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International audience; Purpose: Immune checkpoint blocker (ICB) associated myocarditis (ICB-myocar-ditis) may present similarly and/or overlap with other cardiac pathology including acute cor-onary syndrome presenting a challenge for prompt clinical diagnosis.Methods: An international registry was used to retrospectively identify cases of ICB-myocarditis. Presence of coronary artery disease (CAD) was defined as coronary artery steno-sis >70% in patients undergoing coronary angiogram.Results: Among 261 patients with clinically suspected ICB-myocarditis who underwent a coro-nary angiography, CAD was present in 59/261 patients (22.6%). Coronary revascularization was performed during the index hospitalisation in 19/59 (32.2%) patients. Patients undergoing coro-nary revascularization less frequently received steroids administration within 24 h of admission compared to the other groups (p = 0.029). Myocarditis-related 90-day mortality was 9/17 (52.7%) in the revascularised cohort, compared to 5/31 (16.1%) in those not revascularized and 25/156 (16.0%) in those without CAD (p = 0.001). Immune-related adverse event-related 90-day mortality was 9/17 (52.7%) in the revascularized cohort, compared to 6/31 (19.4%) in those not revascularized and 31/156 (19.9%) in no CAD groups (p = 0.007). All-cause 90-day mortality was 11/17 (64.7%) in the revascularized cohort, compared to 13/31 (41.9%) in no revas-cularization and 60/158 (38.0%) in no CAD groups (p = 0.10). After adjustment of age and sex, coronary revascularization remained associated with ICB-myocarditis-related death at 90 days (hazard ratio [HR] = 4.03, 95% confidence interval [CI] 1.84-8.84, p < 0.001) and was margin-ally associated with all-cause death (HR = 1.88, 95% CI, 0.98-3.61, p = 0.057).Conclusion: CAD may exist concomitantly with ICB-myocarditis and may portend a poorer outcome when revascularization is performed. This is potentially mediated through delayed diag-nosis and treatment or more severe presentation of ICB-myocarditis.

Immune channel inhibitor–induced myocarditis is rare, and its management is challenging. Recently, guidelines were established for all ICIs, yet they do not take into account individual drug toxicities or screening protocols for prevention. We present a rare case of rapidly progressive pembrolizumab-induced fatal myocarditis in an initially asymptomatic patient. (Level of Difficulty: Beginner.), Graphical abstract, Immune channel inhibitor–induced myocarditis is rare, and its management is challenging. Recently, guidelines were established for all ICIs, yet they…

Loss of alveolar type 2 cells (AEC2s) and the ectopic appearance of basal cells in the alveoli characterize severe lung injuries such as idiopathic pulmonary fibrosis (IPF). Here we demonstrate that human alveolar type 2 cells (hAEC2s), unlike murine AEC2s, transdifferentiate into basal cells in response to fibrotic signalling in the lung mesenchyme, in vitro and in vivo. Single-cell analysis of normal hAEC2s and mesenchymal cells in organoid co-cultures revealed the emergence of pathologic fibroblasts and basaloid cells previously described in IPF. Transforming growth factor-β1 and anti-bone morphogenic protein signalling in the organoids promoted transdifferentiation. Trajectory and histologic analyses of both hAEC2-derived organoids and IPF epithelium indicated that hAEC2s transdifferentiate into basal cells through alveolar-basal intermediates that accumulate in proximity to pathologic CTHRC1hi/TGFB1hi fibroblasts. Our study indicates that hAEC2 loss and expansion of alveolar metaplastic basal cells in severe human lung injuries are causally connected through an hAEC2-basal cell lineage trajectory driven by aberrant mesenchyme.

Loss of alveolar type 2 cells (AEC2s) and the ectopic appearance of basal cells in the alveoli characterize severe lung injuries such as idiopathic pulmonary fibrosis (IPF). Here we demonstrate that human alveolar type 2 cells (hAEC2s), unlike murine AEC2s, transdifferentiate into basal cells in response to fibrotic signalling in the lung mesenchyme, in vitro and in vivo. Single-cell analysis of normal hAEC2s and mesenchymal cells in organoid co-cultures revealed the emergence of pathologic fibroblasts and basaloid cells previously described in IPF. Transforming growth factor-β1 and anti-bone morphogenic protein signalling in the organoids promoted transdifferentiation. Trajectory and histologic analyses of both hAEC2-derived organoids and IPF epithelium indicated that hAEC2s transdifferentiate into basal cells through alveolar-basal intermediates that accumulate in proximity to pathologic CTHRC1

Background We previously identified two acute kidney injury (AKI) sub-phenotypes (AKI-SP1 and AKI-SP2) with different risk of poor clinical outcomes and response to vasopressor therapy. Plasma biomarkers of endothelial dysfunction (tumor necrosis factor receptor-1, angiopoietin-1 and 2) differentiated the AKI sub-phenotypes. However, it is unknown whether these biomarkers are simply markers or causal mediators in the development of AKI sub-phenotypes. Methods We tested for associations between single-nucleotide polymorphisms within the Angiopoietin-1, Angiopoietin-2, and Tumor Necrosis Factor Receptor 1A genes and AKI- SP2 in 421 critically ill subjects of European ancestry. Top performing single-nucleotide polymorphisms (FDR Results A genetic variant, rs2920656C > T, near ANGPT2 was associated with reduced risk of AKI-SP2 (odds ratio, 0.45; 95% CI, 0.31–0.66; adjusted FDR = 0.003) and decreased plasma angiopoietin-2 (p = 0.002). Causal inference analysis showed that for each minor allele (T) the risk of developing AKI-SP2 decreases by 16%. Plasma angiopoietin-2 mediated 41.5% of the rs2920656 related risk for AKI-SP2. Human kidney microvascular endothelial cells carrying the T allele of rs2920656 produced numerically lower levels of angiopoietin-2 although this was not statistically significant (p = 0.07). Finally, analyses demonstrated that angiopoietin-2 is minimally renally cleared in critically ill subjects. Conclusion Genetic mediation analysis provides supportive evidence that angiopoietin-2 plays a causal role in risk for AKI-SP2.

IntroductionMore than 93,000 cases of coronavirus disease (COVID-19) have been reported worldwide. We describe the epidemiology, clinical course, and virologic characteristics of the first 12 U.S. patients with COVID-19.MethodsWe collected demographic, exposure, and clinical information from 12 patients confirmed by CDC during January 20–February 5, 2020 to have COVID-19. Respiratory, stool, serum, and urine specimens were submitted for SARS-CoV-2 rRT-PCR testing, virus culture, and whole genome sequencing.ResultsAmong the 12 patients, median age was 53 years (range: 21–68); 8 were male, 10 had traveled to China, and two were contacts of patients in this series. Commonly reported signs and symptoms at illness onset were fever (n=7) and cough (n=8). Seven patients were hospitalized with radiographic evidence of pneumonia and demonstrated clinical or laboratory signs of worsening during the second week of illness. Three were treated with the investigational antiviral remdesivir. All patients had SARS-CoV-2 RNA detected in respiratory specimens, typically for 2–3 weeks after illness onset, with lowest rRT-PCR Ct values often detected in the first week. SARS-CoV-2 RNA was detected after reported symptom resolution in seven patients. SARS-CoV-2 was cultured from respiratory specimens, and SARS-CoV-2 RNA was detected in stool from 7/10 patients.ConclusionsIn 12 patients with mild to moderately severe illness, SARS-CoV-2 RNA and viable virus were detected early, and prolonged RNA detection suggests the window for diagnosis is long. Hospitalized patients showed signs of worsening in the second week after illness onset.

The next frontier of growth for the naturopathic medical profession will be to integrate naturopathic physicians into conventional primary care teams. Our skills and training offer a unique style of primary care, but it is our responsibility to secure our place in the healthcare landscape. In many jurisdictions our scope of practice has been increased to include core primary care responsibilities and privileges (for example: the recent expansion of qualified healthcare professional designation).1,2 As the winds of change begin to gust, it becomes imperative to transform the profession, or risk being left behind as the healthcare world sails on without us.

In this paper, we propose a new end-to-end methodology to optimize energy performance and thermal comfort in office buildings, without any renovation work. The process is decomposed into three steps: metamodel training, model calibration and optimization. We introduce and train a metamodel on thousands of weather and building settings scenarios, using samples from a physical simulation model. Its much faster computation time allows for the calibration of two weakly instrumented buildings with a derivative free optimization procedure. Using historic data from these buildings, we estimate up to 60 unknown parameters defined by energy managers, such as heat capacity, window area or exposition. Energy consumptions are finally minimized while maintaining a target thermal comfort using the Pareto front provided by a multi-objective optimization algorithm. Our approach allows the computation of the entire calibration-optimization pipeline on several types of buildings. Moreover, the numerical experiments illustrate how it may ensure a significant gain in energy efficiency, up to almost 10%, while being computationally much more appealing than simulation programs.

Coronavirus disease 2019 (COVID-19), the respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in Wuhan, China and has since become pandemic. In response to the first cases identified in the United States, close contacts of confirmed COVID-19 cases were investigated to enable early identification and isolation of additional cases and to learn more about risk factors for transmission. Close contacts of nine early travel-related cases in the United States were identified and monitored daily for development of symptoms (active monitoring). Selected close contacts (including those with exposures categorized as higher risk) were targeted for collection of additional exposure information and respiratory samples. Respiratory samples were tested for SARS-CoV-2 by real-time reverse transcription polymerase chain reaction at the Centers for Disease Control and Prevention. Four hundred four close contacts were actively monitored in the jurisdictions that managed the travel-related cases. Three hundred thirty-eight of the 404 close contacts provided at least basic exposure information, of whom 159 close contacts had ≥1 set of respiratory samples collected and tested. Across all actively monitored close contacts, two additional symptomatic COVID-19 cases (i.e., secondary cases) were identified; both secondary cases were in spouses of travel-associated case patients. When considering only household members, all of whom had ≥1 respiratory sample tested for SARS-CoV-2, the secondary attack rate (i.e., the number of secondary cases as a proportion of total close contacts) was 13% (95% CI: 4-38%). The results from these contact tracing investigations suggest that household members, especially significant others, of COVID-19 cases are at highest risk of becoming infected. The importance of personal protective equipment for healthcare workers is also underlined. Isolation of persons with COVID-19, in combination with quarantine of exposed close contacts and practice of everyday preventive behaviors, is important to mitigate spread of COVID-19.

This essay focuses attention on the efforts to include Muslims from the past and present in a series of initiatives during the UK 2014 Centenary Commemorations, including the memorialisation of Muslim soldiers from WWI and the creation of the Poppy Hijab. For the armed forces, the revival of the historical legacy of a multicultural military serves to legitimise the military's image and their contemporary efforts in the War on Terror. On the other hand, the initiatives polarised opinion amongst supportive British Muslims and opponents of the Poppy Hijab. The essay situates these events in critical literature on militarisation and memorialisation. Publisher PDF

Objective To compare the efficacies of oral naproxen and oral tramadol for pain relief after cesarean delivery, and to evaluate administration at fixed intervals versus on request. Methods In a prospective study, 120 women were randomized into 4 groups receiving either oral naproxen or oral tramadol at fixed intervals or on request. Pain was assessed at 6, 12, 24, and 48 hours after delivery, and adverse effects, mobility, breastfeeding, and the need for additional drugs for breakthrough pain were recorded. Results No difference in pain scores was observed at 6, 12, 24, or 48 hours among the 4 groups, between the 2 drugs, or between the 2 methods of administration. Women randomized to receive oral tramadol requested additional drugs for breakthrough pain more frequently. In addition, adverse effects were twice as common in the tramadol group as in the naproxen group, and more women in the tramadol group abandoned the study. Conclusion Although similar in terms of pain scores, oral naproxen might be more effective than oral tramadol for pain relief after cesarean delivery. Naproxen seemed to have a better adverse-effects profile, and therefore might be more suitable for mothers. Administration at fixed intervals might be more efficacious than administration on request.

The objective of this study was to evaluate the effect of sterile ozonated saline endometrial irrigation on sonographic and histological endometrial parameters. This prospective investigation was performed in 12 healthy, ovulating women over three consecutive menstrual cycles: control cycle (endometrial irrigation with 10 cc of normal saline at day 10), no intervention cycle and study cycle (irrigation with 10 cc of sterile ozonated saline at day 10). Endometrial thickness was measured by transvaginal ultrasound at days 10 and 12 of the control and study cycles, and endometrial samplings were obtained from the participants two days after the irrigations (i.e. on day 12) for histological evaluation. Ozonated saline irrigation, compared to normal saline irrigation, resulted in a statistically significant elevation of the columnar epithelial height (30.30 ± 3.04 vs. 25.82 ± 3.28 μm, p

Resume LEDA est une organisation non gouvernementale virtuelle destinee a assurer gratuitement des services de Liaison, d'Education, d'aide au Diagnostic et d'Assistance aux professionnels de la sante, locaux ou expatries, travaillant dans des pays medicalement emergents. Son site , LEDAMED, est le produit d'un groupement d'interet scientifique soutenu par le ministere de la Recherche et associant differents organismes: Centre national d'etudes spatiales et sa filiale medicale MEDES, Centre de pathologie de Dijon, Formation permanente developpement et Sante, Institut de medecine et de physiologie spatiale, Institut Pasteur, Medecins du Monde, Sante Partenaire et Pathologie Cytologie Developpement. Son principe repose sur la mise en place: — d'un reseau de cyto- et/ou d'histodiagnostics assistes a distance par des medecins specialistes anatomo-cyto-pathologistes assurant la formation progressive des personnels locaux sans se substituer a leur autonomie. — d'un centre de teletransmission medicale ouvert a tous permettant le fonctionnement de ce reseau. L'ensemble s'integre dans une logique de soins au sein des structures de sante existantes de facon a assurer la therapeutique adaptee en aval. Une premiere application du concept LEDA a ete la mise en place de la telecytopathogie au Cambodge pour assurer le depistage des lesions precancereuses et cancereuses du col uterin. Chaque annee, 3 500 prelevements ont ete realises dans les structures de soin locales et analyses.

Ci Remember me," demands the ghost of King Hamlet just before he disappears into the pre-dawn light (1.5.91).1 Because this demand comes at the very end of his exchange with his flabbergasted son, the words "remember me" make a prominent imprint on Prince Hamlet's mind.2 Alone after the ghost's disappearance, the Prince ponders the ghost's command in his ensuing soliloquy: "Remember thee?/ Ay, thou poor ghost, while memory holds a seat/ In this distracted globe" (1.5.95-97). Here "globe" has three senses. First, on the most personal level, Hamlet means that memory is a distinct component of his own mind. Within the distracted globe of his mind, there is a place, a seat, a locus for memory. Second, the word "globe" suggests that memory is a crit ical component of the world of the play, the larger social and cultural context in which Prince Hamlet finds himself. This mnemonic landscape has received relatively little critical attention, perhaps because of the tremendous pull which the solitary and self-reflective protagonist provides to readers and viewers of the play. Part of my goal in this essay will be to show that memory is a critical component of the culture of Hamlet's Denmark and, by extension, Shakespeare's England. Third, the word "globe," together with the reference to holding a "seat," is clearly a reference to the actual playing

Resume Les deux contraintes majeures en transplantation sont d'une part le controle du rejet de greffe et d'autre part la limitation des effets secondaires des immunosuppresseurs (IS). Une meilleure comprehension des mecanismes moleculaires du rejet a permis le developpement de nouveaux IS. Chaque type de transplantation a sa propre strategie immunosuppressive. Cette revue analyse les progres dans la connaissance de la presentation de l'antigene au lymphocyte T, les mecanismes d'action, la pharmacocinetique et les effets deleteres des IS. Leur utilisation et les resultats obtenus dans les principales transplantations d'organe sont egalement presentes.