Neurological manifestations of COVID-19 in adults and children

Different neurological manifestations of coronavirus disease 2019 (COVID-19) in adults and children and their impact have not been well characterized. We aimed to determine the prevalence of neurological manifestations and in-hospital complications among hospitalized COVID-19 patients and ascertain differences between adults and children. We conducted a prospective multicentre observational study using the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) cohort across 1507 sites worldwide from 30 January 2020 to 25 May 2021. Analyses of neurological manifestations and neurological complications considered unadjusted prevalence estimates for predefined patient subgroups, and adjusted estimates as a function of patient age and time of hospitalization using generalized linear models. Overall, 161 239 patients (158 267 adults; 2972 children) hospitalized with COVID-19 and assessed for neurological manifestations and complications were included. In adults and children, the most frequent neurological manifestations at admission were fatigue (adults: 37.4%; children: 20.4%), altered consciousness (20.9%; 6.8%), myalgia (16.9%; 7.6%), dysgeusia (7.4%; 1.9%), anosmia (6.0%; 2.2%) and seizure (1.1%; 5.2%). In adults, the most frequent in-hospital neurological complications were stroke (1.5%), seizure (1%) and CNS infection (0.2%). Each occurred more frequently in intensive care unit (ICU) than in non-ICU patients. In children, seizure was the only neurological complication to occur more frequently in ICU versus non-ICU (7.1% versus 2.3%, P < 0.001). Stroke prevalence increased with increasing age, while CNS infection and seizure steadily decreased with age. There was a dramatic decrease in stroke over time during the pandemic. Hypertension, chronic neurological disease and the use of extracorporeal membrane oxygenation were associated with increased risk of stroke. Altered consciousness was associated with CNS infection, seizure and stroke. All in-hospital neurological complications were associated with increased odds of death. The likelihood of death rose with increasing age, especially after 25 years of age. In conclusion, adults and children have different neurological manifestations and in-hospital complications associated with COVID-19. Stroke risk increased with increasing age, while CNS infection and seizure risk decreased with age

Design, Prototyping and Testing of a Rotating Electrical Machine with Linear Geometry for Shipboard Applications

Conventional rotating electrical machines are characterized by stator and rotor structures featuring a cylindrical geometry around the shaft rotational axis. Although advantageous for mechanical reasons, the cylindrical geometry results in overall machine shapes and dimensions that may be unsuitable for installation. This particularly occurs in shipboard applications, where electric motors and generators are subject to stringent room constraints and need to be fit in unusually shaped compartments. This paper presents the development and test of a dual-shaft rotating permanent-magnet electric machine prototype having a linear structure that facilitates its onboard use for such applications as electric propulsion and rudder actuation. In fact, the proposed machine topology has overall dimensions which can be adjusted to fit the space available for installation. The operating concept and the detailed electromechanical design of the machine are first described. Then the manufacturing and factory test of the prototype under inverter supply are illustrated. Finally, the validation of the prototype as a boat propulsion variable-speed inverter-fed motor is presented. It is proved that, despite of its highly non-conventional electromechanical design, the machine can be effectively fed from a general-purpose inverter for permanent magnet motors

Contraction stress, elastic modulus, and degree of conversion of three flowable composites.

The aim of this study was to measure the contraction stress of three flowable resin composites and to correlate the stress with the elastic modulus and the degree of conversion. One low-shrinkage (Venus Diamond Flow) and two conventional (Tetric EvoFlow and X-Flow) flowable composites were polymerized for 40s with a light-emitting diode (LED) curing unit. Contraction force was continuously recorded for 300s using a stress-analyser, and stress values were calculated at 40s and at 300s. The maximum stress rate was also calculated for each specimen. The elastic modulus of each composite was assayed using a biaxial flexural test, and degree of conversion was analysed with Raman spectroscopy. X-Flow exhibited higher stress values than the other tested materials. Venus Diamond Flow showed the lowest stress values at 40s and at 300s, and the lowest maximum stress rate. Stress values were correlated with elastic modulus but not with degree of conversion, which was comparable among all tested materials

The stretch-activated channel blocker Gd3+ reduces palytoxin toxicity in primary cultures of skeletal muscle cells

Palytoxin (PLTX) is one of the most toxic seafood contaminants ever isolated. Reports of human food-borne poisoning ascribed to PLTX suggest skeletal muscle as a primary target site. Primary cultures of mouse skeletal muscle cells were used to study the relationship between Ca(2+) response triggered by PLTX and the development of myotoxic insult. Ca(2+) imaging experiments revealed that PLTX causes a transitory intracellular Ca(2+) response (transient phase) followed by a slower and more sustained Ca(2+) increase (long-lasting phase). The transient phase is due to Ca(2+) release from intracellular stores and entry through voltage-dependent channels and the Na(+)/Ca(2+) exchanger (reverse mode). The long-lasting phase is due to a massive and prolonged Ca(2+) influx from the extracellular compartment. Sulforhodamine B assay revealed that the long-lasting phase is the one responsible for the toxicity in skeletal muscle cells. Our data analyzed, for the first time, pathways of PLTX-induced Ca(2+) entry and their correlation with PLTX-induced toxicity in skeletal muscle cells. The cellular morphology changes induced by PLTX and the sensitivity to gadolinium suggest a role for stretch-activated channels

Prediction and De-Risking of an Unusual API:Epimer Cocrystal in the Commercial Synthesis of Belzutifan

This article reports a rare example of the crystallization of a cocrystal of an organic molecule with its epimer. In this case, belzutifan, a novel treatment for von Hippel–Lindau (VHL) disease-associated renal cell carcinoma (RCC), crystallizes as a 1:1 cocrystal with one of its epimers (inversion of stereochemistry at the hydroxyl position). This observation is of particular importance to controlling the purity of the API in the commercial manufacturing process. After the discovery of this cocrystal, the crystalline structure was determined through a combination of crystal structure prediction (CSP) and powder X-ray diffraction followed by single-crystal X-ray diffraction structure determination. The only lattice interaction that exists between the two epimers is a π–π stacking arrangement created by the alternating fluorobenzonitrile aryl groups of each epimer. The formation of this complex, while unexpected, is a reminder that unexplored crystal forms can pose a significant risk to the robustness of chemical manufacturing processes. At present, the cost of leveraging CSP tools across the entirety of a synthetic process is significant. However, discoveries such as the belzutifan:hydroxy epimer cocrystal highlight why current investments in in silico tools are needed and justify expanding their use to de-risk commercial synthetic routes to expedite the development of life-saving medications

Prediction and De-Risking of an Unusual API:Epimer Cocrystal in the Commercial Synthesis of Belzutifan

This article reports a rare example of the crystallization of a cocrystal of an organic molecule with its epimer. In this case, belzutifan, a novel treatment for von Hippel–Lindau (VHL) disease-associated renal cell carcinoma (RCC), crystallizes as a 1:1 cocrystal with one of its epimers (inversion of stereochemistry at the hydroxyl position). This observation is of particular importance to controlling the purity of the API in the commercial manufacturing process. After the discovery of this cocrystal, the crystalline structure was determined through a combination of crystal structure prediction (CSP) and powder X-ray diffraction followed by single-crystal X-ray diffraction structure determination. The only lattice interaction that exists between the two epimers is a π–π stacking arrangement created by the alternating fluorobenzonitrile aryl groups of each epimer. The formation of this complex, while unexpected, is a reminder that unexplored crystal forms can pose a significant risk to the robustness of chemical manufacturing processes. At present, the cost of leveraging CSP tools across the entirety of a synthetic process is significant. However, discoveries such as the belzutifan:hydroxy epimer cocrystal highlight why current investments in in silico tools are needed and justify expanding their use to de-risk commercial synthetic routes to expedite the development of life-saving medications

Prediction and De-Risking of an Unusual API:Epimer Cocrystal in the Commercial Synthesis of Belzutifan

This article reports a rare example of the crystallization of a cocrystal of an organic molecule with its epimer. In this case, belzutifan, a novel treatment for von Hippel–Lindau (VHL) disease-associated renal cell carcinoma (RCC), crystallizes as a 1:1 cocrystal with one of its epimers (inversion of stereochemistry at the hydroxyl position). This observation is of particular importance to controlling the purity of the API in the commercial manufacturing process. After the discovery of this cocrystal, the crystalline structure was determined through a combination of crystal structure prediction (CSP) and powder X-ray diffraction followed by single-crystal X-ray diffraction structure determination. The only lattice interaction that exists between the two epimers is a π–π stacking arrangement created by the alternating fluorobenzonitrile aryl groups of each epimer. The formation of this complex, while unexpected, is a reminder that unexplored crystal forms can pose a significant risk to the robustness of chemical manufacturing processes. At present, the cost of leveraging CSP tools across the entirety of a synthetic process is significant. However, discoveries such as the belzutifan:hydroxy epimer cocrystal highlight why current investments in in silico tools are needed and justify expanding their use to de-risk commercial synthetic routes to expedite the development of life-saving medications