A Boreing Night of Observations of the Upper Mesosphere and Lower Thermosphere Over the Andes Lidar Observatory

A very high-spatial resolution (∼21-23 m pixel at 85 km altitude) OH airglow imager at the Andes Lidar Observatory at Cerro Pach´on, Chile observed considerable ducted wave activity on the night of October 29-30, 2016. This instrument was collocated with a Na wind-temperature lidar that provided data revealing the occurrence of strong ducts. A large field of view OH and greenline airglow imager showed waves present over a vertical extent consistent with the altitudes of the ducting features identified in the lidar profiles. While waves that appeared to be ducted were seen in all imagers throughout the observation interval, the wave train seen in the OH images at earlier times had a distinct leading non-sinusoidal phase followed by several, lower-amplitude, more sinusoidal phases, suggesting a likely bore. The leading phase exhibited significant dissipation via small-scale secondary instabilities suggesting vortex rings that progressed rapidly to smaller scales and turbulence (the latter not fully resolved) thereafter. The motions of these small-scale features were consistent with their location in the duct at or below ∼83-84 km. Bore dissipation caused a momentum flux divergence and a local acceleration of the mean flow within the duct along the direction of the initial bore propagation. A number of these features are consistent with mesospheric bores observed or modeled in previous studies

Kelvin-Helmholtz Billow Interactions and Instabilities In The Mesosphere Over the Andes Lidar Observatory: 1. Observations

A very high spatial resolution (∼25 m pixel at 90 km altitude) OH airglow imager was installed at the Andes Lidar Observatory on Cerro Pachón, Chile, in February 2016. This instrument was collocated with a Na wind-temperature lidar. On 1 March 2016, the lidar data showed that the atmosphere was dynamically unstable before 0100 UT and thus conducive to the formation of Kelvin-Helmholtz instabilities (KHIs). The imager revealed the presence of a KHI and an apparent atmospheric gravity wave (AGW) propagating approximately perpendicular to the plane of primary KHI motions. The AGW appears to have induced modulations of the shear layer leading to misalignments of the emerging KHI billows. These enabled strong KHI billow interactions, as they achieved large amplitudes and a rapid transition to turbulence thereafter. The interactions manifested themselves as vortex tube and knot features that were earlier identified in laboratory studies, as discussed in Thorpe (1987, https://doi.org/10.1029/ JC092iC05p05231; 2002, https://doi.org/10.1002/qj.200212858307) and inferred to be widespread in the atmosphere based on features seen in tropospheric clouds but which have never been identified in previous upper atmospheric observations. This study presents the first high-resolution airglow imaging observation of these KHI interaction dynamics that drive rapid transitions to turbulence and suggest the potential importance of these dynamics in the mesosphere and at other altitudes. A companion paper (Fritts et al., 2020, https://doi.org/10.1029/2020JD033412) modeling these dynamics confirms that the vortex tubes and knots yield more rapid and significantly enhanced turbulence relative to the internal instabilities of individual KHI billows

Modeling the carbon isotope signatures of methane and dissolved inorganic carbon to unravel mineralization pathways in boreal lake sediments

Vertical profiles of the concentration and isotopic composition (δ13C) of methane (CH4) and dissolved inorganic carbon (DIC), as well as of ancillary parameters, were obtained in the top 25 cm sediment column of a seasonally anoxic basin from an oligotrophic boreal lake. Modeling the profiles of CH4 and DIC concentrations and those of their δ13C signatures with reaction-transport equations allowed us to determine the organic matter (OM) degradation rates according to various reactions and to constrain the in situ isotopic fractionation factors and diffusivity coefficients of CH4 and DIC. This exercise reveals inter alia that (i) CH4 production occurs below 5 cm depth, with the highest production rate between 5 and 7.5 cm depth, (ii) all CH4 is produced through hydrogenotrophy, and (iii) methanogenesis yields a production rate of CH4 about three times greater than that of DIC. This latter observation indicates either that fermentation of OM is not the exclusive source of H2 sustaining hydrogenotrophy, or that the commonly assumed model molecule CH2O does not adequately represent the fermenting OM, since its fermentation yields identical rates of CH4 and DIC production. The porewater profiles of Fe and View the MathML source suggest that some H2 may be produced during the reoxidation of reduced sulfur by Fe(III), but the rate of H2 production via this process, if active, would be insignificant in comparison to that required to sustain the estimated rate of hydrogenotrophy. We deduce that the imbalance between CH4 and DIC production rates is rather due to the fermentation of organic substrates that are more reduced than CH2O, i.e., having a negative average carbon oxidation state (COS). From the constraints on reaction rates and on fermentation pathways imposed by the δ13C data, we infer that the organic substrate fermenting between 5 and 7.5 cm depth should have a COS of −1.87. We thus submit that CH4 is produced in the sediments of the seasonally anoxic basin of our boreal lake through hydrogenotrophy coupled to the fermentation of reduced organic substrates that can be represented by a mixture of fatty acids (e.g. C16H32O2; COS of −1.75) and fatty alcohols (e.g., C16H34O; COS of −2.00). This study emphasizes the importance of characterizing the sedimentary OM undergoing mineralization in order to improve diagenetic model predictions of CH4 cycling in boreal lakes and of its significance in climate change

Sedation and delirium in the intensive care unit

Patients in ICUs often require pain relief and sedation to treat both the underlying medical condition and the unpleasantness associated with being in an ICU. This review provides guidance on the identification and treatment of delirium and sedation. Patients in intensive care units (ICUs) are treated with many interventions (most notably endotracheal intubation and invasive mechanical ventilation) that are observed or perceived to be distressing. Pain is the most common memory patients have of their ICU stay.(1) Agitation can precipitate accidental removal of endotracheal tubes or of intravascular catheters used for monitoring or administration of life-sustaining medications. Consequently, sedatives and analgesics are among the most commonly administered drugs in ICUs. Early intensive care practice evolved from intraoperative anesthetic care at a time when mechanical ventilation was delivered by rudimentary machines that were not capable of synchronizing with patients' ..

Flight Operations of Two Rapidly Assembled CubeSats with Commercial Infrared Cameras: The Rogue-Alpha,Beta Program

The Aerospace Corporation’s Rogue-alpha, betaprogram, co-funded by the Space and Missile Systems Center’s Development Corps, is a rapid prototyping effort that built and launched two 3-Unit CubeSats equipped with modified commercial IR camera payloads, laser communications and precision pointing capabilities in 18-months. Launched on 2 November 2019, the two spacecraft were released from the ISS Cygnus NG-12 robotic resupply spacecraft on 31 January 2020 into a circular 460-km, 52° inclined orbit. The two Rogue spacecraft are serving as testbeds for studying wide-field-of-view fast-framing imaging, on-orbit stellar calibration techniques for small IR payloads, and associated spacecraft flight operations. Precision pointing is enabled by three star sensors. High data rate sensor observations are enabled by the ultra-compact 200 Mbps lasercom system, which downlinks gigabytes of stored data during a single laser contact, using The Aerospace Corporation’s prototype ground stations located in El Segundo, California. The Rogue-alpha, beta IR sensor is a 1.4 micron band, 640x512 pixel, 28° field of view, InGaAs SWIR camera. It is accompanied by a panchromatic, 10-megapixel, 37° field of view visible context camera. Modes of sensor operation have included: 1) horizon-pointed imaging in all directions relative to the spacecraft orbit (fore, aft, port, and starboard) which is designed to maximize the imaged field of view, 2) point-and-stare imaging, 3) nadir-pointed, and 4) stereo fore-aft pointing using both spacecraft. All of these modes of operation are usually conducted in multi-frame collections at 1-20hz for dozens to thousands of frames. Highlights from the Rogue-alpha, beta sensor Earth remote sensing observation experiments will be presented. These have included impressive video imagery of hurricanes, typhoons, thunderstorms, and high clouds in the intra-tropical convergence zone. Infrared and visible point sources studied include gas flares, wildfires, active volcanos, nighttime lights, and other phenomena, including the first infrared CubeSat observations of space launch upper stages in flight. Stereo cloud imaging observations were also conducted with an aim of better understanding Earth backgrounds from low Earth orbit. Highlights from the CubeSat flight operations experiments include: 1) spacecraft-to-spacecraft boresight alignment of Rogue’s lasercom systems, and 2) metric and radiometric calibration of Rogue’s flight cameras using bright infrared stars. The results from the Rogue-alpha, beta460-km orbit show the exciting possibilities for wide-field-of-view missions from low earth orbit

Efgartigimod improved health-related quality of life in generalized myasthenia gravis: results from a randomized, double-blind, placebo-controlled, phase 3 study (ADAPT)

There are substantial disease and health-related quality-of-life (HRQoL) burdens for many patients with myasthenia gravis (MG), especially for those whose disease symptoms are not well controlled. HRQoL measures such as the Myasthenia Gravis Quality of Life 15-item revised (MG-QOL15r) and EuroQoL 5-Dimensions 5-Levels (EQ-5D-5L) are vital for evaluating the clinical benefit of therapeutic interventions in patients with MG, as they assess the burden of disease and the effectiveness of treatment, as perceived by patients. The phase 3 ADAPT study (NCT03669588) demonstrated that efgartigimod-a novel neonatal Fc receptor inhibitor-was well tolerated and that acetylcholine receptor antibody-positive (AChR-Ab+) participants who received efgartigimod had statistically significant improvements in MG-specific clinical scale scores. The ancillary data reported here, which cover an additional treatment cycle, show that these participants had similar significant improvements in HRQoL measures, the MG-QOL15r and EQ-5D-5L utility and visual analog scales, and that these improvements were maintained in the second treatment cycle. Positive effects on HRQoL were rapid, seen as early as the first week of treatment in both treatment cycles, and maintained for up to 4 weeks in the follow-up-only portion of treatment cycles. The pattern of improvements in HRQoL paralleled changes in immunoglobulin G level, and correlational analyses show that improvements were consistent across HRQoL measures and with clinical efficacy measures in the ADAPT study. The substantial and durable improvements in HRQoL end points in this study demonstrate the broader benefit of treatment with efgartigimod beyond relief of immediate signs and symptoms of gMG.Neurological Motor Disorder

Reduced GABAergic Neuron Excitability, Altered Synaptic Connectivity, and Seizures in a KCNT1 Gain-of-Function Mouse Model of Childhood Epilepsy.

Gain-of-function (GOF) variants in K+ channels cause severe childhood epilepsies, but there are no mechanisms to explain how increased K+ currents lead to network hyperexcitability. Here, we introduce a human Na+-activated K+ (KNa) channel variant (KCNT1-Y796H) into mice and, using a multiplatform approach, find motor cortex hyperexcitability and early-onset seizures, phenotypes strikingly similar to those of human patients. Although the variant increases KNa currents in cortical excitatory and inhibitory neurons, there is an increase in the KNa current across subthreshold voltages only in inhibitory neurons, particularly in those with non-fast-spiking properties, resulting in inhibitory-neuron-specific impairments in excitability and action potential (AP) generation. We further observe evidence of synaptic rewiring, including increases in homotypic synaptic connectivity, accompanied by network hyperexcitability and hypersynchronicity. These findings support inhibitory-neuron-specific mechanisms in mediating the epileptogenic effects of KCNT1 channel GOF, offering cell-type-specific currents and effects as promising targets for therapeutic intervention

The English National Lynch Syndrome transformation project: an NHS Genomic Medicine Service Alliance (GMSA) programme

Objective: In England, through the Genomic Medicine Service Alliances (GMSAs), a national transformation project aims to embed robust pathways to deliver universal Lynch syndrome (LS) testing for patients with colorectal and endometrial cancers. Prior to commencement of the project, there was evidence of variation and low testing levels in eligible patients which is consistent with other health systems; however, we believe this is amenable to systematic improvement with responsibility for testing delivery by local cancer teams supported by regional infrastructure. Methods and analysis: A project team and national oversight group was formed in May 2021 with membership including 21×cancer alliances, 7×GMSAs, charities and other stakeholders who agreed key performance indicators. ‘LS champions’ within each cancer team were identified and surveyed. Workforce training focused on effective identification of eligible patients, overcoming barriers and mainstreamed constitutional genetic testing. Comprehensive pathway data analysis was performed in conjunction with the National Disease Registration Service. Results: Survey and baseline testing data illustrated variation, and a disparity between practice and perception, in levels of testing. The main reported barriers related to funding streams and systematic approaches. Multifaceted training programmes were produced to support workforce development. Champions responsible for testing delivery were appointed in >95% of cancer teams. We identified >9000 historically diagnosed LS patients to support ascertainment for a nationally coordinated screening programme. Conclusion: This ongoing transformational project is strongly supported by stakeholders in England. Significant quality improvement has been implemented, facilitating systematic delivery of universal testing for LS nationally and reduction in variation in care

Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus

Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte– endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro- thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations