Patients with COVID-19 who develop severe acute respiratory distress syndrome (ARDS) can have symptoms that rapidly evolve to profound hypoxaemia and death. The efficacy of extracorporeal membrane ...oxygenation (ECMO) for patients with severe ARDS in the context of COVID-19 is unclear. We aimed to establish the clinical characteristics and outcomes of patients with respiratory failure and COVID-19 treated with ECMO.
This retrospective cohort study was done in the Paris-Sorbonne University Hospital Network, comprising five intensive care units (ICUs) and included patients who received ECMO for COVID-19 associated ARDS. Patient demographics and daily pre-ECMO and on-ECMO data and outcomes were collected. Possible outcomes over time were categorised into four different states (states 1-4): on ECMO, in the ICU and weaned off ECMO, alive and out of ICU, or death. Daily probabilities of occupation in each state and of transitions between these states until day 90 post-ECMO onset were estimated with use of a multi-state Cox model stratified for each possible transition. Follow-up was right-censored on July 10, 2020.
From March 8 to May 2, 2020, 492 patients with COVID-19 were treated in our ICUs. Complete day-60 follow-up was available for 83 patients (median age 49 IQR 41-56 years and 61 73% men) who received ECMO. Pre-ECMO, 78 (94%) patients had been prone-positioned; their median driving pressure was 18 (IQR 16-21) cm H
O and PaO
/FiO
was 60 (54-68) mm Hg. At 60 days post-ECMO initiation, the estimated probabilities of occupation in each state were 6% (95% CI 3-14) for state 1, 18% (11-28) for state 2, 45% (35-56) for state 3, and 31% (22-42) for state 4. 35 (42%) patients had major bleeding and four (5%) had a haemorrhagic stroke. 30 patients died.
The estimated 60-day survival of ECMO-rescued patients with COVID-19 was similar to that of studies published in the past 2 years on ECMO for severe ARDS. If another COVID-19 outbreak occurs, ECMO should be considered for patients developing refractory respiratory failure despite optimised care.
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We have previously shown that ultrasonography can detect hyperechogenic crystal deposits in the kidney medulla of patients with gout. In this cross-sectional study we investigated the frequency and ...clinical correlates of hyperechogenic kidney medulla in 502 consecutive primary consultants for gout (ACR/EULAR criteria) at the Vien Gut medical center in Ho Chi Minh City, Vietnam. None of these patients received urate-lowering drugs. Kidney medulla echogenicity on B-mode ultrasonography was compared to that of the kidney cortex. Overall, 36% patients showed a hyperechoic pattern of Malpighi pyramids. On univariate analysis, the pattern was significantly associated with age, estimated gout duration, steroid-dependency, clinical tophi, urate arthropathy, double contour thickness at the scanned joints, coronary heart disease, arterial hypertension, hyperuricemia, proteinuria, leukocyturia, and decreased estimated glomerular filtration rate. On multivariable analysis, the hyperechoic pattern was associated with estimated disease duration, clinical tophi, urate arthropathy, double contour thickness and decreased estimated glomerular filtration rate. No hyperechoic pattern was observed in 515 consecutive consultants without gout. Thus, hyperechoic kidney medulla was frequently demonstrated in Vietnamese patients with tophaceous gout and associated with features of tubulointerstitial nephritis. This finding revives the hypothesis of microcrystalline nephropathy of gout, predominantly seen in untreated gouty patients, which could be an important target for urate-lowering therapy.
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It is reported in this study a new approach for modulation and even suppression of the electroosmotic flow (EOF) to achieve better electrokinetic preconcentration in capillary electrophoresis. This ...is based on the augmentation of the buffer’s concentrations to very high levels (more than a thousand of mM) without recourse to any dynamic/permanent coating nor viscous gel. The use of large weakly charged molecules as background electrolyte’s constituents allows working at extreme concentration ranges without penalty of high electric currents and Joule heating. By this way, the electroosmotic mobility could be modulated over a wide range (2–60 × 10−5 cm2 V−1 s−1 under alkaline conditions), and suppressed to levels equivalent to those obtained with several neutral coatings. The highest buffer concentrations, and the lowest EOF magnitudes, accordingly, were achieved with diethanolamine/3-(Cyclohexylamino)-1-propanesulfonic acid (ionic strength (IS) of 250 mM, pH 9.5), Tris(hydroxymethyl)aminomethane (Tris)/2-(Cyclohexylamino)ethanesulfonic acid (CHES) (IS of 280 mM, pH 8.7) and triethanolamine/2-(Cyclohexylamino)ethanesulfonic acid (IS of 250 mM, pH 8.5). For demonstration, this new approach was applied for sensitive determination of core-shell magnetic nanoparticles (CSMNPs) having high potential for healthcare applications such as imaging agents for diagnostics and controllable cargos for nanomedicine. Different profiles were achieved for purpose-made and commercial magnetic nanoparticles using CE coupled with light-emitting-diode induced fluorescence (LEDIF) detection. The best performance for EOF-assisted preconcentration and CE-LEDIF of CSMNPs was achieved with these nanoparticles prepared in TRIS/CHES (IS 10 mM, pH 8.4) for preconcentration, and separation under BGE of TRIS/CHES (IS 100 mM, pH 8.4). Compared to the conventional capillary electrophoresis (CE-UV) method for characterization of magnetic nanoparticles, our proposed approach with fluorescent detection and EOF-assisted preconcentration offers almost 350-fold sensitivity improvement. Furthermore, our scheme can be used for monitoring the interaction between CSMNPs and target pharmaceutical molecules, serving for drug delivery development. A preliminary study with two antibiotics using this approach revealed that kanamycin interacts better with the target nanoparticles than amikacin.
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•EOF suppression and modulation in silica capillaries without recourse to coating or gel is reported.•A new principle of EOF-assisted electrokinetic preconcentration for CE-LIF is proposed.•The first method for CE-LIF of core-shell magnetic nanoparticles (CSMNPs) was developed.•Detection and interaction study of CSMNPs could be realized with a 350-fold sensitivity improvement.
Large-molecule antibody biologics have revolutionized medicine owing to their superior target specificity, pharmacokinetic and pharmacodynamic properties, safety and toxicity profiles, and ...amenability to versatile engineering. In this review, we focus on preclinical antibody developability, including its definition, scope, and key activities from hit to lead optimization and selection. This includes generation, computational and in silico approaches, molecular engineering, production, analytical and biophysical characterization, stability and forced degradation studies, and process and formulation assessments. More recently, it is apparent these activities not only affect lead selection and manufacturability, but ultimately correlate with clinical progression and success. Emerging developability workflows and strategies are explored as part of a blueprint for developability success that includes an overview of the four major molecular properties that affect all developability outcomes: 1) conformational, 2) chemical, 3) colloidal, and 4) other interactions. We also examine risk assessment and mitigation strategies that increase the likelihood of success for moving the right candidate into the clinic.
Microglia, the resident macrophages of the central nervous system, are highly motile cells that support brain development, provision neuronal signaling, and protect brain cells against damage. Proper ...microglial functioning requires constant cell movement and morphological changes. Interestingly, the transient receptor potential vanilloid 4 (TRPV4) channel, a calcium‐permeable channel, is involved in hypoosmotic morphological changes of retinal microglia and regulates temperature‐dependent movement of microglial cells both in vitro and in vivo. Despite the broad functions of TRPV4 and the recent findings stating a role for TRPV4 in microglial movement, little is known about how TRPV4 modulates cytoskeletal remodeling to promote changes of microglial motility. Here we show that acute inhibition of TRPV4, but not its constitutive absence in the Trpv4 KO cells, affects the morphology and motility of microglia in vitro. Using high‐end confocal imaging techniques, we show a decrease in actin‐rich filopodia and tubulin dynamics upon acute inhibition of TRPV4 in vitro. Furthermore, using acute brain slices we demonstrate that Trpv4 knockout microglia display lower ramification complexity, slower process extension speed and consequently smaller surveyed area. We conclude that TRPV4 inhibition triggers a shift in cytoskeleton remodeling of microglia influencing their migration and morphology.
Main Points
Acute inhibition of TRPV4 abrogates microtubule and actin‐rich filopodia dynamism in microglia in vitro.
Trpv4 KO microglia exhibit less ramification complexity and slower process extension speed in situ.
Vemurafenib is a new‐targeted therapy approved for the treatment of patients with V600E BRAF‐mutant metastatic melanoma. Among the cutaneous adverse events reported, the photosensitivity is ...frequently experienced. We aimed to characterize more deeply the mechanism leading to this photosensitivity as well as the corresponding UV spectrum. Phototests showed that the phototoxicity was UVA‐dependent since from normal value prior to vemurafenib treatment, the UVA‐minimal erythema dose decreased in 17 of 18 patients (94.4%) while the minimal erythema dose remained unchanged. Furthermore, a vemurafenib‐induced erythema appeared quickly during the UVA exposure contrarily to what is observed with a conventional drug‐induced phototoxicity showing an erythema 12–24 h after the phototesting. Vitamin PP concentration decreased, and porphyrin level significantly increased after 2 months of vemurafenib. Our study confirms the high risk of vemurafenib‐induced photosensitivity and indicates that it is possibly vitamin PP‐ and porphyrin dependent.
Abstract
Microtubule (MT)-based transport is an evolutionary conserved process finely tuned by posttranslational modifications. Among them, α-tubulin acetylation, primarily catalyzed by a vesicular ...pool of α-tubulin N-acetyltransferase 1 (Atat1), promotes the recruitment and processivity of molecular motors along MT tracks. However, the mechanism that controls Atat1 activity remains poorly understood. Here, we show that ATP-citrate lyase (Acly) is enriched in vesicles and provide Acetyl-Coenzyme-A (Acetyl-CoA) to Atat1. In addition, we showed that Acly expression is reduced upon loss of Elongator activity, further connecting Elongator to Atat1 in a pathway regulating α-tubulin acetylation and MT-dependent transport in projection neurons, across species. Remarkably, comparable defects occur in fibroblasts from Familial Dysautonomia (FD) patients bearing an autosomal recessive mutation in the gene coding for the Elongator subunit ELP1. Our data may thus shine light on the pathophysiological mechanisms underlying FD.
We consider the finite-time stabilization of homogeneous quasilinear hyperbolic systems with one side controls and with nonlinear boundary condition at the other side. We present time-independent ...feedbacks leading to the finite-time stabilization in any time larger than the optimal time for the null controllability of the linearized system if the initial condition is sufficiently small. One of the key technical points is to establish the local well-posedness of quasilinear hyperbolic systems with nonlinear, non-local boundary conditions.
The purpose of this study was to evaluate the percentage of coronary angiography that can be securely avoided by the interpretation of coronary arteries on pre transcatheter aortic valve implantation ...CT (TAVI-CT), using CT images obtained with deep-learning reconstruction and motion correction algorithms.
All consecutive patients who underwent TAVI-CT and coronary angiography, from December 2021 to July 2022 were screened for inclusion in the study. Patients who had previous coronary artery revascularization or who did not undergo TAVI were excluded. All TAVI-CT examinations were obtained using deep-learning reconstruction and motion correction algorithms. On TAVI-CT examinations, quality and stenosis of coronary artery were analyzed retrospectively. When insufficient image quality and/or when diagnosis or doubt of one significant coronary artery stenosis, patients were considered as having possible coronary artery stenosis. The results of coronary angiography were used as the standard of reference for significant CAS.
A total of 206 patients (92 men; mean age, 80.6 years) were included; of these 27/206 (13%) had significant coronary artery stenosis on coronary angiography and were referred for potential revascularization. Sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of TAVI-CT to identify patients requiring coronary artery revascularization was 100% (95% confidence interval CI: 87.2-100%), 100% (95% CI: 96.3-100%), 54% (95% CI: 46.6-61.6), 25% (95% CI: 17.0-34.0%) and 60% (95% CI: 53.1-66.9%) respectively. Intra- and inter observer variability was substantial agreement for quality and decision to recommend coronary angiography. Mean reading time was 2 ± 1.2 (standard deviation) min (range: 1-5 min). Overall, TAVI-CT could potentially rule out indication for revascularization for 97 patients (47%).
Analysis of coronary artery on TAVI-CT using deep-learning reconstruction and motion correction algorithms can potentially safely avoid coronary angiography in 47% of patients.
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