A Long-term Co-perfused Disseminated Tuberculosis-3D Liver Hollow Fiber Model for Both Drug Efficacy and Hepatotoxicity in Babies

AbstractTreatment of disseminated tuberculosis in children≤6years has not been optimized. The pyrazinamide-containing combination regimen used to treat disseminated tuberculosis in babies and toddlers was extrapolated from adult pulmonary tuberculosis. Due to hepatotoxicity worries, there are no dose–response studies in children. We designed a hollow fiber system model of disseminated intracellular tuberculosis with co-perfused three-dimensional organotypic liver modules to simultaneously test for efficacy and toxicity. We utilized pediatric pharmacokinetics of pyrazinamide and acetaminophen to determine dose-dependent pyrazinamide efficacy and hepatotoxicity. Acetaminophen concentrations that cause hepatotoxicity in children led to elevated liver function tests, while 100mg/kg pyrazinamide did not. Surprisingly, pyrazinamide did not kill intracellular Mycobacterium tuberculosis up to fourfold the standard dose as monotherapy or as combination therapy, despite achieving high intracellular concentrations. Host-pathogen RNA-sequencing revealed lack of a pyrazinamide exposure transcript signature in intracellular bacteria or of phagolysosome acidification on pH imaging. Artificial intelligence algorithms confirmed that pyrazinamide was not predictive of good clinical outcomes in children≤6years who had extrapulmonary tuberculosis. Thus, adding a drug that works inside macrophages could benefit children with disseminated tuberculosis. Our in vitro model can be used to identify such new regimens that could accelerate cure while minimizing toxicity

SKYSURF-4: Panchromatic HST All-Sky Surface-Brightness Measurement Methods and Results

The diffuse, unresolved sky provides most of the photons that the Hubble Space Telescope (HST) receives, yet remains poorly understood. HST Archival Legacy program SKYSURF aims to measure the 0.2-1.6 $\mu$m sky surface brightness (sky-SB) from over 140,000 HST images. We describe a sky-SB measurement algorithm designed for SKYSURF that is able to recover the input sky-SB from simulated images to within 1% uncertainty. We present our sky-SB measurements estimated using this algorithm on the entire SKYSURF database. Comparing our sky-SB spectral energy distribution (SED) to measurements from the literature shows general agreements. Our SKYSURF SED also reveals a possible dependence on Sun angle, indicating either non-isotropic scattering of solar photons off interplanetary dust or an additional component to Zodiacal Light. Finally, we update Diffuse Light limits in the near-IR based on the methods from Carleton et al. (2022), with values of 0.009 MJy sr$^{-1}$ (22 nW m$^{-2}$ sr$^{-1}$) at 1.25 $\mu$m, 0.015 MJy sr$^{-1}$ (32 nW m$^{-2}$ sr$^{-1}$) at 1.4 $\mu$m, and 0.013 MJy sr$^{-1}$ (25 nW m$^{-2}$ sr$^{-1}$) at 1.6 $\mu$m. These estimates provide the most stringent all-sky constraints to date in this wavelength range. SKYSURF sky-SB measurements are made public on the official SKYSURF website and will be used to constrain Diffuse Light in future papers.Comment: Revised based on helpful comments from the reviewer, and accepted to AJ on April 12th, 2023. Main paper: 18 pages, 9 figures, 4 tables. Appendices: 16 pages, 10 figures, 1 table. Main results shown in Figure 7 and Table

SKYSURF: Constraints on Zodiacal Light and Extragalactic Background Light through Panchromatic HST All-Sky Surface-Brightness Measurements: I. Survey Overview and Methods

We give an overview and describe the rationale, methods, and testing of the Hubble Space Telescope (HST) Archival Legacy project "SKYSURF." SKYSURF uses HST's unique capability as an absolute photometer to measure the ~0.2-1.7 $\mu$m sky surface brightness (SB) from 249,861 WFPC2, ACS, and WFC3 exposures in ~1400 independent HST fields. SKYSURF's panchromatic dataset is designed to constrain the discrete and diffuse UV to near-IR sky components: Zodiacal Light (ZL; inner Solar System), Kuiper Belt Objects (KBOs; outer Solar System), Diffuse Galactic Light (DGL), and the discrete plus diffuse Extragalactic Background Light (EBL). We outline SKYSURF's methods to: (1) measure sky-SB levels between its detected objects; (2) measure the integrated discrete EBL, most of which comes from AB$\simeq$17-22 mag galaxies; and (3) estimate how much diffuse light may exist in addition to the extrapolated discrete galaxy counts. Simulations of HST WFC3/IR images with known sky-values and gradients, realistic cosmic ray (CR) distributions, and star plus galaxy counts were processed with nine different algorithms to measure the "Lowest Estimated Sky-SB" (LES) in each image between the discrete objects. The best algorithms recover the inserted LES values within 0.2% when there are no image gradients, and within 0.2-0.4% when there are 5-10% gradients. SKYSURF requires non-standard re-processing of these HST images that includes restoring the lowest sky-level from each visit into each drizzled image. We provide a proof of concept of our methods from the WFC3/IR F125W images, where any residual diffuse light that HST sees in excess of the Kelsall et al. (1998) Zodiacal model prediction does not depend on the total object flux that each image contains. This enables us to present our first SKYSURF results on diffuse light in Carleton et al. (2022).Comment: Accepted to AJ; see accompanying paper Carleton et al. 2022: arXiv:2205.06347. Comments welcome

Amikacin pharmacokinetics/pharmacodynamics in a novel hollow-fiber Mycobacterium abscessus disease model

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SKYSURF-4: Panchromatic Hubble Space Telescope All-Sky Surface-brightness Measurement Methods and Results

The diffuse, unresolved sky provides most of the photons that the Hubble Space Telescope (HST) receives, yet remains poorly understood. The HST Archival Legacy program SKYSURF aims to measure the 0.2–1.6 μ m sky surface brightness (sky-SB) from over 140,000 HST images. We describe a sky-SB measurement algorithm designed for SKYSURF that is able to recover the input sky-SB from simulated images to within 1% uncertainty. We present our sky-SB measurements estimated using this algorithm on the entire SKYSURF database. Comparing our sky-SB spectral energy distribution (SED) to measurements from the literature shows general agreements. Our SKYSURF SED also reveals a possible dependence on the Sun angle, indicating either nonisotropic scattering of solar photons off interplanetary dust or an additional component to zodiacal light. Finally, we update the diffuse light limits in the near-IR based on the methods from Carleton et al., with values of 0.009 MJy sr ^−1 (22 nW m ^−2 sr ^−1 ) at 1.25 μ m, 0.015 MJy sr ^−1 (32 nW m ^−2 sr ^−1 ) at 1.4 μ m, and 0.013 MJy sr ^−1 (25 nW m ^−2 sr ^−1 ) at 1.6 μ m. These estimates provide the most stringent all-sky constraints to date in this wavelength range. SKYSURF sky-SB measurements are made public on the official SKYSURF website and will be used to constrain diffuse light in future papers