Miracle-dz/UniFAR-FTUs huggingface dataset:
Clinicopathological parameters influencing inhibitor development in patients with hemophilia A receiving on-demand therapy

Background: Development of inhibitors to transfused factor VIII in patients with hemophilia A continues to be a challenge for professionals involved in hemophilia care. The majority of patients in India receive ‘on-demand’ rather than prophylactic therapy. The present study was done to assess the prevalence of factor VIII inhibitors in patients with hemophilia A (PWHA) receiving ‘on-demand’ therapy in a North Indian population and to study the clinicopathological parameters influencing the development of inhibitors. Methods: The study group comprised of 300 PWHA. Detailed clinical parameters, treatment history, bleeding profile including family history were recorded. Diagnosis of hemophilia A was confirmed by relevant coagulation tests. Inhibitors were screened using mixing based studies followed by quantification by Bethesda assay and Nijmegen modified Bethesda assay. Samples were collected from five cities in North India where a free supply of factor VIII was available and effectively used in three of these cities. Results: In the 300 PWHA, disease phenotype was severe in 219 (73%), moderate in 62 (20.67%) and mild in 19 (6.34%), based on the factor VIII bioassay. Inhibitor prevalence was 9.6% (n = 29) and seen only in the severe phenotype. Inhibitor titers ranged from 0.8 to 108.8 BU/ml. A total of 12 PWHA had low and 17 had high titers. Correlation of various clinicopathological parameters in inhibitor-positive versus negative PWHA showed significant correlation with age at onset of disease, severity of disease, age at first exposure to treatment, annual factor intake (IU/kg/year), intense treatment episodes and bleeding manifestations like central nervous system bleed and hematuria. The total study sample had blood group B in 33.34% PWHA, followed by O (27.34%), A (24.34%) and AB (15%), however, in inhibitor-positive samples, significant inhibitor formation was associated with the ABO subtype A (19/29, 65.51%). Conclusions: Factor VIII inhibitor prevalence in PWHA receiving ‘on-demand’ therapy was 9.6%. Clinicopathological correlates of inhibitor development in such PWHA have been analyzed in this novel study.
Contribution of Adrenal Glands to Intratumor Androgens and Growth of Castration-Resistant Prostate Cancer

Purpose: Tumor androgens in castration-resistant prostate cancer (CRPC) reflect de novo intratumoral synthesis or adrenal androgens. We used C.B. -17 SCID mice in which we observed adrenal CYP17A activity to isolate the impact of adrenal steroids on CRPC tumors in vivo. Experimental Design: We evaluated tumor growth and androgens in LuCaP35CR and LuCaP96CR xenografts in response to adrenalectomy (ADX). We assessed protein expression of key steroidogenic enzymes in 185 CRPC metastases from 42 patients. Results: Adrenal glands of intact and castrated mice expressed CYP17A. Serum DHEA, androstenedione (AED), and testosterone (T) in castrated mice became undetectable after ADX (all P < 0.05). ADX prolonged median survival (days) in both CRPC models (33 vs. 179; 25 vs. 301) and suppressed tumor steroids versus castration alone (T 0.64 pg/mg vs. 0.03 pg/mg; DHT 2.3 pg/mg vs. 0.23 pg/mg; and T 0.81 pg/mg vs. 0.03 pg/mg, DHT 1.3 pg/mg vs. 0.04 pg/mg; all P ≤ 0.001). A subset of tumors recurred with increased steroid levels, and/or induction of androgen receptor (AR), truncated AR variants, and glucocorticoid receptor (GR). Metastases from 19 of 35 patients with AR positive tumors concurrently expressed enzymes for adrenal androgen utilization and nine expressed enzymes for de novo steroidogenesis (HSD3B1, CYP17A, AKR1C3, and HSD17B3). Conclusions: Mice are appropriate for evaluating adrenal impact of steroidogenesis inhibitors. A subset of ADX-resistant CRPC tumors demonstrate de novo androgen synthesis. Tumor growth and androgens were suppressed more strongly by surgical ADX than prior studies using abiraterone, suggesting reduction in adrenally-derived androgens beyond that achieved by abiraterone may have clinical benefit. Proof-of-concept studies with agents capable of achieving true “nonsurgical ADX” are warranted.
Introgression and gene family contraction drive the evolution of lifestyle and host shifts of hypocrealean fungi

ABSTRACT Hypocrealean fungi (Ascomycota) are known for their diversity of lifestyles. Their vital influences on agricultural and natural ecosystems have resulted in a number of sequenced genomes, which provide essential data for genomic analysis. Totally, 45 hypocrealean fungal genomes constructed a phylogeny. The phylogeny showed that plant pathogens in Nectriaceae diverged earliest, followed by animal pathogens in Cordycipitaceae, Ophiocordycipitaceae and Clavicipitaceae with mycoparasites in Hypocreaceae. Insect/nematode pathogens and grass endophytes in Clavicipitaceae diverged at last. Gene families associated with host-derived nutrients are significantly contracted in diverged lineages compared with the ancestral species. Introgression was detected in certain lineages of hypocrealean fungi, and the main functions of the genes located in the introgressed regions are involved in host recognition, transcriptional regulation, stress response and cell growth regulation. These results indicate that contraction of gene families and introgression might be main mechanisms to drive lifestyle differentiation and evolution and host shift of hypocrealean fungi.
End-to-End Argument Mining for Discussion Threads Based on Parallel Constrained Pointer Architecture

Argument Mining (AM) is a relatively recent discipline, which concentrates on extracting claims or premises from discourses, and inferring their structures. However, many existing works do not consider micro-level AM studies on discussion threads sufficiently. In this paper, we tackle AM for discussion threads. Our main contributions are follows: (1) A novel combination scheme focusing on micro-level inner- and inter- post schemes for a discussion thread. (2) Annotation of large-scale civic discussion threads with the scheme. (3) Parallel constrained pointer architecture (PCPA), a novel end-to-end technique to discriminate sentence types, inner-post relations, and inter-post interactions simultaneously. The experimental results demonstrate that our proposed model shows better accuracy in terms of relations extraction, in comparison to existing state-of-the-art models.
Beyond Error Propagation in Neural Machine Translation: Characteristics of Language Also Matter

Neural machine translation usually adopts autoregressive models and suffers from exposure bias as well as the consequent error propagation problem. Many previous works have discussed the relationship between error propagation and the accuracy drop (i.e., the left part of the translated sentence is often better than its right part in left-to-right decoding models) problem. In this paper, we conduct a series of analyses to deeply understand this problem and get several interesting findings. (1) The role of error propagation on accuracy drop is overstated in the literature, although it indeed contributes to the accuracy drop problem. (2) Characteristics of a language play a more important role in causing the accuracy drop: the left part of the translation result in a right-branching language (e.g., English) is more likely to be more accurate than its right part, while the right part is more accurate for a left-branching language (e.g., Japanese). Our discoveries are confirmed on different model structures including Transformer and RNN, and in other sequence generation tasks such as text summarization.
MULDEF: Multi-model-based Defense Against Adversarial Examples for Neural Networks

Despite being popularly used in many applications, neural network models have been found to be vulnerable to adversarial examples, i.e., carefully crafted examples aiming to mislead machine learning models. Adversarial examples can pose potential risks on safety and security critical applications. However, existing defense approaches are still vulnerable to attacks, especially in a white-box attack scenario. To address this issue, we propose a new defense approach, named MulDef, based on robustness diversity. Our approach consists of (1) a general defense framework based on multiple models and (2) a technique for generating these multiple models to achieve high defense capability. In particular, given a target model, our framework includes multiple models (constructed from the target model) to form a model family. The model family is designed to achieve robustness diversity (i.e., an adversarial example successfully attacking one model cannot succeed in attacking other models in the family). At runtime, a model is randomly selected from the family to be applied on each input example. Our general framework can inspire rich future research to construct a desirable model family achieving higher robustness diversity. Our evaluation results show that MulDef (with only up to 5 models in the family) can substantially improve the target model's accuracy on adversarial examples by 22-74% in a white-box attack scenario, while maintaining similar accuracy on legitimate examples.
Young children's capacity to imagine and prepare for certain and uncertain future outcomes

The current study used a minimalist paradigm to examine young children’s capacity to imagine and prepare for certain and uncertain immediate future outcomes. In a counterbalanced order, 2.5-year-old children (N = 32) completed twelve trials each of two tasks: (1) the forked tube task, which assessed their ability to cover two possible tube exits to ensure they would catch a single target with an uncertain future trajectory, and (2) the double tube task, which assessed their ability to cover two separate tube exits to ensure they would catch two targets with certain future trajectories. Even though the optimal preparatory action was the same across both tasks, children were much more likely to spontaneously and consistently demonstrate this action in the double tube task than the forked tube task. Children’s responses were unaffected by the number of targets seen in the demonstration phase, and instead appeared to be based on the particular contingencies of each apparatus. These results are consistent with the possibility that young children specifically struggle to imagine and prepare for mutually exclusive versions of uncertain future events.
Efficacy of a 4-Week Swallowing Rehabilitation Program Combined With Pyriform Sinus Ballooning in Patients With Post-stroke Dysphagia

Objective To assess the efficacy of a 4-week swallowing rehabilitation program combined with pyriform sinus ballooning in patients with post-stroke dysphagia (PSD). Methods We evaluated a total of 30 patients (n=30) with PSD who were admitted to our medical institution between May of 2014 and October of 2016. These patients were randomly assigned to either the trial group (n=15; a 20-minute conventional rehabilitation followed by a 10-minute pyriform sinus ballooning) or the control group (n=15; a 30-minute conventional rehabilitation). In these patients, the efficacy outcome measures were pharyngeal remnant, the pharyngeal transit time, the Penetration Aspiration Scale (PAS) scores and the Videofluoroscopic Dysphagia Scale (VDS) scores. We compared the differences in efficacy outcome measures at 4 weeks from baseline between the two groups. Results There were significant changes in the pharyngeal remnant, the pharyngeal transit time, the PAS scores and the VDS scores at 4 weeks from baseline between the two groups (p<0.0001, p=0.0001, p<0.0001, and p=0.0048, respectively). There were no treatment-emergent adverse events in our series. Conclusion Our 4-week rehabilitation program combined with pyriform sinus ballooning is an effective and safe modality in patients with PSD. However, further large-scale, long-term, and multi-center studies are needed to corroborate our results.
LRS3-TED: a large-scale dataset for visual speech recognition

This paper introduces a new multi-modal dataset for visual and audio-visual speech recognition. It includes face tracks from over 400 hours of TED and TEDx videos, along with the corresponding subtitles and word alignment boundaries. The new dataset is substantially larger in scale compared to other public datasets that are available for general research.
Chemokine receptors CCR2 and CX3CR1 regulate viral encephalitis-induced hippocampal damage but not seizures

Significance Viral encephalitis is a frequent medical emergency, often resulting in acute seizures and brain damage, which reduce quality of life, promote the development of epilepsy, and can cause death. The relative roles of activation of microglia, the brain-resident innate immune cells, versus invasion of blood-borne immune cells such as monocytes in the acute and chronic consequences of viral encephalitis are only incompletely understood. Here we show that lack of the chemokine receptors CCR2 or CX3CR1, which regulate the responses of myeloid cells such as monocytes and microglia, prevents hippocampal damage but not seizures in a mouse model of viral encephalitis. Treatment strategies aimed at inhibiting peripheral immune cells from entering the brain during encephalitis could reduce brain damage. Viral encephalitis is a major risk factor for the development of seizures, epilepsy, and hippocampal damage with associated cognitive impairment, markedly reducing quality of life in survivors. The mechanisms underlying seizures and hippocampal neurodegeneration developing during and after viral encephalitis are only incompletely understood, hampering the development of preventive treatments. Recent findings suggest that brain invasion of blood-born monocytes may be critically involved in both seizures and brain damage in response to encephalitis, whereas the relative role of microglia, the brain’s resident immune cells, in these processes is not clear. CCR2 and CX3CR1 are two chemokine receptors that regulate the responses of myeloid cells, such as monocytes and microglia, during inflammation. We used Ccr2-KO and Cx3cr1-KO mice to understand the role of these receptors in viral encephalitis-associated seizures and neurodegeneration, using the Theiler’s virus model of encephalitis in C57BL/6 mice. Our results show that CCR2 as well as CX3CR1 plays a key role in the accumulation of myeloid cells in the CNS and activation of hippocampal myeloid cells upon infection. Furthermore, by using Cx3cr1-creER+/−tdTomatoSt/Wt reporter mice, we show that, with regard to CD45 and CD11b expression, some microglia become indistinguishable from monocytes during CNS infection. Interestingly, the lack of CCR2 or CX3CR1 receptors was associated with almost complete prevention of hippocampal damage but did not prevent seizure development after viral CNS infection. These data are compatible with the hypothesis that CNS inflammatory mechanism(s) other than the infiltrating myeloid cells trigger the development of seizures during viral encephalitis.
Assessment of the In Vivo Efficacy of WCK 5222 (Cefepime-Zidebactam) against Carbapenem-Resistant Acinetobacter baumannii in the Neutropenic Murine Lung Infection Model

We evaluated the in vivo efficacy of human-simulated WCK 5222 (cefepime-zidebactam) against cefepime-resistant Acinetobacter baumannii strains (n = 13) in the neutropenic murine lung infection model. Twelve isolates were meropenem resistant. ABSTRACT We evaluated the in vivo efficacy of human-simulated WCK 5222 (cefepime-zidebactam) against cefepime-resistant Acinetobacter baumannii strains (n = 13) in the neutropenic murine lung infection model. Twelve isolates were meropenem resistant. In control animals and those that received cefepime or zidebactam alone, the mean bacterial growth at 24 h was >2 log10 CFU/lung compared with 0-h controls (6.32 ± 0.33 log10 CFU/lung). WCK 5222 produced a decline in the bacterial burden for all isolates (mean reduction, −3.34 ± 0.85 log10 CFU/lung) and demonstrated remarkable potency.
Autologous platelet‐rich gel treatment for diabetic chronic cutaneous ulcers: A meta‐analysis of randomized controlled trials

In recent years, many studies have reported that autologous platelet‐rich gel (APG) is an effective adjuvant treatment for chronic cutaneous ulcers in diabetics. The aim of this study was to explore the efficacy and safety of APG for the topical treatment of diabetic chronic cutaneous ulcers.
Cone-Beam Computed Tomographic Evaluation of Root Canal Morphology of Maxillary Premolars in a Saudi Population

Objective The aim of the study was to investigate the root canal morphology of maxillary first and second premolars in a Saudi population using Cone-Beam Computed Tomography (CBCT). Methods This retrospective cross-sectional study assessed CBCT images of 707 Saudi patients. The number of roots and canal configuration were identified based on Vertucci's classification. Fisher's exact Chi-square tests were performed to analyze the association between sex and number of roots and sex and root canal configuration. Results Most teeth had two roots in maxillary first premolars (75.1%) and one root in maxillary second premolars (85.2%). Type IV was the most prevalent canal configuration in maxillary first premolars (69.1%), while Type I was the most in maxillary second premolars (49.4%). All types of canal configurations were observed in maxillary premolars except Type VII for the maxillary second premolar. Chi-square tests showed no significant association between gender and number of roots and sex and root canal configuration in both maxillary first and second premolars although higher number of roots was seen in men (P > 0.05). Conclusion Most maxillary first premolars had two roots with Type IV being the most predominant canal configuration, while a single root with Type I canal configuration was the most frequently observed morphology in maxillary second premolars. In maxillary first premolars, 21.3% had one canal apically, 75.4% had two canals apically, and 3.3% had three canals apically. In maxillary second premolars, 80.2% had one canal apically, 18.9% had two canals apically, and 0.9% had three canals apically.
Sweet flowers are slow, and weeds make haste: leveraging methodology from research on tobacco, alcohol, and opioid analgesics to make rapid and policy-relevant advances in cannabis science

Abstract The legalization of medical and recreational cannabis use has occurred ahead of science. The current evidence base has poor utility for determining if cannabis products can meet the standards of safety, efficacy, and quality intrinsic to modern medicine, and for informing regulation of cannabis as a legal intoxicant. Individual jurisdictions that pass cannabis reforms may not have adequate resources to support the level of new scientific research needed to inform regulatory actions; this could make it difficult to keep a rapidly growing multi-billion-dollar cannabis industry in check. Further, the present lack of evidence-based regulatory oversight for cannabis parallels the climates that gave rise to the tobacco and prescription opioid epidemics, suggesting that continued omission may result in negative public health consequences. However, translating a methodological framework developed through research on these compounds may promote rapid advances in cannabis science germane to regulatory knowledge gaps. The present review highlights specific advancements in these areas, as well as in alcohol regulation, that are prime for informing policy-relevant cannabis science, and also offers some recommendations for evidence-based regulatory policy. Resulting progress may directly inform both regulation of cannabis in both medical and licit recreational drug frameworks, and new cannabis-related public health initiatives.
Leveraging Deep Visual Descriptors for Hierarchical Efficient Localization

Many robotics applications require precise pose estimates despite operating in large and changing environments. This can be addressed by visual localization, using a pre-computed 3D model of the surroundings. The pose estimation then amounts to finding correspondences between 2D keypoints in a query image and 3D points in the model using local descriptors. However, computational power is often limited on robotic platforms, making this task challenging in large-scale environments. Binary feature descriptors significantly speed up this 2D-3D matching, and have become popular in the robotics community, but also strongly impair the robustness to perceptual aliasing and changes in viewpoint, illumination and scene structure. In this work, we propose to leverage recent advances in deep learning to perform an efficient hierarchical localization. We first localize at the map level using learned image-wide global descriptors, and subsequently estimate a precise pose from 2D-3D matches computed in the candidate places only. This restricts the local search and thus allows to efficiently exploit powerful non-binary descriptors usually dismissed on resource-constrained devices. Our approach results in state-of-the-art localization performance while running in real-time on a popular mobile platform, enabling new prospects for robotics research.
Optimization of the Linker Length of Mannose-Cholesterol Conjugates for Enhanced mRNA Delivery to Dendritic Cells by Liposomes

Liposomes (LPs) as commonly used mRNA delivery systems remain to be rationally designed and optimized to ameliorate the antigen expression of mRNA vaccine in dendritic cells (DCs). In this study, we synthesized mannose-cholesterol conjugates (MPn-CHs) by click reaction using different PEG units (PEG100, PEG1000, and PEG2000) as linker molecules. MPn-CHs were fully characterized and subsequently used to prepare DC-targeting liposomes (MPn-LPs) by a thin-film dispersion method. MPn-LPs loaded with mRNA (MPn-LPX) were finally prepared by a simple self-assembly method. MPn-LPX displayed bigger diameter (about 135 nm) and lower zeta potential (about 40 mV) compared to MPn-LPs. The in vitro transfection experiment on DC2.4 cells demonstrated that the PEG length of mannose derivatives had significant effect on the expression of GFP-encoding mRNA. MP1000-LPX containing MP1000-CH can achieve the highest transfection efficiency (52.09 ± 4.85%), which was significantly superior to the commercial transfection reagent Lipo 3K (11.47 ± 2.31%). The optimal DC-targeting MP1000-LPX showed an average size of 132.93 ± 4.93 nm and zeta potential of 37.93 ± 2.95 mV with nearly spherical shape. Moreover, MP1000-LPX can protect mRNA against degradation in serum with high efficacy. The uptake study indicated that MP1000-LPX enhanced mRNA expression mainly through the over-expressing mannose receptor (CD206) on the surface of DCs. In conclusion, mannose modified LPs might be a potential DC-targeting delivery system for mRNA vaccine after rational design and deserve further study on the in vivo delivery profile and anti-tumor efficacy.