Videolaryngoscopy use before and after the initial phases of the COVID-19 pandemic: The report of the VL-iCUE survey with responses from 96 countries.

BACKGROUND: The potential benefit of videolaryngoscopy use in facilitating tracheal intubation has already been established, however its use was actively encouraged during the COVID-19 pandemic as it was likely to improve intubation success and increase the patient-operator distance. OBJECTIVES: We sought to establish videolaryngoscopy use before and after the early phases of the pandemic, whether institutions had acquired new devices during the COVID-19 pandemic, and whether there had been teaching on the devices acquired. DESIGN: We designed a survey with 27 questions made available via the Joint Information Scientific Committee JISC online survey platform in English, French, Spanish, Chinese, Japanese and Portuguese. This was distributed through 18 anaesthetic and airway management societies. SETTING: The survey was open for 54 to 90 days in various countries. The first responses were logged on the databases on 28 October 2021, with all databases closed on 26 January 2022. Reminders to participate were sent at the discretion of the administering organisations. PARTICIPANTS: All anaesthetists and airway managers who received the study were eligible to participate. MAIN OUTCOME MEASURES: Videolaryngoscopy use before the COVID-19 pandemic and at the time of the survey. RESULTS: We received 4392 responses from 96 countries: 944/4336 (21.7%) were from trainees. Of the 3394 consultants, 70.8% (2402/3394) indicated no change in videolaryngoscopy use, 19.9% (675/3394) increased use and 9.3% (315/3393) reduced use. Among trainees 65.5% (618/943) reported no change in videolaryngoscopy use, 27.7% (261/943) increased use and 6.8% (64/943) reduced use. Overall, videolaryngoscope use increased by 10 absolute percentage points following the pandemic. CONCLUSIONS: Videolaryngoscopy use increased following the early phase of the COVID-19 pandemic but this was less than might have been expected.

The Rubik's cube of doing and being: Factors influencing professional identity transition to the medical registrar.

BACKGROUND: Professional identity transitions, such as the transition to medical registrar, are challenging. How minoritised identities influence transitions during medical training requires further study. This study aimed to explore the factors influencing the transition to the medical registrar in Scotland to guide support during training. METHODS: Interviews exploring this transition with internal medicine trainees were audio recorded, transcribed verbatim and double-coded using template analysis. We applied an initial coding template informed by multiple and multidimensional transition theory of individual, interpersonal, systemic and macro-level factors. Using a critical theory lens, a further template analysis specifically sought to understand how trainees' social identities interacted with the various levels. FINDINGS: Nineteen IM trainees were interviewed between January 2021 and February 2022. Influential factors reflected a parallel process of competence (doing) and identity (being) development. The interaction of social identities, such as gender (being a woman) and country of origin (being an international medical graduate), occurred across levels. This can be conceptualised as a Rubik's cube with the interplay between doing and being from an individual to a macro level with trainees' social identities interacting at all levels. CONCLUSION: The transition to the medical registrar is multifaceted; with a challenging balance between support and independence in providing opportunities to perform (doing) whilst identity develops (being). Identity transitions involve multiple Rubik's-cube-like rotations between the facets of 'doing' and 'being,' until these align. Taking heed of influential factors and the interaction of minoritised social identities could guide a trainee-centred and smoother transition.

Impact of Tigecycline on C. difficile Outcomes: Case Series and Propensity-Matched Retrospective Study.

This case series and propensity-matched cohort study on the use of tigecycline in Clostridioides difficile infection (CDI) evaluated the effect of tigecycline on 30-day mortality. Adjusted for ATLAS Score, hypotension, treatment time period, and serum lactate, tigecycline did not significantly improve 30-day mortality (odds ratio: 0.89; 95% confidence interval: 0.25-3.12; P = 0.853). A randomized controlled trial is needed to determine efficacy and safety of tigecycline in severe or refractory CDI.

Assessing Medical Students' Nontechnical Skills Using Immersive Simulation: What Are the Essential Components?

INTRODUCTION: Nontechnical skills (NTS) have been acknowledged to be important for medical students and can be linked to improved clinical performance. However, existing tools to evaluate these within a simulated setting address only a limited number of NTS. The Medical Students' Nontechnical Skills (Medi-StuNTS) behavioral marker system (BMS) outlines 5 categories of NTS for medical students. This study aimed to seek evidence for completeness and content validity to refine the BMS and to ascertain which NTS are essential for medical students. METHODS: We asked 128 workshop participants if they felt there were any missing or irrelevant items in Medi-StuNTS system. A subject matter expert panel (n = 10) rated how essential they considered each item in the BMS. An Item-Content Validity Index was calculated for each skill element and the Scale-Content Validity Index was calculated as a measure of content validity of the full system. RESULTS: Of the workshop participants, 78.9% felt that there were no missing items and 93% felt that there were no irrelevant items. Potentially missing items highlighted were as follows: "working in a hierarchy," "leadership," "awareness of the emotional state of other team members," and "nonverbal communication." Fourteen of 16 skill elements achieved the recommended level for content validity (Item-Content Validity Index ≥ 0.78), and the Scale-Content Validity Index was higher than the acceptable level (≥0.8). CONCLUSIONS: Evidence for completeness and content validity of Medi-StuNTS has been demonstrated. There is a far wider range of NTS that seem to be essential for medical students than those assessed by tools developed before Medi-StuNTS. Medi-StuNTS provides comprehensive cover of the essential NTS required by medical students, with specific reference to the skill categories "self-awareness" and "escalating care," which do not feature in other tools for assessing NTS in this group.

The physiological and pathological biophysics of phase separation and gelation of RNA binding proteins in amyotrophic lateral sclerosis and fronto-temporal lobar degeneration.

Many RNA binding proteins, including FUS, contain moderately repetitive, low complexity, intrinsically disordered domains. These sequence motifs have recently been found to underpin reversible liquid: liquid phase separation and gelation of these proteins, permitting them to reversibly transition from a monodispersed state to liquid droplet- or hydrogel-like states. This function allows the proteins to serve as scaffolds for the formation of reversible membraneless intracellular organelles such as nucleoli, stress granules and neuronal transport granules. Using FUS as an example, this review examines the biophysics of this physiological process, and reports on how mutations and changes in post-translational state alter phase behaviour, and lead to neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration.

FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions.

Reversible phase separation underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles and is, in part, driven by the intrinsically disordered low-complexity (LC) domain of FUS. Here, we report that cooperative cation-π interactions between tyrosines in the LC domain and arginines in structured C-terminal domains also contribute to phase separation. These interactions are modulated by post-translational arginine methylation, wherein arginine hypomethylation strongly promotes phase separation and gelation. Indeed, significant hypomethylation, which occurs in FUS-associated frontotemporal lobar degeneration (FTLD), induces FUS condensation into stable intermolecular ß-sheet-rich hydrogels that disrupt RNP granule function and impair new protein synthesis in neuron terminals. We show that transportin acts as a physiological molecular chaperone of FUS in neuron terminals, reducing phase separation and gelation of methylated and hypomethylated FUS and rescuing protein synthesis. These results demonstrate how FUS condensation is physiologically regulated and how perturbations in these mechanisms can lead to disease.

Membrane association and release of wild-type and pathological tau from organotypic brain slice cultures.

The spatiotemporal transmission of pathological tau in the brain is characteristic of Alzheimer's disease. Release of both soluble and abnormal tau species from healthy neurons is increased upon stimulation of neuronal activity. It is not yet understood whether the mechanisms controlling soluble tau release from healthy neurons is the same as those involved in the spread of pathological tau species. To begin to understand these events, we have studied tau distribution and release using organotypic brain slice cultures. The slices were cultured from postnatal wild-type and 3xTg-AD mice for up to 1 month. Tau distribution in subcellular compartments was examined by western blotting, and tau release into culture medium was determined using a sensitive sandwich ELISA. We show here that 3xTg-AD cultures have an accelerated development of pathological tau abnormalities including the redistribution of tau to synaptic and membrane compartments. The 3xTg-AD slice cultures show elevated basal tau release relative to total tau when compared with wild-type cultures. However, tau release from 3xTg-AD slices cannot be further stimulated when neuronal activity is increased with potassium chloride. Moreover, we report that there is an increased pool of dephosphorylated membrane-associated tau in conditions where tau release is increased. These data suggest that there may be differential patterns of tau release when using integrated slice culture models of wild-type and transgenic mouse brain, although it will be important to determine the effect of tau overexpression for these findings. These results further increase our knowledge of the molecular mechanisms underlying tau release and propagation in neurodegenerative tauopathies.

Staff education, regular sedation and analgesia quality feedback, and a sedation monitoring technology for improving sedation and analgesia quality for critically ill, mechanically ventilated patients: a cluster randomised trial.

BACKGROUND: Optimal sedation of patients in intensive care units (ICUs) requires the avoidance of pain, agitation, and unnecessary deep sedation, but these outcomes are challenging to achieve. Excessive sedation can prolong ICU stay, whereas light sedation can increase pain and frightening memories, which are commonly recalled by ICU survivors. We aimed to assess the effectiveness of three interventions to improve sedation and analgesia quality: an online education programme; regular feedback of sedation-analgesia quality data; and use of a novel sedation-monitoring technology (the Responsiveness Index [RI]). METHODS: We did a cluster randomised trial in eight ICUs, which were randomly allocated to receive education alone (two ICUs), education plus sedation-analgesia quality feedback (two ICUs), education plus RI monitoring technology (two ICUs), or all three interventions (two ICUs). Randomisation was done with computer-generated random permuted blocks, stratified according to recruitment start date. A 45 week baseline period was followed by a 45 week intervention period, separated by an 8 week implementation period in which the interventions were introduced. ICU and research staff were not masked to study group assignment during the intervention period. All mechanically ventilated patients were potentially eligible. We assessed patients' sedation-analgesia quality for each 12 h period of nursing care, and sedation-related adverse events daily. Our primary outcome was the proportion of care periods with optimal sedation-analgesia, defined as being free from excessive sedation, agitation, poor limb relaxation, and poor ventilator synchronisation. Analysis used multilevel generalised linear mixed modelling to explore intervention effects in a single model taking clustering and patient-level factors into account. A concurrent mixed-methods process evaluation was undertaken to help understand the trial findings. The trial is registered with ClinicalTrials.gov, number NCT01634451. FINDINGS: Between June 1, 2012, and Dec 31, 2014, we included 881 patients (9187 care periods) during the baseline period and 591 patients (6947 care periods) during the intervention period. During the baseline period, optimal sedation-analgesia was present for 5150 (56%) care periods. We found a significant improvement in optimal sedation-analgesia with RI monitoring (odds ratio [OR] 1·44 [95% CI 1·07-1·95]; p=0·017), which was mainly due to increased periods free from excessive sedation (OR 1·59 [1·09-2·31]) and poor ventilator synchronisation (OR 1·55 [1·05-2·30]). However, more patients experienced sedation-related adverse events (OR 1·91 [1·02-3·58]). We found no improvement in overall optimal sedation-analgesia with education (OR 1·13 [95% CI 0·86-1·48]), but fewer patients experienced sedation-related adverse events (OR 0·56 [0·32-0·99]). The sedation-analgesia quality data feedback did not improve quality (OR 0·74 [95% CI 0·54-1·00]) or sedation-related adverse events (OR 1·15 [0·61-2·15]). The process evaluation suggested many clinicians found the RI monitoring useful, but it was often not used for decision making as intended. Education was valued and considered useful by staff. By contrast, sedation-analgesia quality feedback was poorly understood and thought to lack relevance to bedside nursing practice. INTERPRETATION: Combination of RI monitoring and online education has the potential to improve sedation-analgesia quality and patient safety in mechanically ventilated ICU patients. The RI monitoring seemed to improve sedation-analgesia quality, but inconsistent adoption by bedside nurses limited its impact. The online education programme resulted in a clinically relevant improvement in patient safety and was valued by nurses, but any changes to behaviours did not seem to alter other measures of sedation-analgesia quality. Providing sedation-analgesia quality feedback to ICUs did not appear to improve any quality metrics, probably because staff did not think it relevant to bedside practice. FUNDING: Chief Scientist Office, Scotland; GE Healthcare.

Critical residues involved in tau binding to fyn: implications for tau phosphorylation in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by neuropathological deposits of amyloid plaques and neurofibrillary tangles comprised of ß-amyloid and tau protein, respectively. In AD, tau becomes abnormally phosphorylated and aggregates to form intracellular deposits. However, the mechanisms by which tau exerts neurotoxicity in disease remain unclear. Recent studies have suggested that the presence of tau at synapses may indicate a role in neuronal signalling, which could be disrupted in pathological conditions. The non-receptor-associated tyrosine kinase fyn is located at the dendrite in neurons, where it was recently shown to interact with tau to stabilise receptor complexes at the post-synaptic density. Fyn also co-localises with tau in a proportion of neurons containing tau tangles in AD and fyn is also a tau kinase. Hence, tau-fyn interactions could play a pathogenic role in AD. Here we report the identification of critical proline residues, Pro213, Pro216, and Pro219, located within the fifth and sixth Pro-X-X-Pro motifs in the proline-rich region of tau, that are important for its binding to fyn. These residues in tau are flanked by numerous phosphorylation sites and therefore we investigated the relationship between fyn and the degree of tau phosphorylation in human post-mortem brain tissue. We found no difference in the amount of fyn present in control and AD brain. Notably, however, there was a significant correlation between fyn and phosphorylated tau at specific phospho-epitopes in control, but not in AD brain. Our results suggest that the pathological mechanisms underlying AD, that result in increased tau phosphorylation, may disrupt the physiological relationship between tau phosphorylation and fyn.

Upregulation of calpain activity precedes tau phosphorylation and loss of synaptic proteins in Alzheimer's disease brain.

Alterations in calcium homeostasis are widely reported to contribute to synaptic degeneration and neuronal loss in Alzheimer's disease. Elevated cytosolic calcium concentrations lead to activation of the calcium-sensitive cysteine protease, calpain, which has a number of substrates known to be abnormally regulated in disease. Analysis of human brain has shown that calpain activity is elevated in AD compared to controls, and that calpain-mediated proteolysis regulates the activity of important disease-associated proteins including the tau kinases cyclin-dependent kinase 5 and glycogen kinase synthase-3. Here, we sought to investigate the likely temporal association between these changes during the development of sporadic AD using Braak staged post-mortem brain. Quantification of protein amounts in these tissues showed increased activity of calpain-1 from Braak stage III onwards in comparison to controls, extending previous findings that calpain-1 is upregulated at end-stage disease, and suggesting that activation of calcium-sensitive signalling pathways are sustained from early stages of disease development. Increases in calpain-1 activity were associated with elevated activity of the endogenous calpain inhibitor, calpastatin, itself a known calpain substrate. Activation of the tau kinases, glycogen-kinase synthase-3 and cyclin-dependent kinase 5 were also found to occur in Braak stage II-III brain, and these preceded global elevations in tau phosphorylation and the loss of post-synaptic markers. In addition, we identified transient increases in total amyloid precursor protein and pre-synaptic markers in Braak stage II-III brain, that were lost by end stage Alzheimer's disease, that may be indicative of endogenous compensatory responses to the initial stages of neurodegeneration. These findings provide insight into the molecular events that underpin the progression of Alzheimer's disease, and further highlight the rationale for investigating novel treatment strategies that are based on preventing abnormal calcium homeostasis or blocking increases in the activity of calpain or important calpain substrates.

Astrocytes and neuroinflammation in Alzheimer's disease.

Increased production of amyloid ß-peptide (Aß) and altered processing of tau in Alzheimer's disease (AD) are associated with synaptic dysfunction, neuronal death and cognitive and behavioural deficits. Neuroinflammation is also a prominent feature of AD brain and considerable evidence indicates that inflammatory events play a significant role in modulating the progression of AD. The role of microglia in AD inflammation has long been acknowledged. Substantial evidence now demonstrates that astrocyte-mediated inflammatory responses also influence pathology development, synapse health and neurodegeneration in AD. Several anti-inflammatory therapies targeting astrocytes show significant benefit in models of disease, particularly with respect to tau-associated neurodegeneration. However, the effectiveness of these approaches is complex, since modulating inflammatory pathways often has opposing effects on the development of tau and amyloid pathology, and is dependent on the precise phenotype and activities of astrocytes in different cellular environments. An increased understanding of interactions between astrocytes and neurons under different conditions is required for the development of safe and effective astrocyte-based therapies for AD and related neurodegenerative diseases.

Intracellular and extracellular roles for tau in neurodegenerative disease.

Tau has a well-established role as a microtubule-associated protein, in which it stabilizes the neuronal cytoskeleton. This function of tau is influenced by tau phosphorylation state, which is significantly increased in Alzheimer's disease and related tauopathies. Disruptions to the cytoskeleton in disease-affected neurons include reduced length and numbers of stable microtubules, and their diminished stability is associated with increased tau phosphorylation in disease. Tau is also localized in the nucleus and plasma membrane of neurons, where it could have roles in DNA repair and cell signaling. Most recently, potential roles for extracellular tau have been highlighted. The release of tau from neurons is a physiological process that can be regulated by neuronal activity and extracellular tau may play a role in inter-neuronal signaling. In addition, recent studies have suggested that the misfolding of tau in diseased brain leads to abnormal conformations of tau that can be taken up by neighboring neurons. Such a mechanism may be responsible for the apparent prion-like spreading of tau pathology through the brain, which occurs in parallel with clinical progression in the tauopathies. The relationship between tau localization in neurons, tau release, and tau uptake remains to be established, as does the function of extracellular tau. More research is needed to identify disease mechanisms that drive the release and propagation of pathogenic tau and to determine the impact of extracellular tau on cognitive decline in neurodegenerative disease.

Physiological release of endogenous tau is stimulated by neuronal activity.

Propagation of tau pathology is linked with progressive neurodegeneration, but the mechanism underlying trans-synaptic spread of tau is unknown. We show that stimulation of neuronal activity, or AMPA receptor activation, induces tau release from healthy, mature cortical neurons. Notably, phosphorylation of extracellular tau appears reduced in comparison with intracellular tau. We also find that AMPA-induced release of tau is calcium-dependent. Blocking pre-synaptic vesicle release by tetanus toxin and inhibiting neuronal activity with tetrodotoxin both significantly impair AMPA-mediated tau release. Tau secretion is therefore a regulatable process, dysregulation of which could lead to the spread of tau pathology in disease.