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kawasaki kaf 620 mule 3010 4x4 2005 manualAnd by having access to our ebooks online or by storing it on your computer, you have convenient answers with Ebola The Ultimate Guide To Ebola Protection History Symptoms Treatment Ebola Survival Handbook Ebola Prevention Ebola Treatment Ebola Cure Symptoms Ebola Vaccine Plague Ebola Transmission. To get started finding Ebola The Ultimate Guide To Ebola Protection History Symptoms Treatment Ebola Survival Handbook Ebola Prevention Ebola Treatment Ebola Cure Symptoms Ebola Vaccine Plague Ebola Transmission, you are right to find our website which has a comprehensive collection of manuals listed. Our library is the biggest of these that have literally hundreds of thousands of different products represented. I get my most wanted eBook Many thanks If there is a survey it only takes 5 minutes, try any survey which works for you. Learn More. This article has been cited by other articles in PMC. Abstract The current Ebola outbreak in West Africa has already caused substantial mortality and dire human and economic consequences. It continues to represent an alarming public health threat in the region and beyond and jeopardizes the provision of health care and other services in the affected countries. The scale of the epidemic has accelerated research efforts for diagnostics, treatment, and prevention galvanized through increased availability of funding. Our knowledge relating to the virus, disease pathogenesis, risk factors, dynamics of transmission, and epidemic control is increasing, and sociocultural factors have emerged as critical determinants for the success and failure of control efforts. However, there is a long way to go. In this review we summarize the current knowledge, examine the sociocultural context in West Africa, and outline priority areas for future research.Subsequently, transmission became intense in these 3 countries, and by the end of January 2015, it is still ongoing.http://www.greenleafdoors.com/userfiles/how-to-manually-uninstall-microsoft-office-2003.xml

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Simultaneously, a small unrelated EV outbreak took place in the Democratic Republic of Congo between July and October 2014. 2 By the end of January 2015, the outbreak in West Africa had accounted for more than 22,000 cases and 8,800 deaths. 3 Although transmission seems to have slowed down in Liberia and Guinea Conakry, more than 50 new cases are still reported daily in Sierra Leone. 3 The current outbreak has unpredictable economic consequences for the 3 deeply affected countries (Guinea Conakry, Sierra Leone, and Liberia) and the region of West Africa as a whole. Even in neighboring countries within the region, where few or no cases have been reported, tourism (an important source of income) has been heavily hampered while facilities for potential Ebola cases have been prepared. A serious shortage of timely resources in the region is one of the key factors responsible for the disproportionate scale of the ongoing epidemic in West Africa. Although international response eventually occurred, it only arose when the epidemic was already out of control and had been considered an international public health threat. 4 An additional trigger for the international response was the appearance of cases in the United States and Europe. Suddenly, it became obvious that Ebola poses an urgent threat not only to West Africa but also to the international community at large. This review aims to summarize the current scientific knowledge relating to host and pathogen, to analyze drivers of the current epidemic, and to discuss potential mitigation strategies within their ethical and societal context. Epidemiology of Ebola outbreaks in Africa The first human EV outbreak occurred in Zaire (now the Democratic Republic of Congo) in 1976 5 and was named after the nearby Ebola River. The same year, a similar outbreak with a different EV species occurred in Sudan. 6 Since 1976, more than 25 known outbreaks of EV have occurred in Africa, and 5 different EV species have been identified.http://www.analyticgroup.ru/userfiles/how-to-manually-uninstall-mcafee-dlp-agent.xml Currently, EV hemorrhagic fever remains a plague for the population of equatorial Africa, with an increase in the numbers of outbreaks and cases since 2000. 7 The current EV outbreak in West Africa is the largest ever recorded given the number of affected persons, countries involved, and longest persistent transmission ( Fig 1 ). The previous largest outbreak occurred in Uganda in 2000 and involved 425 persons, less than 2 of the affected subjects in the current outbreak. 7 Past outbreaks were confined to relatively rural and isolated areas in Central Africa without spreading to urban sectors, which facilitated the effective intervention of control measures. 5 The delay in identifying the outbreak in urban settings in the current outbreak hindered the timely and effective implementation of control efforts in the region. Open in a separate window Fig 1 Major Ebola outbreaks occurring in Africa from 1976 to 2014. Areas of bubbles represent numbers of cases. Other clinical and epidemiologic characteristics are similar between past and ongoing EV epidemics. Currently, the CFR among all patients from whom a definitive outcome is recorded is 72, and it is slightly less for hospitalized patients (CFR, 60). 12 The incubation period has also been similar between outbreaks, ranging from 2 to 21 days. 8,13 Several mathematic models have attempted to compare the average number of secondary infections per case (R 0 ) in the past and recent outbreaks. Characteristics of EV The genus Ebola are nonsegmented, negative-sense, single-stranded RNA viruses of the Filoviridae family, which is coined from the Latin word “filum,” meaning thread-like. Each subtype was named after the site where it was first isolated. Since 1976, when EV was first described, the first 3 subtypes have been responsible for large outbreaks in Africa, with the Zaire strain causing the most fatalities. The Reston subtype is largely localized to the Western Pacific region.https://labroclub.ru/blog/ef3000iseb-service-manual-pdf Despite being highly pathogenic in nonhuman primates, it has not been reported to cause illness in human subjects. 18 Apart from EV, another member of the Filoviridae family is Marburg virus, which is named after the city in Germany where it was first discovered. EV and Marburg viruses share genome organization and replication mechanisms with rhabdoviruses and paramyxoviruses. 16 Molecular structure of EV The genome of EV consists of a single-stranded RNA approximately 19,000 nucleotides long. The Ebola genome has 7 known nucleotide sequences that code for structural and nonstructural proteins also known as viral proteins (VPs). The core of the virus is made up of RNA genomic molecules comprised of nucleoprotein. 19 There are several types of VPs, each with a different function. VP30 plays an important role in RNA transcription activation, which is strongly dependent on the concentration of VP30. VP24, which is the primary matrix protein, is also the most abundant virion component. Its role is unclear. VP35 plays an important role in viral RNA synthesis. It acts as a type of interferon antagonist. There is a very strong possibility that the potency of VP35 could account for the varying degrees of virulence among different strains of EV. 20 VP40 is a matrix protein from the negative strand of RNA. It mainly participates in the assembly of lipid-enveloped viruses by providing a link between the surrounding membrane and the nucleocapsid structure. The protein, also known as single-surface transmembrane glycoprotein, forms spikes on virions and plays an important role in viral entry into cells by mediating receptor binding, fusion, and entry into the target cell. 19 Immunosuppression caused by EV is largely attributed to a section of the glycoprotein (G1 and G2) that shares a striking homology with another immunosuppressive protein found in oncogenic retroviruses. 20 This particular sequence is thought to aid EV in evading the human immune responses in addition to suppressing MHC. Open in a separate window Fig 2 Viral assembly model of Ebola virus. Viral mRNA transcribed from genomic negative-sense RNA is released into the cytoplasm, where VPs are translated. Nucleoprotein, together with VP35, VP40, VP30, and VP24, forms small inclusions (A), which become larger near the nucleus (B). At the edge of the inclusion bodies, the nucleocapsid (NC) is formed. VP40 associates with the NC, contributing to its transport to the plasma membrane (C1). Alternatively, nucleocapside initially associates with a few VP40 molecules and then moves to the plasma membrane, where it is enveloped with membrane-associated VP40 (C2). Synthesized glycoprotein (GP) is independently transported to the plasma membrane (D). The viral components then assemble, and the progeny virions bud (E). ER, Endoplasmic reticulum. Reprinted with permission from Nanbo et al. 21 Transmission and transmission dynamics Ebola hemorrhagic fever is a classic zoonosis with persistence of EV in a reservoir species thought to be rodents and bats. 27 Bats are present in large numbers at the sites of several outbreaks and are known to maintain other pathogenic RNA viruses, such as rabies. EV antibodies have been measured in fruit bats. 28 However, the virus has never been isolated from these animals. It is supposed that EV might persist as an asymptomatic or subclinical infection in the reservoir species, with little or no transmission, and is only activated by appropriated stimulus (ie, stress and coinfection). 29,30 Apes, humans, and other mammalian species that are susceptible to EV infection are regarded as end hosts. 29 An outbreak of Ebola virus disease (EVD) typically begins through human contact with an infected animal. 30 These transmissions might be an infrequent event, probably also underreported, given the restricted contact with the reservoir species. 29 Once the first human is infected, the disease spreads to other human subjects through direct contact with blood and body fluids of sick patients or persons who have died from EVD. The most infectious body fluids are blood, feces, and vomit, 31 although other fluids, such as urine, saliva, breast milk, semen, and, theoretically, sweat, can also contribute to transmission because EV has been isolated from these fluids. The likelihood of transmission depends on the type of exposure and the viral load. Therefore transmission is unlikely during the incubation period, 32 and the risk is highest during contact with very sick patients and dead bodies. Health care workers caring for patients with EVD are at high risk of infection if they do not use appropriate protective measures. Serosurveys conducted in the region suggest that EV has been endemic in equatorial Africa at least during the last decades 36 and specifically in West Africa for about a decade. 37 Therefore it is likely that asymptomatic infections can occur in some subjects. 38 However, the factors determining the spectrum and range of clinical symptoms from mild to severe manifestations are not well understood at present. Larger seroprevalence surveys in the affected populations and detailed host studies during the time of an epidemic would be mandatory to understand factors influencing susceptibility and possibly protection. It is well established that the virus enters through mucous membranes or cuts and abrasions in contact with infected materials, such as blood, sweat, urine, and other secretions. Ingestion of contaminated food with high viral titers might also play a role. 18 EV can infect a wide range of cell types, with a preference for rapid replication in monocytes, macrophages, and dendritic cells, 39 from which the infection spreads through the lymphatic system and hematogenously. Although not a direct target of infection, large numbers of lymphocytes apoptose and release soluble factors, triggering the inflammatory cascade and causing damage to the endothelial system. 40,41 The exact mechanisms causing the substantial epithelial damage leading to disseminated intravascular coagulopathy and hypotensive shock are incompletely understood. EV replication and ongoing infection lead to extensive necrosis of adrenocortical cells, with a subsequent effect on steroid synthesis, blood pressure regulation, and loss of sodium, resulting in hypovolemic shock. 42 Coagulopathy is a key feature of advanced Ebola disease and is induced by the strong proinflammatory response from monocytes and macrophages, as well as possibly deficiencies in production of liver-derived clotting factors because of liver cell necrosis. The immune mechanisms involved are illustrated in more detail in Fig 3. Open in a separate window Fig 3 Pathogenesis of Ebola at the cellular level. GP, Glycoprotein. The infection of antigen-presenting cells with EV triggers a strong inflammatory response, and clinical outcome depends on the extent of the host's counterregulatory response. The initial diagnosis is often made on clinical grounds in the context of a history of exposure. EV infection is then confirmed in national or international reference laboratories by identifying the viral genome in the blood of patients by using RT-PCR techniques or viral detection ELISAs. 45,46 The host response can be measured as the IgM and later IgG antibody response by using ELISA techniques. In nonfatal cases the increase in antibody titers around day 6 to 11 accompanies the recovery. Whether these are markers of disease activity or have protective potential remains to be established. IgG antibodies are known to persist for many years after infection. 47,48 Although highly accurate, the currently used diagnostic tests have significant logistic challenges, including the requirements for high-level laboratory biosafety and staff with expertise in using sophisticated machines. Lost time means that infected persons might remain in the community, with a severe risk of unknowingly transmitting the virus to others. Moreover, in the absence of rapid laboratory support, persons with other common infectious diseases, such as malaria or dengue, and similar early symptoms might be unjustifiably held in an Ebola “transit” center as a precautionary measure and are thus at risk of contracting Ebola. In October 2014, the World Health Organization (WHO) launched an initiative to stimulate diagnostic innovations to bring novel accurate tests to the point-of-care level. Decreasing the turnaround time for diagnosis through such assays would allow triaging and treating appropriate patients as swiftly as possible. The 2 key initiatives aim to rapidly solicit products that meet a prespecified “ideal profile” of the next generation of diagnostic tests and to provide a rapid review process for assessing a diagnostic test's quality, safety, and performance. 49 Patients with severe disease and often fatal outcomes progress to multisystem involvement, including gastrointestinal (vomiting, diarrhea) and pulmonary symptoms, such as breathlessness and cough. A maculopapular rash has been reported around day 5 to 7 of the illness. The most feared symptoms of widespread hemorrhages from various mucous membranes and disseminated intravascular coagulopathy accompany the devastating multiorgan failure at the peak of viremia and ultimately lead to the death of the infected patient from hypovolemic shock unless comprehensive supportive therapy can be offered in time. 50,51 Abnormal laboratory parameters include leukopenia and lymphopenia, increased liver and pancreatic enzyme levels, abnormal clotting results, and renal failure, all of which are indicative of a severe multisystem disorder with a high rate of fatality. 52 Death rates have varied between 40 and 80 at various times during the current epidemic 50,51 and might be more reflective of the available support measures than differences in host susceptibility or acquisition of immunity on a larger scale. Delay in diagnosis, presentation at an already advanced stage of disease, and absence of treatment centers were clearly associated with higher death rates than have been reported lately. However, judging by previous epidemics and current observations, it is practically certain that differences in host susceptibility and response to infection and therapy exist, which, if better defined through research conducted in the context of the outbreak situation, might help to develop prognostic markers and tailored interventions. Time of presentation, viral load, general state of the patient by the time of arrival at a treatment center, and possibly age and comorbidities can all influence the ultimate outcome of the disease in a subject. Therapeutic interventions The current recommendations for treatment of Ebola comprise the administration of sufficient fluids (oral or intravenously) to maintain circulatory stability, exclusion or treatment of malaria, and administration of broad-spectrum antibiotics to treat potential concomitant bacterial infections, antipyretics, and analgesia. 53 No results from randomized controlled trials (RCTs) comparing different interventions and protocols are available at this point in time. It is widely acknowledged that supportive care has differed between sites and patient populations, varying from basic oral rehydration to intravenous fluid resuscitation. Whether the routine use of antibiotics makes a significant contribution to outcome is unclear. The role of oral potassium supplementation in the absence of close electrolyte monitoring and use of antidiarrheal agents also remains to be established. The pressure on materials, facilities, and skilled personnel in the endemic areas has limited the supportive care that can be provided in this emergency situation when compared with the care delivered to personnel with Ebola infection who were expatriated to resource-rich settings in Europe and North America. Not surprisingly, death rates in the context of modern intensive care have been much lower, as long as the patients arrived at earlier stages of the disease. The different objectives are to test the administration of antibodies from the blood of Ebola survivors to neutralize EV in the patients (passive immunization) or to interfere with transcription and replication of the EV by using antivirals, which have shown promise in other viral diseases. The 2 leading antiviral candidates are brincidofovir (Chimerix, Durham, NC) and favipiravir (Fujifilm, Toyama Chemical, Tokyo, Japan). Brincidofovir is currently in phase III clinical trials for use in human subjects against cytomegalovirus (CMV) and adenovirus after successful testing for safety in more than 1000 human subjects 54 and has received US Food and Drug Administration Fast Track Designation for treatment of CMV, adenovirus, and smallpox. 55 On October 6, 2014, Chimerix received a US Food and Drug Administration authorization for emergency investigational new drug applications of brincidofovir for the treatment of EVD, but of late, the company has decided to focus their efforts on its use in CMV and adenovirus infections. Favipiravir is an experimental antiviral drug being developed by Toyama Chemical of Japan with activity against many RNA viruses, including influenza. 56,57 At the time of writing, clinical trials of this drug have started in Guinea, with more than 100 patients already enrolled. Further therapeutic interventions could also relate to products for correcting the coagulopathy seen in patients with severe Ebola disease, 58 but no clinical trials are announced at present. Prioritized use of experimental drugs in the face of limited supply Because of the life-threatening situation during EV outbreaks and the absence of known treatments, experimental therapies are being deployed for compassionate use. In line with the principles of reciprocity, health workers infected with EV are currently given higher consideration to access the scarce drugs. Although understandable, this practice can promote distrust in health care systems and potentially undermine the social value of clinical research involving the experimental therapies. Therefore it remains critical that fair selection of beneficiaries of the unproved interventions should be transparently and consistently practiced. 59 Vaccines At the time of writing, there was no licensed vaccine against EV, although clinical trials have now commenced in the United States, Europe, and West Africa, and preliminary results on safety and immunogenicity are becoming available. Despite existence of promising vaccine candidates, the low incidence and sporadic nature of outbreaks of Ebola, largely limited to a few countries in Central and East Africa, have discouraged pharmaceutical companies from making huge investments into their development and testing. 60 This situation has dramatically changed with the unprecedented outbreak in West Africa. 61 The sheer scale of the global health concerns has finally energized a consortium of pharmaceutical companies, researchers, and funders to prioritize the clinical development of Ebola vaccines. The first goal of this concerted effort is to protect the frontline health workers who are at increased risk of infections and death when providing care for patients. 59 This is ultimately planned to be extended to the affected countries in an exceptionally fast-tracked process in which vaccine development, testing, and licensure take place in parallel. Because speed is the goal for Ebola vaccine development and rollout, a number of challenges need to be pragmatically addressed to achieve this lofty objective. Table I 62 shows an updated profile of 2 leading candidate Ebola vaccines and others in development. ChAd3 are genetically modified vectors with biosafety level 2 status. Current epidemic in West Africa is caused by the Zaire strain, limiting possible deployment in the event of proved efficacy. Postexposure Has demonstrated efficacy in rodents and nonhuman primates; however, it currently trails behind ChAd3-ZEBOV in phase I trials. Report of arthralgia among volunteers in a Swiss trial led to a temporary halt. Concurrent efficacy trials along with ChAd3-ZEBOV in worst-hit countries Efficacy is likely to depend on filovirus species and early commencement of intervention after exposure. Phase I trials are planned for early 2015. Human trials are scheduled in 2015. Will depend on phase I data Limited safety data in human subjects EBOV GP Vaccine: Recombinant nanoparticle using adjuvant Matrix-M: first Ebola vaccine candidate based on the 2014 Guinea Ebola strain genetic sequence Novavax, Gaithersburg, Md Pre-exposure Robust immune responses demonstrated in preclinical studies; exceptional responses were seen when used with Novavax Matrix-M adjuvant. Nonhuman primate study was initiated. GMP manufacture was initiated. Scaled-up manufacturing is to begin in first quarter of 2015. Phase 1 clinical trial is anticipated to start in December 2014. Will depend on phase I data Limited safety data on Matrix-M adjuvant in human subjects Oral Ad5: Oral tablet vaccine based on human adenovirus Vaxart, South San Francisco, Calif Pre-exposure Protective against challenge in preclinical studies; clinical trials are anticipated in early 2015. Will depend on phase I data High pre-existing antibody against human adenovirus vectors rVSV-EBOV: Another vesicular stomatitis vector based vaccine Profectus Biosciences, Baltimore, Md Pre-exposure Safety data are available in this vaccine component expressing HIV gag. Phase I trials are planned for second quarter of 2015. Will depend on phase I data No safety data in human subjects Three potential vaccines: Triazoverin based on an EV strain and the other 2 based on recombinant mAbs Russian Ministry of Health, Moscow, Russia Preventive and therapeutic Efficiency is said to range between 70 and 90. There are plans to send the vaccines to affected West African countries by December 2014. Will depend on phase I data No safety data in human subjects Open in a separate window Changing dogma to accelerate development of vaccines and therapeutics The utmost urgency required to effectively contain the epidemic has dramatically changed the perception of the need for an Ebola vaccine, and the global response has resulted in substantial funds being released for Ebola. 63 This development is accompanied by renewed interest from researchers and pharmaceutical companies. Interestingly, some drug companies have insisted on securing indemnity from government against loss or damages that might follow use of the products developed from fast-tracked clinical trials. 64 Removing obstacles to accelerate the pace of Ebola vaccine and treatment trials The conduct of clinical trials is commonly characterized by complex heterogeneous, expensive, and time-consuming approval processes, 65,66 and monitoring usually concentrates on retrospective data verification. However, in the current context a risk-based approach to monitoring of clinical trials with emphasis on centralized monitoring is being encouraged. In this context regular review of emerging safety data by independent data and safety monitoring committees needs to remain the highest priority, and emerging data should be appropriately shared with regulatory authorities. 67 The notion of a single submission point for clinical trial authorization with defined timelines for approval would further support these efforts. Ethical issues in the search for effective Ebola control Since the launch of global efforts to accelerate initiatives to identify potent vaccines to control the scourge of Ebola, there have been growing controversies about the appropriate study design to adopt in achieving this. 68,69 Although RCTs are widely accepted as the gold standard to provide credible evidence for vaccine efficacy and subsequent licensing, experts have argued that RCTs are ethically inappropriate because of the lack of effective Ebola treatments, very high mortality rate, and almost comatose health systems in the affected countries. The experts proposed a parallel evaluation of different experimental interventions at different sites while concurrently documenting mortality rates after use of “standard” care. 69 An emerging body of knowledge advocates a prospective cohort, stepped-wedge design. Time periods before the community intervention serve as controls, and efficacy is estimated based on having concurrent preintervention and postintervention follow-up time periods. 71 This approach requires close interactions with major stakeholders, including regulators, investigators, affected communities, and the WHO. If backed with robust data collection, this design could be acceptable to regulators to support licensure. It also offers a unique opportunity for governments, manufacturers, Ebola-affected countries, and funders to work harmoniously together to develop a viable vaccine or treatment that could make the present Ebola epidemic the last in medical history. 62 Apart from this approach, a ring-vaccination strategy is also planned to evaluate Ebola vaccine in an affected West African country. In line with this strategy, when an Ebola case is confirmed, the affected patient's family members, friends, neighbors, and community will be vaccinated, thereby forming a ring of resistance around the patient to prevent further spread of the infection. This strategy was successfully used to eradicate smallpox globally. 72 Because no human data exist on Ebola vaccine efficacy, the adaptive, randomized, observer-blind, controlled trial design still remains attractive because it is the most powerful scientific design for detection of vaccine efficacy and begins with truly randomized groups. This adaptive design allows for discontinuation of the control arm (or vaccination) based on predefined event-driven analyses of near-real time data collected during the trial. 73 Anthropologic and health system factors in Ebola control The role of anthropologic factors in triggering Ebola outbreaks in remote Sub-Saharan Africa settings is well recognized. Because of apparent food insecurity and poverty, wildlife animals, including bats and nonhuman primates, are frequently hunted for subsistence and trade. 74 This anthropogenic activity amplifies human exposure to pernicious zoonosis because deadly viruses harbored by these animals can easily be transmitted to human subjects when their carcasses are being processed for human consumption. 75 Although the mechanism underlying animal-to-human transmission it is not entirely clear, most Ebola outbreaks to date are traceable to a single index case who (or whose family members) had contact with carcasses of bats or nonhuman primates in impoverished remote African villages with obvious food insecurity. 18,76 Once an outbreak has been initiated, spread is often enhanced by an array of cultural beliefs and practices, including adherence to time-honored paradigms of health and illness.