Vacuum Pyrolysis and Related ISRU Techniques

A number of ISRU-related techniques have been developed at NASA Goddard Space Flight Center. The focus of the team has been on development of the vacuum pyrolysis technique for the production of oxygen from the lunar regolith. However, a number of related techniques have also been developed, including solar concentration, solar heating of regolith, resistive heating of regolith, sintering, regolith boiling, process modeling, parts manufacturing, and instrumentation development. An initial prototype system was developed to vaporize regolith simulants using a approx. l square meter Fresnel lens. This system was successfully used to vaporize quantities of approx. lg, and both mass spectroscopy of the gasses produced and Scanning Electron Microscopy (SEM) of the slag were done to show that oxygen was produced. Subsequent tests have demonstrated the use of a larger system With a 3.8m diameter reflective mirror to vaporize the regolith. These results and modeling of the vacuum pyrolysis reaction have indicated that the vaporization of the oxides in the regolith will occur at lower temperature for stronger vacuums. The chemical modeling was validated by testing of a resistive heating system that vaporized quantities of approx. 10g of MLS-1A. This system was also used to demonstrate the sintering of regolith simulants at reduced temperatures in high vacuum. This reduction in the required temperature prompted the development of a small-scale resistive heating system for application as a scientific instrument as well as a proof-of principle experiment for oxygen production

Medulloblastoma Exome Sequencing Uncovers Subtype-Specific Somatic Mutations

Medulloblastomas are the most common malignant brain tumors in children1. Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles2–5. Here, we utilized whole exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas exhibit low mutation rates consistent with other pediatric tumors, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR, and LDB1, novel findings in medulloblastoma. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant but not wild type beta-catenin. Together, our study reveals the alteration of Wnt, Hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signaling in medulloblastoma

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Measurement and analysis of combustion response to transverse combustion instability

This research aimed to gain a better understanding of the response of a gas-centered swirl coaxial injector to transverse combustion instability. The goals of the research were to develop a combustion chamber that would be able to spontaneously produce transverse combustion instability at elevated pressures and temperatures. Methods were also developed to analyze high-speed video images to understand the response of the injector. A combustion chamber was designed that produced high levels of instabilities. The chamber was capable of pressures as high as 1034 kPa (150 psi) and operated using decomposed 90% hydrogen peroxide and JP-8. The chamber used an array of seven gas-centered swirl coaxial injectors that exhibited linear instability to drive the transverse oscillations. The injector elements would operate in a monopropellant configuration flowing only decomposed hydrogen peroxide or in a bipropellant configuration. The location of the bipropellant injectors could be varied to change the level of the instability in the chamber from 10% of the chamber pressure up to 70% of the chamber pressure. A study element was placed in the center of the chamber where it was observed simultaneously by two high-speed video cameras which recorded a backlit video to show the location of the fuel spray and the location of the emitted CH* chemiluminescence. The videos were synchronized with high frequency pressure measurements to gain a full understanding of the physics in the combustion chamber. Results showed that the study element was coupled with the first mode velocity wave. This was expected due to the first mode velocity anti-node being located in the center of the chamber. The velocity is an absolute maximum twice during each cycle so the coupling with the second mode pressure was also investigated showing a possible coupling with both the velocity and pressure. The results of the first mode velocity showed that, as the velocity wave traveled through the chamber, the fuel spray was first displaced into an oxidizer rich region and secondly followed by a reaction in the direction of travel of the velocity wave as the peak velocity traveled through the region. The deflection into the oxidizer rich region was especially apparent in high-level instabilities. In low-level instabilities, the velocity wave was not strong enough to fully displace the fuel, and instead the oxidizer core was deflected into the fuel annulus causing a reaction in the direction of travel of the velocity wave. Neighboring oxidizer only injectors caused a lower reaction upstream as the neighboring oxidizer was deflected into the fuel annulus. The region of the fluctuating emitted light agreed well in size, shape and location with a correlation between the first mode velocity and combustion leading to the conclusion that the first mode is highly coupled with velocity. The second mode variance did not agree well with either the velocity or pressure correlation leading to a conclusion that it is coupled with both velocity and pressure. When comparing the variance to the pressure or velocity correlation, parts of the variance compared in shape and location to the pressure or velocity correlation, however, this was not true for all regions of response. This leads to a conclusion that both the pressure and velocity can be affecting the second mode. The second mode chemiluminescence emission occurs when the velocity is nearly zero in the chamber leading to the reaction to not be deflected and occurring downstream of the injector. At the same time, the second mode pressure is a minimum so an increase in mass flow could be responsible for the increased reaction. The methods and combustion chamber used to study the response of an injector can be used in the future to study any injector or combination of injectors placed at various locations in the chamber to study pressure or velocity coupling. The chemiluminescence data can be used to develop transfer functions for use in low fidelity computational models and can be used to validate high fidelity CFD

Evaluation of a mid-career investigator career development award: Assessing the ability of OppNet K18 awardees to obtain NIH follow-on research funding

<div><p>The National Institutes of Health (NIH) K18 award mechanism provides funded opportunities for established investigators to gain knowledge in fields outside of their primary disciplines, but outcomes associated with these awards have not been evaluated to date. NIH’s Basic Behavioral and Social Sciences Opportunity Network (OppNet) is one of the few initiatives that has used this award mechanism. We explored how the unique features of K18 awards affect the ability of recipients to obtain follow-on NIH research funding. We compared outcomes (<i>ability to obtain follow-on funding</i> and <i>interval between receipt of the primary award and receipt of the first follow-on award</i>) associated with OppNet K18 awards to findings from evaluations of other NIH career development (K) awards, which usually target early-career investigators. We hypothesized that K18 award recipients might be (1) more successful than are other K award recipients in obtaining follow-on NIH research funding due to their career experience or (2) less successful due to the competing demands of other projects. By analyzing follow-on NIH research awards and interview data, we found that OppNet K18 award recipients were at least as successful as were other K award recipients in obtaining follow-on funding and may have been more successful by certain measures. K18 awards produce their outcomes with a lower investment per investigator than do other K awards, suggesting continued or enhanced use of the mechanism.</p></div

Median intervals between K18 award receipt and receipt of K18-related awards (Years) among K18 awardees who received follow-on funding by awardee characteristic.

<p>Median intervals between K18 award receipt and receipt of K18-related awards (Years) among K18 awardees who received follow-on funding by awardee characteristic.</p

OppNet K18 recipient pool and OppNet K18 recipients who received follow-on funding by awardee characteristic.

<p>OppNet K18 recipient pool and OppNet K18 recipients who received follow-on funding by awardee characteristic.</p

Number of OppNet K18 awardees receiving NIH Follow-on research funding, by year of award.

<p>Number of OppNet K18 awardees receiving NIH Follow-on research funding, by year of award.</p