Miracle-dz/UniFAR-FTUs huggingface dataset:
Assessment of the Abuse Potential of Cebranopadol in Nondependent Recreational Opioid Users

Background Cebranopadol is a nociceptin/orphanin FQ peptide/opioid receptor agonist with central antinociceptive activity. We hypothesize that this novel mechanism of action may lead to a lower risk of abuse compared with pure &mgr;-opioid peptide receptor agonists. Methods We conducted a single-dose, nested-randomized, double-blind crossover study in nondependent recreational opioid users to evaluate the abuse potential of single doses of cebranopadol relative to hydromorphone immediate release and placebo. The study consisted of a qualification phase and a 7-period treatment phase (cebranopadol 200, 400, and 800 &mgr;g; hydromorphone 8 and 16 mg; and 2 placebos). The primary end point was the peak effect of drug liking at this moment, measured by visual analog scale (VAS). Various secondary end points (eg, VAS rating for good drug effects, high, bad drug effects, take drug again, drug similarity, and pupillometry) were also investigated. Results Forty-two subjects completed the study. Cebranopadol 200 and 400 &mgr;g did not differentiate from placebo on the abuse potential assessments and generated smaller responses than hydromorphone. Responses observed with cebranopadol 800 &mgr;g were similar to hydromorphone 8 mg and smaller than hydromorphone 16 mg. The maximum effect for VAS drug liking at this moment was delayed compared with hydromorphone (3 and 1.5 hours, respectively). Cebranopadol administration was safe; no serious adverse events or study discontinuation due to treatment-emergent adverse events occurred. Conclusions These results confirm our hypothesis that cebranopadol, a nociceptin/orphanin FQ peptide/opioid receptor agonist, has lower abuse potential than hydromorphone immediate release, a pure &mgr;-opioid peptide agonist.
Hemp (Cannabis sativa L.) Seed Phenylpropionamides Composition and Effects on Memory Dysfunction and Biomarkers of Neuroinflammation Induced by Lipopolysaccharide in Mice

Hempseed has achieved a growing popularity in human nutrition, particularly regarding essential amino acids and fatty acids. The multiple positive attributes of hempseed have led to the further study of its constituents. In this study, hempseed extract containing phenylpropionamides (TPA) was obtained and its chemical profile and content were obtained using high-performance liquid chromatography technology based on previous study. The anti-neuroinflammatory effect of TPA extract was evaluated using a lipopolysaccharide (LPS)-induced mouse model. Fourteen phenylpropionamides (TPA) were identified in the obtained extract with a total content of 233.52 ± 2.50 μg/mg extract. In mice, TPA prevented the learning and spatial memory damage induced by LPS. Increased brain levels of IL-1β, IL-6, and TNF-α in the LPS-induced mice were reduced by TPA treatment. Furthermore, TPA attenuated LPS-induced hippocampal neuronal damage in mice. This study demonstrates the nutraceutical potential of hempseed from a neuroprotective perspective.
Semantic Features Reveal Different Networks During Word Processing: An EEG Source Localization Study

The neural principles behind semantic category representation are still under debate. Dominant theories mostly focus on distinguishing concrete from abstract concepts but, in such theories, divisions into categories of concrete concepts are more developed than for their abstract counterparts. An encompassing theory on semantic category representation could be within reach when charting the semantic attributes that are capable of describing both concept types. A good candidate are the three semantic dimensions defined by Osgood (potency, valence, arousal). However, to show to what extent they affect semantic processing, specific neuroimaging tools are required. Electroencephalography (EEG) is on par with the temporal resolution of cognitive behavior and source reconstruction. Using high-density set-ups, it is able to yield a spatial resolution in the scale of millimeters, sufficient to identify anatomical brain parcellations that could differentially contribute to semantic category representation. Cognitive neuroscientists traditionally focus on scalp domain analysis and turn to source reconstruction when an effect in the scalp domain has been detected. Traditional methods will potentially miss out on the fine-grained effects of semantic features as they are possibly obscured by the mixing of source activity due to volume conduction. For this reason, we have developed a mass-univariate analysis in the source domain using a mixed linear effect model. Our analyses reveal distinct networks of sources for different semantic features that are active during different stages of lexico-semantic processing of single words. With our method we identified differences in the spatio-temporal activation patterns of abstract and concrete words, high and low potency words, high and low valence words, and high and low arousal words, and in this way shed light on how word categories are represented in the brain.
Systematic molecular analysis of hemophilia A patients from Colombia

Abstract Hemophilia A (HA) is an X-linked recessive disorder and the second most common coagulation disorder with an incidence of 1 in 5,000 live born males. Worldwide, there are 178,500 affected individuals, 60% with the severe form of the disease. Intron 22 and 1 inversions (Inv22 and Inv1) are the most frequent molecular alterations found in severe HA patients with a frequency of 45-50% and 0.5-5%, respectively. We have implemented a systematic cost-effective strategy for the identification of the molecular alteration in HA patients using Inverse shifting-PCR for Inv22 and Inv1, followed by the analysis of the F8 gene coding region by means of high resolution melting (HRM) PCR and Sanger sequencing in Inv22 and Inv1 negative patients. A total of 33 male HA patients and 6 women were analyzed. Inversion 22 was detected in 14/33 male patients (42.4%), 3/33 (9.1%) had Inv1, 3/33 (9.1%) had large structural variants, and 11/33 (33.3%) single nucleotide/ small frameshift variants. No genetic variant was found in 2/33 patients (6%). With this systematic approach we detected pathogenic variants in 31 out of 33 male affected individuals (94%) tested for the first time.in a cohort of patients from Colombia.
Lyme Neuroborreliosis: Clinical Outcomes, Controversy, Pathogenesis, and Polymicrobial Infections

Lyme borreliosis is the object of numerous misconceptions. In this review, we revisit the fundamental manifestations of neuroborreliosis (meningitis, cranial neuritis, and radiculoneuritis), as these have withstood the test of time. We also discuss other manifestations that are less frequent. Stroke, as a manifestation of Lyme neuroborreliosis, is considered in the context of other infections. The summary of the literature regarding clinical outcomes of neuroborreliosis leads to its controversies. We also include new information on pathogenesis and on the polymicrobial nature of tick‐borne diseases. In this way, we update the review that we wrote in this journal in 1995. ANN NEUROL 2019;85:21–31.
HER2-targeted therapy: an emerging strategy in advanced colorectal cancer

ABSTRACT Introduction: Colorectal cancer (CRC) is one of the most common malignant tumors; it is a focus of research globally, but the identification of clinically actionable oncogenic drivers remains elusive. Human epidermal growth factor receptor 2 (HER2) activation is present in approximately 5% of CRC and has acquired resistance to epidermal growth factor receptor (EGFR)-targeted therapy. Early clinical trials suggest an emerging role for personalized HER2-targeted therapy in a subset of metastatic CRC. Areas covered: This manuscript reviews the relevance of HER2 activation in CRC and its potential role as a target for therapy. A literature search was conducted in June 2018 of MEDLINE and EMBASE databases for published preclinical and clinical studies; abstracts of international cancer meetings (AACR, ASCO, and ESMO) were also reviewed. Expert opinion: HER2 is activated in a small but relevant proportion of CRC patients (particularly left-side, RAS wild-type, anti-EGFR resistant tumors). Dual HER2 blockade with monoclonal antibodies (mAbs) (trastuzumab and pertuzumab) or the combination of mAbs with tyrosine kinase inhibitors (trastuzumab and lapatinib) induces durable tumor responses in about one-third of HER2-positive CRC refractory to standard systemic therapy. Although immature, these results are remarkable and anticipate an expanding role for HER2 as a therapeutic target in CRC.
HO-1 is a favorable prognostic factor for HBV-HCC patients who underwent hepatectomy

Background More than 500,000 people suffered from hepatocelluar carcinoma (HCC) annually and the relative incidence to mortality rate indicates its unfavorable prognosis. Several studies have proved that heme-oxygenase-1 (HO-1) is indirectly engaged in the invasion and the metastasis of some types of malignancies, including breast cancer, prostate cancer, and lung cancer. The role of HO-1 in hepatitis B virus (HBV)-related HCC is still not clarified. Materials and methods The Western blot, doubling time, cell cycle analysis, migration assay, invasion assay, gene transfection, xenograft animal model, immunohistochemistry staining, and clinical validation study were applied in this study. Results HO-1 overexpression not only decreased the growth but also inhibited the migration and invasion in human HBV-HCC cells (Hep-3B vs PLC/PRF/5). The inhibitory effect on growth, migration, and invasion is further demonstrated by the overexpression of HO-1 in Hep-3B cell by transfection study. Furthermore, HO-1 decreasing the growth of HBV-HCC was confirmed in animal study. The clinical validation illustrated that higher HO1 expression was also associated with favorable disease-free survival of HBV-HCC patients who underwent hepatectomy. Conclusions We identified HO-1 as a favorable prognostic factor for HBV-HCC patients who underwent hepatectomy.
Delphinidin inhibits epidermal growth factor‐induced epithelial‐to‐mesenchymal transition in hepatocellular carcinoma cells

Epithelial‐to‐mesenchymal transition (EMT), important cellular process in metastasis of primary tumors, is characterized by loss of their cell polarity, disruption of cell‐cell adhesion, and gain certain properties of mesenchymal phenotype that enable migration and invasion. Delphinidin is a member of anthocyanidin belong to flavonoid groups, known as having pharmacological and physiological effects including anti‐tumorigenic, antioxidative, anti‐inflammatory, and antiangiogenic effects. However, the effects of delphinidin on EMT is rarely investigated. Epidermal growth factor (EGF) is known as a crucial inducer of EMT in various cancer including hepatocellular carcinoma (HCC). To determine whether delphinidin inhibits EGF‐induced EMT in HCC cells, antiproliferative effect of delphinidin on Huh7 and PLC/PRF/5 cells were measured by Cell Counting Kit‐8 assay. As a result, delphinidin inhibited cell proliferation in a dose‐dependent manner. Based on the result of proliferation, to measure the effects of delphinidin on EGF‐induced EMT, we designated a proper concentration of delphinidin, which is not affected to cell proliferation. We found that delphinidin inhibits morphological changes from epithelial to mesenchymal phenotype by EGF. Moreover, delphinidin increased the messenger RNA and protein expression of E‐cadherin and decreased those of Vimentin and Snail in EGF‐induced HCC cells. Also, delphinidin prevented motility and invasiveness of EGF‐induced HCC cells through suppressing activation of matrix metalloproteinase 2, EGF receptor (EGFR), AKT, and extracellular signal‐regulated kinase (ERK). Taken together, our findings demonstrate that delphinidin inhibits EGF‐induced EMT by inhibiting EGFR/AKT/ERK signaling pathway in HCC cells.
Detection of extracellular vesicles in the mouse vaginal fluid: Their delivery of sperm proteins that stimulate capacitation and modulate fertility

Extracellular vesicles (EVs) were isolated by ultracentrifugation of vaginal luminal fluid (VLF) from superovulated mice and identified for the first time using transmission electron microscopy. Characterized by size and biochemical markers (CD9 and HSC70), EVs were shown to be both microvesicular and exosomal and were dubbed as “Vaginosomes” (VGS). Vaginal cross‐sections were analyzed to visualize EVs in situ: EVs were present in the lumen and also embedded between squamous epithelial and keratinized cells, consistent with their endogenous origin. Western blots detected Plasma membrane Ca2+‐ATPase 1 (PMCA1) and tyrosine‐phosphorylated proteins in the VGS cargo and also in uterosomes. Flow cytometry revealed that following coincubation of caudal sperm and VLF for 30 min, the frequencies of cells with the highest Sperm adhesion molecule 1 (SPAM1), PMCA1/4, and PMCA1 levels increased 16.4‐, 8.2‐, and 27‐fold, respectively; compared with control coincubated in phosphate buffered saline (PBS). Under identical conditions, sperm tyrosine‐phosphorylated proteins were elevated ~3.3‐fold, after VLF coincubation. Progesterone‐induced acrosome reaction (AR) rates were significantly (p < 0.001) elevated in sperm coincubated with VGS for 10–30 min, compared with PBS. Sperm artificially deposited in the vaginas of superovulated females for these periods also showed significant (p < 0.01) increases in AR rates, compared with PBS. Thus in vitro and in vivo, sperm acquire from the vaginal environment factors that induce capacitation, explaining recent findings for their acrosomal status in the isthmus. Overall, VGS appear to deliver higher levels of proteins involved in preventing premature capacitation and AR than those promoting them. Our findings which have implications for humans open the possibility of new approaches to infertility treatment with exosome therapeutics.
Quantitative and Qualitative Assessment of the Posterior Medial Meniscus Anatomy: Defining Meniscal Ramp Lesions

Background: Meniscal ramp lesions have been defined as a tear of the peripheral attachment of the posterior horn of the medial meniscus (PHMM) at the meniscocapsular junction or an injury to the meniscotibial attachment. Precise anatomic descriptions of these structures are limited in the current literature. Purpose: To quantitatively and qualitatively describe the PHMM and posteromedial capsule anatomy pertaining to the location of a meniscal ramp lesion with reference to surgically relevant landmarks. Study Design: Descriptive laboratory study. Methods: Fourteen male nonpaired fresh-frozen cadavers were used. The locations of the posteromedial meniscocapsular and meniscotibial attachments were identified. Measurements to surgically relevant landmarks were performed with a coordinate measuring system. To further analyze the posteromedial meniscocapsular and meniscotibial attachments, hematoxylin and eosin and alcian blue staining were conducted on a separate sample of 10 nonpaired specimens. Results: The posterior meniscocapsular attachment had a mean ± SD length of 20.2 ± 6.0 mm and attached posteroinferiorly to the PHMM at a mean depth of 36.4% of the total posterior meniscal height. The posterior meniscotibial ligament attached on the PHMM 16.5 mm posterior and 7.7 mm medial to the center of the posterior medial meniscal root attachment. The meniscotibial ligament tibial attachment was 5.9 ± 1.3 mm inferior to the articular cartilage margin of the posterior medial tibial plateau. The posterior meniscocapsular attachment converged with the meniscotibial ligament at the most posterior point of the meniscocapsular junction in all specimens. Histological staining of the meniscocapsular and meniscotibial ligament PHMM attachments showed similar structure, cell density, and fiber directionality, with no qualitative difference in the makeup of their collagen matrices across all specimens. Conclusion: The anatomy of the area where a medial meniscal ramp tear occurs revealed that the 2 posterior meniscal attachments merged at a common attachment on the PHMM. Histological analysis validated a shared attachment point of the meniscocapsular and meniscotibial attachments of the PHMM. Clinical Relevance: The findings of this study provide the anatomic foundation for an improved understanding of the meniscocapsular and meniscotibial attachments of the PHMM, which may help provide a more precise definition of a meniscal ramp lesion.
Sexualization of Sexual Harassment Victims Reduces Bystanders’ Help: The Mediating Role of Attribution of Immorality and Blame

Women’s representation in social media is becoming increasingly sexualized, even when they are victims of sexual harassment (SH). In the present research, we adopted a bystander approach to investigate the role of victims’ sexualization on bystanders’ reactions to an episode of SH. In Study 1, female participants read a fictitious newspaper article that described a workplace SH episode: According to condition, the article included a picture of the victim who was wearing either sexualized or nonsexualized clothing. In Study 2, which also included male participants, we used a similar procedure and measured a series of traditional beliefs against women equality. As predicted, participants showed lower willingness to help the sexualized than nonsexualized victim: This effect occurred because they attributed lower morality to the victim and blamed her more for the SH event. Study 2 very well replicated Study 1 results and also showed that higher levels of endorsement of traditional masculine norms further enhanced biased perception of the sexualized (vs. nonsexualized) victim. Together, findings suggest that biased evaluations of workplace SH episodes associated with sexualized victims’ appearance, consistent with traditional masculine norms, may have detrimental consequences by increasing legitimization and tolerance toward SH.
Improved Quality of Life With Anti-TNF Therapy Compared With Continued Corticosteroid Utilization in Crohn's Disease.

BACKGROUND Corticosteroids (CS) and anti-TNF drugs are used to treat Crohn's disease (CD). In this study, we assessed the net health benefit of initiating anti-TNF therapy relative to additional CS use in CD using a novel combination of a retrospective cohort study and a simulation model. METHODS Using Medicaid data from 2001 to 2005 and Medicare data from 2006 to 2013, beneficiaries were identified with CD and CS use who subsequently received either an anti-TNF or reached a cumulative dose of >3000 mg CS during the year. By using overall and latent class-specific remission-time equivalent (RTE) estimates derived from discrete-choice experiments, mean 12-month cumulative RTEs were calculated after propensity score adjustment for baseline characteristics. A Markov model was constructed using transition probabilities derived from the retrospective cohort to perform additional sensitivity analyses of RTE estimates, analytic assumptions, and transition probabilities. Cumulative RTEs were calculated via Monte Carlo simulation in this model. RESULTS In the retrospective cohort, 1563 new anti-TNF initiators and 1563 propensity score-matched prolonged CS users were identified. Anti-TNF use was associated with greater mean RTEs at the end of 1 year (5.34 vs 4.54, incremental benefit: 0.79; 95% CI, 0.53-1.07). This benefit persisted in all latent classes. In the Markov model, anti-TNF therapy was the preferred strategy, and the results were robust in multiple sensitivity analysis and latent class analysis. CONCLUSIONS In both a retrospective cohort study and a simulation model, anti-TNF use was associated with improved quality of life, measured as RTEs, when compared with continued CS utilization for CD.
Influence of Nanofiber Orientation on Morphological and Mechanical Properties of Electrospun Chitosan Mats

This work explored the use of chitosan (Cs) and poly(ethylene oxide) (PEO) blends for the fabrication of electrospun fiber-orientated meshes potentially suitable for engineering fiber-reinforced soft tissues such as tendons, ligaments, or meniscus. To mimic the fiber alignment present in native tissue, the CS/PEO blend solution was electrospun using a traditional static plate, a rotating drum collector, and a rotating disk collector to get, respectively, random, parallel, circumferential-oriented fibers. The effects of the different orientations (parallel or circumferential) and high-speed rotating collector influenced fiber morphology, leading to a reduction in nanofiber diameters and an improvement in mechanical properties.
pyseer: a comprehensive tool for microbial pangenome-wide association studies

Summary Genome-wide association studies (GWAS) in microbes face different challenges to eukaryotes and have been addressed by a number of different methods. pyseer brings these techniques together in one package tailored to microbial GWAS, allows greater flexibility of the input data used, and adds new methods to interpret the association results. Availability and Implementation pyseer is written in python and is freely available at https://github.com/mgalardini/pyseer, or can be installed through pip. Documentation and a tutorial are available at http://pyseer.readthedocs. io. Contact john.lees@nyumc.org and marco@ebi.ac. uk Supplementary information Supplementary data are available online.
Clinical Outcomes Using a Novel Image-Guided Planning System in Patients With Cataract and IOL Implantation.

PURPOSE To determine the proportion of eyes with preexisting astigmatism achieving 0.50 diopters (D) or less of residual refractive cylinder 3 months after either implantation of toric intraocular lenses (IOLs) or corneal incisions using the VERION system (Alcon Laboratories, Inc., Fort Worth, TX) measurement module and digital markers for microscope (M) and laser (L). METHODS Eyes with preexisting astigmatism in the intention-to-treat population were divided into four groups. Eyes in the no laser treatment group underwent toric IOL implantation with the measurement module, vision planner, and digital marker M (n = 102). Eyes in the other three groups underwent implantation of toric (n = 110), monofocal (n = 88), or multifocal (n =100) IOLs using the measurement module, vision planner, and digital marker M, including digital marker L, and LenSx laser (Alcon Laboratories, Inc.). The proportions of eyes achieving 0.50 D or less of relative refractive cylinder and with manifest refraction spherical equivalent (MRSE) deviating 0.50 D or less from the target outcome were evaluated at 3 months. RESULTS The percentages of eyes achieving 0.50 D or less of relative refractive cylinder in the non-laser-treated, toric, monofocal, and multifocal groups at 3 months were 71.6%, 74.5%, 62.5%, and 71.0%, respectively. The percentages of eyes in these four groups with MRSE accuracies deviating 0.50 D or less from the target at 3 months were 69.6%, 80.0%, 77.3%, and 82.0%, respectively. CONCLUSIONS The image-guided surgical planning system was effective in accurate correction of preexisting astigmatism in eyes undergoing refractive cataract surgery with IOL implantation, as shown by residual refractive astigmatism and MRSE at 3 months. [J Refract Surg. 2018;34(12):824-831. ].