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Background Extracellular vesicles are released upon cellular activation and mediate inter-cellular communication. Individual species of extracellular vesicles might have divergent roles in vascular homeostasis and may show different responses to therapies such as exercise training. Aims We examine endothelial effects of medium-size and small extracellular vesicles from the same individual with or without chronic coronary syndrome, and in chronic coronary syndrome patients participating in a four-week high-intensity interval training intervention. Methods Human aortic endothelial cells were exposed to medium-size extracellular vesicles and small extracellular vesicles isolated from plasma samples of study participants. Endothelial cell survival, activation and re-endothelialisation capacity were assessed by respective staining protocols. Extracellular vesicles were quantified by nanoparticle tracking analysis and flow cytometry. Extracellular vesicle microRNA expression was quantified by realtime-quantitative polymerase chain reaction. Results In patients with chronic coronary syndrome (n = 25), plasma counts of leukocyte-derived medium-size extracellular vesicles were higher than in age-matched healthy controls (n = 25; p = 0.04) and were reduced by high-intensity interval training (n = 15; p = 0.01 vs baseline). Re-endothelialisation capacity was promoted by medium-size extracellular vesicles from controls, but not by medium-size extracellular vesicles from chronic coronary syndrome patients. High-intensity interval training for 4 weeks enhanced medium-size extracellular vesicle-mediated support of in vitro re-endothelialisation. Small extracellular vesicles from controls or chronic coronary syndrome patients increased endothelial cell death and reduced repair functions and were not affected by high-intensity interval training. Conclusion The present study demonstrates that medium-size extracellular vesicles and small extracellular vesicles differentially affect endothelial cell survival and repair responses. This equilibrium is unbalanced in patients with chronic coronary syndrome where leukocyte-derived medium-size extracellular vesicles are increased leading to a loss of medium-size extracellular vesicle-mediated endothelial repair. High-intensity interval training partially restored medium-size extracellular vesicle-mediated endothelial repair, underlining its use in cardiovascular prevention and therapy to improve endothelial function.

Dennis Carroll and colleagues call for a global early warning system to detect viruses with pandemic potential

Process mapping is a systems thinking approach used to understand, analyse and optimise processes within complex systems. We aim to demonstrate how this methodology can be applied during disease outbreaks to strengthen response and health systems. Process mapping exercises were conducted during three unique emerging disease outbreak contexts with different: mode of transmission, size, and health system infrastructure. System functioning improved considerably in each country. In Sierra Leone, laboratory testing was accelerated from 6 days to within 24 hours. In the Democratic Republic of Congo, time to suspected case notification reduced from 7 to 3 days. In Nigeria, key data reached the national level in 48 hours instead of 5 days. Our research shows that despite the chaos and complexities associated with emerging pathogen outbreaks, the implementation of a process mapping exercise can address immediate response priorities while simultaneously strengthening components of a health system.

Background: An infodemic is an overabundance of information—some accurate and some not—that occurs during an epidemic. In a similar manner to an epidemic, it spreads between humans via digital and physical information systems. It makes it hard for people to find trustworthy sources and reliable guidance when they need it. Objective: A World Health Organization (WHO) technical consultation on responding to the infodemic related to the coronavirus disease (COVID-19) pandemic was held, entirely online, to crowdsource suggested actions for a framework for infodemic management. Methods: A group of policy makers, public health professionals, researchers, students, and other concerned stakeholders was joined by representatives of the media, social media platforms, various private sector organizations, and civil society to suggest and discuss actions for all parts of society, and multiple related professional and scientific disciplines, methods, and technologies. A total of 594 ideas for actions were crowdsourced online during the discussions and consolidated into suggestions for an infodemic management framework. Results: The analysis team distilled the suggestions into a set of 50 proposed actions for a framework for managing infodemics in health emergencies. The consultation revealed six policy implications to consider. First, interventions and messages must be based on science and evidence, and must reach citizens and enable them to make informed decisions on how to protect themselves and their communities in a health emergency. Second, knowledge should be translated into actionable behavior-change messages, presented in ways that are understood by and accessible to all individuals in all parts of all societies. Third, governments should reach out to key communities to ensure their concerns and information needs are understood, tailoring advice and messages to address the audiences they represent. Fourth, to strengthen the analysis and amplification of information impact, strategic partnerships should be formed across all sectors, including but not limited to the social media and technology sectors, academia, and civil society. Fifth, health authorities should ensure that these actions are informed by reliable information that helps them understand the circulating narratives and changes in the flow of information, questions, and misinformation in communities. Sixth, following experiences to date in responding to the COVID-19 infodemic and the lessons from other disease outbreaks, infodemic management approaches should be further developed to support preparedness and response, and to inform risk mitigation, and be enhanced through data science and sociobehavioral and other research. Conclusions: The first version of this framework proposes five action areas in which WHO Member States and actors within society can apply, according to their mandate, an infodemic management approach adapted to national contexts and practices. Responses to the COVID-19 pandemic and the related infodemic require swift, regular, systematic, and coordinated action from multiple sectors of society and government. It remains crucial that we promote trusted information and fight misinformation, thereby helping save lives., peer-reviewed

Background In acute ischemic stroke (AIS) patients, impaired blood–brain barrier (BBB) integrity is associated with hemorrhagic transformation and worsened outcome. Yet, the mechanisms underlying these relationships are poorly understood and consequently therapeutic strategies are lacking. This study sought to determine whether SIRT5 contributes to BBB damage following I/R brain injury. Methods and results SIRT5 knockout ( SIRT5 −/− ) and wild type (WT) mice underwent transient middle cerebral artery (MCA) occlusion (tMCAO) followed by 48h of reperfusion. Genetic deletion of SIRT5 decreased infarct size, improved neurological function and blunted systemic inflammation following stroke. Similar effects were also achieved by in vivo SIRT5 silencing. Immunohistochemical analysis revealed decreased BBB leakage and degradation of the tight junction protein occludin in SIRT5 −/− mice exposed to tMCAO as compared to WT. In primary human brain microvascular endothelial cells (HBMVECs) exposed to hypoxia/reoxygenation (H/R), SIRT5 silencing decreased endothelial permeability and upregulated occludin and claudin-5; this effect was prevented by the PI3K inhibitor wortmannin. Lastly, SIRT5 gene expression was increased in peripheral blood monocytes (PBMCs) of AIS patients at 6h after onset of stroke compared to sex- and age-matched healthy controls. Conclusion SIRT5 is upregulated in PBMCs of AIS patients and in the MCA of WT mice exposed to tMCAO; SIRT5 mediates I/R-induced brain damage by increasing BBB permeability through degradation of occludin. This effect was reproduced in HBMVECs exposed to H/R, mediated by the PI3K/Akt pathway. Our findings shed new light on the mechanisms of I/R-dependent brain damage and suggest SIRT5 as a novel therapeutic target.

The formulation of accurate clinical case definitions is an integral part of an effective process of public health surveillance. Although such definitions should, ideally, be based on a standardized and fixed collection of defining criteria, they often require revision to reflect new knowledge of the condition involved and improvements in diagnostic testing. Optimal case definitions also need to have a balance of sensitivity and specificity that reflects their intended use. After the 2009-2010 H1N1 influenza pandemic, the World Health Organization (WHO) initiated a technical consultation on global influenza surveillance. This prompted improvements in the sensitivity and specificity of the case definition for influenza - i.e. a respiratory disease that lacks uniquely defining symptomology. The revision process not only modified the definition of influenza-like illness, to include a simplified list of the criteria shown to be most predictive of influenza infection, but also clarified the language used for the definition, to enhance interpretability. To capture severe cases of influenza that required hospitalization, a new case definition was also developed for severe acute respiratory infection in all age groups. The new definitions have been found to capture more cases without compromising specificity. Despite the challenge still posed in the clinical separation of influenza from other respiratory infections, the global use of the new WHO case definitions should help determine global trends in the characteristics and transmission of influenza viruses and the associated disease burden.La formulation de définitions précises de cas cliniques fait partie intégrante d'un processus efficace de surveillance de la santé publique. Alors que ces définitions devraient, dans l'idéal, s'appuyer sur un ensemble standardisé et fixe de critères de définition, elles nécessitent souvent une révision pour tenir compte des nouvelles connaissances relatives à la maladie concernée et des améliorations apportées aux tests diagnostiques. Pour être optimales, les définitions de cas doivent aussi établir un équilibre entre sensibilité et spécificité qui reflète leur utilisation aux fins prévues. À la suite de la pandémie de grippe H1N1 de 2009-2010, l'Organisation mondiale de la Santé (OMS) a lancé une consultation technique sur la surveillance mondiale de la grippe. Cela a conduit à des améliorations concernant la sensibilité et la spécificité de la définition de cas pour la grippe – c'est-à-dire une maladie respiratoire dont seule la symptomatologie reste à définir. Le processus de révision n'a pas seulement modifié la définition du syndrome de type grippal pour inclure une liste simplifiée des critères le mieux à même de prédire une infection grippale, il a également permis de clarifier le langage utilisé dans la définition pour en améliorer l'interprétation. Par ailleurs, afin de tenir compte des cas sévères de grippe qui nécessitaient une hospitalisation, une nouvelle définition de cas a été introduite concernant l'infection aigüe sévère des voies respiratoires dans tous les groupes d'âge. Il a été constaté que les nouvelles définitions reflétaient davantage de cas, sans pour autant compromettre la spécificité. S'il est vrai que la distinction clinique de la grippe des autres infections respiratoires continue de poser problème, l'utilisation mondiale des nouvelles définitions de cas de l'OMS devrait permettre de dégager des tendances mondiales concernant les caractéristiques et la transmission des virus grippaux ainsi que la charge de morbidité qui leur est associée.La elaboración de definiciones precisas de los casos clínicos es una parte fundamental de un proceso efectivo de la vigilancia de la salud pública. Aunque tales definiciones deberían, idealmente, estar basadas en una recopilación estandarizada y fija de criterios de definición, a menudo necesitan una revisión para reflejar el nuevo conocimiento de la enfermedad existente y las mejoras en las pruebas de diagnóstico. Las definiciones óptimas de los casos también deben tener un equilibrio entre sensibilidad y especificidad que refleje su uso previsto. Después de la pandemia de gripe H1N1 en 2009-2010, la Organización Mundial de la Salud (OMS) inició una consulta técnica para la vigilancia mundial de la gripe. Esto dio lugar a mejoras en la sensibilidad y la especificidad de las definiciones de los casos de gripe, es decir, una enfermedad respiratoria que carece de una sintomatología definitoria singular. El proceso de revisión no solo modificó la definición de las enfermedades similares a la gripe para incluir una lista simplificada de los criterios que demostraron ser más predictivos de la infección por gripe, sino que también aclaró el lenguaje utilizado para la definición, con el fin de mejorar su interpretación. Para englobar los casos graves de gripe que requirieron hospitalización, también se desarrolló una nueva definición de los casos de la infección respiratoria aguda grave en todos los grupos de edad. Se ha descubierto que las nuevas definiciones engloban más casos sin comprometer la especificidad. A pesar del desafío que todavía plantea la separación clínica de la gripe de otras infecciones respiratorias, el uso global de las nuevas definiciones de los casos de la OMS debería ayudar a determinar las tendencias mundiales en las características y transmisión de los virus de la gripe y la carga de la enfermedad asociada.إن صياغة تعريفات دقيقة للحالات من الناحية العلاجية جزء أساسي من الإجراءات الفعالة لمراقبة الصحة العامة. وبالرغم من أن مثل هذه التعريفات يجب، من الناحية النظرية، أن تقوم على مجموعة منتقاة من المعايير التعريفية الموحدة والثابتة، فغالبًا ما تحتاج تلك التعريفات إلى المراجعة لكي تعكس المعلومات التي تستجد بشأن الحالة المرتبطة بها والتطورات التي تشهدها الاختبارات التشخيصية. وتحتاج أيضًا التعريفات المثالية للحالات إلى الموازنة بين الحساسية والنوعية بما يتفق مع الاستخدام المزمع. وبعد تفشي فيروس الأنفلونزا准确制定临床病例定义是进行有效公共卫生监督进程中的一个组成部分。虽然理论上此类定义应该以标准化和固定收集的定义标准为基础，但是这些定义通常需要进行修订，以反映所涉及的新症状知识，以及诊断测试的进展。最佳病例定义还需要达到反映其预期用途敏感性与特异性的平衡。2009–2010 年 H1N1 流感大流行之后，世界卫生组织发起了一项有关全球流感监测的技术咨询。该咨询提出改进流感定义的敏感性与特异性，即呼吸道疾病缺乏独特定义的症状。修订过程不仅修改流感样疾病定义，以纳入显示最能预测流感病毒感染的简化标准列表，同时明确了定义使用的语言，以增强解释力。为了获取需要住院治疗的严重流感病例，同时为所有年龄段的严重急性呼吸道感染制定了新的病例定义。目前已经发现新定义能够囊括更多案例，并且不会影响特异性。尽管在临床上将流感与其他呼吸道感染区分开来仍然面临挑战，但是统一使用世界卫生组织的新病例定义有助于确定全球流感病毒的特征和传播趋势以及相关的疾病负担。.Формулировка точных определений клинических случаев является неотъемлемой частью эффективного эпиднадзора. Хотя в идеале такие определения должны основываться на стандартизованном и фиксированном наборе определяющих критериев, они часто требуют пересмотра с учетом новых знаний об этих состояниях и улучшениях в диагностическом тестировании. Оптимальные определения случаев также должны иметь баланс чувствительности и специфичности, который отражает их целевое назначение. После пандемии гриппа H1N1 в 2009–2010 годах Всемирная организация здравоохранения (ВОЗ) инициировала техническую консультацию по глобальному эпиднадзору за гриппом. Это привело к улучшению чувствительности и специфичности определения для гриппа, то есть респираторного заболевания, которое не имеет однозначной определяющей симптоматики. Пересмотр привел не только к изменению определения гриппоподобного заболевания, включив в него упрощенный список критериев, показавших, что гриппозная инфекция является наиболее прогностической, но и для улучшения интерпретируемости был сделан более понятным язык, используемый для этого определения. Для выявления тяжелых случаев гриппа, требующих госпитализации, было разработано новое определение для тяжелой острой респираторной инфекции во всех возрастных группах. Было обнаружено, что новые определения охватывают больше случаев без ущерба для специфичности. Несмотря на сложности, которые все еще возникают при дифференциации гриппа от других респираторных инфекций, глобальное использование новых определений ВОЗ должно помочь выявить всеобщие тенденции в характеристиках и передаче вируса гриппа, а также в связанном с ними бремени болезней.

BACKGROUND\ud \ud On March 23, 2014, the World Health Organization (WHO) was notified of an outbreak of Ebola virus disease (EVD) in Guinea. On August 8, the WHO declared the epidemic to be a "public health emergency of international concern."\ud \ud METHODS\ud \ud By September 14, 2014, a total of 4507 probable and confirmed cases, including 2296 deaths from EVD (Zaire species) had been reported from five countries in West Africa - Guinea, Liberia, Nigeria, Senegal, and Sierra Leone. We analyzed a detailed subset of data on 3343 confirmed and 667 probable Ebola cases collected in Guinea, Liberia, Nigeria, and Sierra Leone as of September 14.\ud \ud RESULTS\ud \ud The majority of patients are 15 to 44 years of age (49.9% male), and we estimate that the case fatality rate is 70.8% (95% confidence interval [CI], 69 to 73) among persons with known clinical outcome of infection. The course of infection, including signs and symptoms, incubation period (11.4 days), and serial interval (15.3 days), is similar to that reported in previous outbreaks of EVD. On the basis of the initial periods of exponential growth, the estimated basic reproduction numbers (R-0) are 1.71 (95% CI, 1.44 to 2.01) for Guinea, 1.83 (95% CI, 1.72 to 1.94) for Liberia, and 2.02 (95% CI, 1.79 to 2.26) for Sierra Leone. The estimated current reproduction numbers (R) are 1.81 (95% CI, 1.60 to 2.03) for Guinea, 1.51 (95% CI, 1.41 to 1.60) for Liberia, and 1.38 (95% CI, 1.27 to 1.51) for Sierra Leone; the corresponding doubling times are 15.7 days (95% CI, 12.9 to 20.3) for Guinea, 23.6 days (95% CI, 20.2 to 28.2) for Liberia, and 30.2 days (95% CI, 23.6 to 42.3) for Sierra Leone. Assuming no change in the control measures for this epidemic, by November 2, 2014, the cumulative reported numbers of confirmed and probable cases are predicted to be 5740 in Guinea, 9890 in Liberia, and 5000 in Sierra Leone, exceeding 20,000 in total.\ud \ud CONCLUSIONS\ud \ud These data indicate that without drastic improvements in control measures, the numbers of cases of and deaths from EVD are expected to continue increasing from hundreds to thousands per week in the coming months.

The emergence of a novel strain of coronavirus in the Arabian Peninsula raised a global health concern in 2012, partly because the majority of human infections were fatal and partly due to its presumed animal origin. An urgent meeting of scientific and public health experts was convened by WHO in January 2013 in view of the limited knowledge available on the epidemiological and natural history of infection with this novel virus. The meeting reviewed current evidence and identified critical knowledge gaps to improve better understanding of the public health risk associated with the virus so as to improve preparedness and to safeguard and protect global health.

Objective— Proangiogenic effects of mobilized bone marrow–derived stem/progenitor cells are essential for cardiac repair after myocardial infarction. MicroRNAs (miRNA/miR) are key regulators of angiogenesis. We investigated the differential regulation of angio-miRs, that is, miRNAs regulating neovascularization, in mobilized CD34 + progenitor cells obtained from patients with an acute ST-segment–elevation myocardial infarction (STEMI) as compared with those with stable coronary artery disease or healthy subjects. Approach and Results— CD34 + progenitor cells were isolated from patients with STEMI (on day 0 and day 5), stable coronary artery disease, and healthy subjects (n=27). CD34 + progenitor cells of patients with STEMI exhibited increased proangiogenic activity as compared with CD34 + cells from the other groups. Using a polymerase chain reaction–based miRNA-array and real-time polymerase chain reaction validation, we identified a profound upregulation of 2 known angio-miRs, that are, miR-378 and let-7b, in CD34 + cells of patients with STEMI. Especially, we demonstrate that miR-378 is a critical regulator of the proangiogenic capacity of CD34 + progenitor cells and its stimulatory effects on endothelial cells in vitro and in vivo, whereas let-7b upregulation in CD34 + cells failed to proof its effect on endothelial cells in vivo. Conclusions— The present study demonstrates a significant upregulation of the angio-miRs miR-378 and let-7b in mobilized CD34 + progenitor cells of patients with STEMI. The increased proangiogenic activity of these cells in patients with STEMI and the observation that in particular miR-378 regulates the angiogenic capacity of CD34 + progenitor cells in vivo suggest that this unique miRNA expression pattern represents a novel endogenous repair mechanism activated in acute myocardial infarction.

Aims MicroRNAs (miRNA) are important non-coding modulators controlling patterns of gene expression. However, profiling and validation of circulating miRNA levels related to adverse cardiovascular outcome has not been performed in patients with an acute coronary syndrome (ACS). Methods and results In a multicentre, prospective ACS cohort, 1002 out of 2168 patients presented with ST-segment elevation myocardial infarction (STEMI). Sixty-three STEMI patients experienced an adjudicated major cardiovascular event (MACE, defined as cardiac death or recurrent myocardial infarction) within 1 year of follow-up. From a miRNA profiling in a matched derivation case–control cohort, 14 miRNAs were selected for validation. Comparing 63 cases vs. 126 controls, 3 miRNAs were significantly differentially abundant. In patients with MACE, miR-26b-5p levels ( P = 0.038) were decreased, whereas miR-320a ( P = 0.047) and miR-660-5p ( P = 0.01) levels were increased. MiR-26b-5p has been suggested to prevent adverse cardiomyocyte hypertrophy, whereas miR-320a promotes cardiomyocyte death and apoptosis, and miR-660-5p has been related to active platelet production. This suggests that miR-26b-5p, miR-320a, and miR-660-5p may reflect alterations of different pathophysiological pathways involved in clinical outcome after ACS. Consistently, these three miRNAs reliably discriminated cases from controls [area under the receiver-operating characteristic curve (AUC) in age- and sex-adjusted Cox regression for miR-26b-5p = 0.707, miR-660-5p = 0.683, and miR-320a =0.672]. Combination of the three miRNAs further increased AUC to 0.718. Importantly, addition of the three miRNAs to both, the Global Registry of Acute Coronary Events (GRACE) score and a clinical model increased AUC from 0.679 to 0.720 and 0.722 to 0.732, respectively, with a net reclassification improvement of 0.20 in both cases. Conclusion This is the first study performing profiling and validation of miRNAs that are associated with adverse cardiovascular outcome in patients with STEMI. MiR-26b-5p, miR-320a, and miR-660-5p discriminated for MACE and increased risk prediction when added to the GRACE score and a clinical model. These findings suggest that the release of specific miRNAs into circulation may reflect the activation of molecular pathways that impact on clinical outcome after STEMI.

Background— MicroRNAs are key regulators of angiogenic processes. Administration of angiogenic early outgrowth cells (EOCs) or CD34 + cells has been suggested to improve cardiac function after ischemic injury, in particular by promoting neovascularization. The present study therefore examines regulation of angiomiRs, microRNAs involved in angiogenesis, in angiogenic EOCs and circulating CD34 + cells from patients with chronic heart failure (CHF) and the role for their cardiac repair capacity. Methods and Results— Angiogenic EOCs and CD34 + cells were isolated from patients with CHF caused by ischemic cardiomyopathy (n=45) and healthy subjects (n=35). In flow cytometry analyses, angiogenic EOCs were largely myeloid and positive for alternatively activated M2 macrophage markers. In vivo cardiac neovascularization and functional repair capacity were examined after transplantation into nude mice with myocardial infarction. Cardiac transplantation of angiogenic EOCs from healthy subjects markedly increased neovascularization and improved cardiac function, whereas no such effect was observed after transplantation of angiogenic EOCs from patients with CHF. Real-time polymerase chain reaction analysis of 14 candidate angiomiRs, expressed in angiogenic EOCs, revealed a pronounced loss of angiomiR-126 and -130a in angiogenic EOCs from patients with CHF that was also observed in circulating CD34 + cells. Anti–miR-126 transfection markedly impaired the capacity of angiogenic EOCs from healthy subjects to improve cardiac function. miR-126 mimic transfection increased the capacity of angiogenic EOCs from patients with CHF to improve cardiac neovascularization and function. Conclusions— The present study reveals a loss of angiomiR-126 and -130a in angiogenic EOCs and circulating CD34 + cells from patients with CHF. Reduced miR-126 expression was identified as a novel mechanism limiting their capacity to improve cardiac neovascularization and function that can be targeted by miR-126 mimic transfection.

Summary Public health research is essential for the development of effective policies and planning to address health security and risks associated with mass gatherings (MGs). Crucial research topics related to MGs and their effects on global health security are discussed in this review. The research agenda for MGs consists of a framework of five major public health research directions that address issues related to reducing the risk of public health emergencies during MGs; restricting the occurrence of non-communicable and communicable diseases; minimisation of the effect of public health events associated with MGs; optimisation of the medical services and treatment of diseases during MGs; and development and application of modern public health measures. Implementation of the proposed research topics would be expected to provide benefits over the medium to long term in planning for MGs.

Sirtuin 5 as a novel target to blunt blood-brain barrier damage induced by cerebral ischemia/reperfusion injury. [Int J Cardiol. 2018]

Claudine Burton-Jeangros : Comment cette medecine de surveillance s’est-elle imposee et comment expliquer qu’autant de moyens aient ete alloues a la grippe A (H1N1) ? Sylvie Briand : Dans les annees 1960, on pensait que l’on en avait fini avec les maladies infectieuses. Il y avait des antibiotiques et des vaccins pour la plupart des maladies graves. Mais avec la pandemie du sida, que l’on decouvre dans les annees 1980, il y a eu un regain d’interet pour les maladies infectieuses. Il y a eu au...

The function of human XPA protein, a key subunit of the nucleotide excision repair pathway, has been examined with site-directed substitutions in its putative DNA-binding cleft. After screening for repair activity in a host-cell reactivation assay, we analyzed mutants by comparing their affinities for different substrate architectures, including DNA junctions that provide a surrogate for distorted reaction intermediates, and by testing their ability to recruit the downstream endonuclease partner. Normal repair proficiency was retained when XPA mutations abolished only the simple interaction with linear DNA molecules. By contrast, results from a K141E K179E double mutant revealed that excision is crucially dependent on the assembly of XPA protein with a sharp bending angle in the DNA substrate. These findings show how an increased deformability of damaged sites, leading to helical kinks recognized by XPA, contributes to target selectivity in DNA repair.

These centers could lead to a decline in cases, even if virus containment is imperfect., In some parts of western Africa, Ebola treatment centers (ETCs) have reached capacity. Unless capacity is rapidly scaled up, the chance to avoid a generalized Ebola epidemic will soon diminish. The World Health Organization and partners are considering additional Ebola patient care options, including community care centers (CCCs), small, lightly staffed units that could be used to isolate patients outside the home and get them into care sooner than otherwise possible. Using a transmission model, we evaluated the benefits and risks of introducing CCCs into Sierra Leone’s Western Area, where most ETCs are at capacity. We found that use of CCCs could lead to a decline in cases, even if virus transmission occurs between CCC patients and the community. However, to prevent CCC amplification of the epidemic, the risk of Ebola virus–negative persons being exposed to virus within CCCs would have to be offset by a reduction in community transmission resulting from CCC use.

Immediate priorities for control of the ongoing Ebola epidemic are early diagnosis, patient isolation, contact tracing, strict adherence to laboratory biosafety guidelines, barrier nursing procedures, use of personal protective equipment by clinicians, and safe burials.

Cellular senescence, a programmed state induced by multiple deleterious triggers, is characterised by permanent cell-cycle exit and altered gene expression and cell morphology. In humans it is considered a tumor suppressor mechanism, mediating removal of damaged or mutated cells from the cell-cycle pool, and may also contribute to the ageing process. In this study, we show that senescent human umbilical vein endothelial cells lose their ability to induce tissue factor (TF), a transmembrane protein with important roles in hemostasis and cancer progression, in response to thrombin or - independently of cell-surface receptors - phorbol-12-myristate-13-acetate. This phenomenon could not be explained by senescence-related alterations in the downstream signal transduction cascade or by accelerated TF mRNA degradation. Rather, using chromatin immuno-precipitation we could show that loss of TF gene inducibility during senescence occurs following chromatin remodelling of the TF promoter resulting from hypo-acetylation of histone H3. These findings were reversible after transduction of presenescent cultures with telomerase reverse transcriptase, enabling late-passage cultures to escape senescence. These results extend the involvement of heterochromatic gene silencing in senescence beyond cell cycle-related genes and suggest a novel anti-cancer mechanism of senescence through inhibition of TF inducibility.

Genetic and biochemical studies have shown that DNA polymerase delta (Poldelta) is the major replicative Pol in the eukaryotic cell. Its functional form is the holoenzyme composed of Poldelta, proliferating cell nuclear antigen (PCNA) and replication factor C (RF-C). In this paper, we describe an N-terminal truncated form of DNA polymerase delta (DeltaN Poldelta) from calf thymus. The DeltaN Poldelta was stimulated as the full-length Poldelta by PCNA in a RF-C-independent Poldelta assay. However, when tested for holoenzyme function in a RF-C-dependent Poldelta assay in the presence of RF-C, ATP and replication protein A (RP-A), the DeltaN Poldelta behaved differently. First, the DeltaN Poldelta lacked holoenzyme functions to a great extent. Second, product size analysis and kinetic experiments showed that the holoenzyme containing DeltaN Poldelta was much less efficient and synthesized DNA at a much slower rate than the holoenzyme containing full-length Poldelta. The present study provides the first evidence that the N-terminal part of the large subunit of Poldelta is involved in holo-enzyme function.

viruspropagationinthewetmarkets,and communications to the public. In combination, these measures rapidly and dramatically stopped the immediate outbreak both among poultry and humans. Within days after the last human cases, formal epidemiological field investigations were started. The findings from those studies suggested that few contacts ofinfectedindividualshadevidenceofinfection [1] and that exposure to wet markets and, by logical extrapolation, to infected poultry or a contaminated envi

International audience; BackgroundThe seventh reported outbreak of Ebola virus disease (EVD) in the equatorial African country of the Democratic Republic of Congo (DRC) began on July 26, 2014, as another large EVD epidemic continued to spread in West Africa. Simultaneous reports of EVD in equatorial and West Africa raised the question of whether the two outbreaks were linked.MethodsWe obtained data from patients in the DRC, using the standard World Health Organization clinical-investigation form for viral hemorrhagic fevers. Patients were classified as having suspected, probable, or confirmed EVD or a non-EVD illness. Blood samples were obtained for polymerase-chain-reaction–based diagnosis, viral isolation, sequencing, and phylogenetic analysis.ResultsThe outbreak began in Inkanamongo village in the vicinity of Boende town in Équateur province and has been confined to that province. A total of 69 suspected, probable, or confirmed cases were reported between July 26 and October 7, 2014, including 8 cases among health care workers, with 49 deaths. As of October 7, there have been approximately six generations of cases of EVD since the outbreak began. The reported weekly case incidence peaked in the weeks of August 17 and 24 and has since fallen sharply. Genome sequencing revealed Ebola virus (EBOV, Zaire species) as the cause of this outbreak. A coding-complete genome sequence of EBOV that was isolated during this outbreak showed 99.2% identity with the most closely related variant from the 1995 outbreak in Kikwit in the DRC and 96.8% identity to EBOV variants that are currently circulating in West Africa.ConclusionsThe current EVD outbreak in the DRC has clinical and epidemiologic characteristics that are similar to those of previous EVD outbreaks in equatorial Africa. The causal agent is a local EBOV variant, and this outbreak has a zoonotic origin different from that in the 2014 epidemic in West Africa. (Funded by the Centre International de Recherches Médicales de Franceville and others.)

Background— Reactive oxygen species are major determinants of vascular aging. JunD, a member of the activated protein-1 family of transcription factors, is emerging as a major gatekeeper against oxidative stress. However, its contribution to reactive oxygen species homeostasis in the vasculature remains unknown. Methods and Results— Endothelium-dependent vasorelaxation was impaired in young and old JunD −/− mice (6 and 22 months old) compared with age-matched wild-type mice. JunD −/− mice displayed an age-independent decline in endothelial nitric oxide release and endothelial nitric oxide synthase activity and increased mitochondrial superoxide formation and peroxynitrite levels. Furthermore, vascular expression and activity of the free radical scavengers manganese and extracellular superoxide dismutase and aldehyde dehydrogenase 2 were reduced, whereas the NADPH oxidase subunits p47phox, Nox2, and Nox4 were upregulated. These redox changes were associated with premature vascular aging, as shown by reduced telomerase activity, increased β-galactosidase–positive cells, upregulation of the senescence markers p16 INK4a and p53, and mitochondrial disruption. Interestingly, old wild-type mice showed a reduction in JunD expression and transcriptional activity resulting from promoter hypermethylation and binding with tumor suppressor menin, respectively. In contrast, JunD overexpression blunted age-induced endothelial dysfunction. In human endothelial cells, JunD knockdown exerted a similar impairment of the O 2 − /nitric oxide balance that was prevented by concomitant NADPH inhibition. In parallel, JunD expression was reduced in monocytes from old versus young healthy subjects and correlated with mRNA levels of scavenging and oxidant enzymes. Conclusions— JunD provides protection in aging-induced endothelial dysfunction and may represent a novel target to prevent reactive oxygen species–driven vascular aging.

Acute respiratory infection (ARI) is a leading cause of mortality worldwide, of which influenza is an important cause that can be prevented with vaccination. We did a systematic review of research published from 1980 to 2009 on seasonal influenza epidemiology in sub-Saharan Africa to identify data strengths and weaknesses that might affect policy decisions, to assess the state of knowledge on influenza disease burden, and to ascertain unique features of influenza epidemiology in the region. We assessed 1203 papers, reviewed 104, and included 49 articles. 1-25% of outpatient ARI visits were caused by influenza (11 studies; mean 9·5%; median 10%), whereas 0·6-15·6% of children admitted to hospital for ARI had influenza identified (15 studies; mean 6·6%; median 6·3%). Influenza was highly seasonal in southern Africa. Other data were often absent, particularly direct measurement of influenza incidence rates for all ages, within different patient settings (outpatient, inpatient, community), and for all countries. Data from sub-Saharan Africa are insufficient to allow most countries to prioritise strategies for influenza prevention and control. Key data gaps include incidence and case-fatality ratios for all ages, the contribution of influenza towards admission of adults to hospital for ARI, representative seasonality data, economic burden, and the interaction of influenza with prevalent disorders in Africa, such as malaria, HIV, and malnutrition.

From September through December 2005, an outbreak of hemorrhagic fever occurred in South Kordofan, Sudan. Initial laboratory test results identified IgM antibodies against yellow fever (YF) virus in patient samples, and a YF outbreak was declared on 14 November. To control the outbreak, a YF mass vaccination campaign was conducted and vector control implemented in parts of South Kordofan. Surveillance data were obtained from the Sudan Federal Ministry of Health. Clinical information and serum samples were obtained from a subset of patients with illness during the outbreak. Nomads, health personnel and village chiefs were interviewed about the outbreak. Mosquitoes were collected in 11 villages and towns in North and South Kordofan. From 10 September to 9 December 2005 a total of 605 cases of outbreak-related illness were reported, of which 45% were in nomads. Twenty-nine percent of 177 patients seen at clinics in Julud and Abu Jubaiyah had illness consistent with YF. Five of 18 unvaccinated persons with recent illness and 4 of 16 unvaccinated asymptomatic persons had IgM antibodies to YF virus. IgM antibodies to chikungunya virus were detected in five (27%) ill persons and three (19%) asymptomatic persons. These results indicate that both chikungunya and YF occurred during the outbreak.

Synthetic glucocorticoids belong to the most frequently administered drugs in livestock production. These synthetic hormones are employed for therapeutic purposes against inflammatory reactions, disorders of the musculoskeletal system, bovine ketosis and many other diseases of farm animals. A widespread illegal use of synthetic glucocorticoids to improve feed intake and weight gain has also been observed. To enforce the residue limits imposed on glucocorticoid drugs and preclude their illicit administration as growth promoters, it is necessary to establish high throughput analytical methods that can be applied to the screening of animal tissues. Here, we developed a dual luciferase reporter assay that detects residues or contaminants with glucocorticoid activity. This screening assay is performed by transfection of human cell lines with two reporter constructs followed by the measurement of two distinct luminescence signals, one of which serves as internal control to correct for assay variabilities and unspecific matrix effects. The limit of detection (1.25 microg for dexamethasone in liver) depends on the biological potency of each synthetic glucocorticoid but, with all drugs tested, the maximal response reaches a 20 to 30 fold induction of luciferase activity. In combination with an appropriate sample clean-up method (recovery of 82%), this luciferase assay has been applied to the analysis of liver samples from calves treated with a single therapeutic injection of either dexamethasone or flumethasone. Thus, the dual luciferase reporter assay provides a new screening tool to detect unwanted glucocorticoid activities in animal tissues or other crude biological samples without knowledge of the precise chemical entity of the parent compounds or their metabolites.

Background and Purpose: Microparticles (MPs) and exosomes are released by cells using different mechanisms. Thus, quantitative as well as qualitative changes of both particle populations, MPs and exosomes, in patients with coronary artery disease (CAD) might reflect an altered activation status of the endothelium, platelets and leukocytes. Moreover, they might exert differential effects on the target organs, such as the endothelium. Yet, alterations in both populations have not been studied side-by-side so far. The aim of the study was to compare the impact of MPs and exosomes from healthy subjects and CAD patients on endothelial cell (EC) functional characteristics. Methods: MPs and exosomes were isolated by stepwise filtration and ultracentrifugation from citrate-plasma and verified by electron microscopy and dynamic light scattering. MP and exosome fractions, as well as the vehicle (PBS), were added to human arterial ECs and EC apoptosis, number, size, capacity for in vitro-reendothelialisation after scratching, expression of adhesion molecules ICAM-1 and VCAM-1 were assessed. In parallel, platelet-, endothelial- and leukocyte-derived MPs were quantified. In a separate sub-study, the same parameters were assessed in plasma of CAD patients undergoing standard medical rehabilitation or an exercise-based cardiac rehabilitation programme. Results: MPs of healthy, but not of CAD patients supported in vitro re-endothelialisation, while exosomes had no influence. Exercise, but not standard rehabilitation improved CAD MP capacity to support in vitro rehabilitation. This was negatively correlated to the number of leukocyte- and endothelial-derived MPs, but not total or platelet MPs. EC number was negatively affected by exposure to CAD MPs. ANCOVA analysis identified disease, but not the particle type as influencing factor. Instead, apoptotic cell death was influenced by particle type, but not by the disease, and was not altered in rehabilitation. Similarly, ICAM-1 and VCAM-1 expression were enhanced on ECs after incubation with exosomes, but not with MPs, with no effect of disease or rehabilitation. Conclusion: MPs and exosomes differentially affect endothelial cell function and underlie differential modulation in disease and rehabilitation. Those findings might in the future help to optimize and monitor cardiovascular therapy.

The presentation aims at introducing the various challenges faced at global level during the first pandemic of the 21st century. On 25 April 2009, Mexico, under the International Health Regulations (2005) (IHR (2005)), notified the World Health Organization (WHO) about an outbreak of influenza-like illness. The responsible virus was identified a few days later by a WHO Collaborating Centre for Reference and Research on Influenza and a reference laboratory in Canada. This was the first reported event related to Influenza A (H1N1). In less than nine weeks, the pandemic virus spread in the six WHO regions. On 11 June 2009, WHO announced a pandemic phase 6. Because of the threat posed by the re emergence of A(H5N1)virus in 2003 in Asia, most of the influenza experts and modellers were predicting that the next pandemic would start in Asia with similar characteristic as the H5N1 disease currently observed with a high case fatality ratio. One of the lessons learned is that predictions are very difficult when related to influenza viruses due their unpredictable evolution and the complexity of factors leading to pandemic. The pandemic (H1N1) 09 is challenging in many aspects: firstly, the uncertainty about the evolution of the virus makes mid term preparedness and planning difficult. Secondly, the weakness of some surveillance system does not allow an easy monitoring of the disease and its spread. The oseltamivir resistance monitoring has also been difficult in some parts of the world. Thirdly, the modern communications means enable rumours to spread faster than ever. Public health authorities have to include risk communication in their strategy to respond to the outbreak. The nature of this pandemic with moderate severity and very rapid spread imposed to revise national pandemic preparedness plans during the course of the event. The public and the media often misunderstood the rational for the modification. The international community has responded quite well to the pandemic threat. In particular, countries have been especially collaborative regarding the exchange of information and the global access to supplies such as vaccine and antiviral drugs.

Social and behavioural factors are critical to the emergence, spread and containment of human disease, and are key determinants of the course, duration and outcomes of disease outbreaks. Recent epidemics of Ebola in West Africa and coronavirus disease 2019 (COVID-19) globally have reinforced the importance of developing infectious disease models that better integrate social and behavioural dynamics and theories. Meanwhile, the growth in capacity, coordination and prioritization of social science research and of risk communication and community engagement (RCCE) practice within the current pandemic response provides an opportunity for collaboration among epidemiological modellers, social scientists and RCCE practitioners towards a mutually beneficial research and practice agenda. Here, we provide a review of the current modelling methodologies and describe the challenges and opportunities for integrating them with social science research and RCCE practice. Finally, we set out an agenda for advancing transdisciplinary collaboration for integrated disease modelling and for more robust policy and practice for reducing disease transmission.

Anne Hébert a toujours pratiqué un art dit manichéen, jouant sur les contrastes, les inversions, les ambivalences. Le roman Les fous de Bassan ne fait pas exception à cette règle, au contraire. L'article propose une lecture de ce roman qui tient compte des dualités thématiques qui le régissent, parmi lesquelles se trouvent les tiraillements entre le réel et l'imaginaire, la polyphonie des voix, et l'écriture apocalyptique., Anne Hébert's writing deals with contrast, inversion, ambivalence. Her novel Les fous de Bassan doesn't make any exception to this. This article studies this novel with regard to its thematic dualism, which are the conflict between fiction and non fiction, the narration polyphony, and the apocalyptical writing.