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      Survival analysis of confirmed elephant endotheliotropic herpes virus cases in Thailand from 2006 – 2018

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          Abstract

          The elephant endotheliotropic herpesvirus (EEHV) has been a known cause of death of young elephants in Thailand for over a decade. In this study, we report on the demography, disease characteristics and mortality of 58 elephants with confirmed EEHV hemorrhagic disease between January 2006 and August 2018 using retrospective data subjected to survival analysis. Median age of EEHV presentation was 29 months, and the mortality rate was 68.97% with a median survival time of 36 h. Most EEHV cases occurred in the north of Thailand, the region where most of the country’s captive elephants reside. The hazard ratio analysis identified application of medical procedures and antiviral medications as being significant factors correlated to the risk of death. Our results indicate a need to focus EEHV monitoring efforts on young elephants and to follow current protocols that advise starting treatments before clinical signs appear.

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          Understanding survival analysis: Kaplan-Meier estimate

          Kaplan-Meier estimate is one of the best options to be used to measure the fraction of subjects living for a certain amount of time after treatment. In clinical trials or community trials, the effect of an intervention is assessed by measuring the number of subjects survived or saved after that intervention over a period of time. The time starting from a defined point to the occurrence of a given event, for example death is called as survival time and the analysis of group data as survival analysis. This can be affected by subjects under study that are uncooperative and refused to be remained in the study or when some of the subjects may not experience the event or death before the end of the study, although they would have experienced or died if observation continued, or we lose touch with them midway in the study. We label these situations as censored observations. The Kaplan-Meier estimate is the simplest way of computing the survival over time in spite of all these difficulties associated with subjects or situations. The survival curve can be created assuming various situations. It involves computing of probabilities of occurrence of event at a certain point of time and multiplying these successive probabilities by any earlier computed probabilities to get the final estimate. This can be calculated for two groups of subjects and also their statistical difference in the survivals. This can be used in Ayurveda research when they are comparing two drugs and looking for survival of subjects.
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            Statistics review 12: Survival analysis

            This review introduces methods of analyzing data arising from studies where the response variable is the length of time taken to reach a certain end-point, often death. The Kaplan–Meier methods, log rank test and Cox's proportional hazards model are described.
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              Review of Elephant Endotheliotropic Herpesviruses and Acute Hemorrhagic Disease.

              More than 100 young captive and wild Asian elephants are known to have died from a rapid-onset, acute hemorrhagic disease caused primarily by multiple distinct strains of two closely related chimeric variants of a novel herpesvirus species designated elephant endotheliotropic herpesvirus (EEHV1A and EEHV1B). These and two other species of Probosciviruses (EEHV4 and EEHV5) are evidently ancient and likely nearly ubiquitous asymptomatic infections of adult Asian elephants worldwide that are occasionally shed in trunk wash secretions. Although only a handful of similar cases have been observed in African elephants, they also have proved to harbor their own multiple and distinct species of Probosciviruses-EEHV2, EEHV3, EEHV6, and EEHV7-found in lung and skin nodules or saliva. For reasons that are not yet understood, approximately 20% of Asian elephant calves appear to be susceptible to the disease when primary infections are not controlled by normal innate cellular and humoral immune responses. Sensitive specific polymerase chain reaction (PCR) DNA blood tests have been developed, routine monitoring has been established, the complete large DNA genomes of each of the four Asian EEHV species have now been sequenced, and PCR gene subtyping has provided unambiguous evidence that this is a sporadic rather than epidemic disease that it is not being spread among zoos or other elephant housing facilities. Nevertheless, researchers have not yet been able to propagate EEHV in cell culture, determine whether or not human antiherpesvirus drugs are effective inhibitors, or develop serology assays that can distinguish between antibodies against the multiple different EEHV species.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: ResourcesRole: Writing – original draft
                Role: Formal analysisRole: Methodology
                Role: MethodologyRole: ResourcesRole: Writing – review & editing
                Role: ResourcesRole: Writing – review & editing
                Role: MethodologyRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                5 July 2019
                2019
                : 14
                : 7
                : e0219288
                Affiliations
                [1 ] Center of Elephant and Wildlife Research, Chiang Mai University, Chiang Mai, Thailand
                [2 ] Department of Food Animal Clinic, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai, Thailand
                [3 ] Elephant Hospital, National Elephant Institute, Forest Industry Organization, Lampang, Thailand
                [4 ] Department of Large Animal and Wildlife Clinical Sciences, Faculty of Veterinary Medicine, Kasetsart University, Kamphaeng Saen Campus, Nakornpathom, Thailand
                [5 ] Department of Companion Animal and Wildlife Clinics, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai, Thailand
                [6 ] Center for Species Survival, Smithsonian Conservation Biology Institute, Front Royal, Virginia, United State of America
                Katholieke Universiteit Leuven Rega Institute for Medical Research, BELGIUM
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                PONE-D-18-33945
                10.1371/journal.pone.0219288
                6611605
                31276571
                5cba892d-04f4-47b9-8b9a-b77beda3a700

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 24 December 2018
                : 20 June 2019
                Page count
                Figures: 4, Tables: 2, Pages: 15
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100002842, Chiang Mai University;
                Award ID: 1/2561
                Financial support was received from Chiang Mai University (1/2561). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Vertebrates
                Amniotes
                Mammals
                Elephants
                People and Places
                Geographical Locations
                Asia
                Thailand
                Biology and Life Sciences
                Veterinary Science
                Veterinary Diseases
                Biology and Life Sciences
                Veterinary Science
                Veterinary Medicine
                Veterinary Diagnostics
                People and Places
                Population Groupings
                Professions
                Veterinarians
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Artificial Gene Amplification and Extension
                Polymerase Chain Reaction
                Research and Analysis Methods
                Molecular Biology Techniques
                Artificial Gene Amplification and Extension
                Polymerase Chain Reaction
                Medicine and Health Sciences
                Diagnostic Medicine
                Custom metadata
                All relevant data are within the manuscript and its Supporting Information files.

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                Uncategorized

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