A sequential test for assessing observed agreement between raters

Assessing the agreement between two or more raters is an important topic in medical practice. Existing techniques, which deal with categorical data, are based on contingency tables. This is often an obstacle in practice as we have to wait for a long time to collect the appropriate sample size of subjects to construct the contingency table. In this paper, we introduce a nonparametric sequential test for assessing agreement, which can be applied as data accrues, does not require a contingency table, facilitating a rapid assessment of the agreement. The proposed test is based on the cumulative sum of the number of disagreements between the two raters and a suitable statistic representing the waiting time until the cumulative sum exceeds a predefined threshold. We treat the cases of testing two raters' agreement with respect to one or more characteristics and using two or more classification categories, the case where the two raters extremely disagree, and finally the case of testing more than two raters' agreement. The numerical investigation shows that the proposed test has excellent performance. Compared to the existing methods, the proposed method appears to require significantly smaller sample size with equivalent power. Moreover, the proposed method is easily generalizable and brings the problem of assessing the agreement between two or more raters and one or more characteristics under a unified framework, thus providing an easy to use tool to medical practitioners.     

On using network RAM as a non‐volatile buffer

File systems and databases usually make several synchronous disk write accesses in order to make sure that the disk always has a consistent view of their data, so that it can be recovered in the case of a system crash. Since synchronous disk operations are slow, some systems choose to employ asynchronous disk write operations that improve performance at the cost of low reliability: in case of a system crash all data that have not yet been written to disk are lost. In this paper we describe a softwarebased NonVolatile RAM system that achieves the high performance of asynchronous write operations without sacrificing the reliability of synchronous write operations. Our system takes a set of volatile main memories residing in independent workstations and transforms it into a nonvolatile memory buffer – much like RAIDS do with magnetic disks. It then uses this nonvolatile buffer as an intermediate storage space in order to acknowledge synchronous write operations before actually writing the data to magnetic disk, but after writing the data to (intermediate) stable storage. We demonstrate the performance advantages of our system using both simulation and experimental evaluation.     

A decision tree--based method for the differential diagnosis of Aortic Stenosis from Mitral Regurgitation using heart sounds

Background  

New technologies like echocardiography, color Doppler, CT, and MRI provide more direct and accurate evidence of heart disease than heart auscultation. However, these modalities are costly, large in size and operationally complex and therefore are not suitable for use in rural areas, in homecare and generally in primary healthcare set-ups. Furthermore the majority of internal medicine and cardiology training programs underestimate the value of cardiac auscultation and junior clinicians are not adequately trained in this field. Therefore efficient decision support systems would be very useful for supporting clinicians to make better heart sound diagnosis. In this study a rule-based method, based on decision trees, has been developed for differential diagnosis between "clear" Aortic Stenosis (AS) and "clear" Mitral Regurgitation (MR) using heart sounds.     

A new approach for evaluating in vivo anti-leukemic activity using the SCE assay. An application on three newly synthesised anti-tumour steroidal esters

Three newly synthesised steroidal esteric derivatives of nitrogen mustard (compounds 1-3) were comparatively studied on a molar basis regarding their ability to induce sister chromatid exchanges (SCEs) in normal human lymphocytes in vitro and therapeutic effects on leukemia P388 bearing mice. Compounds 1 and 3 are modified steroidal esters of p-methyl-m-N,N-bis(2-chloroethyl)amino benzoic acid, and compound 2 is a modified steroidal ester of chlorambucil. All compounds induced statistically significant increases in SCEs and decreases in proliferation rate indices (PRIs) of cultured human lymphocytes and significantly increased the life span of P388 bearing mice. In this study, the doses applied for therapeutic purposes upon leukemia P388 bearing mice in vivo were derived from cytogenetic observations in normal human lymphocytes in vitro. A substantially better therapeutic effect was obtained compared to the effect achieved after the use of quite higher doses related with LD(10) values. We have demonstrated that the order of anti-tumour effectiveness of the treatment schedules of the three newly synthesised compounds tested (at doses derived from cytogenetic observations) coincides with the order of the cytogenetic effects they induce. The SCE assay appears to have an application in the clinical prediction of tumour sensitivity to potential chemotherapeutics.     

Synthetic approaches for the synthesis of a cytostatic steroidal B-D bilactam

A new synthetic procedure and a modification of the original method described in the literature for the synthesis of the steroidal B-D bilactam, 3 beta-hydroxy-7 alpha,17 alpha-diaza-B,D-dihomo-5-androsten-7,17-dione are reported. The key step in the modified method involved protection of the D-lactamic nitrogen atom of 3 beta-acetoxy-17 alpha-aza-D-homo-5-androsten-17-one using a reagent of specific electrophilicity (due to the stereoelectronic properties of the cyclic amide), as Beckmann rearrangement of the B-steroidal ring was hindered, possibly via long range effects, by the presence of the unprotected D-lactamic moiety. Using the 3 beta-acetoxy-5-androsten-17-one as starting material, a new synthetic procedure was developed through ketalization of the 17-ketone and allylic oxidation to the 7-ketone, which was subsequently followed by Beckmann rearrangement of the B- and D-steroid rings. Both approaches resulted in 45 and 67% yields of the desired B,D-bilactam, respectively, in contrast to the 15% yield, which has been reported in the literature.     

Transport-dependent endocytosis and turnover of a uric acid-xanthine permease

In this work we unmask a novel downregulation mechanism of the uric acid/xanthine transporter UapA, the prototype member of the ubiquitous Nucleobase-Ascorbate Transporter family, directly related to its function. In the presence of substrates, UapA is endocytosed, sorted into the multivesicular body pathway and degraded in vacuoles. Substrate-induced endocytosis, unlike ammonium-induced turnover, is absolutely dependent on UapA activity and several lines of evidence showed that the signal for increased endocytosis is the actual translocation of substrates through the UapA protein. The use of several UapA functional mutants with altered kinetics and specificity has further shown that transport-dependent UapA endocytosis occurs through a mechanism, which senses subtle conformational changes associated with the transport cycle. We also show that distinct mechanisms of UapA endocytosis necessitate ubiquitination of a single Lys residue (K572) by HulA^Rsp5. Finally, we demonstrate that in the presence of substrates, non-functional UapA versions can be endocytosed in trans if expressed in the simultaneous presence of active UapA versions, even if the latter cannot be endocytosed themselves.     

Analysis and interpretation of dynamic FDG PET oncological studies using data reduction techniques

Background  

Dynamic positron emission tomography studies produce a large amount of image data, from which clinically useful parametric information can be extracted using tracer kinetic methods. Data reduction methods can facilitate the initial interpretation and visual analysis of these large image sequences and at the same time can preserve important information and allow for basic feature characterization.     

20-Aminosteroids as a novel class of selective and complete androgen receptor antagonists and inhibitors of prostate cancer cell growth

Here, the synthesis and the evaluation of novel 20-aminosteroids on androgen receptor (AR) activity is reported. Compounds 11 and 18 of the series inhibit both the wild type and the T877A mutant AR-mediated transactivation indicating AR antagonistic function. Interestingly, minor structural changes such as stereoisomers of the amino lactame moiety exhibit preferences for antagonism among wild type and mutant AR. Other tested nuclear receptors are only weakly or not affected. In line with this, the prostate cancer cell growth of androgen-dependent but not of cancer cells lacking expression of the AR is inhibited. Further, the expression of the prostate specific antigen used as a diagnostic marker is also repressed. Finally steroid 18 enhances cellular senescence that might explain in part the growth inhibition mediated by this derivative. Steroids 11 and 18 are the first steroids that act as complete AR antagonists and exhibit AR specificity.     

Structural, photolysis and biological studies of the bis(μ2-chloro)-tris(triphenylphosphine)-di-copper(I) and chloro-tris(triphenylphosphine)-copper(I) complexes. Study of copper(I)-copper(I) interactions

Direct reaction of copper(I) chloride with triphenylphosphine (tpp) in molar ratio 2:3 and 1:3, results in the formation of the [(tpp)Cu(μ₂-Cl)₂Cu(tpp)₂] (1) and {[CuCl(tpp)₃]·(CH₃CN)} (2) complexes. The complexes have been characterized by melting point, FT-IR, UV-Vis spectroscopic data and X-ray crystallography. Complex 1 is di-nuclear. Two μ₂-Cl atoms bridge two copper(I) ions with tetrahedral and trigonal geometry respectively. The short copper-copper bond distance of 2.9039(6) ? in case of 1 indicates d¹⁰-d¹⁰ interaction between metal centers. Thus, our studies were extended here in the determination of the quasi-aromaticity, which results in strong Cu-Cu interactions, using the computational method of nucleus-independent chemical shifts (NICS). The NICS calculated at the inner region of the Cu₂Cl₂P₃ core in complex 1 is shielded up to −6.05 ppm. Complex 2 is mono-nuclear where three phosphorus and one chloride atoms form a tetrahedron around the copper(I) ion. Photolysis of both complexes 1 and 2, results in the formation of triphenylphosphine oxide.The complexes 1 and 2, were tested for their in vitro cytotoxic activity against leiomyosarcoma cells (LMS) and human breast adenocarcinoma cells (MCF-7). The type of LMS cell death caused by the complexes was also evaluated by use of a flow cytometry assay. The results show that at concentration of 5 μΜ of complexes 1 and 2, 34.1% (1) and 19.6 (2)% of LMS cells undergo programmed cell death (apoptosis), while at 10 μΜ, 80.4% (1) and 65.2% (2) of LMS cells undergo apoptosis. The light sensitivity of the complex is discussed in relation with the biological activity.