Non-stationary covariance function modelling in 2D least-squares collocation

Standard least-squares collocation (LSC) assumes 2D stationarity and 3D isotropy, and relies on a covariance function to account for spatial dependence in the ob-served data. However, the assumption that the spatial dependence is constant through-out the region of interest may sometimes be violated. Assuming a stationary covariance structure can result in over-smoothing of, e.g., the gravity field in mountains and under-smoothing in great plains. We introduce the kernel convolution method from spatial statistics for non-stationary covariance structures, and demonstrate its advantage fordealing with non-stationarity in geodetic data. We then compared stationary and non-stationary covariance functions in 2D LSC to the empirical example of gravity anomaly interpolation near the Darling Fault, Western Australia, where the field is anisotropic and non-stationary. The results with non-stationary covariance functions are better than standard LSC in terms of formal errors and cross-validation against data not used in the interpolation, demonstrating that the use of non-stationary covariance functions can improve upon standard (stationary) LSC

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity

Spin-Imbalance in a One-Dimensional Fermi Gas

Superconductivity and magnetism generally do not coexist. Changing the relative number of up and down spin electrons disrupts the basic mechanism of superconductivity, where atoms of opposite momentum and spin form Cooper pairs. Nearly forty years ago Fulde and Ferrell and Larkin and Ovchinnikov proposed an exotic pairing mechanism (FFLO) where magnetism is accommodated by formation of pairs with finite momentum. Despite intense theoretical and experimental efforts, however, polarized superconductivity remains largely elusive. Here we report experimental measurements of density profiles of a two spin mixture of ultracold 6Li atoms trapped in an array of one dimensional (1D) tubes, a system analogous to electrons in 1D wires. At finite spin imbalance, the system phase separates with an inverted phase profile in comparison to the three-dimensional case. In 1D we find a partially polarized core surrounded by wings composed of either a completely paired BCS superfluid or a fully polarized Fermi gas, depending on the degree of polarization. Our observations are in quantitative agreement with theoretical calculations in which the partially polarized phase is found to be a 1D analogue of the FFLO state. This study demonstrates how ultracold atomic gases in 1D may be used to create non-trivial new phases of matter, and also paves the way for direct observation and further study of the FFLO phase.Comment: 30 pages, 7 figure

The population-based oncological health care study OVIS – recruitment of the patients and analysis of the non-participants

<p>Abstract</p> <p>Background</p> <p>The ageing of the population is expected to bring an enormous growth in demand for oncological health care. In order to anticipate and respond to future trends, cancer care needs to be critically evaluated. The present study explores the possibility of conducting representative and population-based research on cancer care on the basis of data drawn from the Cancer Registry.</p> <p>Methods</p> <p>A population-based state-wide cohort study (OVIS) has been carried out in Schleswig-Holstein, Germany. All patients with malignant melanoma, breast, or prostate cancer were identified in the Cancer Registry. Epidemiological data were obtained for all the patients and screened for study eligibility. A postal questionnaire requesting information on diagnosis, therapy, QoL and aftercare was sent to eligible patients.</p> <p>Results</p> <p>A total of 11,489 persons diagnosed with the cancer types of interest in the period from January 2002 to July 2004 were registered in the Cancer Registry. Of the 5,354 (47%) patients who gave consent for research, 4,285 (80% of consenters) completed the questionnaire. In terms of relevant epidemiological variables, participants with melanoma were not found to be different from non-participants with the same diagnosis. However, participants with breast or prostate cancer were slightly younger and had smaller tumours than patients who did not participate in our study.</p> <p>Conclusion</p> <p>Population-based cancer registry data proved to be an invaluable resource for both patient recruitment and non-participant analysis. It can help improve our understanding of the strength and nature of differences between participants and non-respondents. Despite minor differences observed in breast and prostate cancer, the OVIS-sample seems to represent the source population adequately.</p

Boussignac continuous positive airway pressure for the management of acute cardiogenic pulmonary edema: prospective study with a retrospective control group

<p>Abstract</p> <p>Background</p> <p>Continuous positive airway pressure (CPAP) treatment for acute cardiogenic pulmonary edema can have important benefits in acute cardiac care. However, coronary care units are usually not equipped and their personnel not adequately trained for applying CPAP with mechanical ventilators. Therefore we investigated in the coronary care unit setting the feasibility and outcome of the simple Boussignac mask-CPAP (BCPAP) system that does not need a mechanical ventilator.</p> <p>Methods</p> <p>BCPAP was introduced in a coronary care unit where staff had no CPAP experience. All consecutive patients transported to our hospital with acute cardiogenic pulmonary edema, a respiratory rate > 25 breaths/min and a peripheral arterial oxygen saturation of < 95% while receiving oxygen, were included in a prospective BCPAP group that was compared with a historical control group that received conventional treatment with oxygen alone.</p> <p>Results</p> <p>During the 2-year prospective BCPAP study period 108 patients were admitted with acute cardiogenic pulmonary edema. Eighty-four of these patients (78%) were treated at the coronary care unit of which 66 (61%) were treated with BCPAP. During the control period 66 patients were admitted over a 1-year period of whom 31 (47%) needed respiratory support in the intensive care unit. BCPAP treatment was associated with a reduced hospital length of stay and fewer transfers to the intensive care unit for intubation and mechanical ventilation. Overall estimated savings of approximately € 3,800 per patient were achieved with the BCPAP strategy compared to conventional treatment.</p> <p>Conclusion</p> <p>At the coronary care unit, BCPAP was feasible, medically effective, and cost-effective in the treatment of acute cardiogenic pulmonary edema. Endpoints included mortality, coronary care unit and hospital length of stay, need of ventilatory support, and cost (savings).</p

Mitochondrial Control Region and microsatellite analyses on harbour porpoise (Phocoena phocoena) unravel population differentiation in the Baltic Sea and adjacent waters

The population status of the harbour porpoise (Phocoena phocoena) in the Baltic area has been a continuous matter of debate. Here we present the by far most comprehensive genetic population structure assessment to date for this region, both with regard to geographic coverage and sample size: 497 porpoise samples from North Sea, Skagerrak, Kattegat, Belt Sea, and Inner Baltic Sea were sequenced at the mitochondrial Control Region and 305 of these specimens were typed at 15 polymorphic microsatellite loci. Samples were stratified according to sample type (stranding vs. by-caught), sex, and season (breeding vs. non-breeding season). Our data provide ample evidence for a population split between the Skagerrak and the Belt Sea, with a transition zone in the Kattegat area. Among other measures, this was particularly visible in significant frequency shifts of the most abundant mitochondrial haplotypes. A particular haplotype almost absent in the North Sea was the most abundant in Belt Sea and Inner Baltic Sea. Microsatellites yielded a similar pattern (i.e., turnover in occurrence of clusters identified by STRUCTURE). Moreover, a highly significant association between microsatellite assignment and unlinked mitochondrial haplotypes further indicates a split between North Sea and Baltic porpoises. For the Inner Baltic Sea, we consistently recovered a small, but significant separation from the Belt Sea population. Despite recent arguments that separation should exceed a predefined threshold before populations shall be managed separately, we argue in favour of precautionary acknowledging the Inner Baltic porpoises as a separate management unit, which should receive particular attention, as it is threatened by various factors, in particular local fishery measures. © Springer Science+Business Media B.V. 2009

Aurora-A/STK15/BTAK overexpression induces centrosome amplification, chromosomal instability, and transformation in human urothelial cells

Aurora-A/STK15/BTAK kinase encoding gene, located on chromosome 20q13, is frequently amplified and overexpressed in human cancers. Sen et al. previously demonstrated that Aurora-A amplification and overexpression are associated with aneuploidy and clinically aggressive bladder cancer (J Natl Cancer Inst (2002) 94, 1320-1329). To examine if this association is the direct result of Aurora-A gene amplification and overexpression, an immortalized human urothelial cell line (SV-HUC) was infected with an adenoviral Aurora-A-green fluorescent protein (Ad-Aurora-A-GFP) fusion construct inducing ectopic expression of the resulting fusion protein. Controls included mock-infected and adenoviral-GFP infected cells. Ectopic expression of transduced Aurora-A did not alter the doubling time of the SV-HUC cells but significantly increased the number of cells with multiple centrosomes displaying aneuploidy and increased colony formation in soft agar. This is the first report demonstrating that overexpression of Aurora-A induces centrosome anomalies together with chromosomal instability and malignant transformation-associated phenotypic changes in immortalized human urothelial cells, thus supporting the hypothesis that this gene plays an important role in the development of aggressive bladder cancer

The value of health care – a matter of discussion in Germany

BACKGROUND: Interest in assessing the value of health-care services in Germany has considerably increased since the foundation of the Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, IQWiG (Institute for Quality and Efficiency in Health Care). The practical application of value assessment illustrates how problematic the process can be. In all decisions made for the provision of health care, data concerning the measurable dimensions (quantity and quality of efficacy and effectiveness, validity of the results and costs) flow into a complex and not yet standardized decision-making process concerning public financing. Some of these decisions are based on data of uncertain validity, unknown reproducibility and unclear appropriateness. DISCUSSION: In this paper we describe the theoretical aspects of value from psychological and economic viewpoints and discuss national and international approaches. Methodic details and difficulties in assessing the value of health-care services are analysed. A definition of the intangible value of health-care services will be proposed which contains only three factors: the absolute risk reduction (usually a measure of efficacy), the validity of the scientific papers examined and the type of the expected effectiveness (prevention of death and disability, restitution of well-being). The intangible value describes the additional benefit when comparing two possible actions, like treatment or observation only. CONCLUSION: The description of intangible value from the viewpoint of different stakeholders is a useful measure for subsequent steps (not discussed here) – the evaluation of costs and of patient benefit. A standardised, transparent, fair and democratic evaluation is essential for the definition of a basic benefit package

DNA Barcode Detects High Genetic Structure within Neotropical Bird Species

BACKGROUND: Towards lower latitudes the number of recognized species is not only higher, but also phylogeographic subdivision within species is more pronounced. Moreover, new genetically isolated populations are often described in recent phylogenies of Neotropical birds suggesting that the number of species in the region is underestimated. Previous COI barcoding of Argentinean bird species showed more complex patterns of regional divergence in the Neotropical than in the North American avifauna. METHODS AND FINDINGS: Here we analyzed 1,431 samples from 561 different species to extend the Neotropical bird barcode survey to lower latitudes, and detected even higher geographic structure within species than reported previously. About 93% (520) of the species were identified correctly from their DNA barcodes. The remaining 41 species were not monophyletic in their COI sequences because they shared barcode sequences with closely related species (N = 21) or contained very divergent clusters suggestive of putative new species embedded within the gene tree (N = 20). Deep intraspecific divergences overlapping with among-species differences were detected in 48 species, often with samples from large geographic areas and several including multiple subspecies. This strong population genetic structure often coincided with breaks between different ecoregions or areas of endemism. CONCLUSIONS: The taxonomic uncertainty associated with the high incidence of non-monophyletic species and discovery of putative species obscures studies of historical patterns of species diversification in the Neotropical region. We showed that COI barcodes are a valuable tool to indicate which taxa would benefit from more extensive taxonomic revisions with multilocus approaches. Moreover, our results support hypotheses that the megadiversity of birds in the region is associated with multiple geographic processes starting well before the Quaternary and extending to more recent geological periods

Search for direct pair production of the top squark in all-hadronic final states in proton-proton collisions at s√=8 TeV with the ATLAS detector

The results of a search for direct pair production of the scalar partner to the top quark using an integrated luminosity of 20.1fb−1 of proton–proton collision data at √s = 8 TeV recorded with the ATLAS detector at the LHC are reported. The top squark is assumed to decay via t˜→tχ˜01 or t˜→ bχ˜±1 →bW(∗)χ˜01 , where χ˜01 (χ˜±1 ) denotes the lightest neutralino (chargino) in supersymmetric models. The search targets a fully-hadronic final state in events with four or more jets and large missing transverse momentum. No significant excess over the Standard Model background prediction is observed, and exclusion limits are reported in terms of the top squark and neutralino masses and as a function of the branching fraction of t˜ → tχ˜01 . For a branching fraction of 100%, top squark masses in the range 270–645 GeV are excluded for χ˜01 masses below 30 GeV. For a branching fraction of 50% to either t˜ → tχ˜01 or t˜ → bχ˜±1 , and assuming the χ˜±1 mass to be twice the χ˜01 mass, top squark masses in the range 250–550 GeV are excluded for χ˜01 masses below 60 GeV