Miracle-dz/UniFAR-FTUs huggingface dataset:
Regulatory and study conditions for the determination of bioequivalence of highly variable drugs.

PURPOSE The FDA Working Group on Highly Variable (HV) Drugs recently presented interim procedures and conditions for determining the bioequivalence (BE) of HV drug products. They included analysis by the method of scaled average BE (SABE), a switching coefficient of variation of CV S = 30% and a regulatory standardized variation of CV 0 = 25% for applying SABE, and the use of a secondary regulatory criterion restricting to 0.80-1.25 the point estimate for the ratio of estimated geometric means (GMR) of the two formulations. These conditions are scrutinized in the present communication. METHODS 3-period BE studies were simulated with various statistical and regulatory assumptions. Power curves, obtained by gradually increasing the true GMR, compared performances of the methods of SABE, a constrained point estimate of GMR (PE/GMR), and the composite of these two approaches. The consumer risk of each procedure was evaluated. RESULTS With CV 0 = 30% and PE/GMR = 0.80-1.25, the composite criterion of BE relied on the confidence limits of SABE. In contrast, with CV 0 = 25% and/or PE/GMR = 0.87-1.15, the composite criterion approached almost completely the features of the GMR point estimate, especially at high within-subject variation. The consumer risk was near 5% with CV 0 = 30% but much higher when CV 0 = 25%. CONCLUSIONS A constraint on GMR is difficult to justify scientifically. Still, if it is introduced then the condition of CV S = CV 0 = 30% and PE/GMR = 0.80-1.25 is recommended as a composite regulatory criterion. With alternative settings of the conditions, such as the recommended CV 0 = 25% and/or PE/GMR = 0.87-1.15, the composite criterion would reflect almost entirely the GMR point estimate. Also, with CV 0 = 25%, the BE limits are discontinuous at CVS = 30% and, as consequences, the consumer risk is substantially larger than 5%, and the regulatory uncertainty for making a decision about acceptance or rejection is enhanced. These would be undesirable outcomes.
A Controlled Study of Caudal Epidural Injections of Triamcinolone Plus Procaine for the Management of Intractable Sciatica

The management of sciatica due to lumbar nerve root compromise remains controversial, probably because few well-controlled studies of conservative management have been performed. This preliminary study assesses the efficacy of epidural injections of 80 mg triamcinolone acetonide plus 0.5% procaine hydrochloride in saline, administered via the caudal route, in a double-blind, placebo controlled trial with 1 year follow-up. Twenty-three patients were entered into the study: 12 received treatment and 11 placebo. The active group showed significant pain relief (P=0.02) and a significant increase in mobility (P=0.01) at 4 weeks, which resulted in improved quality of life (P=0.02). At 1 year, subjective and objective measures improved in both groups. The improvement was greater in the actively treated group, but only the objective assessment (straight leg raise) was statistically significant.
A Spatio-Temporal Defect Process Model for Competing Progressive Breakdown Modes of Ultra-Thin Gate Oxides

Continuous downscaling of metal-oxide-semiconductor field effect transistor (MOSFET) devices has led to reliability concerns, and requires a fundamental understanding of their failure mechanisms. In particular, gate oxide breakdown is a key mechanism limiting the lifetimes of MOSFET devices. By combining stochastic defect generation processes, and the time required to construct percolation paths by the defects, this paper proposes a spatio-temporal percolation model for progressive breakdowns of ultra-thin gate oxide in a convolution form. The model simultaneously considers general patterns of defect generation and defect occurrence times presented in competing modes. The proposed model is consistent with the general statistical features of gate oxide breakdowns observed in existing experimental works. This spatio-temporal model provides more precise results on the failure-time distribution of MOSFET devices, especially at lower quantiles.
Focusing Construction and Selection of Abductive Hypotheses

Many abductive understanding systems explain novel situations by a chaining process that is neutral to explainer needs beyond generating some plausible explanation for the event being explained. This paper examines the relationship of standard models of abductive understanding to the case-based explanation model. In case-based explanation, construction and selection of abductive hypotheses are focused by specific explanations of prior episodes and by goal-based criteria reflecting current information needs. The case-based method is inspired by observations of human explanation of anomalous events during everyday understanding, and this paper focuses on the method's contributions to the problems of building good explanations in everyday domains. We identify five central issues, compare how those issues are addressed in traditional and case-based explanation models, and discuss motivations for using the case-based approach to facilitate generation of plausible and useful explanations in domains that are complex and imperfectly understood.
Python for Teaching Introductory Programming: A Quantitative Evaluation

Abstract This paper compares two different approaches of teaching introductory programming by quantitatively analysing the student assessments in a real classroom. The first approach is to emphasise the principles of object-oriented programming and design using Java from the very beginning. The second approach is to first teach the basic programming concepts (loops, branch, and use of libraries) using Python and then move on to oriented programming using Java. Each approach was adopted for one academic year (2008–09 and 2009–10) with first year undergraduate students. Quantitative analysis of the student assessments from the first semester of each year was then carried out. The results of this analysis are presented in this paper. These results suggest that the later approach leads to enhanced learning of introductory programming concepts by students.
Prevalence and Survey of Verticillium Dahliae on Stone Fruits and Olive Trees in two Regions of Lebanon

Une enquete sur la presence du champignon Verticillium dahliae sur les fruits a noyaux et les oliviers a ete realisee dans la region du centre de la Bekaa et dans le nord du Liban. Au cours de cette enquete, des echantillons des branches et rameaux ont ete collectes: 46 des fruits a noyaux et 50 des oliviers. La severite et l'incidence ont ete evaluees dans les vergers visites. Il a ete demontre que les amandiers sont les plus attaques par la maladie et que l'incidence la plus elevee est rencontree dans la localite de Sariine. Comme les echantillons malades collectes presentaient plusieurs types de symptomes, l'isolement et l'identification du champignon, agent causal de la maladie, ont ete entrepris au laboratoire. Les symptomes de 32 echantillons des 46 collectes des fruits a noyaux ainsi que 13 des 50 echantillons des oliviers sont dus au V. dahliae identifie grâce a l'apparition des microsclerotes et a la forme verticillee des conidiophores. L'etude des caracteristiques morphologiques des isolats obtenus a ete faite en les incubant sous conditions controlees et en notant la couleur et la croissance des colonies ainsi que la date d'apparition des microsclerotes. Les colonies des isolats d'amandiers sont jaunes tandis que celles provenant des isolats des pechers et des oliviers sont blanches. Independamment de l'origine des isolats, la croissance des colonies mesuree sur 28 jours a un intervalle de 2 jours etait parabolique au debut de l'experience puis lineaire a partir du 14 ieme jour. Quant aux microsclerotes, elles etaient apparues 7 a 10 jours apres incubation. Cette etude a montre que la frequence de V. dahliae etait de 69,5 % dans les echantillons collectes a partir des arbres fruitiers a noyaux et de 26 % dans ceux des oliviers. Ainsi, l'attaque de Verticillium dahliae ne doit pas etre negligee.
Regional cloud characteristics over the tropical northwestern Pacific as revealed by Tropical Rainfall Measuring Mission (TRMM) Precipitation Radar and TRMM Microwave Imager

[1] The present study investigates regional cloud characteristics over the tropical northwestern Pacific using Tropical Rainfall Measuring Mission (TRMM) data sets such as rain rate, radar reflectivity, and passive microwave radiometer polarization corrected temperature (PCT). In particular, the tropical northwestern Pacific is divided into two surface rain maxima regions: the South China Sea (SCS) and the Philippine Sea (PS). The TRMM variables are retrieved by a pair of spaceborne microwave sensors, Precipitation Radar (PR) and TRMM Microwave Imager (TMI). It is revealed that the SCS contains more frequent deeply developed convective systems relative to the PS on the basis of the analysis of the PR and TMI version-6 data during a 4-year period (1998–2001) of summers. This is mainly indicated by two factors: strong PR reflectivity (≥30 dBZ) above the freezing level (∼5 km) and TMI ice-scattering signature (PCT at 85.5 GHz ≤ ∼190 K, and PCT at 37.0 GHz ≤ ∼260 K), which are more frequent over the SCS than over the PS. Comparison of TMI and PR rain rates, a relatively small (large) positive PR–TMI bias is observed for an average of rainy areas over the SCS (PS). This region-dependent PR–TMI bias can arise from the regionally different extents of both (1) the PR's underestimate by attenuation correction and (2) the TMI's overestimate by emission from the melting layer (i.e., SCS > PS in (1) and (2)). These differences are due to the excess of heavy rainfall events, high rain rates, strong convective intensities, and high cloud top heights in the SCS compared with the PS.
Efficient Dye-Sensitized Solar Cells Using Red Turnip and Purple Wild Sicilian Prickly Pear Fruits

Dye-sensitized solar cells (DSSCs) were assembled by using the bougainvillea flowers, red turnip and the purple wild Sicilian prickly pear fruit juice extracts as natural sensitizers of TiO2 films. The yellow orange indicaxanthin and the red purple betacyanins are the main components in the cocktail of natural dyes obtained from these natural products. The best overall solar energy conversion efficiency of 1.7% was obtained, under AM 1.5 irradiation, with the red turnip extract, that showed a remarkable current density (Jsc = 9.5 mA/cm2) and a high IPCE value (65% at λ = 470 nm). Also the purple extract of the wild Sicilian prickly pear fruit showed interesting performances, with a Jsc of 9.4 mA/cm2, corresponding to a solar to electrical power conversion of 1.26%.
Geochemical Estimates of Paleorecharge in the Pasco Basin: Evaluation of the Chloride Mass Balance Technique

The Pasco Basin in southeastern Washington State provides a unique hydrogeologic setting for evaluating the chloride mass balance technique for estimating recharge. This basin was affected by late Pleistocene catastrophic floods when glacial dams in western Montana and northern Idaho were breached. It is estimated that multiple Missoula floods occurred between ∼13,000 and 15,000 years B.P. and reached a high water elevation of ∼350 m. These floods removed accumulated chloride from the sediment profile, effectively resetting the chloride mass balance clock at the beginning of the Holocene. The rate of chloride accumulation qCl in the sediments was determined by two methods and compared. The first method measured qCl by dividing the calculated natural fallout of 36Cl by a measured ratio of 36Cl/Cl in the pore water, while the second method used the total mass of chloride in the profile divided by the length of time that atmospheric chloride had accumulated since the last flood. Although the two methods are based on different approaches, they showed close agreement. In laboratory studies the sediment to water ratio for chloride extraction was sensitive to the grain size of the sediments; low extraction ratios in silt loam sediments led to significant underestimation of pore water chloride concentration. Br/Cl ratios were useful for distinguishing nonatmospheric (e.g., rock) sources of chloride. Field studies showed little spatial variability in estimated recharge at a given site within the basin but showed significant topographic control on recharge rates in this semiarid environment. An extension of the conventional chloride mass balance model was used to evaluate chloride profiles under transient, time-varying annual precipitation conditions. This model was inverted to determine the paleorecharge history for a given soil chloride profile, and the parameters of the root extraction model required to estimate paleoprecipitation
Investigating k distribution methods for parameterizing gaseous absorption in the Hadley Centre Climate Model

A technique for generating the coefficients of the k distribution method has been developed which uses very few exponential terms to represent absorption in a spectral region. This new technique, using k distributions derived from HITRAN 1992 spectroscopic data, predicts vertical profiles of irradiances and heating rates due to the major radiatively active gases with a better balance between speed of computation and accuracy than previous methods. Absorption coefficients were specified in a manner similar to that of the correlated k distribution method, whereas the weights of each term were determined using a fitting procedure similar in principle to the exponential-sum fitting of transmissions method. Errors in irradiances and heating rates for various atmospheric profiles and the reference profile (with which fitting of weights was performed) were of a similar magnitude, thereby indicating the technique's suitability for use in global model studies. This parameterization is now used by the Hadley Centre climate model.
Early-Age Running Enhances Activity of Adult-Born Dentate Granule Neurons Following Learning in Rats

Abstract Cognitive reserve, the brain’s capacity to draw on enriching experiences during youth, is believed to protect against memory loss associated with a decline in hippocampal function, as seen in normal aging and neurodegenerative disease. Adult neurogenesis has been suggested as a specific mechanism involved in cognitive (or neurogenic) reserve. The first objective of this study was to compare learning–related neuronal activity in adult-born versus developmentally born hippocampal neurons in juvenile male rats that had engaged in extensive running activity during early development or reared in a standard laboratory environment. The second objective was to investigate the long-term effect of exercise in rats on learning and memory of a contextual fear (CF) response later in adulthood. These aims address the important question as to whether exercise in early life is sufficient to build a reserve that protects against the process of cognitive aging. The results reveal a long-term effect of early running on adult-born dentate granule neurons and a special role for adult-born neurons in contextual memory, in a manner that is consistent with the neurogenic reserve hypothesis.
Suicide in Scandinavia: An epidemiological analysis

Suicide rates in Denmark, Finland, Norway and Sweden for the past few years are presented. Despite the fact that the Nordic countries, both historically and at present, have many features in common, differences between the countries in the frequency of suicide are pronounced. These differences and the reliability of Nordic suicide statistics are discussed.
Tool use imagery triggers tool incorporation in the body schema

Tool-use has been shown to modify the way the brain represents the metrical characteristics of the effector controlling the tool. For example, the use of tools that elongate the physical length of the arm induces kinematic changes affecting selectively the transport component of subsequent free-hand movements. Although mental simulation of an action is known to involve -to a large extent- the same processes as those at play in overt motor execution, whether tool-use imagery can yield similar effects on the body representation remains unknown. Mentally simulated actions indeed elicit autonomic physiological responses and follow motor execution rules that are comparable to those associated with the correspondent overt performance. Therefore, here we investigated the effects of the mental simulation of actions performed with a tool on the body representation by studying subsequent free-hand movements. Subjects executed reach to grasp movements with their hand before and after an imagery task performed with either a tool elongating their arm length or, as a control, with their hand alone. Two main results were found: First, in agreement with previous studies, durations of imagined movements performed with the tool and the hand were similarly affected by task difficulty. Second, kinematics of free-hand movements was affected after tool-use imagery, but not hand-use imagery, in a way similar to that previously documented after actual tool-use. These findings constitute the first evidence that tool-use imagery is sufficient to affect the representation of the user's arm.
Molecular evolution of the sheep prion protein gene

Transmissible spongiform encephalopathies (TSEs) are infectious, fatal neurodegenerative diseases characterized by aggregates of modified forms of the prion protein (PrP) in the central nervous system. Well known examples include variant Creutzfeldt-Jakob Disease (vCJD) in humans, BSE in cattle, chronic wasting disease in deer and scrapie in sheep and goats. In humans, sheep and deer, disease susceptibility is determined by host genotype at the prion protein gene (PRNP). Here I examine the molecular evolution of PRNP in ruminants and show that variation in sheep appears to have been maintained by balancing selection, a profoundly different process from that seen in other ruminants. Scrapie eradication programs such as those recently implemented in the UK, USA and elsewhere are based on the assumption that PRNP is under positive selection in response to scrapie. If, as these data suggest, that assumption is wrong, eradication programs will disrupt this balancing selection, and may have a negative impact on the fitness or scrapie resistance of national flocks.
Preoperative use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers is associated with increased risk for acute kidney injury after cardiovascular surgery.

BACKGROUND AND OBJECTIVES Acute kidney injury (AKI) occurs commonly after cardiac surgery. Most patients who undergo cardiac surgery receive long-term treatment with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB). The aim of this study was to determine whether long-term use of ACEI/ARB is associated with an increased incidence of AKI after cardiac surgery. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a retrospective cohort study of 1358 adult patients who underwent cardiac surgery between January 1, 2001, and December 31, 2005, in two tertiary care hospitals in Buffalo, NY. The incidence of AKI was determined after cardiac surgery. Clinical data were collected using a standardized form that included comorbid condition, use of ACEI/ARB, and intraoperative and postoperative complications. RESULTS Overall, 40.2% of patients developed AKI. Preoperative variables that were significantly associated with development of AKI included increasing age; nonwhite race; combined valve surgery and coronary artery bypass grafting compared with coronary artery bypass grafting alone; American Society of Anesthesiologists (ASA) Risk Score category 4/5 compared with 2 to 3; presence of diabetes, congestive heart failure, or neurologic disease at baseline; use of ACEI/ARB; and emergency surgery. Intra- and postoperative factors that were associated with postoperative AKI were hypotension during surgery, use of vasopressors, and postoperative hypotension. Multiple regression logistic model confirmed an independent and significant association of AKI and preoperative use of ACEI/ARB. This was confirmed using a bivariate-probit and propensity score model that adjusts for confounding by indication of use and selection bias. CONCLUSIONS Preoperative use of ACEI/ARB is associated with a 27.6% higher risk for AKI postoperatively. Stopping ACEI or ARB before cardiac surgery may reduce the incidence of AKI.
Ablation of Oxytocin Neurons Causes a Deficit in Cold Stress Response

The paraventricular nucleus (PVN) is a critical locus of energy balance control. Three sets of neurons in the PVN are involved in regulating energy balance: oxytocin-expressing neurons (OXT-neurons), thyrotropin-releasing hormone–expressing neurons, and corticotrophin-releasing hormone–expressing neurons. To examine the role of OXT-neurons in energy balance, we ablated these neurons in mice by injecting diphtheria toxin into mice possessing both the oxytocin promoter driving cre expression and a cre-inducible diphtheria toxin receptor. Immunohistochemistry and real-time reverse transcriptase polymerase chain reaction confirmed that this injection caused a significant decrease in PVN OXT-neurons and OXT-mRNA abundance. OXT-neuron ablation did not alter food intake, weight, or energy expenditure at room temperature on either chow or a high-fat diet. To further characterize OXT-neuron–ablated mice, we examined their response to 1) intraperitoneal cholecystokinin (CCK) injection and 2) thermogenic stress. OXT-neuron–ablated mice had a blunted decrease in feeding response to CCK. When exposed to the extreme cold (4°C) for 3 hours, OXT-neuron–ablated mice had significant decreases in both rectal and brown adipose tissue temperature relative to controls, which was rescued by OXT treatment. Thermographic imaging revealed that OXT-neuron–ablated mice had increased body surface temperature. Thus, we report that OXT-neuron ablation shows no role for OXT-neurons in energy homeostasis at neutral temperature but reveals a heretofore unappreciated role for OXT-neurons and oxytocin specifically in regulating the thermogenic stress response.
Diverse Host Responses and Outcomes following Simian Immunodeficiency Virus SIVmac239 Infection in Sooty Mangabeys and Rhesus Macaques

ABSTRACT Sooty mangabeys naturally infected with simian immunodeficiency virus (SIV) do not develop immunodeficiency despite the presence of viral loads of 105 to 107 RNA copies/ml. To investigate the basis of apathogenic SIV infection in sooty mangabeys, three sooty mangabeys and three rhesus macaques were inoculated intravenously with SIVmac239 and evaluated longitudinally for 1 year. SIVmac239 infection of sooty mangabeys resulted in 2- to 4-log-lower viral loads than in macaques and did not reproduce the high viral loads observed in natural SIVsmm infection. During acute SIV infection, polyclonal cytotoxic T-lymphocyte (CTL) activity coincident with decline in peak plasma viremia was observed in both macaques and mangabeys; 8 to 20 weeks later, CTL activity declined in the macaques but was sustained and broadly directed in the mangabeys. Neutralizing antibodies to SIVmac239 were detected in the macaques but not the mangabeys. Differences in expression of CD38 on CD8+ T lymphocytes or in the percentage of naive phenotype T cells expressing CD45RA and CD62L-selection did not correlate with development of AIDS in rhesus macaques. In macaques, the proportion of CD4+ T lymphocytes expressing CD25 declined during SIV infection, while in mangabeys, CD25-expressing CD4+T lymphocytes increased. Longitudinal evaluation of cytokine secretion by flow cytometric analysis of unstimulated lymphocytes revealed elevation of interleukin-2 and gamma interferon in a macaque and only interleukin-10 in a concurrently infected mangabey during acute SIV infection. Differences in host responses following experimental SIVmac239 infection may be associated with the divergent outcome in sooty mangabeys and rhesus macaques.