Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary

These guidelines address the diagnosis and management of atherosclerotic, aneurysmal, and thromboembolic peripheral arterial diseases (PADs). The clinical manifestations of PAD are a major cause of acute and chronic illness, are associated with decrements in functional capacity and quality of life, cause limb amputation, and increase the risk of death. Whereas the term “peripheral arterial disease” encompasses a large series of disorders that affect arterial beds exclusive of the coronary arteries, this writing committee chose to limit the scope of the work of this document to include the disorders of the abdominal aorta, renal and mesenteric arteries, and lower extremity arteries. The purposes of the full guidelines are to (a) aid in the recognition, diagnosis, and treatment of PAD of the aorta and lower extremities, addressing its prevalence, impact on quality of life, cardiovascular ischemic risk, and risk of critical limb ischemia (CLI); (b) aid in the recognition, diagnosis, and treatment of renal and visceral arterial diseases; and (c) improve the detection and treatment of abdominal and branch artery aneurysms. Clinical management guidelines for other arterial beds (e.g., the thoracic aorta, carotid and vertebral arteries, and upper-extremity arteries) have been excluded from the current guidelines to focus on the infradiaphragmatic arterial system and in recognition of the robust evidence base that exists for the aortic, visceral, and lower extremity arteries

CANDELS: The Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey - The Hubble Space Telescope Observations, Imaging Data Products and Mosaics

This paper describes the Hubble Space Telescope imaging data products and data reduction procedures for the Cosmic Assembly Near-IR Deep Extragalactic Legacy Survey (CANDELS). This survey is designed to document the evolution of galaxies and black holes at $z\sim1.5-8$, and to study Type Ia SNe beyond $z>1.5$. Five premier multi-wavelength sky regions are selected, each with extensive multiwavelength observations. The primary CANDELS data consist of imaging obtained in the Wide Field Camera 3 / infrared channel (WFC3/IR) and UVIS channel, along with the Advanced Camera for Surveys (ACS). The CANDELS/Deep survey covers \sim125 square arcminutes within GOODS-N and GOODS-S, while the remainder consists of the CANDELS/Wide survey, achieving a total of \sim800 square arcminutes across GOODS and three additional fields (EGS, COSMOS, and UDS). We summarize the observational aspects of the survey as motivated by the scientific goals and present a detailed description of the data reduction procedures and products from the survey. Our data reduction methods utilize the most up to date calibration files and image combination procedures. We have paid special attention to correcting a range of instrumental effects, including CTE degradation for ACS, removal of electronic bias-striping present in ACS data after SM4, and persistence effects and other artifacts in WFC3/IR. For each field, we release mosaics for individual epochs and eventual mosaics containing data from all epochs combined, to facilitate photometric variability studies and the deepest possible photometry. A more detailed overview of the science goals and observational design of the survey are presented in a companion paper.Comment: 39 pages, 25 figure

CANDELS: The Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey

The Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey (CANDELS) is designed to document the first third of galactic evolution, over the approximate redshift (z) range 8--1.5. It will image >250,000 distant galaxies using three separate cameras on the Hubble Space Telescope, from the mid-ultraviolet to the near-infrared, and will find and measure Type Ia supernovae at z>1.5 to test their accuracy as standardizable candles for cosmology. Five premier multi-wavelength sky regions are selected, each with extensive ancillary data. The use of five widely separated fields mitigates cosmic variance and yields statistically robust and complete samples of galaxies down to a stellar mass of 10^9 M_\odot to z \approx 2, reaching the knee of the ultraviolet luminosity function (UVLF) of galaxies to z \approx 8. The survey covers approximately 800 arcmin^2 and is divided into two parts. The CANDELS/Deep survey (5\sigma\ point-source limit H=27.7 mag) covers \sim 125 arcmin^2 within GOODS-N and GOODS-S. The CANDELS/Wide survey includes GOODS and three additional fields (EGS, COSMOS, and UDS) and covers the full area to a 5\sigma\ point-source limit of H \gtrsim 27.0 mag. Together with the Hubble Ultra Deep Fields, the strategy creates a three-tiered "wedding cake" approach that has proven efficient for extragalactic surveys. Data from the survey are nonproprietary and are useful for a wide variety of science investigations. In this paper, we describe the basic motivations for the survey, the CANDELS team science goals and the resulting observational requirements, the field selection and geometry, and the observing design. The Hubble data processing and products are described in a companion paper.Comment: Submitted to Astrophysical Journal Supplement Series; Revised version, subsequent to referee repor

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Multiresidue Analysis of Pesticides in Urine of Healthy Adult Companion Dogs

The objective of this study was to determine the background exposures to pesticides as detected in urine from 21 healthy companion dogs in Northern Colorado. A panel of 301 pesticides was used to screen urine samples collected from dogs using an established ultraperformance liquid chromatography–mass spectrometry (UPLC-MS/MS) platform. Canine food intakes were controlled for one month on diets that were also screened for pesticide contents. Fifteen distinct pesticides were detected in urine. The most frequently detected compounds in canine urine samples collected over a 1 month period were atrazine, fuberidazole, imidacloprid, terbumeton, and clopyralid. Fuberidazole was the only pesticide detected in both the diets and urine. Companion dogs develop many similar chronic diseases as humans and represent a relevant model for biomonitoring combinations of environmental pesticide exposures, as well as for evaluating the potential relationships between environmental exposures and disease risk

De Novo Synthesis of Sphingolipids Is Required for Cell Survival by Down-Regulating c-Jun N-Terminal Kinase in Drosophila Imaginal Discs

Mitogen-activated protein kinase (MAPK) is a conserved eukaryotic signaling factor that mediates various signals, cumulating in the activation of transcription factors. Extracellular signal-regulated kinase (ERK), a MAPK, is activated through phosphorylation by the kinase MAPK/ERK kinase (MEK). To elucidate the extent of the involvement of ERK in various aspects of animal development, we searched for a Drosophila mutant which responds to elevated MEK activity and herein identified a lace mutant. Mutants with mild lace alleles grow to become adults with multiple aberrant morphologies in the appendages, compound eye, and bristles. These aberrations were suppressed by elevated MEK activity. Structural and transgenic analyses of the lace cDNA have revealed that the lace gene product is a membrane protein similar to the yeast protein LCB2, a subunit of serine palmitoyltransferase (SPT), which catalyzes the first step of sphingolipid biosynthesis. In fact, SPT activity in the fly expressing epitope-tagged Lace was absorbed by epitope-specific antibody. The number of dead cells in various imaginal discs of a lace hypomorph was considerably increased, thereby ectopically activating c-Jun N-terminal kinase (JNK), another MAPK. These results account for the adult phenotypes of the lace mutant and suppression of the phenotypes by elevated MEK activity: we hypothesize that mutation of lace causes decreased de novo synthesis of sphingolipid metabolites, some of which are signaling molecules, and one or more of these changes activates JNK to elicit apoptosis. The ERK pathway may be antagonistic to the JNK pathway in the control of cell survival

FasTag: Automatic text classification of unstructured medical narratives.

Unstructured clinical narratives are continuously being recorded as part of delivery of care in electronic health records, and dedicated tagging staff spend considerable effort manually assigning clinical codes for billing purposes. Despite these efforts, however, label availability and accuracy are both suboptimal. In this retrospective study, we aimed to automate the assignment of top-level International Classification of Diseases version 9 (ICD-9) codes to clinical records from human and veterinary data stores using minimal manual labor and feature curation. Automating top-level annotations could in turn enable rapid cohort identification, especially in a veterinary setting. To this end, we trained long short-term memory (LSTM) recurrent neural networks (RNNs) on 52,722 human and 89,591 veterinary records. We investigated the accuracy of both separate-domain and combined-domain models and probed model portability. We established relevant baseline classification performances by training Decision Trees (DT) and Random Forests (RF). We also investigated whether transforming the data using MetaMap Lite, a clinical natural language processing tool, affected classification performance. We showed that the LSTM-RNNs accurately classify veterinary and human text narratives into top-level categories with an average weighted macro F1 score of 0.74 and 0.68 respectively. In the "neoplasia" category, the model trained on veterinary data had a high validation accuracy in veterinary data and moderate accuracy in human data, with F1 scores of 0.91 and 0.70 respectively. Our LSTM method scored slightly higher than that of the DT and RF models. The use of LSTM-RNN models represents a scalable structure that could prove useful in cohort identification for comparative oncology studies. Digitization of human and veterinary health information will continue to be a reality, particularly in the form of unstructured narratives. Our approach is a step forward for these two domains to learn from and inform one another