A phase 1b study evaluating the effect of elacestrant treatment on estrogen receptor availability and estradiol binding to the estrogen receptor in metastatic breast cancer lesions using 18F-FES PET/CT imaging

Background: Elacestrant is an oral selective estrogen receptor (ER) degrader. This phase 1b open-label, non-randomized study (RAD1901-106) was initiated to determine the effect of elacestrant on the availability of ER in lesions from postmenopausal women with ER+ advanced breast cancer (ABC) using 16α-18F-fluoro-17β-estradiol positron emission tomography with low-dose computed tomography (FES-PET/CT). Methods: Eligible patients were postmenopausal women with ER+, HER2- ABC; tumor progression after ≥ 6 months of 1-3 lines of endocrine treatment for ABC; and measurable or evaluable disease. Two 8-patient cohorts were enrolled: one treated with 400 mg elacestrant once daily (QD) and one treated with 200 mg elacestrant QD with dose escalation to 400 mg QD after 14 days. Elacestrant was dosed continuously until progressive disease, toxicity, or withdrawal. FES-PET/CT was performed pre-dose at baseline and 4 h post-dose on day 14. The primary endpoint was the percentage difference in FES uptake in tumor lesions (maximum 20) after 14 days of treatment compared to baseline. Overall response was investigator-assessed by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1. Results: Patients (n = 16; median age, 53.5 years) had ABC with a median 2.5 prior lines of endocrine therapy. Median reduction in tumor FES uptake from baseline to day 14 was 89.1% (Q1, Q3: 75.1%, 94.1%) and was similar in both cohorts (89.1% [Q1, Q3: 67.4%, 94.2%], 200/400 mg and 88.7% [Q1, Q3: 79.5%, 94.1%], 400 mg). Residual ER availability (> 25% persistence in FES uptake) on day 14 was observed in 3 patients receiving 200/400 mg (3/78, 37.5%) and 1 patient receiving 400 mg (1/8, 12.5%). The overall response rate (ORR) was 11.1% (1 partial response), and clinical benefit rate (CBR) was 30.8%. Median percentage change in FES uptake did not correlate with ORR or CBR. Adverse events occurring in > 20% of the patients were nausea (68.8%), fatigue (50.0%), dyspepsia (43.8%), vomiting (37.5%), and decreased appetite, dysphagia, and hot flush (31.3% each). Most events were grade 2 in severity. Conclusion: Elacestrant 200 mg and 400 mg QD greatly reduced ER availability measured by FES-PET/CT. In a heavily pretreated population, elacestrant was associated with antitumor activity. Trial registration: ClinicalTrials.gov, NCT02650817. Registered on 08 January 201

Spectroscopic verification of very luminous galaxy candidates in the early universe

During the first 500 million years of cosmic history, the first stars and galaxies formed and seeded the cosmos with heavy elements. These early galaxies illuminated the transition from the cosmic "dark ages" to the reionization of the intergalactic medium. This transitional period has been largely inaccessible to direct observation until the recent commissioning of JWST, which has extended our observational reach into that epoch. Excitingly, the first JWST science observations uncovered a surprisingly high abundance of early star-forming galaxies. However, the distances (redshifts) of these galaxies were, by necessity, estimated from multi-band photometry. Photometric redshifts, while generally robust, can suffer from uncertainties and/or degeneracies. Spectroscopic measurements of the precise redshifts are required to validate these sources and to reliably quantify their space densities, stellar masses, and star formation rates, which provide powerful constraints on galaxy formation models and cosmology. Here we present the results of JWST follow-up spectroscopy of a small sample of galaxies suspected to be amongst the most distant yet observed. We confirm redshifts z > 10 for two galaxies, including one of the first bright JWST-discovered candidates with z = 11.4, and show that another galaxy with suggested z ~ 16 instead has z = 4.9, with strong emission lines that mimic the expected colors of more distant objects. These results reinforce the evidence for the rapid production of luminous galaxies in the very young Universe, while also highlighting the necessity of spectroscopic verification for remarkable candidates.Comment: Submitted to Natur

Evidence for a Shallow Evolution in the Volume Densities of Massive Galaxies at z=4z=4 to 88 from CEERS

We analyze the evolution of massive (log$_{10}$ [$M_\star/M_\odot$] $>10$) galaxies at $z \sim$ 4--8 selected from the JWST Cosmic Evolution Early Release Science (CEERS) survey. We infer the physical properties of all galaxies in the CEERS NIRCam imaging through spectral energy distribution (SED) fitting with dense basis to select a sample of high redshift massive galaxies. Where available we include constraints from additional CEERS observing modes, including 18 sources with MIRI photometric coverage, and 28 sources with spectroscopic confirmations from NIRSpec or NIRCam wide-field slitless spectroscopy. We sample the recovered posteriors in stellar mass from SED fitting to infer the volume densities of massive galaxies across cosmic time, taking into consideration the potential for sample contamination by active galactic nuclei (AGN). We find that the evolving abundance of massive galaxies tracks expectations based on a constant baryon conversion efficiency in dark matter halos for $z \sim$ 1--4. At higher redshifts, we observe an excess abundance of massive galaxies relative to this simple model. These higher abundances can be explained by modest changes to star formation physics and/or the efficiencies with which star formation occurs in massive dark matter halos, and are not in tension with modern cosmology.Comment: 20 pages, 10 figure

CEERS Epoch 1 NIRCam Imaging: Reduction Methods and Simulations Enabling Early JWST Science Results

We present the data release and data reduction process for the Epoch 1 NIRCam observations for the Cosmic Evolution Early Release Science Survey (CEERS). These data consist of NIRCam imaging in six broadband filters (F115W, F150W, F200W, F277W, F356W and F444W) and one medium band filter (F410M) over four pointings, obtained in parallel with primary CEERS MIRI observations (Yang et al. in prep). We reduced the NIRCam imaging with the JWST Calibration Pipeline, with custom modifications and reduction steps designed to address additional features and challenges with the data. Here we provide a detailed description of each step in our reduction and a discussion of future expected improvements. Our reduction process includes corrections for known pre-launch issues such as 1/f noise, as well as in-flight issues including snowballs, wisps, and astrometric alignment. Many of our custom reduction processes were first developed with pre-launch simulated NIRCam imaging over the full 10 CEERS NIRCam pointings. We present a description of the creation and reduction of this simulated dataset in the Appendix. We provide mosaics of the real images in a public release, as well as our reduction scripts with detailed explanations to allow users to reproduce our final data products. These represent one of the first official public datasets released from the Directors Discretionary Early Release Science (DD-ERS) program.Comment: 27 pages, 14 figures, submitted to ApJ. Accompanying CEERS public Data Release 0.5 available at ceers.github.io/releases.htm

CEERS Spectroscopic Confirmation of NIRCam-Selected z > 8 Galaxy Candidates with JWST/NIRSpec: Initial Characterization of their Properties

We present JWST NIRSpec spectroscopy for 11 galaxy candidates with photometric redshifts of $z\simeq9-13$ and $M_{\rm\,UV} \in[-21,-18]$ newly identified in NIRCam images in the Cosmic Evolution Early Release Science (CEERS) Survey. We confirm emission line redshifts for 7 galaxies at $z=7.762-8.998$ using spectra at $\sim1-5\mu$m either with the NIRSpec prism or its three medium resolution gratings. For $z\simeq9$ photometric candidates, we achieve a high confirmation rate of $\simeq$90\%, which validates the classical dropout selection from NIRCam photometry. No robust emission lines are identified in three galaxy candidates at $z>10$, where the strong [OIII] and H$\beta$ lines would be redshifted beyond the wavelength range observed by NIRSpec, and the Lyman-$\alpha$ continuum break is not detected with the current sensitivity. Compared with HST-selected bright galaxies ($M_{\rm\,UV}\simeq-22$) that are similarly spectroscopically confirmed at $z\gtrsim8$, these NIRCam-selected galaxies are characterized by lower star formation rates (SFR$\simeq4\,M_{\odot}$~yr$^{-1}$) and lower stellar masses ($\simeq10^{8}\,M_{\odot}$), but with higher [OIII]+H$\beta$ equivalent widths ($\simeq$1100$\r{A}$), and elevated production efficiency of ionizing photons ($\log(\xi_{\rm\,ion}/{\rm\,Hz\,erg}^{-1})\simeq25.8$) induced by young stellar populations ($<10$~Myrs) accounting for $\simeq20\%$ of the galaxy mass, highlighting the key contribution of faint galaxies to cosmic reionization. Taking advantage of the homogeneous selection and sensitivity, we also investigate metallicity and ISM conditions with empirical calibrations using the [OIII]/H$\beta$ ratio. We find that galaxies at $z\sim8-9$ have higher SFRs and lower metallicities than galaxies at similar stellar masses at $z\sim2-6$, which is generally consistent with the current galaxy formation and evolution models.Comment: 21 pages, 11 figures, 2 tables. Submitted to ApJL Focus Issu

CEERS Key Paper. V. Galaxies at 4 &lt; z &lt; 9 Are Bluer than They Appear-Characterizing Galaxy Stellar Populations from Rest-frame ∼1 μm Imaging

We present results from the Cosmic Evolution Early Release Survey on the stellar population parameters for 28 galaxies with redshifts 4 &lt; z &lt; 9 using imaging data from the James Webb Space Telescope (JWST) Mid-Infrared Instrument (MIRI) combined with data from the Hubble Space Telescope and the Spitzer Space Telescope. The JWST/MIRI 5.6 and 7.7 μm data extend the coverage of the rest-frame spectral energy distribution to nearly 1 μm for galaxies in this redshift range. By modeling the galaxies’ SEDs the MIRI data show that the galaxies have, on average, rest-frame UV (1600 Å)—I-band colors 0.4 mag bluer than derived when using photometry that lacks MIRI. Therefore, the galaxies have lower ratios of stellar mass to light. The MIRI data reduce the stellar masses by 〈 Δ log M * 〉 = 0.25 dex at 4 &lt; z &lt; 6 and 0.37 dex at 6 &lt; z &lt; 9. This also reduces the star formation rates (SFRs) by 〈ΔlogSFR〉 = 0.14 dex at 4 &lt; z &lt; 6 and 0.27 dex at 6 &lt; z &lt; 9. The MIRI data also improve constraints on the allowable stellar mass formed in early star formation. We model this using a star formation history that includes both a “burst” at z f = 100 and a slowly varying (“delayed-τ”) model. The MIRI data reduce the allowable stellar mass by 0.6 dex at 4 &lt; z &lt; 6 and by ≈1 dex at 6 &lt; z &lt; 9. Applying these results globally, this reduces the cosmic stellar-mass density by an order of magnitude in the early Universe (z ≈ 9). Therefore, observations of rest-frame ≳1 μm are paramount for constraining the stellar-mass buildup in galaxies at very high redshifts.</p

CEERS Key Paper IV: Galaxies at 4<z<94 < z < 9 are Bluer than They Appear -- Characterizing Galaxy Stellar Populations from Rest-Frame ∼1\sim 1 micron Imaging

We present results from the Cosmic Evolution Early Release Survey (CEERS) on the stellar-population parameters for 28 galaxies with redshifts $4<z<9$ using imaging data from the James Webb Space Telescope (JWST) Mid-Infrared Instrument (MIRI) combined with data from the Hubble Space Telescope and the Spitzer Space Telescope. The JWST/MIRI 5.6 and 7.7 $\mu$m data extend the coverage of the rest-frame spectral-energy distribution (SED) to nearly 1 micron for galaxies in this redshift range. By modeling the galaxies' SEDs the MIRI data show that the galaxies have, on average, rest-frame UV (1600 \r{A}) $-$ $I$-band colors 0.4 mag bluer than derived when using photometry that lacks MIRI. Therefore, the galaxies have lower (stellar)-mass-to-light ratios. The MIRI data reduce the stellar masses by $\langle \Delta\log M_\ast\rangle=0.25$ dex at $4<z<6$ (a factor of 1.8) and 0.37 dex at $6<z<9$ (a factor of 2.3). This also reduces the star-formation rates (SFRs) by $\langle \Delta\log\mathrm{SFR} \rangle=0.14$ dex at $4<z<6$ and 0.27 dex at $6<z<9$. The MIRI data also improve constraints on the allowable stellar mass formed in early star-formation. We model this using a star-formation history that includes both a "burst' at $z_f=100$ and a slowly varying ("delayed-$\tau$") model. The MIRI data reduce the allowable stellar mass by 0.6 dex at $4<z< 6$ and by $\approx$1 dex at $6<z<9$. Applying these results globally, this reduces the cosmic stellar-mass density by an order of magnitude in the early universe ($z\approx9$). Therefore, observations of rest-frame $\gtrsim$1 $\mu$m are paramount for constraining the stellar-mass build-up in galaxies at very high-redshifts.Comment: Updated with accepted ApJ version. Part of the CEERS Focus Issue. 27 pages, many figures (4 Figure Sets, available upon reasonable request

The Human Phenotype Ontology in 2024: phenotypes around the world.

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication