Carbon nanotubes (CNTs), having either metallic or semiconducting properties depending on their chirality, are advanced materials that can be used for different devices and materials  due to their excellent electrical conductivity, mechanical strength, and thermal conductivity. Single-walled CNTs (SWNTs) have received special attention due to their outstanding electrical and optical properties; however, the inability to selectively synthesize specific types of CNTs has been a major obstacle for their commercialization. Therefore, researchers have studied different methods for the separation of SWNTs based on their electrical and optical properties. Gel chromatography methods enable the large-scale separation of metallic/semiconducting (m/s) SWNTs and single-chirality SWNTs with specific bandgaps. The core principle of gel chromatography-based SWNT separation is the interaction between the SWNTs and gels, which depends on the unique electrical properties of the former. Controlled pore glass, silica gel, agarose-based gel, and allyl dextran-based gel have been exploited as mediums for gel chromatography. In this paper, the interaction between SWNTs and gels and the different gel chromatography-based SWNT separation technologies are introduced. This paper can serve as a reference for researchers who plan to separate SWNTs with gel chromatography. Carbon nanotubes (CNTs) are tube-like, rolled-up graphene sheets that exhibit unique electrical and optical properties because of their one-dimensional structure . ResearcSWNTs can be used to produce fuel cells ,16, flexIn 1998, researchers proposed the separation of SWNTs with controlled pore glass (CPG) as a medium . SubsequThe general SWNT separation process involving hydrogel and anionic surfactant-based chromatography comprises three stages: adsorption, rinsing, and elution . First, Controlled pore glass (CPG) with approximately 300 nm wide pores was first used in 1998 to separate SWNTs with gel chromatography. The SWNTs dispersed in sodium dodecyl sulfate (SDS) aqueous solution, which is a commonly used anionic surfactant for dispersing SWNTs , was poum/s-SWNT separation with silica gel was achieved utilizing the difference in polarities of SWNT and silica gel. SWNTs functionalized with 4-tert-butylphenyl were used for this separation. The heavily functionalized m-SWNT become nonpolar, promoting the migration from the highly polar static silica gel. m-SWNT enriched fraction was obtained with o-dichlorobenzene as a nonpolar solvent, and s-SWNT enriched fraction was obtained with dimethyl formaldehyde as a polar solvent. However, m/s-SWNT separation using silica gel medium had limitations in that large-diameter s-SWNTs such as , , and  s-SWNTs were also present in m-SWNT enriched fractions, indicating that it is difficult to separate m-SWNTs in high-purity ,70. BecaAgarose-based gel was the first hydrogel used for SWNT separation. Before gel chromatography, agarose gel was used for electrophoresis ,71 or geMost researchers have separated m/s-SWNTs with agarose gel and some others have separated them by dimeter or chirality ,78. The Clar et al. (2013) reported that the main SWNT–gel interaction force is ionic force . In addition, Clar explained the mechanism behind the separation of SWNTs from agarose gel. Agarose gel has four OH groups per monomer with very high hydrophilicity and polarity. The permanent dipoles on the surface of agarose gels promote particle separation. The hydrophilic region exhibits strong ionic interaction with the anionic charged head group of SDS. When the surfaces of m-SWNTs are polarized by free electrons, more negatively charged SDS molecules are induced. m-SWNTs cannot be adsorbed onto agarose gel due to (1) ion dipole repulsion from the charge, and (2) steric repulsion caused by the great amount of SDS molecules . Thus, tAgarose gel has a higher adsorption force for surfactant–SWNT assemblies than allyl dextran-based gel ; the higMost presented SWNT separation studies involved the use of agarose gel for m/s-SWNT separation . Since TSome researchers have successfully separated SWNTs by diameter or chirality with agarose gel. In 2010, Tanaka et al. adjusted the concentration of a DOC aqueous eluant to separate s-SWNTs with small diameters from s-SWNTs with large diameters. Small and large s-SWNTs were obtained with 0.05 and 0.5 wt% DOC eluants, respectively. At low DOC concentrations, DOC cannot adequately cover the s-SWNTs; thus, DOC preferentially adsorbed to small-dimeter SWNTs, which have higher surface energies for interaction . Zhao etAllyl dextran-based gels are synthesized from the backbone, crosslinker, and initiator. Allyl dextran backbone is synthesized from introducing the allyl group to dextran through a reaction with allyl bromide and dextran. Methylene bisacrylamide (MBA) is used as the crosslinker, and ammonium persulfate (APS) as the radical initiator . SephacrWatts et al. (2019) proposed the thermodynamic model of chirality separation according to the length of SWNTs and curvature of Sephacryl gel beads. Since the hydraulic diameter of SWNTs is larger than the pore size of Sephacryl S-200, the chirality selectivity of the gel cannot be illustrated only by the physical pore structures. Watts and co-workers hypothesized that SWNT binding occurs only on the microsphere surface of the hydrogel, and they presented the theory that the proportion of SWNTs irreversibly adsorbed to Sephacryl gel increases with the diameter of the gel beads. As the microsphere size of the gel beads increases, the irreversible adsorption of SWNTs onto the gel also increases, which leads to poor SWNT separation efficiency. Interestingly, grinding the gel and increasing the gel surface area could achieve the same effect as using a large amount of the gel. For example, when 21 mg of Sephacryl S-200 and 2.1 mg of mechanically fractioned Sephacryl S-200 were used as mediums for gel chromatography, a similar level of chirality separation ability was observed, despite the 10-fold mass difference between the two media, suggesting that the cost of the gel filtration process can be greatly reduced .n,m, which represents the relationship between the initial amount  of specific chiral  SWNT and initial adsorption site (θ) of Sephacryl S-200. In this study, the binding sites of the secondary amide group of Sephacryl gel were considered in the kinetic model  compared the chiral selectivity of 12 kinds of commercial hydrogels with different pore sizes and ligands for SWNT separation. The importance of amide groups in Sephacryl gel is highlighted in the study by Zanoni and co-workers, which enabled SWNTs to be adsorbed onto the gel. The 12 kinds of gel were allyl dextran-based gel (Sephacryl), dextran-based gel (Sephadex), agarose-based gel , and MBA-APS gel (synthesized for the experiments). The gel synthesized by polymerization with only MBA and APS exhibited higher elution efficiency than many non-Sephacryl gels. The self-polymerization of the MBA may generate a wider gel area than the allyl dextran backbone. The increase in the gelled area is expected to enable active interaction between SWNT and MBA within Sephacryl gels. Considering that non-Sephacryl gels do not include an amide group, it is estimated that the amide groups in MBA are at the core of SWNT–gel interaction ,86.Dolan et al. (2021) analyzed the effect of the APS concentration  on the repulsive interaction between Sephacryl gel and SDS–SWNT assemblies . In addiAnother important factor for SWNT separation is the pore size. According to Wang et al., physical structure as well as chemical structure of the dextran gel affects the SWNT separation mechanism. That is, even though dextran adsorbs s-SWNT, enabling m/s SWNT separation, if s-SWNT cannot diffuse into the pores because of small pore structure, then s-SWNT cannot be adsorbed onto the gel, leading to low separation yield. Therefore, a dextran concentration of 200 mg/mL formed an optimum pore size for best m/s SWNT separation efficiency  91]. Ho. Ho91]. Sephacryl S-200 has been considered an excellent medium regardless of the SWNT type . Moshammar et al. invented the single- column m/s-SWNT separation with Sephacryl S-200 in 2009 . In 2013Since the interaction between the surfactant and gel plays a key role in SWNT separation, researchers have investigated the effects of the surfactant concentration to optimize separation purity. For instance, Thendie et al. (2017) varied the SDS:SC ratio of the solution eluting s-SWNTs . Inori eIn addition to m/s-SWNT separation, some researchers have analyzed the length distribution of s-SWNTs according to the elution time. In general, shorter s-SWNTs are eluted later. In SEC, larger particles pass faster through beads and become eluted; thus, the observation that longer tubes are eluted first is consistent with the SEC principle. Miyata (2012) obtained high-purity s-SWNTs with multistep SEC and s-SWNTs with an average length of 1.5 μm. The eluted s-SWNTs were filtered several times with the same gel to extract the remaining m-SWNTs in the solution. Before multistep separation, most s-SWNTs had lengths shorter than 1.0 μm; however, SWNTs shorter than 1.0 μm remained in the gel. This is due to the moving speed of the SWNTs inside the gel; the researchers inferred that those short SWNTs have a higher probability of being adsorbed onto the gel due to their slow movement . ThendieSephacryl gel is an excellent medium for chirality-based SWNT separation. As mentioned in the Introduction, SWNTs with different chirality exhibit different absorption properties; if semiconducting SWNTs with specific chirality can be extracted with high purity, they can be used as materials that require absorption or emission at a specific wavelength. For example, when SWNTs are used as photothermal materials, they should exhibit absorbance at 900–1200 nm  .Multi-column chromatography developed by Liu et al. in 2011 enables the separation of HiPco nanotubes with different chirality. By connecting 20 columns packed with Sephacryl gel, the researchers separated SWNTs of different chirality for each column by a single injection of SWNT-dispersed feed solution onto a top column a. The adAs the concentration of surfactants surrounding SWNT determines the interaction between SDS–SWNT and gel, SDS aqueous solutions of various concentrations were applied to the single chirality separation of SWNTs. Blanch et al. (2013) controlled the SDS concentration of the eluant from 0.5 wt% to 4.0 wt% and repeatedly eluted SWNTs. m-SWNTs were separated at 0.5–1.0 wt% concentration, s-SWNTs of large diameter were separated at 1.25–1.75 wt% concentration, s-SWNTs of intermediate diameter were separated at 2–2.75 wt% concentration, and s-SWNTs of small diameter were separated at 3.0 wt% concentration of eluants. The principle of this elution order is related to the curvature rather than the diameter of the SWNTs. That is, in SWNTs with large curvature, surfactants are covered with low density . Flavel In addition, high-purity chirality separation of SWNT has been studied through the mixing of various surfactants as well as controlling the concentration of a single type of surfactant. Gui et al. (2012) separated m-SWNTs by SDS and s-SWNTs by a DOC aqueous solution. The DOC concentration of the eluant was precisely controlled from 0.004 to 0.19 wt%, and s-SWNT separation according to chirality was successful . Zeng etAs described above, surfactants play a key role in SWNT separation using gel chromatography, and surfactants of various types and concentrations are used for effective separation of SWNTs. Nevertheless, the application of SWNT may be limited due to the surfactant remaining on the SWNT surface. The surfactant dissipates electrons on the surface of the SWNT to attenuate the electrical and optical properties of the SWNT ,109. The+ concentration in the solution. The researchers added 100 mM NaOH to the solution with 12.5 pH; the Na+ ions acted as an adsorption inhibitor at a certain concentration or higher  explained in the above-mentioned study that the decrease in the pH level reversibly oxidizes SWNTs and increases the SDS coverage. Since the oxidized SWNTs have a stronger positive charge, the oxidation causes the condensation of the surfactant on the surface of SWNTs due to electrostatic attraction. That is, a decrease in the pH level reduces the interaction between the SDS–SWNT assembly and gel. In a low-pH environment, SWNTs with smaller bandgaps oxidized faster because of the difference in redox potentials. Thus, m-SWNTs are oxidized most radically, followed by large-diameter s-SWNTs, with small bandgaps ,122,123.r higher  81]..+ concen+ and O2 present in the solution, resulting in a change in pH . F. F125]. ge in pH . Yoo et ge in pH .This paper presents the principles of gel chromatography-based SWNT separations and successful examples of SWNT separations according to the gel types. SWNT separation using gel chromatography  commonly requires dispersion of SWNTs in an aqueous solution using a surfactant or surface functionalization and utilizes the difference in interaction strength between SWNT assemblies and gels for various SWNT separations. Regarding length sorting via silica gel and some of the allyl dextran gel, high diffusivity of short SWNTs is the core principle. m/s-SWNT separation via silica gel was achieved by using the difference in polarity between m- and s-SWNTs. In m/s-SWNT separation and single chirality separation via hydrogels, separation was achieved by using electrostatic interactions of gel and SWNT as well as the gel and surfactant. Hydroxy groups of agarose backbone in agarose-based gel, and amide groups of crosslinker MBA in ally dextran-based gel act as an electronic donor, therefore, attracts thee SWNT carbon sidewall. In contrast, negative charged groups on gels such as the organosulfate group on an allyl dextran-based gel repulse the anionic surfactant on SWNTs. Once s-SWNTs are adsorbed onto the allyl dextran-based gel, the repulsion between the organosulfate group (from APS) and SDS surfactant determines the selective elution based on chirality. However, agarose-based gel, which does not have a repulsive element such as APS, shows lower purity in s-SWNT separation and single chirality separation because of the strong binding of SWNTs and the gels.The biggest limitation of gel chromatography for SWNT separation is the high cost of the gels. To compensate for this, researchers have tried to reuse gels; however, the resulting reduction in the number of adsorption sites and damaged porous structure of the gel affect the separation ability. Thus, gels can be reused only to a limited extent. For these reasons, some groups have developed aa next-generation gel medium with excellent separation ability for chromatography. For example, Matsunaga et al. used isomaltodextrin as the chromatography medium. Therefore, we expect that new gels that are inexpensive and exhibit good separation characteristics will be developed. Gel chromatography enables large-scale SWNT separation according to the electrical type , length, diameter, and chirality. Considering that gel chromatography-based SWNT separation can realize large-scale SWNT separation, leading to a broadening of applications of SWNT in various fields, we expect that high-efficiency separation methods for SWNTs will become even more important.


MicroRNAs are ~23 nt, highly conserved non-coding RNA molecules involved in the regulation of target gene expression. Most of the microRNA-target prediction algorithms rely heavily on seed rules and evolutionary conservation. However, such strategies suffer from missing the non-canonical target sites. The aim of this study is to identify the general features of non-canonical targets and their interactions with microRNAs. We found that the bulge-targets were preferentially associated with the microRNAs containing CG dinucleotides in their seed region. This finding indicates that non-canonical targets could be rich due to high mutation frequency of CG within the target mRNAs. Multi-step validation, which included evolutionary, overexpression, correlation, and CLASH data analysis, supports the interactome between the microRNAs with CG dinucleotides in the seed region and their bugle targets. Thus, a major novelty of this work is the identification of a sequence motif, CG dinucleotides, in the seed region of microRNAs, is strongly correlated to bulge targeting patterns.MicroRNAs (miRNAs) are endogenous ~23 nt RNAs which regulate message RNA (mRNA) targets mainly through perfect pairing with their seed region (positions 2–7). Several instances of UTR sequence with an additional nucleotide that might form a bulge within the pairing region, can also be recognized by miRNA as their target (bugle-target). But the prevalence of such imperfect base pairings in human and their roles in the evolution are incompletely understood. We found that human miRNAs with the CG dinucleotides (CG dimer) in their seed region have a significant low mutation rate than their putative binding sites in mRNA targets. Interspecific comparation shows that these miRNAs had very few conservative targets with the perfect seed-pairing, while potentially having a subclass of bulge-targets. Compared with the canonical target (perfect seed-pairing), these bulge-targets had a lower negative correlation with the miRNA expression, and either were down-regulated in the miRNA overexpression experiment or up-regulated in the miRNA knock-down experiment. Our results show that the bulge-targets are widespread in the miRNAs with CG dinucleotide within their seed regions, which could in part explain the rare conserved targets of these miRNAs based on seed rule. Incorporating these bulge-targets, together with conservation information, could more accurately predict the entire targets of these miRNAs. MicroRNAs (miRNAs) are ~23 nucleotide RNAs that regulate eukaryotic gene expression post-transcriptionally . MiRNAs Most of the miRNA-target prediction algorithms rely heavily on seed rules and evolutionary conservation ,6. HowevThese studies strongly suggest the presence of non-canonical miRNA binding sites, but the general features of their interactions with miRNAs are largely unknown, partly due to the difficulty in determining how frequently such atypical sites are used in vivo and which kind of miRNAs might have high frequency of non-canonical binding.Here, we analyzed a group of highly conserved miRNAs in vertebrate, but with relatively fewer conservative targets using the seed rule. We found that these miRNAs share a common feature that their seed region contains cytosine-guanine dinucleotides (hereafter refer as CG dimer). Cytosines at CG dimer are the intensive target of DNA methyltransferases in mammalian genome . Spontanhttp://www.mirbase.org accessed on 9 October 2021) [http://www.targetscan.org/cgi-bin/targetscan/data_download.vert80.cgi accessed on 9 October 2021). All miRNAs were categorized into three groups  using the miRNA Orthology Database (MirGeneDB [Mature miRNA sequences were obtained from the miRBase website (er 2021) . The broirGeneDB  and miROirGeneDB )  and coding gene transcriptome datasets (GSE22570) were used to check expression correlation. The Spearman method was used to calculate the correlation. The canonical seed-target and bulge-targets were compared with the randomly selected mRNA. The same number of genes was randomly selected 1000 times as the control group. To further validate the regulation roles of CG dimer miRNAs and bulge-targets, the in vitro miRNA overexpression datasets, including miR-126 in LM2 breast cancer cell (GSE23905), miR-184 in SY5Y (GSE26545), and miR-210 in MCF-7 cells and MDA-MB-231.cells (GSE25162), and the miRNA knock-down experiments, like miR-126 in MDA-MB-231 cells and miR-1204 in SUM159PT (GSE37185) were downloaded from GEO. The Mann-Whitney-Wilcoxon test was performed to test the seed- and bulge-targets expression change in the transfection experiments.The RNAHybrid  was usedFor the CLASH dataset, the miRNA-mRNA interaction sequences were downloaded from the journal’s website in the supplementary data section . In thishttps://ccb-compute2.cs.uni-saarland.de/mieaa2/ accessed on 3 December 2021) [https://metascape.org accessed on 7 December 2021) [We imported the broadly conserved miRNA and their canonical seed targets into the miEAA website (er 2021)  for funcer 2021) .p < 0.01, For all the human miRNA (n = 1917) annotated by miRBase , there ap < 0.01). For the mammal and primate conservative miRNAs defined by the Orthology Database, the same class of miRNAs with CG dimer in their seed region also have much fewer conservative target sites (p < 0.01). All these results demonstrated that CG dimer miRNAs have very few targets, and even fewer conserved targets based on the seed rule in comparison with the other miRNAs.The newly derived miRNAs in human could have a lower number of targets and conservative targets. So, we used the vertebrate conserved miRNAs defined by the miRNA Orthology Database   converted to thymines (T) by the nearby genes’ neutral mutation number (synonymous mutation and gene length). The CG dimer within the miRNAs (<0.03) has significant lower number of C to T than the CG dimers of the binding sites at the target 3′UTR region  C,D. In gBased on the above results, we speculate that for CG dimer miRNA, beyond the targets predicted by the seed rule, there might be an additional group of targets that don’t have binding site with perfect paring with the seed. To test this, we allow one nucleotide insertion in every position in the seed region E,F for ap < 0.01, To further validate these bugle-targets, we used a dataset with matched mRNA and miRNA expression values across different human ages (human age series data)  to quantp < 0.01, We also used public data on transcriptome changes after over-expression or knock-down individual CG dimer miRNAs from GEO. For miR-126, miR-210, and miR-184, all the bulge-targets were significantly down-regulated after overexpression , and in p < 0.05, We also compared the minimum free energy (MFE) between the canonical seed-targets, bulge-targets, and targets with random bulges using RNAhybrid . The nonTo allow direct mapping of miRNA-target interactions, we use the CLASH dataset  to validThe aim of this study is to identify the general features of non-canonical miRNAs targets and their interactions with miRNA in the evolution. First, we found that the CG dimer miRNAs have surprisingly few conservative seed-targets, and these miRNAs that have been conserved over long periods of vertebrate evolution also have fewer new targets (unconservative target sites) than the other miRNAs. Therefore, we did not find evidence supporting the turnover of target sites. Selection in favor of new target sites appears to be rare: a former study found a strong signal of purifying selection against turnover of target sites , so the The chimeric reads from CLASH data strongly support the interaction between CG dimer miRNAs and bulge-targets. Compared with the seed-targets, however, these bulge-targets had a weaker negative correlation with the miRNA expression, indicating that the perfect seed-pairing remains have stronger interaction. This is consistent with structural accessibility of target sequences, total free energy of miRNA-target hybridization, and topology of base-pairing.The lack of canonical seed-targets makes functional enrichment impossible for each CG dimer miRNA. This makes hard to predict the CG dimer miRNA function. Even pooling all the CG dimer miRNAs together, we only got fewer than one hundred seed-targets. The bulge-targets, however, were much more abundant than the seed-targets. So, we could successfully perform GO analysis for single CG dimer miRNAs. For instance, the bulge-targets for three CG dimer miRNAs  are functionally enriched in the synapse/neuron projection and the RHO GTPase cycle, indicating that fast evolved neuron cells ,28 and GOverall, we found that the bulge-targets were preferentially associated with the miRNAs containing CG dimer in their seed region. Multi-step validation, which included evolutionary, overexpression, correlation, and CLASH data analysis supports the possibility that within the miRNAs with CG dimer in the seed region, there is a group of targets containing a bugle in the binding site.


Disrupted functional asymmetry of cerebral hemispheres may be altered in patients with obsessive-compulsive disorder (OCD). However, little is known about whether anomalous brain asymmetries originate from inter- and/or intra-hemispheric functional connectivity (FC) at rest in OCD. In this study, resting-state functional magnetic resonance imaging was applied to 40 medication-free patients with OCD and 38 gender-, age-, and education-matched healthy controls (HCs). Data were analyzed using the parameter of asymmetry (PAS) and support vector machine methods. Patients with OCD showed significantly increased PAS in the left posterior cingulate cortex, left precentral gyrus/postcentral gyrus, and right inferior occipital gyrus and decreased PAS in the left dorsolateral prefrontal cortex (DLPFC), bilateral middle cingulate cortex (MCC), left inferior parietal lobule, and left cerebellum Crus I. A negative correlation was found between decreased PAS in the left DLPFC and Yale–Brown Obsessive-compulsive Scale compulsive behavior scores in the patients. Furthermore, decreased PAS in the bilateral MCC could be used to distinguish OCD from HCs with a sensitivity of 87.50%, an accuracy of 88.46%, and a specificity of 89.47%. These results highlighted the contribution of disrupted asymmetry of intra-hemispheric FC within and outside the cortico-striato-thalamocortical circuits at rest in the pathophysiology of OCD, and reduced intra-hemispheric FC in the bilateral MCC may serve as a potential biomarker to classify individuals with OCD from HCs. Asymmetry is considered when one side of the brain is structurally or functionally different from the other side . StructuGiven that the corpus callosum connects functional interaction and cooperation between two hemispheres , each inWe have used the voxel-mirrored homotopic connectivity (VMHC) method to investigate the interhemispheric coordination at rest in OCD in a previous study , whereasIn the current research, functional asymmetries of the whole-brain regions at rest in medication-free patients with OCD were investigated using the PAS approach to address the issue whether the asymmetric disruption of OCD results from inter- and/or intra-hemispheric FCs. Based on previous studies, patients with OCD were hypothesized to have significantly abnormal inter- and/or intra-hemispheric FCs within and outside the CSTC circuits. In addition, disrupted asymmetries may be related to clinical characteristics and can be used as potential neurobiological markers to distinguish OCD from healthy controls (HCs).Forty subjects  with OCD were recruited from the Fourth Affiliated Hospital of Qiqihar Medical University and Qiqihar Mental Health Center, China. The diagnosis was based on the Structured Clinical Interview for DMS-IV (SCID), patient version . The YalThis study was approved by the Research Ethics Committee of Qiqihar Medical University. The participants were informed of the study procedures, and they signed a written informed consent.via an echo-planar imaging (EPI) sequence: axial slices = 33, repetition time = 2000 ms, echo time = 30 ms, slice thickness = 3.5 mm, inter-slice gap = 0.6 mm, flip angle = 90°, field of view = 200 × 200 mm2, data matrix = 64 × 64, and 240 volumes (8 min) in total. None of the subjects displayed clinically significant brain structural lesions.For all participants, resting-state functional magnetic resonance imaging (rs-fMRI) using a 3.0-Tesla GE 750 Signa-HDX scanner  with a 12-channel standard head coil was conducted at The Third Affiliated Hospital of Qiqihar Medical University. All individuals were instructed to use foam pads and earplugs to reduce the effect of scanner noise, remain in the supine position, close their eyes, relax, stay awake, and remain motionless . The rs-fMRI data were obtained Data were preprocessed with the Data Processing & Analysis for Brain Imaging (DPABI) software . The firr > 0.2) for PAS calculation  or the opposite hemisphere (interhemispheric coefficient). The intra-hemispheric or interhemispheric FC of this voxel was acquired by taking the mean of intra-hemispheric or interhemispheric coefficients. We used the whole-brain mask to calculate the PAS. Small correlation coefficients between voxels may show the confounding effects in the asymmetric analyses. Therefore, weak correlations were removed with a correlation coefficient threshold . In each group, the one-sample t-test of PAS was performed in the DPABI software; p < 0.05 corrected by Gaussian random field theory  was the significance level. Group differences of PAS were conducted with voxel-wise two-sample t-tests in the DPABI software with p < 0.05 corrected by Gaussian random field (GRF). The mean FD values and age were used as covariates to reduce the potential effects of these variables.The demographic and clinical data were analyzed using two-sample pc < 0.05. Twenty-one Pearson’s correlations were performed (seven brain regions × three scores of the Y-BOCS). The Bonferroni-corrected significance level was set at pc < 0.05/21.Pearson’s correlation analyses between the mean PAS scores and clinical variables were conducted in OCD. The Bonferroni-corrected significance level was set at Support vector machine (SVM) is a well-known and popular supervised machine learning technique with higher accuracy and precision. It effectively defines a set of information as well as the functions of different brain regions to find a maximum boundary delimiter to classify the data, which can differentiate patients from HCs using structural and/or functional neuroimaging data such as rs-fMRI . The orit = 0.05, p = 0.71), gender , educational level , and FD . Among the clinical characteristics, significant group differences were found in Y-BOCS , HAMD , and HAMA .The demographic and clinical data of participants are displayed in t-tests of PAS in each group are shown in Patients with OCD displayed significantly increased PAS in the left posterior cingulate cortex (PCC), left precentral gyrus/postcentral gyrus, and right inferior occipital gyrus, and decreased PAS in the left dorsolateral prefrontal cortex (DLPFC), bilateral middle cingulate cortex (MCC), left inferior parietal lobule (IPL), and left cerebellum Crus I compared to HCs  with abnormal PAS values were discovered in patients with OCD. SVM analysis was applied to these seven brain regions. The classification accuracies were as follows: 1 = 75.64% (59/78); 2 = 88.46% (69/78); 3 = 73.08% (57/78); 4 = 74.36% (58/78); 5 = 70.51% (55/78); 6 = 71.79% (56/78); 7 = 79.49% (62/78) . The resTo the knowledge of the authors, this study was the first to explore the disrupted asymmetries of the inter- and/or intra-hemispheric FC at rest in medication-free patients with OCD by using the PAS method. Consistent with the hypothesis, this study discovered that patients with OCD showed disrupted asymmetry of the intra-hemispheric FC within  and outside  the CSTC circuits. Decreased PAS in the left DLPFC was negatively correlated with Y-BOCS compulsive behavior scores in OCD. Furthermore, the exploratory SVM results suggested that decreased PAS in the bilateral MCC could discriminate patients with OCD from the HCs with appropriate accuracy, specificity, and sensitivity.The authors’ research and other studies previously found decreased FC within the CSTC circuits at rest in OCD . AlthougInterestingly, the results showed that decreased PAS scores in the left DLPFC were negatively correlated with the Y-BOCS compulsive behavior scores in patients with OCD. DLPFC has a core role in cognitive flexibility, set shifting, and executive planning , which aConsistent with the hypothesis, the present study found altered asymmetry of intra-hemispheric FC outside the CSTC circuits in patients with OCD. These brain regions are involved in the default mode network , executive control network , sensorimotor network , and cerebellum network , which might participate in the pathophysiology of OCD . IncreasIn the SVM analysis of the current study, feature selection is an important step to reduce the redundancies and select meaningful features from the original feature sets . Then, tSeveral innovative aspects of the current study must be mentioned. First, the division of the whole-brain FC into interhemispheric FC and intra-hemispheric FC may help explain whether abnormal FC resulted from interhemispheric FC and/or intra-hemispheric FC at rest in OCD. Second, an exploratory SVM analysis was used to investigate whether FC asymmetry could be used as a biological marker to discriminate OCD from HCs at the individual level. Third, medication-free patients with OCD were recruited, which may eliminate the potential effects of the heterogeneity of diseases and drugs on the brain FC at rest.However, several limitations still exist. First, white and gray matters were not assessed, and their potential effects on interhemispheric FC and/or intra-hemispheric FC were unclear. Second, patients with OCD were not classified into subtypes in accordance with their clinical symptoms.In summary, the study showed disrupted asymmetry of the intra-hemispheric FC within and outside the CSTC circuits at rest in medication-free patients with OCD. The reduced intra-hemispheric FC in the bilateral MCC could be used as a biomarker to distinguish individuals with OCD from HCs. Future studies should address these limitations and further explore the clinical utility of using altered asymmetry of the intra-hemispheric FC for differentiation in OCD and prediction of treatment response  in patients with OCD.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by this study was approved by the Research Ethics Committee of Qiqihar Medical University. The participants were informed of the study procedures, and they signed a written informed consent. The patients/participants provided their written informed consent to participate in this study.CJ, YO, and YC engaged in data analysis and wrote the manuscript. PL and WG designed and conducted the study. JM, CZ, DL, RY, TS, LS, YW, GZ, ZS, WW, and XW participated in patient assessment and imaging data collection. 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.


In the HIV-infected individuals, physical activity improves physical strength, quality of life and reduces the risk of developing non-communicable diseases. In Sub-Saharan Africa, HIV-infected patients report being less active compared to HIV-uninfected individuals. We assessed the levels and correlates of objectively measured physical activity and capacity among HIV-infected antiretroviral therapy (ART)-naive individuals compared to HIV-uninfected individuals in Mwanza, Tanzania.We conducted a cross-sectional study among newly diagnosed HIV-infected ART-naive individuals and HIV-uninfected individuals frequency-matched for age and sex. Socio-demographic data, anthropometrics, CD4 counts, haemoglobin level, and C-reactive protein (CRP) were collected. Physical activity energy expenditure (PAEE) was assessed as measure of physical activity whereas sleeping heart rate (SHR) and grip strength were assessed as measures of physical capacity. Multivariable linear regression was used to assess the correlates associated with physical activity and capacity.A total of 272 HIV-infected and 119 HIV-uninfected individuals, mean age 39 years and 60% women participated in the study. Compared to HIV-uninfected individuals, HIV-infected had poorer physical activity and capacity: lower PAEE , elevated SHR  and reduced grip strength . In HIV-infected individuals, low body mass index, moderate-severe anaemia, low CD4 counts and high CRP were associated with lower physical activity and capacity. In HIV-uninfected individuals, abdominal obesity and moderate anaemia were associated with lower physical activity and capacity.HIV-infected participants had lower levels of physical activity and capacity than HIV-uninfected participants. Correlates of physical activity and capacity differed by HIV status. Management of HIV and related conditions needs to be provided effectively in health care facilities. Interventions promoting physical activity in these populations will be of importance to improve their health and reduce the risk of non-communicable diseases. Physical activity improves physical strength and capacity , and redMost of the data on physical activity and capacity among HIV-infected individuals come from high-income countries ,8 and stA previous study in Tanzania which assessed physical activity using similar objective measures among tuberculosis (TB) patients found HIV co-infection was associated with lower levels of physical activity . Besideshttp://clinicaltrials.gov as NCT03106480. The CICADA study design and prevalence of diabetes in the cohort has been published [This was a cross–sectional study conducted from February 2017 to February 2018 in Mwanza, Tanzania, where the prevalence of HIV infection was 7.2% . The stuublished . ParticiWe aimed to have a sample size with adequate power to demonstrate the difference in physical activity and capacity between HIV-infected ART-naïve and HIV-uninfected individuals. Using data available from the CICADA cohort: 272 HIV-infected and 119 HIV-uninfected individuals allowed us to detect an expected difference in physical capacity indicated by grip strength of 4.2 kg (SD 6.7) [HIV-infected participants were recruited if aged ≥18 years, newly diagnosed HIV-infected ART-naïve willing to start ART immediately after study enrolment, not pregnant, and residing in Mwanza. The current Tanzanian HIV policy and the national multi-sectoral strategic framework for HIV and AIDS adopted Test and Treat policy from WHO in 2016 ,28. HencHIV-uninfected individuals were recruited from the same communities as the HIV-infected ART-naive and were frequency-matched for age and sex at a ratio of 2:1. Communities were defined as streets or sub-villages with a minimum of 200 households as per administrative setup of the local government. With the support of the respective community leaders, we obtained a list of households in the community. We then randomly selected three households from which an eligible individual  was identified. In case of refusal to participate, we repeated the process until suitable participants were found. To confirm HIV-negative status, participants in the comparison group were tested for HIV and if found to be HIV-infected, they were invited to participate in the HIV-infected group and were referred for treatment.Information on demographics, socio-economic status, level of education, marital status, and occupation were collected by a trained research staff using electronic structured questionnaire in a CSpro version 6.3 data capturing system .Trained researchers collected anthropometric measurements in triplicate using standardized methods and the median of the three recordings was used for analysis. With minimal clothing and while barefoot, participant’s body weight was measured to the nearest 0.1 kg using a digital scale . Height was measured to the nearest 0.1 cm using a wall fitted stadiometer . Waist circumference was measured at the midpoint between the lower part of the last rib and the top of the hip bone using a tape measure.PAEE (kj/kg/day), as an indicator of habitual physical activity, and SHR (beats/min) as an indicator of physical aerobic capacity, were assessed during daily living using a combined heart rate and accelerometer  ,. The deData on activity level, SHR and heart rate (heart beats per minute) were retrieved from the monitor and were processed using Gaussian robust regression model to remove noisy data . ObservaGrip strength as an indicator of the muscular strength, aspect of physical capacity was measured to the nearest 0.1 kg using a digital grip strength dynamometer . Four measurements were taken and the mean of the two highest measurements (one from each hand) was used for analysis.A whole venous blood sample was collected, processed and used for HIV, CD4 counts, hemoglobin and C-reactive protein (CRP) testing. HIV-infection was diagnosed based on two rapid tests: Bioline  and Unigold . Discordant samples were tested using ELISA . CD4 counts (cells/uL) were determined using Cyflow Partech machine . Hemoglobin level was measured using haematology analyser . CRP was measured using sandwich ELISA .2 and categorised as underweight (<18.5 kg/m2), normal weight (18.5–24.99 kg/m2) and overweight (≥25.0 kg/m2). Waist circumference (cm) was defined as normal  and abdominal obesity  [Data were processed and analysed using Stata version 13 . CD4 counts were categorised as ≤200, 201–499 and ≥500 (cells/uL), based on WHO cut-off points, anaemia was classified as no anaemia , mild , moderate  and severe anaemia  , body ma>102 cm) .All correlates were tested for collinearity with variance inflation factors. No corrective measures were required since all correlates had variance inflation factors <5. Normality of continuous variables was checked using histograms. Log transformation was done to achieve normal distribution for CRP. Participants’ characteristics were summarised as number (percentages), median (IQR), and mean (SD) stratified by HIV-status. For comparison of two means by HIV-status, chi-square tests were used for categorical variables and t-tests were used for continuous variables. Levels of PAEE, SHR, and grip strength were stratified by HIV status and linearly regressed to the assessed correlates: age, sex, education, employment, BMI, waist circumference, haemoglobin levels, CD4 count, and log CRP. In multivariable analysis, the associations between the potential correlates and PAEE, SHR, and grip strength, respectively, were adjusted for age and sex. A test of interaction was included in the adjusted model to assess whether associations with correlates differed significantly between HIV-infected and HIV-uninfected individuals. The correlations were presented as beta coefficients with 95% confidence interval (CI) in HIV-infected and HIV-uninfected individuals, the difference of the beta coefficients, 95%CI of the HIV-infected versus HIV-uninfected individuals and interaction p-value respectively. A p-value <0.05 was regarded as statistically significant.This study was conducted in accordance with the Helsinki declaration of 1964. Ethical approval for the study was provided by the Medical Research Coordinating Committee of the National Institute for Medical Research and the Catholic University of Health and Allied Sciences Ethics Review Board in Tanzania. All eligible participants were informed of the study purpose, procedures and provided oral and written informed consent prior to their enrolment into the study.A total of 457 HIV-infected ART-naive and HIV-uninfected individuals participated in this study. After data processing, 66 (14%) participants were removed from the analysis due to missing data either on acceleration or heart rate or both, leaving 391 (86%) participants for the present analysis with 259 (66%) having completed the step test among HIV-infected and HIV-uninfected individuals. The average recording length of physical activity data was 4.3 days.Participants’ baseline characteristics are displayed in Two-thirds of the participants had normal BMI but there was a higher proportion of underweight among HIV-infected (27% vs 5%) and a higher proportion of overweight (36% vs 16%) and abdominal obesity (24% vs 8%) among HIV-uninfected individuals. Most of HIV-uninfected individuals had normal levels of haemoglobin (80%) whereas specifically moderate anaemia was common among HIV-infected individuals (32%). CRP levels were higher in HIV-infected than in HIV-uninfected individuals.HIV-infected had lower physical activity, PAEE  compared to HIV-uninfected individuals. Likewise, SHR was higher  and grip strength was lower  implying poor physical capacity in HIV-infected compared to HIV-uninfected individuals.Abdominal obesity  was the only correlate associated with lower PAEE among HIV-uninfected individuals. The tests for interaction showed that HIV-status modified the relationship between all the assessed correlates and PAEE (p≤0.05) except for abdominal obesity and BMI.Low BMI and CD4 counts ≤200 cells/uL were associated with elevated SHR  and  respectively in HIV-infected, while they were not associated in HIV-uninfected individuals. The interaction tests were not significant (p = 0.16 and p = 0.28) respectively. Moderate anaemia and log CRP were associated with elevated SHR  in HIV-infected only (interaction p = 0.04 and p<0.001). Abdominal obesity was not associated with SHR in either group .Using objective measures, this study showed newly diagnosed HIV-infected ART-naïve individuals have lower levels of physical activity and capacity compared to HIV-uninfected individuals. The main factors correlated to lower physical activity and capacity in HIV-infected were low BMI, anaemia, low CD4 counts as a marker of disease progression, and increased CRP as a marker of inflammation. Anaemia and abdominal obesity were the only correlates associated with reduced physical activity and capacity in HIV-uninfected individuals.The results found on levels of physical activity indicated by reduced PAEE in HIV-infected, complement results from other studies conducted in high-income countries showing that, HIV-infected have reduced levels of physical activity which is ranging from 19–73% due to HIV-inflammation, opportunistic infections, anaemia, metabolic complications ,36 and uThe present study also highlighted the associations between anaemia and physical activity and capacity among HIV-infected and HIV-uninfected individuals. The prevalence of anemia in the HIV population in other studies was found to be even higher compared to uninfected population, and it ranged from 45%-70 . Anemia In addition, we found that HIV-uninfected individuals with abdominal obesity had reduced physical activity potentially increasing the risk of NCDs. The prevalence of metabolic syndrome has been rising in the SSA over the years. A 2019 review reported that among HIV-uninfected individuals, the prevalence was about 12% . In TanzHIV-associated wasting syndrome is characterised by involuntary loss of body lean mass and fat mass, a case definition of HIV-infection , resulteHigher SHR is a predictor of cardiovascular diseases and all-cause mortality . The curIn SSA, previous studies on physical activity and HIV-infection mainly used subjective measures of physical activity which may have contributed to inconsistent results ,49. In pThe strengths of this study include the use of an objective measure to assess physical activity and capacity using PAEE, and SHR parameters in both HIV-infected and HIV-uninfected individuals. An additional strength is that, we used individual calibration of heart rate via a step test in the majority of the sample and, based on this data, developed a population-specific group calibration equation for estimating PAEE for use in those who did not complete a step test. Nonetheless, participants without a step test were more likely to have more advanced HIV disease and therefore also more likely to be less fit, the result of which would be a small residual positive bias of their PAEE estimates. For this reason, the difference in physical activity levels between HIV-infected and HIV-uninfected individuals may in fact be greater than we report here. Future studies should consider offering alternative exercise testing such as self-paced walk tests for those unable to complete tests with prescribed exercise loads. Further, the present findings add to the literature by comparing the role of HIV-infection and correlates on physical activity, and capacity in HIV-infected compared to HIV-uninfected individuals in a large sample in the SSA.The main limitations for this study were participants’ low compliance with wearing the combined monitors for specific time periods like during sleep or due to allergic skin reactions to the ECG electrodes. In addition, in this study, we could not establish the time or duration of the infection of HIV-infected individuals, which may be of importance to our findings. Furthermore, this study was a cross-sectional, limiting causal inference of the relationship between the correlates and physical activity and capacity. Longitudinal studies will be needed to confirm the observed associations between disease progression and physical activity and capacity among HIV-infected individuals to reduce the burden of morbidity and improve quality of life.To conclude, objectively measured levels of physical activity and capacity among HIV-infected were lower compared to HIV-uninfected individuals. Correlates which may contribute to lower levels of physical activity and capacity in HIV-infected were HIV status (CD4 count), chronic inflammation, HIV related wasting and anaemia. In contrast, for HIV-uninfected individuals, only anaemia and abdominal obesity were found to be correlated with lower physical capacity. Endurance to physical activity and changes in physical capacity depends on regular physical activity regardless of health status. Based on these findings, there is a need to improve management and treatment for HIV- infected, to develop and evaluate interventions on physical activity among HIV-infected as well as HIV-uninfected individuals to improve general health and reduce the risk of NCDs.S1 Questionnaire(DOC)Click here for additional data file.S2 Questionnaire(DOC)Click here for additional data file.


A pandemic disease, COVID-19, has caused trouble worldwide by infecting millions of people. The studies that apply artificial intelligence (AI) and machine learning (ML) methods for various purposes against the COVID-19 outbreak have increased because of their significant advantages. Although AI/ML applications provide satisfactory solutions to COVID-19 disease, these solutions can have a wide diversity. This increase in the number of AI/ML studies and diversity in solutions can confuse deciding which AI/ML technique is suitable for which COVID-19 purposes. Because there is no comprehensive review study, this study systematically analyzes and summarizes related studies. A research methodology has been proposed to conduct the systematic literature review for framing the research questions, searching criteria and relevant data extraction. Finally, 264 studies were taken into account after following inclusion and exclusion criteria. This research can be regarded as a key element for epidemic and transmission prediction, diagnosis and detection, and drug/vaccine development. Six research questions are explored with 50 AI/ML approaches in COVID-19, 8 AI/ML methods for patient outcome prediction, 14 AI/ML techniques in disease predictions, along with five AI/ML methods for risk assessment of COVID-19. It also covers AI/ML method in drug development, vaccines for COVID-19, models in COVID-19, datasets and their usage and dataset applications with AI/ML. COVID-19, novel coronavirus, was announced in Wuhan, China, in December 2019 as a group of fatal respiratory infections and spread quickly as a pandemic . BecauseArtificial intelligence (AI) and machine learning (ML)  have beeThe applicability of AI/ML for epidemiological research of COVID-19 is explored in the literature. Initially, it identifies the relevant key explanatory variables then uses the dimensionality reduction technique to remove redundant features or information. It utilizes Random forest and gradient boosted machine learning models to measure the relative influence of the explanatory variables. This method also determines the interconnections among key explanatory variables, COVID-19 case and death counts. The study shows that air pollution has a high impact on COVID-19 casualties . COVIDetDeep learning (DL) models are very effective for time-series datasets. In the literature, the prediction of COVID-19 cases using time series data is discussed with DL techniques. Some models, such as long short-term memory (LSTM), are used to predict the time-series datasets. Integration of a convolutional neural network (CNN) and Long short-term memory (LSTM) detects COVID-19 automatically using X-ray images. CNN is used for deep feature extraction, and detection is performed using LSTM using the extracted features . The samaccuracy .AI/ML techniques have been widely applied to detect new molecules on the way to ascertain COVID-19. Many data scientists adopt AI tools to discover new medicines for the cure, to use X-rays and computational tomography (CT) scans by image processing, to identify the infectious people . AI toolChest X-ray images have demonstrated a highly effective screening technique for diagnosing the COVID-19. Various hybrid techniques are adopted to detect the COVID-19. Recently, a hybrid DL called COVID-CheXNet is demonstrated to identify the COVID-19. In the beginning, the contrast X-ray image is enhanced using contrast-limited adaptive histogram equalization, and the noise level is reduced with the help of the Butterworth bandpass filter. It uses two pre-trained models such as ResNet34 and HRNet, to identify the COVID-19. Each model’s score is fused to obtain the final class whether the individual is affected by the COVID-19 or not . SimilarThe number of studies on COVID-19 increases day by day because of its popularity and necessity. Researchers need to get a piece of quick information about related studies in this area. In the field of healthcare, AI/ML techniques have been implemented for many applications. For example, because of the availability of MRI, X-ray, and CT images, they have been widely applied for the COVID-19 outbreaks. Although AI/ML applications provide satisfactory solutions to the COVID-19 pandemic, these solutions have a wide diversity in nature. There is no comprehensive study discussing the AI/ML techniques used for the COVID-19 pandemic from different perspectives. Therefore, to fill this scientific gap in the literature, the study’s motivation is to analyze the potential studies using the AI/ML methods , 24 for This study mainly focuses on different AI/ML techniques that were applied for the COVID-19 outbreak.This study highlights the reasons for applying AI/ML techniques to the pandemic.This study explains the data perspective of COVID-19 studies regarding measurement types of study success and data types.This review research gives direction to researchers about the various repositories available for COVID-19 outbreak so that researchers can easily access.This study focuses on the current situation of drug and vaccine discovery and how AI/ML methods can help in the drug development.This study lists various software platforms available to implement AI/ML methods in the COVID-19 outbreak.This study is structured as follows. The next section gives the research methodology based on seven significant considerations. Research questions, which are critical aspects of the review, are determined. Databases and search strategy are explained together with inclusion and exclusion criteria to select relevant studies. Then data extraction and collections steps are considered. Factors that affect validity to know the strengths and weaknesses of the systematic review are discussed. The subsequent section presents the results and discussions considering defined research questions. Then the limitations of the review are given. Finally, the study is concluded.Contributions of this study includeAccording to Brereton et al. , a systeRQ 1: What are the most frequently applied AI/ML techniques in COVID-19?RQ 2: Why AI/ML approaches are applied in COVID-19?RQ 3: What is the data perspective of studies?RQ 4: What is the current situation in drugs preparation?RQ 5: What software platforms are used?RQ 6: Which data sources can be reached?The main objective of this systematic literature review is to describe, analyze and synthesize the studies related to the AI/ML implementations in the COVID-19 outbreak. To obtain a more detailed and comprehensive view of the subject, the overall objective is based on the following six research questions (RQs) with motivations.ACM Digital LibraryArXiv.orgElsevierIEEE Xplore Digital LibraryPubMedSpringerWiley Online LibraryThe search string used to facilitate searching in selected libraries have four dimensions with their sub-domains: AI/ML, study objective, COVID-19, and healthcare.Seven online academic search engines were used to find related studies.After collecting the studies, duplicate articles were removed. If there are more than one studies, only the most complete version was chosen. Later, studies were selected using the following inclusion and exclusion criteria to find answers to identified research questions and identify the most appropriate studies.Studies applying at least one AI/ML algorithmStudies producing solution to at least one of the COVID-19 problemStudies containing experimental work using COVID-19 datasetsStudies that explicitly address the COVID-19 issueStudies written in English onlyExclusion criteria:Studies published before 2019Extended abstracts and poster workStudies that mention AI/ML techniques but are not part of the COVID-19 outbreakStudies that mention COVID-19 techniques but do not use AI/ML techniquesTheoretical studies without applicationInclusion criteria:The articles defined by the search terms from the databases were initially considered only metadata (title and summary). All works related to the subject were scanned. However, since the number of studies found was too large, a second selection was made according to the keywords. The keyword is a way of reducing the time needed to develop the classification scheme and to ensure that the plan considers current work . The fulRQ 1: AI/ML algorithms and techniques used for COVID-19 should be defined.RQ 2: Objective of AI/ML approaches should be given.RQ 3: The data type, data size, study reliability should be investigated.RQ 4: AI architecture for protein structure and drug analysis should be identified.RQ 5: AI/ML-based software specific to COVID-19 outbreak should be given.RQ 6: Data sources should be searched with a direct link.A data extraction form was used to collect relevant data from the selected studies to answer research questions. Selected studies were evaluated three times in different days by different authors.The electronic databases include international indexed journals and conferences searched and defined concerning AI/ML approaches against COVID-19. ACM  classification, (2) prediction, (3) diagnosis and 4) other applications like early warnings and alerts. Classification is the most popular aim for applying AI/ML methods , 89, 105 other apPrediction is the second popular objective in AI/ML approaches –111. RegOther reasons that concluded from the selected studies to apply AI/ML approaches in COVID-19 are given below.Patient outcome prediction AI tools were developed to predict risk status of contracting the coronavirus. It is critical to know the factors that will put the patients at risk. LSTM is a popular method to predict patient outcome. For example, Obaid et al. [d et al.  proposedd et al. –120. Timd et al. , the autAI and ML models are potentially strong to fight with different pandemic  with different methods like classification, forecasting, prediction and pattern recognition. AI/ML tools covering these methods to play an essential role in fighting with the deadly disease . Table 2Risk assessment of pandemic AI/ML models help to assess the risk of the pandemic. DL-based models were developed to predict the duration of the disease [ disease , 142, co disease  and tran disease . Early r disease  proposedWorkload reduction of health professionals Because the sudden spike of COVID-19-affected patients, healthcare workers have a growing burden. Various AI/ML techniques were proposed for early diagnosis of the disease [ disease –149. AI  disease .Social control With high transmissibility of COVID-19, many countries adopted AI for pandemic management [nagement  and are nagement . Model inagement , 154. AInagement .Early warnings and alerts AI is a potential tool to fight against COVID-19, and AI-based systems are used in spotting COVID-19 disease outbreaks. Bots based on AI were used to predict the possible outbreak [outbreak , 157. Beoutbreak  alerted outbreak .Table Table Due to the rapidly spreading across to the world and the lack of effective treatment options, drug developers have adopted the various strategies to fast track the drug discovery. Whereas some studies applied AI/ML techniques to predict, some of them analyzed the molecular structure of coronavirus because drug discovery is an expansive and lengthy process. Table AI is a cost-effective and fast tool in drug discovery to fight against COVID-19. Shin et al.  proposedSome studies identified the drug compounds to fight against SARS CoV-2 coronavirus. Kadioglu et al.  identifiBoth small molecule drugs and small molecule agents are more potential drugs for COVID-19 . Small mScientists are looking for a vaccine at least 95% effective to stop the pandemic . AI techPractitioners encountered severe challenges in the detection of Ncov-2019 because SAR-CoV-2 viruses spread rapidly. Reverse Transcription Polymerase Chain Reaction (RT-PCR) approach is not applicable due to some obstructions . The shoData are presented as an essential aspect of implementing scientific methods. The research community always follows two approaches: closed source or open source . Closed Three main types of datasets in COVID-19 were used, textual data, medical data and speech data. Textual data represents dashboard, mobility data, case reports, social media posts and articles. Medical data generally presents diagnosis and screening of COVID-19 patients since medical images consider X-rays, CT scans, ultrasound or MRI (Magnetic Resonance Imaging). Most of the datasets represent CT scans, X-rays, and AI/ML techniques applied to predict resources in the future. Speech datasets help to detect and diagnose by cough sound, breathing rate and stress detection techniques.Most of the datasets were stored on different repositories, such as Github and Kaggle. Table Total 18 textual datasets were discussed to show the relevancy of different purposes. These datasets consider COVID-19 case reports, report analysis, mobility data, social media data, scholarly articles, tweets, non-pharmaceutical interventions (NPI). Several studies maintained and shared the epidemiological data of COVID-19 cases in China , 263. COMedical datasets, which include CT and X-ray images, are essential in diagnosis of COVID-19. Studies based on COVID-19 diagnosis used different datasets for CT-Scan , 289–297Speech or audio datasets help to detect and diagnosis of infection by three different method such as cough sound analysis –305, breTable Some limitations of the current research should be accepted. The research is limited to selected search terms, databases and selection criteria.This research was conducted in a certain period of time. However, the number of studies on COVID-19 increases day by day because of its popularity and necessity. Because a systematic literature review was presented with this research, it is necessary to limit the research content. To decrease the effect of this situation, the inclusion and exclusion questions were prepared to select the studies published in the research period.Seven online databases were scanned for the review. However, other databases can be scanned. If the research is to be expanded, the number of databases can be increased.Apart from selected studies in this research, there are many different studies. It should not be forgotten that some criteria were set for narrowing the research scope. For example, studies that do not mention the algorithm applied in the implementation or do not give details were ignored. Applied AI/ML studies are generally implemented for different purposes without considering COVID-19 problems. Therefore, COVID-19 problems are not explicitly stated in the publications. By evaluating each study individually, it was determined which problem discussed. At this stage, there may be unobserved publications.This systematic review study investigates 264 studies from seven accessible databases to find answers for six significant research questions. This research aims to explore and organize potential literature so that practitioners, academicians, and researchers can easily access the existing methods, applications, and datasets. The main contribution of this research to identify the AI/ML methods and techniques for disease prediction, measurement and data types, AI/ML method in drug development, available drug and vaccines, and existing models and datasets for the COVID-19 pandemic. CNN, RF, ResNet and SVM approaches are the most used AI/ML approaches against COVID-19. These approaches were applied for various purposes. Classification, prediction and diagnosis are the most popular AI/ML objectives. ResNet applied for classification and diagnosis, whereas regression is used for prediction studies. Apart from these objectives, previous studies benefited from the advantages of AI/ML tools for several additional purposes, such as patient outcome prediction, risk assessment, workload reduction of health professionals, social control and early warnings and alerts. This study concludes that the methods’ success varies widely. Nine major measurement types were considered to evaluate models’ success. Accuracy, sensitivity and specificity were measured 69% of studies. 84% of studies used either CT or X-ray images between 50 and near to 17,000. Case data are the third popular data type with a rate of 16% up to 77 days. Python and R the most preferred software platform to apply AI/ML methods. Some studies used Matlab, Microsoft Excel and more than one software. Data were stored in three main categories, textual, medical, and speech. Because the research has review borders, it has some limitations that were discussed in the study.This study is most significant for new practitioners and researchers who plan to develop an AI/ML model or drug for COVID-19. They can reuse existing models and drugs rather than design from scratch and save time for doing potential research and future studies. Besides, this research provides a backbone for different aspects such as disease diagnosis and detection, drug and vaccine development, AI/ML models and techniques. The conducted literature provides comprehensive details of AI’s potential and existing contribution to combating the pandemic.As it is understood from the literature review, many researchers applied CNN models. The main reason can be that they are powerful for the spatial coherence or local pixel correlations in medical images. CNN technique was usually applied for either classification or diagnosis. However, authors should remind aforementioned drawbacks before applying CNN for COVID-19 studies.For further research, the authors can focus on several points. First of all, researchers can scan other databases such as ERIC, DOAJ and JSTOR. Some additional research questions can be investigated to clarify interesting and meaningful results.Table


The alpha-gal syndrome is an allergic syndrome that comprises two clinical pictures: an immediate hypersensitivity to drugs containing alpha-gal and a delayed hypersensitivity to the ingestion of red mammalian meat. This allergic syndrome is often under-recognized, and patients are mislabeled with diagnosis as spontaneous urticaria or idiopathic anaphylaxis. Even though less frequently, children could also be of interest, especially in tick-endemic areas. In most cases, a positive anamnesis for tick bites months before the onset of symptoms is recorded. The clinical manifestations could range from asymptomatic cases to severe anaphylaxis. The most frequently used diagnostic test is the determination of specific IgE for alpha-gal. Oral provocation test is usually reserved to unclear cases or to verify tolerance after diet. No long-term follow-up studies have been published, although an elimination diet could lead to a decrease of specific IgE for alpha-gal and a possible reintroduction of some avoided foods. This paper provides a literature review, focused on pediatric age, and an evaluation of available diagnostic tests. We analyze the correlation between tick bites and symptom onset and unfold the different clinical pictures to help clinicians to promptly recognized this syndrome. Lastly, we address unmet needs in this specific allergy. Amblyomma americanum; in Australia, Ixodes holocyclus; in Europe, Ixodes ricinus; and in Asia, Ixodes nipponensis.The alpha-gal syndrome (AGS) is an allergic syndrome comprising two scenarios: an immediate hypersensitivity to drugs containing alpha-gal and a delayed hypersensitivity due to the ingestion of red meat . The allergic response observed is due to the production of specific IgE (sIgE) for the disaccharide galactose-α-1,3-galactose , which is expressed on the surface of glycolipids and glycoprotein of mammalian cells and synthesized by the galactosyl-α-1,3-galactosyl-synthetase. In primates, the alpha-gal is not expressed due to a genetic loss-of-function mutation of the GGTA1 gene and is recognized as non-self. Since the 80's, IgG-IgA-IgM for alpha-gal have been described, as a protection against parasitosis and the main cause of xeno-transplant reject reactions , and it could be found in meats, internal organs, meat by-products, gelatin, milk, and dairy products. Alpha-gal is resistant to heat and pepsinic lysis  and is tChondrus crispus and Gigartina mamitiosa), frequently used in food and drug preparations and identified as E407 preservatives. Carrageenan could be found, e.g., as a clarifying agent, as a hydrating agent for foods, in powdered infant's milk, and in toothpaste.Alpha-gal is also found in carrageenan, obtained from boiled red algae  and B cells, directly stimulating sIgE-α-gal production.Tick bite inoculates the alpha-gal and some adjuvants, which drive the isotypic B cell switch from IgG/IgM-α-gal to sIgE-α-gal .Tick bite induces a skin barrier trauma or interferes with skin microbioma, causing the production of pro-allergic molecules, which drive the isotypic B cell switch .However, skin trauma plays a pivotal role in altering the micro-environment, favoring the switch toward IgE and Th2 immunity by promoting the release of TSLP, IL25, and IL33 , 21. BasOnce ingested through a meal with red meat products or by-products, glycolipids and glycoproteins expressing alpha-gal are absorbed in the gastrointestinal tract, through chylomicrons entering the lymphatic system (thoracic duct) and systemic circulation (superior vena cava). In the following 2–4 h, chylomicrons reduce their diameter from 400 to 20 nM in low-density lipoproteins. With this diameter, they could cross skin interstitial tissues or vessel walls and activate mast cells and basophils. Once cross-linked with IgE–FcεRI complex on basophils and mast cells, which express the same high-affinity IgE receptor, degranulation starts with subsequent IgE-mediated reaction. The whole interval time needed for these processes could therefore explain the delay of symptoms in AGS by food ingestion , 26 Fig.via tick bites, which could lead to the following:Sensitization usually occurs through inoculation of alpha-gal A low-grade sensitization to alpha-gal is not always correlated with clinical manifestations. In a study on German adults  with occThis allergy has unusual characteristics: (a) symptoms are delayed (often after 3–6 h as a timing of onset) but clinically immediate; (b) it does not appear after every ingestion; and (c) it could start years after sensitization and for food previously tolerated . A wide Parenteral administration is the main sensitization form, with immediate reactions. In AGS, the most frequent culprit drug is cetuximab, a monoclonal antibody prescribed for colorectal cancer. Vaccines containing gelatin could be responsible for allergic reactions, since gelatin present in vaccines is usually pork derived . Therefoin situ . It may therefore be possible that isolated abdominal pain is an under-reported and under-diagnosed feature of AGS, as also reported by other authors  and environmental conditions that increase the development and spread of ticks;- Non-B blood types;- Allergic co-factors ;- Age: possibly correlated to the studied population, though, e.g., in the study of Mabelane et al.  patients- Atopy: the association has not been clarified yet ;- Cat allergy: alpha-gal epitope is also present on cat, implying a possible association between AGS and cat dander sensitization. However, not all studies agree on this hypothesis ;- Meat type (giblets vs. lean cut): Morisset et al.  demonstr- Type of exposure: parenteral exposure is correlated with more severe reactions compared to ingestion.B/AB blood types seem to act as a protective factor . This isAs in adults, the diagnosis is based on clinical history and allergy tests.Clear up when signs and symptoms appear: delayed reactions begin at least 2 h after meat ingestion, while parenteral administration evokes immediate reactions;Ask for previous tick bites and bite reactions (as persistent itchiness or redness);Evaluate the number and characteristics of episodes;Check for possible allergic co-factors;Think about AGS in any allergic reaction without apparent cause. In a study on teenagers and adults , initialAs suggested by Kennedy et al. , in chilNo pediatric studies have specifically evaluated sensitivity and specificity of allergy tests, and most of them rely on the same positivity cut-off for skin tests and sIgE-α-gal.Commercial prick tests for red meat showed a low sensibility and are not recommended . Cooked Most allergological clinics rely on specific IgE for alpha-gal. Commercially available kits are Phadia-Thermo Fisher in Europe and Viracor-Eurofins in the United States. It is recommended to evaluate both sIgE-α-gal and total IgE and calculate the ratio. Scientific experts suggest to consider as positive an sIgE-α-gal level > 0.1 kUI/l  . HoweverRecently, the basophil activation test has shown a possible usefulness in distinguishing symptomatic patients with AGS from those with laboratory-isolated sensitization .Oral provocation test could be useful to confirm AGS diagnosis in doubtful cases or asymptomatic sensitization, but it is not standardized yet, especially in regard to the quantity and quality of meat to be tested. Morisset et al.  designedOnce the AGS diagnosis is clear, it is important to discuss with the patient about diet adjustment, further tick bite avoidance, and treatment plan.Elimination diet could be set upon clinical history and comprises the elimination of all mammalian meats. The patient should be taught on label reading and instructed to avoid meat and by-products, especially internal organs (spleen and liver), which could be used as an ingredient or as delicatessen, and fat by-products . In some cases, it could also be necessary to avoid dairy products .Additional tick bites must be avoided since they could further increase sIgE-α-gal and the risk of allergic reactions to previously tolerated foods. The patient and family should be instructed on clothing type, repellent products, and the recognition and prompt removal of ticks.Regarding treatment, the symptoms, even if delayed, must be treated as in immediate reactions. For mild reactions, oral antihistamine and steroids could be used. For severe reactions and anaphylaxis, auto-injectable adrenaline must be prescribed. An oral desensitization case report  on a 10-Nowadays, there are no prospective studies on AGS natural history. sIgE-α-gal levels often decline spontaneously in those who avoid tick bites . This deThe rarity of AGS, the diagnostic delay, and the possible under-diagnosis of this allergy suggest that more studies are needed. In particular, the following are suggested:- Epidemiological population study - Determination of allergen content in different foods and drugs- Analysis of the molecular mechanisms of delayed timing- Evaluation of allergic co-factors and dose–response effect- Evaluation of the cooking process and the role of other ingredients and environmental factors- Long-term follow-up (feasibility and usefulness of early detection of sensitization)- Evaluation of high-risk patient screening- Standardization of oral provocation test and desensitization protocols- Standardization and data collection on sensitivity and specificity of diagnostic tests in pediatric age.AGS is a rare, atypical, and under-rated allergy, less frequent in childhood but involving those living in tick-endemic areas. Red meat ingestion usually not only causes delayed reactions  but could also lead to severe reactions. Diagnosis relies on clinical history and sIgE-α-gal determination. It is important to evaluate for AGS every patient with a history of idiopathic urticaria or anaphylaxis and unclear allergic reactions with unusual timing or characteristics. More have to be discovered on natural history, but long-term management is based on solely elimination diet and tick bite avoidance.EN conceived the study and supervised it. FS wrote the manuscript. All the authors performed the research, selection of the sources, contributed to the article, and approved the submitted version.The publication fee was financed by the Italian Society of Pediatric Allergy and Immunology. However, no significant funding source could have influenced the outcomes of this work.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.


Veno-arterial extracorporeal membrane oxygenation (ECMO) is increasingly used to treat high-risk pulmonary embolism (PE). However, its efficacy and safety remain uncertain. This retrospective cohort study aimed to determine whether ECMO could improve the clinical outcomes of patients with high-risk PE.Forty patients with high-risk PE, who were admitted to Kaohsiung Chang Gung Memorial Hospital between January 2012 and December 2019, were included in this study. Demographic data and clinical outcomes were compared between patients treated without ECMO (non-ECMO group) and those treated with ECMO (ECMO group). Appropriate statistical tools were used to compare variables between groups and the survival was analyzed using the Kaplan–Meier method.P = 0.023) and lower in-hospital mortality (P = 0.036). A log-rank test showed a significantly higher cumulative overall survival in the earlier ECMO treatment group (P = 0.033).The overall in-hospital mortality rate was 55%, in which 65% (26/40) of patients presented with cardiac arrest with a mortality rate of 77%, which was higher than that of patients without cardiac arrest (14%). There was no significant difference in major complications and in-hospital mortality between the non-ECMO and ECMO groups. However, in subgroup analysis, compared with patients treated without ECMO, earlier ECMO treatment was associated with a reduced risk of cardiac arrest (In this retrospective cohort study, earlier ECMO treatment was associated with lower in-hospital mortality among unstable patients without cardiac arrest. Our findings suggest that ECMO can be considered as an initial treatment option for patients with high-risk PE in higher-volume hospitals. Acute pulmonary embolism (PE) refers to embolic obstruction of the pulmonary artery that may contribute to cardiopulmonary failure and sudden death. High-risk PE, defined as acute PE with sustained hypotension or cardiac arrest, is associated with high mortality, ranging from 25% for patients with cardiogenic shock to 65% for those requiring cardiopulmonary resuscitation (CPR) . The latVeno-arterial extracorporeal membrane oxygenation (ECMO), a temporary mechanical circulatory support device, has been increasingly used over the past 20 years to treat high-risk PE. Several case series studies –8 have dTo date, there has been no case-control or cohort study to evaluate the efficacy and safety of ECMO in patients with high-risk PE. Therefore, the role of ECMO in the management of patients with life-threatening PE remains unclear. This retrospective cohort study was designed to (i) evaluate whether ECMO reduced in-hospital mortality in high-risk PE patients, and (ii) investigate whether earlier ECMO support improved clinical outcomes in patients without cardiac arrest. We hypothesized that the use of ECMO in patients with high-risk PE is associated with better outcomes.This retrospective cohort study was approved by the institutional review board of Chang Gung Medical Foundation (202000715B0). Informed consent was waived because of the retrospective nature of the study.This study was performed at Kaohsiung Chang Gung Memorial Hospital, a tertiary referral teaching hospital in southern Taiwan, with an annual ECMO volume of > 100 cases. We included consecutive adult patients (aged ≥ 18 years) who were admitted to Kaohsiung Chang Gung Memorial Hospital with high-risk PE between January 2012 and December 2019. The diagnosis of PE was confirmed by the presence of thrombus on spiral computed tomography pulmonary angiography (CTPA) examination, and was indicated by (i) right ventricular (RV) overload or the presence of right heart thrombus on echocardiography, and (ii) high clinical probability of PE with confirmation by high probability ventilation/perfusion scan (V/Q scan). According to the European Society of Cardiology guidelines  outcome was in-hospital mortality. Secondary (safety) outcomes were severe neurologic complications, severe kidney injury, major bleeding complications, and major ECMO-related complications. Severe neurologic complications were defined as severe hypoxic ischaemic encephalopathy , seizure, brain hemorrhage, and brain infarction. Severe kidney injury was defined as kidney disease improving global outcomes in stage 3 . Major bt-test or Mann-Whitney U-test, as appropriate. Categorical variables are expressed as numbers (percentages) and were compared using the chi-squared test or Fisher's exact test. Binary logistic regression was used to identify the influence of ECMO on primary and secondary outcomes, and the results are expressed as odds ratios (ORs) with 95% confidence intervals (CIs). The overall survival was analyzed using the Kaplan–Meier method, and differences in survival between groups were examined using the log-rank test. Statistical significance was set at P < 0.05. All analyses were conducted using the SPSS software .Continuous variables are expressed as mean  for normally distributed data, or as median (25–5% interquartile range [IQR]) for non-normally distributed data, and were analyzed using the Student's A total of 40 patients were included in this study , of whomThe prognostic values and management strategies are summarized in P = 0.623) between the non-ECMO and ECMO groups (P = 0.025). In the non-ECMO group, the most common cause of death was unsuccessful resuscitation in six patients, followed by multiple organ failure after successful resuscitation in two patients, and profound cardiogenic shock with multiple organ failure in one patient. In the ECMO group, 12 patients died from CPR-related severe brain injury, of whom 2 had fatal brain hemorrhages and 1 experienced a fatal pulmonary hemorrhage. One severe trauma patient with lung contusion, brain hemorrhage, splenic laceration, and oliguric renal failure died during ECMO support.The overall in-hospital mortality rate for all patients was 55% (22/40). Most deaths occurred in patients who experienced cardiac arrest, with a mortality rate of 77% (20/26), which was higher than that in patients without cardiac arrest . Univariate logistic regression analysis revealed no significant difference in major complications and in-hospital mortality  patients with cardiac arrest had severe hypoxic ischaemic encephalopathy after cardiac arrest, of whom 2 had seizures and 2 had brain hemorrhages. Active bleeding requiring transarterial embolization was documented in two patients who did not receive thrombolytic therapy, and gastrointestinal bleeding requiring transfusion occurred in six patients. Among patients receiving ECMO, major ECMO-related complications occurred in eight  patients, including cannulation site bleeding in seven patients, and leg ischaemia requiring reperfusion cannula placement in one patient see . At discn = 7); early ECMO group (n = 10), which was defined as ECMO initiation at the time of the cardiogenic shock episode; and salvage ECMO group (n = 3), which was defined as ECMO placement for prior cardiac arrest or during CPR. Compared with patients treated without ECMO, earlier ECMO treatment was associated with a reduced risk of cardiac arrest (P = 0.023). In-hospital mortality was also lower in the early ECMO group  (P = 0.033)  patients with sudden cardiac arrest were excluded from the analysis. The enrolled patients were divided into three groups according to the timing of ECMO placement : non-ECM= 0.036) . Further= 0.033) .Based on the Chang Gung Research Database, the largest multi-institutional electronic medical records for real-world epidemiological studies in Taiwan, we enrolled 421 patients with acute PE, of whom 40 were included in this study. The main findings of this study were as follows: (i) PE could rapidly progress to cardiac arrest before initiation of reperfusion therapy; (ii) cardiac arrest as the initial presentation was also common in patients with PE and resulted in poor outcomes, despite performing aggressive treatment; (iii) overall, ECMO treatment showed no survival benefit in unselected patients with high-risk PE; however, it had obvious effect on survival in those without cardiac arrest. Thus, the early use of ECMO in patients at the onset of shock followed by definitive treatment significantly reduces mortality from cardiac arrest and increase the overall survival rate.Over the last two decades, the risk of mortality in patients with acute PE has decreased –14. ThisSeveral problems have not been resolved in real-world clinical practice. First, the proportion of haemodynamically unstable patients treated with thrombolytic therapy is low. Based on two recent nationwide inpatient cohort studies in Germany  and the The mechanism of circulatory collapse and death in PE is acute RV failure. Reducing RV overload is key to reducing early death. ECMO is a rapid and reliable mechanical circulatory support device that decreases RV volume overload , and is Nevertheless, ECMO implantation is an invasive procedure with a risk of adverse events, such as vascular injury during cannulation, limb ischemia, thromboembolic events, bleeding, infection, and rare life-threatening complications, such as great vessel perforation. The most common complication associated with percutaneous ECMO cannulation is limb ischemia, followed by cannulation site bleeding requiring transfusion or repair . In a stTo the best of our knowledge, this is the first cohort study to investigate the influence of ECMO on the survival of patients with high-risk PE. In this study, ECMO treatment showed no survival benefit in PE patients with cardiac arrest, but it showed excellent results in PE patients without cardiac arrest. There is no clinical value in the prediction of cardiac arrest in patients with PE at the onset of shock. Thus, we suggest that ECMO should be initiated as early as possible in high-risk PE patients. However, considering the complications of ECMO, a well-coordinated ECMO team may improve clinical outcomes and reduce ECMO-related complications .This study had several limitations. First, this was a retrospective study, which may have led to a selection bias. ECMO was frequently performed in younger patients who could tolerate major surgery. This group had better functional performance and cardiopulmonary status, which may affect clinical outcomes. Second, because of the limited sample size, statistically significant differences were only hypothesis-generating. We could not exclude type 2 errors, particularly for categorical assessments. Third, our patients were treated in a high-volume ECMO tertiary referral teaching hospital, which may limit the generalisability of our observations. Fourth, only Asian patients were included, which may not represent all high-risk PE cases. Fifth, in our series, treatment with ECMO plus thrombolysis had a lower mortality rate compared with ECMO alone. There is a selection bias due to the fact that additional thrombolysis was frequently performed in patients without experiencing cardiac arrest or CPR-related severe brain injury. In addition, no patient underwent surgical embolectomy may also affect clinical outcomes. Although the data suggest that earlier ECMO treatment for patients without cardiac arrest may result in favorable outcomes, the definitive treatment to achieve best outcomes may not conclude in this study. Prospective, multicentre, large-scale studies could overcome this limitation.In conclusion, in this retrospective cohort study, earlier ECMO treatment was associated with lower in-hospital mortality among haemodynamically unstable patients without cardiac arrest. However, patients with acute PE requiring CPR had an extremely high in-hospital mortality rate, and ECMO treatment showed no survival benefit. Our findings suggest that ECMO can be considered as an initial treatment option for patients with high-risk PE in higher-volume hospitals. Team based approach with well written protocols may improve outcomes for PE on ECMO better.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Institutional Review Board of Chang Gung Medical Foundation (202000715B0). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.Y-YC: conceptualization, formal analysis, writing—review and editing, and supervision. H-YT: methodology. K-RH: software. C-CW and K-RH: validation. H-YT and W-CL: investigation. W-CL, H-TY, and J-JS: resources. Y-TW and C-ML: data curation. H-YT and Y-TW: writing—original draft preparation. W-CL: visualization. Y-TW, H-TY, Y-CC, and J-JS: project administration. 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.