CHIKV infection leads to a febrile illness known as chikungunya fever (CHIKF), which is characterized by long-lasting and debilitating joint and muscle pain. CHIKV can cause large-scale epidemics with high attack rates, which substantiates the need for development of effective therapeutics suitable for outbreak containment. In this review, we highlight the different strategies used for developing CHIKV small-molecule inhibitors, ranging from high-throughput cell-based screening to  in silico screens and enzymatic assays with purified viral proteins. We further discuss the current status of the most promising molecules, including in vitro and in vivo findings. In particular, we focus on describing host and/or viral targets, mode of action, and mechanisms of antiviral drug resistance and associated mutations. Knowledge of the key molecular determinants of drug resistance will aid selection of the most promising antiviral agent(s) for clinical use. For these reasons, we also summarize the available information about drug-resistant phenotypes in Aedes mosquito vectors. From this review, it is evident that more of the active molecules need to be evaluated in preclinical and clinical models to address the current lack of antiviral treatment for CHIKF.Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that has spread to more than 60 countries worldwide. CHIKV infection leads to a febrile illness known as chikungunya fever (CHIKF), which is characterized by long-lasting and debilitating joint and muscle pain. CHIKV can cause large-scale epidemics with high attack rates, which substantiates the need for development of effective therapeutics suitable for outbreak containment. In this review, we highlight the different strategies used for developing CHIKV small-molecule inhibitors, ranging from high-throughput cell-based screening to  Togaviridae family that can cause explosive epidemics of acute and chronic arthritis in humans. The main vectors responsible for its transmission are the day-biting Aedes aegypti and Aedes albopictus mosquitoes. CHIKV was first isolated from a febrile patient in 1952/1953 in what is currently Tanzania . In Europe, the first autochthonous outbreak was described in Italy in 2007 (7Chikungunya virus (CHIKV) is a mosquito-borne alphavirus belonging to the t Martin , resulti in 2007  and soutin 2007 79.Chikungunya fever (CHIKF) typically begins with a sudden onset of fever 3 to 7 days after a bite of an infected mosquito, followed by symptoms such as rash, myalgia, and polyarthralgia. Polyarthralgia is mainly symmetrical and peripheral, affecting the small joints of wrists, ankles, and phalanges, as well as the larger joints such as the knee and the elbow . The patin silico approaches, and Tables 1 to In this review, a comprehensive overview of small-molecule inhibitors of CHIKV is presented in Tables 1 to in silico virtual screens. Compounds identified by in silico computer-based screening can be further optimized by acquiring an understanding of the compound’s structure-activity relationship (SAR), and improved derivatives can be synthesized for validation in enzymatic and cell-based assays. However, the utility of computer-aided design for compounds targeting the CHIKV replicase is limited because, thus far, only the structures of the N-terminal region and C-terminal region of nonstructural protein 2 (nsP2), representing the RNA helicase and protease domains, respectively, and the N-terminal macrodomain of nsP3 have been resolved  a compound has been widely used to identify the viral target of such compounds. Considering the global distribution of CHIKV and its mosquito vectors, the potential for additional spread, and the impact on human health, development of preventive measures is imperative. Several approaches have been used for identification of potential CHIKV inhibitors, including cell-based high-throughput screening (HTS) campaigns, rational and structure-based drug design using crystal structures, and homology modeling of viral proteins. One of the conventional approaches for CHIKV drug discovery uses cell-based screening with readouts that measure the virus-induced CPE. The CPE reduction assay screens can provide information on antiviral activity of compounds, and their cytotoxicity can be assessed in parallel using uninfected cells in the same plate. Such screens are often deployed to test known clinically approved drugs, in a process referred to as drug repurposing. The advantages of this route are decreased costs related to drug approval and an accelerated process leading to potential licensing of the compound. Due to increased computational power, HTS has emerged recently as an efficient process for screening thousands of compounds from large compound libraries, including FDA-approved and novel molecules. The emergence of computer-aided drug design has also greatly contributed to the development of CHIKV inhibitors. These approaches are based on the structure of a viral protein to perform resolved –13. MoreThe alphavirus virion is composed of a nucleocapsid core with T=4 icosahedral symmetry surrounded by a host-derived lipid bilayer which is decorated with 80 trimeric spikes of E1-E2 heterodimers –16. The –Obatoclax, an anticancer compound, was found to inhibit CHIKV infection early in the replication cycle by neutralizing the acidic endosomal environment required for fusion. The L369I mutation in domain III of the E1 fusion glycoprotein conferred at least partial resistance to obatoclax and generated resistant viruses with enhanced fusogenic potential .Arbidol/umifenovir has been licensed as an anti-influenza agent in both Russia and China and inhibits a wide range of viruses. Arbidol inhibits early stages of the CHIKV replication cycle, which was confirmed by selection of an arbidol-resistant variant carrying a G407R mutation in the structural polyprotein , which cSuramin is an approved drug for treatment of parasitic infections in humans and was shown to inhibit CHIKV entry in three independent studies –27. The –Picolinic acid was found to bind to the hydrophobic pocket of the C protein, which might inhibit the C protein’s interaction with the cytoplasmic domain of the E2 glycoprotein. The antiviral activity of picolinic acid was also confirmed in CHIKV-infected cells, although the inhibitory concentration was rather high for clinical applications .The 6K protein belongs to the family of viroporins or ion channel-forming proteins. It is a highly hydrophobic protein with membrane fusogenic properties. Viroporins enable movement of small molecules and ions across membranes, which can be important during viral entry, replication, and egress. The potential of 6K to serve as a therapeutic target is illustrated by the drug amantadine, a well-known influenza inhibitor that targets the ion channel-forming M2 protein of influenza viruses . Amantadhttps://clinicaltrials.gov/ct2/show/NCT00391313). Moreover, CHL-treated patients had more frequent complaints of arthralgia than placebo recipients  is an old antimalaria drug with a broad range of antiviral activities against a variety of viruses. CHL had been deployed in clinical trials long before its anti-CHIKV activity was established in cell culture. The rationale for this unusual strategy was that CHL had conferred benefits in lessening joint inflammation in patients with rheumatoid arthritis during trials in the late 1950s . The effcipients . In an Icipients . These ast virus . In CHIKst virus .Doxycycline is a tetracycline antibiotic used for treatment of bacterial infections that has also shown promising anti-CHIKV activity. It was postulated that the anti-CHIKV activity of doxycycline is directed toward viral entry rather than viral replication. Docking studies with the CHIKV nsP2 cysteine protease and E2 glycoprotein indicated that the compound could bind to both these viral targets. However, cell-based assays confirmed that doxycycline inhibits viral entry, likely by impairing conformational changes in the E2 glycoprotein. Treatment of adult ICR mice with doxycycline alone did not result in an improved outcome in comparison with combination treatment with ribavirin .Curcumin is a turmeric plant extract that has been used for treatment of gastrointestinal disorders in Asia. The antiviral effect of curcumin on CHIKV has been demonstrated using pseudotyped viral particles , and a sApigenin, a natural compound with a 5,7-dihydroxyflavone structure, has shown moderate anti-CHIKV activity. Flavonoids have been previously reported to suppress the entry pathway of members of other virus families. However, the flavonoids tested against CHIKV, among which apigenin was the most potent, strongly inhibited CHIKV replicon levels and had no effect in an Semliki Forest virus (SFV) entry assay , suggestin silico identification of enzymatic sequence motifs. CHIKV inhibitors targeting individual nsPs are described in The incoming alphavirus genomic RNA is translated into two polyproteins: P123 and P1234. P123 is the more abundant of the two, and P1234 arises as a result of the translational read-through of an opal stop codon (with about 10% efficiency) at the end of nsP3 coding sequence . These p7GTP and releasing S-adenosylhomocysteine (SAH) as a by-product   is a viral mRNA capping enzyme with guanine-N7-methyltransferase (MTase) and guanylyltransferase (GTase) activities responsible for capping of the 5′ ends of the newly synthesized genomic 42S mRNA and 26S subgenomic mRNA. The MTase catalyzes the transfer of the methyl group from S-adenosylmethionine (SAM) to the N7 position of a GTP molecule, forming m-product . The GTate (PPi) . The m7G of nsP2 , to crea of nsP2 . Specifi of nsP2  allows n of nsP2 . Importa of nsP2 .in vitro effects, there was little protection against CHIKV-induced disease in C57BL/6 mice that were fed DFMO in their drinking water prior to infection  is a multifunctional protein which possesses several enzymatic activities, including nucleoside triphosphatase (NTPase) , 69, helde facto the target of these compounds. Computer-aided drug design was combined with cell-free assays for target validation of a set of 12 compounds designed against the CHIKV nsP2 protease using target-based modeling. The most promising compound, compound 8, potently inhibited CHIKV replication in cell culture and was moderately active in the protease assay with recombinant CHIKV nsP2  is the least defined among all CHIKV nsPs. Three domains can be distinguished in nsP3: an N-terminal macrodomain , a Zn-biTo date, only a few small-molecule inhibitors targeting CHIKV nsP3 have been reported, perhaps due to the enigmatic role of nsP3 in viral replication. However, in-depth characterization of the nsP3 functional domains in recent years has contributed to the exploitation of nsP3 as a potential drug target. Given its highly conserved nature and the available crystal structure, the macrodomain represents an ideal site for development of specific anti-CHIKV antivirals. Baicalin is one of the very few compounds that have been shown to interact with nsP3 using a computational approach  with a cThe nsP4 protein (611 aa) is the most conserved protein in the alphavirus family that functions as an RNA-dependent RNA polymerase (RdRp) responsible for replication of 49S genomic (+) strand RNA and transcription of the 26S single guide RNA (sgRNA). In the early phase of the replication cycle, nsP4, together with P123, is part of an early replication complex (RC) that is responsible for the synthesis of full-length (−) strand RNA that serves as the template for synthesis of genomic and sgRNA. Following polyprotein processing, the late RC consisting of fully cleaved nsP1 to nsP4 mediates the synthesis of genomic RNA and 26S sgRNA . NsP4 alin vitro, and its administration to infected adult Swiss mice resulted in reduced arthralgia-related paw inflammation  is a nucleoside analogue that inhibits CHIKV replication after it is converted to its active form, NHC triphosphate. However, a direct relationship between NHC and its mode of action in CHIKV-infected cells has not yet been established. It was proposed that NHC may interfere with CHIKV replication through chain termination or mutagenesis  is a broad-spectrum nucleoside analogue that has also shown inhibitory activity against CHIKV . All of As discussed above, ribavirin can block CHIKV replication by at least two different mechanisms, one of which operates through RdRp inhibition. CHIKV passaging in the presence of ribavirin yielded a high-fidelity mutant containing a C483Y mutation in nsP4 . InteresDespite the majority of nsP4-targeting compounds belonging to well-known classes of nucleoside analogues, compound screens have identified other potential drug candidates. For example, an HTS of advanced clinical candidates identified digoxin, a cardiac glycoside that antagonizes the sodium-potassium ATPase, as a potent CHIKV inhibitor. The V209I mutation in nsP4, situated in a well-conserved region of nsP4, was found to play a pivotal role in the development of digoxin-mediated resistance . Cytopla6-Azauridine is a broad-spectrum nucleoside analogue that has been widely used in patients for other indications. Its metabolite 6-azauridine 5′monophosphate was previously reported to inhibit the replication of several DNA and RNA viruses via targeting of the host orotidylic acid decarboxylase . Others Analysis of a chemical library has identified RYL-634, a novel potent broad-spectrum small-molecule inhibitor with antiviral activity against many pathogenic viruses, including CHIKV. Dihydroorotate dehydrogenase (DHODH) was validated as the target enzyme of RYL-634 using activity-based protein profiling .de novo synthesis of pyrimidine. Recently, atovaquone was found to inhibit CHIKV replication, but the mechanism underlying its precise mode of action remains unstudied. For Zika virus, it was shown that atovaquone blocks DHODH and thereby leads to the depletion of intracellular nucleotide pools  cells or Vero E6 (African green monkey kidney) cells are the most widely used cell lines for CHIKV antiviral drug screening. Fibroblast cell lines, such as MRC-5 (human lung fibroblast) or HFF-1 (human foreskin fibroblast), have also been used in multiple studies. Less frequently used cell lines include immortalized cells such as HeLa , Huh-7 or HepG2 (human hepatocellular carcinoma), and U2OS (human osteosarcoma). Cell lines usually vary with respect to drug uptake and intracellular metabolism. Therefore, it is anticipated that the compounds that first need to be metabolized into their active form, such as nucleoside analogues, might show cell line-dependent differences in their antiviral activity profiles. A study evaluating the anti-CHIKV efficacy of ribavirin and favipiravir, each of which needs to be converted to its active triphosphate form by host cell kinases, revealed differences in antiviral efficacy that depended on the cell line used for evaluation . SimilarThe lack of effective control measures and the spread of new vectors and increased human travel and urbanization greatly contributed to CHIKV reemergence between 2004 and 2020. The origin and scale of a future chikungunya outbreak are hard to predict, which underscores the importance of developing effective countermeasures. Identifying and developing direct-acting and host-targeting antiviral drug options against CHIKV infection offer a promising approach for limiting viral replication and spread.The major complaint of patients suffering from CHIKF is debilitating joint and muscle pain, which results in lost productivity and reduced quality of life. Antiviral treatment would represent a suitable measure to prevent and treat CHIKV infections and significantly lower the burden of disease in affected areas. A combination therapy for CHIKF may prove useful to reduce the likelihood of developing drug resistance, given that compounds with different viral/host targets can produce synergistic effects. In addition, chronic CHIKF patients with exacerbated response of their immune system can also be treated with immunomodulatory agents to alleviate joint arthralgia and inflammation.in vitro and in vivo models. Ideally, in vivo antiviral testing is performed in animal models that replicate the clinical course of CHIKV infection in humans. While the use of an immunocompromised acute model, such as AG129 mice, may provide more-stringent conditions for antiviral evaluation, the use of an immunocompetent arthralgia model is more clinically relevant. The maximum beneficial effect of an antiviral compound for treatment of CHIKF patients would be achieved by early administration during the acute phase of infection, in order to reduce the viral load and decrease the likelihood of developing chronic manifestations. Clinical studies performed with patient material have already indicated that residual viral material (RNA/protein) in joint tissue, rather than replicating virus, likely contributes to the immunopathology that is associated with CHIKV infection (Validation of CHIKV small-molecule inhibitors is currently performed in a variety of nfection . Consequ


Telehealth is a recommended method for monitoring the progression of nonsevere infections in patients with COVID-19. However, telehealth has not been widely implemented to monitor SARS-CoV-2 infection in quarantined individuals. Moreover, studies on the cost-effectiveness of quarantine measures during the COVID-19 pandemic are scarce.In this cohort study, we aimed to use telehealth to monitor COVID-19 infections in 217 quarantined Taiwanese travelers and to analyze the cost-effectiveness of the quarantine program.Travelers were quarantined for 14 days at the Taiwan Yangmingshan quarantine center and monitored until they were discharged. The travelers’ clinical symptoms were evaluated twice daily. A multidisciplinary medical team used the telehealth system to provide timely assistance for ill travelers. The cost of the mandatory quarantine was calculated according to data from the Ministry of Health and Welfare of Taiwan.All 217 quarantined travelers tested negative for SARS-CoV-2 upon admission to the quarantine center. During the quarantine, 28/217 travelers (12.9%) became ill and were evaluated via telehealth. Three travelers with fever were hospitalized after telehealth assessment, and subsequent tests for COVID-19 were negative for all three patients. The total cost incurred during the quarantine was US $193,938, which equated to US $894 per individual.Telehealth is an effective instrument for monitoring COVID-19 infection in quarantined travelers and could help provide timely disease management for people who are ill. It is imperative to screen and quarantine international travelers for SARS-CoV-2 infection to reduce the nationwide spread of COVID-19. COVID-19 is caused by SARS-CoV-2 and was first detected in Wuhan, China, in December 2019. This disease caused a rapidly accelerating global pandemic in 2020 [As the COVID-19 outbreak emerged, the Taiwanese government implemented several strategies to prevent the nationwide spread of COVID-19, including border controls, proactive screening measures, and quarantine procedures ,4. AccorCurrently, no effective pharmacological interventions or vaccines are available to treat or prevent COVID-19 ,8. ThereDuring quarantine, all individuals should be monitored for the onset of symptoms; otherwise, there is risk of delays in the detection and prompt management of the virus. Telehealth through a line of communication is an efficient way to monitor quarantined individuals and can assist in providing timely care for people who require it . AlthougQuarantine strategies have been used in many countries in an attempt to curb the ongoing COVID-19 pandemic. However, the cost-effectiveness of these strategies has not been extensively studied . A curreThis cohort study reports on a model used for screening and quarantining Taiwanese travelers following an evacuation flight from Hubei, China. In this model, telehealth was used to monitor COVID-19 infection among travelers at a centralized quarantine center, and the cost-effectiveness of the 14-day mandatory quarantine strategy was analyzed.In late January 2020, the Taiwanese government established a centralized quarantine center to screen and monitor COVID-19 infections in international travelers who had visited countries with a declared COVID-19 outbreak . On MarcThis cohort study included all the passengers of the charter flight, who were subsequently followed up until their discharge from the quarantine center or until April 15. This study was approved by the Institutional Review Board of Taipei City Hospital (no. TCHIRB-10904014-E).The body temperature of the Taiwanese travelers was checked at the international airport in China, and individuals with fever were not allowed to board the charter flight. All travelers were required to disinfect their hands with alcohol-based hand sanitizer at the boarding port and to wear personal protective equipment (PPE) provided by the Taiwanese government, which included a face mask and medical gown. Meals were not provided during the flight to avoid cross-infection between passengers.Upon arrival at the international airport in Taiwan, National Defense chemical troops used a 1:10 diluted sodium hypochlorite solution (5000 ppm) to disinfect the travelers’ luggage. The travelers then proceeded to the Yangmingshan quarantine center for the 14-day quarantine period. They were required to record their body temperature twice daily with a thermometer that was provided to them. Additionally, daily meals were delivered to the individuals’ rooms, and janitors used a 1:10 diluted sodium hypochlorite solution to clean the quarantine center once daily.During admission to the Yangmingshan centralized quarantine center, the travelers were screened for COVID-19 using a real-time reverse transcriptase–polymerase chain reaction (RT-PCR) test. If an individual tested positive for COVID-19, they were transferred to a hospital for medical isolation and treatment.Travelers’ clinical symptoms were recorded twice daily by their primary care nurses via telephonic communication. If an individual developed fever or became ill, a multidisciplinary team (MDT) consisting of 15 medical workers used telehealth to assess the traveler’s condition.The telehealth system at the Yangmingshan quarantine center was developed based on a popular social media app called LINE, which is a freeware app operated by the NAVER Corporation in South Korea. The LINE-based telehealth system established two-way communication between the MDT and 217 quarantined travelers. Through a unique ID, the quarantined individuals were invited to join an official LINE group in which the quarantined travelers could report their symptoms to the MDT members. When the MDT members received a message regarding a quarantined traveler’s symptoms, the MDT members initiated a one-to-one video call through LINE to clinically evaluate the patient. The MDT members collaboratively discussed the traveler’s condition during the telehealth session and provided appropriate management and treatment interventions for the traveler. If a quarantined traveler presented with fever or shortness of breath, they were transferred to the hospital for further treatment.The personnel who were responsible for overseeing the travelers’ quarantine at the Yangmingshan quarantine center included the MDT, police officers, janitors, a logistics group, and administration staff. The MDT consisted of 3 physicians, 10 nurses, a pharmacist, and a psychologist. Three physicians, including a general practitioner, a pediatrician, and a cardiologist, gave treatment advice according to the traveler’s condition during the telehealth session. The 10 nurses were responsible for taking care of the travelers during 12-hour day and night shifts in the six quarantined wards. The nurses communicated daily with the quarantined travelers to evaluate their clinical condition and record their body temperature. The pharmacist delivered medications to ill quarantined travelers. Physicians and nurses wore PPE when examining the travelers in person.The police officers were responsible for the security of the travelers at five sentry points and ensured that all travelers obeyed the COVID-19 quarantine rules and completed the 14-day mandatory quarantine order. In total, 18 police officers were divided into three groups, with one leader in each group. The three groups of police officers worked in 12-hour day and night shifts. Three janitors were responsible for environmental disinfection in the six quarantined wards, and one janitor was responsible for two quarantined wards on one floor. The logistics group, composed of 10 people, was responsible for meal preparation and ensuring that sufficient supplies were provided to the 217 travelers during the 14-day quarantine.The cost of the quarantine for the travelers at the Yangmingshan quarantine center was covered by the disaster reserve of the national Ministry of Health and Welfare, which included payment of the MDT, nonmedical personnel, and telehealth services as well as the provision of PPE.t tests were used for comparisons between groups. Categorical data were analyzed with Pearson chi-square tests where appropriate.A P value <.05 was considered to indicate statistical significance.First, the participants’ demographic data were analyzed. Continuous data are presented as mean (SD), and two-sample A timeline infographic was used to display the progression of clinical symptoms in hospitalized travelers. The labor and overall costs of the quarantine were calculated according to the disaster reserve data from the Taiwan Ministry of Health and Welfare. All data management and analyses were performed using SPSS 19.0 (IBM Corporation).Our sample comprised 217 Taiwanese travelers who were stranded in Hubei, China, due to the COVID-19 pandemic and who returned to Taiwan on March 30, 2020 . The meaThe symptoms and management of quarantined travelers receiving telehealth care were recorded during the 14-day mandatory quarantine . The mosOf the 28 quarantined travelers evaluated with telehealth, one traveler with diabetes presented with dizziness and weakness on the fifth day and was suspected to be hypoglycemic during the telehealth clinical evaluation. The patient’s blood glucose test indicated a level of 75 mg/dl when health care workers wearing PPE visited this individual.This cohort study reports a model for the screening and quarantining of international travelers who visited countries with a declared COVID-19 outbreak. All travelers tested negative for COVID-19 during the 14-day mandatory quarantine period. Three travelers with fever were hospitalized after the telehealth assessment, and subsequent tests for COVID-19 were negative for all three patients. The total costs during the quarantine were US $193,938, which equated to US $894 per individual. Our study demonstrates that strict infectious control measures, proactive screening, and an MDT integrated with the use of telehealth contributed to the successful quarantine of international travelers while remaining cost-effective for containing the spread of COVID-19.Quarantine is an effective strategy to control and prevent COVID-19 outbreaks  used a tOur report is among the first to analyze the cost-effectiveness of an enforced quarantine program. We found that the total cost of a 14-day quarantine for 217 international travelers was US $193,938, equating to US $894 per traveler. Although none of the 217 Taiwanese travelers tested positive for SARS-CoV-2 during the 14-day mandatory quarantine period, this study highlights the importance of screening and immediately quarantining returning international travelers because of the high risk of COVID-19 in this population . The quaLINE-based telehealth can provide timely assessment and care for patients who require it. During the COVID-19 surge, LINE-based telehealth could provide care for nonsevere COVID-19 cases in hospitals , and heaThe present study has two limitations. First, our study did not compare the cost-effectiveness of a 14-day quarantine for high-risk COVID-19 individuals. In this cohort study, none of the 217 Taiwanese travelers tested positive for SARS-CoV-2 during the 14-day mandatory quarantine period. As SARS-CoV-2 is highly contagious [This prospective cohort study reports an enforced quarantine program integrated with a telehealth system to monitor COVID-19 infection in quarantined individuals. Telehealth not only provided timely management of quarantined individuals with illness but also reduced the risk of COVID-19 infection in health care workers. Our study suggests that it is imperative to screen and quarantine international returning travelers to reduce the nationwide spread of COVID-19.


According to current reporting, the number of active coronavirus disease 2019 (COVID-19) infections is not evenly distributed, both spatially and temporally. Reported COVID-19 infections may not have properly conveyed the full extent of attention to the pandemic. Furthermore, infection metrics are unlikely to illustrate the full scope of negative consequences of the pandemic and its associated risk to communities.In an effort to better understand the impacts of COVID-19, we concurrently assessed the geospatial and longitudinal distributions of Twitter messages about COVID-19 which were posted between March 3rd and April 13th and compared these results with the number of confirmed cases reported for sub-national levels of the United States. Geospatial hot spot analysis was also conducted to detect geographic areas that might be at elevated risk of spread based on both volume of tweets and number of reported cases.Statistically significant aberrations of high numbers of tweets were detected in approximately one-third of US states, most of which had relatively high proportions of rural inhabitants. Geospatial trends toward becoming hotspots for tweets related to COVID-19 were observed for specific rural states in the United States.Population-adjusted results indicate that rural areas in the U.S. may not have engaged with the COVID-19 topic until later stages of an outbreak. Future studies should explore how this dynamic can inform future outbreak communication and health promotion. Between the beginning of March 2020 and the end of April 2020, the number of recorded coronavirus disease 2019 (COVID-19) cases grew from under 100,000 to over 3 million worldwide [Current evidence suggests that COVID-19 has an appreciable case-fatality rate when compared to other diseases of similar epidemiological characteristics and infectiousness . HoweverIn addition, the COVID-19 pandemic has numerous ramifications which extend beyond physical health, including those which are sociocultural, economic, and psychological . IndividThe use of non-traditional forms of epidemiological data, particularly those that originate from online interaction by users, can provide additional insights how much communities pay attention to emerging public health issues, particularly when such data has resolution to geospatial location data and longitudinal data . In thisTweets related to COVID-19 were collected prospectively from March 3rd to April 13th by using the Twitter public streaming Application Programing Interface (API) using a combination of cloud computing using virtual instances in Amazon Web Services (AWS) executed with scripts in the python programming language. Tweets were included if they contained three pieces of information: (1) geo-identifiable characteristics (e.g. geocoded metadata); and (2) keywords related to COVID-19, including: “corona outbreak,” “corona,” “anticorona,” “coronavirus,” “Wuhan virus,” “COVID,” “Wuhan pneumonia,” and “pneumonia of unknown cause.” Tweets were excluded if latitude and longitude coordinates were outside of land masses or if keywords were found outside the body of the tweet text.Confirmed COVID-19 cases, deaths, and recoveries were obtained from Johns Hopkins University Github CSSEGISandData/COVID-19 repository . These dFor normalization, population estimates for secondary administrative levels for the U.S. nationally were obtained from the American Community Survey .e1071 package in R, applied to a document-term matrix computed from the training set. All longitudinal and geospatial analyses utilized tweets detected using this machine learning classifier.In an effort to remove less relevant tweets, such as those relating to news media, machine learning was used to train a classifier to detect tweets exhibiting accounts of first-hand experience with COVID-19. Training data was taken from another study which used tweets that were derived using the same set of keywords as this study . The clasurveillance package.The C3 method of the Early Aberration Reporting System (EARS) was used to identify statistically significant aberrations in daily change in tweets related to COVID-19 for each of the fifty states in the United States. The EARS method is derived from a separate technique, the cumulative sum control chart (CUSUM) for sequential analysis. Furthermore, EARS is a syndromic surveillance approach used by the Centers of Disease Control and Prevention (CDC) and other public health agencies to detect statistically significant aberrations in infectious diseases . All EARGeospatial analyses involved the use of ArcGIS to create choropleth maps with nine intervals to visualize the geospatial distribution of tweets and tweets per capita at the secondary administrative level for the United States. Individual tweets were available as latitude/longitude point coordinates from the Twitter API, and these point coordinates were aggregated within county spatial polygons in ArcMap. For visualization of tweets per capita, the total number of tweets was divided by county-level population. Equal intervals were selected as a blue-yellow-red gradient in the “graduated colors” feature, thereby illustrating a consistent gradient of magnitudes.z-scores for hot spot and cold spot trends for each 2,500 square-kilometer area in the United States. Specifically, this methodology utilizes the Mann Kendall Trend Test to compute z-scores for every square area, thereby relaying the degree to which the given area was becoming “hotter” or “colder.” These z-scores were also visualized as a blue-yellow-red gradient so as to relay the distribution of longitudinal trends for tweets in all areas of the United States.Concurrent longitudinal and geospatial analysis was conducted by computing a space-time cube with 1-day time step intervals for 2,500 square-kilometer areas in the United States. The space-time cube is a construct whereby a record is produced for every combination of time step and space. After the space-time cube was created using built-in tools within ArcMap, the Emerging Hot Spot Analysis feature was used to analyze the space-time cube to compute the Getis Ord Gi* statistic for each area at each time point, thereby identifying of Z-scores for both COVID-19 cases per capita were then averaged for areas within each of the fifty states in the United States and the District of Columbia, as were z-scores for tweets per capita in each state. Ranking of average z-score was then computed for cases and tweets, and the largest discrepancies between rankings were reported.The Emerging Hot Spot Analysis feature was also conducted on space-time cubes for active daily COVID-19 cases per capita within the study time period. Data management, statistical analysis, and geospatial visualization was conducted using R version 3.6.0 and ArcGIS version 10.6.From March 3rd through April 13th, 173,847,058 tweets related to COVID-19 were collected. 1,244,478 of these tweets had geo-identifiable information which could be converted to point coordinates, of which 609,794 were from the United States. Of these US tweets, machine learning classification selected 17,841 with evidence of first-hand experience with COVID-19.In an analysis to detect aberrantly high levels of tweets within the in the 32-day period between March 14th and April 13th, inclusive, approximately two-thirds of statistically significant aberrations at the state level were detected in the seven-day period between March 28th and April 3rd, inclusive . Nearly The number of tweets collected at the secondary administrative division in the United States were especially high in areas with high numbers of people , with lep = 0.0008), and this trend remained consistent after normalizing for county-level population (p = 0.0012). However, a visualization of z-scores across US spatial units revealed discrepancies in trends toward significant hot/cold spots for . Z-scores for trends from the resultant emerging hot spot analysis for COVID-19 cases per capita were compared to z-scores for trends from emerging hot spot analysis for COVID-19 tweets per capita. Average values were then computed for each state and the District of Columbia. The range of state-level z-scores observed for the cases per capita analysis was 1.12 (Alaska) to 8.85 (District of Columbia), and for the tweets per capita analysis was -10.78 (Missouri) to 1.89 (Alabama). Furthermore, ranks were also computed for trend z-scores of normalized cases and normalized tweets, with a rank of 1 for to the highest z-score value and a rank of 51 for the lowest z-score value. The largest discrepancies, in which a state had relatively high trend z-scores for increases in normalized cases while having relatively low trend z-scores for normalized tweets, were for New Hampshire ; Vermont ; and Rhode Island .A time-space cube was computed for population-normalized US daily active cases of COVID-19, using county centroids with 1-day time step intervals. Overall, a statistically significant increase in county-level population-normalized COVID-19 cases was detected . Alternatively, increased social media messaging about COVID-19 may result from higher numbers of people contracting COVID-19 than have been reported in these areas, which itself may be related to insufficient testing capacity and healthcare access, as has been widely reported and remains an acute problem in rural communities –18.This study is unique in that it uses Twitter data as a proxy measure for assessing the concurrent longitudinal and geospatial distributions of attention to COVID-19 across local and regional communities in the United States. However, a number of studies have utilized similar methods in COVID-19 research, although usually for COVID-19 infection cases and/or deaths. For example, time-space methods were used to differentiate the trajectories of COVID-19 prevalence between rural and urban counties in the United States . While TAs these analyses were ecological in nature, this study is primarily intended to generate hypotheses, and the findings in this study should be further corroborated with other sources of data that can better identify specific COVID-19 hot and cold spots in relation to projected number of cases. Other data includes the availability and volume of COVID-19 testing kits, search engine query results (e.g. Google Trends data), COVID-19 hospitalizations data, etc. Tweets themselves were collected on the basis of containing certain keywords related to COVID-19, though the actual content of these tweets may vary in their interpretability for estimating attention to COVID-19 or disease burden. Future work by co-authors is focused on developing machine learning approaches to identify users reporting COVID-19-related symptoms, lack of testing access, and recovery, that could be used in a future study to better assess COVID-19 hot spots and also used to compare against aberrations in reporting.While preliminary, this study suggests that there may exist an appreciable degree of variability in the patterns defining community attention to public health topics, particularly as pertains to online discussion of infectious disease outbreaks. Further study should be conducted to characterize community-level moderators of these patterns and to understand the degree to which they may facilitate improved dissemination and impact of public health messaging. The use of EARS and time-space cubes appear to have utility in identifying longitudinal trends and their discrepancies across space, and further academic research on the topic of community-level attention to public health issues may seek to leverage these analytical techniques.S1 Data(CSV)Click here for additional data file.


Y-chromosomal short tandem repeats (Y-STRs) are widely used in human research for the evaluation of population substructure or population differentiation. Previous studies show that several haplotype sets can be used for the evaluation of population differentiation. However, little is known about whether each Y-STR in these sets performs well during this procedure. In this study, a total of 20,927 haplotypes of a Yfiler Plus set were collected from 41 global populations. Different configurations were observed in multidimensional scaling (MDS) plots based on pairwise genetic distances evaluated using a Yfiler set and a Yfiler Plus set, respectively. Subsequently, 23 single-copy Y-STRs were characterized in the evaluation of population differentiation using the mean of allele frequency difference (mAFD) between populations. Our results indicated that DYS392 had the largest mAFD value (0.3802) and YGATAH4 had the smallest value (0.1845). On the whole, larger pairwise genetic distances could be obtained using the set with the top fifteen markers from these 23 single-copy Y-STRs, and clear clustering or separation of populations could be observed in the MDS plot in comparison with those using the set with the minimum fifteen markers. In conclusion, the mAFD value is reliable to characterize Y-STRs for efficiency in the evaluation of population differentiation. Over the past decade, Y-chromosomal short tandem repeats (Y-STRs) have been widely used in human research and forensic practice to supplement information retrieved from autosomal DNA profiling. Y-STRs can be applied for acquiring male genotypes from stains of unbalanced male/female DNA mixture ,2,3, forBecause of the male-specific inheritance pattern and haploid nature of the Y chromosome, it is more sensitive to genetic drift and founder effect for Y-linked markers than for autosomal ones. Y-STRs are widely used for the evaluation of population substructure or population differentiation by testing pairwise genetic distances. The clustering or separation of populations can further be visualized using multidimensional scaling (MDS) analysis based on the similarity of pairwise genetic distances between populations. Previous studies show that several haplotype sets, such as the minimal haplotype set, Yfiler set, PowerPlex Y23 set and Yfiler Plus set, can be used in the evaluation of population differentiation ,9,10,11.In this study, we characterized 23 single-copy Y-STRs adopted in a Yfiler Plus set in the evaluation of population differentiation using the mean of allele frequency difference (mAFD) between populations. Haplotype profiles of the Yfiler Plus set were compiled from 41 global populations, and an evaluation of population differentiation using the Yfiler set and Yfiler Plus set was performed. Further, the mAFD values of 23 Y-STR loci between 41 populations were calculated, respectively, and the reliability of the mAFD to characterize Y-STRs in the evaluation of population differentiation was estimated based on pairwise genetic distances and MDS analysis from a series of fifteen-marker sets.A total of 41 populations with haplotypes of 27 Y-STR loci in a Yfiler Plus set were collected . To facin is the total number of alleles at a locus, and if-terms denote the frequency of the ith allele in the two populations. As for every Y-STR, the mean of the AFD across all population pairs was obtained based on the AFD for every population pair. Here, the mAFD values of every single-copy Y-STRs were computed using an in-house Python script.The allele frequency difference (AFD) of each Y-STR locus between two populations was defined as follows according to previous reports :AFD=12∑ip values were calculated at a significant level of 0.05 using 10,000 permutations. In addition, MDS analysis estimating similarity quantitatively among populations was performed with the software IBM SPSS® Statistics version 22 . The output of MDS is a plot that reveals the relational structures of objects, where similar objects cluster together, and dissimilar ones are far from each other.The evaluation of population differentiation using a Yfiler set and a Yifler Plus set was carried out. Pairwise genetic distances of these two marker sets were gauged using Arlequin v3.5 , and a lFor validating the efficacy of the mAFD in the evaluation of population differentiation, nine marker sets containing 15 Y-STRs were constructed along with the stepwise reduction of mAFD value (step size: one marker) using the 23 Y-STRs evaluated. Pairwise genetic distances between populations for these Y-STR sets were quantified and compared. To visualize the differences in pairwise genetic distances between populations, MDS analysis of all marker sets was conducted.To evaluate the population differentiation, the pairwise genetic distances between 41 populations were calculated based on a Yfiler set and Yfiler Plus set, respectively, and population differentiation was visualized in a MDS plot. On the whole, the distribution of populations was in accordance with the biogeographic pattern based on pairwise genetic distances tested using a Yfiler set or a Yfiler Plus set A,B. HoweIn this study, the same population sets were employed to evaluate population differentiation using a Yfiler set and a Yfiler Plus set, which can reduce the bias from sampling using different population sets. The Yfiler Plus set seems to more clearly cluster or separate populations than the Yfiler set in MDS analysis A,B, whicTo characterize Y-STRs in the evaluation of population differentiation, the mAFD values of 23 Y-STRs were calculated as described in Material and Methods section. As shown in In this study, the mAFD is described to evaluate the variance of genetic markers in populations, which is somewhat similar to Rogers’ distance ,18. RogeThe difference of allelic frequency between populations might be affected by many factors, such as founder effect, genetic drift and mutation rate. The mutation events of each Y-STR occur independently in the population, although the evaluation of genetic distances is based on the Y-STR haplotypes. A low mutation rate for Y-STRs might make the difference of allelic frequency more sensitive to genetic drift and founder effect. In contrast, a high mutation rate for Y-STRs might help to rapidly establish a permanent allelic configuration in the population. In this study, the mutation rate did not show a close correlation with the mAFD . SimilarTo validate the efficacy of the mAFD in the evaluation of population differentiation, 23 Y-STR markers were ranked in a descending order based on the mAFD, and nine sets were established using a sliding-set method with a set of 15 markers and a step size of one marker. The pairwise genetic distances calculated using these sets could be varied , and theTo visualize population differentiation, MDS analysis was performed based on pairwise genetic distances obtained using the sets with the top fifteen markers and the minimum fifteen markers, respectively. As shown in Genetic distance is defined as the extent of genetic differentiation between populations or species. Previous studies demonstrate the capacity of several haplotype sets in the evaluation of population differentiation through genetic distance, and little attention has been paid to the selection of genetic markers. Unlike autosomal markers, which can reach Hardy–Weinberg equilibrium, Y-STRs are paternally inherited. Currently, it remains unknown whether a Y-STR locus in a haplotype is suitable for the evaluation of population differentiation. Although the method based on the mAFD value for the evaluation of single Y-STR is relatively simple in this study, our results show that the mAFD is suitable for characterizing Y-STRs in the evaluation of population differentiation. In the future, the introduction of more global populations can improve the evaluation of the mAFD value for each Y-STR.


The monoclonal antibodies (mAbs) have significantly changed the treatment of multiple myeloma (MM) patients. However, despite their introduction, MM remains an incurable disease. The mAbs currently used for MM treatment were developed with different mechanisms of action able to target antigens, such as cluster of differentiation 38 (CD38) and SLAM family member 7 (SLAMF7) expressed by both, MM cells and the immune microenvironment cells. In this review, we focused on the mechanisms of action of the main mAbs approved for the therapy of MM, and on the possible novel approaches to improve MM cell killing by mAbs. Actually, the combination of anti-CD38 or anti-SLAMF7 mAbs with the immunomodulatory drugs significantly improved the clinical effect in MM patients. On the other hand, pre-clinical evidence indicates that different approaches may increase the efficacy of mAbs. The use of trans-retinoic acid, the cyclophosphamide or the combination of anti-CD47 and anti-CD137 mAbs have given the rationale to design these types of combinations therapies in MM patients in the future. In conclusion, a better understanding of the mechanism of action of the mAbs will allow us to develop novel therapeutic approaches to improve their response rate and to overcome their resistance in MM patients. In recent years, the introduction of monoclonal antibodies (mAbs) targeting CD38 and the signaling lymphocytic activation molecule family member 7 (SLAMF7) represents an important step towards the treatment of relapsed/refractory multiple myeloma (RRMM) patients ,2,3.More recently, the use of mAbs is moving into the first line treatment of newly diagnosed MM patients with high rate and durable responses ,4,5.Although immunotherapy with mAbs represents an attractive approach because of its well-established clinical efficacy, there is substantial variability in the sensitivity and duration of the response among patients. In this review, we will specifically focus on the mAbs currently used in the treatment of MM, such as the anti-CD38 antibodies daratumumab (DARA), isatuximab (ISA) and the anti- SLAMF7 elotuzumab (ELO). We will provide a summary of their mechanisms of actions and the new strategies to improve their effectiveness and overcome resistance.DARA is the first CD38-targeting mAb approved in MM therapy. It is a fully human immunoglobulin G1 kappa (IgG1κ mAb that targets CD38 . More re+CD16+ monocytes have a role in this mechanism of MM cell killing by DARA [+ (FcγRIIIA) subset of monocytes is fundamental in DARA MM cells-killing activity [Anti-CD38 antibodies kill myeloma cells by different mechanisms of action (MoA), including classical FC-dependent immune effector mechanisms, direct and immunomodulatory effects . Natural by DARA . Moreove by DARA . Recentlactivity . In vitractivity . On the activity .Moreover, the Fc tail of the anti-CD38 mAbs can activate the complement cascade inducing the complement-dependent cytotoxicity (CDC) against MM cells . DARA is+ and CD8+ T cells expansion in MM patients and in particular the effector memory CD8+ T cells concomitant with a decrease of naïve T cells subset [+ cells [DARA also has an immunomodulatory effect in the MM bone marrow (BM) microenvironment, depleting T regulatory cells (T regs), regulatory B cells (B regs), and myeloid-derived suppressors cells (MDSCs) ,14,15. As subset . Moreove[+ cells ,18. IndeFinally, ISA directly induces MM cell death by binding the CD38 on the cell surface, then activating the classical caspase and lysosome death pathways . In contThe tissue expression profile of CD38 explains some of the “off target” effects of DARA. It has been reported that CD38 is also expressed by red blood cells (RBCs). Binding of DARA to CD38 on RBCs leads to panagglutination in indirect antiglobulin test, possibly masking clinically relevant alloantibodies and complicating the selection of compatible RBCs for transfusion . On the The use of therapeutic mAbs may also affect laboratory diagnostics in MM patients. It has been reported that DARA interferes with PCs detection by flow cytometry  and distClinical studies showed that DARA can be detected as an individual monoclonal band in serum IFE. Because M-protein follow-up by IFE is part of the criteria to assess the response to the treatment in MM patients, therefore, DARA band must not be confused with the endogenous M-protein of the patient. To discriminate between endogenous M-protein and DARA, a DARA-specific immunofixation electrophoresis reflex assay (DIRA) was developed using a mouse anti-DARA antibody . SimilarELO is a humanized IgG1 mAb that targets the extracellular domain of SLAMF7, which is expressed on normal PCs and MM cells . SLAMF7 The mechanisms involved in the acquired resistance to therapy with mAbs are not fully understood. Downregulation of the target antigen may be one of the factors that contribute to the development of mAbs resistance. However, in clinical settings, the correlation between CD38 expression before treatment and responses to DARA therapy is still controversial ,30. StudDanhof et al. reported that other factors, like an increased number of NK cells prior to the treatment, could potentiate the patient′s response when treated with ELO . AdditioIn addition, the modulation of CD38 after treatment with a mAb has also been studied as a possible mechanism of acquired resistance. DARA induces the release of CD38 from myeloma cells by microvesicles  and the In addition, DARA resistance was found to be associated with the overexpression of complement inhibitory proteins CD55 and CD59 at the time of disease progression .The expression of targets on the surface of MM cells appears to be the main determinant for the resistance to mAbs. The modulation of the expression of these targets by different agents that can re-sensitize mAbs seems to be a possible key to overcoming resistance to the drug. In vitro and in vivo studies showed that agents such ATRA can be used to overcome resistance by increasing the expression of CD38 in MM cells . Nijhof Among the new potential therapeutic mAbs, CD47 is emerging as a new target in the context of solid tumor and hematological malignancies. Here, we reported the potential role of targeting CD47 as a therapeutic option alone or in combination with the main drugs used in MM treatment, to explain emerging immunotherapeutic approaches.CD47 is an integrin-associated receptor, ubiquitously expressed on the surface of many cell types including RBCs and cancer cells ,39,40. TKim et al. reported that anti-CD47 antibodies require the involvement of phagocytic cells or their progenitors such as monocytes, macrophages, and dendritic cells to perform the anti-MM activity. In particular, they observed that the treatment with anti-CD47 mAb induces phagocytosis of MM cells by macrophages derived from mouse models. In addition, they showed that the anti-CD47 treatment influences the viability of cells; however, CDC or ADCC were not observed. Furthermore, the treatment with anti-CD47 in a mouse model resulted in the inhibition of MM cell growth, without affecting BM microenvironment .+ CD16+ monocytes. Furthermore, they observed that combination treatment DARA/anti-CD47 increases the killing of MM cells that survived only DARA treatment alone [Although the use of anti-CD47 mAbs promotes anti-MM activity alone, it is possible to implement the antitumor effect of this drug in combination with CD38 targeting agents, such as DARA ,53. Stornt alone . For theConversely, the potential role of CD47 blockade in combination with other therapies based on mAbs is still controversial ,55,56. SThe anti-MM effect of DARA could be enhanced by Cy, in particular through an increased ADCP. Cy has been demonstrated to induce an acute secretory activating phenotype in tumor cells, that leads to macrophage infiltration and phagocytic activity in the BM . Some auThese findings suggest that MM cells may be more susceptible to ADCP after treatment with Cy and DARA together .Panobinostat (PANO), is a pan-HDACi able to increase the expression of CD38 by PCs from MM patients . MoreoveRecently, Garcia-Guerrero et al. demonstrated that the specific inhibitor of the histone deacetylase 6 (HDAC6), ricolinostat, also increases CD38 RNA expression levels and CD38 molecules on the surface of MM cells. This upregulation is specific for MM cells and does not occur on T cells, leukemia, or lymphoma cells . MoreoveTogether, these in vitro evidence suggest that HDACi could be used in combination with DARA to potentiate the effect of the anti-CD38 mAb.NK cells acquire CD137 on their surface after having bound a Fc tail of an antibody with their CD16 receptor. Anti-CD137 mAbs, as urelumab, have been shown to enhance T cell mediate anti-tumor immunity and anti-tumor ADCC mediated by mAbs ,63. OchoMoreover, phase I study combining low dose urelumab and ELO is ongoing (NCT02252263).Several clinical trials evaluating the combination of anti-SLAMF7/anti-CD38 mAbs with ImiDs are currently ongoing in MM, with promising results. In this part of the review, we elucidate the rationale of these therapeutic strategies and provide a summary of mechanistic findings from pre-clinical studies in MM models.Preliminary in vitro studies on the anti-SLAMF7 mAb, ELO, showed that the pre-treatment of either effector cells  or target myeloma cells with clinically achievable doses of lenalidomide (LEN) enhanced ADCC-mediated lysis of MM cells triggered by ELO . These r+CD56+ lymphocytes in the presence of ELO+LEN compared with either agent alone was also described. TNF-α directly induced MM cell death, besides increasing NK cell activation; TNF- α neutralizing Abs reduced this effect [Specifically, Balasa et al.  demonstrs effect . The rols effect , as wells effect , thus suMore recently, Pazina et al.  describeOverall, these studies thus explain the significant improvement of survival outcomes in RRMM patients treated with a combination of ELO and LEN.Similarly to ELO, the therapeutic combination of anti-CD38 mAbs with LEN or pomalidomide (POM) has shown encouraging clinical results in the treatment of RRMM patients, which are supported by preclinical data.Van der Veer et al.  demonstr-CD56+ NK cells, with no alterations of T-cell and monocyte compartments, even in patients’ refractory to LEN [Other studies showed that LEN enhances in vitro DARA-induced myeloma cell lysis ADCC-mediated. This effect was mediated by an increased frequency of CD3y to LEN . Ex-vivoy to LEN . These ry to LEN  where thy to LEN  hence suy to LEN .More recently, it has been suggested that vitamin D pathway activation can potentiate the synergism between LEN and MOR202-mediated ADCP  due to LAnother potential explanation for DARA-LEN synergism could be ImiDs ability to decrease the frequency of inhibitory T cell populations in vitro . Indeed,In addition, a study by Bolzoni et al.  previousLastly, Jiang et al.  showed tThese pre-clinical results thus give the rationale to combine ImiDs with anti-CD38 mAbs in the therapy against MM.Up today, the optimal sequence for the administration of anti-SLAM7 and anti-CD38 mAbs in RRMM patients is unknown. DARA and ELO-based regimens have never been compared head-to head in RRMM patients. However, a retrospective clinical study showed that DARA retains its response rate whether administered as the first or second mAb used for the treatment of RRMM. On the other hand, the response rate of ELO seems to be reduced when ELO was administered after DARA . Pre-cliMoreover, in the ELOQUENT-2 clinical study it has been reported that the greatest PFS benefit in favor of ELO treatment was obtained in RRMM patients with a times of diagnosis longer or equal to a median of 3.5 years and those in relapse after a first line of treatment , suggestOverall, these clinical evidences support the hypothesis that the use of ELO would precede the use of DARA in an optimal sequence of treatment in RRMM, whereas the role of ELO in newly diagnosed MM patients remains to be defined.Along with CD38 and SLAMF/7, other possible therapeutic targets were identified in the last years to overcome MM cell drug resistance. B-cell Maturation Antigen (BCMA), also known as TNFRSF-17, is a TNF receptor (TNFR) family protein highly expressed by human MM cells . BCMA haGSK2857916 is the first therapeutic anti-BCMA antibody-drug conjugate . GSK2857GSK2857916 namely Belantamab Mafodotin was investigated in monotherapy in a phase I trial in RRMM patients ,94. The Another approach to target BCMA is based on bispecific antibodies (BsAbs), which deliver T cells against a target antigen through the induction of an immunological synapse . BI 8369In conclusion, the introduction of mAbs have brought new immunotherapeutic approaches improving the clinical outcomes in the treatment of MM patients. However, many patients still relapse or do not respond to these agents. The unique mechanisms of action, low cytotoxicity, and safety profiles make mAbs an ideal constituent to be used in combination with current therapeutic regimens, which could improve the response rate and possibly overcome resistance.® seems to potentiate the effect of the mAbs, anti-CD38 and anti-SLAMF7, compared with single-agent treatment, reaching significant clinical effects even in RRMM patients. Several mAbs able to target CD38 and SLAMF7, expressed by both MM cells and the immune microenvironment cells, have been developed. Combination therapy with IMiDsIn this context, there is a need for novel strategies to improve MM cell killing by mAbs. Pre-clinical evidence indicates that different approaches may increase the efficacy of mAbs as the use of ATRA, Cy, or the combination with the anti-CD47 and anti-CD137 mAbs. These results gave the rationale for the ongoing clinical trials on these combination therapies, which could improve MM patient treatment .New mAbs have been also developed to treat MM patients, refractory to several lines of treatment including those to anti-CD38 mAbs. Among these anti BCMA mAbs seems to be more promising.To conclude, a better understanding of the mechanisms of action of mAbs will permit to develop novel approaches and drug combinations to improve the response rate of the mAbs and to overcome their resistance.


Background: Most biomedical research has focused on sampling COVID-19 patients presenting to hospital with advanced disease, with less focus on the asymptomatic or paucisymptomatic. We established a bioresource with serial sampling of health care workers (HCWs) designed to obtain samples before and during mainly mild disease, with follow-up sampling to evaluate the quality and duration of immune memory.Methods: We conducted a prospective study on HCWs from three hospital sites in London, initially at a single centre (recruited just prior to first peak community transmission in London), but then extended to multiple sites 3 weeks later . Asymptomatic participants attending work complete a health questionnaire, and provide a nasal swab (for SARS-CoV-2 RNA by RT-PCR tests) and blood samples  at 16 weekly study visits, and at 6 and 12 months.Results: Preliminary baseline results for the first 731 HCWs  are presented. Mean age was 38±11 years; 67% are female, 31% nurses, 20% doctors, and 19% work in intensive care units. COVID-19-associated risk factors were: 37% black, Asian or minority ethnicities; 18% smokers; 13% obesity; 11% asthma; 7% hypertension and 2% diabetes mellitus. At baseline, 41% reported symptoms in the preceding 2 weeks. Preliminary test results from the initial cohort (n=400) are available: PCR at baseline for SARS-CoV-2 was positive in 28 of 396  and 15 of 385  had circulating IgG antibodies.Conclusions: This COVID-19 bioresource established just before the peak of infections in the UK will provide longitudinal assessments of incident infection and immune responses in HCWs through the natural time course of disease and convalescence. The samples and data from this bioresource are available to academic collaborators by application https://covid-consortium.com/application-for-samples/. Healthcare workers (HCW) may be at greater infection risk compared to the general population5. Many infections are asymptomatic6, therefore surveillance of symptomatic coronavirus disease 2019 (COVID-19) underestimates the infection burden. This has led to calls for regular surveillance of asymptomatic HCWs10, to ensure that health care facilities do not become transmission hot-spots, to protect the workforce and vulnerable patients and to prevent community reseeding.The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to more than 6 million infections and 300,000 deaths worldwide at the time of writing14. Data are lacking on the host response and biology of asymptomatic or pauci-symptomatic infection as well as the early  stages of disease. This undermines efforts to understand the determinants of disease severity.Most SARS-CoV-2 studies have focused on severe hospitalized COVID-19 caseshttps://covid-consortium.com) and the “COVID-19 Immune Protection and Pathogenesis in Healthcare Worker Bioresource” (NCT04318314). In this manuscript we: (1) provide a description of the study design, (2) present preliminary results of the baseline visit in the first 400 HCWs  and subsequent 331  – focusing on two different time-points in the epidemiologic curve (just before and after the peak of new daily cases in London), and (3) call for research collaborators wishing to access biological samples in participants across the spectrum of COVID-19 to contribute to a range of prespecified objectives, planned by the consortiumhttps://covid-consortium.com/application-for-samples/.We sought to provide a resource to address these gaps by establishing a cohort of HCWs who are well and attending work across selected central London hospitals. We aimed to characterize and quantify the rates of HCW infection (particularly mild or asymptomatic) over the first London COVID-19 pandemic wave, with moderate frequency longitudinal comprehensive sampling before infection and in the weeks to months afterwards. Accordingly, we established the COVID-consortium . All participants provided written informed consent.https://covid-consortium.com). No other inclusion or exclusion criteria were considered.Adult (>18 years) hospital HCWs who were fit and well to attend work in any role and across a range of clinical areas, were invited to participate via hospital email, posters, staff meetings, training sessions and participant information leaflets (seeNCT04318314) uses a prospective cohort design , a secondary care hospital part of Barts and the Royal London NHS Trust to a local population of 3 million, with specialist cancer and cardiovascular services to a supra-regional population of 6 million. In response to the pandemic, the hospital expanded ventilated intensive care provision for COVID-19 patients to 122 beds across five units.Recruitment was initially at St Bartholomew’s Hospital, London, UK  to other local sites: Nightingale Hospital London  and Royal Free NHS Hospital Trust . Collaborations with Cape Town (South Africa) and Sydney  are also in place to explore the impact of different surge rates, ethnicity, vitamin D levels and the 6-month seasonal difference; unlike UK sites, follow-ups there are performed every fortnight. Our team was comprised of researchers and volunteers from outside of the clinical supply chains.To improve statistical power for downstream analyses, we expanded the target sample size to n=1,000 and extended recruitment on 17Participants complete a baseline questionnaire  includinREDCap v8.5.22)16 to capture occupational metadata, new SARS-CoV-2 exposure, symptoms and test results, and biosample collection . Following multi-site expansion, information on exercise, pregnancies/contraception, vitamin supplements, working hours and psychological wellbeing 18 were added. The questionnaires used are summarized inFollowing recruitment (baseline visit), if fit and well to attend work, participants would undertake in-person weekly questionnaires using research electronic data infrastructure  of nasal swabs using Roche cobas® SARS-CoV-2 test- 21.Pathogen sequencing with results via the COVID-19 Genomics UK (COG-UK) consortium- 22.Host DNA extraction, quantification and SNP analysis via the Illumina Infinium® GlobalScreeningArray-24v1.0- 23).IgG antibodies assay to antigen S1, defining seroconversion  are a scarce resource and discussions are ongoing about maximising yield;- Saliva will be diluted and aliquots are available. Further aliquoting will be dependent on demand;- Other antibody, antigen tests may also be made available should they emerge;- Serum and plasma will be aliquoted into 100µL samples and divided into packs for individual research teams. Excess RNA (swab and blood) and host DNA will potentially also be available.The following experimental approaches will be implemented , includihttps://covid-consortium.com/application-for-samples/). The access principles are those standard to many bioresources: to maximise yield of timely science, to make results available to other researchers in a reasonable timeframe via a data lake, to reward researchers with appropriate levels of authorship and, where present, intellectual property in a fair, transparent and swift way. We encourage teams to apply and to link their analysis datasets of hospitalised patients with severe disease. We also encourage applications from commercial entities as long as the core principles above apply.The COVID-19 consortium has developed access systems to facilitate the use of this bioresource by scientists for health-related research of public interest. Research teams can apply to use the bioresource via the study website .Baseline characteristics for the first 400 HCWs  and subsequent 331 multicentre study expansion participants  are presented inThe mean age of all study participants was 38 ± 11 years (0.7% >65 years), 67% female, 37% were black, Asian or minority ethnicities. Demographics are further detailed in2, 97 (13%) participants were obese (BMI >30 kg/m2). The proportion of sedentary participants (reported exercise <1.5 hours/week) was 17%.Co-morbidities and COVID-19 risk factors  reportedMedications are detailed inThe proportion of HCWs with a household size of at least three people was 48% (n=348), with a third of the participants reported having children at home . Only eiRoles of HCWs  includedThe prevalence of COVID-related symptoms in the two weeks prior to recruitment was 34% (n=249/731), significantly higher in the early cohort recruited in March . More HCWs from the multisite cohort recruited at the later time point thought that they had had prior COVID-19 . Overall, the most prevalent symptom was nasal congestion (13%), followed by odynophagia (11%), dry cough (8%) and fatigue (8%). A recent (<3 months) respiratory tract infection was reported in 20% of the participants.SARS-CoV-2 RT-PCR and serology were processed for the first cohort (n=400) and are described. PCR for SARS-CoV-2 was positive in 28 of 396 , of which 20 (71%) were symptomatic in the 14 days before . In the This study is establishing a bioresource (COVID-consortium) derived from health care workers, with samples taken at the time of pre‑symptomatic incident infection, linked to data on clinical outcomes, serology and follow-up sampling to evaluate the quality and duration of immune memory to the virus. Here we present preliminary baseline data on the first 731 participants, comprised of a single-centre cohort recruited in March 2020 just before the time of peak community transmission in London, and a subsequent expanded multicentre cohort recruited from mid-April 2020. This resource should enable collaborative science and approved investigators can apply for sample access or access to the resultant data lake to address specific questions or for incorporation into larger COVID-19 datasets.24. Our cohort is representative of a multi-ethnic urban UK population of working age, and more specifically of the NHS workforce across different clinical roles and departments. Confirmed COVID-19 contacts were low in the community (1%), but much higher in-hospital , particularly in the second cohort (recruited later). All participants were self-reported as fit to attend work on all clinical visits, and at baseline the majority of participants had been asymptomatic and did not think that they had been infected. Nevertheless, 1 out of 10 participants had a confirmed baseline SARS-CoV-2 infection confirmed by PCR and/or positive serology test that could represent current or previous infection, at the beginning of peak transmission in March.SARS-CoV-2 can rapidly spread to patients and HCWs in hospitals, and HCWs generally have been particularly hard hit with high reported rates of infection25, and those recruited a month later more often reported they suspected that they had already had COVID-19.Of interest, two different timepoints are presented here. As one would expect, the proportion of HCWs who reported prior symptoms was significantly higher in participants recruited just before peak community transmissionst May 2020), 160 research projects on COVID-19 received a favourable opinion by the UK NHS Health Research Authority (last updated list on 3rd June 2020), the majority focused on confirmed COVID-19 patients6. Emergent studies are now targeting mild and population disease, but almost all missed peak transmission. Larger-scale community surveillance studies typically also do not have temporal granularity to detect early disease changes and may be more focused on providing data to improve modelling rather than host:pathogen biology. Studying HCWs is a middle ground - subjects are deemed fit to work, but have higher exposure rates to confirmed COVID-19 cases, and can also be frequently assessed. COVID-19 bioresources in the general population and HCWs have already been established. Studies such as the COVID-19 Emergency Response Assessment (CERA)26 and the Rapid European SARS-COV-2 Emergency research Response (RECOVER)27 use qualitative instruments to assess the physical and psychological well-being of frontline doctors at different phases of the pandemic. The SARS-CoV-2 Acquisition in Frontline Health Care Workers – Evaluation to Inform Response (SAFER)28 study will perform qualitative interviews and collect nose and throat swabs twice weekly and serum samples monthly from healthcare staff. Preliminary results from the SAFER study revealed a higher PCR positive rate of 21% among HCWs (42/200), but during the whole first month of observation (starting between 26th March and 8th April 2020)29. The COVID-19 Staff Testing of Antibody Responses Study (CO-STARS) follows a similar design, with serologies performed monthly for 6 months and then 6-monthly for a total of 6 years30.The scientific community has merged forces to tackle this unprecedented pandemic. Since the start of January 2020 (until 31https://covid-consortium.com) and the “COVID-19 Immune Protection and Pathogenesis in Healthcare Worker Bioresource” (NCT04318314) thus encourages research teams to apply and even potentially link their own datasets to ours (with results expected to be returned to the data lake for collaborative science). Some of the fields worth exploring include immune responses during the subclinical phases of infection, properties of the immunoglobulins and immune cellular reactivity , host and viral genetic variation, and other environmental or acquired risk factors.The comprehensive (questionnaires and biosamples) serial assessment of asymptomatic participants starting just before peak community transmission of SARS-CoV-2 makes our bioresource a precious dataset for the scientific community. We expect that the data sampled from HCWs facilitates understanding of mild disease and subclinical infection at a more rapid rate than the general population allowing comparison with those more severely affected or hospitalised for COVID-19. The COVID-19 consortium , the frequency of comorbidities is relatively low, there are no children and elderly subjects are under-represented. In addition, our cohort of hospital HCWs is unlikely to be generalisable to other institutional settings such as care homes, or to the wider population given that all participants are of working age and in good general health. A selection bias could also be present as HCWs who felt at higher risk of exposure could have been more motivated to participate in the study than the rest of the hospital staff. However, it is worth highlighting that participants had to sign consent forms recognising that they would not receive results in real-time (particularly when access to tests was limited early in the pandemic), and therefore it should have minimised bias in recruitment.The three centres initially included reflect the epidemiological curve of a single city (London). The COVID-19 bioresource started at peak community transmission with prevalent asymptomatic infection in 7.1% and seropositivity of 3.8% at baseline. In data from the subsequent four weeks, we have already reported that the incident asymptomatic infections fell in line with reductions in the London wide incidenceJust before the peak of COVID-19 infections in the UK we established a rich and granular bioresource of healthcare workers with the aim of gathering insights into early disease / asymptomatic SARS-CoV-2 infection. Combining exposure with multi-qualitative and quantitative assessments, we envision a more complete picture of immune response in this context. The samples and data securely curated this bioresource are now accessible to the wider scientific community by application.https://covid-consortium.com/application-for-samples/).The COVID-19 consortium has developed access systems to facilitate the use of this bioresource and the data underlying this article by scientists for health-related research of public interest. However, although participants are pseudoanonymsed, there is data regarding home addresses, household characteristics, and other details that could potentially lead to identification. Research teams can therefore apply to use the bioresource via the application form that can be found on the study website  for use as a "bioresource" for research on COVID-19. The study population has a high prevalence of exposure to COVID-19 and evidence of recent SARS-CoV-2 infection.The study population is a relatively select group of healthcare workers. It is essential that this group is described in greater detail in order to best understand the generalisability of any study findings. As such, it is unclear whether any of the HCWs do not have direct patient contact (e.g. laboratory staff). It would also be helpful to have a commentary on whether there is any selection bias among those volunteering to be study participants, beyond the baseline data presented. This is critical in order to understand any study population-level analyses.A cohort study is an observational study by definition. Therefore "observational" is an unnecessary adjective in several places.What definition of ethnicity is being used? Is the same definition being used for different countries? Specific comments: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:Infectious diseases, microbiology, epidemiology.I 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. We thank the reviewer for the time taken to review our manuscript and for the pertinent comments. We provide below a point-by-point response.1. The study population is a relatively select group of healthcare workers. It is essential that this group is described in greater detail in order to best understand the generalisability of any study findings. As such, it is unclear whether any of the HCWs do not have direct patient contact (e.g. laboratory staff). It would also be helpful to have a commentary on whether there is any selection bias among those volunteering to be study participants, beyond the baseline data presented. This is critical in order to understand any study population-level analyses.Thank you. This cohort represents an heterogenous group with different degrees of patient contact and consequently different degrees of exposure – from nurses/doctors to laboratory/pharmacy staff and managers. We, however, believe that this can prove advantageous to understand risk factors. A more detailed description of the HCWs roles is now provided in the results section. The characteristics here described are likely generalisable to HCWs in most institutions - participants recruited across all staff groups with broad baseline demographics. They are not, however, generalisable to the wider population given that all participants are of working age and in good general health. More granular data on exposure will be part of the study investigation and presented in subsequent publications Of note, the factor “patient contact” was taken into account in our questionnaire . We acknowledge a selection bias could be present as HCWs who felt at higher risk of exposure could have been more motivated to participate in the study than the rest of the hospital staff. However, it is worth highlighting that participants had to sign consent forms recognising that they would not receive results in real-time (particularly when access to tests was limited early in the pandemic), and therefore it should have minimised bias in recruitment. This has now been added to the limitations section. 2. A cohort study is an observational study by definition. Therefore "observational" is an unnecessary adjective in several places.Thank you. We agree and have now corrected this.3. What definition of ethnicity is being used? Is the same definition being used for different countries?We have now clarified this - see legend of table 1.


Apart from viral sexually transmitted diseases, viral infections in urology are not common and likely to be underreported. Initially, COVID-19 was thought to be only affecting our practice indirectly through reducing elective work that almost came to a stop. However, recent upcoming reports show that urologists can get involved far beyond that.Genitourinary tract can be directly affected based on the SARS-CoV-2 virus organotropism. The aim of this article is to present a comprehensive review of the data available and to highlight any possible similarity with the few known viral infections involving genitourinary organs with regard to its pathophysiologic impact.Urologists need to extrapolate their experience with viral infections in the urinary tract so as to be able to manage such possible COVID infections and its short- and long-term consequences. COVID-19 pandemic continues to overwhelm the globe. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets primarily the respiratory tract. Nevertheless, other organs have been found to be involved including the kidneys, liver, heart, and brain. Hence, it can be stated that SARS-CoV-2 has a broad organotropism [Apart from viral STDs, viral infections in urology are not common in our daily practice and symptoms related to viral infections of the urinary tract can be frequently missed or underreported. Therefore, we need to highlight the possibility of dealing with SARS-CoV-2 in our practice.Viral replication within the renal tissue, e.g., Epstein-Barr virus and cytomegalovirus, is one particular mechanism of pathogenicity, particularly in immunocompromised patients .On the other hand, hepatitis C or human immunodeficiency virus (HIV) can cause an indirect injury to the renal tissue through immune complex deposition .Viral infections are responsible for significant morbidity and mortality in several renal diseases. This can be through one of two pathways of pathogenicity;Amid the current COVID-19 pandemic, kidneys are found to be among the most common targets of SARS-CoV-2. It was found that RNA for angiotensin-converting enzyme 2 (ACE2) receptor is abundant in the renal tissue. This facilitates SARS-CoV-2-associated kidney injury. Involving all compartments of the kidney, special affinity of SARS-CoV-2 for glomerular cells was confirmed [Based on that, renal tropism is a likely clarification of the clinical findings of kidney injury in patients with COVID-19 even in patients with SARS-CoV-2 disease who are not significantly sick [In a case series of five kidney transplant patients with COVID-19, it was found that severe COVID-19 did not develop although they were immunocompromised. Mild COVID-19 in renal transplant patients can be managed with symptomatic support therapy together with cautious adjustment of their immunosuppressive therapy .Viruses are an uncommon cause of cystitis in an immunocompetent individual. Hemorrhagic cystitis in an immunocompromised patient can be caused by adenovirus, and cytomegalovirus or BK virus. In this case, the antiviral drug of choice is Cidofovir .Regarding SARS-CoV-2, it was found that ACE2 receptor expression was found in about 2.4% of urothelial cells with possible subsequent viral cystitis .Increased urinary frequency has been identified in a small series of some COVID-19 patients with no evidence of urinary tract infection .It is as yet not confirmed whether the ACE 2 receptor is on luminal or basal side of urothelial cells. SARS-CoV-2 might cause viral cystitis through either urine from the luminal side of urothelium or from the basal side during the phase of viremia .Angiotensin-converting enzyme 2 (ACE-2) is the receptor for cellular entry of SARS-CoV-2. ACE-2 is a TMPRSS2 in the renin–angiotensin pathway. Interestingly, TMPRSS2 is highly expressed in human prostate epithelial cells and is androgen responsive. Moreover, it is one of the known dysregulated genes in prostate cancer .In a recent case series, it has been reported that 6 out of 34 men 17.6%) reported scrotal discomfort during their course of COVID-19 infection [.6% reporUrologists’ knowledge about viral infection of the gonads is mainly derived from our experience with patients suffering from mumps orchitis. Orchitis is the most common complication of mumps in post-pubertal men, affecting about 20%-30% of cases within 1–2 weeks of parotitis .Within the first few days of infection, the virus attacks the testicular parenchyma, leading to inflammation. The tunica albugenia is a tough barrier with subsequent rise in intra-testicular pressure leading to pressure-induced testicular atrophy. Mumps orchitis may contribute to subfertility in about 13% of patients. On the other hand, between 30 and 85% of patients with bilateral mumps orchitis experience infertility [In case of COVID-19, results of the few recent studies are still controversial. In one study , no deteIn another study , out of These studies are limited by the small sample size and the short subsequent follow-up. Therefore, further studies are still required.One of the most interesting features of this pandemic is about gender and how COVID-19 is affecting men and women differently. In the USA, for example, twice as many men have been dying from the virus as women. Similarly, 69% of all coronavirus deaths across Western Europe have been males. Several factors have been proposed to explain this observation .One theory is that women’s immune response to the virus is stronger. The immune response throughout life to vaccines and infections is usually more robust and effective in females as compared to males.ACE2 in lung tissue in males as compared to females and a larger proportion of ACE2 + cells in the male type II pneumocytes [Recent research found a higher expression of umocytes .This is partly down to the fact that females have two X chromosomes, whereas males have only one—which is important when it comes to COVID-19. In particular, the protein by which viruses such as SARS-CoV-2 are sensed is encoded on the X chromosome. As a result, this protein is expressed at twice the dose on many immune cells in females compared to males, and the immune response to SARS-CoV-2 is therefore amplified in females .Recent rAnother possibility is that the difference is down to gender-based lifestyle. There are important behavioral differences between the sexes, e.g., smoking. The sex differential in smoking is especially marked in some countries such as China, where 50% of men smoke as compared to 5% in women  . As a rMen are much less likely than women to take advantage of primary care services .Male sexual function can be significantly affected by stresses. Psychogenic erectile dysfunction varies from 10 to 90%. Psychogenic impotence may occur via increased sympathetic stimulation to the sacral segment of spinal cord causing inhibition of the parasympathetic nerve supply to the penis, and thereby inhibiting erection .The emergence of a novel form of coronavirus causing this pandemic crisis created a rapidly evolving stressful situation .To take breaks from watching, reading, or listening to news stories, including social media. Hearing about the pandemic repeatedly can be upsetting.Take deep breaths, stretch, or meditate.Try to eat health.Regular exercise and enough sleep.Avoid alcohol and drugs.To take care of himself physically.To make time to unwind. Try to do some other activities the patient enjoys.To connect with others. Talk with people you trust about your concerns and how you are feeling.To ask for a specialist help if he is struggling to cope with his daily life.This can lead to developing de novo erectile dysfunction (ED) or worsening of a previous base line condition. The first line to manage such cases is to advise the patient of ways to cope with stress ;To take Interestingly, phosphodiesterase 5 inhibitor (PDE5-I) represents the standard medical treatment for erectile dysfunctions. In addition, these drugs have been used in other conditions, e.g., pulmonary fibrosis or pulmonary hypertension .Nitric oxide (NO) can alleviate lung injury through decreasing levels of pro-inflammatory cytokines and inhibiting leukocytes migration into the lungs. In light of the such mechanisms involved in COVID-19 infection and given previous experiences with off-label use of Sildenafil, a possible role for PDE5-I as early supplementary medication in the management of COVID19 infection may be considered .Autopsy studies from severe acute respiratory syndrome (SARS) original outbreak in 2003 had shown degeneration and necrosis of the adrenal glands. Virus has been identified in the adrenal glands, hinting towards its direct cytopathic effect .Impact of SARS on hypothalamic pituitary axis (HPA) was first reported by Leow et al. About 40% of survivors had evidence of central hypocortisolism, majority of which resolved within a year. A prospective study evaluating serum cortisol and ACTH in patients with severe COVID-19 is currently ongoing [The Waterhouse–Friderichsen syndrome (WFS) is described as acute hemorrhagic necrosis of the adrenal glands often caused by infection. Neisseriae meningitidis is the main microorganism causing WFS yet although other infectious agents are known as a possible etiologic agent .Recently, few case reports have been published reporting adrenal hemorrhages as a complication of COVID-19 , 21 If aImpact of COVID-19 on urology practice may not be only indirect through reducing elective surgical work. Based on upcoming reports on SARS-CoV-2 organotropism, genitourinary tract can be directly involved as well. Although uncommon, we, urologist, may extrapolate our experience with viral infection in the urinary tract so as to be able to manage such possible infections and its short- and long-term consequences.