Applying economic principles to health care.

Applying economic thinking to an understanding of resource use in patient care is challenging given the complexities of delivering health care in a hospital. Health-care markets lack the characteristics needed to determine a "market" price that reflects the economic value of resources used. However, resource allocation in a hospital can be analyzed by using production theory to determine efficient resource use. The information provided by hospital epidemiologists is critical to understanding health-care production processes used by a hospital and developing economic incentives to promote antibiotic effectiveness and infection control

New Light on the Systematics of Fungi Associated with Attine Ant Gardens and the Description ofﾠEscovopsis kreiseliiﾠsp. nov.

Since the formal description of fungi in the genus Escovopsis in 1990, only a few studies have focused on the systematics of this group. For more than two decades, only two Escovopsis species were described; however, in 2013, three additional Escovopsis species were formally described along with the genus Escovopsioides, both found exclusively in attine ant gardens. During a survey for Escovopsis species in gardens of the lower attine ant Mycetophylax morschi in Brazil, we found four strains belonging to the pink-colored Escovopsis clade. Careful examination of these strains revealed significant morphological differences when compared to previously described species of Escovopsis and Escovopsioides. Based on the type of conidiogenesis (sympodial), as well as morphology of conidiogenous cells (percurrent), non-vesiculated conidiophores, and DNA sequences, we describe the four new strains as a new species, Escovopsis kreiselii sp. nov. Phylogenetic analyses using three nuclear markers (Large subunit RNA; translation elongation factor 1-alpha; and internal transcribed spacer) from the new strains as well as available sequences in public databases confirmed that all known fungi infecting attine ant gardens comprise a monophyletic group within the Hypocreaceae family, with very diverse morphological characteristics. Specifically, Escovopsis kreiselii is likely associated with gardens of lower-attine ants and its pathogenicity remains uncertain

Valsartan for attenuating disease evolution in early sarcomeric hypertrophic cardiomyopathy: the design of the Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) trial

Background: Hypertrophic cardiomyopathy (HCM) is often caused by sarcomere gene mutations, resulting in left ventricular hypertrophy (LVH), myocardial fibrosis, and increased risk of sudden cardiac death and heart failure. Studies in mouse models of sarcomeric HCM demonstrated that early treatment with an angiotensin receptor blocker (ARB) reduced development of LVH and fibrosis. In contrast, prior human studies using ARBs for HCM have targeted heterogeneous adult cohorts with well-established disease. The VANISH trial is testing the safety and feasibility of disease-modifying therapy with an ARB in genotyped HCM patients with early disease. Methods: A randomized, placebo-controlled, double-blind clinical trial is being conducted in sarcomere mutation carriers, 8 to 45 years old, with HCM and no/minimal symptoms, or those with early phenotypic manifestations but no LVH. Participants are randomly assigned to receive valsartan 80 to 320 mg daily (depending on age and weight) or placebo. The primary endpoint is a composite of 9 z-scores in domains representing myocardial injury/hemodynamic stress, cardiac morphology, and function. Total z-scores reflecting change from baseline to final visits will be compared between treatment groups. Secondary endpoints will assess the impact of treatment on mutation carriers without LVH, and analyze the influence of age, sex, and genotype. Conclusions: The VANISH trial is testing a new strategy of disease modification for treating sarcomere mutation carriers with early HCM, and those at risk for its development. In addition, further insight into disease mechanisms, response to therapy, and phenotypic evolution will be gained

Total Body Irradiation–Based Myeloablative Haploidentical Stem Cell Transplantation Is a Safe and Effective Alternative to Unrelated Donor Transplantation in Patients Without Matched Sibling Donors

AbstractWe enrolled 30 patients on a prospective phase II trial utilizing a total body irradiation (TBI)–based myeloablative preparative regimen (fludarabine 30 mg/m2/day × 3 days and TBI 150 cGy twice per day on day -4 to -1 [total dose 1200 cGy]) followed by infusion of unmanipulated peripheral blood stem cells from a haploidentical family donor (haplo). Postgrafting immunosuppression consisted of cyclophosphamide 50 mg/kg/day on days 3 and 4, mycophenolate mofetil through day 35, and tacrolimus through day 180. Median patient age was 46.5 years (range, 24 to 60). Transplantation diagnosis included acute myelogenous leukemia (n = 16), acute lymphoblastic leukemia (n = 6), chronic myelogenous leukemia (n = 5), myelodysplastic syndrome (n = 1), and non-Hodgkin's lymphoma (n = 2). Using the Dana Farber/Center for International Blood and Marrow Transplant Research/Disease Risk Index (DRI), patients were classified as low (n = 4), intermediate (n = 12), high (n = 11), and very high (n = 3) risk. All patients engrafted with a median time to neutrophil and platelet recovery of 16 and 25 days, respectively. All evaluable patients achieved sustained complete donor T cell and myeloid chimerism by day +30. Acute graft-versus-host disease (GVHD) grades II to IV and III and IV was seen in 43% and 23%, respectively. The cumulative incidence of chronic GVHD was 56% (severe in 10%). After a median follow-up of 24 months, the estimated 2-year overall survival (OS), disease-free survival (DFS), nonrelapse mortality, and relapse rate were 78%, 73%, 3%, and 24%, respectively. Two-year DFS and relapse rate in patients with low/intermediate risk disease was 100% and 0%, respectively, compared with 39% and 53% for patients with high/very high risk disease. When compared with a contemporaneously treated cohort of patients at our institution receiving myeloablative HLA-matched unrelated donor (MUD) transplantation (acute myelogenous leukemia [n = 17], acute lymphoblastic leukemia [n = 15], chronic myelogenous leukemia [n = 7], myelodysplastic syndrome [n = 7], non-Hodgkin lymphoma [n = 1], chronic lymphoblastic leukemia [n = 1]), outcomes were statistically similar, with 2-yr OS and DFS being 78% and 73%, respectively after haplo transplantation versus 71% and 64%, respectively, after MUD transplantation. In patients with DRI low/intermediate risk disease, 2-yr DFS was superior after haplo compared with MUD transplantations (100% versus 74%, P = .032), whereas there was no difference in DFS in patients with high/very high risk disease (39% versus 37% for haplo and MUD respectively, P = .821). Grade II to IV acute GVHD was seen less often after haplo compared with MUD transplantation (43% versus 63%, P = .049), as was moderate-to-severe chronic GVHD (22% versus 58%, P = .003). Myeloablative haplo transplantation using this regimen is a valid option for patients with advanced hematologic malignancies who lack timely access to a conventional donor. Outcomes appear at least equivalent to those seen in contemporaneous patients who underwent transplantation from MUD

Greenland ice sheet surface temperature, melt and mass loss : 2000-06

Author Posting. © International Glaciological Society, 2008. This article is posted here by permission of International Glaciological Society for personal use, not for redistribution. The definitive version was published in Journal of Glaciology 54 (2008): 81-93, doi:10.3189/002214308784409170.A daily time series of 'clear-sky' surface temperature has been compiled of the Greenland ice sheet (GIS) using 1 km resolution moderate-resolution imaging spectroradiometer (MODIS) land-surface temperature (LST) maps from 2000 to 2006. We also used mass-concentration data from the Gravity Recovery and Climate Experiment (GRACE) to study mass change in relationship to surface melt from 2003 to 2006. The mean LST of the GIS increased during the study period by ∼0.27°C a−1. The increase was especially notable in the northern half of the ice sheet during the winter months. Melt-season length and timing were also studied in each of the six major drainage basins. Rapid (<15 days) and sustained mass loss below 2000 m elevation was triggered in 2004 and 2005 as recorded by GRACE when surface melt begins. Initiation of large-scale surface melt was followed rapidly by mass loss. This indicates that surface meltwater is flowing rapidly to the base of the ice sheet, causing acceleration of outlet glaciers, thus highlighting the metastability of parts of the GIS and the vulnerability of the ice sheet to air-temperature increases. If air temperatures continue to rise over Greenland, increased surface melt will play a large role in ice-sheet mass loss.This work was supported by NASA’s Cryospheric Sciences Program

Probabilistic Projections of 21st Century Climate Change over Northern Eurasia

We present probabilistic projections of 21st century climate change over Northern Eurasia using the Massachusetts Institute of Technology (MIT) Integrated Global System Model (IGSM), an integrated assessment model that couples an earth system model of intermediate complexity with a two-dimensional zonal-mean atmosphere, to a human activity model. Regional climate change is obtained by two downscaling methods: a dynamical downscaling, where the IGSM is linked to a three-dimensional atmospheric model; and a statistical downscaling, where a pattern scaling algorithm uses climate-change patterns from 17 climate models. This framework allows for key sources of uncertainty in future projections of regional climate change to be accounted for: emissions projections; climate system parameters (climate sensitivity, strength of aerosol forcing and ocean heat uptake rate); natural variability; and structural uncertainty. Results show that the choice of climate policy and the climate parameters are the largest drivers of uncertainty. We also find that different initial conditions lead to differences in patterns of change as large as when using different climate models. Finally, this analysis reveals the wide range of possible climate change over Northern Eurasia, emphasizing the need to consider all sources of uncertainty when modeling climate impacts over Northern Eurasia.We would like to recognize the Northern Eurasian Earth Science Partnership Initiative (NEESPI) for providing the background that made this study possible. This work was partially funded by the U.S. Department of Energy, Office of Biological and Environmental Research, under grant DE-FG02-94ER61937. The Joint Program on the Science and Policy of Global Change is funded by a number of federal agencies and a consortium of 40 industrial and foundation sponsors. (For the complete list see http://globalchange.mit.edu/sponsors/current.html). This research used the Evergreen computing cluster at the Pacific Northwest National Laboratory. Evergreen is supported by the Office of Science of the US Department of Energy under Contract No. DE-AC05-76RL01830. 20th Century Reanalysis V2 data provided by the NOAA/OAR/ESRL PSD, Boulder, Colorado, USA, from their Web site at http://www.esrl.noaa.gov/psd/

Atypical Case Of Wolfram Syndrome Revealed Through Targeted Exome Sequencing In A Patient With Suspected Mitochondrial Disease

Background: Mitochondrial diseases comprise a diverse set of clinical disorders that affect multiple organ systems with varying severity and age of onset. Due to their clinical and genetic heterogeneity, these diseases are difficult to diagnose. We have developed a targeted exome sequencing approach to improve our ability to properly diagnose mitochondrial diseases and apply it here to an individual patient. Our method targets mitochondrial DNA (mtDNA) and the exons of 1,600 nuclear genes involved in mitochondrial biology or Mendelian disorders with multi-system phenotypes, thereby allowing for simultaneous evaluation of multiple disease loci. Case Presentation: Targeted exome sequencing was performed on a patient initially suspected to have a mitochondrial disorder. The patient presented with diabetes mellitus, diffuse brain atrophy, autonomic neuropathy, optic nerve atrophy, and a severe amnestic syndrome. Further work-up revealed multiple heteroplasmic mtDNA deletions as well as profound thiamine deficiency without a clear nutritional cause. Targeted exome sequencing revealed a homozygous c.1672C > T (p.R558C) missense mutation in exon 8 of WFS1 that has previously been reported in a patient with Wolfram syndrome. Conclusion: This case demonstrates how clinical application of next-generation sequencing technology can enhance the diagnosis of patients suspected to have rare genetic disorders. Furthermore, the finding of unexplained thiamine deficiency in a patient with Wolfram syndrome suggests a potential link between WFS1 biology and thiamine metabolism that has implications for the clinical management of Wolfram syndrome patients

Myeloablative Conditioning with PBSC Grafts for T Cell-Replete Haploidentical Donor Transplantation Using Posttransplant Cyclophosphamide

Relapse is the main cause of treatment failure after nonmyeloablative haploidentical transplant (haplo-HSCT). In an attempt to reduce relapse, we have developed a myeloablative (MA) haplo-HSCT approach utilizing posttransplant cyclophosphamide (PT/Cy) and peripheral blood stem cells as the stem cell source. We summarize the results of two consecutive clinical trials, using a busulfan-based (n=20) and a TBI-based MA preparative regimen (n=30), and analyze a larger cohort of 64 patients receiving MA haplo-HSCT. All patients have engrafted with full donor chimerism and no late graft failures. Grade III-IV acute GVHD and moderate-severe chronic GVHD occurred in 23% and 30%, respectively. One-year NRM was 10%. Predicted three-year overall survival, disease-free survival, and relapse were 53%, 53%, and 26%, respectively, in all patients and 79%, 74%, and 9%, respectively, in patients with a low/intermediate disease risk index (DRI). In multivariate analysis, DRI was the most significant predictor of survival and relapse. Use of TBI (versus busulfan) had no significant impact on survival but was associated with significantly less BK virus-associated hemorrhagic cystitis. We contrast our results with other published reports of MA haplo-HSCT PT/Cy in the literature and attempt to define the comparative utility of MA haplo-HSCT to other methods of transplantation

Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML

CPX-351 is a liposomal formulation of cytarabine: daunorubicin designed to deliver synergistic drug ratios to leukemia cells. In this phase 2 study, newly diagnosed older acute myeloid leukemia (AML) patients were randomized 2: 1 to first-line CPX-351 or 713 treatment. The goal was to determine efficacy and identify patient subgroups that may benefit from CPX-351 treatment. Response rate (complete remission 1 incomplete remission) was the primary end point, with event-free survival (EFS) and overall survival (OS) as secondary end points. The 126 patients entered were balanced for disease and patient-specific risk factors. Overall, CPX-351 produced higher response rates (66.7% vs 51.2%, P = .07), meeting predefined criteria for success (P \u3c .1). Differences in EFS and OS were not statistically significant. A planned analysis of the secondary AML subgroup demonstrated an improved response rate (57.6% vs 31.6%, P = .06), and prolongation of EFS (hazard ratio [HR] = 0.59, P = .08) and OS (HR = 0.46, P = .01). Recovery from cytopenias was slower after CPX-351 (median days to absolute neutrophil count \u3e= 1000: 36 vs 32; platelets \u3e100 000:37 vs 28) with more grade 3-4 infections but without increase in infection-related deaths (3.5% vs 7.3%) or 60-day mortality (4.7% vs 14.6%), indicating acceptable safety. These results suggest a clinical benefit with CPX-351, particularly among patients with secondary AML, and provide the rationale for a phase 3 trial currently underway in newly diagnosed secondary AML patients. This study is registered at Clinicaltrials.gov as #NCT00788892

Myocardial Injury, Obesity, and the Obesity Paradox

To examine whether pre-heart failure (HF) myocardial injury explains the differential mortality after HF across weight categories