Partition Values Research Articles

Black-Box Testing : Analisis Kualitas Aplikasi Source Code Bank Programming

The Source Code Bank Programming application that the researchers built uses Borland Delphi which functions to support software learning activities and as a reference for software developers, especially the Delphi programming language. In the process of developing Source Code Bank Programming is still in the prototype stage and further development is still being carried out so that it can be competitively competitive in the world. It is necessary to do various evaluations of the quality of the application in order to match the expectations of the user, one of which is to analyze the quality of the application using the Black-Box Testing method. Testing the Black-Box Source Code Bank Programming uses 3 methods, namely; 1) Graph-based testing, 2) Equivalence Partitioning, and 3) Boundary Value Analysis. The research results show that graph testing, equivalence partitioning, and boundary value analysis will be able to help the process of making test cases and make testing simpler, There are errors in testing and are included in the defect-list, the test results also show that the fulfillment of user needs for public users with a value 0.90, user registers/member with a value of 1.00, students with a value of 0.90, lecturers with a value of 0.82 and admin with a value of 0.84 are classified as good because the degree of value in each user module is greater than 0.8.

Abstract 16395: Soluble ST2 and Its Association With Echocardiographic Measures of Cardiac Structure

Background: Soluble ST2 (sST2) has emerged as a powerful prognostic marker in chronic systolic heart failure with reduced ejection fraction (HFrEF). Elevated levels of sST2 are associated with adverse cardiac remodeling and fibrosis. We have previously described the prognostic value of sST2 collected from stable patients in the ambulatory setting and correlated it with long term clinical outcomes. However, few studies have demonstrated the association between sST2 levels and echocardiographic measures of cardiac structure and function as well as outcomes. Hypothesis: Baseline circulating levels of sST2, using the partition value of 35 ng/ml, will correlate with echocardiographic measures of cardiac chamber size and function in stable stage C patients in the ambulatory setting. Methods: Single-center, retrospective observational study of subjects presenting to an ambulatory heart failure (HF) clinic from July 2014 to December 2016. There were 156 subjects with stage C heart failure and a baseline sST2 level. For purposes of this analysis in HFrEF, we excluded patients with EF > 40% resulting in a study cohort of 103 subjects. The mean follow-up was 2.20 years ± 1.53 years. Analysis was performed with IBM SPSS Statistics 26. Discrete variables were expressed as counts (percentage) and were compared using the Chi-squared test. Mean differences of continuous variables were expressed as a mean ± standard deviation and compared using the unpaired Student’s t- test. Results: Patients who had baseline sST2 ≥ 35 ng/ml had a greater LA volume index (p=0.05) and RA area (p=0.01) compared to patients with sST2 < 35 ng/ml. Patients with sST2 ≥ 35 ng/ml had a mean LA volume index of 62.72 ± 30.28 ml/m 2 and RA area of 24.59 ± 7.87 ml/m 2 . We also found that sST2 ≥ 35 ng/ml was associated with increased risk for atrial arrhythmias (39.0% vs. 20.5%), a higher New York Heart Association classification (2.73 vs. 2.18), lower hemoglobin (11.5 vs 13.0), and lower systolic blood pressure (109.6 vs 124.8). Conclusion: In our study, subjects with sST2 levels ≥ 35 ng/ml was associated with increased atrial size by echocardiography, increased risk for atrial arrhythmia and higher NYHA class. These findings support the utility of sST2 for risk stratification in ambulatory patients with HFrEF.

Abstract 15520: Prognostic Value of Soluble ST2 Measurements for Morbidity and Mortality in Ambulatory Patients With HFpEF

Background: Soluble ST2 (sST2) has emerged as a powerful prognostic marker in chronic systolic heart failure with reduced ejection fraction (HFrEF). Elevated levels of sST2 are associated with adverse cardiac remodeling and fibrosis. However, few studies have investigated the relative prognostic value of sST2 collected from ambulatory patients with chronic heart failure with preserved ejection fraction (HFpEF) for long term outcomes. Hypothesis: We sought to determine the prognostic utility of a baseline sST2 partition value in the ambulatory setting as it related to risk for heart failure hospitalization and all-cause mortality. Methods: Single-center, retrospective observational study of subjects presenting to an ambulatory heart failure (HF) clinic from July 2014 to December 2016. Baseline sST2 levels were available for 156 subjects with stage C heart failure.. For purposes of this analysis in HFpEF, we excluded patients with EF ≤ 40% resulting in a study cohort of 73 subjects. The mean follow-up was 3.09 years ± 1.46 years. Analysis was performed with IBM SPSS Statistics 26. Discrete variables were expressed as counts (percentage) and were compared using the Chi-squared test. Mean differences of continuous variables were expressed as a mean ± standard deviation and compared using the unpaired Student’s t- test. The log-rank test (Mantel-Cox) was used to compare survival times on Kaplan-Meier curves. Results: Patients who had baseline sST2 ≥ 35 ng/ml were at increased risk for heart failure hospitalization (p=0.189) and all-cause mortality (p=0.073) compared to patients who had sST2 < 35 ng/ml. Patients with sST2 ≥ 35 ng/ml had a mean of 1.03 HF hospitalizations, 24.1% of this group had ≥ 2 HF hospitalizations and 17.2% all-cause mortality. Patients with sST2 < 35 ng/ml had a mean of 0.57 HF hospitalizations, 14.0% had ≥ 2 HF hospitalizations and 4.55% all-cause mortality. Conclusion: Subjects with sST2 levels ≥ 35 ng/ml were at increased risk of recurrent hospitalization and all-cause mortality. The results of this study highlight the value of sST2 concentrations as a prognostic biomarker for identifying patients with HFpEF that are at increased risk for morbidity and mortality in the ambulatory setting.

Influence of AISI D2 Workpiece Roughness on Heat Partition and Plasma Channel Radius in the WEDM Process

As an important advanced machining process, in Wire Electrical Discharge Machining (WEDM) certain fundamental issues remain need to be studied in-depth, such as the effect of part surface roughness on heat transfer mechanisms. In the WEDM process, roughing cut wire goes into the workpiece to do the first shaping and in trim cut the wire sweeps on the outer surface to improve the surface roughness. In both of these two cases, the generation of sparks depends on the passing surface roughness. Therefore, with AISI D2 material and brass wire, this paper presents a study of the influence of part surface roughness on heat partition and the radius of the plasma channel in the WEDM process. Through extensive single discharge experiments, it is shown that the removal capacity per discharge can increase if the discharge occurs on a smoother surface. A Finite Element thermal model was then used for inverse fitting of the values of heat partition and radius of the plasma channel. These parameters completely define the characteristics of the heat conduction problem. The results indicate a strong correlation between an increase in heat partition ratio and a decrease in part surface roughness. The values of plasma channel radius show an increase in this value when discharging on rougher surfaces. It means that with the increasing of plasma channel radius, the heat source goes into the workpiece more dispersed. In the case of rougher surface, although the there is more area that affected by the heat source, finally the temperature of most area cannot reach to the melting point and it causes the smaller crater radius and volume, while the metal removal rate decreases. These results contribute towards a more complete understanding of the influence of surface roughness to the spark occurring.

Prognostic Value of Soluble ST2 Measurements for Morbidity and Mortality in Ambulatory Patients with HFrEF

Background Soluble ST2 (sST2) has emerged as a powerful prognostic marker in chronic systolic heart failure with reduced ejection fraction (HFrEF). Elevated levels of sST2 are associated with adverse cardiac remodeling and fibrosis. However, few studies have demonstrated the relative prognostic value of sST2 collected from stable patients in the ambulatory setting and correlated it with long term clinical outcomes. Hypothesis In our study, we sought to determine the prognostic utility of a baseline sST2 partition value in the ambulatory setting as it related to subsequent risk for heart failure hospitalization and all-cause mortality. Methods Single-center, retrospective observational study of subjects presenting to an ambulatory heart failure (HF) clinic from July 2014 to December 2016. There were 156 subjects with stage C heart failure and a baseline sST2 level. For purposes of this analysis in HFrEF, we excluded patients with EF > 40% resulting in a study cohort of 103 subjects. The mean follow-up was 2.20 years ± 1.53 years. Analysis was performed with IBM SPSS Statistics 26 software package. Discrete variables were expressed as counts (percentage) and were compared using the Chi-squared test. Mean differences of continuous variables were expressed as a mean ± standard deviation and compared using the unpaired Student's t-test. The log-rank test (Mantel-Cox) was used to compare survival times on Kaplan-Meier curves. To determine the diagnostic and prognostic accuracies of sST2 and BNP, receiver operating characteristic (ROC) plots were analyzed, and areas under the curve (AUC) were calculated. Results Patients who had baseline sST2 ≥ 35 ng/ml were at increased risk for heart failure hospitalization and all-cause mortality compared to patients who had sST2 Conclusion Subjects with sST2 levels ≥ 35 ng/ml were at increased risk of recurrent hospitalization and all-cause mortality. Additionally, we saw that elevated sST2 was associated with increased atrial arrhythmia, hypotension, and anemia. The results of this study highlight the value of sST2 concentrations as a prognostic biomarker for identifying patients with HFrEF that are at increased risk for morbidity and mortality in the ambulatory setting. Key words: Soluble ST2, cardiac remodeling, biomarkers, heart failure

Arterial hypertension: a path from unchanged transmitral bloodstream to dysfunction

Objective: assess the parameters characterizing the structural and functional features of the cardiovascular system in patients with arterial hypertension (AH) with signs of diastolic dysfunction of the left ventricle (DDLV), to determine the dynamics of changes in the heart and vessels from the unchanged spectrum of transmitral bloodstream (USTB) to diastolic dysfunction (DD) in AH patients. Material and methods. An open prospective study of patients with essential AH and USTB (n = 34) and with DDLV signs (n = 45) was organized in the state institution «Republican Research Center for Radiation Medicine and Human Ecology». The examined individuals are comparable in terms of sex and age features. Standard transtoracal echocardiography with the determination of standard indices, ultrasonic examination of the extranial department of the brachyocephalic arteries (BCA) with the determination of the thickness of the intima-media complex (CIM), duplex scanning of the arteries of the upper and lower limbs with the determination of the ankle-shoulder index and endothelium-dependent were performed in all the participants of the study. In addition, global longitudinal deformation was evaluated by two-dimensional tracking of the grey spots of the ultrasonic image scale (speckle tracking), parameters of the movement of the fibrous ring of the mitral valve into systole and diastole with the determination of the myocardial index by the method of tissue dopplerography. Results. The examination of the heart by the method of standard transtoracal echocardiography has revealed that AH patients with DDLV (2nd group) in comparison with AH patients with the unchanged spectrum of transmitral bloodstream (1st group) detected higher values of interventricular partition (12 mm versus 9 mm, р = 0.001), relative wall thickness (0.41 versus 0.35, р = 0.033), the index of myocardial mass (65 g versus 58.5 g, р = 0.015). The isovolumetric relaxation time of the PG (81 ms versus 67 ms, p = 0.043), the rate of tricuspidal regurgitation and systolic pressure in the pulmonary artery were significantly higher in the group of AH patients with DDLV (p = 0.005). The analysis of the movement of the fibrous ring of the mitral valve by tissue dopplerography has showed that in the second group of the patients (AH with DDLV), there are signs of regional systolic dysfunction of the medial part of the fibrous ring of the mitral valve (0.08 cm/s versus 0.09, p = 0.047). E/Em was higher in the second group, a statistically significant difference was found for the lateral portion of the fibrous ring of the mitral valve (5.7 vs. 7, p = 0.019). The ultrasonic duplex scanning of the extranial part of the BCA revealed that in the AH patients with DDLV compared to the AH patients with the unchanged spectrum of transmitral bloodstream, the value of the thickness of the CIM is reliably higher (right 0.8 mm versus 0.65 mm, p = 0.001, left 0.8 mm versus 0.7 mm, p = 0.001). The study of the endothelium function has revealed that the second group of the patients compared to the first one, recorded reliably lower values of endothelium dependent vasodilation (10 % versus 14 %, p = 0.009). The analysis of subclinical lesion of the arteries of the lower limbs has revealed that in the group of patients with DDLV compared to the group of the AH patients with the unchanged spectrum of transmitral bloodstream, the ankle-shoulder index value is reliably higher (right 1.1 versus 1.07, p = 0.013, left 1.1 versus 1.07, p = 0.05). Conclusion. The protocol method of research - standard transthoracic echocardiography - does not allow to estimate fully the functional changes of cardiac muscle in AH patients with DDLV in comparison with AH patients with the unchanged spectrum of transmitral bloodstream. The application of additional diagnostic techniques (TDG and speckle tracking) makes it possible to get missing data. Pathologic transformation of transmitral bloodstream occurs when signs of systolic and diastolic dysfunction of the left ventricle already exist. The appearance of signs of diastolic dysfunction of the left ventricle during standard echocardiography is accompanied by pathologic remodeling of the vascular system.

Isometric Path Partition Number of Butterfly Network and X–Trees

A set S of isometric paths that partition the vertex set of a graph G is called an isometric path partition of G. The isometric path partition number of G is the minimum cardinality of such a set S in G. It is denoted by ipp(G). The isometric path partition problem is to find a minimum isometric path partition of a given graph G. The isometric path partition problem has wide applications in the designing of an efficient algorithm in many architectures. The problem of determining the isometric path partition of a given graph G is NP-complete and hence it is interesting to compute the exact value of isometric path partition of different networks. In this paper, we study the isometric path partition problem of butterfly networks, complete binary trees, rooted complete binary trees, X–trees and compute the isometric path partition number of these graphs.

Echocardiographic two-dimensional speckle tracking identifies acute regional myocardial edema and sub-acute fibrosis in pediatric focal myocarditis with normal ejection fraction: comparison with cardiac magnetic resonance

The aim here was to describe the role of speckle tracking echocardiography (STE), in identifying impairment in systolic function in children and adolescents with focal myocarditis and without reduction in ejection fraction. We describe data from 33 pediatric patients (age 4–17 years) admitted for focal myocarditis, confirmed by cardiac magnetic resonance (CMR), and without impaired ejection fraction and/or wall motion abnormalities. All children underwent Doppler echocardiography examination with analysis of global (G) and segmental longitudinal strain (LS) and CMR for the quantification of edema and myocardial fibrosis. Reduction in LS was defined according to age-specific partition values. At baseline, impaired GLS was present in 58% of patients (n = 19), albeit normal ejection fraction. LS was also regionally impaired, according to the area of higher edema at CMR (i.e. most impaired at the level of the infero-lateral segments as compared to other segments (p < 0.05). GLS impairment was also moderately correlated with the percentage edema at CMR (r = − 0.712; p = 0.01). At follow-up, GLS improved in all patients (p < 0.001), and normal values were found in 13/19 patients with baseline reduction. Accordingly persistent global and regional impairment was still observed in 6 patients. Patients with persistent LS reduction demonstrated residual focal cardiac fibrosis at follow-up CMR. Both global and regional LS is able to identify abnormalities in systolic longitudinal mechanics in children and adolescents with focal myocarditis and normal ejection fraction. The reduction in LS is consistent with edema amount and localization at CMR. Furthermore, LS identifies regional recovery or persistent cardiac function impairment, possibly related to residual focal fibrosis.

Utilising Magnetically Isolated Lysosomes for Direct Quantification of Intralysosomal Drug Concentrations by LC-MS/MS Analysis: An Investigatory Study With Imipramine

Lysosomes are acidic intracellular organelles that can extensively sequester basic lipophilic drugs due to pH and membrane partitioning, and therefore may significantly influence subcellular drug concentrations. Current in vitro methods for lysosomal drug sequestration evaluation typically lack the ability to accurately and sensitively quantify drug concentrations directly within the lysosome. In the current study, magnetic lysosomal isolation was used in the lysosome rich rat NR8383 cell line and combined with LC-MS/MS analysis to quantify intralysosomal concentrations and lysosomal partitioning (KpLysosome) values of imipramine. The purity of the isolated lysosomes was validated by enzymatic and electron microscopy analysis. Lysosomal imipramine accumulation was explored using 2 methods: addition of imipramine to cells followed by lysosomal isolation (Method 1), and direct addition of imipramine to isolated lysosomes (Method 2). This work highlighted that both experimental buffers and ATP influence intralysosomal drug concentrations, and non-specific drug binding and re-distribution limits the use of Method 1. Method 2 may benefit future lysosomal drug accumulation studies, as imipramine demonstrated high KpLysosome values (3500), comparable to in silico predictions. This study reports a novel method for the direct quantification of intralysosomal drug concentrations that has the ability to be adapted to other cell types.

Evolution of supersaturation from amorphous solid dispersions in water-insoluble polymer carriers: Effects of swelling capacity and interplay between partition and diffusion.

The use of water-insoluble carriers for amorphous solid dispersions (ASDs) has attracted more recent interest as the kinetic solubility profiles (KSP) from these systems can achieve a more sustained level of supersaturation when compared with ASDs based on water-soluble polymers. However, the effect of swelling capacity of water-insoluble carriers on the resulting KSP of ASDs has not been fully explored in terms of their achievable degree and extent of drug supersaturation. Thus, the objective of this study is to compare kinetic solubility profiles of ASDs based on commercially available water-insoluble carriers in order to bridge this knowledge gap and provide fundamental information important to the design of ASDs based on water-insoluble carriers. This was achieved by comparing the KSP from non-sink dissolution studies of ASDs of two model poorly-water soluble drugs, indomethacin (IND) and posaconazole (PCZ) based on commercially available water-insoluble carriers with different equilibrium water swelling such as fully hydrolyzed (physically crosslinked) poly (vinyl alcohol) (PVA), Eudragit RS PO, as well as chemically crosslinked PHEMA hydrogels . Our results show that the higher the swelling capacity of the water-insoluble carrier, the faster the rate of supersaturation generation, and the shorter the sustained supersaturation due to drug precipitation. The interplay of particle size, total dose and the swelling capacity was also shown to be an essential aspect when tailoring the supersaturation generation from water-insoluble polymer-based ASDs. The importance of the swelling feature was confirmed using firstly different polymer carriers (PVA, Eudragit RS PO, and PHEMA) and then polymer samples of identical composition and drug loading but with different swelling capacities (e.g., PVA, physically crosslinked to different degrees). Furthermore, a large drug partitioning value between the polymer carrier and dissolution medium was found to limit the extent of drug release or supersaturation buildup from these ASDs. Finally, the existence of electrostatic polymer-drug interactions realized from our molecular dynamic simulations supports the observed impact of the large partitioning of the model drug IND between the polymer ED RS PO and the dissolution medium, thereby leading to a lower degree of supersaturation generation (or slower drug release) from this ASD.

Hemodynamic Response to Acute Volume Load in Heart Transplant Recipients

A mean pulmonary wedge pressure (mPAP) ≥ 25 mm Hg following volume load or exercise has been proposed as a partition value for detection of HfpEF. However, the hemodynamic response to volume challenge in heart transplant (Tx) recipients has never been studied. 36 heart Tx recipients (Age: 65 years) with normal LV function (EF: 55 ± 7 %) and without rejection and graft vasculopathy underwent right heart catheterization to measure hemodynamic response to volume loading before and after a rapid saline infusion of 7mL/kg over 10 min. PCWP, right atrial pressure (RAP), mean pulmonary artery pressure(PA) were obtained and the PCWP and indexed(i) stroke volume(SV) data were used to construct Starling (SVindex/PCWP) curves. Pts were categorized in those with elevated filling pressures (Group DD, n=10 pts) defined by a PCWP ≥ 15 mm Hg at rest or ≥ 25 mm Hg following volume loading vs those without (Controls, n=26 pts). No difference in age of donor and transplant, baseline hemodynamics and EF was noted between both groups. Saline infusion significantly increased PCWP and mean PA in both Groups without any significant change in BP and heart rate. Interestingly saline infusion was associated with a significant rise in SV and SVi in Controls not in DD pts(Fig 1). Moreover, in DD pts the Starling curves revealed a larger SVi at any give PCWP compared to Controls pts. In the transplanted heart volume loading increases filling pressures and is able to unmask left ventricular diastolic dysfunction. Interestingly, those with DD are characterized by a blunted Frank Starling response as evidenced by higher PCWP and failure to increase SV for any given PCWP. Further prospective studies are warranted to unravel the underlying mechanisms.

Major and trace element partitioning between majoritic garnet, clinopyroxene, and carbon dioxide-rich liquid in model carbonated peridotite at 10 GPa and interpretations of the element chemistry of majoritic garnet inclusions in diamonds from the subcontinental mantle of Brazil and Guinea

Experimentally determined major and trace element partition coefficients between majoritic garnet, clinopyroxene, and carbon dioxide-rich liquid are reported at 10 GPa and 1800 °C in a model carbonated peridotite composition in the system CaO-MgO-Al2O3-SiO2-CO2. Besides majoritic garnet, the liquid coexists with forsterite, orthopyroxene, and clinopyroxene, making melting phase relations invariant at fixed pressure and temperature conditions. Partition coefficients span a wide range of values - for instance, Sr, Nb, Ba, La, and Ce are highly incompatible in majoritic garnet, while Ca, Y, Nb, and Ho are moderately incompatible, and Lu, Si, Al, and Mg are compatible. Strong fractionation of light rare earth elements (e.g., La, Ce, Nd, Sm) and high field strength elements (e.g., Nb, Ta, Zr, Hf, Th) is seen between majoritic garnet and liquid. The experimentally determined partitioning values are used to calculate compositions of melts in equilibrium with majoritic garnet inclusions in diamonds from select localities in Brazil and Guinea. The calculated melts largely straddle those between documented carbonatites, kimberlites, and alkali basalts, low-degree mantle melting products from carbonated peridotite. This resemblance firmly suggests that majoritic garnet inclusions in diamonds from Brazil and Guinea can simply be interpreted as precipitates from such melts, thereby offering an alternative to the hypothesis that the element chemistry of such inclusions in diamonds can largely, and sometimes only, be ascribed to subducted oceanic crust, and further that, fusion of this crust may limit the terrestrial 'carbon recycling' at depths much beyond corresponding to those of Earth's transition zone.

Estimation Of The Genetic Parameters Of Eight Soybean Varieties In The Wasegi Village At Prafi District Manokwari Regency

This study aims to estimate genetic parameters including genetic diversity coefficient, phenotypic diversity coefficient, heritability value, and the correlation between the character of plants from eight soybean varieties. The research was conducted from August to December 2017, in the Wasafi Village of Prafi District, Manokwari Regency. The study was designed using Randomized Block Design (RBD) with 8 treatments of soybean varieties. Each treatment was repeated 4 times, to obtain 32 experimental units. The data obtained were analyzed using ANOVA and if it had a significant effect, it was further tested using the Duncan Multiple Range Test (DMRT) at the 95% level, through the Costat program. The results of ANOVA analysis were used to obtain Variable Partition values, Genetic Diversity Coefficient (GDC), Phenotype Diversity Coefficient (PDC), and Heritability. Correlations between characters were also analyzed using the Costat program. Estimation results of genetic parameters indicate that the characters selected for selection criteria are based on the value of GDC, PDC, and high heritability are number of branches, number of fertile books, number of filled pods, and number of total pods. The characters that show a positive correlation with the character of the results are plant height, number of trifoliate leaves, harvest age, number of filled pods, number of empty pods, total pods, and number of seeds per plant, while characters that show a negative correlation to a seed weight character are flowering age.

Separation and isolation of major polyphenols from maritime pine (Pinus pinaster) knots by two-step centrifugal partition chromatography monitored by LC-MS and NMR spectroscopy.

Pine knots are a rich source of lignans, flavonoids, and stilbenes. These bioactive compounds are widely known for their roles to combat human disorders but also to protect plants against pathogens. In order to gain knowledge inside their potential activities, a suitable isolation and purification of these high-added value compounds is required. To this end, centrifugal partition chromatography, as a rapid and useful methodology of separation, was employed and developed. The coefficient partition values (KD ) of six major compounds in nine biphasic solvent systems were determined to evaluate the most appropriate system. Two-step centrifugal partition chromatography was required to separate lignans using ARIZONA system K (n-heptane/ethyl acetate/methanol/water 1:2:1:2, v:v) and to isolate stilbenes and flavonoids using ARIZONA system P (n-heptane/ethyl acetate/methanol/water 6:5:6:5, v:v). Eight one-compound enriched-fractions were obtained as follows: nortrachelogenin (70.1%), secoisolariciresinol (53.7%), isolariciresinol (61.1%), taxifolin (48.4%), pinocembrin (91.3%), pinobanksin (91.1%), pinosylvin (91.4%), and pinosylvin monomethyl ether (91.1%). Additionally, the centrifugal partition chromatography allowed to unravel the composition of pine knot owing to the several fractions generated. Twenty-two compounds were characterized by liquid chromatography-mass spectrometry and NMR spectroscopy, some of which are described for the first time in literature.

Mechanism- and Immune Landscape-Based Ranking of Therapeutic Responsiveness of 22 Major Human Cancers to Next Generation Anti-CTLA-4 Antibodies.

Background: CTLA-4 was the first immune checkpoint targeted for cancer therapy and the first target validated by the FDA (Food and Drug Administration) after approval of the anti-CTLA-4 antibody, Ipilimumab. However, clinical response rates to anti-CTLA-4 antibodies are lower while the rates of immunotherapy-related adverse events (irAE) are higher than with anti-PD-1 antibodies. As a result, the effort to target CTLA-4 for cancer immunotherapy has stagnated. To reinvigorate CTLA-4-targeted immunotherapy, we and others have reported that rather than blocking CTLA-4 interaction with its cognate targets, CD80 and CD86, anti-CTLA-4 antibodies achieve their therapeutic responses through selective depletion of regulatory T cells in the tumor microenvironment. Accordingly, we have developed a new generation of anti-CTLA-4 antibodies with reduced irAE and enhanced antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC/ADCP). A major unresolved issue is how to select appropriate cancer types for future clinical development. Methods: We generated a landscape of the immune tumor microenvironment from RNAseq and genomic data of 7279 independent cancer samples belonging to 22 cancer types from The Cancer Genomics Atlas (TCGA) database. Based primarily on genomic and RNAseq data from pre-treatment clinical samples of melanoma patients who were later identified as responders and nonresponders to the anti-CTLA-4 antibody Ipilimumab, we identified 5 ranking components of responsiveness to anti-CTLA-4, including CTLA-4 gene expression, ADCC potential, mutation burden, as well as gene enrichment and cellular composition that favor CTLA-4 responsiveness. The total ranking number was calculated by the sum of 5 independent partitioning values, each comprised of 1–3 components. Results: Our analyses predict metastatic melanoma as the most responsive cancer, as expected. Surprisingly, non-small cell lung carcinoma (NSCLC) is predicted to be highly responsive to anti-CTLA-4 antibodies. Single-cell RNAseq analysis and flow cytometry of human NSCLC-infiltrating T cells supports the potential of anti-CTLA-4 antibodies to selectively deplete intratumoral Treg. Conclusions: Our in silico and experimental analyses suggest that non-small cell lung carcinoma will likely respond to a new generation of anti-CTLA-4 monoclonal antibodies. Our approach provides an objective ranking of the sensitivity of human cancers to anti-CTLA-4 antibodies. The comprehensive ranking of major cancer types provides a roadmap for clinical development of the next generation of anti-CTLA-4 antibodies.

Comparing method equivalence class partitioning and boundary value analysis with study case add medicine module

Software Testing is helpful to alleviate the developers’ task in improving the system. But in doing software testing, there are problems faced by developers, including information that become a benchmark in the feasibility of software testing. Many factors are used to obtain information or benchmarks. These factors can include line code, program structure, business processes and the time used in conducting trials. A test case is needed to ensure one of the two testing processes. The first is to make sure the data type of the entered data. The method of this process is called Equivalence Class Partitioning (ECP). The second is ensuring the lower bound value, the middle bound value, and the upper limit value of the number of strings as inputs of a system module. The method of this process is called Boundary Value Analysis (BVA). The purpose of this study is to compare the ECP and BVA methods. The expected result of this study is to find out the best method between ECP or BVA. Comparison of calculations using standard matrix testing. This study uses 5 parameters as benchmarks. Based on this study, the ECP method is superior to BVA with 5 parameters used as benchmarks.

419 The use of ST/HR Hysteresis as a Diagnostic Tool During Treadmill Exercise Stress Echo

Exercise stress test limitations including relatively low reported sensitivity has prompted research into analysis methods beyond traditional ST-segment depression criteria. ST/HR hysteresis has demonstrated relatively higher diagnostic accuracy as acknowledged by the American Heart Association Scientific Statement (2013). The aim of the present study is to assess the sensitivity and specificity of ST/HR Hysteresis for identifying CAD within a large tertiary referral centre. Data from Exercise Stress Echo (ESE) reports performed at a large tertiary referral centre between October 2017 and May 2018 (n=318) analysed retrospectively. Uninterpretable ECGs (n=24), bundle branch blocks (n=40) , and those with “non-diagnostic” ESE reports (n=33) excluded. ST/HR Hysteresis values calculated via GE-CASE Stress System (leads aVL, aVR, V1 excluded). Positive hysteresis was based on a partition value of ≥0.015mV and compared against a reference test of stress echo to determine sensitivity and specificity. Identification of ‘CAD’ for the purpose of analysis was based upon a positive ESE displaying a new inducible wall-motion abnormality. 225 tests remained after exclusions (24 positive, 201 negative) Both positive ESE and hysteresis occurred in 18 cases (sensitivity-=75%). Of 201 negative tests, 123 displayed negative hysteresis (specificity=62%). ST/HR hysteresis used during ESE does not display superior sensitivity and specificity within this population compared to that of traditional ST-segment criteria reference values. Further research is required using ECG-only based EST, ideally with coronary angiography as the reference test, to explore the potential utility of ST/HR Hysteresis as a diagnostic tool.

38 Prognostic validation of partition values obtained with conventional two-dimensional and doppler echocardiography to grade tricuspid regurgitation severity

Abstract Background Morbidity and mortality associated with severe tricuspid regurgitation (TR) have prompted interest in new corrective transcatheter procedures. However, to properly select patients for interventional procedures, and to assess their effectiveness, a reliable and reproducible grading system of TR severity is mandatory. However, the cut-off values used by current guidelines to differentiate among mild, moderate and severe TR lack clinical validation. Purpose We aimed to obtain the threshold values of the currently recommended quantitative echocardiographic parameters used to grade TR severity using pts’ outcome as a reference. Methods 296 pts, with at least mild TR and complete 2D, 3D and Doppler echocardiographic study, were enrolled and assessed for potential confounders: age, NYHA class, left ventricular ejection fraction, coexistent valvular heart disease and right ventricular (RV) systolic pressure. Average diameter of the vena contracta (VCavg), effective regurgitant orifice area (EROA), regurgitant volume (RVol) and regurgitant fraction (RF) were obtained to grade TR severity. Median follow-up was 47 (17-80) months. The primary composite endpoint was the occurrence of death of any cause or hospitalization for right heart failure (RHF). Survival curves for the composite endpoint were divided in quartiles at median follow-up. Cut-off values for the echo parameters were derived to grade mild (below the 1st quartile), moderate (between 1st and 3rd quartiles), and severe (above the 3r quartile) TR. Results 33 deaths and 72 hospitalizations for RHF occurred. Event-free rate from death or RHF at the end of follow-up was 14%, 46% and 93% in pts with severe, moderate, and mild TR, respectively. Differences reached statistical significance early (at 1 month), and lasted during the whole follow-up period (Figure). The new threshold values for mild, moderate and severe TR are summarized in Table. Conclusions Partition values of quantitative echo-Doppler parameters used to grade mild, moderate and severe TR according to pts’ clinical outcome are significantly lower than those currently reported in guidelines. Further studies are needed to test if these new threshold values for severe TR will translate in earlier referral of pts to valve repair and improved prognosis. Mild Moderate Severe VCavg &amp;lt;3 mm 3-6 mm &amp;gt;6 mm EROA &amp;lt;0.15 cm&amp;sup2; 0.15-0.30 cm&amp;sup2; &amp;gt;0.30 cm&amp;sup2; R Vol &amp;lt;15 ml 15-30 ml &amp;gt;30 ml RF &amp;lt;25% 25-45% &amp;gt;45% Abstract 38 Figure.

P6316Hemodynamic response to rapid saline loading in heart transplant recipients

Abstract Introduction A pulmonary capillary wedge pressure (PCWP) ≥25 mm Hg following volume load or exercise has been proposed as a partition value for detection of HfpEF. However, the hemodynamic response to volume challenge in heart transplant (Tx) recipients has never been studied. Methods 24 heart Tx recipients (age: 65 years) with normal LV function (55±7%) and without rejection and graft vasculopathy underwent right heart catheterization to measure hemodynamic response to volume loading before and after a rapid saline infusion of 7mL/kg over 10 min. PCWP, right atrial pressure (RAP), mean pulmonary artery pressure (AP) were obtained and the PCWP and indexed (i) stroke volume (SV) data were used to construct Starling (SVindex/PCWP) curves. Pts were categorized in those with elevated filling pressures (Group A, n=13 pts) defined by a PCWP ≥15 mm Hg at rest or ≥25 mm Hg following volume loading vs those without (Group B, n=11 pts). Results No difference in age of donor and transplant heart, baseline hemodynamics and EF was noted between both groups. Saline infusion significantly increased PCWP and mean AP in both Groups (table 1) without any significant change in BP and heart rate. Interestingly saline infusion was associated with a significant rise in SV and SVi in Group B not in Group A pts. Moreover, in Group B pts the Starling curves revealed a larger SVi at any give PCWP compared to Group A pts (Fig.1). Table 1 All (n=24) Group A (n=13) Group B (n=11) Baseline Volume Loading Baseline Volume Loading Baseline Volume Loading RAP (mm Hg) 5.3±4.1 9.2±4.8* 7.6±4.8 11.4±5.2* 3.8±2.5 7.3±1.9* Mean AP 18.4±5.4 24.1±5.9* 21.7±5.1 26.8±6.5** 14.9±2.4 20.8±2.6* PCWP 12.1±4.9 16.8±6.7* 15.0±4.9 19.8±6.5** 8.4±1.9 14.6±3.7* SV 71.4±19.6 72.5±23.6 73.2±6.2 72.4±6.2 69.2±14.6 79.2±3.9 SViml/m2) 37.4±9.2 37.9±11.2 36.7±7.1 38.7±9.9 35.3±6.0 40.5±5.2* *p&lt;0.01 compared to baseline; **p&lt;0.05 compared to baseline. Figure 1 Conclusions In the transplanted heart volume loading increases filling pressures and is able to unmask left ventricular diastolic dysfunction. Interestingly, those with HFpEF are characterized by a blunted Frank Starling response as evidenced by higher PCWP and failure to increase SV for any given PCWP. Further prospective studies are warranted to unravel the underlying mechanisms.

Development and prognostic validation of partition values to grade right ventricular dysfunction severity using 3D echocardiography.

Transthoracic 3D echocardiography (3DE) has been shown to be feasible and accurate to measure right ventricular (RV) ejection fraction (EF) when compared with cardiac magnetic resonance (CMR). However, RV EF, either measured with CMR or 3DE, has always been reported as normal (RV EF > 45%) or abnormal (RV EF ≤ 45%). We therefore sought to identify the partition values of RV EF to stratify RV dysfunction in mildly, moderately, or severely reduced as we are used to do with the left ventricle. We used 3DE to measure RV EF in 412 consecutive patients (55 ± 18 years, 65% men) with various cardiac conditions who were followed for 3.7 ± 1.4 years to obtain the partition values which defined mild, moderate, and severe reduction of RV EF (derivation cohort). Then, the prognostic value of these partition values was tested in an independent population of 446 patients (67 ± 14 years, 58% men) (validation cohort). During follow-up, we recorded 59 cardiac deaths (14%) in the derivation cohort. Using K-Adaptive partitioning for survival data algorithm we identified four groups of patients with significantly different mortality according to RV EF: very low > 46%, 40.9% < low ≤ 46%, 32.1% < moderate ≤ 40.9%, and high ≤ 32.1%. To make the partition values easier to remember, we approximated them to 45%, 40%, and 30%. During 4.1 ± 1.2 year follow-up, 38 cardiac deaths and 88 major adverse cardiac events (MACE) (cardiac death, non-fatal myocardial infarction, ventricular fibrillation, or admission for heart failure) occurred in the validation cohort. The partition values of RV EF identified in the derivation cohort were able to stratify both the risk of cardiac death (log-rank = 100.1; P < 0.0001) and MACEs (log-rank = 117.6; P < 0.0001) in the validation cohort too. Our study confirms the independent prognostic value of RV EF in patients with heart diseases, and identifies the partition values of RV EF to stratify the risk of cardiac death and MACE.