تحميل فيلم Maximum Risk
Alfonzo Liebenstein
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The ongoing transmission of the Middle East respiratory syndrome coronavirus (MERS-CoV) in the Middle East and its expansion to other regions are raising concerns of a potential pandemic. An in-depth analysis about both population and molecular epidemiology of this pathogen is needed.
MERS cases reported globally as of June 2020 were collected mainly from World Health Organization official reports, supplemented by other reliable sources. Determinants for case fatality and spatial diffusion of MERS were assessed with Logistic regressions and Cox proportional hazard models, respectively. Phylogenetic and phylogeographic analyses were performed to examine the evolution and migration history of MERS-CoV.
MERS-CoV remains primarily locally transmitted in the Middle East, with opportunistic exportation to other continents and a potential of causing transmission clusters of human cases. Animal contact is associated with a higher risk of death, but the association differs by age and sex. Transportation network is the leading driver for the spatial diffusion of the disease. These findings how this pathogen spread are helpful for targeting public health surveillance and interventions to control endemics and to prevent a potential pandemic.
Middle East respiratory syndrome (MERS) is a respiratory infectious disease first discovered in the Kingdom of Saudi Arabia in September 2012 [1]. The disease is caused by the Middle East respiratory syndrome coronavirus (MERS-CoV) which can be highly pathogenic in humans. Individuals infected with MERS-CoV may experience none, mild or severe respiratory illnesses or even death. As of 30 May 2020, a total of 27 countries in the Middle East, North Africa, Europe, Northeast Asia, and North America have reported 2562 laboratory-confirmed MERS cases and 881 associated deaths, according to the World Health Organization (WHO) [2]. The vast majority of MERS cases were reported by the Saudi Arabia, followed by Republic of Korea [2]. Frequent travelers and worshippers from and to the Middle East have raised the concern about a global pandemic, given the lack of effective treatment and vaccine [3]. In February 2018, WHO formally incorporated MERS into the Research and Development Blueprint (the R&D Blueprint) to promote research in this area [4].
Current epidemiological studies suggest that human-to-human transmission of MERS-CoV is inefficient, and the primary infection mode is via direct/indirect contact with dromedary camels, although other mammals may also serve as the reservoir [5,6,7,8,9,10]. On the other hand, human clusters of MERS have been continuously observed in healthcare and household settings, especially among people with chronic conditions or compromised immunity [11, 12]. Several studies explored risk factors for the transmission of MERS-CoV at the individual level in specific countries and found that infection risk was mainly driven by recent exposure to dromedary or its raw products, chronic conditions, or close contact with other MERS patients [11, 13,14,15,16]. However, very few studies have systematically analyzed spatial diffusion of the virus at the population level and associated risk factors. In addition, while it has been shown that chronic condition and male sex are highly predictive of fatal outcomes [17], no study has examined potential interactions among key predictors for death, e.g., demographic characteristics and animal contact. Some of these predictors are correlated, e.g., males tend to have much more frequent contact with dromedary. Consequently, it is necessary to condition on one predictor when evaluating the effect of another.
In the midst of the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is crucial to understand the epidemiological characteristics and evolutionary history for MERS-CoV as the two coronaviruses are genetically related. The possibility of recombination between the two viruses if co-infection of the same host occurs cannot be totally ruled out, as their host species do overlap, e.g., humans and bats [18]. Thus far, phylogenetic and phylogeographic analyses focusing on MERS-CoV have been either outdated or restricted to small data sets [9, 10, 19,20,21]. In addition, some evolutionary characteristics of MERS-CoV such as which genes are subject to positive selection, need to be closely monitored.
By assembling MERS surveillance and contact tracing data up to June of 2020 from public health agencies and peer-reviewed literature, we summarized the epidemiological features and spatiotemporal spread of MERS around the globe. We investigated risk factors for fatality and how their effects could be modified by each other. In addition, we assessed the roles of a variety of environmental, socioeconomic, and biological factors in the spatial diffusion of MERS-CoV. Using publicly available MERS-CoV full-genome sequences, we further assessed the evolution and migration history of the virus. Piecing these results together, we aim to provide an up-to-date picture about both population and molecular epidemiology of this pathogen.
We assembled three datasets: (1) a list of individual human cases worldwide with demographic, exposure and clinical information, (2) eco-geographic and socioeconomic characteristics (referred to as socioenvironmental variables hereinafter) at the appropriate administrative level in the Middle East (county for Saudi Arabia and province for the other countries), and (3) full-genome sequences of MERS-CoV worldwide.
All the cases had been confirmed following a standard WHO technical guidance ( _infections/case_definition/en/). A valid record of MERS case must include the basic demographic information (gender, age, reporting country, city of residence, being healthcare worker or not, baseline chronic conditions), dates of critical events (such as symptom onset, first hospitalization, laboratory confirmation), and exposure information (whether exposed to animal or its raw production, or exposed to confirmed MERS patients). Cases without any individual information, duplicated records and no-confirmed cases were removed. Each confirmed case was geo-referenced and mapped according to the finest address available using GIS technologies. Thematic maps of cumulative numbers of confirmed MERS cases and clusters were created using ArcGIS 10.5 (Esri Inc, Redlands, CA, USA).
We limited the spatiotemporal diffusion analysis to the Middle East Region, the main endemic region of MERS. Opportunistic long-distance exportations of MERS cases, e.g., to Europe and Republic of Korea, were not considered. The spatial unit used in this study is the second-level administrative unit, e.g., province, for most countries. Provinces of Saudi Arabia are much larger than those of neighboring countries. To make spatial units comparable between countries, we use the third-level administrative area (county) as the spatial unit for Saudi Arabia. Finally, a total of 283 administrative units were included in the spatiotemporal diffusion analysis.
The whole-genome sequences were analyzed using toolkits provided by the Nextstrain framework [22]. Sequences were aligned using MAFFT v7.407 [23], and the alignment was trimmed to a reference genome (GenBank accession ID: NC_019843.3). A phylogenetic tree was built using a maximum likelihood approach implemented in IQ-Tree v1.6.10 [24]. For the phylogeographic analysis, TreeTime was used to infer the divergence time, discrete traits of the ancestral nodes (location and host), and geographic transmission history across the tree [25]. To detect sites under positive selection among CDS of protein genes, for each gene, the original open reading frame (ORF) sequences were first aligned using MAFFT and CDS were aligned using PAL2NAL v14 under the guidance for protein alignment [26]. CodeML in PAML v4.9 as part of the ETE 3 package (v 3.1.1) was used to detect positive selection sites by branch-site test [27, 28]. To balance the sample size of each host species, human and camel sequences were randomly down-sampled to five sequences per host species. After smoothing mortality rate and incidence rate over space and time, we matched these smoothed rates with tree tips (MERS-CoV sequences) by specimen collection year and location to assess potential association of phylogeny with mortality and incidence rates.
Geographic expansion of MERS a and its relationship with transportation network and land cover b in the Middle East. The first invasion time of each space unit was defined as the time lag between the first confirmed case for each unit and September 20, 2012, the symptom onset date of the first confirmed case in the Middle East Region. The time between adjacent contours was fixed at 200 days, and a wide gap between adjacent contours indicates a faster spatial diffusion of the disease. The inset map in panel a was added to present the early onset situation in the whole Middle East during the first 400 days.
In total, 499 MERS-CoV full-genome sequences were obtained from GenBank, including 251 sequences from human patients, 237 from camel, seven from bat, three from hedgehog, and one from Lama glama (llama). These sequences were collected between 2011 and 2019 from 15 countries, and 90.0% of them were from Middle East. IQ-Tree selected the GTR and FreeRate with ten categories as the best substitution model for these sequences.
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