The COVID-19 pandemic led to unprecedented mitigation efforts that disrupted the daily lives of millions. Beyond the general health repercussions of the pandemic itself, these measures also present a challenge to the world’s mental health and health care systems. Considering that traditional survey methods are time-consuming and expensive, we need timely and proactive data sources to respond to the rapidly evolving effects of health policy on our population’s mental health. Many people in the United States now use social media platforms such as Twitter to express the most minute details of their daily lives and social relations. This behavior is expected to increase during the COVID-19 pandemic, rendering social media data a rich field to understand personal well-being.This study aims to answer three research questions: (1) What themes emerge from a corpus of US tweets about COVID-19? (2) To what extent did social media use increase during the onset of the COVID-19 pandemic? and (3) Does sentiment change in response to the COVID-19 pandemic?We analyzed 86,581,237 public domain English language US tweets collected from an open-access public repository in three steps. First, we characterized the evolution of hashtags over time using latent Dirichlet allocation (LDA) topic modeling. Second, we increased the granularity of this analysis by downloading Twitter timelines of a large cohort of individuals  in 20 major US cities to assess changes in social media use. Finally, using this timeline data, we examined collective shifts in public mood in relation to evolving pandemic news cycles by analyzing the average daily sentiment of all timeline tweets with the Valence Aware Dictionary and Sentiment Reasoner (VADER) tool.LDA topics generated in the early months of the data set corresponded to major COVID-19–specific events. However, as state and municipal governments began issuing stay-at-home orders, latent themes shifted toward US-related lifestyle changes rather than global pandemic-related events. Social media volume also increased significantly, peaking during stay-at-home mandates. Finally, VADER sentiment analysis scores of user timelines were initially high and stable but decreased significantly, and continuously, by late March.Our findings underscore the negative effects of the pandemic on overall population sentiment. Increased use rates suggest that, for some, social media may be a coping mechanism to combat feelings of isolation related to long-term social distancing. However, in light of the documented negative effect of heavy social media use on mental health, social media may further exacerbate negative feelings in the long-term for many individuals. Thus, considering the overburdened US mental health care structure, these findings have important implications for ongoing mitigation efforts. Beyond the obvious physical health ramifications of the COVID-19 pandemic, public health and the greater medical community is also bracing for a mental health crisis . Yet, deScientists mobilized quickly to measure many facets of the pandemic, including potential mental health effects. However, the time-consuming and costly nature of survey development  and instIndeed, throughout the COVID-19 pandemic, individuals have sought out crisis-related news at increased capacities , leadingBroadly, this study answers the following three research questions (RQs):RQ1: What themes emerge from a corpus of US tweets about COVID-19?RQ2: To what extent did social media use increase during the onset of the COVID-19 pandemic?RQ3: What patterns emerge from longitudinal tracking of sentiment during the onset of the COVID-19 pandemic?To address these RQs, we analyzed a large-scale set of Twitter data that are strictly relevant to the topic of COVID-19 in the United States from January 22, 2020, onward. Using this data, we also compiled a second corpus of individual geolocated social media timeline data from the same period to understand changes in personal sentiment as a proxy for mental health and evolving US perceptions of the COVID-19 pandemic.topical differences  in the Twitter discussion during the events that marked the onset of the pandemic. The repository provides a list of tweet IDs, which we used to extract tweet content from Twitter’s application programming interface . We downloaded each tweet as well as the standard metadata provided by Twitter. Specifically, we retrieved COVID-19–related tweets posted between January 22, 2020 (first day of data collection and roughly 1 week prior to the first confirmed US COVID-19 case) through April 9, 2020 . Hereafter, we refer to this set of tweets as the “COVID-19 corpus” . Please refer to We collected two distinct data sets, each reflecting different aspects of changes in social media behavior before and during the COVID-19 pandemic. The first data set of tweets, collected from an open-access repository containing all COVID-19–related tweets published in the United States , was desuser timeline data , as shown in To gauge fluctuations of personal activity and mood at the individual  level, we downloaded the Twitter timelines  of individual social media users who contributed to the COVID-19 corpus and resided within the 20 US cities with the most COVID-19 cases per 100,000 people from the Twitter API (end point: GET statuses/user_timeline). These timelines capture the changing behavior and emotions of individual Twitter users during the COVID-19 pandemic but do not strictly pertain to tweets exclusively related to COVID-19. We referred to this data as coronavirus, virus, and the pandemic, the inclusion of those words may not necessarily reflect the individual’s well-being. Note, the resulting sample sizes for each corpora exceeded the mean observed in a recent scoping survey of the literature on social media analytics for public health  [To ensure that we were measuring expressed sentiment in our data, we excluded non-English tweets and, specifically within the user timeline data, retweets and biasing keywords including “coronavirus,” “COVID-19,” and “pandemic,” among others. These words were removed because they inherently carry a negative connotation, and their inclusion would artificially decrease sentiment given that the corpus itself is composed of COVID-19–related content. In other words, because users are naturally tweeting about =20,000) , resulti=20,000)  and how =20,000) . Thus, tLatent Dirichlet allocation (LDA) topic models are unsupervised machine learning tools that perform probabilistic inferences to consolidate large volumes of text data into manageable themes . Simply,virus and its many variations  are not part of the VADER lexicon, meaning changes in the frequency of these words will not bias VADER scores. VADER has been extensively validated for Twitter content [Sentiment analysis refers to a set of supervised or unsupervised machine learning and natural language processing techniques that extract affective or emotional indicators from text . In thi content , showing content .We applied the Pruned Exact Linear Time (PELT) change-point detection algorithm to identify significant changes in tweet volume and sentiment . Change-Hubei and Wuhan were collapsed into the theme China. We then found the frequency ratio  of COVID-19–related themes  and plotted them on a daily basis to show the evolution of topics over time, indicating both the contribution of the theme to all content of that day and the relative ranking of these terms among these themes. We used intercoder agreement methods to arrive at mutually agreeable interpretations of collapsed themes [We divided the COVID-19 corpus into daily segments and generated one topic model per day consisting of 20 topics each. We chose this number to reflect the widest possible span of themes while summarizing the major themes of the online discussion, which is a process used in previous studies ,35. We td themes .most recent postings per individual, we only selected individuals who posted on Twitter before January 22, 2020, retaining 354,738 users. This ensured that our analytic sample captured individual behavior in the 20 most-affected US cities throughout the interval of interest . We performed a seasonal decomposition—a method that separates the baseline, trend, and seasonal components of a time series—to determine whether we can observe increased Twitter use during the pandemic relative to events just prior. We then detected significant points of change using the PELT algorithm [For this analysis we used the user timeline data instead of the general COVID-19 corpus see  because Sentiment can change because individuals discuss different topics  or because of personal, individual changes in how people actually feel. We therefore compared daily VADER sentiment scores for the COVID-19 corpus  and the user timeline within-subjects data  from January 22, 2020  through April 9, 2020. We determined change points in the time series of daily averaged VADER sentiment with the PELT detection algorithm to identify significant changes in sentiment throughout this time period.We consolidated the COVID-19 corpus  into themes using LDA topic models. China became less prominent as more US-centered topics such as “lockdown” and “social distancing” emerged. Although China remained a prominent theme throughout the duration of interest, US-centered topics gradually came to dominate social media spaces.As shown in Using user timeline data, we compared the frequency of social media posts before and during the pandemic of 292,000 users (whose timelines span January 22 onwards) in the 20 most-affected metropolitan cities .Generally, we observed a consistent upward trend in total Twitter volume from early to late March. The PELT change-point algorithm identified two significant volume changes on March 8 and 12, 2020—around the time COVID-19 was declared a global pandemic (March 11) and President Trump declared a national emergency in the United States (March 14). The upward trend stabilized thereafter, albeit at higher observed volumes than prior to the onset of the COVID-19 pandemic. This supports the notion that individuals in our sample were more engaged with social media and made more use of it, possibly to discuss or obtain further information relevant to the news cycle.We applied the VADER sentiment tool to the COVID-19 corpus  and the user timeline data (to track changes in user sentiment using their most recent 3200 tweets). Conversely, the user timeline data (which again contained the most recent 3200 tweets of a given user) showed decreases in sentiment over the same period. The user timeline data had one PELT-identified significant change in sentiment on January 28, 2020 .There was a notable but short-lived drop in sentiment before March 9 (when the WHO classified COVID-19 as a pandemic).The purpose of this study is to draw conclusions about US mental health amid the COVID-19 pandemic using computational social media analytics of a publicly available repository containing all COVID-19–related tweets. Using the COVID-19 tweet repository released by Chen and colleagues , we expanovel coronavirus became coronavirus, COVID-19, and COVID-19 pandemic). The locations that emerged within the topics also corresponded to the movement of COVID-19 from mainland China to the United States. For example, in late January, China was a dominant theme in Twitter content . These findings suggest that, as the COVID-19 pandemic became more prominent in the United States, social media content changed to topics of more direct impact to the United States and with greater frequency of use (evidenced by a PELT-identified significant increase in Twitter volume during that time). This volume increase remained consistently above levels observed prior to the COVID-19 pandemic, which is possibly explained by several factors including increased anxiety as the COVID-19 pandemic reached the United States, the isolating effects of statewide stay-at-home orders, or other social fallouts driven by the pandemic. These findings collectively support those of Castillo and colleagues [Bento and colleagues  predictelleagues , who contopical bias in social media analytics [popular words around a trending topic . Within the VADER lexicon, many of the words commonly used in this context are scored positively , which also artificially inflates sentiment ratings. Thus, we posit that topically driven tweet samples may not validly reflect actual changes in population mood but rather topic-driven language sentiment. This justifies our approach to analyze within-subject timelines of individual posts that are not necessarily bound by the criterion of strictly being COVID-19–related, thereby increasing the odds of reflecting personal changes in mood trajectories.Given the expected negative physical and emotional outcomes of a major pandemic, we were surprised to observe that the sentiment of the COVID-19 corpus trended positively. However, this increase in sentiment is likely not indicative of actual changes in population sentiment but rather the effect of a common nalytics . Our COVnalytics  and shownalytics . Previounalytics . For exalower than it once was. Thus, this comparison gives us deeper insight into underlying mood and sentiment. This finding further supports the assertion that the positivity conveyed in social media posts may not validly reflect what people are feeling at a given moment. Indeed, that positivity may be serving as a veneer posted in the moment to convey positivity during a time of uncertainty. To obtain an accurate assessment of mood and well-being, other reference points  are needed to examine in-the-moment sentiment relative to their prior histories. Within our timeline data, we captured one event that occurred prior to the pandemic that also affected sentiment scores relative to timeline histories—the passing of NBA basketball player Kobe Bryant. The effect of Bryant’s passing led to a sharp decline in sentiment, which lasted approximately 24 hours before returning to levels observed previously. Regarding the pandemic, after the PELT-identified shift on March 8, 2020, sentiment scores (relative to timelines) became not only lower but also consistently lower and did not return to levels observed before the pandemic reached the United States. This trend may hold implications into the longitudinal effects of the pandemic and subsequent impacts on US mood and social sentiment, as this continued trend may be indicative of a long-lasting shift in mood and well-being.By contrast, we found a negative trajectory in sentiment scores for the user timeline data. This means that, although content in the COVID-19 corpus trended positively (possibly due to priming), relative to the totality of their timelines, our sample mood was Analyses of aggregated social media feeds are shown to adequately predict other phenomena including the stock market ; politicAt the time of writing, the US COVID-19 death toll was just over 136,000, with the lives of millions of people disrupted by the various effects of the pandemic. This study elucidates the possible mental health effects of the COVID-19 pandemic among Twitter users using a computational approach to analyze a corpus of all archived US-based COVID-19 tweets from January to April 2020. These analyses revealed, to varying extents, how the pervasiveness of COVID-19 content available on social media and abrupt shift in lifestyles may be negatively affecting social sentiment relative to points just prior to the pandemic. Given that sentiments expressed on social media have been used as a proxy for mental well-being , these fpossibility of mental health decline based on average sentiment scores [Our study is subject to limitations. Twitter requires users to opt in to geotagging features. Consequently, any information inferred about the user’s city of residence is often limited to self-reported data as specified on profile pages. This means that some of our timeline data may not originate from the city specified by a user, as this information can easily be misrepresented  (eg, stat scores . Howevert scores ,18, we c


Even though severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed to principally affect the respiratory system, neurological involvements have already been reported in some published work. We have reviewed original articles, case reports, and existing open-source data-sets to delineate the spectrum of neurological disorders potentially observed in SARS-CoV-2 positive cases. Neurological involvement in coronavirus disease 2019 (COVID-19) corresponds to three situations: (a) neurological manifestations of viral infection, (b) post-infective neurological complications, and (c) infection in patients with neurological co-morbidity. Neurological manifestations can further be subdivided into the central nervous system  and peripheral nervous system  symptomatology. Post-infective neurological complications include demyelinating conditions. Reduced mobility and dementia as co-morbidities may predispose a patient to have a viral infection. It is concluded that the pandemic of COVID-19 presents for a neurologist some unique challenges. We observe that SARS-CoV-2 may have various neurological manifestations and in many cases, neurological features may precede typical respiratory symptoms. Coronavirus disease 2019 (COVID-19) has been declared a pandemic on the 11th of March, 2020 by the World Health Organization. The epicenter of this pandemic has shifted in quick succession from China to Europe to the United States of America in a matter of weeks. Since the middle of March 2020, South-east Asia has also seen a rise in the number of affected persons and it remains to be seen if there will be another twist in the story of this pandemic. One of the essential weapons to fight a pandemic of this stature is to gather as much knowledge as possible about the transmission dynamics and clinical manifestations while the quest for an effective vaccine keeps continuing.Even though severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed to mainly affect the respiratory system, neurological involvements have already been reported in some published work. Several medical news bulletins, blogs, and articles across the globe have also raised concerns about brain invasion by this particular strain of coronavirus. This is actually not surprising given our previous experience of neuro-invasion by severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome-related coronavirus (MERS-CoV). The body of literature on neurological aspects of SARS-CoV-2 is small but growing. However, we believe, an organized summary of the available information at this point would be indispensable to neurologists across the globe. Being well informed about the neurological presentations would not only help them have a high index of clinical suspicion but also take necessary precautions. Therefore, a brief literature review along with a critical appraisal of the evidence gathered so far is presented here from the perspective of a neurologist.In the present paper, we have reviewed the recently published or pre-print original articles, case reports, and existing open-source data-sets in order to delineate the spectrum of neurological disorders in SARS-CoV-2 positive cases.Mechanism of neuro-invasionThe putative mechanisms described to explain the neuro-invasion by a coronavirus  are hematogenous spread and retrograde axonal transport -4. HowevClassification and features of neurological involvementEarly data on COVID-19 suggest neurological involvement in a variable percentage of cases with particular expression in more severe patients . NeuroloNeurological features of viral invasionNeurological manifestations of viral infection reported so far can further be subdivided into CNS and peripheral nervous system (PNS) features. CNS features include headache, dizziness, ataxia, alteration of sensorium, encephalitis, stroke, and seizures, while PNS features mostly refer to skeletal muscle injury and peripheral nerve involvement in the form of hyposmia and hypogeusia.Headache can be a symptom of viral infection and usually remains associated with fever. Studies have reported an incidence of headaches ranging from 6 to 13% in COVID-19 cases -13. HoweAnother noteworthy observation is the occurrence of cerebrovascular events (CVE) associated with this ailment. The initial retrospective case series study from Wuhan, China, reported that 5.7% (5/76) of the cases showing neurological involvement could be attributed to acute CVE . NotablyImpaired consciousness has so far been reported in 7.5% hospitalized patients of COVID-19 . SeverelIn the Wuhan study, ataxia was found in only one patient, although a detailed description or anatomical substrate of this particular symptom was not available in this paper . We at oThe association of seizure and COVID-19 can be multi-faceted. An early report suggested a very low incidence (0.5%) of seizure disorder . HoweverSymptoms of skeletal muscle damage often associated with liver and kidney involvement have already been noted. The reported incidence is 10.7%, and like other neurological features, this one is also associated with a severe form of the illness [It has been reported that hypogeusia, as well as hyposmia, are fairly consistent symptoms of SARS-CoV-2 infection , 19. HypPost-infective neurological complicationsWith more number of patients recovering from the SARS-CoV-2 infection, it is imperative that post-infective complications would draw attention with time. CNS demyelinations have been documented previously following coronavirus infection . An earlAnother report from China describes a case of acute myelitis, possibly affecting the cervical spinal cord, as evidenced by the clinical features, in a known patient of SARS-CoV-2 infection . In thisPatients with neurological co-morbidityDuring this hour of the pandemic, another group of patients will deserve the attention of neurologists. This group comprises of neurologically ill patients who have already been in follow-up for some time. The need for different groups of patients will vary according to the nature of their illness. Data is insufficient at this point in time to conclude if chronic neurology patients are more predisposed to acquire infection. However, patients with reduced mobility and those on immune-suppression therapy may be anticipated to be more susceptible to infection.Recent correspondence has already discussed the challenges that will be faced by dementia patients during this period of social distancing and home isolation . ObviousContemporary neurology has seen wide use of immune-suppressive agents to combat several disorders of both CNS and PNS. The prototypical among these disorders is multiple sclerosis that calls for long term immunosuppression. The data so far on COVID-19 reveals that old age, as well as immune-dysregulated subjects, are more likely not only to acquire the infection but also to manifest increased severity. Therefore, similar to the oncology ward, patients in the neurology ward admitted receiving cyclic immunosuppressive drugs need attention. Appropriate caution has to be practiced while dealing with such cases both from the part of the neurologist as well as the patient's relatives. A recent article on this topic recommends that the benefits of continuing immunotherapy in patients with multiple sclerosis (MS) and related disorders may outweigh the risks of medication withdrawal in the apprehension of COVID-19. This is particularly because most infections, as in the general population, are anticipated to be mild an2d self-limiting. However, the authors emphasize the need for individualized decision-making in such circumstances because one size" may not fit all, and some of the patients may land up in severe infection leading to discontinuation of therapy . Long term impactWith the growing number in recovery from SARS-CoV-2 infection, rehabilitation issue is supposed to become a crucial one. Personal communication with neurologists working in the field in Italy reveals that there is early evidence for the need for rehabilitation, including neurological aspects, in clinically recovered patients. It can be assumed that the psycho-social effects of long term social distancing and home isolation will require adequate psychological rehabilitation measures as the pandemic will start waning off.Since the onset of the SARS-CoV-2 outbreak, if there is one pulmonary manifestation that has received maximum focus, it is ARDS. Evidence suggests a significant percentage of ARDS survivors may suffer long-term cognitive impairment . SeveralOver time, the need to raise awareness among the neurologists is being increasingly recognized. The case record protocol for "First Few Cases (FFX) and their close contacts" published by WHO has a separate column to mention the neurological findings in addition to respiratory signs and symptoms . This unThe pandemic of COVID-19 presents for a neurologist some unique challenges. We observe that SARS-CoV-2 may have various neurological manifestations, and in many cases, neurological features may precede typical respiratory symptoms. Holistic knowledge of the spectrum of neurological consequences of COVID-19 is important to get a hold on the spread of the virus. The most vital clinical information which we gather is that impaired consciousness may be a presenting feature of COVID-19, and therefore, a high index of suspicion for such patients will be the key to prevent or, at least, lessen exposure to health care providers and other patients. With the gradual subsidence of the outbreak, it can be anticipated that several post-infectious complications will surface up while rehabilitation measures will also deserve attention. Adequate caution has to be practiced while managing chronic neurology patients, particularly those requiring immune-modulator therapy since formulated guidelines are lacking at this point. The above summary of the neurological manifestations of COVID-19 will help neurologists have a basic preparation, which is of utmost importance to prevent horizontal infections.


A 60-year-old man suffering from recurrent attacks of yawning-fatigue-syndrome, triggered by mild exercise of his right leg since a temporary lumbar disc herniation 9 years ago, was initially treated with the oral µ-opioid-receptor agonist tilidine before each bout of exercise . During the first few months, this treatment continuously prolonged the time without exercise-triggered yawning and fatigue. In the next few months of treatment, exercise was increased in a graded manner to alleviate the yawning-fatigue-syndrome. The number of repetitions of the physical exercises was gradually increased without taking the opioid beforehand. After several months, almost the same effort level without medication could be achieved by graded activity as before under the influence of opioid medication. Graded physical activity can thus disrupt complex pathophysiological mechanisms leading to yawning and fatigue. We recently described the case of a 60-year-old man who had recurrent attacks of yawning followed by severe fatigue initiated by relatively mild exercise of his right leg . A firstDopamine elicits yawning through activation of D3 receptors in the hypothalamic paraventricular nucleus, whereas opioid agents inhibit yawning through activation of µ-opioid receptors in the paraventricular nucleus ,3,4. OurThe yawning-fatigue attacks in the case of the 60-year-old man began a few months after a herniation of the L4-5 disc that, 9 years ago, affected the right L4 root A even thIn the first 4 months of treatment, tilidine was applied 30 min before each bout of exercise. Application of the opioid increased the period of low-resistance exercise on a bicycle ergometer without attacks from half a minute to more than 10 min. Moreover, higher efforts of the trunk and extremity muscles, especially of the right leg, were possible without triggering yawning and fatigue. The patient’s graded activity program focused primarily on the load on his right leg and the adjacent trunk. During these 4 months, higher weights could be increasingly applied when rotating and stretching the trunk (see the insert images in The final aim of the therapy was to enable the patient to perform appropriate strains of his right leg without the need of preceding opiate administration. The therapeutic technique of graded activity  was subsIn the present case, graded physical activity was successfully used for the treatment of a yawning-fatigue-syndrome. As before, under the influence of opioid medication, physical activity could be gradually increased. Thus, graded activity could replace the drug therapy, a rarely described change in the therapeutic regime.Graded activity programs have been shown to be an effective therapy for a variety of patients, such as those with chronic low back pain . CompareSignificant advances in understanding the genesis of yawning have not yet fully elucidated its physiological role ,15. The Alternative mechanisms should be considered. Yawning has been shown to act as a compensatory brain cooling mechanism ,22. GradIn a rare case of recurrent attacks of yawning and subsequent severe fatigue, triggered by mild exercise of the right leg, graded physical activity treatment has been shown to be a suitable therapy option for decoupling yawning-fatigue from physical exercise. The precise mechanisms remain to be elucidated.


Pharmaceutical therapies are essential for esophageal cancer (EC). For the advanced EC, the neoadjuvant therapy regimen, including chemotherapy plus radiotherapy and/or immunotherapy, is effective to achieve clinical benefit, even pathological complete response. For the unresectable, recurrent, and metastatic EC, the pharmaceutical therapy is the limited effective regimen to alleviate the disease and prolong the progression-free survival and overall survival. In this review, we focus on the pharmaceutical applications in EC treatment including cytotoxic agents, molecular targeted antibodies, and immune checkpoint inhibitors (ICIs). The chemotherapy regimen is based on cytotoxic agents such as platinum-based complexes, fluorinated pyrimidines and taxenes. Although the cytotoxic agents have been developed in past decades, the standard chemotherapy regimen is still the cisplatin and 5-FU or paclitaxel because the derived drugs have no significant advantages of overcoming the shortcomings of side effects and drug resistance. The targeted molecular therapy is an essential supplement for chemotherapy; however, there are only a few targeted therapies available in clinical practice. Trastuzumab and ramucirumab are the only two molecular therapy drugs which are approved by the US Food and Drug Administration to treat advanced and/or metastatic EC. Although the targeted therapy usually achieves effective benefits in the early stage therapy of EC, the patients will always develop drug resistance during treatment. ICIs have had a significant impact on routine clinical practice in cancer treatment. The anti-programmed cell death-1 monoclonal antibodies pembrolizumab and nivolumab, as the ICIs, are recommended for advanced EC by several clinical trials. However, the significant issues of pharmaceutical treatment are still the dose-limiting side effects and primary or secondary drug resistance. These defects of pharmaceutical therapy restrain the clinical application and diminish the effectiveness of treatment. Esophageal cancer (EC) is a global health challenge. It ranks the seventh most common cancer incidence and the sixth most common cause of cancer-related death worldwide . The hisThe treatment regimen for EC is dependent on the general status of patient and the tumor stage, mainly the TNM stage . PatientMost patients seek medical attention because of a period of progressive dysphagia , therefoAlthough the overall survival of EC has improved in the past decades because of medicine development , the oveFor EAC, the FLOT regimen including docetaxel, oxaliplatin, leucovorin, and fluorouracil is recognized as the standard perioperative chemotherapy regimen. The regimen including cisplatin and fluorouracil is the alternative treatment while the FLOT regimen should not be implemented . For ESCcis-dichloro-diammine-platinum (II) is the representative drug of platinum complex. It was first used to a cancer patient in 1971 (Cisplatin or  in 1971 . Since t in 1971 . However in 1971 .2X2] and platinum-based complexes (IV) structure has been summarized as [PtA2X2Y2]. In these chemical structures, the Pt means metal platinum, the A2 mean two monodentate or one bidentate amine ligand, the X2 mean two monodentate or one bidentate anionic ligand and the Y means hydroxo, chloro, or carboxylato , the tumor microenvironment (TME) , cancer-associated fibroblasts (CAFs), and epigenetic regulation  and taxanes (paclitaxel or docetaxel).4H3FN2O2. It was first synthesized as the antitumor agent in 1957 by modified a pyrimidine chemical uracil, in which the hydrogen at the carbon-5 position of the pyrimidine ring was replaced by a fluorine atom (5-Fluorouracil (5-FU) is the representative drug of fluorinated pyrimidine, the chemical formula of which is Cine atom .de novo thymidylate pathway undergo thymineless death  . The 5-FAutophagy and many signaling pathways also affect antitumor activity of 5-FU. Previous study has showed that inhibiting autophagy activity could enhance antitumor activity of 5-FU in colorectal cancers . Many si2+-activated G protein-coupled calcium-sensitive receptor (CaSR)  have failed to improve outcomes for patients with metastatic colorectal cancer . The DPDr (CaSR) . However47H51NO41.Taxanes are naturally occurring compounds and belongs to genus of Taxus. Paclitaxel (PTX) is a key member of taxane family and is a semisynthetic plant alkaloid that restabilizes the microtubule cytoskeleton against depolymerization . PTX hasMicrotubules are the key members of the cytoskeleton, which play a notable role in various biological processes including maintenance of cell shape, molecular signaling pathways, conducing to the transportation of cell organelles, and production of the mitotic spindle to ensure the progression of the cell cycle . PTX hasAlthough the taxanes are highly active cytotoxic antitumor drugs, the serious adverse drug reactions and emergence of drug resistance still affect the clinical application.The effects of antitumor activity could enhance in relation to drug dose increasing, however, the dose increasing not only promotes the drug’s effectiveness but also increases cytotoxicity . The comA lot of molecular pathways and mechanisms are involved in the taxane resistance of cancer cells. Among the molecular mechanisms, autophagy is the most widely known mechanism related to PTX resistance. A study showed that the inhibition of autophagy can enhance antitumor activity of PTX. The self-digestion mechanism can stimulate cancer cells resistance into PTX chemotherapy. In this progress, non-coding RNAs is the most common molecular pathway that dually mediate or inhibit PTX resistance . IntegriTo overcome the drug resistance and dose-limiting side effects, many studies have been proceeding. Many plant derived natural compound such as nobiletin , quercetFor both EAC and ESCC, either adjuvant or neoadjuvant chemotherapy was proven to be superior to surgery alone in overall survival . For theTo overcome these limited therapeutic options and promote overall survival and quality of life, the personalized targeted therapies are designed based on the molecular characterization of EC .Despite the EC being mostly categorized into ESCC and EAC, the treatment options are largely similar both in the different histological types . HoweverThe molecular characterization of EAC is divided into four etiological/genetic subtypes based on gastric adenocarcinoma molecular characterization classification : (1) EBVDespite the ESCC and EAC being similar to the responsiveness of chemotherapeutic agents, ESCC is significantly distinct from EAC at the genomic level . HoweverN-methyl-N0-nitroso-guanidine human osteosarcoma transforming gene)  signaling or receptor tyrosine kinases (RTK), such as the EGFR, erb-b2 receptor tyrosine kinase 2 (ERBB2 or HER2), and MET (ng gene)  (Ilson ang gene) .It is estimated that about 15–20% of advanced gastric and gastroesophageal junction (GEJ) cancers have overexpression or amplification of HER2  and 12–4Cetuximab, as an anti-EGFR monoclonal chimeric antibody, is proven useful for head and neck cancers and colorectal cancer with the wild-type RAS gene. A phase 2 clinical study showed that cetuximab can be safely combined with standard chemotherapy and may increase the overall response rate, median progression-free survival, and median overall survival in advanced ESCC . MoreoveGefitinib is EGFR tyrosine kinase inhibitor and a phase 3 trial did not show overall survival benefits for previous treated advanced EC including squamous-cell cancers .Lapatinib is a dual EGFR and HER2 tyrosine kinase domain. Some studies showed that the lapatinib combined with chemotherapy were efficacious for advanced ESCC . HoweverNimotuzumab is a recombinant humanized monoclonal antibody. It inhibits the EGFR-dependent intracellular signaling pathway via binding to the extracellular domain of EGFR . Many phPanitumumab as an anti-EGFR antibody did not promote survival for first-line chemotherapy for gastroesophageal adenocarcinomas in a phase 3 trial (REAL3) . MoreoveTrastuzumab is a recombinant humanized monoclonal antibody directed against HER2. In a phase 3 trial (ToG A), It was approved for the first-line treatment combined with chemotherapy for the metastatic, gastric, or GEJ cancers which have HER2 overexpression . HoweverVEGFR inhibitors are largely used in gastrointestinal cancer including gastric and GEJ adenocarcinomas .Bevacizumab is a monoclonal antibody targeting VEGF-A which is mediated by two tyrosine kinase receptors, VEGFR-1 and VEGFR-2. Although it is an efficient treatment for several malignancies in combination with chemotherapy including colorectal cancer and lung cancer, it was not proven superior in overall survival time compared to chemotherapy for advanced gastric or GEJ adenocaecinoma (AVAGAST) .Nintedanib is a multikinase inhibitor that potently inhibits VEGFR1-3, FGFR1-3, and PDGFRa/b. A phase 2 trial showed that nintedanib did not have significant benefits in disease progression of first-line chemotherapy or metastatic esophagogastric adenocarcinoma compared with VEGFR2 inhibition alone and it has no value for the further development of EC .Ramucirumab is a fully humanized monoclonal antibody and is designed to inhibit VEGFR-2 via ligand binding which prevents VEGF ligands binding to VEGFR-2 epitopes . A doublMET is a proto-oncogene which encodes a receptor tyrosine kinase c-MET. Activation of c-MET is ordinarily indispensable to cell function such as morphogenesis, scattering and motility, cell proliferation, and protection from apoptosis . RilotumDespite recent advances in genomic drivers of EC, there are only few targeted therapies available in clinical practice. Trastuzumab, ramucirumab, and pembrolizumab are the only three molecular therapy agents approved by the US Food and Drug Administration (FDA) for treatment of advanced and/or metastatic ECs .Although targeted therapy is better tolerated than traditional chemotherapy, it does produce toxicity based on several main mechanisms. The common side effects include hypertension, rash, diarrhea, hypothyroidism, proteinuria, depigmentation, and hepatotoxicity. Either antibodies or small molecular kinase inhibitors, the same target may have similar side effects. VEGFR kinase inhibitors usually cause hypertension and EGFR antibodies and kinase inhibitors usually cause rash .The intratumoral, intermetastatic, intrametastatic, or interpatient heterogeneities are related to various combinations of drivers and pathways. These heterogeneities may explain how the different patients have different treatment responses and even resistance under the same treatment and the favorable response patients initially could develop resistance over time . It is cIn vitro, trastuzumab has been shown to induce autophagy and the basal autophagy of cell line which present intrinsic or acquired resistance to trastuzumab are increased  pathway activation was considered to be one of the mechanisms related to various targeted therapeutic resistance including EGFR TKIs . The FGFAdditional mutations in receptor tyrosine kinases, RAS, and PI3K pathways appear to the mechanism of both intrinsic and acquired resistance to HER2 inhibitor. For patients with these co-alterations, there is a lower benefit from trastuzumab treatment and it has a shorter progression-free survival . The comIn a short, although molecular-targeted therapy is widely used in other solid tumors such as breast, leukemia, colorectal, lung, and ovarian cancers , it has Immunotherapy has entered a new era in cancer treatment . A lot o+ T cells. PD-L1 is also expressed on the surface of non-professional APCs which present antigen to cytotoxic CD8+ T cells (Programmed cell death-1 (PD-1) was first identified in 1992 and also called CD279 . PD-1 is T cells .The PD-1/PD-L1 pathway has a role in promoting mechanisms of tumor immune evasion. This is the theoretical basis of the development of monoclonal antibodies targeting either PD-1 or PD-L1. The block of the binding of PD-1 and its ligands has the potential to make tumor cells exposure to the immune regulatory activity of effector T cells and resume an effective antitumor immune response  Sharpe .The efficiency of the PD-1/PD-L1 inhibitors is associated with the PD-L1 expression and/or tumor mutation burden (TMB) in tumor cells . For EC,Pembrolizumab is a fully humanized IgG4-k monoclonal antibody which is potent and highly selective against PD-1 . In manyNivolumab is a high-affinity, humanized IgG4 monoclonal PD-1 antibody . Many clThere are many clinical trials in progress for other anti-PD-1 antibodies, such as tislelizumab , atezoliIn short, for metastatic or recurrent ESCC patients, ICIs such as pembrolizumab and nivolumab are standard treatment for second-line chemotherapy . HoweverThere are still many questions and important challenges to conquer in ICIs application . FirstlyThe mechanism of ICIs resistance has not been fully elucidated. One cause of it may be related to the heterogeneity of the tumor process and the essence of it is the tumor immune escape. Generally, the drug resistance of ICIs is considered to involve in the interaction of internal and external factors between tumor cells and immune cells within the tumor and the interaction may present a dynamic multilevel change process . The tumThere are many cancer cell alteration processes related to intrinsic resistance. One of them is the alteration of antigen presentation which affects the immune recognition. The surface of tumor cells often present loss or down-regulation of the major histocompatibility complex class I molecules (MHC-1), and this is suggested to be a mechanism of immune escape of the tumor . Every tThere are many gene expression mutations which affect immune response . Loss ofThe DNA damage responses also affect the treatment benefits. Many studies suggest that DNA repair plays an important role in driving sensitivity and response to ICIs . Many reThe expression of different checkpoints to prevent T-cell activation leads to secondary resistance. Single antagonistic PD1/PDL1 pathway has limited function in improving immune cells and is prone to drug resistance . Besides+ regulatory T (Treg) cells is one of the most common immune-suppressive cells in tumors and a highly immune-suppressive subset of CD4+ T cells that maintain immune homeostasis. It can suppress antitumor immunity and promote cancer progression  partly mediated profound immunosuppression in a number of patients which do not respond to immunotherapy. The heterogeneous population of immature myeloid cells can significantly inhibit anti-tumor activities of T and NK cells and stimulate Treg cells, which leads to tumor progression . Activat T cells .+ T cells (Tumor-associated macrophages (TAM) represents immune suppressor cells in the solid tumors that restrict anti-tumor immune reaction induced by CD8 T cells . While t T cells .Pro-inflammatory cytokines such as Interferon-α, Interleukin-2, TNF-α, TGF-β et al. can contribute to cancer immunotherapy, acting on every phase of the cancer immunity cycle . The cel+ tumor-infiltrating lymphocyte in resected ESCC. The results showed that positive LAG-3 expression was significantly correlated with positive CTLA-4 expression and poor prognosis in ESCC (+ NK cells correlated with the poor prognosis. Moreover, IL-6 can induce CD39 expression and CD39+ NK cells presented an exhausted phenotype (Although many mechanisms are assumed to be associated with immunotherapy resistance, it is difficult to get a universal biomarker for resisting drug resistance . Similar in ESCC . The poshenotype . BecauseThe pharmaceutical therapies are essential for EC. For the advanced EC, the neoadjuvant therapy including chemotherapy plus radiotherapy and/or immunotherapy is effective to achieve clinical benefit and even pathological complete response. For the recurrent, unresectable, and metastatic EC, the pharmaceutical therapy is a limited effective regimen to alleviate the disease and prolong the PFS and OS.The regimen of platinum complexes plus fluorinated pyrimidines or taxanes is still the first-line therapy for EC. Although the targeted therapies are effective on other solid tumors such as non-small cell lung cancer, especially adenocarcinoma, the molecular targeted therapy for EC is not as effective as expected and only approved as a second-line therapy by the FDA. Furthermore, the targeted therapeutic effect in EAC is more effective compared with that in ESCC. Immunotherapy has entered a new era in cancer treatment. The ICIs are proven to provide a significant benefit in many malignant tumors compared to traditional therapy and will become the mainstream pharmaceutical therapy for the unresectable and progressive or metastatic EC. Compared to EAC, the ESCC receive more effective benefits from ICIs.However, the significant issues of pharmaceutical treatment are still the dose-limiting side effects and primary or secondary drug resistance. Despite the fact that the mechanisms of drug resistance have achieved many profits, the dose-limiting side effects and drug resistance still restrain the clinical application and diminish the effectiveness of pharmaceutical treatment.CM and XZ contributed to the conceptual idea, reviewed, analyzed the literature, and wrote the manuscript. XX and SL assisted in compiling background material. YuY and CZ edited the manuscript and provided the suggestions for the revision of the manuscript. YZ and YoY provided the conceptual idea, analyzed the literature, and reviewed and edited the manuscript. All the 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.


Moreover, the well-known SARS-CoV receptor (ACE2) might be a putative receptor for the novel virus as well. Actin protein was also suggested as a host factor that participates in cell entry and pathogenesis of SARS-CoV-2; therefore, drugs modulating biological activity of this protein (e.g. ibuprofen) were suggested as potential candidates for treatment of this viral infection. Additional results indicated that civets and poultry are potential candidates for the natural reservoir of the SARS-CoV-2, and that domain 288-330 of S1 protein from the SARS-CoV-2 represents promising therapeutic and/or vaccine target.A novel coronavirus recently identified in Wuhan, China (SARS-CoV-2) has expanded the number of highly pathogenic coronaviruses affecting humans. The SARS-CoV-2 represents a potential epidemic or pandemic threat, which requires a quick response for preparedness against this infection. The present report uses the informational spectrum methodology to identify the possible origin and natural host of the new virus, as well as putative therapeutic and vaccine targets. The performed However, many questions about SARS-CoV-2 remain unanswered: (i) what is the origin and/or natural reservoir of the virus? (ii) is it easily transmitted from human to human? and (iii) what are the potential diagnostic, therapeutic and vaccine targets? Currently, only nucleotide sequences of eight human SARS-CoV-2 isolates are available without any additional information about biological properties of the virus, beyond the morphological confirmation of the virion using electronic microscopy. This is likely not enough information to answer the important abovementioned questions.Fears are mounting worldwide over the cross-border spread of the new coronavirus (denoted as SARS-CoV-2) that originated in Wuhan, the largest city in central China, after its spread to many countries around the world. The newly emerging pathogen belongs to the same virus family as the deadly severe acute respiratory syndrome and Middle East respiratory syndrome coronaviruses . The World Health Organization (WHO) has1. For this reason, ISM was previously used for analysis of novel viruses for which little or no information were available5. Here, the SARS-CoV-2 was analyzed with ISM to identify its possible origin and natural host, as well as putative therapeutic and vaccine targets.The informational spectrum method (ISM), a virtual spectroscopy method for analysis of proteins, is based on the fundamental electronic properties of amino acids and requires only nucleotide sequence availability to investigate proteinsGISAID database , were analyzed by ISM. The studied sequences were BetaCoV/Wuhan/IVDC-HB-04/2020, BetaCoV/Wuhan/IVDC-HB-01/2019, BetaCoV/Wuhan/IVDC-HB-05/2019, BetaCoV/Wuhan/IPBCAMS-WH-01/2019, BetaCoV/Wuhan/WIV04/2019, BetaCoV/Wuhan-Hu-1/2019, BetaCoV/Nonthaburi/61/2020, and BetaCoV/Nonthaburi/74/2020.The S1 surface protein sequences from the first 8 human SARS-CoV-2, deposited in the publicly availableGISAID database); and (ii) S1 proteins from three first isolated human MERS-CoV: AGG22542, AFS88936, AFY13307, deposited in the GISAID databaseIn the phylogenetic analysis, different amino acid sequences of other coronaviruses were also included: (i) S1 proteins from the following viruses: AVP78042, AVPvp78031, AY304486, AY559093, JX163927, YN2018B, KY417146, used already by other authors in the study of the phylogenetic relationship between SARS-CoV-2 and nearest bat and SARS-like CoVs  are transformed into signals by assignment of numerical values of each element (amino acid or nucleotide). These values correspond to electron-ion interaction potential6, determining electronic properties of amino acid/nucleotides, which are essential for their intermolecular interactions. The signal obtained is then decomposed in a periodical function by the Fourier transformation. The result is a series of frequencies and their amplitudes. The obtained frequencies correspond to the distribution of structural motifs (primary structure) with defined physico-chemical characteristics responsible for the biological function of the putative protein corresponding to the analyzed sequence. When comparing proteins that share same biological or biochemical function, the technique allows detection of code/frequency pairs that are specific for their common biological properties. The method is insensitive to the location of the motifs and, therefore, does not require previous alignment of the sequences. In addition, this is the only method that allows immediate functional analysis.Detailed description of the sequence analysis based on ISM has been published elsewhere7. In the presented analysis, we calculated the distance matrix with the amplitude on the frequency F(0.257) as the distance measure between sequences.The phylogenetic tree of S1 proteins from coronaviruses was generated with the ISM-based phylogenetic algorithm ISTREE, previously described in detail elsewhereIn order to compare informational similarity between SARS-CoV-2, SARS-CoV, MERS-CoV and Bat SARS-like CoV, the cross-spectra (CS) of S1 proteins from these viruses were calculated.https://platform.gisaid.org/epi3/frontend#lightbox1296857287).To confirm this conclusion, the ISM-base phylogenetic tree for S1 proteins was calculated . In this8. The ISM analysis showed that the frequency component F(0.257) is present in the CS of S1 SARS-CoV and its receptor angiotensin converting enzyme 2 (ACE2)9, but not in the CS of S1 MERS-CoV and its main receptor dipeptidyl peptidase 4 (DPP4)10. Of note is that both receptors ACE2 and DPP4 are expressed in airway epithelia. Presence of F(0.257) in the informational spectrum of MERS-CoV  correspond to ACE2 from civet and chicken. This result indicates that these species can be included as potential candidates for the natural reservoir of the SARS-CoV-2. However, it is possible that SARS-CoV-2 viruses use very different receptors in the natural host(s) and not only the ACE2 as it is the putative case in humans. An experimental study performed on chicken, however, indicated lack of susceptibility of this species to the novel virus13; civets so far have not been tested, but the indicated study confirmed susceptibility of domestic cat to SARS-CoV-2.As it is shown inFinally, the S1 amino acid sequence from the SARS-CoV-2 was scanned to look for the domain that gives the highest contribution to the information represented by the frequency F(0.257) . This anFurther, S1 spike proteins from SARS-CoV  and SARShttps://www.uniprot.org) was screened by ISM for human proteins with the dominant peak on the frequency F(0.478). The list of human proteins that have a dominant peak in IS at the frequency F(0.478) are given in14. Actin proteins were selected as the best candidate interactors for the SARS-CoV-2 among the host proteins that are characterized with frequency F(0.478).To identify the host proteins involved in the attachment and/or internalization of the SARS-CoV-2, the UniProt database (www.ncbi.nlm.nih.gov/pubmed/) also showed that actin protein plays an important role in the rapid virus cell-to-cell spread and dissemination of infection15. Additionally, the actin filament reorganization is a key step in lung inflammation induced by systemic inflammatory responses caused by infectious agents16. These findings indicate that interaction between actin proteins and the S1 could be involved in the infection and pathogenesis of SARS-CoV-2. In consequence, the possibility to interfere on this interaction might represent a valid hypothesis for development of promising prevention and therapeutic strategies.The data mining of the PubMed database  attenuates interleukin-1β-induced inflammation as well as actin reorganizationIn silico methods are considered very important tools to generate first hypotheses and identify first drug candidates against newly discovered agents, like in the case of SARS-CoV-2, especially in the short-term. ISM, a technology based on electronic biology, allowed identifying potential importance of human actin proteins for viral infection/dissemination as well as one FDA approved drug that may have an indirect antiviral activity within weeks of the initial outbreak. However, additional experiments are required to confirm our initial findings.in silico analysis suggest the following: (i) the newly emerging SARS-CoV-2 is highly related to SARS-CoV and, to a lesser degree, MERS-CoV, and ACE2 is a likely receptor of it; (ii) civets and poultry are potential candidates for the natural reservoir of the SARS-CoV-2, (iii) human actin proteins possibly participate in attachment/internalisation of SARS-CoV-2, (iv) drugs which interact with actin proteins  should be investigated as possible therapeutics for treatment of SARS-CoV-2 infection, and (v) domain 266-330 of S1 protein from the SARS-CoV-2 represents promising therapeutic and/or vaccine target. Further research on these issues are needed, including the development of reverse genetics and animal models to study the biology of SARS-CoV-2. Due to the fast evolving of scientific knowledge on SARS-CoV-2, the first prediction has been already confirmed, while the chicken as potential candidate as intermediate host has not been supported. Importantly, link between ibuprofen/actin interactions and viral entry remains an exciting path for future therapeutic investigations.In conclusion, results of the presentedGISAID EpiFlu™ Database. To access the database each individual user should complete the “Registration Form For Individual Users”, which is available alongside detailed instructions. After submission of the Registration form, the user will receive a password. There are not any other restrictions for the access to GISAID. Conditions of access to, and use of, the GISAID EpiFlu™ Database and Data are defined by theTerms of Use.Sequence data of the viruses were obtained from the It is unclear which new data demonstrate that actin is an important new therapeutic and preventing target for COVID-19 disease. Is it the data referred from other authors? The cross-spectra frequency of .478 of Mammalian Actin and SARS-CoV-2 are the same, but does this vary depending on whether the actin species and the SARS-CoV host species match? In other words, does a human SARS-CoV2 have the same frequency as a bat actin? The figure legend should specify which mammalian host the "mammalian" actins represent.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Immunology, viral pathogenesis, viral geneticsI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The authors have made the minor corrections requested and the manuscript looks like a valuable contribution to the literature.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Immunology, viral pathogenesis, viral geneticsI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. This manuscript presents a machine-learning analysis of the published sequences of the novel 2019-nCoV. The authors use the Informational Spectrum Method (ISM), a virtual spectroscopy method for protein analysis based on the electronic properties of each amino acid. Their goal is to identify sites on the virus most likely to interact with other molecules like drugs, antibodies or viral receptors.  Due to the rapidity of this field and the time elapsed since the manuscript was submitted (Jan 27), most of their conclusions are no longer new: nCoV is most related to SARS-CoV and less to MERS-CoV, ACE2 is a likely receptor, the natural reservoir might be civets and poultry, human actin proteins participate in internalization, ibuprofen that interacts with actin proteins should be investigated as a therapeutic, and finally that domain 266-330 of the S1 protein should be targeted by drugs or vaccines. It is a nice piece of work. The conclusions could be updated, for example they could say that the first of these predictions are supported by recent publications, that bat CoVs now appear to be the most closely related and bats are more likely to be the natural reservoir, and the link between ibuprofen/actin interactions and viral entry remains an exciting path for future therapeutics. Minor correctionsIn the first sentence of “Update” the authors refer to ‘these proteins’…do they mean Actin and SARS-CoV proteins? If they only mean actin they should say so, and then the sentence would read: “…actin protein is suggested as a host factor that participates in infection and pathogenesis of 2019-nCoV. Drugs modulating the biological activity of actin  were suggested as candidates that should be investigated for the treatment of 2019-nCoV infection.“In the UPDATE, last sentences should say "...which are presented in Figure 5."Introduction pg 3 “Fears are mounting worldwide over the cross-border spread of the new strain of coronavirus (denoted as 2019-nCoV) originated in Wuhan,….” Instead say “…that originated in Wuhan…”Introduction pg 3 “…eight human 2019-nCoV isolates are available without any additional information about biological properties of the virus, beyond the morphological confirmation…” Replace “morphology” with “morphological”, it is an adjective.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Immunology, viral pathogenesis, viral geneticsI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. et al,1 Science 2020 4 March, beautifully detailed the putative region of the virus/ACE2 interaction. I recommend the authors quote this finding as well and if possible add the reference. This would help in validating a quite interesting method of sequence analysis.Possibly the ISM method invented by the authors has high potentiality. Here, apparently, the method is applied to answer urgent questions in relation to sequence analysis of the novel coronavirus 2019-nCoV. It is interesting to verify that different papers at the moment seem to have reached the same conclusions, although in my opinion a comparison with other methods which are already published would add to the paper. On top, R.YanIs the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?PartlyAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?PartlyReviewer Expertise:Computational Biology, Structural bioinformatics, Functional annotation, Machine and deep learningI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


The pandemic of SARS-CoV-2 is a serious global challenge affecting millions of people worldwide. Cancer patients are at risk for infection exposure and serious complications. A prompt diagnosis of SARS-CoV-2 infection is crucial for the timely adoption of isolation measures and the appropriate management of cancer treatments. In lung cancer patients the symptoms of infection 19 may resemble those exhibited by the underlying oncologic condition, possibly leading to diagnostic overlap and delays. Moreover, cancer patients might display a prolonged positivity of nasopharyngeal RT-PCR assays for SARS-CoV-2, causing long interruptions or delay of cancer treatments. However, the association between the positivity of RT-PCR assays and the patient’s infectivity remains uncertain. We describe the case of a patient with non-small cell lung cancer, and a severe ab extrinseco compression of the trachea, whose palliative radiotherapy was delayed because of the prolonged positivity of nasopharyngeal swabs for SARS-CoV-2. The patient did not show clinical symptoms suggestive of active infection, but the persistent positivity of RT-PCR assays imposed the continuation of isolation measures and the delay of radiotherapy for over two months. Finally, the negative result of SARS-CoV-2 viral culture allowed us to verify the absence of viral activity and to rule out the infectivity of the patient, who could finally continue her cancer treatment. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a complex global challenge affecting millions of people worldwide . Cancer On 1 April 2020, a 72-year-old Caucasian woman affected by non-small cell lung cancer of the upper right lobe, was referred to the Istituto Oncologico Veneto (IOV) of Padua, Italy, for the acute onset of progressive shortness of breath and dry cough. Her past medical history was relevant for glaucoma, depression, and Parkinson disease. The patient had undergone a right upper lobe lung resection with ilo-mediastinic lymph node dissection in 2015; the histo-pathological examination revealed an EGFR exon19 deletion mutated adenocarcinoma. After four courses of adjuvant chemotherapy (cisplatin plus gemticitabine), due to disease progression, in 2018 targeted therapy with osimertinib was started with partial response according to RECIST .At hospital admission, the physical examination revealed moderate inspiratory retraction and diffuse inspiratory wheezing; the body temperature was 36.8 °C; heart rate 68 bpm; blood pressure 125/80 mm Hg; respiratory rates 25 per minute; oxygen saturation 98% with 3 L/min oxygen supplement. Her ECOG PS (Eastern Cooperative Oncology Group performance status) was 2.Laboratory investigations were all within the normal range, including lactate dehydrogenase (LDH), C-reactive protein (CRP), and procalcitonin. The nasopharyngeal swab for the detection of SARS-CoV-2 RNA by RT-PCR  was negaDuring the hospital stay, the patient was exposed to an asymptomatic SARS-CoV-2 virus carrier. On 6 April 2020, she underwent screening nasopharyngeal swab for detection of SARS-CoV-2, which was positive. The scheduled radiotherapy was postponed and the patient was transferred to the infectious diseases unit. At admission she presented with mild inspiratory retraction but all the vital signs were normal. Blood examinations showed a moderate elevation of CRP . Because of the high-risk condition, she was treated with the therapy currently recommended: hydroxychloroquine (HCQ)  and azithromycin (AZI) (500 mg qd) . Both drThe patient did not develop any coronavirus disease 2019 (COVID-19)-related symptoms, but nasopharyngeal swabs were persistently positive for SARS-CoV-2 for over one month. On 13 May after two consecutive negative swabs, she was transferred to the oncology ward to start radiotherapy treatment. Her ECOG PS was 3. Unfortunately, on May 19, the nasopharyngeal swab for SARS-CoV-2 RNA was positive. Once again the radiotherapy was postponed and the patient was isolated in the infectious diseases ward. The clinical conditions remained stable and the nasopharyngeal swabs were repeated at regular intervals with alternating results . On 30 MInterestingly, serological tests showed the presence of high levels of anti-SARS-CoV-2 IgG  and high titers persisted during the whole observation period; IgM title was persistently negative .On the basis of these results, a single-fraction radiotherapy was performed on 4 June and the patient continued her regular follow-up with no need of oxygen supplementation. The last total body CT scan performed in July 2020 confirmed stable disease.SARS-CoV-2 pandemic caught clinicians and health authorities unprepared to manage cancer patients. Diagnostic and treatment guidelines were lacking at the beginning of the outbreak. Clinicians were challenged to manage COVID-19 disease with clinical characteristics which might be partly masked or confounded by coexisting cancer conditions. Moreover, the risk of nosocomial transmission of SARS-CoV-2 and the need for isolation contributed to the risk of progression of the malignant disease because of cancer treatments’ delays ,15,16.After the detection of SARS-CoV-2 our patient did not show any acute signs of infection and her symptoms could be attributed to her lung cancer. However SARS-CoV-2 swabs remained positive for more than 90 days, showing alternating results: in five occasions they turned out positive after one or two consecutive negative tests. It has been described that, after clinical resolution, some COVID-19 patients may experience a prolonged nucleic acid conversion ,18. XiaoAn Italian group has recently proposed an algorithm for the management of oncologic patients who need radiation therapy. Their recommendation is to delay or discontinue the radiation treatment in symptomatic and asymptomatic patients diagnosed with COVID-19 and to carefully start the treatment only when the patients are declared no longer exhibiting infection by the infectious diseases specialist .In line with this recommendation we could discontinue hospital isolation owing to the repeatedly negative cell culture results, which allowed us to verify the absence of viral activity despite the persistent positivity of nasopharyngeal swabs. In this way the patient could finally undergo palliative radiotherapy for airway obstruction with a delay of eight weeks from the initial scheduled time. Although it is unlikely that the delayed palliative radiotherapy affected the short-term poor prognosis, it surely prolonged the length of hospitalization and negatively affected the patient’s quality of life.This clinical case emphasizes the multifaceted and challenging approach to SARS-CoV-2 infection in the oncological setting. Clinicians must protect the vulnerable cancer population from a potentially severe infection without jeopardizing cancer care and support. The development of diagnostic tests able to determine the activity of the disease and patients’ infectivity may contribute to the fight against SARS-CoV-2, limiting the number of COVID-19-related deaths and the excess indirect mortality and morbidity in patients suffering from cancer.


European guidelines recommend the use of the Systematic COronary Risk Evaluation (SCORE) to assess 10-year risk of fatal cardiovascular events in people aged 40 to 65. The SCORE Older Persons  was recently developed for people aged 65 or older. We assessed the performance of these risk scores in predicting fatal cardiovascular events in older persons in Berlin.Data from the Berlin Initiative Study (BIS), a prospective, population-based study of older persons recruited from a German public health insurance company database were used. 1,657 participants aged 70 or older without reported previous myocardial infarction were included. We assessed calibration by comparing predicted risks to observed  or projected (for 10-year versions) probabilities. During follow-up (median: 4.8 years), 118 cardiovascular deaths occurred. The calibration assessment of the SCORE OP-H 5y and SCORE OP-L 5y equations revealed 2.1- and 1.5-fold overestimation. Comparing 10-year versions, the SCORE OP showed better discrimination ability compared to the SCORE (C-indices of around 0.80 compared to 0.72) and the SCORE for high-risk regions showed the best calibration (chi-square = 29.68). The SCORE OP overestimated the true risk; 519 and 677 events were predicted using the low-risk and high-risk region SCORE OP equations compared to 397 to 399 events projected based on BIS follow-up data .Given the low transportability of the SCORE OP observed in our population, we caution against its use in routine clinical practice until further information is available to avoid possible overtreatment among older persons in Berlin. Cardiovascular (CV) diseases are a leading cause of morbidity and are responsible for approximately 40% of deaths in the European Union and 30% More than 363 prediction models for CV disease have been developed over the last decades. GeneralSince the majority of risk scores have been developed using data from primarily middle-aged populations, it remains unknown how well they perform in older populations,20. WithBased on this rationale, an updated version of SCORE was developed in 2015 to predict the risk of fatal CV events specifically for persons aged ≥65 .Until recently, the SCORE OP had not been externally validated; the newly published study calls for further validations of this risk tool. Our objWe used data from the ongoing Berlin Initiative Study, a longitudinal, population-based cohort study of adults aged ≥70 with biennial follow-up visits. Details of the study design have been previously described. In brieThe following risk scores were selected for external validation:SCORE OP-H 5y: European risk score for 5-year fatal CV events among older persons in high-risk regionsSCORE OP-L 5y: European risk score for 5-year fatal CV events among older persons in low-risk regionsSCORE OP-H: European risk score for 10-year fatal CV events among older persons in high-risk regionsSCORE OP-L: European risk score for 10-year fatal CV events among older persons in low-risk regionsSCORE-H: European risk score for 10-year fatal CV events among adults in high-risk regionsSCORE-L: European risk score for 10-year fatal CV events among adults in low-risk regionsSince Germany is considered to be between a high- and low-risk region, we valiR) was estimated as the sum of two risks; the risk for coronary heart disease death (RCHD) and risk for non-coronary CV disease death (Rnon-CHD CVD) as follows:The published formulas, parameters, and coefficients were used for the computation of the risk scores. Of the two original parallel SCORE estimation models, we used the simpler version , since no superiority was demonstrated by the model including total cholesterol to the high-density lipoprotein cholesterol ratio. AdditionDefining the risk of CV mortality in this way is not suitable for participants with high-risk profiles since the sum of the two specific risks can exceed one. For this reason, we used a simple correction to estimate the overall risk, assuming cause-specific risk independence:et al. as the first step in their approach aiming to account for competing events in the SCORE model.[This correction was initially proposed by Støvring RE model.Since we are validating these scores in an increased risk population due to advanced age, we have applied this approach to avoid implausible probabilities exceeding 100%.The following variables used in the models were assessed at baseline during a face-to-face interview: age as an integer, sex, the mean value of two consecutive blood pressure measurements, HDL and total cholesterol levels (converted from mg/dl to mmol/l dividing by 38.67), self-reported current smoking status, diabetes mellitus status (as determined by self-reported use of antidiabetic medication and/or measured HbA1c level >6.5%), and self-reported use of antihypertensive medication.In the Berlin Initiative Study, information about participant deaths was obtained from several sources. When no reply to a follow-up invitation letter was received and the participant could not be reached, the general practitioner on file for the participant was contacted to inquire about vital status . Occasionally, participants’ relatives contacted the study team directly about death events. If no information could be obtained from these sources, AOK Nordost records were used to determine vital status. Berlin Initiative Study staff additionally obtained records from the Berlin death certificates archive to validate all deaths, confirm dates, and obtain information on causes of death. Independent of the death certificate information, the study team attempted to obtain archived medical discharge letters for all in-hospital deaths as supplemental information to help correctly classify the cause of death. CV death was defined as death due to fatal myocardial infarction, fatal coronary heart disease, sudden cardiac death, death due to other cardiac diseases such as heart failure, fatal cerebrovascular disease , and death due to peripheral occlusive arterial disease . Ambiguous cause of death information were discussed and final coding decisions were made by two medical doctors without knowledge of individuals’ risk factor profiles. In cases where mortality was confirmed but cause of death could not be ascertained due to insufficient information, we assumed death by non-CV cause in the primary analysis.Participants’ baseline risk factors are reported as frequencies and percentages or using means and standard deviations for categorical and continuous variables. Person-years were calculated from the date of recruitment to the individual’s death date (as confirmed by a death certificate), or the date of the last available study visit in cases of loss to follow-up, or the date of administrative censorship .Associations between the predicted risks from each of the risk estimation systems were assessed using pairwise Spearman's rank correlation coefficients. We then computed overall and CV-specific mortality rates as ratios of the number of observed events to the total amount of observed person-years with 95% Poisson exact confidence intervals.For each prognostic model, and for both high- and low-risk region versions, we computed predicted risks for all individuals. In a second step, we grouped individuals according to deciles of the predicted risk and assessed calibration for each predicted risk decile group. The “actual” probability of an event was compared to the mean of the predicted risks in each decile group. This comparison was conducted both graphically using a calibration plot and, to allow for comparability with previous studies, using the Nam-D’Agostino chi-square test. We furtGiven that the Berlin Initiative Study follow-up was shorter than 10 years, we performed calibration assessment using five years of the observed follow-up data for the SCORE OP risk equations (SCORE OP-H 5y and SCORE OP-L 5y) as the primary analysis. In this analysis, the calibration assessment was performed using the Kaplan-Meier estimates as “actual” probabilities. The original SCORE-L and SCORE-H risk equations were unfortunately only reported as 10-year versions. For calibration assessment of the SCORE risk equations, it was therefore necessary to project probabilities of the endpoints beyond the observed follow-up. Specifically, after creating the predicted risk decile groups, we ran Weibull regression survival models treating the predicted risk groups as a categorical covariate and the 10-year probabilities for each decile group projected by the Weibull models were considered “actual” probabilities. In this secondary analysis, assessment of 10-year calibration was also performed for the SCORE OP risk equations.The discrimination ability of each risk score was assessed using the concordance index (C-index) on the eWe computed projected probability estimates and the C-index along with their 95% bias-corrected and accelerated bootstrapped confidence intervals with 2,000 bootstrap replications.To check for robustness of our primary results treating unknown causes of death as non-CV, we re-ran all analyses making the most extreme assumption that all deaths of unknown cause were of CV nature. Moreover, to confirm that our external validation study findings are applicable to the general older Berlin population as a whole, we performed an additional sensitivity analysis. All analytical steps described above were repeated in five resampled datasets (by age and sex strata of the BIS study population), which were generated to create a pseudopopulation exactly representative in terms of size and demographic structure of the 2010 Berlin population aged 70 or older  and calculated the number of very-high-risk persons based on 10-year predicted risks using the various risk scores. We also computed the percentage of participants classified as very-high-risk at the various thresholds based on a full Weibull model  fitted on BIS data to give a near description of the projected reality at 10 years for our cohort.https://www.R-project.org/) and RStudio v1.0.153 (https://www.rstudio.com/).All statistical analyses were performed using R v3.4.3 . However, the SCORE OP-H overestimated risk in each decile group . The SCOWe have provided a summary of all the results previously described in To determine the impact of potential misclassification due to 44 fatalities with unknown cause of death information, we performed all analyses again under a ‘worst-case’ scenario assuming that all 44 individuals died due to CV reasons. In this sensitivity analysis, the SCORE-H still underestimated risk , and the SCORE OP-L overestimated risk (ratio = 1.22)  in an attempt to correct the expected overestimation. Based on this rationale, the use of SCORE OP is currently suggested as an alternative by the European Society of Cardiology and European Society of Hypertension guidelines for the management of arterial hypertension in older individuals (aged ≥65).all ages 65 and above.The idea that the SCORE gives higher estimates of risk compared to the SCORE OP among older persons was reinforced by findings from a cross-sectional study in Spain,36 and tIn our cohort comprised of older persons, we found that SCORE OP yielded higher risk estimates than SCORE . The same result was found in the only published external validation of the SCORE OP. While tMoreover, we found a lower transportability of the SCORE OP compared to the original SCORE. This is likely explained by a difference in the distribution of unmeasured risk factors and baseline CV fatal risk in our cohort compared to the SCORE OP development dataset. The SCORE OP development dataset was composed of 85% individuals from Norway and included no German cohorts, while the SCORE development dataset included a German cohort and a balanced distribution of individuals from several European countries. Differences in the definition of CV risk factors included in the models or in the true underlying hazard ratios may have led to the unsuitability of the SCORE OP coefficients. For example, in the SCORE OP development dataset, included cohort prevalences of diabetes mellitus ranged from 6% to 7% in females and 4% to 7% in males. These pWe found the best performing risk score among older persons in Berlin was the SCORE-H developed for high-risk regions despite that Germany’s fatal CV risk is considered to be between that of high- and low-risk regions, with a tendency towards the latter. The facIn general, the performance of the SCORE equations was surprisingly good, especially considering that this risk score was developed in 2003 using data from cohort studies with recruitment periods between 1967 and 1991 and that the incidence and treatment strategies for CV diseases changed substantially over the last decades.Recently, the SCORE OP was subjected to external validation for the first time in a cohort of 6,590 older individuals aged between 65 and 79 living in Norfolk, UK. Their rFinally, the SCORE and SCORE-OP were developed without accounting for possible competing events, thus, our calibration used a consistent approach; neither the Weibull model projections nor the Kaplan-Meier estimates accounted for competing events. We acknowledge, however, that competing risks do pose a large problem for practical use among older persons, in whom competing fatal events are common. For this reason, methods have been suggested for the development of local, updated, recalibrated scores that can be used to inform regional risk prediction accounting for mortality due to other causes.Strengths include the prospective design, population-based setting, and availability of comprehensive health-related information, providing unique insights into the health of the very old, a population often excluded from larger studies. Death information is considered to be complete and was obtained from the Berlin death certificates archive and supplemented with information from medical records. Specific cause of death information was consistently extracted when available. Furthermore, a total of 118 fatal CV endpoints were recorded during observed follow-up, exceeding the minimum amount needed to properly validate a 10-year prognostic model over the entire time span (at least 100).Some limitations should be considered when interpreting our findings. First, we compared predicted probabilities to projected ones since the Berlin Initiative Study follow-up data were available for less than 10 years. However, the Weibull diagnostic plots indicate fulfillment of the assumptions of all projection models, and our analyses predicting 5-year risk using observed data were consistent with the findings using 10-year projected probabilities and thus confirm our results. A minor drawback to our approach is that the number of “actual” events is not constant across calibration assessments because it depends on decile groupings of participants, which differed for each risk score. However, these “actual” event numbers did not differ substantially (range: 382 to 399).Second, the reliability of cause of death information on death certificates is known to be error-prone, especially among older persons. However, we believe this potential misclassification is similar for most population-based settings and was also present in the risk score development studies.The impaFurthermore, all of the original SCORE endpoints are well-represented in our definition, with the exception of non-aortic aneurysms, which are very rare events.Finally, the exclusion of subjects with previous history of myocardial infarction was based on self-reported information. However, the self-reported nature of this information in our study is unlikely to be problematic, since this exclusion criterion was introduced during the SCORE development only to ensure overall CV health in the considered sample and not for the purpose of excluding participants not at risk for the outcome.Nonetheless, we suggest against excluding people with a predefined CV event from future prognostic models developed to predict CV mortality risk, as this limits prediction score usability. This is a particularly important consideration among older persons, in whom prevalent non-fatal CV events are common.This external validation study shows that the SCORE OP overestimates CV mortality risk among Berlin older persons, which ultimately leads to the classification of more individuals to higher levels of CV mortality risk at most hypothetical very-high-risk thresholds, above which intervention strategies would be indicated. We believe our results may have important implications since overestimation of risk in these individuals may lead to overtreatment in a potentially vulnerable population already prone to polypharmacy, which iIn our external validation study, the original SCORE developed for high-risk regions performed best in older persons living in Berlin. Our findings are very different from the ones obtained in the first SCORE OP external validation study conducted among older adults in the UK; however, both studies do not support the use of SCORE OP in clinical practice. Therefore, the challenge of finding a valid tool for profiling risk among older European individuals may not yet be solved.S1 File(PDF)Click here for additional data file.


In this paper, we present to achieve a broadband miniaturized transmission waveguide based on complementary spoof surface plasmon polaritons (CSSPPs). For this purpose, a novel SSPP design that consists of a corrugated slot line and a group of additional interdigital structures (ISs) is proposed, which brings in an extra solution to control the cut-off property of CSSPPs. The transmission cut-off frequency of the proposed design decreases with the increasing of the number of the ISs. Since the width of CSSPP waveguide is directly related to the operating frequency, the degree of miniaturization can be modulated freely by carefully choosing the number of the ISs. A prototype of device with four-ISs introduced is designed and fabricated. And the cut-off frequency of the design decreases from 10 GHz to 5.3 GHz, when the ISs are added. Experimental results agree well with the numerical simulations. The proposed design illustrates great potentials in modern plasmonic integrated circuits. Such modes exhibit significant properties of near-field confinement, shorter operating wavelength and perfect low-pass transmission, which have been studied in a broad range of applications such as high-resolution imaging6, electromagnetically induced transparency (EIT)9, photovoltaic improvement and biosensing13.Surface plasmon polaritons (SPPs) are classical surface modes excited along interface of metal and dielectric at visible and near-infrared wavelengths14. In order to take advantages of the significant properties of SPP modes in the lower frequencies in high-efficient and less-mutual-coupling applications, metamaterials are introduced to achieve novel surface responses that have similar dispersive properties with SPP modes – the spoof SPP (SSPP) mode. In 2004 and 2005, Pendry et al. and Hibbins et al. predicted theoretically and verified experimentally such SSPP surface mode on the surface with periodic subwavelength cubic holes16. Then a series of plasmonic designs have been reported to obtain the SSPP waves at both microwave and terahertz frequencies20. High-order SSPP mode along corrugated metallic strip was also studied to achieve extra working bands21. And spoof surface magnon polaritons was theoretically analyzed along corrugated PMC surface22.However, in the longer-wavelength spectra, like microwave and terahertz waves, SPP mode cannot be excited directly, due to the perfect-electrical-conductor property of metal. And the traditional Sommerfield-Zenneck surface electromagnetic responses show weak field-confinement25. A series of matching approaches were reported to connect the SSPP waveguides and traditional transmission lines30. High-efficient transmissions of SSPP mode were experimental excited via co-planar waveguides, microstrip lines, and corrugated slot lines. Based on these designs, plenty of functional SSPP devices and circuits have been presented. Tunable multi-band and broadband filters were proposed by introducing additional metamaterial resonators33, coupling with oppositely oriented corrugated strips34 and cooperating with Substrate Integrated Waveguide (SIW)37. SSPP modes have been widely studied in applications of radiation, such as leaky-wave antennas38, end-fire radiation39, compact antenna designs40, and performance enhancement41. Broadband vortex beams carrying orbital angular momentum was reported by controlling the phase distribution of the unit cells43. Other kinds of devices of power dividers45, directional transmissions46, active excitations47 were also reported. With the development of integrated circuits, SSPP modes have become a research hotspot in forming plasmonic circuits. Multi-layer and multi-channel transmissions of SSPP have been proposed49. Co-planar devices have also been discussed in conformal applications50. Constructing miniaturized design of SSPP becomes an imperative requirement to meet challenges in modern plasmonic integrated circuits.In order to excite the SSPP mode efficiently, the dispersion properties related to geometry dimensions and field distribution in both homogeneous and inhomogeneous media are studiedIn this paper, we proposed a novel complementary SSPP (CSSPP) waveguide consisting of a corrugated slot line and a group of IS slabs inside the grooves. The corrugated slot line plays the key role in exciting the SSPP mode and the loaded IS array modulates the cut-off frequency into lower frequency band. The novel design shows properties of high efficiency and better field confinement. In addition, by changing the number of IS slabs, the cut-off property could be shifted in a wide range. A prototype with four IS slabs loaded in the grooves is proposed. The cut-off frequency decreases by 46% compared with that of the traditional CSSPP waveguide with the same widths. The miniaturized CSSPP waveguides show great potentials in the future plasmonic integrated circuits and systems.The schematic structure of a IS-loaded CSSPP waveguide is shown in Fig. 27, the cutoff properties of the SSPP mode in homogeneous media are mainly determined by the depths of grooves. The bigger the depths are, the lower the cutoff frequencies would be. Therefore, to realize a lower operating frequency band usually requires a much larger dimension. The appearance of IS slabs enhances the capacitive resonance of the unit cell. The dispersion properties of the proposed structure performed on a homogeneous substrate are studied and illustrated in Fig. As has been fully discussed in literaturesk0, k|| and k⊥ are wave number in free space, along and perpendicular to the direction of propagation. For CSSPP mode, it always has relationship of k|| > k0. The larger the wave number k|| is, the larger the imaginary part of k⊥ would be. And this leads to faster attenuation of field intensity perpendicular to the direction of propagation. Hence, the near-field confinement is enhanced.Meanwhile, the dispersion curves of the IS-loaded design deviate more quickly from the curve of slot line, which means that it has a larger wave number. According to basic dispersive model of SPP,Figures Another important property of CSSPP mode is the shorter operating wavelength. For CSSPP mode, according to the dispersion properties, we could obtain the equivalent wavelength of the mode through relationship:entclass1pt{minimaFigure The photos of the proposed compact CSSPP waveguide are illustrated in Fig. A novel CSSPP waveguide consisting of a corrugated slot line loaded with IS slabs is proposed to achieve lower operating frequency band with smaller widths. It has been shown that the novel design has have better ability of near field enhancement and shorter operating wavelength, compared with the traditional CSSPP structures. A prototype with four IS slabs loaded is demonstrated. The cutoff frequency drops to 5.3 GHz without occupying extra space. The miniaturized transmission design could work as the basis of coplanar plasmonic circuits, showing great potentials in the applications of complex and compact plasmonic systems.The commercial software, CST Microwave Studio, were used to simulate the transmission, power distribution and return loss of the proposed miniaturized CSSPP waveguide. Eigen-mode calculation was performed to studied the dispersion properties of the unit structures. The sample was fabricated on printed circuit board of F4B, with relative permittivity of 2.65 and loss tangent of 0.001. In experiments, both terminals of the design were connected to the Agilent vector network analyzer via coaxial cables to measure transmission and reflection.