A Bayesian decision support sequential model for severity of illness predictors and intensive care admissions in pneumonia.

BACKGROUND: Community-acquired pneumonia (CAP) is one of the leading causes of morbidity and mortality in the USA. Our objective was to assess the predictive value on critical illness and disposition of a sequential Bayesian Model that integrates Lactate and procalcitonin (PCT) for pneumonia. METHODS: Sensitivity and specificity of lactate and PCT attained from pooled meta-analysis data. Likelihood ratios calculated and inserted in Bayesian/ Fagan nomogram to calculate posttest probabilities. Bayesian Diagnostic Gains (BDG) were analyzed comparing pre and post-test probability. To assess the value of integrating both PCT and Lactate in Severity of Illness Prediction we built a model that combined CURB65 with PCT as the Pre-Test markers and later integrated the Lactate Likelihood Ratio Values to generate a combined CURB 65 + Procalcitonin + Lactate Sequential value. RESULTS: The BDG model integrated a CUBR65 Scores combined with Procalcitonin (LR+ and LR-) for Pre-Test Probability Intermediate and High with Lactate Positive Likelihood Ratios. This generated for the PCT LR+ Post-test Probability (POSITIVE TEST) Posterior probability: 93% (95% CI [91,96%]) and Post Test Probability (NEGATIVE TEST) of: 17% (95% CI [15-20%]) for the Intermediate subgroup and 97% for the high risk sub-group POSITIVE TEST: Post-Test probability:97% (95% CI [95,98%]) NEGATIVE TEST: Post-test probability: 33% (95% CI [31,36%]) . ANOVA analysis for CURB 65 (alone) vs CURB 65 and PCT (LR+) vs CURB 65 and PCT (LR+) and Lactate showed a statistically significant difference (P value = 0.013). CONCLUSIONS: The sequential combination of CURB 65 plus PCT with Lactate yielded statistically significant results, demonstrating a greater predictive value for severity of illness thus ICU level care

Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.

The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation

Apoptosis induction in Jurkat cells and sCD95 levels in women's sera are related with the risk of developing cervical cancer

<p>Abstract</p> <p>Background</p> <p>Currently, there is clear evidence that apoptosis plays an important role in the development and progression of tumors. One of the best characterized apoptosis triggering systems is the CD95/Fas/APO-1 pathway; previous reports have demonstrated high levels of soluble CD95 (sCD95) in serum of patients with some types of cancer. Cervical cancer is the second most common cancer among women worldwide. As a first step in an attempt to design a minimally invasive test to predict the risk of developing cervical cancer in patients with precancerous lesions, we used a simple assay based on the capacity of human serum to induce apoptosis in Jurkat cells. We evaluated the relationship between sCD95 levels and the ability to induce apoptosis in Jurkat cells in cervical cancer patients and controls.</p> <p>Methods</p> <p>Jurkat cells were exposed to serum from 63 women (20 healthy volunteers, 21 with cervical intraepithelial neoplasia grade I [CIN 1] and 22 with cervical-uterine carcinoma). The apoptotic rate was measured by flow cytometry using Annexin-V-Fluos and Propidium Iodide as markers. Serum levels of sCD95 and soluble CD95 ligand (sCD95L) were measured by ELISA kits.</p> <p>Results</p> <p>We found that serum from almost all healthy women induced apoptosis in Jurkat cells, while only fifty percent of the sera from women with CIN 1 induced cell death in Jurkat cells. Interestingly, only one serum sample from a patient with cervical-uterine cancer was able to induce apoptosis, the rest of the sera protected Jurkat cells from this killing. We were able to demonstrate that elimination of Jurkat cells was mediated by the CD95/Fas/Apo-1 apoptotic pathway. Furthermore, the serum levels of sCD95 measured by ELISA were significantly higher in women with cervical cancer.</p> <p>Conclusion</p> <p>Our results demonstrate that there is a strong correlation between low levels of sCD95 in serum of normal women and higher apoptosis induction in Jurkat cells. We suggest that an analysis of the apoptotic rate induced by serum in Jurkat cells and the levels of sCD95 in serum could be helpful during the prognosis and treatment of women detected with precancerous lesions or cervical cancer.</p

JWST's PEARLS: TN J1338-1942 -- I. Extreme jet triggered star-formation in a z=4.11 luminous radio galaxy

We present the first JWST observations of the z = 4.11 luminous radio galaxy TN J1338–1942, obtained as part of the ‘Prime Extragalactic Areas for Reionization and Lensing Science’ (‘PEARLS’) project. Our NIRCam observations, designed to probe the key rest-frame optical continuum and emission line features at this redshift, enable resolved spectral energy distribution modelling that incorporates both a range of stellar population assumptions and radiative shock models. With an estimated stellar mass of log10(M/M) ∼ 10.9, TN J1338–1942 is confirmed to be one of the most massive galaxies known at this epoch. Our observations also reveal extremely high equivalent-width nebular emission coincident with the luminous AGN jets that is best fit by radiative shocks surrounded by extensive recent star formation. We estimate the total star-formation rate (SFR) could be as high as ∼ 1600 M yr−1 , with the SFR that we attribute to the jet induced burst conservatively 500 M yr−1. The mass-weighted age of the star-formation, tmass < 4 Myr, is consistent with the likely age of the jets responsible for the triggered activity and significantly younger than that measured in the core of the host galaxy. The extreme scale of the potential jet-triggered star-formation activity indicates the potential importance of positive AGN feedback in the earliest stages of massive galaxy formation, with our observations also illustrating the extraordinary prospects for detailed studies of high-redshift galaxies with JWST.KJD acknowledges funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement number 892117 (HIZRAD) and support from the STFC through an Ernest Rutherford Fellowship (grant number ST/W003120/1). RAW, SHC, and RAJ acknowledge support from NASA JWST Interdisciplinary Scientist grants NAG5-12460, NNX14AN10G, and 80NSSC18K0200 from GSFC. Work by CJC acknowledges support from the European Research Council (ERC) Advanced Investigator Grant EPOCHS (788113). BLF thanks the Berkeley Center for Theoretical Physics for their hospitality during the writing of this paper. MAM acknowledges the support of a National Research Council of Canada Plaskett Fellowship, and the Australian Research Council center of Excellence for All Sky Astrophysics in 3 Dimensions (ASTRO 3D), through project number CE17010001. CNAW acknowledges funding from the JWST/NIRCam contract NASS-0215 to the University of Arizona. TAH is supported by an appointment to the NASA Postdoctoral Program (NPP) at NASA Goddard Space Flight Center, administered by Oak Ridge Associated Universities under contract with NASA.Peer reviewe

Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2

Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty&nbsp;years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating

Antiviral mode of action of bovine dialyzable leukocyte extract against human immunodeficiency virus type 1 infection

<p>Abstract</p> <p>Background</p> <p>Bovine dialyzable leukocyte extract (bDLE) is derived from immune leukocytes obtained from bovine spleen. DLE has demonstrated to reduce transcription of Human Immunodeficiency Virus Type 1 (HIV-1) and inactivate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. Therefore, we decided to clarify the mode of antiviral action of bDLE on the inhibition of HIV-1 infection through a panel of antiviral assays.</p> <p>Results</p> <p>The cytotoxicity, HIV-1 inhibition activity, residual infectivity of bDLE in HIV-1, time of addition experiments, fusion inhibition of bDLE for fusogenic cells and the duration of cell protection even after the removal of bDLE were all assessed in order to discover more about the mode of the antiviral action.</p> <p>HIV-1 infectivity was inhibited by bDLE at doses that were not cytotoxic for HeLa-CD4-LTR-β-gal cells. Pretreatment of HIV-1 with bDLE did not decrease the infectivity of these viral particles. Cell-based fusion assays helped to determine if bDLE could inhibit fusion of Env cells against CD4 cells by membrane fusion and this cell-based fusion was inhibited only when CD4 cells were treated with bDLE. Infection was inhibited in 80% compared with the positive (without EDL) at all viral life cycle stages in the time of addition experiments when bDLE was added at different time points. Finally, a cell-protection assay against HIV-1 infection by bDLE was performed after treating host cells with bDLE for 30 minutes and then removing them from treatment. From 0 to 7 hours after the bDLE was completely removed from the extracellular compartment, HIV-1 was then added to the host cells. The bDLE was found to protect the cells from HIV-1 infection, an effect that was retained for several hours.</p> <p>Conclusions</p> <p>bDLE acted as an antiviral compound and prevented host cell infection by HIV-1 at all viral life cycle stages. These cell protection effects lingered for hours after the bDLE was removed. Interestingly, bDLE inhibited fusion of fusogenic cells by acting only on CD4 cells. bDLE had no virucidal effect, but could retain its antiviral effect on target cells after it was removed from the extracellular compartment, protecting the cells from infection for hours.</p> <p>bDLE, which has no reported side effects or toxicity in clinical trials, should therefore be further studied to determine its potential use as a therapeutic agent in HIV-1 infection therapy, in combination with known antiretrovirals.</p

A matrix approach to tropical marine ecosystem service assessments in South east Asia

Ecosystem service assessments are increasingly used to support natural resource management, but there is a bias in their application towards terrestrial systems and higher income countries. Tropical marine applications are particularly scarce, especially in SE Asia. Given the growing coastal population and expansion in blue economy sectors in SE Asia, evidence to support effective marine planning, such as ecosystem service assessments, is urgently needed. Data deficiencies for marine systems, especially (but not only) in lower income countries is a significant obstacle for ecosystem service assessments. To overcome this, we develop an ecosystem service potential matrix which combines evidence taken from an extensive literature review together with expert opinion. The matrix includes both natural and modified habitats as the service providing units. The ecosystem service potential for habitats are scored at the macro level (e.g. mangrove) due to insufficient evidence to score micro-habitats (e.g. fringe, basin or riverine mangroves). The majority of evidence is available for biogenic habitats (mangroves, coral reefs and seagrass meadows) with comparatively little for sedimentary habitats. While provisioning, regulating and cultural services are scored, published evidence is more readily available for provisioning and regulating services. Confidence scores, indicating the uncertainty in the ecosystem service potential scores are included in the matrix. To our knowledge this is the first attempt to systematically capture the provision of ecosystem services from tropical marine habitats. Although initially developed for four marine biosphere reserves and protected areas in SE Asia, the generic nature of the evidence included suggests that the matrix constitutes a valuable baseline for marine ecosystem service assessments within SE Asia and provides a robust foundation for development in future work

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

TNOs are cool: a survey of the transneptunian region

Over one thousand objects have so far been discovered orbiting beyond Neptune. These trans-Neptunian objects (TNOs) represent the primitive remnants of the planetesimal disk from which the planets formed and are perhaps analogous to the unseen dust parent-bodies in debris disks observed around other main-sequence stars. The dynamical and physical properties of these bodies provide unique and important constraints on formation and evolution models of the Solar System. While the dynamical architecture in this region (also known as the Kuiper Belt) is becoming relatively clear, the physical properties of the objects are still largely unexplored. In particular, fundamental parameters such as size, albedo, density and thermal properties are difficult to measure. Measurements of thermal emission, which peaks at far-IR wavelengths, offer the best means available to determine the physical properties. While Spitzer has provided some results, notably revealing a large albedo diversity in this population, the increased sensitivity of Herschel and its superior wavelength coverage should permit profound advances in the field. Within our accepted project we propose to perform radiometric measurements of 139 objects, including 25 known multiple systems. When combined with measurements of the dust population beyond Neptune (e.g. from the New Horizons mission to Pluto), our results will provide a benchmark for understanding the Solar debris disk, and extra-solar ones as well