Miracle-dz/UniFAR-FTUs huggingface dataset:
Phase 3 adaptive trial design options in treatment of complicated urinary tract infection

New antimicrobial drugs for treatment of complicated urinary tract infection (cUTI) are generally assessed in randomized, double‐blind, noninferiority clinical trials. Robust historical data for the active comparator inform on treatment effect estimation, yet typically do not substitute for the active comparator data in the proposed trial. We report design options for a phase 3 trial of cUTI using a Bayesian hierarchical model and historical data from 2 well‐executed phase 3 registrational trials of doripenem. The methodology is directly applicable to other phase 3 noninferiority settings. In addition to the research design application, we provide a novel methodology for assessing the robustness of type I error control. The model borrows heavily from the prior data when the current active comparator parameter estimate approximated the historical estimate. In contrast, the model had restricted borrowing when the 2 estimates were very different. The alternative trial design, with or without the inclusion of futility stopping criteria, provides a framework for future cUTI phase 3 trials.
Next Item Recommendation with Self-Attention

In this paper, we propose a novel sequence-aware recommendation model. Our model utilizes self-attention mechanism to infer the item-item relationship from user's historical interactions. With self-attention, it is able to estimate the relative weights of each item in user interaction trajectories to learn better representations for user's transient interests. The model is finally trained in a metric learning framework, taking both short-term and long-term intentions into consideration. Experiments on a wide range of datasets on different domains demonstrate that our approach outperforms the state-of-the-art by a wide margin.
simNet: Stepwise Image-Topic Merging Network for Generating Detailed and Comprehensive Image Captions

The encode-decoder framework has shown recent success in image captioning. Visual attention, which is good at detailedness, and semantic attention, which is good at comprehensiveness, have been separately proposed to ground the caption on the image. In this paper, we propose the Stepwise Image-Topic Merging Network (simNet) that makes use of the two kinds of attention at the same time. At each time step when generating the caption, the decoder adaptively merges the attentive information in the extracted topics and the image according to the generated context, so that the visual information and the semantic information can be effectively combined. The proposed approach is evaluated on two benchmark datasets and reaches the state-of-the-art performances.
Analyzing the Transcriptome Profile of Human Cumulus Cells Related to Embryo Quality via RNA Sequencing

Selecting excellent oocytes is required to improve the outcomes of in vitro fertilization (IVF). Cumulus cells (CCs) are an integral part of the oocyte maturation process. Therefore, we sought to identify differentially expressed genes in CCs to assess oocyte quality and embryo development potential. We divided the participants' embryos into the high-quality embryo group and low-quality embryo group by the information including age, body mass index, and the levels of luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone. We analyzed a total of 7 CC samples after the quality control in RNA sequencing. We found that 2499 genes were unregulated and 5739 genes were downregulated in high-quality embryo group compared to the low-quality embryo group (Padj < 0.05). Interestingly, MSTN, CTGF, NDUFA1, VCAN, SCD5, and STAR were significantly associated with the quality of embryo. In accordance with the results of RNA sequencing, the association of the expression levels of MSTN, CTGF, NDUFA1, VCAN, SCD5, and STAR with the embryo quality was verified by quantitative reverse-transcription polymerase chain reaction (RT-qPCR) in 50 CC samples. Despite the small sample size and lack of validation in animal models, our study supports the fact that differential gene expression profile of human CCs, including MSTN, CTGF, NDUFA1, VCAN, SCD5, and STAR, can serve as potential indicator for embryo quality.
N-terminal Acetylation Levels Are Maintained During Acetyl-CoA Deficiency in Saccharomyces cerevisiae*

Nt-acetylation is a prevalent protein modification catalyzed by N-terminal acetyltransferases using acetyl-CoA as acetyl donor. Here, we performed a global analysis of Nt-acetylation in yeast following nutrient starvation. Contrary to histone acetylation, which is sensitive to acetyl-CoA levels, we demonstrate that Nt-acetylation remains largely unaffected to changes in cellular metabolism. We did, however, identify two protein groups that were differentially Nt-acetylated, one showing the same sensitivity to acetyl-CoA as histones. We propose that specific, rather than global, Nt-acetylation events are subject to metabolic regulation. Graphical Abstract Highlights First global study on metabolic regulation of Nt-acetylation. Yeast cells maintain global Nt-acetylation levels during prolonged starvation. Nt-acetylation can in some cases be either up- or downregulated by starvation. Naa10/NatA affects the steady-state protein levels of Rsa3 and Rpl7a. N-terminal acetylation (Nt-acetylation) is a highly abundant protein modification in eukaryotes and impacts a wide range of cellular processes, including protein quality control and stress tolerance. Despite its prevalence, the mechanisms regulating Nt-acetylation are still nebulous. Here, we present the first global study of Nt-acetylation in yeast cells as they progress to stationary phase in response to nutrient starvation. Surprisingly, we found that yeast cells maintain their global Nt-acetylation levels upon nutrient depletion, despite a marked decrease in acetyl-CoA levels. We further observed two distinct sets of protein N termini that display differential and opposing Nt-acetylation behavior upon nutrient starvation, indicating a dynamic process. The first protein cluster was enriched for annotated N termini showing increased Nt-acetylation in stationary phase compared with exponential growth phase. The second protein cluster was conversely enriched for alternative nonannotated N termini (i.e. N termini indicative of shorter N-terminal proteoforms) and, like histones, showed reduced acetylation levels in stationary phase when acetyl-CoA levels were low. Notably, the degree of Nt-acetylation of Pcl8, a negative regulator of glycogen biosynthesis and two components of the pre-ribosome complex (Rsa3 and Rpl7a) increased during starvation. Moreover, the steady-state levels of these proteins were regulated both by starvation and NatA activity. In summary, this study represents the first comprehensive analysis of metabolic regulation of Nt-acetylation and reveals that specific, rather than global, Nt-acetylation events are subject to metabolic regulation.
Climatic factors and species range position predict sexually antagonistic selection across taxa

Sex differences in selection are ubiquitous in sexually reproducing organisms. When the genetic basis of traits is shared between the sexes, such sexually antagonistic selection (SAS) creates a potential constraint on adaptive evolution. Theory and laboratory experiments suggest that environmental variation and the degree of local adaptation may all affect the frequency and intensity of SAS. Here, we capitalize on a large database of over 700 spatially or temporally replicated estimates of sex-specific phenotypic selection from wild populations, combined with data on microclimates and geographical range information. We performed a meta-analysis to test three predictions from SAS theory, that selection becomes more concordant between males and females: (1) in more stressful environments, (2) in more variable environments and (3) closer to the edge of the species' range. We find partial empirical support for all three predictions. Within-study analyses indicate SAS decreases in extreme environments, as indicated by a relationship with maximum temperature, minimum precipitation and evaporative potential (PET). Across studies, we found that the average level of SAS at high latitudes was lower, where environmental conditions are typically less stable. Finally, we found evidence for reduced SAS in populations that are far from the centre of their geographical range. However, and notably, we also found some evidence of reduced average strength of selection in these populations, which is in contrast to predictions from classical theoretical models on range limit evolution. Our results suggest that environmental lability and species range position predictably influence sex-specific selection and sexual antagonism in the wild. This article is part of the theme issue ‘Linking local adaptation with the evolution of sex differences’.
Ceramide Metabolism Balance, a Multifaceted Factor in Critical Steps of Breast Cancer Development

Ceramides are key lipids in energetic-metabolic pathways and signaling cascades, modulating critical physiological functions in cells. While synthesis of ceramides is performed in endoplasmic reticulum (ER), which is altered under overnutrition conditions, proteins associated with ceramide metabolism are located on membrane arrangement of mitochondria and ER (MAMs). However, ceramide accumulation in meta-inflammation, condition that associates obesity with a chronic low-grade inflammatory state, favors the deregulation of pathways such as insulin signaling, and induces structural rearrangements on mitochondrial membrane, modifying its permeability and altering the flux of ions and other molecules. Considering the wide biological processes in which sphingolipids are implicated, they have been associated with diseases that present abnormalities in their energetic metabolism, such as breast cancer. In this sense, sphingolipids could modulate various cell features, such as growth, proliferation, survival, senescence, and apoptosis in cancer progression; moreover, ceramide metabolism is associated to chemotherapy resistance, and regulation of metastasis. Cell–cell communication mediated by exosomes and lipoproteins has become relevant in the transport of several sphingolipids. Therefore, in this work we performed a comprehensive analysis of the state of the art about the multifaceted roles of ceramides, specifically the deregulation of ceramide metabolism pathways, being a key factor that could modulate neoplastic processes development. Under specific conditions, sphingolipids perform important functions in several cellular processes, and depending on the preponderant species and cellular and/or tissue status can inhibit or promote the development of metabolic and potentially breast cancer disease.
Economic Evaluation of Letrozole for Early Breast Cancer in a Health Resource-Limited Setting

Objective Long-term aromatase inhibitor (AI) therapy is expected to improve the health outcomes with high health resource consumption in early breast cancer. The aim of the study was to assess the cost-effectiveness of letrozole for postmenopausal women with estrogen receptor positive early breast cancer in a health resource-limited setting. Methods A Markov model was developed to project the lifetime outcomes based on the clinical course of early breast cancer. The clinical and utility data were derived from reported results. Costs were estimated from the perspective of Chinese health care. The quality-adjusted life-year (QALY) and incremental cost-effective ratio (ICER) were measured. Probabilistic sensitivity and one-way analyses were conducted. Results Compared to 5 years of tamoxifen therapy, 5 years of AI treatment with letrozole improved the QALYs (10.44 versus 10.84) and increased the lifetime costs (CNY ¥13,613 versus CNY ¥28,797), resulting in an ICER of CNY ¥38,092 /QALY. The ICER of 5 years of letrozole versus 2–3 years of tamoxifen and then letrozole was CNY ¥68,233 /QALY. Sensitivity analyses showed that the age of initiating adjuvant endocrine therapy was the most influential parameter. Conclusions In health resource-limited settings, adjuvant endocrine therapy with letrozole is a cost-effective strategy compared to tamoxifen in women with early breast cancer.
Integrating Curriculum-Based Dynamic Assessment in Computerized Adaptive Testing: Development and Predictive Validity of the EDPL-BAI Battery on Reading Competence

In recent decades there have been significant changes in the conceptualization of reading as well as in the perception of how this activity should be assessed. Interest in the analysis of reading processes has led to the emergence of new explanatory models based primarily on the contributions of cognitive psychology. In parallel, there have been notable advances in measurement procedures, especially in models based on Item Response Theory (IRT), as well as in the capacity and performance of specific software programs that allow data to be managed and analyzed. These changes have contributed significantly to the rise of testing procedures such as computerized adaptive tests (CATs), whose fundamental characteristic is that the sequence of items presented in the tests is adapted to the level of competence that the subject manifests. Likewise, the incorporation of elements of dynamic assessment (DA) as the prompts are gradually offered allows for obtaining information about the type and degree of support required to optimize the subject’s performance. In this sense, the confluence of contributions from DA and CATs offers a new possibility for approaching the assessment of learning processes. In this article, we present a longitudinal research developed in two phases, through which a computerized dynamic adaptive assessment battery of reading processes (EDPL-BAI) was configured. The research frame involved 1,831 students (46% girls) from 13 public schools in three regions of Chile. The purpose of this study was to analyze the differential contribution on reading competence of dynamic scores obtained in a subsample composed of 324 (47% girls) students from third to sixth grade after the implementation of a set of adaptive dynamic tests of morpho-syntactic processes. The results achieved in the structural equation modeling indicate a good global fit. Individual relationships show a significant contribution of calibrated score that reflects estimated knowledge level on reading competence, as well as dynamic scores based on the assigned value of graduated prompts required by the students. These results showed significant predictive values on reading competence and incremental validity in relation to predictions made by static criterion tests.
Fecal Hyodeoxycholic Acid Is Correlated With Tylosin-Induced Microbiome Changes in Growing Pigs

The changes in the gut microbiome play an important role in the promoting effects of antibiotics, such as tylosin, to the health, and productivity of farm animals. Microbial metabolites are expected to be key mediators between antibiotics-induced microbiome changes and growth-promoting effects. The objective of this study was to extend the identification of tylosin-responsive microbes to the identification of tylosin-responsive metabolites in growing pigs. The feeding trial was conducted on a commercial farm using two pens of pigs fed diets with and without tylosin (40 mg/kg of diet). Fecal samples were collected from 10 pigs per pen at weeks 10, 13, 16, 19, and 22 of age, and subsequently analyzed using liquid chromatography-mass spectrometry (LC-MS) analysis. The multivariate model of LC-MS data showed that time-dependent changes occurred in the fecal metabolome of both control and tylosin-treated pigs. More importantly, the metabolomic profiles were similar between the tylosin treatment and control groups in weeks 10 and 22, but diverged during weeks 13–19. Subsequent analyses of the fecal metabolites contributing to the separation of two groups of pigs showed that hyodeoxycholic acid (HDCA), together with tylosin and its metabolites in feces, was greatly increased during weeks 13–19 (P < 0.05) in the group of pigs fed tylosin. The integration of current metabolomics data and the microbiome data from a previous study revealed the consistency between HDCA and a specific genus of microbes in the Clostridia family. Further studies are required to determine the causative relations between tylosin-elicited changes in HDCA and the microbiome as well as the role of HDCA in the growth promoting effects of tylosin.
Guiding Deep Learning System Testing Using Surprise Adequacy

Deep Learning (DL) systems are rapidly being adopted in safety and security critical domains, urgently calling for ways to test their correctness and robustness. Testing of DL systems has traditionally relied on manual collection and labelling of data. Recently, a number of coverage criteria based on neuron activation values have been proposed. These criteria essentially count the number of neurons whose activation during the execution of a DL system satisfied certain properties, such as being above predefined thresholds. However, existing coverage criteria are not sufficiently fine grained to capture subtle behaviours exhibited by DL systems. Moreover, evaluations have focused on showing correlation between adversarial examples and proposed criteria rather than evaluating and guiding their use for actual testing of DL systems. We propose a novel test adequacy criterion for testing of DL systems, called Surprise Adequacy for Deep Learning Systems (SADL), which is based on the behaviour of DL systems with respect to their training data. We measure the surprise of an input as the difference in DL system's behaviour between the input and the training data (i.e., what was learnt during training), and subsequently develop this as an adequacy criterion: a good test input should be sufficiently but not overtly surprising compared to training data. Empirical evaluation using a range of DL systems from simple image classifiers to autonomous driving car platforms shows that systematic sampling of inputs based on their surprise can improve classification accuracy of DL systems against adversarial examples by up to 77.5% via retraining.
Dynamics of Simultaneous and Imitative Bodily Coordination in Trust and Distrust

Body synchronization between interacting people involves coordinative movements in time, space and form. The introduction of newer technologies for automated video analysis and motion tracking has considerably improved the accurate measurement of coordination, particularly in temporal and spatial terms. However, the form of interpersonal coordination has been less explored. In the present study we address this gap by exploring the effect of trust on temporal and morphological patterns of interpersonal coordination. We adapted an optical motion-capture system to record spontaneous body movements in pairs of individuals engaged in natural conversations. We conducted two experiments in which we manipulated trust through a breach of expectancy (Study 1: 10 trustful and 10 distrustful participants) and friendship (Study 2: 20 dyads of friends and 20 dyads of strangers). In Study 1, results show the participants' strong, early mirror-like coordination in response to the confederates' breach of trust. In Study 2, imitative coordination tended to be more pronounced in pairs of friends than in pairs of non-friends. Overall, our results show not only that listeners move in reaction to speakers, but also that speakers react to listeners with a chain of dynamic coordination patterns affected by the immediate disposition of, and long-term relationship with, their interlocutors.
Trends in the use of digital libraries by scientists in 2000-2005: A case study of finelib

This study explores the trends in the use of electronic material and digital libraries by university faculty between the years 2000 and 2005. The data consist of nationwide web-based surveys of the end-users of FinELib, Finnish Electronic Library, at all Finnish universities. Although material provision has grown tremendously and consequently the use of electronic literature and of FinELib, the clients were polarizing into frequent and infrequent users. Perceived availability of the material provided was a major factor influencing this polarization. Availability was significantly stronger predictor of the use than users’ discipline. It seems that availability underlies the disciplinary variation in the use of digital libraries.
Impact of early analgesia on hospitalization outcomes for sickle cell pain crisis

Painful events are the leading cause of hospitalizations for patients with sickle cell disease. Individualized pain plans targeting patient‐specific maximum opioid dosing may shorten hospitalization length and are recommended by national guidelines. Prior to implementing individualized sickle cell pain plans, we tested the hypothesis that a shorter time to achieve a maximum opioid dose would improve hospitalization outcomes.
Somatic mutation load and spectra: A record of DNA damage and repair in healthy human cells

Somatic genome instability is a hallmark of cancer genomes and has been linked to aging and a variety of other pathologies. Large‐scale cancer genome and exome sequencing have revealed that mutation load and spectra in cancers can be influenced by environmental exposures, the anatomical site of exposures, and tissue type. There is now an abundance of data favoring the hypothesis that a substantial portion of the mutations in cancers originate prior to carcinogenesis in stem cells of the healthy individual. Rapid advances in sequencing of noncancer cells from healthy humans have shown that their mutation loads and spectra resemble cancer data. Similar to cancer genomes, mutation profiles of healthy cells show marked intra‐individual variation, thus providing a metric of the various factors—environmental and endogenous—involved in mutagenesis in these individuals. This review focuses on the current methodologies to measure mutation loads and to determine mutation signatures for evaluating the environmental and endogenous sources of DNA damage in human somatic cells. We anticipate that in future, such large‐scale studies aimed at exploring the landscapes of somatic mutations across different cell types in healthy people would provide a valuable resource for designing personalized preventative strategies against diseases associated with somatic genome instability. Environ. Mol. Mutagen. 59:672–686, 2018. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.
The blue paradox: Preemptive overfishing in marine reserves

Most large-scale conservation policies are anticipated or announced in advance. This risks the possibility of preemptive resource extraction before the conservation intervention goes into force. We use a high-resolution dataset of satellite-based fishing activity to show that anticipation of an impending no-take marine reserve undermines the policy by triggering an unintended race-to-fish. We study one of the world’s largest marine reserves, the Phoenix Islands Protected Area (PIPA), and find that fishers more than doubled their fishing effort once this area was earmarked for eventual protected status. The additional fishing effort resulted in an impoverished starting point for PIPA equivalent to 1.5 y of banned fishing. Extrapolating this behavior globally, we estimate that if other marine reserve announcements were to trigger similar preemptive fishing, this could temporarily increase the share of overextracted fisheries from 65% to 72%. Our findings have implications for general conservation efforts as well as the methods that scientists use to monitor and evaluate policy efficacy.