Miracle-dz/UniFAR-FTUs huggingface dataset:
The Procrustes Problem for Orthogonal Kronecker Products

The Procrustes problem for orthogonal Kronecker products is considered. Given matrices $A\in \mathbb{R}^{n^2\times k^2}$, $T\in \mathbb{R}^{n^2\times n^2},$ $n\ge k$, we minimize the Frobenius norm $\|T(Q\otimes Q)-A\|$ for all orthogonal Stiefel matrices $Q\in \mathbb{R}^{n\times k}$, $Q^TQ=I_{k}$. We introduce and implement left and right relaxation methods for minimization. Numerical results for the data in general and Kronecker product form are given to illustrate convergence of both methods.
Unreplaced sex steroid deficiency, corticotropin deficiency, and lower IGF-I are associated with lower bone mineral density in adults with growth hormone deficiency: a KIMS database analysis.

CONTEXT GH deficiency (GHD) is associated with low bone mineral density (BMD). Risk factors for lower BMD in this GHD population have not been fully elucidated. In particular, there are limited published data in GH-naïve subjects. OBJECTIVE The objective of the study was to identify endocrine correlates of low BMD in treatment-naïve adult GHD subjects. DESIGN This was a retrospective analysis of data extracted from the (Pfizer International Metabolic Study) KIMS database. SETTING The study was an international epidemiological survey of more than 15,000 adult GHD patients from 31 countries. PATIENTS A total of 1218 subjects with stringently defined GHD of adult onset (641 women and 577 men) who were GH naïve and had BMD measured in the posterior anterior lumbar spine and femoral neck by dual-energy X-ray absorptiometry. MAIN OUTCOME MEASURES Variables associated with standardized BMD (sBMD) in adult-onset GHD were examined. RESULTS In the LS, body mass index (r = 0.13, P < 0.01), unreplaced sex steroid deficiency (r = -0.17, P < 0.0001), and corticotropin deficiency (r = -0.11, P < 0.01) were independently associated with sBMD. In the FN, age (r = -0.19, P < 0.0001), female gender (r = -0.18, P < 0.0001), body mass index (r = 0.21, P < 0.0001), and decreased IGF-I SD scores (r = 0.10, P < 0.001) were independently associated with sBMD. CONCLUSIONS Hormone variables associated with lower sBMD in patients with adult-onset GHD include unreplaced sex steroid deficiency and corticotropin deficiency in the LS and lower IGF-I SDS in the FN.
Absence of circadian rhythms of gonadotropin secretion in women.

CONTEXT Diurnal rhythms of LH and FSH have been reported in normal women, but it is unclear whether these reflect underlying circadian control from the suprachiasmatic nucleus and/or external influences. OBJECTIVE The aim of this study was to determine whether endogenous circadian rhythms of LH, FSH, and the glycoprotein free α-subunit (FAS) are present in reproductive-aged women. DESIGN AND SETTING Subjects were studied in the early follicular phase using a constant routine protocol in a Clinical Research Center at an academic medical center. SUBJECTS Subjects were healthy, normal-cycling women aged 23-29 yr (n = 11). MAIN OUTCOME MEASURES Temperature data were collected, and blood samples were assayed for LH, FSH, FAS, and TSH. RESULTS Core body temperature and TSH were best fit by a sinusoid model, indicating that known circadian rhythms were present in this population. However, the patterns of FSH, LH, and FAS over 24 h were best fit by a linear model. Furthermore, there were no differences in LH and FAS interpulse intervals or pulse amplitudes between evening, night, and morning. CONCLUSIONS Under conditions that control for sleep/wake, light/dark, activity, position, and nutritional cues, there is no circadian rhythm of LH, FSH, or FAS in women during the early follicular phase despite the presence of endogenous rhythms of TSH and core body temperature. These studies indicate that endogenous circadian control does not contribute to previously reported diurnal rhythms in reproductive-aged women and emphasizes the importance of environmental cues in controlling normal reproductive function.
The Sp1 transcription factor is crucial for the expression of 11beta-hydroxysteroid dehydrogenase type 2 in human placental trophoblasts.

CONTEXT Overexposure of the fetus to glucocorticoids early in gestation is detrimental to fetal development. Glucocorticoid concentrations in the fetal circulation are kept low by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2, encoded by HSD11B2) in the placental syncytiotrophoblasts. However, cytotrophoblasts, the progenitors of syncytiotrophoblasts, express low levels of 11β-HSD2. Here we studied the molecular mechanisms underlying 11β-HSD2 induction upon syncytialization. METHODS Freshly isolated human term placental cytotrophoblasts and in vitro differentiated syncytiotrophoblasts were examined to determine the methylation status of HSD11B2 promoter. The transcription factor responsible for 11β-HSD2 induction was identified by observing its expression upon syncytialization, the effect of its attenuation, and its binding to the HSD11B2 promoter. RESULTS 11β-HSD2 expression was markedly increased upon syncytialization in vitro. No methylation differences of HSD11B2 promoter were found between cytotrophoblasts and syncytiotrophoblasts. Expression of the transcription factor Sp1 was markedly induced during syncytialization and further increased by activation of the cAMP pathway, which correlated with 11β-HSD2 expression. Importantly, small interfering RNA-mediated knockdown of Sp1 expression or inhibition of Sp1 activity with mithramycin A markedly attenuated not only basal but also cAMP pathway-stimulated expression of 11β-HSD2 in the syncytiotrophoblasts. Stimulation of the cAMP pathway also increased the binding of Sp1 and RNA polymerase II to HSD11B promoter in syncytiotrophoblasts. Concomitantly, acetylation at histone H3K9 was increased whereas methylation at histone H3K9 was decreased. CONCLUSIONS 11β-HSD2 induction upon syncytialization is at least in part due to the increased expression of Sp1 upon activation of the cAMP pathway rather than the differential methylation of the HSD11B2 promoter.
The effects of ronacaleret, a calcium-sensing receptor antagonist, on bone mineral density and biochemical markers of bone turnover in postmenopausal women with low bone mineral density.

CONTEXT Ronacaleret, a calcium-sensing receptor antagonist that stimulates PTH release from the parathyroid glands, was evaluated as an oral osteoanabolic agent for the treatment of osteoporosis. OBJECTIVE Our objective was to compare the effects of ronacaleret, teriparatide, and alendronate on bone mineral density (BMD) and markers of bone turnover. DESIGN AND SETTING In this randomized, placebo-controlled, dose-ranging trial, spine and hip BMD were assessed by dual-energy x-ray absorptiometry and bone turnover markers were measured. PATIENTS Patients included 569 postmenopausal women with low BMD. INTERVENTIONS Subjects were offered open-label 20 μg teriparatide sc once daily or were randomized to 100, 200, 300, or 400 mg oral ronacaleret once daily, 70 mg alendronate once weekly, or placebo and were followed for up to 12 months. MAIN OUTCOME MEASURE Percentage change from baseline in lumbar spine BMD was assessed at month 12. RESULTS With ronacaleret, the increases in lumbar spine BMD at 12 months (0.3-1.6%) were significantly lower than those attained with teriparatide (9.1%) or alendronate (4.5%). There were small decreases in total hip, femoral neck, and trochanter BMD at month 12 with ronacaleret compared with increases in the teriparatide and alendronate arms. Bone turnover markers increased in the ronacaleret and teriparatide arms and decreased in the alendronate arm. PTH elevations with ronacaleret were prolonged relative to those previously reported with teriparatide. CONCLUSION The densitometric findings in the context of prolonged PTH elevation and increased bone turnover suggest ronacaleret induces mild hyperparathyroidism. Ronacaleret only modestly increased lumbar spine BMD and decreased BMD at hip sites.
Diabetes in the Himalayas: Psychosocial barriers and solutions

Abstract Psychosocial problems are common in diabetic population. Apart from the common issues faced by the diabetics everywhere, the Himalayan population suffer unique psychosocial burden arising out of poor social infrastructures, low economy and education, and extreme bio-geographical disadvantages. The patients are deprived of modern state-of-art scientific health care and mostly depend on conventional medicine. Stress, hostility, and depression emerging out of this misery affect the health of diabetics through modified behaviors, lifestyles, and psychology. Studies have demonstrated that addressing psychosocial issues is unequivocally associated with better outcomes in diabetes management. The psychosocial support and education highlighted by the DAWN study can be rightly adopted to solve the psychosocial problems and improve the daily life of the diabetic people in general as well as in the Himalayas.
An Analysis of Approximate Nonlinear Elimination

We present a method for solving systems of nonlinear equations suitable for problems where convergence of an approximate Newton method is initially slow. The method, nonlinear elimination (NlEm), eliminates the nonlinear equations and appropriate variables deemed to be causing the problem. An analysis of the method is given and leads to a detailed algorithm that reduces automatically to an approximate Newton method near the root of the system of nonlinear equations. Several examples are given that demonstrate the efficacy of the method.
Patient Satisfaction with Telemedicine

The objective of this study was to evaluate patient satisfaction when telemedicine is used for clinical consultations. Patient satisfaction data from 495 real-time interactive telemedicine clinical consultations at the Telemedicine Center at East Carolina University School of Medicine in Greenville, NC were collected and evaluated. Patient satisfaction was examined in relation to patient age, gender, race, income, education, and insurance. Overall patient satisfaction was found to be 98.3%. Because so few patients were dissatisfied with their telemedicine consultation, correlation with the sociodemographic variables was limited. Patients are highly satisfied with consultations through telemedicine, and report that care was easier to obtain. The sample size in this study is larger than other reported telemedicine studies, but its findings are consistent with those of previous studies. In non-telemedicine settings where patient satisfaction has been studied, several significant factors have been correlated .
A large‐scale computational study of inhibitor risk in non‐severe haemophilia A

Over 500 missense F8 mutations have been reported to cause non‐severe haemophilia A. Some F8 genotypes appear to confer a higher risk of inhibitor formation than others and individuals with the same F8 genotype may have differing risks of inhibitor formation. We present an in silico strategy demonstrating the heterogeneity of factor VIII (FVIII)‐derived antigen presentation whilst identifying patterns of human leucocyte antigen (HLA) peptide binding that might predict future inhibitor risk. A well‐validated computational tool, NetMHCII, enabled large‐scale comparison of predicted antigen presentation between endogenous, mutated FVIII‐derived peptides and wild‐type, therapeutic FVIII‐derived peptides spanning all F8 missense mutation positions reported to The Haemophilia A Mutation, Structure and Resource Site (HADB). We identify 40 F8 genotypes to be ‘low risk’ at a 50% inhibitory concentration (IC50)‐binding threshold of 300 nmol/l (P = 0·00005), defined as absence of novel peptide‐major histocompatibility complex (MHC) surfaces for all 14 common HLA‐DR alleles assessed. Analysing each of the possible 7280 F8 genotype/HLA‐DR permutations individually at an IC50 threshold of 300 nmol/l, 65% are predicted to not generate a novel peptide‐MHC surface that would be necessary to engage T cell help for subsequent anti‐FVIII antibody generation. This study demonstrates the future importance of interpreting F8 genotype in the context of an individual's HLA profile to personalize inhibitor risk prediction.
Long-term high urinary potential renal acid load and low nitrogen excretion predict reduced diaphyseal bone mass and bone size in children.

BACKGROUND Longitudinal diet assessment data in children suggest bone anabolic effects of protein intake and concurrent catabolic effects of dietary acid load. However, studies using valid biomarker measurements of corresponding dietary intakes are lacking. OBJECTIVE The aim of the study was to examine whether the association of long-term dietary acid load and protein intake with children's bone status can be confirmed using approved urinary biomarkers and whether these diet influences may be independent of potential bone-anabolic sex steroids. METHOD Urinary nitrogen (uN), urinary net acid excretion (uNAE), and urinary potential renal acid load (uPRAL) were quantified in 789 24-h urine samples of 197 healthy children who had at least three urine collections during the 4 yr preceding proximal forearm bone analyses by peripheral quantitative computed tomography. uPRAL was determined by subtracting measured mineral cations (sodium + potassium + calcium + magnesium) from measured nonbicarbonate anions (chloride + phosphorus + sulfate). In a subsample of 167 children, dehydroepiandrosterone metabolites were quantified by gas chromatography-mass spectrometry. Multivariable regression models adjusted for age, sex, pubertal stage, forearm muscle area, forearm length, and urinary calcium were run with uN and/or uPRAL or uNAE as predictors. RESULTS uN was positively associated with bone mineral content, cortical area, periosteal circumference, and strength strain index. uPRAL (but not uNAE) showed negative associations with bone mineral content and cortical area (P < 0.05), both with and without adjustment for the dehydroepiandrosterone-derived sex steroid androstenediol. CONCLUSIONS In line with dietary assessment findings, urinary biomarker analyses substantiate long-term positive effects of protein intake and concomitant negative effects of higher dietary acid load on bone status of children, independent of bone-anabolic sex steroid action.
A Differentiation Index for Partial Differential-Algebraic Equations

A differentiation index for nonlinear partial differential-algebraic equations is presented. Determination of the differentiation index with respect to a direction in the space of independent variables uncovers all equations that must be satisfied by Cauchy data on the hyperplane orthogonal to that direction. This index is thus a generalization of the differentiation index of differential-algebraic equations. The motivation for this work is consistent initialization of partial differential-algebraic systems. The analysis is demonstrated through several examples, including some taken from fluid dynamics and chemical engineering.
Revised reference curves for bone mineral content and areal bone mineral density according to age and sex for black and non-black children: results of the bone mineral density in childhood study.

CONTEXT Deficits in bone acquisition during growth may increase fracture risk. Assessment of bone health during childhood requires appropriate reference values relative to age, sex, and population ancestry to identify bone deficits. OBJECTIVE The objective of this study was to provide revised and extended reference curves for bone mineral content (BMC) and areal bone mineral density (aBMD) in children. DESIGN The Bone Mineral Density in Childhood Study was a multicenter longitudinal study with annual assessments for up to 7 yr. SETTING The study was conducted at five clinical centers in the United States. PARTICIPANTS Two thousand fourteen healthy children (992 males, 22% African-Americans) aged 5-23 yr participated in the study. INTERVENTION There were no interventions. MAIN OUTCOME MEASURES Reference percentiles for BMC and aBMD of the total body, lumbar spine, hip, and forearm were obtained using dual-energy x-ray absorptiometry for Black and non-Black children. Adjustment factors for height status were also calculated. RESULTS Extended reference curves for BMC and aBMD of the total body, total body less head, lumbar spine, total hip, femoral neck, and forearm for ages 5-20 yr were constructed relative to sex and age for Black and non-Black children. Curves are similar to those previously published for 7-17 year olds. BMC and aBMD values were greater for Black vs. non-Black children at all measurement sites. CONCLUSIONS We provide here dual-energy x-ray absorptiometry reference data on a well-characterized cohort of 2012 children and adolescents. These reference curves provide the most robust reference values for the assessment and monitoring of bone health in children and adolescents in the literature to date.
Lipodystrophies: Genetic and Acquired Body Fat Disorders

Context: Lipodystrophies are heterogeneous, genetic or acquired disorders characterized by selective loss of body fat and predisposition to insulin resistance. The extent of fat loss determines the severity of associated metabolic complications such as diabetes mellitus, hypertriglyceridemia, and hepatic steatosis. Evidence Acquisition and Synthesis: Both original and review articles were found via PubMed search reporting on clinical features and management of various types of lipodystrophies and were integrated with the author's knowledge of the field. Conclusion: The autosomal recessive congenital generalized lipodystrophy and autosomal dominant familial partial lipodystrophy (FPL) are the two most common types of genetic lipodystrophies. Mutations in AGPAT2, BSCL2, CAV1, and PTRF have been reported in congenital generalized lipodystrophy and in LMNA, PPARG, AKT2, and PLIN1 in FPL. CIDEC is the disease gene for autosomal recessive, FPL and LMNA and ZMPSTE24 for autosomal recessive, mandibuloacral dyspla.
Positivity-Preserving Schemes in Multidimensions

The performance of the MUSCL--Hancock upwind scheme is examined on problems of two-dimensional advection. It is found that when the advection direction is skewed relative to the mesh, most discrete total variation (TVD) limiters give rise to large spurious oscillations near discontinuities. The cause of these oscillations is traced to reconstructions that are not bounded by neighboring cell averages. It is proved that if the reconstruction in each cell is bounded by the cell averages of first order neighbors, then the MUSCL--Hancock scheme is positivity preserving. A simple limiter that achieves such bounded reconstructions is presented next along with a variant that is uniformly second order accurate. Numerical experiments show that the new schemes are accurate and efficient and compare favorably with other schemes.
Entinostat, a novel histone deacetylase inhibitor is active in B‐cell lymphoma and enhances the anti‐tumour activity of rituximab and chemotherapy agents

Histone deacetylases (HDACs) inhibitors are active in T‐cell lymphoma and are undergoing pre‐clinical and clinical testing in other neoplasms. Entinostat is an orally bioavailable class I HDAC inhibitor with a long half‐life, which is under evaluation in haematological and solid tumour malignancies. To define the activity and biological effects of entinostat in B‐cell lymphoma we studied its anti‐tumour activity in several rituximab‐sensitive or ‐resistant pre‐clinical models. We demonstrated that entinostat is active in rituximab‐sensitive cell lines (RSCL), rituximab‐resistant cell lines (RRCL) and primary tumour cells isolated from lymphoma patients (n = 36). Entinostat exposure decreased Bcl‐XL (BCL2L1) levels and induced apoptosis in cells. In RSCL and RRCL, entinostat induced p21 (CDKN1A) expression leading to G1 cell cycle arrest and exhibited additive effects when combined with bortezomib or cytarabine. Caspase inhibition diminished entinostat activity in some primary tumour cells suggesting that entinostat has dual mechanisms‐of‐action. In addition, entinostat increased the expression of CD20 and adhesion molecules. Perhaps related to these effects, we observed a synergistic activity between entinostat and rituximab in a lymphoma‐bearing severe combined immunodeficiency (SCID) mouse model. Our data suggests that entinostat is an active HDAC inhibitor that potentiates rituximab activity in vivo and supports its further clinical development in B‐cell lymphoma.
Possible Disadvantages of Gonadal Suppression Therapy

Gonadal suppression therapy is now used experimentally to improve the final height of children who enter puberty at the normal age but with short stature. For this purpose a long-acting analog of LH-releasing hormone (LHRHa) is usually used. To improve the final height, gonadal suppression must be continued for at least several years, and artificial delayed puberty may cause psychosocial problems. The accumulation of bone mineral is reported to be most active during puberty and it is related to the increased secretion of sex steroids. Suppression of sex steroid secretion at the normal pubertal age may result in poor bone mineral accumulation at this critical period and may become a risk factor for osteoporosis later in life. Gonadotropins are knownto be secreted in a pulsatile fashion even at prepubertal age. LHRHa abolishes gonadotropin secretion completely and may deteriorate pubertal development after completion of the therapy. There are reports of IgE antibody production and anaphylaxis caused by LHRHa treatment. If an antibody that cross-reacts with native LHRH is generated, it can be a cause of hypogonadism. We should take into account these possible disadvantages when giving gonadal suppression therapy to patients with basically normal puberty.
Comparison of efficacy and safety of leptin replacement therapy in moderately and severely hypoleptinemic patients with familial partial lipodystrophy of the Dunnigan variety.

CONTEXT Leptin replacement therapy improves metabolic complications in patients with lipodystrophy and severe hypoleptinemia (SH), but whether the response is related to the degree of hypoleptinemia remains unclear. OBJECTIVE The aim of the study was to compare efficacy of leptin therapy in familial partial lipodystrophy, Dunnigan variety (FPLD) patients with SH (serum leptin<7th percentile of normal) vs. those with moderate hypoleptinemia (MH; serum leptin in 7th to 20th percentiles). DESIGN, SETTING, AND PATIENTS We conducted an open-label, parallel group, observational study in 14 SH (mean±sd, serum leptin, 1.9±1.1 ng/ml) and 10 MH (serum leptin, 5.3±1.0 ng/ml) women with FPLD. INTERVENTION Patients received 0.08 mg/kg·d of metreleptin by twice daily sc injections for 6 months. MAIN OUTCOME MEASURES The primary outcome variable was change in fasting serum triglycerides. Other secondary variables were fasting plasma glucose and insulin, insulin sensitivity, hemoglobin A1c, and hepatic triglyceride content. RESULTS Median fasting serum triglycerides decreased from 228 to 183 mg/dl in the SH group (P=0.04) and from 423 to 339 mg/dl in the MH group (P=0.02), but with no difference between the groups (P value for interaction=0.96). Hepatic triglyceride levels similarly declined significantly from 8.8 to 4.9% in the SH group and from 23.7 to 9.2% in the MH group (P value for interaction=0.9). Loss of body weight and body fat occurred in both groups. Fasting glucose, insulin, glucose tolerance, and hemoglobin A1c levels did not change. K value on insulin tolerance test improved slightly in the SH group (0.98 to 1.24%; P=0.01), but not in the MH group (1.1 to 1.27%; P=0.4). CONCLUSION Metreleptin replacement therapy is equally effective in FPLD patients with both SH and MH in reducing serum and hepatic triglyceride levels, but did not improve hyperglycemia.