Costs of Measuring Outcomes of Acute Hospital Care in a Longitudinal Outcomes Measurement System

It is widely acknowledged that the measurement of outcomes of care and the comparison of outcomes over time within health care providers and risk-adjusted comparisons among providers are important parts of improving quality and cost-effectiveness of care. However, few studies have assessed the costs of measuring outcomes of care. We sought to evaluate the personnel and financial resources spent for a prospective assessment of outcomes of acute hospital care by health professionals in internal medicine. The study included 15 primary care hospitals participating in a longitudinal outcomes measurement program and 2005 patients over an assessment period with an average duration of 6 months. Each hospital project manager participated in a previously-tested structured 30-minute telephone interview. Outcome measures include time spent by the individual job titles in implementing and running the outcomes measurement program. Job-title-specific times were used to calculate costs from the hospitals' perspective. One-time costs (C2132 + 1352) and administrative costs (95 97 per week) varied substantially. Costs per patient were fairly stable at around 20. We estimated that the total cost for each hospital to assess outcomes of care for accreditation (10 tracer diagnoses over 6 months) would be 9700 and that continuous monitoring of outcomes (5 tracer diagnoses) would cost 12,400 per year. This study suggests that outcomes of acute hospital care can be assessed with limited resources and that standardized training programs would reduce variability in overall costs. This study should help hospital decision makers to estimate the necessary funding for outcomes measurement initiatives

De Novo Genesis of Enhancers in Vertebrates

Whole genome duplication in teleost fish reveals that a few changes in non-regulatory genomic sequences are a source for generating new enhancers

Environmental and Molecular Mutagenesis Meeting Report Assessing Human Germ-Cell Mutagenesis in the Post-Genome Era: A Celebration of the Legacy of William Lawson (Bill) Russell

ABSTRACT Although numerous germ-cell mutagens have been identified in animal model systems, to date, no human germ-cell mutagens have been confirmed. Because the genomic integrity of our germ cells is essential for the continuation of the human species, a resolution of this enduring conundrum is needed. To facilitate such a resolution, we organized a workshop at The Jackson Laboratory in Bar Harbor, Maine on September [28][29][30] 2004. This interactive workshop brought together scientists from a wide range of disciplines to assess the applicability of emerging molecular methods for genomic analysis to the field of human germ-cell mutagenesis. Participants recommended that focused, coordinated human germ-cell mutation studies be conducted in relation to important societal exposures. Because cancer survivors represent a unique cohort with well-defined exposures, there was a consensus that studies should be designed to assess the mutational impact on children born to parents who had received certain types of mutagenic cancer chemotherapy prior to conceiving their children. Within this high-risk cohort, parents and children could be evaluated for inherited changes in (a) gene sequences and chromosomal structure, (b) repeat sequences and minisatellite regions, and (c) global gene expression and chromatin. Participants also recommended studies to examine trans-generational effects in humans involving mechanisms such as changes in imprinting and methylation patterns, expansion of nucleotide repeats, or induction of mitochondrial DNA mutations. Workshop participants advocated establishment of a bio-bank of human tissue samples that could be used to conduct a multiple-endpoint, comprehensive, and collaborative effort to detect exposure-induced heritable alterations in the human genome. Appropriate animal models of human germ-cell mutagenesis should be used in parallel with human studies to provide insights into the mechanisms of mammalian germ-cell mutagenesis. Finally, participants recommended that 4 scientific specialty groups be convened to address specific questions regarding the potential germ-cell mutagenicity of environmental, occupational, and lifestyle exposures. Strong support from relevant funding agencies and engagement of scientists outside the fields of genomics and germ-cell mutagenesis will be required to launch a full-scale assault on some of the most pressing and enduring questions in environmental mutagenesis: Do human germ-cell mutagens exist, what risk do they pose to future generations, and are some parents at higher risk than others for acquiring and transmitting germ-cell mutations?

Hox Function Is Required for the Development and Maintenance of the Drosophila Feeding Motor Unit

Feeding is an evolutionarily conserved and integral behavior that depends on the rhythmic activity of feeding muscles stimulated by specific motoneurons. However, critical molecular determinants underlying the development of the neuromuscular feeding unit are largely unknown. Here, we identify the Hox transcription factor Deformed (Dfd) as essential for feeding unit formation, from initial specification to the establishment of active synapses, by controlling stage-specific sets of target genes. Importantly, we found Dfd to control the expression of functional components of synapses, such as Ankyrin2-XL, a protein known to be critical for synaptic stability and connectivity. Furthermore, we uncovered Dfd as a potential regulator of synaptic specificity, as it represses expression of the synaptic cell adhesion molecule Connectin (Con). These results demonstrate that Dfd is critical for the establishment and maintenance of the neuromuscular unit required for feeding behavior, which might be shared by other group 4 Hox genes

Combinatorial binding leads to diverse regulatory responses:Lmd is a tissue-specific modulator of Mef2 activity

Understanding how complex patterns of temporal and spatial expression are regulated is central to deciphering genetic programs that drive development. Gene expression is initiated through the action of transcription factors and their cofactors converging on enhancer elements leading to a defined activity. Specific constellations of combinatorial occupancy are therefore often conceptualized as rigid binding codes that give rise to a common output of spatio-temporal expression. Here, we assessed this assumption using the regulatory input of two essential transcription factors within the Drosophila myogenic network. Mutations in either Myocyte enhancing factor 2 (Mef2) or the zinc-finger transcription factor lame duck (lmd) lead to very similar defects in myoblast fusion, yet the underlying molecular mechanism for this shared phenotype is not understood. Using a combination of ChIP-on-chip analysis and expression profiling of loss-of-function mutants, we obtained a global view of the regulatory input of both factors during development. The majority of Lmd-bound enhancers are co-bound by Mef2, representing a subset of Mef2's transcriptional input during these stages of development. Systematic analyses of the regulatory contribution of both factors demonstrate diverse regulatory roles, despite their co-occupancy of shared enhancer elements. These results indicate that Lmd is a tissue-specific modulator of Mef2 activity, acting as both a transcriptional activator and repressor, which has important implications for myogenesis. More generally, this study demonstrates considerable flexibility in the regulatory output of two factors, leading to additive, cooperative, and repressive modes of co-regulation

A Novel Mammal-Specific Three Partite Enhancer Element Regulates Node and Notochord-Specific <em>Noto</em> Expression

<div><p>The vertebrate organizer and notochord have conserved, essential functions for embryonic development and patterning. The restricted expression of developmental regulators in these tissues is directed by specific cis-regulatory modules (CRMs) whose sequence conservation varies considerably. Some CRMs have been conserved throughout vertebrates and likely represent ancestral regulatory networks, while others have diverged beyond recognition but still function over a wide evolutionary range. Here we identify and characterize a mammalian-specific CRM required for node and notochord specific (NNC) expression of NOTO, a transcription factor essential for node morphogenesis, nodal cilia movement and establishment of laterality in mouse. A 523 bp enhancer region (NOCE) upstream the <em>Noto</em> promoter was necessary and sufficient for NNC expression from the endogenous <em>Noto</em> locus. Three subregions in NOCE together mediated full activity in vivo. Binding sites for known transcription factors in NOCE were functional in vitro but dispensable for NOCE activity in vivo. A FOXA2 site in combination with a novel motif was necessary for NOCE activity in vivo. Strikingly, syntenic regions in non-mammalian vertebrates showed no recognizable sequence similarities. In contrast to its activity in mouse NOCE did not drive NNC expression in transgenic fish. NOCE represents a novel, mammal-specific CRM required for the highly restricted <em>Noto</em> expression in the node and nascent notochord and thus regulates normal node development and function.</p> </div

NOCE responds to FOXA2, TEAD and TCF/LEF in vitro, but binding sites are dispensable in vivo.

<p>(A) Schematic view of location and sequences of transcription factor binding sites in NOCE. Red characters indicate exchanged nucleotides of mutated sites. (B) Transactivation of wild type and mutated NOCE constructs. Arabical numbers indicate different mutated binding sites: (1) FOXA2, (2) TCF/LEF, (3) TEAD. Cotransfected constructs of transcription factors are indicated below. (C) β-galactosidase staining of chimeric embryos carrying promoter-reporter transgenes with mutated FOXA2, TEAD and TCF/LEF binding sites (NOCE 3x mut) and an additional mutation in the HOX binding site (in NOCE 4x mut) in NOCE.</p

NOCE is necessary and sufficient for reporter gene activity in the NNC.

<p>(A) Schematic view of <i>Noto</i> upstream regions of various tested transgenes. (B) Corresponding chimeric embryos stained for β-galactosidase activity at E7.5 or E9.5. Transgenes are indicated on the left site.</p