Miracle-dz/UniFAR-FTUs huggingface dataset:
Imputation and Reanalysis of ExomeChip Data Identifies Novel, Conditional and Joint Genetic Effects on Parkinson’s Disease Risk

Given that improved imputation software and high-coverage whole genome sequence (WGS)-based haplotype reference panels now enable inexpensive approximation of WGS genotype data, we hypothesised that WGS-based imputation and analysis of existing ExomeChip-based genome-wide association (GWA) data will identify novel intronic and intergenic single nucleotide polymorphism (SNP) effects associated with complex disease risk. In this study, we reanalysed a Parkinson’s disease (PD) dataset comprising 5540 cases and 5862 controls genotyped using the ExomeChip-based NeuroX array. After genotype imputation and extensive quality control, GWA analysis was performed using PLINK and a recently developed machine learning approach (GenEpi), to identify novel, conditional and joint genetic effects associated with PD. In addition to improved validation of previously reported loci, we identified five novel genome-wide significant loci associated with PD: three (rs137887044, rs78837976 and rs117672332) with 0.01 < MAF < 0.05, and two (rs187989831 and rs12100172) with MAF < 0.01. Conditional analysis within genome-wide significant loci revealed four loci (p < 1 × 10−5) with multiple independent risk variants, while GenEpi analysis identified SNP–SNP interactions in seven genes. In addition to identifying novel risk loci for PD, these results demonstrate that WGS-based imputation and analysis of existing exome genotype data can identify novel intronic and intergenic SNP effects associated with complex disease risk.
Choosing New Therapies for Gonorrhoea: We Need to Consider the Impact on the Pan-Neisseria Genome. A Viewpoint

The development of new gonorrhoea treatment guidelines typically considers the resistance-inducing effect of the treatment only on Neisseria gonorrhoeae. Antimicrobial resistance in N. gonorrhoeae has, however, frequently first emerged in commensal Neisseria species and then been passed on to N. gonorrhoeae via transformation. This creates the rationale for considering the effect of gonococcal therapies on resistance in commensal Neisseria. We illustrate the benefits of this pan-Neisseria strategy by evaluating three contemporary treatment options for N. gonorrhoeae—ceftriaxone plus azithromycin, monotherapy with ceftriaxone and zoliflodacin.
Protein Expression Correlates Linearly with mRNA Dose over Up to Five Orders of Magnitude In Vitro and In Vivo

Messenger RNA is rapidly gaining significance as a therapeutic modality. Here, we address the dependence of dose–response functions on the type of delivery vehicle, cell line, and incubation time. Knowledge of these characteristics is crucial for the application of mRNA. As delivery vehicles, a lipid-based formulation and the cell-penetrating peptide Pepfect14 (PF14) were employed. As cell lines, we included a glomerular endothelial cell line (mGEnC) as a model for differentiated cells, HeLa cells, and SKOV-3 ovarian carcinoma cells. Uptake and expression were detected by flow cytometry, using a Cy5-labelled mRNA coding for enhanced green fluorescent protein (EGFP). There was a linear correlation of dose, uptake, and expression, and this correlation was maintained for over up to 72 h. Through application of a multistep kinetic model, we show that differences in expression levels can already be explained by the number of mRNAs packaged per delivery vehicle. Using luciferase as a reporter protein, linearity of expression was observed over 5 orders of magnitude in vitro and 3 orders of magnitude in vivo. Overall, the results demonstrate that mRNA provides excellent quantitative control over protein expression, also over extended periods of time.
Global Changes in Asexual Epichloë Transcriptomes during the Early Stages, from Seed to Seedling, of Symbiotum Establishment

Asexual Epichloë fungi are strictly seed-transmitted endophytic symbionts of cool-season grasses and spend their entire life cycle within the host plant. Endophyte infection can confer protective benefits to its host through the production of bioprotective compounds. Inversely, plants provide nourishment and shelter to the resident endophyte in return. Current understanding of the changes in global gene expression of asexual Epichloë endophytes during the early stages of host-endophyte symbiotum is limited. A time-course study using a deep RNA-sequencing approach was performed at six stages of germination, using seeds infected with one of three endophyte strains belonging to different representative taxa. Analysis of the most abundantly expressed endophyte genes identified that most were predicted to have a role in stress and defence responses. The number of differentially expressed genes observed at early time points was greater than those detected at later time points, suggesting an active transcriptional reprogramming of endophytes at the onset of seed germination. Gene ontology enrichment analysis revealed dynamic changes in global gene expression consistent with the developmental processes of symbiotic relationships. Expression of pathway genes for biosynthesis of key secondary metabolites was studied comprehensively and fuzzy clustering identified some unique expression patterns. Furthermore, comparisons of the transcriptomes from three endophyte strains in planta identified genes unique to each strain, including genes predicted to be associated with secondary metabolism. Findings from this study highlight the importance of better understanding the unique properties of individual endophyte strains and will serve as an excellent resource for future studies of host-endophyte interactions.
Effectiveness of Ultrasound Therapy on the Management of Chronic Non-Specific Low Back Pain: A Systematic Review

Abstract Non-specific chronic low back pain is the most common self-reported kind of musculoskeletal ache associated with substantial health and socioeconomic problem and responsible for most years lived with a disability as compared with any other medical condition. So treating chronic non-specific low back pain is one of the main problems faced among physical therapists in the rehabilitation area. The effects of ultrasound for patients with non-specific chronic low back pain remain unknown, however it is commonly used to treat clients with low back pain in rehabilitation setting. Therefore, the main aim of this review was to evaluate the up-to-date confirmation in the efficacy of ultrasound therapy on the treatment of non-specific chronic low back pain. A comprehensive search of four computerized electronic databases was performed to identify the effectiveness of ultrasound therapy on the management of chronic non-specific low back pain. Searching was done through the Google Scholar, PubMed, ScienceDirect, and Physiotherapy Evidence Databases (PEDro) and reported using preferred reporting items for systematic reviews and meta-analyses guidelines. The qualities of articles were appraised by the PEDro scale. The primary outcome measure visual analog scale was used. Six randomized clinical trials with a total sample size of 699 patients from the electronic database published in English were identified. In this review, the effect of UST in five articles was statically significant in reducing the visual analog scale (p<0.05) score. So this systematic review found ultrasound therapy could be an alternative treatment to reduce the intensity of pain in subjects with non-specific chronic LBP.
Age-Specific Seasonal Influenza Vaccine Effectiveness against Different Influenza Subtypes in the Hospitalized Population in Lithuania during the 2015–2019 Influenza Seasons

Background: Continuous monitoring of seasonal influenza vaccine effectiveness (SIVE) is needed due to the changing nature of influenza viruses and it supports the decision on the annual update of vaccine composition. Age-specific SIVE was evaluated against different influenza subtypes in the hospitalized population in Lithuania during four influenza seasons. Methods: A test-negative case-control study design was used. SIVE and its 95% confidence intervals (95% CI) were calculated as (1 – odds ratio (OR)) × 100%. Results: Adjusted SIVE in 18–64-year-old individuals against influenza A, A(H1N1)pdm09 and B/Yamagata were 78.0% (95% CI: 1.7; 95.1%), 88.6% (95% CI: −47.4; 99.1%), and 76.8% (95% CI: −109.9; 97.4%), respectively. Adjusted SIVE in individuals aged 65 years and older against influenza A, influenza B, and B/Yamagata were 22.6% (95% CI: −36.5; 56.1%), 75.3% (95% CI: 12.2; 93.1%) and 73.1% (95% CI: 3.2; 92.5%), respectively. Unadjusted SIVE against influenza A(H3N2) among 18–64-year-old patients was 44.8% (95% CI: −171.0; 88.8%) and among those aged 65 years and older was 5.0% (95% CI: −74.5; 48.3%). Conclusions: Point estimates suggest high SIVE against influenza A in 18–64-year-old participants, and against influenza B and B/Yamagata in those 65 years old and older.
High-Frequency Magnetoimpedance (MI) and Stress-MI in Amorphous Microwires with Different Anisotropies

Magnetoimpedance (MI) in Co-based microwires with an amorphous and partially crystalline state was investigated at elevated frequencies (up to several GHz), with particular attention paid to the influence of tensile stress on the MI behavior, which is called stress-MI. Two mechanisms of MI sensitivity related to the DC magnetization re-orientation and AC permeability dispersion were discussed. Remarkable sensitivity of impedance changes with respect to applied tensile stress at GHz frequencies was obtained in partially crystalline wires subjected to current annealing. Increasing the annealing current enhanced the axial easy anisotropy of a magnetoelastic origin, which made it possible to increase the frequency of large stress-MI: for 90mA-annealed wire, the impedance at 2 GHz increased by about 300% when a stress of 450 MPa was applied. Potential applications included sensing elements in stretchable substrates for flexible electronics, wireless sensors, and tunable smart materials. For reliable microwave measurements, an improved SOLT (short-open-load-thru) calibration technique was developed that required specially designed strip cells as wire holders. The method made it possible to precisely measure the impedance characteristics of individual wires, which can be further employed to characterize the microwave scattering at wire inclusions used as composites fillers.
Effects of cytokine blocking agents on hospital mortality in patients admitted to ICU with acute respiratory distress syndrome by SARS-CoV-2 infection: retrospective cohort study

Background The use of cytokine-blocking agents has been proposed to modulate the inflammatory response in patients with COVID-19. Tocilizumab and anakinra were included in the local protocol as an optional treatment in critically ill patients with acute respiratory distress syndrome (ARDS) by SARS-CoV-2 infection. This cohort study evaluated the effects of therapy with cytokine blocking agents on in-hospital mortality in COVID-19 patients requiring mechanical ventilation and admitted to intensive care unit. Methods The association between therapy with tocilizumab or anakinra and in-hospital mortality was assessed in consecutive adult COVID-19 patients admitted to our ICU with moderate to severe ARDS. The association was evaluated by comparing patients who received to those who did not receive tocilizumab or anakinra and by using different multivariable Cox models adjusted for variables related to poor outcome, for the propensity to be treated with tocilizumab or anakinra and after patient matching. Results Sixty-six patients who received immunotherapy (49 tocilizumab, 17 anakinra) and 28 patients who did not receive immunotherapy were included. The in-hospital crude mortality was 30,3% in treated patients and 50% in nontreated (OR 0.77, 95% CI 0.56-1.05, p=0.069). The adjusted Cox model showed an association between therapy with immunotherapy and in-hospital mortality (HR 0.40, 95% CI 0.19-0.83, p=0.015). This protective effect was further confirmed in the analysis adjusted for propensity score, in the propensity-matched cohort and in the cohort of patients with invasive mechanical ventilation within 2 hours after ICU admission. Conclusions Although important limitations, our study showed that cytokine-blocking agents seem to be safe and to improve survival in COVID-19 patients admitted to ICU with ARDS and the need for mechanical ventilation.
Current Use, Perceived Barriers, and Learning Preference of Point of Care Ultrasound (POCUS) in the Emergency Medicine in Qatar – A Mixed Design

Introduction Point of care ultrasound (POCUS) has been a part of emergency medicine (EM) training for almost two decades. EM training program has a very broad and rigorous POCUS curricula which, in several cases, does not translate to routine application in clinical settings. This study therefore sought to compare the indications, utilization, barriers, and preferred POCUS educational method in a large Middle Eastern academic EM. Methodology A validated questionnaire was emailed to 50 EM faculties between April and May 2019. Volunteer faculty members partook in a semi-structured interview to better understand the indications, current use, barriers, and preferred learning method. Responses were anonymous, and data were analyzed with descriptive statistics. Results This was a mixed design study. 30/50 (60%) of faculty responded to the survey, with a mean age of 39.2 years and a mean number of years in practice, 13.1. 55% (n=28) completed POCUS training in less than five years, while 45% completed more than five years ago and 5% never completed it. Forty percent of EM physicians were trained in Africa, while 55% were qualified in Asia and 5% completed their training in Europe. The indications and frequently performed procedures were consistent with the previous research. The common barrier reported was lack of time, lack of credentialing, lack of quality assurance, and national guidelines. The majority of the faculty preferred a blended learning approach for POCUS. Conclusion POCUS perceived barriers to its full use include time constraints, lack of national guidelines, and credentialing (awarding POCUS qualifications) of the faculty. Blended learning appears to be the preferred approach towards acquiring the knowledge and skills of POCUS.
An Entropy-Based Approach to Measurement of Stock Market Depth

The aim of this study is to investigate market depth as a stock market liquidity dimension. A new methodology for market depth measurement exactly based on Shannon information entropy for high-frequency data is introduced and utilized. The proposed entropy-based market depth indicator is supported by an algorithm inferring the initiator of a trade. This new indicator seems to be a promising liquidity measure. Both market entropy and market liquidity can be directly measured by the new indicator. The findings of empirical experiments for real-data with a time stamp rounded to the nearest second from the Warsaw Stock Exchange (WSE) confirm that the new proxy enables us to effectively compare market depth and liquidity for different equities. Robustness tests and statistical analyses are conducted. Furthermore, an intra-day seasonality assessment is provided. Results indicate that the entropy-based approach can be considered as an auspicious market depth and liquidity proxy with an intuitive base for both theoretical and empirical analyses in financial markets.
Genome-Wide Analysis of Sex Disparities in the Genetic Architecture of Lung and Colorectal Cancers

Almost all complex disorders have manifested epidemiological and clinical sex disparities which might partially arise from sex-specific genetic mechanisms. Addressing such differences can be important from a precision medicine perspective which aims to make medical interventions more personalized and effective. We investigated sex-specific genetic associations with colorectal (CRCa) and lung (LCa) cancers using genome-wide single-nucleotide polymorphisms (SNPs) data from three independent datasets. The genome-wide association analyses revealed that 33 SNPs were associated with CRCa/LCa at P < 5.0 × 10−6 neither males or females. Of these, 26 SNPs had sex-specific effects as their effect sizes were statistically different between the two sexes at a Bonferroni-adjusted significance level of 0.0015. None had proxy SNPs within their ±1 Mb regions and the closest genes to 32 SNPs were not previously associated with the corresponding cancers. The pathway enrichment analyses demonstrated the associations of 35 pathways with CRCa or LCa which were mostly implicated in immune system responses, cell cycle, and chromosome stability. The significant pathways were mostly enriched in either males or females. Our findings provided novel insights into the potential sex-specific genetic heterogeneity of CRCa and LCa at SNP and pathway levels.
The Effect of Chemical Structure of OEG Ligand Shells with Quaternary Ammonium Moiety on the Colloidal Stabilization, Cellular Uptake and Photothermal Stability of Gold Nanorods

Purpose Plasmonic photothermal cancer therapy by gold nanorods (GNRs) emerges as a promising tool for cancer treatment. The goal of this study was to design cationic oligoethylene glycol (OEG) compounds varying in hydrophobicity and molecular electrostatic potential as ligand shells of GNRs. Three series of ligands with different length of OEG chain (ethylene glycol units = 3, 4, 5) and variants of quaternary ammonium salts (QAS) as terminal functional group were synthesized and compared to a prototypical quaternary ammonium ligand with alkyl chain – (16-mercaptohexadecyl)trimethylammonium bromide (MTAB). Methods Step-by-step research approach starting with the preparation of compounds characterized by NMR and HRMS spectra, GNRs ligand exchange evaluation through characterization of cytotoxicity and GNRs cellular uptake was used. A method quantifying the reshaping of GNRs was applied to determine the effect of ligand structure on the heat transport from GNRs under fs-laser irradiation. Results Fourteen out of 18 synthesized OEG compounds successfully stabilized GNRs in the water. The colloidal stability of prepared GNRs in the cell culture medium decreased with the number of OEG units. In contrast, the cellular uptake of OEG+GNRs by HeLa cells increased with the length of OEG chain while the structure of the QAS group showed a minor role. Compared to MTAB, more hydrophilic OEG compounds exhibited nearly two order of magnitude lower cytotoxicity in free state and provided efficient cellular uptake of GNRs close to the level of MTAB. Regarding photothermal properties, OEG compounds evoked the photothermal reshaping of GNRs at lower peak fluence (14.8 mJ/cm2) of femtosecond laser irradiation than the alkanethiol MTAB. Conclusion OEG+GNRs appear to be optimal for clinical applications with systemic administration of NPs not-requiring irradiation at high laser intensity such as drug delivery and photothermal therapy inducing apoptosis.
Care-Seeking for Fever for Children Under the Age of Five Before and After the Free Healthcare Initiative in Burkina Faso: Evidence from Three Population-Based Surveys

Background In 2016, a free healthcare policy (FHP) was implemented in Burkina Faso for children under the age of five. In our study, we aimed to determine the prevalence of care-seeking for a fever in children under the age of five before and after the implementation of the FHP and to analyze the determinants of not seeking care under the FHP. Methods The data of three nationally representative surveys were used to evaluate the trends of the prevalence of care-seeking. We performed a modified Poisson regression using a generalized estimating equation to determine the factors associated with not seeking care. Results The prevalence for care seeking increased from 57.5% (95% CI, 54.2–60.8) in 2014 to 72.3% (95% CI, 68.1–76.2) in 2017. Children from the poor quintile were less likely to seek care when compared to children from the poorest quintile (prevalence ratio (PR) = 0.7 (95% CI, 0.5–0.9)). Caregivers who did not have messages regarding malaria in the past six months were more likely not to seek care (PR = 0.8 (95% CI, 0.7–0.9)). Caregivers of children aged 36–59 months were more likely not to seek care compared to those aged <12 months (PR = 1.6 (95% CI, 1.2–2.1)). Children from the Boucle du Mouhoun region (PR = 1.9 (95% CI, 1.2–3.2)) and the Centre-Est region (PR = 1.9 (95% CI, 1.2–3.0)) were more likely not to seek care compared to children from the Sud Ouest region. Conclusion Our study showed an increase in the prevalence of care-seeking after the implementation of the FHP. Even if this is encouraging, these findings highlight the critical importance of non-financial barriers to care-seeking. Maintaining FHP and tackling the barriers should be considered by policy makers to increase care-seeking.
Fabrication of X-ray Gratings for Interferometric Imaging by Conformal Seedless Gold Electroplating

We present a method to produce small pitch gratings for X-ray interferometric imaging applications, allowing the phase sensitivity to be increased and/or the length of the laboratory setup to be minimized. The method is based on fabrication of high aspect ratio silicon microstructures using deep reactive ion etching (Bosch technique) of dense grating arrays and followed by conformal electroplating of Au. We demonstrated that low resistivity Si substrates (<0.01 Ohm·cm) enable the metal seeding layer deposition step to be avoided, which is normally required to initiate the electroplating process. Etching conditions were optimized to realize Si recess structures with a slight bottom tapering, which ensured the void-free Au filling of the trenches. Vapor HF was used to remove the native oxide layer from the Si grating surface prior to electroplating in the cyanide-based Au electrolyte. Fabrication of Au gratings with pitch in the range 1.2–3.0 µm was successfully realized. A substantial improved aspect ratio of 45:1 for a pitch size of 1.2 µm was achieved with respect to the prior art on 4-inch wafer-based technology. The fabricated Au gratings were tested with X-ray interferometers in Talbot–Laue configuration with measured visibility of 13% at an X-ray design energy of 26 keV.
Involvement of a Multidrug Efflux Pump and Alterations in Cell Surface Structure in the Synergistic Antifungal Activity of Nagilactone E and Anethole against Budding Yeast Saccharomyces cerevisiae

Nagilactone E, an antifungal agent derived from the root bark of Podocarpus nagi, inhibits 1,3-β glucan synthesis; however, its inhibitory activity is weak. Anethole, the principal component of anise oil, enhances the antifungal activity of nagilactone E. We aimed to determine the combinatorial effect and underlying mechanisms of action of nagilactone E and anethole against the budding yeast Saccharomyces cerevisiae. Analyses using gene-deficient strains showed that the multidrug efflux pump PDR5 is associated with nagilactone E resistance; its transcription was gradually restricted in cells treated with the drug combination for a prolonged duration but not in nagilactone-E-treated cells. Green-fluorescent-protein-tagged Pdr5p was intensively expressed and localized on the plasma membrane of nagilactone-E-treated cells but not in drug-combination-treated cells. Quick-freeze deep-etch electron microscopy revealed the smoothening of intertwined fiber structures on the cell surface of drug-combination-treated cells and spheroplasts, indicating a decline in cell wall components and loss of cell wall strength. Anethole enhanced the antifungal activity of nagilactone E by enabling its retention within cells, thereby accelerating cell wall damage. The combination of nagilactone E and anethole can be employed in clinical settings as an antifungal, as well as a food preservative to restrict food spoilage.