Takshan/R1 huggingface dataset:
Persistence of and switches from teriparatide treatment among women and men with osteoporosis in the real world: a claims database analysis.

This study investigated the real-world persistence rate and switches of teriparatide-treated patients using a claims database in Japan. The persistence rate of teriparatide at 12 months was 34.9%, and approximately one-third of the patients were not treated with any osteoporosis drugs after teriparatide. Improvement in persistence and switches are desired. PURPOSE: We aimed to elucidate the persistence rates and switches before and after teriparatide treatment in real-world osteoporosis patients based on data from a medical claims database in Japan. METHODS: We reviewed the records of patients with diagnoses of osteoporosis who were prescribed teriparatide at least once from January 2005 to June 2017. Patients with a follow-up ≤ 90 days before the first and ≤ 90 days after the last prescription of teriparatide were excluded. Discontinuation was defined as no treatment for > 90 days. We investigated treatment duration, compared characteristics of patients with persistence ≤ 12 and > 12 months, and osteoporotic medications before and after teriparatide by weekly or daily teriparatide. RESULTS: Among the 553 patients extracted for the study, 81.9% were women, 45.6% were aged ≥ 65 years, and 67.3% had a fracture. The most common fracture site was the spine (39.2%). The overall persistence rate of teriparatide > 12 months was 34.9% (weekly, 23.5%; daily, 43.1%). The subjects with persistence > 12 months comprised a higher proportion of women and they had a higher prevalence of rib and sternum fractures than those with ≤ 12 months. After teriparatide, 38.2% were switched to active vitamin D3, 35.1% to bisphosphonates, and 13.7% to denosumab allowing duplication. However, 34.0% of the patients were not switched to any subsequent medication for osteoporosis. CONCLUSIONS: Persistence rate over 12 months of teriparatide treatment was 34.9% in Japan. Approximately one-third of patients had no subsequent treatment immediately after teriparatide. Monitoring persistence and considering subsequent drugs for osteoporosis are necessary for teriparatide treatment.
Statistical evaluation of methods for identification of differentially abundant genes in comparative metagenomics.

BACKGROUND: Metagenomics is the study of microbial communities by sequencing of genetic material directly from environmental or clinical samples. The genes present in the metagenomes are quantified by annotating and counting the generated DNA fragments. Identification of differentially abundant genes between metagenomes can provide important information about differences in community structure, diversity and biological function. Metagenomic data is however high-dimensional, contain high levels of biological and technical noise and have typically few biological replicates. The statistical analysis is therefore challenging and many approaches have been suggested to date. RESULTS: In this article we perform a comprehensive evaluation of 14 methods for identification of differentially abundant genes between metagenomes. The methods are compared based on the power to detect differentially abundant genes and their ability to correctly estimate the type I error rate and the false discovery rate. We show that sample size, effect size, and gene abundance greatly affect the performance of all methods. Several of the methods also show non-optimal model assumptions and biased false discovery rate estimates, which can result in too large numbers of false positives. We also demonstrate that the performance of several of the methods differs substantially between metagenomic data sequenced by different technologies. CONCLUSIONS: Two methods, primarily designed for the analysis of RNA sequencing data (edgeR and DESeq2) together with a generalized linear model based on an overdispersed Poisson distribution were found to have best overall performance. The results presented in this study may serve as a guide for selecting suitable statistical methods for identification of differentially abundant genes in metagenomes.
Prenatal and early-life antibiotic use and risk of childhood asthma: A retrospective cohort study.

BACKGROUND: Although associations between antibiotic exposure in infants and asthma development are reported, few studies have examined the effects of prenatal exposure to antibiotics. We evaluated this association considering the antibiotic types using a large-scale claim database in Japan. METHODS: This retrospective study using health insurance administrative claim data in Japan included children born between January 2005 and September 2014. We constructed 2 cohorts: initial cohort, with information on children's mothers, and sibling cohort, with at least one sibling. Cox proportional hazard regression and sibling-matched cohort analyses were performed to determine the association between exposure to antibiotics in utero or the first year of life and asthma development until age 6. RESULTS: In the initial cohort, antibiotic exposure during the foetal period was associated with early asthma development (until age 3; HR: 1.18, 95% CI: 1.08-1.30). However, this association disappeared after 3 years. The association between antibiotic exposure in the first year of life and asthma was stronger in early (HR: 2.43, 95% CI: 2.20-2.69) than later (HR: 1.23, 95% CI: 1.11-1.36) life. In the sibling cohort, we observed positive associations between foetal exposure and asthma by adjusting for familial factors (HR: 1.34, 95% CI: 1.05-1.72), which remained during the first year of life (HR: 1.62, 95% CI: 1.27-2.07). CONCLUSIONS: Exposure to antibiotics during the first year of life was associated with childhood asthma even after adjusting for familial factors. However, a weak association was observed between prenatal antibiotic exposure and asthma development.
Real-world evidence analysis of palbociclib prescribing patterns for patients with advanced/metastatic breast cancer treated in community oncology practice in the USA one year post approval.

BACKGROUND: Rapidly evolving understanding of cancer biology has presented novel opportunities to translate that understanding into clinically relevant therapy. Palbociclib, a novel, first-in-class cyclin-dependent kinase (CDK) 4/6 inhibitor was approved in the USA in February 2015 for the treatment of advanced/metastatic breast cancer. We examined real-world evidence in the first year post approval to understand the clinical and demographic characteristics of patients treated with palbociclib in community oncology practices and the dosing, treatment, and complete blood count (CBC) monitoring patterns. METHODS: This was a retrospective observational study of structured data from a US electronic medical record (EMR) database. Female patients receiving palbociclib after 31 January 2015 were followed through 31 March 2016. Our methodological rules were constructed to aggregate drugs received according to the order in which they are given, i.e., identify the line of therapy as first, second, or third line, etc., using treatment order and course description fields from the EMR. RESULTS: There were 763 patients initiating palbociclib who met the selection criteria. Of those, 612 (80.2%) received palbociclib concomitantly with letrozole. Mean follow up was 6.4 months and mean age at palbociclib initiation was 64 years. Of patients with a known starting dose (n = 417), 79.9% started on palbociclib 125 mg. Dose reductions were observed in 20.1% of patients. Percentages of patients according to line of therapy at initiation of palbociclib were first-line, 39.5%; second-line, 15.7%; third-line, 13.1%; and fourth-line therapy or later, 31.7%. On average, two CBC tests were conducted during the first cycle of palbociclib treatment. Overall, 74.6% of patients had a neutropenic event during follow up including 47.3% and 8.0% of patients with a grade 3 or 4 occurrence, respectively. CONCLUSIONS: Real-world palbociclib use one year post US approval demonstrates a more heterogeneous patient population than that studied in the clinical trials with more than half of the patients receiving palbociclib plus letrozole in later lines of therapy. CBC testing rates suggested good provider compliance with monitoring guidelines in the USA prescribing information. The occurrence of grade 3 and 4 neutropenia (based on laboratory results) was consistent with the rates of grade 3 and 4 neutropenia in two phase-III studies (PALOMA-2, 56% and 10%; PALOMA-3, 55% and 11%, respectively). Understanding palbociclib utilization in real-world patients and how drug dosing and monitoring are performed aids in the understanding of safe and effective use of the drug.
Changes in the secretome of tri-dimensional spheroid-cultured human mesenchymal stem cells in vitro by interleukin-1 priming.

BACKGROUND: Mesenchymal stem cells (MSCs) are one of the most promising candidates for the treatment of major neurological disorders. Desirable therapeutic properties of MSCs include reparative and regenerative potential but, despite their proven safety, the efficacy of MSCs remains controversial. Therefore, it is essential to optimise culture protocols to enhance the therapeutic potential of the MSC secretome. Here we aimed to: assess the increase in secretion of cytokines that may induce repair, regeneration, or immunomodulation when cultured in three dimensions; study the effect of interleukin (IL)-1 priming on two- (2D) and three-dimensional (3D) cultures of MSC; and evaluate the potential use of the modified secretome using microglial-MSC co-cultures. METHODS: We established a 3D spheroid culture of human MSCs, and compared the secretome in 2D and 3D cultures under primed (IL-1) and unprimed conditions. BV2 microglial cells were stimulated with lipopolysaccharide (LPS) and treated with spheroid conditioned media (CM) or were co-cultured with whole spheroids. Concentrations of secreted cytokines were determined by enzyme-linked immunosorbent assay (ELISA). Protein arrays were used to further evaluate the effect of IL-1 priming in 2D and 3D cultures. RESULTS: 3D culture of MSCs significantly increased secretion of the IL-1 receptor antagonist (IL-1Ra), vascular endothelial growth factor (VEGF), and granulocyte-colony stimulating factor (G-CSF) compared with 2D culture, despite priming treatments with IL-1 being more effective in 2D than in 3D. The addition of CM of 3D-MSCs reduced LPS-induced tumour necrosis factor (TNF)-α secretion from BV2 cells, while the 3D spheroid co-cultured with the BV2 cells induced an increase in IL-6, but had no effect on TNF-α release. Protein arrays indicated that priming treatments trigger a more potent immune profile which is necessary to orchestrate an effective tissue repair. This effect was lost in 3D, partly because of the overexpression of IL-6. CONCLUSIONS: Increased secretion of anti-inflammatory markers occurs when MSCs are cultured in 3D, but this specific secretome did not translate into anti-inflammatory effects on LPS-treated BV2 cells in co-culture. These data highlight the importance of optimising priming treatments and culture conditions to maximise the therapeutic potential of MSC spheroids.
Similarity of the dog and human gut microbiomes in gene content and response to diet.

BACKGROUND: Gut microbes influence their hosts in many ways, in particular by modulating the impact of diet. These effects have been studied most extensively in humans and mice. In this work, we used whole genome metagenomics to investigate the relationship between the gut metagenomes of dogs, humans, mice, and pigs. RESULTS: We present a dog gut microbiome gene catalog containing 1,247,405 genes (based on 129 metagenomes and a total of 1.9 terabasepairs of sequencing data). Based on this catalog and taxonomic abundance profiling, we show that the dog microbiome is closer to the human microbiome than the microbiome of either pigs or mice. To investigate this similarity in terms of response to dietary changes, we report on a randomized intervention with two diets (high-protein/low-carbohydrate vs. lower protein/higher carbohydrate). We show that diet has a large and reproducible effect on the dog microbiome, independent of breed or sex. Moreover, the responses were in agreement with those observed in previous human studies. CONCLUSIONS: We conclude that findings in dogs may be predictive of human microbiome results. In particular, a novel finding is that overweight or obese dogs experience larger compositional shifts than lean dogs in response to a high-protein diet.
Determining the subcellular location of new proteins from microscope images using local features.

MOTIVATION: Evaluation of previous systems for automated determination of subcellular location from microscope images has been done using datasets in which each location class consisted of multiple images of the same representative protein. Here, we frame a more challenging and useful problem where previously unseen proteins are to be classified. RESULTS: Using CD-tagging, we generated two new image datasets for evaluation of this problem, which contain several different proteins for each location class. Evaluation of previous methods on these new datasets showed that it is much harder to train a classifier that generalizes across different proteins than one that simply recognizes a protein it was trained on. We therefore developed and evaluated additional approaches, incorporating novel modifications of local features techniques. These extended the notion of local features to exploit both the protein image and any reference markers that were imaged in parallel. With these, we obtained a large accuracy improvement in our new datasets over existing methods. Additionally, these features help achieve classification improvements for other previously studied datasets. AVAILABILITY: The datasets are available for download at http://murphylab.web.cmu.edu/data/. The software was written in Python and C++ and is available under an open-source license at http://murphylab.web.cmu.edu/software/. The code is split into a library, which can be easily reused for other data and a small driver script for reproducing all results presented here. A step-by-step tutorial on applying the methods to new datasets is also available at that address. CONTACT: murphy@cmu.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Transcriptome profiling of the honeybee parasite Varroa destructor provides new biological insights into the mite adult life cycle.

BACKGROUND: The parasite Varroa destructor represents a significant threat to honeybee colonies. Indeed, development of Varroa infestation within colonies, if left untreated, often leads to the death of the colony. Although its impact on bees has been extensively studied, less is known about its biology and the functional processes governing its adult life cycle and adaptation to its host. We therefore developed a full life cycle transcriptomic catalogue in adult Varroa females and included pairwise comparisons with males, artificially-reared and non-reproducing females (10 life cycle stages and conditions in total). RESULTS: Extensive remodeling of the Varroa transcriptome was observed, with an upregulation of energetic and chitin metabolic processes during the initial and final phases of the life cycle (e.g. phoretic and post-oviposition stages), whereas during reproductive stages in brood cells genes showing functions related to transcriptional regulation were overexpressed. Several neurotransmitter and neuropeptide receptors involved in behavioural regulation, as well as active compounds of salivary glands, were also expressed at a higher level outside the reproductive stages. No difference was detected between artificially-reared phoretic females and their counterparts in colonies, or between females who failed to reproduce and females who successfully reproduced, indicating that phoretic individuals can be reared outside host colonies without impacting their physiology and that mechanisms underlying reproductive failure occur before oogenesis. CONCLUSIONS: We discuss how these new findings reveal the remarkable adaptation of Varroa to its host biology and notably to the switch from living on adults to reproducing in sealed brood cells. By spanning the entire adult life cycle, our work captures the dynamic changes in the parasite gene expression and serves as a unique resource for deciphering Varroa biology and identifying new targets for mite control.
Infective endocarditis due to Burkholderia cepacia in a neonate: a case report.

BACKGROUND: Burkholderia is a pathogen that is rarely seen in clinical cases. However, this organism is being found more commonly in hospitals. CASE PRESENTATION: A female Indonesian newborn was referred to our neonatal intensive care unit because of respiratory distress. The newborn had been delivered the previous night via cesarean section. A physical examination revealed intercostal retractions and weak cry. The newborn's gestational history was preterm, small for gestational age, and preterm premature ruptured membrane for 14 hours. Continuous positive airway pressure was administered. A multiple-antibiotic regimen consisting of ampicillin-sulbactam, gentamicin, meropenem, and ceftriaxone was initiated. Insertion of a central catheter was performed. The patient's laboratory results were low blood albumin and globulin, anemia, and leukopenia. A blood culture revealed Burkholderia cepacia that was resistant to multiple antimicrobial agents. A chest x-ray showed infiltrate on both lung fields. Echocardiography showed two vegetations on the tricuspid valve. CONCLUSIONS: B. cepacia is a rare cause of infective endocarditis. With its capability to colonize water and grow on microbicides, the presence of B. cepacia in a patient's blood warrants further investigation in institutions providing care. This might not be the first publication on this topic.
Potential Diarrheal Pathogens Common Also in Healthy Children in Angola.

BACKGROUND: Globally, diarrhea kills almost 1500 children daily. In diagnostics, molecular methods are replacing traditional assays. We aimed to investigate enteropathogens in children with and without diarrhea in Luanda, the capital of Angola. METHODS: One hundred and ninety-four stool samples from 98 children with acute diarrhea and 96 children without diarrhea were investigated for 17 enteropathogens with multiplex real-time polymerase chain reaction. RESULTS: The median age of children was 10.5 months. Enteropathogens, bacteria, viruses and parasites were detected in 91%, 78%, 50% and 25%, respectively. A positive finding was significantly (P = 0.003) more common in diarrhea when testing for all pathogens combined, for bacteria alone and for viruses alone. More than one pathogen was found more frequently in diarrhea than in non-diarrhea stool samples, in 87% and in 59% (P < 0.0001), respectively. The median number (interquartile range) of pathogens detected was 3 (2) versus 1.5 (2; P < 0.0001), respectively. When age was taken into account, diarrhea was found to be associated with enterotoxigenic and enteroaggregative Escherichia coli, Shigella, Campylobacter, rotavirus, sapovirus and Cryptosporidium. CONCLUSIONS: Multiplex polymerase chain reaction detected enteropathogens in almost all stool samples of children in Luanda, albeit this occurred more often in diarrhea. Children with diarrhea showed more mixed infections than children without diarrhea.
Species conservation profiles of a random sample of world spiders I: Agelenidae to Filistatidae.

Background: The IUCN Red List of Threatened Species is the most widely used information source on the extinction risk of species. One of the uses of the Red List is to evaluate and monitor the state of biodiversity and a possible approach for this purpose is the Red List Index (RLI). For many taxa, mainly hyperdiverse groups, it is not possible within available resources to assess all known species. In such cases, a random sample of species might be selected for assessment and the results derived from it extrapolated for the entire group - the Sampled Red List Index (SRLI). With the current contribution and the three following papers, we intend to create the first point in time of a future spider SRLI encompassing 200 species distributed across the world. New information: A sample of 200 species of spiders were randomly selected from the World Spider Catalogue, an updated global database containing all recognised species names for the group. The 200 selected species where divided taxonomically at the family level and the familes were ordered alphabetically. In this publication, we present the conservation profiles of 46 species belonging to the famillies alphabetically arranged between Agelenidae and Filistatidae, which encompassed Agelenidae, Amaurobiidae, Anyphaenidae, Araneidae, Archaeidae, Barychelidae, Clubionidae, Corinnidae, Ctenidae, Ctenizidae, Cyatholipidae, Dictynidae, Dysderidae, Eresidae and Filistatidae.
A two-state model for the kinetics of competitive radioligand binding.

BACKGROUND AND PURPOSE: Ligand-receptor binding kinetics is receiving increasing attention in the drug research community. The Motulsky and Mahan model, a one-state model, offers a method for measuring the binding kinetics of an unlabelled ligand, with the assumption that the labelled ligand has no preference while binding to distinct states or conformations of a drug target. As such, the one-state model is not applicable if the radioligand displays biphasic binding kinetics to the receptor. EXPERIMENTAL APPROACH: We extended the Motulsky and Mahan model to a two-state model, in which the kinetics of the unlabelled competitor binding to different receptor states (R1 and R2 ) can be measured. With this extended model, we determined the binding kinetics of unlabelled N-5'-ethylcarboxamidoadenosine (NECA), a representative agonist for the adenosine A1 receptor. Subsequently, an application of the model was exemplified by measuring the binding kinetics of other A1 receptor ligands. In addition, limitations of the model were investigated as well. KEY RESULTS: The kinetic rate constants of unlabelled NECA were comparable with the results of kinetic radioligand binding assays in which [3 H]-NECA was used. The model was further validated by good correlation between simulated results and the experimental data. CONCLUSION: The two-state model is sufficient to analyse the binding kinetics of an unlabelled ligand, when a radioligand shows biphasic association characteristics. We expect this two-state model to have general applicability for other targets as well.
Phylogenetic convolutional neural networks in metagenomics.

BACKGROUND: Convolutional Neural Networks can be effectively used only when data are endowed with an intrinsic concept of neighbourhood in the input space, as is the case of pixels in images. We introduce here Ph-CNN, a novel deep learning architecture for the classification of metagenomics data based on the Convolutional Neural Networks, with the patristic distance defined on the phylogenetic tree being used as the proximity measure. The patristic distance between variables is used together with a sparsified version of MultiDimensional Scaling to embed the phylogenetic tree in a Euclidean space. RESULTS: Ph-CNN is tested with a domain adaptation approach on synthetic data and on a metagenomics collection of gut microbiota of 38 healthy subjects and 222 Inflammatory Bowel Disease patients, divided in 6 subclasses. Classification performance is promising when compared to classical algorithms like Support Vector Machines and Random Forest and a baseline fully connected neural network, e.g. the Multi-Layer Perceptron. CONCLUSION: Ph-CNN represents a novel deep learning approach for the classification of metagenomics data. Operatively, the algorithm has been implemented as a custom Keras layer taking care of passing to the following convolutional layer not only the data but also the ranked list of neighbourhood of each sample, thus mimicking the case of image data, transparently to the user.