Hematopoietic Lineage Transcriptome Stability and Representation in PAXgene™ Collected Peripheral Blood Utilising SPIA Single-Stranded cDNA Probes for Microarray

Peripheral blood as a surrogate tissue for transcriptome profiling holds great promise for the discovery of diagnostic and prognostic disease biomarkers, particularly when target tissues of disease are not readily available. To maximize the reliability of gene expression data generated from clinical blood samples, both the sample collection and the microarray probe generation methods should be optimized to provide stabilized, reproducible and representative gene expression profiles faithfully representing the transcriptional profiles of the constituent blood cell types present in the circulation. Given the increasing innovation in this field in recent years, we investigated a combination of methodological advances in both RNA stabilisation and microarray probe generation with the goal of achieving robust, reliable and representative transcriptional profiles from whole blood. To assess the whole blood profiles, the transcriptomes of purified blood cell types were measured and compared with the global transcriptomes measured in whole blood. The results demonstrate that a combination of PAXgene™ RNA stabilising technology and single-stranded cDNA probe generation afforded by the NuGEN Ovation RNA amplification system V2™ enables an approach that yields faithful representation of specific hematopoietic cell lineage transcriptomes in whole blood without the necessity for prior sample fractionation, cell enrichment or globin reduction. Storage stability assessments of the PAXgene™ blood samples also advocate a short, fixed room temperature storage time for all PAXgene™ blood samples collected for the purposes of global transcriptional profiling in clinical studies

Reply to Ellis et al.: human niche construction and evolutionary theory

We are pleased Ellis et al. found value in our recent synthesis of the deep history of human impacts on global ecosystems and agree that our paper should influence the current debate on if and how an Anthropocene epoch is defined. We also agree that the ecological consequences of human niche construction have profound and growing effects on the evolutionary trajectories of humans and other species living within human-altered ecosystems. Niche construction theory (NCT) provides an explicit framework for linking evolutionary and ecological processes into a coherent theory of biological evolution. Of special appeal to us as archaeologists is that NCT bridges biological and cultural evolution by including human culture and social learning within the mechanisms of evolutionary change, allowing scientists to address issues at the interface of human and natural systems. Some of us have contributed significantly to human NCT, addressing some of the very issues raised by Ellis et al. Finally, we agree that human transformations of ecosystems are inherently social processes—clearly humans are intensely social organisms—and that such processes result from long-term melding of biological and cultural evolution

Reply to Westaway and Lyman: emus, dingoes, and archaeology’s role in conservation biology

In a curious comment on our PNAS Perspective, Westaway and Lyman offer two Australian zooarchaeological case studies—one involving eggshells and the other dingoes—that they argue undercut one of our main points: that archaeological data and deep time perspectives have much to offer conservation biology. Neither example provides a specific substantive critique of our perspective: there are no dingoes in our article, no eggshells, and we mention the long and rich record of human management and alteration of Australian environments only briefly. Nor do we suggest that all archaeological assemblages can effectively inform current conservation biology efforts. Such datasets obviously vary in their quality and potential applicability to modern situations. When considered more closely, both of Westaway and Lyman’s case studies underscore rather than undercut the importance of archaeological and paleoecological data in conservation biology initiatives

Guidance for the treatment of deep vein thrombosis and pulmonary embolism

This guidance document focuses on the diagnosis and treatment of venous thromboembolism (VTE). Efficient, cost effective diagnosis of VTE is facilitated by combining medical history and physical examination with pre-test probability models, D dimer testing and selective use of confirmatory imaging. Clinical prediction rules, biomarkers and imaging can be used to tailor therapy to disease severity. Anticoagulation options for acute VTE include unfractionated heparin, low molecular weight heparin, fondaparinux and the direct oral anticoagulants (DOACs). DOACs are as effective as conventional therapy with LMWH and vitamin K antagonists. Thrombolytic therapy is reserved for massive pulmonary embolism (PE) or extensive deep vein thrombosis (DVT). Inferior vena cava filters are reserved for patients with acute VTE and contraindications to anticoagulation. Retrievable filters are strongly preferred. The possibility of thoracic outlet syndrome and May-Thurner syndrome should be considered in patients with subclavian/axillary and left common iliac vein DVT, respectively in absence of identifiable triggers. The optimal duration of therapy is dictated by the presence of modifiable thrombotic risk factors. Long term anticoagulation should be considered in patients with unprovoked VTE as well as persistent prothrombotic risk factors such as cancer. Short-term therapy is sufficient for most patients with VTE associated with transient situational triggers such as major surgery. Biomarkers such as D dimer and risk assessment models such the Vienna risk prediction model offer the potential to customize VTE therapy for the individual patient. Insufficient data exist to support the integration of bleeding risk models into duration of therapy planning

A FUSE Survey of Interstellar Molecular Hydrogen in the Small and Large Magellanic Clouds

We describe a moderate-resolution FUSE survey of H2 along 70 sight lines to the Small and Large Magellanic Clouds, using hot stars as background sources. FUSE spectra of 67% of observed Magellanic Cloud sources (52% of LMC and 92% of SMC) exhibit absorption lines from the H2 Lyman and Werner bands between 912 and 1120 A. Our survey is sensitive to N(H2) >= 10^14 cm^-2; the highest column densities are log N(H2) = 19.9 in the LMC and 20.6 in the SMC. We find reduced H2 abundances in the Magellanic Clouds relative to the Milky Way, with average molecular fractions = 0.010 (+0.005, -0.002) for the SMC and = 0.012 (+0.006, -0.003) for the LMC, compared with = 0.095 for the Galactic disk over a similar range of reddening. The dominant uncertainty in this measurement results from the systematic differences between 21 cm radio emission and Lya in pencil-beam sight lines as measures of N(HI). These results imply that the diffuse H2 masses of the LMC and SMC are 8 x 10^6 Msun and 2 x 10^6 Msun, respectively, 2% and 0.5% of the H I masses derived from 21 cm emission measurements. The LMC and SMC abundance patterns can be reproduced in ensembles of model clouds with a reduced H2 formation rate coefficient, R ~ 3 x 10^-18 cm^3 s^-1, and incident radiation fields ranging from 10 - 100 times the Galactic mean value. We find that these high-radiation, low-formation-rate models can also explain the enhanced N(4)/N(2) and N(5)/N(3) rotational excitation ratios in the Clouds. We use H2 column densities in low rotational states (J = 0 and 1) to derive a mean kinetic and/or rotational temperature = 82 +/- 21 K for clouds with N(H2) >= 10^16 cm^-2, similar to Galactic gas. We discuss the implications of this work for theories of star formation in low-metallicity environments. [Abstract abridged]Comment: 30 pages emulateapj, 14 figures (7 color), 7 tables, accepted for publication in the Astrophysical Journal, figures 11 and 12 compressed at slight loss of quality, see http://casa.colorado.edu/~tumlinso/h2/ for full version

Long term health care use and costs in patients with stable coronary artery disease : a population based cohort using linked electronic health records (CALIBER)

Aims To examine long term health care utilisation and costs of patients with stable coronary artery disease (SCAD). Methods and results Linked cohort study of 94,966 patients with SCAD in England, 1st January 2001 to 31st March 2010, identified from primary care, secondary care, disease and death registries. Resource use and costs, and cost predictors by time and 5-year cardiovascular (CVD) risk profile were estimated using generalised linear models. Coronary heart disease hospitalisations were 20.5% in the first year and 66% in the year following a non-fatal (myocardial infarction, ischaemic or haemorrhagic stroke) event. Mean health care costs were £3,133 per patient in the first year and £10,377 in the year following a non-fatal event. First year predictors of cost included sex (mean cost £549 lower in females); SCAD diagnosis (NSTEMI cost £656 more than stable angina); and co-morbidities (heart failure cost £657 more per patient). Compared with lower risk patients (5-year CVD risk 3.5%), those of higher risk (5-year CVD risk 44.2%) had higher 5-year costs (£23,393 vs. £9,335) and lower lifetime costs (£43,020 vs. £116,888). Conclusion Patients with SCAD incur substantial health care utilisation and costs, which varies and may be predicted by 5-year CVD risk profile. Higher risk patients have higher initial but lower lifetime costs than lower risk patients as a result of shorter life expectancy. Improved cardiovascular survivorship among an ageing CVD population is likely to require stratified care in anticipation of the burgeoning demand

Thermal stability of heterotrimeric pMHC proteins as determined by circular dichroism spectroscopy

T cell receptor (TCR) recognition of foreign peptide fragments, presented by peptide major histocompatibility complex (pMHC), governs T-cell mediated protection against pathogens and cancer. Many factors govern T-cell sensitivity, including the affinity of the TCR-pMHC interaction and the stability of pMHC on the surface of antigen presenting cells. These factors are particularly relevant for the peptide vaccination field, in which more stable pMHC interactions could enable more effective protection against disease. Here, we discuss a method for the determination of pMHC stability that we have used to investigate HIV immune escape, T-cell sensitivity to cancer antigens and mechanisms leading to autoimmunity

Massive stars in the giant molecular cloud G23.3−0.3 and W41

Context. Young massive stars and stellar clusters continuously form in the Galactic disk, generating new Hii regions within their natal giant molecular clouds and subsequently enriching the interstellar medium via their winds and supernovae.Aims. Massive stars are among the brightest infrared stars in such regions; their identification permits the characterisation of the star formation history of the associated cloud as well as constraining the location of stellar aggregates and hence their occurrence as a function of global environment.Methods. We present a stellar spectroscopic survey in the direction of the giant molecular cloud G23.3−0.3. This complex is located at a distance of ~4–5 kpc, and consists of several Hii regions and supernova remnants.Results. We discovered 11 OfK+ stars, one candidate luminous blue variable, several OB stars, and candidate red supergiants. Stars with K-band extinction from ~1.3–1.9 mag appear to be associated with the GMC G23.3−0.3; O and B-types satisfying this criterion have spectrophotometric distances consistent with that of the giant molecular cloud. Combining near-IR spectroscopic and photometric data allowed us to characterize the multiple sites of star formation within it. The O-type stars have masses from ~25–45 M⊙, and ages of 5–8 Myr. Two new red supergiants were detected with interstellar extinction typical of the cloud; along with the two RSGs within the cluster GLIMPSE9, they trace an older burst with an age of 20–30 Myr. Massive stars were also detected in the core of three supernova remnants – W41, G22.7−0.2, and G22.7583−0.4917.Conclusions. A large population of massive stars appears associated with the GMC G23.3−0.3, with the properties inferred for them indicative of an extended history of stars formation