Miracle-dz/UniFAR-FTUs huggingface dataset:
Steady-State Pharmacokinetics of a Double-Boosting Regimen of Saquinavir Soft Gel plus Lopinavir plus Minidose Ritonavir in Human Immunodeficiency Virus-Infected Adults

ABSTRACT Management of treatment-experienced human immunodeficiency virus patients has become complex, and therapy may need to include two protease inhibitors at therapeutic doses. The objective of this study was to characterize the pharmacokinetics in serum of saquinavir (1,000 mg twice daily [b.i.d.]), lopinavir (400 mg b.i.d.), and ritonavir (100 mg b.i.d.) in a multidrug rescue therapy study and to investigate whether steady-state pharmacokinetics of lopinavir-ritonavir are affected by coadministration of saquinavir. Forty patients were included (25 given ritonavir, lopinavir, and saquinavir and 15 given ritonavir and lopinavir). The median pharmacokinetic parameters of lopinavir were as follows: area under the concentration-time curve from 0 to 12 h (AUC0-12), 85.1 μg/ml · h; maximum concentration of drug in serum (Cmax), 10.0 μg/ml; trough concentration of drug in serum (Ctrough), 7.3 μg/ml; and minimum concentration of drug in serum (Cmin), 5.5 μg/ml. Lopinavir concentrations were similar in patients with and without saquinavir. The median pharmacokinetic parameters for saquinavir were as follows: AUC0-12, 22.9 μg/ml · h; Cmax, 2.9 μg/ml; Ctrough, 1.6 μg/ml; and Cmin, 1.4 μg/ml. There was a strong linear correlation between lopinavir and ritonavir and between saquinavir and ritonavir concentrations in plasma. The correlation between lopinavir and saquinavir levels was weaker. We found higher saquinavir concentrations in women than in men, with no difference in lopinavir levels. Only patients with very high body weight presented lopinavir and saquinavir concentrations lower than the overall group. Ritonavir has a double-boosting function for both lopinavir and saquinavir, and in terms of pharmacokinetics, the drug doses selected seemed appropriate for combining these agents in a dual protease inhibitor-based antiretroviral regimen for patients with several prior virologic failures.
Risk measures versus ruin theory for the calculation of solvency capital for long-term life insurances

Abstract The purpose of this paper is twofold. First we consider a ruin theory approach along with risk measures in order to determine the solvency capital of long-term guarantees such as life insurances or pension products. Secondly, for such products,we challenge the definition of the Solvency Capital Requirement (SCR) under the Solvency II (SII) regulatory framework based on a yearly viewpoint. Several methods for the calculation of the solvency capital are presented. We start our study with risk measures as considered in the SII framework and then proceed with the ruin theory approach. Instead of considering the continuous time setting of the ruin theory,we consider the discrete time—the yearly basis—of the accounting viewpoint.We finally give an illustration with a fixed guaranteed rate product along with the equity, interest rate and longevity risks. The latter risk brings us to consider zero-coupon longevity bonds in which we invest the capital. We show that long-term guarantees might be overloaded under the SII regulation.
Comparison of Two 3ABC Enzyme-Linked Immunosorbent Assays for Diagnosis of Multiple-Serotype Foot-and-Mouth Disease in a Cattle Population in an Area of Endemicity

ABSTRACT The development of a serological test for foot-and-mouth disease virus (FMDV) which is quick and easy to use, which can identify all seven serotypes, and which can differentiate vaccinated from convalescing or potential virus carriers would be a major advance in the epidemiological toolkit for FMDV. The nonstructural polyprotein 3ABC has recently been proposed as such an antigen, and a number of diagnostic tests are being developed. This paper evaluates the performance of two FMDV tests for antibodies to nonstructural proteins in an unvaccinated cattle population from a region of Cameroon with endemic multiple-serotype FMD. The CHEKIT-FMD-3ABC bo-ov (CHEKIT) enzyme-linked immunosorbent assay (ELISA) (Bommeli Diagnostics/Intervet) is a commercially available test that was compared with a competitive 3ABC ELISA (C-ELISA) developed in Denmark. The tests were compared with the virus neutralization test as the “gold standard. ” Diagnostic sensitivity and specificity were examined over a range of test cutoffs by using receiver operating characteristic curves, which allowed comparison of the overall performance of each test. The results indicated that the CHEKIT ELISA kit was 23% sensitive and 98% specific and the Danish C-ELISA was 71% sensitive and 90% specific at the recommended cutoff. These results have important implications if the tests are to be used to screen herds or individual cattle in surveillance programs, at border crossings for import-export clearance, or following emergency vaccination in an outbreak situation.
Coping with Pressures in Acute Medicine – the Second RCP Consultant Questionnaire Survey

The second questionnaire survey of consultant physicians involved in acute unselected takes in 1999 achieved a 76% response rate, and the results have been compared with those from the first survey of 1997. The proportion of consultants whose trainees worked partial shifts had increased from 42% to 61%, although these patterns of duty were adjudged to have detrimental effects on the quality and continuity of care, and on junior staff education and training. The benefits of ward-based systems were counterbalanced by their disadvantages, but introductions of admission wards and assessment units were considered a resounding success. The number of hospitals with 'physician of the week' schemes had increased from 12 to 23, but opinion of their value was sharply divided. The provision and competence of all grades of locums was identified as an increasing problem. Seventy per cent of respondents stated that they would never participate in 'hands-on' emergency care, although 86% thought that future consultants might have to do so. Seventy-nine per cent reported increases in the pressures of their posts and in their working hours, and the tensions between general and specialist duties were highlighted. Most consultants considered that the only long-term solution to the staffing crisis was a marked expansion in the numbers of all grades of medical staff.
Construction of an adenovirus type 7a E1A- vector

A strategy for constructing replication-defective adenovirus vectors from non-subgroup C viruses has been successfully demonstrated with adenovirus type 7 strain a (Ad7a) as the prototype. An E1A-deleted Ad7a reporter virus expressing the chloramphenicol acetyltransferase (CAT) gene from the cytomegalovirus promoter enhancer was constructed with DNA fragments isolated from Ad7a, an Ad7a recombination reporter plasmid, and the 293 cell line. The Ad7a-CAT virus particle transduces A549 cells as efficiently as Ad5-based vectors. Intravenous infections in a murine model indicate that the Ad7a-CAT virus infects a variety of tissues, with maximal levels of CAT gene expression found in the liver. The duration of Ad7a-CAT transgene expression in the liver was maximally maintained 2 weeks postinfection, with a decline to baseline activity by the week 4 postinfection. Ad7a-CAT represents the first example of a non-subgroup C E1A- adenovirus gene transfer vector.
First Mouse Model for Combined Osteogenesis Imperfecta and Ehlers‐Danlos Syndrome

By using a genome‐wide N‐ethyl‐N‐nitrosourea (ENU)‐induced dominant mutagenesis screen in mice, a founder with low bone mineral density (BMD) was identified. Mapping and sequencing revealed a T to C transition in a splice donor of the collagen alpha1 type I (Col1a1) gene, resulting in the skipping of exon 9 and a predicted 18‐amino acid deletion within the N‐terminal region of the triple helical domain of Col1a1. Col1a1Jrt/+ mice were smaller in size, had lower BMD associated with decreased bone volume/tissue volume (BV/TV) and reduced trabecular number, and furthermore exhibited mechanically weak, brittle, fracture‐prone bones, a hallmark of osteogenesis imperfecta (OI). Several markers of osteoblast differentiation were upregulated in mutant bone, and histomorphometry showed that the proportion of trabecular bone surfaces covered by activated osteoblasts (Ob.S/BS and N.Ob/BS) was elevated, but bone surfaces undergoing resorption (Oc.S/BS and N.Oc/BS) were not. The number of bone marrow stromal osteoprogenitors (CFU‐ALP) was unaffected, but mineralization was decreased in cultures from young Col1a1Jrt/+ versus +/+ mice. Total collagen and type I collagen content of matrices deposited by Col1a1Jrt/+ dermal fibroblasts in culture was ∼40% and 30%, respectively, that of +/+ cells, suggesting that mutant collagen chains exerted a dominant negative effect on type I collagen biosynthesis. Mutant collagen fibrils were also markedly smaller in diameter than +/+ fibrils in bone, tendon, and extracellular matrices deposited by dermal fibroblasts in vitro. Col1a1Jrt/+ mice also exhibited traits associated with Ehlers‐Danlos syndrome (EDS): Their skin had reduced tensile properties, tail tendon appeared more frayed, and a third of the young adult mice had noticeable curvature of the spine. Col1a1Jrt/+ is the first reported model of combined OI/EDS and will be useful for exploring aspects of OI and EDS pathophysiology and treatment. © 2014 American Society for Bone and Mineral Research.
Applying variance-based Learning Classifier System without Convergence of Reward Estimation into various Reward distribution

This paper focuses on a generalization of classifiers in noisy problems and aims at exploring learning classifier systems (LCSs) that can evolve accurately generalized classifiers as an optimal solution in several environments which include different type of noise. For this purpose, this paper employs XCS-CRE (XCS without Convergence of Reward Estimation) which can correctly identify classifiers as either accurate or inaccurate ones even in a noisy problem, and investigates its effectiveness in several noisy problems. Through intensive experiments of three LCSs (i.e., XCS as the conventional LCS, XCS-SAC (XCS with Self-adaptive Accuracy Criterion) as our previous LCS, and XCS-CRE) on the noisy 11-multiplexer problem where reward value changes according to (a) Gaussian distribution, (b) Cauchy distribution, or (c) Lognormal distribution, the following implications have been revealed: (1) the correct rate of the classifier of XCS-CRE and XCS-SAC converge to 100% in all three types of the reward distribution while that of XCS cannot reach 100%; (2) the population size of XCS-CRE is smallest followed by that of XCS-SAC and XCS; and (3) the percentage of the acquired optimal classifiers of XCS-CRE is highest followed by that of XCS-SAC and XCS.
Weight Changes in Subthalamic Nucleus vs Globus Pallidus Internus Deep Brain Stimulation: Results From the COMPARE Parkinson Disease Deep Brain Stimulation Cohort

BACKGROUND:Parkinson's patients, on average, gain weight after deep brain stimulation (DBS). OBJECTIVE:To determine potential differences in weight gain when comparing the subthalamic nucleus and the globus pallidus internus target. METHODS:A retrospective analysis was performed on the prospective, randomized cohort of National Institutes of Health COMPARE trial DBS patients who received unilateral subthalamic nucleus or globus pallidus internus DBS. Baseline weights were recorded before DBS surgery and at 6, 12, and 18 months postoperatively. Relationships between weight change and changes in Beck Depression Inventory score, Unified Parkinson's Disease Rating Scale (UPDRS) motor score (part III) (also the dyskinesia duration and disability subscores from UPDRS IV), and Hoehn-Yahr stage were determined via Spearman's rank-order correlation coefficients. Regression analyses were performed to investigate the effects of potential factors on weight change over time. RESULTS:Patients in the COMPARE DBS cohort gained a significant amount of weight, a mean of 4.86 lb (standard deviation = 8.73) (P = .001), but there was no significant difference between subthalamic nucleus and globus pallidus internus targets (weight gain of 4.29 ± 6.79 and 5.38 ± 10.32 lb, respectively; P = .68). Weight gain did not correlate with Beck Depression Inventory score change, UPDRS motor score, dyskinesia duration, dyskinesia disability change, or the Hoehn-Yahr stage (P = .62, .21, and .31, respectively). No specific variable was associated with weight gain, and there were no differences in binge eating post-surgery in either target. CONCLUSION:There were significant changes in weight over time after DBS therapy. However, neither Beck Depression Inventory score change nor UPDRS score change or dyskinesia was correlated with weight gain. No significant factor was associated with the weight change.
The Determinant and Trade Potential of Export of the Indonesia's Textile Products: A Gravity Model

The objective of this paper is examining the determinant factors that are influential in the export of Indonesia’s textile products, especially in two aggregate products, fibre (SITC 26) and yarn and fabric (SITC 65). This paper utilizes standard and augmented gravity models, which estimate the impact of GDP, per capita income and population to export. The result concludes that the geographical distance and size of partner countries’ economies significantly impact the pattern of textile product export growth. However, the size of the reporters’ (Indonesia’s) economy is not significant for the yarn and fabric products export. Moreover, Indonesia tends to export to partner countries with a similar level of per capita income. Finally, Indonesia needs to diversify its export destinations to countries that still experience under-traded conditions, so that Indonesia’s textile industry can evade any risks concerning excessive market dependency to any country.
Off-service residents in the emergency department: the need for learner-centredness.

OBJECTIVES Standard learning objectives enable residency directors to develop effective programs and evaluate residents based on key goals and parameters. While standards are important for ensuring basic competence, the usual process has little flexibility to address the unique needs and desires of a given resident. Our objective was to determine whether the expectations of off-service residents rotating through an emergency department (ED) rotation were being met. METHODS We developed a 144-item questionnaire using a 5-point Likert scale and surveyed 25 off-service residents at the beginning and end of their ED rotation. The survey was divided into 3 sections: presentations, skills and diagnoses. RESULTS The results demonstrate that certain expectations are consistently underachieved while others represent individual variations. CONCLUSION We propose a learner-centred approach to ensure an optimal emergency educational experience for all trainees.
Review Paper: Host-Pathogen Interactions in the Kidney during Chronic Leptospirosis

Pathogenic species of Leptospira cause leptospirosis, a global zoonotic disease. Leptospira colonize renal tubules of chronically infected maintenance hosts, from where they are shed in urine to the environment and survive in suitable moist conditions. Transmission of disease to new hosts is facilitated by contact with contaminated urine or water sources, because Leptospira can penetrate broken skin or mucosal surfaces of new hosts. Infection of new hosts may be asymptomatic, as with chronically infected maintenance hosts, or may result in an acute disease process in which clinical signs can include fever, jaundice, renal failure, and pulmonary hemorrhage. Those factors that determine if an animal will suffer an acute or a chronic infection are not fully understood but include host animal species, infecting serovar, and infecting dose. During chronic infection, renal colonization and leptospiruria persist despite cellular and humoral responses by the host. Tubulointerstitial nephritis is the most common lesion associated with chronic infection, and this may progress to fibrosis and subsequent renal failure. This review aims to address how Leptospira cause tubulointerstitial nephritis during chronic leptospirosis and to summarize the mechanisms by which Leptospira might evade host immune responses during chronic colonization of the renal tubule.
Minimizing Number of Tardy Jobs on a Batch Processing Machine with Incompatible Job Families

In this paper we prove that the problem of scheduling jobs with incompatible job families on a single batch processing machine to minimize number of tardy jobs is strongly (unary) NP-hard. We then develop a dynamic programming algorithm for minimizing weighted number of tardy jobs on a single batch processing machine with incompatible job families.
Financial incentive to control paratuberculosis (Johne’s disease) on dairy farms in the United Kingdom

This paper estimates the financial incentive to control paratuberculosis on dairy farms by establishing the level of expenditure that would minimise the total cost of the disease (output losses plus control expenditure). Given the late onset of the clinical signs and the lack of treatments, control was focused on minimising the financial impact of paratuberculosis by adjusting the dairy cow replacement policy. The optimum replacement policies for disease-free herds and infected herds were compared by using dynamic programming. At the standard settings, the disease justified adjusting the culling policy; under constant bioeconomic assumptions, it reduced the expected annuity from milk production under the optimal replacement policy by about 10 per cent (£27 per cow annually), a considerably lower figure than for other major endemic diseases that affect dairy cows in the UK. The effect was even less at lower milk prices, suggesting that there is at present little incentive for dairy farmers to put more resources into controlling the disease. However, the incentive could be increased if more information were available about how best to manage the disease under specific farm circumstances. Any effect that paratuberculosis may have on the future demand for milk and hence on milk prices would also be an important consideration.
Anion Activation Site of Insulin-degrading Enzyme*

Insulin-degrading enzyme (IDE) (insulysin) is a zinc metallopeptidase that metabolizes several bioactive peptides, including insulin and the amyloid β peptide. IDE is an unusual metallopeptidase in that it is allosterically activated by both small peptides and anions, such as ATP. Here, we report that the ATP-binding site is located on a portion of the substrate binding chamber wall arising largely from domain 4 of the four-domain IDE. Two variants having residues in this site mutated, IDEK898A,K899A,S901A and IDER429S, both show greatly decreased activation by the polyphosphate anions ATP and PPPi. IDEK898A,K899A,S901A is also deficient in activation by small peptides, suggesting a possible mechanistic link between the two types of allosteric activation. Sodium chloride at high concentrations can also activate IDE. There are no observable differences in average conformation between the IDE-ATP complex and unliganded IDE, but regions of the active site and C-terminal domain do show increased crystallographic thermal factors in the complex, suggesting an effect on dynamics. Activation by ATP is shown to be independent of the ATP hydrolysis activity reported for the enzyme. We also report that IDEK898A,K899A,S901A has reduced intracellular function relative to unmodified IDE, consistent with a possible role for anion activation of IDE activity in vivo. Together, the data suggest a model in which the binding of anions activates by reducing the electrostatic attraction between the two halves of the enzyme, shifting the partitioning between open and closed conformations of IDE toward the open form.
Poor mental health in severely obese patients is not explained by the presence of comorbidities

The prevalence of obesity, especially severe obesity where body mass index (BMI) exceeds 40 kg m−2 and where the physical risks are greatest, is increasing. However, little is known about the impact of severe obesity on psychological well‐being and self‐rated health (SRH). We aimed to investigate this relationship in patients attending an Irish weight management clinic. SRH was measured with a single‐item inventory (excellent = 1, poor = 5). Well‐being was measured with the validated World Health Organization‐Five Well‐being Index (WHO‐5), in which scores <13 indicate poor well‐being. Previous studies of the Irish population have reported mean SRH = 2.56 (males) and 2.53 (females) and mean well‐being = 16.96. One hundred eighty‐two (46.8%) completed questionnaires were returned. The sample was representative of the clinic population with a mean age of 47.1, mean baseline BMI of 51.9 kg m−2 and 64.3% females. Mean SRH was 3.73 in males and 3.30 in females; mean well‐being was 10.27 in males and 10.52 in females. In the final multivariable models, number of medications, depression and obstructive sleep apnoea, WHO‐5 and current BMI were significant predictors of SRH, and secondary level education, social support and mindfulness scores were significant predictors of psychological well‐being. Number of medications was not significant. The results suggest that the poor psychological well‐being seen is not explained by the presence of comorbidities and that social support and mindfulness may be important targets for improving psychological well‐being. Improving psychological well‐being in addition to weight loss and effective management of comorbidities may be important for improving SRH.
Numerical simulations of the scattered field near a statistically rough air-ground interface

The two-dimensional problem of horizontally polarized wave scattering from an air-ground interface is considered. The diffraction problem is formulated by means of the extinction theorem, leading to a system of two simultaneous surface integral equations. The small-slope approximation has been used to solve this system. This solution was used as a fast forward solver in the Monte Carlo simulations of the scattered field near to the rough interface. Properties of the reflected field have been investigated for a single realization of the rough interface as well as for a statistical ensemble of such interfaces. Special attention has been paid to the phase of the reflected field (in the case of a single realization) and to the variance of the reflected field (in the case of a statistical ensemble), which has direct relation with the surface clutter in ground penetrating radars. A principal possibility to retrieve a surface profile from interferometric measurements of the reflected field near the surface is demonstrated.
Early stages of service business - review and synthesis

Many stage models have been introduced to clarify management priorities during the early stages of business growth. However, many of these models are conceptual and universal, providing only limited benefits to specific industries and business contexts. The early stages of technology-based ventures have attracted interest, while little attention has been paid to the early stages of service-based firms. This study examines the early stages of growth in service-based firms. The following research questions are posed: What are the basic characteristics of recent empirical studies on the early stages of service-based firms? What are the themes and sequential patterns in the early stages of service-based firms as revealed in the recent empirical literature? This study provides a meta-analytical review designed to answer the research questions. A group of recent empirical-stage models of the early stages of service-based business were selected for meta-analysis and synthesis. The meta-analysis integrates the findings of these models and introduces a self-evaluation framework for the early stages of service-based companies.