Miracle-dz/UniFAR-FTUs huggingface dataset:
A new class of biologic agents facing the therapeutic paradigm in psoriasis: anti-IL-23 agents.

ABSTRACT Introduction: Psoriasis is a chronic inflammatory skin disease whose pathogenesis is driven by multiple cytokine-mediated pathways. In this immunologic setting, the centrality of the IL-23/IL-17 axis and its therapeutic relevance has emerged. Areas covered: This review is aimed at collecting preliminary data on IL23p19 blockers developed for the treatment of plaque psoriasis. Three agents, guselkumab, risankizumab, and tildrakizumab, are currently being tested in phase III trials, while LY2525623 is currently being tested in phase II trials. Treatment with these agents resulted in a marked improvement in disease severity, confirming the pathogenic relevance of IL-23 in psoriasis. Expert opinion: Selective neutralization of IL-23 is an advantageous strategy for treating psoriasis. Preliminary data from phase II and III trials have shown the capability of this therapeutic class in inducing complete clearance or almost complete clearance in many patients: the highest PASI 90 rates were achieved by guselkumab, tildrakizumab, and risankizumab in 73.3%, 74% and 77% of cases, respectively. Moreover, the highest PASI 100 rates were achieved in 33%, 14%, and 48% of patients treated with guselkumab, tildrakizumab, and risankizumab, respectively. Further studies are needed to confirm this remarkable efficacy over long-term treatment periods.
Hyperandrogenism in polycystic ovary syndrome. Evidence of dysregulation of 11 beta-hydroxysteroid dehydrogenase.

BACKGROUND Hyperandrogenemia is the hallmark of the polycystic ovary syndrome, yet the relative contributions of the adrenal cortex and ovary to the overproduction of androgen remain unclear. To identify possible causes of adrenocortical overactivity, we studied the metabolism of adrenal and ovarian steroid hormones in women with this disorder. METHODS We measured 24-hour urinary excretion of steroid hormone metabolites by high-resolution capillary gas chromatography in 65 women with the polycystic ovary syndrome and 45 normal women matched for body-mass index. RESULTS After adjustment for body-mass index, the urinary excretion of testosterone and androstenedione metabolites was 1.9 times higher in the women with the syndrome than in the normal women, and the excretion of dehydroepiandosterone metabolites (C19 steroid sulfates) and cortisol metabolites was 1.5 and 1.3 times higher, respectively (P < 0.01 for all comparisons). The affected women also had significantly higher ratios of 11-oxo (oxygenated) metabolites to 11-hydroxy metabolites of cortisol (1.4 times higher, P < 0.001) and of 11-oxo to 11-hydroxy metabolites of corticosterone (1.8 times higher, P < 0.001). In the group with the polycystic ovary syndrome, 55 percent of the nonobese women and 24 percent of the obese women had ratios above the upper limit of normal; the ratios in the obese women did not differ significantly from those in the nonobese women. CONCLUSIONS Adrenal secretion of cortisol and androgens is increased in women with the polycystic ovary syndrome. The increases may be explained by dysregulation of 11 beta-hydroxysteroid dehydrogenase causing increased oxidation of cortisol to cortisone, which cannot be accounted for by obesity.
Initial Pharmacokinetics and Bioavailability of PSC 833, a P‐Glycoprotein Antagonist

Resistant cancer cells have been shown to overexpress a 170‐kd membrane glycoprotein called P‐glycoprotein. P‐glycoprotein, a product of the multidrug resistance 1 gene, functions as an energy‐dependent efflux pump that decreases intracellular drug concentrations. A variety of nonchemotherapeutic agents have been shown to inhibit P‐glycoprotein—dependent drug efflux including cyclosporin. PSC 833 is a nonimmunosuppressive derivative of cyclosporin D with the ability to reverse multidrug resistance because of P‐glycoprotein overexpression in vitro. As part of early clinical development of PSC 833, the authors investigated the bioavailability of an oral formulation of PCS 833. PSC 833 (3 mg/kg) was administered as a 2‐hour intravenous infusion on day 1 of the treatment cycle. Serial blood samples for the determination of PSC 833 whole blood concentrations were obtained after both the intravenous and oral doses. On day 5 of the study, patients received a single oral dose (9 mg/kg) of PSC 833. A total of 14 patients were treated. The intravenous data were best described by a two‐compartment open model. The oral data also were described using a two‐compartment model, with oral absorption incorporating a lag time to account for possible delays in absorption. There was large intra‐ and interpatient variability in the pharmacokinetics of PSC 833 in these patients. The absolute bioavailability of PSC 833 was 34% but ranged from 3% to 58% of the administered dose. The clearance (Cl) of PSC 833, in general, was consistent between the two dose forms administered. The pharmacokinetic behavior of PSC 833 appears to be similar to that of cyclosporine.
Exogeneity of money supply evidence from Nigeria

This study investigates the exogeneity of the money supply using annual data from 1970-2008. The tests applied investigated the plausibility of the classical hypotheses. We employed the two stage least square method, the Johansen’s cointegration procedures and the Granger causality approach. The findings show that there exists a long run relationship between money supply and the included variables. The real interest rate and real income Granger cause the growth of money. Moreover, Granger’s causal relation between them was unidirectional from real interest rate, real income to money supply. Our main contribution is having demonstrated that money supply was endogenous with respect to the value of money, real income and real interest rate meaning that the monetary policy had influence to some extent on money supply but economic activities had greater influence in determining the rate of money growth. This study, therefore, recommends that the government and monetary authorities should undertake regulated/guided policies that would enhance economic activities for steady growth of money supply.
Immune-Mediated Positive Selection Drives Human Immunodeficiency Virus Type 1 Molecular Variation and Predicts Disease Duration

ABSTRACT Using likelihood-based evolutionary methods, we demonstrate that the broad genetic diversity of human immunodeficiency virus type 1 (HIV-1) in an infected individual is a consequence of site-specific positive selection for diversity, a likely consequence of immune recognition. In particular, the extent of positive selection appears to be a good predictor of disease duration. Positively selected sites along HIV-1 partial env sequences are numerous but not distributed uniformly. In a sample of eight patients studied longitudinally, the proportion of sites per sample under positive selection was a statistically significant predictor of disease duration. Among long-term progressors, positive selection persisted at sites over time and appears to be associated with helper T-cell epitopes. In contrast, sites under positive selection shifted from one longitudinal sample to the next in short-term progressors. Our study is consistent with the hypothesis that a broad and persistent immunologic response is associated with a slower rate of disease progression. In contrast, narrow, shifting immune responses characterize short-term progressors.
Combined effects of humic acids and salinity on solid‐phase microextraction of DDT and chlorpyrifos, an estimator of their bioavailability

The unbound portion of dissolved hydrophobic environmental contaminants generally is presumed to be the most bioavailable to aquatic organisms. The effects of differing concentrations of Aldrich humic acid (HA) and salinity on the freely dissolved fraction of chlorpyrifos (CPF) and 4,4′‐dichlorodiphenyltrichloroethane (DDT) in water were assessed through their relative uptake by solid‐phase microextraction (SPME). This extraction method has been recently suggested as a valuable biomimetic tool. Increasing salinity (0–20 parts per thousand [%]) alone had no effect on the uptake of DDT by the SPME fiber, but generally enhanced the SPME uptake of the more water soluble CPF. Solid‐phase microextraction uptake of DDT was decreased at an HA concentration of 10 mg/L, but 100 mg/L was required to decrease CPF uptake. Binding of CPF and DDT by HA was greatly reduced by the presence of salt at 5 to 20%. The extent of the HA and salinity effects appeared to be pesticide‐dependent. These factors may ultimately impact the contaminant's environmental fate, transport, and bioavailability, for example, in estuarine situations.
The Impact of Deposit Money Bank’s Agricultural Credit on Agricultural Productivity in Nigeria: Evidence from an Error Correction Model

This paper examined the impact of deposit money bank agricultural credit on agricultural productivity in Nigeria using an error correction model and annual time series data for the period 1981-2014. The results indicate that an equilibrium relationship exists between the variables. In addition, we find that deposit money bank’s agricultural credit impacts positively and significantly on agricultural productivity in the long-run, but this impact is quite negligible in the short-run. We also find that agricultural land and labour force impact negatively on agricultural productivity both in the long-run and short-run. However, the impact of climate change variables, namely annual rainfall and average temperature remained negligible throughout. The paper therefore supports policies that will enhance and sustain the availability of bank credits at affordable interest rates for the agricultural sector, ensure easy access to land for agricultural purposes, and mechanize the agricultural system to attract the youth population.
Highlights from the 42nd annual meeting of the American Society of Clinical Oncology

The results of ~ 3700 preclinical and clinical studies were presented at the 42nd annual meeting of the American Society of Clinical Oncology (ASCO) held 2 – 6 June 2006, in Atlanta, Georgia. The annual ASCO meeting is the largest forum in which oncology professionals from around the world report the latest advances in cancer research, encompassing a wide spectrum of subjects on molecular biology, prevention, diagnosis and therapy of tumours. The present report summarises some of the more important results of the studies presented at the meeting. In particular, the authors focused on findings from randomised Phase III trials that, in their opinion, are most likely to have an immediate effect on clinical practice. The top advances were grouped into four major themes (breast cancer, colorectal cancer, non-small cell lung cancer and selected presentations from the plenary session). In addition, selected Phase I and II studies on promising novel therapeutic agents were briefly described. Finally, a ‘question and answer’ format was adopted to report results of interesting studies on some hot topics.
Structural basis of the therapeutic anti-PD-L1 antibody atezolizumab

Monoclonal antibodies targeting PD-1/PD-L1 signaling pathway have achieved unprecedented success in cancer treatment over the last few years. Atezolizumab is the first PD-L1 monoclonal antibody approved by US FDA for cancer therapy; however the molecular basis of atezolizumab in blocking PD-1/PD-L1 interaction is not fully understood. Here we have solved the crystal structure of PD-L1/atezolizumab complex at 2.9 angstrom resolution. The structure shows that atezolizumab binds the front beta-sheet of PD-L1 through three CDR loops from the heavy chain and one CDR loop from the light chain. The binding involves extensive hydrogen-bonding and hydrophobic interactions. Notably there are multiple aromatic residues from the CDR loops forming Pi-Pi stacking or cation-Pi interactions within the center of the binding interface and the buried surface area is more than 2000 Å2, which is the largest amongst all the known PD-L1/antibody structures. Mutagenesis study revealed that two hot-spot residues (E58, R113) of PD-L1 contribute significantly to the binding of atezolizumab. The structure also shows that atezolizumab binds PD-L1 with a distinct heavy and light chain orientation and it blocks PD-1/PD-L1 interaction through competing with PD-1 for the same PD-L1 surface area. Taken together, the complex structure of PD-L1/atezolizumab solved here revealed the molecular mechanism of atezolizumab in immunotherapy and provides basis for future monoclonal antibody optimization and rational design of small chemical compounds targeting PD-L1 surface.
Time‐resolved observations of shock waves and cavitation bubbles generated by femtosecond laser pulses in corneal tissue and water

Photodisruption in ocular media with high power pulsed lasers working at non‐absorbing frequencies have become a well established surgical tool since the late seventies. Shock waves and cavitation bubbles generated by the optical breakdown may strongly influence the surgical effect of photodisruptive lasers. We have investigated the shock wave and cavitation bubble effects of femtosecond laser pulses generated during photodisruption in corneal tissue and water. The results are compared to those obtained with longer laser pulses.
Stacked Open-Loop Square Ring Antenna for Circular Polarization Operation

In this letter, a novel circular polarized (CP) open-loop square ring antenna using a stacked structure is proposed. The proposed antenna consists of two open-loop square ring resonators and a T-shaped feed structure. The resonant frequency of the ring resonator is adjusted mainly by changing the width of the ring. Depending on the location of the gap in the square ring, each open-loop square ring antenna exhibits different linear polarizations. By selecting a suitable ring width and gap position, two orthogonal resonant modes with equal amplitude and a 90 ° phase difference are excited, and good CP is achieved. The measured 10-dB reflection coefficient and 3-dB axial ratio bandwidth of the antenna prototype are 3.93% and 1.2%, respectively.
Monopolistic Competition, Sticky Prices, and the Minimal Mark-Up in Steady State

This note reports the rate of inflation that minimizes the mark-up of prices over marginal costs in the steady-state solution of a monopolistic competition model with either Taylor (1980) or Calvo (1983) pricing. The minimal mark-up is always found at a positive and low rate of inflation for any sensible parameter calibration. Actually, the rate of inflation that minimizes the mark-up is very close to ratio between the real rate of discount and the Dixit-Stiglitz elasticity. This result is robust to altenative sticky-price specifications.
304520_Journal May

Sleep deprivation exerts transient antidepressant efficacy. As a potential mechanism of action an enhancement of serotonergic and dopaminergic neurotransmission within the CNS is discussed. Because genetic variations influencing neurotransmission could have an impact on therapeutic outcome and stability of improvement, we investigated the functional polymorphism of the serotonin transporter (5-HTT) gene, the 5-HTTlinked polymorphic region (5-HTTLPR), to examine the serotonergic pathway. We included 56 patients with major depression (DSM-IV). Psychiatric ratings including the HAMD21 and HAM-D6 scale were assessed on the day prior to partial sleep deprivation (PSD) and on day 1 and 2 after PSD and related to the different genotypes. The 5-HTTLPR variants were determined following PCR amplification using genomic DNA. 58.1% of the patients were responders to PSD. A significant overall reduction in depression scores could be observed on day 1. Subdivision according 5HTTLPR gene variants showed no differences in clinical outcome on day 1. As expected the therapeutical effect of PSD was only transient and most patients experienced an exacerbation of depressive symptoms on day 2. 5-HTTLPR variants had no influence on reduction of depressive symptoms on day 2 or relapse on day 3. Thus, the previously reported influence of the serotonin transporter gene on PSD outcome in bipolar depression could not be confirmed in unipolar depressed patients
Fast-track regional anaesthesia

Regional anaesthesia plays an important role in day case surgery because it combines reliable effects with low risk and the possibility of local postoperative analgesia without systemic side-effects. Fast-track regional anaesthesia allows short-term postoperative surveillance or even bypassing the post-anaesthesia care unit. Peripheral nerve blocks provide long-lasting pain relief, and can accelerate timely discharge if a persisting motor block is accepted. Multiple peripheral nerve stimulation and injection techniques may help to realize differential blockades with a pronounced analgesic rather than a motor blocking effect. Nerve blocks with local anaesthetics in combination with alpha2-adrenoceptor agonists or non-steroidal anti-inflammatory drugs and short-acting parenteral opioids represent an effective multimodal concept for ambulatory surgery.
Reliable H∞ filter design for nonlinear networked control systems with probabilistic sensor failure

This paper investigates robust and reliable H∞ filter design for a class of nonlinear networked control systems: (i) a T-S fuzzy model with its own uncertainties is used to approximate the nonlinear dynamics of the plant, (ii) a new sensor failure model with uncertainties is proposed, and (iii) the signal transfer of the closed-loop system is under a networked communication scheme, and therefore is subject to time-delay, packet loss and/or out-of-order. Four new theorems are proved to cover the conditions for the robust mean square stability of the systems under study in terms of LMIs and a decoupling method for the filter design. One example, which is based on a model of an inverted pendulum, is provided to demonstrate the design method.
Warfarin and reduced central venous thrombosis in home total parenteral nutrition patients.

Central venous thrombosis is a potentially life-threatening complication in patients on long-term home total parenteral nutrition (HTPN). Lack of venous access due to recurrent thromboses can prevent delivery of life-saving nutritional support. The long-term anticoagulation management to prevent thromboses in patients with central venous catheters for HTPN has not been well established. We have reviewed the role of warfarin in reducing the incidence of thromboses and its safety in our HTPN patients. Ninety consecutive HTPN patients were studied retrospectively. Twenty-two thromboses occurred during 1312 patient-mo in 53 HTPN patients on minidose warfarin. A minidose of warfarin is defined as 1-2 mg and does not prolong the prothrombin time. Seven thromboses occurred over 619 mo in 18 patients on a therapeutic dose of warfarin (minidose compared to therapeutic dose, p > 0.05). A therapeutic dose of warfarin is a dose that increases the prothrombin time to 1.2-1.5 times that of control. Twelve patients who had 18 thromboses in 323 patient-mo while on minidose warfarin were subsequently converted to therapeutic warfarin. The incidence of thromboses decreased to 2 in 369 patient-mo (p < 0.005). There were no hemorrhagic complications in the minidose warfarin group and four nonfatal hemorrhagic complications in the therapeutic dose warfarin group (p > 0.05). A therapeutic dose of warfarin is effective in reducing the incidence of thromboses in patients who experience central venous thrombosis despite minidose warfarin with a minimal increase in hemorrhagic complications.
Three-Dimensional Selective-Scale Texture Analysis of Computed Tomography Pulmonary Angiograms

Objectives:This feasibility study aims to develop 3-dimensional (3D) selective-scale texture analysis of computed tomography pulmonary angiography to identify texture correlates for ventilated and vascular lung for visual and quantitative assessment of pulmonary disorders with altered vasculature. Materials and Methods:Computed tomography pulmonary angiography examinations of 8 patients were considered in this study; 3 had normal lungs, 3 had pulmonary embolism (PE1, PE2, and PE3), 1 had only emphysema (PEmp), whereas the final patient had both emphysema and embolism (PEE). Before texture analysis, an initial automated segmentation procedure to include only the lung parenchyma and generation of isometric volume were carried out. From this segmented volume, ventilated lung and pulmonary vessels were separately selected. Texture analysis comprised 2 stages: 1) volume filtration using 3D Laplacian of Gaussian filter to highlight fine and coarse textures within ventilated and vascular lung, followed by 2) quantification of texture using mean gray-level intensity, entropy and uniformity both globally and at 3 anatomic sections of the lung, ie, anterior, middle, and posterior. Quantification of texture was also performed on the unfiltered computed tomography lung dataset. Volume rendering and image fusion of ventilated and vascular lung texture were employed for visualization. Results:For fine texture quantified as mean gray-level intensity in ventilated lung, a postural gradient compatible with known pulmonary physiology was demonstrated and texture was different in emphysematous lung (PEmp and PEE) when compared with nonemphysematous lung (normals, PE1, PE2, and PE3) consistent with altered ventilation. Coarse texture in vascular lung demonstrated a descending trend in entropy (or ascending trend in uniformity) for normals, followed by embolism only (PE1, PE2, and PE3) and finally for emphysematous lung (PEmp and PEE) suggesting a correlation with degree of vascularity (or perfusion). 3D images of ventilated and vascular lung texture highlighted mismatched and matched defects in patients with pulmonary disorders. Conclusions:This feasibility study demonstrated that 3D filtered texture analysis can potentially provide correlates for ventilated and vascular lung, which may be useful in the diagnosis of PE in the presence of other causes of altered vascularity.
Gender Congruency From a Neutral Point of View: The Roles of Gender Classes and Conceptual Connotations

The question of whether language affects thought is long-standing, with grammatical gender being one of the most contended instances. Empirical evidence focuses on the gender congruency effect, according to which referents of masculine nouns are conceptualized more strongly as male and those of feminine nouns more strongly as female. While some recent studies suggest that this effect is driven by conceptual connotations rather than grammatical properties, research remains theoretically inconclusive because of the confounding of grammatical gender and conceptual connotations in gendered (masculine or feminine) nouns. Taking advantage of the fact that German also includes a neuter gender, the current study attempted to disentangle the relative contributions of grammatical properties and connotations to the emergence of the gender congruency effect. In three pairs of experiments, neuter and gendered nouns were compared in an Extrinsic Affective Simon Task based on gender associations, controlled for a possible role of gender-indicating articles. A congruency effect emerged equally strongly for neuter and gendered nouns, but disappeared when including connotations as covariate, thereby effectively excluding grammatical gender as the (only) driving force for this effect. Based on a critical discussion of these findings, we propose a possible mechanism for the emergence of the effect that also has the potential to accommodate conflicting patterns of findings from previous research.