Feasibility Study of SDAS Instrumentation's Ability to Identify Mobile Launcher (ML)/Crawler-Transporter (CT) Modes During Rollout Operations

The Space Launch System (SLS) and its Mobile Launcher (ML) will be transported to the launch pad via the Crawler-Transporter (CT) system. Rollout (i.e., transportation) loads produce structural loads on the integrated SLS/Orion Multi-Purpose Crew Vehicle (MPCV) launch vehicle which are of a concern with respect to fatigue. As part of the risk reduction process and in addition to the modal building block test approach that has been adopted by the SLS Program, acceleration data will be obtained during rollout for use in modal parameter estimation. There are several occurrences where the ML/CT will be transported either into the Vertical Assembly Building (VAB) or to the launch pad and back without the SLS stack as part of the Kennedy Space Center (KSC) Exploration Ground Systems (EGS) Integrated Test and Checkout (ITCO). NASA KSC EGS has instrumentation installed on both the ML and CT to record data during rollout, at the launch pad, and during liftoff. The EGS instrumentation on the ML, which includes accelerometers, is referred to as the Sensor Data Acquisition System (SDAS). The EGS instrumentation on the CT, which also includes accelerometers, is referred to as the CT Data Acquisition System (CTDAS). The forces and accelerations applied to the ML and CT during a rollout event will be higher than any of the planned building block modal tests. This can be very beneficial in helping identify nonlinear behavior in the structure. Developing modal parameters from the same test hardware in multiple boundary conditions and under multiple levels of excitation is a key step in developing a well correlated FEM. The purpose of this study was three fold. First, determine the target modes of the ML/CT in its rollout configuration. Second, determine if the test degrees of freedom (DOF) corresponding to the layout of the SDAS/CTDAS accelerometers (i.e. position and orientation) is sufficient to identify the target modes. Third, determine if the Generic Rollout Forcing Functions (GRFF's) is sufficient for identifying the ML/CT target modes accounting for variations in CT speed, modal damping, and sensor/ambient background noise levels. The finding from the first part of this study identified 28 target modes of the ML/CT rollout configuration based upon Modal Effective Mass Fractions (MEFF) and engineering judgement. The finding from the second part of this study showed that the SDAS/CTDAS accelerometers (i.e. position and orientation) are able to identify a sufficient number of the target modes to support model correlation of the ML/CT FEM. The finding from the third part of this study confirms the GRFFs sufficiently excite the ML/CT such that varying quantities of the defined target modes should be able to be extracted when utilizing an Experimental Modal Analysis (EMA) Multi-Input Multi-Output (MIMO) analysis approach. An EMA analysis approach was used because Operational Modal Analysis (OMA) tools were not available and the GRFFs were sufficiently uncorrelated. Two key findings from this third part of the study are that the CT speed does not show a significant impact on the ability to extract the modal parameters and that keeping the ambient background noise observed at each accelerometer location at or below 30 grms is essential to the success of this approach

Bayesian Optimization for Personalized Dose-Finding Trials with Combination Therapies

Identification of optimal dose combinations in early phase dose-finding trials is challenging, due to the trade-off between precisely estimating the many parameters required to flexibly model the dose-response surface, and the small sample sizes in early phase trials. Existing methods often restrict the search to pre-defined dose combinations, which may fail to identify regions of optimality in the dose combination space. These difficulties are even more pertinent in the context of personalized dose-finding, where patient characteristics are used to identify tailored optimal dose combinations. To overcome these challenges, we propose the use of Bayesian optimization for finding optimal dose combinations in standard ("one size fits all") and personalized multi-agent dose-finding trials. Bayesian optimization is a method for estimating the global optima of expensive-to-evaluate objective functions. The objective function is approximated by a surrogate model, commonly a Gaussian process, paired with a sequential design strategy to select the next point via an acquisition function. This work is motivated by an industry-sponsored problem, where focus is on optimizing a dual-agent therapy in a setting featuring minimal toxicity. To compare the performance of the standard and personalized methods under this setting, simulation studies are performed for a variety of scenarios. Our study concludes that taking a personalized approach is highly beneficial in the presence of heterogeneity.Comment: 26 pages, 4 figures, 1 tabl

Structural Verification of the First Orbital Wonder of the World - The Structural Testing and Analysis of the International Space Station (ISS)

The International Space Station (ISS) can be considered one of the structural engineering wonders of the world. On par with the World Trade Center, the Colossus of Rhodes, the Statue of Liberty, the Great Pyramids, the Petronas towers and the Burj Khalifa skyscraper of Dubai, the ambition and scope of the ISS structural design, verification and assembly effort is a truly global success story. With its on-orbit life projected to be from its beginning in 1998 to the year 2020 (and perhaps beyond), all of those who participated in its development can consider themselves part of an historic engineering achievement representing all of humanity. The structural design and verification of the ISS could be the subject of many scholarly papers. Several papers have been written on the structural dynamic characterization of the ISS once it was assembled on-orbit [1], but the ground-based activities required to assure structural integrity and structural life of the individual elements from delivery to orbit through assembly and planned on-orbit operations have never been totally summarized. This paper is intended to give the reader an overview of some of the key decisions made during the structural verification planning for the elements of the U.S. On-Orbit Segment (USOS) as well as to summarize the many structural tests and structural analyses that were performed on its major elements. An effort is made for this paper to be summarily comprehensive, but as with all knowledge capture efforts of this kind, there are bound to be errors of omission. Should the reader discover any of these, please feel free to contact the principal author. The ISS (Figure 1) is composed of pre-integrated truss segments and pressurized elements supplied by NASA, the Russian Federal Space Agency (RSA), the European Space Agency (ESA) and the Japanese Aerospace Exploration Agency (JAXA). Each of these elements was delivered to orbit by a launch vehicle and connected to one another either robotically or autonomously. The primary structure of each element was assembled and verified by teams of responsible structural engineers within and among their respective agencies and agency contractors

Early Start Peritoneal Dialysis: Technique Survival in Long-Term Follow-Up

Background/Aims: Peritoneal dialysis (PD) has gained interest over the last decade as a viable option for early start dialysis. It is still unknown if shorter break-in periods and less time for proper patient evaluation and training could influence technique survival in comparison to planned-start PD. Methods: A prospective and observational study that compared technique survival in a cohort of patients who started either early or planned PD. Early start PD was defined as break-in period from 3 to 14 days with no previous nephrologist follow-up or patient training. Results: A total of 154 patients were included (40 as early start PD), followed by a median time of 381 days. Comparing early vs. planned-start PD, groups were similar concerning age 56 (40; 70) vs. 48 (32; 63) years, p=0.071, body mass index (BMI) 23.3 ± 4.2 vs. 23.8 ± 4.0 kg/m2, p=0.567 and male gender (60 vs. 48%, p=0.201), respectively. Comparing early vs. planned-start groups, there were no differences regarding PD dropout for peritonitis (7.5 vs. 11.4%, p=0.764), catheter dysfunction (12.5 vs. 17.5%, p=0.619) and patient burnout (0 vs. 4.4%, p=0.328), respectively. Less patients in early start group quit PD for peritoneal membrane failure in comparison to planned-start group (2.5 vs. 16.7%, p=0.026). In multivariate cox-regression analysis, the only factors independently associated with technique failure were BMI> 25 kg/m² (p=0.033) and Diabetes Mellitus (p=0.013), whereas no differences regarding early vs. planned-PD start were observed (p=0.184). Conclusion: Despite the adverse scenario for initiating dialysis, early start PD had similar outcomes in comparison to planned-start PD in long-term follow-up

Amniotic band syndrome and limb body wall complex in Europe 1980–2019

Amniotic band syndrome (ABS) and limb body wall complex (LBWC) have an overlapping phenotype of multiple congenital anomalies and their etiology is unknown. We aimed to determine the prevalence of ABS and LBWC in Europe from 1980 to 2019 and to describe the spectrum of congenital anomalies. In addition, we investigated maternal age and multiple birth as possible risk factors for the occurrence of ABS and LBWC. We used data from the European surveillance of congenital anomalies (EUROCAT) network including data from 30 registries over 1980–2019. We included all pregnancy outcomes, including live births, stillbirths, and terminations of pregnancy for fetal anomalies. ABS and LBWC cases were extracted from the central EUROCAT database using coding information responses from the registries. In total, 866 ABS cases and 451 LBWC cases were included in this study. The mean prevalence was 0.53/10,000 births for ABS and 0.34/10,000 births for LBWC during the 40 years. Prevalence of both ABS and LBWC was lower in the 1980s and higher in the United Kingdom. Limb anomalies and neural tube defects were commonly seen in ABS, whereas in LBWC abdominal and thoracic wall defects and limb anomalies were most prevalent. Twinning was confirmed as a risk factor for both ABS and LBWC. This study includes the largest cohort of ABS and LBWC cases ever reported over a large time period using standardized EUROCAT data. Prevalence, clinical characteristics, and the phenotypic spectrum are described, and twinning is confirmed as a risk factor.publishedVersio

JADES: Probing interstellar medium conditions at z∼5.5−9.5z\sim5.5-9.5 with ultra-deep JWST/NIRSpec spectroscopy

We present emission line ratios from a sample of 26 Lyman break galaxies from $z\sim5.5-9.5$ with $-17.0<M_{1500}<-20.4$, measured from ultra-deep JWST/NIRSpec MSA spectroscopy from JADES. We use 28 hour deep PRISM/CLEAR and 7 hour deep G395M/F290LP observations to measure, or place strong constraints on, ratios of widely studied rest-frame optical emission lines including H$\alpha$, H$\beta$, [OII] $\lambda\lambda$3726,3729, [NeIII] $\lambda$3869, [OIII] $\lambda$4959, [OIII] $\lambda$5007, [OI] $\lambda$6300, [NII] $\lambda$6583, and [SII] $\lambda\lambda$6716,6731 in individual $z>5.5$ spectra. We find that the emission line ratios exhibited by these $z\sim5.5-9.5$ galaxies occupy clearly distinct regions of line-ratio space compared to typical z~0-3 galaxies, instead being more consistent with extreme populations of lower-redshift galaxies. This is best illustrated by the [OIII]/[OII] ratio, tracing interstellar medium (ISM) ionisation, in which we observe more than half of our sample to have [OIII]/[OII]>10. Our high signal-to-noise spectra reveal more than an order of magnitude of scatter in line ratios such as [OII]/H$\beta$ and [OIII]/[OII], indicating significant diversity in the ISM conditions within the sample. We find no convincing detections of [NII] in our sample, either in individual galaxies, or a stack of all G395M/F290LP spectra. The emission line ratios observed in our sample are generally consistent with galaxies with extremely high ionisation parameters (log $U\sim-1.5$), and a range of metallicities spanning from $\sim0.1\times Z_\odot$ to higher than $\sim0.3\times Z_\odot$, suggesting we are probing low-metallicity systems undergoing periods of rapid star-formation, driving strong radiation fields. These results highlight the value of deep observations in constraining the properties of individual galaxies, and hence probing diversity within galaxy population.Comment: 20 pages, 9 figures, submitted to Astronomy & Astrophysics, updated values in table

Comparative effectiveness of initial computed tomography and invasive coronary angiography in women and men with stable chest pain and suspected coronary artery disease: multicentre randomised trial

To assess the comparative effectiveness of computed tomography and invasive coronary angiography in women and men with stable chest pain suspected to be caused by coronary artery disease

Spectroscopy of four metal-poor galaxies beyond redshift ten

Finding and characterising the first galaxies that illuminated the early Universe at cosmic dawn is pivotal to understand the physical conditions and the processes that led to the formation of the first stars. In the first few months of operations, imaging from the James Webb Space Telescope (JWST) have been used to identify tens of candidates of galaxies at redshift (z) greater than 10, less than 450 million years after the Big Bang. However, none of these candidates has yet been confirmed spectroscopically, leaving open the possibility that they are actually low-redshift interlopers. Here we present spectroscopic confirmation and analysis of four galaxies unambiguously detected at redshift 10.3<z<13.2, previously selected from NIRCam imaging. The spectra reveal that these primeval galaxies are extremely metal poor, have masses between 10^7 and a few times 10^8 solar masses, and young ages. The damping wings that shape the continuum close to the Lyman edge are consistent with a fully neutral intergalactic medium at this epoch. These findings demonstrate the rapid emergence of the first generations of galaxies at cosmic dawn.Comment: 32 pages, 9 figures, Submitte

JADES NIRSpec Spectroscopy of GN-z11: Lyman-α\alpha emission and possible enhanced nitrogen abundance in a z=10.60z=10.60 luminous galaxy

We present JADES JWST/NIRSpec spectroscopy of GN-z11, the most luminous candidate $z>10$ Lyman break galaxy in the GOODS-North field with $M_{UV}=-21.5$. We derive a redshift of $z=10.603$ (lower than previous determinations) based on multiple emission lines in our low and medium resolution spectra over $0.8-5.3\,\mu$m. We significantly detect the continuum and measure a blue rest-UV spectral slope of $\beta=-2.4$. Remarkably, we see spatially-extended Lyman-$\alpha$ in emission (despite the highly-neutral IGM expected at this early epoch), offset 555 km/s redward of the systemic redshift. From our measurements of collisionally-excited lines of both low- and high-ionization (including [O II] $\lambda3727$, [Ne III] $\lambda 3869$ and C III] $\lambda1909$) we infer a high ionization parameter ($\log U\sim -2$). We detect the rarely-seen N IV] $\lambda1486$ and N III]$\lambda1748$ lines in both our low and medium resolution spectra, with other high ionization lines seen in low resolution spectrum such as He II (blended with O III]) and C IV (with a possible P-Cygni profile). Based on the observed rest-UV line ratios, we cannot conclusively rule out photoionization from AGN. The high C III]/He II ratios, however, suggest a likely star-formation explanation. If the observed emission lines are powered by star formation, then the strong N III] $\lambda1748$ observed may imply an unusually high $N/O$ abundance. Balmer emission lines (H$\gamma$, H$\delta$) are also detected, and if powered by star formation rather than an AGN we infer a star formation rate of $\sim 20-30 M_{\odot}\,\rm yr^{-1}$ (depending on the IMF) and low dust attenuation. Our NIRSpec spectroscopy confirms that GN-z11 is a remarkable galaxy with extreme properties seen 430 Myr after the Big Bang.Comment: Submitted to Astronomy & Astrophysics, 14 pages, 9 figure

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS), NIH (R01NS109858, to VAG); the Paul A. Marks Scholar Program at the Columbia University Vagelos College of Physicians and Surgeons (to VAG); a TIGER grant from the TAUB Institute at the Columbia Vagelos College of Physicians and Scientists (to VAG); the Swiss National Science Foundation (SNF 31003A-179371, to TH); the European Joint Program on Rare Diseases (EJP RD+SNF 32ER30-187505, to TH); the Swiss Cancer League (KFS-4999-02-2020, to GD); the EPFL institutional fund (to GD); the Kristian Gerhard Jebsen Foundation (to GD); the Swiss National Science Foundation (SNSF) (310030_184926, to GD); the Swiss Foundation for Research on Muscle Disease (FSRMM, to MAL); the Natural Science and Engineering Research Council of Canada (Discovery Grant 2020-04241, to JEB); the Italian Ministry of Health Young Investigator Grant (GR-2011-02347754, to EL); the Fondazione Istituto di Ricerca Pediatrica – Città della Speranza (18-04, to EL); the Wroclaw Medical University (SUB.E160.21.004, to RS); the National Science Centre, Poland (2017/27/B/NZ5/0222, to RS); Telethon Undiagnosed Diseases Program (TUDP) (GSP15001); the Temple Street Foundation/Children’s Health Foundation Ireland (RPAC 19-02, to IK); the Deutsche Forschungsgemeinschaft (DFG) (PO2366/2–1, to BP); the Instituto de Salud Carlos III, Spain (to ELM, EBS, and BMD); the National Natural Science Foundation of China (81871079 and 81730036, to HG and KX); and the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH (R01 DK115574, to SSC).The DEFIDIAG study is funded by grants from the French Ministry of Health in the framewok of the national French initiative for genomic medicine. The funders were not involved in the study design, data acquisition, analysis, or writing of the manuscript. Funding for the DECIPHER project was provided by Wellcome. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.S