Miracle-dz/UniFAR-FTUs huggingface dataset:
Shared decision making: Does a physician's decision‐making style affect patient participation in treatment choices for primary immunodeficiency?

Abstract Overall health care spending in the United States is equivalent to more than 15% of GDP, yet outcomes rank below the top 25 in most quality categories when compared with other Organization for Economic Cooperation and Development (OECD) countries. The majority of spending is consumed by small patient populations with chronic diseases. Experts believe increased patient‐physician shared decision making (SDM) should result in better overall longitudinal care but understanding the physician's role in facilitating SDM is limited. Structural equation modelling was applied to results of a 2016 questionnaire‐based survey of 330 US physicians who treat approximately 55% of primary immune deficiency requiring immune globulin therapy; it tested the relationship between slow/rational vs fast/intuitive decision‐making styles and SDM as mediated by patient‐centric care and moderated by physician's trust in the patient. The results showed a statistically significant relationship between slow/rational decision making and SDM. The results also suggest differences related to age, gender, education, and race but no differences related to trust.
A metaanalysis of bat phylogenetics and positive selection based on genomes and transcriptomes from 18 species

Significance This work represents a large, order-wide evolutionary analysis of the order Chiroptera (bats). Our pipeline for assembling sequence data and curating orthologous multiple sequence alignments includes methods for improving results when combining genomic and transcriptomic data sources. The resulting phylogenetic tree divides the order Chiroptera into Yinpterochiroptera and Yangochiroptera, in disagreement with the previous division into Megachiroptera and Microchiroptera and in agreement with some other recent molecular studies, and also provides evidence for other contested branch placements. We also performed a genome-wide analysis of positive selection and found 181 genes with signatures of positive selection. Enrichment analysis shows these positively selected genes to be primarily related to immune responses but also, surprisingly, collagen formation. Historically, the evolution of bats has been analyzed using a small number of genetic loci for many species or many genetic loci for a few species. Here we present a phylogeny of 18 bat species, each of which is represented in 1,107 orthologous gene alignments used to build the tree. We generated a transcriptome sequence of Hypsignathus monstrosus, the African hammer-headed bat, and additional transcriptome sequence for Rousettus aegyptiacus, the Egyptian fruit bat. We then combined these data with existing genomic and transcriptomic data from 16 other bat species. In the analysis of such datasets, there is no clear consensus on the most reliable computational methods for the curation of quality multiple sequence alignments since these public datasets represent multiple investigators and methods, including different source materials (chromosomal DNA or expressed RNA). Here we lay out a systematic analysis of parameters and produce an advanced pipeline for curating orthologous gene alignments from combined transcriptomic and genomic data, including a software package: the Mismatching Isoform eXon Remover (MIXR). Using this method, we created alignments of 11,677 bat genes, 1,107 of which contain orthologs from all 18 species. Using the orthologous gene alignments created, we assessed bat phylogeny and also performed a holistic analysis of positive selection acting in bat genomes. We found that 181 genes have been subject to positive natural selection. This list is dominated by genes involved in immune responses and genes involved in the production of collagens.
Prevention of Lateral Ankle Sprains.

CONTEXT Given the frequency of ankle sprains, especially in the athletic population, prevention is a primary task of athletic trainers and other sports health care professionals. OBJECTIVE To discuss the current evidence as it relates to prophylactic programs for the prevention of ankle sprains and to provide critical interpretation of the evidence supporting and refuting the implementation of preventive programs. CONCLUSIONS External prophylactic supports and preventive exercise programs are effective for reducing the risk of ankle sprains in both uninjured and previously injured populations. Ankle bracing appears to offer the best outcomes in terms of cost and risk reduction. However, there remains a paucity of well-designed, prospective randomized controlled trials relevant to the primary prevention of lateral ankle sprains, especially across a range of sport settings.
An open design, multicentre, randomized trial of percutaneous transluminal coronary angioplasty versus stenting, with a heparin-coated stent, of totally occluded coronary arteries: rationale, trial design and baseline patient characteristics. Total Occlusion Study of Canada (TOSCA) Investigators.

BACKGROUND Percutaneous transluminal coronary angioplasty (PTCA) of totally occluded coronary arteries is performed in a variety of clinical settings and for a variety of indications. Most commonly it is performed for relief of symptoms of myocardial ischemia. Studies have also suggested that PTCA of occluded arteries beyond the acute phase of myocardial infarction may improve left ventricular function even in the absence of objective evidence of ischemia. One of the major limitations of total occlusion PTCA is a high rate of reocclusion, reported to be as high as 40%. Recently, small studies have suggested that stenting may improve the long term outcome after PTCA of total coronary occlusions. OBJECTIVES To determine in a prospective, randomized trial whether long term patency and clinical outcome following successful PTCA of a totally occluded coronary can be improved by the use of of a heparin-coated stent. PATIENTS AND METHODS Subjects were randomly assigned to one of two strategies once the guide wire had crossed the occluded segment of the target artery: PTCA alone, or PTCA followed by insertion of Palmaz-Shatz heparin-coated stent(s). Randomization was stratified according to duration of the coronary occlusion: six weeks or less, and more than six weeks. The primary end-point is failure of sustained patency (Thrombolysis in Myocardial Infarction [TIMI] flow grade less than 3) at six months. Secondary end-points are change in minimal luminal diameter, target vessel revascularization at one year, cardiovascular events at one year, and change in global and regional left ventricular function. BASELINE CHARACTERISTICS All 410 patients have been randomly assigned to the PTCA alone (n = 208) or PTCA plus stent (n = 202) group. Mean age was 58 +/- 11 years and 18% were female. Prior myocardial infarction had been documented in 67% of patients. The duration of occlusion was six weeks or less in 40% and more than six weeks in 60% of patients. In 64% of patients TIMI flow was grade 0 and in 36% it was grade 1. STUDY IMPLICATIONS: The trial will demonstrate whether the use of a heparin-bonded stent can improve long term patency and clinical outcome in patients undergoing clinically indicated PTCA of totally occluded coronary arteries. If a significant reduction in reocclusion and clinical events is demonstrated, the Total Occlusion Study of Canada (TOSCA) would offer a more effective long term revascularization strategy in future trials testing the open artery hypothesis.
The ERBB2 gene polymorphisms rs2643194, rs2934971, and rs1058808 are associated with increased risk of gastric cancer

Gastric cancer (GC) is the third most lethal type of cancer worldwide. Single nucleotide polymorphisms (SNPs) in regulatory sites or coding regions can modify the expression of genes involved in gastric carcinogenesis, as ERBB2, which encodes for the tyrosine-kinase receptor HER-2. The aim of this work was to analyze the association of the polymorphisms: rs2643194, rs2517951, rs2643195, rs2934971, and rs1058808 with GC, as they have not yet been analyzed in GC patients, as well as to report their frequency in the general Mexican population (GMP). We studied genomic DNA from subjects with GC (n=74), gastric inflammatory diseases (GID, n=76 control subjects), and GMP (n=102). Genotypes were obtained by means of real-time PCR and DNA-sequencing. The risks for GC were estimated through odds ratio (OR) using the Cochran-Armitage trend test and multinomial logistic regression. Increased risk for GC was observed under the dominant inheritance model for the rs2643194 TT or CT genotypes with an OR of 2.75 (95%CI 1.12−6.75, P=0.023); the rs2934971 TT or GT genotypes with an OR of 2.41 (95%CI 1.01−5.76, P=0.043), and the rs1058808 GG or CG genotypes with an OR of 2.21 (95%CI 1.00−4.87, P=0.046). The SNPs rs2643194, rs2934971, and rs1058808 of the ERBB2 gene were associated with increased risk for GC.
A meta‐analysis of the effect of chromium supplementation on anthropometric indices of subjects with overweight or obesity

The role of chromium as a weight loss agent remains questionable, and although previous meta‐analyses findings have reported small reductions in body weight in individuals with overweight/obesity following chromium supplementation, there have been significant limitations with these findings. The objective of this meta‐analysis was to evaluate the current evidence for the efficacy of oral chromium supplementation in individuals with overweight/obesity from randomized controlled trials. Studies were identified by a search of electronic databases from inception to November 2018 and combined and stratified analyses were used. Twenty‐one trials from 19 studies were identified which met all inclusion criteria which were suitable for statistical pooling, and data from 1316 participants were included. Pooled analysis showed significant reductions in anthropometric indices associated with body composition; for weight loss (weighted mean difference [WMD]: −0.75 kg, 95% confidence interval [CI], −1.04, −0.45, P < 0.001), body mass index (WMD: −0.40, 95% CI, −0.66, −0.13, P = 0.003 and body fat percentage (WMD: −0.68%, 95% CI, −1.32, −0.03, P = 0.04) in individuals with overweight/obesity. No changes were detected in controls. Subgroup analysis showed significant improvements in weight loss and body fat percentage, particularly for study durations ≤12 weeks and doses ≤400 μg/d. Chromium supplementation was associated with some improvements in body composition in subjects with obesity/overweight. The effect size was medium and the clinical relevance of chromium as a weight loss aid remains uncertain. Further investigation from larger and well‐designed randomized controlled studies, especially in patients with diabetes, is warranted.
Gaussian mixture models for probabilistic classification of breast cancer.

In the era of omics-driven research, it remains a common dilemma to stratify individual patients based on the molecular characteristics of their tumors. To improve molecular stratification of breast cancer patients, we developed the Gaussian Mixture Model (GMM)-based classifier. This probabilistic classifier was built on mRNA expression data from more than 300 clinical samples of breast cancer and healthy tissue and was validated on datasets of ESR1, PGR1, and ERBB2, which encode standard clinical markers and therapeutic targets. To demonstrate how a GMM approach could be exploited for multi-class classification using data from a candidate marker, we analyzed the insulin-like growth factor I receptor (IGF-IR), a promising target, but a marker of uncertain importance in breast cancer. The GMM defined subclasses with downregulated (40%), unchanged (39%), upregulated (19%), and overexpressed (2%) IGF1R levels; inter- and intra-patient analyses of IGF1R transcript and protein levels supported these predictions. Overexpressed IGF-IR was observed in a small percentage of tumors. Samples with unchanged and upregulated IGF-IR were differentiated tumors, and downregulation of IGF-IR correlated with poorly-differentiated, high-risk hormone receptor-negative and human epidermal growth factor receptor 2-positive tumors. A similar correlation was found in the independent cohort of carcinoma in situ, suggesting that loss or low expression of IGF-IR is a marker of aggressiveness in subsets of pre-invasive and invasive breast cancer. These results demonstrate the importance of probabilistic modeling that delves deeper into molecular data and aims to improve diagnostic classification, prognostic assessment, and treatment selection.
mTORC1 amplifies the ATF4-dependent de novo serine-glycine pathway to supply glycine during TGF-β1–induced collagen biosynthesis

Through mTORC1 signaling, TGF-β1 stimulates glycine synthesis from glucose to support collagen production in lung fibroblasts. Glucose supports fibrosis Transforming growth factor–β (TGF-β) stimulates fibrosis by promoting the differentiation of fibroblasts into collagen-secreting myofibroblasts, a process associated with alterations in cellular metabolism. Selvarajah et al. found that TGF-β1 promoted the expression of glycine biosynthesis genes in primary human lung fibroblasts, which depended on Smad3 signaling and mTORC1-dependent generation of the transcription factor ATF4. ATF4 stimulated the expression of genes encoding the glucose transporter GLUT1 and enzymes for the biosynthesis of glycine from glucose. Interfering with the mTOR-ATF4 axis reduced the incorporation of glucose-derived glycine into collagen in TGF-β1 stimulated fibroblasts. The mTORC1-ATF4 axis therefore enhances the de novo glycine pathway to meet the biosynthetic requirements associated with TGF-β1–induced collagen production and could potentially be therapeutically targeted as an anti-fibrotic strategy. The differentiation of fibroblasts into a transient population of highly activated, extracellular matrix (ECM)–producing myofibroblasts at sites of tissue injury is critical for normal tissue repair. Excessive myofibroblast accumulation and persistence, often as a result of a failure to undergo apoptosis when tissue repair is complete, lead to pathological fibrosis and are also features of the stromal response in cancer. Myofibroblast differentiation is accompanied by changes in cellular metabolism, including increased glycolysis, to meet the biosynthetic demands of enhanced ECM production. Here, we showed that transforming growth factor–β1 (TGF-β1), the key pro-fibrotic cytokine implicated in multiple fibrotic conditions, increased the production of activating transcription factor 4 (ATF4), the transcriptional master regulator of amino acid metabolism, to supply glucose-derived glycine to meet the amino acid requirements associated with enhanced collagen production in response to myofibroblast differentiation. We further delineated the signaling pathways involved and showed that TGF-β1–induced ATF4 production depended on cooperation between canonical TGF-β1 signaling through Smad3 and activation of mechanistic target of rapamycin complex 1 (mTORC1) and its downstream target eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). ATF4, in turn, promoted the transcription of genes encoding enzymes of the de novo serine-glycine biosynthetic pathway and glucose transporter 1 (GLUT1). Our findings suggest that targeting the TGF-β1–mTORC1–ATF4 axis may represent a novel therapeutic strategy for interfering with myofibroblast function in fibrosis and potentially in other conditions, including cancer.
Imaging modalities for the in vivo surveillance of mesenchymal stromal cells

Bone marrow stromal cells exist as mesenchymal stromal cells (MSCs) and have the capacity to differentiate into multiple tissue types when subjected to appropriate culture conditions. This property of MSCs creates therapeutic opportunities in regenerative medicine for the treatment of damage to neural, cardiac and musculoskeletal tissues or acute kidney injury. The prerequisite for successful cell therapy is delivery of cells to the target tissue. Assessment of therapeutic outcomes utilize traditional methods to examine cell function of MSC populations involving routine biochemical or histological analysis for cell proliferation, protein synthesis and gene expression. However, these methods do not provide sufficient spatial and temporal information. In vivo surveillance of MSC migration to the site of interest can be performed through a variety of imaging modalities such as the use of radiolabelling, fluc protein expression bioluminescence imaging and paramagnetic nanoparticle magnetic resonance imaging. This review will outline the current methods of in vivo surveillance of exogenously administered MSCs in regenerative medicine while addressing potential technological developments. Furthermore, nanoparticles and microparticles for cellular labelling have shown that migration of MSCs can be spatially and temporally monitored. In vivo surveillance therefore permits time‐stratified assessment in animal models without disruption of the target organ. In vivo tracking of MSCs is non‐invasive, repeatable and non‐toxic. Despite the excitement that nanoparticles for tracking MSCs offer, delivery methods are difficult because of the challenges with imaging three‐dimensional systems. The current advances and growth in MSC research, is likely to provide a wealth of evidence overcoming these issues. Copyright © 2014 John Wiley & Sons, Ltd.
Recent Insights into Kidney Injury and Repair from Transcriptomic Analyses

Injured tubular epithelium exhibits cellular plasticity in that it can dedifferentiate, reenter the cell cycle, and subsequently either redifferentiate or adopt a chronically injured phenotype. Although some nephrogenic genes are reexpressed during injury and repair, developmental pathways are only partially recapitulated and the process is more accurately viewed as an entirely new program intrinsic to the regenerative response to injury. Recent advances in our understanding of the molecular circuitry underpinning epithelial plasticity have come from bulk, cell-specific, and single-cell transcriptomic analyses. These results have begun to define the signaling pathways and gene regulatory networks governing the epithelial injury response. In this review, we highlight recent transcriptomic analyses in kidney injury, repair and fibrosis, and outline the ways that these studies are improving our understanding of kidney regeneration.
Ultrastructural Characterization of Arterivirus Replication Structures: Reshaping the Endoplasmic Reticulum To Accommodate Viral RNA Synthesis

ABSTRACT Virus-induced membrane structures support the assembly and function of positive-strand RNA virus replication complexes. The replicase proteins of arteriviruses are associated with double-membrane vesicles (DMVs), which were previously proposed to derive from the endoplasmic reticulum (ER). Using electron tomography, we performed an in-depth ultrastructural analysis of cells infected with the prototypic arterivirus equine arteritis virus (EAV). We established that the outer membranes of EAV-induced DMVs are interconnected with each other and with the ER, thus forming a reticulovesicular network (RVN) resembling that previously described for the distantly related severe acute respiratory syndrome (SARS) coronavirus. Despite significant morphological differences, a striking parallel between the two virus groups, and possibly all members of the order Nidovirales, is the accumulation in the DMV interior of double-stranded RNA, the presumed intermediate of viral RNA synthesis. In our electron tomograms, connections between the DMV interior and cytosol could not be unambiguously identified, suggesting that the double-stranded RNA is compartmentalized by the DMV membranes. As a novel approach to visualize and quantify the RNA content of viral replication structures, we explored electron spectroscopic imaging of DMVs, which revealed the presence of phosphorus in amounts equaling on average a few dozen copies of the EAV RNA genome. Finally, our electron tomograms revealed a network of nucleocapsid protein-containing protein tubules that appears to be intertwined with the RVN. This potential intermediate in nucleocapsid formation, which was not observed in coronavirus-infected cells, suggests that arterivirus RNA synthesis and assembly are coordinated in intracellular space.
What factors explain the geographical range of mammalian parasites?

Free-living species vary substantially in the extent of their spatial distributions. However, distributions of parasitic species have not been comprehensively compared in this context. We investigated which factors most influence the geographical extent of mammal parasites. Using the Global Mammal Parasite Database we analysed 17 818 individual geospatial records on 1806 parasite species (encompassing viruses, bacteria, protozoa, arthropods and helminths) that infect 396 carnivore, ungulate and primate host species. As a measure of the geographical extent of each parasite species we quantified the number and area of world ecoregions occupied by each. To evaluate the importance of variables influencing the summed area of ecoregions occupied by a parasite species, we used Bayesian network analysis of a subset (n = 866) of the parasites in our database that had at least two host species and complete information on parasite traits. We found that parasites that covered more geographical area had a greater number of host species, higher average phylogenetic relatedness between host species and more sampling effort. Host and parasite taxonomic groups had weak and indirect effects on parasite ecoregion area; parasite transmission mode had virtually no effect. Mechanistically, a greater number of host species probably increases both the collective abundance and habitat breadth of hosts, providing more opportunities for a parasite to have an expansive range. Furthermore, even though mammals are one of the best-studied animal classes, the ecoregion area occupied by their parasites is strongly sensitive to sampling effort, implying mammal parasites are undersampled. Overall, our results support that parasite geographical extent is largely controlled by host characteristics, many of which are subsumed within host taxonomic identity.
Context-dependent signaling of coincident auditory and visual events in primary visual cortex

Detecting rapid, coincident changes across sensory modalities is essential for recognition of sudden threats or events. Using two-photon calcium imaging in identified cell types in awake, head-fixed mice, we show that, among the basic features of a sound envelope, loud sound onsets are a dominant feature coded by the auditory cortex neurons projecting to primary visual cortex (V1). In V1, a small number of layer 1 interneurons gates this cross-modal information flow in a context-dependent manner. In dark conditions, auditory cortex inputs lead to suppression of the V1 population. However, when sound input coincides with a visual stimulus, visual responses are boosted in V1, most strongly after loud sound onsets. Thus, a dynamic, asymmetric circuit connecting AC and V1 contributes to the encoding of visual events that are coincident with sounds.