Escherichia coli ST8196 is a novel, locally evolved, and extensively drug resistant pathogenic lineage within the ST131 clonal complex

The H30Rx subclade of Escherichia coli ST131 is a clinically important, globally dispersed pathogenic lineage that typically displays resistance to fluoroquinolones and extended spectrum β-lactams. Isolates EC233 and EC234, variants of ST131-H30Rx with a novel sequence type (ST) 8196, isolated from unrelated patients presenting with bacteraemia at a Sydney Hospital in 2014 are characterised here. EC233 and EC234 are phylogroup B2, serotype O25:H4A, and resistant to ampicillin, amoxicillin, cefoxitin, ceftazidime, ceftriaxone, ciprofloxacin, norfloxacin and gentamicin and are likely clonal. Both harbour an IncFII_2 plasmid (pSPRC_Ec234-FII) that carries most of the resistance genes on an IS26 associated translocatable unit, two small plasmids and a novel IncI1 plasmid (pSPRC_Ec234-I). SNP-based phylogenetic analysis of the core genome of representatives within the ST131 clonal complex places both isolates in a subclade with three clinical Australian ST131-H30Rx clade-C isolates. A MrBayes phylogeny analysis of EC233 and EC234 indicates ST8196 share a most recent common ancestor with ST131-H30Rx strain EC70 isolated from the same hospital in 2013. Our study identified genomic hallmarks that define the ST131-H30Rx subclade in the ST8196 isolates and highlights a need for unbiased genomic surveillance approaches to identify novel high-risk MDR E. coli pathogens that impact healthcare facilities

Designing for Dissemination: Lessons in Message Design from 1-2-3 Pap

Despite a large number of evidence-based health communication interventions tested in private, public, and community health settings, there is a dearth of research on successful secondary dissemination of these interventions to other audiences. This article presents the case study of 1-2-3 Pap, a health communication intervention to improve human papillomavirus (HPV) vaccination uptake and Pap testing outcomes in Eastern Kentucky, and explores strategies used to disseminate this intervention to other populations in Kentucky, North Carolina, and West Virginia. Through this dissemination project, we identified several health communication intervention design considerations that facilitated our successful dissemination to these other audiences; these intervention design considerations include (a) developing strategies for reaching other potential audiences, (b) identifying intervention message adaptations that might be needed, and (c) determining the most appropriate means or channels by which to reach these potential future audiences. Using 1-2-3 Pap as an illustrative case study, we describe how careful planning and partnership development early in the intervention development process can improve the potential success of enhancing the reach and effectiveness of an intervention to other audiences beyond the audience for whom the intervention messages were originally designed

The FLASH pilot survey: an HI absorption search against MRC 1-Jy radio sources

We report an ASKAP search for associated HI 21-cm absorption against bright radio sources from the Molonglo Reference Catalogue (MRC) 1-Jy sample. The search uses pilot survey data from the ASKAP First Large Absorption Survey in \hi (FLASH) covering the redshift range $0.42 < z < 1.00$. From a sample of 62 MRC 1-Jy radio galaxies and quasars in this redshift range we report three new detections of associated HI 21-cm absorption, yielding an overall detection fraction of $1.8\%^{+4.0\%}_{-1.5\%}$. The detected systems comprise two radio galaxies (MRC 2216$-$281 at $z=0.657$ and MRC 0531$-$237 at $z=0.851$) and one quasar (MRC 2156$-$245 at $z=0.862$). The MRC 0531$-$237 absorption system is the strongest found to date, with a velocity integrated optical depth of $\rm 143.8 \pm 0.4 \ km \ s^{-1}$. All three objects with detected HI 21-cm absorption are peaked-spectrum or compact steep-spectrum (CSS) radio sources, classified based on our SED fits to the spectra. Two of them show strong interplanetary scintillation at 162 MHz, implying that the radio continuum source is smaller than 1 arcsec in size even at low frequencies. Among the class of peaked-spectrum and compact steep-spectrum radio sources, the HI detection fraction is $23\%^{+22\%}_{-13\%}$. This is consistent within $1\sigma$ with a detection fraction of $\approx 42\%^{+21\%}_{-15\%}$ in earlier reported GPS and CSS samples at intermediate redshifts ($0.4 < z < 1.0$). All three detections have a high 1.4 GHz radio luminosity, with MRC 0531$-$237 and MRC 2216$-$281 having the highest values in the sample, $\rm > 27.5 \ W \ Hz^{-1}$. The preponderance of extended radio sources in our sample could partially explain the overall low detection fraction, while the effects of a redshift evolution in gas properties and AGN UV luminosity on the neutral gas absorption still need to be investigated.Comment: 28 pages, 9 figures and 7 Tables. Submitted to MNRA

Real-Time Monitoring of Tumorigenesis, Dissemination, & Drug Response in a Preclinical Model of Lymphangioleiomyomatosis/Tuberous Sclerosis Complex

Background: TSC2-deficient cells can proliferate in the lungs, kidneys, and other organs causing devastating progressive multisystem disorders such as lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC). Preclinical models utilizing LAM patient-derived cells have been difficult to establish. We developed a novel animal model system to study the molecular mechanisms of TSC/LAM pathogenesis and tumorigenesis and provide a platform for drug testing. Methods and Findings: TSC2-deficient human cells, derived from the angiomyolipoma of a LAM patient, were engineered to co-express both sodium-iodide symporter (NIS) and green fluorescent protein (GFP). Cells were inoculated intraparenchymally, intravenously, or intratracheally into athymic NCr nu/nu mice and cells were tracked and quantified using single photon emission computed tomography (SPECT) and computed tomography (CT). Surprisingly, TSC2-deficient cells administered intratracheally resulted in rapid dissemination to lymph node basins throughout the body, and histopathological changes in the lung consistent with LAM. Estrogen was found to be permissive for tumor growth and dissemination. Rapamycin inhibited tumor growth, but tumors regrew after the drug treatment was withdrawn. Conclusions: We generated homogeneous NIS/GFP co-expressing TSC2-deficient, patient-derived cells that can proliferate and migrate in vivo after intratracheal instillation. Although the animal model we describe has some limitations, we demonstrate that systemic tumors formed from TSC2-deficient cells can be monitored and quantified noninvasively over time using SPECT/CT, thus providing a much needed model system for in vivo drug testing and mechanistic studies of TSC2-deficient cells and their related clinical syndromes

Integrated genomic characterization of oesophageal carcinoma

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

The OPAL conspiracy : the influence of politics and gender on the development of the Brisbane Aboriginal rights movement, 1958-1962

It has been commonly believed that the Aboriginal rights movement which developed in Australia in the 1960s gained its greatest momentum from activities initiated in the southern states - New South Wales, Victoria and South Australia. This thesis argues that such a depiction is incorrect. Based on oral interviews and unpublished personal documents and substantiated by official reports, published commentary and parliamentary debates as well as internal records from Department of Native Affairs, I maintain that between the years of 1958 and 1962 a minor revolution occurred in Brisbane which influenced the direction of Black rights - both locally and nationally - into the following decade. This thesis traces the development of this uprising, and its aftermath. It explores the motivations of a White society which paid lip service to tolerance and social equity while accepting a system which denied Black basic human rights; and identifies the individuals and organisations which overcame obstacles to blaze a trail of resistance which dramatically changed White attitudes and Black lifestyles. The effects of this attack on the status quo were observable on three fronts: in the political arena, in the Brisbane media and in the wider community. The movement for change peaked between May 1961 and February 1962, when representatives of the Queensland government, Department of Native Affairs (DNA), Queensland Labor Party (QLP) and Queensland Police Special Branch conspired to transfer power from a left-wing Black rights organization perceived as a political threat, to one created to perpetuate DNA policy. This study identifies the pivotal role of women - particularly Murri women - as the catalyst which transformed the Brisbane movement from a gaggle of factions divided by antithetical ideologies into a cohesive grouping capable of taking on the forces of oppression in Queensland. I argue that without their leadership, the movement may never have taken off to the extent required to persuade a conservative Queensland public to deliver the affirmative vote to carriage of the 1967 referendum proposal on Black rights

Gender, ethnicity, development, and risk: Mentoring and the consideration of individual differences

Individual differences shape the needs and characteristics of protégés, the processes through which mentoring may influence protégés\u27 developmental trajectories, and the social networks into which the mentors enter. The literature on the influences of gender, ethnicity, and age on mentoring is reviewed and discussed as examples of how mentoring programs may have different influences on, and outcomes for, specific groups of youth. A focus on individual differences will help facilitate the development of mentoring programs that create a close fit between the needs of protégés and the services offered by the programs, as well as greater insight into what are the key elements of program effectiveness. © 2006 Wiley Periodicals, Inc