Miracle-dz/UniFAR-FTUs huggingface dataset:
Mendelian randomization: a novel approach for the prediction of adverse drug events and drug repurposing opportunities

Identification of unintended drug effects, specifically drug repurposing opportunities and adverse drug events, maximizes the benefit of a drug and protects the health of patients. However, current observational research methods are subject to several biases. These include confounding by indication, reverse causality, and missing data. We propose that Mendelian randomization (MR) offers a novel approach for the prediction of unintended drug effects. In particular, we advocate the synthesis of evidence from this method and other approaches, in the spirit of triangulation, to improve causal inferences concerning drug effects. MR overcomes some of the limitations associated with the existing methods in this field. Furthermore, it can be applied either pre- or post-approval of the drug and could therefore prevent the potentially harmful exposure of patients in clinical trials and beyond. The potential of MR as a pharmacovigilance and drug repurposing tool is yet to be realized and could both help prevent adverse drug events and identify novel indications for existing drugs in the future.
Antibody-based targeted delivery of interleukin-4 synergizes with dexamethasone for the reduction of inflammation in arthritis

Objectives We have previously reported that F8-IL4, a fusion protein consisting of the F8 antibody specific to the alternatively-spliced extra domain A of fibronectin and of murine IL-4, cures mice with established arthritis, when used in combination with dexamethasone (DXM). The goal of this study was to assess whether other therapeutic agents, besides DXM, could induce cures in combination with F8-IL4 and to elucidate which leucocytes are most affected by the pharmacological treatment. Methods We performed therapy experiments in mice with CIA, using intravenous administrations of F8-IL4 in combination with DXM, MTX, murine cytotoxic T-lymphocyte-associated protein 4 fused to the fragment crystallizable portion of murine IgG2a, as well as mAbs to murine IL17A or the p40 subunit of murine IL12/IL23. Histology and immunohistochemistry for the identification of the various leucocytes were performed on the paws of mice euthanized at different therapy time points. Results Only the use of F8-IL4 in combination with DXM induced complete remissions, while all other combinations did not lead to cures. The light microscopical evaluation of paws with arthritis revealed a predominant infiltration of neutrophils, which substantially decreased 24 h after treatment with F8-IL4 and DXM. Conclusion The combination of F8-IL4 with DXM promotes a rapid anti-arthritic action by potently inhibiting neutrophil activity. A fully human analogue of F8-IL4 may find clinical utility for the treatment of neutrophil-driven chronic inflammatory conditions.
Energy minimising multi-crack growth in linear-elastic materials using the extended finite element method with application to Smart-CutTM silicon wafer splitting

We investigate multiple crack evolution under quasi-static conditions in an isotropic linear-elastic solid based on the principle of minimum total energy, i.e. the sum of the potential and fracture energies, which stems directly from the Griffith’s theory of cracks. The technique, which has been implemented within the extended finite element method, enables minimisation of the total energy of the mechanical system with respect to the crack extension directions. This is achieved by finding the orientations of the discrete crack-tip extensions that yield vanishing rotational energy release rates about their roots. In addition, the proposed energy minimisation technique can be used to resolve competing crack growth problems. Comparisons of the fracture paths obtained by the maximum tension (hoop-stress) criterion and the energy minimisation approach via a multitude of numerical case studies show that both criteria converge to virtually the same fracture solutions albeit from opposite directions. In other words, it is found that the converged fracture path lies in between those obtained by each criterion on coarser numerical discretisations. Upon further investigation of the energy minimisation approach within the discrete framework, a modified crack growth direction criterion is proposed that assumes the average direction of the directions obtained by the maximum hoop stress and the minimum energy criteria. The numerical results show significant improvements in accuracy (especially on coarse discretisations) and convergence rates of the fracture paths. The XFEM implementation is subsequently applied to model an industry relevant problem of silicon wafer cutting based on the physical process of Smart-CutTM technology where wafer splitting is the result of the coalescence of multiple pressure-driven micro-crack growth within a narrow layer of the prevailing micro-crack distribution. A parametric study is carried out to assess the influence of some of the Smart-CutTM process parameters on the post-split fracture surface roughness. The parameters that have been investigated, include: mean depth of micro-crack distribution, distribution of micro-cracks about the mean depth, damage (isotropic) in the region of micro-crack distribution, and the influence of the depth of the buried-oxide layer (a layer of reduced stiffness) beneath the micro-crack distribution. Numerical results agree acceptably well with experimental observations.
A questionnaire study to explore the views of people with multiple sclerosis of using smartphone technology for health care purposes

Abstract Purpose: Delivering interventions over the lifetime of people with chronic conditions is an international healthcare challenge. The benefits of technology in healthcare have been demonstrated in many health conditions. This study aims to seek the views of People with multiple sclerosis (MS) of the feasibility and perceived acceptability of smartphone use for healthcare purposes. Methods: Using SurveyMonkey™, respondents answered 21 items about their smartphone use and acceptance of smartphones in healthcare. Descriptive statistics were used to summarize data from closed questions. Content analysis was used for open questions. Results: Most of the self-selected 197 respondents were female (138/197;70.1%), aged 42.78 ± 10.29 years, had relapsing-remitting MS (143/187;76.5%), and mobilized without an aid (154/197;78.17%). Most respondents reported having smartphone access (174/191;91.1%) and owning smartphones (167/192;86.97%). Perceived benefits of smartphones included improved healthcare access (119/190;62.63%) and greater independence (124/190;65.26%). The top three concerns included reduced contact with Healthcare Professionals (66/186;35.48%), data security (60/186;32.26%) and visual impairment (47/184;25.54%). Conclusion: These findings suggest that smartphone use is extensive, frequent, and acceptable for healthcare purposes in this self-selected sample. People with MS should be consulted during the design of smartphone-based interventions, as specific concerns were raised. Future studies should explore how this technology may be best used and implemented in practice. Implications for Rehabilitation Smartphones may have the potential to improve the implementation of best practice among people with multiple sclerosis (MS) This study found that smartphone use is widespread among people with MS, the majority of whom would accept using smartphones in healthcare. Some potential issues were raised, and would need to be considered during the development and implementation of smartphone-based interventions. Issues included potential lack of contact with health-care professionals, data security, and visual impairment.
Fast Domain Decomposition for Global Image Smoothing

Edge-preserving smoothing (EPS) can be formulated as minimizing an objective function that consists of data and regularization terms. At the price of high-computational cost, this global EPS approach is more robust and versatile than a local one that typically has a form of weighted averaging. In this paper, we introduce an efficient decomposition-based method for global EPS that minimizes the objective function of ${L_{2}}$ data and (possibly non-smooth and non-convex) regularization terms in linear time. Different from previous decomposition-based methods, which require solving a large linear system, our approach solves an equivalent constrained optimization problem, resulting in a sequence of 1-D sub-problems. This enables applying fast linear time solver for weighted-least squares and - $L_{1}$ smoothing problems. An alternating direction method of multipliers algorithm is adopted to guarantee fast convergence. Our method is fully parallelizable, and its runtime is even comparable to the state-of-the-art local EPS approaches. We also propose a family of fast majorization–minimization algorithms that minimize an objective with non-convex regularization terms. Experimental results demonstrate the effectiveness and flexibility of our approach in a range of image processing and computational photography applications.
Methane- and ammonia-oxidizing bacteria at the chemocline of Lake Kinneret (Israel)

The vertical distribution of methane- and ammonia-oxidizing bacteria (MOB and AOB, respectively), and the physicochemical conditions in the chemocline of Lake Kinneret (Israel) were studied at a resolution of 10 cm from 16.2 to 17.7 m depth. Profiles of the chemical parameters indicated decreasing concentrations of methane (from 22.4 to 0.11 mu mol l(-1)) and ammonia (from 14.2 to 8.4 mu mol l(-1)) towards the water surface and in close proximity to the chemocline, The disappearance of methane coincided with methane oxidation that could be corroborated throughout this layer with highest rates at 17.4 to 17.6 m. Disappearance of ammonia could not be linked to ammonia oxidation exclusively. The genes pmoA and the homologous amoA (coding for subunit a of the methane and ammonia monooxygenase, respectively) were amplified by PCR. The products were analyzed by terminal restriction fragment length polymorphism (T-RFLP) and sequencing of clone libraries. The results demonstrated that different MOB and AOB communities are established along the concentration gradient within the narrow layer of the metalinmetic chemocline. Changes in the intensity of the T-RFLP peaks and the frequency of different groups of alpha- and gammaproteobacterial MOB, and betaproteobacterial AOB, coincided with the concentration gradients of methane, ammonia, nitrate, and oxygen in the chemocline. This suggests that different communities of MOB, and to a lesser extent AOB, contribute to the formation of chemical gradients of their particular substrates in the chemocline.
Toward a structural understanding of nucleic acid‐sensing Toll‐like receptors in the innate immune system

The history of mankind has been plagued by the tug of war with viral infections. Toll‐like receptors (TLRs) and other receptors of the innate immune system constitute an early defense system against invading viruses by recognizing the viral genetic material, the nucleic acids (NAs). Agonistic ligands of NA‐sensing TLRs play an emerging role in the treatment of viral diseases, demonstrating a crucial role of these receptors. Recently, crystal structures have afforded new insights into TLR recognition of NAs. An aberrant activation by self‐NAs, which leads to the inflammation and autoimmunity, is avoided by strict regulation of NA–TLR interaction at multiple check‐points. This Review summarizes the novel structural understanding of NA‐sensing by TLRs and regulatory mechanisms of these receptors.
Research Review: Language problems in children with Attention‐Deficit Hyperactivity Disorder – a systematic meta‐analytic review

BACKGROUND Children with Attention-Deficit Hyperactivity Disorder (ADHD) appear to have a higher risk of language problems compared with typically developing children, although the types of language problems experienced are less clear. This review aims to establish the types of language problems experienced by children with ADHD according to systematically reviewed literature and determine the empirical evidence for language problems in children with ADHD compared with non-ADHD controls. METHODS A standardized search protocol was used on databases: CINAHL, Medline, and PsychINFO. We identified studies with the following inclusion criteria: (a) confirmed ADHD status at the time of the study, (b) inclusion of a non-ADHD control group, (c) use of a validated language measure, and (d) age ≤ 18. t-Tests, Pearson's r, and Hedges g effect sizes (ES) were calculated using summary statistics. Random effects meta-analyses were conducted for the language domain suitable for analysis. Publication bias was investigated using both the trim and fill and p-curve techniques. RESULTS Twenty-one studies were included in the systematic review (ADHD = 1,209; Control = 1,101), within which 60 of 68 separate analyses found significant differences between the ADHD and control group on the language measures (p < .05). Follow-up meta-analyses found evidence for large deficits in the ADHD groups overall (10/11 studies met p < .05; weighted mean ES [WMES]: 1.04); expressive (10/10 met p < .05; WMES: 1.23); receptive (12/14 met p < .05; WMES: 0.97), and pragmatic language (4/4 studies met p < .05; WMES: 0.98) compared with controls. CONCLUSIONS This study demonstrates that children with ADHD have poorer performance on measures of overall, expressive, receptive, and pragmatic language compared with controls. A screening of language functioning may be a valuable addition to the assessment of ADHD.
ChREBP Rather Than SHP Regulates Hepatic VLDL Secretion

The regulation of hepatic very-low-density lipoprotein (VLDL) secretion plays an important role in the pathogenesis of dyslipidemia and fatty liver diseases. VLDL is controlled by hepatic microsomal triglyceride transfer protein (MTTP). Mttp is regulated by carbohydrate response element binding protein (ChREBP) and small heterodimer partner (SHP). However, it is unclear whether both coordinately regulate Mttp expression and VLDL secretion. Here, adenoviral overexpression of ChREBP and SHP in rat primary hepatocytes induced and suppressed Mttp mRNA, respectively. However, Mttp induction by ChREBP was much more potent than suppression by SHP. Promoter assays of Mttp and the liver type pyruvate kinase gene revealed that SHP and ChREBP did not affect the transcriptional activity of each other. Mttp mRNA and protein levels of Shp−/− mice were similar to those of wild-types; however, those of Chrebp−/−Shp−/− and Chrebp−/− mice were significantly much lower. Consistent with this, the VLDL particle number and VLDL secretion rates in Shp−/− mice were similar to wild-types but were much lower in Chrebp−/− and Chrebp−/−Shp−/− mice. These findings suggest that ChREBP, rather than SHP, regulates VLDL secretion under normal conditions and that ChREBP and SHP do not affect the transcriptional activities of each other.
σ Phase Formed in Conformationally Asymmetric AB-Type Block Copolymers.

The stability of various spherical phases formed in conformationally asymmetric AB diblock and architecture asymmetric ABm miktoarm block copolymers is investigated using self-consistent field theory. Both the conformational and architecture asymmetries are unified into a parameter of conformationally asymmetric degree, ε. We find that a complex spherical phase, the σ phase, becomes stable and its phase region expands between bcc and hexagonal phases as increasing ε. Only for large conformational asymmetry, for example, ε = 9 (or m = 3), the A15 phase becomes stable in the region between the σ phase and the hexagonal phase and its phase region terminates at the intermediate segregation region. Compared with the σ phase, the A15 phase has more favorable interfacial energy by enabling the formation of larger spherical domains, and therefore, it becomes more stable in the region of more symmetric volume fraction and stronger segregation.
A randomized, open-label study of the efficacy and safety of AZD4547 monotherapy versus paclitaxel for the treatment of advanced gastric adenocarcinoma with FGFR2 polysomy or gene amplification

Background Approximately 5%-10% of gastric cancers have a fibroblast growth factor receptor-2 (FGFR2) gene amplification. AZD4547 is a selective FGFR-1, 2, 3 tyrosine kinase inhibitor with potent preclinical activity in FGFR2 amplified gastric adenocarcinoma SNU16 and SGC083 xenograft models. The randomized phase II SHINE study (NCT01457846) investigated whether AZD4547 improves clinical outcome versus paclitaxel as second-line treatment in patients with advanced gastric adenocarcinoma displaying FGFR2 polysomy or gene amplification detected by fluorescence in situ hybridization. Patients and methods Patients were randomized 3:2 (FGFR2 gene amplification) or 1:1 (FGFR2 polysomy) to AZD4547 or paclitaxel. Patients received AZD4547 80 mg twice daily, orally, on a 2 weeks on/1 week off schedule of a 21-day cycle or intravenous paclitaxel 80 mg/m2 administered weekly on days 1, 8, and 15 of a 28-day cycle. The primary end point was progression-free survival (PFS). Safety outcomes were assessed and an exploratory biomarker analysis was undertaken. Results Of 71 patients randomized (AZD4547 n = 41, paclitaxel n = 30), 67 received study treatment (AZD4547 n = 40, paclitaxel n = 27). Among all randomized patients, median PFS was 1.8 months with AZD4547 and 3.5 months with paclitaxel (one-sided P = 0.9581); median follow-up duration for PFS was 1.77 and 2.12 months, respectively. The incidence of adverse events was similar in both treatment arms. Exploratory biomarker analyses revealed marked intratumor heterogeneity of FGFR2 amplification and poor concordance between amplification/polysomy and FGFR2 mRNA expression. Conclusions AZD4547 did not significantly improve PFS versus paclitaxel in gastric cancer FGFR2 amplification/polysomy patients. Considerable intratumor heterogeneity for FGFR2 gene amplification and poor concordance between FGFR2 amplification/polysomy and FGFR2 expression indicates the need for alternative predictive biomarker testing. AZD4547 was generally well tolerated.
Four artemisinin-based treatments in African pregnant women with malaria.

BACKGROUND Information regarding the safety and efficacy of artemisinin combination treatments for malaria in pregnant women is limited, particularly among women who live in sub-Saharan Africa. METHODS We conducted a multicenter, randomized, open-label trial of treatments for malaria in pregnant women in four African countries. A total of 3428 pregnant women in the second or third trimester who had falciparum malaria (at any parasite density and regardless of symptoms) were treated with artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate, or dihydroartemisinin-piperaquine. The primary end points were the polymerase-chain-reaction (PCR)-adjusted cure rates (i.e., cure of the original infection; new infections during follow-up were not considered to be treatment failures) at day 63 and safety outcomes. RESULTS The PCR-adjusted cure rates in the per-protocol analysis were 94.8% in the artemether-lumefantrine group, 98.5% in the amodiaquine-artesunate group, 99.2% in the dihydroartemisinin-piperaquine group, and 96.8% in the mefloquine-artesunate group; the PCR-adjusted cure rates in the intention-to-treat analysis were 94.2%, 96.9%, 98.0%, and 95.5%, respectively. There was no significant difference among the amodiaquine-artesunate group, dihydroartemisinin-piperaquine group, and the mefloquine-artesunate group. The cure rate in the artemether-lumefantrine group was significantly lower than that in the other three groups, although the absolute difference was within the 5-percentage-point margin for equivalence. The unadjusted cure rates, used as a measure of the post-treatment prophylactic effect, were significantly lower in the artemether-lumefantrine group (52.5%) than in groups that received amodiaquine-artesunate (82.3%), dihydroartemisinin-piperaquine (86.9%), or mefloquine-artesunate (73.8%). No significant difference in the rate of serious adverse events and in birth outcomes was found among the treatment groups. Drug-related adverse events such as asthenia, poor appetite, dizziness, nausea, and vomiting occurred significantly more frequently in the mefloquine-artesunate group (50.6%) and the amodiaquine-artesunate group (48.5%) than in the dihydroartemisinin-piperaquine group (20.6%) and the artemether-lumefantrine group (11.5%) (P<0.001 for comparison among the four groups). CONCLUSIONS Artemether-lumefantrine was associated with the fewest adverse effects and with acceptable cure rates but provided the shortest posttreatment prophylaxis, whereas dihydroartemisinin-piperaquine had the best efficacy and an acceptable safety profile. (Funded by the European and Developing Countries Clinical Trials Partnership and others; ClinicalTrials.gov number, NCT00852423.).
Understanding scientific collaboration: Homophily, transitivity, and preferential attachment

Scientific collaboration is essential in solving problems and breeding innovation. Coauthor network analysis has been utilized to study scholars' collaborations for a long time, but these studies have not simultaneously taken different collaboration features into consideration. In this paper, we present a systematic approach to analyze the differences in possibilities that two authors will cooperate as seen from the effects of homophily, transitivity, and preferential attachment. Exponential random graph models (ERGMs) are applied in this research. We find that different types of publications one author has written play diverse roles in his/her collaborations. An author's tendency to form new collaborations with her/his coauthors' collaborators is strong, where the more coauthors one author had before, the more new collaborators he/she will attract. We demonstrate that considering the authors' attributes and homophily effects as well as the transitivity and preferential attachment effects of the coauthorship network in which they are embedded helps us gain a comprehensive understanding of scientific collaboration.
The Study of Female Postgraduate Career Development base on Social Cognitive Theory

There have been few researches on social cognition on Taiwanese females. The topics of female business start-up and the female empirical research on social cogniti on are the principle areas for recent researches. L ent, Brown & Hackett (1994) proposed the social cognitive career theory, which addresses the relationship between i ndividual expectation to capability and career, target select ion, and current representation. This research is b ase on the social cognitive theory and discusses the correlation betw een female postgraduates in the Research Institutio n, in universities of science and technology and their future career d evelopment. It examines female traits for carrying out development and career plans and their future organization. The goal is to cultivate the optimal human resource an d devote it to society and progress. The research sample was 359 f emale postgraduates in science and technology unive rsities in Taiwan, who were given a questionnaire survey. Pear son Correlation and stepwise multi-regression analy zed the data. The research discovered that career development has a significant positive correlation to social cogni tion, and the perspectives of self-efficiency, outcome expectatio n, and individual target all have a significant pos itive correlation to career. However, perspective of outcome expectation does not achieve significant correlation with soci al cognition. The research has value preference for both academic and professional practice.