Miracle-dz/UniFAR-FTUs huggingface dataset:
Switching from tenofovir and nucleoside analogue therapy to tenofovir monotherapy in virologically suppressed chronic hepatitis B patients with antiviral resistance

It is unclear whether chronic hepatitis B (CHB) patients with antiviral resistance, who achieve a complete virologic response (CVR) with tenofovir disoproxil fumarate (TDF) and nucleoside analogue (NUC) combination therapy, maintain CVR if switched to TDF monotherapy. We investigated the persistence of CVR after cessation of NUC in virologically suppressed antiviral resistant CHB patients using TDF+NUC combination therapy. This study recruited 76 antiviral‐resistant CHB patients showing CVR on TDF+entecavir (ETV) (n = 52), TDF+lamivudine (LAM; n = 14), and TDF+telbivudine (LdT; n = 10) combination therapy, who were switched to TDF monotherapy as step‐down therapy. At baseline, 47 patients were male and the median age was 53.0 years (range: 30‐78 years); 72.3% cases were hepatitis B e antigen‐positive (HBeAg+) and 23.7% were of liver cirrhosis. The median duration of TDF+NUC combination therapy was 20.8 months (range: 3‐46 months). At a median follow‐up of 24.7 months (range: 12‐48 months) after switching to TDF monotherapy, all 76 patients maintained CVR, regardless of the duration of combination therapy and the type of prior NUC and antiviral resistance. Renal dysfunction was not observed during the treatment period. The step‐down strategy of switching from TDF+NUC combination therapy to TDF monotherapy in virologically suppressed CHB patients with antiviral resistance should be considered.
Reduction of Child Poverty in Serbia: Improved Cash-Transfers or Higher Work Incentives for Parents?

Based on the 2013 Serbian Survey of Income and Living Conditions (SILC) and on the Serbian version of the EUROMOD platform, we evaluate the poverty and distributive effects on children of various reform (benefit and employment) strategies concerning the two major social benefit programs in Serbia: child allowance and social monetary assistance. Both the first and second-order effects of the proposed reforms are considered. For the second-round impacts, a structural labour supply model on parents has been estimated. Our results show that a benefit strategy (which also combats fiscal evasion) is preferred to an employment strategy which aims at raising the work incentives by parents
Tolerability, safety, and pharmacokinetics of the novel cathepsin A inhibitor SAR164653 in healthy subjects

Cathepsin A (CathA) is a lysosomal protein where it forms a stable complex with neuraminidase and ß‐galactosidase. CathA also has enzymatic activity and is involved in the degradation of many peptides. CathA was recently discovered as a target for heart failure, fostering the development of CathA inhibitors with SAR164653 as a frontrunner. The first‐in‐man study investigated single oral doses from 20 to 800 mg of SAR164653 followed by repeat dose studies at doses up to 800 mg in healthy young and elderly subjects. SAR164653 was safe and well tolerated at doses up to 800 mg in healthy subjects, and a maximum tolerated dose could not be determined from the study. Activity of ß‐galactosidase measured in leukocytes did not show any abnormalities. The tmax was 1.0 to 2.5 hours, and the t1/2 was ∼5–11 after single dosing; exposure increased less than dose proportional. Following multiple dosing, accumulation was not observed, Cmax and AUC0–24 increased in a dose‐proportional manner, and t1/2 was around 14–20 hours. The novel CathA inhibitor SAR164653 was found to have a favorable safety profile in these early phase 1 studies, but further studies are required to confirm if SAR164653 is equally safe in patients undergoing long‐term treatment.
Promoting Long-Term Health among People with Spinal Cord Injury: What’s New?

A key ingredient to successful health promotion is a primary care provider who can offer an informed first response to lifestyle issues, emerging problems and chronic challenges. This article aims to assist family physicians to play their role in promoting the health of people with SCI, by summarizing the latest evidence in the management of spinal cord injury in primary care. This study used a scoping review methodology to survey peer-reviewed journal articles and clinical guidelines published between January 2012 to June 2016. This search strategy identified 153 articles across 20 topics. A prevention framework is used to identify five primary, nine secondary, four tertiary, and two quaternary prevention issues about which family physicians require current information. Major changes in the management of SCI in primary care were noted for 8 of the 20 topics, specifically in the areas of pharmacological management of neuropathic pain and urinary tract infection; screening for bowel and bladder cancer; improvements in wound care; and clarification of dietary fibre recommendations. All of these changes are represented in the 3rd edition of Actionable Nuggets—an innovative tool to assist family physicians to be aware of the best practices in primary care for spinal cord injury.
Dynamic Modeling and Control of DFIG-Based Wind Turbines Under Unbalanced Network Conditions

This paper presents an analysis and control design of a doubly-fed induction generator (DFIG)-based wind generation system operating under unbalanced network conditions. A DFIG system model in the positive and negative synchronous reference frames is presented. Variations of stator active and reactive powers and generator torque are fully defined in the presence of negative sequence voltage and current. Alternative DFIG control targets during network unbalance, such as reducing stator current unbalance, torque, and power pulsations minimization, are identified. A rotor current control strategy based on positive and negative (dq) reference frames is used to provide precise control of the rotor positive and negative sequence currents. Simulation results using EMTDC/PSCAD are presented for a 2-MW DFIG wind generation system. It shows that conventional vector control of DFIG without considering network unbalance results in excessive oscillations on the stator active/reactive power, electromagnetic torque, and stator/rotor currents even with a small stator voltage unbalance. In contrast, with the proposed control strategy, enhanced system control and operation such as minimizing oscillations in either active power, or electromagnetic torque, or stator or rotor currents can be achieved
Fibroblast Growth Factor-based Signaling through Synthetic Heparan Sulfate Blocks Copolymers Studied Using High Cell Density Three-dimensional Cell Printing*

Background: Fibroblast growth factor-receptor-heparan sulfate (FGF-HS-FGFR) signals cell proliferation. Results: HS synthesized with sulfated domains at its non-reducing ends actively promotes cellular proliferation in a three-dimensional cell microarray. Conclusion: A symmetric 2:2:2 FGF-HS-FGFR complex is preferred over an asymmetric 2:1:2 model by these data. Significance: This paper suggests a preference for symmetry in the signal transduction complex having two FGF-FGFR on the non-reducing end of two HS chains. Four well-defined heparan sulfate (HS) block copolymers containing S-domains (high sulfo group content) placed adjacent to N-domains (low sulfo group content) were chemoenzymatically synthesized and characterized. The domain lengths in these HS block co-polymers were ∼40 saccharide units. Microtiter 96-well and three-dimensional cell-based microarray assays utilizing murine immortalized bone marrow (BaF3) cells were developed to evaluate the activity of these HS block co-polymers. Each recombinant BaF3 cell line expresses only a single type of fibroblast growth factor receptor (FGFR) but produces neither HS nor fibroblast growth factors (FGFs). In the presence of different FGFs, BaF3 cell proliferation showed clear differences for the four HS block co-polymers examined. These data were used to examine the two proposed signaling models, the symmetric FGF2-HS2-FGFR2 ternary complex model and the asymmetric FGF2-HS1-FGFR2 ternary complex model. In the symmetric FGF2-HS2-FGFR2 model, two acidic HS chains bind in a basic canyon located on the top face of the FGF2-FGFR2 protein complex. In this model the S-domains at the non-reducing ends of the two HS proteoglycan chains are proposed to interact with the FGF2-FGFR2 protein complex. In contrast, in the asymmetric FGF2-HS1-FGFR2 model, a single HS chain interacts with the FGF2-FGFR2 protein complex through a single S-domain that can be located at any position within an HS chain. Our data comparing a series of synthetically prepared HS block copolymers support a preference for the symmetric FGF2-HS2-FGFR2 ternary complex model.
Event‐related activity and phase locking during a psychomotor vigilance task over the course of sleep deprivation

There is profound knowledge that sleep restriction increases tonic (event‐unrelated) electroencephalographic (EEG) activity. In the present study we focused on time‐locked activity by means of phasic (event‐related) EEG analysis during a psychomotor vigilance task (PVT) over the course of sleep deprivation. Twenty healthy subjects (10 male; mean age ± SD: 23.45 ± 1.97 years) underwent sleep deprivation for 24 h. Subjects had to rate their sleepiness hourly (Karolinska Sleepiness Scale) and to perform a PVT while EEG was recorded simultaneously. Tonic EEG changes in the δ (1–4 Hz), θ (4–8 Hz) and α (8–12 Hz) frequency range were investigated by power spectral analyses. Single‐trial (phase‐locking index, PLI) and event‐related potential (ERP) analyses (P1, N1) were used to examine event‐related changes in EEG activity. Subjective sleepiness, PVT reaction times and tonic EEG activity (delta and theta spectral power) significantly increased over the night. In contrast, event‐related EEG parameters decreased throughout sleep deprivation. Specifically, the ERP component P1 diminished in amplitude, and delta and theta PLI estimates decreased progressively over the night. It is suggested that event‐related EEG measures (such as the amplitude of the P1 and especially delta/theta phase‐locking) serve as a complimentary method to track the deterioration of attention and performance during sleep loss. As these measures actually reflect the impaired response to specific events rather than tonic changes during sleep deprivation they are a promising tool for future sleep research.
Gli indicatori economici, ambientali e sociali nei rendiconti di sostenibilità delle società quotate alla Borsa italiana

Our paper aims to achieve two main objectives. First of all, in order to identify the most accounted economic, environmental and social indicators, we used the content analysis to examine the GRI-based sustainability report issued by companies listed on the Italian Stock Exchange. Secondly, we aimed to verify the extent some variables related to profitability, size and sector can explain the behavior of companies according to the number and type of indicators presented, as well as how it usually takes place. Moreover our research was motivated by the fact that in literature there are very few studies that have analyzed the adoption of GRI indicators in the sustainability reports. Unlike others, this study outlines, through the regression trees technique, what characteristics diversify companies in the use of GRI indicators. The results show the widespread use of those indicators, with relevant levels of disclosure. The most used category of indicators is the one related to the Working Practices, followed by Economic and Environmental ones. Finally, we can say that the ROE and the business sector of the companies played a significant role considering their classification related to the different number and type of accounted indicators
Clopidogrel Has No Clinically Meaningful Effect on the Pharmacokinetics of the Organic Anion Transporting Polypeptide 1B1 and Cytochrome P450 3A4 Substrate Simvastatin

Simvastatin and clopidogrel are commonly used together in the treatment of cardiovascular diseases. Organic anion transporting polypeptide (OATP) 1B1 activity markedly affects the hepatic uptake of simvastatin acid, whereas both simvastatin and simvastatin acid are sensitive to changes in cytochrome P450 3A4 activity. Clopidogrel and its metabolites inhibit OATP1B1 and CYP3A4 in vitro. We studied the effect of clopidogrel on the pharmacokinetics of simvastatin in a randomized crossover study. Twelve healthy volunteers ingested either a dose of placebo (control) or 300 mg of clopidogrel on day 1 and 75 mg on days 2 and 3. Simvastatin 40 mg was administered 1 hour after placebo and after clopidogrel on days 1 and 3. Plasma drug concentrations were measured for up to 12 hours. Clopidogrel 300 mg (day 1) increased the concentrations of simvastatin and simvastatin acid during the absorption phase. After clopidogrel 300 mg, the area under the concentration time curve (AUC) of simvastatin from 0 to 2 hours was 156% (P = 0.02) and its AUC0–12 hours was 132% (P = 0.08) of that during placebo, whereas the AUC0–2 hours and the AUC0–12 hours of simvastatin acid were 148% (P = 0.04) and 112% (P = 0.52) of control. Clopidogrel 75 mg (day 3) had no significant effect on the pharmacokinetic variables of simvastatin or simvastatin acid compared with placebo. The effect of clopidogrel seemed independent of the SLCO1B1 c.521T>C genotype. In conclusion, as clopidogrel did not have significant effects on the total exposure to simvastatin or simvastatin acid, clopidogrel does not seem to inhibit OATP1B1 or CYP3A4 to a clinically relevant extent.
The Production of Curli Amyloid Fibers Is Deeply Integrated into the Biology of Escherichia coli

Curli amyloid fibers are the major protein component of the extracellular matrix produced by Enterobacteriaceae during biofilm formation. Curli are required for proper biofilm development and environmental persistence by Escherichia coli. Here, we present a complete and vetted genetic analysis of functional amyloid fiber biogenesis. The Keio collection of single gene deletions was screened on Congo red indicator plates to identify E. coli mutants that had defective amyloid production. We discovered that more than three hundred gene products modulated curli production. These genes were involved in fundamental cellular processes such as regulation, environmental sensing, respiration, metabolism, cell envelope biogenesis, transport, and protein turnover. The alternative sigma factors, σS and σE, had opposing roles in curli production. Mutations that induced the σE or Cpx stress response systems had reduced curli production, while mutant strains with increased σS levels had increased curli production. Mutations in metabolic pathways, including gluconeogenesis and the biosynthesis of lipopolysaccharide (LPS), produced less curli. Regulation of the master biofilm regulator, CsgD, was diverse, and the screen revealed several proteins and small RNAs (sRNA) that regulate csgD messenger RNA (mRNA) levels. Using previously published studies, we found minimal overlap between the genes affecting curli biogenesis and genes known to impact swimming or swarming motility, underlying the distinction between motile and sessile lifestyles. Collectively, the diversity and number of elements required suggest curli production is part of a highly regulated and complex developmental pathway in E. coli.
Crecimiento económico y ecoinnovación en la Unión Europea

espanolEl objetivo del texto es mostrar la relacion entre ecoinnovacion y crecimiento economico para los paises de la Union Europea. Para ello, analizamos estudios teoricos sobre innovacion (y ecoinnovacion) y el crecimiento economico, para posteriormente hacer una revision de las politicas de la Union Europea en relacion a la ecoinnovacion. Nuestros resultados muestran que la ecoinnovacion tiene un impacto positivo sobre el crecimiento economico en la Union Europea en el periodo 2002-2010, debido a que el gasto en inversion en el medio ambiente de los gobiernos, los ingresos fiscales ambientales y las exportaciones de productos de ecoindustrias tienen un impacto positivo con el crecimiento economico. Nuestra conclusion es que las politicas publicas que incentivan la ecoinnovacion podrian tener un impacto positivo en el crecimiento economico EnglishThe aim of the paper is to show the relationship between ecoinnovation and economic growth for the countries of the European Union. For that, we analyze theoretical studies on innovation (and ecoinnovation) and economic growth, later we review the European Union ecoinnovation policies. Our results show that ecoinnovation has a positive impact on economic growth in the European Union in the period 2002-2010, due to investment in the environment (of governments), environmental tax revenues and ecoproducts exports have a positive impact on economic growth. Our conclusion is that public policies that encourage ecoinnovation could have a positive impact on economic growth.
Gender Differences in Pain and Cardiovascular Responses to Forearm Ischemia

ObjectiveTo examine gender-related differences in pain and cardiovascular responses to forearm ischemia. DesignForearm ischemia was produced by the submaximal effort tourniquet procedure. Participants performed 2 min of dynamic hand exercise at 30% maximum grip strength. Forearm ischemia was maintained until the report of ischemic pain tolerance or until 20 min elapsed. Arterial blood pressure, heart rate, and verbal reports of ischemic pain were assessed at 2 min intervals. SubjectsThirty four male and 33 female participants of similar age. ResultsThe times to ischemic pain onset and ischemic pain tolerance were similar for both male and female participants. However, during the ischemic period, females reported ischemic pain to be more intense and of greater unpleasantness than male participants. The relative changes in arterial blood pressure and heart rate during the exercise and occlusion period were equivalent for both male and female participants. In contrast, arterial blood pressure responses during the postexercise ischemic period were gender-dependent. Arm ischemia evoked pressor responses in male participants and either a decrease or no change in arterial pressure in female participants. Changes in arterial pressure during the postexercise ischemic period were significantly and positively correlated with verbal measures of ischemic pain for male subjects but not for female subjects. ConclusionsThe data demonstrated that gender influences both the sensory and the cardiovascular responses to a tonic noxious stressor.
Ultrasonographic-Guided Ilioinguinal/Iliohypogastric Nerve Block in Pediatric Anesthesia: What is the Optimal Volume?

Recently, our study group demonstrated the usefulness of ultrasonographic guidance in ilioinguinal/iliohypogastric nerve blocks in children. As a consequence, we designed a follow-up study to evaluate the optimal volume of local anesthetic for this regional anesthetic technique. Using a modified step-up-step-down approach, with 10 children in each study group, a starting dose of 0.2 mL/kg of 0.25% levobupivacaine was administered to perform an ilioinguinal/iliohypogastric nerve block under ultrasonographic guidance. After each group of 10 patients, the results were analyzed, and if all blocks were successful, the volume of local anesthetic was decreased by 50%, and a further 10 patients were enrolled into the study. Failure to achieve a 100% success rate within a group subjected patients to an automatic increase of half the previous volume reduction to be used in the subsequent group. Using 0.2 and 0.1 mL/kg of 0.25% levobupivacaine, the success rate was 100%. With a volume of 0.05 mL/kg of 0.25% levobupivacaine, 4 of 10 children received additional analgesia because of an inadequate block. Therefore, according to the protocol, the amount was increased to 0.075 mL/kg of 0.25% levobupivacaine, where the success rate was again 100%. We conclude that ultrasonographic guidance for ilioinguinal/iliohypogastric nerve blocks in children allowed a reduction of the volume of local anesthetic to 0.075 mL/kg.
Targeting the mineralocorticoid receptor in cardiovascular disease

Introduction: Over the last two decades, the known functions of the mineralocorticoid receptor (MR) have expanded beyond regulation of sodium and potassium in epithelial cells to encompass physiological and pathophysiological effects in many tissues throughout the body. It is now well accepted that the MR plays a critical role in many aspects of cardiovascular disease. Areas covered: Recent studies employing tissue-selective MR null mice have added valuable insights into the cellular mechanisms that translate MR activation into cardiac remodeling and dysfunction. Together with earlier pharmacological studies using MR antagonists the apparent protective effects of tissue-selective MR deletion support the observed clinical benefits of MR antagonists in heart failure. Given the potential risk of side effects of current therapies, a key goal is the identification of tissue-selective MR antagonists that will provide cardiovascular protection, but spare renal function. As such, the specific cellular mechanisms regulated by MR located in the cardiovascular system may provide the basis for the development of targeted therapies. Expert opinion: This review will address the function of the MR, and its regulation of the cellular mechanisms that determine cell-specific MR signaling in cardiovascular disease and briefly discuss the potential for novel therapeutic targets that will allow for cardiac selective MR blockade.
Effect of nicotine on dynamic function of brain catecholamine neurons.

Burst firing in the mesolimbocortical dopamine (DA) neurons, originating in the ventral tegmental area (VTA), is facilitated by systemic administration of nicotine. Pharmacological results show that bursting in VTA-DA cells is critically dependent on a tonic, excitatory amino acid drive, probably originating from the medial prefrontal cortex. Cold inactivation of the prefrontal cortex caused pacemaker-like firing of VTA-DA cells, an effect partly antagonized by systemic nicotine. Clinically, hypofrontality has been associated with negative symptoms in chronic schizophrenia and with chronic alcoholism. Thus, smoking may provide a means to partially restore the dynamics of the VTA-DA system in such disorders. Intravenous nicotine also induces a selective activation of bursting in noradrenaline neurons of the pontine nucleus locus ceruleus. Pharmacological and physiological experiments clearly suggest that this effect is indirect, e.g. peripherally elicited and relayed to the locus ceruleus through its excitatory amino acid input from the paragigantocellular nucleus. The locus ceruleus activation is rapid in onset, dose dependent, short lasting and can be repeated within minutes. This effect of nicotine, which would imply an instant coping response, may be relevant to nicotine dependence, particularly in depressive states.