Miracle-dz/UniFAR-FTUs huggingface dataset:
Why do trainees leave hospital-based specialty training? A nationwide survey study investigating factors involved in attrition and subsequent career choices in the Netherlands

Objective To gain insight into factors involved in attrition from hospital-based medical specialty training and future career plans of trainees who prematurely left their specialty training programme. Design Nationwide online survey study. Setting Postgraduate education of all hospital-based specialties in the Netherlands. Participants 174 trainees who prematurely left hospital-based medical specialty training between January 2014 and September 2017. Main outcome measures Factors involved in trainees’ decisions to leave specialty training and their subsequent career plans. Results The response rate was 38%. Of the responders, 25% left their programme in the first training year, 50% in year 2–3 and 25% in year 4–6. The most frequently reported factors involved in attrition were: work-life balance, job content, workload and specialty culture. Of the leaving trainees, 66% switched to another specialty training programme, of whom two-thirds chose a non-hospital-based training programme. Twelve per cent continued their career in a non-clinical role and the remainder had no specific plans yet. Conclusions This study provides insight in factors involved in attrition and in future career paths. Based on our findings, possible interventions to reduce attrition are: (1) enable candidates to develop a realistic view on job characteristics and demands, prior to application; (2) provide individual guidance during specialty training, with emphasis on work-life balance and fit with specialty.
An agonist of the MscL channel affects multiple bacterial species and increases membrane permeability and potency of common antibiotics

The bacterial MscL channel normally functions as an emergency release valve discharging cytoplasmic solutes upon osmotic stress. The channel opens and passes molecules up to 30 Å and its pore is the largest of any gated channel. Opening the MscL pore inappropriately is detrimental to the bacterial cell, suggesting MscL as a potential novel drug target. A small‐molecule compound, 011A, has been shown to increase sensitivity of the Escherichia coli MscL channel, slow growth, and even decrease viability of quiescent cultures. The mscL gene is highly conserved and found in the vast majority of bacterial species, including pathogens. Here, we test the hypothesis that 011A can influence the growth and viability of other bacterial species, specifically Staphylococcus aureus and Mycobacterium smegmatis, in a MscL‐dependent manner. Furthermore, we demonstrate that the 011A compound can increase potency of other antibiotics, presumably by permeabilizing the membrane and allowing easier access of the antibiotic into the cytoplasm. Thus, MscL activators have potential as novel broad‐spectrum antibiotics or adjuvants that work with antibiotics to selectively allow passage across bacterial membranes.
Surveillance for Adenoviruses in Bats in Italy

Adenoviruses are important pathogens of humans and animals. Bats have been recognized as potential reservoirs of novel viruses, with some viruses being regarded as a possible zoonotic threat to humans. In this study, we report the detection and analysis of adenoviruses from different bat species in northern Italy. Upon sequence and phylogenetic analysis, based on a short diagnostic fragment of the highly-conserved DNA polymerase gene, we identified potential novel candidate adenovirus species, including an avian-like adenovirus strain. An adenovirus isolate was obtained in simian cell lines from the carcass of a Pipistrellus kuhlii, and the complete genome sequence was reconstructed using deep sequencing technologies. The virus displayed high nucleotide identity and virtually the same genome organization as the Pipistrellus pipistrellus strain PPV1, isolated in Germany in 2007. Gathering data on epidemiology and the genetic diversity of bat adenoviruses may be helpful to better understand their evolution in the mammalian and avian hosts.
Prediction of ventricular arrhythmias in patients with a spontaneous Brugada type 1 pattern: the key is in the electrocardiogram.

AIMS There is currently no reliable tool to quantify the risks of ventricular fibrillation or sudden cardiac arrest (VF/SCA) in patients with spontaneous Brugada type 1 pattern (BrT1). Previous studies showed that electrocardiographic (ECG) markers of depolarization or repolarization disorders might indicate elevated risk. We aimed to design a VF/SCA risk prediction model based on ECG analyses for adult patients with spontaneous BrT1. METHODS AND RESULTS This retrospective multicentre international study analysed ECG data from 115 patients (mean age 45.1 ± 12.8 years, 105 males) with spontaneous BrT1. Of these, 45 patients had experienced VF/SCA and 70 patients did not experience VF/SCA. Among 10 ECG markers, a univariate analysis showed significant associations between VF/SCA and maximum corrected Tpeak-Tend intervals ≥100 ms in precordial leads (LMaxTpec) (P < 0.001), BrT1 in a peripheral lead (pT1) (P = 0.004), early repolarization in inferolateral leads (ER) (P < 0.001), and QRS duration ≥120 ms in lead V2 (P = 0.002). The Cox multivariate analysis revealed four predictors of VF/SCA: the LMaxTpec [hazard ratio (HR) 8.3, 95% confidence interval (CI) 2.4-28.5; P < 0.001], LMaxTpec + ER (HR 14.9, 95% CI 4.2-53.1; P < 0.001), LMaxTpec + pT1 (HR 17.2, 95% CI 4.1-72; P < 0.001), and LMaxTpec + pT1 + ER (HR 23.5, 95% CI 6-93; P < 0.001). Our multidimensional penalized spline model predicted the 1-year risk of VF/SCA, based on age and these markers. CONCLUSION LMaxTpec and its association with pT1 and/or ER indicated elevated VF/SCA risk in adult patients with spontaneous BrT1. We successfully developed a simple risk prediction model based on age and these ECG markers.
Finding problems in, proposing solutions to, and performing analysis on imbalanced data

The data mining and machine learning research communities have focused on developing specialized algorithms and methods to handle a multitude of potential complications which may confront the traditional supervised learning task. Of these, class imbalance is among the most persistent in real-world applications. Less attention has been garnered for the set of problems in which the data distribution changes, potentially wiping out the gains from expensive data mining methods. To an even lesser degree has the combination of problems been considered. It is the purpose of this dissertation to explore concepts of distributional change, particularly within the context of imbalanced data problems and the effects of the performance on solutions from this realm. Based on this exploration, the proposed dissertation will derive methods to identify and handle both problems simultaneously.
An update on advanced dual-energy CT for head and neck cancer imaging

ABSTRACT Introduction: Dual-energy-computed tomography (DECT) is an advanced form of computed tomography (CT) that enables spectral tissue characterization beyond what is possible with conventional CT scans. DECT can improve non-invasive diagnostic evaluation of the neck, especially for the evaluation of head and neck cancer. Areas covered: This article is a review of current applications of DECT for the evaluation of head and neck cancer, focusing largely on squamous cell carcinoma (HNSCC). The article will begin with a brief overview of principles and different approaches for DECT scanning. This will be followed by a review of different DECT applications in diagnostic imaging and radiation oncology, practical and workflow considerations, and various emerging advanced applications for tumor analysis, including the use of DECT datasets for radiomics and machine learning applications. Expert opinion: Using a multi-parametric approach, different DECT reconstructions can be used to improve diagnostic evaluation and surveillance of head and neck cancer, including improving visibility of HNSCC, determination of tumor boundaries and extent, and invasion of critical organs such as the thyroid cartilage. In the future, the large amount of quantitative information on DECT scans may be leveraged for improving radiomic and machine learning models for tumor characterization.
In vitro human helper T-cell assay to screen antibody drug candidates for immunogenicity

Abstract Monoclonal antibody (mAb) drugs offer a number of valuable treatments. Many newly developed mAb drugs include artificial modification of amino acid sequences from human origin, which may cause higher immunogenicity to induce anti-drug antibodies (ADA). If the immunogenicity of a new candidate can be understood in the nonclinical phase, clinical studies will be safer and the success rate of development improved. Empirically, in vitro immunogenicity assays with human cells have proved to be sufficiently sensitive to nonhuman proteins, but not to human/humanized mAb. To detect the weaker immunogenicity of human-based mAb, a more sensitive biomarker for in vitro assays is needed. The in vitro study here developed a proliferation assay (TH cell assay) using flow cytometry analysis that can detect a slight increase in proliferating TH cells. Samples from 218 donors treated with a low-immunogenic drug (etanercept) were measured to determine a positive threshold level. With this threshold, positive donor percentages among PBMC after treatment with higher-immunogenicity mAb drugs were noted, that is, 39.5% with humanized anti-human A33 antibody (hA33), 27.3% with abciximab, 25.9% with adalimumab, and 14.8% with infliximab. Biotherapeutics with low immunogenicity yielded values of 0% for basiliximab and 3.7% for etanercept. These data showed a good comparability with previously reported incidences of clinical ADA with the evaluated drugs. Calculations based on the data here showed that a TH cell assay with 40 donors could provide statistically significant differences when comparing low- (etanercept) versus highly immunogenic mAb (except for infliximab). Based on the outcomes here, for screening purposes, a practical cutoff point of 3/20 positives with 20 donors was proposed to alert immunogenicity of mAb drug candidates.
Mitochondrial and autophagic alterations in skin fibroblasts from Parkinson disease patients with Parkin mutations

PRKN encodes an E3-ubiquitin-ligase involved in multiple cell processes including mitochondrial homeostasis and autophagy. Previous studies reported alterations of mitochondrial function in fibroblasts from patients with PRKN mutation-associated Parkinson’s disease (PRKN-PD) but have been only conducted in glycolytic conditions, potentially masking mitochondrial alterations. Additionally, autophagy flux studies in this cell model are missing. We analyzed mitochondrial function and autophagy in PRKN-PD skin-fibroblasts (n=7) and controls (n=13) in standard (glucose) and mitochondrial-challenging (galactose) conditions. In glucose, PRKN-PD fibroblasts showed preserved mitochondrial bioenergetics with trends to abnormally enhanced mitochondrial respiration that, accompanied by decreased CI, may account for the increased oxidative stress. In galactose, PRKN-PD fibroblasts exhibited decreased basal/maximal respiration vs. controls and reduced mitochondrial CIV and oxidative stress compared to glucose, suggesting an inefficient mitochondrial oxidative capacity to meet an extra metabolic requirement. PRKN-PD fibroblasts presented decreased autophagic flux with reduction of autophagy substrate and autophagosome synthesis in both conditions. The alterations exhibited under neuron-like oxidative environment (galactose), may be relevant to the disease pathogenesis potentially explaining the increased susceptibility of dopaminergic neurons to undergo degeneration. Abnormal PRKN-PD phenotype supports the usefulness of fibroblasts to model disease and the view of PD as a systemic disease where molecular alterations are present in peripheral tissues.
Immune System Stimulation Reduces the Efficiency of Whole-Body Protein Deposition and Alters Muscle Fiber Characteristics in Growing Pigs

Simple Summary Disease reduces growth and protein retention in pigs. Protein retention is the balance between two energy-consuming processes in the body of pigs: protein synthesis and breakdown. Previous reports on the effects of disease on these components of protein metabolism and their consecutive effects on protein retention are inconsistent. In addition, limited information is available about the effects of disease on the composition of muscle fibers in pigs. Thus, we evaluated these parameters, since they help us to understand protein metabolism during disease in pigs. We used twelve gilts; five were used as a control and seven were made ill. Experimental diets were designed to supply nutrients that closely met the daily requirements of each group. Protein synthesis, protein breakdown, and protein retention were measured over 72 h. Pigs were then euthanized and various muscles were sampled. Our findings suggested that disease not only reduces protein retention by decreasing protein synthesis and protein breakdown, but also by reducing the efficiency of protein deposition. In other words, ill pigs synthesize more protein per unit of protein retention, compared to healthy pigs. In addition, disease reduces muscle mass and changes the composition of the muscle fibers. The latter might negatively affect pork quality. Abstract The effects of immune system stimulation (ISS), induced by repeated injection of Escherichia coli lipopolysaccharide, on the whole-body protein synthesis versus degradation rates, the efficiency of protein deposition (PD), and muscle fiber characteristics in pigs were evaluated. Twelve growing gilts were assigned to two levels of amino acid intake that was predicted based on the potential of each group’s health status for PD and feed intake. Isotope tracer, nitrogen balance, and immunohistochemical staining techniques were used to determine protein turnover, PD, and muscle fiber characteristics, respectively. Protein synthesis, degradation, and PD were lower in immune-challenged pigs than in control pigs (p < 0.05). Strong tendencies for a higher protein synthesis-to-PD ratio (p = 0.055) and a lower protein synthesis-to-degradation ratio (p = 0.065) were observed in immune-challenged pigs. A decrease in muscle cross-sectional area of fibers and a shift from myosin heavy chain (MHC)-II towards MHC-I fibers (p < 0.05) were observed in immune-challenged pigs. These results indicated that ISS reduces PD not only by suppressing the whole-body protein synthesis and degradation rates, but also by decreasing the efficiency of PD in growing pigs. In addition, ISS induces atrophy in skeletal muscles and favors a slow-twitch oxidative fiber type composition.
Dissecting macromolecular recognition sites in ribosome: implication to its self-assembly

ABSTRACT Interactions between macromolecules play a crucial role in ribosome assembly that follows a highly coordinated process involving RNA folding and binding of ribosomal proteins (r-proteins). Although extensive studies have been carried out to understand macromolecular interactions in ribosomes, most of them are confined to either large or small ribosomal-subunit of few species. A comparative analysis of macromolecular interactions across different domains is still missing. We have analyzed the structural and physicochemical properties of protein-protein (PP), protein-RNA (PR) and RNA-RNA (RR) interfaces in small and large subunits of ribosomes, as well as in between the two subunits. Additionally, we have also developed Random Forest (RF) classifier to catalog the r-proteins. We find significant differences as well as similarities in macromolecular recognition sites between ribosomal assemblies of prokaryotes and eukaryotes. PR interfaces are substantially larger and have more ionic interactions than PP and RR interfaces in both prokaryotes and eukaryotes. PP, PR and RR interfaces in eukaryotes are well packed compared to those in prokaryotes. However, the packing density between the large and the small subunit interfaces in the entire assembly is strikingly low in both prokaryotes and eukaryotes, indicating the periodic association and dissociation of the two subunits during the translation. The structural and physicochemical properties of PR interfaces are used to predict the r-proteins in the assembly pathway into early, intermediate and late binders using RF classifier with an accuracy of 80%. The results provide new insights into the classification of r-proteins in the assembly pathway.
Subclinical arterial damage in children and adolescents with type 1 diabetes: A systematic review and meta‐analysis

Type 1 diabetes is an important risk factor for the development of cardiovascular disease. Pulse wave velocity (PWV) and carotid intima‐media thickness (cIMT) measurements are well recognized as independent predictors for future cardiovascular disease. The aim of the present study was to systematically review the literature and conduct a meta‐analysis assessing measures of subclinical arterial damage in children and adolescents with type 1 diabetes in comparison to healthy controls.
Comparison of diets enriched in stearic, oleic, and palmitic acids on inflammation, immune response, cardiometabolic risk factors, and fecal bile acid concentrations in mildly hypercholesterolemic postmenopausal women-randomized crossover trial.

BACKGROUND Direct comparisons between SFAs varying in chain length, specifically palmitic acid (16:0) and stearic acid (18:0), relative to the latter's metabolic product, oleic acid (18:1), on cardiometabolic risk factors are limited. OBJECTIVE The aim of this study was to determine the relative comparability of diets enriched in palmitic acid, stearic acid, and oleic acid on inflammation and coagulation markers, T lymphocyte proliferation/ex-vivo cytokine secretion, plasma cardiometabolic risk factors, and fecal bile acid concentrations. METHODS Hypercholesterolemic postmenopausal women (n = 20, mean ± SD age 64 ± 7 y, BMI 26.4 ± 3.4 kg/m2, LDL cholesterol ≥ 2.8 mmol/L) were provided with each of 3 diets [55% energy (%E) carbohydrate, 15%E protein, 30%E fat, with ∼50% fat contributed by palmitic acid, stearic acid, or oleic acid in each diet; 5 wk/diet phase] using a randomized crossover design with 2-wk washouts between phases. Outcome measures were assessed at the end of each phase. RESULTS Fasting LDL-cholesterol and non-HDL-cholesterol concentrations were lower after the stearic acid and oleic acid diets than the palmitic acid diet (all P < 0.01). Fasting HDL-cholesterol concentrations were lower after the stearic acid diet than the palmitic acid and oleic acid diets (P < 0.01). The stearic acid diet resulted in lower lithocholic acid (P = 0.01) and total secondary bile acid (SBA) concentrations (P = 0.04) than the oleic acid diet. All other outcome measures were similar between diets. Lithocholic acid concentrations were positively correlated with fasting LDL-cholesterol concentrations (r = 0.33; P = 0.011). Total SBA, lithocholic acid, and deoxycholic acid concentrations were negatively correlated with fasting HDL cholesterol (r = -0.51 to -0.44; P < 0.01) concentrations and positively correlated with LDL cholesterol:HDL cholesterol (r = 0.37-0.54; P < 0.01) ratios. CONCLUSIONS Dietary stearic acid and oleic acid had similar effects on fasting LDL-cholesterol and non-HDL-cholesterol concentrations and more favorable ones than palmitic acid. Unlike oleic acid, the hypocholesterolemic effect of stearic acid may be mediated by inhibition of intestinal hydrophobic SBA synthesis. These findings add to the data suggesting there should be a reassessment of current SFA dietary guidance and Nutrient Facts panel labeling.This trial was registered at clinicaltrials.gov as NCT02145936.
Brain Metastasis and Renal Cell Carcinoma: Prognostic Scores Assessment in the Era of Targeted Therapies

Aim: This study aimed at exploring several brain metastatic prognostic scores in patients with renal cell carcinoma. Patients and Methods: We retrospectively analyzed data of 93 metastatic renal cell carcinoma patients who were diagnosed with brain metastases between October 2005 and July 2016 who received targeted therapy. Potential prognostic factors (RTOG RPA, BS-BM, and a newly developed score CERENAL) were analyzed. Results: A total of 75 patients received targeted therapy. All scores showed prognostic value in progression-free survival after first-line treatment with CERENAL being the sole independent prognostic factor associated with improved duration of first-line treatment. Both RTOG RPA and CERENAL were potential prognosticators for overall survival, whereas only the CERENAL score was associated with prolonged disease-specific survival. Conclusion: Several prognostic scores can be useful to predict survival of patients with brain metastases from renal cancer, especially the newly developed CERENAL score.
Medial Temporal Atrophy in Amyloid-Negative Amnestic Type Dementia Is Associated with High Cerebral White Matter Hyperintensity.

BACKGROUND Non-amyloid mechanisms behind neurodegeneration and cognition impairment are unclear. Cerebrovascular disease (CVD) may play an important role in suspected non-Alzheimer's pathophysiology (SNAP), especially in Asia. OBJECTIVE To examine the association between CVD and medial temporal lobe atrophy (MTA) in amyloid-β negative patients with mild amnestic type dementia. METHODS Thirty-six mild dementia patients with complete neuropsychological, cerebrospinal fluid (CSF) biomarker, and neuroimaging information were included. Only patients with clinically significant MTA were recruited. Patients were categorized based on their CSF Aβ levels. Neuroimaging and neuropsychological variables were analyzed. RESULTS Despite comparable MTA between Aβ positive and negative patients, Aβ-negative patients had significantly greater white matter hyperintensities (WMH; Total Fazekas Rating) than their Aβ-positive counterparts (6.42 versus 4.19, p = 0.03). A larger proportion of Aβ-negative patients also had severe and confluent WMH. Regression analyses controlling for baseline characteristics yielded consistent results. CONCLUSION Our findings demonstrate that MTA is associated with greater CVD burden among Aβ-negative patients with amnestic type dementia. CVD may be an important mechanism behind hippocampal atrophy. This has implications on clinical management strategies, where measures to reduce CVD may slow neurodegeneration and disease progression.