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Understanding Drug Resistance and Antibody Neutralization Escape in Antivirals: A Dissertation

Tue, 11/29/2016 - 12:01pm

Antiviral drug resistance is a major problem in the treatment of viral infections, including influenza and hepatitis C virus (HCV). Influenza neuraminidase (NA) is a viral sialidase on the surface of the influenza virion and a primary antiviral target in influenza. Two subtypes of NA predominate in humans, N1 and N2, but different patterns of drug resistance have emerged in each subtype. To provide a framework for understanding the structural basis of subtype specific drug resistance mutations in NA, we used molecular dynamics simulations to define dynamic substrate envelopes for NA to determine how different patterns of drug resistance have emerged in N1 and N2 NA. Furthermore, we used the substrate envelope to analyze HCV NS3/4A protease inhibitors in clinical development. In addition, influenza hemagglutinin (HA) is a primary target of neutralizing antibodies against influenza. Novel broadly neutralizing antibodies (BnAbs) against the stem region of HA have been described and inhibit several influenza viral subtypes, but antibody neutralization escape mutations have emerged. We identified potential escape mutations in broadly neutralizing antibody F10 that may impact protein dynamics in HA that are critical for function. We also solved crystal structures of antibody fragments that are important for understanding the structural basis of antibody binding for influenza BnAbs. These studies can inform the design of improved therapeutic strategies against viruses by incorporating an understanding of structural elements that are critical for function, such as substrate processing and protein dynamics, into the development of novel therapeutics that are robust against resistance.

The Drosophila Homolog of the Intellectual Disability Gene ACSL4 Acts in Glia to Regulate Morphology and Neuronal Activity: A Dissertation

Tue, 11/29/2016 - 12:01pm

Recent developments in neurobiology make it clear that glia play fundamental and active roles, in the adult and in development. Many hereditary cognitive disorders have been linked to developmental defects, and in at least two cases, Rett Syndrome and Fragile X Mental Retardation, glia are important in pathogenesis. However, most studies of developmental disorders, in particular intellectual disability, focus on neuronal defects. An example is intellectual disability caused by mutations in ACSL4, a metabolic enzyme that conjugates long-chain fatty acids to Coenzyme A (CoA). Depleting ACSL4 in neurons is associated with defects in dendritic spines, a finding replicated in patient tissue, but the etiology of this disorder remains unclear. In a genetic screen to discover genes necessary for visual function, I identified the Drosophila homolog of ACSL4, Acsl, as a gene important for the magnitude of neuronal transmission, and found that it is required in glia. I determined that Acsl is required in a specific subtype of glia in the Drosophila optic lobe, and that depletion of Acsl from this population causes morphological defects. I demonstrated that Acsl is required in development, and that the phenotype can be rescued by human ACSL4. Finally, I discovered that ACSL4 is expressed in astrocytes in the mouse hippocampus. This study is highly significant for understanding glial biology and neurodevelopment. It provides information on the role of glia in development, substantiates a novel role for Acsl in glia, and advances our understanding of the potential role that glia play in the pathogenesis of intellectual disability.

The Mechanistic Role and Therapeutic Potential of microRNA-122 in Alcoholic Liver Disease: A Dissertation

Tue, 11/29/2016 - 12:01pm

Chronic alcohol use results in accelerated liver injury, leading to alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. However, due to the complex nature of this disease process, a central, druggable mechanism has remained elusive. microRNAs are potent post-transcriptional regulators of gene expression. A single miRNA has the ability to regulate hundreds of pathways simultaneously, defining cellular fate and function. microRNA-122 (miR-122), the most abundant miRNA in hepatocytes, has a demonstrated role as an tumor suppressor, regulator of hepatocyte metabolism, and hepatic differentiation.

In this dissertation I demonstrate the role of miR-122 on alcoholic liver disease (ALD) pathogenesis over four parts. In chapter II, I will demonstrate chronic alcoholic patients, free of neoplastic changes, have a reduction of miR-122 and that this miRNA regulates HIF-1α, a determinant of ALD pathogenesis. In chapter III, using hepatocytetropic adeno-associated virus 8 (AAV8) vector, I demonstrate that miR-122 inhibition mimics ALD pathogenesis, and furthermore, using hepatocyte-specific HIF-1α-null (HIF1hepKO) mice that this phenomenon is HIF-1α dependent. Given this finding, in chapter IV, I demonstrate that ectopic expression of miR-122 in vivo can reverse alcoholinduced liver damage, steatosis, and inflammation by directly targeting HIF-1α. Finally, in chapter V, I present evidence that alcohol-induced dysregulation of grainyhead-like proteins 1 and 2 (GRHL2), mediate the inhibition of miR-122 at the transcriptional level. These findings dissect a novel mechanistic regulatory axis of miR-122 and indicate a potential opportunity for restoration of miR-122 as a therapy in early ALD.

A Role for TNMD in Adipocyte Differentiation and Adipose Tissue Function: A Dissertation

Tue, 11/29/2016 - 12:01pm

Adipose tissue is one of the most dynamic tissues in the body and is vital for metabolic homeostasis. In the case of excess nutrient uptake, adipose tissue expands to store excess energy in the form of lipids, and in the case of reduced nutrient intake, adipose tissue can shrink and release this energy. Adipocytes are most functional when the balance between these two processes is intact. To understand the molecular mechanisms that drive insulin resistance or conversely preserve the metabolically healthy state in obese individuals, our laboratory performed a screen for differentially regulated adipocyte genes in insulin resistant versus insulin sensitive subjects who had been matched for BMI. From this screen, we identified the type II transmembrane protein tenomodulin (TNMD), which had been previously implicated in glucose tolerance in gene association studies. TNMD was upregulated in omental fat samples isolated from the insulin resistant patient group compared to insulin sensitive individuals. TNMD was predominantly expressed in primary adipocytes compared to the stromal vascular fraction from this adipose tissue. Furthermore, TNMD expression was greatly increased in human preadipocytes by differentiation, and silencing TNMD blocked adipogenic gene induction and adipogenesis, suggesting its role in adipose tissue expansion.

Upon high fat diet feeding, transgenic mice overexpressing Tnmd specifically in adipose tissue developed increased epididymal adipose tissue (eWAT) mass without a difference in mean cell size, consistent with elevated in vitro adipogenesis. Moreover, preadipocytes isolated from transgenic epididymal adipose tissue demonstrated higher BrdU incorporation than control littermates, suggesting elevated preadipocyte proliferation. In TNMD overexpressing mice, lipogenic genes PPARG, FASN, SREBP1c and ACLY were upregulated in eWAT as was UCP-1 in brown fat, while liver triglyceride content was reduced. Transgenic animals displayed improved systemic insulin sensitivity, as demonstrated by decreased inflammation and collagen accumulation and increased Akt phosphorylation in eWAT. Thus, the data we present here suggest that TNMD plays a protective role during visceral adipose tissue expansion by promoting adipogenesis and inhibiting inflammation and tissue fibrosis.

Plague and the Defeat of Mammalian Innate Immunity: Systematic Genetic Analysis of Yersinia pestis Virulence Factors: A Dissertation

Tue, 11/29/2016 - 12:00pm

Yersinia pestis, the causative agent of plague, specializes in causing dense bacteremia following intradermal deposition of a small number of bacteria by the bite of an infected flea. This robust invasiveness requires the ability to evade containment by the innate immune system. Of the various mechanisms employed by Y. pestis to subvert the innate immune response and to proliferate rapidly in mammalian tissue, only a few are well-characterized. Here, I present two complementary genetic analyses of Y. pestis adaptations to the mammalian environment. In the first, genome-wide fitness profiling for Y. pestis by Tn-seq demonstrates that the bacterium has adapted to overcome limitation of diverse nutrients during mammalian infection. In the second, a series of combinatorial targeted mutations disentangles apparent functional redundancy among the effectors of the Y. pestis type III secretion system, and we report that YpkA, YopT, and YopJ contribute to virulence in mice. We have also begun to investigate a novel relationship between Y. pestis and mammalian platelets, a highly abundant cell type in plasma. I present evidence that Y. pestis has evolved specific mechanisms to interfere with platelet activation, likely in order to evade immune responses and promote maintenance of bacteremia by undermining platelet thrombotic and innate immune functions. The principles guiding this work – systematic genetic analysis of complex systems, coupled with rational modification of in vitro assays to more closely mimic the in vivo environment – are a generalizable approach for increasing the efficiency of discovering new virulence determinants in bacterial pathogens.

Neuromodulators signal through astrocytes to alter neural circuit activity and behaviour

Mon, 11/28/2016 - 11:32am

Astrocytes associate with synapses throughout the brain and express receptors for neurotransmitters that can increase intracellular calcium (Ca2+). Astrocytic Ca2+ signalling has been proposed to modulate neural circuit activity, but the pathways that regulate these events are poorly defined and in vivo evidence linking changes in astrocyte Ca2+ levels to alterations in neurotransmission or behaviour is limited. Here we show that Drosophila astrocytes exhibit activity-regulated Ca2+ signalling in vivo. Tyramine and octopamine released from neurons expressing tyrosine decarboxylase 2 (Tdc2) signal directly to astrocytes to stimulate Ca2+ increases through the octopamine/tyramine receptor (Oct-TyrR) and the transient receptor potential (TRP) channel Water witch (Wtrw), and astrocytes in turn modulate downstream dopaminergic neurons. Application of tyramine or octopamine to live preparations silenced dopaminergic neurons and this inhibition required astrocytic Oct-TyrR and Wtrw. Increasing astrocyte Ca2+ signalling was sufficient to silence dopaminergic neuron activity, which was mediated by astrocyte endocytic function and adenosine receptors. Selective disruption of Oct-TyrR or Wtrw expression in astrocytes blocked astrocytic Ca2+ signalling and profoundly altered olfactory-driven chemotaxis and touch-induced startle responses. Our work identifies Oct-TyrR and Wtrw as key components of the astrocytic Ca2+ signalling machinery, provides direct evidence that octopamine- and tyramine-based neuromodulation can be mediated by astrocytes, and demonstrates that astrocytes are essential for multiple sensory-driven behaviours in Drosophila.

Circadian rhythms identified in Caenorhabditis elegans by in vivo long-term monitoring of a bioluminescent reporter

Mon, 11/28/2016 - 11:32am

Circadian rhythms are based on endogenous clocks that allow organisms to adjust their physiology and behavior by entrainment to the solar day and, in turn, to select the optimal times for most biological variables. Diverse model systems-including mice, flies, fungi, plants, and bacteria-have provided important insights into the mechanisms of circadian rhythmicity. However, the general principles that govern the circadian clock of Caenorhabditis elegans have remained largely elusive. Here we report robust molecular circadian rhythms in C elegans recorded with a bioluminescence assay in vivo and demonstrate the main features of the circadian system of the nematode. By constructing a luciferase-based reporter coupled to the promoter of the suppressor of activated let-60 Ras (sur-5) gene, we show in both population and single-nematode assays that C elegans expresses approximately 24-h rhythms that can be entrained by light/dark and temperature cycles. We provide evidence that these rhythms are temperature-compensated and can be re-entrained after phase changes of the synchronizing agents. In addition, we demonstrate that light and temperature sensing requires the photoreceptors LITE and GUR-3, and the cyclic nucleotide-gated channel subunit TAX-2. Our results shed light on C elegans circadian biology and demonstrate evolutionarily conserved features in the circadian system of the nematode.

Obesity, health-care utilization, and health-related quality of life after fracture in postmenopausal women: Global Longitudinal Study of Osteoporosis in Women (GLOW)

Tue, 11/22/2016 - 2:21pm

Fractures may be associated with higher morbidity in obese postmenopausal women than in nonobese women. We compared health-care utilization, functional status, and health-related quality of life (HRQL) in obese, nonobese, and underweight women with fractures. Information from the GLOW study, started in 2006, was collected at baseline and at 1, 2, and 3 years. In this subanalysis, self-reported incident clinical fractures, health-care utilization, HRQL, and functional status were recorded and examined. Women in GLOW (n = 60,393) were aged ≥55 years, from 723 physician practices at 17 sites in 10 countries. Complete data for fracture and body mass index were available for 90 underweight, 3,270 nonobese, and 941 obese women with one or more incident clinical fractures during the 3-year follow-up. The median hospital length of stay, adjusted for age, comorbidities, and fracture type, was significantly greater in obese than nonobese women (6 vs. 5 days, p = 0.017). Physical function and vitality score were significantly worse in obese than in nonobese women, both before and after fracture; but changes after fracture were similar across groups. Use of antiosteoporosis medication was significantly lower in obese than in nonobese or underweight women. In conclusion, obese women with fracture undergo a longer period of hospitalization for treatment and have poorer functional status and HRQL than nonobese women. Whether these differences translate into higher economic costs and adverse effects on longer-term outcomes remains to be established.

Biomedical Research Data Management Open Online Education: Challenges & Lessons Learned

Sun, 11/20/2016 - 7:52pm

The Best Practices for Biomedical Big Data project is a two year collaboration between Harvard Medical School and University of Massachusetts Medical School, funded by the NIH Big Data to Knowledge (BD2K) Initiative for Resource Development. The Best Practices for Biomedical Research Data Management Massive Open Online Course (MOOC) provides training to librarians, biomedical researchers, undergraduate and graduate biomedical students, and other interested individuals on recommended practices facilitating the discoverability, access, integrity, reuse value, privacy, security, and long term preservation of biomedical research data. This poster highlights lessons learned from the first year of this project.

Built upon the New England Collaborative Data Management Curriculum, the development team sought to use existing curricular materials to create a fully online course. The course is designed with an open course platform, WordPress Learning Management System (WPLMS), in order to facilitate broad access. Each of the MOOC’s nine modules is dedicated to a specific component of data management best practices and includes video lectures, presentation slides, research teaching cases, readings, activities, and interactive quizzes.

The project team overcame multiple challenges related to creating an open online course: curriculum, audience and software.

Working towards overcoming these, the Best Practices for Biomedical Research Data Management MOOC development team has moved slowly and deliberately, created additional content, and added content experts to provide guidance. These lessons learned will assist course development beyond this project, adding to best practices for creating massive open online courseware. Lessons learned include: teaching method influences the curriculum and content should not be developed in isolation from the teaching method; content is dependent on audience and supplementary content can be used to bridge audience gaps; and implementing new or unfamiliar technologies is challenging so allow more time in the timeline for project team to work with open source platform.

Gallbladder opacification on gadoxetate disodium-enhanced CT scan

Fri, 11/18/2016 - 8:23am

This study aimed to evaluate the radiologist's ability to identify excreted gadoxetate disodium within the gallbladder on CT scan. Thirty three healthy adults underwent imaging of the liver during work-up for potential liver donation. Three patients had undergone prior cholecystectomy and therefore were excluded. Imaging consisted of gadoxetate disodium-enhanced magnetic resonance cholangiography (MRC) and multiphase contrast-enhanced CT scan of the abdomen and pelvis. Two fellowship-trained abdominal imaging radiologists, who were blinded to the MRC images and the contrast agent used during MRC, independently reviewed the CT scans of the 30 patients that were included. The scans were evaluated for the presence or absence of abnormal hyperdensity within the gallbladder. Three patients did not receive intravenous gadoxetate disodium, 4 patients had their MRC after the CT scan, and 1 patient had the CT scans 5 days following the MRC. Twenty two patients had the CT scan within 24 h following the gadoxetate disodium-enhanced MRC. Of the 22 patients expected to have gadolinium in the gallbladder, both reviewers identified hyperdensity in the same 20 patients (90%). Both reviewers reported no abnormal hyperdensity within the gallbladder in the remaining 10 patients. CT scan can reveal excreted gadoxetate disodium within the gallbladder lumen and therefore gadoxetate disodium-enhanced CT scan can potentially play a role in the evaluation of cystic duct patency and work-up of acute cholecystitis.

Transfusion practices in evolution, not revolution*

Thu, 11/17/2016 - 12:31pm

Comment on: Survey on stated transfusion practices in PICUs*. [Pediatr Crit Care Med. 2014]

Determinants of red blood cell transfusion in pediatric trauma patients admitted to the intensive care unit

Thu, 11/17/2016 - 12:31pm

BACKGROUND: There are no well-designed prospective studies evaluating transfusion practices in pediatric trauma. We sought to describe red blood cell (RBC) transfusion practices in trauma patients who were admitted to a pediatric intensive care unit (PICU).

STUDY DESIGN AND METHODS: This study is a post-hoc analysis of a prospective, 6-month observational study in 30 PICUs. We studied a total of 580 patients aged less than 18 years who had been admitted to a PICU for more than 48 hours, including 95 who were trauma patients.

RESULTS: Trauma patients more frequently received transfusion before PICU admission (p < 0.001), were older (p < 0.0001), and more frequently were mechanically ventilated (p = 0.05). In the PICU, trauma patients received more transfusions (55% vs. 37%; p < 0.001), although admission hemoglobin levels were similar in both groups (p = 0.86). The mean (+/- standard deviation) pretransfusion hemoglobin level in the PICU was 9.0 +/- 2.4 g/dL for trauma patients compared with 8.3 +/- 2.4 g/dL for nontrauma patients (p = 0.09). Among the trauma patients, transfusion was associated with younger age, higher Pediatric Logistic Organ Regression scores, mechanical ventilation, bleeding, and transfusion before PICU admission. Multivariate regression demonstrated that receiving an RBC transfusion before admission was strongly associated with receiving a blood transfusion in the PICU (p = 0.008).

CONCLUSION: Trauma patients are at high risk for receiving an RBC transfusion both before and during their PICU stay, despite a similar transfusion threshold compared with nontrauma patients. Transfusion before PICU admission is a strong determinant, suggesting ongoing bleeding that will require re-transfusion. Further studies are needed to evaluate whether a restrictive transfusion strategy can safely be considered in these patients.

1274: Pediatric Critical Care Transfusion and Anemia Expertise Initiative

Thu, 11/17/2016 - 12:31pm

Abstract no. 1974 for the Critical Care Congress, Research Snapshot Theater: Quality and Safety XXV.

A Longitudinal Study of Peripubertal Serum Organochlorine Concentrations and Semen Parameters in Young Men: The Russian Children's Study

Wed, 11/16/2016 - 9:02pm

BACKGROUND: Exposures to endocrine disrupting chemicals during critical phases of testicular development may be related to poorer semen parameters. However, few studies have assessed the association between childhood organochlorine (OC) exposure and adult semen parameters.

OBJECTIVE: We examined whether peripubertal serum OC concentrations are associated with semen parameters among young Russian men.

METHODS: From 2003 to 2005, 516 boys were enrolled at age 8-9 years and followed for up to ten years. Serum OCs were measured in the enrollment samples using high-resolution mass spectrometry. At age 18-19 years, 133 young men provided one or two semen samples (256 samples) collected approximately one week apart, which were analyzed for volume, sperm concentration and motility. Unadjusted and adjusted linear mixed models were used to examine the associations of quartiles of lipid-standardized concentrations of dioxins [2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated dibenzo-p-dioxins (PCDDs)], furans, polychlorinated biphenyls (PCBs) and corresponding toxic equivalents (TEQs) with semen parameters.

RESULTS: The median (range) for TCDD was 2.9 (0.4, 12.1) pg/g lipid and PCDD TEQs was 8.7 (1.0, 36.0) pg TEQ/g lipid. Higher quartiles of TCDD and PCDD TEQs were associated with lower sperm concentration, total sperm count and total motile sperm count (p-trends < /=0.05). The highest quartile of peripubertal serum TCDD concentrations was associated with a decrease (95% Confidence Interval) of 40% (18, 66%), 29% (3, 64%) and 30% (2, 70%) in sperm concentration, total sperm count, and total motile sperm count, respectively, compared with the lowest quartile. Similar associations were observed for serum PCDD TEQs with semen parameters. Serum PCBs, furans and total TEQs were not associated with semen parameters.

CONCLUSION: Higher peripubertal serum TCDD concentrations and PCDD TEQs were associated with poorer semen parameters.

WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects

Wed, 11/16/2016 - 9:02pm

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature. The Seattle International Registry recruits patients from all over the world to investigate genetic causes of a wide variety of progeroid syndromes in order to contribute to the knowledge of basic mechanisms of human aging. Given the unusually high prevalence of WS patients and heterozygous carriers in Japan, the major goal of the Japanese Consortium is to develop effective therapies and to establish management guidelines for WS patients in Japan and elsewhere. This review will also discuss potential translational approaches to this disorder, including those currently under investigation.

Impact of Microbiota on Resistance to Ocular Pseudomonas aeruginosa-Induced Keratitis

Wed, 11/16/2016 - 9:02pm

The existence of the ocular microbiota has been reported but functional analyses to evaluate its significance in regulating ocular immunity are currently lacking. We compared the relative contribution of eye and gut commensals in regulating the ocular susceptibility to Pseudomonas aeruginosa-induced keratitis. We find that in health, the presence of microbiota strengthened the ocular innate immune barrier by significantly increasing the concentrations of immune effectors in the tear film, including secretory IgA and complement proteins. Consistent with this view, Swiss Webster (SW) mice that are typically resistant to P. aeruginosa-induced keratitis become susceptible due to the lack of microbiota. This was exemplified by increased corneal bacterial burden and elevated pathology of the germ free (GF) mice when compared to the conventionally maintained SW mice. The protective immunity was found to be dependent on both eye and gut microbiota with the eye microbiota having a moderate, but significant impact on the resistance to infection. These events were IL-1ss-dependent as corneal IL-1ss levels were decreased in the infected GF and antibiotic-treated mice when compared to the SPF controls, and neutralization of IL-1ss increased the ocular bacterial burden in the SPF mice. Monocolonizing GF mice with Coagulase Negative Staphylococcus sp. isolated from the conjunctival swabs was sufficient to restore resistance to infection. Cumulatively, these data underline a previously unappreciated role for microbiota in regulating susceptibility to ocular keratitis. We predict that these results will have significant implications for contact lens wearers, where alterations in the ocular commensal communities may render the ocular surface vulnerable to infections.

Evaluating Patient-Centered Outcomes in Clinical Trials of Procedural Sedation, Part 1 Efficacy: Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations

Wed, 11/16/2016 - 9:02pm

The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research, established by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks public-private partnership with the US Food and Drug Administration, convened a meeting of sedation experts from a variety of clinical specialties and research backgrounds with the objective of developing recommendations for procedural sedation research. Four core outcome domains were recommended for consideration in sedation clinical trials: (1) safety, (2) efficacy, (3) patient-centered and/or family-centered outcomes, and (4) efficiency. This meeting identified core outcome measures within the efficacy and patient-centered and/or family-centered domains. Safety will be addressed in a subsequent meeting, and efficiency will not be addressed at this time. These measures encompass depth and levels of sedation, proceduralist and patient satisfaction, patient recall, and degree of pain experienced. Consistent use of the recommended outcome measures will facilitate the comprehensive reporting across sedation trials, along with meaningful comparisons among studies and interventions in systematic reviews and meta-analyses.

And the survey said.... evaluating rationale for participation in gun buybacks as a tool to encourage higher yields

Wed, 11/16/2016 - 9:02pm

BACKGROUND: Gun buyback programs represent one arm of a multipronged approach to raise awareness and education about gun safety.

METHODS: The city of Worcester, MA has conducted an annual gun buyback at the Police Department Headquarters since 2002. We analyzed survey responses from a voluntary, 18-question, face-to-face structured interview from December 2009 to June 2015 using descriptive statistics to determine participant demographics and motivations for participation.

RESULTS: A total of 943 guns were collected, and 273 individuals completed surveys. The majority of participants were white males older than 55years (42.4%). Participants represented 61 zip codes across Worcester County, with 68% having prior gun safety training and 61% with weapons remaining in the home (27% of which children could potentially access). The top reasons for turning in guns were "no longer needed" (48%) and "fear of children accessing the gun" (14%). About 1 in 3 respondents knew someone injured/killed by gun violence. Almost all (96%) respondents claimed the program raised community awareness of firearm risk.

CONCLUSION: The Worcester Goods for Guns Buyback has collected more than 900 guns between 2009 and 2015. The buyback removes unwanted guns from homes and raises community awareness about firearm safety.

Differences in the Quality of Pediatric Resuscitative Care Across a Spectrum of Emergency Departments

Wed, 11/16/2016 - 9:02pm

Importance: The quality of pediatric resuscitative care delivered across the spectrum of emergency departments (EDs) in the United States is poorly described. In a recent study, more than 4000 EDs completed the Pediatric Readiness Survey (PRS); however, the correlation of PRS scores with the quality of simulated or real patient care has not been described.

Objective: To measure and compare the quality of resuscitative care delivered to simulated pediatric patients across a spectrum of EDs and to examine the correlation of PRS scores with quality measures.

Design, Setting, and Participants: This prospective multicenter cohort study evaluated 58 interprofessional teams in their native pediatric or general ED resuscitation bays caring for a series of 3 simulated critically ill patients (sepsis, seizure, and cardiac arrest).

Main Outcomes and Measures: A composite quality score (CQS) was measured as the sum of 4 domains: (1) adherence to sepsis guidelines, (2) adherence to cardiac arrest guidelines, (3) performance on seizure resuscitation, and (4) teamwork. Pediatric Readiness Survey scores and health care professional demographics were collected as independent data. Correlations were explored between CQS and individual domain scores with PRS.

Results: Overall, 58 teams from 30 hospitals participated (8 pediatric EDs [PEDs], 22 general EDs [GEDs]). The mean CQS was 71 (95% CI, 68-75); PEDs had a higher mean CQS (82; 95% CI, 79-85) vs GEDs (66; 95% CI, 63-69) and outperformed GEDs in all domains. However, when using generalized estimating equations to estimate CQS controlling for clustering of the data, PED status did not explain a higher CQS (beta = 4.28; 95% CI, -4.58 to 13.13) while the log of pediatric patient volume did explain a higher CQS (beta = 9.57; 95% CI, 2.64-16.49). The correlation of CQS to PRS was moderate (r = 0.51; P < .001). The correlation was weak for cardiac arrest (r = 0.24; P = .07), weak for sepsis (rho = 0.45; P < .001) and seizure (rho = 0.43; P = .001), and strong for teamwork (rho = 0.71; P < .001).

Conclusions and Relevance: This multicenter study noted significant differences in the quality of simulated pediatric resuscitative care across a spectrum of EDs. The CQS was higher in PEDs compared with GEDs. However, when controlling for pediatric patient volume and other variables in a multivariable model, PED status does not explain a higher CQS while pediatric patient volume does. The correlation of the PRS was moderate for simulation-based measures of quality.

Medicare Facility Diagnosis Related Groups Have Outpaced Individual Physician Payment

Wed, 11/16/2016 - 9:01pm

INTRODUCTION: We set out to compare the rates of Medicare reimbursement to physicians versus hospitals for several major vascular procedures over a period of five years.

METHODS: We queried the Wolters Luwer MediRegs database to collect Medicare reimbursement data from fiscal years 2011 to 2015. We surveyed reimbursements for carotid endarterectomy (CEA), carotid angioplasty and stenting (CAS), femoropopliteal bypass, and lower extremity fem-pop revascularization with stenting. Based on data availability, we surveyed physician reimbursement data on the national level and in both medically over-served and underserved areas. Hospital reimbursement rates were examined on a national level and by hospitals' teaching and wage index statuses.

RESULTS: We found that for all four vascular procedures, Medicare reimbursements to hospitals increased by a greater percentage than to physicians. By region, underserved areas had lower physician reimbursements than the national average, while the opposite was true for overserved areas. Additionally, for hospital Medicare reimbursements, location in a high wage index accounted for a significant increase in reimbursement over the national average, with teaching status contributing to this increase to a smaller extent.

CONCLUSIONS: This data on Medicare reimbursements indicate that payments to hospitals are increasing more significantly than to physicians. This disparity in pay changes affects both independent and academic vascular surgeons. Medicare should consider pay increases to independent providers in accordance to the hospital pay increase.