Miracle-dz/UniFAR-FTUs huggingface dataset:
On VU-theory for Functions with Primal-Dual Gradient Structure

We consider a general class of convex functions having what we call primal-dual gradient structure. It includes finitely determined max-functions and maximum eigenvalue functions as well as other infinitely defined max-functions. For a function in this class, we discuss a space decomposition that allows us to identify a subspace on which the function appears to be smooth. Moreover, using the special structure of such a function, we compute smooth trajectories along which certain second-order expansions can be obtained. We also give an explicit expression for the Hessian of a related Lagrangian.
A Domain Decomposition Method for Advection-Diffusion Processes with Application to Blood Solutes

In the present paper we consider a heterogeneous model for the dynamics of a blood solute both in the vascular lumen and inside the arterial wall. In the lumen, we consider an advection-diffusion equation, where the convective field is provided by the velocity of blood, which is in turn obtained by solving the Navier--Stokes equations. Inside the arterial wall we consider a pure diffusive dynamics. Since the endothelial layer at the interface between the lumen and the wall acts as a permeable membrane, whose permeability depends on the shear rate exerted by the blood, the solute concentration is discontinuous across this membrane. A possible approach for the numerical study of this kind of problem is inspired by domain decomposition techniques. In particular, we introduce a splitting in the computation and alternate the solution of the advection-diffusion equation in the lumen with that of the diffusion equation in the wall. We set up an efficient iterative method, based on a suitable reformulation of the problem in terms of a Steklov--Poincare interface equation. This formulation is a nonstandard one because of the concentration discontinuity at the lumen-wall interface and plays a key role in the proof of convergence of our method. In particular, we prove that the convergence rate performed by the proposed method is independent of the finite element space discretization and provides a criterion for the selection of an acceleration parameter. Several numerical results, referred to as biomedical applications, support our theoretical conclusions and illustrate the efficiency of this algorithm.
A Moving Mesh Method Based on the Geometric Conservation Law

A new adaptive mesh movement strategy is presented, which, unlike many existing moving mesh methods, targets the mesh velocities rather than the mesh coordinates. The mesh velocities are determined in a least squares framework by using the geometric conservation law, specifying a form for the Jacobian determinant of the coordinate transformation defining the mesh, and employing a curl condition. By relating the Jacobian to a monitor function, one is able to directly control the mesh concentration. The geometric conservation law, an identity satisfied by any nonsingular coordinate transformation, is an important tool which has been used for many years in the engineering community to develop cell-volume-preserving finite-volume schemes. It is used here to transform the algebraic expression specifying the Jacobian into an equivalent differential relation which is the key formula for the new mesh movement strategy. It is shown that the resulting method bears a close relation with the Lagrangian method. Advantages of the new approach include the ease of controlling the cell volumes (and therefore mesh adaption) and a theoretical guarantee for existence and nonsingularity of the coordinate transformation. It is shown that the method may suffer from the mesh skewness, a consequence resulting from its close relation with the Lagrangian method. Numerical results are presented to demonstrate various features of the new method.
Pretreatment serum anti-müllerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer.

CONTEXT Administration of chemotherapy to premenopausal women shortens their reproductive lifespan by depleting nonrenewable oocytes. Preservation of fertility is a priority for many such women, and identification of women at risk of infertility is therefore important. However, age is the only patient characteristic currently recognized to be predictive of long-term ovarian function after chemotherapy. OBJECTIVE Our objective was to assess markers of ovarian reserve and age as long-term predictors of ovarian function after chemotherapy. DESIGN AND SETTING We conducted a prospective, longitudinal study at a university hospital and research institute. PATIENTS Patients included women who were premenopausal at the time of diagnosis of early breast cancer. MAIN OUTCOME MEASURES Ovarian function was assessed at 5 yr follow-up in relation to pretreatment hormonal and ultrasound markers of ovarian reserve. RESULTS Forty-two women received (neo-)adjuvant chemotherapy. Continuing menses 4-5 yr after diagnosis closely reflected ovarian activity as assessed by a range of serum markers, including estradiol, inhibin B, FSH, and anti-müllerian hormone (AMH). Pretreatment serum AMH, FSH, antral follicle count, and age predicted late ovarian activity by univariate analysis. However, only AMH was predictive in a multivariate logistic regression (odds ratio = 13.0; 95% confidence interval = 2.5-66.7); 0.71 ng/ml gave peak likelihood ratio of 7.0 with 54% sensitivity and 92% specificity. Bone mineral density fell over the 4-5 yr after diagnosis with greater loss in women with lower ovarian activity. Higher pretreatment AMH was associated with lower bone mineral density at both lumbar spine and hip at 5 yr (P < 0.02). CONCLUSION Measurement of AMH at cancer diagnosis predicts long-term ovarian function after chemotherapy. Use of this in clinical practice may allow better prediction of chemotherapy-related risk to future fertility.
Orderings for Parallel Conjugate Gradient Preconditioners

The efficient solution of the linear system of equations $A\mathbf{x} = \mathbf{b}$ on parallel computers sometimes requires a reordering of the unknowns. We investigate the effects of various orderings on the rate of convergence and the computation rate of the preconditioned conjugate method with SSOR as the preconditioner. As a model problem, we use a generalized Poisson equation $\nabla (K \nabla u ) = f$, discretized with finite differencing in two and three dimensions. The natural ordering has the highest rate of convergence yet results in poor to modest parallelism, whereas the classical red/black (RB) ordering fully exploits vector/parallel properties but has a deleterious effect on the rate of convergence. Intermediate between the RB and natural orderings are the ``many-color'' orderings studied by Harrar and Ortega, but we show that these have rather poor communication properties. Alternatives are domain decomposition orderings, which we consider with and without separator sets. We investigate the effectiveness of these orderings on parallel machines, the Intel iPSC/860 hypercube in particular. We also examine the effect of the remainder matrix on the rate of convergence.
Convergence Rates for Uniform B-Spline Density Estimators Part I: One Dimension

A B-spline nonparametric density estimator with uniform knots, convenient for solving problems in computer graphics, was discussed by Gehringer and Redner in 1992 [ Comm. Stat. Simulation Methods, 21 (1992) pp. 849--878]. These ideas were later extended to density function estimation on metric spaces using partitions of unity in Redner and Gehringer in 1994 [Comm. Stat. Theory Methods, 23 (1994) pp. 2059--2076]. In the current paper we return to the uniform B-spline density estimator in one dimension. We show, under very natural assumptions, that the B-spline density estimator and all of its nontrivial derivatives converge in mean integrated squared error. Asymptotic rates of convergence are determined for the density estimate and its derivatives.
Unique gene expression profile associated with an early-onset multiple endocrine neoplasia (MEN1)-associated pituitary adenoma.

CONTEXT Multiple endocrine neoplasia type 1 (MEN1) is caused by mutations in the menin (MEN1) gene. The mechanism(s) by which MEN1 mutations lead to pituitary tumor formation remain(s) unknown. OBJECTIVE The aim of the study was to identify the pediatric MEN1-associated pituitary tumor transcriptome. PATIENTS AND METHODS A patient harboring a MEN1 mutation (c.525C>G; p.H139D) who presented with an early-onset mammosomatotroph pituitary adenoma was studied. Microarray analysis was performed in the tumor sample and compared with the profile observed in normal pituitaries and in a sporadic mammosomatotropinoma. Validation of the microarray results was performed using quantitative real-time PCR and immunohistochemical analysis for selected genes. RESULTS In the MEN1-associated pituitary adenoma, 59 and 24 genes were found to be significantly up- and down-regulated, respectively. The up-regulated genes included those involved in cell growth and maintenance, apoptosis, growth arrest, and tumorigenesis. Moreover, we observed decreased expression in genes neuroendocrine in nature and related to growth or apoptosis. Only 21 of the 59 genes differentially expressed in the MEN1-associated adenoma showed a similar expression profile to that seen in the sporadic mammosomatotropinoma; for some genes an opposite expression profile was observed. CONCLUSIONS We identified changes in the transcriptome that occur in pituitary GH- and PRL-producing cells after the loss of menin expression; some of the gene changes are necessary for tumor evolution, and others may be tertiary. Nevertheless, the rare overlap between the expression profiles of the MEN1 tumor vs. that of its sporadic counterpart suggests that these tumors evolve along different molecular pathways.
Comparison of adiposity measures as risk factors in postmenopausal women.

CONTEXT There is a continuing debate about which adiposity measure is the best risk factor. OBJECTIVES This study compared the associations of 14 health outcomes with combinations of four adiposity measures: body mass index (BMI), waist to hip ratio (WHR), waist, and waist to height ratio. DESIGN Data were from the Women's Health Initiative, a prospective study of women enrolled from 1993-1998 with a median follow-up time of 8 yr. Regression models were used to test the association of adiposity measures with outcome after adjusting for a number of variables related to demographic characteristics and health behavior. SETTING The women were recruited from 40 clinical centers throughout the United States. PARTICIPANTS The sample analyzed included 141,652 postmenopausal women age 50-79 yr who met the criteria for the Women's Health Initiative randomized control trials. MAIN OUTCOME MEASURES Outcomes included death and eight medical conditions. RESULTS Adiposity measures were most strongly associated with diabetes, hypertension, joint replacement, and gallbladder disease; moderately associated with myocardial infarction, endometrial cancer, and death; and least strongly associated with colon cancer, stroke, and breast cancer. Associations were nearly identical for waist and waist to height ratio. For most outcomes, waist was a stronger individual risk factor than BMI or WHR. However, BMI and WHR were the most useful combination of adiposity measures for stratifying participants according to risk of hypertension or diabetes. CONCLUSIONS The adiposity measure most useful for stratifying persons on the basis of risk depends on the outcome of interest. When the outcome is diabetes or hypertension in postmenopausal women, the best indication of risk is a combination BMI and WHR.
Manual Traction Versus Isometric Exercises in Patients with Herniated Intervertebral Lumbar Discs

Fifty patients with lumbago-sciatica due to a proven herniated intervertebral lumbar disc were randomised between two treatment groups: manual traction and careful isometric exercises. Treatment was given daily over a period of 5-7 days. A blind overall assessment subsequent to treatment showed that in both groups approximately 40% of the patients had improved, corresponding to that which could be expected from placebo. The effect of both manual traction and isometric exercises is doubtful in patients with lumbago-sciatica and herniated lumbar discs. In further research, discriminant analysis is recommended to elucidate what characterises responders and non-responders to lumbar traction.
A functional allelic variant of the FGF23 gene is associated with renal phosphate leak in calcium nephrolithiasis.

BACKGROUND A significant percentage of patients with calcium nephrolithiasis and normal parathyroid function have renal phosphate leak. This disorder is characterized by idiopathic hypophosphatemia and reduced renal phosphate threshold normalized for the glomerular filtration rate (TmPi/GFR). The majority of these patients harbor high or inappropriately normal circulating levels of fibroblast growth factor 23 (FGF23), a hormone regulating phosphate homeostasis. AIM The aim of this study was to define the role of FGF23 allelic variants in the pathogenesis of hypophosphatemic nephrolithiasis. SUBJECTS AND METHODS We sequenced the regulative and coding regions of the FGF23 gene in 106 stone formers, 17 of which had renal phosphate leak, and in 87 healthy controls. We subsequently performed in vitro studies. RESULTS A C716T nonsynonymous change (T239M, rs7955866) in the FGF23 gene was detected in seven of the 17 stone formers with renal phosphate leak. The prevalence of the T allele and of the CT genotype in stone formers with renal phosphate leak was significantly higher compared to that observed in stone formers without renal phosphate leak and in controls (P < 0.03 in all cases). In the whole study population, FGF23(716T) subjects showed levels of serum phosphate and TmPi/GFR significantly lower compared to FGF23(716C) subjects. In vitro studies showed that the T239M change increases FGF23 secretion and that the FGF23(239M) variant induces a higher activation of the FGF receptor/ERK pathway compared to FGF23(239T). CONCLUSION Our results highlight a novel significant association between the C716T missense variation in the FGF23 gene and calcium nephrolithiasis with renal phosphate leak.
Positive impact of long-term antithyroid drug treatment on the outcome of children with Graves' disease: national long-term cohort study.

CONTEXT Drug-based therapy is usually the initial treatment for Graves' disease (GD) hyperthyroidism in children, but there is some debate about treatment duration. OBJECTIVE Our objective was to assess the effect of long-term carbimazole therapy on GD remission in children and its determinants. DESIGN AND SETTING This was an observational prospective multicenter follow-up cohort study. PARTICIPANTS Participants included 154 children newly diagnosed with GD between 1997 and 2002. The intention was to treat patients with three consecutive courses of carbimazole, each lasting 2 yr. Definitive treatment was performed in cases of poor compliance with antithyroid drug (ATD) treatment, thyrotoxicosis relapse, or major adverse effects of ATD treatment. MAIN OUTCOME MEASURE The main outcome measure was remission for at least 18 months after the completion of each course of ATD treatment. RESULTS The median duration of follow-up was 10.4 (9.0-12.1) yr. Overall estimated remission rates (95% confidence interval) 18 months after the withdrawal of ATD treatment increased with time and were 20 (13-26), 37 (29-45), 45 (35-54), and 49 (40-57)% after 4, 6, 8, and 10 yr follow-up, respectively. A multivariate competing risk model revealed an independent positive effect of less severe forms of hyperthyroidism at diagnosis [subhazard ratio of 1 for patients with free T(4) <35 pmol/liter vs. 0.4 (0.20-0.80) for free T(4) ≥ 35 pmol/liter; P = 0.01] and of the presence of other autoimmune conditions [subhazard ratio of 2.23 (1.19-4.18); P = 0.01] on remission rate after medical treatment. CONCLUSION About half the patients achieved remission after carbimazole discontinuation, and there seems to be a plateau in the incidence of remission achieved after 8-10 yr ATD therapy.
HbA2: biology, clinical relevance and a possible target for ameliorating sickle cell disease

HbA2, a tetramer of α‐ and δ‐globin chains, provides a diagnostic clue to the presence of β‐thalassaemia trait. This minor haemoglobin, which forms about 2–3% of the total, has no known physiological role, but has the interesting property of preventing polymerization of deoxy‐sickle haemoglobin. If it were possible to increase the level of HbA2 sufficiently it could have a benefit in sickle cell disease similar to that of foetal haemoglobin. Moreover, HbA2 is present in all erythrocytes, an advantage not found with foetal haemoglobin, which is heterocellularly expressed. The molecular basis of HbA2 gene (HBD) expression is partially understood, and with new molecular tools, it might be possible to induce levels of HbA2 that could be clinically important. However, high concentrations of this positively charged haemoglobin might damage the erythrocyte membrane; also, the reciprocal relationship of δ‐ and γ‐globin gene (HBD and HBG1/2, respectively) expression might negate any benefit of increasing transcription of the former.
Retroperitoneal Laparoscopic Living–Donor Nephrectomy

Purpose: Living–donor nephrectomy is performed via a standard flank approach during open surgery in contrast to laparoscopy where kidneys are procured transperitoneally. Being more familiar with retroperitoneal laparoscopy for the surgery of the upper urinary tract, we investigated the feasibility of live donor nephrectomy by this approach. Material and Methods: We performed laparoscopic retroperitoneal left–sided nephrectomy in 3 living donors. The patients were placed in lumbotomy position. The retroperitoneal space was developed with blunt finger dissection, through a 2–cm mini–lumbotomy under the 12th rib in the posterior axillary line. 5 trocars were inserted. After primary access to the renal artery and vein, these were dissected to their junctions with the aorta and inferior vena cava, respectively, before freeing the kidney of its perinephric attachments. The kidney was delivered manually, through the slightly enlarged initial subcostal incision. Results: The average duration of surgery was 83 min; warm ischemia time less than 5 min. Average blood loss was 120 cm3. Donors did not present any postoperative morbidity and were discharged after an average of 2.3 days. Mean analgesic requirement was 5 mg morphine sulphate equivalent (0–15). Average convalescence was 13.3 days (10–18). All 3 kidneys harvested laparoscopically had immediate function with urine production after graft revascularization; serum creatinine levels returned to normal within 1 week. The first patient presented ureteral stenosis 2 months after surgery. He underwent ureteropyeloplasty using his native ureter. Conclusions: Laparoscopic living–related–donor nephrectomy become a new standard for organ harvesting. Our data suggest that retroperitoneal laparoscopic donor nephrectomy may represent a reasonable option in centers in which more extensive experience has been accumulated with retroperitoneal than with transperitoneal laparoscopy for the surgery of the upper urinary tract.
25-hydroxyvitamin D assay variations and impact on clinical decision making.

CONTEXT Laboratories are increasingly shifting to new automated 25-hydroxyvitamin D (25-OHD) assays, with subsequent variability in results. OBJECTIVE/SETTING We describe the experience at our center with such a shift and illustrate its clinical implications. METHODS 25-OHD levels were measured in 494 patients using Immunodiagnostic Systems RIA (IDS-RIA) and DiaSorin Liaison assays. Sources of variability between the assays were investigated in a subset of 83 samples, retested in the reference laboratory in the United States, and by reviewing the performance reports issued by the International Vitamin D External Quality Assessment Scheme, DEQAS. 25-OHD cut-points for target levels were used to compare the two assays. RESULTS 25-OHD concentrations were significantly lower when measured with Liaison as compared to IDS-RIA: mean bias was -5 ng/ml, range was -38.1 to 18.7 ng/ml, P<0.001; the absolute bias was independent of 25-OHD value. Interassay variability was also detected in values obtained in the reference laboratory and in DEQAS reports. Using 20 ng/ml as the target 25-OHD level, 52% of patients required treatment when tested by Liaison, as opposed to 36% by IDS-RIA (P<0.001). Using 30 ng/ml as the desirable level, the proportions were 79 and 64%, respectively (P<0.001). The two assays agreed in only 41-68% of subjects, proportions that depended on criteria used to define agreement. CONCLUSION A change in 25-OHD assays has a significant impact on results, patient classification, and treatment recommendations. Such variability cannot be ignored when deriving and applying vitamin D guidelines. It also renders universal assay standardization a pressing call.
Quantitative high-throughput drug screening identifies novel classes of drugs with anticancer activity in thyroid cancer cells: opportunities for repurposing.

CONTEXT Despite increased understanding of the pathogenesis and targets for thyroid cancer and other cancers, developing a new anticancer chemical agent remains an expensive and long process. An alternative approach is the exploitation of clinically used and/or bioactive compounds. OBJECTIVE Our objective was to identify agents with an anticancer effect in thyroid cancer cell lines using quantitative high-throughput screening (qHTS). DESIGN We used the newly assembled National Institutes of Health Chemical Genomic Center's pharmaceutical collection, which contains 2816 clinically approved drugs and bioactive compounds to perform qHTS. RESULTS Multiple agents, across a variety of therapeutic categories and with different modes of action, were found to have an antiproliferative effect. We found the following therapeutic categories were the most enriched categories with antiproliferative activity: cardiotonic and antiobesity agents. Sixteen agents had an efficacy of greater than 60% and a 50% inhibitory concentration (IC50) in the nanomolar range. We validated the results of the qHTS using two agents (bortezomib and ouabain) in additional cell lines representing different histological subtypes of thyroid cancer and with different mutations (BRAF V600E, RET/PTC1, p53, PTEN). Both agents induced apoptosis, and ouabain also caused cell cycle arrest. CONCLUSIONS To our knowledge, this is the first study to use qHTS of a large drug library to identify candidate drugs for anticancer therapy. Our results indicate such a screening approach can lead to the discovery of novel agents in different therapeutic categories and drugs with nonclassic chemotherapy mode of action. Our approach could lead to drug repurposing and accelerate clinical trials of compounds with well-established pharmacokinetics and toxicity profiles.