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Validation of an algorithm to identify antiretroviral-naive status at time of entry into a large, observational cohort of HIV-infected patients

Fri, 06/27/2014 - 3:11pm

PURPOSE: Large, observational HIV cohorts play an important role in answering questions which are difficult to study in randomized trials; however, they often lack detailed information regarding previous antiretroviral treatment (ART). Knowledge of ART treatment history is important when ascertaining the long-term impact of medications, co-morbidities, or adverse reactions on HIV outcomes. METHODS: We performed a retrospective study to validate a prediction algorithm for identifying ART-naive patients using the Veterans Aging Cohort Study's Virtual Cohort-an observational cohort of 40 594 HIV-infected veterans nationwide. Medical records for 3070 HIV-infected patients were reviewed to determine history of combination ART treatment. An algorithm using Virtual Cohort laboratory data was used to predict ART treatment status and compared to medical record review. RESULTS: Among 3070 patients' medical records reviewed, 1223 were eligible for analysis. Of these, 990 (81%) were ART naive at cohort entry based on medical record review. The prediction algorithm's sensitivity was 86%, specificity 47%, positive predictive value (PPV) 87%, and negative predictive value 45%, using a viral load threshold of <400 copies/ml. Sensitivity analysis revealed that PPV would be maximized by increasing the viral load threshold, whereas sensitivity would be maximized by lowering the viral load threshold. CONCLUSIONS: A prediction algorithm using available laboratory data can be used to accurately identify ART-naive patients in large, observational HIV cohorts. Use of this algorithm will allow investigators to accurately limit analyses to ART-naive patients when studying the contribution of ART to outcomes and adverse events.

Sexual victimization, health status, and VA healthcare utilization among lesbian and bisexual OEF/OIF veterans

Fri, 06/27/2014 - 3:11pm

BACKGROUND: Many lesbian and bisexual (LB) women veterans may have been targets of victimization in the military based on their gender and presumed sexual orientation, and yet little is known regarding the health or mental health of LB veterans, nor the degree to which they feel comfortable receiving care in the VA. OBJECTIVE: The purpose of this study was to examine the prevalence of mental health and gender-specific conditions, VA healthcare satisfaction and trauma exposure among LB veterans receiving VA care compared with heterosexually-identified women veterans receiving. DESIGN: Prospective cohort study of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) women veterans at two large VA facilities. PARTICIPANTS: Three hundred and sixty five women veterans that completed a baseline survey. Thirty-five veterans (9.6 %) identified as gay or lesbian (4.7 %), or bisexual (4.9 %). MAIN MEASURES: Measures included sexual orientation, military sexual trauma, mental and gender-specific health diagnoses, and VA healthcare utilization and satisfaction. KEY RESULTS: LB OEF/OIF veterans were significantly more likely to have experienced both military and childhood sexual trauma than heterosexual women (MST: 31 % vs. 13 %, p < .001; childhood sexual trauma: 60 % vs. 36 %, p = .01), to be hazardous drinkers (32 % vs. 16 %, p = .03) and rate their current mental health as worse than before deployment (35 % vs. 16 %, p < .001). CONCLUSIONS: Many LB veterans have experienced sexual victimization, both within the military and as children, and struggle with substance abuse and poor mental health. Health care providers working with female Veterans should be aware of high rates of military sexual trauma and childhood abuse and refer women to appropriate VA treatment and support groups for sequelae of these experiences. Future research should focus on expanding this study to include a larger and more diverse sample of lesbian, gay, bisexual, and transgender veterans receiving care at VA facilities across the country.

Five-year trends in women veterans' use of VA maternity benefits, 2008-2012

Fri, 06/27/2014 - 3:11pm

BACKGROUND: An increasing number of young women veterans are returning from war and military service and are seeking reproductive health care from the Veterans Health Administration (VHA). Many of these women seek maternity benefits from the VHA, and yet little is known regarding the number of women veterans utilizing VHA maternity benefits nor the characteristics of pregnant veterans using these benefits. In May 2010, VHA maternity benefits were expanded to include 7 days of infant care, which may serve to entice more women to use VHA maternity benefits. Understanding the changing trends in women veterans seeking maternity benefits will help the VHA to improve the quality of reproductive care over time. OBJECTIVE: The goal of this study was to examine the trends in delivery claims among women veterans receiving VHA maternity benefits over a 5-year period and the characteristics of pregnant veterans utilizing VHA benefits. DESIGN: We undertook a retrospective, national cohort study of pregnant veterans enrolled in VHA care with inpatient deliveries between fiscal years (FY) 2008 and 2012. PARTICIPANTS: We included pregnant veterans using VHA maternity benefits for delivery. MAIN MEASURES: Measures included annualized numbers and rates of inpatient deliveries and delivery-related costs, as well as cesarean section rates as a quality indicator. KEY RESULTS: During the 5-year study period, there was a significant increase in the number of deliveries to women veterans using VHA maternity benefits. The overall delivery rate increased by 44% over the study period from 12.4 to 17.8 deliveries per 1,000 women veterans. A majority of women using VHA maternity benefits were age 30 or older and had a service-connected disability. From FY 2008 to 2012, the VHA paid more than $46 million in delivery claims to community providers for deliveries to women veterans ($4,993/veteran). CONCLUSIONS: Over a 5-year period, the volume of women veterans using VHA maternity benefits increased by 44%. Given this sizeable increase, the VHA must increase its capacity to care for pregnant veterans and ensure care coordination systems are in place to address the needs of pregnant veterans with service-connected disabilities.

Improving care of chronic conditions for women veterans: identifying opportunities for comparative effectiveness research

Fri, 06/27/2014 - 3:11pm

This article aims to critically analyze research focused on the findings for five chronic conditions: chronic pain, diabetes, cardiovascular disease, HIV and cancer among women veterans to identify opportunities for comparative effectiveness research. We provide a descriptive analysis from the relevant articles in prior systematic reviews. In order to identify potential gaps in research for these specific conditions, we also conducted a literature search to highlight studies focusing on women veterans published since the last systematic review. While the scientific knowledge base has grown for these chronic conditions among women veterans, the vast majority of the published literature remains descriptive and/or observational, with only a few studies examining gender differences and even fewer clinical trials. There is a need to conduct comparative effectiveness research on chronic conditions among women veterans to improve health and healthcare.

Contraceptive Provision in the VA Healthcare System to Women Who Report Military Sexual Trauma

Fri, 06/27/2014 - 3:11pm

Abstract Background: Women Veterans who suffered military sexual trauma (MST) may be at high risk for unintended pregnancy and benefit from contraceptive services. The objective of this study is to compare documented provision of contraceptives to women Veterans using the Department of Veterans Affairs (VA) health system who report or deny MST. Methods: This retrospective cohort study included women Veterans aged 18-45 years who served in Operation Enduring or Iraqi Freedom and had at least one visit to a VA medical center between 2002 and 2010. Data were obtained from VA administrative and clinical databases. Chi-squared tests and logistic regression were conducted to evaluate the association between MST, ascertained by routine clinical screening, and first documented receipt of hormonal or long-acting contraception. Results: Of 68,466 women Veterans, 13% reported, 59% denied and 28% had missing data for the MST screen. Among the entire study cohort, 30% of women had documented receipt of a contraceptive method. Women reporting MST were significantly more likely than those denying MST to receive a method of contraception (adjusted odds ratio [aOR] 1.12, 95% confidence interval [CI] 1.07-1.18) including an intrauterine device (odds ratio [OR] 1.29, 95% CI 1.17-1.41) or contraceptive injection (OR 1.17, 95% CI 1.05-1.29). Women who were younger, unmarried, seen at a women's health clinic, or who had more than one visit were more likely to receive contraception. Conclusions: A minority of women Veterans of reproductive age receive contraceptive services from the VA. Women Veterans who report MST, and particularly those who seek care at VA women's health clinics, are more likely to receive contraception.

The Science and Psychology of Infertility

Fri, 06/27/2014 - 2:56pm

An evidence-based presentation on the science/etiologies of infertility and its psychological impact. Outline: Prevalence and Etiology of Infertility. Basic Evaluation. Treatment Options. Psychological Effects of Infertility. Depression/Anxiety. Social, Cultural, and Gender Issues. Relationship Issues. Patient Distress and Pregnancy Rates. Psychological Support. Evidence-Based Psychological Interventions.

Preoperative Pain and Function Profiles Reflect Consistent TKA Patient Selection Among US Surgeons

Fri, 06/27/2014 - 11:29am

BACKGROUND: As the number of primary total knee arthroplasties (TKAs) performed in the United States increases, policymakers have questioned whether the indications and timing of TKA have evolved so that surgery is offered earlier.

QUESTIONS/PURPOSES: We analyzed data from a US national TKA cohort to evaluate variation in surgeon selection criteria for elective unilateral TKA based on preoperative patient-reported pain and function scores.

METHODS: Preoperative SF-36 (Physical Component Summary [PCS]/physical function) scores and Knee Injury and Osteoarthritis Outcome Score (KOOS) (pain, activities of daily living/function) of 4900 patients undergoing elective unilateral TKA enrolled in this national database of prospectively followed patients from 22 states were evaluated. The 25(th), 50(th), and 75(th) percentile pain and function scores for patients cared for in 24 orthopaedic offices with 20 or more patients in the database were compared to assess whether consistent preoperative criteria are used in selecting patients undergoing TKA across settings.

RESULTS: The preoperative global function (PCS median, 32.6; national norm, 50; SD, 10) and knee-specific function (KOOS median, 51.5; maximum score, 100; SD, 17) percentile scores represented substantial patient disability, because both values approached 2 SDs below ideal. Consistency in patients across 24 surgeon offices, and more than 100 surgeons, was noted because site-specific medians varied from the national median by less than the minimum clinically important change.

CONCLUSIONS: These data suggest that despite the rapidly growing use of TKA, surgeons in the participating sites use consistent patient criteria in scheduling TKA. Today's patients report significant pain and disability, supporting the need for TKA.

Childhood maltreatment, emotional dysregulation, and psychiatric comorbidities

Thu, 06/26/2014 - 2:31pm

Affect dysregulation, defined as the impaired ability to regulate or tolerate negative emotional states, has been associated with interpersonal trauma and posttraumatic stress. Affect-regulation difficulties play a role in many psychiatric conditions, including anxiety and mood disorders, and especially major depression in youth and bipolar disorder throughout the life span. Exposure to traumatic events and interpersonal trauma in childhood is associated with wide-ranging psychosocial, developmental, and medical impairments in children, adolescents, and adults, with emotional dysregulation being a core feature that may help to account for this heightened risk. In order to understand how the developmental effects of childhood maltreatment contribute to emotional dysregulation and psychiatric sequelae, we review emotional regulation and its developmental neurobiology, and examine the research evidence of associations between childhood trauma, emotional dysregulation, and psychiatric comorbidities in children, adolescents, and adults.

Teaching tobacco dependence treatment and counseling skills during medical school: rationale and design of the Medical Students helping patients Quit tobacco (MSQuit) group randomized controlled trial

Wed, 06/25/2014 - 9:20am

INTRODUCTION: Physician-delivered tobacco treatment using the 5As is clinically recommended, yet its use has been limited. Lack of adequate training and confidence to provide tobacco treatment is cited as leading reasons for limited 5A use. Tobacco dependence treatment training while in medical school is recommended, but is minimally provided. The MSQuit trial (Medical Students helping patients Quit tobacco) aims to determine if a multi-modal and theoretically-guided tobacco educational intervention will improve tobacco dependence treatment skills (i.e. 5As) among medical students.

METHODS/DESIGN: 10 U.S. medical schools were pair-matched and randomized in a group-randomized controlled trial to evaluate whether a multi-modal educational (MME) intervention compared to traditional education (TE) will improve observed tobacco treatment skills. MME is primarily composed of TE approaches (i.e. didactics) plus a 1st year web-based course and preceptor-facilitated training during a 3rd year clerkship rotation. The primary outcome measure is an objective score on an Objective Structured Clinical Examination (OSCE) tobacco-counseling smoking case among 3rd year medical students from schools who implemented the MME or TE.

DISCUSSION: MSQuit is the first randomized to evaluate whether a tobacco treatment educational intervention implemented during medical school will improve medical students' tobacco treatment skills. We hypothesize that the MME intervention will better prepare students in tobacco dependence treatment as measured by the OSCE. If a comprehensive tobacco treatment educational learning approach is effective, while also feasible and acceptable to implement, then medical schools may substantially influence skill development and use of the 5As among future physicians.

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

A Qualitative Exploration of Smoking Influences and Quit Attempts among Nondaily Smokers

Wed, 06/25/2014 - 9:20am

Objectives: We examined social cognitive constructs in relation to nondaily smoking and cessation-related behaviors in a community sample of adult nondaily smokers (>24 years of age).

Methods: We conducted six focus groups using a semi-structured interview format. Participants were 28 African-American and 24 white nondaily smokers.

Results: Participants described a sense of control over their smoking but previous failed quit attempts had negative implications for self-efficacy. Participants perceived themselves as reducing their health risks relative to daily smokers. Potential impediments to quitting include social influences to smoke and skepticism of using smoking cessation medications.

Conclusions: Smoking cessation messaging should specifically address nondaily smoking. Targeted health communications may help increase relevance to nondaily smokers and increase treatment utilization.

Debi Lang and Sharon Grundel on Youth Program Ingredients: How to Measure Success and Tell the Story

Tue, 06/24/2014 - 3:59pm

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.

Judy Savageau and Kathy Muhr on Working with Different Data Sources

Tue, 06/24/2014 - 3:59pm

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.

Caenorhabditis elegans metabolic gene regulatory networks govern the cellular economy

Mon, 06/23/2014 - 3:50pm

Diet greatly impacts metabolism in health and disease. In response to the presence or absence of specific nutrients, metabolic gene regulatory networks sense the metabolic state of the cell and regulate metabolic flux accordingly, for instance by the transcriptional control of metabolic enzymes. Here, we discuss recent insights regarding metazoan metabolic regulatory networks using the nematode Caenorhabditis elegans as a model, including the modular organization of metabolic gene regulatory networks, the prominent impact of diet on the transcriptome and metabolome, specialized roles of nuclear hormone receptors (NHRs) in responding to dietary conditions, regulation of metabolic genes and metabolic regulators by miRNAs, and feedback between metabolic genes and their regulators.

Defining functional DNA elements in the human genome

Mon, 06/23/2014 - 3:50pm

With the completion of the human genome sequence, attention turned to identifying and annotating its functional DNA elements. As a complement to genetic and comparative genomics approaches, the Encyclopedia of DNA Elements Project was launched to contribute maps of RNA transcripts, transcriptional regulator binding sites, and chromatin states in many cell types. The resulting genome-wide data reveal sites of biochemical activity with high positional resolution and cell type specificity that facilitate studies of gene regulation and interpretation of noncoding variants associated with human disease. However, the biochemically active regions cover a much larger fraction of the genome than do evolutionarily conserved regions, raising the question of whether nonconserved but biochemically active regions are truly functional. Here, we review the strengths and limitations of biochemical, evolutionary, and genetic approaches for defining functional DNA segments, potential sources for the observed differences in estimated genomic coverage, and the biological implications of these discrepancies. We also analyze the relationship between signal intensity, genomic coverage, and evolutionary conservation. Our results reinforce the principle that each approach provides complementary information and that we need to use combinations of all three to elucidate genome function in human biology and disease.

Predictive polymer modeling reveals coupled fluctuations in chromosome conformation and transcription

Mon, 06/23/2014 - 3:49pm

A new level of chromosome organization, topologically associating domains (TADs), was recently uncovered by chromosome conformation capture (3C) techniques. To explore TAD structure and function, we developed a polymer model that can extract the full repertoire of chromatin conformations within TADs from population-based 3C data. This model predicts actual physical distances and to what extent chromosomal contacts vary between cells. It also identifies interactions within single TADs that stabilize boundaries between TADs and allows us to identify and genetically validate key structural elements within TADs. Combining the model's predictions with high-resolution DNA FISH and quantitative RNA FISH for TADs within the X-inactivation center (Xic), we dissect the relationship between transcription and spatial proximity to cis-regulatory elements. We demonstrate that contacts between potential regulatory elements occur in the context of fluctuating structures rather than stable loops and propose that such fluctuations may contribute to asymmetric expression in the Xic during X inactivation.

A nanoparticle-based combination chemotherapy delivery system for enhanced tumor killing by dynamic rewiring of signaling pathways

Mon, 06/23/2014 - 3:49pm

Exposure to the EGFR (epidermal growth factor receptor) inhibitor erlotinib promotes the dynamic rewiring of apoptotic pathways, which sensitizes cells within a specific period to subsequent exposure to the DNA-damaging agent doxorubicin. A critical challenge for translating this therapeutic network rewiring into clinical practice is the design of optimal drug delivery systems. We report the generation of a nanoparticle delivery vehicle that contained more than one therapeutic agent and produced a controlled sequence of drug release. Liposomes, representing the first clinically approved nanomedicine systems, are well-characterized, simple, and versatile platforms for the manufacture of functional and tunable drug carriers. Using the hydrophobic and hydrophilic compartments of liposomes, we effectively incorporated both hydrophobic (erlotinib) and hydrophilic (doxorubicin) small molecules, through which we achieved the desired time sequence of drug release. We also coated the liposomes with folate to facilitate targeting to cancer cells. When compared to the time-staggered application of individual drugs, staggered release from tumor-targeted single liposomal particles enhanced dynamic rewiring of apoptotic signaling pathways, resulting in improved tumor cell killing in culture and tumor shrinkage in animal models.

Multiple transcription factors directly regulate Hox gene lin-39 expression in ventral hypodermal cells of the C. elegans embryo and larva, including the hypodermal fate regulators LIN-26 and ELT-6

Mon, 06/23/2014 - 3:49pm

BACKGROUND: Hox genes encode master regulators of regional fate specification during early metazoan development. Much is known about the initiation and regulation of Hox gene expression in Drosophila and vertebrates, but less is known in the non-arthropod invertebrate model system, C. elegans. The C. elegans Hox gene lin-39 is required for correct fate specification in the midbody region, including the Vulval Precursor Cells (VPCs). To better understand lin-39 regulation and function, we aimed to identify transcription factors necessary for lin-39 expression in the VPCs, and in particular sought factors that initiate lin-39 expression in the embryo.

RESULTS: We used the yeast one-hybrid (Y1H) method to screen for factors that bound to 13 fragments from the lin-39 region: twelve fragments contained sequences conserved between C. elegans and two other nematode species, while one fragment was known to drive reporter gene expression in the early embryo in cells that generate the VPCs. Sixteen transcription factors that bind to eight lin-39 genomic fragments were identified in yeast, and we characterized several factors by verifying their physical interactions in vitro, and showing that reduction of their function leads to alterations in lin-39 levels and lin-39::GFP reporter expression in vivo. Three factors, the orphan nuclear hormone receptor NHR-43, the hypodermal fate regulator LIN-26, and the GATA factor ELT-6 positively regulate lin-39 expression in the embryonic precursors to the VPCs. In particular, ELT-6 interacts with an enhancer that drives GFP expression in the early embryo, and the ELT-6 site we identified is necessary for proper embryonic expression. These three factors, along with the factors ZTF-17, BED-3 and TBX-9, also positively regulate lin-39 expression in the larval VPCs.

CONCLUSIONS: These results significantly expand the number of factors known to directly bind and regulate lin-39 expression, identify the first factors required for lin-39 expression in the embryo, and hint at a positive feedback mechanism involving GATA factors that maintains lin-39 expression in the vulval lineage. This work indicates that, as in other organisms, the regulation of Hox gene expression in C. elegans is complicated, redundant and robust.

Calmodulation meta-analysis: Predicting calmodulin binding via canonical motif clustering

Fri, 06/20/2014 - 2:52pm

The calcium-binding protein calmodulin (CaM) directly binds to membrane transport proteins to modulate their function in response to changes in intracellular calcium concentrations. Because CaM recognizes and binds to a wide variety of target sequences, identifying CaM-binding sites is difficult, requiring intensive sequence gazing and extensive biochemical analysis. Here, we describe a straightforward computational script that rapidly identifies canonical CaM-binding motifs within an amino acid sequence. Analysis of the target sequences from high resolution CaM-peptide structures using this script revealed that CaM often binds to sequences that have multiple overlapping canonical CaM-binding motifs. The addition of a positive charge discriminator to this meta-analysis resulted in a tool that identifies potential CaM-binding domains within a given sequence. To allow users to search for CaM-binding motifs within a protein of interest, perform the meta-analysis, and then compare the results to target peptide-CaM structures deposited in the Protein Data Bank, we created a website and online database. The availability of these tools and analyses will facilitate the design of CaM-related studies of ion channels and membrane transport proteins.

Amyotrophic Lateral Sclerosis Association

Thu, 06/19/2014 - 12:25pm

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord, leading to muscular atrophy, progressive loss of muscle control, paralysis, and death. This is a review of the ALS Association web site. The site continues to provide ALS patients and caregivers with current resources for managing life with ALS, and it provides researchers and healthcare professionals with access to evidence-based information on the latest scholarship, and guidelines for the most effective therapies and treatments for ALS. The ALS Association website remains an authoritative resource for anyone seeking quality information about ALS.