Non-antibiotic pharmaceuticals are toxic against <i>Escherichia coli</i> with no evolution of cross-resistance to antibiotics

Antimicrobial resistance can arise in the natural environment via prolonged exposure to the effluent released by manufacturing facilities. In addition to antibiotics, pharmaceutical plants also produce non-antibiotic pharmaceuticals, both the active ingredients and other components of the formulations. The effect of these on the surrounding microbial communities is less clear. We aimed to assess whether non-antibiotic pharmaceuticals and other compounds produced by pharmaceutical plants have inherent toxicity, and whether long-term exposure might result in significant genetic changes or select for cross-resistance to antibiotics. To this end, we screened four non-antibiotic pharmaceuticals (acetaminophen, ibuprofen, propranolol, metformin) and titanium dioxide for toxicity against Escherichia coli K-12 MG1655 and conducted a 30 day selection experiment to assess the effect of long-term exposure. All compounds reduced the maximum optical density reached by E. coli at a range of concentrations including one of environmental relevance, with transcriptome analysis identifying upregulated genes related to stress response and multidrug efflux in response ibuprofen treatment. The compounds did not select for significant genetic changes following a 30 day exposure, and no evidence of selection for cross-resistance to antibiotics was observed for population evolved in the presence of ibuprofen in spite of the differential gene expression after exposure to this compound. This work suggests that these compounds, at environmental concentrations, do not select for cross-resistance to antibiotics in E. coli

Mode of birth and risk of infection-related hospitalisation in childhood: A population cohort study of 7.17 million births from 4 high-income countries

BACKGROUND: The proportion of births via cesarean section (CS) varies worldwide and in many countries exceeds WHO-recommended rates. Long-term health outcomes for children born by CS are poorly understood, but limited data suggest that CS is associated with increased infection-related hospitalisation. We investigated the relationship between mode of birth and childhood infection-related hospitalisation in high-income countries with varying CS rates. METHODS AND FINDINGS: We conducted a multicountry population-based cohort study of all recorded singleton live births from January 1, 1996 to December 31, 2015 using record-linked birth and hospitalisation data from Denmark, Scotland, England, and Australia (New South Wales and Western Australia). Birth years within the date range varied by site, but data were available from at least 2001 to 2010 for each site. Mode of birth was categorised as vaginal or CS (emergency/elective). Infection-related hospitalisations (overall and by clinical type) occurring after the birth-related discharge date were identified in children until 5 years of age by primary/secondary International Classification of Diseases, 10th Revision (ICD-10) diagnosis codes. Analysis used Cox regression models, adjusting for maternal factors, birth parameters, and socioeconomic status, with results pooled using meta-analysis. In total, 7,174,787 live recorded births were included. Of these, 1,681,966 (23%, range by jurisdiction 17%-29%) were by CS, of which 727,755 (43%, range 38%-57%) were elective. A total of 1,502,537 offspring (21%) had at least 1 infection-related hospitalisation. Compared to vaginally born children, risk of infection was greater among CS-born children (hazard ratio (HR) from random effects model, HR 1.10, 95% confidence interval (CI) 1.09-1.12, p < 0.001). The risk was higher following both elective (HR 1.13, 95% CI 1.12-1.13, p < 0.001) and emergency CS (HR 1.09, 95% CI 1.06-1.12, p < 0.001). Increased risks persisted to 5 years and were highest for respiratory, gastrointestinal, and viral infections. Findings were comparable in prespecified subanalyses of children born to mothers at low obstetric risk and unchanged in sensitivity analyses. Limitations include site-specific and longitudinal variations in clinical practice and in the definition and availability of some data. Data on postnatal factors were not available. CONCLUSIONS: In this study, we observed a consistent association between birth by CS and infection-related hospitalisation in early childhood. Notwithstanding the limitations of observational data, the associations may reflect differences in early microbial exposure by mode of birth, which should be investigated by mechanistic studies. If our findings are confirmed, they could inform efforts to reduce elective CS rates that are not clinically indicated

The effectiveness and cost effectiveness of a hospital avoidance program in a residential aged care facility: a prospective cohort study and modelled decision analysis

Background Residential aged care facility residents experience high rates of hospital admissions which are stressful, costly and often preventable. The EDDIE program is a hospital avoidance initiative designed to enable nursing and care staff to detect, refer and quickly respond to early signals of a deteriorating resident. The program was implemented in a 96-bed residential aged care facility in regional Australia. Methods A prospective pre-post cohort study design was used to collect data on costs of program delivery, hospital admission rates and length of stay for the 12months prior to, and following, the intervention. A Markov decision model was developed to synthesize study data with published literature in order to estimate the costeffectiveness of the program. Quality adjusted life years (QALYs) were adopted as the measure of effectiveness. Results The EDDIE program was associated with a 19% reduction in annual hospital admissions and a 31% reduction in the average length of stay. The cost-effectiveness analysis found the program to be both more effective and less costly than usual care, with 0.06 QALYs gained and $249,000 health system costs saved in a modelled cohort of 96 residents. A probabilistic sensitivity analysis estimated that there was an 86% probability that the program was cost-effective after taking the uncertainty of the model inputs into account. Conclusions This study provides promising evidence for the effectiveness and cost-effectiveness of a nurse led, early intervention program in preventing unnecessary hospital admissions within a residential aged care facility. Further research in multi-site randomised studies is needed to confirm the generalisability of these results

Open science in archaeology

No abstract available

Symmetric dimethylarginine (SDMA) is a stronger predictor of mortality risk than asymmetric dimethylarginine (ADMA) amongst older people with kidney disease

Background Circulating asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are increased in patients with kidney disease. SDMA is considered a good marker of glomerular filtration rate (GFR) whilst ADMA is a marker of cardiovascular risk. However, a link between SDMA and all-cause mortality has been reported. In the present study we evaluated both dimethylarginines as risk and GFR markers in a cohort of elderly white individuals, both with and without CKD. Methods GFR was measured in 394 individuals aged >74 years using an iohexol clearance method. Plasma ADMA, SDMA and iohexol were measured simultaneously using isotope dilution tandem mass spectrometry. Results Plasma ADMA concentrations were increased (P60 mL/min/1.73 m², but did not differ (P>0.05) between those with GFR 30-59 mL/min/1.73 m² and <30 mL/min/1.73 m². Plasma SDMA increased consistently across declining GFR categories (P<0.0001). GFR had an independent effect on plasma ADMA concentration whilst GFR, gender, body mass index and haemoglobin had independent effects on plasma SDMA concentration. Participants were followed for a median of 33 months. There were 65 deaths. High plasma ADMA (P=0.0412) and SDMA (P<0.0001) concentrations were independently associated with reduced survival. Conclusions Amongst elderly white individuals with a range of kidney function, SDMA was a better marker of GFR and a stronger predictor of outcome than ADMA. Future studies should further evaluate the role of SDMA as a marker of outcome and assess its potential value as a marker of GFR

A Review of Discourse Analysis in Literacy Research: Equitable Access

This review represents research employing discourse analysis conducted by scholars interested in literacy issues in education across the age span—preschool to adult—during the last 10 years. Drawing from more than 300 studies, we discerned that a common theme was understanding how the literacy education of all students can be successfully accomplished. We organized the review into two complementary sections. The first section highlights discourse analytic approaches taken to investigate: Whose literacies count? Which literacies count? The second section explains the contributions the studies made organized according to five questions: What are literate identities, how are they constructed, and by whom? How are disciplinary knowledges, discourses, and identities constructed? How can schools provide students with access to school‐based literacies? What are the shifting roles of literacy teachers and learners within and outside of school? How does discourse analysis research address movement within and across literacy sites and practices in a contemporary, globalized, and increasingly digitally influenced world? تلخيص البحث: تمثل هذه المراجعة الأبحاث التي يوجد فيها تحليل الخطاب الذي قام به الباحثون المهتمون بشؤون تعلم القراءة والكتابة في التعليم عبر الأعمار—من الروضة حتى بالغ سن الرشد—في السنوات العشرة الماضية. لقد حددنا موضوعاً مشتركاً من استجماع أكثر من 300 دراسة وهو الطريقة التي قد يتم فيها تعليم القراءة والكتابة لجميع الطلاب بالنجاح. وقد نظمنا المراجعة في قسمين متكاملين الأول يسلط الضوء على طرق الخطاب التحليلية المأخوذة للتحقيق في: لمن معارف القراءة والكتابة التي نحتاج إلى أخذها بعين الاعتبار؟ وأية معارف من هذه يجب الأخذ في الحسبان؟ والقسم الثاني يشرح مساهمات الدراسات المندرجة تحت الأصناف المبنية على خمسة أسئلة: ما هي هويات معرفة القراءة والكتابة وكيف يتم تشكيلها ومن يشكلها؟ وكيف يتم تشكيل المعارف الدراسية والخطابية والهوية؟ وكيف تستطيع المدارس أن توفر الطلاب بوسيلة للمعارف القائمة في المدرسة؟ ما هي الأدوار المتغيرة لمعلمي القراءة والكتابة وطلابهم داخل المدرسة وخارجها؟ وكيف يعالج التحليل الخطابي الحركات في مواقع القراءة والكتابة وعبرها وكذلك الممارسات التي تتم في عالم معاصر عولمي فيه يزداد التأثير الرقمي؟ 本文旨在阐述过去10年期间，学者致力于不同学龄（由学前以至成人）的读写教育问题研究时所使用的语篇分析方法。作者从300多个研究里整理出一个共通的主题，就是去理解如何使到所有学生的读写教育取得成功。本文献综述是由两个互补的章节组成。第一节重点介绍研究调查所采用的两个语篇分析的处理方法：是谁的读写文化有重要意义？哪些读写文化有重要意义？第二节根据五个问题来阐釋这些研究的贡献：1.有读写文化的人的身份认同，所指的是什么？是怎样建构而成的？由谁所建构而成的？2.各种学科知识、话语及身份认同是如何建构而成的？3.学校如何为学生提供获取校本读写文化知识的门路？4.读写教学教师与学生在校内及校外在角色上有什么转移？5.在当前全球化和日益受数码化影响的世界中，语篇分析研究如何处理流动于各种写文化网站以内及之间的文化信息及各种文化实践的问题？ Cet état de la question présente l'analyse du discours dans les recherches des chercheurs qui s'intéressent aux questions de littératie en éducation— du niveau préscolaire à l'adulte — au cours des dix dernières années. En nous basant sur plus de 300 études, une préoccupation commune nous est apparue qui est de comprendre comment l'enseignement de la littératie peut permettre à tous les élèves de réussir. Nous avons organisé l'état de la question en deux parties complémentaires. La première partie s'intéresse au discours des approches analytiques réalisées pour étudier les questions suivantes: prendre en compte les littératies de qui ? prendre en compte quelles littératies? La seconde partie explique ce qu'ont apporté les études effectuées en réponse à cinq questions: que sont les identités lettrées ? comment sont‐elles construites, et par qui ? Comment sont construits les avoirs disciplinaires, les discours, et les identités ? Comment les écoles fournissent‐elles aux élèves un accès aux littératies basées sur l'école ? Quels sont les changements de rôles des professeurs de littératie et des apprenants dans l'école et hors de celle‐ci ? Comment le discours de la recherche analysé prend‐il en compte le mouvement au sein et au travers des sites de littératie et des pratiques dans un monde contemporain globalisé et de plus en plus influencé par l'informatique. В этом обзоре представлены исследования, проведенные на протяжении последних десяти лет с помощью дискурс‐анализа и посвященные проблемам развития грамотности людей разного возраста – от дошкольников до взрослых. Общая тема для более чем трехсот рассмотренных авторами источников: как добиться успеха в становлении грамотности? Обзор состоит из двух взаимодополняющих разделов. В первом описаны подходы к анализу дискурса, которые помогают понять, что принимается за образцы грамотности и кто может им соответствовать. Во втором разделе результаты исследований рассмотрены согласно пяти категориям: Как человек осознает себя в плане грамотности, на чем и кем строится эта идентичность? Как конструируется предметное или дисциплинарное знание, дискурс и идентичность? Как может школа дать учащимся доступ к школьной академической грамотности? В чем состоят и как меняются роли преподавателей грамотности и учащихся в стенах школы и за ее пределами? Как исследования дискурс‐анализа отражают перемещения участников дискурса в реальном и виртуальном пространстве в современном глобализированном мире? Este repaso presenta investigación que ha sido llevada a cabo usando análisis del discurso por estudiosos interesados en cuestiones de alfabetización en la educación a todas las edades—preescolar hasta adulto—en los últimos diez años. Al examinar más de 300 estudios, vimos que un tema común es el de entender cómo lograr exitosamente la educación de competencias de todos los estudiantes. Organizamos el repaso en dos secciones complementarias. Enfocamos la primera en los acercamientos analíticos del discurso que se han usado para investigar: ¿Cuáles competencias cuentan o valen? ¿Las competencias de quiénes cuentan o valen? La segunda sección explica las contribuciones que hicieron los estudios organizadas de acuerdo a cinco temas: ¿Qué son identidades competentes, cómo se construyen, y por quiénes? ¿Cómo se construyen el conocimiento, el discurso y las identidades de las disciplinas? ¿Cómo pueden las escuelas darles acceso a los estudiantes a las competencias basadas en la escuela? ¿Cuáles son los papeles cambiantes de los maestros y los estudiantes de competencias dentro y fuera de la escuela? ¿Cómo plantea la investigación del análisis del discurso el movimiento dentro y a través de los sitios de competencias y prácticas en este mundo contemporáneo, globalizado y digital?Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/88086/1/RRQ.45.1.5.pd

STXBP1 promotes Weibel-Palade body exocytosis through its interaction with the Rab27A effector Slp4-a.

Vascular endothelial cells contain unique rod-shaped secretory organelles, called Weibel-Palade bodies (WPBs), which contain the hemostatic protein von Willebrand factor (VWF) and a cocktail of angiogenic and inflammatory mediators. We have shown that the Rab27A effector synaptotagmin-like protein 4-a (Slp4-a) plays a critical role in regulating hormone-evoked WPB exocytosis. Using a nonbiased proteomic screen for targets for Slp4-a, we now identify syntaxin-binding protein 1 (STXBP1) and syntaxin-2 and -3 as endogenous Slp4-a binding partners in endothelial cells. Coimmunoprecipitations showed that STXBP1 interacts with syntaxin-2 and -3, but not with syntaxin-4. Small interfering RNA-mediated silencing of STXBP1 expression impaired histamine- and forskolin-induced VWF secretion. To further substantiate the role of STXBP1, we isolated blood outgrowth endothelial cells (BOECs) from an early infantile epileptic encephalopathy type 4 (EIEE4) patient carrying a de novo mutation in STXBP1. STXBP1-haploinsufficient EIEE4 BOECs contained similar numbers of morphologically normal WPBs compared with control BOECs of healthy donors; however, EIEE4 BOECs displayed significantly impaired histamine- and forskolin-stimulated VWF secretion. Based on these findings, we propose that the Rab27A-Slp4-a complex on WPB promotes exocytosis through an interaction with STXBP1, thereby controlling the release of vaso-active substances in the vasculature

Multi-tiered genomic analysis of head and neck cancer ties TP53 mutation to 3p loss

Head and neck squamous cell carcinoma (HNSCC) is characterized by aggressive behavior with a propensity for metastasis and recurrence. Here we report a comprehensive analysis of the molecular and clinical features of HNSCC that govern patient survival. We find that TP53 mutation is frequently accompanied by loss of chromosome 3p, and that the combination of both events associates with a surprising decrease in survival rates (1.9 years versus >5 years for TP53 mutation alone). The TP53-3p interaction is specific to chromosome 3p, rather than a consequence of global genome instability, and validates in HNSCC and pan-cancer cohorts. In Human Papilloma Virus positive (HPV+) tumors, in which HPV inactivates TP53, 3p deletion is also common and associates with poor outcomes. The TP53-3p event is modified by mir-548k expression which decreases survival even further, while it is mutually exclusive with mutations to RAS signaling. Together, the identified markers underscore the molecular heterogeneity of HNSCC and enable a new multi-tiered classification of this disease

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes