The Risk of West Nile Virus Infection Is Associated with Combined Sewer Overflow Streams in Urban Atlanta, Georgia, USA

BACKGROUND: At present, the factors favoring transmission and amplification of West Nile Virus (WNV) within urban environments are poorly understood. In urban Atlanta, Georgia, the highly polluted waters of streams affected by combined sewer overflow (CSO) represent significant habitats for the WNV mosquito vector Culex quinquefasciatus. However, their contribution to the risk of WNV infection in humans and birds remains unclear.\ud \ud OBJECTIVES: Our goals were to describe and quantify the spatial distribution of WNV infection in mosquitoes, humans, and corvids, such as blue jays and American crows that are particularly susceptible to WNV infection, and to assess the relationship between WNV infection and proximity to CSO-affected streams in the city of Atlanta, Georgia.\ud \ud MATERIALS AND METHODS: We applied spatial statistics to human, corvid, and mosquito WNV surveillance data from 2001 through 2007. Multimodel analysis was used to estimate associations of WNV infection in Cx. quinquefasciatus, humans, and dead corvids with selected risk factors including distance to CSO streams and catch basins, land cover, median household income, and housing characteristics.\ud \ud RESULTS: We found that WNV infection in mosquitoes, corvids, and humans was spatially clustered and statistically associated with CSO-affected streams. WNV infection in Cx. quinquefasciatus was significantly higher in CSO compared with non-CSO streams, and WNV infection rates among humans and corvids were significantly associated with proximity to CSO-affected streams, the extent of tree cover, and median household income.\ud \ud CONCLUSIONS: Our study strongly suggests that CSO-affected streams are significant sources of Cx. quinquefasciatus mosquitoes that may facilitate WNV transmission to humans within urban environments. Our findings may have direct implications for the surveillance and control of WNV in other urban centers that continue to use CSO systems as a waste management practice

Unplanned readmission rates, length of hospital stay, mortality, and medical costs of ten common medical conditions: a retrospective analysis of Hong Kong hospital data

<p>Abstract</p> <p>Background</p> <p>Studies on readmissions attributed to particular medical conditions, especially heart failure, have generally not addressed the factors associated with readmissions and the implications for health outcomes and costs. This study aimed to investigate the factors associated with 30-day unplanned readmission for 10 common conditions and to determine the cost implications.</p> <p>Methods</p> <p>This population-based retrospective cohort study included patients admitted to all public hospitals in Hong Kong in 2007. The sample consisted of 337,694 hospitalizations in Internal Medicine. The disease-specific risk-adjusted odd ratio (OR), length of stay (LOS), mortality and attributable medical costs for the year were examined for unplanned readmissions for 10 medical conditions, namely malignant neoplasms, heart diseases, cerebrovascular diseases, pneumonia, injury and poisoning, nephritis and nephrosis, diabetes mellitus, chronic liver disease and cirrhosis, septicaemia, and aortic aneurysm.</p> <p>Results</p> <p>The overall unplanned readmission rate was 16.7%. Chronic liver disease and cirrhosis had the highest OR (1.62, 95% confidence interval (CI) 1.39-1.87). Patients with cerebrovascular disease had the longest LOS, with mean acute and rehabilitation stays of 6.9 and 3.0 days, respectively. Malignant neoplasms had the highest mortality rate (30.8%) followed by aortic aneurysm and pneumonia. The attributed medical cost of readmission was highest for heart disease (US$3 199 418, 95$2 579 443-803 393).</p> <p>Conclusions</p> <p>Our findings showed variations in readmission rates and mortality for different medical conditions which may suggest differences in the quality of care provided for various medical conditions. In-hospital care, comprehensive discharge planning, and post-discharge community support for patients need to be reviewed to improve the quality of care and patient health outcomes.</p

Barriers to effective discharge planning: a qualitative study investigating the perspectives of frontline healthcare professionals

<p>Abstract</p> <p>Background</p> <p>Studies have shown that effective discharge planning is one of the key factors related to the quality of inpatient care and unnecessary hospital readmission. The perception and understanding of hospital discharge by health professionals is important in developing effective discharge planning. The aims of this present study were to explore the perceived quality of current hospital discharge from the perspective of health service providers and to identify barriers to effective discharge planning in Hong Kong.</p> <p>Methods</p> <p>Focus groups interviews were conducted with different healthcare professionals who were currently responsible for coordinating the discharge planning process in the public hospitals. The discussion covered three main areas: current practice on hospital discharge, barriers to effective hospital discharge, and suggested structures and process for an effective discharge planning system.</p> <p>Results</p> <p>Participants highlighted that there was no standardized hospital-wide discharge planning and policy-driven approach in public health sector in Hong Kong. Potential barriers included lack of standardized policy-driven discharge planning program, and lack of communication and coordination among different health service providers and patients in both acute and sub-acute care provisions which were identified as mainly systemic issues. Improving the quality of hospital discharge was suggested, including a multidisciplinary approach with clearly identified roles among healthcare professionals. Enhancement of health professionals' communication skills and knowledge of patient psychosocial needs were also suggested.</p> <p>Conclusions</p> <p>A systematic approach to develop the structure and key processes of the discharge planning system is critical in ensuring the quality of care and maximizing organization effectiveness. In this study, important views on barriers experienced in hospital discharge were provided. Suggestions for building a comprehensive, system-wide, and policy-driven discharge planning process with clearly identified staff roles were raised. Communication and coordination across various healthcare parties and provisions were also suggested to be a key focus.</p

Multisite Phosphorylation of the Guanine Nucleotide Exchange Factor Cdc24 during Yeast Cell Polarization

BACKGROUND:Cell polarization is essential for processes such as cell migration and asymmetric cell division. A common regulator of cell polarization in most eukaryotic cells is the conserved Rho GTPase, Cdc42. In budding yeast, Cdc42 is activated by a single guanine nucleotide exchange factor, Cdc24. The mechanistic details of Cdc24 activation at the onset of yeast cell polarization are unclear. Previous studies have suggested an important role for phosphorylation of Cdc24, which may regulate activity or function of the protein, representing a key step in the symmetry breaking process. METHODOLOGY/PRINCIPAL FINDINGS:Here, we directly ask whether multisite phosphorylation of Cdc24 plays a role in its regulation. We identify through mass spectrometry analysis over thirty putative in vivo phosphorylation sites. We first focus on sites matching consensus sequences for cyclin-dependent and p21-activated kinases, two kinase families that have been previously shown to phosphorylate Cdc24. Through site-directed mutagenesis, yeast genetics, and light and fluorescence microscopy, we show that nonphosphorylatable mutations of these consensus sites do not lead to any detectable consequences on growth rate, morphology, kinetics of polarization, or localization of the mutant protein. We do, however, observe a change in the mobility shift of mutant Cdc24 proteins on SDS-PAGE, suggesting that we have indeed perturbed its phosphorylation. Finally, we show that mutation of all identified phosphorylation sites does not cause observable defects in growth rate or morphology. CONCLUSIONS/SIGNIFICANCE:We conclude that lack of phosphorylation on Cdc24 has no overt functional consequences in budding yeast. Yeast cell polarization may be more tightly regulated by inactivation of Cdc42 by GTPase activating proteins or by alternative methods of Cdc24 regulation, such as conformational changes or oligomerization

RNA metabolism is the primary target of formamide in vivo

The synthesis, processing and function of coding and non-coding RNA molecules and their interacting proteins has been the focus of a great deal of research that has boosted our understanding of key molecular pathways that underlie higher order events such as cell cycle control, development, innate immune response and the occurrence of genetic diseases. In this study, we have found that formamide preferentially weakens RNA related processes in vivo. Using a non-essential Schizosaccharomyces pombe gene deletion collection, we identify deleted loci that make cells sensitive to formamide. Sensitive deletions are significantly enriched in genes involved in RNA metabolism. Accordingly, we find that previously known temperature-sensitive splicing mutants become lethal in the presence of the drug under permissive temperature. Furthermore, in a wild type background, splicing efficiency is decreased and R-loop formation is increased in the presence of formamide. In addition, we have also isolated 35 formamide-sensitive mutants, many of which display remarkable morphology and cell cycle defects potentially unveiling new players in the regulation of these processes. We conclude that formamide preferentially targets RNA related processes in vivo, probably by relaxing RNA secondary structures and/or RNA-protein interactions, and can be used as an effective tool to characterize these processes

Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines

Recent data suggest that expression of the membrane P170-glycoprotein (P-gp) may confer resistance to the topoisomerase- I-interactive agent topotecan. The present study describes the cellular effects of a new dihydropyridine analogue, PAK-200S, on P-gp-mediated resistance to topotecan in human breast and ovarian tumour cells. PAK-200S at a non-cytotoxic concentration of 2.0 μM completely reversed resistance to topotecan in P-gp-expressing MCF-7/adr (breast) and A2780/Dx5 (ovarian) tumour cells, respectively, with no effects on parental cells. Cellular pharmacokinetic studies by reversed-phase high-performance liquid chromatography analysis showed significantly lower cellular drug concentrations of the pharmacologically active closed-ring lactone of topotecan in multidrug-resistant cells than in parental cells. PAK-200S was effective in restoring the cellular lactone concentrations of topotecan in resistant MCF-7/adr cells to levels comparable to those obtained in parental cells. Furthermore, exposure of MCF-7/adr cells to topotecan in the presence of PAK-200S significantly increased the induction of protein-linked DNA breaks. PAK-200S did not alter nuclear topoisomerase I-mediated ex vivo pBR322 DNA plasmid unwinding activity and topoisomerase-I protein expression. These results suggest that reversal of P-gp-mediated resistance to topotecan by PAK-200S was related to the restoration of cellular drug concentrations of the active lactone form of topotecan rather than a direct effect on topoisomerase-I function. © 1999 Cancer Research Campaig

Hsf1 Activation Inhibits Rapamycin Resistance and TOR Signaling in Yeast Revealed by Combined Proteomic and Genetic Analysis

TOR kinases integrate environmental and nutritional signals to regulate cell growth in eukaryotic organisms. Here, we describe results from a study combining quantitative proteomics and comparative expression analysis in the budding yeast, S. cerevisiae, to gain insights into TOR function and regulation. We profiled protein abundance changes under conditions of TOR inhibition by rapamycin treatment, and compared this data to existing expression information for corresponding gene products measured under a variety of conditions in yeast. Among proteins showing abundance changes upon rapamycin treatment, almost 90% of them demonstrated homodirectional (i.e., in similar direction) transcriptomic changes under conditions of heat/oxidative stress. Because the known downstream responses regulated by Tor1/2 did not fully explain the extent of overlap between these two conditions, we tested for novel connections between the major regulators of heat/oxidative stress response and the TOR pathway. Specifically, we hypothesized that activation of regulator(s) of heat/oxidative stress responses phenocopied TOR inhibition and sought to identify these putative TOR inhibitor(s). Among the stress regulators tested, we found that cells (hsf1-R206S, F256S and ssa1-3 ssa2-2) constitutively activated for heat shock transcription factor 1, Hsf1, inhibited rapamycin resistance. Further analysis of the hsf1-R206S, F256S allele revealed that these cells also displayed multiple phenotypes consistent with reduced TOR signaling. Among the multiple Hsf1 targets elevated in hsf1-R206S, F256S cells, deletion of PIR3 and YRO2 suppressed the TOR-regulated phenotypes. In contrast to our observations in cells activated for Hsf1, constitutive activation of other regulators of heat/oxidative stress responses, such as Msn2/4 and Hyr1, did not inhibit TOR signaling. Thus, we propose that activated Hsf1 inhibits rapamycin resistance and TOR signaling via elevated expression of specific target genes in S. cerevisiae. Additionally, these results highlight the value of comparative expression analyses between large-scale proteomic and transcriptomic datasets to reveal new regulatory connections

Parsimonious Higher-Order Hidden Markov Models for Improved Array-CGH Analysis with Applications to Arabidopsis thaliana

Array-based comparative genomic hybridization (Array-CGH) is an important technology in molecular biology for the detection of DNA copy number polymorphisms between closely related genomes. Hidden Markov Models (HMMs) are popular tools for the analysis of Array-CGH data, but current methods are only based on first-order HMMs having constrained abilities to model spatial dependencies between measurements of closely adjacent chromosomal regions. Here, we develop parsimonious higher-order HMMs enabling the interpolation between a mixture model ignoring spatial dependencies and a higher-order HMM exhaustively modeling spatial dependencies. We apply parsimonious higher-order HMMs to the analysis of Array-CGH data of the accessions C24 and Col-0 of the model plant Arabidopsis thaliana. We compare these models against first-order HMMs and other existing methods using a reference of known deletions and sequence deviations. We find that parsimonious higher-order HMMs clearly improve the identification of these polymorphisms. Moreover, we perform a functional analysis of identified polymorphisms revealing novel details of genomic differences between C24 and Col-0. Additional model evaluations are done on widely considered Array-CGH data of human cell lines indicating that parsimonious HMMs are also well-suited for the analysis of non-plant specific data. All these results indicate that parsimonious higher-order HMMs are useful for Array-CGH analyses. An implementation of parsimonious higher-order HMMs is available as part of the open source Java library Jstacs (www.jstacs.de/index.php/PHHMM)

Pancreatic β-Cell Death in Response to Pro-Inflammatory Cytokines Is Distinct from Genuine Apoptosis

A reduction in functional β-cell mass leads to both major forms of diabetes; pro-inflammatory cytokines, such as interleukin-1beta (IL-1β) and gamma-interferon (γ-IFN), activate signaling pathways that direct pancreatic β-cell death and dysfunction. However, the molecular mechanism of β-cell death in this context is not well understood. In this report, we tested the hypothesis that individual cellular death pathways display characteristic phenotypes that allow them to be distinguished by the precise biochemical and metabolic responses that occur during stimulus-specific initiation. Using 832/13 and INS-1E rat insulinoma cells and isolated rat islets, we provide evidence that apoptosis is unlikely to be the primary pathway underlying β-cell death in response to IL-1β+γ-IFN. This conclusion was reached via the experimental results of several different interdisciplinary strategies, which included: 1) tandem mass spectrometry to delineate the metabolic differences between IL-1β+γ-IFN exposure versus apoptotic induction by camptothecin and 2) pharmacological and molecular interference with either NF-κB activity or apoptosome formation. These approaches provided clear distinctions in cell death pathways initiated by pro-inflammatory cytokines and bona fide inducers of apoptosis. Collectively, the results reported herein demonstrate that pancreatic β-cells undergo apoptosis in response to camptothecin or staurosporine, but not pro-inflammatory cytokines

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700