Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone

Inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD) is a dominantly inherited degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. VCP (p97 in mouse, TER94 in Drosophila melanogaster and CDC48 in Saccharomyces cerevisiae) is a highly conserved AAA+-ATPase that regulates a wide array of cellular processes. The mechanism of IBMPFD pathogenesis is unknown. Towards elucidating the pathogenic mechanism we have developed and characterized transgenic mice with ubiquitous expression of wild-type and disease-causing versions of human VCP/p97. Here, we report that mice expressing VCP/p97 harboring the mutations R155H or A232E develop pathology that is limited to muscle, brain and bone, recapitulating the spectrum of disease in humans with IBMPFD. The mice exhibit progressive muscle weakness and pathological examination of muscle shows classic characteristics of inclusion body myopathy including rimmed vacuoles and TDP-43 pathology. The mice exhibit abnormalities in behavioral testing and pathological examination of the brain shows widespread TDP-43 pathology. Furthermore, radiological examination of the skeleton reveals that mutant mice develop severe osteopenia accompanied by focal lytic and sclerotic lesions in vertebrae and femur. In vitro studies indicate that mutant VCP causes inappropriate activation of the NF-κB signaling cascade, which could contribute to the mechanism of pathogenesis in multiple tissues including muscle, bone and brai

A sensitive high performance liquid chromatography assay for the quantification of doxorubicin associated with DNA in tumor and tissues

A HPLC method was validated to quantify doxorubicin associated to DNA from tissue.Successfully applied to an in vivo mouse-based pharmacokinetic study.Important tool for future studies evaluating intracellular pharmacokinetics.Doxorubicin, a widely used anticancer agent, exhibits antitumor activity against a wide variety of malignancies. The drug exerts its cytotoxic effects by binding to and intercalating within the DNA of tumor and tissue cells. However, current assays are unable to accurately determine the concentration of the intracellular active form of doxorubicin. Thus, the development of a sample processing method and a high-performance liquid chromatography (HPLC) methodology was performed in order to quantify doxorubicin that is associated with DNA in tumors and tissues, which provided an intracellular cytotoxic measure of doxorubicin exposure after administration of small molecule and nanoparticle formulations of doxorubicin. The assay uses daunorubicin as an internal standard; liquid–liquid phase extraction to isolate drug associated with DNA; a Shimadzu HPLC with fluorescence detection equipped with a Phenomenex Luna C18 (2 μm, 2.0 × 100 mm) analytical column and a gradient mobile phase of 0.1% formic acid in water or acetonitrile for separation and quantification. The assay has a lower limit of detection (LLOQ) of 10 ng/mL and is shown to be linear up to 3000 ng/mL. The intra- and inter-day precision of the assay expressed as a coefficient of variation (CV%) ranged from 4.01 to 8.81%. Furthermore, the suitability of this assay for measuring doxorubicin associated with DNA in vivo was demonstrated by using it to quantify the doxorubicin concentration within tumor samples from SKOV3 and HEC1A mice obtained 72 h after administration of PEGylated liposomal doxorubicin (Doxil®; PLD) at 6 mg/kg IV x 1. This HPLC assay allows for sensitive intracellular quantification of doxorubicin and will be an important tool for future studies evaluating intracellular pharmacokinetics of doxorubicin and various nanoparticle formulations of doxorubicin

Analysis of Hypertension Control Rates Among Participants in the Georgia Hypertension Management and Outreach Program

Background: This study utilized health department electronic medical records retrospectively to evaluate hypertension control rates achieved by the Georgia Hypertension Management and Outreach Program (HMOP), an education, screening, and treatment control program that provides services, including blood pressure screening and assessment, referral to physicians, counseling, educational material, disease case management, and treatment. Methods: Hypertension control rates after at least 6 months of study participation were determined for patients participating in the program for at least 6 months between 2010 and 2014, and for African American and uninsured subgroups. Results: The overall hypertension control rate was 61.1%, above the 2012 national average of 51.8%. The control rates for African Americans and the uninsured were 58.9% and 62%, respectively, compared to 41.7% and 28.7% nationally. Conclusions: Although potential bias sources in the use of retrospectively obtained electronic medical records should be considered, this analysis suggests that the Georgia HMOP provides substantial improvements in hypertension control for a population of patients with otherwise poor control. Key words: hypertension, blood pressure, cardiovascular diseases, African Americans, medically uninsure

Informant-based screening tools for dementia: an overview of systematic reviews

Background: Informant-based questionnaires may have utility for cognitive impairment or dementia screening. Reviews describing the accuracy of respective questionnaires are available, but their focus on individual questionnaires precludes comparisons across tools. We conducted an overview of systematic reviews to assess the comparative accuracy of informant questionnaires and identify areas where evidence is lacking. Methods: We searched six databases to identify systematic reviews describing diagnostic test accuracy of informant questionnaires for cognitive impairment or dementia. We pooled sensitivity and specificity data for each questionnaire and used network approaches to compare accuracy estimates across the differing tests. We used grading of recommendations, assessment, development and evaluation (GRADE) to evaluate the overall certainty of evidence. Finally, we created an evidence ‘heat-map’, describing the availability of accurate data for individual tests in different populations and settings. Results: We identified 25 reviews, consisting of 93 studies and 13 informant questionnaires. Pooled analysis (37 studies; 11 052 participants) ranked the eight-item interview to ascertain dementia (AD8) highest for sensitivity [90%; 95% credible intervals (CrI) = 82–95; ‘best-test’ probability = 36]; while the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) was most specific (81%; 95% CrI = 66–90; ‘best-test’ probability = 29%). GRADE-based evaluation of evidence suggested certainty was ‘low’ overall. Our heat-map indicated that only AD8 and IQCODE have been extensively evaluated and most studies have been in the secondary care settings. Conclusions: AD8 and IQCODE appear to be valid questionnaires for cognitive impairment or dementia assessment. Other available informant-based cognitive screening questionnaires lack evidence to justify their use at present. Evidence on the accuracy of available tools in primary care settings and with specific populations is required

Gettysburg College Sustainability Proposal

In the fall of 2011, the Environmental Studies capstone class led by Professor Rutherford Platt was asked to write Gettysburg College’s first Sustainability Plan. The goal of the plan was to develop specific sustainable practices for the campus that were related to the three pillars of sustainability: economic, social, and environmental, and how integrating diligent sustainable practices into each of these respected pillars will result in a more conscious campus, community, and future. In 2010, Gettysburg College turned to the Sustainability Tracking Assessment and Rating System (STARS) to quantify the institution’s sustainability efforts, providing a self-check mechanism to encourage sustainability applications to all aspects of the College. The American College and University Presidents’ Climate Commitment was signed in 2007 by former Gettysburg College President Katherine Haley Will, declaring that Gettysburg College would become carbon neutral by 2032. Gettysburg College has made large strides in the search for sustainability, and aims to continue its dedication to furthering sustainable practice. The following plan outlines the six priority areas identified by the Capstone class: progress of the American College and University Presidents’ Climate Commitment, Dining Services, campus green space, community outreach, integration of sustainability into the Gettysburg College Curriculum, and the Sustainability Advisory Committee. The first priority area identified was monitoring and upholding the American College and University Presidents’ Climate Commitment (ACUPCC). Though creating new sustainability initiatives on campus is the driving force towards an increasingly sustainable college and community, it is imperative that these goals be carried out in full to maximize beneficial returns. In order to reach carbon neutrality, Gettysburg College hopes to increase energy efficiency in buildings, incorporate renewable energy sources on campus, and mitigate remaining emissions through the purchase of carbon offsets. To further the College’s progress, it is proposed that Gettysburg College continue its energy-efficient appliance purchasing policy, as well as create a policy to offset all greenhouse gas emissions generated by air travel for students study abroad. As stated by the ACUPCC, a Sustainability Committee should take responsibility for the updates and progress reports required to meet the goal of carbon neutrality. The second priority area identified was sustainability in Dining Services. Gettysburg College is home to 2,600 students, all of whom require three full meals a day. Dining Services accounts for a large fraction of Gettysburg College’s sustainability efforts, already implementing sustainability through composting, buying local produce, and using biodegradable products. The proposed on-campus sales cuts of non-reusable to-go items, a change in campus mentality on food waste, and improved composting practices will translate to an increasingly sustainable campus, as well as a well-fed campus body. The third priority was maintaining green space on campus. Ranked as the 23rd most beautiful campus in the United States by The Best Colleges, Gettysburg College utilizes campus green space to create an atmosphere that is conducive to activity as well as tranquility. The plan proposes that Gettysburg College and its grounds facilities continue their exceptional efforts, focusing on increasing the use of the student garden, creating a new rain garden or social area on campus, and converting unnecessary parking lots into green space. As these additions are completed, they must be introduced to the student body and faculty alike to assure these areas are known and utilized. The fourth priority was utilizing community outreach to spread awareness of sustainability initiatives on and off campus. To connect the sustainability-geared changes proposed in this plan, community outreach at Gettysburg College is assessed to estimate how well these initiatives are communicated and promoted to both potential and enrolled students, faculty, and other concerned parties. To evaluate the efficiency of communication at Gettysburg College, a quantitative assessment is presented to measure the ease of finding the sustainability webpage, the quality of sustainability-related topics available on the webpage, and quality of webpage design. The webpage is in need of improved text to image ratios, locations of sustainability topics, and data displays. Despite not having a link to the sustainability webpage on the Gettysburg College homepage, sustainability events should be covered and presented on the rotational news feed found on the homepage to maximize outreach to interested parties or simply to add to the definition of Gettysburg College. The fifth priority was integrating sustainability into the Curriculum to build a culture on campus that values academic rigor, supports students as they cultivate intellectual and civic passions, and promotes the development of healthy social relationships and behaviors. The proposed Sustainability Committee on Sustainability in the Curriculum (SCC) will hold sustainability workshops for faculty with the aim to instill sustainability into all academic disciplines, providing all Gettysburg graduates with a means to approach their professional careers in a fashion that is conscious of sustainability. The sixth and last priority was the Sustainability Advisory Committee. Established in 2007, the Sustainability Advisory Committee is currently under review, but it is recommended that the committee restructure itself in accordance with the new Sustainability Committee Bylaws. These bylaws aim to define the purposes, membership, governance, and involvement with the college. With a clearly defined set of goals and methodology, the Sustainability Advisory Committee will be able to improve the solidarity of the sustainability movement on campus as a whole. By following the propositions laid out in the Gettysburg College Sustainability Plan, the student body, faculty, and community alike will become a part of a multi-faceted progression toward a more sustainable future

ESTABLISHING TRAINING PARAMETERS FOR A DEEP NEURAL NETWORK TO ASSESS 2D, FRONTAL PLANE KINEMATICS

The purpose of this study was to establish the optimal training parameters to assess frontal plane, 2D kinematics using DeepLabCut. DeepLabCut is an open-source platform that allows the user to train neural networks for customized feature detection in 2D videos. Deep neural networks were trained using frontal plane videos from 41 participants who completed single- and double-leg drop landings. Networks were trained with an increasing number of training iterations (25-250k) and training frames (200-800). Our results indicate that a minimum of 175k training iterations and 400 training frames were adequate for stable network performance (training/test errors= 2.8/3.7 pixels)

Building the field of health policy and systems research: framing the questions.

In the first of a series of articles addressing the current challenges and opportunities for the development of Health Policy & Systems Research (HPSR), Kabir Sheikh and colleagues lay out the main questions vexing the field

Informant-based screening tools for diagnosis of dementia, an overview of systematic reviews of test accuracy studies protocol

Background: Robust diagnosis of dementia requires an understanding of the accuracy of the available diagnostic tests. Informant questionnaires are frequently used to assess for dementia in clinical practice. Recent systematic reviews have sought to establish the diagnostic test accuracy of various dementia informant screening tools. However, most reviews to date have focused on a single diagnostic tool and this does not address which tool is ‘best’. A key aim of the overview of systematic reviews is to present a disparate evidence base in a single, easy to access platform. Methods: We will conduct an overview of systematic reviews in which we ‘review the systematic reviews’ of diagnostic test accuracy studies evaluating informant questionnaires for dementia. As an overview of systematic reviews of test accuracy is a relatively novel approach, we will use this review to explore methods for visual representation of complex data, for highlighting evidence gaps and for indirect comparative analyses. We will create a list of informant tools by consulting with dementia experts. We will search 6 databases (EMBASE (OVID); Health and Psychosocial Instruments (OVID); Medline (OVID); CINAHL (EBSCO); PSYCHinfo (EBSCO) and the PROSPERO registry of review protocols) to identify systematic reviews that describe the diagnostic test accuracy of informant questionnaires for dementia. We will assess review quality using the AMSTAR-2 (Assessment of Multiple Systematic Reviews) and assess reporting quality using PRISMA-DTA (Preferred Reporting Items for Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies) checklists. We will collate the identified reviews to create an ‘evidence map’ that highlights where evidence does and does not exist in relation to informant questionnaires. We will pool sensitivity and specificity data via meta-analysis to generate a diagnostic test accuracy summary statistic for each informant questionnaire. If data allow, we will perform a statistical comparison of the diagnostic test accuracy of each informant questionnaire using a network approach. Discussion: Our overview of systematic reviews will provide a concise summary of the diagnostic test accuracy of informant tools and highlight areas where evidence is currently lacking in this regard. It will also apply network meta-analysis techniques to a new area