Comparison of 16 Pediatric Acute Respiratory Distress Syndrome-Associated Plasma Biomarkers With Changing Lung Injury Severity.

OBJECTIVES: Pediatric acute respiratory distress syndrome (PARDS) is a source of substantial morbidity and mortality in the PICU, and different plasma biomarkers have identified different PARDS and ARDS subgroups. We have a poor understanding of how these biomarkers change over time and with changing lung injuries. We sought to determine how biomarker levels change over PARDS course, whether they are correlated, and whether they are different in critically ill non-PARDS patients. DESIGN: Two-center prospective observational study. SETTING: Two quaternary care academic children's hospitals. PATIENTS: Subjects under 18 years of age admitted to the PICU who were intubated and met the Second Pediatric Acute Lung Injury Consensus Conference-2 PARDS diagnostic criteria and nonintubated critically ill subjects without apparent lung disease. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma samples were obtained on study days 1, 3, 7, and 14. The levels of 16 biomarkers were measured using a fluorometric bead-based assay. Compared with non-PARDS subjects, on day 1 PARDS subjects had increased concentrations of tumor necrosis factor-alpha, interleukin (IL)-8, interferon-γ, IL17, granzyme B, soluble intercellular adhesion molecule-1 (sICAM1), surfactant protein D, and IL18 but reduced matrix metalloproteinase 9 (MMP-9) concentrations (all p < 0.05). Day 1 biomarker concentrations and PARDS severity were not correlated. Over PARDS course, changes in 11 of the 16 biomarkers positively correlated with changing lung injury with sICAM1 ( R = 0.69, p = 2.2 × 10 -16 ) having the strongest correlation. By Spearman rank correlation of biomarker concentrations in PARDS subjects, we identified two patterns. One had elevations of plasminogen activator inhibitor-1, MMP-9, and myeloperoxidase, and the other had higher inflammatory cytokines. CONCLUSIONS: sICAM1 had the strongest positive correlation with worsening lung injury across all study time points suggesting that it is perhaps the most biologically relevant of the 16 analytes. There was no correlation between biomarker concentration on day 1 and day 1 PARDS severity; however, changes in most biomarkers over time positively correlated with changing lung injury. Finally, in day 1 samples, 7 of the 16 biomarkers were not significantly different between PARDS and critically ill non-PARDS subjects. These data highlight the difficulty of using plasma biomarkers to identify organ-specific pathology in critically ill patients.

Multi-omic characterization of pediatric ARDS via nasal brushings.

RATIONALE: While nasal brushing transcriptomics can identify disease subtypes in chronic pulmonary diseases, it is unknown whether this is true in pediatric acute respiratory distress syndrome (PARDS). OBJECTIVES: Determine whether nasal transcriptomics and methylomics can identify clinically meaningful PARDS subgroups that reflect important pathobiological processes. METHODS: Nasal brushings and serum were collected on days 1, 3, 7, and 14 from control and PARDS subjects from two centers. PARDS duration was the primary endpoint. MEASUREMENTS AND MAIN RESULTS: Twenty-four control and 39 PARDS subjects were enrolled. Two nasal methylation patterns were identified. Compared to Methyl Subgroup 1, Subgroup 2 had hypomethylation of inflammatory genes and was enriched for immunocompromised subjects. Four transcriptomic patterns were identified with temporal patterns indicating injury, repair, and regeneration. Over time, both inflammatory (Subgroup B) and cell injury (Subgroup D) patterns transitioned to repair (Subgroup A) and eventually homeostasis (Subgroup C). When control specimens were included, they were largely Subgroup C. In comparison with 17 serum biomarkers, the nasal transcriptome was more predictive of prolonged PARDS. Subjects with initial Transcriptomic Subgroup B or D assignment had median PARDS duration of 8 days compared to 2 in A or C (p = 0.02). For predicting PARDS duration ≥ 3 days, nasal transcriptomics was more sensitive and serum biomarkers more specific. CONCLUSIONS: PARDS nasal transcriptome may reflect distal lung injury, repair, and regeneration. A combined nasal PCR and serum biomarker assay could be useful for predictive and diagnostic enrichment. Trial registration Clinicaltrials.gov NCT03539783 May 29, 2018.

Long-Term Earth-Moon Evolution With High-Level Orbit and Ocean Tide Models.

Tides and Earth-Moon system evolution are coupled over geological time. Tidal energy dissipation on Earth slows E a r t h ' s rotation rate, increases obliquity, lunar orbit semi-major axis and eccentricity, and decreases lunar inclination. Tidal and core-mantle boundary dissipation within the Moon decrease inclination, eccentricity and semi-major axis. Here we integrate the Earth-Moon system backwards for 4.5 Ga with orbital dynamics and explicit ocean tide models that are "high-level" (i.e., not idealized). To account for uncertain plate tectonic histories, we employ Monte Carlo simulations, with tidal energy dissipation rates (normalized relative to astronomical forcing parameters) randomly selected from ocean tide simulations with modern ocean basin geometry and with 55, 116, and 252 Ma reconstructed basin paleogeometries. The normalized dissipation rates depend upon basin geometry and E a r t h ' s rotation rate. Faster Earth rotation generally yields lower normalized dissipation rates. The Monte Carlo results provide a spread of possible early values for the Earth-Moon system parameters. Of consequence for ocean circulation and climate, absolute (un-normalized) ocean tidal energy dissipation rates on the early Earth may have exceeded t o d a y ' s rate due to a closer Moon. Prior to ∼ 3 Ga , evolution of inclination and eccentricity is dominated by tidal and core-mantle boundary dissipation within the Moon, which yield high lunar orbit inclinations in the early Earth-Moon system. A drawback for our results is that the semi-major axis does not collapse to near-zero values at 4.5 Ga, as indicated by most lunar formation models. Additional processes, missing from our current efforts, are discussed as topics for future investigation.

CPR Blitzkrieg: Training 500 High School Students in less than 48 hours.

BACKGROUND Many states, including Arkansas, require CPR training before high school graduation. METHODS We modified the American Heart Association's CPR in Schools curriculum to deliver CPR and AED training with maximal individual practice. RESULTS 520 students were trained over a two-day period at Little Rock Central High School. Three students were unable to effectively participate due to physical limitations. The model was later applied at the five other district public high schools. CONCLUSIONS Training large numbers of students in a time-compressed formal is feasible with a highly dedicated, practiced instructor team. This model may be applicable to workplace settings.

Gravity field of the Orientale basin from the Gravity Recovery and Interior Laboratory Mission.

The Orientale basin is the youngest and best-preserved major impact structure on the Moon. We used the Gravity Recovery and Interior Laboratory (GRAIL) spacecraft to investigate the gravitational field of Orientale at 3- to 5-kilometer (km) horizontal resolution. A volume of at least (3.4 ± 0.2) × 106 km3 of crustal material was removed and redistributed during basin formation. There is no preserved evidence of the transient crater that would reveal the basin's maximum volume, but its diameter may now be inferred to be between 320 and 460 km. The gravity field resolves distinctive structures of Orientale's three rings and suggests the presence of faults associated with the outer two that penetrate to the mantle. The crustal structure of Orientale provides constraints on the formation of multiring basins.

Lunar impact basins revealed by Gravity Recovery and Interior Laboratory measurements.

Observations from the Gravity Recovery and Interior Laboratory (GRAIL) mission indicate a marked change in the gravitational signature of lunar impact structures at the morphological transition, with increasing diameter, from complex craters to peak-ring basins. At crater diameters larger than ~200 km, a central positive Bouguer anomaly is seen within the innermost peak ring, and an annular negative Bouguer anomaly extends outward from this ring to the outer topographic rim crest. These observations demonstrate that basin-forming impacts remove crustal materials from within the peak ring and thicken the crust between the peak ring and the outer rim crest. A correlation between the diameter of the central Bouguer gravity high and the outer topographic ring diameter for well-preserved basins enables the identification and characterization of basins for which topographic signatures have been obscured by superposed cratering and volcanism. The GRAIL inventory of lunar basins improves upon earlier lists that differed in their totals by more than a factor of 2. The size-frequency distributions of basins on the nearside and farside hemispheres of the Moon differ substantially; the nearside hosts more basins larger than 350 km in diameter, whereas the farside has more smaller basins. Hemispherical differences in target properties, including temperature and porosity, are likely to have contributed to these different distributions. Better understanding of the factors that control basin size will help to constrain models of the original impactor population.

Leveraging the national cyberinfrastructure for biomedical research.

In the USA, the national cyberinfrastructure refers to a system of research supercomputer and other IT facilities and the high speed networks that connect them. These resources have been heavily leveraged by scientists in disciplines such as high energy physics, astronomy, and climatology, but until recently they have been little used by biomedical researchers. We suggest that many of the 'Big Data' challenges facing the medical informatics community can be efficiently handled using national-scale cyberinfrastructure. Resources such as the Extreme Science and Discovery Environment, the Open Science Grid, and Internet2 provide economical and proven infrastructures for Big Data challenges, but these resources can be difficult to approach. Specialized web portals, support centers, and virtual organizations can be constructed on these resources to meet defined computational challenges, specifically for genomics. We provide examples of how this has been done in basic biology as an illustration for the biomedical informatics community.

The past and present Earth-Moon system: the speed of light stays steady as tides evolve.

Tides induce a semimajor axis rate of +38.08 ± 0.19 mm/yr, corresponding to an acceleration of the Moon's orbital mean longitude of -25.82 ± 0.13 "/cent2, as determined by the analysis of 43 yr of Lunar Laser Ranging (LLR) data. The LLR result is consistent with analyses made with different data spans, different analysis techniques, analysis of optical observations, and independent knowledge of tides. Plate motions change ocean shapes, and geological evidence and model calculations indicate lower rates of tidal evolution for extended past intervals. Earth rotation has long-term slowing due to tidal dissipation, but it also experiences variations for times up to about 105 yr due to changes in the moment of inertia. An analysis of LLR data also tests for any rate of change in either the speed of light c or apparent mean distance. The result is (-2.8 ± 3.4)×10-12 /yr for either scale rate or -(dc/dt)/c, or equivalently -1.0 ± 1.3 mm/yr for apparent distance rate. The lunar range does not reveal any change in the speed of light.

Ancient igneous intrusions and early expansion of the Moon revealed by GRAIL gravity gradiometry.

The earliest history of the Moon is poorly preserved in the surface geologic record due to the high flux of impactors, but aspects of that history may be preserved in subsurface structures. Application of gravity gradiometry to observations by the Gravity Recovery and Interior Laboratory (GRAIL) mission results in the identification of a population of linear gravity anomalies with lengths of hundreds of kilometers. Inversion of the gravity anomalies indicates elongated positive-density anomalies that are interpreted to be ancient vertical tabular intrusions or dikes formed by magmatism in combination with extension of the lithosphere. Crosscutting relationships support a pre-Nectarian to Nectarian age, preceding the end of the heavy bombardment of the Moon. The distribution, orientation, and dimensions of the intrusions indicate a globally isotropic extensional stress state arising from an increase in the Moon's radius by 0.6 to 4.9 kilometers early in lunar history, consistent with predictions of thermal models.

Gravity field of the Moon from the Gravity Recovery and Interior Laboratory (GRAIL) mission.

Spacecraft-to-spacecraft tracking observations from the Gravity Recovery and Interior Laboratory (GRAIL) have been used to construct a gravitational field of the Moon to spherical harmonic degree and order 420. The GRAIL field reveals features not previously resolved, including tectonic structures, volcanic landforms, basin rings, crater central peaks, and numerous simple craters. From degrees 80 through 300, over 98% of the gravitational signature is associated with topography, a result that reflects the preservation of crater relief in highly fractured crust. The remaining 2% represents fine details of subsurface structure not previously resolved. GRAIL elucidates the role of impact bombardment in homogenizing the distribution of shallow density anomalies on terrestrial planetary bodies.

The crust of the Moon as seen by GRAIL.

High-resolution gravity data obtained from the dual Gravity Recovery and Interior Laboratory (GRAIL) spacecraft show that the bulk density of the Moon's highlands crust is 2550 kilograms per cubic meter, substantially lower than generally assumed. When combined with remote sensing and sample data, this density implies an average crustal porosity of 12% to depths of at least a few kilometers. Lateral variations in crustal porosity correlate with the largest impact basins, whereas lateral variations in crustal density correlate with crustal composition. The low-bulk crustal density allows construction of a global crustal thickness model that satisfies the Apollo seismic constraints, and with an average crustal thickness between 34 and 43 kilometers, the bulk refractory element composition of the Moon is not required to be enriched with respect to that of Earth.

Progress in lunar laser ranging tests of relativistic gravity.

Analyses of laser ranges to the Moon provide increasingly stringent limits on any violation of the equivalence principle (EP); they also enable several very accurate tests of relativistic gravity. These analyses give an EP test of Delta(MG/MI)EP=(-1.0+/-1.4) x 10(-13). This result yields a strong equivalence principle (SEP) test of Delta(MG/MI)SEP=(-2.0+/-2.0) x 10(-13). Also, the corresponding SEP violation parameter eta is (4.4+/-4.5) x 10(-4), where eta=4beta-gamma-3 and both beta and gamma are post-Newtonian parameters. Using the Cassini gamma, the eta result yields beta-1=(1.2+/-1.1) x 10(-4). The geodetic precession test, expressed as a relative deviation from general relativity, is Kgp=-0.0019+/-0.0064. The search for a time variation in the gravitational constant results in G /G=(4+/-9) x 10(-13) yr(-1); consequently there is no evidence for local (approximately 1 AU) scale expansion of the solar system.