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INTRODUCTION: Procalcitonin (PCT) is a biomarker more specific for bacterial infection and responds quicker than other commonly used biomarkers such as C reactive protein, but is not routinely used in the National Health Service (NHS). Studies mainly in adults show that using PCT to guide clinicians may reduce antibiotic use, reduce hospital stay, with no associated adverse effects such as increased rates of hospital re-admission, incomplete treatment of infections, relapse or death. A review conducted for National Institute for Health and Care Excellence recommends further research on PCT testing to guide antibiotic use in children. METHODS AND ANALYSIS: Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection is a multi-centre, prospective, two-arm, individually Randomised Controlled Trial (RCT) with a 28-day follow-up and internal pilot. The intervention is a PCT-guided algorithm used in conjunction with best practice. The control arm is best practice alone. We plan to recruit 1942 children, aged between 72 hours and up to 18 years old, who are admitted to the hospital and being treated with intravenous antibiotics for suspected or confirmed bacterial infection. Coprimary outcomes are duration of antibiotic use and a composite safety measure. Secondary outcomes include time to switch from broad to narrow spectrum antibiotics, time to discharge, adverse drug reactions, health utility and cost-effectiveness. We will also perform a qualitative process evaluation. Recruitment commenced in June 2018 and paused briefly between March and May 2020 due to the COVID-19 pandemic. ETHICS AND DISSEMINATION: The trial protocol was approved by the HRA and NHS REC (North West Liverpool East REC reference 18/NW/0100). We will publish the results in international peer-reviewed journals and present at scientific meetings. TRIAL REGISTRATION NUMBER: ISRCTN11369832.

BACKGROUND: Limited data exist regarding checkpoint inhibitor efficacy for pediatric CNS malignancies. METHODS: CheckMate 908 is an open-label, sequential-arm, phase 1b/2 study investigating nivolumab (NIVO) and NIVO + ipilimumab (IPI) in 5 cohorts of pediatric patients previously treated with standard-of-care (NCT03130959). Patients received NIVO-3mg/kg Q2W or NIVO-3mg/kg + IPI-1mg/kg Q3W (4 doses) followed by NIVO-3mg/kg Q2W. Primary endpoints included OS (newly diagnosed DIPG) and PFS (other CNS cohorts); secondary endpoints included other efficacy metrics/safety. Exploratory endpoints included pharmacokinetics/biomarker analyses. Comparisons between treatments/cohorts were not planned. RESULTS: At data cutoff (13-Jan-2021), 166 patients received NIVO (n=85) or NIVO+IPI (n=81) at median (m) ages of 10.0yrs (range, 1-21) and 11.0yrs (1-21), respectively. In newly diagnosed DIPG, mOS (80% CI) was 11.7mos (10.3-16.5) with NIVO (n=23) and 10.8mos (9.1-15.8) with NIVO+IPI (n=22). In recurrent/progressive HGG, mPFS (80% CI) was 1.7mos (1.4-2.7) with NIVO (n=16) and 1.3mos (1.2-1.5) with NIVO+IPI (n=15). In relapsed/resistant medulloblastoma, mPFS (80% CI) was 1.4mos (1.2-1.4) with NIVO (n=15) and 2.8mos (1.5-4.5) with NIVO+IPI (n=15). In relapsed/resistant ependymoma, mPFS (80% CI) was 1.4mos (1.4-2.6) with NIVO (n=12) and 4.6mos (1.4-5.4) with NIVO+IPI (n=10). In other recurrent/progressive CNS tumors, mPFS (95% CI) was 1.2mos (1.1-1.3) with NIVO (n=19) and 1.6mos (1.3-3.5) with NIVO+IPI (n=19). Median treatment duration was 2.1mos (range, 0-41.7+ [NIVO]/0-29.6+ [NIVO+IPI]). Grade 3/4 treatment-related AEs occurred in 14.1% (NIVO) and 27.2% (NIVO+IPI) of patients. NIVO and IPI first dose trough concentrations were lower in youngest and lowest-weight patients. Baseline tumor PD-L1 expression was not associated with survival. Tumor mutational burden was high in 1 patient (NIVO+IPI) with HGG (OS=11.0mos). CONCLUSIONS: NIVO±IPI demonstrated no clinical benefit in

INTRODUCTION: Procalcitonin (PCT) is a biomarker more specific for bacterial infection and responds quicker than other commonly used biomarkers such as C reactive protein, but is not routinely used in the National Health Service (NHS). Studies mainly in adults show that using PCT to guide clinicians may reduce antibiotic use, reduce hospital stay, with no associated adverse effects such as increased rates of hospital re-admission, incomplete treatment of infections, relapse or death. A review conducted for National Institute for Health and Care Excellence recommends further research on PCT testing to guide antibiotic use in children. METHODS AND ANALYSIS: Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection is a multi-centre, prospective, two-arm, individually Randomised Controlled Trial (RCT) with a 28-day follow-up and internal pilot. The intervention is a PCT-guided algorithm used in conjunction with best practice. The control arm is best practice alone. We plan to recruit 1942 children, aged between 72 hours and up to 18 years old, who are admitted to the hospital and being treated with intravenous antibiotics for suspected or confirmed bacterial infection. Coprimary outcomes are duration of antibiotic use and a composite safety measure. Secondary outcomes include time to switch from broad to narrow spectrum antibiotics, time to discharge, adverse drug reactions, health utility and cost-effectiveness. We will also perform a qualitative process evaluation. Recruitment commenced in June 2018 and paused briefly between March and May 2020 due to the COVID-19 pandemic. ETHICS AND DISSEMINATION: The trial protocol was approved by the HRA and NHS REC (North West Liverpool East REC reference 18/NW/0100). We will publish the results in international peer-reviewed journals and present at scientific meetings. TRIAL REGISTRATION NUMBER: ISRCTN11369832.

We report how data from the University of California (UC) Davis mission-based reporting system (MBR) can be used to define contributions for each division within a Department of Pathology based on faculty rank and series, and to evaluate whether these contributions are in alignment with the missions of the department and the goals of the school's leadership. MBR summary reports were generated for each division within the Department of Pathology; these reports illustrated the average contribution for each faculty rank and series in each of the following missions: investigative/creative work (research), teaching, clinical service, and administrative/community service. All divisions contributed equally to the teaching mission, averaging approximately 1/3 of a faculty member's time. Research was the primary mission for faculty in both the Research and the Clinical Pathology divisions, whereas clinical service was the primary mission for Anatomic Pathology. Both Anatomic Pathology and Clinical Pathology also played a large role in the administration/community service mission. These roles were appropriate based on the division's distribution of faculty in each of the faculty series. The average contribution to both the research and administrative/community service missions were larger for the Department of Pathology than it was for the school as a whole. The Department of Pathology's average contribution to both the teaching and clinical service missions was less than the school's average. We conclude that MBR data creates unique profiles for divisions and the department and enables interdepartmental comparisons that would not be possible by other means. Within the context of our school, the present analysis illustrates that the Department of Pathology is fulfilling the expectations of the school's leadership. In a more general sense, these profiles allow appropriate monitoring of the workforce, funds flow analysis, allocation of resources, and strategic planning in an ac

Although the ETV6-RUNX1 fusion is a frequent initiating event in childhood leukemia, its role in leukemogenesis is only partly understood. The main impact of the fusion itself is to generate and sustain a clone of clinically silent pre-leukemic B cell progenitors (BCP). Additional oncogenic hits, occurring even several years later, are required for overt disease. The understanding of the features and interactions of ETV6-RUNX1 positive cells during this "latency" period may explain how these silent cells can persist, and whether they could be prone to additional genetic changes. In this study, two in vitro murine models were employed to investigate whether ETV6-RUNX1 alters the cellular adhesion and migration properties of BCP. ETV6-RUNX1 expressing cells showed a significant defect in the chemotactic response to CXCL12, caused by a block in CXCR4 signaling, as demonstrated by inhibition of CXCL12-associated calcium flux and lack of ERK kinase phosphorylation. Moreover, the induction of ETV6-RUNX1 caused changes in the expression of cell-surface adhesion molecules. The expression of genes regulating the cytoskeleton was also affected, resulting in a block of CDC42 signaling. The abnormalities described here could alter the interaction of ETV6-RUNX1 pre-leukemic BCP with the microenvironment and contribute to the pathogenesis of the disease.

1 juli 2012, Item does not contain fulltext, BACKGROUND: Interventions promoting evidence based antibiotic prescribing and use frequently build on the concept of antibiotic resistance but patients and clinicians may not share the same assumptions about its meaning. OBJECTIVE: To explore patients' interpretations of 'antibiotic resistance' and to consider the implications for strategies to contain antibiotic resistance. DESIGN: Multi country qualitative interview study. PARTICIPANTS: One hundred and twenty-one adult patients from primary care research networks based in nine European countries who had recently consulted a primary care clinician with symptoms of Lower Respiratory Tract Infection (LRTI). APPROACH: Semi-structured interviews with patients following their consultation and subjected to a five-stage analytic framework approach (familiarization, developing a thematic framework from the interview questions and the themes emerging from the data, indexing, charting, and mapping to search for interpretations in the data), with local network facilitators commenting on preliminary reports. RESULTS: The dominant theme was antibiotic resistance as a property of a 'resistant human body', where the barrier to antibiotic effectiveness was individual loss of responsiveness. Less commonly, patients correctly conceptualized antibiotic resistance as a property of bacteria. Nevertheless, the over-use of antibiotics was a strong central concept in almost all patients' explanations, whether they viewed resistance as located in either the body or in bacteria. CONCLUSIONS: Most patients were aware of the link between antibiotic use and antibiotic resistance. The identification of the misinterpretation of antibiotic resistance as a property of the human body rather than bacterial cells could inform clearer clinician-patient discussions and public health interventions through emphasising the transferability of resistance, and the societal contribution individuals can make through more appropriate antibiotic prescribing and

We present a formulation for multigroup radiation hydrodynamics that is correct to order $O(v/c)$ using the comoving-frame approach and the flux-limited diffusion approximation. We describe a numerical algorithm for solving the system, implemented in the compressible astrophysics code, CASTRO. CASTRO uses an Eulerian grid with block-structured adaptive mesh refinement based on a nested hierarchy of logically-rectangular variable-sized grids with simultaneous refinement in both space and time. In our multigroup radiation solver, the system is split into three parts, one part that couples the radiation and fluid in a hyperbolic subsystem, another part that advects the radiation in frequency space, and a parabolic part that evolves radiation diffusion and source-sink terms. The hyperbolic subsystem and the frequency space advection are solved explicitly with high-order Godunov schemes, whereas the parabolic part is solved implicitly with a first-order backward Euler method. Our multigroup radiation solver works for both neutrino and photon radiation., Comment: accepted by ApJS, 27 pages, 20 figures, high-resolution version available at https://ccse.lbl.gov/Publications/wqzhang/castro3.pdf

BACKGROUND: Collagen has proved valuable as biomedical materials for a range of clinical applications, particularly in wound healing. It is normally produced from animal sources, such as from bovines, but concerns have emerged over transmission of diseases. Recombinant collagens would be preferable, but are difficult to produce. Recently, studies have shown that 'collagens' from bacteria, including Streptococcus pyogenes, can be produced in the laboratory as recombinant products, and that these are biocompatible. In the present study we have established that examples of bacterial collagens can be produced in a bioreactor with high yields providing proof of manufacture of this important group of proteins. RESULTS: Production trials in shake flask cultures gave low yields of recombinant product, < 1 g/L. Increased yields, of around 1 g/L, were obtained when the shake flask process was transferred to a stirred tank bioreactor, and the yield was further enhanced to around 10 g/L by implementation of a high cell density fed-batch process and the use of suitably formulated fully defined media. Similar yields were obtained with 2 different constructs, one containing an introduced heparin binding domain. The best yields, of up to 19 g/L were obtained using this high cell density strategy, with an extended 24 h production time. CONCLUSIONS: These data have shown that recombinant bacterial collagen from S. pyogenes, can be produced in sufficient yield by a scalable microbial production process to give commercially acceptable yields for broad use in biomedical applications.

We describe the development of a flux-limited gray radiation solver for the compressible astrophysics code, CASTRO. CASTRO uses an Eulerian grid with block-structured adaptive mesh refinement based on a nested hierarchy of logically-rectangular variable-sized grids with simultaneous refinement in both space and time. The gray radiation solver is based on a mixed-frame formulation of radiation hydrodynamics. In our approach, the system is split into two parts, one part that couples the radiation and fluid in a hyperbolic subsystem, and another parabolic part that evolves radiation diffusion and source-sink terms. The hyperbolic subsystem is solved explicitly with a high-order Godunov scheme, whereas the parabolic part is solved implicitly with a first-order backward Euler method., Comment: accepted for publication in ApJS, high-resolution version available at https://ccse.lbl.gov/Publications/wqzhang/castro2.pdf

We present a new code, CASTRO, that solves the multicomponent compressible hydrodynamic equations for astrophysical flows including self-gravity, nuclear reactions and radiation. CASTRO uses an Eulerian grid and incorporates adaptive mesh refinement (AMR). Our approach to AMR uses a nested hierarchy of logically-rectangular grids with simultaneous refinement in both space and time. The radiation component of CASTRO will be described in detail in the next paper, Part II, of this series., Comment: accepted to Astrophysical Journal Suppliment (http://iop.org), 52 pages, 16 figures

Nuclear hormone receptors, such as the ecdysone receptor, often display a large amount of induced fit to ligands. The size and shape of the binding pocket in the EcR subunit changes markedly on ligand binding, making modelling methods such as docking extremely challenging. It is, however, possible to generate excellent 3D QSAR models for a given type of ligand, suggesting that the receptor adopts a relatively restricted number of binding site configurations or [`]attractors'. We describe the synthesis, in vitro binding and selected in vivo toxicity data for [gamma]-methylene [gamma]-lactams, a new class of high-affinity ligands for ecdysone receptors from Bovicola ovis (Phthiraptera) and Lucilia cuprina (Diptera). The results of a 3D QSAR study of the binding of methylene lactams to recombinant ecdysone receptor protein suggest that this class of ligands is indeed recognized by a single conformation of the EcR binding pocket.

The nuclear reaction e+p+d -----> He3 + e is considered at thermonuclear energies. The motion of the electron is treated within the adiabatic approximation and the pd scattering state is constructed in the form of an antisymmetrized product of the bound state wave function of the deuteron and of the wave function of the pd relative motion. The latter is calculated using an effective pd potential constructed via the Marchenko inverse scattering method. The bound state wave function of He3 is obtained using Faddeev--type integrodifferential equations. The reaction rate thus obtained for the solar interior conditions is approximately 10^{-4} of the corresponding rate for the radiative capture pd ----> He3 + gamma ., Comment: RevTeX, 18 pages, 2 figures, submitted to Nucl.Phys.A

Angiosperms, http://name.umdl.umich.edu/IC-HERB00IC-X-1421787%5DMICH-V-1421787, https://quod.lib.umich.edu/cgi/i/image/api/thumb/herb00ic/1421787/MICH-V-1421787/!250,250, The University of Michigan Library provides access to these materials for educational and research purposes. Some materials may be protected by copyright. If you decide to use any of these materials, you are responsible for making your own legal assessment and securing any necessary permission. If you have questions about the collection, please contact the Herbarium professional staff: herb-dlps-help@umich.edu. If you have concerns about the inclusion of an item in this collection, please contact Library Information Technology: libraryit-info@umich.edu., https://www.lib.umich.edu/about-us/policies/copyright-policy

Six healthy men were exposed to a +Gx acceleration (chest to back) profile with peak +Gx levels of 5, 8, and 9 G. Platelet factor 4 levels and platelet counts were measured prior to and immediately following the acceleration exposure. The +Gx acceleration exposure did not affect either parameter, however elevated pre-acceleration platelet factor 4 levels were found in five of six subjects. The possible significance of this is discussed. Future space missions will expose man to unique combinations of environmental stresses. Decompression and +Gx acceleration exposure is one such combination. It is important to determine if there are some features of these stresses which by themselves are benign, but in combination can result in problems for the astronaut. At acceleration levels greater +4 Gx, the subject experiences chest pain. Breathing becomes difficult, causing the subject to become dyspneic and to breathe using his abdominal muscles. Above +6Gx, pulmonary volumes are reduced, and the subject is unable to move his arms and legs.

The problem of sonar bearing estimation in the presence of highly anisotropic noise fields is examined for both conventional and optimal array processors. In some situations, the presence of one or more (high level) interfering noise source precludes bearing estimation by conventional, non-adaptive array processors. However, in some target tracking problems (e.g. TMA) the performance loss due to noise anisotropy is not total. In the context of such problems, the effects of multiple, unidirectional interferers on the conventional, split-beam tracker and the maximum likelihood estimator are investigated for linear receiving arrays.

Background: Four out of five people living with osteoarthritis (OA) also suffer with at least one other long-term health condition. The complex interaction between OA and multiple long-term conditions (MLTCs) can result in difficulties with self-care, restricted mobility, pain, anxiety, depression and reduced quality of life. The aim of the MulTI-domain Self-management in Older People wiTh OstEoarthritis and Multi-Morbidities (TIPTOE) trial is to evaluate the clinical and cost-effectiveness of the Living Well self-management support intervention, co-designed with people living with OA, integrated into usual care, in comparison to usual care alone. Methods: TIPTOE is a multi-centre, two-arm, individually randomised controlled trial where 824 individuals over 65 years old with knee and/or hip joint pain from their OA affected joint and at least one other long-term health condition will be randomised to receive either the Living Well Self-Management support intervention or usual care. Eligible participants can self-refer onto the trial via a website or be referred via NHS services across Wales and England. Those randomised to receive the Living Well support intervention will be offered up to six one-to-one coaching sessions with a TIPTOE-trained healthcare practitioner and a co-designed book. Participants will be encouraged to nominate a support person to assist them throughout the study. All participants will complete a series of self-reported outcome measures at baseline and 6- and 12-month follow-up. The primary outcome is symptoms and quality of life as assessed by the Musculoskeletal Health Questionnaire (MSK-HQ). Routine data will be used to evaluate health resource use. A mixed methods process evaluation will be conducted alongside the trial to inform future implementation should the TIPTOE intervention be found both clinically and cost-effective. An embedded ‘Study Within A Project’ (SWAP) will explore and address barriers to the inclusion of under-served patie