Prediction of Critical Illness During Out-of-Hospital Emergency Care

CONTEXT: Early identification of nontrauma patients in need of critical care services in the emergency setting may improve triage decisions and facilitate regionalization of critical care. OBJECTIVES: To determine the out-of-hospital clinical predictors of critical illness and to characterize the performance of a simple score for out-of-hospital prediction of development of critical illness during hospitalization. DESIGN AND SETTING: Population-based cohort study of an emergency medical services (EMS) system in greater King County, Washington (excluding metropolitan Seattle), that transports to 16 receiving facilities. PATIENTS: Nontrauma, non-cardiac arrest adult patients transported to a hospital by King County EMS from 2002 through 2006. Eligible records with complete data (N = 144,913) were linked to hospital discharge data and randomly split into development (n = 87,266 [60%]) and validation (n = 57,647 [40%]) cohorts. MAIN OUTCOME MEASURE: Development of critical illness, defined as severe sepsis, delivery of mechanical ventilation, or death during hospitalization. RESULTS: Critical illness occurred during hospitalization in 5% of the development (n = 4835) and validation (n = 3121) cohorts. Multivariable predictors of critical illness included older age, lower systolic blood pressure, abnormal respiratory rate, lower Glasgow Coma Scale score, lower pulse oximetry, and nursing home residence during out-of-hospital care (P < .01 for all). When applying a summary critical illness prediction score to the validation cohort (range, 0-8), the area under the receiver operating characteristic curve was 0.77 (95% confidence interval [CI], 0.76-0.78), with satisfactory calibration slope (1.0). Using a score threshold of 4 or higher, sensitivity was 0.22 (95% CI, 0.20-0.23), specificity was 0.98 (95% CI, 0.98-0.98), positive likelihood ratio was 9.8 (95% CI, 8.9-10.6), and negative likelihood ratio was 0.80 (95% CI, 0.79- 0.82). A threshold of 1 or greater for critical illness improved sensitivity (0.98; 95% CI, 0.97-0.98) but reduced specificity (0.17; 95% CI, 0.17-0.17). CONCLUSIONS: In a population-based cohort, the score on a prediction rule using out-of-hospital factors was significantly associated with the development of critical illness during hospitalization. This score requires external validation in an independent populationPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/85143/1/Seymour - JAMA-2010-747-54.pdf11

Discovery of a Transiting Planet Near the Snow-Line

In most theories of planet formation, the snow-line represents a boundary between the emergence of the interior rocky planets and the exterior ice giants. The wide separation of the snow-line makes the discovery of transiting worlds challenging, yet transits would allow for detailed subsequent characterization. We present the discovery of Kepler-421b, a Uranus-sized exoplanet transiting a G9/K0 dwarf once every 704.2 days in a near-circular orbit. Using public Kepler photometry, we demonstrate that the two observed transits can be uniquely attributed to the 704.2 day period. Detailed light curve analysis with BLENDER validates the planetary nature of Kepler-421b to >4 sigmas confidence. Kepler-421b receives the same insolation as a body at ~2AU in the Solar System and for a Uranian albedo would have an effective temperature of ~180K. Using a time-dependent model for the protoplanetary disk, we estimate that Kepler-421b's present semi-major axis was beyond the snow-line after ~3Myr, indicating that Kepler-421b may have formed at its observed location.Comment: 14 pages, 10 figures, 3 tables. Accepted in Ap

The Protein Storage Vacuole: A Unique Compound Organelle

doi: 10.1083/jcb.200107012Storage proteins are deposited into protein storage vacuoles (PSVs) during plant seed development and maturation and stably accumulate to high levels; subsequently, during germination the storage proteins are rapidly degraded to provide nutrients for use by the embryo. Here, we show that a PSV has within it a membrane-bound compartment containing crystals of phytic acid and proteins that are characteristic of a lytic vacuole. This compound organization, a vacuole within a vacuole whereby storage functions are separated from lytic functions, has not been described previously for organelles within the secretory pathway of eukaryotic cells. The partitioning of storage and lytic functions within the same vacuole may reflect the need to keep the functions separate during seed development and maturation and yet provide a ready source of digestive enzymes to initiate degradative processes early in germination.This work was supported by grants from the National Science Foundation (MCB-9974429), Department of Energy (DE-FG03-97ER20277), and Human Frontier Science Program (RG0018/2000) to J.C. Rogers, and from the Department of Energy (DE-FG02-91ER20055) to P.A. Rea. Y.M. Drozdowicz is an NSF/DOE/USDA Plant Training Grant fellow. L. Jiang is supported by a Direct Grant (project code 2030238) and a Special Grant for Conducting Research Abroad in the Summer of 2001 from the Chinese University of Hong Kong, and a grant from the Research Grants Council of the Hong Kong Special Administrative Region, China (project CUHK4156/ 01M)

Prehospital Systolic Blood Pressure Thresholds: A Community‐based Outcomes Study

Objectives Emergency medical services (EMS) personnel commonly use systolic blood pressure ( sBP ) to triage and treat acutely ill patients. The definition of prehospital hypotension and its associated outcomes are poorly defined. The authors sought to determine the discrimination of prehospital sBP thresholds for 30‐day mortality and to compare patient classification by best‐performing thresholds to traditional cutoffs. Methods In a community‐based cohort of adult, nontrauma, noncardiac arrest patients transported by EMS between 2002 and 2006, entries to state hospital discharge data and death certificates were linked. Prehospital sBP thresholds between 40 and 140 mm Hg in derivation ( n =  132,624) and validation ( n =  22,020) cohorts and their discrimination for 30‐day mortality, were examined. Cutoffs were evaluated using the 0/1 distance, Youden index, and adjusted Z‐statistics from multivariable logistic regression models. Results In the derivation cohort, 1,594 (1.2%) died within 24 hours, 7,404 (6%) were critically ill during hospitalization, and 6,888 (5%) died within 30 days. The area under the receiver operating characteristic (ROC) curve for sBP was 0.60 (95% confidence interval [CI] = 0.59, 0.61) for 30‐day mortality and 0.64 (95% CI = 0.62 0.66) for 24‐hour mortality. The 0/1 distance, Youden index, and adjusted Z‐statistics found best‐performing sBP thresholds between 110 and 120 mm Hg. When compared to an sBP ≤ 90 mm Hg, a cutoff of 110 mm Hg would identify 17% ( n =  137) more deaths at 30 days, while overtriaging four times as many survivors. Conclusions Prehospital sBP is a modest discriminator of clinical outcomes, yet no threshold avoids substantial misclassification of 30‐day mortality among noninjured patients. Resumen Los Umbrales de la Presión Arterial Sistólica Prehospitalaria: Un Estudio de Base Comunitaria Acerca de la Evolución de los Pacientes Objetivos El personal de los sistemas de emergencias médicas ( SEM ) usa frecuentemente la presión arterial sistólica ( PAS ) para clasificar y tratar a los pacientes agudos. Las definiciones de hipotensión prehospitalaria y sus resultados asociados están pobremente definidos. Se determinó la discriminación de los umbrales de PAS prehospitalaria para la mortalidad a los 30 días, y se comparó la clasificación del paciente por los mejores umbrales con los puntos de corte tradicionales. Metodología Estudio de cohorte de base comunitaria de pacientes adultos no traumatológicos ni con paradas cardiorrespiratorias transportados por los SEM entre 2002 y 2006, cuyas historias estaban vinculadas con los datos de alta hospitalaria y los certificados de mortalidad. Se examinaron los umbrales de PAS prehospitalaria entre 40 mm Hg y 140 mm Hg en las cohortes de derivación ( n =  132.624), y validación ( n =  22,020), y su discriminación para la mortalidad a los 30 días. Los puntos de corte se evaluaron usando la distancia 0/1, el índice de Youden y los estadísticos Z ajustados de los modelos de regresión logística multivariable. Resultados: En la cohorte de derivación, 1.594 (1,2%) fallecieron en las primeras 24 horas, 7.404 (6%) estuvieron críticamente enfermos durante el ingreso y 6.888 (5%) fallecieron en los 30 primeros días. El área bajo la curva de la ROC para PAS fue 0,60 ( IC 95% = 0,59–0,61) para la mortalidad a los 30 días y 0,64 ( IC 95% = 0,62–0,66) para la mortalidad a las 24 horas. La distancia 0/1, el índice de Youden y las estadísticas Z ajustadas hallaronque los mejores umbrales de PAS estaban entre 110 y 120 mm Hg. Cuando se comparó con una PAS ≤ 90 mm Hg, un punto de corte de 110 mm Hg identificaría un 17% ( n =  137) más de muertes a los 30 días, mientras que sobreclasificaría cuatro veces más a los supervivientes. Conclusiones La presión arterial sistólica es un discriminador modesto de resultados clínicos. No obstante, ningún umbral evita una mala clasificación de la mortalidad a los 30 días entre los pacientes no traumatológicos.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98303/1/acem12142-sup-0002-DataSupplementS2_FigS1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/98303/2/acem12142-sup-0007-DataSupplementS7_FigS4.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/98303/3/acem12142-sup-0006-DataSupplementS6_FigS3.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/98303/4/acem12142-sup-0009-DataSupplementS9_TableS3.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/98303/5/acem12142-sup-0003-DataSupplementS3.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/98303/6/acem12142-sup-0008-DataSupplementS8_TableS2.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/98303/7/acem12142-sup-0004-DataSupplementS4_TableS1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/98303/8/acem12142-sup-0001-DataSupplementS1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/98303/9/acem12142.pd

Validation of Twelve Small Kepler Transiting Planets in the Habitable Zone

We present an investigation of twelve candidate transiting planets from Kepler with orbital periods ranging from 34 to 207 days, selected from initial indications that they are small and potentially in the habitable zone (HZ) of their parent stars. Few of these objects are known. The expected Doppler signals are too small to confirm them by demonstrating that their masses are in the planetary regime. Here we verify their planetary nature by validating them statistically using the BLENDER technique, which simulates large numbers of false positives and compares the resulting light curves with the Kepler photometry. This analysis was supplemented with new follow-up observations (high-resolution optical and near-infrared spectroscopy, adaptive optics imaging, and speckle interferometry), as well as an analysis of the flux centroids. For eleven of them (KOI-0571.05, 1422.04, 1422.05, 2529.02, 3255.01, 3284.01, 4005.01, 4087.01, 4622.01, 4742.01, and 4745.01) we show that the likelihood they are true planets is far greater than that of a false positive, to a confidence level of 99.73% (3 sigma) or higher. For KOI-4427.01 the confidence level is about 99.2% (2.6 sigma). With our accurate characterization of the GKM host stars, the derived planetary radii range from 1.1 to 2.7 R_Earth. All twelve objects are confirmed to be in the HZ, and nine are small enough to be rocky. Excluding three of them that have been previously validated by others, our study doubles the number of known rocky planets in the HZ. KOI-3284.01 (Kepler-438b) and KOI-4742.01 (Kepler-442b) are the planets most similar to the Earth discovered to date when considering their size and incident flux jointly.Comment: 27 pages in emulateapj format, including tables and figures. To appear in The Astrophysical Journa

Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance

The acquisition of language and speech is uniquely human, but how genetic changes might have adapted the nervous system to this capacity is not well understood. Two human-specific amino acid substitutions in the transcription factor forkhead box P2 (FOXP2) are outstanding mechanistic candidates, as they could have been positively selected during human evolution and as FOXP2 is the sole gene to date firmly linked to speech and language development. When these two substitutions are introduced into the endogenous Foxp2 gene of mice (Foxp2[superscript hum]), cortico-basal ganglia circuits are specifically affected. Here we demonstrate marked effects of this humanization of Foxp2 on learning and striatal neuroplasticity. Foxp2[superscript hum/hum] mice learn stimulus–response associations faster than their WT littermates in situations in which declarative (i.e., place-based) and procedural (i.e., response-based) forms of learning could compete during transitions toward proceduralization of action sequences. Striatal districts known to be differently related to these two modes of learning are affected differently in the Foxp2[superscript hum/hum] mice, as judged by measures of dopamine levels, gene expression patterns, and synaptic plasticity, including an NMDA receptor-dependent form of long-term depression. These findings raise the possibility that the humanized Foxp2 phenotype reflects a different tuning of corticostriatal systems involved in declarative and procedural learning, a capacity potentially contributing to adapting the human brain for speech and language acquisition.Nancy Lurie Marks Family FoundationSimons Foundation (Autism Research Initiative Grant 137593)National Institutes of Health (U.S.) (Grant R01 MH060379)Wellcome Trust (London, England) (Grant 075491/Z/04)Wellcome Trust (London, England) (Grant 080971)Fondation pour la recherche medicaleMax Planck Society for the Advancement of Scienc

The deglacial history of 79N glacier and the Northeast Greenland Ice Stream

The Northeast Greenland Ice Stream (NEGIS) is the main artery for ice discharge from the northeast sector of the Greenland Ice Sheet (GrIS) to the North Atlantic. Understanding the past, present and future stability of the NEGIS with respect to atmospheric and oceanic forcing is of global importance as it drains around 17% of the GrIS and has a sea-level equivalent of 1.6 m. This paper reconstructs the deglacial and Holocene history of Nioghalvfjerdsbræ (or 79N Glacier); a major outlet of the NEGIS.At high elevation (>900 m asl) autochthonous blockfield, a lack of glacially moulded bedrock and pre LGM exposure ages point to a complex exposure/burial history extending back over half a million years. However, post Marine Isotope Stage 12, enhanced glacial erosion led to fjord incision and plateaux abandonment. Between 900 and 600 m asl the terrain is largely unmodified by glacial scour but post LGM erratics indicate the advection of cold-based ice through the fjord. In contrast, below ∼600 m asl Nioghalvfjerdsfjorden exhibits a geomorphological signal indicative of a warm-based ice stream operating during the last glacial cycle. Dated ice marginal landforms and terrain along the fjord walls show initial thinning rates were slow between ∼23 and 10 ka, but post-10 ka it is evident that Nioghalvfjerdsfjorden deglaciated extremely quickly with complete fjord deglaciation below ∼500 m asl between 10.0 and 8.5 ka.Both increasing air and ocean temperatures were pivotal in driving surface lowering and submarine melt during deglaciation, but the final withdrawal of ice through Nioghalvfjerdsfjorden was facilitated by the action of marine ice sheet instability. Our estimates show that thinning and retreat rates reached a maximum of 5.29 ma−1 and 613 ma−1, respectively, as the ice margin withdrew westwards. This would place the Early Holocene disintegration of this outlet of the NEGIS at the upper bounds of contemporary thinning and retreat rates seen both in Greenland and Antarctica. Combined with recent evidence of ice stream shutdown during the Holocene, as well as predictions of changing ice flow dynamics within downstream sections of the NEGIS catchment, this suggests that significant re-organisation of the terminal zone of the ice stream is imminent over the next century

The deglacial history of 79N glacier and the Northeast Greenland Ice Stream

Acknowledgements This work was funded by NERC Standard Grant NE/N011228/1. We thank the Alfred Wegner Institute, and particularly Hicham Rafiq and Daniel Steinhage, for their significant logistic support through the iGRIFF project. Additional support was provided from Station Nord (Jørgen Skafte), Nordland Air, Air Greenland, the Joint Arctic Command and the Department of Geography, Durham University. Naalakkersuisut, Government of Greenland, provided Scientific Survey (VU-00121) and Export (046/2017) licences for this work. We would also like to thank our Field Ranger Isak (Nanu-Travel) and dog Ooni for keeping us safe in the field. TCN Sample preparation was carried out at the National Environmental Isotope Facility, Scottish Universities Environmental Research Centre under grant allocation 9185.0814. Chris Orton in the Cartographic Unit, Geography, Durham University edited several figures. This paper is dedicated to Mr Arnold Jones – a true Quaternarist.Peer reviewe

Comparing Breast Cancer Multiparameter Tests in the OPTIMA Prelim Trial: No Test Is More Equal Than the Others

Background: Previous reports identifying discordance between multiparameter tests at the individual patient level have been largely attributed to methodological shortcomings of multiple in silico studies. Comparisons between tests, when performed using actual diagnostic assays, have been predicted to demonstrate high degrees of concordance. OPTIMA prelim compared predicted risk stratification and subtype classification of different multiparameter tests performed directly on the same population. Methods: Three hundred thirteen women with early breast cancer were randomized to standard (chemotherapy and endocrine therapy) or test-directed (chemotherapy if Oncotype DX recurrence score &gt;25) treatment. Risk stratification was also determined with Prosigna (PAM50), MammaPrint, MammaTyper, NexCourse Breast (IHC4-AQUA), and conventional IHC4 (IHC4). Subtype classification was provided by Blueprint, MammaTyper, and Prosigna. Results: Oncotype DX predicted a higher proportion of tumors as low risk (82.1%, 95% confidence interval [CI] = 77.8% to 86.4%) than were predicted low/intermediate risk using Prosigna (65.5%, 95% CI = 60.1% to 70.9%), IHC4 (72.0%, 95% CI = 66.5% to 77.5%), MammaPrint (61.4%, 95% CI = 55.9% to 66.9%), or NexCourse Breast (61.6%, 95% CI = 55.8% to 67.4%). Strikingly, the five tests showed only modest agreement when dichotomizing results between high vs low/intermediate risk. Only 119 (39.4%) tumors were classified uniformly as either low/intermediate risk or high risk, and 183 (60.6%) were assigned to different risk categories by different tests, although 94 (31.1%) showed agreement between four of five tests. All three subtype tests assigned 59.5% to 62.4% of tumors to luminal A subtype, but only 121 (40.1%) were classified as luminal A by all three tests and only 58 (19.2%) were uniformly assigned as nonluminal A. Discordant subtyping was observed in 123 (40.7%) tumors. Conclusions: Existing evidence on the comparative prognostic information provided by different tests suggests that current multiparameter tests provide broadly equivalent risk information for the population of women with estrogen receptor (ER)–positive breast cancers. However, for the individual patient, tests may provide differing risk categorization and subtype information