School Institutional Review Board has approved this study, Declaration of Helsinki protocols are being followed, and patients will give written informed consent. The Independent Monitoring Committee will monitor protocol adherence. Results from the study will be disseminated to the medical community at conferences and submitted for publication in peer-reviewed journals when the last patient included has been followed up for 12 months.

TRIAL REGISTRATION NUMBER: NCT02189187.

Activation of WNT/beta-Catenin Signaling Enhances Pancreatic Cancer Development and the Malignant Potential Via Up-regulation of Cyr61

Fri, 04/14/2017 - 11:33am

Pancreatic ductal adenocarcinoma (PDAC), a poor prognostic cancer, commonly develops following activating mutations in the KRAS oncogene. Activation of WNT signaling is also commonly observed in PDAC. To ascertain the impact of postnatal activation of WNT-stimulated signaling pathways in PDAC development, we combined the Elastase-tva-based RCAS-TVA pancreatic cancer model with the established LSL-KrasG12D, Ptf1a-cre model. Delivery of RCAS viruses encoding beta-cateninS37A and WNT1 stimulated the progression of premalignant pancreatic intraepithelial neoplasias (PanIN) and PDAC development. Moreover, mice injected with RCAS-beta-cateninS37A or RCAS-Wnt1 had reduced survival relative to RCAS-GFP-injected controls (P < .05). Ectopic expression of active beta-catenin, or its DNA-binding partner TCF4, enhanced transformation associated phenotypes in PDAC cells. In contrast, these phenotypes were significantly impaired by the introduction of ICAT, an inhibitor of the beta-catenin/TCF4 interaction. By gene expression profiling, we identified Cyr61 as a target molecule of the WNT/beta-catenin signaling pathway in pancreatic cancer cells. Nuclear beta-catenin and CYR61 expression were predominantly detected in moderately to poorly differentiated murine and human PDAC. Indeed, nuclear beta-catenin- and CYR61-positive PDAC patients demonstrated poor prognosis (P < .01). Knockdown of CYR61 in a beta-catenin-activated pancreatic cancer cell line reduced soft agar, migration and invasion activity. Together, these data suggest that the WNT/beta-catenin signaling pathway enhances pancreatic cancer development and malignancy in part via up-regulation of CYR61.