Search

Inflammation is a defense mechanism that restores tissue damage and eliminates pathogens. Among the pattern recognition receptors that recognize danger or pathogenic signals, nucleotide oligomerization domains 1 and 2 (NOD1/2) have been identified to play an important role in innate immunity responses, and inhibition of NOD1 could be interesting to treat severe infections and inflammatory diseases. In this work, we identified the first selective NOD1 versus NOD2 pathway inhibitors at the nanomolar range based on a 4-anilinoquinazoline scaffold. We demonstrated that NOD1 inhibition occurs through the inhibition of receptor interacting protein kinase 2 (RIPK2), which is involved in its downstream signaling pathways. Compound 37demonstrates no cytotoxicity, a selectivity for RIPK2 over epithelial and vascular endothelial growth factor receptors (EGFR/VEGFR), and a capacity to reduce pro-inflammatory cytokine IL-8 secretion. The structure of the RIPK2–compound 37complex was resolved by crystallography. The 4-anilinoquinazoline scaffold offers novel perspectives to design NOD1-RIPK2 signaling inhibitors.

Although they are not often in explicit conversation with each other, several scholarly contributions about the otherwise and grace, respectively, echo each other in striking ways. In this article, the author explores some of these echoes. Assembling theoretically various approaches to the otherwise and grace allows him to show that they both tread on similar theopolitical paths, and to identify three points on which they converge: excess, incarnation and turbulence. The article is structured around these three confluences. Each section begins with a description of a particular way of approaching the otherwise, which is then compared with a similar way of approaching grace. Each section concludes with reflections on the spaces of convergence thus identified, and it is argued that they constitute promising sites for the deployment of a ‘theopolitical analytics’ in anthropology.

MicroIC enables display attributes unattainable from polycrystalline thin‐film transistors, and the complimentary metal‐oxide semiconductor (CMOS) microICs support a wide range of applications beyond driving pixels. Integrating sensors within displays can add value to products, reduce costs and improve performance versus conventional solutions. As evidenced by touch and display integration in mobile displays via TDDI ICs, in‐cell sensing can reduce cost and improve performance to levels that are not available with all display types. Capacitive touch, optical touch, 3D scanning, and proximity sensing can also benefit from the inherent coordination between sensors and display. We present multiple sensing architectures and demonstrations of integration within microLED displays and describe CMOS microIC circuits for touch sensing applications. With diverse heterogenous semiconductor technology tightly woven into displays, the potential for intuitive gesture controls, adaptive interfaces, and enhanced sensory feedback paves the way for more natural and effortless interactions between humans and machines.

Background:Unused opioid prescriptions can be a driver of opioid misuse. Our objective was to determine the optimal quantity of opioids to prescribe to patients with acute pain at emergency department discharge, in order to meet their analgesic needs while limiting the amount of unused opioids.Methods:In a prospective, multicentre cohort study, we included consecutive patients aged 18 years and older with an acute pain condition present for less than 2 weeks who were discharged from emergency department with an opioid prescription. Participants completed a pain medication diary for real-time recording of quantity, doses, and names of all analgesics consumed during a 14-day follow-up period.Results:We included 2240 participants, who had a mean age of 51 years; 48% were female. Over 14 days, participants consumed a median of 5 (quartiles, 1–14) morphine 5 mg tablet equivalents, with significant variation across pain conditions (p< 0.001). Most opioid tablets prescribed (63%) were unused. To meet the opioid need of 80% of patients for 2 weeks, we found that those experiencing renal colic or abdominal pain required fewer opioid tablets (8 morphine 5 mg tablet equivalents) than patients who had fractures (24 tablets), back pain (21 tablets), neck pain (17 tablets), or other musculoskeletal pain (16 tablets).Interpretation:Two-thirds of opioid tablets prescribed at emergency department discharge for acute pain were unused, whereas opioid requirements varied significantly based on the cause of acute pain. Smaller, cause-specific opioid prescriptions could provide adequate pain management while reducing the risk of opioid misuse. Trial registration:ClinicalTrials.gov, no. NCT03953534.

Electrochemical Impedance Spectroscopy (EIS) is a widely used tool for selecting a pertinent Equivalent Circuit Model (ECM) of Li-ion cells which is characterized by non integer order operators. The main drawback of EIS is the long time required to scan a whole spectrum down to low frequencies. Thus, chronopotentiometry (CP) is an alternative method which consists in identifying impedance parameters using an excitation current sequence lasting a few seconds and the corresponding induced voltage variations. An impedance fractional model needs to be synthesized in order to allow simulation also in the time domain. The pertinence of CP is demonstrated using experimental results obtained with a Samsung 3.4 Ah Li-ion cell. Due to its inability to take into account the inductive behavior, fractional model used in the time domain exhibit limitations. Nevertherless, parameters identified in the time domain present similar results to the ones identified in the frequency domain under the condition of a restricted frequency range.

Electrochemical Impedance Spectroscopy (EIS) is a useful tool for selecting a pertinent Equivalent Circuit Model (ECM) of a Li-ion battery. Impedance model is designed to describe low, middle and high frequency electrochemical processes involved. When considering low frequency restricted in the Warburg zone, diffusion impedance is modeled thanks to a Constant Phase Element (CPE) which behaves as a fractional integrator of order n close to 0.5. Phenomena observed in middle frequency are described using specific circuits called Zarc which consist in connecting a CPE in parallel with a resistor. Therefore, the global impedance model is characterized by non integer order operators and parameters can be estimated by a Complex Non linear Least Squares (CNLS) algorithm which requires a proper initialization in order to guarantee the convergence to a global optimum. The paper presents a method to analyze EIS data measurements in order to select automatically the number of middle frequency Zarc circuits required (one or two) and to initialize properly the CNLS algorithm. The method is validated using experimental open source EIS data.

Stem cell therapy represents one of the most promising approaches for tissue repair and regeneration. However, the full potential of stem cell therapy remains to be realized. One major challenge is the insufficient homing and retention of stem cells at the desired sites after in vivodelivery. Here, we provide a proof-of-principle demonstration of magnetic targeting and retention of human muscle-derived stem cells (hMDSCs) in vitrothrough magnetic force-mediated internalization of magnetic iron oxide nanoparticles (MIONs) and the use of a micropatterned magnet. We found that the magnetic force-mediated cellular uptake of MIONs occurs through an endocytic pathway, and the MIONs were exclusively localized in the lysosomes. The intracellular MIONs had no detrimental effect on the proliferation of hMDSCs or their multilineage differentiation, and no MIONs were translocated to other cells in a coculture system. Using hMDSCs and three other cell types including human umbilical vein endothelial cells (HUVECs), human dermal fibroblasts (HDFs), and HeLa cells, we further discovered that the magnetic force-mediated MION uptake increased with MION size and decreased with cell membrane tension. We found that the cellular uptake rate was initially increased with MION concentration in solution and approached saturation. These findings provide important insight and guidance for magnetic targeting of stem cells in therapeutic applications.

POINTS CLÉSLa recherche et le suivi des contacts sont des éléments essentiels des programmes de lutte antituberculeuse (TB) au Canada et du cadre de l’Organisation mondiale de la Santé (OMS) pour l’élimination de la TB dans les pays où le nombre de cas est faible par rapport à sa population.À quelques exceptions près, seules les TB pulmonaire et laryngée sont contagieuses. Il est recommandé d’établir un ordre de priorité pour la recherche des contacts selon la contagiosité du cas source, l’ampleur de l’exposition et la vulnérabilité immunitaire des personnes exposées; cette recherche devrait être réalisée tant auprès des cas dont le frottis d’expectorations était positif que de ceux dont le frottis était négatif. La recherche des contacts est itérative: elle devrait être étendue si les résultats initiaux indiquent qu’une transmission est survenue.La recherche des contacts a pour but d’identifier de manière rapide et de traiter tous les cas secondaires et d’identifier les contacts atteints d’une infection tuberculeuse latente (ITL) afin de leur offrir un ­traitement préventif. La recherche du cas source (« recherche de contacts inversée en remontant au cas source ») est recommandée pour les enfants de moins de 5 ans atteints de TB active.Les contacts familiaux sont toujours les plus à risque, même lorsque le cas index a obtenu un résultat négatif au frottis d’expectorations. En théorie, aucune exposition à un cas contagieux de TB n’est absolument sans risque; en pratique, presque toutes les transmissions se produisent suivant un contact étroit, prolongé ou répété pendant des jours ou des mois.L’évaluation clinique, le dépistage de la TB et le suivi des contacts devraient être effectués conformément aux pratiques normatives; et les programmes de lutte antituberculeuse devraient clairement indiquer les services d’intervention clinique.

L’objectif était de déterminer les effets de la perfusion continue de solutions salines hypertoniques sur les résultats des patients souffrant de lésions cérébrales.

L’érythème polymorphe est une éruption cutanée généralement secondaire à une infection ou un médicament. Plus rarement, une dermatite de contact peut survenir sous une forme dite « érythème polymorphe-like ».

Perceived competence plays a crucial role in establishing environments favorable to individual development in youth sport. As most assessment tools of perceived competence are not sport-specific, they have limited usefulness for sport practitioners and researchers. This study had two-fold aims: (i) to develop a perceived competence assessment tool specific to ice hockey; and (ii) to examine its factorial structure and internal consistency. We first developed an initial 29-item version of this ice hockey competence self-report scale, using a group of ice hockey stakeholders and sports science experts to develop the items and a pilot sample of 42 hockey players to confirm test-retest reliability. Finally, we validated the scale among a cohort of 770 adolescent ice hockey players (Mage = 14.78, SD= 1.60 years). Results from exploratory factor analysis (EFA) revealed that perceived competence in ice hockey was defined by six dimensions, with rejection of seven items. Confirmatory factor analysis (CFA) suggested that the 6-factor first order model was the best fit with the conceptualization of perceived competence in ice hockey (CFI = 0.938, RMSEA = 0.044). The final, 22-item questionnaire now provides a reliable and valid measure of perceived competence in hockey for adolescent participants. It has promise for evaluating future interventions aiming to foster young athletes’ perceived confidence through sport.

The article discusses Gerry Torres' innovative concept for his latest City Tacos restaurant in Ocean Beach - a playground with various amenities, including a remodeled van for small businesses, games, picnic areas, and murals.

Eosinophils may reside in the lower intestine to play several homeostatic functions. Regulation of IgA+plasma-cell (PC) homeostasis is one of these functions. Here, we assessed regulation of expression for a proliferation-inducing ligand (APRIL), a key factor from the TNF superfamily for PC homeostasis, in eosinophils from the lower intestine. We observed a strong heterogeneity, since duodenum eosinophils did not produce APRIL at all, whereas a large majority of eosinophils from the ileum and right colon produced it. This was evidenced both in the human and mouse adult systems. At these places, the human data showed that eosinophils were the only cellular sources of APRIL. The number of IgA+PCs did not vary along the lower intestine, but ileum and right colon IgA+PC steady-state numbers significantly diminished in APRIL-deficient mice. Use of blood cells from healthy donors demonstrated that APRIL expression in eosinophils is inducible by bacterial products. Use of germ-free and antibiotics-treated mice confirmed the dependency on bacteria for APRIL production by eosinophils from the lower intestine. Taken together, our study shows that APRIL expression by eosinophils is spatially regulated in the lower intestine with a consequence on the APRIL dependency for IgA+PC homeostasis.The study demonstrates that microbiotal component(s) from the ileum and colon induce(s) APRIL expression in bloodborne eosinophils to mediate plasma-cell survival in the lamina propria. This APRIL-dependent survival pathway is not active in the duodenum.

A central goal of any quantum technology consists in demonstrating an advantage in their performance compared to the best possible classical implementation. A quantum radar improves the detection of a target placed in a noisy environment by exploiting quantum correlations between two modes, probe and idler. The predicted quantum enhancement is not only less sensitive to loss than most quantum metrological applications, but it is also supposed to improve with additional noise. Here we demonstrate a superconducting circuit implementing a microwave quantum radar that can provide more than 20% better performance than any possible classical radar. The scheme involves joint measurement of entangled probe and idler microwave photon states after the probe has been reflected from the target and mixed with thermal noise. By storing the idler state in a resonator, we mitigate the detrimental impact of idler loss on the quantum advantage. Measuring the quantum advantage over a wide range of parameters, we find that the purity of the initial probe-idler entangled state is the main limiting factor and needs to be considered in any practical application.

Objectives: Our aim was to compare some of the health outcomes and costs associated with value of care in emergency departments (ED) and walk-in clinics for ambulatory patients presenting with an acute respiratory disease. Methods: A health records review was conducted from April 2016 through March 2017 in one ED and one walk-in clinic. Inclusion criteria were: (i) ambulatory patients at least 18 years old, (ii) discharged home with a diagnosis of upper respiratory tract infection (URTI), pneumonia, acute asthma, or acute exacerbation of chronic obstructive pulmonary disease. Primary outcome was the proportion of patients returning to any ED or walk-in clinic within three and seven days of the index visit. Secondary outcomes were the mean cost of care and the incidence of antibiotic prescription for URTI patients. The cost of care was estimated from the Ministry of Health’s perspectives using time-driven activity-based costing. Results: The ED group included 170 patients and the walk-in clinic group 326 patients. The return visit incidences at three and seven days were, respectively, 25.9% and 38.2% in the ED vs. 4.9% and 14.7% in the walk-in clinic (adjusted relative risk (arr) of 4.7 (95% CI 2.6–8.6) and 2.7 (1.9–3.9)). The mean cost ($Cdn) of the index visit care was 116.0 (106.3–125.7) in the ED vs. 62.5 (57.7–67.3) in the walk-in clinic (mean difference of 56.4 (45.7–67.1)). Antibiotic prescription for URTI was 5.6% in the ED vs. 24.7% in the walk-in clinic (arr 0.2, 0.01–0.6). Conclusions: This study is the first in a larger research program to compare the value of care between walk-in clinics and the ED. The potential advantages of walk-in clinics over EDs (lower costs, lower incidence of return visits) for ambulatory patients with respiratory diseases should be considered in healthcare planning.

Despite their rarity, PIK3CAmutations in meningiomas have raised interest as potentially targetable, ubiquitous mutations owing to their presence in sporadic benign and malignant tumors but also in hormone-related cases. Using new genetically engineered mouse models, we here demonstrate that Pik3camutations in postnatal meningeal cells are sufficient to promote meningioma formation but also tumor progression in mice. Conversely, hormone impregnation, whether alone or in association with Pik3caand Nf2mutations, fails to induce meningioma tumorigenesis while promoting breast tumor formation. We then confirm in vitro the effect of Pik3camutations but not hormone impregnation on the proliferation of primary cultures of mouse meningeal cells. Finally, we show by exome analysis of breast tumors and meninges that hormone impregnation promotes breast tumor formation without additional somatic oncogenic mutation but is associated with an increased mutational burden on Pik3ca-mutant background. Taken together, these results tend to suggest a prominent role of Pik3camutations over hormone impregnation in meningioma tumorigenesis, the exact effect of the latter is still to be discovered.

An arsenal of molecular tools with increasingly diversified mechanisms of action is being developed by the scientific community to enable biological interrogation and pharmaceutical modulation of targets and pathways of ever increasing complexity. While most small molecules interact with the target of interest in a 1 : 1 relationship, a noteworthy number of recent examples were reported to bind in a sub-stoichiometric manner to a homomeric protein complex. This approach requires molecular understanding of the physiologically relevant protein assemblies and in-depth characterization of the compound's mechanism of action. The recent literature examples summarized here were selected to illustrate methods used to identify and characterize molecules with such mechanisms. The concept of one small molecule targeting a homomeric protein assembly is not new but the subject deserves renewed inspection in light of emerging technologies and increasingly diverse target biology, to ensure relevant in vitrosystems are used and valuable compounds with potentially novel sub-stoichiometric mechanisms of action aren't overlooked.

L’immunothérapie (I) a amélioré le pronostic des patients atteints de mélanome métastatique. Un défi demeure pour ceux présentant une maladie leptoméningée (MLM), soit 5 à 25 % des patients. Des données récentes ont été publiées sur l’association nivolumab intrathécal (IT) et intraveineux (IV) dans le mélanome avec MLM. Nous présentons le cas d’un patient atteint de MLM associée à un mélanome, traité avec succès par nivolumab IT et thérapie ciblée (TC).

Le syringo-fibroadénome eccrine (SFAE) est une tumeur annexielle rare dérivée des cellules de l’acrosyringium des glandes sudoripares eccrines, initialement décrit par Mascaro en 1993. Les présentations cliniques sont multiples: un nodule isolé, de multiples papules, voire un placard érythémateux.

La périartérite noueuse (PAN) est une vascularite systémique rare. Les manifestations cutanées sont habituellement au premier plan et sont souvent réfractaires ou récidivantes malgré l’utilisation de corticoïdes oraux et d’immunosuppresseurs conventionnels. L’IL-6 est une cytokine pro-inflammatoire dont les taux sériques sont élevés chez les patients atteints de PAN ; cependant il n’existe que peu de données sur l’efficacité des anti-IL6 dans cette maladie. L’objectif de ce travail est de décrire l’utilisation du tocilizumab, un anti-IL-6, chez des patients avec une atteinte cutanée réfractaire de PAN.

Heart failure is among the first major consequences of heat stress in aquatic ectotherms. Mitochondria produce most of the ATP used by the heart and represent almost half of the volume in cardiac cells. It has therefore been hypothesized that mitochondrial dysfunction may be a major cause of heart failure associated with heat stress. The present study aims to investigate if CTmax is linked to the thermal sensitivity of cardiac mitochondria in the three-spined stickleback (Gasterosteus aculeatus), and if it is influenced by heart fatty acid composition and age. To do so, we measured the CTmax of 30 fish. The cardiac mitochondrial oxygen consumption was measured by high resolution respirometry at three temperatures and heart lipid profiles were obtained by gas chromatography (GC) coupled with a flame ionization detector (FID). Fish age was estimated via otolith readings. Fatty acid profiles showed no correlation with CTmax, but EPA levels were higher in older individuals. Mitochondrial respiration was measured in 35 fish using high-resolution respirometry. It was strongly affected by temperature and showed a drastic drop in OXPHOS respiration fed by complex I and complex I+complex II, while uncoupled respiration plateaued at CTmax temperature. Our results suggest that complex I is an important modulator of the impact of temperature on mitochondrial respiration at high temperatures but is not the main limiting factor in physiological conditions (maximal OXPHOS). Mitochondrial respiration was also affected by fish age, showing a general decrease in older individuals.

Fibro‐adipogenic progenitors (FAPs) in the muscles have been found to interact closely with muscle progenitor/stem cells (MPCs) and facilitate muscle regeneration at normal conditions. However, it is not clear how FAPs may interact with MPCs in aged muscles. Senolytics have been demonstrated to selectively eliminate senescent cells and generate therapeutic benefits on ageing and multiple age‐related disease models. By studying the muscles and primary cells of age matched WT mice and Zmpste24−/−(Z24−/−) mice, an accelerated ageing model for Hutchinson–Gilford progeria syndrome (HGPS), we examined the interaction between FAPs and MPCs in progeria‐aged muscle, and the potential effect of senolytic drug fisetin in removing senescent FAPs and improving the function of MPCs. We observed that, compared with muscles of WT mice, muscles of Z24−/−mice contained a significantly increased number of FAPs (2.4‐fold; n> =6, P< 0.05) and decreased number of MPCs (2.8‐fold; n> =6, P< 0.05). FAPs isolated from Z24−/−muscle contained about 44% SA‐β‐gal+ senescent cells, in contrast to about 3.5% senescent cells in FAPs isolated from WT muscle (n> =6, P< 0.001). The co‐culture of Z24−/−FAPs with WT MPCs resulted in impaired proliferation and myogenesis potential of WT MPCs, with the number of BrdU positive proliferative cells being reduced for 3.3 times (n> =6, P< 0.001) and the number of myosin heavy chain (MHC)‐positive myotubes being reduced for 4.5 times (n> =6, P< 0.001). The treatment of the in vitroco‐culture system of Z24−/−FAPs and WT MPCs with the senolytic drug fisetin led to increased apoptosis of Z24−/−FAPs (14.5‐fold; n> =6, P< 0.001) and rescued the impaired function of MPCs by increasing the number of MHC‐positive myotubes for 3.1 times (n> =6, P< 0.001). Treatment of Z24−/−mice with fisetin in vivowas effective in reducing the number of senescent FAPs (2.2‐fold, n> =6, P< 0.05) and restoring the number of muscle stem cells (2.6‐fold, n> =6, P< 0.05), leading to improved muscle pathology in Z24−/−mice. These results indicate that the application of senolytics in the progeria‐aged muscles can be an efficient strategy to remove senescent cells, including senescent FAPs, which results in improved function of muscle progenitor/stem cells. The senescent FAPs can be a potential novel target for therapeutic treatment of progeria ageing related muscle diseases.

Discovery efforts leading to the identification of ervogastat (PF-06865571), a systemically acting diacylglycerol acyltransferase (DGAT2) inhibitor that has advanced into clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) with liver fibrosis, are described herein. Ervogastat is a first-in-class DGAT2 inhibitor that addressed potential development risks of the prototype liver-targeted DGAT2 inhibitor PF-06427878. Key design elements that culminated in the discovery of ervogastat are (1) replacement of the metabolically labile motif with a 3,5-disubstituted pyridine system, which addressed potential safety risks arising from a cytochrome P450-mediated O-dearylation of PF-06427878 to a reactive quinone metabolite precursor, and (2) modifications of the amide group to a 3-THF group, guided by metabolite identification studies coupled with property-based drug design.

This article proposes an analysis of local politics through an ethnographic exploration of headship. It approaches the experience and enactment of politics by describing a day in the life of a headman in rural lowland Myanmar to show how an individual embodies and fashions headship through successive social settings. More specifically, this ethnographic device is a way to analyze what a headman, as a situated figure and a political institution embedded in a local society, mediates in context. The paper discusses how a headman composes with multiple layers of responsibilities and chains of relationships, delineating uncertain boundaries between the personal, the political, and the government domains that partly organize local politics. While updating the literature on Bamar lowland society after more than half a century of dictatorship, the paper suggests a position from which we might reconsider the village headman as an ethnographic starting point for an anthropology concerned with history.

The article discusses the commercial development at downtown San Diego, California, as of April 2022. Topics include downtown projects that are in the planning stages; comments from Stath Karras of Burnham-Moores Center for Real Estate at the University of San Diego, on downtown's evolution; downtown's move toward respectability in the 1980s, and population at the downtown.

Background:Severe COVID-19 appears to disproportionately affect people who are immunocompromised, although Canadian data in this context are limited. We sought to determine factors associated with severe COVID-19 outcomes among recipients of organ transplants across Canada.Methods:We performed a multicentre, prospective cohort study of all recipients of solid organ transplants from 9 transplant programs in Canada who received a diagnosis of COVID-19 from March 2020 to November 2021. Data were analyzed to determine risk factors for oxygen requirement and other metrics of disease severity. We compared outcomes by organ transplant type and examined changes in outcomes over time. We performed a multivariable analysis to determine variables associated with need for supplemental oxygen.Results:A total of 509 patients with solid organ transplants had confirmed COVID-19 during the study period. Risk factors associated with needing (n= 190), compared with not needing (n= 319), supplemental oxygen included age (median 62.6 yr, interquartile range [IQR] 52.5–69.5 yr v. median 55.5 yr, IQR 47.5–66.5; p< 0.001) and number of comorbidities (median 3, IQR 2–3 v. median 2, IQR 1–3; p< 0.001), as well as parameters associated with immunosuppression. Recipients of lung transplants (n= 48) were more likely to have severe disease with a high mortality rate (n= 15, 31.3%) compared with recipients of other organ transplants, including kidney (n= 48, 14.8%), heart (n= 1, 4.4%), liver (n= 9, 11.4%) and kidney–pancreas (n= 3, 12.0%) transplants (p= 0.02). Protective factors against needing supplemental oxygen included having had a liver transplant and receiving azathioprine. Having had 2 doses of SARS-CoV-2 vaccine did not have an appreciable influence on oxygen requirement. Multivariable analysis showed that older age (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.02–1.07) and number of comorbidities (OR 1.63, 95% CI 1.30–2.04), among other factors, were associated with the need for supplemental oxygen. Over time, disease severity did not decline significantly.Interpretation:Despite therapeutic advances and vaccination of recipients of solid organ transplants, evidence of increased severity of COVID-19, in particular among those with lung transplants, supports ongoing public health measures to protect these at-risk people, and early use of COVID-19 therapies for recipients of solid organ transplants.

RésuméContexte:La forme grave de COVID-19 semble affecter de manière disproportionnée les gens immunovulnérables, même si les données canadiennes dans ce contexte sont limitées. Nous avons voulu déterminer quels facteurs sont associés aux paramètres de la forme grave de COVID-19 chez les receveurs de transplantations au Canada.Méthodes:Nous avons procédé à une étude de cohorte multicentrique prospective regroupant tous les receveurs d’une transplantation d’organe plein ayant reçu un diagnostic de COVID-19 suivis dans 9 programmes de transplantation au Canada entre mars 2020 et novembre 2021. Les données ont été analysées afin de dégager les facteurs de risque à l’égard du recours à l’oxygénothérapie et autres critères de la gravité de la maladie. Nous avons comparé les paramètres selon le type d’organe transplanté et suivi l’évolution des paramètres au fil du temps. Nous avons procédé à une analyse multivariée pour déterminer quelles variables sont associées au recours à l’oxygénothérapie.Résultats:En tout, 509 patients ayant reçu une transplantation d’organe plein ont contracté la COVID-19 durant la période de l’étude. Les facteurs de risque associés au recours à l’oxygénothérapie (n= 190) ou non (n= 319) incluaient l’âge (âge médian 62,6 ans, intervalle interquartile [II] 52,5–69,5 ans c. âge médian 55,5 ans, II 47,5–66,5; p< 0,001) et le nombre de comorbidités (nombre médian 3, II 2–3 c. nombre médian 2, II 1–3; p< 0,001), de même que les paramètres concernant l’immunosuppression. Les receveurs d’une transplantation pulmonaire (n= 48) étaient plus susceptibles de souffrir d’une forme grave de la maladie, avec un taux de mortalité élevé (n= 15, 31,3 %) comparativement aux receveurs d’autres organes, y compris le rein (n= 48, 14,8 %), le cœur (n= 1, 4,4 %), le foie (n= 9, 11,4 %) et le rein–pancréas (n= 3, 12,0 %) (p= 0,02). Les facteurs protecteurs contre le recours à l’oxygénothérapie incluaient le fait d’avoir subi une transplantation hépatique et de recevoir de l’azathioprine. Le fait d’avoir reçu 2 doses de vaccin anti-SRAS-CoV-2 n’a pas eu d’influence appréciable sur le recours à l’oxygénothérapie. L’analyse multivariée a montré que l’âge avancé (rapport des cotes [RC] 1,04, intervalle de confiance [IC] de 95 % 1,02–1,07) et le nombre de comorbidités (RC 1,63, IC de 95 % 1,30–2,04), entre autres facteurs, étaient associés au recours à l’oxygénothérapie. La gravité de la maladie n’a pas considérablement diminué au fil du temps.Interprétation :Malgré les progrès thérapeutiques et la vaccination des receveurs d’une transplantation d’organe plein, les signes de gravité accrue de la COVID-19, en particulier chez les receveurs d’une transplantation pulmonaire, justifient le maintien des mesures de santé publique pour protéger ces personnes à risque, et l’utilisation hâtive de traitements contre la COVID-19 chez les receveurs d’une transplantation d’organe plein.

The coronavirus disease 2019 (COVID-19) pandemic has demonstrated a clear need for high-throughput, multiplexed and sensitive assays for detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory viruses and their emerging variants. Here, we present a cost-effective virus and variant detection platform, called microfluidic Combinatorial Arrayed Reactions for Multiplexed Evaluation of Nucleic acids (mCARMEN), which combines CRISPR-based diagnostics and microfluidics with a streamlined workflow for clinical use. We developed the mCARMEN respiratory virus panel to test for up to 21 viruses, including SARS-CoV-2, other coronaviruses and both influenza strains, and demonstrated its diagnostic-grade performance on 525 patient specimens in an academic setting and 166 specimens in a clinical setting. We further developed an mCARMEN panel to enable the identification of 6 SARS-CoV-2 variant lineages, including Delta and Omicron, and evaluated it on 2,088 patient specimens with near-perfect concordance to sequencing-based variant classification. Lastly, we implemented a combined Cas13 and Cas12 approach that enables quantitative measurement of SARS-CoV-2 and influenza A viral copies in samples. The mCARMEN platform enables high-throughput surveillance of multiple viruses and variants simultaneously, enabling rapid detection of SARS-CoV-2 variants.

Autologous platelet-rich plasma (PRP) has gained popularity as a less invasive treatment for various musculoskeletal tissue injuries and conditions due to its favorable safety profile, minimal manipulation and cost-effectiveness. Although PRP treatment has been clinically used for the treatment of osteoarthritis (OA) and damaged cartilage, evidence on therapeutic efficacy has been inconsistent, which calls for a methodology to achieve consistent and improved treatment outcomes. Given that PRP contains numerous proteins, we hypothesized that attenuation of a growth factor known to be detrimental to the healing tissue would enhance efficacy of PRP treatment. Considering that VEGF-mediated angiogenesis inhibits the repair of articular cartilage, we developed VEGF-attenuated PRP by sequestering VEGF in PRP using VEGF-binding microspheres. We demonstrated that VEGF attenuation in PRP did not inhibit the effect of PRP on chondrogenic differentiation of stem cells in vitro. In addition, healing of rat OA cartilage was significantly improved after treatment with VEGF-attenuated PRP when compared to the PRP treatment group or PBS control group. We expect that attenuation of unwanted biological activity using growth factor-binding microspheres could provide a new PRP customization method broadly applicable to various tissue repair processes.

Osteoarthritis (OA) pain is often associated with expression of tumor necrosis factor (TNF-α), suggesting that TNF-α is one of the main contributing factors that causes inflammation, pain and OA pathology. Thus, inhibition of TNF-α could potentially improve OA symptoms and slow disease progression. Anti-TNF-α treatments with antibodies, however, require multiple treatments and cannot entirely block TNF-α. Tumor necrosis factor α-induced protein 8-like 2 (TIPE2) was found to regulate the immune system’s homeostasis, and inflammation, through different mechanisms from anti-TNF-α therapies. With a single treatment of AAV-TIPE2 gene delivery in the accelerated aging Z24-/- mouse model, we found differences in Safranin O staining intensity within the AC region of knee between TIPE2 treated mice and control mice. The glycosaminoglycan content (orange-red) was degraded in the Z24-/- cartilage while shown to be restored in the TIPE2 treated Z24-/- cartilage. We also observed that chondrocytes in Z24-/- mice exhibited a variety of senescent-associated phenotypes. Treatment with TIPE2 decreased TNF-α positive cells, β-Gal activity and p16 expression seen in Z24 -/- mice. Our study demonstrated that AAV-TIPE2 gene delivery effectively blocked TNF-α induced inflammation and senescence and result resulting in the prevention or delay of knee OA in our accelerated aging Z24-/- mouse model.

Tissue invasion by tumor cells induces a host inflammatory response that variably impacts tumorigenesis. This has been well documented for tumor-associated macrophages (TAMs) that could play a pro/M2- or an anti/M1-tumoral function. TAMs frequently infiltrate diffuse large B-cell lymphoma (DLBCL), an aggressive neoplasm arising from germinal center–experienced B cells. However, the pathway leading to the presence of TAMs in DLBCL remains unknown, and their impact is unclear. Here, we show that some DLBCL tumor cells expressed the chemokine CCL5, enabling the differential recruitment of blood monocytes through their expression of CCR1 and CCR5. CCL5 expression by DLBCL was not related to molecular subtypes, and healthy tonsillar B cells did not produce this chemokine, implying a posttransformation event. A single-cell analysis revealed that most DLBCL TAMs had a noncanonical gene signature with the concomitant expression of M1 and M2 genes. The presence of noncanonical TAMs may explain the lack of impact of macrophages on DLBCL development reported in some survival studies.

Tissue invasion by tumor cells induces a host inflammatory response that variably impacts tumorigenesis. This has been well documented for tumor-associated macrophages (TAMs) that could play a pro/M2- or an anti/M1-tumoral function. TAMs frequently infiltrate diffuse large B-cell lymphoma (DLBCL), an aggressive neoplasm arising from germinal center–experienced B cells. However, the pathway leading to the presence of TAMs in DLBCL remains unknown, and their impact is unclear. Here, we show that some DLBCL tumor cells expressed the chemokine CCL5, enabling the differential recruitment of blood monocytes through their expression of CCR1 and CCR5. CCL5 expression by DLBCL was not related to molecular subtypes, and healthy tonsillar B cells did not produce this chemokine, implying a posttransformation event. A single-cell analysis revealed that most DLBCL TAMs had a noncanonical gene signature with the concomitant expression of M1 and M2 genes. The presence of noncanonical TAMs may explain the lack of impact of macrophages on DLBCL development reported in some survival studies.

ABSTRACTMacrophage autophagy is a highly anti-atherogenic process that promotes the catabolism of cytosolic lipid droplets (LDs) to maintain cellular lipid homeostasis. Selective autophagy relies on tags such as ubiquitin and a set of selectivity factors including selective autophagy receptors (SARs) to label specific cargo for degradation. Originally described in yeast cells, “lipophagy” refers to the degradation of LDs by autophagy. Yet, how LDs are targeted for autophagy is poorly defined. Here, we employed mass spectrometry to identify lipophagy factors within the macrophage foam cell LD proteome. In addition to structural proteins (e.g., PLIN2), metabolic enzymes (e.g., ACSL) and neutral lipases (e.g., PNPLA2), we found the association of proteins related to the ubiquitination machinery (e.g., AUP1) and autophagy (e.g., HMGB, YWHA/14-3-3 proteins). The functional role of candidate lipophagy factors (a total of 91) was tested using a custom siRNA array combined with high-content cholesterol efflux assays. We observed that knocking down several of these genes, including Hmgb1, Hmgb2, Hspa5, and Scarb2, significantly reduced cholesterol efflux, and SARs SQSTM1/p62, NBR1 and OPTN localized to LDs, suggesting a role for these in lipophagy. Using yeast lipophagy assays, we established a genetic requirement for several candidate lipophagy factors in lipophagy, including HSPA5, UBE2G2 and AUP1. Our study is the first to systematically identify several LD-associated proteins of the lipophagy machinery, a finding with important biological and therapeutic implications. Targeting these to selectively enhance lipophagy to promote cholesterol efflux in foam cells may represent a novel strategy to treat atherosclerosis.Abbreviations:ADGRL3: adhesion G protein-coupled receptor L3; agLDL: aggregated low density lipoprotein; AMPK: AMP-activated protein kinase; APOA1: apolipoprotein A1; ATG: autophagy related; AUP1: AUP1 lipid droplet regulating VLDL assembly factor; BMDM: bone-marrow derived macrophages; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; BSA: bovine serum albumin; CALCOCO2: calcium binding and coiled-coil domain 2; CIRBP: cold inducible RNA binding protein; COLGALT1: collagen beta(1-O)galactosyltransferase 1; CORO1A: coronin 1A; DMA: deletion mutant array; Faa4: long chain fatty acyl-CoA synthetase; FBS: fetal bovine serum; FUS: fused in sarcoma; HMGB1: high mobility group box 1; HMGB2: high mobility group box 2: HSP90AA1: heat shock protein 90: alpha (cytosolic): class A member 1; HSPA5: heat shock protein family A (Hsp70) member 5; HSPA8: heat shock protein 8; HSPB1: heat shock protein 1; HSPH1: heat shock 105kDa/110kDa protein 1; LDAH: lipid droplet associated hydrolase; LIPA: lysosomal acid lipase A; LIR: LC3-interacting region; MACROH2A1: macroH2A.1 histone; MAP1LC3: microtubule-associated protein 1 light chain 3; MCOLN1: mucolipin 1; NBR1: NBR1, autophagy cargo receptor; NPC2: NPC intracellular cholesterol transporter 2; OPTN: optineurin; P/S: penicillin-streptomycin; PLIN2: perilipin 2; PLIN3: perilipin 3; PNPLA2: patatin like phospholipase domain containing 2; RAB: RAB, member RAS oncogene family; RBBP7, retinoblastoma binding protein 7, chromatin remodeling factor; SAR: selective autophagy receptor; SCARB2: scavenger receptor class B, member 2; SGA: synthetic genetic array; SQSTM1: sequestosome 1; TAX1BP1: Tax1 (human T cell leukemia virus type I) binding protein 1; TFEB: transcription factor EB; TOLLIP: toll interacting protein; UBE2G2: ubiquitin conjugating enzyme E2 G2; UVRAG: UV radiation resistance associated gene; VDAC2: voltage dependent anion channel 2; VIM: vimentin

In the context of finite mixture models one considers the problem of classifying as many observations as possible in the classes of interest while controlling the classification error rate in these same classes. Similar to what is done in the framework of statistical test theory, different type I and type II-like classification error rates can be defined, along with their associated optimal rules, where optimality is defined as minimizing type II error rate while controlling type I error rate at some nominal level. It is first shown that finding an optimal classification rule boils down to searching an optimal region in the observation space where to apply the classical Maximum A Posteriori (MAP) rule. Depending on the misclassification rate to be controlled, the shape of the optimal region is provided, along with a heuristic to compute the optimal classification rule in practice. In particular, a multiclass FDR-like optimal rule is defined and compared to the thresholded MAP rules that is used in most applications. It is shown on both simulated and real datasets that the FDR-like optimal rule may be significantly less conservative than the thresholded MAP rule.

Airway surgery involving trachea or main stem bronchi in neonates and children is challenging. The use of extracorporeal support for such unusual indications is poorly described. Here, we report on three patients receiving peripheral extracorporeal membrane oxygenation (ECMO) to maintain adequate ventilation while improving surgical site exposure. Case 1 is a 9-year-old boy diagnosed with proximal left stem bronchus endoluminal tumor; cases 2 and 3 are a neonate and a young infant diagnosed with a subcarinal bronchogenic cyst. Planned ECMO use consisted in peripheral venoarterial cannulation through jugular and carotid access. There was no bleeding complication during and after surgical care. Hemodynamic and respiratory supports were optimized in all cases. Children were successfully weaned off ECMO immediately after surgery. Planned peripheral ECMO cannulation offers optimal conditions for high-risk airway surgery in neonates and children.

L’incendie de l’usine chimique Lubrizol à Rouen le 26 septembre 2019 a généré une immense colonne de fumée dirigée nord-est vers l’agglomération. L’œil pouvant particulièrement être touché par les fumées et autres dégagements toxiques de l’incendie, nous avons évalué l’impact de cette catastrophe industrielle et écologique sur les pathologies irritatives de surface oculaire dans la semaine suivant l’accident.

Western populations are ageing. With age comes an increased risk of mild cognitive impairment (MCI) and fragility that leads to higher fatal car crashes. This study develops a driving simulation paradigm that seeks to detect unsafe drivers, particularly among older drivers with MCI. The paradigm includes repeated urban intersection crossings at three difficulty levels while eye movements are tracked. The internal validity of this part of the paradigm was tested with young adults (N= 7). Results indicated that the simulator tests elicited unsafe driving behaviors that varied across difficulty and avoided ceiling and floor effects. Eye movement metrics associated with cognitive load also varied with difficulty and predicted safe crosses. The strongest predictors were gaze transition entropy, gaze variability, and pupil size entropy. These findings indicate internal validity of the tests. Future research should test the external validity of this paradigm with a larger, more diverse sample.

The prevalence of pressure injuries (PIs) in critically ill patients has been extensively studied, but there is uncertainty regarding the risk factors. The main objective of this study was to describe the prevalence of PIs in critically ill patients. Secondary objectives were to describe PI, use of preventive measures for PI, and factors associated with occurrence of PI in the intensive care unit (ICU).

RÉSUMÉCette étude expose une analyse phénoménologique de 16 textes écrits lors d’un projet de disque de raps et d’un atelier d’écriture de slams par les membres de gang de rue en centre jeunesse à Montréal. Peu loquaces en thérapie, nous avons cherché ce que ces jeunes y ont dévoilé de leur vécu, afin d’éclairer leur parole et de fournir une validation supplémentaire du dispositif en contexte thérapeutique chez cette population. Nos résultats démontrent la validité du rap et du slam pour libérer leur expression, en plus de leur pertinence pour aborder les enjeux mis en lumière, notamment l’insécurité possiblement liée au trauma et le désespoir découlant d’un milieu manquant de ressources. D’autres études seraient nécessaires afin d’approfondir les connaissances sur les troubles intériorisés de ces jeunes, ainsi que sur le vécu ambivalent de leur prise en charge.

Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly1,2. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence5–7in the immune system only. We show that Vav-iCre+/−;Ercc1−/flmice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice8–10. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/−;Ercc1−/flor aged wild-type mice into young mice induced senescence intrans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/−;Ercc1−/flmice with rapamycin reduced markers of senescence in immune cells and improved immune function11,12. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.

The article highlights Justin Isaac's assumption of leadership at the Lawyer in Blue Jeans Group, a family law firm, in San Diego, California, U.S. It states that Justin Isaac embraces modern media through a podcast and publishes "The Wacky World of Laws" while continuing his family firm's legacy in estate planning, with a focus on staying small and approachable.