Physician Approaches to Antithrombotic Therapies for Recently Symptomatic Carotid Stenosis.

BACKGROUND: Whereas the beneficial effect of antiplatelet therapy for recurrent stroke prevention has been well established, uncertainties remain regarding the optimal antithrombotic regimen for recently symptomatic carotid stenosis. We sought to explore the approaches of stroke physicians to antithrombotic management of patients with symptomatic carotid stenosis. METHODS: We employed a qualitative descriptive methodology to explore the decision-making approaches and opinions of physicians regarding antithrombotic regimens for symptomatic carotid stenosis. We conducted semi-structured interviews with a purposive sample of 22 stroke physicians (11 neurologists, 3 geriatricians, 5 interventional-neuroradiologists, and 3 neurosurgeons) from 16 centers on four continents to discuss symptomatic carotid stenosis management. We then conducted thematic analysis on the transcripts. RESULTS: Important themes revealed from our analysis included limitations of existing clinical trial evidence, competing surgeon versus neurologist/internist preferences, and the choice of antiplatelet therapy while awaiting revascularization. There was a greater concern for adverse events while using multiple antiplatelet agents (e.g., dual-antiplatelet therapy (DAPT)) in patients undergoing carotid endarterectomy compared to carotid artery stenting. Regional variations included more frequent use of single antiplatelet agents among European participants. Areas of uncertainty included antithrombotic management if already on an antiplatelet agent, implications of nonstenotic features of carotid disease, the role of newer antiplatelet agents or anticoagulants, platelet aggregation testing, and timing of DAPT. CONCLUSION: Our qualitative findings can help physicians critically examine the rationale underlying their own antithrombotic approaches to symptomatic carotid stenosis. Future clinical trials may wish to accommodate identified variations in practice patterns and areas of uncertainty to better inform clinical practice.

Distribution of cholesterol in asymmetric membranes driven by composition and differential stress.

Many lipid membranes of eukaryotic cells are asymmetric, which means the two leaflets differ in at least one physical property, such as lipid composition or lateral stress. Maintaining this asymmetry is helped by the fact that ordinary phospholipids rarely transition between leaflets, but cholesterol is an exception: its flip-flop times are in the microsecond range, so that its distribution between leaflets is determined by a chemical equilibrium. In particular, preferential partitioning can draw cholesterol into a more saturated leaflet, and phospholipid number asymmetry can force it out of a compressed leaflet. Combining highly coarse-grained membrane simulations with theoretical modeling, we investigate how these two driving forces play against each other until cholesterol's chemical potential is equilibrated. The theory includes two coupled elastic sheets and a Flory-Huggins mixing free energy with a χ parameter. We obtain a relationship between χ and the interaction strength between cholesterol and lipids in either of the two leaflets, and we find that it depends, albeit weakly, on lipid number asymmetry. The differential stress measurements under various asymmetry conditions agree with our theoretical predictions. Using the two kinds of asymmetries in combination, we find that it is possible to counteract the phospholipid number bias, and the resultant stress in the membrane, via the control of cholesterol mixing in the leaflets.

Neurological and Head/Eyes/Ears/Nose/Throat Manifestations of COVID-19: A Systematic Review and Meta-Analysis.

BACKGROUND/OBJECTIVE: Coronavirus disease 2019 (COVID-19) has been associated with various neurological and atypical head/eyes/ears/nose/throat (HEENT) manifestations. We sought to review the evidence for these manifestations. METHODS: In this systematic review and meta-analysis, we compiled studies published until March 31, 2021 that examined non-respiratory HEENT, central, and peripheral nervous system presentations in COVID-19 patients. We included 477 studies for qualitative synthesis and 59 studies for meta-analyses. RESULTS: Anosmia, ageusia, and conjunctivitis may precede typical upper/lower respiratory symptoms. Central nervous system (CNS) manifestations include stroke and encephalopathy, potentially with brainstem or cranial nerve involvement. MRI studies support CNS para-/postinfectious etiologies, but direct neuroinvasion seems very rare, with few cases detecting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the CNS. Peripheral nervous system (PNS) manifestations include muscle damage, Guillain-Barre syndrome (GBS), and its variants. There was moderate-to-high study heterogeneity and risk of bias. In random-effects meta-analyses, anosmia/ageusia was estimated to occur in 56% of COVID-19 patients (95% CI: 0.41-0.71, I2:99.9%), more commonly than in patients without COVID-19 (OR: 14.28, 95% CI: 8.39-24.29, I2: 49.0%). Neurological symptoms were estimated to occur in 36% of hospitalized patients (95% CI: 0.31-0.42, I2: 99.8%); ischemic stroke in 3% (95% CI: 0.03-0.04, I2: 99.2%), and GBS in 0.04% (0.033%-0.047%), more commonly than in patients without COVID-19 (OR[stroke]: 2.53, 95% CI: 1.16-5.50, I2: 76.4%; OR[GBS]: 3.43,1.15-10.25, I2: 89.1%). CONCLUSIONS: Current evidence is mostly from retrospective cohorts or series, largely in hospitalized or critically ill patients, not representative of typical community-dwelling patients. There remains a paucity of systematically gathered prospective data on neurological manifestations. Nevertheless, these findings support a high index of suspicion to identify HEENT/neurological presentations in patients with known COVID-19, and to test for COVID-19 in patients with such presentations at risk of infection.

Elastic and thermodynamic consequences of lipid membrane asymmetry.

Many cellular lipid bilayers consist of leaflets that differ in their lipid composition - a non-equilibrium state actively maintained by cellular sorting processes that counter passive lipid flip-flop. While this lipidomic aspect of membrane asymmetry has been known for half a century, its elastic and thermodynamic ramifications have garnered attention only fairly recently. Notably, the torque arising when lipids of different spontaneous curvature reside in the two leaflets can be counterbalanced by a difference in lateral mechanical stress between them. Such membranes can be essentially flat in their relaxed state, despite being compositionally strongly asymmetric, but they harbor a surprisingly large but macroscopically invisible differential stress. This hidden stress can affect a wide range of other membrane properties, such as the resistance to bending, the nature of phase transitions in its leaflets, and the distribution of flippable species, most notably sterols. In this short note we offer a concise overview of our recently proposed basic framework for capturing the interplay between curvature, lateral stress, leaflet phase behavior, and cholesterol distribution in generally asymmetric membranes, and how its implied signatures might be used to learn more about the hidden but physically consequential differential stress.

Practice Current: How do you manage mild cognitive impairment?

Mild cognitive impairment (MCI) is characterized by evidence of cognitive impairment with minimal disruption of instrumental activities of daily living and carries a substantial risk of progression of dementia. Whereas current guidelines support a relatively minimalistic workup to identify reversible or structural causes, the field has witnessed the rapid development of various sophisticated imaging, biomarker, and genetic investigations in the past few years. The role of these investigations in routine practice is uncertain. Similarly, although there are no approved treatments for MCI, neurologists may experience uncertainty about using cholinesterase inhibitors or other medications or supplements that have been studied in MCI with limited success, particularly when patients or families are keen to try pharmacologic options. Given these uncertainties, and the paucity of high-quality data in the literature, we sought expert opinion from around the globe on how to investigate and treat patients with MCI. Similar questions were posed to the rest of our readership in an online survey, the preliminary results of which are also presented.