Background Perioperative myocardial infarction (MI) is a serious complication after noncardiac surgery. We hypothesized that preoperative cardiac troponin T detected with a novel high-sensitivity ...(hs-cTnT) assay will identify patients at risk for acute MI and long-term mortality after major noncardiac surgery. Methods This was a prospective cohort study within the VINO trial (n = 608). Patients had been diagnosed with or had multiple risk factors for coronary artery disease and underwent major noncardiac surgery. Cardiac troponin I (contemporary assay) and troponin T (high-sensitivity assay) and 12-lead electrocardiograms were obtained before and immediately after surgery and on postoperative days 1, 2, and 3. Results At baseline before surgery, 599 patients (98.5%) had a detectable hs-cTnT concentration, and 247 (41%) were >14 ng/L (99th percentile). After surgery, 497 patients (82%) had a rise in hs-cTnT (median change in hs-cTnT +2.7 ng/L interquartile range 0.7-6.8). During the first 3 postoperative days, there were 9 patients (2.5%) with a preoperative hs-cTnT <14 ng/L with acute MI, compared with 21 patients (8.6%) with a preoperative hs-cTnT >14 ng/L (odds ratio 3.67, 95% CI 1.65-8.15). During long-term follow-up, 80 deaths occurred. The 3-year mortality rate was 11% in patients with a preoperative hs-cTnT concentration <14 ng/L compared with 25% in patients with a preoperative hs-cTnT >14 ng/L (adjusted hazard ratio 2.17, 95% CI 1.19-3.96). Conclusions In this cohort of high-risk patients, preoperative hs-cTnT concentrations were significantly associated with postoperative MI and long-term mortality after noncardiac surgery.
Identifying priority areas for marine vertebrate conservation is complex because species of conservation concern are highly mobile, inhabit dynamic habitats and are difficult to monitor. Many marine ...vertebrates are known to associate with oceanographic fronts – physical interfaces at the transition between water masses – for foraging and migration, making them important candidate sites for conservation. Here, we review associations between marine vertebrates and fronts and how they vary with scale, regional oceanography and foraging ecology. Accessibility, spatiotemporal predictability and relative productivity of front‐associated foraging habitats are key aspects of their ecological importance. Predictable mesoscale (10s–100s km) regions of persistent frontal activity (‘frontal zones’) are particularly significant. Frontal zones are hotspots of overlap between critical habitat and spatially explicit anthropogenic threats, such as the concentration of fisheries activity. As such, they represent tractable conservation units, in which to target measures for threat mitigation. Front mapping via Earth observation (EO) remote sensing facilitates identification and monitoring of these hotspots of vulnerability. Seasonal or climatological products can locate biophysical hotspots, while near‐real‐time front mapping augments the suite of tools supporting spatially dynamic ocean management. Synthesis and applications. Frontal zones are ecologically important for mobile marine vertebrates. We surmise that relative accessibility, predictability and productivity are key biophysical characteristics of ecologically significant frontal zones in contrasting oceanographic regions. Persistent frontal zones are potential priority conservation areas for multiple marine vertebrate taxa and are easily identifiable through front mapping via EO remote sensing. These insights are useful for marine spatial planning and marine biodiversity conservation, both within Exclusive Economic Zones and in the open oceans.
The current extinction and climate change crises pressure us to predict population dynamics with ever‐greater accuracy. Although predictions rest on the well‐advanced theory of age‐structured ...populations, two key issues remain poorly explored. Specifically, how the age‐dependency in demographic rates and the year‐to‐year interactions between survival and fecundity affect stochastic population growth rates. We use inference, simulations and mathematical derivations to explore how environmental perturbations determine population growth rates for populations with different age‐specific demographic rates and when ages are reduced to stages. We find that stage‐ vs. age‐based models can produce markedly divergent stochastic population growth rates. The differences are most pronounced when there are survival‐fecundity‐trade‐offs, which reduce the variance in the population growth rate. Finally, the expected value and variance of the stochastic growth rates of populations with different age‐specific demographic rates can diverge to the extent that, while some populations may thrive, others will inevitably go extinct.
With no impending global controls on HFCs, the Montreal Protocol offers a near-term path to preserve its climate benefits.
The Montreal Protocol is perhaps the most successful international ...environmental treaty, responsible for global phaseout of the consumption and production of ozone-depleting substances (ODSs), e.g., chlorofluorocarbons (CFCs) and hydrochlorofluorocarbons (HCFCs). Hydrofluorocarbons (HFCs), which do not destroy stratospheric ozone, were considered long-term substitutes for ODSs and are not controlled by the Montreal Protocol. Because most HFCs are potent greenhouse gases (GHGs), they are included in the Kyoto Protocol. But climate benefits provided by this protocol are limited as they apply only to developed countries and over a short time (2008–2012). As we describe below, with no impending global controls on HFCs, inclusion of HFCs under the Montreal Protocol offers a path, starting in the short term, to preserve the climate benefits already achieved by this protocol.
An updated analysis of observed stratospheric temperature variability and trends is presented on the basis of satellite, radiosonde, and lidar observations. Satellite data include measurements from ...the series of NOAA operational instruments, including the Microwave Sounding Unit covering 1979–2007 and the Stratospheric Sounding Unit (SSU) covering 1979–2005. Radiosonde results are compared for six different data sets, incorporating a variety of homogeneity adjustments to account for changes in instrumentation and observational practices. Temperature changes in the lower stratosphere show cooling of ∼0.5 K/decade over much of the globe for 1979–2007, with some differences in detail among the different radiosonde and satellite data sets. Substantially larger cooling trends are observed in the Antarctic lower stratosphere during spring and summer, in association with development of the Antarctic ozone hole. Trends in the lower stratosphere derived from radiosonde data are also analyzed for a longer record (back to 1958); trends for the presatellite era (1958–1978) have a large range among the different homogenized data sets, implying large trend uncertainties. Trends in the middle and upper stratosphere have been derived from updated SSU data, taking into account changes in the SSU weighting functions due to observed atmospheric CO2 increases. The results show mean cooling of 0.5–1.5 K/decade during 1979–2005, with the greatest cooling in the upper stratosphere near 40–50 km. Temperature anomalies throughout the stratosphere were relatively constant during the decade 1995–2005. Long records of lidar temperature measurements at a few locations show reasonable agreement with SSU trends, although sampling uncertainties are large in the localized lidar measurements. Updated estimates of the solar cycle influence on stratospheric temperatures show a statistically significant signal in the tropics (∼30°N–S), with an amplitude (solar maximum minus solar minimum) of ∼0.5 K (lower stratosphere) to ∼1.0 K (upper stratosphere).
Genetic variation contributes to host responses and outcomes following infection by influenza A virus or other viral infections. Yet narrow windows of disease symptoms and confounding environmental ...factors have made it difficult to identify polymorphic genes that contribute to differential disease outcomes in human populations. Therefore, to control for these confounding environmental variables in a system that models the levels of genetic diversity found in outbred populations such as humans, we used incipient lines of the highly genetically diverse Collaborative Cross (CC) recombinant inbred (RI) panel (the pre-CC population) to study how genetic variation impacts influenza associated disease across a genetically diverse population. A wide range of variation in influenza disease related phenotypes including virus replication, virus-induced inflammation, and weight loss was observed. Many of the disease associated phenotypes were correlated, with viral replication and virus-induced inflammation being predictors of virus-induced weight loss. Despite these correlations, pre-CC mice with unique and novel disease phenotype combinations were observed. We also identified sets of transcripts (modules) that were correlated with aspects of disease. In order to identify how host genetic polymorphisms contribute to the observed variation in disease, we conducted quantitative trait loci (QTL) mapping. We identified several QTL contributing to specific aspects of the host response including virus-induced weight loss, titer, pulmonary edema, neutrophil recruitment to the airways, and transcriptional expression. Existing whole-genome sequence data was applied to identify high priority candidate genes within QTL regions. A key host response QTL was located at the site of the known anti-influenza Mx1 gene. We sequenced the coding regions of Mx1 in the eight CC founder strains, and identified a novel Mx1 allele that showed reduced ability to inhibit viral replication, while maintaining protection from weight loss.
Recent studies have suggested that fatty acid oxidation (FAO) is a key metabolic pathway for the growth of triple negative breast cancers (TNBCs), particularly those that have high expression of MYC. ...However, the underlying mechanism by which MYC promotes FAO remains poorly understood.
We used a combination of metabolomics, transcriptomics, bioinformatics, and microscopy to elucidate a potential mechanism by which MYC regulates FAO in TNBC.
We propose that MYC induces a multigenic program that involves changes in intracellular calcium signalling and fatty acid metabolism. We determined key roles for fatty acid transporters (CD36), lipases (LPL), and kinases (PDGFRB, CAMKK2, and AMPK) that each contribute to promoting FAO in human mammary epithelial cells that express oncogenic levels of MYC. Bioinformatic analysis further showed that this multigenic program is highly expressed and predicts poor survival in the claudin-low molecular subtype of TNBC, but not other subtypes of TNBCs, suggesting that efforts to target FAO in the clinic may best serve claudin-low TNBC patients.
We identified critical pieces of the FAO machinery that have the potential to be targeted for improved treatment of patients with TNBC, especially the claudin-low molecular subtype.
Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and ...non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAF(V600E) mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAF(V600E)-wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAF(V600E)-wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders.
We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders.
1. Ecologists have long been interested in the processes that determine patterns of species occurrence and co-occurrence. Potential short-comings of many existing empirical approaches that address ...these questions include a reliance on patterns of occurrence at a single time point, failure to account properly for imperfect detection and treating the environment as a static variable. 2. We fit detection and non-detection data collected from repeat visits using a dynamic site occupancy model that simultaneously accounts for the temporal dynamics of a focal prey species, its predators and its habitat. Our objective was to determine how disturbance and species interactions affect the co-occurrence probabilities of an endangered toad and recently introduced non-native predators in stream breeding habitats. For this, we determined statistical support for alternative processes that could affect co-occurrence frequency in the system. 3. We collected occurrence data at stream segments in two watersheds where streams were largely ephemeral and one watershed dominated by perennial streams. Co-occurrence probabilities of toads with non-native predators were related to disturbance frequency, with low co-occurrence in the ephemeral watershed and high co-occurrence in the perennial watershed. This occurred because once predators were established at a site, they were rarely lost from the site except in cases when the site dried out. Once dry sites became suitable again, toads colonized them much more rapidly than predators, creating a period of predator-free space. 4. We attribute the dynamics to a storage effect, where toads persisting outside the stream environment during periods of drought rapidly colonized sites when they become suitable again. Our results support that even in highly connected stream networks, temporal disturbance can structure frequencies with which breeding amphibians encounter non-native predators. 5. Dynamic multi-state occupancy models are a powerful tool for rigorously examining hypotheses about inter-species and species—habitat interactions. In contrast to previous methods that infer dynamic processes based on static patterns in occupancy, the approach we took allows the dynamic processes that determine species—species and species—habitat interactions to be directly estimated.
Sixteen global general circulation models were used to develop probabilistic projections of temperature (T) and precipitation (P) changes over California by the 2060s. The global models were ...downscaled with two statistical techniques and three nested dynamical regional climate models, although not all global models were downscaled with all techniques. Both monthly and daily timescale changes in T and P are addressed, the latter being important for a range of applications in energy use, water management, and agriculture. The T changes tend to agree more across downscaling techniques than the P changes. Year-to-year natural internal climate variability is roughly of similar magnitude to the projected T changes. In the monthly average, July temperatures shift enough that that the hottest July found in any simulation over the historical period becomes a modestly cool July in the future period. Januarys as cold as any found in the historical period are still found in the 2060s, but the median and maximum monthly average temperatures increase notably. Annual and seasonal P changes are small compared to interannual or intermodel variability. However, the annual change is composed of seasonally varying changes that are themselves much larger, but tend to cancel in the annual mean. Winters show modestly wetter conditions in the North of the state, while spring and autumn show less precipitation. The dynamical downscaling techniques project increasing precipitation in the Southeastern part of the state, which is influenced by the North American monsoon, a feature that is not captured by the statistical downscaling.
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