Search

Abstract Rationale COVID-19 ARDS could differ from typical forms of the syndrome. Objective Pulmonary microvascular injury and thrombosis are increasingly reported as constitutive features of COVID-19 respiratory failure. Our aim was to study pulmonary mechanics and gas exchanges in COVID-2019 ARDS patients studied early after initiating protective invasive mechanical ventilation, seeking after corresponding pathophysiological and biological characteristics. Methods Between March 22 and March 30, 2020 respiratory mechanics, gas exchanges, circulating endothelial cells (CEC) as markers of endothelial damage, and D-dimers were studied in 22 moderate-to-severe COVID-19 ARDS patients, 1 [1–4] day after intubation (median [IQR]). Measurements and main results Thirteen moderate and 9 severe COVID-19 ARDS patients were studied after initiation of high PEEP protective mechanical ventilation. We observed moderately decreased respiratory system compliance: 39.5 [33.1–44.7] mL/cmH2O and end-expiratory lung volume: 2100 [1721–2434] mL. Gas exchanges were characterized by hypercapnia 55 [44–62] mmHg, high physiological dead-space (V D/V T): 75 [69–85.5] % and ventilatory ratio (VR): 2.9 [2.2–3.4]. V D/V T and VR were significantly correlated: r 2 = 0.24, p = 0.014. No pulmonary embolism was suspected at the time of measurements. CECs and D-dimers were elevated as compared to normal values: 24 [12–46] cells per mL and 1483 [999–2217] ng/mL, respectively. Conclusions We observed early in the course of COVID-19 ARDS high V D/V T in association with biological markers of endothelial damage and thrombosis. High V D/V T can be explained by high PEEP settings and added instrumental dead space, with a possible associated role of COVID-19-triggered pulmonary microvascular endothelial damage and microthrombotic process.

Context: Objective Structured Clinical Examinations (OSCEs) are an increasingly popular evaluation modality for medical students. While the face-to-face interaction allows for more in-depth assessment, it may cause standardization problems. Methods to quantify, limit or adjust for examiner effects are needed., Methods: Data originated from 3 OSCEs undergone by 900-student classes of 5 th - and 6 th -year medical students at Université Paris Cité in the 2022-2023 academic year. Sessions had five stations each, and one of the three sessions was scored by consensus by two raters (rather than one). We report OSCEs' longitudinal consistency for one of the classes and staff-related and student variability by session. We also propose a statistical method to adjust for inter-rater variability by deriving a statistical random student effect that accounts for staff-related and station random effects., Results: From the four sessions, a total of 16,910 station scores were collected from 2615 student sessions, with two of the sessions undergone by the same students, and 36, 36, 35 and 20 distinct staff teams in each station for each session. Scores had staff-related heterogeneity (p<10 -15 ), with staff-level standard errors approximately doubled compared to chance. With mixed models, staff-related heterogeneity explained respectively 11.4%, 11.6%, and 4.7% of station score variance (95% confidence intervals, 9.5-13.8, 9.7-14.1, and 3.9-5.8, respectively) with 1, 1 and 2 raters, suggesting a moderating effect of consensus grading. Student random effects explained a small proportion of variance, respectively 8.8%, 11.3%, and 9.6% (8.0-9.7, 10.3-12.4, and 8.7-10.5), and this low amount of signal resulted in student rankings being no more consistent over time with this metric, rather than with average scores (p=0.45)., Conclusion: Staff variability impacts OSCE scores as much as student variability, and the former can be reduced with dual assessment or adjusted for with mixed models. Both are small compared to unmeasured sources of variability, making them difficult to capture consistently., (© 2024. The Author(s).)

A bullous and cystic lung disease diagnosed in the context of a clinically and genetically diagnosed PROS https://bit.ly/48GnoJy., Competing Interests: Conflict of interest: P. Halitim, J. Pastré, T. Mirault and D. Israël-Biet have no conflicts to declare. Conflict of interests: G. Canaud declares a patent application (“BYL719 (alpelisib) for use in the treatment of PIK3CA-related overgrowth spectrum” #WO2017140828A1) has been filed by INSERM (Institut National de la Santé et de la Recherche Médicale), Centre National De La Recherche Scientifique, Université Paris Descartes and Assistance Publique-Hôpitaux De Paris for the use of BYL719 (alpelisib) in the treatment of PIK3CA-related overgrowth spectrum (PROS/CLOVES syndrome). G. Canaud is the inventor. This patent is licensed to Novartis. G. Canaud receives or has received consulting fees from Novartis, Fresenius Medical Care, Vaderis, Alkermes, IPSEN and BridgeBio., (Copyright ©The authors 2024.)

Lower extremity peripheral artery disease (PAD) often results from atherosclerosis, and is highly prevalent in patients with type 2 diabetes mellitus (T2DM). Individuals with T2DM exhibit a more severe manifestation and a more distal distribution of PAD compared to those without diabetes, adding complexity to the therapeutic management of PAD in this particular patient population. Indeed, the management of PAD in patients with T2DM requires a multidisciplinary and individualized approach that addresses both the systemic effects of diabetes and the specific vascular complications of PAD. Hence, cardiovascular prevention is of the utmost importance in patients with T2DM and PAD, and encompasses smoking cessation, a healthy diet, structured exercise, careful foot monitoring, and adherence to routine preventive treatments such as statins, antiplatelet agents, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. It is also recommended to incorporate glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) in the medical management of patients with T2DM and PAD, due to their demonstrated cardiovascular benefits. However, the specific impact of these novel glucose-lowering agents for individuals with PAD remains obscured within the background of cardiovascular outcome trials (CVOTs). In this review article, we distil evidence, through a comprehensive literature search of CVOTs and clinical guidelines, to offer key directions for the optimal medical management of individuals with T2DM and lower extremity PAD in the era of GLP-1RA and SGLT2i., (© 2024. The Author(s).)

Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK, an endothelial transmembrane receptor signaling through PIK3CA. Venous malformations are associated with pain, bleedings, thrombosis, pulmonary embolism, esthetic deformities and, in severe cases, life-threatening situations. No authorized medical treatment exists for patients with venous malformations. Here, we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient phenotypes. We showed that these malformations only partially signal through AKT proteins. We compared the efficacy of different drugs, including rapamycin, a mTORC1 inhibitor, miransertib, an AKT inhibitor and alpelisib, a PI3Kα inhibitor at improving the lesions seen in the mouse model. We demonstrated the effectiveness of alpelisib in preventing vascular malformations' occurrence, improving the already established ones, and prolonging survival. Considering these findings, we were authorized to treat 25 patients with alpelisib, including 7 children displaying PIK3CA (n = 16) or TEK (n = 9)-related capillary venous malformations resistant to usual therapies including sirolimus, debulking surgical procedures or percutaneous sclerotherapies. We assessed the volume of vascular malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib demonstrated improvement in all 25 patients. Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated. MRI showed a decrease of 33.4% and 27.8% in the median volume of PIK3CA and TEK malformations respectively, over 6 months on alpelisib. In conclusion, this study supports PI3Kα inhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations., (© 2024. The Author(s).)

The PIK3CA-related overgrowth spectrum (PROS) encompasses various conditions caused by mosaic activating PIK3CA variants. PIK3CA somatic variants are also involved in various cancer types. Some generalized overgrowth syndromes are associated with an increased risk of Wilms tumor (WT). In PROS, abdominal ultrasound surveillance has been advocated to detect WT. We aimed to determine the risk of embryonic and other types of tumors in patients with PROS in order to evaluate surveillance relevance. We searched the clinical charts from 267 PROS patients for the diagnosis of cancer, and reviewed the medical literature for the risk of cancer. In our cohort, six patients developed a cancer (2.2%), and Kaplan Meier analyses estimated cumulative probabilities of cancer occurrence at 45 years of age was 5.6% (95% CI = 1.35%-21.8%). The presence of the PIK3CA variant was only confirmed in two out of four tumor samples. In the literature and our cohort, six cases of Wilms tumor/nephrogenic rests (0.12%) and four cases of other cancers have been reported out of 483 proven PIK3CA patients, in particular the p.(His1047Leu/Arg) variant. The risk of WT in PROS being lower than 5%, this is insufficient evidence to recommend routine abdominal imaging. Long-term follow-up studies are needed to evaluate the risk of other cancer types, as well as the relationship with the extent of tissue mosaicism and the presence or not of the variant in the tumor samples., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Blood pressure measurement is the most widely performed clinical exam to predict mortality risk. The gold standard for its noninvasive assessment is the auscultatory method, which relies on listening to the so-called "Korotkoff sounds" in a stethoscope placed at the outlet of a pneumatic arm cuff. However, more than a century after their discovery, the origin of these sounds is still debated, which implies a number of clinical limitations. We imaged the Korotkoff sound generation in vivo at thousands of images per second using ultrafast ultrasound. We showed with both experience and theory that Korotkoff sounds are paradoxically not sound waves emerging from the brachial artery but rather shear vibrations conveyed in surrounding tissues by the nonlinear pulse wave propagation. When these shear vibrations reached the stethoscope, they were synchronous, correlated, and comparable in intensity with the Korotkoff sounds. Understanding this mechanism could ultimately improve blood pressure measurement and provide additional understanding of arterial mechanical properties.

Background: Aortitis is a group of disorders characterized by the inflammation of the aorta. The large-vessel vasculitides are the most common causes of aortitis. Aortitis long-term outcomes are not well known., Objectives: The purpose of this study was to assess the long-term outcome and prognosis of noninfectious surgical thoracic aortitis., Methods: This was a retrospective multicenter study of 5,666 patients with thoracic aorta surgery including 217 (3.8%) with noninfectious thoracic aortitis (118 clinically isolated aortitis, 57 giant cells arteritis, 21 Takayasu arteritis, and 21 with various systemic autoimmune disorders). Factors associated with vascular complications and a second vascular procedure were assessed by multivariable analysis., Results: Indications for aortic surgery were asymptomatic aneurysm with a critical size (n = 152 [70%]), aortic dissection (n = 28 [13%]), and symptomatic aortic aneurysm (n = 30 [14%]). The 10-year cumulative incidence of vascular complication and second vascular procedure was 82.1% (95% CI: 67.6%-90.6%), and 42.6% (95% CI: 28.4%-56.1%), respectively. Aortic arch aortitis (HR: 2.08; 95% CI: 1.26-3.44; P = 0.005) was independently associated with vascular complications. Descending thoracic aortitis (HR: 2.35; 95% CI: 1.11-4.96; P = 0.031) and aortic dissection (HR: 3.08; 95% CI: 1.61-5.90; P = 0.002) were independently associated with a second vascular procedure, while treatment with statins after aortitis diagnosis (HR: 0.47; 95% CI: 0.24-0.90; P = 0.028) decreased it. After a median follow-up of 3.9 years, 19 (16.1%) clinically isolated aortitis patients developed features of a systemic inflammatory disease and 35 (16%) patients had died., Conclusions: This multicenter study shows that 82% of noninfectious surgical thoracic aortitis patients will experience a vascular complication within 10 years. We pointed out specific characteristics that identified those at highest risk for subsequent vascular complications and second vascular procedures., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Coronavirus disease 2019 (COVID-19) is associated with an inflammatory cytokine burst and a prothrombotic coagulopathy. Platelets may contribute to microthrombosis, and constitute a therapeutic target in COVID-19 therapy., Aim: To assess if platelet activation influences mortality in COVID-19., Methods: We explored two cohorts of patients with COVID-19. Cohort A included 208 ambulatory and hospitalized patients with varying clinical severities and non-COVID patients as controls, in whom plasma concentrations of the soluble platelet activation biomarkers CD40 ligand (sCD40L) and P-selectin (sP-sel) were quantified within the first 48hours following hospitalization. Cohort B was a multicentre cohort of 2878 patients initially admitted to a medical ward. In both cohorts, the primary outcome was in-hospital mortality., Results: In cohort A, median circulating concentrations of sCD40L and sP-sel were only increased in the 89 critical patients compared with non-COVID controls: sP-sel 40,059 (interquartile range 26,876-54,678)pg/mL; sCD40L 1914 (interquartile range 1410-2367)pg/mL (P<0.001 for both). A strong association existed between sP-sel concentration and in-hospital mortality (Kaplan-Meier log-rank P=0.004). However, in a Cox model considering biomarkers of immunothrombosis, sP-sel was no longer associated with mortality, in contrast to coagulopathy evaluated with D-dimer concentration (hazard ratio 4.86, 95% confidence interval 1.64-12.50). Moreover, in cohort B, a Cox model adjusted for co-morbidities suggested that prehospitalization antiplatelet agents had no significant impact on in-hospital mortality (hazard ratio 1.05, 95% CI 0.80-1.37; P=0.73)., Conclusions: Although we observed an association between excessive biomarkers of platelet activation and in-hospital mortality, our findings rather suggest that coagulopathy is more central in driving disease progression, which may explain why prehospitalization antiplatelet drugs were not a protective factor against mortality in our multicentre cohort., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Ultrasound localization microscopy (ULM) based on ultrafast ultrasound imaging of circulating microbubbles (MB) can image microvascular blood flows in vivo up to the micron scale. Takayasu arteritis (TA) has an increased vascularisation of the thickened arterial wall when active. We aimed to perform vasa vasorum ULM of the carotid wall and demonstrate that ULM can provide imaging markers to assess the TA activity., Methods: Patients with TA were consecutively included with assessment of activity by the National Institute of Health criteria: 5 had active TA (median age 35.8 [24.5-46.0] years) and 11 had quiescent TA (37.2 [31.7-47.3] years). ULM was performed using a 6.4 MHz probe and a dedicated imaging sequence (plane waves with 8 angles, frame rate 500 Hz), coupled with the intravenous injection of MB. Individual MB were localised at a subwavelength scale then tracked, allowing the reconstruction of the vasa vasorum flow anatomy and velocity., Findings: ULM allowed to show microvessels and to measure their flow velocity within the arterial wall. The number of MB detected per second in the wall was 121 [80-146] in active cases vs. 10 [6-15] in quiescent cases (p = 0.0005), with a mean velocity of 40.5 [39.0-42.9] mm.s -1 in active cases., Interpretation: ULM allows visualisation of microvessels within the thickened carotid wall in TA, with significantly greater MB density in active cases. ULM provides a precise visualisation in vivo of the vasa vasorum and gives access to the arterial wall vascularisation quantification., Funding: French Society of Cardiology. ART (Technological Research Accelerator) biomedical ultrasound program of INSERM, France., Competing Interests: Declaration of interests All authors have no conflicts of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To assess the perception of Advanced Nurse Practitioners (ANP) by physicians and nurses in vascular medicine. As the status of ANP in France was recently enacted by law in 2018, we aimed to investigate physicians and nurses working with patients suffering from Peripheral Artery Disease (PAD) to gather their opinions and draw the cooperation outlines these practitioners could have with an ANP., Methods: A qualitative study based on in-depth interviews was conducted among healthcare practitioners taking care of patients with PAD: 10 physicians working either in a private practice settings or hospital settings or both, and eight nurses working within a hospital inpatients vascular unit. Verbatim responses were extracted and coded according to a continuous thematization method., Results: Three main features emerged from participants' responses. Vascular medicine has a specific organization with a significant lack of time and staff to fulfill the mission regarding patients' severity of illness. Second, the ANP is wanted to fill part of this gap. The expected benefits include a smoother care pathway and increased capacity for cardiovascular education and prevention, especially during consultations. Lastly, some clarification is required to integrate such new practitioners within vascular teams already in place., Conclusion: Advanced nurse practitioners could be the missing link in a "Vascular team" by creating a continuum in the care of patients with PAD, ensuring clinical assessment, nursing supervision, adverse event screening, and renewing drug prescriptions with the required adaptations while ensuring essential part of therapeutic education adapted to each patient., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kubiak, Sitruk, Durivage, Khider, Mohamedi, Détriché, Messas, Mirault and Goudot.)

Purpose: Aortic maximal rate of systolic distention (MRSD) is a prognosis factor of ascending aorta dilatation with magnetic resonance imaging. Its calculation requires precise continuous tracking of the aortic diameter over the cardiac cycle, which is not feasible by focused ultrasound. We aimed to develop an automatic aortic acquisition using ultrafast ultrasound imaging (UUI) to provide access to the aortic MRSD. Methods: A phased array probe and developed sequences at 2000 frames/s were used. A created interface automatically tracked the anterior and posterior aortic walls over the cardiac cycle. Tissue Doppler allowed a precise estimation of the walls' movements. MRSD was the maximum derivative of the aortic diameter curve over time. To assess its feasibility, 34 patients with bicuspid aortic valve (BAV) and 31 controls were consecutively included to evaluate the BAV-associated aortopathy at the sinus of Valsalva, the tubular ascending aorta, and the aortic arch. Results: UUI acquisitions and the dedicated interface allow tracking of the aortic diameter and calculating the MRSD for the BAV patients and controls (mean age of 34 vs. 43 years, p = 0.120). A trend toward lower deformation in the different aortic segments was observed, as expected. Still, only the MRSD with UUI was significantly different at the sinus of Valsalva in this small series: (0.61 .10 3 .s -1 [0.37-0.72] for BAV patients vs. 0.92 .10 3 .s -1 [0.72-1.02] for controls, p = 0.025). Conclusion: Aortic deformation evaluated with UUI deserves attention with a simple and automated measurement technique that could assess the segmental aortic injury associated with BAV., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Goudot, Cheng, Guédon, Mirault, Pedreira, Dahan, Wang, Pernot and Messas.)

Background: Objective structured clinical examinations (OSCEs) are known to be a fair evaluation method. These recent years, the use of online OSCEs (eOSCEs) has spread. This study aimed to compare remote versus live evaluation and assess the factors associated with score variability during eOSCEs., Methods: We conducted large-scale eOSCEs at the medical school of the Université de Paris Cité in June 2021 and recorded all the students' performances, allowing a second evaluation. To assess the agreement in our context of multiple raters and students, we fitted a linear mixed model with student and rater as random effects and the score as an explained variable., Results: One hundred seventy observations were analyzed for the first station after quality control. We retained 192 and 110 observations for the statistical analysis of the two other stations. The median score and interquartile range were 60 out of 100 (IQR 50-70), 60 out of 100 (IQR 54-70), and 53 out of 100 (IQR 45-62) for the three stations. The score variance proportions explained by the rater (ICC rater) were 23.0, 16.8, and 32.8%, respectively. Of the 31 raters, 18 (58%) were male. Scores did not differ significantly according to the gender of the rater (p = 0.96, 0.10, and 0.26, respectively). The two evaluations showed no systematic difference in scores (p = 0.92, 0.053, and 0.38, respectively)., Conclusion: Our study suggests that remote evaluation is as reliable as live evaluation for eOSCEs., (© 2022. The Author(s).)

The COVID-19 pandemic has led health schools to cancel many on-site training and exams. Teachers were looking for the best option to carry out online OSCEs, and Zoom was the obvious choice since many schools have used it to pursue education purposes., Methods: We conducted a feasibility study during the 2020-2021 college year divided into six pilot phases and the large-scale eOSCEs on Zoom on June 30th, 2021. We developed a specific application allowing us to mass create Zoom meetings and built an entire organization, including a technical support system (an SOS room and catching-up rooms) and teachers' training sessions. We assessed satisfaction via an online survey., Results: On June 30th, 531/794 fifth-year medical students (67%) participated in a large-scale mock exam distributed in 135 Zoom meeting rooms with the mobilization of 298 teachers who either participated in the Zoom meetings as standardized patients (N =135, 45%) or examiners (N =135, 45%) or as supervisors in the catching-up rooms (N =16, 6%) or the SOS room (N =12, 4%). In addition, 32/270 teachers (12%) experienced difficulties connecting to their Zoom meetings and sought the help of an SOS room member. Furthermore, 40/531 students (7%) were either late to their station or had technical difficulties and declared those issues online and were welcomed in one of the catching-up rooms to perform their eOSCE stations. Additionally, 518/531 students (98%) completed the entire circuit of three stations, and 225/531 students (42%) answered the online survey. Among them, 194/225 (86%) found eOSCES helpful for training and expressed their satisfaction with this experience., Conclusion: Organizing large-scale eOSCEs on Zoom is feasible with the appropriate tools. In addition, eOCSEs should be considered complementary to on-site OSCEs and to train medical students in telemedicine.

Objective: This study aimed to report outcomes of patients with symptomatic acute isolated mesenteric artery dissection (IMAD) treated within a French intestinal stroke centre (ISC)., Methods: All patients with symptomatic IMAD referred to the ISC from January 2016 to January 2020 were included prospectively. Patients with aortic dissection and asymptomatic IMAD were not included. The standardised medical protocol included anticoagulation and antiplatelet therapy, gastrointestinal resting, and oral antibiotics. Operations were considered for acute mesenteric ischaemia (AMI)., Results: Among the 453 patients admitted to an ISC during the study period, 34 (median age, 53 years [41 - 67]; 82% men) with acute symptomatic IMAD were included. According to the classification of Yun et al., IMADs were reported as follows: type I (n = 7, 20%), type IIa (n = 6, 18%), type IIb (n = 15, 44%), and type III (i.e., complete superior mesenteric artery [SMA] occlusion; n = 6, 18%). Overall, nine (26%) patients had AMI (type I/II, n = 3; type III, n = 6). On initial computerised tomography angiogram, nine (26%) patients had an associated visceral arterial dissection or pseudoaneurysm. All patients with types I/II (n = 28, 82%) followed a favourable clinical course with conservative therapy, with no need for any operation. All patients with type III (n = 6, 18%) underwent urgent laparotomy with SMA revascularisation (open, n = 4; stenting, n = 1) and or bowel resection (early, n = 3; late, n = 1). Rates of intestinal resection and short bowel syndrome were 12% and 8.8%, respectively. After a median follow up of 26 months [18 - 42], recurrence of symptoms occurred in four (12%) patients and aneurysmal change in 14 (41%), with no re-intervention., Conclusion: Although IMAD was associated with a high frequency of AMI, a standardised protocol produced a low rate of intestinal resection. Conservative therapy seems appropriate in types I/II patients, whereas urgent SMA revascularisation should aim to avoid intestinal resection or death in type III patients., (Copyright © 2022 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Importance: High lipoprotein(a) (Lp[a]) levels are involved in the development of cardiovascular events, particularly in myocardial infarction, stroke, and peripheral artery disease. Studies assessing the Lp(a) levels associated with adverse lower-limb events are lacking., Objective: To assess the association between Lp(a) levels and incidence of major adverse limb events in unselected hospitalized patients., Design, Setting, and Participants: This large retrospective monocentric cohort study was conducted from January 1, 2000, to December 31, 2020. Data were derived from the clinical information system of the Hôpital Européen Georges-Pompidou, a Paris-based university hospital. Patients who underwent at least 1 Lp(a) measurement at the center during the study period were included. Patients who had no follow-up data or who had the first Lp(a) measurement after the study outcome had occurred were excluded. Data analyses were performed from May 2021 to January 2022., Main Outcomes and Measures: The primary outcome was the first inpatient major adverse limb event, defined as a major amputation, peripheral endovascular revascularization, or peripheral surgical revascularization, during follow-up. Secondary outcomes included individual components of the primary outcome. Lipoprotein(a) levels were categorized as follows: normal (<50 mg/dL), high (50 to <134 mg/dL), and very high (≥134 mg/dL); to convert Lp(a) values to milligrams per liter, multiply by 0.1., Results: A total of 16 513 patients (median [IQR] age, 58.2 [49.0-66.7] years; 9774 men [59.2%]) were included in the cohort. The median (IQR) Lp(a) level was 24 (10.0-60.0) mg/dL. The 1-year incidence of major adverse limb event was 2.44% in the overall population and 4.54% among patients with very high Lp(a) levels. High (adjusted accelerated failure time [AFT] exponential estimate: 0.43; 95% CI, 0.24-0.78; Benjamini-Hochberg-corrected P = .01) and very high (adjusted AFT exponential estimate: 0.17; 95% CI, 0.07-0.40; Benjamini-Hochberg-corrected P < .001) Lp(a) levels were independently associated with an increased risk of major adverse limb event., Conclusions and Relevance: Results of this study showed that higher Lp(a) levels were independently associated with an increased risk of a major adverse limb event in hospitalized patients. The Lp(a) measurement needs to be taken into account to improve lower-limb vascular risk assessment.

JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development and complications remains unknown. In a cohort of patients with myeloproliferative neoplasm, JAK2V617F mutation was identified as an independent risk factor for dilation of both the ascending and descending thoracic aorta. Using single-cell RNA-seq, complementary genetically-modified mouse models, as well as pharmacological approaches, we found that JAK2V617F mutation was associated with a pathogenic pro-inflammatory phenotype of perivascular tissue-resident macrophages, which promoted deleterious aortic wall remodeling at early stages, and dissecting aneurysm through the recruitment of circulating monocytes at later stages. Finally, genetic manipulation of tissue-resident macrophages, or treatment with a Jak2 inhibitor, ruxolitinib, mitigated aortic wall inflammation and reduced aortic dilation and rupture. Overall, JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm., (© 2022. The Author(s).)

Type 2 diabetes (T2D) induces hyperglycemia, alters hemoglobin (Hb), red blood cell (RBC) deformability and impairs hemorheology. The question remains whether RBC breakdown and intravascular hemolysis (IVH) occur in T2D patients. We characterized RBC-degradation products and vesiculation in a case-control study of 109 T2D patients and 65 control subjects. We quantified heme-related absorbance by spectrophotometry and circulating extracellular vesicles (EV) by flow cytometry and electron microscopy. Heme-related absorbance was increased in T2D vs. control plasma (+57%) and further elevated in obese T2D plasma (+27%). However, large CD235a+ EV were not increased in T2D plasma. EV from T2D plasma, or shed by isolated T2D RBC, were notably smaller in diameter (-27%) and carried heme-related absorbance. In T2D plasma, higher heme-related absorbance (+30%) was associated to peripheral sensory neuropathy, and no other vascular complication. In vitro, T2D RBC-derived EV triggered endothelial stress and thrombin activation in a phosphatidylserine- and heme-dependent fashion. We concluded that T2D was associated with low-grade IVH. Plasma absorbance may constitute a novel biomarker of peripheral neuropathy in T2D, while flow cytometry focusing on large EV may be maladapted to characterize RBC EV in T2D. Moreover, therapeutics limiting IVH or neutralizing RBC breakdown products might bolster vasculoprotection in T2D., Competing Interests: The authors have declared that no competing interests exist.

Background: Vascular Ehlers-Danlos syndrome (vEDS) is a rare inherited connective tissue disorder due to pathogenic variants in COL3A1 leading to medium-size-artery (MSA) dissection, aneurysm, rupture. Aortic lesions are rarer and less investigated. The objective was to describe the distribution of MSA and aortic lesions and the type of COL3A1 variants in a multicentric cohort of 330 adult vEDS patients., Methods: At the time of the study, 87% were alive, 60.3% were index cases, and 60.0% were women. COL3A1 variants were identified using NGS and/or Sanger sequencing and classified according to functional consequences: 80.6% leading to dominant-negative (DN) and 19.4% leading to haploinsufficiency (HI). Imaging was systematically performed during the initial workup. Carotid mechanics were assessed by echo tracking in a subgroup of patients., Results: Arterial lesions were reported in 82.4% of the patients ( N = 272): 83.5% had MSA lesions alone, 3.3% had aortic lesions alone, and 13.2% both. DN variants were associated with a higher prevalence of arterial lesions ( P < 0.044), especially in supra-aortic trunks and renal arteries. The prevalence of aortic lesions in HI patients with arterial lesions was higher than that in patients with DN ( P 0.027), but not anymore when adjusted for age ( P < 0.559). Carotid Young's modulus was lower in patients with DN, in association with the higher incidence of MSA lesions in this group., Conclusion: The prevalence of aortic lesions is not influenced by the COL3A1 genotype when adjusted for age. Patients with DN variant vEDS have a higher frequency of MSA lesions, especially in supra-aortic trunks associated with lower carotid stiffness. These results support optimized care and follow-up for these vulnerable patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Adham, Legrand, Bruno, Billon, Dalens, Boutouyrie, Mazzella, Gueguen, Frank, Mirault and Jeunemaitre.)

Background: Severe COVID-19 is associated with a high circulating level of calprotectin, the S100A8/S100A9 alarmin heterodimer. Baseline calprotectin amount measured in peripheral blood at diagnosis correlates with disease severity. The optimal use of this biomarker along COVID-19 course remains to be delineated., Methods: We focused on patients with a WHO-defined moderate COVID-19 requiring hospitalization in a medical ward. We collected plasma and serum from three independent cohorts (N = 626 patients) and measured calprotectin amount at admission. We performed longitudinal measures of calprotectin in 457 of these patients (1461 samples) and used a joint latent class mixture model in which classes were defined by age, body mass index and comorbidities to identify calprotectin trajectories predicting the risk of transfer into an intensive care unit or death., Findings: After adjustment for age, sex, body mass index and comorbidities, the predictive value of baseline calprotectin in patients with moderate COVID19 could be refined by serial monitoring of the biomarker. We discriminated three calprotectin trajectories associated with low, moderate, and high risk of poor outcome, and we designed an algorithm available as online software (https://calpla.gustaveroussy.fr:8443/) to monitor the probability of a poor outcome in individual patients with moderate COVID-19., Interpretation: These results emphasize the clinical interest of serial monitoring of calprotectin amount in the peripheral blood to anticipate the risk of poor outcomes in patients with moderate COVID-19 hospitalized in a standard care unit., Funding: The study received support (research grants) from ThermoFisher immunodiagnostics (France) and Gustave Roussy Foundation., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Takayasu arteritis (TA) is a large vessel vasculitis that may complicate with cerebrovascular ischemic events. The objective was to describe clinical and vascular features of TA patients with cerebrovascular ischemic events and to identify risk factors for these events., Methods: We analyzed the prevalence and type of stroke/transient ischemic attack (TIA), factors associated with cerebrovascular ischemic events, and stroke-free survival in a large cohort fulfilling the American College of Rheumatology or Ishikawa criteria of TA., Results: Among 320 patients with TA (median age at diagnosis, 36 [25-47] years; 261 [86%] women), 63 (20%) had a stroke (n=41; 65%) or TIA (n=22; 35%). Ischemic event localized in the carotid territory for 55 (87%) patients and the vertebral artery territory in 8 (13%) patients. Multiple stenosis were observed in 33 (52%) patients with a median number of stenosis of 2 (minimum, 0 to maximum, 11), and aneurysms were observed in 10 (16%) patients. A history of stroke or TIA before TA diagnosis (hazard ratio [HR], 4.50 [2.45-8.17]; P <0.0001), smoking (HR, 1.75 [1.01-3.02]; P =0.05), myocardial infarction history (HR, 0.21 [0.05-0.89]; P =0.039), thoracic aorta involvement (HR, 2.05 [1.30-3.75]; P =0.023), time from first symptoms to diagnosis >1 year (HR, 2.22 [1.30-3.80]; P =0.005), and aspirin treatment (HR, 1.82 [1.04-3.19]; P =0.035) were associated with cerebrovascular ischemic event. In multivariate analysis, time from first symptoms to TA diagnosis >1 year (HR, 2.16 [1.27-3.70]; P =0.007) was independently associated with cerebrovascular ischemic events in patients with TA. The HR for cerebrovascular ischemic event in patients who already experienced a stroke/TIA was 5.11 (2.91-8.99; P <0.0001), compared with those who had not., Conclusions: Carotid stroke/TIA is frequent in TA. We identified factors associated with cerebrovascular ischemic events.

Vascular Ehlers-Danlos syndrome is a rare inherited disorder caused by genetic variants in type III collagen. Its prognosis is especially hampered by unpredictable arterial ruptures and there is no therapeutic consensus. We created a knock-in Col3a1+/G182R mouse model and performed a complete genetic, molecular and biochemical characterization. Several therapeutic strategies were also tested. Col3a1+/G182R mice showed a spontaneous mortality caused by thoracic aortic rupture that recapitulates the vascular Ehlers-Danlos syndrome with a lower survival rate in males, thin non-inflammatory arteries and an altered arterial collagen. Transcriptomic analysis of aortas showed upregulation of genes related to inflammation and cell stress response. Compared to water, survival rate of Col3a1+/G182R mice was not affected by beta-blockers (propranolol or celiprolol). Two other vasodilating anti-hypertensive agents (hydralazine, amlodipine) gave opposite results on aortic rupture and mortality rate. There was a spectacular beneficial effect of losartan, reversed by the cessation of its administration, and a marked deleterious effect of exogenous angiotensin II. These results suggest that blockade of the renin angiotensin system should be tested as a first-line medical therapy in patients with vascular Ehlers-Danlos syndrome., Competing Interests: The authors have declared that no competing interests exist.

Although women have lower age-standardized cardiovascular disease incidence, prevalence, and death-related rates than men, there are also reports indicating that women with cardiovascular disease receive less care, fewer investigations, and have poorer outcomes after a coronary event. The aims of this study were to compare the characteristics of men and women hospitalized for peripheral artery disease (PAD), their cardiovascular and limb outcomes, and their 1-year mortality. The study is a prospective registry collecting data about all consecutive patients hospitalized for PAD within the vascular department of the tertiary center Georges-Pompidou European Hospital (Paris, France). Patients were required to have one of three inclusion criteria: previous revascularization of the lower limb or any lower limb artery occlusion due to an atherosclerotic vascular disease or hemodynamic evidence of PAD. Exclusion criteria were patients with lower extremity arterial occlusion due to another cause. All patients were followed-up for at least 12 months after the initial hospitalization. Among the 235 patients included, there were 61 women (26%), older than men with a median age of 75.6 and 68.3 years, respectively. Main cardiovascular risk factors and comorbidities were similar for men and women except more former or current smokers [145 (83.4%) vs. 33 (54.1%)] and more history of coronary heart disease [42 (24.1%) vs. 7 (11.5%)] in men. Most patients [138 (58.8%)] had critical limb ischemia and 97 (41.3%) had claudication, with no difference for sex. After discharge, 218 patients received an antithrombotic therapy (93.2%), 195 a lipid-lowering drug (83.3%), 185 an angiotensin converting enzyme inhibitor or angiotensin-receptor blocker (78.9%), similarly between sex. At 1-year, overall mortality, major adverse cardiovascular events, major adverse limb events did not differ with 23 (13.2%), 11 (6.3%) and 32 (18.4%) in men, and 8 (13.1%), 3 (4.9%), 15 (24.6%) in women, respectively, despite the difference in age. Overall mortality, cardiovascular outcomes, limb revascularization or amputation did not differ between men and women, 1-year after hospitalization for PAD although the latter were older, less smoker and had less coronary artery disease. Due to the small size of this cohort, larger studies and future research are needed to better understand sex-specific mechanisms in the pathophysiology and natural history of PAD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Détriché, Guédon, Mohamedi, Sellami, Cheng, Galloula, Goudot, Khider, Mortelette, Sitruk, Gendron, Sapoval, Julia, Smadja, Mirault and Messas.)

Background: The impact of estrogen and testosterone on atherosclerotic cardiovascular disease is well known, but the role of the gonadotropins follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL) to some extent remain less studied., Objectives: To explore the angiogenic potential of gonadotropins on endothelial colony-forming cells (ECFCs)., Methods: We examined the effects of various doses of gonadotropins on ECFCs obtained from cord blood by assessing colony number, proliferation, migration, and sprouting ability. Moreover, we studied thrombin generation in ECFCs exposed to gonadotropins by performing a thrombin generation assay. Finally, we determined the levels of circulating gonadotropins in 30 men, to exclude the effect of estrogen, with lower extremity arterial disease (LEAD), in comparison with age- and sex-matched controls., Results: Exposure to FSH, LH, or PRL resulted in an increase in ECFC migration but showed no effect on proliferation or ECFC commitment from cord blood mononuclear cells. Using a three-dimensional fibrin gel assay, we showed that ECFC sprouting was significantly enhanced by gonadotropins. Exposure to FSH also increased the thrombin generation of ECFCs exposed to FSH. Finally, FSH and LH levels in men with LEAD were higher than those in controls., Conclusion: Gonadotropins increase ECFC-related angiogenesis and may be involved in thrombin generation in cardiovascular disease. Gonadotropins may act as biomarkers; moreover, we hypothesize that gonadotropin-blocking strategies may be a novel interesting therapeutic approach in atherosclerotic cardiovascular disease., (© 2021 International Society on Thrombosis and Haemostasis.)

Background: FLNA Loss-of-Function (LoF) causes periventricular nodular heterotopia type 1 (PVNH1), an acknowledged cause of seizures of various types. Neurological symptoms are inconstant, and cardiovascular (CV) defects or connective tissue disorders (CTD) have regularly been associated. We aimed at refining the description of CV and CTD features in patients with FLNA LoF and depicting the multisystemic nature of this condition., Methods: We retrospectively evaluated FLNA variants and clinical presentations in FLNA LoF patient with at least one CV or CTD feature, from three cohorts: ten patients from the French Reference Center for Rare Vascular Diseases, 23 patients from the national reference diagnostic lab for filaminopathies-A, and 59 patients from literature review., Results: Half of patients did not present neurological symptoms. Most patients presented a syndromic association combining CV and CTD features. CV anomalies, mostly aortic aneurysm and/or dilation were present in 75% of patients. CTD features were present in 75%. Variants analysis demonstrated an enrichment of coding variants in the CH1 domain of FLNA protein., Conclusion: In FLNA LoF patients, the absence of seizures should not be overlooked. When considering a diagnosis of PVNH1, the assessment for CV and CTD anomalies is of major interest as they represent interlinked features. We recommend systematic study of FLNA within CTD genes panels, regardless of the presence of neurological symptoms., (© 2021. The Author(s).)

Purpose: PIK3CA pathogenic variants in the PIK3CA-related overgrowth spectrum (PROS) activate phosphoinositide 3-kinase signaling, providing a rationale for targeted therapy, but no drug has proven efficacy and safety in this population. Our aim was to establish the six-month tolerability and efficacy of low-dose taselisib, a selective class I PI3K inhibitor, in PROS patients., Methods: Patients over 16 years with PROS and PIK3CA pathogenic variants were included in a phase IB/IIA multicenter, open-label single-arm trial (six patients at 1 mg/day of taselisib, then 24 at 2 mg/day). The primary outcome was the occurrence of dose limiting toxicity (DLT). Efficacy outcomes were the relative changes after treatment of (1) tissue volume at affected and unaffected sites, both clinically and on imaging; (2) cutaneous vascular outcomes when relevant; (3) biologic parameters; (4) quality of life; and (5) patient-reported outcomes., Results: Among 19 enrolled patients, 2 experienced a DLT (enteritis and pachymeningitis) leading to early trial termination (17 treated, 10 completed the study). No serious adverse reaction occurred in the 1 mg cohort (n = 6). No significant reduction in affected tissue volume was observed (mean -4.2%; p = 0.81; SD 14.01). Thirteen (76.4%) participants reported clinical improvement (pain reduction, chronic bleeding resolution, functional improvement)., Conclusion: Despite functional improvement, the safety profile of low-dose taselisib precludes its long-term use., (© 2021. The Author(s).)

Objective: The clinical relevance of antiphospholipid antibodies (aPLs) in COVID-19 is controversial. This study was undertaken to investigate the prevalence and prognostic value of conventional and nonconventional aPLs in patients with COVID-19., Methods: This was a multicenter, prospective observational study in a French cohort of patients hospitalized with suspected COVID-19., Results: Two hundred forty-nine patients were hospitalized with suspected COVID-19, in whom COVID-19 was confirmed in 154 and not confirmed in 95. We found a significant increase in lupus anticoagulant (LAC) positivity among patients with COVID-19 compared to patients without COVID-19 (60.9% versus 23.7%; P < 0.001), while prevalence of conventional aPLs (IgG and IgM anti-β 2 -glycoprotein I and IgG and IgM anticardiolipin isotypes) and nonconventional aPLs (IgA isotype of anticardiolipin, IgA isotype of anti-β 2 -glycoprotein I, IgG and IgM isotypes of anti-phosphatidylserine/prothrombin, and IgG and IgM isotypes of antiprothrombin) was low in both groups. Patients with COVID-19 who were positive for LAC, as compared to patients with COVID-19 who were negative for LAC, had higher levels of fibrinogen (median 6.0 gm/liter [interquartile range 5.0-7.0] versus 5.3 gm/liter [interquartile range 4.3-6.4]; P = 0.028) and C-reactive protein (CRP) (median 115.5 mg/liter [interquartile range 66.0-204.8] versus 91.8 mg/liter [interquartile range 27.0-155.1]; P = 0.019). Univariate analysis did not show any association between LAC positivity and higher risks of venous thromboembolism (VTE) (odds ratio 1.02 [95% confidence interval 0.44-2.43], P = 0.95) or in-hospital mortality (odds ratio 1.80 [95% confidence interval 0.70-5.05], P = 0.24). With and without adjustment for CRP level, age, and sex, Kaplan-Meier survival curves according to LAC positivity confirmed the absence of an association with VTE or in-hospital mortality (unadjusted P = 0.64 and P = 0.26, respectively; adjusted hazard ratio 1.13 [95% confidence interval 0.48-2.60] and 1.80 [95% confidence interval 0.67-5.01], respectively)., Conclusion: Patients with COVID-19 have an increased prevalence of LAC positivity associated with biologic markers of inflammation. However, LAC positivity at the time of hospital admission is not associated with VTE risk and/or in-hospital mortality., (© 2021, American College of Rheumatology.)

Background: Microthrombosis and large-vessel thrombosis are the main triggers of COVID-19 worsening. The optimal anticoagulant regimen in COVID-19 patients hospitalized in medical wards remains unknown. Objectives: To evaluate the effects of intermediate-dose vs. standard-dose prophylactic anticoagulation (AC) among patients with COVID-19 hospitalized in medical wards. Methods and results: We used a large French multicentric retrospective study enrolling 2,878 COVID-19 patients hospitalized in medical wards. After exclusion of patients who had an AC treatment before hospitalization, we generated a propensity-score-matched cohort of patients who were treated with intermediate-dose or standard-dose prophylactic AC between February 26 and April 20, 2020 (intermediate-dose, n = 261; standard-dose prophylactic anticoagulation, n = 763). The primary outcome of the study was in-hospital mortality; this occurred in 23 of 261 (8.8%) patients in the intermediate-dose group and 74 of 783 (9.4%) patients in the standard-dose prophylactic AC group ( p = 0.85); while time to death was also the same in both the treatment groups (11.5 and 11.6 days, respectively, p = 0.17). We did not observe any difference regarding venous and arterial thrombotic events between the intermediate dose and standard dose, respectively (venous thrombotic events: 2.3 vs. 2.4%, p=0.99; arterial thrombotic events: 2.7 vs. 1.2%, p = 0.25). The 30-day Kaplan-Meier curves for in-hospital mortality demonstrate no statistically significant difference in in-hospital mortality (HR: 0.99 (0.63-1.60); p = 0.99). Moreover, we found that no particular subgroup was associated with a significant reduction in in-hospital mortality. Conclusion: Among COVID-19 patients hospitalized in medical wards, intermediate-dose prophylactic AC compared with standard-dose prophylactic AC did not result in a significant difference in in-hospital mortality., Competing Interests: DS, NG, OS, AC, and RC acknowledge the following without any relation with the current manuscript. DS received consultant, lecture fees, or travel awards from Aspen, Bayer, Carmat, Alliance BMS-Pfizer, LEO-Pharma, and Boehringer-Ingelheim. NG discloses consulting fees by Boehringer-Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer, and LEO-Pharma. OS received grants, personal fees, or nonfinancial support from Bayer, Alliance BMS-Pfizer, Sanofi Aventis, Daiichi Sankyo, MSD, Boston Scientifics, and Chiesi. AC received a research grant from RESICARD (research nurses) and consultant and lecture fees from Amgen, AstraZeneca, Bayer Pharma, Alliance BMS-Pfizer, Novartis, and Sanofi-Aventis. RC received Consultant fees from Aspen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Smadja, Bonnet, Gendron, Weizman, Khider, Trimaille, Mirault, Fauvel, Diehl, Mika, Philippe, Pezel, Goudot, Sutter, Planquette, Waldmann, Sanchez, Cohen and Chocron.)

We aimed to compare the influence of cardiometabolic disorders on the incidence of severe COVID-19 vs. non-COVID pneumonia. We included all consecutive patients admitted with SARS-CoV-2-positive pneumonia between 12 March 2020 and 1 April 2020 and compared them to patients with influenza pneumonia hospitalized between December 2017 and December 2019 at the same tertiary hospital in Paris. Patients with COVID-19 were significantly younger and more frequently male. In the analysis adjusted for age and sex, patients with COVID-19 were more likely to be obese (adjOR: 2.25; 95% CI 1.24-4.09; p = 0.0076) and receive diuretics (adjOR: 2.13; 95% CI 1.12-4.03; p = 0.021) but were less likely to be smokers (adjOR: 0.40; 95% CI 0.24-0.64; p = 0.0002), have COPD (adjOR: 0.25; 95% CI 0.11-0.56; p = 0.0008), or have a previous or active cancer diagnosis (adjOR: 0.54, 95% CI 0.32-0.91; p = 0.020). The rate of ICU admission was significantly higher in patients with COVID-19 (32.4% vs. 5.2% p < 0.0001). Obesity was significantly associated with the risk of direct ICU admission in patients with COVID-19 but not in patients with influenza pneumonia. Likewise, pre-existing hypertension was significantly associated with mortality in patients with COVID-19 but not in patients with influenza pneumonia. Cardiometabolic disorders differentially influenced the risk of presenting with severe COVID-19 or influenza pneumonia.

Objective: Coronavirus disease 19 is a well-established cause of rare arterial thrombosis. Nevertheless, the exact mechanism of arterial thrombosis remains to be elucidated. We herein report the case of a large floating thrombus of the aortic arch, its surgical management and histological analysis. Case: A 65-year-old patient presented to the emergency department with a suspected stroke. He was non-smoker, but presented cardiovascular risk factors, namely hypertension, type 2 diabetes and hyperlipidaemia. A computed tomography of the aorta revealed a large floating thrombus of the aortic arch, at the base of the brachiocephalic trunk, suspected to be the etiology of stroke. Therapeutic anticoagulation was immediately started. The decision was made to perform an open aortic replacement surgery because of the symptomatic thromboembolic event with recent cerebral infarction and the potential harmfulness of the thrombus due to its size. A mobile thrombus was observed at the base of the brachiocephalic trunk by echocardiography. It was attached to a small area of the upper aortic wall and had an irregular surface. Histology revealed a platelet-rich thrombus lying on an aortic atherosclerotic plaque without pronounced inflammation. No plaque ulceration was present but endothelial cell desquamation was observed consistent with plaque erosion. Conclusion: In our case, there was a thrombus lying on an atherosclerotic plaque with intact thick fibrous cap, but associated with a plaque erosion mechanism. The thrombus formation appeared more likely to relate to a very localized endothelial injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Goudot, Amrane, El Ayoubi, Bel, Gendron, Khider, Durivage, Smadja, Messas, Achouh and Mirault.)

The aim of this National Diagnostic and Care Protocol (PNDS) is to explain to the professionals involved the current optimal diagnosis and therapeutic management and care approach for a patient with Takayasu's arteritis. Its purpose is to optimize and harmonize the management and follow-up of this rare disease throughout the country. It also identifies pharmaceutical specialties used in an indication not provided for in the Marketing Authorization, as well as the specialties, products or services necessary for the care of patients but not usually paid for or reimbursed., (© 2021. The Author(s).)

Background: Microvascular, arterial and venous thrombotic events have been largely described during severe coronavirus disease 19 (COVID-19). However, mechanisms underlying hemostasis dysregulation remain unclear., Methods: We explored two independent cross-sectional cohorts to identify soluble markers and gene-expression signatures that discriminated COVID-19 severity and outcomes., Results: We found that elevated soluble (s)P-selectin at admission was associated with disease severity. Elevated sP-selectin was predictive of intubation and death (ROC AUC = 0.67, p = 0.028 and AUC = 0.74, p = 0.0047, respectively). An optimal cutoff value was predictive of intubation with 66% negative predictive value (NPV) and 61% positive predictive value (PPV), and of death with 90% NPV and 55% PPV. An unbiased gene set enrichment analysis revealed that critically ill patients had increased expression of genes related to platelet activation. Hierarchical clustering identified ITG2AB, GP1BB, PPBP and SELPLG to be upregulated in a grade-dependent manner. ROC curve analysis for the prediction of intubation was significant for SELPLG and PPBP (AUC = 0.8, p = 0.046 for both). An optimal cutoff value for PBPP was predictive of intubation with 100% NPV and 45% PPV, and for SELPLG with 100% NPV and 50% PPV., Conclusion: We provide evidence that platelets contribute to COVID-19 severity. Plasma sP-selectin level was associated with severity and in-hospital mortality. Transcriptional analysis identified PPBP/CXCL7 and SELPLG as biomarkers for intubation. These findings provide additional evidence for platelet activation in driving critical COVID-19. Specific studies evaluating the performance of these biomarkers are required., (© 2021. The Author(s).)

[Figure: see text].

Background: Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with vascular inflammation and endothelial injury., Objectives: To correlate circulating angiogenic markers vascular endothelial growth factor A (VEGF-A), placental growth factor (PlGF), and fibroblast growth factor 2 (FGF-2) to in-hospital mortality in COVID-19 adult patients., Methods: Consecutive ambulatory and hospitalized patients with COVID-19 infection were enrolled. VEGF-A, PlGF, and FGF-2 were measured in each patient ≤48 h following admission., Results: The study enrolled 237 patients with suspected COVID-19: 208 patients had a positive diagnostic for COVID-19, of whom 23 were mild outpatients and 185 patients hospitalized after admission. Levels of VEGF-A, PlGF, and FGF-2 significantly increase with the severity of the disease (P < .001). Using a logistic regression model, we found a significant association between the increase of FGF-2 or PlGF and mortality (odds ratio [OR] 1.11, 95% confidence interval [CI; 1.07-1.16], P < .001 for FGF-2 and OR 1.07 95% CI [1.04-1.10], P < .001 for PlGF) while no association were found for VEGF-A levels. Receiver operating characteristic curve analysis was performed and we identified PlGF above 30 pg/ml as the best predictor of in-hospital mortality in COVID-19 patients. Survival analysis for PlGF confirmed its interest for in-hospital mortality prediction, by using a Kaplan-Meier survival curve (P = .001) and a Cox proportional hazard model adjusted to age, body mass index, D-dimer, and C-reactive protein (3.23 95% CI [1.29-8.11], P = .001)., Conclusion: Angiogenic factor PlGF is a relevant predictive factor for in-hospital mortality in COVID-19 patients. More than a biomarker, we hypothesize that PlGF blocking strategies could be a new interesting therapeutic approach in COVID-19., (© 2021 International Society on Thrombosis and Haemostasis.)

Doppler ultrasound is the premier modality to analyze blood flow dynamics in clinical practice. With conventional systems, Doppler can either provide a time-resolved quantification of the flow dynamics in sample volumes (spectral Doppler) or an average Doppler velocity/power [color flow imaging (CFI)] in a wide field of view (FOV) but with a limited frame rate. The recent development of ultrafast parallel systems made it possible to evaluate simultaneously color, power, and spectral Doppler in a wide FOV and at high-frame rates but at the expense of signal-to-noise ratio (SNR). However, like conventional Doppler, ultrafast Doppler is subject to aliasing for large velocities and/or large depths. In a recent study, staggered multi-pulse repetition frequency (PRF) sequences were investigated to dealias color-Doppler images. In this work, we exploit the broadband nature of pulse-echo ultrasound and propose a dual-wavelength approach for CFI dealiasing with a constant PRF. We tested the dual-wavelength bandpass processing, in silico, in laminar flow phantom and validated it in vivo in human carotid arteries ( n = 25 ). The in silico results showed that the Nyquist velocity could be extended up to four times the theoretical limit. In vivo, dealiased CFI were highly consistent with unfolded Spectral Doppler ( r 2 =0.83 , y=1.1x+0.1 , N=25 ) and provided consistent vector flow images. Our results demonstrate that dual-wavelength processing is an efficient method for high-velocity CFI.

Competing Interests: Conflict of Interest None.