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AimsCalcific aortic valve disease (CAVD) is the most common valve disease, which consists of a chronic interplay of inflammation, fibrosis, and calcification. In this study, sortilin (SORT1) was identified as a novel key player in the pathophysiology of CAVD, and its role in the transformation of valvular interstitial cells (VICs) into pathological phenotypes is explored.Methods and resultsAn aortic valve (AV) wire injury (AVWI) mouse model with sortilin deficiency was used to determine the effects of sortilin on AV stenosis, fibrosis, and calcification. In vitro experiments employed human primary VICs cultured in osteogenic conditions for 7, 14, and 21 days; and processed for imaging, proteomics, and transcriptomics including single-cell RNA-sequencing (scRNA-seq). The AVWI mouse model showed reduced AV fibrosis, calcification, and stenosis in sortilin-deficient mice vs. littermate controls. Protein studies identified the transition of human VICs into a myofibroblast-like phenotype mediated by sortilin. Sortilin loss-of-function decreased in vitro VIC calcification. ScRNA-seq identified 12 differentially expressed cell clusters in human VIC samples, where a novel combined inflammatory myofibroblastic-osteogenic VIC (IMO-VIC) phenotype was detected with increased expression of SORT1, COL1A1, WNT5A, IL-6, and serum amyloid A1. VICs sequenced with sortilin deficiency showed decreased IMO-VIC phenotype.ConclusionSortilin promotes CAVD by mediating valvular fibrosis and calcification, and a newly identified phenotype (IMO-VIC). This is the first study to examine the role of sortilin in valvular calcification and it may render it a therapeutic target to inhibit IMO-VIC emergence by simultaneously reducing inflammation, fibrosis, and calcification, the three key pathological processes underlying CAVD.

Background: Rheumatic heart valve disease (RHVD) is a leading cause of cardiovascular death in low- and middle-income countries and affects predominantly women. The underlying mechanisms of chronic valvular damage remain unexplored and regulators of sex predisposition are unknown. Methods: Proteomics analysis of human heart valves (nondiseased aortic valves, nondiseased mitral valves [NDMVs], valves from patients with rheumatic aortic valve disease, and valves from patients with rheumatic mitral valve disease; n=30) followed by system biology analysis identified ProTα (prothymosin alpha) as a protein associated with RHVD. Histology, multiparameter flow cytometry, and enzyme-linked immunosorbent assay confirmed the expression of ProTα. In vitro experiments using peripheral mononuclear cells and valvular interstitial cells were performed using multiparameter flow cytometry and quantitative polymerase chain reaction. In silico analysis of the RHVD and Streptococcus pyogenes proteomes were used to identify mimic epitopes. Results: A comparison of NDMV and nondiseased aortic valve proteomes established the baseline differences between nondiseased aortic and mitral valves. Thirteen unique proteins were enriched in NDMVs. Comparison of NDMVs versus valves from patients with rheumatic mitral valve disease and nondiseased aortic valves versus valves from patients with rheumatic aortic valve disease identified 213 proteins enriched in rheumatic valves. The expression of the 13 NDMV-enriched proteins was evaluated across the 213 proteins enriched in diseased valves, resulting in the discovery of ProTα common to valves from patients with rheumatic mitral valve disease and valves from patients with rheumatic aortic valve disease. ProTα plasma levels were significantly higher in patients with RHVD than in healthy individuals. Immunoreactive ProTα colocalized with CD8 + T cells in RHVD. Expression of ProTα and estrogen receptor alpha correlated strongly in circulating CD8 + T cells from patients with RHVD. Recombinant ProTα induced expression of the lytic proteins perforin and granzyme B by CD8 + T cells as well as higher estrogen receptor alpha expression. In addition, recombinant ProTα increased human leukocyte antigen class I levels in valvular interstitial cells. Treatment of CD8 + T cells with specific estrogen receptor alpha antagonist reduced the cytotoxic potential promoted by ProTα. In silico analysis of RHVD and S pyogenes proteomes revealed molecular mimicry between human type 1 collagen epitope and bacterial collagen-like protein, which induced CD8 + T-cell activation in vitro. Conclusions: ProTα-dependent CD8 + T-cell cytotoxicity was associated with estrogen receptor alpha activity, implicating ProTα as a potential regulator of sex predisposition in RHVD. ProTα facilitated recognition of type 1 collagen mimic epitopes by CD8 + T cells, suggesting mechanisms provoking autoimmunity.

BACKGROUND: Rheumatic heart valve disease (RHVD) is a leading cause of cardiovascular death in low-middle-income countries and affects predominantly women. However, the underlying mechanisms of valvular damage remain scant, and regulators of sex predisposition are unknown. METHODS: Proteomics analysis of human heart valves (Non-Diseased Aortic Valves/NDAV; Non-Diseased Mitral Valves/NDMV; Rheumatic Aortic Valve Disease/RAVD; Rheumatic Mitral Valve Disease/RMVD; n=30), followed by system biology analysis, identified prothymosin alpha (ProTα) as a protein associated with RHVD. Histology, multiparameter flow cytometry and ELISA confirmed the expression of ProTα. In vitro experiments using peripheral mononuclear cells and valvular interstitial cells (VICs) were performed using multiparameter flow cytometry and qPCR. In silico analysis of the RHVD and S. pyogenes proteomes were employed to identify mimic epitopes. RESULTS: A comparison of NDMV and NDAV proteomes established the baseline differences between non-diseased aortic and mitral valves. Thirteen unique proteins were enriched in NDMV. Comparison of NDMV vs. RMVD and NDAV vs. RAVD identified 213 proteins enriched in rheumatic valves. The expression of the 13 NDMV-enriched proteins was evaluated across the 213 proteins enriched in diseased valves, resulting in the discovery of ProTα common to RMVD and RAVD. ProTα plasma levels were significantly higher in RHVD than healthy individuals. Immunoreactive ProTα colocalized with CD8(+) T-cells in RHVD. Expression of ProTα and estrogen receptor alpha (ERα) correlated strongly in circulating CD8(+) T-cells from RHVD patients. Recombinant ProTα induced expression of lytic proteins: perforin and granzyme-B, by CD8(+) T-cells as well as higher ERα expression. In addition, recombinant ProTα increased levels of HLA-I in VICs. Treatment of CD8(+) T-cells with specific ERα antagonist reduced cytotoxic potential promoted by ProTα. In silico analysis of RHVD and S. pyogenes proteomes revealed cross-reactivity between human type 1 collagen epitope and bacterial collagen-like protein, which induced CD8+ T-cells activation in vitro. CONCLUSIONS: ProTα-dependent CD8(+) T-cell cytotoxicity was associated with ERα activity, implicating ProTα as a potential regulator of sex predisposition in RHVD. Moreover, ProTα facilitated recognition of type 1 collagen cross-reactive epitopes by CD8 T-cells, suggesting mechanisms provoking autoimmunity.

Novel drug discovery is a lengthy process, and for head and neck cancer (HNC), few antineoplastics have been developed in the past decades. This has led to a relative stagnation of HNC survival rates. Phase 0 trials offer a solution to the slow cancer drug development. By injecting a microdose of a novel antineoplastic agent directly into a tumor in-vivo, drug pharmacokinetics and pharmacodynamics can be studied after tumor resection and offers more accurate findings than with the utilization of animal models. Phase 0 trials do not offer therapeutic benefit to the participants but also carry minimal risk. Challenges with patient enrollment in phase 0 trials have hindered a more widespread implementation. The aim of this study was to better understand patient motivations and perceptions of phase 0 trials when considering whether to enroll. A hypothetical vignette survey was administered to 80 HNC patients presenting to their otolaryngology clinic. Among the sample, a majority of participants (78.8%) reported being likely to participate in a phase 0 trial, whereas a minority (21.2%) reported being unlikely to participate. Patients’ main reason to agree to participate was a desire to help future cancer patients (73%). Younger participants were significantly more likely to choose to participate. Reasons not to participate were more varied. Concern for injection complications (25%), fear of being experimented on (20%), and not wanting to be in a clinical trial (19%) were the most frequently selected answers. Black-identifying participants were 9.3 times more likely (95% CI 2.04, 43.06) to choose fear of being experimented on than non-black participants (p=0.0017). Only 10% of responders chose the lack of therapeutic benefit as a reason not to participate. Several patients mentioned logistical concerns, including transportation and financial support, as being potential deterrents to their participation. These findings showcase a number of barriers and challenges faced by patients that need to be addressed in order to improve enrollment in phase 0 trials.

Background: Activated macrophages contribute to the pathogenesis of vascular disease. Vein graft failure is a major clinical problem with limited therapeutic options. PCSK9 (proprotein convertase subtilisin/kexin 9) increases low-density lipoprotein (LDL)-cholesterol levels via LDL receptor (LDLR) degradation. The role of PCSK9 in macrophage activation and vein graft failure is largely unknown, especially through LDLR-independent mechanisms. This study aimed to explore a novel mechanism of macrophage activation and vein graft disease induced by circulating PCSK9 in an LDLR-independent fashion. Methods: We used Ldlr -/- mice to examine the LDLR-independent roles of circulating PCSK9 in experimental vein grafts. Adeno-associated virus (AAV) vector encoding a gain-of-function mutant of PCSK9 (rAAV8/D377Y-mPCSK9) induced hepatic PCSK9 overproduction. To explore novel inflammatory targets of PCSK9, we used systems biology in Ldlr -/- mouse macrophages. Results: In Ldlr -/- mice, AAV-PCSK9 increased circulating PCSK9, but did not change serum cholesterol and triglyceride levels. AAV-PCSK9 promoted vein graft lesion development when compared with control AAV. In vivo molecular imaging revealed that AAV-PCSK9 increased macrophage accumulation and matrix metalloproteinase activity associated with decreased fibrillar collagen, a molecular determinant of atherosclerotic plaque stability. AAV-PCSK9 induced mRNA expression of the pro-inflammatory mediators IL-1β (interleukin-1 beta), TNFα (tumor necrosis factor alpha), and MCP-1 (monocyte chemoattractant protein-1) in peritoneal macrophages underpinned by an in vitro analysis of Ldlr -/- mouse macrophages stimulated with endotoxin-free recombinant PCSK9. A combination of unbiased global transcriptomics and new network-based hyperedge entanglement prediction analysis identified the NF-κB (nuclear factor-kappa B) signaling molecules, lectin-like oxidized LOX-1 (LDL receptor-1), and SDC4 (syndecan-4) as potential PCSK9 targets mediating pro-inflammatory responses in macrophages. Conclusions: Circulating PCSK9 induces macrophage activation and vein graft lesion development via LDLR-independent mechanisms. PCSK9 may be a potential target for pharmacologic treatment for this unmet medical need.

COVID-19 related acute respiratory distress syndrome (ARDS) has specific characteristics compared to ARDS in other populations. Proning is recommended by analogy with other forms of ARDS, but few data are available regarding its physiological effects in this population. This study aimed to assess the effects of proning on oxygenation parameters (PaO 2 /FiO 2 and alveolo-arterial gradient (Aa-gradient)), blood gas analysis, ventilatory ratio (VR), respiratory system compliance (C RS ) and estimated dead space fraction (V D /V T HB). We also looked for variables associated with treatment failure. Retrospective monocentric study of intubated COVID-19 ARDS patients managed with an early intubation, low to moderate positive end-expiratory pressure and early proning strategy hospitalized from March 6 to April 30 2020. Blood gas analysis, PaO 2 /FiO 2 , Aa-gradient, VR, C RS and V D /V T HB were compared before and at the end of each proning session with paired t-tests or Wilcoxon tests (p < 0.05 considered as significant). Proportions were assessed using Fischer exact test or Chi square test. Forty-two patients were included for a total of 191 proning sessions, median duration of 16 (5-36) hours. Considering all sessions, PaO 2 /FiO 2 increased (180 [148-210] vs 107 [90-129] mmHg, p < 0.001) and Aa-gradient decreased (127 [92-176] vs 275 [211-334] mmHg, p < 0.001) with proning. C RS (36.2 [30.0-41.8] vs 32.2 [27.5-40.9] ml/cmH 2 O, p = 0.003), VR (2.4 [2.0-2.9] vs 2.3 [1.9-2.8], p = 0.028) and V D /V T HB (0.72 [0.67-0.76] vs 0.71 [0.65-0.76], p = 0.022) slightly increased. Considering the first proning session, PaO 2 /FiO 2 increased (186 [165-215] vs 104 [94-126] mmHg, p < 0.001) and Aa-gradient decreased (121 [89-160] vs 276 [238-321] mmHg, p < 0.001), while C RS , VR and V D /V T HB were unchanged. Similar variations were observed during the subsequent proning sessions. Among the patients who experienced treatment failure (defined as ICU death or need for extracorporeal membrane oxygenation), fewer expressed a positive response in terms of oxygenation (defined as increase of more than 20% in PaO 2 /FiO 2 ) to the first proning (67 vs 97%, p = 0.020). Proning in COVID-19 ARDS intubated patients led to an increase in PaO 2 /FiO 2 and a decrease in Aa-gradient if we consider all the sessions together, the first one or the 4 subsequent sessions independently. When considering all sessions, C RS increased and VR and V D /V T HB only slightly increased.

BackgroundTo evaluate the safety and tolerability of ranibizumab 0.5 mg in patients with uni/bilateral neovascular age-related macular degeneration (nAMD) and best-corrected visual acuity (BCVA)MethodsIn this 12-month, prospective, multicentre, open-label, single arm, pragmatic interventional study, patients (N=941) aged ≥ 50 years were to receive ranibizumab as per approved label, monthly until maximum stable visual acuity (VA) was achieved (initially, three or more injections may be required). Thereafter, patients were to be monitored monthly for VA and treatment was to be resumed if VA was reduced due to disease activity.ResultsOf the 936 patients treated with ranibizumab at least once during the study, 823/113 were unilaterally/bilaterally (not simultaneously) treated . The mean (SD) number of ranibizumab injections during the study was 5.4 (2.9)/10.6 (5.0) injections in uni/bilaterally treated patients. Three systemic drug-related adverse events (AEs) (all serious, all in unilaterally treated patients) and 18 systemic AE of special interest (AESIs) (11 serious, 16/2 in unilaterally/bilaterally treated patients) occurred during the study. The annual incidence rate (AIR) (events/1000 person-years) for systemic drug-related AEs, considering a 15-day/30-day risk period, 11.0/8.5 for unilaterally treated patients. Considering the same risk period, the AIR (events/1000 person-years) for systemic AESIs for unilaterally treated patients was 22.1/19.9. Considering a 30-day risk period, the AIR (events/1000 treated eye-years) of ocular drug-related AEs was 23 and AESIs was 11.5.ConclusionsThe low incidence of AEs and AESIs demonstrated the good safety and tolerability of ranibizumab in unilaterally/bilaterally treated patients with nAMD in this real-world setting.

The transition of healthy arteries and cardiac valves into dense, cell-rich, calcified, and fibrotic tissues is driven by a complex interplay of both cellular and molecular mechanisms. Specific cell types in these cardiovascular tissues become activated following the exposure to systemic stimuli including circulating lipoproteins or inflammatory mediators. This activation induces multiple cascades of events where changes in cell phenotypes and activation of certain receptors may trigger multiple pathways and specific alterations to the transcriptome. Modifications to the transcriptome and proteome can give rise to pathological cell phenotypes and trigger mechanisms that exacerbate inflammation, proliferation, calcification, and recruitment of resident or distant cells. Accumulating evidence suggests that each cell type involved in vascular and valvular diseases is heterogeneous. Single-cell RNA sequencing is a transforming medical research tool that enables the profiling of the unique fingerprints at single-cell levels. Its applications have allowed the construction of cell atlases including the mammalian heart and tissue vasculature and the discovery of new cell types implicated in cardiovascular disease. Recent advances in single-cell RNA sequencing have facilitated the identification of novel resident cell populations that become activated during disease and has allowed tracing the transition of healthy cells into pathological phenotypes. Furthermore, single-cell RNA sequencing has permitted the characterization of heterogeneous cell subpopulations with unique genetic profiles in healthy and pathological cardiovascular tissues. In this review, we highlight the latest groundbreaking research that has improved our understanding of the pathological mechanisms of atherosclerosis and future directions for calcific aortic valve disease.

Despite the focus placed on cardiovascular research, the prevalence of vascular and valvular calcification is increasing and remains a leading contributor of cardiovascular morbidity and mortality. Accumulating studies provide evidence that cardiovascular calcification is an inflammatory disease in which innate immune signaling becomes sustained and/or excessive, shaping a deleterious adaptive response. The triggering immune factors and subsequent inflammatory events surrounding cardiovascular calcification remain poorly understood, despite sustained significant research interest and support in the field. Most studies on cardiovascular calcification focus on innate cells, particularly macrophages' ability to release pro-osteogenic cytokines and calcification-prone extracellular vesicles and apoptotic bodies. Even though substantial evidence demonstrates that macrophages are key components in triggering cardiovascular calcification, the crosstalk between innate and adaptive immune cell components has not been adequately addressed. The only therapeutic options currently used are invasive procedures by surgery or transcatheter intervention. However, no approved drug has shown prophylactic or therapeutic effectiveness. Conventional diagnostic imaging is currently the best method for detecting, measuring, and assisting in the treatment of calcification. However, these common imaging modalities are unable to detect early subclinical stages of disease at the level of microcalcifications; therefore, the vast majority of patients are diagnosed when macrocalcifications are already established. In this review, we unravel the current knowledge of how innate and adaptive immunity regulate cardiovascular calcification; and put forward differences and similarities between vascular and valvular disease. Additionally, we highlight potential immunomodulatory drugs with the potential to target calcification and propose avenues in need of further translational inquiry.

Tracheostomy is often performed in the intensive care unit (ICU) when mechanical ventilation (MV) weaning is prolonged to facilitate daily care. Tracheostomized patients require important healthcare resources and have poor long-term prognosis after the ICU. However, data lacks regarding prediction of outcomes at hospital discharge. We looked for patients' characteristics, ventilation parameters, sedation and analgesia use (pre-tracheostomy) that are associated with favorable and poor outcomes (post-tracheostomy) using univariate and multivariate logistic regressions.Eighty tracheostomized patients were included (28.8% women, 60 [52-71] years). Twenty-three (28.8%) patients were intubated for neurological reasons. Time from intubation to tracheostomy was 14.7 [10-20] days. Thirty patients (37.5%) had poor outcome (19 patients deceased and 11 still tracheostomized at hospital discharge). All patients discharged with tracheostomy (n = 11) were initially intubated for a neurological reason. In univariate logistic regressions, older age and higher body-mass index (BMI) were associated with poor outcome (OR 1.18 [1.07-1.32] and 1.04 [1.01-1.08], p 0.001 and p = 0.025). No MV parameters were associated with poor outcome. In the multiple logistic regression model higher BMI and older age were also associated with poor outcome (OR 1.21 [1.09-1.36] and 1.04 [1.00-1.09], p 0.001 and p = 0.046).Hospital mortality of patients tracheostomized because of complex MV weaning was high. Patients intubated for neurological reasons were frequently discharged from the acute care hospital with tracheostomy in place. Both in univariate and multivariate logistic regressions, only BMI and older age were associated with poor outcome after tracheostomy for patients undergoing prolonged MV weaning.

Additional file 2. Patients’ general characteristics, comorbidities and admission data for study population andseparated by cause for intubation.

Additional file 6. Univariate and multivariate logistic regression models for factors potentially associated with poor outcome.

Additional file 5. Ventilation and norepinephrine use 2-hours before tracheostomy.

Additional file 1: Table S1. Physiological, ventilatory and hemodynamic data for all the sessions considered together (n=191) and for the first (n=42), the second (n=37), the third (n=31), the fourth (n=18) and the fifth (n=14) proning sessions). Table S2. Variations in physiological and ventilatory parameters during the fourth (n=18), the fifth (n=14) proning sessions. Comparisons between the success and failure group.

Additional file 4. General characteristics & comorbidities, admission data, ventilation data, sedation, opioids, NMBA use, tracheostomy data and outcomes data with patients intubated for neurological reasons only.

Additional file 1. Data collection details.

Additional file 3. General characteristics & comorbidities, admission data, ventilation data, sedation, opioids, NMBA use, tracheostomy data and outcomes data for patients intubated for non-neurological reasons.

Additional file 7. Univariate analyses and multivariate logistic regression model for factors potentially associated with poor outcome for patients intubated for non-neurological reasons only.

The interaction of regular quasi-monochromatic waves with a weakly submerged rectangular shelf is studied by means of CFD simulations. The fundamental incident wave frequency is kept constant for the full set of simulated cases, while the incident wave amplitude is made increase progressively, so that the interaction with the shelf is dominated by almost inviscid non-linear flow for the smallest and by breaking for the highest incident waves. A parameter identification (PI) procedure is used to adapt a reduced model to the highly resolved time-space matrix of wave elevations obtained from the numerical simulations, on the weather and lee side respectively. In particular the wave number and the frequency of the component waves in the reduced model are left uncoupled, thus computed by the PI independently. The comparison of simulated data with experiments generally shows a very good agreement. Free/locked, incident/reflected, first/higher order wave components are quantified accurately by the PI and the energy transfer to super-harmonics is clearly evidenced. Moreover the results of the PI show clearly a very large increase in the phase speed of the higher order free waves on the lee side of the shelf, with increasing deviation from the linear behavior with increasing incident wave amplitude.

Does overseas development aid necessarily translate into more generous national policies for refugees? Evidence from Jordan suggests that this is not always the case. Since the arrival of an estima...

This article examines the role of external financing as a form of transnational economic interdependency in shaping healthcare system change in Jordan. More specifically, this exploratory study traces the trajectory of Jordan’s healthcare policy such as regards public financing, investment in infrastructure, and policy priorities – especially, efforts at universalism and health as a human right – over the years 2008–2018. During this period of observation, the Jordanian healthcare system was subject to various exogenous shocks in the form of recurrent and large influxes of refugees from Iraq and Syria. Regarded as a crisis, the growing presence of the refugee population introduced a significant increase in humanitarian and development aid that brought with it resources for both the displaced and host populations. This study examines whether increased external financing in the form of overseas development aid necessarily translates into healthcare system expansion for both citizens and refugees. This article will contribute to filling the gap in knowledge and understanding of the complex interdependencies which influence the evolution of healthcare policies in a country not only affected by an ongoing refugee crisis, but also at the geopolitical crossroads of international interests in the Middle East region.

In recent years, the pace at which apparent refugee and health ���crises��� ��� and their humanitarian responses ��� are being subsumed within foreign policy agendas appears to be accelerating. From the Syrian ���refugee crisis��� in Europe in 2015, to the outbreak of Ebola, the Zika virus and, more recently, Covid-19, attempts at tackling these ���crises��� have not only conflated cross-border mobility with illness and disease, but have also served as a justification for sealing national borders. Yet there has been surprisingly little research on the intersection between forced migration, global health, and humanitarian assistance, particularly in the context of refugee hosting countries in the Global South. Building on scholarship on refugee and forced migration studies, global health security, and international relations, this thesis provides a new perspective on how the politics of health care undertaken by donors, host states, and non-governmental organizations affects the priorities of refugee health responses. This thesis considers the case study of Jordan, a country in the Middle East which hosts one of the largest refugee populations relative to its national population in the world. Based on six months of fieldwork, I investigate the ways in which the arrival of an estimated 650,000 Syrian refugees between 2012 and 2019 transformed Jordan into an arena in which large- scale national and international interests, foreign policy objectives, and power dynamics collide. Findings show that health policies affecting refugees have been increasingly co- opted within the foreign policy agendas of both donor and refugee receiving states, with wide-ranging effects on the allocation of humanitarian assistance. Such effects include a disproportionate focus on infectious diseases at the expense of more prevalent chronic diseases, and gendered and racialized constructions of ���vulnerable��� refugees. As a result, I contend that some refugee groups ��� mainly women and children ��� are championed by certain powerful actors, while other groups within the same refugee population ��� such as older people and young men ��� are consistently overlooked.

Background: Following myocardial infarction, mitral regurgitation (MR) is a common complication. Previous animal studies demonstrated the association of endothelial-to-mesenchymal transition (EndMT) with mitral valve (MV) remodeling. Nevertheless, little is known about how MV tissue responds to ischemic heart changes in humans. Methods: MVs were obtained by the Cardiothoracic Surgical Trials Network from 17 patients with ischemic mitral regurgitation (IMR). Echo-doppler imaging assessed MV function at time of resection. Cryosections of MVs were analyzed using a multi-faceted histology and immunofluorescence examination of cell populations. MVs were further analyzed using unbiased label-free proteomics. Echo-Doppler imaging, histo-cytometry measures and proteomic analysis were then integrated. Results: MVs from patients with greater MR exhibited proteomic changes associated with proteolysis-, inflammatory- and oxidative stress-related processes compared to MVs with less MR. Cryosections of MVs from patients with IMR displayed activated valvular interstitial cells (aVICs) and double positive CD31+ αSMA+ cells, a hallmark of EndMT. Univariable and multivariable association with echocardiography measures revealed a positive correlation of MR severity with both cellular and geometric changes (e.g., aVICs, EndMT, leaflet thickness, leaflet tenting). Finally, proteomic changes associated with EndMT showed gene-ontology enrichment in vesicle-, inflammatory- and oxidative stress-related processes. This discovery approach indicated new candidate proteins associated with EndMT regulation in IMR. Conclusion: We describe an atypical cellular composition and distinctive proteome of human MVs from patients with IMR, which highlighted new candidate proteins implicated in EndMT-related processes, associated with maladaptive MV fibrotic remodeling., Graphical Abstract

Aim: To evaluate the role of vitronectin-enriched protein corona on systemic delivery of siRNA-encapsulated cationic lipid nanoparticles (LNPs) to αvβ3 integrin expressing solid tumors. Materials & methods: 1,2-Dioleoyl-3-trimethylammonium-propane LNPs were formulated, protein corona formed in nude mice serum and its impact on drug delivery were analyzed. Results: 1,2-Dioleoyl-3-trimethylammonium-propane-containing LNP led to enhanced recruitment of vitronectin and showed preferential transfection to αvβ3-expressed cells relative to controls. Upon systemic administration in mice, the LNPs accumulated in the αvβ3-expressing endothelial lining of the tumor blood vessels before reaching tumor cells. Conclusion: These results present an optimized LNP that selectively recruits endogenous proteins in situ to its corona which may lead to enhanced delivery and transfection in tissues of interest.

Introduction: Acute rheumatic fever (ARF) results from autoimmune responses to group A streptococcus. ARF can cause chronic rheumatic heart valve disease (RHVD), a major public health burden in low- and middle-income countries. Although ARF affects both sexes equally, females have a higher prevalence of RHVD. We identified a target protein, ProTα, that may contribute to pathophysiology of and gender predisposition in RHVD. Estradiol regulates ProTα, which influences transcriptional activity of the estrogen receptor (ER). Methods: Human heart valves (n=120) obtained from heart transplantation and valve replacement surgeries, including non-diseased mitral and aortic valves (NDMV and NDAV, n=17/group), rheumatic mitral and aortic valves (RMVD, n=45; RAVD, n=8) and calcifying valves from patients with calcific aortic valve disease (CAVD, n=33) underwent proteomic and network analyses, and immunohistochemical assessment of CD68, CD4, CD8 and ProTα. ProTα levels were measured in plasma and peripheral mononuclear cells (PBMCs) from RHVD patients and healthy donors (n=14/group) by ELISA and flow cytometry. Results: A comparison of proteomes from NDMV and NDAV established the baseline differences between valve types. 12 proteins were enriched (q Conclusion: We propose that ProTα is a novel contributor to the immunopathogenesis of RHVD and may regulate sex predisposition in this disease.

In a crisis, there is widespread recognition and acceptance that not all lives can be saved. But whose lives can legitimately be saved and who decides? Recent scholarship has begun to examine how refugees perceived as 'vulnerable', such as women and children, are frequently prioritized over other groups in humanitarian responses. Such analyses, however, fail to adequately explain why some groups - such as older persons - are considered vulnerable and yet are largely neglected. Based on the case of older Syrian refugees in Jordan, this article critically examines the ways in which humanitarian health actors make sense of the humanitarian principle of 'impartiality' in the face of limited resources. Based on 61 interviews and observational data collected in Jordan between 2017 and 2019, my results show that humanitarians routinely classify older refugees as 'vulnerable' and in need of medical assistance. Yet I find that three neoliberal considerations - including perceptions of the reduced lifespan, disproportionate disease burden, and limited contributions to the economy of older refugees - make this demographic low 'value for money'. This article expands our understanding of how medical humanitarian understandings of 'deservingness' are increasingly shaped by market-driven logics, and how these (re)create ageist, gendered and racialized hierarchies within refugee health.

Additional file 1. Supplementary figures and tables.

Diffuse optical tomography (DOT) is an emerging imaging technique which uses light for diagnostic purposes in a non-invasive and non-ionizing way. In this paper, we focus on DOT application to female breast screening, where the surface of the breast is illuminated by light sources and the outgoing light is collected on the surface. The comparison of measured light data with the equivalent field obtained from a relevant mathematical model yields the DOT inverse problem whose solution provides an estimate of the optical coefficients of the tissue. These latter, in turn, can be related to clinical markers for cancer detection. The goal of this work is to propose a mathematical and computational approach tailored to the concept of a DOT imaging device able to perform fast and accurate screenings at an affordable cost. Namely, we address two original points about the crucial issue of the solution of the severely ill-conditioned DOT inverse problem: (a) a computational approach based on Green's functions which do not require the exact knowledge of the tissue geometry, proposed here in the declination of the Method of Fundamental Solutions, which allows to enforce correct boundary conditions; (b) the elastic net regularization technique that shares the desirable properties of both the l2 - and l1 -norm penalization approaches and opens the possibility for sparsity recognition in the optical coefficients field and refinement procedures.

Nous avons explore les origines du mandeisme et la possibilite d’une connexion historique avec la figure de Jean le Baptiste, puis l’histoire de la « decouverte » des mandeens par les Europeens au xvie siecle et la construction d’un « mythe des origines », selon lequel les mandeens ont ete consideres des Chretiens, disciples de Jean l’Evangeliste et, apres, de Jean le Baptiste. Apres quelques renseignements sur la structure socioreligieuse traditionnelle des communautes mandeennes, nous avons...

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease.

International audience; AimsDefects in efficient endothelial healing have been associated with complication of atherosclerosis such as post-angioplasty neoatherosclerosis and plaque erosion leading to thrombus formation. However, current preventive strategies do not consider re-endothelialization in their design. Here, we investigate mechanisms linking immune processes and defect in re-endothelialization. We especially evaluate if targeting phosphoinositide 3-kinase γ immune processes could restore endothelial healing and identify immune mediators responsible for these defects.Methods and resultsUsing in vivo model of endovascular injury, we showed that both ubiquitous genetic inactivation of PI3Kγ and hematopoietic cell-specific PI3Kγ deletion improved re-endothelialization and that CD4+ T-cell population drives this effect. Accordingly, absence of PI3Kγ activity correlates with a decrease in local IFNγ secretion and its downstream interferon-inducible chemokine CXCL10. CXCL10 neutralization promoted re-endothelialization in vivo as the same level than those observed in absence of PI3Kγ suggesting a role of CXCL10 in re-endothelialization defect. Using a new established ex vivo model of carotid re-endothelialization, we showed that blocking CXCL10 restore the IFNγ-induced inhibition of endothelial healing and identify smooth muscle cells as the source of CXCL10 secretion in response to Th1 cytokine.ConclusionAltogether, these findings expose an unforeseen cellular cross-talk within the arterial wall whereby a PI3Kγ-dependent T-cell response leads to CXCL10 production by smooth muscle cells which in turn inhibits endothelial healing. Therefore, both PI3Kγ and the IFNγ/CXCL10 axis provide novel strategies to promote endothelial healing.

Cardiovascular diseases are the most common cause of death around the world. This includes atherosclerosis and the adverse effects of its treatment, such as restenosis and thrombotic complications. The development of these arterial pathologies requires a series of highly-intertwined interactions between immune and arterial cells, leading to specific inflammatory and fibroproliferative cellular responses. In the last few years, the study of phosphoinositide 3-kinase (PI3K) functions has become an attractive area of investigation in the field of arterial diseases, especially since inhibitors of specific PI3K isoforms have been developed. The PI3K family includes 8 members divided into classes I, II or III depending on their substrate specificity. Although some of the different isoforms are responsible for the production of the same 3-phosphoinositides, they each have specific, non-redundant functions as a result of differences in expression levels in different cell types, activation mechanisms and specific subcellular locations. This review will focus on the functions of the different PI3K isoforms that are suspected as having protective or deleterious effects in both the various immune cells and types of cell found in the arterial wall. It will also discuss our current understanding in the context of which PI3K isoform(s) should be targeted for future therapeutic interventions to prevent or treat arterial diseases.

Anthracyclines such as doxorubicin, daunorubicin, epirubicin, mitoxantrone and idarubicin, are powerful chemotherapeutic drugs used both in children and adult populations. Their properties made them particularly suitable for a large variety of neoplasms including breast adenocarcinoma, small cell lung cancer and acute leukemia. Early and late anthracycline-induced cardiotoxicity is a well-known phenomenon, and the incidence of heart failure in patients receiving doxorubicin is 2.2%, with a mortality rate over 60% at 2 years. Prognosis can be improved by prevention, early detection and treatment. A specific treatment for anthracycline-induced cardiotoxicity is not yet available, but non-pharmacological measures such as exercise, lifestyle changes and control of risk factors have shown a cardioprotective effect. Exercise training represents a viable non-pharmacological treatment as it increases cardiovascular reserve and endothelial function, regulates proapoptotic signaling, protects against reactive oxygen species (ROS), and decreases autophagy/lysosomal signaling. However, no current guidelines are available for prevention management in cancer patients. Pharmacological measures both for prevention and treatment are those used for heart failure (β-blockers, angiotensin-receptor blockers, angiotensin-converting enzyme inhibitors, statins, dexrazoxane and aldosteron antagonists). In this chapter, we will discuss how the evaluation, monitoring and prevention of chemotherapy-related cardiomyopathy is correlated with physical exercise.

Diffuse optical tomography (DOT) is an emerging diagnostic technique which uses near–infra–red light to investigate the optical coefficients distribution in biological tissues. The surface of the tissue is illuminated by light sources, then the outgoing light is measured by detectors placed at various locations on the surface itself. In order to reconstruct the optical coefficients, a mathematical model of light propagation is employed: such model leads to the minimization of the discrepancy between the detected data and the corresponding theoretical field. Due to severe ill–conditioning, regularization techniques are required: common procedures consider mainly ℓ 1–norm (LASSO) and ℓ 2–norm (Tikhonov) regularization. In the present work we investigate two original approaches in this context: the elastic–net regularization, previously used in machine learning problems, and the Bregman procedure. Numerical experiments are performed on synthetic 2D geometries and data, to evaluate the performance of these approaches. The results show that these techniques are indeed suitable choices for practical applications, where DOT is used as a cheap, first–level and almost real–time screening technique for breast cancer detection.

Over the past decade, several research initiatives have investigated and proposed innovative solutions for transport logistics. However, the level of adoption in the transport industry has been low, in particular in comparison with other industry sectors. This is on one side related to the transport industry itself, facing issues like market fragmentation, price pressure and a high degree of outsourcing. The other reason for this is a lack in dissemination strategies towards relevant stakeholders being indentified in several logistics innovation projects. The EU-funded project LOGINN - Logistic Innovation Uptake - aims at coordinating and supporting RTD projects in the logistics area to improve their capabilities to bridge the gap between pilot implementation and marketable solutions. In addition, the project aims at disseminating innovative logistics practices, technologies and business models to the logistics community, thus establishing an information hub for logistics innovation and contributing to education and training of logistics enterprises’ employees. Here we present the first findings.

Nazism - corruption of language and the language of corruption - Language is a powerful instrument of persuasion, able to influence the thoughts and actions of speakers. How did the German people react to Nazi ideology in the religious sphere? Against the expectations of the Nazis and Hitler himself, language proved reluctant to replace the terms of Catholicism with the new idiom promoted by the Nazi regime

While a positive operator valued measure gives the probabilities in a quantum measurement, an instrument gives both the probabilities and the a posteriori states. By interpreting the instrument as a quantum channel and by using the monotonicity theorem for relative entropies many bounds on the classical information extracted in a quantum measurement are obtained in a unified manner. In particular, it is shown that such bounds can all be stated as inequalities between mutual entropies. This approach based on channels gives rise to a unified picture of known and new bounds on the classical information (the bounds by Holevo, by Shumacher, Westmoreland and Wootters, by Hall, by Scutaru, a new upper bound and a new lower one). Some examples clarify the mutual relationships among the various bounds.

In this paper we will give a short presentation of the quantum Levy-Khinchin formula and of the formulation of quantum continual measurements based on stochastic differential equations, matters which we had the pleasure to work on in collaboration with Prof. Holevo. Then we will begin the study of various entropies and relative entropies, which seem to be promising quantities for measuring the information content of the continual measurement under consideration and for analysing its asymptotic behaviour., Comment: 15 pages, requires Rinton-P9x6.cls. For the volume on the occasion of Alexander Holevo's 60th birthday