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DOE OSTI2020

Trabecula: A Random Generator of Computational Phantoms for Bone Marrow Dosimetry

This study was motivated by the efforts on evaluation of radiation risk for leukemia incidence in the Techa River Cohort, where the main bone marrow dose contributors were 89,90Sr (bone-seeking beta emitters). Energy deposition in bone marrow targets was evaluated by simulating radiation particle transport using computational phantoms. The present paper describes the computer program “Trabecula” implementing an algorithm for parametric generation of computational phantoms, which serve as the basis for calculating bone marrow doses. “Trabecula” is a user-friendly tool that automatically converts analytical models into voxelized representations that are directly compatible as input to MCNP.

Shishkina, Elena A.↗

DOE OSTI2025

Combining Machine Learning and Comparative Effectiveness Methodology to Study Primary Care Pharmacotherapy Pathways for Veterans With Depression

Our objective is to demonstrate an innovative method combining machine learning with comparative effectiveness research techniques and to investigate a hitherto unstudied question about the effectiveness of common prescribing patterns. For Operation Enduring Freedom/Operation Iraqi Freedom veterans with major depressive disorder, we generate pharmacotherapy pathways (of antidepressants) using process mining and machine learning. We select the medication episodes that were started at subtherapeutic doses by the first assigned primary care physician and observe the paths that those medication episodes follow. Using 2-stage least squares, we test the effectiveness of starting at a low dose and staying low for longer versus ramping up fast while balancing observable and unobservable characteristics of patients and providers through instrumental variables. We leverage predetermined provider practice patterns as instruments. We collected outpatient pharmacy data for selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors, patient and provider characteristics (as control variables), and the instruments for our cohort. All data were extracted for the period between 2006 and 2020. There is a statistically significant positive effect (0.68, 95% CI 0.11–1.25) of “ramping up fast” on engagement in care. When we examine the effect of “ramping up slow”, we see an insignificant negative impact on engagement in care (−0.82, 95% CI −1.89 to 0.25). As expected, the probability of drop-out also seems to have a negative effect on engagement in care (−0.39, 95% CI −0.94 to 0.17). We further validate these results by testing with medication possession ratios calculated periodically as an alternative engagement in care metric. Our findings contradict the “Start low, go slow” adage, indicating that ramping up the dose of an antidepressant faster has a significantly positive effect on engagement in care for our population.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2025

Assessment of diagenesis in archaeological human second metacarpal bones using the intensity of the small angle X-ray scattering D -period peak

Bone consists mainly of carbonated apatite (cAp) nanoplatelets embedded in a matrix of collagen fibrils. Earlier, high-energy small angle X-ray scattering (SAXS) studies of archaeological adult human second metacarpal bones (mc2) found collagen D-period peaks with high-intensity I D in specimens in which microcomputed tomography (microCT) showed little diagenesis and I D ~ 0 for specimens where microCT revealed severe diagenesis (Park et al. 2022 Int. J. Osteoarchaeol. 32, 170–181 (doi:10.1002/oa.3053); Stock et al. 2022 Int. J. Osteoarchaeol. 32, 120–131 (doi:10.1002/oa.3049)). Here, the present paper uses SAXS at beamline 1-ID, Advanced Photon Source, Argonne National Laboratory and other techniques to study a set of 10 mc2 from an early Medieval cemetery at Greding, Germany. We hypothesized that non-invasive measurement of I D would provide an accurate and rapid (approx. 6 min/specimen) assessment of diagenesis in archaeological mc2. Results of Raman spectroscopy, laboratory microCT and backscattered electron, reflected light and polarized transmitted light microscopies confirmed the SAXS determinations, but lattice parameter values from X-ray diffraction were uncorrelated with I D value. Age-at-death estimates placed the 10 mc2 in three age categories (young adult, middle adult, old adult): lattice parameters from X-ray diffraction were uncorrelated with age at death. Cross-sectional bone area fraction from microCT dropped noticeably for the older age cohort.

Raman spectroscopy↗

DOE OSTI2023

Past-completeness of inflationary spacetimes

Here, we discuss the question of whether or not inflationary spacetimes can be geodesically complete in the infinite past. Geodesic completeness is a necessary condition for averting an initial singularity during eternal inflation. It is frequently argued that cosmological models which are expanding sufficiently fast (having average Hubble expansion rate H avg > 0) must be incomplete in null and timelike past directions. This well-known conjecture relies on specific bounds on the integral of the Hubble parameter over a past- directed timelike or null geodesic. As stated, we show this claim is an open issue. We show that the calculation of H avg yields a continuum of results for a given spacetime predicated upon the underlying topological assumptions. We present an improved definition for H avg and introduce an uncountably infinite cohort of cosmological solutions which are geodesically complete despite having H avg > 0. We discuss a standardized definition for inflationary spacetimes as well as quantum (semiclassical) cosmological concerns over physically reasonable scale factors.

79 ASTRONOMY AND ASTROPHYSICS↗

DOE OSTI2021

A Knowledge Network-Based Approach to Facilitate Annotation of Clinical Pathway Component Clusters

Mining electronic health records (EHRs) to identify contextually related clinical concept clusters that tend to co-occur temporarily and consistently could improve data-driven clinical pathway (CP) construction. However, the automatic extraction of contextually related clinical concept clusters contains a vast amount of irrelevant information. Hence, this paper proposes a knowledge network-enabled literature-based discovery (LBD) approach to remove noise from clusters. The authors used published literature to filter spurious concepts from the clusters and used data from the US Department of Veterans Affairs’s major depressive disorder (MDD) cohort of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) for their experimentation. The approach was applied to 2,967 clusters extracted from the MDD OEF/OIF database. The experimental results demonstrate that the proposed approach can filter 94% of the irrelevant information. Moreover, the authors applied various network mining algorithms to analyze the clusters and demonstrated that LBD, along with network mining techniques, is a useful method for finding accurate contextually related clinical concept clusters. This could help domain researchers perform advanced analytics in CPs.

Hasan, S M Shamimul↗

DOE OSTI2023

What Role Do Aggregators Play in Power System Security and Resilience?

Barriers to the participation of distributed energy resources (DERs) in wholesale electricity markets have limited the use of DERs for power system security and resilience. In September 2020, the Federal Energy Regulatory Commission (FERC) approved an order to reduce these barriers. FERC Order No. 2222 enables the participation of DER aggregators in wholesale electricity markets. DERs include renewable generation and technologies that support the integration of renewable generation by increasing grid flexibility and resilience. Requiring wholesale energy markets to allow DER aggregator participation provides a path for DERs to become competitive in these markets. As the contribution from aggregated DERs continues to increase, the aggregator's role in supporting grid security and resilience will become more critical. This paper reviews work that demonstrates how DER aggregators can provide resilience support through technical capabilities, operational strategies, and secure communication architectures. Socioeconomic influences and impacts of aggregators, including implications for social resilience, are presented. In surveying the current state-of-the-art across different but interconnected topics, we illustrate how aggregators can be power system participants that enhance grid security. There is no one-size-fits-all approach to enhancing resilience in a power grid that includes a growing cohort of DER aggregators, but there are many options for aggregators to contribute to a more resilient and secure power grid.

aggregator↗

DOE OSTI2021

PET Imaging of Leg Arteries for Determining the Input Function in PET/MRI Brain Studies Using a Compact, MRI-Compatible PET System

In this work, we used a compact, high-resolution, and magnetic resonance imaging (MRI)-compatible positron emission tomography (PET) camera (VersaPET) to assess the feasibility of measuring the image-derived input function (IDIF) from arteries in the leg with the ultimate goal of enabling fully quantitative PET brain imaging without blood sampling. We used this approach in five 18 F-FDG PET/MRI brain studies in which the input function was also acquired using the gold standard of serial arterial blood sampling. After accounting for partial volume, dispersion, and calibration effects, we compared the metabolic rates of glucose (MRglu) quantified from VersaPET IDIFs in 80 brain regions to those using the gold standard and achieved a bias and variability of <5% which is within the range of reported test-retest values for this type of study. We also achieved a strong linear relationship (R 2 >0.97) against the gold standard across regions. The results of this preliminary study are promising and support further studies to optimize methods, validate in a larger cohort, and extend to the modeling of other radiotracers.

47 OTHER INSTRUMENTATION↗

DOE OSTI2024

Signatures of cysteine oxidation on muscle structural and contractile proteins are associated with physical performance and muscle function in older adults: Study of Muscle, Mobility and Aging (SOMMA)

Oxidative stress is considered a contributor to declining muscle function and mobility during aging; however, the underlying molecular mechanisms remain poorly described. We hypothesized that greater levels of cysteine (Cys) oxidation on muscle proteins are associated with decreased measures of mobility. Herein, we applied a novel redox proteomics approach to measure reversible protein Cys oxidation in vastus lateralis muscle biopsies collected from 56 subjects in the Study of Muscle, Mobility and Aging (SOMMA), a community-based cohort study of individuals aged 70 years and older. We tested whether levels of Cys oxidation on key muscle proteins involved in muscle structure and contraction were associated with muscle function (leg power and strength), walking speed, and fitness (VO 2 peak on cardiopulmonary exercise testing) using linear regression models adjusted for age, sex, and body weight. Higher oxidation levels of select nebulin Cys sites were associated with lower VO 2 peak, while greater oxidation of myomesin-1, myomesin-2, and nebulin Cys sites was associated with slower walking speed. Higher oxidation of Cys sites in key proteins such as myomesin-2, alpha-actinin-2, and skeletal muscle alpha-actin were associated with lower leg power and strength. We also observed an unexpected correlation (R = 0.48) between a higher oxidation level of eight Cys sites in alpha-actinin-3 and stronger leg power. Despite this observation, the results generally support the hypothesis that Cys oxidation of muscle proteins impairs muscle power and strength, walking speed, and cardiopulmonary fitness with aging.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

Herbicide‐resistant weed management with robots: A weed ecological–economic model

The heavy reliance on herbicides for weed control has led to an increase in resistant weeds in the United States. Robotic weed control is emerging as an alternative technology for removing weeds mechanically using artificial intelligence. We develop an integrated weed ecological and economic dynamic (I‐WEED) model to examine the biophysical and economic drivers of adopting robotic weed management and simulate the optimal timing and intensity of robotic adoption within and across growing seasons. We specify a cohort‐based weed growth model that relates yield damages to effective weed density and treats the susceptibility of weeds to herbicides as a renewable resource that can be regenerated by using mechanical weeding robots, due to a fitness cost that makes resistant weeds less prolific. Compared to myopic weed management which ignores resistance development, forward‐looking management leads to earlier adoption of robots and treating robots as complements instead of substitutes to herbicides. This weed management results in adopting fewer robots, deploying robots on a smaller portion of the land, higher profitability, and lower yield loss in the long run, relative to myopic management. Counterintuitively, myopic management leads to a lower resistance level through its higher robot adoption intensity. We also find that a lower level of initial weed seed resistance and/or a higher fitness cost result in a higher level of resistance because they create incentives for farmers to delay the adoption of robotic weed control. Our analysis shows the importance of jointly considering the interactions between weed ecology and economics in analyzing the incentives and effects of robotic weed management on weed resistance.

agricultural robotics↗

DOE OSTI2022

The association between vaginal microbiota disorders and early missed abortion: A prospective study

Abstract Introduction The objective of this study was to explore the association between disordered vaginal microbiota and missed abortion to ascertain potential causes of missed abortion related to vaginal microbiology. Material and methods This study was a prospective cohort study with a comparison group (reference group). Vaginal secretions from the posterior fornix of women in the early stages of pregnancy were collected in the Xiangya Third Hospital of Central South University in Changsha, Hunan, China, from November 2018 to November 2019. A total of 54 cases of missed abortion (case group) and 50 cases of normal pregnancy requiring induced abortion (reference group) were analyzed. Bacterial DNA was extracted, hybridized with gene‐specific primers, and then detected using a bacterial chip. The composition and relative abundance of vaginal microbiota in the two groups were compared using α‐diversity analysis, β‐diversity analysis, and the linear discriminant analysis effect size method. Results The α‐diversity analysis showed that the Simpson index of the case group was lower than that of the reference group, whereas the Shannon index in the case group was higher. The relative abundance of Firmicutes in the case group (42.52%) was lower than in the reference group (51.03%, p < 0.05), as was the relative abundance of Lactobacillus (case group 16.51%, reference group 23.00%; p < 0.05). Interestingly, levels of Mycoplasma genitalium and Ureaplasma were lower in the case group ( p < 0.05). The relative abundance of Lactobacillus crispatus , Lactobacillus jensenii , and Lactobacillus gasseri was also significantly lower in the case group than in the reference group ( p < 0.05). The pathways enriched in the case group were predominantly related to metabolism, whereas the genetics‐related pathways were predominantly enriched in the reference group. Conclusions Bacteria are more diverse and unevenly distributed in patients with missed abortion. Decreases in the proportion of vaginal Lactobacillus and changes in Lactobacillus species in these patients may increase the chance of genital tract pathogenic bacterial infection. To our knowledge, our study was the first to observe that a decrease of Firmicutes levels in the vaginal microbiota might impair energy metabolism and have an association with missed abortion.

Sun, Dan↗

DOE OSTI2023

Neurobehavioral symptoms in children born extremely preterm: A Swedish National Study

Abstract Aim To determine the prevalence of neurobehavioral symptoms at 6.5 years in children born extremely preterm (EPT, <27 weeks' gestation). Methods Population‐based cohort study of infants born EPT in Sweden from 2004 to 2007. Of 486 survivors 375 were assessed and compared with 369 matched term‐born controls. EPT children free from neurosensory and intellectual disabilities (neurodevelopmental disabilities [NDD]‐free, n = 236) were compared separately. Standardised questionnaires were used to assess parental ratings of hyperactivity and attention, emotional, peer‐relation, conduct and social problems; and deficits in perception, language and memory. Results EPT children had more reported problems in all assessed neurobehavioral domains than controls, with more than three times greater odds for most outcomes. Except for conduct problems, increased problems were identified also in NDD–free children. The odds of having neurobehavioral problems in ≥3 co‐occurring domains were five (whole EPT group) and three (NDD‐free group) times higher than in controls. Conclusion EPT children with or without NDD have more neurobehavioral problems in multiple domains than term peers. Ongoing assessments of behaviour until school age or beyond should recognise early symptoms of attention, everyday social problems, perceptual, emotional or language difficulties.

Serenius, Fredrik↗

DOE OSTI2020

Cross talk between RNA N6‐methyladenosine methyltransferase‐like 3 and miR‐186 regulates hepatoblastoma progression through Wnt/β‐catenin signalling pathway

Abstract Objectives N6‐methyladenosine (m6A) is a ubiquitous epigenetic RNA modification that plays a pivotal role in tumour development and metastasis. In this study, we aimed to investigate the expression profiling, clinical significance, biological function and the regulation of m6A‐related genes in hepatoblastoma (HB). Materials and Methods The mRNA and protein expression levels of m6A‐related genes were analysed using Gene Expression Omnibus (GEO) and tissue microarray (TMA) cohort. Kaplan‐Meier analysis was performed to evaluate the prognostic value of m6A‐related genes in HB. Knockdown of m6A‐related genes was conducted to analyse its function on cell proliferation, migration and invasion. Furthermore, bioinformatics analysis and experimental verification were used to explore the potential molecular mechanism and signalling pathway. Results We found that most m6A‐related genes were significantly upregulated in HB tumour tissues. High levels of methyltransferase‐like 3 (METTL3, P = .013), YTHDF2 ( P = .037) and FTO ( P = .032) indicated poor clinical outcomes, and the upregulation of METTL3 was an independent prognostic factor in HB patients. Functional assays showed that knockdown of METTL3 could dramatically suppress the proliferation, migration and invasion of HB cells. In addition, METTL3 was identified to be a direct target of microRNA‐186 (miR‐186). Consistently, miR‐186 was low expressed in HB tumour tissues. Moreover, overexpression of miR‐186 significantly inhibited cell aggressive phenotype both in vitro and in vivo, while the inhibitory effect could be reversed by METTL3 overexpression. Mechanism study indicated that miR‐186/METTL3 axis contributed to the progression of HB via the Wnt/β‐catenin signalling pathway. Conclusions M6A‐related genes were frequently dysregulated in HB. miR‐186/METTL3/Wnt/β‐catenin axis might serve as novel therapeutic targets and prognostic biomarkers in HB.

Cui, Xichun↗

DOE OSTI2021

Joint effects of climate, tree size, and year on annual tree growth derived from tree–ring records of ten globally distributed forests

Tree rings provide an invaluable long-term record for understanding how climate and other drivers shape tree growth and forest productivity. However, conventional tree-ring analysis methods were not designed to simultaneously test effects of climate, tree size, and other drivers on individual growth. This has limited the potential to test ecologically relevant hypotheses on tree growth sensitivity to environmental drivers and their interactions with tree size. Here, we develop and apply a new method to simultaneously model nonlinear effects of primary climate drivers, reconstructed tree diameter at breast height (DBH), and calendar year in generalized least squares models that account for the temporal autocorrelation inherent to each individual tree's growth. We analyze data from 3811 trees representing 40 species at 10 globally distributed sites, showing that precipitation, temperature, DBH, and calendar year have additively, and often interactively, influenced annual growth over the past 120 years. Growth responses were predominantly positive to precipitation (usually over ≥3-month seasonal windows) and negative to temperature (usually maximum temperature, over ≤3-month seasonal windows), with concave-down responses in 63% of relationships. Climate sensitivity commonly varied with DBH (45% of cases tested), with larger trees usually more sensitive. Trends in ring width at small DBH were linked to the light environment under which trees established, but basal area or biomass increments consistently reached maxima at intermediate DBH. Accounting for climate and DBH, growth rate declined over time for 92% of species in secondary or disturbed stands, whereas growth trends were mixed in older forests. These trends were largely attributable to stand dynamics as cohorts and stands age, which remain challenging to disentangle from global change drivers. By providing a parsimonious approach for characterizing multiple interacting drivers of tree growth, our method reveals a more complete picture of the factors influencing growth than has previously been possible.

generalized least squares (GLS)↗

DOE OSTI2021

Congenital malformation and hemoglobin A1c in the first trimester among Japanese women with pregestational diabetes

Abstract Aim To investigate the incidence of major congenital malformations in Japanese women with pregestational diabetes, and to determine the cutoff value of hemoglobin A1c (HbA1c) in the first trimester associated with congenital malformations. Methods This retrospective cohort study included singleton pregnancies in Japanese women with pregestational diabetes, including type 1 and type 2 diabetes, and specific types of diabetes due to other causes. The primary outcome was the incidence of major congenital malformations. The secondary outcome was the incidence of all congenital malformations. The cutoff value of HbA1c for congenital malformations was calculated using receiver operating characteristic curve analysis. The adjusted odds ratios (aOR) of major congenital malformations were calculated using multiple logistic regression analyses. Results This study enrolled 292 patients, including 132 (45.2%) with type 1 diabetes, 156 (53.4%) with type 2 diabetes, and 4 (1.4%) with other specific types. The incidence rates of major congenital malformations and all congenital malformations were 7.2% (21/292) and 12.7% (37/292), respectively. The cutoff value of HbA1c in the first trimester for major malformations and for all congenital malformations was 6.5%. HbA1c ≥ 6.5% was significantly associated with major malformations (aOR 3.5; 95% confidence interval: 1.2–12.6; p = 0.018). Conclusion The incidence of major congenital malformations significantly increased in pregnant Japanese women with HbA1c values of 6.5% or higher. The recommended HbA1c value during the first trimester used in other countries can be applied to pregnant Japanese women.

Nakanishi, Kentaro↗

DOE OSTI2023

Pressured cytotoxic T cell epitope strength among SARS-CoV-2 variants correlates with COVID-19 severity

Heterogeneity in susceptibility among individuals to COVID-19 has been evident through the pandemic worldwide. Cytotoxic T lymphocyte (CTL) responses generated against pathogens in certain individuals are known to impose selection pressure on the pathogen, thus driving emergence of new variants. In this study, we probe the role played by host genetic heterogeneity in terms of HLA-genotypes in determining differential COVID-19 severity in patients. We use bioinformatic tools for CTL epitope prediction to identify epitopes under immune pressure. Using HLA-genotype data of COVID-19 patients from a local cohort, we observe that the recognition of pressured epitopes from the parent strain Wuhan-Hu-1 correlates with COVID-19 severity. We also identify and rank list HLA-alleles and epitopes that offer protectivity against severe disease in infected individuals. Finally, we shortlist a set of 6 pressured and protective epitopes that represent regions in the viral proteome that are under high immune pressure across SARS-CoV-2 variants. In conclusion, identification of such epitopes, defined by the distribution of HLA-genotypes among members of a population, could potentially aid in prediction of indigenous variants of SARS-CoV-2 and other pathogens.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2022

Bioenergy sorghum stem growth regulation: intercalary meristem localization, development, and gene regulatory network analysis

SUMMARY Bioenergy sorghum is a highly productive drought tolerant C 4 grass that accumulates 80% of its harvestable biomass in approximately 4 m length stems. Stem internode growth is regulated by development, shading, and hormones that modulate cell proliferation in intercalary meristems (IMs). In this study, sorghum stem IMs were localized above the pulvinus at the base of elongating internodes using magnetic resonance imaging, microscopy, and transcriptome analysis. A change in cell morphology/organization occurred at the junction between the pulvinus and internode where LATERAL ORGAN BOUNDARIES ( SbLOB ), a boundary layer gene, was expressed. Inactivation of an AGCVIII kinase in DDYM ( dw2 ) resulted in decreased SbLOB expression, disrupted IM localization, and reduced internode cell proliferation. Transcriptome analysis identified approximately 1000 genes involved in cell proliferation, hormone signaling, and other functions selectively upregulated in the IM compared with a non‐meristematic stem tissue. This cohort of genes is expressed in apical dome stem tissues before localization of the IM at the base of elongating internodes. Gene regulatory network analysis identified connections between genes involved in hormone signaling and cell proliferation. The results indicate that gibberellic acid induces accumulation of growth regulatory factors (GRFs) known to interact with ANGUSTIFOLIA (SbAN3), a master regulator of cell proliferation. GRF:AN3 was predicted to induce SbARF3/ETT expression and regulate SbAN3 expression in an auxin‐dependent manner. GRFs and ARFs regulate genes involved in cytokinin and brassinosteroid signaling and cell proliferation. The results provide a molecular framework for understanding how hormone signaling regulates the expression of genes involved in cell proliferation in the stem IM.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2026

A Critical Review of Heliostat Design for Concentrating Solar Thermal Technologies

Heliostat designs have undergone a widespread and eclectic development process, with many unique designs demonstrated. However, recent developments do not show the overall cohort converging toward a globally accepted universal design. Here, this study characterizes heliostats by breaking down and evaluating design traits based on emergent patterns from a comprehensive compilation of known heliostat designs spanning several decades. Four main categories for evaluation emerged: heliostat base, heliostat primary axis, heliostat drive, and facet support. Each of these four categories is further defined by four subtypes so that all heliostats fall into a single subtype within each category. The classified heliostats are ranked, yielding several view slices into the heliostat compilation or a breakdown of heliostats by type. An analysis of the breakdown shows several trends: a scale-up of established designs, new approaches at small to medium scales, and a movement toward greater adoption of linear drives. These trends reflect the most meaningful contributing factors to a proposed trajectory for a new era of heliostat designs striving to meet widely considered cost targets of $\$$50/m 2 or $\$$75/m 2 .

14 SOLAR ENERGY↗

DOE OSTI2020

JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.

59 BASIC BIOLOGICAL SCIENCES↗