Comparative outcomes between COVID-19 and influenza patients placed on veno-venous extracorporeal membrane oxygenation for severe ARDS

Background ECMO is an established supportive adjunct for patients with severe, refractory ARDS from viral pneumonia. However, the exact role and timing of ECMO for COVID-19 patients remains unclear. Methods We conducted a retrospective comparison of the first 32 patients with COVID-19-associated ARDS to the last 28 patients with influenza-associated ARDS placed on V-V ECMO. We compared patient factors between the two cohorts and used survival analysis to compare the hazard of mortality over sixty days post-cannulation.Results COVID-19 patients were older (mean 47.8 vs. 41.2 years, p = 0.033), had more ventilator days before cannulation (mean 4.5 vs. 1.5 days, p < 0.001). Crude in-hospital mortality was significantly higher in the COVID-19 cohort at 65.6% (n = 21/32) versus 36.3% (n = 11/28, p = 0.041). The adjusted hazard ratio over sixty days for COVID-19 patients was 2.81 (95% CI 1.07, 7.35) after adjusting for age, race, ECMO-associated organ failure, and Charlson Comorbidity Index. Conclusion ECMO has a role in severe ARDS associated with COVID-19 but providers should carefully weigh patient factors when utilizing this scarce resource in favor of influenza pneumonia

The Panchromatic Hubble Andromeda Treasury I: Bright UV Stars in the Bulge of M31

As part of the Panchromatic Hubble Andromeda Treasury (PHAT) multi-cycle program, we observed a 12' \times 6.5' area of the bulge of M31 with the WFC3/UVIS filters F275W and F336W. From these data we have assembled a sample of \sim4000 UV-bright, old stars, vastly larger than previously available. We use updated Padova stellar evolutionary tracks to classify these hot stars into three classes: Post-AGB stars (P-AGB), Post-Early AGB (PE-AGB) stars and AGB-manqu\'e stars. P-AGB stars are the end result of the asymptotic giant branch (AGB) phase and are expected in a wide range of stellar populations, whereas PE-AGB and AGB-manqu\'e (together referred to as the hot post-horizontal branch; HP-HB) stars are the result of insufficient envelope masses to allow a full AGB phase, and are expected to be particularly prominent at high helium or {\alpha} abundances when the mass loss on the RGB is high. Our data support previous claims that most UV-bright sources in the bulge are likely hot (extreme) horizontal branch stars (EHB) and their progeny. We construct the first radial profiles of these stellar populations, and show that they are highly centrally concentrated, even more so than the integrated UV or optical light. However, we find that this UV-bright population does not dominate the total UV luminosity at any radius, as we are detecting only the progeny of the EHB stars that are the likely source of the UVX. We calculate that only a few percent of MS stars in the central bulge can have gone through the HP-HB phase and that this percentage decreases strongly with distance from the center. We also find that the surface density of hot UV-bright stars has the same radial variation as that of low-mass X-ray binaries. We discuss age, metallicity, and abundance variations as possible explanations for the observed radial variation in the UV-bright population.Comment: Accepted for publication in Ap

PHAT Stellar Cluster Survey I. Year 1 Catalog and Integrated Photometry

The Panchromatic Hubble Andromeda Treasury (PHAT) survey is an on-going Hubble Space Telescope (HST) multi-cycle program to obtain high spatial resolution imaging of one-third of the M31 disk at ultraviolet through near-infrared wavelengths. In this paper, we present the first installment of the PHAT stellar cluster catalog. When completed, the PHAT cluster catalog will be among the largest and most comprehensive surveys of resolved star clusters in any galaxy. The exquisite spatial resolution achieved with HST has allowed us to identify hundreds of new clusters that were previously inaccessible with existing ground-based surveys. We identify 601 clusters in the Year 1 sample, representing more than a factor of four increase over previous catalogs within the current survey area (390 arcmin^2). This work presents results derived from the first \sim25% of the survey data; we estimate that the final sample will include \sim2500 clusters. For the Year 1 objects, we present a catalog with positions, radii, and six-band integrated photometry. Along with a general characterization of the cluster luminosities and colors, we discuss the cluster luminosity function, the cluster size distributions, and highlight a number of individually interesting clusters found in the Year 1 search.Comment: 26 pages, 22 figures, Accepted by Ap

Investigating the tradeoffs between spatial resolution and diffusion sampling for brain mapping with diffusion tractography: Time well spent?: Spatial vs. Q-Space Sampling for Tractography

Interest in mapping white matter pathways in the brain has peaked with the recognition that altered brain connectivity may contribute to a variety of neurologic and psychiatric diseases. Diffusion tractography has emerged as a popular method for postmortem brain mapping initiatives, including the ex-vivo component of the human connectome project, yet it remains unclear to what extent computer-generated tracks fully reflect the actual underlying anatomy. Of particular concern is the fact that diffusion tractography results vary widely depending on the choice of acquisition protocol. The two major acquisition variables that consume scan time, spatial resolution, and diffusion sampling, can each have profound effects on the resulting tractography. In this analysis we determined the effects of the temporal tradeoff between spatial resolution and diffusion sampling on tractography in the ex-vivo rhesus macaque brain, a close primate model for the human brain. We used the wealth of autoradiography-based connectivity data available for the rhesus macaque brain to assess the anatomic accuracy of six time-matched diffusion acquisition protocols with varying balance between spatial and diffusion sampling. We show that tractography results vary greatly, even when the subject and the total acquisition time are held constant. Further, we found that focusing on either spatial resolution or diffusion sampling at the expense of the other is counterproductive. A balanced consideration of both sampling domains produces the most anatomically accurate and consistent results

Time to Cannulation after ICU Admission Increases Mortality for Patients Requiring Veno-Venous ECMO for COVID-19 Associated Acute Respiratory Distress Syndrome

Objective: COVID-19 can cause acute respiratory distress syndrome (ARDS) that is rapidly progressive, severe, and refractory to conventional therapies. Extracorporeal membrane oxygenation (ECMO) can be used as a supportive therapy to improve outcomes but evidence-based guidelines have not been defined. Summary Background Data: Initial mortality rates associated with ECMO for ARDS in COVID-19 were high, leading some to believe that there was no role for ECMO in this viral illness. With more experience, outcomes have improved. The ideal candidate, timing of cannulation, and best post-cannulation management strategy, however, has not yet been defined. Methods: We conducted a retrospective review from April 1 to July 31 2020 of the first 25 patients with COVID-19 associated ARDS placed on V-V ECMO at our institution. We analyzed the differences between survivors to hospital discharge and those who died. Modified Poisson regression was used to model adjusted risk factors for mortality. Results: 44% of patients (11/25) survived to hospital discharge. Survivors were significantly younger (40.5 years vs. 53.1 years; p < 0.001) with no differences between cohorts in mean body mass index, diabetes, or PaO2:FiO2 at cannulation. Survivors had shorter duration from symptom onset to cannulation (12.5 days vs. 19.9 days, p = 0.028) and shorter duration of intensive care unit (ICU) length of stay (LOS) prior to cannulation (5.6 days vs. 11.7 days, p = 0.045). Each day from ICU admission to cannulation increased the adjusted risk of death by 4% and each year increase in age increased the adjusted risk 6%. Conclusions: ECMO has a role in severe, refractory ARDS associated with COVID-19. Increasing age and time from ICU admission were risk factors for mortality and should be considered in patient selection. Further studies are needed to define best practices for V-V ECMO use in COVID-19

A diffusion tensor MRI atlas of the postmortem rhesus macaque brain

The rhesus macaque (Macaca mulatta) is the most widely used nonhuman primate for modeling the structure and function of the brain. Brain atlases, and particularly those based on magnetic resonance imaging (MRI), have become important tools for understanding normal brain structure, and for identifying structural abnormalities resulting from disease states, exposures, and/or aging. Diffusion tensor imaging (DTI) -based MRI brain atlases are widely used in both human and macaque brain imaging studies because of the unique contrasts, quantitative diffusion metrics, and diffusion tractography that they can provide. Previous MRI and DTI atlases of the rhesus brain have been limited by low contrast and/or low spatial resolution imaging. Here we present a microscopic resolution MRI/DTI atlas of the rhesus brain based on 10 postmortem brain specimens. The atlas includes both structural MRI and DTI image data, a detailed three-dimensional segmentation of 241 anatomic structures, diffusion tractography, cortical thickness estimates, and maps of anatomic variability amongst atlas specimens. This atlas incorporates many useful features from previous work, including anatomic label nomenclature and ontology, data orientation, and stereotaxic reference frame, and further extends prior analyses with the inclusion of high-resolution multi-contrast image data

LUMINOS-102: Lerapolturev with and without α-PD- 1 in unresectable α-PD- 1 refractory melanoma

Lerapolturev (lera, formerly PVSRIPO) is a novel poliovirus based intratumoral immunotherapy that infects both cancer cells and antigen-presenting cells (APCs) via CD155, the poliovirus receptor. Lera has direct anticancer effects while also generating type I/III interferon-dominated inflammation and anti-tumor T-cell priming and activation via infection of local APCs. LUMINOS-102 (NCT04577807) is a multi-center, open-label, two-arm randomized Phase 2 study investigating the efficacy and safety of lera ± α-PD- 1 in patients with unresectable melanoma who failed prior α-PD- 1 therapy. Cross-over to the α-PD- 1 arm is permitted after progression, PR for ≥6 mo or 6 mo on treatment with SD. The maximum initial lera dose was 6x108 TCID50 /visit every 3 or 4 weeks (Q3/4 W). As of March 2022, the maximum lera dose was increased to 1.6 x 109 TCID50/visit, every week (QW) for 7 weeks (induction), followed by Q3/4 W dosing (maintenance). As of 20-Jun- 2022, 21 participants (10 male, 11 female, median 64 yrs) received lera (n = 14 at initial dose, Q3/4 W; n = 4 at increased dose, Q3/4 W; n = 3 at increased dose, QW) ± αPD-1. Five patients are currently on treatment. With the initial regimen, no objective responses and a CBR of 7% were observed. However, with the higher dose regimen, 1 complete response and a CBR of 71% (5/7) has been observed. Two of 4 participants with stable disease have evidence of response (1 with resolution of uninjected lung metastasis, 1 with decreased PET signal in injected and uninjected lesions receiving combination therapy). The only treatment related AE in \u3e1 pt was fatigue (19%, all grade 1 or 2). No dose-limiting toxicities or treatment-related SAEs were reported. Multiplex-IF analysis of on-treatment tumor biopsies will be presented. Lera ± αPD-1 is well tolerated, with early signs of efficacy at the higher dose level. Enrollment and randomization are ongoing

best practices in bioassay development to support registration of biopharmaceuticals

Biological activity is a critical quality attribute for biopharmaceuticals, which is accurately measured using an appropriate relative potency bioassay. Developing a bioassay is a complex, rigorous undertaking that needs to address several challenges including modelling all of the mechanisms of action associated with the biotherapeutic. Bioassay development is also an exciting and fast evolving field, not only from a scientific, medical and technological point of view, but also in terms of statistical approaches and regulatory expectations. This has led to an industry-wide discussion on the most appropriate ways to develop, validate and control the bioassays throughout the drug lifecycle

An ontology-based segmentation scheme for tracking postnatal changes in the developing rodent brain with MRI

The postnatal period of neurodevelopment has been implicated in a number of brain disorders including autism and schizophrenia. Rodent models have proven to be invaluable in advancing our understanding of the human brain, and will almost certainly play a pivotal role in future studies on postnatal neurodevelopment. The growing field of magnetic resonance microscopy has the potential to revolutionize our understanding of neurodevelopment, if it can be successfully and appropriately assimilated into the vast body of existing neuroscience research. In this study, we demonstrate the utility of a developmental neuro-ontology designed specifically for tracking regional changes in MR biomarkers throughout postnatal neurodevelopment. Using this ontological classification as a segmentation guide, we track regional changes in brain volume in rats between postnatal day zero and postnatal day 80 and demonstrate differential growth rates in axial versus paraxial brain regions. Both the ontology and the associated label volumes are provided as a foundation for future MR-based studies of postnatal neurodevelopment in normal and disease states