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Soccer for dummies
Learn the basics, improve your game knowledge, and reach your soccer playing goals. This guide gives you the history, stats, and rules of this popular sport.
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After an initial positive blood culture, when are repeat blood cultures necessary in the Neonatal Intensive Care Unit (NNICU)?
Background: Data in adults and older children demonstrate repeat blood cultures (BlCx) are not always necessary. Indications for repeat BlCx include Staphylococcus aureus or yeast in the initial blood culture, or the presence of a central venous catheter (CVC). Blood collection in premature babies can be challenging and there are little data regarding when repeat BlCxs are necessary after an initial positive. The goal of this study is to determine risk factors for persistent bloodstream infection (BSI) to determine when unnecessary blood cultures can be avoided. Methods: The Yale New Haven Children’s Hospital NNICU is a 68-bed level 4 unit. Babies in the NNICU with a positive blood culture from 8/1/16 to 12/31/21 were included. Persistent BSI was defined as a repeat positive BlCx with the same organism >48 hrs. after the original culture. A BlCx > 7 days after the original BlCx was considered a new event. Babies who died within 48 hrs. of the initial culture were excluded. In preliminary analysis we did not distinguish between true BSI and contamination. Data were extracted from the medical record by the Yale Data Analytics Team and by manual chart review. Data were stored in excel for descriptive statistics. Additional statistical analysis in SPSS is on-going to account for multiple variables. Results: 142 babies had a positive BlCx with 122 babies alive at 48 hrs. and included in the study. These 124 babies had 139 positive BlCx growing 145 organisms. Persistent BSI occurred in 17.3% (24/139) of BlCxs. Factors associated with persistence in univariate analyses included the presence of a CVC and recovery of S. aureus. (Table 1) No babies with either streptococcal infection or early onset sepsis had persistent BSI. (Table 1) Additional variables under evaluation in a multiple regression model to determine the probability of persistent BSI include other sources of infection, white blood cell count at the time of BlCx, congenital heart disease, immunosuppressive agents such as steroids and whether empiric antibiotic therapy was appropriate. We will also define probable contaminants and repeat the analyses with and without these BSI episodes. Conclusions: Preliminary analysis shows that neonates have similar risk factors for persistent BSI as adults including the presence of a CVC and the recovery of S. aureus that require repeat BlCx to confirm clearance. For babies with streptococcal infection, repeat BlCx may not be routinely required. Current work is examining additional potential risk factors in multi-variable models.
Journal Article
The haunting in Connecticut 2 : ghosts of Georgia
Building on the terror of The Haunting in Connecticut, this horrifying tale traces a young family's nightmarish descent into a centuries-old Southern hell. When Andy Wyrick moves his wife Lisa and daughter Heidi to an historic home in Georgia, they quickly discover they are not the house's only inhabitants. The family soon comes face-to-face with a bone-chilling mystery born of a deranged desire, a haunting secret rising from underground and threatening to bring down anyone in its path.
DVD
HIF activation enhances FcγRIIb expression on mononuclear phagocytes impeding tumor targeting antibody immunotherapy
Background
Hypoxia is a hallmark of the tumor microenvironment (TME) and in addition to altering metabolism in cancer cells, it transforms tumor-associated stromal cells. Within the tumor stromal cell compartment, tumor-associated macrophages (TAMs) provide potent pro-tumoral support. However, TAMs can also be harnessed to destroy tumor cells by monoclonal antibody (mAb) immunotherapy, through antibody dependent cellular phagocytosis (ADCP). This is mediated via antibody-binding activating Fc gamma receptors (FcγR) and impaired by the single inhibitory FcγR, FcγRIIb.
Methods
We applied a multi-OMIC approach coupled with in vitro functional assays and murine tumor models to assess the effects of hypoxia inducible factor (HIF) activation on mAb mediated depletion of human and murine cancer cells. For mechanistic assessments, siRNA-mediated gene silencing, Western blotting and chromatin immune precipitation were utilized to assess the impact of identified regulators on
FCGR2B
gene transcription.
Results
We report that TAMs are FcγRIIb
bright
relative to healthy tissue counterparts and under hypoxic conditions
,
mononuclear phagocytes markedly upregulate FcγRIIb. This enhanced FcγRIIb expression is transcriptionally driven through HIFs and Activator protein 1 (AP-1). Importantly, this phenotype reduces the ability of macrophages to eliminate anti-CD20 monoclonal antibody (mAb) opsonized human chronic lymphocytic leukemia cells in vitro and EL4 lymphoma cells in vivo in human FcγRIIb
+
/
+
transgenic mice. Furthermore, post-HIF activation, mAb mediated blockade of FcγRIIb can partially restore phagocytic function in human monocytes.
Conclusion
Our findings provide a detailed molecular and cellular basis for hypoxia driven resistance to antitumor mAb immunotherapy, unveiling a hitherto unexplored aspect of the TME. These findings provide a mechanistic rationale for the modulation of FcγRIIb expression or its blockade as a promising strategy to enhance approved and novel mAb immunotherapies.
Journal Article
Reducing MSSA Invasive Infection and Transmission in the NNICU using Whole Genome Sequencing and Environmental Surveillance
Background: A Quality Improvement (QI) initiative to reduce invasive Staphylococcus aureus (SA) infections in a level IV neonatal intensive care unit (NICU) successfully eliminated Methicillin-resistant (MRSA) but not Methicillin-susceptible (MSSA) infections. A combination of SA whole genome sequencing (WGS) and environmental culturing helped to better understand the epidemiology of MSSA colonization and infection in the NICU and drive new infection prevention interventions. Methods: Environmental surveillance of high-touchpoint surfaces for SA was performed using Dey and Engley neutralizing agar. Selected isolates were confirmed as SA using Columbia Sheep’s Blood agar and Staphaurex testing. Statistical analyses examined correlations between monthly effective cleaning, hand hygiene compliance, and colonization rates. To better understand MSSA spread in the NICU, WGS was performed on a convenience sample of 42 MSSA isolates, sampled one month before and after an invasive MSSA infection. Data extracted from electronic health records were used for retrospective room tracing of colonized patients with related isolates to determine modes of transmission. Results: WGS analysis MSSA isolates revealed four MSSA strains from 29 patients suggesting within unit transmission, while 13 patients were colonized with unique MSSA isolates suggesting external sources. Retrospective room tracing of colonized patients identified three transmission patterns: subsequent room occupant transmission, intra-pod spread, and inter-pod transmission without patient transfer, with evidence that these strains were endemic within the unit for at least 3-12 months. Statistical analyses showed no significant correlation between environmental cleaning or hand hygiene compliance and colonization rates. Conclusions: Persistent MSSA colonization and invasive infections in the NICU result from both within-unit transmission and the introduction of unique isolates. These findings are being used to inform the development of new interventions, including updated below-the-elbow hand hygiene protocols, revised environmental cleaning plans, nurse-parent communication training, and a virtual reality hand hygiene training program for parents and staff. WGS of pathogenic organisms is a useful tool to drive QI initiatives aimed at reducing hospital-acquired infections.
Journal Article
Impact of isotype on the mechanism of action of agonist anti-OX40 antibodies in cancer: implications for therapeutic combinations
BackgroundOX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer.MethodsAnti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in (KI) mice and syngeneic tumor models. The impact of FcγR engagement was evaluated in hOX40 KI mice deficient for Fc gamma receptors (FcγR). Additionally, combination studies using anti-mouse programmed cell death protein-1 (mPD-1) were assessed. In vitro experiments using peripheral blood mononuclear cells (PBMCs) examining possible anti-hOX40 mAb mechanisms of action were also performed.ResultsIsotype variants of the clinically relevant mAb GSK3174998 showed immunomodulatory effects that differed in mechanism; mIgG1 mediated direct T-cell agonism while mIgG2a acted indirectly, likely through depletion of regulatory T cells (Tregs) via activating FcγRs. In both the OT-I and EG.7-OVA models, hIgG1 was the most effective human isotype, capable of acting both directly and through Treg depletion. The anti-hOX40 hIgG1 synergized with anti-mPD-1 to improve therapeutic outcomes in the EG.7-OVA model. Finally, in vitro assays with human peripheral blood mononuclear cells (hPBMCs), anti-hOX40 hIgG1 also showed the potential for T-cell stimulation and Treg depletion.ConclusionsThese findings underline the importance of understanding the role of isotype in the mechanism of action of therapeutic mAbs. As an hIgG1, the anti-hOX40 mAb can elicit multiple mechanisms of action that could aid or hinder therapeutic outcomes, dependent on the microenvironment. This should be considered when designing potential combinatorial partners and their FcγR requirements to achieve maximal benefit and improvement of patient outcomes.
Journal Article
Specialist emergency care and COPD outcomes
IntroductionIn exacerbation of chronic obstructive pulmonary disease (ECOPD) requiring hospitalisation greater access to respiratory specialists improves outcome, but is not consistently delivered. The UK National Confidential Enquiry into Patient Outcome and Death 2015 enquiry showed over 25% of patients receiving acute non-invasive ventilation (NIV) for ECOPD died in hospital. On 16 June 2015 the Northumbria Specialist Emergency Care Hospital (NSECH) opened, introducing 24/7 specialty consultant on-call, direct admission from the emergency department to specialty wards and 7-day consultant review. A Respiratory Support Unit opened for patients requiring NIV. Before NSECH the NIV service included mandated training and competency assessment, 24/7 single point of access, initiation of ventilation in the emergency department, a door-to-mask time target, early titration of ventilation pressures and structured weaning. Pneumonia or hypercapnic coma complicating ECOPD have never been considered contraindications to NIV. After NSECH staff-patient ratios increased, the NIV pathway was streamlined and structured daily multidisciplinary review introduced. We compared our outcomes with historical and national data.MethodsPatients hospitalised with ECOPD between 1 January 2013 and 31 December 2016 were identified from coding, with ventilation status and radiological consolidation confirmed from records. Age, gender, admission from nursing home, consolidation, revised Charlson Index, key comorbidities, length of stay, and inpatient and 30-day mortality were captured. Outcomes pre-NSECH and post-NSECH opening were compared and independent predictors of survival identified via logistic regression.ResultsThere were 6291 cases. 24/7 specialist emergency care was a strong independent predictor of lower mortality. Length of stay reduced by 1 day, but 90-day readmission rose in both ventilated and non-ventilated patients.ConclusionProvision of 24/7 respiratory specialist emergency care improved ECOPD survival and shortened length of stay for both non-ventilated and ventilated patients. The potential implications in respect to service design and provision nationally are substantial and challenging.
Journal Article
Coordinating the Complexity of Tools, Tasks, and Users: On Theory-based Approaches to Authoring Tool Usability
Intelligent Tutoring Systems authoring tools are highly complex educational software applications used to produce highly complex software applications (i.e. ITSs). How should our assumptions about the target users (authors) impact the design of authoring tools? In this article I first reflect on the factors leading to my original 1999 article on the state of the art in ITS authoring tools and consider some challenges facing authoring tool researchers today. Then, in the bulk of the paper, I propose some principled foundations for future authoring tool design, focusing on operationalizing the construct of complexity—for tool, task, and user. ITS authoring tools are major undertakings and to redeem this investment it is important to anticipate actual user needs and capacities. I propose that one way to do this is to match the complexity of tool design to the complexity of authoring tasks and the complexity capacity of users and user communities. Doing so entails estimating the complexity of the mental models that a user is expected to build in order to use a tool as intended. The goal is not so much to support the design of more powerful authoring tools as it is to design tools that meet the needs of realistic user audiences. This paper presents some exploratory ideas on how to operationalize the concept of complexity for tool, task, and user. The paper draws from the following theories and frameworks to weave this narrative: Complexity Science, Activity Theory, Epistemic Forms and Games, and adult cognitive developmental theory (Hierarchical Complexity Theory). This exploration of usability and complexity is applicable to the design of any type of complex authoring application, though the application area that motivated the exploration is ITS authoring.
Journal Article
Authoring Knowledge-Based Tutors: Tools for Content, Instructional Strategy, Student Model, and Interface Design
Although Intelligent Tutoring Systems (ITSs), also called knowledge-based tutors, are becoming more common and proving to be increasingly effective, each one must still be built from scratch at a significant cost. At the University of Massachusetts, Amherst, we have developed domain independent tools for authoring all aspects of a knowledge-based tutor: the domain model, the teaching strategies, the student model, and the learning environment. In this article, I describe these tools, discuss a number of design issues and design tradeoffs that are involved in building ITS authoring tools, and discuss knowledge acquisition and representation issues encountered in my work. I also describe how we plan to use these tools (collectively called Eon), including ontology objects, as a meta-authoring tool for designing special-purpose authoring tools tailored for specific domain types.
Journal Article
Remote Musculoskeletal Assessment Framework: A Guide for Primary Care
Introduction Remote consulting has exploded into primary care following the initial COVID-19 surge as a measure to reduce potential cross-infection (staff-patient or patient-patient). Musculoskeletal (MSK) conditions comprise up to 21% of the annual primary care caseload in England. Established techniques for MSK examination, however, rely on face-to-face attendance. Evidence-based guidance for remote MSK assessment is required to ensure the quality of care is maintained with the move from face-to-face to virtual consultations. Method A literature review of published evidence and current guidelines was conducted. The most appropriate remote consultation techniques and MSK examinations were identified and where there was no evidence, modified examination tests were developed from established face-to-face examination techniques. A concise, accessible framework for remote MSK assessment in primary care was then created and tested on a non-medically trained volunteer. Results Over 2232 papers and articles were identified by search headings, reducing to 28 sources that had relevant content. At the time of searching, there was no published evidence relating to MSK remote consultation in a primary care setting. However, evidence was found in the physiotherapy and rehabilitation literature for the efficacy and practicality of MSK teleconsultation. MSK remote examination framework From this literature and with the addition of modified established examinations, an MSK assessment framework was constructed. This framework provides pre-consultation guidance and step-by-step remote examination instructions. Patient and clinician resources (including a patient information leaflet and photographic examples of examinations) were created as supplementary material. Conclusion Due to the frameshift away from face-to-face consultation, primary care clinicians have found themselves lacking an evidence base or practical guidance to support remote MSK assessment. This paper is a systematic literature review of MSK telemedicine from which practical advice and evidence-based MSK tests have been developed. Where there is no evidence, modified traditional tests are suggested to allow a complete framework for remote MSK examination - using a system approach of 'look, point, move' followed by modified special tests, for use in a primary care setting as a 'ready-to-use' practical guide to remote MSK assessment, presented in a downloadable format. What did this add? With 21% of primary care consultations relating to MSK conditions and limited means of performing face-to-face MSK examination due to COVID-19, there needs to be a recognised framework for assessing the MSK system remotely. To the best of our knowledge, this evidence does not exist for primary care remote MSK examination. This paper demonstrates evidence-based practical advice (from non-primary care settings) and modified MSK examinations to be used in a primary care MSK remote consultation.
Journal Article