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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.

Older refugees are often a neglected population, particularly when it comes to health. In Jordan, the specific health needs of older Syrian refugees tend to be overlooked, due in part to a lack of data, institutional biases and the nature of the humanitarian response.

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.

Refugees and displaced persons have been severely affected by the Covid-19 pandemic. Yet findings from this narrative review reveal that the health needs of refugees have been largely neglected within global healthcare responses. Such gaps include: (1) responding to the needs of refugees in camps and detention centers; (2) providing adequate public health information; (3) providing access to healthcare and mental health services; (4) and including refugees as decision-makers within health responses. More research is urgently needed to investigate why these gaps exists and to provide recommendations for improving the inclusiveness of healthcare policies during a pandemic.

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.

Invasive mechanical ventilation is part of the daily practice of the intensivist and anesthetist. The comprehensive knowledge of ventilatory modes is mandatory for managing the ventilated patients. The objective of this article is to explain the characteristics of the barometric and volumetric modes and the differences between controlled, assist-controlled, and assisted ventilation. The most common modes (volume and pressure assist-control, dual modes and pressure support) are described in detail. Parameters that must be set and those that must be monitored in each mode are also described. Finally, suggestions for initial settings are provided in order to offer the reader unfamiliar with mechanical ventilation a practical decision-making aid.La ventilation mécanique invasive est un outil indispensable à la pratique de l’intensiviste et de l’anesthésiste. La connaissance des modes ventilatoires est nécessaire pour la prise en charge des patients ventilés. L’objectif de cet article est, d’une part, de distinguer les caractéristiques des modes barométriques et volumétriques, et de comprendre les différences entre les modes contrôlé, assisté-contrôlé et assisté et, d’autre part, de distinguer les paramètres qui doivent être réglés de ceux qui doivent être monitorés. Les modes les plus utilisés (volume contrôlé, pression contrôlée, modes mixtes et aide inspiratoire) font l’objet d’une description détaillée. Des suggestions de réglages initiaux sont proposées pour ces modes afin d’offrir au lecteur peu familier avec la ventilation mécanique une aide décisionnelle pratique.

The work concerns numerical simulations of a cone mill used for emulsion preparation. Hydrodynamics, power consumption and population balance are investigated for various operating conditions at high phase volume emulsions and for different rheologies. Cone mills are usually simplified as a simple gap between rotor and stator but by increasing the complexity of the geometry till it represents the commercial device identifies a wealth of additional features such as recirculation zones above (which enhance breakage) and below (which allow for coalescence) the rotor-stator gap. Two separate sets of population balance modelling constants are required to capture all the experiment results – even with the most complex geometries. Some suggestions are made for improvements and further studies will consider other rotor-stator devices.

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.

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.

Psychotic patients hospitalized in psychiatry are subjected to a lot of constraints whenever tide to the psychiatric disorders themselves, the treatment or the legislation. The therapeutic setting, that is considered here as a multidisciplinary one, establishes some rules, limits, constraints but by doing so doesn't it help the patients to develop their autonomy and their freedom? When exploring the roles of the therapeutic setting, it appears that by containing, enveloping, offering some points of reference, it makes the therapeutic process possible and gives a secure base to the patient, which is absolutely necessary to gain freedom. The therapeutic alliance where patient and therapist engage with each other is key to deal with and accept the different constraints rather than being subjected to them and then to be free. The therapeutic setting, both resistant and flexible, gradually guides the patient in conquering his new areas of freedom.; Les contraintes subies par les patients psychotiques hospitalisés en psychiatrie sont nombreuses, qu'elles soient liées à la pathologie elle-même, aux modalités de soin, à la législation. Le cadre thérapeutique, envisagé ici dans une perspective pluridisciplinaire, vient certes poser des règles, des limites, des contraintes, mais ce faisant, ne contribue-t-il pas aussi à l'autonomisation du patient et à sa liberté ? En explorant le rôle du cadre thérapeutique, il apparait qu'en venant contenir, envelopper, donner des repères, il rend possible le processus de soin et offre une base de sécurité au patient, prérequis indispensables pour retrouver de la liberté. L'alliance thérapeutique, véritable collaboration entre patient et thérapeute, est clé pour intégrer les contraintes du cadre, du soin et de la pathologie plutôt que de les subir, et exercer ainsi sa liberté. Le cadre thérapeutique, à la fois solide et élastique, accompagne progressivement le patient dans la conquête de ses nouveaux espaces de liberté.

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.