Miracle-dz/UniFAR-FTUs huggingface dataset:
Modifiers of symptomatic embolic risk in infective endocarditis.

OBJECTIVE To ascertain the impact of prior antiplatelet and statin therapy on symptomatic embolic events in [corrected] infective endocarditis (IE). PATIENTS AND METHODS We studied a retrospective cohort of adult patients with a diagnosis of IE who presented to Mayo Clinic (Rochester, MN) from January 1, 2003, to December 31, 2006. Patients were grouped into those who received treatment before infection or controls who did not receive treatment for both antiplatelet therapy and, separately, statin therapy. Because of the retrospective study design and thus the nonrandomized treatment groups, a propensity score approach was used to account for the confounding factors that may have influenced treatment allocation. Antiplatelet therapy included aspirin, dipyridamole, clopidogrel, ticlopidine or any combination of these agents. Statin therapy included atorvastatin, simvastatin, pravastatin, lovastatin, rosuvastatin, or fluvastatin. The primary end point was a symptomatic embolic event that occurred before or during hospitalization. Multivariable logistic regression was used to assess the propensity-adjusted effects of continuous daily therapy with antiplatelet and statin agents on risk of symptomatic emboli. Likewise, Cox proportional hazards regression was used to test for an independent association with 6-month mortality for each of the treatments. RESULTS The study cohort comprised 283 patients with [corrected] IE. Twenty-eight patients (24.1%) who received prior continuous antiplatelet therapy developed a symptomatic embolic event compared with 66 (39.5%) who did not receive such treatment. After adjusting for propensity to treat, the effect of antiplatelet therapy on embolic risk was not statistically significant (odds ratio, 0.71; 95% confidence interval [CI], 0.37-1.36; P=.30). Only 14 patients (18.2%) who received prior continuous statin therapy developed a symptomatic embolic event compared with 80 (39.4%) of the 203 patients who did not. After adjusting for propensity to treat with statin therapy, the benefit attributable to statins was significant (odds ratio, 0.30; 95% CI, 0.14-0.62; P=.001). The 6-month mortality rate of the entire cohort was 28% (95% CI, 23%-34%). No significant difference was found in the propensity-adjusted rate of 6-month mortality between patients who had and had not undergone prior antiplatelet therapy (P=.91) or those who had and had not undergone prior statin therapy (P=.87). CONCLUSION The rate of symptomatic emboli associated with IE was reduced in patients who received continuous daily statin therapy before onset of IE. Despite fewer embolic events observed in patients who received antiplatelet agents, a significant association was not found after adjusting for propensity factors. A continued evaluation of these drugs and their potential impact on subsequent embolism among IE patients is warranted.
Becoming a doctor

Medical training cannot be equated with merely studying for a degree. It encompasses much more, challenging one's values, self perception and perspective on life itself. During five years at medical school, the individual irreversibly alters to become “a medic”, not just “a student of medicine”, no matter how much detachment from the course and its associated lifestyle the individual has endeavoured to preserve. In the following article, we intend to explore the different stages of training and discuss how each shapes the student. “Becoming a medic” intellectually, emotionally and spiritually is the inevitable consequence of spending five years at medical school, and the assumption of this role is indeed crucial to survival in medical practice. The importance of bringing our own individual qualities to the profession must, however, not be overlooked. Personal flair and abilities should be nurtured, not suppressed during medical school. A diversity of interests serves both to ease the pressures laid upon us at medical school, and to broaden our characters and deepen our understanding of humanity. Medical students, while necessarily adapting to the role of a doctor, should emerge from their training not as narrow “medics” but as enthusiastic, compassionate people equipped to treat patients to the best of their ability.
Purification and Characterization of Mouse Soluble Receptor for Advanced Glycation End Products (sRAGE)*

The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface proteins that has been implicated as a progression factor in a number of pathologic conditions from chronic inflammation to cancer to Alzheimer's disease. In such conditions, RAGE acts to facilitate pathogenic processes. Its secreted isoform, soluble RAGE or sRAGE, has the ability to prevent RAGE signaling by acting as a decoy. sRAGE has been used successfully in animal models of a range of diseases to antagonize RAGE-mediated pathologic processes. In humans, sRAGE results from alternative splicing of RAGE mRNA. This study was aimed to determine whether the same holds true for mouse sRAGE and, in addition, to biochemically characterize mouse sRAGE. The biochemical characteristics examined include glycosylation and disulfide patterns. In addition, sRAGE was found to bind heparin, which may mediate its distribution in the extracellular matrix and cell surfaces of tissues. Finally, our data indicated that sRAGE in the mouse is likely produced by carboxyl-terminal truncation, in contrast to the alternative splicing mechanism reported in humans.
Biological properties of fructooligosaccharides with different contents of kestose and nystose in rats

Abstract In a four-week experiment on rats' diets containing 5% of sucrose or fructooligosaccharides (FOS) diversified in terms of kestose and nystose contents: 6:1 (FOS-K), 3:1 (FOS-KN), and 0.5:1 (FOS-N) were applied. All FOS preparations, primarily FOS-N, considerably increased the mass of caecum, lowered pH of caecal digesta, and increased concentrations of protein. The glycolytic activity of the caecal digesta was generally alike in all groups, except for the control group where the activity of β-glucosidase was negligibly lower and that of α-galactosidase higher. The administration of FOS preparation with a diet increased the concentration and the pool of total VFA in the caecal digesta, especially in the case of butyric and propionic acids and decreased the concentration of iso-butyric and valeric acids. When compared with the kestose-rich preparation, the nystose-rich preparation increased the production of total VFA in the caecum, primarily of n-butyrate and propionate. Different length of kestose and nystose chains had no effect on the activity of bacterial enzymes in the caecum nor the biochemical indices of serum, concentration of cholesterol, glucose, urea, Ca, P and Mg.
The asheville project: long-term clinical and economic outcomes of a community pharmacy diabetes care program.

OBJECTIVE To assess the persistence of outcomes for up to 5 years following the initiation of community-based pharmaceutical care services (PCS) for patients with diabetes. DESIGN Quasi-experimental, longitudinal pre-post cohort study. SETTING Twelve community pharmacies in Asheville, N.C. PATIENTS AND OTHER PARTICIPANTS Patients with diabetes covered by self-insured employers' health plans. Community pharmacists trained in a diabetes certificate program and reimbursed for PCS. INTERVENTIONS Education by certified diabetes educators, long-term community pharmacist follow-up using scheduled consultations, clinical assessment, goal setting, monitoring, and collaborative drug therapy management with physicians. MAIN OUTCOME MEASURES Changes in glycosylated hemoglobin (A1c) and serum lipid concentrations and changes in diabetes-related and total medical utilization and costs over time. RESULTS Mean A1c decreased at all follow-ups, with more than 50% of patients demonstrating improvements at each time. The number of patients with optimal A1c values (< 7 %) also increased at each follow-up. More than 50% showed improvements in lipid levels at every measurement. Multivariate logistic regressions suggested that patients with higher baseline A1c values or higher baseline costs were most likely to improve or have lower costs, respectively. Costs shifted from inpatient and outpatient physician services to prescriptions, which increased significantly at every follow-up. Total mean direct medical costs decreased by $1,200 to $1,872 per patient per year compared with baseline. Days of sick time decreased every year (1997-2001) for one employer group, with estimated increases in productivity estimated at $18,000 annually. CONCLUSION Patients with diabetes who received ongoing PCS maintained improvement in A1c over time, and employers experienced a decline in mean total direct medical costs.
Speedup from a different parametrization within the Neural Net algorithm

A different parametrization of the hyperplanes is used in the neural network algorithm. As demonstrated on several autoencoder examples it significantly outperforms the usual parametrization, reaching lower training error values with only a fraction of the number of epochs. It's argued that it makes it easier to understand and initialize the parameters.
The rise of Astyanax cavefish

Numerous animals have invaded subterranean caverns and evolved remarkably similar features. These features include loss of vision and pigmentation, and gains in nonvisual sensation. This broad convergence echoes smaller‐scale convergence, in which members of the same species repeatedly evolve the same cave‐associated phenotypes. The blind Mexican tetra of the Sierra de El Abra region of northeastern Mexico has a complex origin, having recurrently colonized subterranean environments through numerous invasions of surface‐dwelling fish. These colonizations likely occurred ∼1–5 MYa. Despite evidence of historical and contemporary gene flow between cave and surface forms, the cave‐associated phenotype appears to remain quite stable in nature. This model system has provided insight to the mechanisms of phenotypic regression, the genetic basis for constructive trait evolution, and the origin of behavioral novelties. Here, we document the rise of this model system from its discovery by a Mexican surveyor in 1936, to a powerful system for cave biology and contemporary genetic research. The recently sequenced genome provides exciting opportunities for future research, and will help resolve several long‐standing biological problems. Developmental Dynamics 244:1031–1038, 2015. © 2015 Wiley Periodicals, Inc.
Nicotinic receptor signaling in nonexcitable cells.

The finding that neuronal nicotinic acetylcholine receptors (nAChRs) are present in non-neuronal cells both within and outside the nervous system raises some interesting issues. The mechanisms underlying receptor signaling and its downstream consequences in these cells remain to be elucidated. Factors controlling the release of acetylcholine and the extent of its diffusion are likely to be different for these cells than for traditional neuronal synapses. Recent advances on the physiologic functions of some of these cell types have provided a better insight into possible functional roles for nAChRs in nonexcitable cells. The presence of nAChRs on these cells also implies a broader scope for the actions of nicotine that needs to be considered from a clinical viewpoint. Revealing the potential physiologic roles for nAChRs on nonexcitable cells is likely to provide a more complete understanding of cholinergic signaling.
Mechanistic Characterization of RASGRP1 Variants Identifies an hnRNP-K-Regulated Transcriptional Enhancer Contributing to SLE Susceptibility

Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic component. We recently identified a novel SLE susceptibility locus near RASGRP1, which governs the ERK/MAPK kinase cascade and B-/T-cell differentiation and development. However, precise causal RASGRP1 functional variant(s) and their mechanisms of action in SLE pathogenesis remain undefined. Our goal was to fine-map this locus, prioritize genetic variants according to likely functionality, experimentally validate the contribution of three SNPs to SLE risk, and experimentally determine their biochemical mechanisms of action. We performed a meta-analysis across six Asian and European cohorts (9,529 cases; 22,462 controls), followed by in silico bioinformatic and epigenetic analyses to prioritize potentially functional SNPs. We experimentally validated the functional significance and mechanism of action of three SNPs in cultured T-cells. Meta-analysis identified 18 genome-wide significant (p<5×10−8) SNPs, mostly concentrated in two haplotype blocks, one intronic and the other intergenic. Epigenetic fine-mapping, allelic, eQTL and imbalance analyses predicted three transcriptional regulatory regions with four SNPs (rs7170151, rs11631591-rs7173565, and rs9920715) prioritized for functional validation. Luciferase reporter assays indicated significant allele-specific enhancer activity for intronic rs7170151 and rs11631591-rs7173565 in T-lymphoid (Jurkat) cells, but not in HEK293 cells. Following up with EMSA, mass spectrometry and ChIP-qPCR, we detected allele-dependent interactions between heterogeneous nuclear ribonucleoprotein K (hnRNP-K) and rs11631591. Furthermore, inhibition of hnRNP-K in Jurkat and primary T-cells downregulated RASGRP1 and ERK/MAPK signaling. Comprehensive association, bioinformatics, and epigenetic analyses yielded putative functional variants of RASGRP1, which were experimentally validated. Notably, intronic variant (rs11631591) is located in a cell type-specific enhancer sequence, where its risk allele binds to the hnRNP-K protein and modulates RASGRP1 expression in Jurkat and primary T-cells. As risk allele dosage of rs11631591 correlates with increased RASGRP1 expression and ERK activity, we suggest that this SNP may underlie SLE risk at this locus.
Targeted Greybox Fuzzing with Static Lookahead Analysis

Automatic test generation typically aims to generate inputs that explore new paths in the program under test in order to find bugs. Existing work has, therefore, focused on guiding the exploration toward program parts that are more likely to contain bugs by using an offline static analysis. In this paper, we introduce a novel technique for targeted greybox fuzzing using an online static analysis that guides the fuzzer toward a set of target locations, for instance, located in recently modified parts of the program. This is achieved by first semantically analyzing each program path that is explored by an input in the fuzzer's test suite. The results of this analysis are then used to control the fuzzer's specialized power schedule, which determines how often to fuzz inputs from the test suite. We implemented our technique by extending a state-of-the-art, industrial fuzzer for Ethereum smart contracts and evaluate its effectiveness on 27 real-world benchmarks. Using an online analysis is particularly suitable for the domain of smart contracts since it does not require any code instrumentation-adding instrumentation to contracts changes their semantics. Our experiments show that targeted fuzzing significantly outperforms standard greybox fuzzing for reaching 83% of the challenging target locations (up to 14x of median speed-up).
Cannabinoid Receptor Activation Differentially Regulates the Various Adenylyl Cyclase Isozymes

Abstract: Two cannabinoid receptors belonging to the superfamily of G protein‐coupled membrane receptors have been identified and cloned: the neuronal cannabinoid receptor (CB1) and the peripheral cannabinoid receptor (CB2). They have been shown to couple directly to the Gi/o subclass of G proteins and to mediate inhibition of adenylyl cyclase upon binding of a cannabinoid agonist. In several cases, however, cannabinoids have been reported to stimulate adenylyl cyclase activity, although the mechanism by which they did so was unclear. With the cloning of nine adenylyl cyclase isozymes with various properties, including different sensitivities to αs, αi/o, and βγ subunits, it became important to assess the signaling pattern mediated by each cannabinoid receptor via the different adenylyl cyclase isozymes. In this work, we present the results of cotransfection experiments between the two types of cannabinoid receptors and the nine adenylyl cyclase isoforms. We found that independently of the method used to stimulate specific adenylyl cyclase isozymes (e.g., ionomycin, forskolin, constitutively active αs, thyroid‐stimulating hormone receptor activation), activation of the cannabinoid receptors CB1 and CB2 inhibited the activity of adenylyl cyclase types I, V, VI, and VIII, whereas types II, IV, and VII were stimulated by cannabinoid receptor activation. The inhibition of adenylyl cyclase type III by cannabinoids was observed only when forskolin was used as stimulant. The activity of adenylyl cyclase type IX was inhibited only marginally by cannabinoids.
Relationship Between Obesity and Surgical Complications After Reduction Mammaplasty: A Systematic Literature Review and Meta-Analysis

Background Although many patients who undergo reduction mammaplasty are obese, reports on whether obesity is a risk factor for postoperative complications have been conflicting. Objectives This systematic literature review and meta-analysis aimed to evaluate the relationship between obesity and surgical complications after reduction mammaplasty. Methods The PubMed, Medline, and Embase databases were searched between 1998 and 2016 using the MeSH terms and keywords “reduction mammoplasty (mammaplasty),” “breast reduction,” “obesity,” “body weight,” “body mass index,” and “risk factor. ” Results Among 26 studies that reported surgical complication risk and patient body weight, 11 concluded that obesity is not a risk factor and 15 reported that high body mass index increases surgical risk. On comparing obese and non-obese patients, we found that obese patients had a higher relative risk of surgical complications (1.38, 95% confidence interval 1.13-1.69), particularly skin and fat necrosis (2.01, 95% confidence interval 1.54-2.63). The pooled risk further increased with an increase in body mass index, and it was 1.71 for body mass index >35 kg/m2 and 2.05 for body mass index >40 kg/m2. Conclusions Our meta-analysis indicated that the risk of surgical complications and tissue necrosis after reduction mammaplasty is higher in obese patients than in non-obese patients and that the risk gradually increases with an increase in the severity of obesity. The findings of this study could form a basis for preoperative patient education, surgical method selection, and determination of the extent of postoperative care.
Potential role of bioactive peptides in prevention and treatment of chronic diseases: a narrative review

In the past few years, increasing interest has been directed to bioactive peptides of animal and plant origin: in particular, researchers have focused their attention on their mechanisms of action and potential role in the prevention and treatment of cancer, cardiovascular and infective diseases. We have developed a search strategy to identify these studies in PubMed (January 1980 to May 2016); particularly those papers presenting comprehensive reviews or meta‐analyses, plus in vitro and in vivo studies and clinical trials on those bioactive peptides that affect cardiovascular diseases, immunity or cancer, or have antioxidant, anti‐inflammatory and antimicrobial effects. In this review we have mostly focused on evidence‐based healthy properties of bioactive peptides from different sources. Bioactive peptides derived from fish, milk, meat and plants have demonstrated significant antihypertensive and lipid‐lowering activity in clinical trials. Many bioactive peptides show selective cytotoxic activity against a wide range of cancer cell lines in vitro and in vivo, whereas others have immunomodulatory and antimicrobial effects. Furthermore, some peptides exert anti‐inflammatory and antioxidant activity, which could aid in the prevention of chronic diseases. However, clinical evidence is at an early stage, and there is a need for solid pharmacokinetic data and for standardized extraction procedures. Further studies on animals and randomized clinical trials are required to confirm these effects, and enable these peptides to be used as preventive or therapeutic treatments.
A computational model of radiolytic oxygen depletion during FLASH irradiation and its effect on the oxygen enhancement ratio

Recent results from animal irradiation studies have demonstrated the potential of ultra-high dose rate irradiation (also known as FLASH) for reducing radiation toxicity in normal tissues. However, despite mounting evidence of a ‘FLASH effect’, a mechanism has yet to be elucidated. This article hypothesizes that the radioprotecting effect of FLASH irradiation could be due to the specific sparing of hypoxic stem cell niches, which have been identified in several organs including the bone marrow and the brain. To explore this hypothesis, a new computational model is presented that frames transient radiolytic oxygen depletion (ROD) during FLASH irradiation in terms of its effect on the oxygen enhancement ratio (OER). The model takes into consideration oxygen diffusion through the tissue, its consumption by metabolic cells, and its radiolytic depletion to estimate the relative decrease in radiosensitivity of cells receiving FLASH irradiation. Based on this model and the following parameters (oxygen diffusion constant = 2 · 10−5 cm2 s−1, oxygen metabolic rate m = 3 mmHg s−1, ROD rate LROD = mmHg Gy−1, prescribed dose Dp = 10 Gy, and capillary oxygen tension p 0 = 40 mmHg), several predictions are made that could be tested in future experiments: (1) the FLASH effect should gradually disappear as the radiation pulse duration is increased from <1 s to 10 s; (2) dose should be deposited using the smallest number of radiation pulses to achieve the greatest FLASH effect; (3) a FLASH effect should only be observed in cells that are already hypoxic at the time of irradiation; and (4) changes in capillary oxygen tension (increase or decrease) should diminish the FLASH effect.
TERMINATOR: better automated UI test case prioritization

Automated UI testing is an important component of the continuous integration process of software development. A modern web-based UI is an amalgam of reports from dozens of microservices written by multiple teams. Queries on a page that opens up another will fail if any of that page's microservices fails. As a result, the overall cost for automated UI testing is high since the UI elements cannot be tested in isolation. For example, the entire automated UI testing suite at LexisNexis takes around 30 hours (3-5 hours on the cloud) to execute, which slows down the continuous integration process. To mitigate this problem and give developers faster feedback on their code, test case prioritization techniques are used to reorder the automated UI test cases so that more failures can be detected earlier. Given that much of the automated UI testing is "black box" in nature, very little information (only the test case descriptions and testing results) can be utilized to prioritize these automated UI test cases. Hence, this paper evaluates 17 "black box" test case prioritization approaches that do not rely on source code information. Among these, we propose a novel TCP approach, that dynamically re-prioritizes the test cases when new failures are detected, by applying and adapting a state of the art framework from the total recall problem. Experimental results on LexisNexis automated UI testing data show that our new approach (which we call TERMINATOR), outperformed prior state of the art approaches in terms of failure detection rates with negligible CPU overhead.