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Eaten alive: novel insights into autophagy from multicellular model systems

Mon, 05/18/2015 - 3:05pm

Autophagy delivers cytoplasmic material to lysosomes for degradation. First identified in yeast, the core genes that control this process are conserved in higher organisms. Studies of mammalian cell cultures have expanded our understanding of the core autophagy pathway, but cannot reveal the unique animal-specific mechanisms for the regulation and function of autophagy. Multicellular organisms have different types of cells that possess distinct composition, morphology, and organization of intracellular organelles. In addition, the autophagic machinery integrates signals from other cells and environmental conditions to maintain cell, tissue and organism homeostasis. Here, we highlight how studies of autophagy in flies and worms have identified novel core autophagy genes and mechanisms, and provided insight into the context-specific regulation and function of autophagy.

Structural Basis for VEGF-C Binding to Neuropilin-2 and Sequestration by a Soluble Splice Form

Mon, 05/18/2015 - 3:05pm

Vascular endothelial growth factor C (VEGF-C) is a potent lymphangiogenic cytokine that signals via the coordinated action of two cell surface receptors, Neuropilin-2 (Nrp2) and VEGFR-3. Diseases associated with both loss and gain of VEGF-C function, lymphedema and cancer, respectively, motivate studies of VEGF-C/Nrp2 binding and inhibition. Here, we demonstrate that VEGF-C binding to Nrp2 is regulated by C-terminal proteolytic maturation. The structure of the VEGF-C C terminus in complex with the ligand binding domains of Nrp2 demonstrates that a cryptic Nrp2 binding motif is released upon proteolysis, allowing specific engagement with the b1 domain of Nrp2. Based on the identified structural requirements for Nrp2 binding to VEGF-C, we hypothesized that the endogenous secreted splice form of Nrp2, s9Nrp2, may function as a selective inhibitor of VEGF-C. We find that s9Nrp2 forms a stable dimer that potently inhibits VEGF-C/Nrp2 binding and cellular signaling. These data provide critical insight into VEGF-C/Nrp2 binding and inhibition.

UMCCTS Newsletter, May 2015

Mon, 05/18/2015 - 2:21pm

This is the May 2015 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.

The CPEB protein Orb2 has multiple functions during spermatogenesis in Drosophila melanogaster

Sat, 05/16/2015 - 9:05pm

Cytoplasmic Polyadenylation Element Binding (CPEB) proteins are translational regulators that can either activate or repress translation depending on the target mRNA and the specific biological context. There are two CPEB subfamilies and most animals have one or more genes from each. Drosophila has a single CPEB gene, orb and orb2, from each subfamily. orb expression is only detected at high levels in the germline and has critical functions in oogenesis but not spermatogenesis. By contrast, orb2 is broadly expressed in the soma; and previous studies have revealed important functions in asymmetric cell division, viability, motor function, learning, and memory. Here we show that orb2 is also expressed in the adult male germline and that it has essential functions in programming the progression of spermatogenesis from meiosis through differentiation. Like the translational regulators boule (bol) and off-schedule (ofs), orb2 is required for meiosis and orb2 mutant spermatocytes undergo a prolonged arrest during the meiotic G2-M transition. However, orb2 differs from boule and off-schedule in that this arrest occurs at a later step in meiotic progression after the synthesis of the meiotic regulator twine. orb2 is also required for the orderly differentiation of the spermatids after meiosis is complete. The differentiation defects in orb2 mutants include abnormal elongation of the spermatid flagellar axonemes, a failure in individualization and improper post-meiotic gene expression. Amongst the orb2 differentiation targets are orb and two other mRNAs, which are transcribed post-meiotically and localized to the tip of the flagellar axonemes. Additionally, analysis of a partial loss of function orb2 mutant suggests that the orb2 differentiation phenotypes are independent of the earlier arrest in meiosis.

The CTSA Consortium's Catalog of Assets for Translational and Clinical Health Research (CATCHR)

Sat, 05/16/2015 - 9:05pm

The 61 CTSA Consortium sites are home to valuable programs and infrastructure supporting translational science and all are charged with ensuring that such investments translate quickly to improved clinical care. Catalog of Assets for Translational and Clinical Health Research (CATCHR) is the Consortium's effort to collect and make available information on programs and resources to maximize efficiency and facilitate collaborations. By capturing information on a broad range of assets supporting the entire clinical and translational research spectrum, CATCHR aims to provide the necessary infrastructure and processes to establish and maintain an open-access, searchable database of consortium resources to support multisite clinical and translational research studies. Data are collected using rigorous, defined methods, with the resulting information made visible through an integrated, searchable Web-based tool. Additional easy-to-use Web tools assist resource owners in validating and updating resource information over time. In this paper, we discuss the design and scope of the project, data collection methods, current results, and future plans for development and sustainability. With increasing pressure on research programs to avoid redundancy, CATCHR aims to make available information on programs and core facilities to maximize efficient use of resources.

Academic medical product development: an emerging alliance of technology transfer organizations and the CTSA

Sat, 05/16/2015 - 9:05pm

To bring the benefits of science more quickly to patient care, the NIH National Center Advancing Translational Sciences (NCATS) supports programs that enhance the development, testing, and implementation of new medical products and procedures. The NCATS clinical and translational science award (CTSA) program is central to that mission; creating an academic home for clinical and translational science and supporting those involved in the discovery and development of new health-related inventions. The technology transfer Offices (TTO) of CTSA-funded universities can be important partners in the development process; facilitating the transfer of medical research to the commercial sector for further development and ultimately, distribution to patients. The Aggregating Intellectual Property (IP) Working Group (AWG) of the CTSA public private partnerships key function committee (PPP-KFC) developed a survey to explore how CTSA-funded institutions currently interface with their respective TTOs to support medical product development. The results suggest a range of relationships across institutions; approximately half have formal collaborative programs, but only a few have well-connected programs. Models of collaborations are described and provided as examples of successful CTSA/TTO partnerships that have increased the value of health-related inventions as measured by follow-on funding and industry involvement; either as a consulting partner or licensee.

Macrophages clean up: efferocytosis and microbial control

Fri, 05/15/2015 - 9:40am

Phagocytic leukocytes, predominantly macrophages, not only ingest and destroy invading pathogens, but are charged with clearing dead and dying host cells. The process of engulfing apoptotic cells is called efferocytosis and has long been appreciated for its role in the resolution of inflammation. New evidence is emerging that efferocytosis represents a double-edged sword in microbial immunity. Although efferocytosis of influenza and Mycobacterium tuberculosis-infected cells results in pathogen destruction, efferocytosis of Leishmania-infected neutrophils may promote infection. Understanding how macrophages, dendritic cells (DC) and neutrophils process pathogens encased within a dying cell could lead to the development of novel therapeutics that simultaneously suppress inflammation and promote pathogen clearance.

In search of a new paradigm for protective immunity to TB

Fri, 05/15/2015 - 9:40am

Clinical trials of vaccines against Mycobacterium tuberculosis are well under way and results are starting to come in. Some of these results are not so encouraging, as exemplified by the latest Aeras-422 and MVA85A trials. Other than empirically determining whether a vaccine reduces the number of cases of active tuberculosis, which is a daunting prospect given the chronic nature of the disease, we have no way of assessing vaccine efficacy. Therefore, investigators seek to identify biomarkers that predict vaccine efficacy. Historically, focus has been on the production of interferon-gamma by CD4(+) T cells, but this has not been a useful correlate of vaccine-induced protection. In this Opinion article, we discuss recent advances in our understanding of the immune control of M. tuberculosis and how this knowledge could be used for vaccine design and evaluation.

Age at first intercourse and subsequent sexual partnering among adult women in the United States, a cross-sectional study

Wed, 05/13/2015 - 2:53pm

BACKGROUND: Concurrency and serial monogamy may increase risk for STIs when gaps fall within the infectious period. This study examined the association between early sexual debut and concurrent or serial sexual partnering among heterosexual adult women.

METHODS: We identified 6,791 heterosexually active women, ages 21-44, from the 2006-2010 National Survey of Family Growth, a multi-stage probability sample of women in the United States. Self-reported age at first intercourse was categorized as < 15, 15-17 and > /=18 years (referent). Sexual partnering was defined as concurrency (within the same month), serial monogamy with either a 1-3 month, or > /=4 month gap between partners, or monogamy (referent) in the year prior to interview. Polytomous logistic models provided adjusted odds ratios (aOR) and 95% confidence intervals (CI).

RESULTS: Concurrent partnerships in the year prior to interview were reported by 5.2% of women. Serial monogamy with a 1-3 month gap was reported by 2.5% of women. Compared with women whose sexual debut was > /=18 years, those < 15 years at sexual initiation had 3.7 times the odds of reporting concurrent partnerships (aOR: 3.72; 95% CI: 2.46-5.62). Women < 15 years of age at sexual debut had twice the odds of serial monogamy with gap lengths of 1-3 months between partners (aOR1-3 months: 2.13; 95% CI 1.15-3.94) as compared to women > /=18 years at sexual debut.

CONCLUSIONS: Sexual debut at < 15 years is associated with both concurrency and serial monogamy with 1-3 month gaps between partners in U.S. women aged 21-44.

Association of objectively measured physical activity and metabolic syndrome among U.S. adults with osteoarthritis

Wed, 05/13/2015 - 2:53pm

OBJECTIVE: To investigate the association between objectively-measured physical activity and metabolic syndrome among adults with osteoarthritis (OA).

METHODS: Using cross-sectional data from 2003-2006 NHANES, we identified 566 adults with OA with available accelerometer data assessed using Actigraph AM-7164 and measurements necessary to determine metabolic syndrome by Adult Treatment Panel III. Analysis of variance was conducted to examine the association between continuous variables in each activity level and metabolic syndrome components. Logistic models estimated the relationship of quartile of daily minutes of different physical activity levels to odds of metabolic syndrome adjusted for socioeconomic and health factors.

RESULTS: Among persons with OA, most were female with average age 62.1 years and average duration of disease of 12.9 years. Half of adults with OA had metabolic syndrome (51.0%; 95% Confidence Interval (CI): 44.2% to 57.8%), and only 9.6% engaged in the recommended 150 minutes per week of moderate/vigorous physical activity. Total sedentary time was associated with higher rates of metabolic syndrome and its components while light and moderate/vigorous objectively-measured physical activity were inversely associated with metabolic syndrome and its components. Higher levels of light activity was associated with lower prevalence of metabolic syndrome (quartile 4 versus quartile 1: adjusted odds ratio: 0.45; 95% CI: 0.24 to 0.84; p-value for linear trend < 0.005).

CONCLUSION: Most U.S. adults with OA are sedentary. Increased daily minutes in physical activity, especially in light intensity, is more likely to be associated with decreasing prevalence of metabolic syndrome among persons with OA. This article is protected by copyright. All rights reserved.

Performance of the Present-on-Admission Indicator for Clostridium difficile Infection

Wed, 05/13/2015 - 2:53pm

The performance of a hospital- and community-onset Clostridium difficile infection definition using administrative data with a present-on-admission indicator was compared with definitions using clinical surveillance. For hospital-onset C. difficile infection, there was moderate sensitivity (68%) and high specificity (93%); for community-onset, sensitivity and specificity were high (both 85%). Infect Control Hosp Epidemiol 2015;00(0): 1-3.

Pain management in nursing home residents with cancer

Wed, 05/13/2015 - 2:53pm

OBJECTIVES: To assess improvements in pain management of nursing home (NH) residents with cancer since the implementation of pain management quality indicators.

DESIGN: Cross-sectional.

SETTING: One thousand three hundred eighty-two U.S. NHs (N = 1,382).

PARTICIPANTS: Newly admitted, Medicare-eligible NH residents with cancer (N = 8,094).

MEASUREMENTS: Nationwide data on NH resident health from Minimum Data Set 2.0 linked to all-payer pharmacy dispensing records (February 2006-June 2007) were used to determine prevalence of pain, including frequency and intensity, and receipt of nonopioid and opioid analgesics. Multinomial logistic regression was used to evaluate resident-level correlates of pain and binomial logistic regression to identify correlates of untreated pain. RESULTS: More than 65% of NH residents with cancer had any pain (28.3% daily, 37.3% < daily), 13.5% of whom had severe and 61.3% had moderate pain. Women; residents admitted from acute care or who were bedfast; and those with compromised activities of daily living, depressed mood, an indwelling catheter, or a terminal prognosis were more likely to have pain. More than 17% of residents in daily pain (95% confidence interval (CI) = 16.0-19.1%) received no analgesics, including 11.7% with daily severe pain (95% CI = 8.9-14.5%) and 16.9% with daily moderate pain (95% CI = 15.1-18.8%). Treatment was negatively associated with age of 85 and older (adjusted OR (aOR) = 0.67, 95% CI = 0.55-0.81 vs aged 65-74), cognitive impairment (aOR = 0.71, 95% CI = 0.61-0.82), presence of feeding tube (aOR = 0.77, 95% CI = 0.60-0.99), and restraints (aOR = 0.50, 95% CI = 0.31-0.82).

CONCLUSION: Untreated pain is still common in NH residents with cancer and persists despite pain management quality indicators. Geriatrics Society.

Adherence to guidelines for glucose assessment in starting second-generation antipsychotics

Wed, 05/13/2015 - 2:16pm

OBJECTIVES: In 2003, the US Food and Drug Administration issued warnings about hyperglycemia and diabetes with second-generation antipsychotics (SGAs); guidelines have recommended metabolic screening since 2004. However, little is known of contemporary practices of glucose screening among youth initiating SGAs. Our objective was to evaluate baseline glucose assessment among youth in the Mini-Sentinel Distributed Database starting an SGA.

METHODS: The cohort included youth ages 2 through 18 newly initiating SGAs January 1, 2006, through December 31, 2011, across 10 sites. Baseline glucose was defined as fasting/random glucose or hemoglobin A1c (GLU) measurement occurring relative to first SGA dispensing. Differences in GLU assessment were evaluated with chi(2) tests and logistic regression.

RESULTS: The cohort included 16,304 youth; 60% boys; mean age 12.8 years. Risperidone was most commonly started (43%). Eleven percent (n = 1858) had GLU assessed between 90 days before and 3 days after first dispensing. Assessment varied across SGAs (olanzapine highest), sites (integrated health care systems higher), ages (16-18 highest), years (2007 highest), and gender (female higher; all P < .001). GLU assessment among those starting olanzapine was more likely than among those starting quetiapine (odds ratio [OR]: 1.72 [95% confidence interval (CI): 1.37-2.18]), aripiprazole (OR: 1.49 [95% CI: 1.18-1.87]), or risperidone (OR: 1.61 [95% CI: 1.28-2.03]).

CONCLUSIONS: Few children and adolescents starting SGA have baseline glucose assessed. This is concerning because those at high diabetes risk may not be identified. Further, lack of screening impedes determining the contribution of SGAs to hyperglycemia development.

Trends in elective labor induction for six United States health plans, 2001-2007

Wed, 05/13/2015 - 2:16pm

BACKGROUND: To describe trends in labor induction, including elective induction, from 2001 to 2007 for six U.S. health plans and to examine the validity of induction measures derived from birth certificate and health plan data.

METHODS: This retrospective cohort study included 339,123 deliveries at 35 weeks' gestation or greater. Linked health plan and birth certificate data provided information about induction, maternal medical conditions, and pregnancy complications. Induction was defined from diagnosis and procedure codes and birth certificate data and considered elective if no accepted indication was coded. We calculated induction prevalence across health plans and years. At four health plans, we reviewed medical records to validate induction measures.

RESULTS: Based on electronic data, induction prevalence rose from 28% in 2001 to 32% in 2005, then declined to 29% in 2007. The trend was driven by changes in the prevalence of apparent elective induction, which rose from 11% in 2001 to 14% in 2005 and then declined to 11% in 2007. The trend was similar for subgroups by parity and gestational age. Elective induction prevalence varied considerably across plans. On review of 86 records, 36% of apparent elective inductions identified from electronic data were confirmed as valid.

CONCLUSIONS: Elective induction appeared to peak in 2005 and then decline. The decrease may reflect quality improvement initiatives or changes in policies, patient or provider attitudes, or coding practices. The low validation rate for measures of elective induction defined from electronic data has important implications for existing quality measures and for research studies examining induction's outcomes.

Home medication support for childhood cancer: family-centered design and testing

Wed, 05/13/2015 - 2:16pm

PURPOSE: Errors in the use of medications at home by children with cancer are common, and interventions to support correct use are needed. We sought to (1) engage stakeholders in the design and development of an intervention to prevent errors in home medication use, and (2) evaluate the acceptability and usefulness of the intervention.

METHODS: We convened a multidisciplinary team of parents, clinicians, technology experts, and researchers to develop an intervention using a two-step user-centered design process. First, parents and oncologists provided input on the design. Second, a parent panel and two oncology nurses refined draft materials. In a feasibility study, we used questionnaires to assess usefulness and acceptability. Medication error rates were assessed via monthly telephone interviews with parents.

RESULTS: We successfully partnered with parents, clinicians, and IT experts to develop Home Medication Support (HoMeS), a family-centered Web-based intervention. HoMeS includes a medication calendar with decision support, a communication tool, adverse effect information, a metric conversion chart, and other information. The 15 families in the feasibility study gave HoMeS high ratings for acceptability and usefulness. Half recorded information on the calendar to indicate to other caregivers that doses were given; 34% brought it to the clinic to communicate with their clinician about home medication use. There was no change in the rate of medication errors in this feasibility study.

CONCLUSION: We created and tested a stakeholder-designed, Web-based intervention to support home chemotherapy use, which parents rated highly. This tool may prevent serious medication errors in a larger study.

Statin discontinuation in nursing home residents with advanced dementia

Wed, 05/13/2015 - 2:16pm

OBJECTIVES: To describe patterns of, and factors associated with, statin use and discontinuation in nursing home (NH) residents progressing to advanced dementia and followed for at least 90 days.

DESIGN: Retrospective inception cohort using a dataset linking 2007 to 2008 Minimum Data Set (MDS) to Medicare denominator and Part D files.

SETTING: All NHs in five states (Minnesota, Massachusetts, Pennsylvania, California, Florida).

PARTICIPANTS: NH residents with dementia.

MEASUREMENTS: Residents who developed advanced dementia were observed from baseline (date of progression to very severe cognitive impairment with eating problems) and followed for at least 90 days to statin discontinuation or death. Logistic regression was used to identify baseline factors associated with statin use. Cox proportional hazard regression was used to identify factors associated with time to statin discontinuation.

RESULTS: Of 10,212 residents, 16.6% (n = 1,699) used statins. Greater odds of statin use were associated with having diabetes mellitus (adjusted odds ratio (AOR) = 1.24, 95% confidence interval (CI) = 1.09-1.40), stroke (AOR = 1.31, 95% CI = 1.16-1.48), and hypertension (AOR = 1.35, 95% CI = 1.18-1.54); hospice enrollment was associated with lower odds (AOR = 0.75, 95% CI = 0.64-0.89). In follow-up, 37.2% (n = 632) discontinued statins. Median time to discontinuation was 36 days (interquartile range 12-110 days). Shorter time to discontinuation was associated with hospitalization in past 30 days (adjusted hazard ratio (AHR) = 1.67, 95% CI = 1.40-1.99) and more daily medications (AHR = 1.02, 95% CI = 1.01-1.04). When statins were discontinued, 15.0% (n = 95) of residents stopped only statins, and 47.5% (n = 300) stopped at least one other medication.

CONCLUSION: Most NH residents who use statins at the time of progression to advanced dementia continue use in follow-up. Geriatrics Society.

Medication adherence among pediatric patients with sickle cell disease: a systematic review

Wed, 05/13/2015 - 2:16pm

OBJECTIVES: Describe rates of adherence for sickle cell disease (SCD) medications, identify patient and medication characteristics associated with nonadherence, and determine the effect of nonadherence and moderate adherence (defined as taking 60%-80% of doses) on clinical outcomes.

METHODS: In February 2012 we systematically searched 6 databases for peer-reviewed articles published after 1940. We identified articles evaluating medication adherence among patients < 25 years old with SCD. Two authors reviewed each article to determine whether it should be included. Two authors extracted data, including medication studied, adherence measures used, rates of adherence, and barriers to adherence.

RESULTS: Of 24 articles in the final review, 23 focused on 1 medication type: antibiotic prophylaxis (13 articles), iron chelation (5 articles), or hydroxyurea (5 articles). Adherence rates ranged from 16% to 89%; most reported moderate adherence. Medication factors contributed to adherence. For example, prophylactic antibiotic adherence was better with intramuscular than oral administration. Barriers included fear of side effects, incorrect dosing, and forgetting. Nonadherence was associated with more vaso-occlusive crises and hospitalizations. The limited data available on moderate adherence to iron chelation and hydroxyurea indicates some clinical benefit.

CONCLUSIONS: Moderate adherence is typical among pediatric patients with SCD. Multicomponent interventions are needed to optimally deliver life-changing medications to these children and should include routine monitoring of adherence, support to prevent mistakes, and education to improve understanding of medication risks and benefits.

Association of Early Post-Discharge Follow-Up by a Primary Care Physician and 30-Day Rehospitalization Among Older Adults

Wed, 05/13/2015 - 2:16pm

BACKGROUND: Rehospitalizations within 30 days of discharge are responsible for a large portion of healthcare spending. One approach to preventing rehospitalizations is early follow-up, usually defined as an office visit with a primary care physician within 7 days of discharge-an approach that is being incentivized by health plans. However, evidence regarding its effectiveness is limited.

OBJECTIVE: We aimed to determine whether an office visit with a primary care physician within 7 days after discharge is associated with 30-day rehospitalization.

DESIGN: This was an observational study set within a randomized trial.

PARTICIPANTS: The study included patients age 65 and older receiving care from a multi-specialty group practice and discharged from hospital to home between 26 August 2010 and 25 August 2011. To control for confounding, we identified characteristics of patients and hospital stays that are predictive of rehospitalization, and also developed high-dimensional propensity scores. Analyses used Cox proportional hazards models and took into account varying amounts of opportunity time for office visits.

MAIN MEASURES: We looked at 30-day rehospitalizations at any hospital.

KEY RESULTS: Of 3,661 patients discharged to home during the study year, 707 (19.3 %) were rehospitalized within 30 days. Patients receiving an office visit within 7 days numbered 1,808 (49.4 %), and of these, 1,000 (27.3 %) were with a primary care physician. In models predicting rehospitalization, stratified on deciles of propensity score and controlling for additional confounders, the hazard ratios associated with office visits with a primary care physician within 7 days were 0.98 (95 % CI 0.80, 1.21); for visits with any physician, the hazard ratio was HR 1.04, (95 % CI 0.87, 1.25).

CONCLUSIONS: We found no protective effect for office visits within 7 days. Such visits may need to be specifically focused on a range of issues related to the specific reasons why patients are rehospitalized. It is likely that outpatient visits will need to be set within comprehensive transition programs.