bluuebunny/crossref_metadata_2025_split huggingface dataset:
Model-based evaluation of the long-term cost-effectiveness of systematic case-finding for COPD in primary care
Authors: Lambe Tosin , Adab Peymane , Jordan Rachel E , Sitch Alice , Enocson Alex , Jolly Kate , Marsh Jen , Riley Richard , Miller Martin , Cooper Brendan G , Turner Alice Margaret , Ayres Jon G , Stockley Robert , Greenfield Sheila , Siebert Stanley , Daley Amanda , Cheng KK , Fitzmaurice David , Jowett Sue 
Published: July 2019

Introduction‘One-off’ systematic case-finding for COPD using a respiratory screening questionnaire is more effective and cost-effective than routine care at identifying new cases. However, it is not known whether early diagnosis and treatment is beneficial in the longer term. We estimated the long-term cost-effectiveness of a regular case-finding programme in primary care.MethodsA Markov decision analytic model was developed to compare the cost-effectiveness of a 3-yearly systematic case-finding programme targeted to ever smokers aged ≥50 years with the current routine diagnostic process in UK primary care. Patient-level data on case-finding pathways was obtained from a large randomised controlled trial. Information on the natural history of COPD and treatment effects was obtained from a linked COPD cohort, UK primary care database and published literature. The discounted lifetime cost per quality-adjusted life-year (QALY) gained was calculated from a health service perspective.ResultsThe incremental cost-effectiveness ratio of systematic case-finding versus current care was £16 596 per additional QALY gained, with a 78% probability of cost-effectiveness at a £20 000 per QALY willingness-to-pay threshold. The base case result was robust to multiple one-way sensitivity analyses. The main drivers were response rate to the initial screening questionnaire and attendance rate for the confirmatory spirometry test.DiscussionRegular systematic case-finding for COPD using a screening questionnaire in primary care is likely to be cost-effective in the long-term despite uncertainties in treatment effectiveness. Further knowledge of the natural history of case-found patients and the effectiveness of their management will improve confidence to implement such an approach.
Use of Circulating Tumor DNA for Cancer Immunotherapy
Authors: Snyder Alexandra , Morrissey Michael P. , Hellmann Matthew D. 
Published: July 2019

Abstract
Liquid biopsy offers a versatile, noninvasive opportunity to diagnose, characterize, and monitor disease in patients with cancer. There are particularly promising applications with which to use liquid biopsies to predict and evaluate response to immunotherapy. Circulating tumor DNA (ctDNA) can reflect the genomic state of a patient's overall disease and, thus, might identify prognostic and predictive biomarkers for immune checkpoint inhibitor therapy. ctDNA might also be a proxy for a patient's overall disease burden, which could be used for early diagnosis and monitoring treatment response. These applications can enable novel trial designs, such as enrollment of early-stage patients with a high risk for relapse, and the evaluation of response patterns unique to immunotherapies. However, barriers to the widespread adoption of ctDNA assessment remain, including the absence of standardized procedures for collecting and processing ctDNA samples and relatively limited data on clinical utility. Identifying and solving these challenges could allow ctDNA to become a powerful clinical and research tool in the era of personalized immunotherapy.
Bispecific Antibodies Enable Synthetic Agonistic Receptor-Transduced T Cells for Tumor Immunotherapy
Authors: Karches Clara H. , Benmebarek Mohamed-Reda , Schmidbauer Moritz L. , Kurzay Mathias , Klaus Richard , Geiger Martina , Rataj Felicitas , Cadilha Bruno L. , Lesch Stefanie , Heise Constanze , Murr Ramona , vom Berg Johannes , Jastroch Martin , Lamp Daniel , Ding Jian , Duewell Peter , Niederfellner Gerhard , Sustmann Claudio , Endres Stefan , Klein Christian , Kobold Sebastian 
Published: July 2019

Abstract

Purpose:
Genetically engineered T cells are powerful anticancer treatments but are limited by safety and specificity issues. We herein describe an MHC-unrestricted modular platform combining autologous T cells, transduced with a targetable synthetic agonistic receptor (SAR), with bispecific antibodies (BiAb) that specifically recruit and activate T cells for tumor killing.

Experimental Design:
BiAbs of different formats were generated by recombinant expression. T cells were retrovirally transduced with SARs. T-cell activation, proliferation, differentiation, and T-cell–induced lysis were characterized in three murine and human tumor models in vitro and in vivo.

Results:
Murine T cells transduced with SAR composed of an extracellular domain EGFRvIII fused to CD28 and CD3ζ signaling domains could be specifically recruited toward murine tumor cells expressing EpCAM by anti-EGFRvIII × anti-EpCAM BiAb. BiAb induced selective antigen-dependent activation, proliferation of SAR T cells, and redirected tumor cell lysis. Selectivity was dependent on the monovalency of the antibody for EGFRvIII. We identified FAS ligand as a major mediator of killing utilized by the T cells. Similarly, human SAR T cells could be specifically redirected toward mesothelin-expressing human pancreatic cancer cells. In vivo, treatment with SAR T cells and BiAb mediated antitumoral activity in three human pancreatic cancer cell xenograft models. Importantly, SAR activity, unlike CAR activity, was reversible in vitro and in vivo.

Conclusions:
We describe a novel ACT platform with antitumor activity in murine and human tumor models with a distinct mode of action that combines adoptive T-cell therapy with bispecific antibodies.
A Phase 0 Trial of Ribociclib in Recurrent Glioblastoma Patients Incorporating a Tumor Pharmacodynamic- and Pharmacokinetic-Guided Expansion Cohort
Authors: Tien An-Chi , Li Jing , Bao Xun , Derogatis Alanna , Kim Seongho , Mehta Shwetal , Sanai Nader 
Published: July 2019

Abstract

Purpose:
CDK4/6-dependent cell-cycle regulation is disrupted in most glioblastomas. This study assesses the central nervous system (CNS) pharmacokinetics and tumor pharmacodynamics of ribociclib, a highly selective CDK4/6 inhibitor, in patients with recurrent glioblastoma.

Patients and Methods:
Patients with recurrent glioblastoma with intact retinoblastoma protein (RB) expression and CDKN2A deletion or CDK4/6 amplification were treated with ribociclib daily (900 mg) for 5 days before tumor resection. Blood, tumor, and cerebrospinal fluid (CSF) samples were collected, and total and unbound ribociclib concentrations were determined. Pharmacodynamic effects, assessed by RB and FOXM1 phosphorylation, were compared with matched archival tissue. Patients with positive pharmacokinetic and pharmacodynamic effects were enrolled into the expansion cohort for preliminary assessment of progression-free survival (PFS).

Results:
Twelve patients were enrolled. The mean unbound ribociclib concentrations in CSF, nonenhancing, and enhancing tumor regions were 0.374 μmol/L, 0.560, and 2.152 μmol/kg, respectively, which were more than 5-fold the in vitro IC50 for inhibition of CDK4/6 (0.04 μmol/L). G1-to-S phase suppression was inferred by decreases in phosphorylation of RB (P &lt; 0.01) and cellular proliferation (P &lt; 0.05). Six of 12 patients were enrolled into the pharmacokinetic/pharmacodynamic-guided expansion cohort and demonstrated a median PFS of 9.7 weeks. Examination of recurrent tumors following monotherapy indicated upregulation of the PI3K/mTOR pathway.

Conclusions:
Ribociclib exhibited good CNS penetration, and target modulation was indicated by inhibition of RB phosphorylation and tumor proliferation. Ribociclib monotherapy showed limited clinical efficacy in patients with recurrent glioblastoma. Combination therapy with CDK4/6 and PI3K/mTOR inhibitors may be explored for treating recurrent glioblastoma.
YENİLİKÇİLİK TUTUMLARI VE BÖLGESEL İNOVASYON SİSTEMLERİNE GÖRE PERAKENDECİ KÜMELENMELERİ: TÜRK PERAKENDECİLER FEDERASYONU ÜYELERİ ÜZERİNE BİR ARAŞTIRMA
Authors: KARA Adnan 
Published: July 2019

Bu
çalışma perakende yenilikçiliği ve bölgesel inovasyon sistemleri arasındaki bağıntının
kümeleme analizi yöntemiyle incelenmesini kapsamaktadır. Araştırmanın amacı
perakende yenilikçiliği tutumu ve bölgesel inovasyon sistemleri arasındaki
bağıntıyı ortaya çıkarmaktır. Araştırmanın ana kütlesini Türkiye Perakendeciler
Federasyonuna üye perakendeciler oluşturmaktadır. Araştırmada telefon
yöntemiyle toplanan anket verileri iki adımlı kümeleme analizine tabi
tutulmuştur. Araştırma sonucunda
perakende yenilikçiliklerine göre dört küme elde edilmiştir. Her bir kümedeki
perakendecilerin bölgesel inovasyon indeks puanları ve perakende yenilikçiliği
tutumları karşılaştırılmıştır. Perakende yenilikçiliği gelişmiş ülkelerde
önemli görülmektedir. Günümüzde perakendecilik üretici ve tüketici arasındaki
dengesizlikleri giderebilmesinden dolayı ekonomide önemli bir yer edinmiştir.
Gelişmekte olan ülkeler de bu nedenle perakendeciliği ekonomik kalkınmanın bir
aracı olarak önemli konumda görmektedirler. Araştırma bölgesel inovasyon
sistemleri ve perakendeci yenilikçilik tutumlarının bir arada incelendiği özgün
bir çalışmadır.
Evaluation of the Assumptions in the Steady-State Tropical Cyclone Self-Stratified Outflow Using Three-Dimensional Convection-Allowing Simulations
Authors: Tao Dandan , Emanuel Kerry , Zhang Fuqing , Rotunno Richard , Bell Michael M. , Nystrom Robert G. 
Published: July 2019

Abstract
The criteria and assumptions that were used to derive the steady-state tropical cyclone intensity and structure theory of Emanuel and Rotunno are assessed using three-dimensional convection-allowing simulations using the Weather Research and Forecasting Model. One real-data case of Hurricane Patricia (2015) and two idealized simulations with and without vertical wind shear are examined. In all three simulations, the gradient wind balance is valid in the inner-core region above the boundary layer. The angular momentum M and saturation entropy surfaces s* near the top of the boundary layer, in the outflow region and along the angular momentum surface that passes the low-level radius of maximum wind MRMW are nearly congruent, satisfying the criterion of slantwise moist neutrality in the vicinity of MRMW. The theoretically derived maximum wind magnitude above the boundary layer compares well with the simulated maximum tangential wind and gradient wind using the azimuthally averaged pressure field during the intensification and quasi-steady state of the simulated storms. The Richardson number analysis of the simulated storms shows that small Richardson number (0 &lt; Ri ≤1) exists in the outflow region, related to both large local shear and small static stability. This criticality of the Richardson number indicates the existence of small-scale turbulence in the outflow region. We also show that the stratification of temperature along the M surfaces at the outflow region for steady-state hurricanes is approximately applicable in these three-dimensional simulations, while the radial distribution of gradient wind is qualitatively comparable to the theoretical radial profiles. Some caveats regarding the theory are also discussed.
Effects of Tropical Cyclones on ENSO
Authors: Lian Tao , Ying Jun , Ren Hong-Li , Zhang Chan , Liu Ting , Tan Xiao-Xiao 
Published: July 2019

AbstractNumerous studies have investigated the role of El Niño–Southern Oscillation (ENSO) in modulating the activity of tropical cyclones (TCs) in the western Pacific on interannual time scales, but the effects of TCs on ENSO are less discussed. Some studies have found that TCs sharply increase surface westerly anomalies over the equatorial western–central Pacific and maintain them there for a few days. Given the strong influence of equatorial surface westerly wind bursts on ENSO, as confirmed by much recent literature, the effects of TCs on ENSO may be much greater than previously expected. Using recently released observations and reanalysis datasets, it is found that the majority of near-equatorial TCs (simply TCs hereafter) are associated with strong westerly anomalies at the equator, and the number and longitude of TCs are significantly correlated with ENSO strength. When TC-related wind stresses are added into an intermediate coupled model, the simulated ENSO becomes more irregular, and both ENSO magnitude and skewness approach those of observations, as compared with simulations without TCs. Adding TCs into the model system does not break the linkage between the heat content anomaly and subsequent ENSO event in the model, which manifest the classic recharge–discharge ENSO dynamics. However, the influence of TCs on ENSO is so strong that ENSO magnitude and sometimes its final state—that is, either El Niño or La Niña—largely depend on the number and timing of TCs during the event year. Our findings suggest that TCs play a prominent role in ENSO dynamics, and their effects must be considered in ENSO forecast models.
Interannual to Decadal Variability of Upper-Ocean Salinity in the Southern Indian Ocean and the Role of the Indonesian Throughflow
Authors: Hu Shijian , Zhang Ying , Feng Ming , Du Yan , Sprintall Janet , Wang Fan , Hu Dunxin , Xie Qiang , Chai Fei 
Published: July 2019

AbstractVariability of oceanic salinity, an indicator of the global hydrological cycle, plays an important role in the basin-scale ocean circulation. In this study, interannual to decadal variability of salinity in the upper layer of the Indian Ocean is investigated using Argo observations since 2004 and data assimilating model outputs (1992–2015). The southeastern Indian Ocean shows the strongest interannual to decadal variability of upper-ocean salinity in the Indian Ocean. Westward propagation of salinity anomalies along isopycnal surfaces is detected in the southern Indian Ocean and attributed to zonal salinity advection anomalies associated with the Indonesian Throughflow and the South Equatorial Current. Composite and salinity budget analyses show that horizontal advection is a major contributor to the interannual to decadal salinity variability of the southern Indian Ocean, and the local air–sea freshwater flux plays a secondary role. The Pacific decadal oscillation (PDO) and El Niño–Southern Oscillation (ENSO) modulate the salinity variability in the southeastern Indian Ocean, with low salinity anomalies occurring during the negative phases of the PDO and ENSO and high salinity anomalies during their positive phases. The Indonesian Throughflow plays an essential role in transmitting the PDO- and ENSO-related salinity signals into the Indian Ocean. A statistical model is proposed based on the PDO index, which successfully predicts the southeastern Indian Ocean salinity variability with a lead time of 10 months.
Evolution of the Asian–African Monsoonal Precipitation over the last 21 kyr and the Associated Dynamic Mechanisms
Authors: Shi Jian , Yan Qing 
Published: July 2019

Abstract
The Asian–African monsoonal precipitation (AAMP) has a significant impact on the water availability, biodiversity, and livelihoods of billions of people. A comprehensive understanding of the AAMP behavior over Earth’s history will help to make better future projections. Using a set of transient climate simulations over the last 21 000 years (21 ka), the variation of the AAMP and its responses to various external forcings, including orbital insolation, greenhouse gases (GHGs), and ice sheets, are explored. The precipitation evolutions in the individual monsoon domains have the characteristic of hemispheric synchrony over the last 21 ka. Specifically, the AAMP increased from the Last Glacial Maximum to the early Holocene with several abrupt events and then decreased subsequently. The raised orbital insolation and GHGs lead to an overall AAMP increase, but the enhanced insolation tends to induce a systematic northward shift of the Asian–African monsoon domain. Decreased meltwater discharge could promote the African and Indian monsoonal precipitation through strengthening the Atlantic Ocean meridional overturning circulation. However, the lowering of ice sheets (i.e., orographic effect) results in an anomalous dipole precipitation pattern between North China and India. An analysis of the moisture budget suggests that, although different external forcings may lead to the same sign of precipitation change (e.g., both increased insolation and GHGs can cause the enhanced AAMP), the thermodynamic and dynamic contributions to precipitation could vary greatly by region and forcing. This study provides a reference for the long-term behavior of the AAMP with rising GHGs, higher insolation, and potential melting of the Greenland Ice Sheet.
Horizontal Residual Mean: Addressing the Limited Spatial Resolution of Ocean Models
Authors: Li Yuehua , McDougall Trevor , Keating Shane , de Lavergne Casimir , Madec Gurvan 
Published: July 2019

AbstractHorizontal fluxes of heat and other scalar quantities in the ocean are due to correlations between the horizontal velocity and tracer fields. However, the limited spatial resolution of ocean models means that these correlations are not fully resolved using the velocity and temperature evaluated on the model grid, due to the limited spatial resolution and the boxcar-averaged nature of the velocity and the scalar field. In this article, a method of estimating the horizontal flux due to unresolved spatial correlations is proposed, based on the depth-integrated horizontal transport from the seafloor to the density surface whose spatially averaged height is the height of the calculation. This depth-integrated horizontal transport takes into account the subgrid velocity and density variations to compensate the standard estimate of horizontal transport based on staircase-like velocity and density. It is not a parameterization of unresolved eddies, since it utilizes data available in ocean models without relying on any presumed parameter such as diffusivity. The method is termed the horizontal residual mean (HRM). The method is capable of estimating the spatial-correlation-induced water transport in a 1/4° global ocean model, using model data smoothed to 3/4°. The HRM extra overturning has a peak in the Southern Ocean of about 1.5 Sv (1 Sv ≡ 106 m3 s−1). This indicates an extra heat transport of 0.015 PW on average in the same area. It is expected that implementing the scheme in a coarse-resolution ocean model will improve its representation of lateral heat fluxes.
Arctic Fog Detection Using Infrared Spectral Measurements
Authors: Yi Li , Li King-Fai , Chen Xianyao , Tung Ka-Kit 
Published: July 2019

AbstractThe rapid increase in open-water surface area in the Arctic, resulting from sea ice melting during the summer likely as a result of global warming, may lead to an increase in fog [defined as a cloud with a base height below 1000 ft (~304 m)], which may imperil ships and small aircraft transportation in the region. There is a need for monitoring fog formation over the Arctic. Given that ground-based observations of fog over Arctic open water are very sparse, satellite observations may become the most effective way for Arctic fog monitoring. We developed a fog detection algorithm using the temperature difference between the cloud top and the surface, called ∂T in this work. A fog event is said to be detected if ∂T is greater than a threshold, which is typically between −6 and −12 K, depending on the time of the day (day or night) and the surface types (open water or sea ice). We applied this method to the coastal regions of Chukchi Sea and Beaufort Sea near Barrow, Alaska (now known as Utqiaġvik), during the months of March–October. Training with satellite observations between 2007 and 2014 over this region, the ∂T method can detect Arctic fog with an optimal probability of detection (POD) between 74% and 90% and false alarm rate (FAR) between 5% and 17%. These statistics are validated with data between 2015 and 2016 and are shown to be robust from one subperiod to another.
Numerical Calibration of a Low-Speed sUAS Flush Air Data System
Authors: Laurence III Roger J. , Argrow Brian M. 
Published: July 2019

AbstractA method using computational fluid dynamics to numerically calibrate a flush air data system is presented. A small unmanned aircraft system (sUAS) has been equipped with a flush air data system and experimentally tested. The flush air data system uses computational fluid dynamics to train neural networks and is validated using the in-flight data that were previously collected. Results of the flight validation are presented, along with ways to improve the accuracy of the system. Several different calibration approaches are presented and compared with each other. The best-case results with the in-flight calibration are 0.59° and 0.66° for angle of attack and sideslip, respectively, whereas the best-case results when calibrated with computational fluid dynamics data are 0.78° and 0.90°. It is also possible to estimate other air data parameters, such as dynamic pressure, static pressure, and density, with neural networks, but the direct calculation is more accurate. Calibrating the system numerically, such as with the use of computational fluid dynamics, removes the need for any calibration flights. Although not as accurate as the in-flight calibration, numerical calibration is possible and can save the user time and expense.
Observation Error Statistics for Doppler Radar Radial Wind Superobservations Assimilated into the DWD COSMO-KENDA System
Authors: Waller J. A. , Bauernschubert E. , Dance S. L. , Nichols N. K. , Potthast R. , Simonin D. 
Published: July 2019

AbstractCurrently in operational numerical weather prediction (NWP) the density of high-resolution observations, such as Doppler radar radial winds (DRWs), is severely reduced in part to avoid violating the assumption of uncorrelated observation errors. To improve the quantity of observations used and the impact that they have on the forecast requires an accurate specification of the observation uncertainties. Observation uncertainties can be estimated using a simple diagnostic that utilizes the statistical averages of observation-minus-background and observation-minus-analysis residuals. We are the first to use a modified form of the diagnostic to estimate spatial correlations for observations used in an operational ensemble data assimilation system. The uncertainties for DRW superobservations assimilated into the Deutscher Wetterdienst convection-permitting NWP model are estimated and compared to previous uncertainty estimates for DRWs. The new results show that most diagnosed standard deviations are smaller than those used in the assimilation, hence, it may be feasible to assimilate DRWs using reduced error standard deviations. However, some of the estimated standard deviations are considerably larger than those used in the assimilation; these large errors highlight areas where the observation processing system may be improved. The error correlation length scales are larger than the observation separation distance and influenced by both the superobbing procedure and observation operator. This is supported by comparing these results to our previous study using Met Office data. Our results suggest that DRW error correlations may be reduced by improving the superobbing procedure and observation operator; however, any remaining correlations should be accounted for in the assimilation.