Synthesis and Biological Evaluation of Substituted Pyrazole-Fused Oleanolic Acid Derivatives as Novel Selective α-Glucosidase Inhibitors.

A series of novel substituted pyrazole-fused oleanolic acid derivative were synthesized and evaluated as selective α-glucosidase inhibitors. Among these analogs, compounds 4a-4f exhibited more potent inhibitory activities compared with their methyl ester derivatives, and standard drugs acarbose and miglitol as well. Besides, all these analogs exhibited good selectivity towards α-glucosidase over α-amylase. Analog 4d showed potent inhibitory activity against α-glucosidase (IC50 =2.64±0.13 µM), and greater selectivity towards α-glucosidase than α-amylase by ∼33-fold. Inhibition kinetics showed that compound 4d was a non-competitive α-glucosidase inhibitor, which was consistent with the result of its simulation molecular docking. Moreover, the in vitro cytotoxicity of compounds 4a-4f towards hepatic LO2 and HepG2 cells was tested.

Least squares regression methods for clustered ROC data with discrete covariates.

The receiver operating characteristic (ROC) curve is a popular tool to evaluate and compare the accuracy of diagnostic tests to distinguish the diseased group from the nondiseased group when test results from tests are continuous or ordinal. A complicated data setting occurs when multiple tests are measured on abnormal and normal locations from the same subject and the measurements are clustered within the subject. Although least squares regression methods can be used for the estimation of ROC curve from correlated data, how to develop the least squares methods to estimate the ROC curve from the clustered data has not been studied. Also, the statistical properties of the least squares methods under the clustering setting are unknown. In this article, we develop the least squares ROC methods to allow the baseline and link functions to differ, and more importantly, to accommodate clustered data with discrete covariates. The methods can generate smooth ROC curves that satisfy the inherent continuous property of the true underlying curve. The least squares methods are shown to be more efficient than the existing nonparametric ROC methods under appropriate model assumptions in simulation studies. We apply the methods to a real example in the detection of glaucomatous deterioration. We also derive the asymptotic properties of the proposed methods.

Combining markers with and without the limit of detection.

In this paper, we consider the combination of markers with and without the limit of detection (LOD). LOD is often encountered when measuring proteomic markers. Because of the limited detecting ability of an equipment or instrument, it is difficult to measure markers at a relatively low level. Suppose that after some monotonic transformation, the marker values approximately follow multivariate normal distributions. We propose to estimate distribution parameters while taking the LOD into account, and then combine markers using the results from the linear discriminant analysis. Our simulation results show that the ROC curve parameter estimates generated from the proposed method are much closer to the truth than simply using the linear discriminant analysis to combine markers without considering the LOD. In addition, we propose a procedure to select and combine a subset of markers when many candidate markers are available. The procedure based on the correlation among markers is different from a common understanding that a subset of the most accurate markers should be selected for the combination. The simulation studies show that the accuracy of a combined marker can be largely impacted by the correlation of marker measurements. Our methods are applied to a protein pathway dataset to combine proteomic biomarkers to distinguish cancer patients from non-cancer patients.

WHICH CRIMINOGENIC NEED CHANGES ARE MOST IMPORTANT IN PROMOTING DESISTANCE FROM CRIME AND SUBSTANCE USE?

Andrews and Bonta identified the following criminogenic needs as important to reducing offending: substance use, antisocial cognition, antisocial associates, family and marital relations, employment, and leisure and recreational activities. This study examines dynamic criminogenic need changes across a 12-month period and identifies which need changes are the best predictors of criminal offending and illicit drug use among a sample of drug-involved probationers who participated in an intervention (N = 251). Probationers had significant changes in several need areas, and treatment participation moderated some changes. Probationers who had reductions in criminally involved family members they associate with, improved work performance, and decreased alcohol use had the greatest reductions in offending. Those who increased time spent engaged in leisure and recreational activities were less likely to self-report subsequent drug use. These findings suggest that certain dynamic need changes may be more important than others, and designing interventions to impact these needs might improve outcomes.

A general framework of marker design with optimal allocation to assess clinical utility.

This paper proposes a general framework of marker validation designs, which includes most of existing validation designs. The sample size calculation formulas for the proposed general design are derived on the basis of the optimal allocation that minimizes the expected number of treatment failures. The optimal allocation is especially important in the targeted design which is often motivated by preliminary evidence that marker-positive patients respond to one treatment better than the other. Our sample size calculation also takes into account the classification error of a marker. The numerical studies are conducted to investigate the expected reduction on the treatment failures and the relative efficiency between the targeted design and the traditional design based on the optimal ratios. We illustrate the calculation of the optimal allocation and sample sizes through a hypothetical stage II colon cancer trial.

Nonparametric ROC summary statistics for correlated diagnostic marker data.

We propose efficient nonparametric statistics to compare medical imaging modalities in multi-reader multi-test data and to compare markers in longitudinal ROC data. The proposed methods are based on the weighted area under the ROC curve, which includes the area under the curve and the partial area under the curve as special cases. The methods maximize the local power for detecting the difference between imaging modalities. We develop the asymptotic results of the proposed methods under a complex correlation structure. Our simulation studies show that the proposed statistics result in much better powers than existing statistics. We apply the proposed statistics to an endometriosis diagnosis study.

The Properties of Modified Bagasse Fiber/Nano-TiO2 Composite Asphalt in a High-Temperature and High-Humidity Salt Environment.

The southern tropical coastal areas of China are high-temperature and high-humidity salt environments, which hinder the durability and service life of ordinary asphalt pavement. To enhance the durability of asphalt pavement in these areas, modified bagasse fiber combined with nano-TiO2 was used to improve the corrosion resistance of asphalt pavement in high-temperature and high-humidity salt environments. The micro-morphology, high-temperature oil absorption, high-temperature heat resistance, and hygroscopicity of bagasse fiber modified using three silane coupling agents combined with NaOH were compared, and the best silane coupling agent/NaOH modification scheme for bagasse fiber was found. Based on conventional physical tests (penetration, softening point, ductility), rheological property tests (rotational viscosity, dynamic shear rheological test, multi-stress creep recovery test, linear amplitude scanning test), and a four-point bending fatigue test of the asphalt mixture, the properties of modified bagasse fiber asphalt binder and mixture after cyclic dry-wet erosion under pure water and salt solution (NaCl, Na2SO4) were determined, and the effects of the erosion environment and fiber ratio on the basic physical and rheological properties of the asphalt were clarified. Compared with the silane coupling agents KH550 and KH590, the bagasse fiber modified with KH570/NaOH had a better high-temperature oil absorption capacity, heat stability capacity, and matrix asphalt compatibility. The worst erosion environment was Na2SO4, but the increase in test temperature and fiber content weakened the sensitivity of the asphalt binder performance in different erosion environments. The erosion capacity order was as follows: Na2SO4 > NaCl > pure water. In the worst erosion environment, 0.5% modified bagasse fiber/Nano-TiO2 asphalt binder (Bn-570-0.5) had the best corrosion resistance in a high-temperature and high-humidity salt environment. The penetration, softening point, creep recovery rate R3.2, non-recoverable creep compliance Jnr3.2, and fatigue life after long-term aging (with 5% strain) of Bn-570-0.5 were, respectively, increased by -16.9%, 37.5%, 37.95%, -27.86%, and 38.30% compared with unblended base asphalt binder (B). In addition, the four-point flexural fatigue life of Bn-570-0.5 was 169.2% higher than that of the unblended base mixture.

Acute toxicity and genotoxicity studies on new melatonergic antidepressant GW117.

GW117, a novel derivate compound of agomelatine that acts as both a 5-HT2C receptor antagonist and a MT1/MT2 receptor agonist, likely underlines the potent antidepressant action with less hepatotoxicity than agomelatine. We evaluated the acute toxicity of GW117, and the genotoxicity of GW117 using bacterial reverse mutation test, mammalian chromosomal aberration test in Chinese hamster lung cells (CHL) and mouse bone marrow micronucleus test. The acute toxicity test results showed that maximum tolerated dose (MTD) of GW117 was 2000 mg/kg, under which mean Cmax and AUC0→t was 10,782 ng/mL and 81,046 ng/mL × h, respectively. The result of bacterial reverse mutation test showed that the number of bacterial colonies in each dose group of GW117 did not increase significantly compared with that in the solvent control group with or without S9 metabolic activation system. In vitro chromosome aberration test of CHL cells, the chromosome aberration rate of each dose group of GW117 did not increase with or without S9 metabolic activation system. In mouse micronucleus test, the highest dose was 2000 mg/kg, the micronucleus rate did not increase significantly. Under the conditions of this study, the MTD of a single GW117 administration was 2000 mg/kg, there was no genotoxicity effect of GW117.

Homogeneity tests of clustered diagnostic markers with applications to the BioCycle Study.

Diagnostic trials often require the use of a homogeneity test among several markers. Such a test may be necessary to determine the power both during the design phase and in the initial analysis stage. However, no formal method is available for the power and sample size calculation when the number of markers is greater than two and marker measurements are clustered in subjects. This article presents two procedures for testing the accuracy among clustered diagnostic markers. The first procedure is a test of homogeneity among continuous markers based on a global null hypothesis of the same accuracy. The result under the alternative provides the explicit distribution for the power and sample size calculation. The second procedure is a simultaneous pairwise comparison test based on weighted areas under the receiver operating characteristic curves. This test is particularly useful if a global difference among markers is found by the homogeneity test. We apply our procedures to the BioCycle Study designed to assess and compare the accuracy of hormone and oxidative stress markers in distinguishing women with ovulatory menstrual cycles from those without.

Comprehensive study on identification of water inrush sources from deep mining roadway.

To accurately identify the location of the water inrush sources, correlation analysis and factor analysis were used to discuss the similarity of hydrochemical control mechanism of different aquifers and inrush water. On this basis, Fisher and BP neural network are used to judge the probability of inrush water. Finally, it is verified by hydrological observation holes. According to the water sources mixing model, the water inrush sources of 11601 working face were mainly No. 13 stratum Carboniferous limestone water with a small amount of No. 10 stratum Carboniferous limestone water, and the mixing ratio is 11:1. Combining the results of water inrush source identification, water yield mutation, geophysical exploration results, and underground drilling, it is speculated that there are two faults in this working face. The normal fault stops at the top of No. 13 stratum Carboniferous limestone aquifer, and the reverse fault develops to No. 13 stratum Carboniferous limestone aquifer. This research is of great significance for the identification of mine water sources and guidance for the prevention and control of water inrush.

United Network for Organ Sharing Rule Changes and Their Effects on Kidney and Liver Transplant Outcomes.

OBJECTIVES: Recent national organ distribution rule changes could have implications on distance between donor and recipient hospitals and cold ischemia time. With cold ischemia time being an unavoidable detriment to organ quality, any strategies that minimize it should maximize organ quality. This study evaluated the significance of the kidney allocation system and the Share 35 rule changes on kidney and liver transplant outcomes. MATERIALS AND METHODS: This retrospective study included deceased liver and kidney donor and their recipient data from the Organ Procurement and Transplantation Network. Variables were analyzed using propensity score matching and Cox hazards model distance (from donor hospital to organ recovery center), and effects on survival outcomes of trans-planted livers and kidneys in the context of the recent rule changes were analyzed. RESULTS: Transplanted organs have significantly better outcomes when the distance is 0 miles versus median distances for locally transported organs of 18 and 22 miles for kidney and liver, respectively. Cold ischemia time, when corrected, accounts for this finding, thus suggesting that cold ischemia time is the factor most responsible for viability of a transplanted organ. This significance remains evident for liver transplants even after the Share 35 rule change but not for kidney transplants following the December 2014 kidney allocation system change. CONCLUSIONS: Liver transplants showed a higher risk of lower viability with travel, and the Share 35 rule did not appear to change this result. Kidney transplant outcomes appear to have improved after the kidney allocation system change. Potential strategies for minimizing cold ischemia time and improving outcomes include more free-standing organ recovery centers in centralized locations.

Forensic facial examiners versus super-recognizers: Evaluating behavior beyond accuracy.

We evaluated the detailed, behavioral properties of face matching performance in two specialist groups: forensic facial examiners and super-recognizers. Both groups compare faces to determine identity with high accuracy and outperform the general population. Typically, facial examiners are highly trained; super-recognizers rely on natural ability. We found distinct behaviors between these two groups. Examiners used the full 7-point identity judgment scale (-3: "different"; +3: "same"). Super-recognizers' judgments clustered toward highly confident decisions. Examiners' judgments for same- and different-identities were symmetric across the scale midpoint (0); super-recognizers' judgments were not. Examiners showed higher identity judgment agreement than super-recognizers. Despite these qualitative differences, both groups showed insight into their own accuracy: more confident people and those who rated the task to be easier tended to be more accurate. Altogether, we show to better understand and interpret judgments according to the nature of someone's facial expertise, evaluations should assess more than accuracy.

Sample size recalculation in sequential diagnostic trials.

Before a comparative diagnostic trial is carried out, maximum sample sizes for the diseased group and the nondiseased group need to be obtained to achieve a nominal power to detect a meaningful difference in diagnostic accuracy. Sample size calculation depends on the variance of the statistic of interest, which is the difference between receiver operating characteristic summary measures of 2 medical diagnostic tests. To obtain an appropriate value for the variance, one often has to assume an arbitrary parametric model and the associated parameter values for the 2 groups of subjects under 2 tests to be compared. It becomes more tedious to do so when the same subject undergoes 2 different tests because the correlation is then involved in modeling the test outcomes. The calculated variance based on incorrectly specified parametric models may be smaller than the true one, which will subsequently result in smaller maximum sample sizes, leaving the study underpowered. In this paper, we develop a nonparametric adaptive method for comparative diagnostic trials to update the sample sizes using interim data, while allowing early stopping during interim analyses. We show that the proposed method maintains the nominal power and type I error rate through theoretical proofs and simulation studies.

A random-sum Wilcoxon statistic and its application to analysis of ROC and LROC data.

The Wilcoxon-Mann-Whitney statistic is commonly used for a distribution-free comparison of two groups. One requirement for its use is that the sample sizes of the two groups are fixed. This is violated in some of the applications such as medical imaging studies and diagnostic marker studies; in the former, the violation occurs since the number of correctly localized abnormal images is random, while in the latter the violation is due to some subjects not having observable measurements. For this reason, we propose here a random-sum Wilcoxon statistic for comparing two groups in the presence of ties, and derive its variance as well as its asymptotic distribution for large sample sizes. The proposed statistic includes the regular Wilcoxon rank-sum statistic. Finally, we apply the proposed statistic for summarizing location response operating characteristic data from a liver computed tomography study, and also for summarizing diagnostic accuracy of biomarker data.

Estimating the AUC with a Graphical Lasso Method for High-dimensional Biomarkers with LOD.

This manuscript estimates the area under the receiver operating characteristic curve (AUC) of combined biomarkers in a high-dimensional setting. We propose a penalization approach to the inference of precision matrices in the presence of the limit of detection. A new version of expectation-maximization algorithm is then proposed for the penalized likelihood, with the use of numerical integration and the graphical lasso method. The estimated precision matrix is then applied to the inference of AUCs. The proposed method outperforms the existing methods in numerical studies. We apply the proposed method to a data set of brain tumor study. The results show a higher accuracy on the estimation of AUC compared with the existing methods.

Case-mix adjustment and enabled reporting of the health care experiences of adults with disabilities.

OBJECTIVES: To develop activity limitation clusters for case-mix adjustment of health care ratings and as a population profiler, and to develop a cognitively accessible report of statistically reliable quality and access measures comparing the health care experiences of adults with and without disabilities, within and across health delivery organizations. DESIGN: Observational study. SETTING: Three California Medicaid health care organizations. PARTICIPANTS: Adults (N = 1086) of working age enrolled for at least 1 year in Medicaid because of disability. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Principal components analysis created 4 clusters of activity limitations that we used to characterize case mix. We identified and calculated 28 quality measures using responses from a proposed enabled version of the Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey. We calculated scores for overall care as the weighted mean of the case-mix adjusted ratings. RESULTS: Disability caused a greater bias on health plan ratings and specialist ratings than did demographic factors. Proxy respondents rated care the same as self-respondents. Telephone and mail administration were equivalent for service reports, but telephone respondents tended to offer more positive global ratings. Plan-level reliability estimates for new composites on shared decision making and advice on healthy living are .79 and .87, respectively. Plan-level reliability estimates for a new composite measure on family planning did not discriminate between health plans because respondents rated all health plans poorly. Approximately 125 respondents per site are necessary to detect group differences. CONCLUSIONS: Self-reported activity limitations incorporating standard questions from the American Community Survey can be used to create a disability case-mix index and to construct profiles of a population's activity limitations. The enabled comparative report, which we call the Assessment of Health Plans and Providers by People with Activity Limitations, is more cognitively accessible than typical CAHPS report templates for state Medicaid plans. The CAHPS Medicaid reporting tools may provide misleading ratings of health plan and physician quality by people with disabilities because the mean ratings do not account for systematic biases associated with disability. More testing on larger populations would help to quantify the strength of various reporting biases.

Compare diagnostic tests using transformation-invariant smoothed ROC curves().

Receiver operating characteristic (ROC) curve, plotting true positive rates against false positive rates as threshold varies, is an important tool for evaluating biomarkers in diagnostic medicine studies. By definition, ROC curve is monotone increasing from 0 to 1 and is invariant to any monotone transformation of test results. And it is often a curve with certain level of smoothness when test results from the diseased and non-diseased subjects follow continuous distributions. Most existing ROC curve estimation methods do not guarantee all of these properties. One of the exceptions is Du and Tang (2009) which applies certain monotone spline regression procedure to empirical ROC estimates. However, their method does not consider the inherent correlations between empirical ROC estimates. This makes the derivation of the asymptotic properties very difficult. In this paper we propose a penalized weighted least square estimation method, which incorporates the covariance between empirical ROC estimates as a weight matrix. The resulting estimator satisfies all the aforementioned properties, and we show that it is also consistent. Then a resampling approach is used to extend our method for comparisons of two or more diagnostic tests. Our simulations show a significantly improved performance over the existing method, especially for steep ROC curves. We then apply the proposed method to a cancer diagnostic study that compares several newly developed diagnostic biomarkers to a traditional one.

In situ synthesis of poly (γ- glutamic acid)/alginate/AgNP composite microspheres with antibacterial and hemostatic properties.

In the present work, a poly(γ-glutamic acid)/alginate/silver nanoparticle (PGA/Alg/AgNP) composite microsphere with excellent antibacterial and hemostatic properties was prepared by the in situ UV reduction and emulsion internal gelation method, and its potential application for antibacterial hemostatic dressing was explored. Well dispersed AgNPs were in situ synthesized by a UV reduction method with alginate as stabilizer and reductant. The AgNPs showed excellent antibacterial activities against both gram-negative and gram-positive bacteria. Additionally, the AgNPs prepared by the in-situ UV reduction exhibited better biocompatibility and antibacterial effects than those prepared by the conventional chemical reduction method. PGA/Alg/AgNP composite microspheres were then prepared with the AgNPs by an emulsion internal gelation method. Such microspheres were found to be a porous and hollow network with pH-sensitive swelling properties and excellent hemostatic performance, indicating its application potentials as an advanced antibacterial hemostatic material.

Effect of Cross-Linked Hyaluronate Scaffold on Cartilage Repair: An In Vivo Study.

OBJECTIVE: To determine the safety and effectiveness of a cross-linked sodium hyaluronate (CHA) scaffold in cartilage repair. METHODS: Physicochemical properties of the scaffold were determined. The safety and effectiveness of the scaffold for cartilage repair were evaluated in a minipig model of a full-thickness cartilage defect with microfracture surgery. Postoperative observation and hematological examination were used to evaluate the safety of the CHA scaffold implantation. Pathological examination as well as biomechanical testing, including Young's modulus, stress relaxation time, and creep time, were conducted at 6 and 12 months postsurgery to assess the effectiveness of the scaffold for cartilage repair. Furthermore, type II collagen and glycosaminoglycan content were determined to confirm the influence of the scaffold in the damaged cartilage tissue. RESULTS: The results showed that the routine hematological indexes of the experimental animals were within the normal physiological ranges, which confirmed the safety of CHA scaffold implantation. Based on macroscopic observation, it was evident that repair of the defective cartilage in the animal knee joint began during the 6 months postoperation and was gradually enhanced from the central to the surrounding region. The repair smoothness and color of the 12-month cartilage samples from the operation area were better than those of the 6-month samples, and the results for the CHA scaffold implantation group were better than the control group. Greater cell degeneration and degeneration of the adjacent cartilage was found in the implantation group compared with the control group at both 6 and 12 months postoperation, evaluated by O'Driscoll Articular Cartilage Histology Scoring. Implantation with the CHA scaffold matrix promoted cartilage repair and improved its compression capacity. The type II collagen level in the CHA scaffold implantation group tended to be higher than that in the control group at 6 months (2.33 ± 1.50 vs 1.68 ± 0.56) and 12 months postsurgery (3.37 ± 1.70 vs 2.06 ± 0.63). The GAG content in the cartilage of the control group was significantly lower than that of the experimental group (2.17 ± 0.43 vs 3.64 ± 1.17, P = 0.002 at 6 months and 2.27 ± 0.38 vs 4.12 ± 1.02, P = 0.002 at 12 months). Type II collagen and glycosaminoglycan content also demonstrated that CHA was beneficial for the accumulation of both these vital substances in the cartilage tissue. CONCLUSIONS: The CHA scaffold displayed the ability to promote cartilage repair when applied in microfracture surgery, which makes it a promising material for application in the area of cartilage tissue engineering.

Nonparametric and semiparametric group sequential methods for comparing accuracy of diagnostic tests.

SUMMARY: Comparison of the accuracy of two diagnostic tests using the receiver operating characteristic (ROC) curves from two diagnostic tests has been typically conducted using fixed sample designs. On the other hand, the human experimentation inherent in a comparison of diagnostic modalities argues for periodic monitoring of the accruing data to address many issues related to the ethics and efficiency of the medical study. To date, very little research has been done on the use of sequential sampling plans for comparative ROC studies, even when these studies may use expensive and unsafe diagnostic procedures. In this article we propose a nonparametric group sequential design plan. The nonparametric sequential method adapts a nonparametric family of weighted area under the ROC curve statistics (Wieand et al., 1989, Biometrika 76, 585-592) and a group sequential sampling plan. We illustrate the implementation of this nonparametric approach for sequentially comparing ROC curves in the context of diagnostic screening for nonsmall-cell lung cancer. We also describe a semiparametric sequential method based on proportional hazard models. We compare the statistical properties of the nonparametric approach with alternative semiparametric and parametric analyses in simulation studies. The results show the nonparametric approach is robust to model misspecification and has excellent finite-sample performance.