The recent advancements in high-throughput sequencing have resulted in the availability of annotated genomes, as well as of multi-omics data for many living organisms. This has increased the need for graphic tools that allow the concurrent visualization of genomes and feature-associated multi-omics data on single publication-ready plots.We present chromoMap, an R package, developed for the construction of interactive visualizations of chromosomes/chromosomal regions, mapping of any chromosomal feature with known coordinates , and chromosomal regional characteristics  of organisms with a genome assembly. ChromoMap can also integrate multi-omics data  in relation to their occurrence across chromosomes. ChromoMap takes tab-delimited files (BED like) or alternatively R objects to specify the genomic co-ordinates of the chromosomes and elements to annotate. Rendered chromosomes are composed of continuous windows of a given range, which, on hover, display detailed information about the elements annotated within that range. By adjusting parameters of a single function, users can generate a variety of plots that can either be saved as static image or as HTML documents.ChromoMap’s flexibility allows for concurrent visualization of genomic data in each strand of a given chromosome, or of more than one homologous chromosome; allowing the comparison of multi-omic data between genotypes  or between homologous chromosomes of phased diploid/polyploid genomes. chromoMap is an extensive tool that can be potentially used in various bioinformatics analysis pipelines for genomic visualization of multi-omics data.The online version contains supplementary material available at 10.1186/s12859-021-04556-z. Recent dramatic decrease in Next Generation Sequencing costs, and its application to the analysis of multiple levels of biological information , has rapidly increased the number of multi-omics datasets available in public repositories. This has sifted the interest of researchers towards the annotation and comparison of such information at a genome or chromosome level. Besides identifying structural differences, comparison of genomic annotations can help understanding how variability within and between species affect phenotypes.chromoMap, is capable of annotating multiple genomic features, for the generation of interactive graphics. This allows the visualization in a single plot of chromosomes or chromosome sections of any living organism. The large genome size of certain species presents practical graphical challenges of displaying whole chromosomes within the available canvas space suitable for publications. ChromoMap, renders chromosomes as a continuous composition of windows, to surmount this restriction. Each window, consisting of a specific genomic range determined algorithmically based on chromosome length, displays information about the annotation in that region as a tooltip, allowing for plot interactivity.Currently, genomes are viewed using interactive web-based genome browser applications like JBrowse . There ichromoMap is built using two languages, R and JavaScript. The R code, written using a procedural approach (as opposed to an object-oriented paradigm), handles the data input and data pre-processing part. The graphics rendering is entirely handled by the JavaScript part, constructed using vanilla JavaScript and D3 JavaScript library (version 4.0). The package was designed and tested using R version 4.0 and is compatible to run with R version 4.0 (or later) on multiple OS (Windows/macOS/Linux). R was chosen due its open-source nature as well as due to its general preference within the bioinformatics community. Annotated chromosomes are constructed by providing genomic co-ordinates, and optional secondary data, as either tab-delimited BED files or directly through R objects. A single R function is used for constructing a variety of different plots by changing its arguments values. For example, Fig. As shown in the example code above, the user inputs to the function fall into two categories: (1) the BED files or R objects, which specify the genomic coordinates of the chromosomes/chromosomal regions as well as the genomic coordinates for the studied genomic features, , along with their associated data , and (2) the various ‘option’ arguments that are used to specify the graphic-properties of the plot, used for instance to turn a feature ON/OFF etc. Errors caused by the first type, such as user-provided files with incorrect structure or files created in an unsupported format, is handled in the implementation such that the program will first validate the file and will terminate the program with message on the console if the input file was incorrect. In addition to the detection of unsupported file format and/or structure, we implemented an out-of-bound annotations  detection step. First, out-of-bound annotations are identified by the program and removed from the analysis. Then, the plot is rendered with the remaining annotations, together with an error message, displayed on the console to alert the user of the presence of such errors in their input files. The errors caused by the second type of inputs , are also handled in the implementation in a similar way .https://pouya-dini.github.io/equine-gene-db/#tab2) that contains an interactive plot that can be included in webpage accessible formats (e.g. Shiny Apps), as additional files in publications , in relation to their regional occurrence across chromosomes for any living organism with an available genome assembly. ChromoMap’s flexible plots permits the comparison of data uniquely associated to each strand of a given chromosome, and of homologous chromosome independently of their size. ChromoMap will allow the individual visualization of multi-omics data in all homologous chromosomes of phased diploid/polyploid genomes.https://CRAN.R-project.org/package=chromoMap. A vignette is included for comprehensive description of its features. ChromoMap is also available as a containerized web application, referred as chromoMap App, that provides a GUI that will allow researchers to utilize all the above-mentioned features in an R-independent manner. The app can be run locally on the user’s computer. chromoMap App is available as a Docker Image at Docker Hub (https://hub.docker.com/r/lakshay57/chromomap-app). The datasets used and/or analyzed during the current study are available from the corresponding references.ChromoMap is available under the GPL-3 Open Source license from: Project name: chromoMap.https://lakshay-anand.github.io/chromoMap/index.html.Project home page: Operating system(s): Platform independent.Programming language: R, JavaScript.Other requirements: None.License: GPL3.Any restrictions to use by non-academics: license needed.Additional file 1. Example of chromoMap interactive plot constructed using various features of chromoMap including polyploidy (used as multi-track), feature-associated data visualization (scatter and bar plots), chromosome heatmaps, data filters (color-coded scatter and bars). Differential gene expression in a cohort of patients positive for COVID19 and healthy individuals (NCBI Gene Expression Omnibus id: GSE162835) [E162835) . Each seAdditional file 2. Example of interactive plot generated using chromLinks: Normalized expression of the top 50 highly expressed orthologous genes in mouse (Mus musculus) and rat (Rattus norvegicus) during pluripotent cell determination (NCBI Gene Expression Omnibus id: GSE42081) [SE42081) . Ortholo


Myocastor coypus) escaped captivity in the 1990s in Korea; these individuals rapidly established wild populations, causing substantial environmental issues, including biodiversity loss, local habitat disturbance, and agricultural damage. The South Korean government initiated the Nutria Eradication Project in 2014 to control nutrias on a national scale. The aim of this research was to support the eradication efforts by improving our understanding of nutria movements based on biological and environmental factors. In this study, the geo-self-organizing map software was applied to radio-tracking data from individuals, and it was determined that males dominate nutria movement. Movement patterns were seasonal and varied with vegetation types between sexes and within each sex. Tall grassland was mainly associated with interactions between individuals of opposite sexes (possibly related to mating), whereas floating-leaved hydrophytes were related to same-sex interactions (possible feeding grounds). Data from this large-scale monitoring provide initial results for a more targeted and effective eradication program. Further large-scale population dynamics research is needed for a successful eradication program in the future.Nutrias (Myocastor coypus) were imported to South Korea for farming in 1985; individuals escaped captivity and established wild populations in natural ecosystems in the late 1990s. Numerous studies have focused on their monitoring and management; however, information on the continuous movement of individuals is not available. In this study, telemetry data from field conditions were used to identify the nearest-neighbor distances of individuals in association with environmental factors, including plant type, land cover, and biological parameters. The minimum nearest-neighbor distances for the different sexes were, overall, according to the minimum distances for the same sex. Local co-occurrences of individuals, either of the same or different sex, were seasonal. Tall grasslands, followed by herbaceous vegetation, were associated with the co-occurrence of different sexes. Conversely, floating-leaved hydrophytes, followed by xeric herbaceous vegetation, were correlated with the co-occurrence of the same sex. Local female–male co-occurrences were negatively associated with male–male co-occurrences but not with female–female co-occurrences, suggesting male dominance in group formations. Movement and co-occurrence information extracted using Geo-self-organizing maps furthers our understanding of population dispersal and helps formulate management strategies for nutria populations.Nutrias ( Myocastor coypus) further exacerbate existing anthropogenic disturbances, including human population aggregations, resource utilization, habitat reduction following urbanization, and environmental pollution, especially under the stressful conditions of global warming ), including #3, #4, #6, #15, and #17 , had limited minimum distances for females and males. Minimum DDS were associated with OA for female #19 and R for female #10 . The minimum level of nearest-neighbor distances was consistent for minimum DDS, between the same sexes (DSS), and between all individuals  on the component map , intermediate for Y (further toward the south) for location, and intermediately high for WT regarding temperature. Sex ratio (SR) was defined as the proportion of females and males  in this study. SR is the average of all females and males belonging to a clustered group. If the group consisted of more females than males, the average value would be positive (>0 < 1.0), whereas the value would be negative if more males belonged to the group. Note that values in all the component maps were normalized between 0 and 1.0 for training  to reveal neighbor distances. Cluster 5, located at the top right corner of both p = 0.216) in Cluster 4, all other clustered distances in p < 0.001), according to the multiple comparison test [Distances between individuals were further checked in the clusters corresponding to maximum and minimum distances trained by Geo-SOM b. Five cson test .p < 0.005 between females and males within the minimum-distance cluster and p < 0.001, between all other distances) [stances) .Y-axis, X-axis, To determine the distance for observing the local co-occurrence of neighbor individuals, all distances from each individual to nearest neighbors were checked across 50 m to 2000 m in a radius from the individual position Y-axis, , accordin ≥ 38) and seven males (n ≥ 34). k = 3) when the training was conducted using females as the target sex. The variable range in the co-occurrence incidence included temperature, plant types, habitat cover states, and biological parameters for training with Geo-SOM, and are presented in Geo-SOM was used to examine how co-occurrences between two individuals within a distance of 250 m, either the same or different sex, were associated with spatial locations and habitat types. Since observations were made individually and sample numbers were variable for different animals, individuals were selected that had enough samples, including six females  associated with environmental and biological factors according to sex . By matcWith males as target individuals, M-F co-occurrences were associated with TG , followed by HHV (#3 and #24), FL (#6 and #17), XHV (#17), and HWV (#15)  was mostly associated with co-occurrences between the different sexes, followed by HHV (34 cases) and XHV (34 cases), whereas FL (5 cases) was mostly associated with co-occurrences between the same sex, followed by XHV (4 cases) .Investigating the land cover states, OA and R had limited co-occurrences . The maximum co-occurrence of F-M inversely matched the minimum incidence of M-M co-occurrences  and biological  factors, as stated above. This is essential information for the successful management of nutrias currently being undertaken by the Korean government. Once nutrias invade new ecosystems, the invading populations select life strategies that optimize the new environment. Information on individual movement, in association with environmental and biological factors, is essential for determining the most effective control practices, and can serve as a basis for establishing large-scale management strategies at the national level.Lutra lutra [Geo-SOM provides explicit spatial information, allowing the development of space-oriented management policies that can be used to further extending our knowledge of habitat preference in population expansion, as observed with another mammalian species, otter, ra lutra . Geo-SOMra lutra , notablyra lutra . This stra lutra . In addira lutra ,78. The In this study, few samples were recorded because of the difficulty in making continuous telemetry measurements in the wild. Furthermore, the survey only occurred over three days per month . Although individuals with relatively a large number of observations  were used for training with Geo-SOM, data for a longer period were not available in this study. Therefore, detailed information on the associations with environmental factors and biological parameters could not be collated. The observation times were also recorded, but the time of the day was not included as a covariate for the Geo-SOM training, owing to the small number of samples obtained in this study. Future research should include more surveys over extended periods to monitor movements and habitat preferences in the spatial framework.The spatial distribution patterns of nutrias are effectively illustrated, in association with diverse environmental and biological factors, using a machine learning technique, Geo-SOM. Valuable information was obtained regarding the nearest minimum distances and local co-occurrences of neighbors, according to sex. The minimum DDS were, overall, related to the minimum DSS. F-M local co-occurrences were more frequently observed than F-F and M-M co-occurrences and varied with season. Local co-occurrence patterns between females and males were negatively associated with M-M co-occurrences compared with F-F co-occurrence, suggesting a male dominance in determining the co-occurrence of nutria individuals. TG was mostly associated with co-occurrences between different sexes, followed by HHV. Conversely, FL was mainly associated with co-occurrences between the same sexes, followed by herbaceous vegetation. Unique behavioral research investigating movement behavior, based on the information extracted by informatics, is essential for monitoring and managing nutrias. In the future, more detailed research is required to understand behavioral states and identify spatial management strategies for nutria populations.


Objective: Internet addiction has emerged as a growing concern worldwide. This study aimed to compare the prevalence of Internet addiction between left-behind children (LBC) and non-left-behind children (non-LBC), and explore the role of paternal and maternal parent-child communication on LBC.Methods: We conducted a cross-sectional survey in rural areas in Anhui, China. The complete data were available from 699 LBC and 740 non-LBC. Multivariable logistic regression was used to examine 1) whether LBC were more likely to develop Internet addiction, and 2) the association between parent-child communication and Internet addiction among LBC.Results: LBC had a higher likelihood to report Internet addiction when compared to non-LBC . Among LBC, parent-child communication (both mother-child and father-child) was protective factor for children’s Internet addiction. The role of mother-child communication played well among male LBC.Conclusions: The lack of parental supervision may lead to Internet addiction. It is highly recommended for migrant parents to improve the quality of communication with their children. Also, gender-matching effects should be considered in the relationship between children’s behavior and parental factors. The past few decades have witnessed rapid urbanization in China, with a sizable number of rural job hunters migrating from economically deprived areas to developed cities. Due to Chinese household registration systems , some soThe term “Internet addiction” is defined as an obsessive state and uncontrolled internet use . Accordin = 593) were more likely to develop Internet addiction than non-LBC (n = 353) using a self-assessment questionnaire for adolescent problem behavior [n = 1,143) when compared to their rural counterparts  [n = 796) in the risk of Internet addiction [To date, there has been some disagreement on the variation in Internet addiction behaviour between LBC and non-left-behind children (non-LBC). One school-based survey in three Chinese counties, enrolling students from grade 7 to grade 9, revealed LBC  . Accordiddiction . DiverseRecent studies ,21,22 emMoreover, few research has looked at the potentially modifying role of parent-child communication in LBC’s Internet addiction behavior. The gender difference was also found for children’s Internet addiction and the quality of parent-child communication. A meta-analysis  of 119 iThe current study aimed to compare the prevalence of Internet addiction between LBC and non-LBC and investigated the association between parent-child communication and Internet addiction among LBC. We hypothesize that gender-specific association would be found between parent-child communication and Internet addiction among the LBC community.We conducted a cross-sectional study in a school-based setting in Anhui Province in 2018. Anhui, a pioneering province in Southeastern China in the process of migration, had 16 million migrants for export in 2017 . ParticiLocal permission to conduct this survey was obtained from local government, school principals or administrators. All eligible students and their guardians were provided with a detailed description of the study design and an informed consent form. Anonymous questionnaires were distributed to students who provided informed consent. Voluntary participation, withdrawn at any time, and the absence of a teacher ensured the anonymity of this investigation.Students’ Internet addiction behavior was assessed by using Young’s Internet Addiction Test for Chinese (YIAT-C) ,29, a moPaternal and maternal migration status and presence was examined by two questions respectively, “Has your father/your mother migrated into other places for work and been absent for over 6 months?”. The child was identified as LBC if his/her response to both questions were “Yes, currently absent,” and those living with both parents were considered as non-LBC.The quality of parent-child communication was measured by the Chinese version Parent-Adolescent Communication Scale (PACS), which has been validated in the Chinese context . PACS haThe social-demographic characteristics included gender, age, grade, siblings, family income level, pocket money, and possession of a computer. Family income level was measured by subjective feelings of children because of the difficulty for children to judge the objective economic conditions of their families. The response item varies from “much poorer” to “much better” corresponding to their perception. Children were required to comment how much  pocket money do they have a day.p < 0.05) between LBC and non-LBC. Finally, we conducted logistic regressions to explore the association between parent-child communication and Internet addiction among LBC, and to determine whether the effects of parent-child communication had a gender-specific pattern through the interaction term.We presented participants’ socio-demographic characteristics in counts and percentages. Mann-Whitney test (for continuous variables) and chi-square test  were employed to examine demographic characteristics and Internet addiction among LBC and non-LBC. The multivariate logistic regressions after adjustment for covariates were performed to examine whether LBC carried a higher risk of developing Internet addiction. The covariates included grade, gender, possession of a computer, pocket money, any siblings and number of friends. Besides, interaction analyses of each covariate and parental migration status (LBC vs non-LBC) were tested to detect if the risk factors  for Internet addiction differ statistically (with p = 0.188), gender (p = 0.622), and family income level (p = 0.622), but LBC group reported significantly less ownership of computers than non-LBC group (p < 0.05). A higher proportion of (20.0%) LBC reported Internet addiction than non-LBC .A total of 1,439 students agreed to participate in this study, of which 699 were LBC. p < 0.001). We did not observe any significant interaction terms between parental migration and other risk factors, implying that these risk factors for Internet addiction were equally important for LBC and non-LBC.p < 0.001) and father-child communication  were both protective against Internet addiction among LBC. Compared with female LBC, mother-child communication showed significantly more effect on preventing male LBC from Internet addiction . What is interesting in this data is that there exists no gender difference in father-child communication.The uncontrolled use of the internet has led to disorders in psychological adjustments and health behaviors. Given the importance of parental company and supervision on preventing Internet addiction, this study aimed to explore the prevalence of Internet addiction and its risk factors across LBC and non-LBC. Based on our results, we have two main findings: 1) LBC were more vulnerable to Internet addiction; 2) Parent-child communication was protective against Internet addiction among LBC, and the association varied remarkably across gender of the parent and the child. Compared with father-child communication, the protective role of mother-child communication was specific to the child’s gender, where mother-son communication was more effective than mother-daughter communication.Parental absence has been well acknowledged as a risk factors for child development ,13. In tOur study also served as the first-hand evidence for the protective role of parent-child communication against LBC’s Internet addiction. A possible explanation for this might be that parent-child communication could attenuate Internet addiction through harmonious parent-child relationship. Good parent-child communication represented a good parent-child relationship , while aInterestingly, our study identified a gender-specific influence of mother-child communication on Internet addiction: mother-child communication appeared to have a stronger effect on boys than girls. Traditionally, mothers take on more responsibilities as caregivers  and tendThis study supplements the evidence of Internet addiction among LBC, expands our knowledge of protective role of high-quality parent-child communication in Internet addiction, and indicates gender-match patterns existing in family interactions. Several limitations, however, need to be acknowledged. First, the cross-sectional design limited our ability to draw a causal interpretation from our findings, especially the gender-specific influence. Our study firstly introduced gender-match patterns, among LBC group, into the association between parent-child communication and Internet addiction, and a longitudinal design is recommended for future studies to explore these issues. Second, we lacked the information on major caregivers and children’s living condition. Although we considered this information in the design process, it was difficult to connect their parents in our pre-investigation. Thirdly, this survey relied on self-reports which could introduce bias . Finally, this study was only conducted in two counties in the southeast of China, which required more caution in extrapolating these findings to the whole country.Our study highlighted the high likelihood of Internet addiction in LBC community and suggested migrant parents keep good communication with their children. In order to help the transition from evidence to practice, we proposed four main suggestions to strengthen child protection, as well as reinforce the role of family in caring for left-behind children. First, for targeted policy development and implementation, government should lead an interdepartmental collaboration to figure out the amount of LBC, collect family information, and keep this information updated. Second, collaborative effort should be put into the examination and trajectory of bio-psycho-social health of children, especially those left behind. The partnership between educational and medical systems is encouraged to promote early detection and intervention of children’s health problems. Third, governments should pay more attention and give financial incentives to provide migrating parents with training programs to improve their communication skills with children. Last, governments could make efforts for short-term reunion of migrating families, for example, reunion in winter and summer vacation, which may directly enhance the communication between parents and children.


Diet-related chronic diseases, such as hypertension and obesity, are prevalent in Native American (NA) communities where poor food environments are prominent and healthy food access is limited. The Chickasaw Healthy Eating Environments Research Study (CHEERS) is an NIH-funded study aimed to improve Body Mass Index and blood pressure control among NA adults with uncontrolled hypertension. This multi-level randomized trial, guided by a community-based participatory research orientation, was co-created by tribal and university partners and is implemented within the Chickasaw Nation of Oklahoma. We created hypertension-specific food boxes that contained DASH diet foods, coupons for purchasing vegetables and fruits, educational materials, and heart-healthy recipes for supporting healthy eating. Food boxes were packed and shipped monthly to intervention participants with a 30-day supply of: one fruit serving/day, one vegetable serving/day, one serving of unsalted nuts or seeds/day, one serving of beans or lentils/day, and two servings of fatty fish/week. We will present our participatory approach in co-developing the CHEERS study methods, findings with a focus on older adults, and lessons learned. CHEERS is the first innovative food box intervention to be conducted in NA communities. Food box interventions show promise in improving dietary intake and reducing hypertension and obesity in rural and poor food environments.


Viral infections are emerging with diverse clinical relevance both in endemic environments and non-endemic regions of the world. Some of the viruses cause co-infections that are of public health importance. The progress of studies on human immunodeficiency virus / Human papillomavirus (HIV/HPV) co-infection is not well documented especially in Africa where cases are endemic.Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a global three-decade meta-synthesis and science mapping analysis on HIV/HPV co-infections. Assessment of progress, Author/Country productivity/trends, topic conceptual framework, and international collaborative networks were analyzed.We recovered 196 documents of 115 sources from the web of science database. The meta-synthesis revealed 1203 prolific authors containing nine solo authors, an annual growth rate of 8.09%, a significant average citation per article of 20.7%, and an average citation per year per document of 2.1. A significant high correlation between the mean/TC per article and the mean total citation (TC) per year showed 80.98% of the articles produced between 2005 and 2007 on HPV/HIV co-infection. The co-author per document index were 7.0 and the collaboration index was 6.4. The meta-analysis also revealed inadequate funding from individual or governmental organizations; among the 196 documents dataset, 114 (58.2%) were funded, and only 31 (15.8%) were funded in Africa where HIV/HPV co-infection cases are endemic.Authors’ collaboration network, countries’ collaboration, authors’ citations and implementation of research-based finding in previous studies are yet to receive the relevant outcome, especially as various countries in the African continent have received poor funding with a repeated reporting of co-infection associated with HIV/HPV. African needs to re-awaken and stir up research-based interest in HPV/HIV co-infection studies to resolve indigenous public health concerns associated with the viral endemicity. Vibrio Cholera [As of 2018, World Health Organization (WHO) describes the human immunodeficiency virus (HIV) as a ‘global epidemic’ due to the increasing distribution of the infection with types 1 , 133, an Cholera , Malaria Cholera , Drug re Cholera . Meanwhi Cholera . Current Cholera , 133. An Cholera . Accordi Cholera  living w Cholera . More ch Cholera , 130. It Cholera , 130 whi Cholera , 130, by Cholera , 97, 105 Cholera , 96, 135In recent times, reports from various investigations have shown HIV/HPV co-infection of both viruses in clinical cases. HIV/HPV co-infection is shown to be ravaging lives of many living in resources limited settlements, and conducting integrated analyses , 110, ofIn the USA, reports have revealed that there is a high incidence of cancer-related infections among HIV- infected patients with a simultaneous post-report of HPV infection amongst the general population , 115. InRecently, there has been a decrease in the HIV morbidity and mortality since the introduction of antiretroviral therapy (ART) and highly active antiretroviral therapy (HAART) , 85 for The science mapping hinged on Author/country, productivity/trends, topic conceptual framework, and international collaborative networks were analyzed. Integrated content analytics and science mapping bibliometrics analysis remains a useful research tool with an increasing potential for monitoring, handling, supporting and appraising decisions in scientific/technological progress and research development , 110. InThe “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) guidelines were used to search the Web of Science (WoS) database for relevant studies on HIV/HPV/Coinfection .clarivate.libguides.com [We collated published articles, editorial material, meeting abstract, proceedings paper, review article, on HIV/HPV co-infections from global repository data by searching the Web of Science (WoS) core collection database on 19th July 2020 at about 10.25 GMT + 2). The Boolean topic search approach applied included “(HIV* AND HPV* AND Co-infection$) OR (HIV* AND HPV* AND Coinfection$) OR (HIV-HPV* AND Coinfection$) OR (HIV-HPV* AND Co-infection$) OR (HIV/HPV* AND Coinfection$) OR (HIV/HPV* AND Co-infection$) OR (Human Immunodeficiency Syndrome* AND human papillomavirus* AND Coinfection$) OR (Human Immunodeficiency virus* AND human papillomavirus* AND Coinfection$) to recoup all available documents on the subject, “HIV/HPV co-infection” between 1990 and 2019. The Web of Science Core Collection database adopted in this study has a high reputable academic research database covering thousands of journals, books, conferences as well as millions of records from ides.com , 137. ToAll the bibliometric variables were retrieved filtered and normalized for quality control. The results were analyzed in biblioshiny package , 51, 127Our study recovered a total of 196 documents relevant to HIV/HPV co-infection from the web of science database within the survey period 1990 – 2019), with informatics and attributes as presented in Table 019, withFrom Fig. The Table In Table In Table Author co-citation network map is shown in Fig. This network confirms the position of the Authors as regards HIV/HPV coinfection research; that Munoz’s global visibility and relevance in HIV/HVP co-infection studies are attributed to researchers being specific about the content of the research than the number of publications from the research.In Fig. The top 20 institutional collaboration is presented in Fig. In Fig. The goal of this study was to provide an overview of global research publications and progress on HIV/HPV coinfection. Thereby identifying authors production/production trends, inter institutional/international research activities, conceptual topic thematic and gaps for future prospects. The findings denote a moderately increased over time number of publications, contributing countries, and the average number of authors per document. However, the number of publications that made significant contributions to the subject, the countries and the average number of citations per document was limited to the developed world.Furthermore, based on the fact that HPV infection alone is an indication of candidacy for carcinogenesis a chronic immune humiliating disease. When HPV was found in the same individuals with HIV the master of immunodeficiency in humans, then we saw the justification for the magnitude of observed co-infections in several diseases ranging from common benign warts to invasive carcinoma at various anatomical sites of infection, including the cervix, vulva, vagina, penis, anus, and oropharynx.In response to increasing global epidemic of HIV, limited studies have been gar towards its associated coinfections such as HPV. Globally, approximately 80% of the sexually active women become infected with one of the 13 high-risk HPV (hr-HPV) in their life time . Also, HHowever, the progress of studies to curbing the prevalence of HIV/HPV co-infection among women  around tFrom the forgoing in Table Here, as expected, the keyword analysis shows the search terms of interest “HIV/HPV/Co-infection” as appeared in the author keywords network Figs. , 8. The Co-citation analysis help to identify documents that contain concept, ideas, experiments, or methods that has a noble recognition, as indicated by their co-occurrence of citations . Hence, In the present day, research collaboration has increased among researchers in different field of studies , 26. ColFrom the foregoing, it is clear that the African related interest in HPV/HIV co-infection studies is relatively poor, which may have accounted for the low knowledge-scape and progress despite the introduction of vaccination and other diagnostic strides. The authors’ research collaboration network, countries collaboration, authors collaboration, citations and implementation of research-based findings in previous studies are yet to receive the aftermath, especially as various countries in the African continent have not received any related collaboration yet she is reporting co-infection associated with HIV/HPV. African needs to awake and stir up the responsibility of research-based interest in HPV/HIV co-infection studies to resolve indigenous public health concerns.Nevertheless, an increased attention and interest-based studies on the endemicity and prevalence of HPV/HIV co-infection as well as other viral pathogens be added with a view to addressing the indigenous public health concerns associated with the viral endemicity.The current study examines HIV/HPV co-infections from a bibliometric perspective. However, there was a sluggish annual growth rate, and the most relevant papers to the subject were written between 2005 and 2019, as measured by the association between the mean/TC per article and the mean total citation (TC) per year. The most prominent authors by research impact were JM Nicol AF and Williamson AL. Plos One and BMC infect. Dis. been the leading journal publishing on HIV/HPV co-infection. The conceptual factorial analysis identified two sub-fields, including cancer in women and HIV/HPV co-infection epidemiology characteristics for research engagement. In addition, the multiple-country publications and cooperation index revealed a substantial network of collaboration among researchers in developing nations. We observed that the world’s most powerful governments are investing in HIV/HPV co-infection research through disbursing funds and increasing mentorship among scholars in the region, which is missing in Africa. This study’s findings may be valuable in identifying potential partners for younger academics interested in joining the field. The study’s strength is evidenced as the first holistic content analysis and systematic science mapping of HIV/HPV co-infection research as a possible tool for widening knowledge with the ultimate goal of lowering the associated viral infection, a public health burden in Africa.However, the use of a single database may limit the identification of additional pieces of literature. Also, the keywords for data collection may have restricted the scope of the research directions. Using a threshold for co-citation analysis based on the number of total citations may hinder the use of the complete published article within the timeframe.In this bibliometric analysis, the results revealed low global research in HIV/HPV co-infection, and the publications of 2005 and 2007 were of more significant scientific relevant research outputs. The network analysis suggests that high-income countries have better interrelationship drives than low- and middle-income countries with a high prevalence of HIV/HPV co-infection and limited collaboration networks.With the increasing prevalence of HPV and high-risk HPV genotypes among HIV-infected men and women couple with asymptomatic genital distress of different degrees of severities, we recommend a reviewed narrative for future study to elaborate emerging themes and gar research focus.Countries/Regions with a high incidence of HIV/HPV co-infections requires a long-term follow up of individuals with dysplastic lesions associated with HIV infections.Based on the analysis, we recommend further scientometrics studies using a combination database involving the mapping of knowledge structure. In contract, future research should be directed towards developing and implementing vaccination and programs to reinforce the current trends of HIV/HPV coinfection. At the same time stakeholders and governments in Africa region to engage in funding and its effective ultiazation for research to the benefit of the African population.


YAP (Yes-associated protein) and TAZ  are transcription co-regulators that make up the terminal components of the Hippo signaling pathway, which plays a role in organ size control and derived tissue homeostasis through regulation of the proliferation, differentiation and apoptosis of a wide variety of differentiated and stem cells. Hippo/YAP signaling contributes to normal development of the nervous system, as it participates in self-renewal of neural stem cells, proliferation of neural progenitor cells and differentiation, activation and myelination of glial cells. Not surprisingly, alterations in this pathway underlie the development of severe neurological diseases. In glioblastomas, YAP and TAZ levels directly correlate with the amount of the actin-binding molecule WIP (WASP interacting protein), which regulates stemness and invasiveness. In neurons, WIP modulates cytoskeleton dynamics through actin polymerization/depolymerization and acts as a negative regulator of neuritogenesis, dendrite branching and dendritic spine formation. Our working hypothesis is that WIP regulates the YAP/TAZ pools using a Hippo-independent pathway. Thus, in this review we will present some of the data that links WIP, YAP and TAZ, with a focus on their function in cells from the central and peripheral nervous systems. It is hoped that a better understanding of the mechanisms involved in brain and nervous development and the pathologies that arise due to their alteration will reveal novel therapeutic targets for neurologic diseases. Proper neuritogenesis in post-mitotic neurons is a requisite for dendritic arborization and neuronal function. Neurite extension, sprouting and axonal polarization is directed by microtubule (MT) dynamics and polymerized actin microfilaments (MF), which form actin-rich structures (lamellipodia and filopodia) in the tip of the growth cone. The tip of the growth cone is more a filamentous actin (F-actin) field whereas the intermediate and proximal regions of the growth cone are MT filled . These tIn almost all cell types, including neurons, the dynamics of branched MF rely on actin polymerization controlled by the Arp2/3 (actin-related protein) complex and by NPF (nucleation-promoting factors) such as cortactin and N-WASP/WASP  . Much leWIP was initially described as a regulator of the formation of actin-rich cerebriform projections in B lymphocytes . It is v45KLKK48. In lymphocytes, around 80% of cellular WIP exists in a constitutive complex with WASP, which itself directly binds actin (WIP binds monomeric globular actin (G-actin) and polymerized F-actin with different affinities , and theds actin . The WIPds actin .We reported WIP expression in the adult mouse brain  and cultured embryonic cortical and hippocampal neurons. We demonstrated that WIP acts as a negative regulator of early neurite emission and branching: development of WIP-deficient cortical neurons from knockout embryos was accelerated, whereas neurite protrusion was retarded by WIP-overexpression. In contrast, WIP-deficient neurons did not have modified axon formation, number or complexity . The obsFrom these data, several working hypotheses may be proposed about how WIP controls the process of neuritogenesis. A structure-related option based on the regulatory role of actin dynamics points to WIP as a negative regulator of the actin polymerization complex Arp2/3 cortactin-N-WASP. A second option focuses on signaling, with WIP modulating cytoplasmic pathways that control neuritic outgrowth and promote axonal polarity, such as PI3K-Akt-GSK3 pathway, Par3/Par6/aPKC or the multiprotein complex mTORC1 .One of the main cytoplasmic regulators of actin polymerization is the Rho-GTPase superfamily, which is regulated by the PI3K-Akt pathway, among others. For example, RhoA, Rac1, and Cdc42 are major modulators of the cytoskeleton that act through actin-binding proteins such as N-WASP and WIP . It has All these data strongly suggest that WIP may play two complementary roles in neurogenesis: regulating actin polymerization levels through N-WASP and by modulating the signaling activity of mTORC1.Drosophila to mammals), although they can also perform Hippo-independent activities. In contrast to ordinary transduction signaling based on single ligand-receptor interaction, the Hippo pathway integrates multiple upstream stimuli ignited by soluble factors, activation of adhesion molecules and forces driven by the actin cytoskeleton. Therefore, there is a strong cooperative effect among Hippo signaling with cytoskeletal regulation and a combination of extracellular cues, initiating directed migration and mechanotransduction.Actin dynamics regulate axonogenesis and neuronal polarity, as demonstrated by the generation of multi-axons in primary neurons subjected to actin depolymerization, favored either by latrunculin or cytochalasin D . Actin dDrosophila) rapidly fluctuates between the cytosol and the nucleus, where it locates to mitotic chromatin  . These khromatin . The Hiphromatin .In the cytoplasm, YAP/TAZ have been associated with adhesion molecules such as cadherin, or linked to cytoplasmic actin or actin-binding proteins such as the angiomotin family (AMOT) . YAP/TAZYAP/TAZ regulate and are regulated by the actin cytoskeleton. For instance, CYR61 and CTGF, two genes whose transcription is usually induced by the complex YAP/TAZ-TEAD, encode extracellular matrix proteins that work as integrin ligands and are functionally important for cell adhesion to the extracellular matrix . As a geA second cytoplasmic element that regulates actin and YAP/TAZ activity is the GTPase RhoA. While the conventional regulation of RhoA–mediated actin polymerization is broadly documented, the detailed mechanism of how RhoA specifically inhibits the Hippo kinase cascade is not completely understood. It is known that ROCK (Rho-associated protein kinase) is partially involved, and that F-actin mediates the effect of Rho on Hippo regulation since the disruption/depolymerization of F-actin by latrunculin or cytochalasin D strongly induces LATS1/2-mediated phosphorylation, preventing the nuclear shuttling of YAP/TAZ .In almost all cell types, actin polymerization is regulated by a variety of G- and F-actin-binding, actin-capping and actin-severing proteins , such as gelsolin, CapZ, profilin, cofilin, thymosin β-4, and formins . AlthougInterestingly, the pool of nuclear F-actin may exert a role in cell cycle regulation through control of chromatin organization at mitotic exit , and it It appears that YAP/TAZ regulation is not directed by the total levels of F-actin, but rather by its subcellular organization, fine structure, tension and resistance offered by the cytoskeleton and by the whole nucleus. This dual cytoplasmic/nuclear role is not exclusive to YAP/TAZ, as other similar co-transcriptional regulators have been described, for instance β-catenin or myocardin-related transcription factor (MRTF), through the TCF family of transcription factors and the transcription mediator serum response factor (SRF), respectively .The MRTF and YAP transcriptional pathways contribute to the response to cell proliferation and mechanotransduction. Several observations suggest that MRTFs and YAP/TAZ may functionally interact despite not sharing a common DNA targeting factor. In cancer-associated fibroblasts (CAFs), the MRTF–SRF and YAP pathways are required for the contractile and pro-invasive properties of these cells. It has been reported that in CAFs, expression of direct MRTF–SRF genomic targets is also dependent on YAP–TEAD activity and, conversely, YAP–TEAD target gene expression depends on MRTF–SRF signaling. In normal fibroblasts, expression of activated MRTF versions induces YAP, while activated YAP stimulates MRTF. Cross-talk between the pathways requires recruitment of MRTF and YAP to DNA via their respective DNA-binding partners (SRF and TEAD), and is therefore indirect. However, YAP/TAZ mechanotransduction differs substantially from actin regulation of the MRTF family, as a sensor of F-actin/G-actin ratio binds directly to free nuclear G-actin in a manner that inhibits its association with SRF .It has also been reported that WIP can promote nuclear transit of MRTF-SRF via actin polymerization , similarSeveral data support common regulatory steps between YAP/TAZ and β-catenin. When the Wnt pathway is inactive, YAP/TAZ are sequestered in the β-catenin destruction complex where they recruit βTrCP, which is needed for β-catenin inactivation. In contrast, when Wnt is activated, YAP/TAZ are released from the complex and accumulate in the nucleus .The extracellular matrix protein/integrin interaction serves as a first responder to collect mechanosignals and transmit the information to the regulatory machinery of YAP/TAZ, possibly not only through the Hippo pathway . It is tin vivo in the stem cell niche, and increases the size of cultured neurospheres. Moreover, this YAP/TAZ function restricting differentiation is dependent on the transcriptional co-activator TEAD  and posterior differentiation into diverse neural lineages. NSCs are the group of self-renewing cells that can generate neurons and several glial cell types during embryonic development . Recentltor TEAD .Considering the previously described interaction between YAP/TAZ and β-catenin and the role of the Wnt pathway in neuronal development, it is tempting to speculate that some of the neuronal actions of Wnt signaling might be a combination of YAP/TAZ and β-catenin-dependent effects. Besides Hippo, pathways including Notch, Shh, FGFs, TGF-β, retinoic acid, and reelin are well-known to regulate NSC proliferation, neurogenesis and gliogenesis. Consequently, the crosstalk between Hippo and some of these signaling pathways and the final impact of these signals on target genes is an open question .de novo purine/pyrimidine biosynthesis, gluconeogenesis, amino acid uptake, and cholesterol and lipid biosynthesis  and actin-independent (it was not modified by either actin depolymerization or polymerization agents) . The speIn contrast to the pro-oncogenic version of WIP-YAP/TAZ in glioma, WASP and WIP act as onco-suppressor proteins in ALK-dependent lymphomas . ALK traWIPF1 gene have been identified (WIPF1 gene was the only common genomic region shared by 6–8 patients suffering from neurological diseases (As previously indicated, prolonged activation of YAP/TAZ enhances stemness . Howeverentified . Studiesdiseases . WIP-KO diseases . Mouse bDespite a limited understanding of WIP’s contribution to the functionality of the nervous system, the role of WIP-YAP/TAZ in the brain is still an open question. A potentially relevant player is the phosphatase PP2AC, suggested to support cortical neuronal growth and cognitive function by modulating the Hippo-p73 signaling cascade and the glutamate/glutamine cycle . PP2AC mNeuronal functional morphogenesis relies on coordinated modulation of the reorganization of the actin cytoskeleton by actin-binding proteins like N-WASP and WIP, with the activity of transcriptional co-regulators such as YAP and TAZ, whose nuclear distribution depends on actin. The multiple intertwined connections between these players provide a fascinating working niche with many relevant questions that need to be addressed. For example, is the predominant role of WIP in actin dynamics in complete cellular systems universal, or does it depend on the cell type? Is phosphorylation status of YAP/TAZ the master regulator of their subcellular distribution in mature neurons, astrocytes or glioblastomas? Is the WIP-mediated control of YAP/TAZ stability stronger than the actin-dependent modulation of YAP/TAZ activity? Does WIP indirectly contribute to YAP/TAZ nuclear distribution through actin depolymerization? How is actin and YAP/TAZ crosstalk regulated in a two-way manner? Future work in the field will provide clear answers and, hopefully, lead to novel diagnostic and therapeutic tools for neurological diseases or nervous system tumors.IA and FW: conceived the manuscript, writing of the manuscript, approved its final content, conceptualization, and writing—review and editing. FW: writing original draft preparation. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Residing at the apex of the hematopoietic hierarchy, hematopoietic stem and progenitor cells (HSPCs) give rise to all mature blood cells. In the last decade, significant progress has been made in single-cell RNA sequencing as well as multi-omics technologies that have facilitated elucidation of the heterogeneity of previously defined human HSPCs. From the embryonic stage through the adult stage to aging, single-cell studies have enabled us to trace the origins of hematopoietic stem cells (HSCs), demonstrating different hematopoietic differentiation during development, as well as identifying novel cell populations. In both hematological benign diseases and malignancies, single-cell omics technologies have begun to reveal tissue heterogeneity and have permitted mapping of microenvironmental ecosystems and tracking of cell subclones, thereby greatly broadening our understanding of disease development. Furthermore, advances have also been made in elucidating the molecular mechanisms for relapse and identifying therapeutic targets of hematological disorders and other non-hematological diseases. Extensive exploration of hematopoiesis at the single-cell level may thus have great potential for broad clinical applications of HSPCs, as well as disease prognosis. The hematopoietic system is one of the most highly regenerative tissues, which is composed of billions of erythrocytes, platelets, myeloid cells, innate and adaptive immune cells. It is involved in blood cell formation, coagulation function, immune response, and other physiological processes. Residing at the hierarchical top of hematopoiesis, hematopoietic stem and progenitor cells (HSPCs) give rise to all mature blood cells , and eve− HSCs in human cord blood (CB) may exist [In 1961, Till and McCulloch first demonstrated the existence of multipotent HSCs through observing colony-forming units in the spleen following in vivo lethally irradiated transplantation . The subay exist –10. To day exist , 12, CD4ay exist , CD90 [1ay exist , CD49f, ay exist , GPI80 [ay exist , etc. haay exist . These iay exist , immunopFunctional assays such as in vivo xenograft and in vitro colony formation are the “gold standard” to confirm the existence of human HSCs and progenitor cells . HSCs arThe heterogeneity of immunophenotype-defined HSPC populations has restricted further understanding of human hematopoiesis in normal and disease states, thus, to overcome these limitations, researchers have turned to study HSPCs at more precise levels, even at the single-cell level. From a single-cell perspective, in vitro single-cell culture cannot fully display all blood lineages due to technical limitations and differentiation bias caused by different culture systems. Moreover, the insufficient cell numbers (or just one cell) make the in vivo xenograft experiments extremely difficult. Therefore, neither immunophenotype nor functional experiments can entirely define true HSPCs. With recent advances in single-cell technologies, single-cell transcriptomics became another powerful means to recognize hematopoiesis as well as HSPCs within the past few years. Through this new technology, new subpopulations of HSPCs , a revis. [. [Since Tang et al.  first es. [.  used a m. [.  and InDr. [. , which c. [.  and inDr. [. , tens of. [.  using mi. [.  utilizedTo achieve high efficiency and low bias of single-cell sequencing, researchers developed various assays: STRT-seq  and Smar. generated a single-cell proteo-genomic reference map, which linked the expression of 197 surface markers to cellular identities and biological processes across main hematopoietic cell types of BM and peripheral blood from human adults, aged and AML patients. Moreover, they developed computational tools that enable the automatic design of high-throughput cytometry schemes to isolate the molecularly defined cell state from blood and BM. However, most integrating data from DNA, RNA, or ATAC are not from the same cell. We suggest that the integration of these single-cell sequencing datasets should be used cautiously in hematological studies. Moreover, single-cell multi-omics sequencing usually generated a large number of heterogeneous data including different numbers of distributions, variables and diverse data modalities. Thus, developing a method to excavate data-specific information and to use different molecular layers information at the same time is crucial for data processing [Although single-cell transcriptomics is a great tool to quantify expression variability between individual cells, it is not possible to use it to explore the correlation of genotype, phenotype, gene expression, or even chromatin structure in single cells. It was a great challenge for scientists to integrate transcriptomics, genomics, proteomics and epigenomics in a single cell. However, in 2015, DR-Seq  and G&T-ocessing . In conc. [The development of hematopoiesis is a complex process that switches from different organs in the embryonic period , 61. Dur.  applied . . Recentl. . Integra. , which w. [. [. demonstrated several B-cell progenitor populations by constructing the human fetal B-lymphocyte development hierarchy in fetal BM and liver. The PreProB-progenitor was confirmed as the first B-lymphoid–restricted progenitor and upstream of ProB-progenitors at the fetal stage [The development and origin of the immune system have also been revealed at the single-cell level in the human embryo. Macrophage is a regulator which is essential to tissue development and homeostasis. Bian et al.  comprehe. [.  portrayeal stage . Meanwhial stage  has alsoIn summary, single-cell technologies have greatly assisted the investigation of the detailed developmental processes underlying embryonic hematopoiesis and prenatal disease initiation. It may give us more information about hematopoietic development. In the future, we might be able to improve HSC reconstitution in the patient with delayed engraftment, and manipulate the lineage bias of progenitor cells for cell therapy.highCD34low HSCs with multipotency and more quiescence and CLEC9AlowCD34high HSCs with myeloid and lymphoid potential [− HSCs, CD33+ HSCs have more durable regenerative potential [After the embryonic stage, BM is the most important microenvironment for maintaining hematopoiesis. As estimated by somatic clonal dynamics, there are approximately 50,000–200,000 HSPCs that contribute to white blood cells in adult BM . Using sotential . Anotherotential . For theotential . Karamitotential .. [The molecular mechanisms of fate decision that play an important role in hematopoiesis have also been investigated. Recently, Lu et al.  demonstr. . Taken tTo date, several studies have challenged the classical tree-like hierarchy Fig.  21, 24,, 82. RecIn summary, single-cell omics plays an important role in understanding human hematopoiesis. It is of critical importance to integrate the tools of immunophenotyping, functional validation, and transcriptomics to properly define HSPCs and gain a better understanding of the blood system.. combined spatial, population, and single-cell transcriptomics to interrogate signaling in the human HSC embryonic niche. By using LCM coupled with RNA sequencing, molecular differences between orsal-ventral and the dorsal aorta were carefully explored. And it focused on cell layers close to intra-aortic hematopoietic cell clusters (IAHCs) formation. By analysis of the ventrally polarized molecular landscape, endothelin 1 was identified as an important secreted regulator for human HSC development. Interestingly, cardiac EGF pathway was enriched next to developing IAHCs/HSCs, and endothelin 1, secreted by ventral portions, was found to promote the development of HSCs. However, studies related to the niche of human adult hematopoiesis were still lacking [Single-cell omics are great tools to explore HSPC niche, which represents a three-dimensional space comprising several types of components interact with and regulate HSPCs , 85. Rec lacking . The imm. [Hematopoietic aging in humans always manifests a high risk of myeloid malignancies and functional decline of HSCs. With an integrative characterization of epigenomic and transcriptomic changes, Adelman et al.  portrayeIn benign diseases like BM failure (BMF) syndromes and aplastic anemia (AA), chromosomal abnormalities were frequently observed and monosomy 7 in BMF was associated with poor clinical outcomes. Young’s group  used scR. [Though single-cell omics have been applied to explore numerous hematopoietic disorders, a few studies related to rare disorders of the hematopoietic system have not been reported. Diamond-Blackfan anemia (DBA) is a rare ribosomopathy. Patients who develop DBA usually receive limited therapeutic options. Using single-cell transcriptomes, Deena et al.  presenteParoxysmal nocturnal hemoglobinuria (PNH), which is a rare clonal hematopoietic stem cell disorder that manifests with hemolytic anemia, thrombosis and peripheral blood cytopenia. PNH begins with the expansion of a HSC that has a severe deficiency or absence for GPI, a glycolipid moiety that anchors > 150 different proteins to the cell surface which deficiency in virtually all PNH cases is the result of a somatic mutation in PIGA . The mecOn the other hand, although the increased throughput and decreased cost of single-cell omics sequencing emerged recently, it is still a problem how to change it from descriptive research towards mechanistic insights and/or precision medicine. Further research is needed to explore physiological regulation of human hematopoietic development and discover potential gene targets for directed therapy.A series of mutations and/or epigenetic events in HSCs can lead to the occurrence of malignant hematopoiesis. In this section, we will discuss the application of single-cell omics to malignant hematopoiesis Table , which h. [. [. [. [. [AML is an aggressive hematological malignancy which leads to a poor clinical outcome. Most patients die from the disease relapse that is related to clonal evolution at the level of cytogenetics , 95. ScR.  integrat. . Velten . [.  revealed. [. [.  demonstr[. [. [.  also add[. [. [. . These s[. [. [. , 103. Th+CD38− multipotent progenitor cells to reveal the genetic basis of disease initiation in T-cell ALL (T-ALL). In half of the cases, mutations could be detected in CD34+CD38− cells, which proved that the order of mutation acquisition in T-ALL may initiate from the multipotent progenitor cells [To date, there have been limited such studies regarding acute lymphoblastic leukemia (ALL) initiation and progression in comparison with AML , 105. Coor cells . Additioor cells . In addior cells  and chimor cells . Immune or cells . Furtheror cells .Taken together, such studies have offered new insights into heterogeneity, clonal evolution and cellular hierarchies during disease initiation and progression of acute leukemia at the single-cell level that could not be unraveled by bulk analysis. In future studies, determining the precise kinetics of clonal evolution from diagnosis and remission to relapse and response to new therapies would be promising avenues for the further application of single-cell methodologies.. developed a new method, which combined high-sensitivity mutation detection with whole transcriptome analysis in the same cell, to analyze more than 2,000 CML-SCs from patients. Through this method, BCR-ABL+ SCs can be separated from BCR-ABL− SCs, and a subpopulation of BCR-ABL+ SCs resistant to TKIs was identified, which may become a putative therapeutic target. [Chronic myeloid leukemia (CML) is primarily caused by the oncogenic fusion protein BCR-ABL, and tyrosine kinase inhibitors (TKIs) have shown potent efficacy in the treatment of CML. Nonetheless, many patients relapse after treatment, mainly due to selective resistance of CML stem cells (CML-SCs) to TKIs , 111. Re target. . In addi target. . Another target. . Additio target. .. [Chronic lymphocytic leukemia (CLL) is a complex heterogeneous cancer with substantial genetic diversity and evolution during disease progression and treatment –118. Com.  utilized. .. [. merged single-cell and bulk sample information to illustrate genetic aberrations, the pertinent clonal architectures, and DNA methylation patterns during the progression of MDS into AML [Myelodysplastic syndrome (MDS) progress to AML in approximately one-third of patients. A series of studies showed that MDS originated from a small group of disease-induced HSCs, which was sustained and expanded by conventional therapy and became a major factor in disease progression and relapse . However.  performeinto AML . Single-. [+ HSCs exhibited a bias towards megakaryocyte differentiation. This finding was in accordance with other studies in which megakaryocyte differentiation bias in myelofibrosis [JAK2-V617F is the most common mutation in myeloproliferative neoplasm (MPN). Recently, combined with scRNA-seq and mutation detection, Tong et al.  revealedfibrosis  and incrfibrosis  were obs. [Multiple myeloma (MM) is a neoplastic hematologic disorder manifested by a clonal proliferation of malignant plasma cells in the BM . Single-.  performe. , implyinIn conclusion, single-cell omics, combined with integrative bioinformatic analysis, provides new insights into pHSCs, cancer stem cells in hematopoietic malignancies. In spite of this, we usually used mixed samples from different patients in the experiment, it is hard to apply it into individual level. If we want to target some subpopulations or clonal mutations, more meticulous sequencing that personalized to the individual patients is needed. Although it is difficult to apply it into clinical use in a short period of time, that’s making it possible to provide a novel targeted therapy aimed at complex heterogeneous subsets, identify new biomarkers for prediction of prognosis, refine personalized medicine for patients, MRD detection, therapeutic target discovery and even predict response to certain therapies.+ HSPCs expressed markers of Colony Forming Unit—Granulocyte, Erythrocyte, Monocyte, Megakaryocyte (CFU-GEMM) were infected for viral replication [. [In human cytomegalovirus (CMV) infection, the molecular mechanisms underlying the latent stage and reactivation still require further research. Through scRNA-seq, it was determined that a small group of CD34lication . Howeverlication . Since 2ation [.  demonstration [. . Thus, aIn summary, single-cell omics technologies present a powerful means to reveal the heterogeneity of human HSPCs. Functionally defined, immunophenotyped and transcriptomic-defined HSPCs represent fruitful avenues for future research. The application of single-cell omics to malignant hematopoiesis in recent years has provided new insights into the molecular mechanisms of clonal evolution, disease relapse, and the screening of targeted drugs. Gene and cell therapy areas including hematopoietic stem cell transplantation are important therapies in the treatment of hematologic diseases. However, the intricate operation and high detection cost limit the promotion of single-cell omics. In the future, new simplified single-cell technologies with low cost and high throughput may also lead the way in quality control in the gene and cell therapy arena.


Left atrial (LA) function is linked to atrial fibrillation (AF) pathogenesis. AF catheter ablation decreases disease burden with potentially favorable effects on cardiac function. Atrial volume-pressure loops can optimally assess the LA function.To investigate changes in LA function by volume-pressure loops after paroxysmal AF ablation and explored potential differences between the radiofrequency and cryoballoon ablation.We analyzed 44 patients undergoing paroxysmal AF ablation from 2 centers, 22 treated with radiofrequency and 22 with cryoablation. Pre- and post-procedure, all patients underwent a real-time three-dimensional transthoracic ECG to evaluate LA volume, while simultaneously recording LA pressure following transseptal puncture. Volume-pressure loops pre- and post-procedure were created by paired data. Areas of A-loop (LA booster pump function) and V-loop (LA reservoir function), and the stiffness constant determining the slope of the exponential curve during LA filling were calculated.p < 0.001). Overall, A-loop area decreased (p = 0.001) and V-loop area tended to increase (p = 0.07). The change in both A-loop and V-loop areas was similar between radiofrequency- and cryoballoon-treated patients . However, compared with cryoballoon-treated patients, radiofrequency-treated patients had higher increase in the stiffness constant .Average LA pressure, A-wave amplitude, and V-wave amplitude were increased post-procedurally (AF catheter ablation by the radiofrequency or cryoballoon is associated with the decrease of the booster pump function and increase of the reservoir function. Moreover, there is a post-procedural increase of LA pressure which is associated with an acute increase in LA stiffness in radiofrequency ablation, but not in cryoablation. Atrial fibrillation (AF) is associated with significant patient morbidity and mortality . Recent Atrial volume-pressure loops are the optimal method to assess LA function, based on the classic Newtonian mechanics , 7, 8. TThe aim of this prospective study was (1) to investigate potential changes in LA function by volume-pressure loop assessment after catheter ablation of AF by PV antral isolation and PV-LA junction ablation in patients with paroxysmal atrial fibrillation (PAF), and (2) to explore a potential difference in this response between the radiofrequency catheter and cryoballoon ablation.post-hoc analysis.This is a prospective observational study of patients undergoing catheter ablation of PAF. Consecutive patients over 18 years old with PAF undergoing for the first time catheter ablation of PAF by PV antral isolation and PV-LA junction ablation, either with a radiofrequency or a cryoballoon catheter, as per clinical indication, were enrolled from 2 high-volume centers from 1 December 2017 to 31 October 2018. Each center enrolled consecutive patients undergoing PV antral isolation using the same method; i.e., radiofrequency ablation for “Evangelismos” General Hospital and cryoablation for Athens Medical Center. All patients included were required to have ≥2 paroxysms of PAF defined as self-terminating AF paroxysms or cardioverted within 7 days, were on sinus rhythm at the time of the ablation, and maintained sinus rhythm immediately after the procedure. Patients with severe mitral stenosis or regurgitation, previous cardiac surgery, any prosthetic valve, evidence of ischemia, LA thrombus, or severe LV systolic or diastolic dysfunction were excluded. Additionally, patients with echocardiographic images of suboptimal quality  or poor quality ECG recordings were excluded from the Patients underwent PV isolation either by a radiofrequency or a cryoballoon catheter, according to the institutional practice and local standards, as described in the “Ablation Procedure” section. Before and after the procedure, all patients underwent a real-time 3D transthoracic ECG to evaluate LA volume changes during an entire cardiac cycle, while simultaneously recording LA pressure following the transseptal puncture. After the procedure, LA volume and pressure recordings were gated offline by ECG, and recorded values were used to plot the LA pressure as a function of LA volume. Demographic, clinical, and 2d-echocardiographic variables were prospectively obtained. All patients gave written informed consent. The protocol was approved by the institutional ethics committees and complied with the Declaration of Helsinki.All procedures were performed under conscious sedation according to institutional practices, either by radiofrequency ablation or cryoablation , 10. ConCryoablation was performed without the 3D mapping. A 15-F steerable sheath  was used to introduce the cryoballoon catheter system into the LA. A 28 mm cryoballoon  was then advanced through the FlexCath sheath, and positioned at the antrum of each PV guided by the circular mapping catheter . The ablation strategy was wide antral isolation and additional LA lesions were not allowed. The protocol recommended the use of 240 s cryoapplications using a freeze-thaw-freeze technique. An additional freeze was delivered in the case of failure to isolate the PV, if time to isolation was >60 s, and in cases where a mapping catheter was unable to monitor the real-time isolation. To minimize the risk of phrenic nerve injury, right phrenic nerve pacing was performed by an electrode catheter in the superior vena cava and capture was confirmed by palpation and intermittent fluoroscopy. Application of cryoenergy was terminated immediately upon attenuation or loss of phrenic nerve capture.For both procedures, entrance and exit block of the PVs were evaluated 30 min after the initial isolation. The procedure was considered complete once all PVs with conduction recovery were re-isolated. In cases where AF occurred during the procedure, when not terminated by ablation, sinus rhythm was restored by cardioversion.total atrial emptying volume was calculated as LAESV minus LAEDV and active atrial emptying volume as LA volume pre-contraction minus LAEDV  using a Vivid-E9 system with a 4 V probe  at two time points: pre- and post-ablation. By real-time 3D echocardiography, apical full-volume datasets, taking care to avoid foreshortening, were recorded during end-expiratory apnoea. After the procedure, images were analyzed offline at the independent echocardiographic laboratory of Hippokration Hospital, blinded to the ablation method and timing of acquisition. Images were analyzed by two observers  with a consensus approach, and images were re-evaluated by a third reviewer (CA) to ensure contingency of the analysis, with disagreements resolved by consensus. The LA borders were traced at multiple planes during the cardiac cycle using a semiautomated contour tracing algorithm  of the Echopac software , excluding the PVs and the LA appendage from the volume measurement , 12. TheFollowing the transseptal puncture, LA pressure was measured by an oscillometric device  connected to a fluid-filled 6F multipurpose angiographic catheter or to the cryoballoon catheter after removing the Achieve circular mapping catheter. This measurement was performed after transseptal puncture and LA catheterization, just before the ablation procedure, and repeated before the sheath withdrawal. No chronotropic or inotropic agents were administered during measurements. Measurements from a single beat were used for each volume-pressure loop pre- and post-ablation, at an end-expiratory phase and with stable sinus rhythm for at least three beats. All pressure, electrogram, and surface ECG measurements were recorded by the Labsystem Pro software (Boston Scientific), and exported to digital format, containing synchronous values of ECG amplitude and instantaneous pressure at 1 ms intervals.b × ea·V, where P = instantaneous LA pressure and V = LA volume  that determines the slope of the exponential curve and quantifies LA stiffness, while b is the elastic constant (mmHg) representing baseline LA pressure conditions.Recorded values of volume and pressure were gated offline using the ECG recordings, after adjusting for ultrasound signal delay due to the imaging depth . TherebyA volume , 13. Thead hoc. Continuous variables are presented as mean ± SD or as median , as appropriate, and nominal variables as n (%). Normality was assessed by the Shapiro–Wilk test. Between-patient normally distributed variables were compared by t-test, while non-normally distributed variables by Mann–Whitney test. Nominal variables were compared by Fisher's exact test. As most echocardiographic, haemodynamic, and volume-pressure loop variables were non-normally distributed, a Generalized Estimating Equation with repeated effects was used to assess the impact of the ablation procedure and of the applied method on these variables. The value of p <0.05 indicated statistical significance.All analyses were performed with SPSS 25.0. As this is a pilot study, no official study sample was calculated We enrolled 59 patients with PAF. The study flow diagram is presented in The mean age was 62.2 ± 10.7 years and 31 patients (70.5%) were men. There were no significant differences in baseline characteristics between patients treated with radiofrequency or cryoballoon .p = 0.05 and p = 0.10, respectively), while all other changes pre- and post-procedure in real-time 3D-echocardiographic variables were not significantly different between patients treated with radiofrequency or cryoballoon.p < 0.001 for all). A-loop area decreased (p = 0.001), whereas V-loop area tended to increase (p = 0.07). Although the elastic constant increased (p < 0.001), there was no significant difference in the passive chamber elastic constant overall (p = 0.63).p = 0.35), but A-wave amplitude tended to be lower in radiofrequency-treated patients , and average pressure was lower . There were no significant differences in A-loop or V-loop area between the two groups, although both tended to be higher in radiofrequency-treated patients , whereas increase in A-wave amplitude was lower in radiofrequency-treated patients compared with cryoballoon-treated patients  and so was the change in average pressure . The extent of change in both A-loop and V-loop areas was similar between radiofrequency- and cryoballoon-treated patients . However, compared with cryoballoon-treated patients, radiofrequency-treated patients had lower increase in the elastic constant , and higher increase in the passive elastic chamber stiffness constant . To assess a potential impact of peri-procedural fluid administration, especially with the irrigated radiofrequency catheter, we investigated the potential association of total fluid volume, procedural duration, and radiofrequency duration with all post-procedural volume-pressure variables . Representative examples of volume-pressure loops in patients with radiofrequency and cryoballoon ablation are presented in Differences in haemodynamic and volume-pressure loop variables between radiofrequency- and cryoballoon-treated patients are demonstrated in In this prospective pilot study, we thoroughly investigated the acute impact of PV antral isolation and LA-PV junction ablation on morphometric and haemodynamic metrics of LA function, as well as on metrics derived by volume-pressure loops which can quantify the work of the LA, during both the reservoir and active contraction phases, and the LA stiffness. Moreover, we investigated a possible effect of the applied energy source  on these changes. The main findings of the present study are that: (1) there is a significant increase of average pressure, A-wave amplitude and V-wave amplitude after the procedure observed in both radiofrequency- and cryoballoon-treated patients; (2) although the total volume emptied from LA to LV does not change post-procedurally, the volume ejected during atrial systole is reduced; (3) both in radiofrequency- and cryoballoon-treated patients, there is a decrease in the LA booster pump function and trend for increase in the reservoir function; and (4) in radiofrequency-treated patients, the increase in LA pressure is mainly due to acute increase in LA stiffness, whereas in cryoballoon-treated patients, this increase is observed without such change in LA stiffness.AF ablation by PV antral isolation and PV-LA junction ablation is a procedure that decreases the disease burden and improves AF-free survival . SeveralMoreover, LA hemodynamics have a potential impact on ablation procedure outcome. The increased pre-procedural LA pressure has been associated with adverse LA remodeling and AF recurrence post radiofrequency catheter ablation , while vNevertheless, no study has used an integrated approach to characterize the acute impact of the ablation procedure on LA function. While the main determinants of the LA reservoir function are the LA myocardial compliance and the LV longitudinal displacement, LA contraction is to a greater extent dependent on ventricular filling pressures . In our In our study, both radiofrequency and cryoablation resulted in similar changes in LA function and hemodynamics: reservoir function was increased and booster pump function was decreased in the same extent, while average LA pressure was similarly increased in both methods. This increase in pressure might share common mechanisms in the two groups, such as change of preload with periprocedural fluid administration, or a potential impact of increased vagal stimulation, given the increased passive emptying and reduction of booster function. However, the increase in LA pressure for patients treated with radiofrequency ablation was clearly associated with a higher increase in LA stiffness, as assessed by the passive elastic chamber stiffness constant, which determines the slope in the exponential equation that expresses the changes in LA pressure as a function of volume , 13. A sUsing an integrated approach, we documented several important changes underlying catheter ablation of AF. Namely, we observed an acute decrease in active atrial emptying volume with a preservation of the total volume, an acute decrease of the LA booster pump function and an increase of the reservoir function, increase in LA pressures, and in radiofrequency ablation increased LA stiffness. These changes were observed in varying extents among individual patients, and future studies need to examine whether these changes can be used as surrogate markers for assessing the long-term success of the procedure, and whether they might translate to changes in diastolic function over long term, given the well-defined relationship between LA physiology and diastolic filling of the LV .ad-hoc study sample was not predefined, and thus our study might be underpowered for endpoints with high variability, such as echocardiographic measurements. However, we used a real-time three-dimensional echocardiographic approach which improves reproducibility of the measurements and thus reduces bias (Although the study was not randomized, we included consecutive patients from two different hospitals with each hospital performing a single AF ablation method. Thus, there were no significant baseline differences between the groups. Moreover, the analysis was blinded to the method applied. An ces bias . As we eces bias , 21. Addces bias . NeverthCatheter ablation of AF either by radiofrequency or cryoballoon is associated with functional changes of the left atrium, with a decrease of the booster pump function and an increase in the reservoir function. Moreover, there is a post-procedural increase in LA pressures which in radiofrequency ablation is associated with an acute increase in LA stiffness, but not in cryoablation. Further studies are needed to elucidate the significance of this change on the patient outcome and the long-term diastolic function.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee of Hippokration Hospital. The patients/participants provided their written informed consent to participate in this study.AKa: conception of the design, drafting of the manuscript, and data analysis. KT, DTs, ME, and AKo: data analysis and revising the manuscript. MK, EP, SK, and CA: data analysis. DTo, KG, and CT: revising the manuscript. KPT: conception of the idea and design, revising the manuscript, and final approval. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


We examined the relationship between ratios of select biomarkers of kidney and liver function on all-cause and coronary heart disease (CHD) mortality, both in isolation, and in combination with metabolic syndrome (MetS), among adults .Data was derived from the U.S. National Health and Nutrition Examination Survey (1999–2016) including public-use linked mortality follow-up files through December 31, 2015.Select biomarker ratios of kidney  and liver (AST-ALT and GGT-ALP) function in isolation and in combination with MetS were associated with all-cause and CHD mortality. Compared to individuals with neither elevated biomarker ratios nor MetS , increased risk of all-cause mortality was observed in the following groups: MetS with elevated UACR , MetS with elevated AST-ALT , elevated UACR without MetS , and elevated AST-ALT without MetS ; no other biomarker ratios were associated with all-cause mortality. For cause-specific deaths, elevated risk of CHD mortality was associated with MetS with elevated UACR , MetS with elevated AST-ALT , and elevated BUN-CR without MetS ; no other biomarker ratios were associated with CHD mortality.Future longitudinal studies are necessary to examine the utility of these biomarker ratios in risk stratification for chronic disease management.The online version contains supplementary material available at 10.1186/s12872-021-02160-w. Current estimates are that one-third of all adults in the United States (U.S.) have the metabolic syndrome (MetS)—a cluster of cardiometabolic conditions that are leading contributors to an elevated risk for cardiovascular disease (CVD) and type II diabetes –3. WhileOver the past three decades, the contribution of a host of biomarkers to morbidity and mortality has received increasing attention , 16–25. Until recently, little was known about the co-occurrence of these biomarkers in cardiometabolic disease, but in recent years, the application of validated molecular biomarkers in the study of cardiovascular and metabolic pathways has been increasing , 19–25. To date, the use of various kidney or liver biomarker ratios to predict mortality, are nevertheless lacking in large-scale or population-based studies involving cardiovascular disease endpoints. Moreover, the combined effect of biomarkers and MetS on mortality has not been fully evaluated, however, even as emerging evidence now supports their use in diagnostic algorithms to help in the identification of high-risk groups , 25, 29.The purpose of this study is to examine the independent and joint associations of kidney and liver biomarker ratios with MetS on all-cause and CHD mortality, using public-use linked mortality files for the U.S. NHANES. We hypothesize that elevated ratios of biomarkers both in isolation, and in combination with MetS will be associated with all-cause and cause-specific deaths, compared to the referent groups—adults with (1) no MetS nor elevated ratios, and; (2) prevalent MetS only.Data for this study was derived from multiple cycles of the cross-sectional Continuous NHANES. The Continuous NHANES uses a complex, multistage, probability cluster design in order to yield a nationally representative survey of the health and nutritional status of the non-institutionalized civilian population in the U.S., full details on which are described in the NHANES survey methods and analytic guidelines . Ethics The original sample is an amalgamation of nine consecutive cycles collected in 2-year increments from 1999 through 2016 of the continuous NHANES. The initial unweighted sample size was 92,062  cholesterol was analyzed in 1999–2002 primarily by heparin manganese precipitation or by direct HDL immunoassay depending on the participant age and amount of specimen . BeginniUrinary albumin (UA) was measured using a solid-phase fluorescent immunoassay, which is a non-competitive, double-antibody method . A BeckmThe outcomes for this study were all-cause and CHD mortality. The public-use versions of the LMF include a limited set of mortality variables for adult participants only after files were processed to reduce the participant disclosure risk. The public-use LMF provides mortality follow-up data from the date of survey participation through the end of the mortality period—December 31, 2015 . Data collected from the National Center for Health Statistics (NCHS) has linked several population surveys with death certificate records from the National Death Index (NDI) . All-cauScreening for MetS included the presence of three or more of the following five risk factors: high triglycerides ≥ 150 mg/dl); reduced high-density lipoprotein cholesterol ; high fasting glucose (≥ 100 mg/dl or diabetes medications); high blood pressure , and; high waist circumference  50 mg/dl;.Johns Hopkins Hospital’s Harriet Lane Handbook was consulted for the general population or sex-specific reference ranges [For serum biomarkers, the e ranges . For urie ranges . Biomarke ranges , 15, 23.e ranges ; survey e ranges . Establie ranges .Participants were subsequently cross-classified into four discrete groups: (1) non-MetS with non-elevated biomarker ratio; (2) non-MetS with elevated biomarker ratio; (3) MetS with non-elevated biomarker ratio, and; (4) MetS with elevated biomarker ratio.had at least 12 drinks in a year”), lifetime smoking status (“had at least 100 cigarettes in life”), self-reported general health, health insurance coverage, healthcare utilization , physical activity (PA), and survey collection year [All analyses were adjusted for age, sex, ethnicity , education, income status (a ratio of household income to the related poverty cut-off level), alcohol status , and the prevalence of elevated biomarker ratios, were compared between groups with and without MetS using t-tests and chi-square, respectively. Unadjusted and fully adjusted  logistic regression models were used to assess the independent and joint associations of the MetS/biomarker groups with CVD in a sensitivity analysis . Using these groups, the proportional hazards assumption was subsequently assessed and upheld. For the mortality analysis , a final series of Cox proportional hazards regression models (semi-parametric) were developed to examine the unadjusted and fully adjusted (for covariates) relationship for each discrete category of biomarkers with the referent  and all-cause or CHD mortality . A hazard ratio greater than the null value (HR = 1.00) suggests a higher risk for the event (or lower risk when less than the null). Data analysis was performed with SAS software version 9.4 , weighted with the master survey weights to ensure national representativeness of the data. Statistical significance was set at alpha = 0.05.Our first objective was to determine the prevalence and cross-sectional association between biomarkers ratios and MetS with prevalent CVD. In an initial step, socio-demographic, health, and behavioral characteristics of the sample were compared between those p < 0.01). Of note, MetS was more prevalent in older age, and had a higher proportion of males, Mexican Americans, and non-Hispanic Whites, compared to the non-MetS group. The MetS group had a higher proportion of individuals without college education and lower incomes, compared to the non-MetS group. The MetS group also had a higher proportion of smokers, more frequent hospital visits, insurance coverage, lower self-rated health, and more inactivity, compared to the non-MetS group.Table Overall, the prevalence of elevated biomarker ratios for MetS and non-MetS groups showed that the MetS group had a higher proportion with elevated kidney biomarkers , and elevated liver biomarkers GGT-ALP. As well, the MetS group tended to have higher mean ratios for UACR, BUN-CR, GGT-ALP, compared to the non-MetS group.Results of the unadjusted and fully adjusted (for covariates) Cox proportional hazards models of the association between all-cause mortality and co-occurrence of MetS with kidney, or liver, biomarker ratios are presented in tables , we explored the contribution of MetS to CHD mortality using prevalent MetS as the referent group Table  and founThe extent of missing covariate data was evaluated in a sample  without individuals < 20 years, and the analytic sample . Overall, no differences in socio-demographics, behavioral factors, or healthcare utilization and insurance coverage were found between the full and analytic sample.The present study was an analysis of adults without self-identified kidney or liver conditions in the United States from 1999 to 2016. We aimed to identify the relationship between well-known surrogates of kidney and liver dysfunction with (and without) MetS, and all-cause, and CHD mortality. Among the one-third of U.S. adults who have MetS, most biomarker ratios tended to be higher than that of individuals without MetS. Positive associations with all-cause mortality were observed for elevated UACR or albuminuria, and elevated AST-ALT, both with and without MetS. Positive associations with CHD mortality were observed for elevated UACR, and elevated AST-ALT, with MetS. As well, positive associations with CHD mortality were observed for elevated BUN-CR without MetS, and; positive associations with all-cause mortality for elevated GGT-ALP with MetS in participants without CVD, diabetes, or hypertension.All-cause/CHD mortality was not associated with prevalent MetS (without elevated biomarker ratios), nor groups with neither elevated biomarker ratio nor MetS. As an intermediary step, a sensitivity analysis was performed (see Additional file Similar to the findings from this study, the presence of elevated kidney or liver biomarkers has previously been found to be associated with a higher risk of all-cause , 22, 34,Routine measurements of AST and ALT support the detection of liver dysfunction , 6, 44. Evidence in support of the use of elevated AST-ALT ratio in mortality, MetS, or its comorbid risk factors is mixed, and an area of ongoing research , 45–47. The main advantages of this study were: its multicycle cross-sectional design and mortality linkage, which allowed for the determination of prevalence of elevated biomarker levels and 6.9 year average survival estimates with adjustment for a host of potential confounders. The main limitations of this study were the single baseline measure of analytes and that directionality and causality could not be determined for the inter-relationship between biomarkers and MetS. Despite a large representative sample, our analyses were limited to thresholds of biomarker ratios, rather than a full examination of dose–response patterns.This study is among a few studies to use a national representative sample of the U.S. adult population to compare the effects of biomarkers on MetS, and their related effects on all-cause and CHD mortality. MetS with albuminuria or with elevated AST-ALT was positively related to CHD mortality, while albuminuria, and elevated AST-ALT, with and without MetS, were positively related to all-cause death. Further work is therefore necessary to understand the utility of kidney and liver biomarker ratios in the prediction of all-cause and cause-specific mortality. Future longitudinal studies should make available the in-depth tracking and analyses of the long-term impact of these components in subpopulations of at-risk adults in order to improve risk stratification for chronic disease management.Additional file 1: Table S1. Association between cardiovascular disease and kidney or liver biomarker ratio with or without MetS. Data derived from NHANES 1999–2015; referent group has neither elevated biomarker ratio nor MetS. Unadjusted and Fully adjusted models of the analytic subsample. Covariates include age, sex, ethnicity, education, income ratio, alcohol use, smoking, hospital visits, insurance coverage, self-rated health, and physical activity.