Elevated Uptake of Plasma Macromolecules by Regions of Arterial Wall Predisposed to Plaque Instability in a Mouse Model

Atherosclerosis may be triggered by an elevated net transport of lipid-carrying macromolecules from plasma into the arterial wall. We hypothesised that whether lesions are of the thin-cap fibroatheroma (TCFA) type or are less fatty and more fibrous depends on the degree of elevation of transport, with greater uptake leading to the former. We further hypothesised that the degree of elevation can depend on haemodynamic wall shear stress characteristics and nitric oxide synthesis. Placing a tapered cuff around the carotid artery of apolipoprotein E -/- mice modifies patterns of shear stress and eNOS expression, and triggers lesion development at the upstream and downstream cuff margins; upstream but not downstream lesions resemble the TCFA. We measured wall uptake of a macromolecular tracer in the carotid artery of C57bl/6 mice after cuff placement. Uptake was elevated in the regions that develop lesions in hyperlipidaemic mice and was significantly more elevated where plaques of the TCFA type develop. Computational simulations and effects of reversing the cuff orientation indicated a role for solid as well as fluid mechanical stresses. Inhibiting NO synthesis abolished the difference in uptake between the upstream and downstream sites. The data support the hypothesis that excessively elevated wall uptake of plasma macromolecules initiates the development of the TCFA, suggest that such uptake can result from solid and fluid mechanical stresses, and are consistent with a role for NO synthesis. Modification of wall transport properties might form the basis of novel methods for reducing plaque rupture

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Optimal parameters of transcranial electrical stimulation for intraoperative monitoring of motor evoked potentials of the tibialis anterior muscle during pediatric scoliosis surgery.

International audienceOBJECTIVE: Transcranial electric stimulation elicited muscle motor evoked potentials (TESmMEPs) is one of the best methods for corticospinal tract's function monitoring during spine and spinal cord surgeries. A train of multipulse electric stimulation is required for eliciting TESmMEPs under general anaesthesia. Here, we investigated the best stimulation parameters for eliciting and recording tibialis anterior's TESmMEPs during paediatric scoliosis surgery. PATIENTS AND METHODS: Numbers of pulses (NOP), inter-stimulus intervals (ISI) and current intensities allowing the best size tibialis anterior muscle's TESmMEPs under general anaesthesia, were tested and collected during 77 paediatric scoliosis surgery monitoring procedures in our hospital. Individual pulse duration was kept at 0.5 ms and stimulating electrodes were positioned at C1 and C2 (International 10-20-EEG-System) during all the tests. RESULTS: The NOP used for eliciting the best tibialis anterior TESmMEPs response was 5, 6, and 7 respectively in 21 (27%), 47 (61%) and 9 (12%) out of the 77 patients. The ISI was 2, 3 and 4 ms respectively in 13 (17%), 55 (71%) and 9 (12%) of them. The current intensity used varied from 300 to 700 V (mean: 448±136 V). CONCLUSION: Most patients had 6 as best NOP (61%) and 3 ms as best ISI (71%). These findings support that a NOP of 6 and an ISI of 3 ms should be preferentially used as optimal stimulation settings for intraoperative tibialis anterior muscle's TESmMEPs eliciting and recording during paediatric scoliosis surgery

Mean and minimum WSS along vessels with the cuff in the conventional orientation.

<p>Plot of circumferential minimum and circumferential mean WSS versus distance along the vessel for the mouse with the cuff in the forward direction. Flow direction, cuff location and cuff orientation are indicated as described for <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115728#pone-0115728-g002" target="_blank">Fig 2</a>.</p

Tracer uptake along vessels in mice administered tracer just before death.

<p>Fluorescence intensity along the length of carotid arteries of mice having the cuff placed in the conventional direction and administered tracer 1 minute rather than 10 minutes before sacrifice. Intensity is shown separately for the cuffed left carotid (“LCA”) and uncuffed right carotid (“RCA”). Flow direction, cuff location and cuff orientation are indicated as described for <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115728#pone-0115728-g002" target="_blank">Fig. 2</a>. Mean (dark lines) +1 SEM (light lines), n = 3.</p