Miracle-dz/UniFAR-FTUs huggingface dataset:
Optimization of Drug-Drug Interaction Study Design: Comparison of Minimal Physiologically Based Pharmacokinetic Models on Prediction of CYP3A Inhibition by Ketoconazole

Ketoconazole is a potent CYP3A inhibitor used to assess the contribution of CYP3A to drug clearance and quantify the increase in drug exposure due to a strong inhibitor. Physiologically based pharmacokinetic (PBPK) models have been used to evaluate treatment regimens resulting in maximal CYP3A inhibition by ketoconazole but have reached different conclusions. We compare two PBPK models of the ketoconazole-midazolam interaction, model 1 (Chien et al., 2006) and model 2 implemented in Simcyp (version 11), to predict 16 published treatment regimens. With use of model 2, 41% of the study point estimates of area under the curve (AUC) ratio and 71% of the 90% confidence intervals were predicted within 1.5-fold of the observed, but these increased to 82 and 100%, respectively, with model 1. For midazolam, model 2 predicted a maximal midazolam AUC ratio of 8 and a hepatic fraction metabolized by CYP3A (fm) of 0.97, whereas model 1 predicted 17 and 0.90, respectively, which are more consistent with observed data. On the basis of model 1, ketoconazole (400 mg QD) for at least 3 days and substrate administration within 2 hours is required for maximal CYP3A inhibition. Ketoconazole treatment regimens that use 200 mg BID underestimate the systemic fraction metabolized by CYP3A (0.86 versus 0.90) for midazolam. The systematic underprediction also applies to CYP3A substrates with high bioavailability and long half-lives. The superior predictive performance of model 1 reflects the need for accumulation of ketoconazole at enzyme site and protracted inhibition. Model 2 is not recommended for inferring optimal study design and estimation of fraction metabolized by CYP3A.
Childhood trauma increases the risk of post-traumatic stress disorder in response to first-episode psychosis

Objective: To investigate the relationship between childhood trauma, post-traumatic stress symptoms due to the experience of childhood trauma, and post-traumatic stress symptoms due to the experience of psychosis. Method: The current study assessed childhood trauma and post-traumatic stress disorder (PTSD) symptoms as a result of both childhood trauma and psychosis using the Impact of Events Scale - Revised, in a group of 36 people with first-episode psychosis. Results: Reported rates of clinical level post-psychotic PTSD symptoms, childhood trauma and childhood trauma-related clinical level PTSD symptoms were 47% (95% CI 31–64%), 64% (95% CI 48–80%) and 39% (95% CI 23–55%), respectively. Reporting childhood trauma increased the risk of developing post-psychosis PTSD 27-fold (95% CI 2.96–253.80, p = 0.01). Having childhood trauma-related PTSD increased the risk of developing post-psychosis PTSD 20-fold (95% CI 3.38–123.25, p = 0.01). These risks were not explained by illness factors such as duration of untreated psychosis, age of onset or severity of psychotic symptoms. Those without post-psychotic PTSD symptoms at clinical levels were unlikely to report childhood trauma (6%; 95% CI 3–8%). Conclusions: These results suggest the cognitive, social and biological consequences of childhood trauma can prevent effective recovery from the trauma of acute first-episode psychosis resulting in post-psychotic PTSD. Treatment strategies for post-psychotic PTSD must address childhood trauma and related PTSD.
Democracy and National Education Standards

This article intervenes in the debate about whether democracies should adopt national education standards. For many democrats, national education standards may promote economic growth, social justice, and a common set of interests. In this article, I reconstruct John Dewey’s warning against oligarchs using standardization to control the schools as well as his argument that democracy requires student, teacher, and community autonomy. The article argues that the Common Core State Standards Initiative has been a top-down policy that aims to prepare children for the economy rather than democracy, and for the foreseeable future, economic elites will tend to dominate efforts to create national education standards. In the conclusion, I make a pragmatic argument for local education control and address objections such as that democracies need national educational standards to ensure racial equity.
Density clustering pruning method based on reconstructed support vectors for sparse LSSVM

In least squares support vector machine (LSSVM), nonlinear function estimation is done by solving a linear set of equations instead of solving a quadratic programming problem, and a nonsparse solution is obtained. Several sparse algorithms have been developed to obtain reduced support vectors to improve the generalization performance of LSSVM. However, all of them iteratively look for support vectors in training datasets, which may are not the most superior choice for building the function model. In this paper, we propose a method of reconstructed support vectors based on the training datasets. The support vectors reconstructed are near the hyper plane of target function and uniformly distributed, which have more contribution to target function. In addition, the method we proposed converges at a faster rate than those iterative algorithms, because one-step selecting strategy is adapted without repeated training. To show the efficacy and feasibility of our proposed algorithm, some comparing experiments are conducted, which are all favorable for our viewpoints. That is, the method we proposed needs less number of support vectors to reach the almost same generalization performance, most important, which has the better robustness and accuracy prediction for the real operating mode.
Faith, hope, and charity: an in-depth interview study of cancer patients' information needs and information-seeking behavior

OBJECTIVE: To explore why cancer patients do not want or seek information about their condition beyond that volunteered by their physicians at times during their illness. DESIGN: Qualitative study based on in-depth interviews. SETTING: Outpatient oncology clinics at a London cancer center. PARTICIPANTS: 17 patients with cancer diagnosed in previous 6 months. Main outcome measures Analysis of patients' narratives to identify key themes and categories. RESULTS: While all patients wanted basic information on diagnosis and treatment, not all wanted further information at all stages of their illness. Three overarching attitudes to their management of cancer limited patients' desire for and subsequent efforts to obtain further information : faith, hope, and charity. Faith in their doctor's medical expertise precluded the need for patients to seek further information themselves. Hope was essential for patients to carry on with life as normal and could be maintained through silence and avoiding information, especially too detailed or "unsafe" information. Charity to fellow patients, especially those seen as more needy than themselves, was expressed in the recognition that scarce resources-including information and explanations-had to be shared and meant that limited information was accepted as inevitable. CONCLUSIONS: Cancer patients' attitudes to cancer and their strategies for coping with their illness can constrain their wish for information and their efforts to obtain it. In developing recommendations, the government's cancer information strategy should attend to variations in patients' desires for information and the reasons for them.
Haplotypes of the monoamine oxidase genes and the risk for substance use disorders

Monoamine oxidase A (MAOA) locus is an attractive candidate for exploring genetic contribution to the variation in the risk for substance use disorders (SUD) because of its important role in the metabolism of neurotransmitters, including dopamine and serotonin. Prior findings have suggested an association of the MAOA gene with the risk for early onset SUD. To extend this research, we genotyped four MAOA markers (two VNTR polymorphisms and two SNPs) and built a cladogram reflecting the evolutionary history of MAOA haplotypes [Nguyen et al., under review]. The cladogram served as the framework for nested ANOVA and logit analyses of association between MAOA and indices of liability to SUD (diagnosis, age of onset, and a dimensional index of substance use related problems) in a sample of adult males of European ancestry. Whereas no association was found for the categorical diagnosis, a significant relationship was detected between the dimensional liability indices and MAOA haplotypes. Overall, our results, albeit not definitive, are consistent with the hypothesis that variants in MAOA account for a small portion of the variance of SUD risk, possibly mediated by liability to early onset behavioral problems. © 2003 Wiley‐Liss, Inc.
Comparison of Two Protocols in the Management of Glucocorticoid-induced Hyperglycemia among Hospitalized Patients

Context: There is limited literature focusing on the management of glucocorticoid-induced hyperglycemia (GCIH). Aims: The primary objective was to compare the mean blood glucose between the experimental group (new protocol) and the control group (standard protocol) in the management of GCIH. The secondary objective was to compare other parameters of glycemic efficacy, variability, and safety parameters. Methods: This was a randomized, open-labeled, parallel arm trial. Adult patients who were given glucocorticoid (minimum dose equivalent to prednisolone 10 mg) in the past 24 h and had 2 h postmeal plasma glucose ≥200 mg/dl were included in the study. Patients randomized to control group received standard basal-bolus insulin. In the experimental group, a “correctional insulin” matching the glycemic profile of the glucocorticoid administered was provided with or without “background” basal-bolus insulin. The parameters of glycemic efficacy, variability, and safety were compared. P < 0.05 was considered statistically significant. Results: Data of 67 patients included in the study were analyzed, of which 33 patients were in the experimental group and 34 patients in the control group. The mean blood glucose in the experimental and the control group was 170.32 ± 33.46 mg/dl and 221.05 ± 49.72, respectively (P = 0.0001). The parameters for glycemic variability were all significantly lower in patients in the experimental group. The hypoglycemia event rate was low in both the groups. Conclusion: When compared to the standard basal-bolus insulin protocol, the new protocol showed lower mean blood glucose and lower glycemic variability.
CSR, agency costs and investment-cash flow sensitivity: a mediated moderation analysis

Purpose The purpose of this paper is to document the relation between investment-cash flow sensitivity and a firm’s engagement in corporate social responsibility (CSR) activities in European context. Specifically, this paper aims to empirically examine how CSR moderates the sensitivity between investment spending and firm internal funds. Design/methodology/approach The Euler equation technique approach is applied to test the sensitivity of investment to internally generated funds for a panel data set of 398 European companies listed in the STOXX Europe 600 during 2009-2014. Furthermore, a mediated moderation model is developed in order to examine the moderating role of CSR in the investment-cash flow sensitivity, as well as the mediating role of agency costs on the moderation effect of CSR. Findings The results show that CSR performance weakens the sensitivity of investment to internal funds; agency costs of free cash flow mediate the negative moderating effect of CSR on investment-cash flow sensitivity. Thus, this study demonstrates empirically that firms with socially responsible practices are better positioned to obtain financing in the capital markets through reducing market frictions as well as agency costs. Practical implications Firms are invited to engage more in CSR activities that reduce agency conflicts between management and shareholders. Originality/value The originality of this paper consists in proposing the establishment of both direct and indirect link between CSR and investment-cash flow sensitivity.
Ligand binding to the FeMo-cofactor: Structures of CO-bound and reactivated nitrogenase

Making nitrogen available for biosynthesis Nitrogen gas (N2) is abundant in Earth's atmosphere; however, it must be converted into a bioavailable form before it can be incorporated into biomolecules. The enzyme nitrogenase, which is made up of two metalloproteins, converts N2 into bioavailable ammonia. One of these, the MoFe-protein, contains a complex metal center, the FeMo cofactor, where the triple N2 bond is reduced. Understanding how nitrogenase achieves the reduction of N2 has been a long-term goal. Spatzal et al. present the structure of MoFe-protein bound to carbon monoxide (see the Perspective by Hogbom). Although this is an inhibitor rather than the natural substrate, the structure gives insight into how the FeMo metallocluster rearranges to achieve substrate reduction. Science, this issue p. 1620 The structure of an inhibitor bound to nitrogenase reveals rearrangements in the active-site metallocluster. [Also see Perspective by Hognom] The mechanism of nitrogenase remains enigmatic, with a major unresolved issue concerning how inhibitors and substrates bind to the active site. We report a crystal structure of carbon monoxide (CO)–inhibited nitrogenase molybdenum-iron (MoFe)–protein at 1.50 angstrom resolution, which reveals a CO molecule bridging Fe2 and Fe6 of the FeMo-cofactor. The μ2 binding geometry is achieved by replacing a belt-sulfur atom (S2B) and highlights the generation of a reactive iron species uncovered by the displacement of sulfur. The CO inhibition is fully reversible as established by regain of enzyme activity and reappearance of S2B in the 1.43 angstrom resolution structure of the reactivated enzyme. The substantial and reversible reorganization of the FeMo-cofactor accompanying CO binding was unanticipated and provides insights into a catalytically competent state of nitrogenase.
Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division

Cells expressing indoleamine 2,3‐dioxygenase (IDO), an enzyme which catabolizes tryptophan, prevent T‐cell proliferation in vitro, suppress maternal antifetal immunity during pregnancy and inhibit T‐cell‐mediated responses to tumour‐associated antigens. To examine the mechanistic basis of these phenomena we activated naïve murine T cells in chemically defined tryptophan‐free media. Under these conditions T cells expressed CD25 and CD69 and progressed through the first 12 hr of G0/G1 phase but did not express CD71, cyclin D3, cdk4, begin DNA synthesis, or differentiate into cytotoxic effector cells. In addition, activated T cells with their growth arrested by tryptophan deprivation exhibited enhanced tendencies to die via apoptosis when exposed to anti‐Fas antibodies. Apoptosis was inhibited by caspase inhibitor and was not observed when T cells originated from Fas‐deficient mice. These findings suggest that T cells activated in the absence of free tryptophan entered the cell cycle but cell cycle progression ceased in mid‐G1 phase and T cells became susceptible to death via apoptosis, in part though Fas‐mediated signalling. Thus, mature antigen‐presenting cells expressing IDO and Fas‐ligand may induce antigen‐specific T‐cell tolerance by blocking T‐cell cycle progression and by rapid induction of T‐cell activation induced cell death in local tissue microenvironments.
Analytical and Equivalent Circuit Models to Elucidate Power Balance in Scattering Problems

Analytical and equivalent circuit models are presented to elucidate the balance of powers in scattering processes. Specifically, closed-form expressions of the associated maximal extracted, scattered, absorbed and reactive powers are formulated. The circuit model then helps to characterize in a straightforward manner these powers, to provide physical insights into the inter-relationships among this set, and thus guides the resolution of their fundamental limits. The analysis demonstrates that the absorbed power can not exceed 25% of the power extracted from the incident field (extracted power) for the lossless case and helps extricate the conditions for which the scattered and absorbed powers are equal or significantly different. A coated sphere illuminated by a plane wave under both resonant and cloaked states is selected as an illustrative example. Although the analysis and circuit models are rigorously derived for spheroidal particles, their extrapolation to arbitrary scatterers is also discussed.
Risk factors for suicide in China's youth: a case-control study

Background Suicide is the most common cause of death among youth in China. Method A case-control psychological autopsy study in 23 geographically representative disease surveillance points around China collected information from family members and close associates of 114 persons aged 15–24 years who died by suicide (cases) and 91 who died of other injuries (controls). Results Among the 114 suicides 61% were female, 88% lived in rural villages, 70% died by ingesting pesticides (most commonly stored in the home), 24% previously attempted suicide, and 45% met criteria of a mental illness at the time of death. Multivariate logistic regression identified several independent risk factors: severe life events within 2 days before death (OR 31.8, 95% CI 2.6–390.6), presence of any depressive symptoms within 2 weeks of death (OR 21.1, 95% CI 4.6–97.2), low quality of life in the month before death (OR 9.7, 95% CI 2.8–34.1), and acute stress at time of death (moderate: OR 3.1, 95% CI 0.8–11.9; high: OR 9.1, 95% CI 1.2–66.8). A significant interaction between mental illness at time of death and gender indicated that diagnosis was an important predictor of suicide in males (OR 14.0, 95% CI 2.6–76.5) but not in females (OR 0.3, 95% CI 0.0–3.6). Prior suicide attempt was related to suicide in the univariate analysis (OR 57.5) but could not be included in the multivariate model because no controls had made prior attempts. Conclusions Suicide prevention efforts for youth in China must focus on restricting access to pesticides, early recognition and management of depressive symptoms and mental illnesses, improving resiliency, and enhancing quality of life.
Statistical parametric mapping of LORETA using high density EEG and individual MRI: Application to mismatch negativities in Schizophrenia

We describe a method for the statistical parametric mapping of low resolution electromagnetic tomography (LORETA) using high‐density electroencephalography (EEG) and individual magnetic resonance images (MRI) to investigate the characteristics of the mismatch negativity (MMN) generators in schizophrenia. LORETA, using a realistic head model of the boundary element method derived from the individual anatomy, estimated the current density maps from the scalp topography of the 128‐channel EEG. From the current density maps that covered the whole cortical gray matter (up to 20,000 points), volumetric current density images were reconstructed. Intensity normalization of the smoothed current density images was used to reduce the confounding effect of subject specific global activity. After transforming each image into a standard stereotaxic space, we carried out statistical parametric mapping of the normalized current density images. We applied this method to the source localization of MMN in schizophrenia. The MMN generators, produced by a deviant tone of 1,200 Hz (5% of 1,600 trials) under the standard tone of 1,000 Hz, 80 dB binaural stimuli with 300 msec of inter‐stimulus interval, were measured in 14 right‐handed schizophrenic subjects and 14 age‐, gender‐, and handedness‐matched controls. We found that the schizophrenic group exhibited significant current density reductions of MMN in the left superior temporal gyrus and the left inferior parietal gyrus (P < 0. 0005). This study is the first voxel‐by‐voxel statistical mapping of current density using individual MRI and high‐density EEG. Hum. Brain Mapping 17:168–178, 2002. © 2002 Wiley‐Liss, Inc.
Time Reversal and Zero-Forcing Equalization for Fixed Wireless Access Channels

We consider a wideband system with an M -element transmit array. In this paper we combine conventional zeroforcing pre-equalization and time reversal: we present a beamformer that perfectly equalizes the channel and preserves the spatial focusing properties of time reversal. We compare it to a pure zero-forcing beamformer and a pure time reversal system and demonstrate its superior bit error rate performance and low probability of intercept properties using actual measurements of a fixed wireless access system in an urban environment.
The Research of Multiple Regression Analysis in Rural-Urban Income Disparity

lijian_hucm@163.com Abstract The multiple linear regression model contains more than one predictor variable and it shows the relationship among multiple variables. In the existing research field of rural-urban income disparity, the method of multiple regression analysis is mainly employed. But the linear relationship among variables is estimated mainly depending on principal component analysis. Principal component analysis is used to convert a set of observations of possibly correlated variables into a set of values of linearly uncorrelated variables called principal components. The principal component analysis is widely used for feature extraction to reveal the most main factors from the multiple aspects. A multiply linear regression model integrating principal components analysis is proposed to address on the income gap between the city and country. The influential factors are given and the analysis results are discussed in this paper. The experimental results on income data from 1990 to 2013 show that the proposed method is effective in predicting the income ratio and analyzing the influential
Business ethics in the accountancy profession: a South African perspective

iii OPSOMMING . vi ACKNOWLEDGEMENTS . ix LIST OF ABBREVIATIONS . xi LIST OF TABLES . xiv LIST OF SCHEMATIC REPRESENTATIONS . xviii LIST OF GRAPHIC REPRESENTATIONS . xix CHAPTER 1 INTRODUCTION AND STUDY LAYOUT . 8 1.1 BACKGROUND TO THE STUDY . 8 1.2 RECENT INTERNATIONAL CASES OF UNETHICAL ECONOMIC PRACTICES . 13 1.2. 1 BARCLAYS . 13 1.2. 2 THE RESERVE BANK OF AUSTRALIA . 14 1.2. 3 RUPERT MURDOCH’S “NEWS OF THE WORLD” . 15 1.2. 4 INDIA’S TELECOMMUNICATION SCANDAL . 17 1.2. 5 BAYERN LANDESBANK AND FORMULA ONE’S BERNIE ECCLESTONE. 18 1.2. 6 GREECE’S GOVERNMENTAL CORRUPTION . 18 1.2. 7 SIEMENS . 19 1.2. 8 PHILIPS ELECTRONICS. 20 1.2. 9 OLYMPUS . 20
How family networks drive residential location choices: Evidence from a stated preference field experiment in Bogotá, Colombia

This research quantifies the relative importance of proximity to extended family networks in the stated residential location choices of Bogotá‘s low-to-middle-income residents by applying a conditional logistic regression model and using data from an original choice experiment. I find that the surveyed individuals prefer living near their extended family and, on average, prioritise it more than accessibility to the central business district. Those who have relied on help from extended family members in a personal or economic crisis situation have a stronger preference for living near extended family compared with those who have not, as do those who are able to rely on extended family ties for childcare assistance.