Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacokinetic and pharmacodynamic considerations of cephalosporin use in children

ABSTRACT Introduction: Cephalosporins are a major class of antibiotics, frequently used in children because of their remarkable antibacterial activity and excellent safety profile. Time above the minimal inhibitory concentration of the non-protein-bound fraction (fT>MIC) is the pharmacokinetic/pharmacodynamic parameter that correlates with the therapeutic efficacy. In the pediatric population, the inter-individual variability in cephalosporin pharmacokinetics is large because of maturational changes. However, the prescription of cephalosporins promotes emergence of Enterobacteriaceae producing broad-spectrum ß-lactamases. Areas covered: Here we describe in vitro activities and the main pharmacokinetic characteristics of cephalosporins in children. On the basis of these characteristics, we propose an estimation of the fT>MIC for each molecule as a tool to help optimize the use of cephalosporins. We also provide an inventory of the clinical use of cephalosporins and present prospects for the development of new molecules or associations to address the emergence of resistant strains. Expert opinion: Cephalosporins represent a heterogeneous group of antibiotics with various pharmacokinetics and in vitro antimicrobial activity that the clinician needs to master to optimize their use. However, their broad use plays a role in the emergence of broad-spectrum ß-lactamase–producing strains and must thus be restricted to probabilistic broad-spectrum therapy and situations without therapeutic alternatives.
Influence of Inflammation in Uveitis on Confocal Scanning Laser Tomography and Optical Coherence Tomography Measurements

ABSTRACT Purpose: To evaluate the influence of active inflammation in uveitis on confocal scanning laser tomography (CSLT) and optical coherence tomography (OCT) measurements. Methods: Prospective enrollment of patients (64 eyes) with non-infectious uveitis. Retinal nerve fiber layer (RNFL), rim-area and -volume for CSLT and Bruch’s-membrane-opening minimum-rim-width (BMO-MRW) and retinal nerve fiber layer thickness (RNFL-O) for OCT were recorded. Results: No significant differences between eyes with active inflammation (31) vs no inflammation (33) were observed for all investigated CSLT parameters and BMO-MRW. The RNFL-O in OCT was significantly increased (1st p = .0439, 2nd p = .0327, 3rd p = .0313) while actively inflamed. CSLT did not show a significant difference between glaucomatous and non-glaucomatous eyes albeit all OCT derived parameters did. Conclusion: CSLT measurements were not affected by inflammation but unreliable in glaucomatous eyes. RNFL-O was significantly influenced by inflammation while BMO-MRW was not. BMO-MRW seems to be the best approach in uveitic eyes.
Evaluation of Data Augmentation of MR Images for Deep Learning

Data augmentation is a process to create new artificial data by altering the available data set. It has by many been considered a key factor for increasing robustness and performance of image classification tasks using deep learning methods, such as the convolutional neural network. This report aims to investigate the effect of data augmentation for the segmentation of magnetic resonance (MR) images using neural networks. Geometric data augmentation techniques such as rotation, scaling, translation and elastic deformation are evaluated for different data set sizes. Also, motion artifacts are simulated in MR images as an augmentation to increase segmentation performance on images containing real artifacts. A method for simulating these artificial motion artifacts is developed, where the k-space of the image is altered to simulate patient movement due to breathing. Results showed that geometric data augmentation improved performance of the network for smaller data sets, but lost importance as the amount of available training data grew bigger. Segmentation performance of images containing motion artifacts significantly increased if the neural network had been trained on a training set augmented with simulated artifacts.
Detection of Colistin Resistance in Escherichia coli by Use of the MALDI Biotyper Sirius Mass Spectrometry System

Polymyxin antibiotics are a last-line treatment for multidrug-resistant Gram-negative bacteria. However, the emergence of colistin resistance, including the spread of mobile mcr genes, necessitates the development of improved diagnostics for the detection of colistin-resistant organisms in hospital settings. ABSTRACT Polymyxin antibiotics are a last-line treatment for multidrug-resistant Gram-negative bacteria. However, the emergence of colistin resistance, including the spread of mobile mcr genes, necessitates the development of improved diagnostics for the detection of colistin-resistant organisms in hospital settings. The recently developed MALDIxin test enables detection of colistin resistance by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) in less than 15 min but is not optimized for the mass spectrometers commonly found in clinical microbiology laboratories. In this study, we adapted the MALDIxin test for the MALDI Biotyper Sirius MALDI-TOF MS system (Bruker Daltonics). We optimized the sample preparation protocol by using a set of 6 mobile colistin resistance (MCR) protein-expressing Escherichia coli clones and validated the assay with a collection of 40 E. coli clinical isolates, including 19 confirmed MCR protein producers, 12 colistin-resistant isolates that tested negative for commonly encountered mcr genes (i.e., likely chromosomally resistant isolates), and 9 polymyxin-susceptible isolates. We calculated polymyxin resistance ratio (PRR) values from the acquired spectra; PRR values of 0, indicating polymyxin susceptibility, were obtained for all colistin-susceptible E. coli isolates, whereas positive PRR values, indicating resistance to polymyxins, were obtained for all resistant strains, independent of the genetic basis of resistance. Thus, we report a preliminary feasibility study showing that an optimized version of the MALDIxin test adapted for the routine MALDI Biotyper Sirius system provides an unbiased, fast, reliable, cost-effective, and high-throughput way of detecting colistin resistance in clinical E. coli isolates.
GHB roller-coaster: serotonin syndrome and withdrawal.

BACKGROUND In this paper we focus on adolescents in transition towards young adulthood (ATYA). We know from international studies that the transition process makes adolescents vulnerable to mental illness. However, little is known about Belgian ATYA mental-health status. Nor are risk factors associated with their mental illness understood, in particular with regard to depressive and anxiety disorder. The aim of this study is (1) to discuss evolution in time of prevalence of depressive disorder (DD) and anxiety disorder (AD) among Belgian ATYA and (2), to identify risk factors associated with these disorders among ATYA. SUBJECTS AND METHODS Data was extracted from the Belgian Health Interview Survey (BHIS), which is a cross-sectional population survey, carried out in 2001, 2004, 2008, and 2013. Information about the population's background characteristics, health services utilization, health behaviours and mental health status were extracted and statistically analyzed. RESULTS ATYA prevalence of DD and AD was higher in 2013 in comparison with previous years. These changes were significant only for DD (F=4.466, p=0.004). In contrast with younger adolescents, among ATYA odds of DD were 28.2% higher (OR 1.282, 95% CI 0.967-1.698, p=0.084) and, odds of AD were 55.2% higher (OR 1.552, 95% CI 1.137-2.119, p=0.006). For ATYA, a poor quality of social support was the most predictive factor of DD (OR 11.187, 95% CI 5.530-22.629, p<0.0001) and AD (OR 6.238, 95% CI 2.845-13.676, p<0.0001); whereas, having a paid job was the most protective factor with regard to DD (OR 0.282, 95% CI 0.169-0.470, p<0.0001) and AD (OR 0.552, 95% CI 0.330-0.924, p<0.024). CONCLUSION Prevalence of mental illness among Belgian ATYA appears to worsen in time. In comparison with younger adolescents, ATYA are more vulnerable to anxiety disorders. Adverse and protective risk factors were identified and discussed in a way to improve access, continuity and mental healthcare pathways for Belgian ATYA.
Strategies for improving clinical teaching in the emergency department: Applicable to clinical teachers and especially emergency medicine

The emergency department (ED) is one of the challenging educational environments in medical education. Clinical teaching at ED requires balancing the provision of patient care services, clinical teaching, and clinical experiences for learners at different levels of learning. Accordingly, using effective teaching strategies at teachable moments and getting feedback from learners provide a balance between patient care and education. This narrative review aimed to review strategies for improving clinical teaching in the ED. Searching the literature was done in ProQuest, PubMed, ISI Web of Science, as well as Science Direct databases, and Google Scholar search engine with the keywords, including "teaching model", "learning", "educational strategy", "training", "emergency department", "emergency medicine", "clinical teaching", "resident", and "medical student", in English language with no time limit for searching. Finally, after reviewing 53 abstracts, 19 articles were included in the present study. In this review, effective training in the ED and important determinants of adequate educational encounters were provided with suggestions on how to implement them in clinical settings. The eight main themes related to the study were extracted, including professional reflection, obvious expectations, interprofessional training, strategies for clinical teaching with limited time, strategies for effective bedside teaching, selecting a teaching strategy for ENGAGE multilevel learner, and applying the principles of adult learning and faculty development. Accordingly, to maximize learning opportunities in the ED, the faculty members' development is recommended for fulfilling accountability in the community.
Venlafaxine ER-related strong suicidal intent in an adult with lithium-treated severe major depression: a phenomenological proximity with other paradoxical reactions of psychoactive agents.

VENLAFAXINE ER-RELATED STRONG SUICIDAL INTENT IN AN ADULT WITH LITHIUM-TREATED SEVERE MAJOR DEPRESSION: A PHENOMENOLOGICAL PROXIMITY WITH OTHER PARADOXICAL REACTIONS OF PSYCHOACTIVE AGENTS Udo Bonnet & Uwe Knierim Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, Evangelisches Krankenhaus Castrop-Rauxel, Academic Teaching Hospital of the University of Duisburg/Essen, Castrop-Rauxel, Germany LVR Hospital Essen, Department of for Psychiatry and Psychotherapy, Medical Faculty, University of Duisburg-Essen, Essen, Germany
From childhood financial hardship to late-life depression: socioeconomic pathways

Abstract Objective Childhood financial hardship is associated with depression throughout the life course, including older adulthood. However, it is still unclear the extent to which occupation, education level and household income are mediators of this association. We aimed to examine the association between childhood financial hardship and late-life depression, and potential socioeconomic mediators using community-based data. Methods A nationally representative sample of 3623 non-institutionalized older Spanish adults aged 50+ was used. The associations between childhood financial hardship and depression, socioeconomic mediator variables and confounding variables such as chronic physical conditions, number of close people, and loneliness, were assessed through logistic regression models. Mediation analyses of socioeconomic variables were carried out. Results Older Spanish adults who experienced a poor childhood financial situation were nine times more likely to obtain a lower level of education than those with a good childhood financial situation, and about three times more likely to suffer from depression. Participants’ education level mediated about 35–40% of the association between childhood financial hardship and late-life depression whereas we found no significant mediation effect of household income and occupation skill. Conclusion Improving access to the educational system during the life course might result in a reduction in the prevalence of depression in the general population of older adults and particularly among individuals with low socioeconomic status.
Activity of Insula to Basolateral Amygdala Projecting Neurons is Necessary and Sufficient for Taste Valence Representation

Conditioned taste aversion (CTA) is an associative learning paradigm, wherein consumption of an appetitive tastant (e.g., saccharin) is paired to the administration of a malaise-inducing agent, such as intraperitoneal injection of LiCl. Aversive taste learning and retrieval require neuronal activity within the anterior insula (aIC) and the basolateral amygdala (BLA). Here, we labeled neurons of the aIC projecting to the BLA in adult male mice using a retro-AAV construct and assessed their necessity in aversive and appetitive taste learning. By restricting the expression of chemogenetic receptors in aIC-to-BLA neurons, we demonstrate that activity within the aIC-to-BLA projection is necessary for both aversive taste memory acquisition and retrieval, but not for its maintenance, nor its extinction. Moreover, inhibition of the projection did not affect incidental taste learning per se, but effectively suppressed aversive taste memory retrieval when applied either during or before the encoding of the unconditioned stimulus for CTA (i.e., malaise). Remarkably, activation of the projection after novel taste consumption, without experiencing any internal discomfort, was sufficient to form an artificial aversive taste memory, resulting in strong aversive behavior upon retrieval. Our results indicate that aIC-to-BLA projecting neurons are an essential component in the ability of the brain to associate taste sensory stimuli with body states of negative valence and guide the expression of valence-specific behavior upon taste memory retrieval. SIGNIFICANCE STATEMENT In the present study we subjected mice to the conditioned taste aversion paradigm, where animals learn to associate novel taste with malaise (i.e., assign it negative valence). We show that activation of neurons in the anterior insular cortex (aIC) that project into the basolateral amygdala (BLA) in response to conditioned taste aversion is necessary to form a memory for a taste of negative valence. Moreover, artificial activation of this pathway (without any feeling of pain) after the sampling of a taste can also lead to such associative memory. Thus, activation of aIC-to-BLA projecting neurons is necessary and sufficient to form and retrieve aversive taste memory.
Toward a rational approach to design split G-quadruplex probes.

Hybridization probes have become an indispensable tool for nucleic acid analysis. Systematic efforts in probe optimization resulted in their improved binding affinity, turn-on ratios, and ability to discriminate single nucleotide substitutions (SNSs). Split (or multicomponent) probes is a promising strategy to improve probe selectivity and enable analysis of folded analytes. Here, we developed criteria for the rational design of split G-quadruplex (G4) peroxidase-like deoxyribozyme (sPDz) probe that provides visual output signal. The sPDz probe consists of two DNA strands that hybridize to the abutting positions of a DNA/RNA target and form a G4 structure catalyzing, in the presence of a hemin cofactor, H2O2-mediated oxidation of organic compounds into their colored oxidation products. We have demonstrated that probe design becomes complicated in case of target sequences containing clusters (two or more) of cytosine residues, and developed strategies to overcome the challenges to achieve high signal-to-noise and excellent SNS discrimination. Specifically, to improve selectivity, a conformational constraint that stabilizes the probe's dissociated state is beneficial. If the signal intensity is compromised, introduction of flexible non-nucleotide linkers between the G4-forming and target-recognizing elements of the probe helps to decrease the steric hindrance for G4 PDz formation observed as a signal increase. Varying the modes of G4 core splitting is another instrument for the optimal sPDz design. The suggested algorithm was successfully utilized for the design of the sPDz probe interrogating a fragment of Influenza A virus genome (subtype H1N1), which can be of practical use for flu diagnostics and surveillance.
Environmental Toxicology and Chemistry

No‐observed‐effect concentrations (NOECs) are used in environmental hazard classification and labeling of chemicals and their environmental risk assessment. They are typically obtained using standard tests such as the fish early‐life stage (FELS) toxicity test, the chronic Daphnia reproduction test, and the algae growth inhibition test. Given the demand to replace and reduce animal tests, we explored the impact of the FELS toxicity test on the determination of effect concentrations by comparing the FELS toxicity test and the Daphnia and algae acute or chronic toxicity tests. Lowest‐observed‐ effect concentrations (LOECs) were used instead of NOECs for better comparison with median lethal or effect concentration data. A database of FELS toxicity data for 223 compounds was established. Corresponding Daphnia and algae toxicity tests were identified using established databases (US Environmental Protection Agency ECOTOX, Organisation for Economic Co‐operation and Development QSAR Toolbox, eChemPortal, EnviroTox, and OpenFoodTox). Approximately 9.5% of the investigated compounds showed a 10‐fold higher sensitivity with the FELS toxicity test in comparison with the lowest effect concentrations obtained with any of the other tests. Some of these compounds have been known or considered as endocrine disrupting, or are other non‐narcotic chemicals, indicating that the higher sensitivity in the FELS toxicity test is related to a specific mechanism of action. Targeting these mechanisms by alternative test systems or endpoints, using fish embryos for instance, may allow reduction or replacement of the FELS toxicity test or may allow us to prioritize compounds for conduction of the FELS toxicity test. Environ Toxicol Chem 2020;39:30–41. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.
‘Oil-drop’ pigmentation in psoriatic arthritis

A 48-year-old man was suffering from psoriasis with psoriatic arthritis for 8 years. His symptoms worsened over the last 3 months and he presented to our hospital with pain and swelling in the knees and ankles, skin lesions over shins, and elbows and discolouration of toenails. He was being treated with methotrexate 15 mg weekly. Examination revealed effusion in both knees. Psoriatic plaques were present over the anterior aspect of the …
Reciprocal interactions between mtDNA and lifespan control in budding yeast

Loss of mitochondrial DNA (mtDNA) results in loss of mitochondrial respiratory activity, checkpoint-regulated inhibition of cell cycle progression, defects in growth, and nuclear genome instability. However, after several generations, yeast cells can adapt to the loss of mtDNA. During this adaptation, rho0 cells, which have no mtDNA, exhibit increased growth rates and nuclear genome stabilization. Here, we report that an immediate response to loss of mtDNA is a decrease in replicative lifespan (RLS). Moreover, we find that adapted rho0 cells bypass the mtDNA inheritance checkpoint, exhibit increased mitochondrial function, and undergo an increase in RLS as they adapt to the loss of mtDNA. Transcriptome analysis reveals that metabolic reprogramming to compensate for defects in mitochondrial function is an early event during adaptation and that up-regulation of stress response genes occurs later in the adaptation process. We also find that specific subtelomeric genes are silenced during adaptation to loss of mtDNA. Moreover, we find that deletion of SIR3, a subtelomeric gene silencing protein, inhibits silencing of subtelomeric genes associated with adaptation to loss of mtDNA, as well as adaptation-associated increases in mitochondrial function and RLS extension.
Single-sample landscape entropy reveals the imminent phase transition during disease progression

Motivation: The time evolution or dynamic change of many biological systems during disease progression is not always smooth but occasionally abrupt, that is, there is a tipping point during such a process at which the system state shifts from the normal state to a disease state. It is challenging to predict such disease state with the measured omics data, in particular when only a single sample is available. Results: In this study, we developed a novel approach, i.e. single-sample landscape entropy (SLE) method, to identify the tipping point during disease progression with only one sample data. Specifically, by evaluating the disorder of a network projected from a single-sample data, SLE effectively characterizes the criticality of this single sample network in terms of network entropy, thereby capturing not only the signals of the impending transition but also its leading network, i.e. dynamic network biomarkers. Using this method, we can characterize sample-specific state during disease progression and thus achieve the disease prediction of each individual by only one sample. Our method was validated by successfully identifying the tipping points just before the serious disease symptoms from four real datasets of individuals or subjects, including influenza virus infection, lung cancer metastasis, prostate cancer and acute lung injury. Availability and implementation: https://github.com/rabbitpei/SLE. Contact: chenpei@scut.edu. cn or lnchen@sibs.ac. cn Supplementary information: Supplementary data are available at Bioinformatics online.
Star-PAP controlled alternative polyadenylation coupled poly(A) tail length regulates protein expression in hypertrophic heart

Abstract Alternative polyadenylation (APA)-mediated 3′-untranslated region (UTR) shortening is known to increase protein expression due to the loss of miRNA regulatory sites. Yet, mRNAs with longer 3′-UTR also show enhanced protein expression. Here, we identify a mechanism by which longer transcripts generated by the distal-most APA site leads to increased protein expression compared to the shorter transcripts and the longer transcripts are positioned to regulate heart failure (HF). A Star-PAP target gene, NQO1 has three poly(A) sites (PA-sites) at the terminal exon on the pre-mRNA. Star-PAP selects the distal-most site that results in the expression of the longest isoform. We show that the NQO1 distal-specific mRNA isoform accounts for the majority of cellular NQO1 protein. Star-PAP control of the distal-specific isoform is stimulated by oxidative stress and the toxin dioxin. The longest NQO1 transcript has increased poly(A) tail (PA-tail) length that accounts for the difference in translation potentials of the three NQO1 isoforms. This mechanism is involved in the regulation of cardiac hypertrophy (CH), an antecedent condition to HF where NQO1 downregulation stems from the loss of the distal-specific transcript. The loss of NQO1 during hypertrophy was rescued by ectopic expression of the distal- but not the proximal- or middle-specific NQO1 mRNA isoforms in the presence of Star-PAP expression, and reverses molecular events of hypertrophy in cardiomyocytes.