Relativistic heavy ion collisions --- Where are we now? Where do we go?

Various aspects of the current status of ultrarelativistic heavy ion collisions are reviewed. Perspectives of heavy ion physics in the future are given as well.Comment: 8 pages, 4 postscript figures, LaTex, Invited talk presented at the KEK-Tanashi International Symposium on ``Physics of Hadrons and Nuclei'', Dec.14-17, 1998 Tokyo, Japan, Submitted to Nuclear Physics

A pharmacodynamic analysis of resistance trends in pathogens from patients with infection in intensive care units in the United States between 1993 and 2004

<p>Abstract</p> <p>Background</p> <p>Increasing nosocomial pathogen resistance to available antimicrobial agents is of growing concern. While higher MICs can diminish antimicrobial effectiveness, dose adjustments often mitigate this effect. This study's objective was to ascertain whether MICs among major pathogens in the ICU to several commonly used agents have increased enough to significantly impact their ability to achieve bactericidal effect.</p> <p>Methods</p> <p>Cefepime, ceftriaxone, imipenem and piperacillin-tazobactam MICs were determined with 74,394 Gram-negative bacilli obtained from ICU patients with various infections in the US between 1993 and 2004. Results were grouped into four 3-year periods. The predicted cumulative fraction of response (CFR) was estimated based on patient-derived pharmacokinetic values and Monte Carlo simulation. Trends in CFR over the four study periods were assessed using the Cochran-Armitage test. The primary analysis included all organisms combined; <it>Pseudomonas aeruginosa </it>and <it>Acinetobacter </it>species were also evaluated individually.</p> <p>Results</p> <p>In the primary analysis, imipenem 500 mg q6h showed CFRs from 87% to 90% across all four study periods, with a trend toward slightly improved bactericidal target attainment (p < 0.01). CFRs for cefepime 2 g q12h and piperacillin-tazobactam 4.5 g q6h both declined by 2% (p < 0.01 and p < 0.05, respectively), reflecting upward shifts in the underlying MIC distributions. Ceftriaxone had <52% CFR for all regimens in all periods, with no significant trend. Against <it>P. aeruginosa</it>, significant declines in CFR were seen for (range, p-value): imipenem 1 g q8h (82%–79%, p < 0.01), cefepime 1 g q12h (70%–67%, p < 0.01), cefepime 2 g q12h (84%–82%, p < 0.05), piperacillin-tazobactam 3.375 g q6h (76%–73%, p < 0.01), piperacillin-tazobactam 4.5 g q8h (71%–68%, p < 0.01), and piperacillin-tazobactam 4.5 g q6h (80%–77%, p < .01). Against <it>Acinetobacter </it>spp., all regimens of imipenem, cefepime and piperacillin-tazobactam showed significant declines in CFR over time (p < 0.01).</p> <p>Conclusion</p> <p>Our observations suggest that as a result of increasing antimicrobial resistance among ICU pathogens in the US, drug effectiveness, assessed as a function of individual agents' ability to attain pharmacodynamic targets, has declined, especially with <it>P. aeruginosa </it>and <it>Acinetobacter </it>spp. Cefepime 2 g q8h and imipenem were the most potent agents against these species, respectively. More aggressive dosing of all of the agents characterized could preserve their clinical utility, but this must be balanced with safety and tolerability issues by the physician.</p

National priority setting partnership using a Delphi consensus process to develop neonatal research questions suitable for practice-changing randomised trials in the UK

BACKGROUND: The provision of neonatal care is variable and commonly lacks adequate evidence base; strategic development of methodologically robust clinical trials is needed to improve outcomes and maximise research resources. Historically, neonatal research topics have been selected by researchers; prioritisation processes involving wider stakeholder groups have generally identified research themes rather than specific questions amenable to interventional trials. OBJECTIVE: To involve stakeholders including parents, healthcare professionals and researchers to identify and prioritise research questions suitable for answering in neonatal interventional trials in the UK. DESIGN: Research questions were submitted by stakeholders in population, intervention, comparison, outcome format through an online platform. Questions were reviewed by a representative steering group; duplicates and previously answered questions were removed. Eligible questions were entered into a three-round online Delphi survey for prioritisation by all stakeholder groups. PARTICIPANTS: One hundred and eight respondents submitted research questions for consideration; 144 participants completed round one of the Delphi survey, 106 completed all three rounds. RESULTS: Two hundred and sixty-five research questions were submitted and after steering group review, 186 entered into the Delphi survey. The top five ranked research questions related to breast milk fortification, intact cord resuscitation, timing of surgical intervention in necrotising enterocolitis, therapeutic hypothermia for mild hypoxic ischaemic encephalopathy and non-invasive respiratory support. CONCLUSIONS: We have identified and prioritised research questions suitable for practice-changing interventional trials in neonatal medicine in the UK at the present time. Trials targeting these uncertainties have potential to reduce research waste and improve neonatal care

National priority setting partnership using a Delphi consensus process to develop neonatal research questions suitable for practice-changing randomised trials in the UK

BACKGROUND: The provision of neonatal care is variable and commonly lacks adequate evidence base; strategic development of methodologically robust clinical trials is needed to improve outcomes and maximise research resources. Historically, neonatal research topics have been selected by researchers; prioritisation processes involving wider stakeholder groups have generally identified research themes rather than specific questions amenable to interventional trials. OBJECTIVE: To involve stakeholders including parents, healthcare professionals and researchers to identify and prioritise research questions suitable for answering in neonatal interventional trials in the UK. DESIGN: Research questions were submitted by stakeholders in population, intervention, comparison, outcome format through an online platform. Questions were reviewed by a representative steering group; duplicates and previously answered questions were removed. Eligible questions were entered into a three-round online Delphi survey for prioritisation by all stakeholder groups. PARTICIPANTS: One hundred and eight respondents submitted research questions for consideration; 144 participants completed round one of the Delphi survey, 106 completed all three rounds. RESULTS: Two hundred and sixty-five research questions were submitted and after steering group review, 186 entered into the Delphi survey. The top five ranked research questions related to breast milk fortification, intact cord resuscitation, timing of surgical intervention in necrotising enterocolitis, therapeutic hypothermia for mild hypoxic ischaemic encephalopathy and non-invasive respiratory support. CONCLUSIONS: We have identified and prioritised research questions suitable for practice-changing interventional trials in neonatal medicine in the UK at the present time. Trials targeting these uncertainties have potential to reduce research waste and improve neonatal care

Excitonic Strings in one dimensional organic compounds

Important questions concern the existence of excitonic strings in organic compounds and their signatures in the photophysics of these systems. A model in terms of Hard Core Bosons is proposed to study this problem in one dimension. Mainly the cases with two and three particles are studied for finite and infinite lattices, where analytical results are accessible. It is shown that if bi-excitonic states exist, three-excitonic and even, n-excitonic strings, at least in a certain range of parameters, will exist. Moreover, the behaviour of the transitions from one exciton to the biexciton is fully clarified. The results are in agreement with exact finite cluster diagonalizations of several model Hamiltonians.Comment: 36 pages, 4 eps figs. to appear in Phys. Rev.

CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response.

Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune-mediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.Stand Up 2 Cancer, Lustgarten Foundation, NIH

Rapid generation of a mouse model for Middle East respiratory syndrome

The Middle East respiratory syndrome (MERS)-coronavirus, a newly identified pathogen, causes severe pneumonia in humans, with a mortality of nearly 44%. Human-to-human spread has been demonstrated, raising the possibility that the infection could become pandemic. Mice and other small laboratory animals are not susceptible to infection. Here, we describe the development of a small-animal model for MERS, in which we use an adenovirus expressing the human host-cell receptor to sensitize mice for infection. We show that these mice are useful for determining immune responses and for evaluation of an anti-MERS vaccine and an antiviral therapy. This approach will be generally useful for the rapid (2–3 wk) development of relevant mouse and other animal models for emerging viral infections

National priority setting partnership using a Delphi consensus process to develop neonatal research questions suitable for practice-changing randomised trials in the United Kingdom

Introduction: Methodologically robust clinical trials are required to improve neonatal care and reduce unwanted variations in practice. Previous neonatal research prioritisation processes have identified important research themes rather than specific research questions amenable to clinical trials. Practice-changing trials require well-defined research questions, commonly organised using the Population, Intervention, Comparison, Outcome (PICO) structure. By narrowing the scope of research priorities to those which can be answered in clinical trials and by involving a wide range of different stakeholders, we aim to provide a robust and transparent process to identify and prioritise research questions answerable within the National Healthcare System to inform future practice-changing clinical trials. Methods and analysis: A steering group comprising parents, doctors, nurses, allied health professionals, researchers and representatives from key organisations (Neonatal Society, British Association of Perinatal Medicine, Neonatal Nurses Association and Royal College of Paediatrics and Child Health) was identified to oversee this project. We will invite submissions of research questions formatted using the PICO structure from the following stakeholder groups using an online questionnaire: parents, patients, healthcare professionals and academic researchers. Unanswered, non-duplicate research questions will be entered into a three-round eDelphi survey of all stakeholder groups. Research questions will be ranked by mean aggregate scores. Ethics and dissemination: The final list of prioritised research questions will be disseminated through traditional academic channels, directly to key stakeholder groups through representative organisations and on social media. The outcome of the project will be shared with key research organisations such as the National Institute for Health Research. Research ethics committee approval is not required

Climatically driven changes in the supply of terrigenous sediment to the East China Sea

Author Posting. © American Geophysical Union, 2018. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry, Geophysics, Geosystems 19 (2018): 2463-2477, doi:10.1029/2017GC007339.We examine the paleoceanographic record over the last ∼400 kyr derived from major, trace, and rare earth elements in bulk sediment from two sites in the East China Sea drilled during Integrated Ocean Drilling Program Expedition 346. We use multivariate statistical partitioning techniques (Q‐mode factor analysis, multiple linear regression) to identify and quantify five crustal source components (Upper Continental Crust (UCC), Luochuan Loess, Xiashu Loess, Southern Japanese Islands, Kyushu Volcanics), and model their mass accumulation rates (MARs). UCC (35–79% of terrigenous contribution) and Luochuan Loess (16–55% contribution) are the most abundant end‐members through time, while Xiashu Loess, Southern Japanese Islands, and Kyushu Volcanics (1–22% contribution) are the lowest in abundance when present. Cycles in UCC and Luochuan Loess MARs may indicate continental and loess‐like material transported by major rivers into the Okinawa Trough. Increases in sea level and grain size proxy (e.g., SiO2/Al2O3) are coincident with increased flux of Southern Japanese Islands, indicating localized sediment supply from Japan. Increases in total terrigenous MAR precede minimum relative sea levels by several thousand years and may indicate remobilization of continental shelf material. Changes in the relative contribution of these end‐members are decoupled from total MAR, indicating compositional changes in the sediment are distinct from accumulation rate changes but may be linked to variations in sea level, riverine and eolian fluxes, and shelf‐bypass processes over glacial‐interglacials, complicating accurate monsoon reconstructions from fluvial dominated sediment.U.S. National Science Foundation Grant Numbers: NSF‐EAR1434175, NSF‐EAR1433665, NSF‐EAR143413

Correlating Radiomic Features of Heterogeneity on CT with Circulating Tumor DNA in Metastatic Melanoma

Clinical imaging methods, such as computed tomography (CT), are used for routine tumor response monitoring. Imaging can also reveal intratumoral, intermetastatic, and interpatient heterogeneity, which can be quantified using radiomics. Circulating tumor DNA (ctDNA) in the plasma is a sensitive and specific biomarker for response monitoring. Here we evaluated the interrelationship between circulating tumor DNA mutant allele fraction (ctDNAmaf), obtained by targeted amplicon sequencing and shallow whole genome sequencing, and radiomic measurements of CT heterogeneity in patients with stage IV melanoma. ctDNAmaf and radiomic observations were obtained from 15 patients with a total of 70 CT examinations acquired as part of a prospective trial. 26 of 39 radiomic features showed a significant relationship with log(ctDNAmaf). Principal component analysis was used to define a radiomics signature that predicted ctDNAmaf independent of lesion volume. This radiomics signature and serum lactate dehydrogenase were independent predictors of ctDNAmaf. Together, these results suggest that radiomic features and ctDNAmaf may serve as complementary clinical tools for treatment monitoring