Patterns of Cost for Patients Dying in the Intensive Care Unit and Implications for Cost Savings of Palliative Care Interventions.

BACKGROUND: Terminal intensive care unit (ICU) stays represent an important target to increase value of care. OBJECTIVE: To characterize patterns of daily costs of ICU care at the end of life and, based on these patterns, examine the role for palliative care interventions in enhancing value. DESIGN: Secondary analysis of an intervention study to improve quality of care for critically ill patients. SETTING/PATIENTS: 572 patients who died in the ICU between 2003 and 2005 at a Level-1 trauma center. METHODS: Data were linked with hospital financial records. Costs were categorized into direct fixed, direct variable, and indirect costs. Patterns of daily costs were explored using generalized estimating equations stratified by length of stay, cause of death, ICU type, and insurance status. Estimates from the literature of effects of palliative care interventions on ICU utilization were used to simulate potential cost savings under different time horizons and reimbursement models. MAIN RESULTS: Mean cost for a terminal ICU stay was 39.3K ± 45.1K. Direct fixed costs represented 45% of total hospital costs, direct variable costs 20%, and indirect costs 34%. Day of admission was most expensive (mean 9.6K ± 7.6K); average cost for subsequent days was 4.8K ± 3.4K and stable over time and patient characteristics. CONCLUSIONS: Terminal ICU stays display consistent cost patterns across patient characteristics. Savings can be realized with interventions that align care with patient preferences, helping to prevent unwanted ICU utilization at end of life. Cost modeling suggests that implications vary depending on time horizon and reimbursement models

North American Breeding Bird Survey Underestimates Regional Bird Richness Compared to Breeding Bird Atlases

Standardized data on large-scale and long-term patterns of species richness are critical for understanding the consequences of natural and anthropogenic changes in the environment. The North American Breeding Bird Survey (BBS) is one of the largest and most widely used sources of such data, but so far, little is known about the degree to which BBS data provide accurate estimates of regional richness. Here, we test this question by comparing estimates of regional richness based on BBS data with spatially and temporally matched estimates based on state Breeding Bird Atlases (BBA). We expected that estimates based on BBA data would provide a more complete (and therefore, more accurate) representation of regional richness due to their larger number of observation units and higher sampling effort within the observation units. Our results were only partially consistent with these predictions: while estimates of regional richness based on BBA data were higher than those based on BBS data, estimates of local richness (number of species per observation unit) were higher in BBS data. The latter result is attributed to higher land-cover heterogeneity in BBS units and higher effectiveness of bird detection (more species are detected per unit time). Interestingly, estimates of regional richness based on BBA blocks were higher than those based on BBS data even when differences in the number of observation units were controlled for. Our analysis indicates that this difference was due to higher compositional turnover between BBA units, probably due to larger differences in habitat conditions between BBA units and a higher likelihood of observing geographically restricted species. Our overall results indicate that estimates of regional richness based on BBS data suffer from incomplete detection of a large number of rare species, and that corrections of these estimates based on standard extrapolation techniques are not sufficient to remove this bias. Future applications of BBS data in ecology and conservation, and in particular, applications in which the representation of rare species is important (e.g., those focusing on biodiversity conservation), should be aware of this bias, and should integrate BBA data whenever possible

Variants Within Genes \u3ci\u3eEDIL3\u3c/i\u3e and \u3ci\u3eADGRB3\u3c/i\u3e are Associated With Divergent Fecal Egg Counts in Katahdin Sheep at Weaning

Gastrointestinal nematodes (GIN) pose a severe threat to sheep production worldwide. Anthelmintic drug resistance coupled with growing concern regarding potential environmental effects of drug use have demonstrated the necessity of implementing other methods of GIN control. The aim of this study was to test for genetic variants associated with resistance or susceptibility to GIN in Katahdin sheep to improve the current understanding of the genetic mechanisms responsible for host response to GIN. Linear regression and casecontrol genome-wide association studies were conducted with high-density genotype data and cube-root transformed weaning fecal egg counts (tFEC) of 583 Katahdin sheep. The casecontrol GWAS identified two significant SNPs (P-values 1.49e-08 to 1.01e-08) within introns of the gene adhesion G protein-coupled receptor B3 (ADGRB3) associated with lower fecal egg counts. With linear regression, four significant SNPs (P-values 7.82e-08 to 3.34e-08) were identified within the first intron of the gene EGF-like repeats and discoidin domains 3 (EDIL3). These identified SNPs were in very high linkage disequilibrium (r2 of 0.996–1), and animals with alternate homozygous genotypes had significantly higher median weaning tFEC phenotypes compared to all other genotypes. Significant SNPs were queried through public databases to identify putative transcription factor binding site (TFBS) and potential lncRNA differences between reference and alternate alleles. Changes in TFBS were predicted at two SNPs, and one significant SNPwas found to bewithin a predicted lncRNA sequencewith greater than 90% similarity to a known lncRNA in the bovine genome. The gene EDIL3 has been described in other species for its roles in the inhibition and resolution of inflammation. Potential changes of EDIL3 expression mediated through lncRNA expression and/or transcription factor binding may impact the overall immune response and reduce the ability of Katahdin sheep to control GIN infection. This study lays the foundation for further research of EDIL3 and ADGRB3 towards understanding genetic mechanisms of susceptibility to GIN, and suggests these SNPs may contribute to genetic strategies for improving parasite resistance traits in sheep

The transcriptional regulator CtrA controls gene expression in Alphaproteobacteria phages: Evidence for a lytic deferment pathway

Pilitropic and flagellotropic phages adsorb to bacterial pili and flagella. These phages have long been used to investigate multiple aspects of bacterial physiology, such as the cell cycle control in the Caulobacterales. Targeting cellular appendages for adsorption effectively constrains the population of infectable hosts, suggesting that phages may have developed strategies to maximize their infective yield. Brevundimonas phage vB_BsubS-Delta is a recently characterized pilitropic phage infecting the Alphaproteobacterium Brevundimonas subvibrioides. Like other Caulobacterales, B. subvibrioides divides asymmetrically and its cell cycle is governed by multiple transcriptional regulators, including the master regulator CtrA. Genomic characterization of phage vB_BsubS-Delta identified the presence of a large intergenic region with an unusually high density of putative CtrA-binding sites. A systematic analysis of the positional distribution of predicted CtrA-binding sites in complete phage genomes reveals that the highly skewed distribution of CtrA-binding sites observed in vB_BsubS-Delta is an unequivocal genomic signature that extends to other pilli- and flagellotropic phages infecting the Alphaproteobacteria. Moreover, putative CtrA-binding sites in these phage genomes localize preferentially to promoter regions and have higher scores than those detected in other phage genomes. Phylogenetic and comparative genomics analyses show that this genomic signature has evolved independently in several phage lineages, suggesting that it provides an adaptive advantage to pili/flagellotropic phages infecting the Alphaproteobacteria. Experimental results demonstrate that CtrA binds to predicted CtrA-binding sites in promoter regions and that it regulates transcription of phage genes in unrelated Alphaproteobacteria-infecting phages. We propose that this focused distribution of CtrA-binding sites reflects a fundamental new aspect of phage infection, which we term lytic deferment. Under this novel paradigm, pili- and flagellotropic phages exploit the CtrA transduction pathway to monitor the host cell cycle state and synchronize lysis with the presence of infectable cells

The transcriptional regulator CtrA controls gene expression in Alphaproteobacteria phages : Evidence for a lytic deferment pathway

Pilitropic and flagellotropic phages adsorb to bacterial pili and flagella. These phages have long been used to investigate multiple aspects of bacterial physiology, such as the cell cycle control in the Caulobacterales. Targeting cellular appendages for adsorption effectively constrains the population of infectable hosts, suggesting that phages may have developed strategies to maximize their infective yield. Brevundimonas phage vB_BsubS-Delta is a recently characterized pilitropic phage infecting the Alphaproteobacterium Brevundimonas subvibrioides. Like other Caulobacterales, B. subvibrioides divides asymmetrically and its cell cycle is governed by multiple transcriptional regulators, including the master regulator CtrA. Genomic characterization of phage vB_BsubS-Delta identified the presence of a large intergenic region with an unusually high density of putative CtrA-binding sites. A systematic analysis of the positional distribution of predicted CtrA-binding sites in complete phage genomes reveals that the highly skewed distribution of CtrA-binding sites observed in vB_BsubS-Delta is an unequivocal genomic signature that extends to other pilli- and flagellotropic phages infecting the Alphaproteobacteria. Moreover, putative CtrA-binding sites in these phage genomes localize preferentially to promoter regions and have higher scores than those detected in other phage genomes. Phylogenetic and comparative genomics analyses show that this genomic signature has evolved independently in several phage lineages, suggesting that it provides an adaptive advantage to pili/flagellotropic phages infecting the Alphaproteobacteria. Experimental results demonstrate that CtrA binds to predicted CtrA-binding sites in promoter regions and that it regulates transcription of phage genes in unrelated Alphaproteobacteria-infecting phages. We propose that this focused distribution of CtrA-binding sites reflects a fundamental new aspect of phage infection, which we term lytic deferment. Under this novel paradigm, pili- and flagellotropic phages exploit the CtrA transduction pathway to monitor the host cell cycle state and synchronize lysis with the presence of infectable cells

Speaking vocabulary of first grade children

Thesis (Ed.M.)--Boston Universit

Metabolic Profiling Reveals a Dependency of Human Metastatic Breast Cancer on Mitochondrial Serine and One-Carbon Unit Metabolism.

Breast cancer is the most common cancer among American women and a major cause of mortality. To identify metabolic pathways as potential targets to treat metastatic breast cancer, we performed metabolomics profiling on the breast cancer cell line MDA-MB-231 and its tissue-tropic metastatic subclones. Here, we report that these subclones with increased metastatic potential display an altered metabolic profile compared with the parental population. In particular, the mitochondrial serine and one-carbon (1C) unit pathway is upregulated in metastatic subclones. Mechanistically, the mitochondrial serine and 1C unit pathway drives the faster proliferation of subclones through enhanced de novo purine biosynthesis. Inhibition of the first rate-limiting enzyme of the mitochondrial serine and 1C unit pathway, serine hydroxymethyltransferase (SHMT2), potently suppresses proliferation of metastatic subclones in culture and impairs growth of lung metastatic subclones at both primary and metastatic sites in mice. Some human breast cancers exhibit a significant association between the expression of genes in the mitochondrial serine and 1C unit pathway with disease outcome and higher expression of SHMT2 in metastatic tumor tissue compared with primary tumors. In addition to breast cancer, a few other cancer types, such as adrenocortical carcinoma and kidney chromophobe cell carcinoma, also display increased SHMT2 expression during disease progression. Together, these results suggest that mitochondrial serine and 1C unit metabolism plays an important role in promoting cancer progression, particularly in late-stage cancer. IMPLICATIONS: This study identifies mitochondrial serine and 1C unit metabolism as an important pathway during the progression of a subset of human breast cancers

Combined carbonate carbon isotopic and cellular ultrastructural studies of individual benthic foraminifera : method description

Author Posting. © American Geophysical Union, 2010. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Paleoceanography 25 (2010): PA2211, doi:10.1029/2009PA001846.Carbon isotopes of foraminiferal tests provide a widely used proxy for past oceanographic environmental conditions. This proxy can be calibrated using live specimens, which are reliably identified with observations of cell ultrastructure. Observations of ultrastructures can also be used for studies of biological characteristics such as diet and presence of symbionts. Combining biological and isotopic studies on individual foraminifera could provide novel information, but standard isotopic methods destroy ultrastructures by desiccating specimens and observations of ultrastructure require removal of carbonate tests, preventing isotope measurements. The approach described here preserves cellular ultrastructure during isotopic analyses by keeping the foraminifera in an aqueous buffer (Phosphate Buffered Saline (PBS)). The technique was developed and standardized with 36 aliquots of NBS-19 standard of similar weight to foraminiferal tests (5 to 123 μg). Standard errors ranged from ± 0.06 to ± 0.85‰ and were caused by CO2 contaminants dissolved in the PBS. The technique was used to measure δ13C values of 96 foraminifera, 10 of which do not precipitate carbonate tests. Calcareous foraminiferal tests had corrected carbon isotope ratios of −8.5 to +3.2‰. This new technique allows comparisons of isotopic compositions of tests made by foraminifera known to be alive at the time of collection with their biological characteristics such as prey composition and presence or absence of putative symbionts. The approach may be applied to additional biomineralizing organisms such as planktonic foraminifera, pteropods, corals, and coccolithophores to elucidate certain biological controls on their paleoceanographic proxy signatures.Support was provided by NSF grants OCE‐0550396 (to J.B.M.), OCE‐0551001 (to J.M.B.), and OCE‐ 0550401 (to A.E.R.)

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

Modification of BRCA1-associated breast cancer risk by HMMR overexpression

Breast cancer risk for carriers of BRCA1 pathological variants is modified by genetic factors. Genetic variation in HMMR may contribute to this effect. However, the impact of risk modifiers on cancer biology remains undetermined and the biological basis of increased risk is poorly understood. Here, we depict an interplay of molecular, cellular, and tissue microenvironment alterations that increase BRCA1-associated breast cancer risk. Analysis of genome-wide association results suggests that diverse biological processes, including links to BRCA1-HMMR profiles, influence risk. HMMR overexpression in mouse mammary epithelium increases Brca1-mutant tumorigenesis by modulating the cancer cell phenotype and tumor microenvironment. Elevated HMMR activates AURKA and reduces ARPC2 localization in the mitotic cell cortex, which is correlated with micronucleation and activation of cGAS-STING and non-canonical NF-kappa B signaling. The initial tumorigenic events are genomic instability, epithelial-to-mesenchymal transition, and tissue infiltration of tumor-associated macrophages. The findings reveal a biological foundation for increased risk of BRCA1-associated breast cancer. The effect of hyaluronan-mediated motility receptor (HMMR) expression in BRCA1-associated breast cancer risk remains unknown. Here, HMMR overexpression induces the activation of cGAS-STING and non-canonical NF-kappa B signalling, instigating an immune permissive environment for breast cancer development