Miracle-dz/UniFAR-FTUs huggingface dataset:
Aflibercept: A review of its effect on the treatment of exudative age-related macular degeneration

Considerable improvement has been achieved in the way in which exudative age-related macular degeneration is conventionally treated and in the associated visual outcomes and prognosis, thanks to the agents with effects against vascular endothelial growth factor (anti-VEGF). By comparison to earlier treatment approaches that involved the use of lasers, the anti-VEGF agents have made it possible to accomplish more positive visual and anatomical outcomes in cases of exudative age-related macular degeneration. Indeed, owing to their positive effects, anti-VEGF agents have quickly come to be considered the gold standard for the treatment of wet age-related macular degeneration. Aflibercept, the most recently approved intravitreally administered anti-VEGF, seems to mark another milestone in the treatment of wet age-related macular degeneration. This anti-VEGF agent presents a series of singular pharmacodynamic and pharmacokinetic attributes that provide it a number of biological benefits in relation to the treatment of choroidal neovascularization compared to other agents. These attributes include high level of affinity for the VEGF-A factor, an intravitreal half-life of great length, as well as the ability to serve as an antagonist for other growth factors besides VEGF. The impact of Aflibercept on the manner in which exudative age-related macular degeneration is managed was demonstrated by thoroughly reviewing the related literature. The present review article highlights the pharmacology, pharmacokinetics, safety and effectiveness of this anti-VEGF agent as well as the landmark clinical studies that have been carried out to establish this drug as a gold standard in the therapy of neovascular age-related macular degeneration. In addition, studies regarding the outcomes and effectiveness of the various dosage regimens, either as monotherapy or in combination with other agents, are also reviewed.
Clinical Use of Epidermal Growth Factor Receptor Testing in Patients With Advanced Lung Cancer by Physicians: Survey of US and International Patterns

PURPOSE Guidelines recommend testing for EGFR mutation at diagnosis of advanced non–small-cell lung cancer to guide treatment. Two surveys, 18 months apart, aimed to identify changes in EGFR mutation testing and treatment practices in non–small-cell lung cancer. METHODS The first survey of 562 physicians from Canada, France, Germany, Italy, Japan, South Korea, Spain, Taiwan, the United Kingdom, and the United States was conducted between December 2014 and January 2015. The second, between July and August 2016, surveyed 707 physicians in the same countries with the addition of China; China was excluded from year-on-year comparisons. RESULTS Globally (excluding China), physicians requested EGFR mutation testing in 80% (excluding China; 2015: 81%) of patients before first-line therapy. In 2016, 18% of results were not received before initiating treatment, a significant improvement over 2015 (23%). Reasons for not testing included tumor histology, insufficient tissue, poor performance status, and long turnaround time, although this had significantly improved in 2016 from 2015. Prolonging of survival/extending life was deemed the most important therapy goal in first-line treatment of both cohorts. CONCLUSION Improvements in availability of test results before first-line therapy were seen, but incomplete implementation of guidelines is still observed, resulting in a large proportion of patients not receiving tyrosine kinase inhibitor treatment on the basis of mutation status. The reasons for not testing remained the same, year-on-year: tumor histology, insufficient tissue, poor performance status, and long test turnaround time. Receiving timely results must be addressed, if treatment parity for eligible patients can be achieved. Physician education and closer guideline concordance are key steps to improve outcomes.
Long-term functioning outcomes are predicted by cognitive symptoms in working patients with major depressive disorder treated with vortioxetine: results from the AtWoRC study

Objective AtWoRC (Assessment in Work productivity and the Relationship with Cognitive symptoms) was an interventional, open-label, Canadian study (NCT02332954) designed to assess the association between cognitive symptoms and workplace productivity in working patients with major depressive disorder (MDD) receiving vortioxetine. Methods Eligible patients with MDD received vortioxetine (10–20 mg/day) and were assessed over 52 weeks at visits emulating a real-life setting (n = 199). Partial correlation between changes in patient-reported cognitive symptoms (20-item Perceived Deficits Questionnaire–Depression; PDQ-D-20) and workplace productivity (Work Limitations Questionnaire; WLQ) was assessed at 12 and 52 weeks. Additional assessments included depression severity, cognitive performance, and patient-reported functioning. Structural equations model (SEM) analyses assessed causal relationships between changes in measures of cognition and functioning over time, adjusted for improvements in depressive symptoms. Results Statistically significant improvements in all outcomes from baseline to week 52 were seen in the overall population and both subgroups (first treatment and switch). Response and remission rates were 77% and 56%, respectively. Improvements in PDQ-D-20 and WLQ productivity loss scores at weeks 12 and 52 were significantly correlated. SEM analyses found patient-rated cognitive symptoms (PDQ-D-20) at weeks 12 and 26 were significantly predictive (p < 0.05) of patient-reported functioning (Sheehan Disability Scale) at the subsequent visit. Depression severity and objectively measured cognitive performance did not significantly predict functional outcomes at any timepoint. Conclusion These results demonstrate the long-term benefits of vortioxetine treatment in working patients with MDD and emphasize the strong association between cognitive symptoms and functioning in a real-world setting.
Transient Liquid Phase Bonding of Ti-6Al-4V and Mg-AZ31 Alloys Using Zn Coatings

Ti-6Al-4V and Mg-AZ31 were bonded together using the Transient Liquid Phase Bonding Process (TLP) after coating both surfaces with zinc. The zinc coatings were applied using the screen printing process of zinc paste. Successful bonds were obtained in a vacuum furnace at 500 °C and under a uniaxial pressure of 1 MPa using high frequency induction heat sintering furnace (HFIHS). Various bonding times were selected and all gave solid joints. The bonds were successfully achieved at 5, 10, 15, 20, 25, and 30 min. The energy dispersive spectroscopy (EDS) line scan confirmed the diffusion of Zn in both sides but with more diffusion in the Mg side. Diffusion of Mg into the joint region was detected with significant amounts at bonds made for 20 min and above, which indicate that the isothermal solidification was achieved. In addition, Ti and Al from the base alloys were diffused into the joint region. Based on microstructural analysis, the joint mechanism was attributed to the formation of solidified mixture of Mg and Zn at the joint region with a presence of diffused Ti and Al. This conclusion was also supported by structural analysis of the fractured surfaces as well as the analysis across the joint region. The fractured surfaces were analyzed and it was concluded that the fractures occurred within the joint region where ductile fractures were observed. The strength of the joint was evaluated by shear test and found that the maximum shear strength achieved was 30.5 MPa for the bond made at 20 min.
Dapsone intoxication: clinical course and characteristics

Background and objectives. Dapsone is used as an antibiotic for leprosy and for dermatological disorders and may cause methemoglobinemia. The aims of this study are to analyze the clinical characteristics of patients presenting to the emergency department (ED) with dapsone ingestion to identify risk factors associated with mortality. Methods. We conducted a retrospective observational study of adult ED patients with methemoglobinemia because of dapsone intoxication admitted to a tertiary care hospital from September 2003 to December 2008. Data collected included demographic, clinical, and laboratory characteristics, as well as survival to discharge. Characteristics of young (less than or equal to 55 years) and older (greater than age 55) patients were compared. The main outcome was in-hospital mortality. Results. There were 46 patients included in the study. The minimum intoxication dose was two 100 mg tablets and the maximum was 100 tablets. Changes in mental status were more common in the older patients. Methemoglobin levels were slightly higher in the younger patients, but both groups were treated with similar doses of methylene blue. Shock and death were more common in the older patients. Conclusions. Late presentation to medical care and an altered mental status at the time of presentation were predictive of death after dapsone intoxication. Methemoglobin levels tended to be higher in those who died.
Physiological Gain Leads to High ISI Variability in a Simple Model of a Cortical Regular Spiking Cell

To understand the interspike interval (ISI) variability displayed by visual cortical neurons (Softky & Koch, 1993), it is critical to examine the dynamics of their neuronal integration, as well as the variability in their synaptic input current. Most previous models have focused on the latter factor. We match a simple integrate-and-fire model to the experimentally measured integrative properties of cortical regular spiking cells (McCormick, Connors, Lighthall, & Prince, 1985). After setting RC parameters, the postspike voltage reset is set to match experimental measurements of neuronal gain (obtained from in vitro plots of firing frequency versus injected current). Examination of the resulting model leads to an intuitive picture of neuronal integration that unifies the seemingly contradictory and random walk pictures that have previously been proposed. When ISIs are dominated by postspike recovery, arguments hold and spiking is regular; after the memory of the last spike becomes negligible, spike threshold crossing is caused by input variance around a steady state and spiking is Poisson. In integrate-and-fire neurons matched to cortical cell physiology, steady-state behavior is predominant, and ISIs are highly variable at all physiological firing rates and for a wide range of inhibitory and excitatory inputs.
Reduced phosphodiesterase-2 activity in the amygdala results in anxiolytic-like effects on behavior in mice

Background: Phosphodiesterase-2 (PDE2) is a cyclic nucleotide phosphodiesterase and is highly expressed in the amygdala, which suggests its important role in anxiety-like behavior. Aims: The present study examined whether reduced PDE2A expression in the central nucleus of the amygdala (CeA) produces anxiolytic-like effects in mice. Methods: PDE2A knockdown in amygdaloid (AR5) cells or the CeA was established using a lentiviral vector-based siRNA system. The anxiety-like behaviors were detected by the elevated plus maze (EPM) and hole-board tests in mice. The related proteins involved in cAMP/cGMP-dependent signaling, such as specific marker VASPser239, CREBser133 and BDNF were detected by immunoblot analysis. Results: PDE2A inhibition in AR-5 cells resulted in increases in cAMP/cGMP-related pVASPser239 and pCREBser133. Behavioral tests showed that PDE2A knockdown in the CeA induced anxiolytic-like effects as evidenced by the increases in percentages of open-arm entries and time spent in the open arms in the EPM test, and the increases in head dips and time spent in head dipping in the hole-board test. However, these anxiolytic-like effects were antagonized by pre-treatment of soluble guanylyl cyclase inhibitor ODQ or adenylate cyclase inhibitor SQ. Furthermore, PDE2A knockdown significantly increased pVASPSer239, pCREBSer133 and decreased BDNF expression in the amygdala. Pre-intra-CeA of ODQ or SQ reversed or partially prevented the eﬀects of PDE2A knockdown on these proteins. Conclusions: The results suggest that PDE2A plays a crucial role in the regulation of anxiety by the cGMP/cAMP-dependent pVASP-pCREB-BDNF signaling pathway.
Opioid prescribing habits differ between Denmark, Sweden and Norway – and they change over time

Abstract Background and aims The medical use of opioids in different countries is often subject to public concern and debate, frequently based on rough figures from prescription databases made for registration of consumption. However, public access to some of these databases allow for further exploration of the prescription data, which can be processed to increase knowledge and insight into national opioid prescribing-behavior. Denmark, Sweden and Norway are considered closely related with regard to health care and culture. So, this study aims to provide a more detailed picture of opioid prescribing and its changes in the three Scandinavian countries during 2006–2014, using public assessable prescription data. Methods Data on dispensed opioid prescriptions (ATC; N02A, and R05DA04) were downloaded from each country’s prescription-databases. The amounts of dispensed opioids were used as proxy for consumption or use of opioids. Potential differences between dispensed prescriptions and actual use cannot be drawn from these databases. Consumption-data were converted from defined daily doses (DDDs) to mg oral morphine equivalents (omeqs). Changes in the choice of opioid-types, consumption and number of users were presented using descriptive statistics and compared. Results Opioid users: during the whole period, Norway had the highest, and Denmark the lowest, number of opioid users/1,000 inhabitants. From 2006 to 2014 the numbers of users/1,000 inhabitants changed from 98 to 105 in Norway, from 66 to 75 in Denmark, and from 79 to 78 in Sweden. Opioid consumption/1,000 inhabitants: The results depended much on the unit of measurement. The differences between the countries in consumption/1,000 inhabitants were small when DDDs was used as unit, while using mg omeqs significant differences between the countries appeared. Denmark had a much higher consumption of omeqs per 1,000 inhabitants compared to Sweden and Norway. Opioid consumption/user: during the whole period, Norway had the lowest, and Denmark the highest consumption/user. In 2006, the annual average consumption/user was 1979, 3615, 6025 mg omeq/user in Norway, Sweden and Denmark, respectively. In 2014 the corresponding consumption was 2426, 3473, 6361 mg omeq/user. The preferred choices of opioid-types changed during the period in all three countries. The balance between use of weak or strong opioids showed more prominent changes in Norway and Sweden compared to Denmark. Conclusions This study has shown how public assessable opioid prescription data can provide insight in the doctors’ prescribing behavior, and how it might change over time. The amounts of dispensed opioids, opioid prescribing habits and changes were compared between the countries, and significant differences appeared. Within each country, the overall picture of opioid consumption appeared rather stable. Implications Studies like this can contribute to qualify the ongoing debates of use of opioids in different nations and to monitor effects of initiatives taken by health-care authorities and health-care policy-makers.
Tcf1 and Lef1 are required for the immunosuppressive function of regulatory T cells

Tcf1 and Lef1 have versatile functions in regulating T cell development and differentiation, but intrinsic requirements for these factors in regulatory T (T reg) cells remain to be unequivocally defined. Specific ablation of Tcf1 and Lef1 in T reg cells resulted in spontaneous multi-organ autoimmunity that became more evident with age. Tcf1/Lef1-deficient T regs showed reduced protection against experimentally induced colitis, indicative of diminished immuno-suppressive capacity. Transcriptomic analysis revealed that Tcf1 and Lef1 were responsible for positive regulation of a subset of T reg–overrepresented signature genes such as Ikzf4 and Izumo1r. Unexpectedly, Tcf1 and Lef1 were necessary for restraining expression of cytotoxic CD8+ effector T cell–associated genes in T reg cells, including Prdm1 and Ifng. Tcf1 ChIP-seq revealed substantial overlap between Tcf1 and Foxp3 binding peaks in the T reg cell genome, with Tcf1-Foxp3 cooccupancy observed at key T reg signature and cytotoxic effector genes. Our data collectively indicate that Tcf1 and Lef1 are critical for sustaining T reg suppressive functions and preventing loss of self-tolerance.
Transcranial alternating current stimulation entrains single-neuron activity in the primate brain

Significance Neurostimulation is a common therapy for a variety of neurological disorders, but the most effective stimulation approaches are often highly invasive, requiring electrodes to be implanted deep within brain structures like the hippocampus and basal ganglia. Here, we show that transcranial electrical stimulation (tES), a neuromodulatory technique that uses electrodes placed outside the scalp, can also affect patterns of neural activity in these areas. We find that tES can reliably control the timing, but not the rate, of spikes in individual neurons. Because changes in spike timing are thought to play a key role in many brain functions, the data shown here suggest that tES may be a valuable tool for clinical and fundamental studies of the human brain. Spike timing is thought to play a critical role in neural computation and communication. Methods for adjusting spike timing are therefore of great interest to researchers and clinicians alike. Transcranial electrical stimulation (tES) is a noninvasive technique that uses weak electric fields to manipulate brain activity. Early results have suggested that this technique can improve subjects’ behavioral performance on a wide range of tasks and ameliorate some clinical conditions. Nevertheless, considerable skepticism remains about its efficacy, especially because the electric fields reaching the brain during tES are small, whereas the likelihood of indirect effects is large. Our understanding of its effects in humans is largely based on extrapolations from simple model systems and indirect measures of neural activity. As a result, fundamental questions remain about whether and how tES can influence neuronal activity in the human brain. Here, we demonstrate that tES, as typically applied to humans, affects the firing patterns of individual neurons in alert nonhuman primates, which are the best available animal model for the human brain. Specifically, tES consistently influences the timing, but not the rate, of spiking activity within the targeted brain region. Such effects are frequency- and location-specific and can reach deep brain structures; control experiments show that they cannot be explained by sensory stimulation or other indirect influences. These data thus provide a strong mechanistic rationale for the use of tES in humans and will help guide the development of future tES applications.
Survival of periviable infants: 5-year experience at a single center

Abstract Objectives: The primary aim of the present study was to investigate the survival rates of periviable births in a referral Level III NICU center in Turkey; the secondary aim was to determine the perinatal and natal risk factors related to mortality. Methods: This retrospective cross-sectional study was conducted at the Neonatal Intensive Care Unit between 1 January 2011 and 31 December 2015. All live deliveries occurring from 22 0/7 weeks to 25 6/7 week of gestation were included in the study (total n = 165). We documented prenatal, natal, and postnatal clinical processes in each case and assessed morbidity, mortality, and factors related to long-term prognosis. Results: While none of the infants born at 22 weeks of gestation survived until discharge, the survival rates for those admitted to the NICU were 7.5% for infants born at 23 weeks, 29.1% at 24 weeks, and 43.5% at 25 weeks. A total of 46 survived (27.9%), and follow-up data beyond 12 months were available for 22. The prevalence of neurodevelopmental impairment or neurosensory impairment was inversely associated with gestational age. Conclusions: The most important risk factors associated with mortality in periviable infants were SNAPPE score, antenatal corticosteroid use, and gestational age.
Feasibility and Initial Results: Fluciclovine Positron Emission Tomography/Ultrasound Fusion Targeted Biopsy of Recurrent Prostate Cancer.

PURPOSE We assessed the feasibility and cancer detection rate of fluciclovine (18F) positron emission tomography-ultrasound fusion targeted biopsy vs standard template biopsy in the same patient with biochemical failure after nonsurgical therapy for prostate cancer. MATERIALS AND METHODS A total of 21 patients with a mean ± SD prostate specific antigen of 7.4 ± 6.8 ng/ml and biochemical failure after nonoperative prostate cancer treatment underwent fluciclovine (18F) positron emission tomography-computerized tomography (mean 364.1 ± 37.7 MBq) and planning transrectal prostate ultrasound with 3-dimensional image reconstruction. Focal prostatic activity on positron emission tomography was delineated and co-registered with planning ultrasound. During the subsequent biopsy session computer generated 12-core template biopsies were performed and then fluciclovine defined targets were revealed and biopsied. Histological analysis of template and targeted cores were completed. RESULTS Template biopsy was positive for malignancy in 6 of 21 patients (28.6%), including 10 of 124 regions and 11 of 246 cores, vs targeted biopsy in 10 or 21 (47.6%), including 17 of 50 regions and 40 of 125 cores. Five of 21 patients had positive findings on targeted biopsy only and 1 of 21 had positive findings on template biopsy only. An additional case was upgraded from Grade Group 2 to 3 on targeted biopsy. Extraprostatic disease was detected in 8 of 21 men (38.1%) with histological confirmation in all 3 who underwent lesion biopsy. CONCLUSIONS Fluciclovine positron emission tomography real-time ultrasound fusion guidance for biopsy in patients with biochemical failure after no prostatectomy is feasible. It identifies more recurrent prostate cancer using fewer cores compared with template biopsy in the same patient. Further study is required to determine in what manner targeted biopsy may augment template biopsy of recurrent prostate cancer.
Characterization and Structure–Property Relationships of Organic–Inorganic Hybrid Composites Based on Aluminum–Magnesium Hydroxycarbonate and Azo Chromophore

In this study, novel organic–inorganic composites were prepared by the complexation of dicarboxylic azo dye (AD) with aluminum–magnesium hydroxycarbonate (AlMg–LH). This procedure provides an effective method for the stabilization of dicarboxylic organic chromophores on an AlMg−LH host. The structures of the hybrid composites were examined by X-ray diffraction (XRD), secondary ion mass spectrometry (TOF-SIMS), 27-Al solid-state nuclear magnetic resonance (NMR) spectroscopy, thermogravimetric analysis (TGA) and scanning transmission electron microscopy (STEM). The TOF-SIMS method was applied to investigate the metal–dye interactions and to monitor the thermal stability of the organic–inorganic complexes. Secondary ion mass spectrometry confirmed the presence of a characteristic peak for C18H10O5N2Mg22+, indicating that both carboxylic groups interacted with AlMg−LH by forming complexes with two Mg2+ ions. Modification with hybrid pigments affected the crystal structure of the AlMg−LH mineral, as shown by the appearance of new peaks on the X-ray diffraction patterns. Adsorption of the dicarboxylic chromophore not only led to significantly enhanced solvent resistance but also improved the thermal and photostability of the hybrid pigments. We propose a possible arrangement of the azo dye in the inorganic matrix, as well as the presumed mechanism of stabilization.