We present a study of the dust-to-gas ratios in five nearby galaxies: NGC 628 (M74), NGC 6503, NGC 7793, UGC 5139 (Holmberg I), and UGC 4305 (Holmberg II). Using Hubble Space Telescope broadband ...WFC3/UVIS UV and optical images from the Treasury program Legacy ExtraGalactic UV Survey (LEGUS) combined with archival HST/Advanced Camera for Surveys data, we correct thousands of individual stars for extinction across these five galaxies using an isochrone-matching (reddening-free Q) method. We generate extinction maps for each galaxy from the individual stellar extinctions using both adaptive and fixed resolution techniques and correlate these maps with neutral H i and CO gas maps from the literature, including the H i Nearby Galaxy Survey and the HERA CO-Line Extragalactic Survey. We calculate dust-to-gas ratios and investigate variations in the dust-to-gas ratio with galaxy metallicity. We find a power-law relationship between dust-to-gas ratio and metallicity, consistent with other studies of dust-to-gas ratio compared to metallicity. We find a change in the relation when H2 is not included. This implies that underestimation of N H 2 in low-metallicity dwarfs from a too-low CO-to-H2 conversion factor XCO could have produced too low a slope in the derived relationship between dust-to-gas ratio and metallicity. We also compare our extinctions to those derived from fitting the spectral energy distribution (SED) using the Bayesian Extinction and Stellar Tool for NGC 7793 and find systematically lower extinctions from SED fitting as compared to isochrone matching.
The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop ...standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information.
Abstract Case-control studies are commonly used to evaluate effectiveness of licensed vaccines after deployment in public health programs. Such studies can provide policy-relevant data on vaccine ...performance under ‘real world’ conditions, contributing to the evidence base to support and sustain introduction of new vaccines. However, case-control studies do not measure the impact of vaccine introduction on disease at a population level, and are subject to bias and confounding, which may lead to inaccurate results that can misinform policy decisions. In 2012, a group of experts met to review recent experience with case-control studies evaluating the effectiveness of several vaccines; here we summarize the recommendations of that group regarding best practices for planning, design and enrollment of cases and controls. Rigorous planning and preparation should focus on understanding the study context including healthcare-seeking and vaccination practices. Case-control vaccine effectiveness studies are best carried out soon after vaccine introduction because high coverage creates strong potential for confounding. Endpoints specific to the vaccine target are preferable to non-specific clinical syndromes since the proportion of non-specific outcomes preventable through vaccination may vary over time and place, leading to potentially confusing results. Controls should be representative of the source population from which cases arise, and are generally recruited from the community or health facilities where cases are enrolled. Matching of controls to cases for potential confounding factors is commonly used, although should be reserved for a limited number of key variables believed to be linked to both vaccination and disease. Case-control vaccine effectiveness studies can provide information useful to guide policy decisions and vaccine development, however rigorous preparation and design is essential.
We describe catalog-level simulations of Type Ia Supernova (SN Ia) light curves in the Dark Energy Survey Supernova Program (DES-SN), and in low-redshift samples from the Center for Astrophysics ...(CfA) and the Carnegie Supernova Project (CSP). These simulations are used to model biases from selection effects and light curve analysis, and to determine bias corrections for SN Ia distance moduli that are used to measure cosmological parameters. To generate realistic light curves the simulation uses a detailed SN Ia model, incorporates information from observations (PSF, sky noise, zero point), and uses summary information (e.g., detection efficiency vs. signal to noise ratio) based on 10,000 fake SN light curves whose fluxes were overlaid on images and processed with our analysis pipelines. The quality of the simulation is illustrated by predicting distributions observed in the data. Averaging within redshift bins, we find distance modulus biases up to 0.05 mag over the redshift ranges of the low-z and DES-SN samples. For individual events, particularly those with extreme red or blue color, distance biases can reach 0.4 mag. Therefore, accurately determining bias corrections is critical for precision measurements of cosmological parameters. Files used to make these corrections are available at https://des.ncsa.illinois.edu/releases/sn.
Abstract
We describe the rapid and ongoing emergence across multiple US cities of a new multidrug-resistant Escherichia coli clone-sequence type (ST) 1193-resistant to fluoroquinolones (100%), ...trimethoprim-sulfamethoxazole (55%), and tetracycline (53%). ST1193 is associated with younger adults (age <40 years) and currently comprises a quarter of fluoroquinolone-resistant clinical E. coli urine isolates.
Objectives
Staging of upper extremity lymphedema is needed to guide surgical management, but is not standardized due to lack of accessible, quantitative, or precise measures. Here, we established an ...MRI-based staging system for lymphedema and validate it against existing clinical measures.
Methods
Bilateral upper extremity MRI and lymphoscintigraphy were performed on 45 patients with unilateral secondary lymphedema, due to surgical intervention, who were referred to our multidisciplinary lymphedema clinic between March 2017 and October 2018. MRI short-tau inversion recovery (STIR) images were retrospectively reviewed. A grading system was established based on the cross-sectional circumferential extent of subcutaneous fluid infiltration at three locations, labeled MRI stage 0–3, and was compared to L-Dex®, ICG lymphography, volume, lymphedema quality of life (LYMQOL), International Society of Lymphology (ISL) stage, and lymphoscintigraphy. Linear weighted Cohen’s kappa was calculated to compare MRI staging by two readers.
Results
STIR images on MRI revealed a predictable pattern of fluid infiltration centered on the elbow and extending along the posterior aspect of the upper arm and the ulnar side of the forearm. Patients with higher MRI stage were more likely to be in ISL stage 2 (
p
= 0.002) or to demonstrate dermal backflow on lymphoscintigraphy (
p
= 0.0002). No correlation was found between MRI stages and LYMQOL. Higher MRI stage correlated with abnormal ICG lymphography pattern (
r
s
= 0.63,
p
< 0.0001), larger % difference in limb volume (
r
s
= 0.68,
p
< 0.0001), and higher L-Dex® ratio (
r
s
= 0.84,
p
< 0.0001). Cohen’s kappa was 0.92 (95% CI, 0.85–1.00).
Conclusion
An MRI staging system for upper extremity lymphedema offers an improved non-invasive precision marker for lymphedema for therapeutic planning.
Key Points
•
Diagnosis and staging of patients with secondary upper extremity lymphedema may be performed with non-contrast MRI, which is non-invasive and more readily accessible compared to lymphoscintigraphy and evaluation by lymphedema specialists.
•
MRI-based staging of secondary upper extremity lymphedema is highly reproducible and could be used for long-term follow-up of patients.
•
In patients with borderline clinical measurements, MRI can be used to identify patients with early-stage lymphedema.
Objectives
Solid renal masses have unknown malignant potential with commonly utilized imaging. Biopsy can offer a diagnosis of cancer but has a high non-diagnostic rate and complications. Reported ...use of multiparametric magnetic resonance imaging (mpMRI) to diagnose aggressive histology (i.e., clear cell renal cell carcinoma (ccRCC)) via a clear cell likelihood score (ccLS) was based on retrospective review of cT1a tumors. We aim to retrospectively assess the diagnostic performance of ccLS prospectively assigned to renal masses of all stages evaluated with mpMRI prior to histopathologic evaluation.
Methods
In this retrospective cohort study from June 2016 to November 2019, 434 patients with 454 renal masses from 2 institutions with heterogenous patient populations underwent mpMRI with prospective ccLS assignment and had pathologic diagnosis. ccLS performance was assessed by contingency table analysis. The association between ccLS and ccRCC was assessed with logistic regression.
Results
Mean age and tumor size were 60 ± 13 years and 5.4 ± 3.8 cm. Characteristics were similar between institutions except for patient age and race (both
p
< 0.001) and lesion laterality and histology (both
p
= 0.04). The PPV of ccLS increased with each increment in ccLS (ccLS1 5% 3/55, ccLS2 6% 3/47, ccLS3 35% 20/57, ccLS4 78% 85/109, ccLS5 93% 173/186). Pooled analysis for ccRCC diagnosis revealed sensitivity 91% (258/284), PPV 87% (258/295) for ccLS ≥ 4, and specificity 56% (96/170), NPV 94% (96/102) for ccLS ≤ 2. Diagnostic performance was similar between institutions.
Conclusions
We confirm the optimal diagnostic performance of mpMRI to identify ccRCC in all clinical stages. High PPV and NPV of ccLS can help inform clinical management decision-making.
Key Points
• The positive predictive value of the clear cell likelihood score (ccLS) for detecting clear cell renal cell carcinoma was 5% (ccLS1), 6% (ccLS2), 35% (ccLS3), 78% (ccLS4), and 93% (ccLS5). Sensitivity of ccLS ≥ 4 and specificity of ccLS ≤ 2 were 91% and 56%, respectively.
• When controlling for confounding variables, ccLS is an independent risk factor for identifying clear cell renal cell carcinoma.
• Utilization of the ccLS can help guide clinical care, including the decision for renal mass biopsy, reducing the morbidity and risk to patients.
Does hypo-glycosylated human recombinant FSH (hFSH18/21) have greater in vivo bioactivity that drives follicle development in vivo compared to fully-glycosylated human recombinant FSH (hFSH24)?
...Compared with fully-glycosylated hFSH, hypo-glycosylated hFSH has greater bioactivity, enabling greater follicular health and growth in vivo, with enhanced transcriptional activity, greater activation of receptor tyrosine kinases (RTKs) and elevated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling.
Glycosylation of FSH is necessary for FSH to effectively activate the FSH receptor (FSHR) and promote preantral follicular growth and formation of antral follicles. In vitro studies demonstrate that compared to fully-glycosylated recombinant human FSH, hypo-glycosylated FSH has greater activity in receptor binding studies, and more effectively stimulates the PKA pathway and steroidogenesis in human granulosa cells.
This is a cross-sectional study evaluating the actions of purified recombinant human FSH glycoforms on parameters of follicular development, gene expression and cell signaling in immature postnatal day (PND) 17 female CD-1 mice. To stimulate follicle development in vivo, PND 17 female CD-1 mice (n = 8-10/group) were treated with PBS (150 µl), hFSH18/21 (1 µg/150 µl PBS) or hFSH24 (1 µg/150 µl PBS) by intraperitoneal injection (i.p.) twice daily (8:00 a.m. and 6:00 p.m.) for 2 days. Follicle numbers, serum anti-Müllerian hormone (AMH) and estradiol levels, and follicle health were quantified. PND 17 female CD-1 mice were also treated acutely (2 h) in vivo with PBS, hFSH18/21 (1 µg) or hFSH24 (1 µg) (n = 3-4/group). One ovary from each mouse was processed for RNA sequencing analysis and the other ovary processed for signal transduction analysis. An in vitro ovary culture system was used to confirm the relative signaling pathways.
The purity of different recombinant hFSH glycoforms was analyzed using an automated western blot system. Follicle numbers were determined by counting serial sections of the mouse ovary. Real-time quantitative RT-PCR, western blot and immunofluorescence staining were used to determine growth and apoptosis markers related with follicle health. RNA sequencing and bioinformatics were used to identify pathways and processes associated with gene expression profiles induced by acute FSH glycoform treatment. Analysis of RTKs was used to determine potential FSH downstream signaling pathways in vivo. Western blot and in vitro ovarian culture system were used to validate the relative signaling pathways.
Our present study shows that both hypo- and fully-glycosylated recombinant human FSH can drive follicular growth in vivo. However, hFSH18/21 promoted development of significantly more large antral follicles compared to hFSH24 (P < 0.01). In addition, compared with hFSH24, hFSH18/21 also promoted greater indices of follicular health, as defined by lower BAX/BCL2 ratios and reduced cleaved Caspase 3. Following acute in vivo treatment with FSH glycoforms RNA-sequencing data revealed that both FSH glycoforms rapidly induced ovarian transcription in vivo, but hypo-glycosylated FSH more robustly stimulated Gαs and cAMP-mediated signaling and members of the AP-1 transcription factor complex. Moreover, hFSH18/21 treatment induced significantly greater activation of RTKs, PI3K/AKT and MAPK/ERK signaling compared to hFSH24. FSH-induced indices of follicle growth in vitro were blocked by inhibition of PI3K and MAPK.
RNA sequencing of mouse ovaries. Data will be shared upon reasonable request to the corresponding author.
The observations that hFSH glycoforms have different bioactivities in the present study employing a mouse model of follicle development should be verified in nonhuman primates. The gene expression studies reflect transcriptomes of whole ovaries.
Commercially prepared recombinant human FSH used for ovarian stimulation in human ART is fully-glycosylated FSH. Our findings that hypo-glycosylated hFSH has greater bioactivity enabling greater follicular health and growth without exaggerated estradiol production in vivo, demonstrate the potential for its development for application in human ART.
This work was supported by NIH 1P01 AG029531, NIH 1R01 HD 092263, VA I01 BX004272, and the Olson Center for Women's Health. JSD is the recipient of a VA Senior Research Career Scientist Award (1IK6 BX005797). This work was also partially supported by National Natural Science Foundation of China (No. 31872352). The authors declared there are no conflicts of interest.
We describe a process for evaluating proposed ecosystem restoration projects intended to improve survival of juvenile salmon in the Columbia River estuary (CRE). Changes in the Columbia River basin ...(northwestern USA), including hydropower development, have contributed to the listing of 13 salmon stocks as endangered or threatened under the U.S. Endangered Species Act. Habitat restoration in the CRE, from Bonneville Dam to the ocean, is part of a basin-wide, legally mandated effort to mitigate federal hydropower impacts on salmon survival. An Expert Regional Technical Group (ERTG) was established in 2009 to improve and implement a process for assessing and assigning “survival benefit units” (SBUs) to restoration actions. The SBU concept assumes site-specific restoration projects will increase juvenile salmon survival during migration through the 234 km CRE. Assigned SBUs are used to inform selection of restoration projects and gauge mitigation progress. The ERTG standardized the SBU assessment process to improve its scientific integrity, repeatability, and transparency. In lieu of experimental data to quantify the survival benefits of individual restoration actions, the ERTG adopted a conceptual model composed of three assessment criteria—certainty of success, fish opportunity improvements, and habitat capacity improvements—to evaluate restoration projects. Based on these criteria, an algorithm assigned SBUs by integrating potential fish density as an indicator of salmon performance. Between 2009 and 2014, the ERTG assessed SBUs for 55 proposed projects involving a total of 181 restoration actions located across 8 of 9 reaches of the CRE, largely relying on information provided in a project template based on the conceptual model, presentations, discussions with project sponsors, and site visits. Most projects restored tidal inundation to emergent wetlands, improved riparian function, and removed invasive vegetation. The scientific relationship of geomorphic and salmonid responses to restoration actions remains the foremost concern. Although not designed to establish a broad strategy for estuary restoration, the scoring process has adaptively influenced the types, designs, and locations of restoration proposals. The ERTG process may be a useful model for others who have unique ecosystem restoration goals and share some of our common challenges.
•The expert panel's work has likely improved the effectiveness and longevity of restoration projects.•Developing a conceptual ecosystem model improved the scoring process, consistency, and communication.•Clear goals and quantitative objectives improved consistency and communication.•Collaborative, critical discussion by the panel reduced evaluation uncertainty.•Active learning during the expert panel process improved outcomes.
We report the first search for a nonstandard-model resonance decaying into τ pairs in e^{+}e^{-}→μ^{+}μ^{-}τ^{+}τ^{-} events in the 3.6-10 GeV/c^{2} mass range. We use a 62.8 fb^{-1} sample of ...e^{+}e^{-} collisions collected at a center-of-mass energy of 10.58 GeV by the Belle II experiment at the SuperKEKB collider. The analysis probes three different models predicting a spin-1 particle coupling only to the heavier lepton families, a Higgs-like spin-0 particle that couples preferentially to charged leptons (leptophilic scalar), and an axionlike particle, respectively. We observe no evidence for a signal and set exclusion limits at 90% confidence level on the product of cross section and branching fraction into τ pairs, ranging from 0.7 to 24 fb, and on the couplings of these processes. We obtain world-leading constraints on the couplings for the leptophilic scalar model for masses above 6.5 GeV/c^{2} and for the axionlike particle model over the entire mass range.
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