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Using joint registry data from FORCE-TJR to improve the accuracy of risk-adjustment prediction models for thirty-day readmission after total hip replacement and total knee replacement

Tue, 01/05/2016 - 10:27am

The recent release of publicly reported total joint replacement outcomes illustrates the growing importance that public health officials place on measuring and comparing outcomes after total joint replacement across hospitals and surgeons.

Factors Associated With Early Improvement in Low Back Pain After Total Hip Arthroplasty: A Multi-Center Prospective Cohort Analyses

Tue, 01/05/2016 - 10:27am

This study identified factors associated with an improvement in low back pain (LBP) at six-month follow-up after total hip arthroplasty (THA). Data from a national registry of 3054 patients were analyzed. Factors under analysis included demographics, comorbid conditions, operative and nonoperative joint pain severity, physical function, and mental health. Differences in these factors between patients with and without improvement in LBP were examined. Among patients reporting severe or moderate LBP preoperatively, 56% improved 6months after surgery. Patients without improvement were more likely to be on Medicare, have a high school education or less, have household income less than $45,000 and have one or more comorbid conditions. Patients with improvement in LBP experienced more resolution of pain in both the operative and nonoperative hip.

The bundle "plus": the effect of a multidisciplinary team approach to eradicate central line-associated bloodstream infections

Tue, 01/05/2016 - 8:41am

BACKGROUND: Central line-associated bloodstream infections (CLABSIs) have decreased significantly over the last decade. Further reductions in CLABSI rates should be possible. We describe a multidisciplinary approach to the reduction of CLABSIs.

METHODS: This was an observational study of critically ill patients requiring central venous catheters in 8 intensive care units in a tertiary medical center. We implemented a catheter bundle that included hand hygiene, education of providers, chlorhexidine skin preparation, use of maximum barrier precautions, a dedicated line cart, checklist, avoidance of the femoral vein for catheter insertion, chlorhexidine-impregnated dressings, use of anti-infective catheters, and daily consideration of the need for the catheter. Additional measures included root cause analyses of all CLABSIs, creation of a best practice atlas for internal jugular catheters, and enhanced education on blood culture collection. Data were analyzed using the Poisson test and regression.

RESULTS: CLABSI, catheter use, and microbiology were tracked from 2004 to 2012. There was a 92% reduction in CLABSIs (95% lower confidence limit: 67.4% reduction, P < 0.0001). Central venous catheter use decreased significantly from 2008 to 2012 (P = 0.032, -151 catheters per year, 95% confidence limits: -277 to -25), whereas peripherally inserted central catheter use increased (P = 0.005, 89 catheters per year, 95% confidence limits: 50 to 127). There was no apparent association between unit-specific Acute Physiology And Chronic Health Evaluation III/IV scores and CLABSI. Three units have not had a CLABSI in more than a year. The most common organism isolated was coagulase-negative staphylococcus. Since the implementation of minocycline/rifampin catheters, no cases of methicillin-resistant Staphylococcus aureus CLABSI have occurred.

CONCLUSIONS: The implementation of a standard catheter bundle combined with chlorhexidine dressings, minocycline/rifampin catheters, and other behavioral changes was associated with a sustained reduction in CLABSIs.

Lung Cancer and Mesothelioma

Mon, 01/04/2016 - 4:23pm

This chapter in Cancer Concepts: A Guidebook for the Non-Oncologist presents an overview of lung cancer and mesothelioma, including epidemiology, etiology, screening, pathology, staging, and treatment.

The Significance of Isolated Antibody to Hepatitis B Core Antigen Seropositivity in Patients Infected with Human Immunodeficiency Virus

Mon, 01/04/2016 - 2:50pm

To decrease transmission of hepatitis B virus (HBV), immunization with the HBV vaccine has been recommended for individuals in high-risk populations who are seronegative for antibodies to hepatitis B [1]. Isolated antibody to hepatitis B core antigen (antiHBc) seropositivity is found in about 2.5% of volunteer blood donors in the United States and is often considered a false-positive serological response [2]. However, in a retrospective review of HIV-infected patients in Worcester, Massachusetts, we unexpectedly noted isolated anti-HBc seropositivity in > 30% of our population. To gain insight into the meaning of the isolated anti-HBc seropositivity, we further analyzed this patient population.

Active Complex Event Processing: Applications in Real-Time Health Care

Mon, 01/04/2016 - 2:50pm

Our analysis of many real-world event based applications has revealed that existing Complex Event Processing technology (CEP), while effective for efficient pattern matching on event stream, is limited in its capability of reacting in realtime to opportunities and risks detected or environmental changes. We are the first to tackle this problem by providing active rule support embedded directly within the CEP engine, henceforth called Active Complex Event Processing technology, or short, Active CEP. We design the Active CEP model and associated rule language that allows rules to be triggered by CEP system state changes and correctly executed during the continuous query process. Moreover we design an Active CEP infrastructure, that integrates the active rule component into the CEP kernel, allowing finegrained and optimized rule processing. We demonstrate the power of Active CEP by applying it to the development of a collaborative project with UMass Medical School, which detects potential threads of infection and reminds healthcare workers to perform hygiene precautions in real-time.

Active Complex Event Processing over Event Streams

Mon, 01/04/2016 - 2:50pm

State-of-the-art Complex Event Processing technology (CEP), while effective for pattern query execution, is limited in its capability of reacting to opportunities and risks detected by pattern queries. Especially reactions that affect the query results in turn have not been addressed in the literature. We propose to tackle these unsolved problems by embedding active rule support within the CEP engine, henceforth called Active CEP (ACEP). Active rules in ACEP allow us to specify a pattern query’s dynamic condition and real-time actions. The technical challenge is to handle interactions between queries and reactions to queries in the high-volume stream execution. We hence introduce a novel stream-oriented transactional model along with a family of stream transaction scheduling algorithms that ensure the correctness of concurrent stream execution. We demonstrate the power of ACEP technology by applying it to the development of a healthcare system being deployed in UMass Medical School hospital. Through extensive performance experiments using real data streams, we show that our unique Low-Water-Mark stream transaction scheduler, customized for streaming environments, successfully achieves near-realtime system responsiveness and gives orders-of-magnitude better throughput than our alternative schedulers.

Active Complex Event Processing infrastructure: Monitoring and reacting to event streams

Mon, 01/04/2016 - 2:50pm

State-of-the-art Complex Event Processing technology (CEP), while effective for pattern matching on event streams, is limited in its capability of reacting in real-time to opportunities and risks detected when monitoring the physical or virtual world. We propose to tackle this problem by embedding active rule support within the CEP engine, henceforth called Active Complex Event Processing technology, or short, ACEP. We design an ACEP infrastructure that integrates the active rule component into the CEP kernel. This not only allows fine-grained but also more efficient rule processing. Based on the infrastructure we develop optimization techniques to improve the responsiveness of our system. We demonstrate the power of ACEP technology by applying it to the development of our real-time healthcare system being deployed in Univ. of Massachusetts Medical School hospital. Through performance experiments using real-world workloads collected from the hospital, we show that our ACEP solution is effective and efficient at supporting business process in event-based systems compared to possible alternatives.

Acute Pneumonia

Mon, 01/04/2016 - 2:50pm

Book chapter discussing the epidemiology, etiology, diagnosis, treatment, and prevention of acute pneumonia.

Toxin-Mediated Illnesses (Toxic Shock Syndrome, Tetanus, and Botulism)

Mon, 01/04/2016 - 2:50pm

Book chapter discussing the general principles, pathogenesis, diagnosis, and treatment of Toxic Shock Syndrome, Tetanus, and Botulism.

Severe Community-Acquired Respiratory Viral Infections

Mon, 01/04/2016 - 2:50pm

Book chapter discusses general principles, pathogenesis, diagnosis, and treatment of human influenza and Avian influenza (H5N1), Hantavirus cardiopulmonary syndrome, and other viral infections.

Malaria and other Vector-Borne Illnesses

Mon, 01/04/2016 - 2:50pm

Book chapter discusses general principles, pathogenesis, diagnosis, and treatment of malaria, West Nile virus, Tularemia, Rocky Mountain spotted fever, Babesiosis, Ehrlichiosis, and Anaplasmosis.

NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis

Wed, 12/23/2015 - 9:31am

IkappaB kinase/necrosis factor kappaB (IKK/NF-kappaB) signaling exhibits important yet opposing functions in hepatocarcinogenesis. Mice lacking NEMO in liver parenchymal cells (LPC) spontaneously develop steatohepatitis and hepatocellular carcinoma (HCC) suggesting that NF-kappaB prevents liver disease and cancer. Here, we show that complete NF-kappaB inhibition by combined LPC-specific ablation of RelA, c-Rel, and RelB did not phenocopy NEMO deficiency, but constitutively active IKK2-mediated NF-kappaB activation prevented hepatocellular damage and HCC in NEMO(LPC-KO) mice. Knock-in expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) prevented hepatocyte apoptosis and HCC, while RIPK1 ablation induced TNFR1-associated death domain protein (TRADD)-dependent hepatocyte apoptosis and liver tumors in NEMO(LPC-KO) mice, revealing distinct kinase-dependent and scaffolding functions of RIPK1. Collectively, these results show that NEMO prevents hepatocarcinogenesis by inhibiting RIPK1 kinase activity-driven hepatocyte apoptosis through NF-kappaB-dependent and -independent functions.

R loops regulate promoter-proximal chromatin architecture and cellular differentiation

Wed, 12/23/2015 - 9:31am

Numerous chromatin-remodeling factors are regulated by interactions with RNA, although the contexts and functions of RNA binding are poorly understood. Here we show that R loops, RNA-DNA hybrids consisting of nascent transcripts hybridized to template DNA, modulate the binding of two key chromatin-regulatory complexes, Tip60-p400 and polycomb repressive complex 2 (PRC2) in mouse embryonic stem cells (ESCs). Like PRC2, the Tip60-p400 histone acetyltransferase complex binds to nascent transcripts; however, transcription promotes chromatin binding of Tip60-p400 but not PRC2. Interestingly, we observed higher Tip60-p400 and lower PRC2 levels at genes marked by promoter-proximal R loops. Furthermore, disruption of R loops broadly decreased Tip60-p400 occupancy and increased PRC2 occupancy genome wide. In agreement with these alterations, ESCs partially depleted of R loops exhibited impaired differentiation. These results show that R loops act both positively and negatively in modulating the recruitment of key pluripotency regulators.

Venous-derived angioblasts generate organ-specific vessels during embryonic development

Wed, 12/23/2015 - 9:31am

Formation and remodeling of vascular beds are complex processes orchestrated by multiple signaling pathways. While it is well accepted that vessels of a particular organ display specific features that enable them to fulfill distinct functions, the embryonic origins of tissue-specific vessels, as well as the molecular mechanisms regulating their formation, are poorly understood. The subintestinal plexus of the zebrafish embryo comprises vessels that vascularize the gut, liver and pancreas, and as such represents an ideal model to investigate the early steps of organ-specific vessel formation. Here we show that both arterial and venous components of the subintestinal plexus originate from a pool of specialized angioblasts residing in the floor of the Posterior Cardinal Vein (PCV). Using live imaging of zebrafish embryos, in combination with photoconvertable transgenic reporters, we demonstrate that these angioblasts undergo two phases of migration and differentiation. Initially, a subintestinal vein (SIV) forms and expands ventrally through a bone morphogenetic protein (BMP)-dependent step of collective migration. Concomitantly, a VEGF-dependent shift in the directionality of migration, coupled to the upregulation of arterial markers is observed, which culminates with the generation of the supraintestinal artery (SIA). Altogether our results establish the zebrafish subintestinal plexus as an advantageous model for the study of organ-specific vessel development, and provide new insights into the molecular mechanisms controlling its formation. More broadly, our findings suggest that PCV-specialized angioblasts contribute not only to the formation of the early trunk vasculature, but also to the establishment of late forming-, tissue specific vascular beds.

DNA-binding-domain fusions enhance the targeting range and precision of Cas9

Wed, 12/23/2015 - 9:31am

The CRISPR-Cas9 system is commonly used in biomedical research; however, the precision of Cas9 is suboptimal for applications that involve editing a large population of cells (for example, gene therapy). Variations on the standard Cas9 system have yielded improvements in the precision of targeted DNA cleavage, but they often restrict the range of targetable sequences. It remains unclear whether these variants can limit lesions to a single site in the human genome over a large cohort of treated cells. Here we show that by fusing a programmable DNA-binding domain (pDBD) to Cas9 and attenuating Cas9's inherent DNA-binding affinity, we were able to produce a Cas9-pDBD chimera with dramatically improved precision and an increased targeting range. Because the specificity and affinity of this framework can be easily tuned, Cas9-pDBDs provide a flexible system that can be tailored to achieve extremely precise genome editing at nearly any genomic locus.

Hedgehog-driven myogenic tumors recapitulate skeletal muscle cellular heterogeneity

Wed, 12/23/2015 - 9:31am

Hedgehog (Hh) pathway activation in R26-SmoM2;CAGGS-CreER mice, which carry a tamoxifen-inducible activated Smoothened allele (SmoM2), results in numerous microscopic tumor foci in mouse skeletal muscle. These tumors exhibit a highly differentiated myogenic phenotype and resemble human fetal rhabdomyomas. This study sought to apply previously established strategies to isolate lineally distinct populations of normal mouse myofiber-associated cells in order to examine cellular heterogeneity in SmoM2 tumors. We demonstrate that established SmoM2 tumors are composed of cells expressing myogenic, adipocytic and hematopoietic lineage markers and differentiation capacity. SmoM2 tumors thus recapitulate the phenotypic and functional hetereogeneity observed in normal mouse skeletal muscle. SmoM2 tumors also contain an expanded population of PAX7+ and MyoD+ satellite-like cells with extremely low clonogenic activity. Selective activation of Hh signaling in freshly isolated muscle satellite cells enhanced terminal myogenic differentiation without stimulating proliferation. Our findings support the conclusion that SmoM2 tumors represent an aberrant skeletal muscle state and demonstrate that, similar to normal muscle, myogenic tumors contain functionally distinct cell subsets, including cells lacking myogenic differentiation potential.