Delayed Rewarming Thrombocytopenia: A Suggested Preventable and Treatable Cause of Rewarming Deaths.

The lack of a consensus of accepted prognostic factors in hypothermia suggests an additional factor has been overlooked. Delayed rewarming thrombocytopenia (DRT) is a novel candidate for such a role. At body temperature, platelets undergoing a first stage of aggregation are capable of progression to a second irreversible stage of aggregation. However, we have shown that the second stage of aggregation does not occur below 32°C and that this causes the first stage to become augmented (first-stage platelet hyperaggregation). In aggregometer studies performed below 32°C, the use of quantities of ADP that cause a marked first-stage hyperaggregation can cause an augmented second-stage activation of the platelets during rewarming (second-stage platelet hyperaggregation). In vivo, after 24 hours of hypothermia, platelets on rewarming seem to undergo second-stage hyperaggregation, from ADP released from erythrocytes, leading to life-threatening thrombocytopenia. This hyperaggregation is avoidable if heparin is given before the hypothermia or if aspirin, alcohol or platelet transfusion is given during the hypothermia before reaching 32°C on rewarming. Many of the open questions existing in this field are explained by DRT. Prevention and treatment of DRT could be of significant value in preventing rewarming deaths and some cases of rescue collapse. Performing platelet counts during rewarming will demonstrate potentially fatal thrombocytopenia and enable treatment with platelet infusions aspirin or alcohol.

Particle Acceleration by Magnetic Reconnection in Geospace.

Particles are accelerated to very high, non-thermal energies during explosive energy-release phenomena in space, solar, and astrophysical plasma environments. While it has been established that magnetic reconnection plays an important role in the dynamics of Earth's magnetosphere, it remains unclear how magnetic reconnection can further explain particle acceleration to non-thermal energies. Here we review recent progress in our understanding of particle acceleration by magnetic reconnection in Earth's magnetosphere. With improved resolutions, recent spacecraft missions have enabled detailed studies of particle acceleration at various structures such as the diffusion region, separatrix, jets, magnetic islands (flux ropes), and dipolarization front. With the guiding-center approximation of particle motion, many studies have discussed the relative importance of the parallel electric field as well as the Fermi and betatron effects. However, in order to fully understand the particle acceleration mechanism and further compare with particle acceleration in solar and astrophysical plasma environments, there is a need for further investigation of, for example, energy partition and the precise role of turbulence.

Plasma Environment, Radiation, Structure, and Evolution of the Uranian System (PERSEUS): A Dedicated Orbiter Mission Concept to Study Space Physics at Uranus.

The Plasma Environment, Radiation, Structure, and Evolution of the Uranian System (PERSEUS) mission concept defines the feasibility and potential scope of a dedicated, standalone Heliophysics orbiter mission to study multiple space physics science objectives at Uranus. Uranus's complex and dynamic magnetosphere presents a unique laboratory to study magnetospheric physics as well as its coupling to the solar wind and the planet's atmosphere, satellites, and rings. From the planet's tilted and offset, rapidly-rotating non-dipolar magnetic field to its seasonally-extreme interactions with the solar wind to its unexpectedly intense electron radiation belts, Uranus hosts a range of outstanding and compelling mysteries relevant to the space physics community. While the exploration of planets other than Earth has largely fallen within the purview of NASA's Planetary Science Division, many targets, like Uranus, also hold immense scientific value and interest to NASA's Heliophysics Division. Exploring and understanding Uranus's magnetosphere is critical to make fundamental gains in magnetospheric physics and the understanding of potential exoplanetary systems and to test the validity of our knowledge of magnetospheric dynamics, moon-magnetosphere interactions, magnetosphere-ionosphere coupling, and solar wind-planetary coupling. The PERSEUS mission concept study, currently at Concept Maturity Level (CML) 4, comprises a feasible payload that provides closure to a range of space physics science objectives in a reliable and mature spacecraft and mission design architecture. The mission is able to close using only a single Mod-1 Next-Generation Radioisotope Thermoelectric Generator (NG-RTG) by leveraging a concept of operations that relies of a significant hibernation mode for a large portion of its 22-day orbit.

A Comprehensive Review of Neuropsychologic Studies Supports the Concept That Adequate Folinic Acid Rescue Prevents Post Methotrexate Neurotoxicity.

PURPOSE: To review all studies providing evidence of the correlation between folinic acid (FA) rescue inadequacy and long-term cognitive damage in neuropsychological studies of children with acute lymphoblastic leukemia or osteogenic sarcoma treated under protocols using high-dose methotrexate and FA rescue. METHODS: A comprehensive literature search was performed of all databases of the Web of Science Citation Index, during 1990-2020, for the terms: neuropsychological, neurocognitive, and cognitive, together with acute lymphoblastic (and lymphocytic) leukemia and osteogenic sarcoma. English-language peer-reviewed articles on neuropsychological assessments of children who had been treated with high-dose methotrexate without irradiation, and which included details of methotrexate and FA schedules, were selected. In addition, a personal database of over 500 reprints of articles from over 130 journals was reviewed on the subjects of methotrexate and FA and their side effects. RESULTS: Three groups of studies were found and analyzed, with (1) no evidence of cognitive deterioration, (2) evidence of cognitive deterioration, and (3) more than 1 protocol grouped together, preventing separate analysis of any protocols, Protocols without cognitive deterioration reported adequate FA rescue, and those with cognitive deterioration reported inadequate FA rescue. CONCLUSION: Neuropsychological evaluation supported inadequate FA being the cause of neurocognitive damage after high-dose methotrexate and that adequate FA rescue prevents this complication.

Three-dimensional network of filamentary currents and super-thermal electrons during magnetotail magnetic reconnection.

Magnetic reconnection is a fundamental plasma process by which magnetic field lines on two sides of the current sheet flow inward to yield an X-line topology. It is responsible for producing energetic electrons in explosive phenomena in space, astrophysical, and laboratorial plasmas. The X-line region is supposed to be the important place for generating energetic electrons. However, how these energetic electrons are generated in such a limited region is still poorly understood. Here, using Magnetospheric multiscale mission data acquired in Earth's magnetotail, we present direct evidence of super-thermal electrons up to 300 keV inside an X-line region, and the electrons display a power-law spectrum with an index of about 8.0. Concurrently, three-dimensional network of dynamic filamentary currents in electron scale is observed and leads to electromagnetic turbulence therein. The observations indicate that the electrons are effectively accelerated while the X-line region evolves into turbulence with a complex filamentary current network.

New Approaches Promise to Improve Local Ewing Sarcoma Results.

The study by Whelan and colleagues showed that addition of busulfan and melphalan conditioning and autologous stem cell rescue to conventional EURO-E.W.I.N.G STUDY chemotherapy in local nonmetastatic Ewing sarcoma improves prognosis. However, almost 30% of these study patients will have relapsed before this stage of therapy is reached, and 78% of his patients were at high risk because of inadequate response to the initial chemotherapy given. Further improvement could be achieved by the integration of other novel advances with this approach. Ash and colleagues have shown that the separation of such cases into high- and low-risk groups by using CD56 negativity of the tumor cells is an improvement over current methods with a 100% 10-year progression-free survival in CD56- nonpelvic local isolated Ewing sarcoma patients. Their patients were treated on the SCMCIE 94 protocol, associated with no relapses before 30 months in 24 consecutive patients independent of the CD status. Integration of these novel approaches in diagnosis and treatment would allow truly high-risk patients, who would benefit from the procedure, to reach the busulfan and melphalan stage of therapy and delineate those patients who can be cured without such therapy. Details of the SCMCIE 94 protocol are given and the possible reasons for the different relapse patterns are discussed.

Properties and Acceleration Mechanisms of Electrons Up To 200 keV Associated With a Flux Rope Pair and Reconnection X-Lines Around It in Earth's Plasma Sheet.

The properties and acceleration mechanisms of electrons (<200 keV) associated with a pair of tailward traveling flux ropes and accompanied reconnection X-lines in Earth's plasma sheet are investigated with MMS measurements. Energetic electrons are enhanced on both boundaries and core of the flux ropes. The power-law spectra of energetic electrons near the X-lines and in flux ropes are harder than those on flux rope boundaries. Theoretical calculations show that the highest energy of adiabatic electrons is a few keV around the X-lines, tens of keV immediately downstream of the X-lines, hundreds of keV on the flux rope boundaries, and a few MeV in the flux rope cores. The X-lines cause strong energy dissipation, which may generate the energetic electron beams around them. The enhanced electron parallel temperature can be caused by the curvature-driven Fermi acceleration and the parallel electric potential. Betatron acceleration due to the magnetic field compression is strong on flux rope boundaries, which enhances energetic electrons in the perpendicular direction. Electrons can be trapped between the flux rope pair due to mirror force and parallel electric potential. Electrostatic structures in the flux rope cores correspond to potential drops up to half of the electron temperature. The energetic electrons and the electron distribution functions in the flux rope cores are suggested to be transported from other dawn-dusk directions, which is a 3-dimensional effect. The acceleration and deceleration of the Betatron and Fermi processes appear alternately indicating that the magnetic field and plasma are turbulent around the flux ropes.

Unrecognized platelet physiology is the cause of rewarming deaths in accidental hypothermia and neonatal cold injury.

BACKGROUND: The lack of improvement in prognosis of accidental hypothermia and neonatal cold injury suggests that a major cause of mortality has not been appreciated. AIM OF THE ARTICLE: To show that thrombocytopenia that deepens on rewarming under certain conditions is that missing factor. SCIENTIFIC BASIS: Below 34 °C the first stage of aggregation is accentuated, the platelets are more sensitive to ADP and aggregation studies show an increased response "first stage hyper aggregation". We have confirmed that the irreversible second stage of platelet aggregation does not occur below 34 °C. On rewarming, the first stage of aggregation is followed by disaggregation. When platelets are warmed to 34 °C the potential exists for the platelets to undergo an irreversible second stage of aggregation "second stage platelet hyper aggregation" that can cause a further drop in platelet count and a bleeding diathesis. This only occurs if the platelets have been sufficiently primed when cold and may not be appreciated if platelet counts are not followed. SIGNIFICANCE OF THIS DATA AND CORRELATION WITH THE LITERATURE: This thesis explains many other open questions. Why has the overall prognosis remained without improvement over the last half century? Why hypothermic cardiac surgery is free of this problem? Why the depth of hypothermia is alone not prognostic? Has following platelet counts been associated with improved prognosis? Why cardiac arrest does not affect prognosis? Why some patients die suddenly after recovering from hypothermia? Why are so many different rewarming techniques used? Why is the prognosis better in hypothermic suicide attempts? What is the pathophysiological explanation for reversible sequestration of platelets to the liver and spleen in hypothermia? Is DIC (diffuse intravascular coagulation) a problem in hypothermia? And how this new approach could improve prognosis? CONCLUSION: Prognosis can be improved by following platelet counts during rewarming. In patients with prolonged hypothermia, this will show a life-threatening drop in such counts easily treated by platelet infusion.

Folinic acid over rescue of high dose methotrexate: How problematic citations conserve discredited concepts.

BACKGROUND: The outdated axiom that the dose of Folinic acid (FA) rescue used after high dose Methotrexate (HDMTX) should be kept to a minimum in order to prevent a reduction of prognosis ("over rescue") continues to be expressed even though the concept has been seriously challenged. Study aim The ways "problematic citations" are used to support an old theory, such as this, was examined. RESULTS: Ten patterns of "problematic citation" use were identified. In 8 of these patterns the articles used were scientifically sound and the problem was with the articles citing them. However in 2 other pattens, the articles and their conclusions were flawed and citing them, apparently, resulted from accepting the presented data or conclusions as sound and valid. The patterns were 1. Claims based on data that are not present in the cited article. 2. Selective inclusion of data from cited articles. 3. Citation of misleading data presented only in the abstract. 4. Reporting trends as statistically significant. 5. Copying the citations used by others without checking the article. 6. Acceptance of illusionary truth in spite of knowledge to the contrary. 7. Citation of reports not relevant to the population under discussion 8. Presenting opinions as facts without any citation. 9. Selective presentation of data sets that support the thesis while ignoring the data sets that show the opposite results. 10. Use of a title expressing what the authors intended to show but not what was found. IMPLICATIONS: The containing acceptance of this old insupportable conjecture, in part, because of "problematic citations" has resulted in unnecessary neurocognitive damage to patients and may have resulted in the misconception that it is the outcome of HDMTX that may have lead to its abandonment in favour of more toxic therapies. Realisation that this is a significant problem in data analysis should lead authors and reviewers to be even more carefully in checking all references. The importance of high-quality reviews is clearly evident. The effect of "Canonization of false facts" is a serious impairment to the acceptance of new hypotheses that better express reality and could lead to improved treatment results. Authors are advised only to cite articles they have read in entirety not relying on the title, abstract or previous use and to check the content of citations before submission.

Ice giant system exploration in the 2020s: an introduction.

The international planetary science community met in London in January 2020, united in the goal of realizing the first dedicated robotic mission to the distant ice giants, Uranus and Neptune, as the only major class of solar system planet yet to be comprehensively explored. Ice-giant-sized worlds appear to be a common outcome of the planet formation process, and pose unique and extreme tests to our understanding of exotic water-rich planetary interiors, dynamic and frigid atmospheres, complex magnetospheric configurations, geologically-rich icy satellites (both natural and captured), and delicate planetary rings. This article introduces a special issue on ice giant system exploration at the start of the 2020s. We review the scientific potential and existing mission design concepts for an ambitious international partnership for exploring Uranus and/or Neptune in the coming decades. This article is part of a discussion meeting issue 'Future exploration of ice giant systems'.

Cross-NASA divisional relevance of an Ice Giant mission.

Robotic space exploration to the outer solar system is difficult and expensive and the space science community works inventively and collaboratively to maximize the scientific return of missions. A mission to either of our solar system Ice Giants, Uranus and Neptune, will provide numerous opportunities to address high-level science objectives relevant to multiple disciplines and deliberate cross-disciplinary mission planning should ideally be woven in from the start. In this review, we recount past successes as well as (NASA-focused) challenges in performing cross-disciplinary science from robotic space exploration missions and detail the opportunities for broad-reaching science objectives from potential future missions to the Ice Giants. This article is part of a discussion meeting issue 'Future exploration of ice giant systems'.

Ice giant magnetospheres.

The ice giant planets provide some of the most interesting natural laboratories for studying the influence of large obliquities, rapid rotation, highly asymmetric magnetic fields and wide-ranging Alfvénic and sonic Mach numbers on magnetospheric processes. The geometries of the solar wind-magnetosphere interaction at the ice giants vary dramatically on diurnal timescales due to the large tilt of the magnetic axis relative to each planet's rotational axis and the apparent off-centred nature of the magnetic field. There is also a seasonal effect on this interaction geometry due to the large obliquity of each planet (especially Uranus). With in situ observations at Uranus and Neptune limited to a single encounter by the Voyager 2 spacecraft, a growing number of analytical and numerical models have been put forward to characterize these unique magnetospheres and test hypotheses related to the magnetic structures and the distribution of plasma observed. Yet many questions regarding magnetospheric structure and dynamics, magnetospheric coupling to the ionosphere and atmosphere, and potential interactions with orbiting satellites remain unanswered. Continuing to study and explore ice giant magnetospheres is important for comparative planetology as they represent critical benchmarks on a broad spectrum of planetary magnetospheric interactions, and provide insight beyond the scope of our own Solar System with implications for exoplanet magnetospheres and magnetic reversals. This article is part of a discussion meeting issue 'Future exploration of ice giant systems'.

Gaucher disease type 3c: New patients with unique presentations and review of the literature.

Gaucher disease (GD) is the most prevalent lysosomal disorder caused by GBA mutations and abnormal glucocerebrosidase function, leading to glucocerebrosideaccumulation mainly in the liver, spleen, bone marrow, lungs, and occasionally in the central nervous system. Gaucher disease type 3c (GD3c) is a rare subtype of the subacute/chronic neuronopathic GD3, caused by homozygosity for the GBA p.Asp448His (D409H) mutation. GD3c is characterized mainly by cardiovascular and neuro-ophthalmological findings. In this paper, we describe four new GD3c patients exhibiting rare cardiovascular, pulmonary and psychiatric findings, as well as atypical disease courses. Review of the GD3c-related literature revealed clinical descriptions of 36 patients, presenting predominantly with cardiovascular calcifications; 15%, including Patient 1b in this study, had non-calcified lesions - fibrosis and atherosclerosis. Only 7.5% of patients have been described without heart disease, including Patient 3; however, Patient 2 had a fulminant coronary disease. Neurological findings in GD3c consist mainly of oculomotor apraxia (80%), which is absent in Patient 3, while other neurological findings are common (65%) but diverse. Patient 1b developed a psychiatric behavioral disorder, which has not been previously described in GD3c. Patient 1b also had interstitial lung disease, which was only described in one GD3c patient as pulmonary fibrosis. In view of these unique features, we recommend a revised surveillance protocol; however, further studies are required to establish the management of these patients and the role of GBA in the described pathologies.