Miracle-dz/UniFAR-FTUs huggingface dataset:
Population pharmacokinetic approach to evaluate the effect of CYP2D6, CYP3A, ABCB1, POR and NR1I2 genotypes on donepezil clearance.

AIMS A large interindividual variability in plasma concentrations has been reported in patients treated with donepezil, the most frequently prescribed antidementia drug. We aimed to evaluate clinical and genetic factors influencing donepezil disposition in a patient population recruited from a naturalistic setting. METHODS A population pharmacokinetic study was performed including data from 129 older patients treated with donepezil. The patients were genotyped for common polymorphisms in the metabolic enzymes CYP2D6 and CYP3A, in the electron transferring protein POR and the nuclear factor NR1I2 involved in CYP activity and expression, and in the drug transporter ABCB1. RESULTS The average donepezil clearance was 7.3 l h(-1) with a 30% interindividual variability. Gender markedly influenced donepezil clearance (P < 0.01). Functional alleles of CYP2D6 were identified as unique significant genetic covariate for donepezil clearance (P < 0.01), with poor metabolizers and ultrarapid metabolizers demonstrating, respectively, a 32% slower and a 67% faster donepezil elimination compared with extensive metabolizers. CONCLUSION The pharmacokinetic parameters of donepezil were well described by the developed population model. Functional alleles of CYP2D6 significantly contributed to the variability in donepezil disposition in the patient population and should be further investigated in the context of individual dose optimization to improve clinical outcome and tolerability of the treatment.
THE RELATIONSHIP BETWEEN CLINICAL STEREOTESTS

THE RELATIONSHIP BETWEEN CLINICAL STEREOTESTS Hall’s recent article on this topic (Hall, 1982) contains two points that need clarification. (1) Rescaling the binocular disparities created by the Titmus test when used at 80 cm requires multiplying the 40-cm values by 0.50, not 0.25 as shown in his Fig. 1 (Walraven, 1975). (2) Table 1 is perplexing because it shows rank-correlation values that do not appear to match significance levels. For example, the 0.35 value is indicated to be significant at the 0.05 level, the 0.25 value at the 0.02 level and the 0.41 value at the 0.001 level. Perhaps this is the result of a misprint. These issues aside, the author is to be complimented upon making additional data on clinical stereopsis available and for listing additional considerations that can produce different results from the same patient when two separate tests are used.
DIAGNOSTIC VALUE OF THE LEUCOCYTE FORMULA IN PERTUSSIS.

IMPORTANCE OF BLOOD EXAMINATION. Whooping-cough is a far more serious disease than is generally supposed, and its diagnosis in the early stage is a matter of great importance, as it is at this time that the infection is most frequently spread. Any measure, therefore, which may help to its early recognition is worthy of careful study and investigation. The examination of the blood in this disease, as in many other infections, has unexpectedly shown a condition which, in a certain number of cases, is abnormal and perhaps of diagnostic value. This condition consists of an increase, both relative and absolute, in the number of the lymphocytes—a lymphocytosis. Several series of cases have been reported showing this increase in these cells, but the number on record is still comparatively small. Therefore I have made some investigations on this subject with the object of determining how frequently this condition is found, how
Neurofeedback Treatment of Type I Diabetes Mellitus: Perceptions of Quality of Life and Stabilization of Insulin Treatment–Two Case Studies

Background. This article is a case study review of the neurofeedback treatment of two female subjects with Type I diabetes mellitus. Both women had received regular medical treatment including the use of a restricted diet and short-term insulin treatment using an insulin pump. The study sought to discover the effects of neurofeedback treatment on the individuals’ perceptions of their quality of life and, any effects on measured glucose blood levels. Method. Both the subjects received 20 sessions of neurofeedback training. These sessions took place three times a week, each session lasting approximately 45 minutes to 1 hour. The treatment consisted of training at C3, C4, and interhemispheric (C3-C4). The women were given symptom report checklists following each session and were interviewed prior to beginning of the treatment, at the conclusion of the 20 sessions, and 16 days after their final session. The interviews focused on self-reported changes in symptoms and the effect of these changes on their quality of life. Both the women also recorded their daily glucose levels and insulin dosage throughout the study. Results. The subjects reported improvement in their perception of their quality of life (QOL). Additionally, both reported improvement in glucose levels as well as fluctuations and reduced dosages of insulin required on a daily basis. Discussion. The existing research on the effectiveness of neurofeedback training for a broad variety of physical and emotional problems lead us to wonder if it might be helpful for either the physical or emotional aspects of Type I diabetes mellitus. Given the higher incidence of this condition, the significance of this research was considered to be important. The results of the study provide preliminary evidence that neurofeedback can be an important and valuable treatment for both the physical and emotional symptoms associated with Type I diabetes mellitus. Furthermore, research with larger numbers and stricter controls in the field is warranted.
Dried plasma/blood spots for monitoring antiretroviral treatment efficacy and pharmacokinetics: a cross-sectional study in rural Burundi.

AIMS In limited resource settings monitoring antiretroviral (ARV) treatment efficacy is restrained by the lack of access to technological equipment. The aim of the study was to assess the use of dried plasma (DPS) and blood spots (DBS) to facilitate ARV monitoring in remote settings where clinical monitoring is the primary strategy. METHODS A cross-sectional study in HIV-positive ARV-treated patients in Kiremba, Burundi was performed. DBS were used for HIV-1 viral load (limit of the assay 250 copies ml(-1)) and genotypic drug resistance tests and dried plasma spots were used for concentration measurements. RESULTS Three hundred and seven patients [201 female (88.6%), 14 children (4.5%)] were enrolled. HIV-1 viral load was <250, 250-1000 and >1000 copies ml(-1) in 250 (81.7%), 33 (10.8%) and 23 patients (7.5%). Eleven samples out of 23 were successfully amplified revealing nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistance associated mutations [in seven (58.3%) and six patients (50%)]. Nevirapine trough concentrations were <3000 ng ml(-1) in 28/189 patients (14.8%) and efavirenz 12 h concentrations were <1000 ng ml(-1) in 2/16 patients (12.5%). Children and patients with nevirapine exposure <3000 ng ml(-1) presented a higher risk of viral replication. CONCLUSIONS Viral loads <250 copies ml(-1) were observed in 81.7% of patients (83.6% adults and 42.9% children). Children and patients with low nevirapine concentrations had higher risk of viral replication. Dried blood and plasma spots may be useful for monitoring HIV-positive patients including viral load and drug level measurement as part of treatment management in remote areas.
Eigenvalues of the Jacobian of a Galerkin-Projected Uncertain ODE System

Projection onto polynomial chaos (PC) basis functions is often used to reformulate a system of ordinary differential equations (ODEs) with uncertain parameters and initial conditions as a deterministic ODE system that describes the evolution of the PC modes. The deterministic Jacobian of this projected system is different and typically much larger than the random Jacobian of the original ODE system. This paper shows that the location of the eigenvalues of the projected Jacobian is largely determined by the eigenvalues of the original Jacobian, regardless of PC order or choice of orthogonal polynomials. Specifically, the eigenvalues of the projected Jacobian always lie in the convex hull of the numerical range of the Jacobian of the original system.
Characterisation of a novel 49·3 kb Gγ(Aγδβ)0‐thalassaemia deletion in seven families of Asian descent

The human b-globin gene cluster consists of five functional genes located on the short arm of chromosome 11 and arranged in the linear order e-c-c)d)b (centomere fi telomere). More than 40 different deletions of the b-globin gene cluster have been reported, the phenotype of which depends on the number of genes affected (Giardine et al, 2007). The c(cdb)-thalassaemias are due to deletions or rearrangements that abolish expression from the c, d, and b-globin genes while leaving the c-globin gene intact. Ten different c(cdb)-thalassaemia deletions and rearrangements have been reported in a wide range of ethnic groups (Higgs et al, 2001; Wood, 2001). The 5¢ deletion endpoints are tightly clustered immediately upstream and within the c-globin gene, and extend downstream of the b-globin gene for varying distances. Carriers of c(cdb)-thalassaemia typically have mild microcytosis and hypochromia, coupled with elevated levels of Hb F (a2c2). Herein, we describe a novel deletion identified in multiple unrelated individuals with c(cdb)-thalassaemia trait. Southern hybridisation using a probe specific for c-globin genes (c-IVS2) detected the following deletion-specific fragments: Bam HI (4Æ6 kb), Bgl II (8Æ2 kb), Xba I (5Æ9 kb) and Eco RV (9Æ3 kb). Based on the Southern hybridisation results, the 5¢ deletion endpoint was localised to a region immediately
Career Paths and Expectations of Recent Doctoral Graduates in Student Affairs

Personal issues and career development processes of individuals working in student affairs who have recently completed a doctorate were explored in this study. Results indicated that almost 70% were employed at the completion of their doctorate either by accepting a new position or remaining in their current position. New doctoral graduates obtained a position at a significantly lower level than they expected; however, a significant positive correlation between expected and actual starting salary range indicates graduates were able to accurately predict their starting salary range. Over 75% of respondents were still employed in their first post-doctoral position at the time they completed the survey. Implications for student affairs graduate programs are discussed.
Staff in-service training on post-stroke psychological and communication issues

Aims This article describes the development, content and evaluation to date of an in-service, interdisciplinary training programme on psychological and communication problems after stroke. The training is open to all staff but is particularly focused towards qualified and unqualified nursing staff and therapy assistants who work in acute stroke care and rehabilitation both in hospital and community settings. Content The programme, developed by the authors whose backgrounds include speech and language therapy, occupational therapy, and clinical psychology, aims for all staff to develop an integrated, patient-centred approach to care, and addresses issues such as improving the patient and carer experience of rehabilitation, as well as reducing the negative psychosocial consequences of stroke. Service users are involved in delivering the training. Informal evaluation highlighted improvements for trained staff in knowledge and perceived confidence in the recognition and basic management of communication, cogn.
Chasing Bulges or Rotations? A Metamorphosis of the QR-Algorithm

The $QR$-algorithm is a renowned method for computing all eigenvalues of an arbitrary matrix. A preliminary unitary similarity transformation to Hessenberg form is indispensable for keeping the computational complexity of the subsequent $QR$-steps under control. When restraining computing time is the vital issue, we observe that the prominent role played by the Hessenberg matrix is sufficient but perhaps not necessary to fulfill this goal. In this paper, a whole new family of matrices, sharing the major qualities of Hessenberg matrices, will be put forward. This gives rise to the development of innovative implicit $QR$-type algorithms, pursuing rotations instead of bulges. The key idea is to benefit from the $QR$-factorization of the matrices involved. The prescribed order of rotations in the decomposition of the $Q$-factor uniquely characterizes several matrix types such as Hessenberg, inverse Hessenberg, and $CMV$ matrices. Loosening the fixed ordering of these rotations provides us the class of matrices under consideration. Establishing a new implicit $QR$-type algorithm for these matrices requires a generalization of diverse well-established concepts. We consider the preliminary unitary similarity transformation, a proof of uniqueness of this reduction, an extension of the $CMV$-decomposition to a double Hessenberg factorization, and an explicit and implicit $QR$-type algorithm. A detailed complexity analysis illustrates the competitiveness of the novel method with the traditional Hessenberg approach. The numerical experiments show comparable accuracy for a wide variety of matrix types, but disclose an intriguing difference between the average number of iterations before deflation can be applied.
Deflation, Projector Preconditioning, and Balancing in Iterative Substructuring Methods: Connections and New Results

In this paper, projector preconditioning, also known as the deflation method, as well as the balancing preconditioner are applied to the dual-primal finite element tearing and interconnecting (FETI-DP) and balancing domain decomposition by constraints (BDDC) methods in order to create a second, independent coarse problem. This may help to extend the parallel scalability of classical FETI-DP and BDDC methods without the use of inexact solvers and may also be used to improve the robustness, e.g., for almost incompressible elasticity problems. Connections of FETI-DP methods applying a transformation of basis using a larger coarse space with a corresponding FETI-DP method using projector preconditioning or balancing are pointed out. It is then shown that the methods have essentially the same spectrum. Numerical results for compressible and almost incompressible linear elasticity are provided. The sensitivity of the projection methods to an inexact computation of the projections is numerically investigated and a different behavior for projector preconditioning and the balancing preconditioner is found.
Improving Risk Assessment: Priorities for Epidemiologic Research

The Epidemiology Work Group at the Workshop on Future Research for Improving Risk Assessment Methods, Of Mice, Men, and Models, held August 16 to 18, 2000, at Snowmass Village, Aspen, Colorado, concluded that in order to improve the utility of epidemiologic studies for risk assessment, methodologic research is needed in the following areas: (1) aspects of epidemiologic study designs that affect doseresponse estimation; (2) alternative methods for estimating dose in human studies; and (3) refined methods for dose-response modeling for epidemiologic data. Needed research in aspects of epidemiologic study design includes recognition and control of study biases, identification of susceptible subpopulations, choice of exposure metrics, and choice of epidemiologic risk parameters. Much of this research can be done with existing data. Research needed to improve determinants of dose in human studies includes additional individual-level data (e.g., diet, co-morbidity), development of more extensive human data for physiologically based pharmacokinetic (PBPK) dose modeling, tissue registries to increase the availability of tissue for studies of exposure/dose and susceptibility biomarkers, and biomarker data to assess exposures in humans and animals. Research needed on dose-response modeling of human studies includes more widespread application of flexible statistical methods (e.g., general additive models), development of methods to compensate for epidemiologic bias in dose-response models, improved biological models using human data, and evaluation of the benchmark dose using human data. There was consensus among the Work Group that, whereas most prior risk assessments have focused on cancer, there is a growing need for applications to other health outcomes. Developmental and reproductive effects, injuries, respiratory disease, and cardiovascular disease were identified as especially high priorities for research. It was also a consensus view that epidemiologists, industrial hygienists, and other scientists focusing on human data need to play a stronger role throughout the risk assessment process. Finally, the group agreed that there was a need to improve risk communication, particularly on uncertainty inherent in risk assessments that use epidemiologic data.
Simplex Stochastic Collocation with Random Sampling and Extrapolation for Nonhypercube Probability Spaces

Stochastic collocation (SC) methods for uncertainty quantification (UQ) in computational problems are usually limited to hypercube probability spaces due to the structured grid of their quadrature rules. Nonhypercube probability spaces with an irregular shape of the parameter domain do, however, occur in practical engineering problems. For example, production tolerances and other geometrical uncertainties can lead to correlated random inputs on nonhypercube domains. In this paper, a simplex stochastic collocation (SSC) method is introduced, as a multielement UQ method based on simplex elements, that can efficiently discretize nonhypercube probability spaces. It combines the Delaunay triangulation of randomized sampling at adaptive element refinements with polynomial extrapolation to the boundaries of the probability domain. The robustness of the extrapolation is quantified by the definition of the essentially extremum diminishing (EED) robustness principle. Numerical examples show that the resulting SSC-EED method achieves superlinear convergence and a linear increase of the initial number of samples with increasing dimensionality. These properties are demonstrated for uniform and nonuniform distributions, and correlated and uncorrelated parameters in problems with 15 dimensions and discontinuous responses.
Global Dynamics of a Tritrophic Model for Two Patches with Cost of Dispersal

To understand how cost of dispersal affects population dynamics, we study a three-trophic level food chain model, proposed by DeAngelis et al. [D. DeAngelis, G. S. K. Wolkowicz, Y. Lou, Y. X. Jiang, M. Novak, R. Svanback, M. Araujo, Y. S. Jo, and E. A. Cleary, Am. Nat., 178 (2011), pp. 15–29], in two patches. The system consists of one resource species, two consumers, and a top predator. The top predator feeds on two consumers and both consumers feed on the resource. Only consumers move between the patches, possibly with a fraction of loss in population during the movement. The two competing consumers are identical in every aspect except their dispersal rates between two patches. If two consumers have the same dispersal rate from patch 1 to patch 2, we completely determine the global dynamics of the model and show that there exists an “optimal” dispersal rate from patch 2 to patch 1 for the consumer such that, in terms of the theory of adaptive dynamics, it is a globally evolutionarily stable strategy and.
Approximation Algorithms for Minimum-Cost $k\hbox{-}(S, T)$ Connected Digraphs

In the minimum-cost $k\hbox{-}(S,T)$ connected digraph (abbreviated as $k\hbox{-}(S,T)$ connectivity) problem we are given a positive integer $k$, a directed graph $G=(V,E)$ with nonnegative costs on the edges, and two subsets $S,T$ of $V$; the goal is to find a subset of edges $\widehat{E}$ of minimum cost such that the subgraph $(V,\widehat{E})$ has $k$ edge-disjoint directed paths from each vertex in $S$ to each vertex in $T$. Most of our results focus on a specialized version of the problem that we call the standard version, where every edge of positive cost has its tail in $S$ and its head in $T$. This version of the problem captures NP-hard problems such as the minimum-cost $k$-vertex connected spanning subgraph problem. We give an approximation algorithm with a guarantee of $O((\log{k})(\log{n}))$ for the standard version of the $k\hbox{-}(S,T)$ connectivity problem, where $n$ denotes the number of vertices. For $k=1$, we give a simple 2-approximation algorithm that generalizes a well-known 2-appro.
Elevated serum levels of macrophage migration inhibitory factor and their significant correlation with rheumatoid vasculitis disease activity

Macrophage migration inhibitory factor (MIF) is recognized to be an important mediator in several inflammatory disorders, including rheumatoid arthritis (RA) and vasculitis. To evaluate the role of MIF in rheumatoid vasculitis (RV), we determined serum levels of MIF by enzyme-linked immunosorbent assay in RA patients with and without vasculitis and assessed their relationship to disease activity. Serum was obtained from 95 RA patients during active disease states [49 without vasculitis, 35 with extra-articular manifestations without histologically proven vasculitis, and 11 with histologically proven vasculitis] and from 22 healthy individuals. Vasculitis disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). MIF levels were significantly higher in RA patients than in controls. Moreover, MIF levels were significantly higher in RA patients with vasculitis than in those without vasculitic complications. In all RA patients, a statistically significant positive correlation was observed between serum MIF levels and each of the following: serum levels of C-reactive protein, rheumatoid factor, and thrombomodulin; and the erythrocyte sedimentation rate. In the RV group, the elevation of MIF levels correlated with the BVAS. Our findings suggest that MIF may serve as an additional serologic inflammatory marker of disease activity in RV, and it may be implicated in the pathogenesis of RV.
Induction of Murine Neonatal Tolerance Against Graves ’ Disease Using Recombinant Adenovirus Expressing the TSH Receptor A-Subunit

Graves’ disease is a common organ-specific autoimmune disease. The identity of its autoantigen, the TSH receptor (TSHR), was established and used to induce a typical animal model. A-subunit, the shed portion of TSHR, either initiates or amplifies the autoimmune response of the thyroid gland, thereby causing Graves’ disease in humans. In the present study, we investigate the effect of the TSHR A-subunit on the induction of murine neonatal tolerance for the development of Graves’ disease. Female BALB/c mice were pretreated with different doses of adenovirus expressing the A-subunit of TSHR (Ad-TSHR289) by either ip or im injection within the first 24 h after their birth. Graves’ disease was induced after the animals reached adulthood. Nearly all mice pretreated with the high dose of Ad-TSHR289 failed to develop TSHR antibodies, detected by the TSH-binding inhibition assay, hyperthyroidism, and thyroid follicular hyperplasia. The mice preimmunized im with the lower doses of Ad-TSHR289 developed a relatively low level of TSH-binding inhibition and the low incidence of hyperthyroidism. Accordingly, the percentages of splenic CD4 CD25 /CD4 and CD25 Foxp3 /CD4 Treg cells were increased in mice pretreated with the high dose of Ad-TSHR289. Taken together, our data strongly indicate that the immunotolerance against Graves’ disease could be induced in neonatal mice using a specific TSHR antigen in a high dose either by ip or im injection, preventing the development of Graves’ disease. (Endocrinology 152: 1165–1171, 2011)