Miracle-dz/UniFAR-FTUs huggingface dataset:
Usefulness of Health Registers for detection of bleeding events in outcome studies

Summary Administrative and claims databases are attractive for safety studies of anticoagulant and antithrombotic drugs. However, the validity of such data is often uncertain. It was our aim to assess the usefulness of the Swedish administrative health databases for detection of major bleeding events. All individuals with atrial fibrillation in Stockholm County from 2006 to 2013 (n=78,022) were identified from the Swedish Patient register. A search for bleeding diagnoses was done in the Patient register and in the Cause of Death register. The medical records of a random sample of 761 patients were studied and classified in a blinded and pre-specified way. The highest sensitivity (99.5%) and specificity (94.0%) were obtained by counting fatal bleeding events with the bleeding diagnosis recorded as first or second cause of death, and all hospitalisations without regard to the position of the diagnosis. Codes for transfusions were unreliable and did not increase accuracy. The registries identified 99.4% of intracranial bleeding events and 82.6% of gastrointestinal bleeding events correctly. All patients classified as „no bleedings” were indeed without bleeding. Overall the sensitivity was 85.5% and the specificity 95.9% for major bleeding events. In conclusion, Swedish nationwide health registries are well suited for conducting outcome studies involving identification of bleeding events. The use of a diagnostic code for bleeding, irrespective of its position as primary or secondary diagnosis, provided the best sensitivity and specificity for detection of bleeding events, as long as it was limited to contacts resulting in hospital admission.
Methyl pyruvate protects a normal lung fibroblast cell line from irinotecan-induced cell death: Potential use as adjunctive to chemotherapy

The Warburg Effect, characterized by increased rate of glycolysis even under normoxic conditions, is one of the hallmarks of cancer. Relatively lower oxidative phosphorylation (OXPHOS) is also a characteristic feature in cancer cells. We hypothesized that interference with this phenomenon, by introducing exogenous pyruvate, would upset this cancer phenotype and boost the energy requirements of normal cells. We find that methyl pyruvate protects irinotecan-treated normal lung fibroblast cell line (MRC-5) probably by turning off the p53/p21 axis of the apoptotic pathways. When the MRC-5 fibroblasts recover in drug-free medium, the intrinsic apoptotic pathway is also turned off and the cells survive with no discernible exponential growth during the observation period. In contrast, the mere introduction of exogenous pyruvate kills the lung cancer cell line (A549). Although, functional p53 is important in the drug-induced cancer cell death, it is probably not essential because cancer cell lines with mutated p53 also die albeit less efficiently. We conclude that methyl pyruvate may preferentially kill cancer cells and protect normal cells during chemotherapy.
Implantable contraception

ABSTRACT This article reviews the advantages and disadvantages of progestogen-only contraceptive implants in light of the development of Implanon®, a new, single-rod, etonogestrel-releasing system. Implants rapidly produce serum progestogen levels sufficient to ensure contraception for 1–5 years. The steady release of progestogen avoids the peaks and troughs associated with oral contraceptives, the profound ovarian suppression observed with depot injections and the need for user compliance. Implants have few serious complications. Ectopic pregnancy rates are low, and follicular hypertrophy is generally self-limiting. The principal acceptability limitation to both users and providers of Norplant® is insertion and removal. Implanon® is easy to insert and remove with minimal complications and pain. The main adverse event causing discontinuation of implants is a change in bleeding pattern. However, with good counselling, this is well tolerated by most women. Implants thus provide an effective, safe, economical and convenient alternative to oral, injectable or intrauterine contraceptives. Implanon® is an extremely effective single-rod implant with a Pearl index of 0. It employs a new polymer and a less androgenic progestogen. These features provide easier insertion and removal for both users and clinicians, a more stable release rate and potentially fewer adverse androgenic effects compared with existing formulations.
Vitamin D levels in a large Mediterranean cohort: reconsidering normal cut-off values

OBJECTIVE: The determination of the normal range of 25-hydroxyvitamin D [25-(OH)D], though currently based on suppression of PTH levels, still remains a controversial issue. The 25-(OH)D levels exhibit gender and seasonal variability, the latter attributed in part to changes of insolation. DESIGN: The aim of this cross-sectional study was to estimate the levels of 25-(OH)D on the island of Crete and their correlation with metabolic, hormonal and bone turnover parameters. The study was performed over a period of five years and involved 8,183 male and female individuals (8,042 analyzed). RESULTS: Our results are as follows: (1) 25-(OH)D was significantly lower than expected (19.48±9.51 and 18.01±9.01 (ng/mL±SD) in males and females, respectively); (2) seasonal variation of 25-(OH)D was observed in both sexes (females < males), with values peaking in August; (3) a decline of 25-(OH)D was evident with advancing age, with lower levels in females compared to males up to menopause and no apparent difference between the genders thereafter; (4) levels of 25-(OH)D were lower in renal function impairment, diabetes/insulin resistance and inflammation, while no correlation was detectable in thyroid dysfunction; (5) normalization of PTH levels was observed at ∼20 ng/mL 25-(OH)D. At the same cut-off level, a significant decrease of all measured bone turnover indices (b-ALP, osteocalcin and CTX) was evident. CONCLUSION: Based on the above data, it appears that a cut-off level of 25-(OH)D close to 20 ng/mL better reflects the physiology of our population.
Signaling pathway profiling using reverse-phase protein array and its clinical applications

ABSTRACT Introduction: Increased accessibility to next-generation sequencing within the last decade has led to a paradigm shift in cancer treatment from one-size-fits-all medicine to precision medicine providing therapeutic strategies tailored to the requirements of individual patients. However, the effect of even the most successful agent yet tested is only transient, and durable efficacy has yet to be achieved. Genome- and transcriptome-based approaches cannot fully predict the diversity of protein expression patterns or post-translational modifications that directly contribute to cancer pathogenesis and physiology. This underscores the need for concordant proteomic analysis in the next stage of precision medicine. Areas covered: This review begins with an overview of the recent advances and trends in precision medicine that currently rely on genomics, and highlights the utility of antibody-based reverse-phase protein array (RPPA) technology as a proteomic tool in this context. Expert commentary: RPPA is well suited for pharmacodynamics analysis in view of its ability to precisely map signaling status using limited amounts of clinical samples. In addition, the cost-effectiveness and rapid turn-around time of the RPPA platform offer a substantial advantage over existing molecular profiling technologies in clinical settings.
Non-cell autonomous control of precerebellar neuron migration by Slit and Robo proteins

ABSTRACT During development, precerebellar neurons migrate tangentially from the dorsal hindbrain to the floor plate. Their axons cross it but their cell bodies stop their ventral migration upon reaching the midline. It has previously been shown that Slit chemorepellents and their receptors, Robo1 and Robo2, might control the migration of precerebellar neurons in a repulsive manner. Here, we have used a conditional knockout strategy in mice to test this hypothesis. We show that the targeted inactivation of the expression of Robo1 and Robo2 receptors in precerebellar neurons does not perturb their migration and that they still stop at the midline. The selective ablation of the expression of all three Slit proteins in floor-plate cells has no effect on pontine neurons and only induces the migration of a small subset of inferior olivary neurons across the floor plate. Likewise, we show that the expression of Slit proteins in the facial nucleus is dispensable for pontine neuron migration. Together, these results show that Robo1 and Robo2 receptors act non-cell autonomously in migrating precerebellar neurons and that floor-plate signals, other than Slit proteins, must exist to prevent midline crossing. Highlighted Article: The conditional ablation of Slit proteins and Robo receptors in precerebellar neurons and floor plate reveals that, in the mouse, the migration of hindbrain precerebellar neurons is independent of Slit and Robo signaling.
Hypothalamic-pituitary-adrenal axis in patients with ankylosing spondylitis

Objective: To investigate the hypothalamic-pituitary-adrenal (HPA) axis via the insulintolerance test (ITT), standard-dose (250 µg) ACTH test (SDT) and low-dose (1 µg) ACTH test (LDT) in patients with ankylosing spondylitis (AS). DESIGN: The study group included 13 male patients with AS who were diagnosed according to the Modified New York criteria, and 8 healthy male subjects and was carried out at the Department of Physical Medicine and Rehabilitation, Erciyes University Medical School. ACTH stimulation tests were carried out by using 1 µg and 250 µg i.v. ACTH as a bolus injection, and blood samples were drawn at 0, 30 and 60 min. ITT was performed by using intravenous (i.v.) soluble insulin, and serum glucose and cortisol levels were measured before and after 30, 60, 90 and 120 min. All of the tests were performed consecutively with 3-day intervals, after an overnight fast. Results: There were no significant differences between the patients with AS (mean age 36.9±6.7 years) and the healthy subjects (mean age 37.4±5.7 years) in terms of age. The basal cortisol levels in the AS group measured during LDT, SDT and ITT (556±204 nmol/l; 524±169 nmol/l; 418±232 nmol/l, respectively) were comparable to the values of the control group (572±199 nmol/l; 520±182 nmol/l; 424±194 nmol/l, respectively). There were also no significant differences in peak cortisol responses between the two groups using LDT (patients 1025±339 nmol/l; controls 844±236 nmol/l), SDT (patients 1082±243 nmol/l; controls 1120±131 nmol/l) and ITT (patients 834±256 nmol/; controls 820±239 nmol/). Conclusion: In contrast with findings in other inflammatory diseases such as rheumatoid arthritis and polymyalgia rheumatica, the present data indicate that there is no apparent abnormality of the HPA axis activity in patients with AS.
Optimal Linear Estimation under Unknown Nonlinear Transform

Linear regression studies the problem of estimating a model parameter β* ∈ℝ p , from n observations [Formula: see text] from linear model yi = 〈xi , β*〉 + ε i . We consider a significant generalization in which the relationship between 〈xi , β*〉 and yi is noisy, quantized to a single bit, potentially nonlinear, noninvertible, as well as unknown. This model is known as the single-index model in statistics, and, among other things, it represents a significant generalization of one-bit compressed sensing. We propose a novel spectral-based estimation procedure and show that we can recover β* in settings (i.e., classes of link function f) where previous algorithms fail. In general, our algorithm requires only very mild restrictions on the (unknown) functional relationship between yi and 〈xi , β*〉. We also consider the high dimensional setting where β* is sparse, and introduce a two-stage nonconvex framework that addresses estimation challenges in high dimensional regimes where p ≫ n. For a broad class of link functions between 〈xi , β*〉 and yi , we establish minimax lower bounds that demonstrate the optimality of our estimators in both the classical and high dimensional regimes.
Creating Roadmaps in Aerial Images with Generative Adversarial Networks and Smoothing-Based Optimization

Recognizing roads and intersections in aerial images is a challenging problem in computer vision with many real world applications, such as localization and navigation for unmanned aerial vehicles (UAVs). The problem is currently gaining momentum in computer vision and is still far from being solved. While recent approaches have greatly improved due to the advances in deep learning, they provide only pixel-level semantic segmentations. In this paper, we argue that roads and intersections should be recognized at the higher semantic level of road graphs - with roads being edges that connect nodes. Towards this goal we present a method consisting of two stages. During the first stage, we detect roads and intersections with a novel, dual-hop generative adversarial network (DH-GAN) that segments images at the level of pixels. At the second stage, given the pixelwise road segmentation, we find its best covering road graph by applying a smoothing-based graph optimization procedure. Our approach is able to outperform recent published methods and baselines on a large dataset with European roads.
Modafinil/armodafinil in obstructive sleep apnoea: a systematic review and meta-analysis

Modafinil is used internationally to treat residual sleepiness despite continuous positive airway pressure in obstructive sleep apnoea (res-OSA). In 2011, the European Medicines Agency removed the indication based on an unfavourable risk–benefit profile in two trials for efficacy and all accumulated safety data. We performed a meta-analysis of all randomised controlled trials of modafinil (or armodafinil) in res-OSA to quantify efficacy and safety. We systematically searched and assessed studies from major databases, conferences and trials registries to find randomised, placebo-controlled trials of modafinil/armodafinil for ≥2 weeks in adult res-OSA treating sleepiness. We analysed 10 of the 232 articles identified that met inclusion criteria (1466 patients). Modafinil/armodafinil improved the Epworth Sleepiness Scale score (2.2 points, 95% CI 1.5–2.9) and the Maintenance of Wakefulness Test over placebo (3 min, 95% CI 2.1–3.8 min). Modafinil/armodafinil tripled adverse events and doubled adverse events leading to withdrawal but did not increase serious adverse events (hospitalisations or death). Modafinil and armodafinil improve subjective and objective daytime sleepiness in res-OSA. We believe our analysis is a fairer analysis of the risk–benefit profile of this indication. Clinicians may want to use this data to balance the risks and benefits on a case-by-case basis with their patients. An EMA risk–benefit analysis of modafinil in OSA was negative. Does analysing extra trials change the conclusion? http://ow.ly/VYvO8
Microdiversification of a Pelagic Polynucleobacter Species Is Mainly Driven by Acquisition of Genomic Islands from a Partially Interspecific Gene Pool

ABSTRACT Microdiversification of a planktonic freshwater bacterium was studied by comparing 37 Polynucleobacter asymbioticus strains obtained from three geographically separated sites in the Austrian Alps. Genome comparison of nine strains revealed a core genome of 1.8 Mb, representing 81% of the average genome size. Seventy-five percent of the remaining flexible genome is clustered in genomic islands (GIs). Twenty-four genomic positions could be identified where GIs are potentially located. These positions are occupied strain specifically from a set of 28 GI variants, classified according to similarities in their gene content. One variant, present in 62% of the isolates, encodes a pathway for the degradation of aromatic compounds, and another, found in 78% of the strains, contains an operon for nitrate assimilation. Both variants were shown in ecophysiological tests to be functional, thus providing the potential for microniche partitioning. In addition, detected interspecific horizontal exchange of GIs indicates a large gene pool accessible to Polynucleobacter species. In contrast to core genes, GIs are spread more successfully across spatially separated freshwater habitats. The mobility and functional diversity of GIs allow for rapid evolution, which may be a key aspect for the ubiquitous occurrence of Polynucleobacter bacteria. IMPORTANCE Assessing the ecological relevance of bacterial diversity is a key challenge for current microbial ecology. The polyphasic approach which was applied in this study, including targeted isolation of strains, genome analysis, and ecophysiological tests, is crucial for the linkage of genetic and ecological knowledge. Particularly great importance is attached to the high number of closely related strains which were investigated, represented by genome-wide average nucleotide identities (ANI) larger than 97%. The extent of functional diversification found on this narrow phylogenetic scale is compelling. Moreover, the transfer of metabolically relevant genomic islands between more distant members of the Polynucleobacter community provides important insights toward a better understanding of the evolution of these globally abundant freshwater bacteria.
Identification of a putative binding site critical for general anesthetic activation of TRPA1

Significance General anesthetics are an important class of drugs that suppress the activity of neurons in the brain to produce reversible unconsciousness. In addition, several general anesthetics, including the intravenous drug, propofol, and the inhaled gas, isoflurane, cause pain/irritation upon administration and a reduction in blood pressure. These side effects arise from activation of the transient receptor potential ankyrin repeat 1 (TRPA1) ion channel but the underlying mechanisms are unknown. In this study we identify a potential binding pocket for propofol and isoflurane, including several critical amino acid residues, located in the channel pore region of TRPA1. These results confirm an important role for the pore region in regulating channel activity. Further, the information may be useful in designing drugs to counter anesthetic-mediated activation of TRPA1. General anesthetics suppress CNS activity by modulating the function of membrane ion channels, in particular, by enhancing activity of GABAA receptors. In contrast, several volatile (isoflurane, desflurane) and i.v. (propofol) general anesthetics excite peripheral sensory nerves to cause pain and irritation upon administration. These noxious anesthetics activate transient receptor potential ankyrin repeat 1 (TRPA1), a major nociceptive ion channel, but the underlying mechanisms and site of action are unknown. Here we exploit the observation that pungent anesthetics activate mammalian but not Drosophila TRPA1. Analysis of chimeric Drosophila and mouse TRPA1 channels reveal a critical role for the fifth transmembrane domain (S5) in sensing anesthetics. Interestingly, we show that anesthetics share with the antagonist A-967079 a potential binding pocket lined by residues in the S5, S6, and the first pore helix; isoflurane competitively disrupts A-967079 antagonism, and introducing these mammalian TRPA1 residues into dTRPA1 recapitulates anesthetic agonism. Furthermore, molecular modeling predicts that isoflurane and propofol bind to this pocket by forming H-bond and halogen-bond interactions with Ser-876, Met-915, and Met-956. Mutagenizing Met-915 or Met-956 selectively abolishes activation by isoflurane and propofol without affecting actions of A-967079 or the agonist, menthol. Thus, our combined experimental and computational results reveal the potential binding mode of noxious general anesthetics at TRPA1. These data may provide a structural basis for designing drugs to counter the noxious and vasorelaxant properties of general anesthetics and may prove useful in understanding effects of anesthetics on related ion channels.
Dynamic cross-correlations between entangled biofilaments as they diffuse

Significance Highly entangled biofilaments are ubiquitous in the cytoskeleton and present a paradigm in polymer physics and biophysics. Here, rather than conventionally seeking to understand the self-diffusion of a single tagged entangled polymer we inquire into dynamic cross-correlations between nearby filaments as they diffuse anisotropically in aqueous solution. Our combined fluorescence tracking experiments and statistical mechanical modeling show that the continuum limit is reached only at distances beyond the filament length, in this system beyond the large distance of ≈15 µm. This noncontinuum behavior at micron-scale distance may be related to the “crowding” problem in biological function. Entanglement in polymer and biological physics involves a state in which linear interthreaded macromolecules in isotropic liquids diffuse in a spatially anisotropic manner beyond a characteristic mesoscopic time and length scale (tube diameter). The physical reason is that linear macromolecules become transiently localized in directions transverse to their backbone but diffuse with relative ease parallel to it. Within the resulting broad spectrum of relaxation times there is an extended period before the longest relaxation time when filaments occupy a time-averaged cylindrical space of near-constant density. Here we show its implication with experiments based on fluorescence tracking of dilutely labeled macromolecules. The entangled pairs of aqueous F-actin biofilaments diffuse with separation-dependent dynamic cross-correlations that exceed those expected from continuum hydrodynamics up to strikingly large spatial distances of ≈15 µm, which is more than 104 times the size of the solvent water molecules in which they are dissolved, and is more than 50 times the dynamic tube diameter, but is almost equal to the filament length. Modeling this entangled system as a collection of rigid rods, we present a statistical mechanical theory that predicts these long-range dynamic correlations as an emergent consequence of an effective long-range interpolymer repulsion due to the de Gennes correlation hole, which is a combined consequence of chain connectivity and uncrossability. The key physical assumption needed to make theory and experiment agree is that solutions of entangled biofilaments localized in tubes that are effectively dynamically incompressible over the relevant intermediate time and length scales.