Background: We evaluated vorasidenib (VOR), a dual inhibitor of mIDH1/2, in patients with mIDH1/2 glioma (Phase 3; NCT04164901). Methods: Patients with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (age ≥12; Karnofsky Performance Score ≥80; measurable non-enhancing disease; surgery as only prior treatment; not in immediate need of chemoradiotherapy). Patients were stratified by 1p19q status and baseline tumor size and randomized 1:1 to VOR 40 mg or placebo (PBO) daily in 28-day cycles. Endpoints included imaging-based progression-free survival (PFS), time to next intervention (TTNI), tumor growth rate (TGR), health-related quality of life (HRQoL), neurocognition and seizure activity. Results: 331 patients were randomized (VOR, 168; PBO, 163). The median age was 40.0 years. 172 and 159 patients had histologically confirmed oligodendroglioma and astrocytoma, respectively. Treatment with VOR significantly improved PFS and TTNI. Median PFS: VOR, 27.7 mos; PBO, 11.1 mos (P=0.000000067). Median TTNI: VOR, not reached; PBO, 17.8 mos (P=0.000000019). Treatment with VOR resulted in shrinkage of tumor volume. Post-treatment TGR: VOR, -2.5% (95% CI: -4.7, -0.2); PBO, 13.9% (95% CI: 11.1, 16.8). HRQoL and neurocognition were preserved and seizure control was maintained. VOR had a manageable safety profile. Conclusions: VOR was effective in mIDH1/2 diffuse glioma not in immediate need of chemoradiotherapy.

Introduction: Cricothyrotomy is an intervention performed to salvage “can't intubate, can't ventilate” situations. Studies have shown poor accuracy landmarking the cricothyroid membrane, particularly in female patients by surgeons and anesthesiologists. There is less data available about emergency physician performance. This study examines the perceived versus actual success rate of landmarking the cricothyroid membrane by resident and staff emergency physicians using obese and non-obese models. Methods: Five male and female volunteers were selected as models. Each model was placed supine, and a point-of-care ultrasound expert landmarked the borders of each cricothyroid membrane. 20 residents and 15 staff emergency physicians were given one attempt to landmark five models. Data was gathered on each participant's perceived likelihood of success and attempt difficulty. Overall accuracy and accuracy stratified by sex and obesity status were calculated. Results: Overall landmarking accuracy amongst all participants was 58% (SD 18%). A difference in accuracy was found for obese males (88%) versus obese females (40%) (difference = 48%, 95% CI = 30-65%, p < 0.0001); and non-obese males (77%) versus non-obese females (46%) (difference = 31%, 95% CI = 12-51%, p = 0.004). There was no association between perceived difficulty and success (correlation = 0.07, 95% CI=−0.081-0.214, p = 0.37). Confidence levels overall were higher amongst staff physicians (3.0) than residents (2.7) (difference = 0.3, 95% CI = 0.1-0.6, p = 0.02), but there was no correlation between confidence in an attempt and its success (p = 0.33). Conclusion: We found that physicians demonstrate significantly lower accuracy when landmarking cricothyroid membranes of females. Emergency physicians were unable to predict their own accuracy while landmarking, which can potentially lead to increased failed attempts and longer time to secure the airway. Improved training techniques and a modified approach to cricothyrotomy may reduce failed attempts and improve the time to secure the airway.

Introduction: Several recent observational studies have presented concerning data regarding the safety of cardioversion (CV) for acute atrial fibrillation and flutter (AAFF). We conducted this systematic review to determine whether it is safe to cardiovert AAFF patients without prescribing oral anticoagulation (OAC) post-CV for those who are CHADS-65 negative. Methods: We conducted a librarian assisted search of MEDLINE, Embase, and Cochrane from inception through November 23, 2019. We included observational studies and randomized trials reporting thromboembolic (TE) events (i.e. stroke, transient ischemic attack, or systemic thromboembolism) within 30 days following CV in patients with AAFF, where onset of symptoms was <48 hours. Two reviewers independently screened studies and extracted data. The main outcome was risk of TE events within 30 days post-CV, stratified by OAC use. Risk of bias was assessed with the Quality in Prognostic Studies (QUIPS) tool. The primary analysis was based on prospective studies and the secondary analysis was based on retrospective studies. We performed meta-analyses for TE events where 2 or more studies were available, by applying the DerSimonian-Laird random-effects model. We implemented analyses stratified by study design using Open MetaAnalyst and generated the forest plots. Results: Our search yielded 969 titles; 74 were selected for full-text review and 20 studies were included in the review. The primary meta-analysis of 6 prospective studies, including two randomized trials, found a TE event rate of 0.15% (2 TE events/1,314 CVs). Within this prospective group, lack of OAC use was associated with a decreased risk of TE events (RR = 2.15 where RR >1 indicates increased risk of TE events with OAC compared to no OAC; 95% CI 0.50 to 9.31; I2 = 0%). Five of the 6 prospective studies had a low or moderate risk of bias in all QUIPS domains. Secondary meta-analysis of 6 retrospective studies revealed a TE event rate of 0.53% (56 TE events/10,521 CVs). This subgroup showed a trend favouring OAC use with decreased risk of TE events (RR = 0.34 where RR <1 suggests decreased risk of TE events with OAC; 95% CI 0.17 to 0.72; I2 = 0%). Conclusion: In the primary analysis of prospective studies, we found a low TE event rate following CV of AAFF, irrespective of OAC use. This contradicts previous analyses of retrospective studies. Our study supports the longstanding practice of not necessarily prescribing OAC post-CV in the ED for AAFF patients who are CHADS-65 negative.

The deviation from thermodynamic equilibrium of the ion velocity distribution functions (VDFs), as measured by the Magnetospheric Multiscale (MMS) mission in the Earth’s turbulent magnetosheath, is quantitatively investigated. Making use of the unprecedented high-resolution MMS ion data, and together with Vlasov–Maxwell simulations, this analysis aims at investigating the relationship between deviation from Maxwellian equilibrium and typical plasma parameters. Correlations of the non-Maxwellian features with plasma quantities such as electric fields, ion temperature, current density and ion vorticity are found to be similar in magnetosheath data and numerical experiments, with a poor correlation between distortions of ion VDFs and current density, evidence that questions the occurrence of VDF departure from Maxwellian at the current density peaks. Moreover, strong correlation has been observed with the magnitude of the electric field in the turbulent magnetosheath, while a certain degree of correlation has been found in the numerical simulations and during a magnetopause crossing by MMS. This work could help shed light on the influence of electrostatic waves on the distortion of the ion VDFs in space turbulent plasmas.

Introduction: Elevated intracranial pressure (ICP) is a devastating complication of brain injury, such as traumatic brain injury, subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, and other conditions. Delay to diagnosis and treatment are associated with increased morbidity and mortality. For Emergency Department (ED) physicians, invasive ICP measurement is typically not available. We sought to summarize and compare the accuracy of physical examination, imaging, and ultrasonography of the optic nerve sheath diameter (ONSD) for diagnosis of elevated ICP. Methods: We searched Medline, EMBASE and 4 other databases from inception through August 2018. We included only English studies (randomized controlled trials, cohort and case-control studies). Gold standard was ICP≥20 mmHg on invasive ICP monitoring. Two reviewers independently screened studies and extracted data. We assessed risk of bias using Quality Assessment of Diagnostic Accuracy Studies 2 criteria. Hierarchical Summary Receiver Operating Characteristic model generated summary diagnostic accuracy estimates. Results: We included 37 studies (n = 4,768, kappa = 0.96). Of exam signs, pooled sensitivity and specificity for increased ICP were: mydriasis (28.2% [95% CI: 16.0-44.8], 85.9.0% [95% CI: 74.9-92.5]), motor posturing (54.3% [95% CI: 36.6-71.0], 63.6% [95% CI: 46.5-77.8]) and Glasgow Coma Scale (GCS) ≤8 (75.8% [95% CI: 62.4-85.5], 39.9% [95% CI: 26.9-54.5]). Computed tomography findings: compression of basal cisterns had 85.9% [95% CI: 58.0-96.4] sensitivity and 61.0% [95% CI: 29.1-85.6] specificity; any midline shift had 80.9% [95% CI: 64.3-90.9] sensitivity and 42.7% [95% CI: 24.0-63.7] specificity; midline shift≥1cm had 20.7% [95% CI: 13.0-31.3] sensitivity and 89.2% {95% CI: 77.5-95.2] specificity. Finally, pooled area under the ROC curve describing accuracy for ONSD sonography for ICP was 0.94 (95% CI: 0.91-0.96). Conclusion: The absence of any one physical exam feature (e.g. mydriasis, posturing, or decreased GCS) is not sufficient to rule-out elevated ICP. Significant midline shift is highly suggestive of elevated ICP, but absence of shift does not rule it out. ONSD sonography may be useful in diagnosing elevated ICP. High suspicion of elevated ICP may necessitate treatment and transfer to a centre capable of invasive ICP monitoring.

Introduction: Necrotizing soft tissue infection (NSTI), a potentially life-threatening diagnosis, is often not immediately recognized by clinicians. Delays in diagnosis are associated with increased morbidity and mortality. We sought to summarize and compare the accuracy of physical exam, imaging, and Laboratory Risk Indicator of Necrotizing Fasciitis (LRINEC) Score used to confirm suspected NSTI in adult patients with skin and soft tissue infections. Methods: We searched Medline, Embase and 4 other databases from inception through November 2017. We included only English studies (randomized controlled trials, cohort and case-control studies) that reported the diagnostic accuracy of testing or LRINEC Score. Outcome was NSTI confirmed by surgery or histopathology. Two reviewers independently screened studies and extracted data. We assessed risk of bias using the Quality Assessment of Diagnostic Accuracy Studies 2 criteria. Diagnostic accuracy summary estimates were obtained from the Hierarchical Summary Receiver Operating Characteristic model. Results: We included 21 studies (n=6,044) in the meta-analysis. Of physical exam signs, pooled sensitivity and specificity for fever (49.4% [95% CI: 41.4-57.5], 78.0% [95% CI: 52.2-92.0]), hemorrhagic bullae (30.8% [95% CI: 16.2-50.6], 94.2% [95% CI: 82.9-98.2]) and hypotension (20.8% [95% CI: 7.7-45.2], 97.9% [95% CI: 89.1-99.6]) were generated. Computed tomography (CT) had 88.5% [95% CI: 55.5-97.9] sensitivity and 93.3% [95% CI: 80.8-97.9] specificity, while plain radiography had 48.9% [95% CI: 24.9-73.4] sensitivity and 94.0% [95% CI: 63.8-99.3] specificity. Finally, LRINEC 6 (traditional threshold) had 67.5% [95% CI: 48.3-82.3] sensitivity and 86.7% [95% CI: 77.6-92.5] specificity, while a LRINEC 8 had 94.9% [95% CI: 89.4-97.6] specificity but 40.8% [95% CI: 28.6-54.2] sensitivity. Conclusion: The absence of any one physical exam feature (e.g. fever or hypotension) is not sufficient to rule-out NSTI. CT is superior to plain radiography. The LRINEC Score had poor sensitivity, suggesting that a low score is not sufficient to rule-out NSTI. For patients with suspected NSTI, further evaluation is warranted. While no single test is sensitive, patients with high-risk features should receive early surgical consultation for definitive diagnosis and management.

Additions of montmorillonite clay and soil of high organic matter content to growth media consisting of sand and nutrient solution significantly decreased the phytotoxicity of 2-methylthio-4,6-bis(isopropylamino)-s-triazine (prometryne) to wheat [Triticum aestivum L. em. Thell. (aestivum group) “Wakeland”]. Phytotoxicity was decreased to a greater extent at pH 4.5 than at pH 6.5. The reduction in phytotoxicity was attributed to adsorption of the herbicide by the additives. A larger proportion of the prometryne was present in the protonated form at the lower pH and the increased adsorption probably resulted from the coulombic bonding of these cations to the soil additives. Adsorption mechanisms are postulated and discussed.

Accurate models of X-ray absorption and re-emission in partly stripped ions are necessary to calculate the structure of stars, the performance of hohlraums for inertial confinement fusion and many other systems in high-energy-density plasma physics. Despite theoretical progress, a persistent discrepancy exists with recent experiments at the Sandia Z facility studying iron in conditions characteristic of the solar radiative–convective transition region. The increased iron opacity measured at Z could help resolve a longstanding issue with the standard solar model, but requires a radical departure for opacity theory. To replicate the Z measurements, an opacity experiment has been designed for the National Facility (NIF). The design uses established techniques scaled to NIF. A laser-heated hohlraum will produce X-ray-heated uniform iron plasmas in local thermodynamic equilibrium (LTE) at temperatures ${\geqslant}150$  eV and electron densities ${\geqslant}7\times 10^{21}~\text{cm}^{-3}$ . The iron will be probed using continuum X-rays emitted in a ${\sim}200$  ps, ${\sim}200~\unicode[STIX]{x03BC}\text{m}$ diameter source from a 2 mm diameter polystyrene (CH) capsule implosion. In this design, $2/3$ of the NIF beams deliver 500 kJ to the ${\sim}6$  mm diameter hohlraum, and the remaining $1/3$ directly drive the CH capsule with 200 kJ. Calculations indicate this capsule backlighter should outshine the iron sample, delivering a point-projection transmission opacity measurement to a time-integrated X-ray spectrometer viewing down the hohlraum axis. Preliminary experiments to develop the backlighter and hohlraum are underway, informing simulated measurements to guide the final design.

Experiments on the National Ignition Facility show that multi-dimensional effects currently dominate the implosion performance. Low mode implosion symmetry and hydrodynamic instabilities seeded by capsule mounting features appear to be two key limiting factors for implosion performance. One reason these factors have a large impact on the performance of inertial confinement fusion implosions is the high convergence required to achieve high fusion gains. To tackle these problems, a predictable implosion platform is needed meaning experiments must trade-off high gain for performance. LANL has adopted three main approaches to develop a one-dimensional (1D) implosion platform where 1D means measured yield over the 1D clean calculation. A high adiabat, low convergence platform is being developed using beryllium capsules enabling larger case-to-capsule ratios to improve symmetry. The second approach is liquid fuel layers using wetted foam targets. With liquid fuel layers, the implosion convergence can be controlled via the initial vapor pressure set by the target fielding temperature. The last method is double shell targets. For double shells, the smaller inner shell houses the DT fuel and the convergence of this cavity is relatively small compared to hot spot ignition. However, double shell targets have a different set of trade-off versus advantages. Details for each of these approaches are described.

Improving neurocognitive outcomes following treatment for brain metastases have become increasingly important. We propose that a brief telephone-based neurocognitive assessment may improve follow-up cognitive assessments in this palliative population. Aim: To prospectively assess the feasibility and reliability of a telephone based brief neurocognitive assessment compared to the same tests delivered face-to-face. Methods: Brain metastases patients to be treated with whole brain radiotherapy (WBRT) were assessed using a brief validated neurocognitive battery at baseline, at 1 month and 3 months following WBRT (in person and over the phone). The primary outcome was feasibility and inter-procedural (in person versus telephone) reliability. The secondary objective was to evaluate the change in neurocognitive function before and after WBRT. Results: Out of 39 patients enrolled, 82% of patients completed the baseline in-person and telephone neurocognitive assessments. However, at 1 month, only 41% of enrolled patients completed the in-person and telephone cognitive assessments and at 3 months, only 10% of patients completed them. Results pertaining to reliability and change in neurocognitive function will be updated. Conclusion: The pre-defined definition of feasibility (at least 80% completion for face to face and telephone neurocognitive assessments) was met at baseline. However, a large proportion of participants did not complete either telephone or in person neurocognitive follow-up at 1 month and at 3 months post-WBRT. Attrition remained a challenge for neurocognitive testing in this population even when a telephone-based brief assessment was used.

The introduction of the original time delay method of Beddoes, an engineering model for the unsteady response of an aerofoil section including dynamic stall, had a profound effect on the design and development of rotor systems in the UK. Over the years, the model expanded to include more and more features of the unsteady flow, with many contributors. It is now in use throughout the world as part of rotor analysis packages. Nevertheless, it retains its essential simplicity. Work to confirm the ability of the most recent version of the dynamic stall model from the University of Glasgow to replicate the complicated behaviour of an advanced rotor aerofoil section at full scale Reynolds and Mach numbers provides an opportunity to review the use of this new engineering model in the helicopter rotor design environment.

This note discusses the application of dynamic stall synthesis methods to the problem of classifying and comparing aerofoil sections when designing rotors for the retreating blade stall condition that determines the rotor blade area requirement of the helicopter. The development of the dynamic stall models employed in UK rotor designs is reviewed in this paper and their use in the design process explained, with emphasis on the assumptions that overcome the limitations of the models and exploit their simplicity, enabling accurate and conservative rotor designs. The paper shows how the model may be used to structure the analysis of complex sets of dynamic aerofoil data. It illustrates how structured comparison between the model and the data yields a concise appreciation of the behaviour of the aerofoil and an understanding of the physical processes involved. Some previously unappreciated effects are identified and the model is used to transfer experience of the aerofoil section behaviour from the non-rotating wind-tunnel environment to that of the rotor. Finally, the application of the new engineering model developed at Glasgow University in the rotor design process is outlined. Some remarks on the use of engineering models in comparison with CFD models in the design context are included.

Adenoid cystic carcinoma, or cylindroma, usually presents in the salivary glands or in the upper respiratory passages. We report an unusual case of adenoid cystic carcinoma in a 45-year-old woman who presented with a three-year history of progressive right trigeminal sensory palsy, most pronounced in the second division. There was, in addition, a right trigeminal motor palsy and a partial right 6th nerve palsy. CT scanning showed only a small soft tissue mass spanning an enlarged right foramen ovale. Solid adenoid cystic carcinoma was resected from Meckel’s cave via a middle cranial fossa approach. A subsequent biopsy of the right maxillary antral mucosa found tumor tissue. We concluded that the tumor originated in the maxillary antrum and spread posteriorly along the infraorbital nerve to enlarge in the foramen ovale. Radiation to a total of 5,000 cGy was given. At 22 months there was neither radiographic nor clinical evidence of recurrence. At 30 months, the development of unsteady gait signalled the presence of recurrent tumor extending backwards from Meckel’s cave into the right cerebello-pontine angle.

Plasmas are ubiquitous in nature, surround our local geospace environment, and permeate the universe. Plasma phenomena in space give rise to energetic particles, the aurora, solar flares and coronal mass ejections, as well as many energetic phenomena in interstellar space. Although plasmas can be studied in laboratory settings, it is often difficult, if not impossible, to replicate the conditions (density, temperature, magnetic and electric fields, etc.) of space. Single-point space missions too numerous to list have described many properties of near-Earth and heliospheric plasmas as measured both in situ and remotely (see http://www.nasa.gov/missions/#.U1mcVmeweRY for a list of NASA-related missions). However, a full description of our plasma environment requires three-dimensional spatial measurements. Cluster is the first, and until data begin flowing from the Magnetospheric Multiscale Mission (MMS), the only mission designed to describe the three-dimensional spatial structure of plasma phenomena in geospace. In this paper, we concentrate on some of the many plasma phenomena that have been studied using data from Cluster. To date, there have been more than 2000 refereed papers published using Cluster data but in this paper we will, of necessity, refer to only a small fraction of the published work. We have focused on a few basic plasma phenomena, but, for example, have not dealt with most of the vast body of work describing dynamical phenomena in Earth's magnetosphere, including the dynamics of current sheets in Earth's magnetotail and the morphology of the dayside high latitude cusp. Several review articles and special publications are available that describe aspects of that research in detail and interested readers are referred to them (see for example, Escoubet et al. 2005Multiscale Coupling of Sun-Earth Processes, p. 459, Keith et al. 2005Sur. Geophys.26, 307–339, Paschmann et al. 2005Outer Magnetospheric Boundaries: Cluster Results, Space Sciences Series of ISSI. Berlin: Springer, Goldstein et al. 2006Adv. Space Res.38, 21–36, Taylor et al. 2010The Cluster Mission: Space Plasma in Three Dimensions, Springer, pp. 309–330 and Escoubet et al. 2013Ann. Geophys.31, 1045–1059).