Miracle-dz/UniFAR-FTUs huggingface dataset:
Drug-induced Neuropsychiatric Adverse Events Using Post-Marketing Surveillance

Background Several studies reported that abnormal behavior was noted in pediatric pa- tients receiving several drugs, including neuraminidase inhibitors (NIs). However, the information on drugs associated with abnormal behavior in a real-world setting remains limited. The purpose of this study was to clarify the drugs associated with abnormal behavior using a spontaneous reporting sys- tem database. Methods We performed a retrospective pharmacovigilance disproportionality analysis using the Jap- anese Adverse Drug Event Report database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency were analyzed, and the reporting odds ratio at 95% confidence interval were calculated. Results A total of 1,144 reports of abnormal behavior were identified. The signals were detected through the association of 4 neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir, and peram- ivir) with the abnormal behaviour. These signals were stronger for oseltamivir than other neuramini- dase inhibitors. The signals were also detected for acetaminophen and montelukast. Conclusion Our results should be able to raise physicians’ awareness of drugs associated with ab- normal behavior, but further investigation of these medications is warranted.
Exploratory Assessment of Levosimendan in Infants With Congenital Diaphragmatic Hernia

Supplemental Digital Content is available in the text. OBJECTIVES: Infants with congenital diaphragmatic hernia frequently suffer from cardiac dysfunction and pulmonary hypertension during the postnatal course. With the use of the inodilator levosimendan, a therapeutic approach is available in situations with catecholamine-refractory low-cardiac-output failure and severe pulmonary hypertension. DESIGN: Retrospective single-center cohort study. SETTING: University-based, tertiary-care children’s hospital neonatal ICU. PATIENTS: Cohort of 24 infants with congenital diaphragmatic hernia and levosimendan therapy, without underlying major cardiac defect, treated at the University Children´s Hospital Bonn, Germany, between January 2017 and December 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty-four infants with congenital diaphragmatic hernia were treated with levosimendan (41% of hospitalized congenital diaphragmatic hernia infants in the study period). In 88%, the congenital diaphragmatic hernia was left-sided. The median observed-to-expected lung-to-head ratio was 36%. About 60% of the infants were supported with venovenous extracorporeal membrane oxygenation and the mortality was 38% (9/24 infants). Levosimendan administration was associated with improvement of pulmonary hypertension severity (p = 0.013 and p = 0.000) and right ventricular dysfunction (p = 0.011 and p = 0.000) at 24 hours and 7 days after treatment. Similarly, the prevalence of left ventricular dysfunction decreased from 50% at baseline to 10% after 7 days (p = 0.026). A significant reduction in the peak inspiratory pressure was observed after drug application (p = 0.038) and a significant decrease of the Vasoactive-Inotropic Score was apparent (p = 0.022). A relevant arterial hypotension as a drug-related adverse event occurred in one patient. CONCLUSIONS: This is the first study exploring clinical and hemodynamic changes after levosimendan treatment in a cohort of infants with congenital diaphragmatic hernia. An association of levosimendan application and an improvement in pulmonary hypertension, right ventricular, and left ventricular dysfunction were observed within 7 days after drug infusion. However, due to the retrospective design of this study, the results should be interpreted carefully.
Longitudinal symptom network structure in first-episode psychosis: a possible marker for remission

Abstract Background Network approach has been applied to a wide variety of psychiatric disorders. The aim of the present study was to identify network structures of remitters and non-remitters in patients with first-episode psychosis (FEP) at baseline and the 6-month follow-up. Methods Participants (n = 252) from the Korean Early Psychosis Study (KEPS) were enrolled. They were classified as remitters or non-remitters using Andreasen's criteria. We estimated network structure with 10 symptoms (three symptoms from the Positive and Negative Syndrome Scale, one depressive symptom, and six symptoms related to schema and rumination) as nodes using a Gaussian graphical model. Global and local network metrics were compared within and between the networks over time. Results Global network metrics did not differ between the remitters and non-remitters at baseline or 6 months. However, the network structure and nodal strengths associated with positive-self and positive-others scores changed significantly in the remitters over time. Unique central symptoms for remitters and non-remitters were cognitive brooding and negative-self, respectively. The correlation stability coefficients for nodal strength were within the acceptable range. Conclusion Our findings indicate that network structure and some nodal strengths were more flexible in remitters. Negative-self could be an important target for therapeutic intervention.
Secretion of Phospholipase Dδ Functions as a Regulatory Mechanism in Plant Innate Immunity[OPEN]

Membrane microdomains and PLDδ exocytosis regulate PLDδ accumulation during penetration resistance in plant innate immunity. Plant phospholipase Ds (PLDs), essential regulators of phospholipid signaling, function in multiple signal transduction cascades; however, the mechanisms regulating PLDs in response to pathogens remain unclear. Here, we found that Arabidopsis (Arabidopsis thaliana) PLDδ accumulated in cells at the entry sites of the barley powdery mildew fungus, Blumeria graminis f. sp hordei. Using fluorescence recovery after photobleaching and single-molecule analysis, we observed higher PLDδ density in the plasma membrane after chitin treatment; PLDδ also underwent rapid exocytosis. Fluorescence resonance energy transfer with fluorescence lifetime imaging microscopy showed that the interaction between PLDδ and the microdomain marker AtREMORIN1.3 (AtREM1.3) increased in response to chitin, indicating that exocytosis facilitates rapid, efficient sorting of PLDδ into microdomains upon pathogen stimulus. We further unveiled a trade-off between brefeldin A (BFA)–resistant and –sensitive pathways in secretion of PLDδ under diverse conditions. Upon pathogen attack, PLDδ secretion involved syntaxin-associated VAMP721/722-mediated exocytosis sensitive to BFA. Analysis of phosphatidic acid (PA), hydrogen peroxide, and jasmonic acid (JA) levels and expression of related genes indicated that the relocalization of PLDδ is crucial for its activation to produce PA and initiate reactive oxygen species and JA signaling pathways. Together, our findings revealed that the translocation of PLDδ to papillae is modulated by exocytosis, thus triggering PA-mediated signaling in plant innate immunity.
A Crocheted Model Activity for Teaching Embryonic Lateral Folding to Medical Students

Knowledge of embryology is foundational for understanding normal anatomy and birth defects, yet, embryology is a notoriously difficult subject for medical students. Embryonic lateral folding in particular is one of the most challenging concepts in embryology. Highly effective teaching methods that promote active engagement with dynamic, three‐dimensional models may be helpful for teaching this content. The aim of this study was to determine whether a hands‐on modeling activity utilizing premade crocheted pieces constructed from durable, inexpensive yarn helped medical students enrolled in a pre‐matriculation course to understand embryonic lateral folding. Change in knowledge was assessed using a pre–post design. Students also completed subjective evaluations regarding their satisfaction with the activity. Quiz scores in means (±SD) increased from 62.7 (±24.1) % before the activity to 77.0 (±17.1) % after the activity (P = 0.0495, two‐tailed paired t test; d = 0.68). Generally, students reported that the activity was helpful and enjoyable, and the model pieces were easy to manipulate. These promising results suggest that hands‐on activities with dynamic, three‐dimensional models constitute an effective method for teaching embryology.
Mas receptor activation attenuates allergic airway inflammation via inhibiting JNK/CCL2-induced macrophage recruitment.

BACKGROUND Defective absorption of acute allergic airway inflammation is involved in the initiation and development of chronic asthma. After allergen exposure, there is a rapid recruitment of macrophages around the airways, which promote acute inflammatory responses. The Ang-(1-7)/Mas receptor axis reportedly plays protective roles in various tissue inflammation and remodeling processes in vivo. However, the exact role of Mas receptor and their underlying mechanisms during the pathology of acute allergic airway inflammation remains unclear. OBJECTIVE We investigated the role of Mas receptor in acute allergic asthma and explored its underlying mechanisms in vitro, aiming to find critical molecules and signal pathways. METHODS Mas receptor expression was assessed in ovalbumin (OVA)-induced acute asthmatic murine model. Then we estimated the anti-inflammatory role of Mas receptor in vivo and explored expressions of several known inflammatory cytokines as well as phosphorylation levels of MAPK pathways. Mas receptor functions and underlying mechanisms were studied further in the human bronchial epithelial cell line (16HBE). RESULTS Mas receptor expression decreased in acute allergic airway inflammation. Multiplex immunofluorescence co-localized Mas receptor and EpCAM, indicated that Mas receptor may function in the bronchial epithelium. Activating Mas receptor through AVE0991 significantly alleviated macrophage infiltration in airway inflammation, accompanied with down-regulation of CCL2 and phosphorylation levels of MAPK pathways. Further studies in 16HBE showed that AVE0991 pre-treatment inhibited LPS-induced or anisomycin-induced CCL2 increase and THP-1 macrophages migration via JNK pathways. CONCLUSION Our findings suggested that Mas receptor activation significantly attenuated CCL2 dependent macrophage recruitments in acute allergic airway inflammation through JNK pathways, which indicated that Mas receptor, CCL2 and phospho-JNK could be potential targets against allergic airway inflammation.
YtkA (CtaK) and YozB (CtaM) function in the biogenesis of cytochrome c oxidase in Bacillus subtilis

Cytochrome c oxidase in the respiratory chain of bacteria and mitochondria couples the reduction of molecular oxygen to form water with the generation of a transmembrane proton gradient. Bacillus subtilis has two heme A‐containing heme–copper oxidases: the menaquinol oxidase cytochrome aa3 and the cytochrome c oxidase cytochrome caa3. By screening three collections of mutants for defective cytochrome c oxidase, we found the genes for two, new membrane‐bound assembly factors in B. subtilis: ytkA and yozB (renamed ctaK and ctaM, respectively). CtaK is a lipoprotein without sequence similarity to any protein of known function. We show that CtaK functions together with Sco1 (YpmQ) in a pathway, leading to the assembly of the CuA center in cytochrome caa3 and seems to be a functional analogue to proteins of the periplasmic CuA chaperone family (PCuAC). CtaM is required for the activity of both cytochrome caa3 and cytochrome aa3 and dispensable for the insertion of heme A into these oxidases. The orthologous Bacillus anthracis protein and the distantly related Staphylococcus aureus CtaM complemented CtaM deficiency in B. subtilis, establishing a common function of CtaM in these bacteria. As the overall result of our work, 12 different proteins are known to function in the biosynthesis of cytochrome c oxidase in B. subtilis.
Tectorigenin attenuates the OGD/R-induced HT-22 cell damage through regulation of the PI3K/AKT and the PPARγ/NF-κB pathways

Tectorigenin (TEC) is an effective compound that derived from many plants, such as Iris unguicularis, Belamcanda chinensis and Pueraria thunbergiana Benth. Evidence suggested that TEC has anti-tumor, anti-oxidant activity, anti-bacterial and anti-inflammatory effects. In addition, there has some evidence indicated that TEC is a potential anti-stroke compound; however, its specific roles and associated mechanism have not yet been elucidated. In the present study, we aimed to investigate the anti-inflammatory, anti-oxidant activity and anti-apoptosis effects of TEC on oxygen-glucose deprivation/reperfusion (OGD/R)-induced HT-22 cells, and clarified the relevant mechanisms. Here, we observed that TEC significantly promoted cell survival, impeded cell apoptosis, inhibited ROS and inflammatory cytokines IL-1β, IL-6, TNF-α production in OGD/R-induced HT-22 cells. Moreover, TEC activated PI3K/AKT signal pathway, increased PPARγ expression and inhibited NF-κB pathway activation in OGD/R-induced HT-22 cells. Further studies indicated that PPARγ inhibitor GW9662 activated NF-κB pathway after TEC treatment in OGD/R-induced HT-22 cells. Also, PI3K/AKT inhibitor LY294002, PPARγ inhibitor GW9662 and NF-κB activator LPS both reversed the effects of TEC on OGD/R-induced HT-22 cell biology. Taken together, this research confirmed that TEC benefit to HT-22 cell survival and against OGD/R damage through the PI3K/AKT and PPARγ/NF-κB pathways. These results indicated that TEC might be an effective compound in the treatment for ischemic brain injury.
Reliability and sensitivity of the Notio Konect to quantify coefficient of drag area in elite track cyclists

ABSTRACT Elite level cycling events are performed at speeds in excess of 50 km/h. At these speeds, over 90% of the resistance forces come from aerodynamic resistance (CDA). Recently bicycle-mounted pitot tubes, such as the Notio Konect (NK) have become more commercially available making CDA easier to measure. Its reliability and sensitivity would be useful for riders and coaches to be able to understand what constitutes as a change in CDA. Accordingly, the aim of this study was to establish the intra- and inter-effort reliability and sensitivity of the CDA measures of the NK. Seven elite level track riders were used in this study which was broken into two parts: (1) Reliability and (2) Sensitivity. For both parts of the experiment, riders performed identical efforts, riding at ∼50 km/h for six laps of a 250 m indoor velodrome. For reliability, the riders performed six efforts without any changes in position or resistance. For sensitivity, they performed the efforts with a rod with discs of a known diameters attached at each end to vary the CDA by a known amount. For the reliability assessment, low coefficient of variation of intra – (0.47%) and inter-effort (0.9%) reliability were measured. With regards to sensitivity, the smallest changes in resistance (from 5 – 6 cm, i.e. 1.2% or 0.002 m2) was identified by the NK. The data in this experiment suggests that the NK is a highly reliable in measuring CDA can detect changes up to at least 1.2% in an indoor velodrome using elite level track riders. Highlights The Notio Konect showed high levels of inter- and intra-effort reliability. The Notio Konect could detect a change as small as 1.2% in aerodynamic drag. The findings suggest that the Notio Konect is suitable for detecting small changes in aerodynamic drag in a velodrome setting.
Fabrication of Organized Mesoporous TiO2 Films Assembled via Different Template and Characterization of their Photocatalytic Activity

Hexagonal and cubic mesoporous TiO2 materials were synthesized via a sol-gel route modified by evaporation–induced self–assembly process with different templates. XRD and TEM results confirmed that the mesoporous films were highly organized. Furthermore, the hexagonal mesoporous TiO2 films were formed in the P123-templated films, whereas the cubic structure ones were found in the F127-templated films. Both the hexagonal and cubic mesoporous films showed photocatalytic activity in decomposing methyl orange solution under UV region, among which the cubic mesostructure presented superior potocatalytic activity because of larger surface area, more open framework and less obstructed diffusion paths of guest molecules.
Emergence of dengue virus 4 as the predominant serotype during the outbreak of 2017 in South India

Context: Dengue virus (DENV) causes acute febrile illness in tropical and subtropical countries. In India there is a steady increase in incidence since 1950s which could be attributed to emergence of new serotype or lineage\clade shifts in circulating DENV. Aims: We aimed to perform molecular characterisation and phylogenetic analysis on samples from the recent outbreak (August–October 2017). Settings and Design: Retrospective epidemiological analysis of dengue outbreak. Subjects and Methods: Samples positive for non-steroidal 1 antigen by enzyme-linked immunosorbent assay (n = 147) were included. The study was approved by our institute ethics committee (JIP/IEC/2018/496). Five hundred and eleven base pair of capsid and pre-membrane encoding genes (CprM) region was amplified using Lanciotti primers, followed by second round of polymerase chain reaction using serotype specific primers. Samples which were positive by second round (n = 68) were sequenced and genotyped using Basic Local Alignment Search Tool analysis and phylogenetic tree was constructed by MEGA7 software. Results: Phylogenetic analysis of CprM sequences identified all 4 serotypes in circulation during this outbreak. We observed both single (n = 50) and concurrent infections (n = 18), with DENV4 as the major contributor (64%). Within Genotype I of DENV4 we observed a distinct new clade (Clade E) which was 2.6% ± 0.9%–5.5% ± 1.1% divergent from the other clades. Among the concurrent infection, DENV 4 and DENV 2 combination was observed to form the majority (77.8%). Conclusions: Overall this study documents the emergence of DENV4 as the major serotype in circulation, replacing DENV1, 2 and 3 which had been previously reported from Tamil Nadu and Puducherry. This substantiates the need for continuous monitoring in endemic countries like India, where such data may impact the formulation of vaccine policy for dengue.
Vascular reconstitution in the tumor for more effective tumor immunotherapy

It has been widely accepted that the regulation of the tumor microenvironment is an important strategy in cancer treatment. Particularly, control of the tumor vasculature has been suggested to be critical for antitumor immunotherapy. Effectiveness of cancer immunotherapy depends on the quality and quantity of immune cells infiltrating into tumor tissues, which may be affected by the status of the tumor vasculature. Under physiological conditions, immune cells migrate from the intravascular lumen into the parenchyma especially by passing through the vascular wall of venulae. Extravasation of immune cells is induced from venulae where endothelial cells (ECs) are fully covered with pericytes from the basal side. Interaction of pericytes with ECs contributes to immune cell extravasation by several steps, ie, adhesion of immune cells to intraluminal ECs, transmigration, and chemotaxis of immune cells. Blood vessels are structurally immature and non‐functional in tumors, and therefore, induction of maturation in the tumor vasculature is a promising strategy for effective cancer therapies and is relevant not only for immune cell migration but also drug delivery.
Serum milk fat globule-EGF factor 8 protein as a potential biomarker for metabolic syndrome

Background/Aims Useful biomarkers for metabolic syndrome have been insufficient. We investigated the performance of serum milk fat globule-EGF factor-8 (MFG-E8), the key mediator of inflammatory pathway, in diagnosis of metabolic syndrome. Methods Subjects aged between 30 and 64 years were prospectively enrolled in the Seoul Metabolic Syndrome cohort. Serum MFG-E8 levels were measured at baseline. Results A total of 556 subjects were included, comprising 279 women (50.2%) and 277 men (49.8%). Metabolic syndrome was diagnosed in 236 subjects (42.4%), and the mean MFG-E8 level of subjects with metabolic syndrome was significantly higher than that of subjects without metabolic syndrome (P<0.001). MFG-E8 level was significantly correlated with all metabolic syndrome components and pulse wave velocity (all P<0.05). Subjects were categorized into two groups according to the best MFG-E8 cut-off value as follows: group 1, MFG-E8 level <4,745.1 pg/mL (n=401, 72.1%); and group 2, MFG-E8 level ≥4,745.1 (n=155, 27.9%). At baseline, metabolic syndrome in group 2 was significantly more prevalent than in group 1 (63.9% vs. 34.2%, P<0.001). During median follow-up of 17 months, metabolic syndrome developed in 122 (38.1%) subjects among 320 subjects without it at baseline. The incidence of metabolic syndrome in group 2 was significantly higher than that in group 1 (55.4% vs. 34.5%, P=0.003). On multivariate analysis, MFG-E8 level ≥4,745.1 pg/mL was an independent predictor for diagnosis and development of metabolic syndrome after adjusting other factors (all P<0.05). Conclusions Serum MFG-E8 level is a potent biomarker for the screening and prediction of metabolic syndrome.
Copy number variations in Japanese children with autism spectrum disorder

Supplemental Digital Content is available in the text. Objective Although autism spectrum disorder (ASD) occurs worldwide, most genomic studies on ASD were performed on those of Western ancestry. We hypothesized ASD-related copy number variations (CNVs) of Japanese individuals might be different from those of Western individuals. Methods Subjects were recruited from the Hirosaki 5-year-old children’s developmental health check-up (HFC) between 2013 and 2016 (ASD group; n = 68, control group; n = 124). This study conducted CNV analysis using genomic DNA from peripheral blood of 5-year-old Japanese children. Fisher’s exact test was applied for profiling subjects and CNV loci. Results Four ASD-related CNVs: deletion at 12p11.1, duplications at 4q13.2, 8p23.1 and 18q12.3 were detected (P = 0.015, 0.024, 0.009, 0.004, respectively). Specifically, the odds ratio of duplication at 18q12.3 was highest among the 4 CNVs (odds ratio, 8.13). Conclusions Four CNVs: microdeletion at 12p11.1, microduplications at 4q13.2, 8p23.1 and 18q12.3 were detected as ASD-related CNVs in Japanese children in this study. Although these CNVs were consistent with several reports by Western countries at cytoband levels, these did not consistent at detailed genomic positions and sizes. Our data indicate the possibility that these CNVs are characteristic of Japanese children with ASD. We conclude that Japanese individuals with ASD may harbor CNVs different from those of Western individuals with ASD.
Pharmacogenomics of statins and familial hypercholesterolemia

Purpose of review To collect evidence on statin pharmacogenomics, and review what is known in this field for familial hypercholesterolemia (FH) patients. Recent findings There are well-known associations between specific single nucleotide polymorphisms involved in statin transport and metabolism and either adverse effects or altered lipid-lowering efficacy. However, the applicability of this knowledge is uncertain, especially in high-risk populations. There are alternative approaches to study plasma concentrations of statins and new insights on why some association studies fail to be replicated. Summary Statin therapy recommendations are not always followed in primary and secondary prevention and, even when followed, patients often fail to reach therapeutic target values. Considering the stringent 2019 European Atherosclerosis Society and European Society of Cardiology recommended target lipid levels, as well as the persistently high cost for alternative lipid-lowering therapies such as PCSK9 inhibitors, the variability in low-density lipoprotein cholesterol reductions on statin therapy is still an important factor that needs to be addressed to ensure better cardiovascular disease risk management, especially for FH patients, who have not been well studied historically in this context.