Miracle-dz/UniFAR-FTUs huggingface dataset:
Aggregation Strategies in Reachable Set Computation of Hybrid Systems

Computing the set of reachable states is a widely used technique for proving that a hybrid system satisfies its safety specification. Flow-pipe construction methods interleave phases of computing continuous successors and phases of computing discrete successors. Directly doing this leads to a combinatorial explosion problem, though, as with each discrete successor there may be an interval of time where the transition can occur, so that the number of paths becomes exponential in the number of discrete transitions. For this reason, most reachable set computation tools implement some form of set aggregation for discrete transitions, such as, performing a template-based overapproximation or convex hull aggregation. These aggregation methods, however, in theory can lead to unbounded error, and in practice are often the root cause of why a safety specification cannot be proven. This paper proposes techniques for improving the accuracy of the aggregation operations performed for reachable set computation. First, we present two aggregation strategies over generalized stars, namely convex hull aggregation and template based aggregation. Second, we perform adaptive deaggregation using a data structure called Aggregated Directed Acyclic Graph (AGGDAG). Our deaggregation strategy is driven by counterexamples and hence has soundness and relative completeness guarantees. We demonstrate the computational benefits of our approach through two case studies involving satellite rendezvous and gearbox meshing.
High GILT Expression and an Active and Intact MHC Class II Antigen Presentation Pathway Are Associated with Improved Survival in Melanoma

Key Points High GILT mRNA expression is associated with improved overall survival in melanoma. IFN-γ, TNF-α and IL-1β induce GILT expression in melanocytes. An active and intact MHC class II pathway correlates with improved melanoma survival. The MHC class I Ag presentation pathway in melanoma cells has a well-established role in immune-mediated destruction of tumors. However, the clinical significance of the MHC class II Ag presentation pathway in melanoma cells is less clear. In Ag-presenting cells, IFN-γ–inducible lysosomal thiol reductase (GILT) is critical for MHC class II–restricted presentation of multiple melanoma Ags. Although not expressed in benign melanocytes of nevi, GILT and MHC class II expression is induced in malignant melanocytes in a portion of melanoma specimens. Analysis of The Cancer Genome Atlas cutaneous melanoma data set showed that high GILT mRNA expression was associated with improved overall survival. Expression of IFN-γ, TNF-α, and IL-1β was positively associated with GILT expression in melanoma specimens. These cytokines were capable of inducing GILT expression in human melanoma cells in vitro. GILT protein expression in melanocytes was induced in halo nevi, which are nevi undergoing immune-mediated regression, and is consistent with the association of GILT expression with improved survival in melanoma. To explore potential mechanisms of GILT’s association with patient outcome, we investigated pathways related to GILT function and expression. In contrast to healthy skin specimens, in which the MHC class II pathway was nearly uniformly expressed and intact, there was substantial variation in the MHC class II pathway in the The Cancer Genome Atlas melanoma specimens. Both an active and intact MHC class II pathway were associated with improved overall survival in melanoma. These studies support a role for GILT and the MHC class II Ag presentation pathway in melanoma outcome.
Arf6 regulates RhoB subcellular localization to control cancer cell invasion

Zaoui et al. provide the first mechanistic evidence supporting a regulatory mechanism for RhoB localization and stability by Arf6. These findings establish that Arf6 is essential for RhoB-specific subcellular targeting to endosomes and, thus, the regulation of membrane trafficking and cell motility following activation of the oncogenic receptor tyrosine kinase, Met.
Strategic Development of the Public Health Workforce: A Unified Logic Model for a Multifaceted Program at the Centers for Disease Control and Prevention.

CONTEXT Public health has a responsibility to ensure the ability of its workforce to deliver essential services, including mastering the core public health competencies. PROGRAM The Division of Scientific Education and Professional Development (DSEPD) of the Centers for Disease Control and Prevention has a mission to improve health outcomes through a competent, sustainable, and empowered public health workforce. The DSEPD programs offer fellowships and other training opportunities, develop and disseminate quality public health training, and advance public health workforce development science. EVALUATION The DSEPD developed a unified division logic model to describe the combined activities and intended outcomes of all DSEPD programs and their intended contribution to a robust public health workforce and to support ongoing program planning and evaluation. The logic model has 4 streams of work that include (1) producing and disseminating quality learning products; (2) implementing and managing fellowship programs that support learning; (3) providing public health service through fellows; and (4) advancing workforce development science through collaboration with other public health leaders.The underlying program theory is that a robust workforce has sufficient workforce, organizational, and systems capacity to deliver public health essential services and, therefore, to protect the public's health. Three scientific theories support the program theory: the quality of learning; the accepted practice of competency-based programs and the service-learning model; and use of evidence-guided decision making in workforce development programs. DISCUSSION A unified division logic model allows DSEPD to describe its combined approaches to workforce development as a coherent portfolio with well-defined goals and measureable outcomes. The logic model effectively communicates the relationship among division programs, their shared outcomes, and their combined contributions to developing and maintaining a robust public health workforce. A unified logic model can serve as effective frame of reference for division evaluation and as evidence in public health workforce development science.
Hairy cell leukemia: 2020 update on diagnosis, risk stratification, and treatment

Hairy cell leukemia (HCL) and HCL‐like disorders, including HCL variant (HCL‐V) and splenic diffuse red pulp lymphoma (SDRPL), are a very heterogeneous group of mature lymphoid B‐cell disorders. They are characterized by the identification of hairy cells, a specific genetic profile, a different clinical course and the need for appropriate treatment.
Totem de Personnalisation : Conception d'une Interface Tangible pour le Choix de Parcours de Visite dans les Musées

De nos jours, les musees doivent rivaliser avec le marche du divertissement pour attirer un large public. Une solution envisagee pour les rendre plus attractifs tient dans la personnalisation des parcours de visite en fonction des preferences des visiteurs. En se basant sur l'analyse des besoins realisee aupres de cinq musees, nous avons concu cinq storyboards d'interface permettant a un groupe de visi-teurs de choisir un parcours en fonction de leurs personnal-ites et envies. Nous avons egalement identifie grâce a cette analyse, ainsi que la litterature, douze exigences qui nous ont permis d'evaluer les solutions proposees. Enfin, nous avons concu un prototype basse fidelite de "totem de per-sonnalisation", permettant a chaque membre du groupe de renseigner ses caracteristiques propres puis de collaborer dans le choix de caracteristiques communes.
Geometrical characterization of T cell receptor binding modes reveals class‐specific binding to maximize access to antigen

Recognition of antigenic peptides bound to major histocompatibility complex (MHC) proteins by αβ T cell receptors (TCRs) is a hallmark of T cell mediated immunity. Recent data suggest that variations in TCR binding geometry may influence T cell signaling, which could help explain outliers in relationships between physical parameters such as TCR‐pMHC binding affinity and T cell function. Traditionally, TCR binding geometry has been described with simple descriptors such as the crossing angle, which quantifies what has become known as the TCR's diagonal binding mode. However, these descriptors often fail to reveal distinctions in binding geometry that are apparent through visual inspection. To provide a better framework for relating TCR structure to T cell function, we developed a comprehensive system for quantifying the geometries of how TCRs bind peptide/MHC complexes. We show that our system can discern differences not clearly revealed by more common methods. As an example of its potential to impact biology, we used it to reveal differences in how TCRs bind class I and class II peptide/MHC complexes, which we show allow the TCR to maximize access to and “read out” the peptide antigen. We anticipate our system will be of use in not only exploring these and other details of TCR‐peptide/MHC binding interactions, but also addressing questions about how TCR binding geometry relates to T cell function, as well as modeling structural properties of class I and class II TCR‐peptide/MHC complexes from sequence information. The system is available at https://tcr3d.ibbr. umd.edu/tcr_com or for download as a script.
Ensuring electronic medical record simulation through better training, modeling, and evaluation

OBJECTIVE Electronic medical records (EMRs) can support medical research and discovery, but privacy risks limit the sharing of such data on a wide scale. Various approaches have been developed to mitigate risk, including record simulation via generative adversarial networks (GANs). While showing promise in certain application domains, GANs lack a principled approach for EMR data that induces subpar simulation. In this article, we improve EMR simulation through a novel pipeline that (1) enhances the learning model, (2) incorporates evaluation criteria for data utility that informs learning, and (3) refines the training process. MATERIALS AND METHODS We propose a new electronic health record generator using a GAN with a Wasserstein divergence and layer normalization techniques. We designed 2 utility measures to characterize similarity in the structural properties of real and simulated EMRs in the original and latent space, respectively. We applied a filtering strategy to enhance GAN training for low-prevalence clinical concepts. We evaluated the new and existing GANs with utility and privacy measures (membership and disclosure attacks) using billing codes from over 1 million EMRs at Vanderbilt University Medical Center. RESULTS The proposed model outperformed the state-of-the-art approaches with significant improvement in retaining the nature of real records, including prediction performance and structural properties, without sacrificing privacy. Additionally, the filtering strategy achieved higher utility when the EMR training dataset was small. CONCLUSIONS These findings illustrate that EMR simulation through GANs can be substantially improved through more appropriate training, modeling, and evaluation criteria.
Parenting stress in caregivers of young children with ASD concerns prior to a formal diagnosis

Robust findings demonstrate that parents of children with autism spectrum disorder (ASD) experience high levels of parenting stress that are associated with negative outcomes for families. Although the majority of research on parenting stress has focused on parents of children with an existing diagnosis, parents of young children with concerns about ASD‐related behaviors also face many unique challenges before the time of diagnosis. However, no study to date has examined patterns of parenting stress among parents of children with ASD concerns prior to a formal ASD diagnosis. Therefore, the current study investigated longitudinal trajectories of parenting stress among parents of young children with ASD concerns compared to parents of children with non‐ASD developmental concerns (e.g., language delay), and parents of children with no developmental concerns. Known predictors of parenting stress were also examined. Results from multilevel model analyses revealed that parents of children with ASD concerns experienced consistently higher levels of parenting stress across early child development compared to parents of children with non‐ASD developmental concerns and those with no concerns. Additionally, parenting efficacy, psychological functioning, social satisfaction, and child social communication behaviors predicted levels of parenting stress for all parents. Autism Res 2020, 13: 82–92. © 2019 International Society for Autism Research, Wiley Periodicals, Inc.
Fermented Goat Milk Consumption Enhances Brain Molecular Functions during Iron Deficiency Anemia Recovery

Iron deficiency anemia (IDA) is one of the most prevalent nutritional deficiencies worldwide. Iron plays critical roles in nervous system development and cognition. Despite the known detrimental consequences of IDA on cognition, available studies do not provide molecular mechanisms elucidating the role of iron in brain functions during iron deficiency and recovery with dairy components. In this study, 100 male Wistar rats were placed on a pre-experimental period of 40 days and randomly divided in two groups: a control group receiving a normal-Fe diet, (45 mg/kg), and an Fe-deficient group receiving a low-Fe diet (5 mg/kg). At day 40, 10 rats per group were sacrificed to anemia control, and 80 rats were divided into eight experimental groups fed with fermented goat or cow milk-based diets, with normal Fe content or Fe overload (450 mg/kg) for 30 days. IDA decreased most of the parameters related to brain molecular functions, namely dopamine, irisin, MAO-A, oxytocin, β-endorphin, and α-MSH, while it increased synaptophysin. These alterations result in an impairment of brain molecular functions. In general, during anemia recovery, fermented goat milk diet consumption increased dopamine, oxytocin, serotonin, synaptophysin, and α-MSH, and decreased MAO-A and MAO-B, suggesting a potential neuroprotective effect in brain functions, which could enhance brain molecular functions.
Screening for Anemia in Children with Down Syndrome.

OBJECTIVE As part of the 2011 American Academy of Pediatrics (AAP) health supervision guidelines for children with Down syndrome (DS), annual screening for iron deficiency anemia is recommended between the ages of 1 and 18 years, but the evidence supporting this recommendation is limited. This study aimed to assess the prevalence of anemia in patients with DS between the ages of 1 and 18 years to provide additional evidence for the AAP 2011 guideline recommendations for annual hemoglobin and ferritin screening in patients with DS. METHODS A retrospective cohort study was completed by obtaining data from the electronic health record (EHR) for patients meeting the following inclusion criterion: a diagnosis of DS in patients aged 1 to 18 years seen at our institution with hemoglobin drawn between July 2012 and 2016. Data were analyzed by the Fisher exact test and χ test. RESULTS A total of 200 patients were identified. 22.5% had anemia, defined as a hemoglobin concentration less than 2 SDs for normed age. The National Health and Nutrition Examination Survey (2007-2010) reported prevalence of anemia for children aged 1 to 5 years is 3.2% when compared with 18.7% in our sample. Of the 45 children with anemia, 5% had a microcytic, 67.5% a normocytic, and 27.5% a macrocytic anemia. Only 10 received a diagnosis of anemia in the EHR. CONCLUSION The prevalence of anemia in this cohort of children with DS is significantly higher than that in the general population, supporting the AAP guidelines for an annual screening until the age of 18 years.
Association of Surgical Hematoma Evacuation vs Conservative Treatment With Functional Outcome in Patients With Cerebellar Intracerebral Hemorrhage.

Importance The association of surgical hematoma evacuation with clinical outcomes in patients with cerebellar intracerebral hemorrhage (ICH) has not been established. Objective To determine the association of surgical hematoma evacuation with clinical outcomes in cerebellar ICH. Design, Setting, and Participants Individual participant data (IPD) meta-analysis of 4 observational ICH studies incorporating 6580 patients treated at 64 hospitals across the United States and Germany (2006-2015). Exposure Surgical hematoma evacuation vs conservative treatment. Main Outcomes and Measures The primary outcome was functional disability evaluated by the modified Rankin Scale ([mRS] score range: 0, no functional deficit to 6, death) at 3 months; favorable (mRS, 0-3) vs unfavorable (mRS, 4-6). Secondary outcomes included survival at 3 months and at 12 months. Analyses included propensity score matching and covariate adjustment, and predicted probabilities were used to identify treatment-related cutoff values for cerebellar ICH. Results Among 578 patients with cerebellar ICH, propensity score-matched groups included 152 patients with surgical hematoma evacuation vs 152 patients with conservative treatment (age, 68.9 vs 69.2 years; men, 55.9% vs 51.3%; prior anticoagulation, 60.5% vs 63.8%; and median ICH volume, 20.5 cm3 vs 18.8 cm3). After adjustment, surgical hematoma evacuation vs conservative treatment was not significantly associated with likelihood of better functional disability at 3 months (30.9% vs 35.5%; adjusted odds ratio [AOR], 0.94 [95% CI, 0.81 to 1.09], P = .43; adjusted risk difference [ARD], -3.7% [95% CI, -8.7% to 1.2%]) but was significantly associated with greater probability of survival at 3 months (78.3% vs 61.2%; AOR, 1.25 [95% CI, 1.07 to 1.45], P = .005; ARD, 18.5% [95% CI, 13.8% to 23.2%]) and at 12 months (71.7% vs 57.2%; AOR, 1.21 [95% CI, 1.03 to 1.42], P = .02; ARD, 17.0% [95% CI, 11.5% to 22.6%]). A volume range of 12 to 15 cm3 was identified; below this level, surgical hematoma evacuation was associated with lower likelihood of favorable functional outcome (volume ≤12 cm3, 30.6% vs 62.3% [P = .003]; ARD, -34.7% [-38.8% to -30.6%]; P value for interaction, .01), and above, it was associated with greater likelihood of survival (volume ≥15 cm3, 74.5% vs 45.1% [P < .001]; ARD, 28.2% [95% CI, 24.6% to 31.8%]; P value for interaction, .02). Conclusions and Relevance Among patients with cerebellar ICH, surgical hematoma evacuation, compared with conservative treatment, was not associated with improved functional outcome. Given the null primary outcome, investigation is necessary to establish whether there are differing associations based on hematoma volume.
Evaluation of Different Techniques for Size Determination of Drug Nanocrystals: A Case Study of Celecoxib Nanocrystalline Solid Dispersion

Celecoxib (CEL) Nanocrystalline Solid Dispersion (CEL_NCSD) was generated by spray drying CEL, mannitol (MAN) and sodium lauryl sulfate (SLS) from a solvent mixture of methanol, acetone and water. The purpose of the work was to determine the size of CEL nanocrystals, investigate agglomeration and inspect dissolution of CEL_NCSD. Size determination was challenging as CEL nanocrystals are embedded in the matrix of MAN. Firstly, neat CEL_NCSD was analyzed using Scherrer equation. Secondly, MAN was dissolved in an aqueous stabilizer medium to selectively measure the size of CEL nanocrystals. Raman Spectra captured in Morphologi G3-ID confirmed the presence of CEL-only particles in the media. This dispersion gave D90 values of 882 ± 170.34 nm in Zetasizer. Discriminatory dissolution studies confirmed total release of 34.61 ± 1.59%, 47.42 ± 0.24%, and 44.61 ± 1.11% at 120 min from a microsuspension (size 3 µm), a nanosuspension (media milled; size 660 nm) and CEL_NCSD, respectively. The dissolution profile of CEL_NCSD was similar to that of a nanosuspension (f2 72.24) instead of a coarse microsuspension. Thus, the present study revealed that optimized sample preparation is critical for the size determination of embedded drug nanocrystals in NCSD. Further, a discriminatory dissolution study substantiated that the size of CEL nanocrystals in CEL_NCSD is well below 1000 nm, thus showing a size-dependent improved dissolution profile.
Effects of Single Nucleotide Polymorphism Ala270Ser (rs316019) on the Function and Regulation of hOCT2

The human organic cation transporter 2 (hOCT2) is highly expressed in proximal tubules of the kidneys, where it plays an important role in the secretion of organic cations. Since many drugs are organic cations, hOCT2 has relevant pharmacological implications. The hOCT2 gene is polymorphic, and the nonsynonymous single nucleotide polymorphism (SNP) causing the substitution of alanine at position 270 of the protein sequence with serine (Ala270Ser) is present with high frequency in the human population. Therefore, Ala270Ser has potentially important pharmacologic consequences. Here, we analyzed the transport properties and rapid regulation of hOCT2 wildtype and hOCT2 Ala270Ser expressed in human embryonic kidney cells using real-time uptake measurements. Moreover, we compared the expression of hOCT2 in the plasma membrane determined by biotinylation experiments and the cellular transport and toxicity of cisplatin measured by inductively coupled plasma mass spectrometry and a viability test, respectively. The transport characteristics and regulation of the wildtype and mutated hOCT2 were very similar. Interestingly, a higher affinity of hOCT2 Ala270Ser for creatinine was observed. Compared with hOCT2 wildtype, the plasma membrane expression, cisplatin transport, and cisplatin-associated toxicity of hOCT2 Ala270Ser were significantly lower. In conclusion, these findings suggest that Ala270Ser has subtle but important effects on hOCT2 function, which are probably difficult to detect in studies with patients.
The bidirectional association between maternal speech and child characteristics

Abstract Our aim was to assess whether infants influence the quantity and quality of their mothers’ speech to them and, in turn, whether this maternal speech influences children's later language. As 189 mothers interacted with each of their twins at age 0;5, we calculated the number of utterances, the proportion of sensitive utterances, and the proportion of self-repeated utterances they produced. We later assessed the twins’ language comprehension and production when they were 1;6, 2;6, and 5;2. Quantity of maternal speech predicted child language at 5;2, whereas sensitivity predicted child language at 2;6 and 5;2 and partial self-repetition predicted child language at 1;6. Conversely, sensitivity and partial self-repetition in maternal speech at 0;5 were associated with genetic factors from the child, indicating that infant characteristics influence the quality of maternal speech. Overall, our findings stress the importance of considering both directions in the association between maternal speech and child characteristics.