Influence of safety warnings on ESA prescribing among dialysis patients using an interrupted time series

BACKGROUND: In March, 2007, a black box warning was issued by the Food and Drug Administration (FDA) to use the lowest possible erythropoiesis-stimulating agents (ESA) doses for treatment of anemia associated with renal disease. The goal is to determine if a change in ESA use was observed following the warning among US dialysis patients. METHODS: ESA therapy was examined from September 2004 through August 2009 (thirty months before and after the FDA black box warning) among adult Medicare hemodialysis patients. An interrupted time series model assessed the impact of the warnings. RESULTS: The FDA black box warning did not appear to influence ESA prescribing among the overall dialysis population. However, significant declines in ESA therapy after the FDA warnings were observed for selected populations. Patients with a hematocrit ≥36% had a declining month-to-month trend before (−164 units/week, p = <0.0001) and after the warnings (−80 units/week, p = .001), and a large drop in ESA level immediately after the black box (−4,744 units/week, p = <.0001). Not-for-profit facilities had a declining month-to-month trend before the warnings (−90 units/week, p = .009) and a large drop in ESA dose immediately afterwards (−2,487 units/week, p = 0.015). In contrast, for-profit facilities did not have a significant change in ESA prescribing. CONCLUSIONS: ESA therapy had been both profitable for providers and controversial regarding benefits for nearly two decades. The extent to which a FDA black box warning highlighting important safety concerns influenced use of ESA therapy among nephrologists and dialysis providers was unknown. Our study found no evidence of changes in ESA prescribing for the overall dialysis population resulting from a FDA black box warning

LMSD: LIPID MAPS structure database

The LIPID MAPS Structure Database (LMSD) is a relational database encompassing structures and annotations of biologically relevant lipids. Structures of lipids in the database come from four sources: (i) LIPID MAPS Consortium's core laboratories and partners; (ii) lipids identified by LIPID MAPS experiments; (iii) computationally generated structures for appropriate lipid classes; (iv) biologically relevant lipids manually curated from LIPID BANK, LIPIDAT and other public sources. All the lipid structures in LMSD are drawn in a consistent fashion. In addition to a classification-based retrieval of lipids, users can search LMSD using either text-based or structure-based search options. The text-based search implementation supports data retrieval by any combination of these data fields: LIPID MAPS ID, systematic or common name, mass, formula, category, main class, and subclass data fields. The structure-based search, in conjunction with optional data fields, provides the capability to perform a substructure search or exact match for the structure drawn by the user. Search results, in addition to structure and annotations, also include relevant links to external databases. The LMSD is publicly available a

Tularemia Outbreak Investigation in Kosovo: Case Control and Environmental Studies

A large outbreak of tularemia occurred in Kosovo in the early postwar period, 1999-2000. Epidemiologic and environmental investigations were conducted to identify sources of infection, modes of transmission, and household risk factors. Case and control status was verified by enzyme-linked immunosorbent assay, Western blot, and microagglutination assay. A total of 327 serologically confirmed cases of tularemia pharyngitis and cervical lymphadenitis were identified in 21 of 29 Kosovo municipalities. Matched analysis of 46 case households and 76 control households suggested that infection was transmitted through contaminated food or water and that the source of infection was rodents. Environmental circumstances in war-torn Kosovo led to epizootic rodent tularemia and its spread to resettled rural populations living under circumstances of substandard housing, hygiene, and sanitation

Post-Collision-Interaction Effects in HCl Following Photofragmentation Near the Chlorine K Edge

Ion time-of-flight mass spectroscopy was used to study the relaxation dynamics of HCl following photoexcitation in the vicinity of the Cl K threshold (~2.8 keV). Detailed observations of molecular fragmentation mediated by postcollision interaction between a photoelectron and an Auger electron are presented, evidenced by the recapture of Cl K photoelectrons by either Cln+ or H+ dissociation fragments. [S1050-2947(98)51206-1

Photofragmentation of Third-Row Hydrides Following Photoexcitation at Deep-Core Levels

The relaxation dynamics of HCl, DCl, H2S, and D2S following photoexcitation in the vicinities of the Cl and S K-shell thresholds (∼2.8keV for Cl, ∼2.5 keV for S) were studied by means of ion time-of-flight mass spectroscopy. In all cases, the onset of pre-edge core-shell photoionization precedes the formation on resonance of a significant amount of neutral hydrogen as well as postcollision-interaction effects above threshold. Examination of the width of the H+ peak in spectra taken with the analyzer parallel and perpendicular to the polarization vector of the incident light indicates that on resonance, the photofragmentation asymmetry parameter, β, is approximately two for HCl, and is clearly positive for H2S

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect approximately 1 billion individuals worldwide. However, the drivers of progressive steatohepatitis remain incompletely defined. Ketogenesis can dispose of much of the fat that enters the liver, and dysfunction in this pathway could promote the development of NAFLD. Here, we evaluated mice lacking mitochondrial 3-hydroxymethylglutaryl CoA synthase (HMGCS2) to determine the role of ketogenesis in preventing diet-induced steatohepatitis. Antisense oligonucleotide–induced loss of HMGCS2 in chow-fed adult mice caused mild hyperglycemia, increased hepatic gluconeogenesis from pyruvate, and augmented production of hundreds of hepatic metabolites, a suite of which indicated activation of the de novo lipogenesis pathway. High-fat diet feeding of mice with insufficient ketogenesis resulted in extensive hepatocyte injury and inflammation, decreased glycemia, deranged hepatic TCA cycle intermediate concentrations, and impaired hepatic gluconeogenesis due to sequestration of free coenzyme A (CoASH). Supplementation of the CoASH precursors pantothenic acid and cysteine normalized TCA intermediates and gluconeogenesis in the livers of ketogenesis-insufficient animals. Together, these findings indicate that ketogenesis is a critical regulator of hepatic acyl-CoA metabolism, glucose metabolism, and TCA cycle function in the absorptive state and suggest that ketogenesis may modulate fatty liver disease

Genetic Ancestry, Self-Reported Race and Ethnicity in African Americans and European Americans in the PCaP Cohort

Family history and African-American race are important risk factors for both prostate cancer (CaP) incidence and aggressiveness. When studying complex diseases such as CaP that have a heritable component, chances of finding true disease susceptibility alleles can be increased by accounting for genetic ancestry within the population investigated. Race, ethnicity and ancestry were studied in a geographically diverse cohort of men with newly diagnosed CaP.Individual ancestry (IA) was estimated in the population-based North Carolina and Louisiana Prostate Cancer Project (PCaP), a cohort of 2,106 incident CaP cases (2063 with complete ethnicity information) comprising roughly equal numbers of research subjects reporting as Black/African American (AA) or European American/Caucasian/Caucasian American/White (EA) from North Carolina or Louisiana. Mean genome wide individual ancestry estimates of percent African, European and Asian were obtained and tested for differences by state and ethnicity (Cajun and/or Creole and Hispanic/Latino) using multivariate analysis of variance models. Principal components (PC) were compared to assess differences in genetic composition by self-reported race and ethnicity between and within states.Mean individual ancestries differed by state for self-reporting AA (p = 0.03) and EA (p = 0.001). This geographic difference attenuated for AAs who answered "no" to all ethnicity membership questions (non-ethnic research subjects; p = 0.78) but not EA research subjects, p = 0.002. Mean ancestry estimates of self-identified AA Louisiana research subjects for each ethnic group; Cajun only, Creole only and both Cajun and Creole differed significantly from self-identified non-ethnic AA Louisiana research subjects. These ethnicity differences were not seen in those who self-identified as EA.Mean IA differed by race between states, elucidating a potential contributing factor to these differences in AA research participants: self-reported ethnicity. Accurately accounting for genetic admixture in this cohort is essential for future analyses of the genetic and environmental contributions to CaP

A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP

The innate immune system responds to unique molecular signatures that are widely conserved among microbes but that are not normally present in host cells. Compounds that stimulate innate immune pathways may be valuable in the design of novel adjuvants, vaccines, and other immunotherapeutics. The cyclic dinucleotide cyclic-di–guanosine monophosphate (c-di-GMP) is a recently appreciated second messenger that plays critical regulatory roles in many species of bacteria but is not produced by eukaryotic cells. In vivo and in vitro studies have previously suggested that c-di-GMP is a potent immunostimulatory compound recognized by mouse and human cells. We provide evidence that c-di-GMP is sensed in the cytosol of mammalian cells via a novel immunosurveillance pathway. The potency of cytosolic signaling induced by c-di-GMP is comparable to that induced by cytosolic delivery of DNA, and both nucleic acids induce a similar transcriptional profile, including triggering of type I interferons and coregulated genes via induction of TBK1, IRF3, nuclear factor κB, and MAP kinases. However, the cytosolic pathway that senses c-di-GMP appears to be distinct from all known nucleic acid–sensing pathways. Our results suggest a novel mechanism by which host cells can induce an inflammatory response to a widely produced bacterial ligand

Industrial mining heritage and the legacy of environmental pollution in the Derbyshire Derwent catchment: quantifying contamination at a regional scale and developing integrated strategies for management of the wider historic environment

The Derwent Valley Mills World Heritage Site (DVMWHS) exemplifies and records the 18th century birth of the factory or mill technology, and for the industrial spinning of cotton. The site is therefore a key global heritage asset. The Derbyshire Derwent catchment also contains another significant cultural asset with a long history – that of mining and, in particular, lead (Pb) mining. In this paper research on mining- and non-mining related Pb contamination of the Derwent catchment is reviewed and used to identify the risks it poses to the DVMWHS. The upper Derwent soils, though not impacted by mining, have high sediment-borne Pb concentrations, and the Pb is sourced from local conurbations (principally Manchester) and carried to the upper Derwent on the wind. River sediments in the middle and lower parts of the Derwent catchment are contaminated with Pb mined mainly between the 18th and 19th centuries and before, possibly as far back to the Bronze Age. The potential for large-scale, acidity-related chemical remobilization of this Pb is low in the Derwent catchment due to the largely alkaline nature of the underlying soils, but the potential for oxidation-reduction-related, and physical (flood-related), remobilization, is higher. Management guidelines for mining heritage assets and the DVMWHS are developed from the reviewed information, with the view that these will provide a framework for future work in, and management of, the DVMWHS that will be applicable to other World Heritage Sites affected by ongoing and past metal-mining. Focused collaborative work between archaeologists, geochemists, geomorphologists and mineralogistsis vital if the risks to the DVMWHS and other similarly-affected World Heritage Sites are to be quantified and, if necessary, mitigated