Predicting sepsis severity at first clinical presentation:The role of endotypes and mechanistic signatures

BACKGROUND: Inter-individual variability during sepsis limits appropriate triage of patients. Identifying, at first clinical presentation, gene expression signatures that predict subsequent severity will allow clinicians to identify the most at-risk groups of patients and enable appropriate antibiotic use. METHODS: Blood RNA-Seq and clinical data were collected from 348 patients in four emergency rooms (ER) and one intensive-care-unit (ICU), and 44 healthy controls. Gene expression profiles were analyzed using machine learning and data mining to identify clinically relevant gene signatures reflecting disease severity, organ dysfunction, mortality, and specific endotypes/mechanisms. FINDINGS: Gene expression signatures were obtained that predicted severity/organ dysfunction and mortality in both ER and ICU patients with accuracy/AUC of 77–80%. Network analysis revealed these signatures formed a coherent biological program, with specific but overlapping mechanisms/pathways. Given the heterogeneity of sepsis, we asked if patients could be assorted into discrete groups with distinct mechanisms (endotypes) and varying severity. Patients with early sepsis could be stratified into five distinct and novel mechanistic endotypes, named Neutrophilic-Suppressive/NPS, Inflammatory/INF, Innate-Host-Defense/IHD, Interferon/IFN, and Adaptive/ADA, each based on ∼200 unique gene expression differences, and distinct pathways/mechanisms (e.g., IL6/STAT3 in NPS). Endotypes had varying overall severity with two severe (NPS/INF) and one relatively benign (ADA) groupings, consistent with reanalysis of previous endotype studies. A 40 gene-classification tool (accuracy=96%) and several gene-pairs (accuracy=89–97%) accurately predicted endotype status in both ER and ICU validation cohorts. INTERPRETATION: The severity and endotype signatures indicate that distinct immune signatures precede the onset of severe sepsis and lethality, providing a method to triage early sepsis patients

Reconstructing Native American Population History

The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved1–5. One contentious issue is whether the settlement occurred via a single6–8 or multiple streams of migration from Siberia9–15. The pattern of dispersals within the Americas is also poorly understood. To address these questions at higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. We show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call “First American”. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan-speakers on both sides of the Panama Isthmus, who have ancestry from both North and South America

Mapping Zika virus infection using geographical information systems in Tolima, Colombia, 2015-2016 [version 1; referees: 2 approved]

Objective: Geographical information systems (GIS) have been extensively used for the development of epidemiological maps of tropical diseases, however not yet specifically for Zika virus (ZIKV) infection. Methods: Surveillance case data of the ongoing epidemics of ZIKV in the Tolima department, Colombia (2015-2016) were used to estimate cumulative incidence rates (cases/100,000 pop.) to develop the first maps in the department and its municipalities, including detail for the capital, Ibagué. The GIS software used was Kosmo Desktop 3.0RC1®. Two thematic maps were developed according to municipality and communes incidence rates. Results: Up to March 5, 2016, 4,094 cases of ZIKV were reported in Tolima, for cumulated rates of 289.9 cases/100,000 pop. (7.95% of the country). Burden of ZIKV infection has been concentrated in its east area, where municipalities have reported >500 cases/100,000 pop. These municipalities are bordered by two other departments, Cundinamarca (3,778 cases) and Huila (5,338 cases), which also have high incidences of ZIKV infection. Seven municipalities of Tolima ranged from 250-499.99 cases/100,000 pop., of this group five border with high incidence municipalities (>250), including the capital, where almost half of the reported cases of ZIKV in Tolima are concentrated. Conclusions: Use of GIS-based epidemiological maps helps to  guide decisions for the prevention and control of diseases that represent significant issues in the region and the country, but also in emerging conditions such as ZIKV

The genetics of Mexico recapitulates Native American substructure and affects biomedical traits

Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-wide variation from this region remain largely uncharacterized. We studied genomic variation within Mexico from over 1000 individuals representing 20 indigenous and 11 mestizo populations. We found striking genetic stratification among indigenous populations within Mexico at varying degrees of geographic isolation. Some groups were as differentiated as Europeans are from East Asians. Pre-Columbian genetic substructure is recapitulated in the indigenous ancestry of admixed mestizo individuals across the country. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican Americans showed a significant association between subcontinental ancestry and lung function. Thus, accounting for fine-scale ancestry patterns is critical for medical and population genetic studies within Mexico, in Mexican-descent populations, and likely in many other populations worldwide

Resolving the Inner Parsec of the Blazar J1924–2914 with the Event Horizon Telescope

The blazar J1924–2914 is a primary Event Horizon Telescope (EHT) calibrator for the Galactic center's black hole Sagittarius A*. Here we present the first total and linearly polarized intensity images of this source obtained with the unprecedented 20 μas resolution of the EHT. J1924–2914 is a very compact flat-spectrum radio source with strong optical variability and polarization. In April 2017 the source was observed quasi-simultaneously with the EHT (April 5–11), the Global Millimeter VLBI Array (April 3), and the Very Long Baseline Array (April 28), giving a novel view of the source at four observing frequencies, 230, 86, 8.7, and 2.3 GHz. These observations probe jet properties from the subparsec to 100 pc scales. We combine the multifrequency images of J1924–2914 to study the source morphology. We find that the jet exhibits a characteristic bending, with a gradual clockwise rotation of the jet projected position angle of about 90° between 2.3 and 230 GHz. Linearly polarized intensity images of J1924–2914 with the extremely fine resolution of the EHT provide evidence for ordered toroidal magnetic fields in the blazar compact core

Characterizing and mitigating intraday variability : reconstructing source structure in accreting black holes with mm-VLBI

The extraordinary physical resolution afforded by the Event Horizon Telescope has opened a window onto the astrophysical phenomena unfolding on horizon scales in two known black holes, M87* and Sgr A*. However, with this leap in resolution has come a new set of practical complications. Sgr A* exhibits intraday variability that violates the assumptions underlying Earth aperture synthesis, limiting traditional image reconstruction methods to short timescales and data sets with very sparse (u, v) coverage. We present a new set of tools to detect and mitigate this variability. We develop a data-driven, model-agnostic procedure to detect and characterize the spatial structure of intraday variability. This method is calibrated against a large set of mock data sets, producing an empirical estimator of the spatial power spectrum of the brightness fluctuations. We present a novel Bayesian noise modeling algorithm that simultaneously reconstructs an average image and statistical measure of the fluctuations about it using a parameterized form for the excess variance in the complex visibilities not otherwise explained by the statistical errors. These methods are validated using a variety of simulated data, including general relativistic magnetohydrodynamic simulations appropriate for Sgr A* and M87*. We find that the reconstructed source structure and variability are robust to changes in the underlying image model. We apply these methods to the 2017 EHT observations of M87*, finding evidence for variability across the EHT observing campaign. The variability mitigation strategies presented are widely applicable to very long baseline interferometry observations of variable sources generally, for which they provide a data-informed averaging procedure and natural characterization of inter-epoch image consistency.Academia Sinica, Academy of Finland, Agencia Nacional de Investigación, Desarrollo (ANID), Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT), Alexander von Humboldt Foundation, Alfred P. Sloan Research Fellowship, Allegro, ALMA Regional Centre, Nederlandse Onderzoekschool Voor Astronomie (NOVA), University of Amsterdam, Leiden University, Radboud University, ALMA North America Development Fund, Black Hole Initiative ,John Templeton Foundation, Gordon and Betty Moore Foundation, NASA Chandra, China Scholarship Council, Consejo Nacional de Ciencia y Tecnología, and Junta de Andalucía.https://discovery.ucl.ac.uk/id/eprint/10149240Physic

Resolving the Inner Parsec of the Blazar J1924–2914 with the Event Horizon Telescope

The blazar J1924–2914 is a primary Event Horizon Telescope (EHT) calibrator for the Galactic center's black hole Sagittarius A*. Here we present the first total and linearly polarized intensity images of this source obtained with the unprecedented 20 μas resolution of the EHT. J1924–2914 is a very compact flat-spectrum radio source with strong optical variability and polarization. In April 2017 the source was observed quasi-simultaneously with the EHT (April 5–11), the Global Millimeter VLBI Array (April 3), and the Very Long Baseline Array (April 28), giving a novel view of the source at four observing frequencies, 230, 86, 8.7, and 2.3 GHz. These observations probe jet properties from the subparsec to 100 pc scales. We combine the multifrequency images of J1924–2914 to study the source morphology. We find that the jet exhibits a characteristic bending, with a gradual clockwise rotation of the jet projected position angle of about 90° between 2.3 and 230 GHz. Linearly polarized intensity images of J1924–2914 with the extremely fine resolution of the EHT provide evidence for ordered toroidal magnetic fields in the blazar compact core