Martinez-Colòn GJ, Ratnasari K, Chen H, et al. SARS-CoV-2 infects human adipose tissue and elicits an inflammatory response consistent with severe COVID-19. bioRxiv 2021.10.24.465626; doi: https:// doi.org/10.1101/2021.10.24.465626. Adipose tissue has previously been shown to serve as a reservoir for influenza A virus as well as human immunodeficiency virus, and obesity is associated with unfavorable outcomes of influenza A virus infection [1]. Obesity is also a strong independent risk factor for coronavirus disease 2019 (COVID-19) infection, as well as for disease severity and associated mortality. Although obesity, especially with associated insulin resistance, is known to be a proinflammatory and hypercoagulable state, the reasons for the detrimental relationship between obesity and COVID-19 have remained undefined. In order to examine the potential role of adipose tissue in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the pathophysiology of the inflammatory response in COVID19, Martinez-Colòn et al secured freshly obtained subcutaneous, visceral, pericardial, and epicardial tissues from individuals undergoing bariatric or cardiac surgery. In addition, they obtained multiple samples from autopsy material of patients who died with COVID-19. Stromal vascular cells (SVCs) were separated from mature adipocytes by collagenase digestion of these tissues. The investigators demonstrated in vitro infection of SVCs and, by flow cytometry, that viral N protein expression was primarily restricted to macrophages. Angiotensin-converting enzyme 2 (ACE-2) expression was, however, very limited in SVCs, with its detection in only approximately 3% of macrophages and with none detected in other tissue types. The macrophages that were infectable were predominantly (85%) type C2, while >11% were C12. Infected C2 macrophages had enrichment of interleukin 10–associated signaling pathways as well as of chemokine and other pathways associated with the innate immune system. At the same time, there was reduced enrichment in host cell translation machinery. Both freshly isolated mature adipocytes and adipocytes differentiated in in vitro culture were susceptible to infection. Genomic RNA and positive sense subgenomic RNA consistent with productive infection were detected. Preadipocytes were not infected but had undergone proinflammatory activation as associates of infected SVCs. In vivo infection of adipose tissue was also demonstrated. SARS-CoV-2 was detected in epicardial, visceral, and subcutaneous adipose tissue as well as in lung, heart, and kidney. The highest concentrations were found in lung, followed by adipose tissue. The investigators have provided evidence that contributes to our understanding of the relationship between obesity and COVID-19 risk. They demonstrated that SARS-CoV-2 primarily infects macrophages in SVCs and that it enters these cells by a means that appears to be independent of host cell ACE-2 expression. This leads
{"title":"A Link Between Obesity and Coronavirus Disease 2019","authors":"S. Deresinski","doi":"10.1093/cid/ciac016","DOIUrl":"https://doi.org/10.1093/cid/ciac016","url":null,"abstract":"Martinez-Colòn GJ, Ratnasari K, Chen H, et al. SARS-CoV-2 infects human adipose tissue and elicits an inflammatory response consistent with severe COVID-19. bioRxiv 2021.10.24.465626; doi: https:// doi.org/10.1101/2021.10.24.465626. Adipose tissue has previously been shown to serve as a reservoir for influenza A virus as well as human immunodeficiency virus, and obesity is associated with unfavorable outcomes of influenza A virus infection [1]. Obesity is also a strong independent risk factor for coronavirus disease 2019 (COVID-19) infection, as well as for disease severity and associated mortality. Although obesity, especially with associated insulin resistance, is known to be a proinflammatory and hypercoagulable state, the reasons for the detrimental relationship between obesity and COVID-19 have remained undefined. In order to examine the potential role of adipose tissue in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the pathophysiology of the inflammatory response in COVID19, Martinez-Colòn et al secured freshly obtained subcutaneous, visceral, pericardial, and epicardial tissues from individuals undergoing bariatric or cardiac surgery. In addition, they obtained multiple samples from autopsy material of patients who died with COVID-19. Stromal vascular cells (SVCs) were separated from mature adipocytes by collagenase digestion of these tissues. The investigators demonstrated in vitro infection of SVCs and, by flow cytometry, that viral N protein expression was primarily restricted to macrophages. Angiotensin-converting enzyme 2 (ACE-2) expression was, however, very limited in SVCs, with its detection in only approximately 3% of macrophages and with none detected in other tissue types. The macrophages that were infectable were predominantly (85%) type C2, while >11% were C12. Infected C2 macrophages had enrichment of interleukin 10–associated signaling pathways as well as of chemokine and other pathways associated with the innate immune system. At the same time, there was reduced enrichment in host cell translation machinery. Both freshly isolated mature adipocytes and adipocytes differentiated in in vitro culture were susceptible to infection. Genomic RNA and positive sense subgenomic RNA consistent with productive infection were detected. Preadipocytes were not infected but had undergone proinflammatory activation as associates of infected SVCs. In vivo infection of adipose tissue was also demonstrated. SARS-CoV-2 was detected in epicardial, visceral, and subcutaneous adipose tissue as well as in lung, heart, and kidney. The highest concentrations were found in lung, followed by adipose tissue. The investigators have provided evidence that contributes to our understanding of the relationship between obesity and COVID-19 risk. They demonstrated that SARS-CoV-2 primarily infects macrophages in SVCs and that it enters these cells by a means that appears to be independent of host cell ACE-2 expression. This leads","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":"19 1","pages":"i - ii"},"PeriodicalIF":0.0,"publicationDate":"2022-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84630163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-01-03DOI: 10.1101/2022.01.03.474769
Céline Boschi, P. Colson, Audrey Bancod, V. Moal, B. La Scola
Monocolonal antibodies (mAbs) are currently used for active immunization of COVID-19 in immunocompromised patients. We herein show that in spite there are variations in susceptibility to available mAbs that are authorized for clinical use in France tested on the original B.1.1 virus and 9 variants of concern or of interest, the cocktail casirivimab/imdevimab (REGN-CoV-2) showed a major synergistic effect. However, none of the four mAbs either alone or in combination neutralized the new Omicron variant. Our data strongly warrant a reinforcement of protective measures against infection for immunocompromised patients.
{"title":"Omicron Variant Escapes Therapeutic Monoclonal Antibodies (mAbs) Including Recently Released Evusheld®, Contrary to 8 Prior Main Variant of Concern (VOC)","authors":"Céline Boschi, P. Colson, Audrey Bancod, V. Moal, B. La Scola","doi":"10.1101/2022.01.03.474769","DOIUrl":"https://doi.org/10.1101/2022.01.03.474769","url":null,"abstract":"Monocolonal antibodies (mAbs) are currently used for active immunization of COVID-19 in immunocompromised patients. We herein show that in spite there are variations in susceptibility to available mAbs that are authorized for clinical use in France tested on the original B.1.1 virus and 9 variants of concern or of interest, the cocktail casirivimab/imdevimab (REGN-CoV-2) showed a major synergistic effect. However, none of the four mAbs either alone or in combination neutralized the new Omicron variant. Our data strongly warrant a reinforcement of protective measures against infection for immunocompromised patients.","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":"47 1","pages":"e534 - e535"},"PeriodicalIF":0.0,"publicationDate":"2022-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88822024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-12-25DOI: 10.1101/2021.12.23.21267853
P. Drawz, M. DeSilva, Peter J. Bodurtha, Gabriela Vazquez Benitez, A. Murray, A. Chamberlain, R. Dudley, S. Waring, A. Kharbanda, Daniel P Murphy, Miriam H. Muscoplat, V. Meléndez, K. Margolis, Lynn McFarling, Roxana A. Lupu, T. Winkelman, Steven M. Johnson
Using vaccine data combined with electronic health records, we report that mRNA boosters provide greater protection than a two-dose regimen against SARS-CoV-2 infection and related hospitalizations. The benefit of a booster was more evident in the elderly and those with comorbidities. These results support the case for COVID-19 boosters.
{"title":"Effectiveness of BNT162b2 and mRNA-1273 Second Doses and Boosters for SARS-CoV-2 infection and SARS-CoV-2 Related Hospitalizations: A Statewide Report from the Minnesota Electronic Health Record Consortium","authors":"P. Drawz, M. DeSilva, Peter J. Bodurtha, Gabriela Vazquez Benitez, A. Murray, A. Chamberlain, R. Dudley, S. Waring, A. Kharbanda, Daniel P Murphy, Miriam H. Muscoplat, V. Meléndez, K. Margolis, Lynn McFarling, Roxana A. Lupu, T. Winkelman, Steven M. Johnson","doi":"10.1101/2021.12.23.21267853","DOIUrl":"https://doi.org/10.1101/2021.12.23.21267853","url":null,"abstract":"Using vaccine data combined with electronic health records, we report that mRNA boosters provide greater protection than a two-dose regimen against SARS-CoV-2 infection and related hospitalizations. The benefit of a booster was more evident in the elderly and those with comorbidities. These results support the case for COVID-19 boosters.","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":"58 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84178712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-11-18DOI: 10.21203/rs.3.rs-1090075/v1
P. Strid, L. Zapata, Van T. Tong, Laura D. Zambrano, K. Woodworth, Aspen P. Riser, R. Galang, S. Gilboa, S. Ellington
Abstract Background Information on the severity of COVID-19 attributable to the Delta variant in the United States among pregnant people is limited. We assessed the risk for severe COVID-19 by pregnancy status in the period of Delta variant predominance compared with the pre-Delta period. Methods Laboratory-confirmed SARS-CoV-2 infections among symptomatic women of reproductive age (WRA) were assessed. We calculated adjusted risk ratios for severe disease including intensive care unit (ICU) admission, receipt of invasive ventilation or extracorporeal membrane oxygenation (ECMO), and death comparing the pre-Delta period (January 1, 2020 – June 26, 2021) and the Delta period (June 27, 2021 – December 25, 2021) for pregnant and nonpregnant WRA. Results Compared with the pre-Delta period, the risk of ICU admission during the Delta period was 41% higher (adjusted risk ratio [aRR] 1.41; 95% CI, 1.17-1.69) for pregnant WRA and 9% higher (aRR 1.09; 95% CI, 1.00-1.18) for nonpregnant WRA. The risk of invasive ventilation or ECMO was higher for pregnant (aRR 1.83; 95% CI, 1.26-2.65) and nonpregnant WRA (aRR 1.34; 95% CI, 1.17-1.54) in the Delta period. During the Delta period, the risk of death was 3.33 (95% CI, 2.48-4.46) times the risk in the pre-Delta period among pregnant WRA and 1.62 (95% CI, 1.49-1.77) among nonpregnant WRA. Conclusions Compared with the pre-Delta period, pregnant and nonpregnant WRA were at increased risk for severe COVID-19 in the Delta period.
{"title":"COVID-19 Severity among Women of Reproductive Age with Symptomatic Laboratory-Confirmed SARS-CoV-2 by Pregnancy Status – United States, Jan 1, 2020 – Dec 25, 2021","authors":"P. Strid, L. Zapata, Van T. Tong, Laura D. Zambrano, K. Woodworth, Aspen P. Riser, R. Galang, S. Gilboa, S. Ellington","doi":"10.21203/rs.3.rs-1090075/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-1090075/v1","url":null,"abstract":"Abstract Background Information on the severity of COVID-19 attributable to the Delta variant in the United States among pregnant people is limited. We assessed the risk for severe COVID-19 by pregnancy status in the period of Delta variant predominance compared with the pre-Delta period. Methods Laboratory-confirmed SARS-CoV-2 infections among symptomatic women of reproductive age (WRA) were assessed. We calculated adjusted risk ratios for severe disease including intensive care unit (ICU) admission, receipt of invasive ventilation or extracorporeal membrane oxygenation (ECMO), and death comparing the pre-Delta period (January 1, 2020 – June 26, 2021) and the Delta period (June 27, 2021 – December 25, 2021) for pregnant and nonpregnant WRA. Results Compared with the pre-Delta period, the risk of ICU admission during the Delta period was 41% higher (adjusted risk ratio [aRR] 1.41; 95% CI, 1.17-1.69) for pregnant WRA and 9% higher (aRR 1.09; 95% CI, 1.00-1.18) for nonpregnant WRA. The risk of invasive ventilation or ECMO was higher for pregnant (aRR 1.83; 95% CI, 1.26-2.65) and nonpregnant WRA (aRR 1.34; 95% CI, 1.17-1.54) in the Delta period. During the Delta period, the risk of death was 3.33 (95% CI, 2.48-4.46) times the risk in the pre-Delta period among pregnant WRA and 1.62 (95% CI, 1.49-1.77) among nonpregnant WRA. Conclusions Compared with the pre-Delta period, pregnant and nonpregnant WRA were at increased risk for severe COVID-19 in the Delta period.","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":"80 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73353480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-10-30DOI: 10.1101/2021.10.29.21265669
S. Strathdee, D. Abramovitz, Alicia Y Harvey-Vera, Carlos F. Vera, G. Rangel, Irina Artamonova, T. Patterson, Rylie A Mitchell, A. Bazzi
Background: People who inject drugs (PWID) are vulnerable to acquiring SARS-CoV-2 but their barriers to COVID-19 vaccination are under-studied. We examined correlates of COVID-19 vaccine hesitancy among PWID in the U.S.-Mexico border region, of whom only 7.6% had received [≥]one COVID-19 vaccine dose by September, 2021. Methods: Between October, 2020 and September, 2021, participants aged [≥]18 years from San Diego, California, USA and Tijuana, Baja California, Mexico who injected drugs within the last month completed surveys and SARS-CoV-2, HIV, and HCV serologic testing. Logistic regressions with robust standard error estimation via generalized estimating equations identified factors associated with COVID-19 vaccine hesitancy, defined as being unsure or unwilling to receive COVID-19 vaccines. Results: Of 393 participants, 127 (32.3%) were vaccine hesitant. Older participants, those with greater food insecurity, and those with greater concern about acquiring SARS-CoV-2 were more willing to be vaccinated. Higher numbers of chronic health conditions, having access to a smart phone or computer, and citing social media as one's most important source of COVID-19 information were independently associated with vaccine hesitancy. COVID-19-related disinformation was independently associated with vaccine hesitancy (adjusted odds ratio: 1.51 per additional conspiracy theory endorsed; 95% confidence interval: 1.31-1.74). Conclusions: Nearly one third of PWID in the San Diego-Tijuana border region reported COVID-19 vaccine hesitancy, which was significantly influenced by exposure to disinformation. Interventions that improve accurate knowledge and trust in COVID-19 vaccines are needed to increase vaccination in this vulnerable population.
{"title":"Correlates of COVID-19 Vaccine Hesitancy among People who Inject Drugs in the San Diego-Tijuana Border Region","authors":"S. Strathdee, D. Abramovitz, Alicia Y Harvey-Vera, Carlos F. Vera, G. Rangel, Irina Artamonova, T. Patterson, Rylie A Mitchell, A. Bazzi","doi":"10.1101/2021.10.29.21265669","DOIUrl":"https://doi.org/10.1101/2021.10.29.21265669","url":null,"abstract":"Background: People who inject drugs (PWID) are vulnerable to acquiring SARS-CoV-2 but their barriers to COVID-19 vaccination are under-studied. We examined correlates of COVID-19 vaccine hesitancy among PWID in the U.S.-Mexico border region, of whom only 7.6% had received [≥]one COVID-19 vaccine dose by September, 2021. Methods: Between October, 2020 and September, 2021, participants aged [≥]18 years from San Diego, California, USA and Tijuana, Baja California, Mexico who injected drugs within the last month completed surveys and SARS-CoV-2, HIV, and HCV serologic testing. Logistic regressions with robust standard error estimation via generalized estimating equations identified factors associated with COVID-19 vaccine hesitancy, defined as being unsure or unwilling to receive COVID-19 vaccines. Results: Of 393 participants, 127 (32.3%) were vaccine hesitant. Older participants, those with greater food insecurity, and those with greater concern about acquiring SARS-CoV-2 were more willing to be vaccinated. Higher numbers of chronic health conditions, having access to a smart phone or computer, and citing social media as one's most important source of COVID-19 information were independently associated with vaccine hesitancy. COVID-19-related disinformation was independently associated with vaccine hesitancy (adjusted odds ratio: 1.51 per additional conspiracy theory endorsed; 95% confidence interval: 1.31-1.74). Conclusions: Nearly one third of PWID in the San Diego-Tijuana border region reported COVID-19 vaccine hesitancy, which was significantly influenced by exposure to disinformation. Interventions that improve accurate knowledge and trust in COVID-19 vaccines are needed to increase vaccination in this vulnerable population.","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90069614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-09-27DOI: 10.1101/2021.09.25.21264097
D. Fisman, A. Tuite
Background: Novel variants of concern (VOCs) have been associated with both increased infectivity and virulence of SARS-CoV-2. The virulence of SARS-CoV-2 is closely linked to age. Whether relative increases in virulence of novel VOCs is similar across the age spectrum, or is limited to some age groups, is unknown. Methods: We created a retrospective cohort of people in Ontario, Canada testing positive for SARS-CoV-2 and screened for VOCs, with dates of test report between February 7 and August 30, 2021 (n=233,799). Cases were classified as N501Y-positive VOC, probable Delta VOC, or VOC undetected. We constructed age-specific logistic regression models to evaluate the effects of N501Y-postive or Delta VOC infections on infection severity, using hospitalization, intensive care unit (ICU) admission, and death as outcome variables. Models were adjusted for sex, time, health unit, vaccination status, comorbidities, immune compromise, long-term care residence, healthcare worker status, and pregnancy. Results: Infection with either N501Y-positive or Delta VOCs was associated with significant elevations in risk of hospitalization, ICU admission, and death in younger and older adults, compared to infections where a VOC was not detected. Delta VOC increased hospitalization risk in children under 10 by a factor of 2.5 (adjusted odds ratio, 95% confidence interval: 1.2 to 5.1) compared to non-VOC. For most VOC-outcome combinations there was no heterogeneity in adverse outcomes by age. However, there was an inverse relationship between age and relative increase in risk of death with delta VOC, with younger age groups showing a greater relative increase in risk of death than older individuals. Interpretation: SARS-CoV-2 VOCs appear to be associated with increased relative virulence of infection in all age groups, though low absolute numbers of outcomes in younger individuals make estimates in these groups imprecise.
{"title":"Age-Specific Changes in Virulence Associated with SARS-CoV-2 Variants of Concern","authors":"D. Fisman, A. Tuite","doi":"10.1101/2021.09.25.21264097","DOIUrl":"https://doi.org/10.1101/2021.09.25.21264097","url":null,"abstract":"Background: Novel variants of concern (VOCs) have been associated with both increased infectivity and virulence of SARS-CoV-2. The virulence of SARS-CoV-2 is closely linked to age. Whether relative increases in virulence of novel VOCs is similar across the age spectrum, or is limited to some age groups, is unknown. Methods: We created a retrospective cohort of people in Ontario, Canada testing positive for SARS-CoV-2 and screened for VOCs, with dates of test report between February 7 and August 30, 2021 (n=233,799). Cases were classified as N501Y-positive VOC, probable Delta VOC, or VOC undetected. We constructed age-specific logistic regression models to evaluate the effects of N501Y-postive or Delta VOC infections on infection severity, using hospitalization, intensive care unit (ICU) admission, and death as outcome variables. Models were adjusted for sex, time, health unit, vaccination status, comorbidities, immune compromise, long-term care residence, healthcare worker status, and pregnancy. Results: Infection with either N501Y-positive or Delta VOCs was associated with significant elevations in risk of hospitalization, ICU admission, and death in younger and older adults, compared to infections where a VOC was not detected. Delta VOC increased hospitalization risk in children under 10 by a factor of 2.5 (adjusted odds ratio, 95% confidence interval: 1.2 to 5.1) compared to non-VOC. For most VOC-outcome combinations there was no heterogeneity in adverse outcomes by age. However, there was an inverse relationship between age and relative increase in risk of death with delta VOC, with younger age groups showing a greater relative increase in risk of death than older individuals. Interpretation: SARS-CoV-2 VOCs appear to be associated with increased relative virulence of infection in all age groups, though low absolute numbers of outcomes in younger individuals make estimates in these groups imprecise.","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77606198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-09-22DOI: 10.1101/2021.09.20.21263527
K. Murugesan, P. Jagannathan, J. Altamirano, Y. Maldonado, H. Bonilla, K. Jacobson, J. Parsonnet, J. Andrews, R. Shi, S. Boyd, B. Pinsky, U. Singh, N. Banaei
Background: An immunodiagnostic assay that sensitively detects a cell-mediated immune response to SARS-CoV-2 is needed for epidemiological investigation and for clinical assessment of T cell-mediated immune response to vaccines, particularly in the context of emerging variants that might escape antibody responses. Methods: The performance of a whole blood interferon-gamma (IFN-{gamma}) release assay (IGRA) for the detection of SARS-CoV-2 antigen-specific CD4 and CD8 T cells was evaluated in COVID-19 convalescents tested serially up to 10 months post-infection and in healthy blood donors. SARS-CoV-2 IGRA was applied in contacts of households with index cases. Freshly collected blood in the lithium heparin tube was left unstimulated, stimulated with a SARS-CoV-2 peptide pool, and stimulated with mitogen. Results: The overall sensitivity and specificity of IGRA were 84.5% (153/181; 95% confidence interval [CI] 79.0-89.0) and 86.6% (123/142; 95% CI;80.0-91.2), respectively. The sensitivity declined from 100% (16/16; 95% CI 80.6-100) at 0.5-month post-infection to 79.5% (31/39; 95% CI 64.4-89.2) at 10 months post-infection (P<0.01). The IFN-{gamma} response remained relatively robust at 10 months post-infection (3.8 vs. 1.3 IU/mL, respectively). In 14 households, IGRA showed a positivity rate of 100% (12/12) and 65.2% (15/23), and IgG of 50.0% (6/12) and 43.5% (10/23) in index cases and contacts, respectively, exhibiting a difference of +50% (95% CI +25.4-+74.6) and +21.7% (95% CI, +9.23-+42.3), respectively. Either IGRA or IgG was positive in 100% (12/12) of index cases and 73.9% (17/23) of contacts. Conclusions: The SARS-CoV-2 IGRA is a useful clinical diagnostic tool for assessing cell-mediated immune response to SARS-CoV-2.
背景:流行病学调查和T细胞介导的疫苗免疫应答的临床评估需要一种能够敏感检测细胞介导的SARS-CoV-2免疫应答的免疫诊断试验，特别是在可能逃避抗体应答的新变体的背景下。方法:采用全血干扰素- γ (IFN-{γ})释放试验(IGRA)检测SARS-CoV-2抗原特异性CD4和CD8 T细胞，对感染后连续检测10个月的COVID-19恢复期患者和健康献血者进行评价。对有指示病例的家庭接触者应用SARS-CoV-2 IGRA。肝素锂管中新鲜采集的血液不受刺激，用SARS-CoV-2肽池刺激，并用有丝分裂原刺激。结果:IGRA的总体敏感性和特异性为84.5% (153/181;95%置信区间[CI] 79.0-89.0)和86.6% (123/142;95% CI;80.0-91.2)。灵敏度从100% (16/16;感染后0.5个月95% CI为80.6-100)至79.5% (31/39;感染后10个月95% CI 64.4 ~ 89.2) (P<0.01)。在感染后10个月，IFN-{γ}反应仍然相对强劲(分别为3.8和1.3 IU/mL)。14户家庭IGRA阳性率分别为100%(12/12)和65.2% (15/23)，IgG阳性率分别为50.0%(6/12)和43.5%(10/23)，差异分别为+50% (95% CI +25.4 ~ +74.6)和+21.7% (95% CI +9.23 ~ +42.3)。100%(12/12)的指示病例和73.9%(17/23)的接触者IGRA或IgG阳性。结论:SARS-CoV-2 IGRA是评估细胞介导的SARS-CoV-2免疫应答的有效临床诊断工具。
{"title":"Long Term Accuracy of SARS-CoV-2 Interferon-γ Release Assay and its Application in Household Investigation","authors":"K. Murugesan, P. Jagannathan, J. Altamirano, Y. Maldonado, H. Bonilla, K. Jacobson, J. Parsonnet, J. Andrews, R. Shi, S. Boyd, B. Pinsky, U. Singh, N. Banaei","doi":"10.1101/2021.09.20.21263527","DOIUrl":"https://doi.org/10.1101/2021.09.20.21263527","url":null,"abstract":"Background: An immunodiagnostic assay that sensitively detects a cell-mediated immune response to SARS-CoV-2 is needed for epidemiological investigation and for clinical assessment of T cell-mediated immune response to vaccines, particularly in the context of emerging variants that might escape antibody responses. Methods: The performance of a whole blood interferon-gamma (IFN-{gamma}) release assay (IGRA) for the detection of SARS-CoV-2 antigen-specific CD4 and CD8 T cells was evaluated in COVID-19 convalescents tested serially up to 10 months post-infection and in healthy blood donors. SARS-CoV-2 IGRA was applied in contacts of households with index cases. Freshly collected blood in the lithium heparin tube was left unstimulated, stimulated with a SARS-CoV-2 peptide pool, and stimulated with mitogen. Results: The overall sensitivity and specificity of IGRA were 84.5% (153/181; 95% confidence interval [CI] 79.0-89.0) and 86.6% (123/142; 95% CI;80.0-91.2), respectively. The sensitivity declined from 100% (16/16; 95% CI 80.6-100) at 0.5-month post-infection to 79.5% (31/39; 95% CI 64.4-89.2) at 10 months post-infection (P<0.01). The IFN-{gamma} response remained relatively robust at 10 months post-infection (3.8 vs. 1.3 IU/mL, respectively). In 14 households, IGRA showed a positivity rate of 100% (12/12) and 65.2% (15/23), and IgG of 50.0% (6/12) and 43.5% (10/23) in index cases and contacts, respectively, exhibiting a difference of +50% (95% CI +25.4-+74.6) and +21.7% (95% CI, +9.23-+42.3), respectively. Either IGRA or IgG was positive in 100% (12/12) of index cases and 73.9% (17/23) of contacts. Conclusions: The SARS-CoV-2 IGRA is a useful clinical diagnostic tool for assessing cell-mediated immune response to SARS-CoV-2.","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84778364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-31DOI: 10.1101/2021.07.30.21260912
L. Williams, N. Ferguson, C. Donnelly, N. Grassly
Background Phase III trials have estimated COVID-19 vaccine efficacy (VE) against symptomatic and asymptomatic infection. We explore the direction and magnitude of potential biases in these estimates and their implications for vaccine protection against infection and against disease in breakthrough infections. Methods We developed a mathematical model that accounts for natural and vaccine-induced immunity, changes in serostatus and imperfect sensitivity and specificity of tests for infection and antibodies. We estimated expected biases in VE against symptomatic, asymptomatic and any SARS-CoV-2 infections and against disease following infection for a range of vaccine characteristics and measurement approaches, and the likely overall biases for published trial results that included asymptomatic infections. Results VE against asymptomatic infection measured by PCR or serology is expected to be low or negative for vaccines that prevent disease but not infection. VE against any infection is overestimated when asymptomatic infections are less likely to be detected than symptomatic infections and the vaccine protects against symptom development. A competing bias towards underestimation arises for estimates based on tests with imperfect specificity, especially when testing is performed frequently. Our model indicates considerable uncertainty in Oxford-AstraZeneca ChAdOx1 and Janssen Ad26.COV2.S VE against any infection, with slightly higher than published, bias-adjusted values of 59.0% (95% uncertainty interval [UI] 38.4 to 77.1) and 70.9% (95% UI 49.8 to 80.7) respectively. Conclusion Multiple biases are likely to influence COVID-19 VE estimates, potentially explaining the observed difference between ChAdOx1 and Ad26.COV2.S vaccines. These biases should be considered when interpreting both efficacy and effectiveness study results.
{"title":"Measuring Vaccine Efficacy Against Infection and Disease in Clinical Trials: Sources and Magnitude of Bias in Coronavirus Disease 2019 (COVID-19) Vaccine Efficacy Estimates","authors":"L. Williams, N. Ferguson, C. Donnelly, N. Grassly","doi":"10.1101/2021.07.30.21260912","DOIUrl":"https://doi.org/10.1101/2021.07.30.21260912","url":null,"abstract":"Background Phase III trials have estimated COVID-19 vaccine efficacy (VE) against symptomatic and asymptomatic infection. We explore the direction and magnitude of potential biases in these estimates and their implications for vaccine protection against infection and against disease in breakthrough infections. Methods We developed a mathematical model that accounts for natural and vaccine-induced immunity, changes in serostatus and imperfect sensitivity and specificity of tests for infection and antibodies. We estimated expected biases in VE against symptomatic, asymptomatic and any SARS-CoV-2 infections and against disease following infection for a range of vaccine characteristics and measurement approaches, and the likely overall biases for published trial results that included asymptomatic infections. Results VE against asymptomatic infection measured by PCR or serology is expected to be low or negative for vaccines that prevent disease but not infection. VE against any infection is overestimated when asymptomatic infections are less likely to be detected than symptomatic infections and the vaccine protects against symptom development. A competing bias towards underestimation arises for estimates based on tests with imperfect specificity, especially when testing is performed frequently. Our model indicates considerable uncertainty in Oxford-AstraZeneca ChAdOx1 and Janssen Ad26.COV2.S VE against any infection, with slightly higher than published, bias-adjusted values of 59.0% (95% uncertainty interval [UI] 38.4 to 77.1) and 70.9% (95% UI 49.8 to 80.7) respectively. Conclusion Multiple biases are likely to influence COVID-19 VE estimates, potentially explaining the observed difference between ChAdOx1 and Ad26.COV2.S vaccines. These biases should be considered when interpreting both efficacy and effectiveness study results.","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":"15 1","pages":"e764 - e773"},"PeriodicalIF":0.0,"publicationDate":"2021-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80095115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-05DOI: 10.1101/2021.06.30.21259721
J. Lewnard, K. Bruxvoort, Heidi Fischer, V. Hong, L. Grant, L. Jodar, A. Cane, B. Gessner, S. Tartof
Importance: In 2014, the US Advisory Committee on Immunization Practices (ACIP) extended existing pneumococcal vaccination recommendations for adults aged [≥]65 years to include 13-valent pneumococcal conjugate vaccine (PCV13), primarily to prevent non-bacteremic pneumonia. Objective: To determine PCV13 effectiveness against all-cause inpatient plus outpatient medically-attended lower-respiratory tract infection (LRTI) and pneumonia among US older adults. Design: Prospective, open cohort study following participants from 2016 to 2019. We conducted analyses in a self-matched framework, comparing outcomes during participants' follow-up periods before and after receipt of PCV13. Setting: Kaiser Permanente Southern California (KPSC) integrated healthcare delivery system. Participants: Adults aged [≥]65 years who received PCV13 between 2016-2019. Exposures: Receipt of PCV13 at ages [≥]65 years, concordant with ACIP guidelines. Main outcomes and measures: We estimated the adjusted hazards ratio (aHR) for first LRTI and pneumonia episodes during each respiratory season, comparing PCV13-exposed and PCV13-unexposed time at risk for each participant using a self-matched inference framework. We computed aHR estimates using Cox proportional hazards models. We defined vaccine effectiveness (VE) as (1-aHR)*100%. We also estimated PCV13-attributable absolute reductions in incidence of LRTI and pneumonia. Results: Observations were available both before and after PCV13 receipt for 42,700 participants. Among these individuals, 1,419 experienced LRTI and 969 experienced pneumonia over approximately 26,000 combined years of follow-up before PCV13 receipt; 3,849 experienced LRTI and 2,727 experienced pneumonia over approximately 74,000 combined years of follow-up after PCV13 receipt. In adjusted analyses, VE was 9.5% (95% confidence interval: 2.2% to 16.3%) against all-cause medically-attended LRTI and 8.8% (-0.2% to 17.0%) against all-cause medically-attended pneumonia. In contrast, we did not identify evidence of protection against LRTI and pneumonia following receipt of 23-valent pneumococcal polysaccharide vaccine. We estimated that PCV13 prevented 0.7 (0.2 to 1.4) and 0.5 (0.0 to 1.0) cases of LRTI and pneumonia, respectively, per 100 vaccinated persons annually. Over a five-year time horizon, one case of LRTI and pneumonia, respectively, was prevented for every 27 (14 to 116) and 42 (-97 to 268) individuals receiving PCV13. Conclusions and relevance: PCV13 vaccination among older adults reduced the burden of medically-attended respiratory illness in this population.
{"title":"Effectiveness of 13-valent pneumococcal conjugate vaccine against medically-attended lower respiratory tract infection and pneumonia among older adults","authors":"J. Lewnard, K. Bruxvoort, Heidi Fischer, V. Hong, L. Grant, L. Jodar, A. Cane, B. Gessner, S. Tartof","doi":"10.1101/2021.06.30.21259721","DOIUrl":"https://doi.org/10.1101/2021.06.30.21259721","url":null,"abstract":"Importance: In 2014, the US Advisory Committee on Immunization Practices (ACIP) extended existing pneumococcal vaccination recommendations for adults aged [≥]65 years to include 13-valent pneumococcal conjugate vaccine (PCV13), primarily to prevent non-bacteremic pneumonia. Objective: To determine PCV13 effectiveness against all-cause inpatient plus outpatient medically-attended lower-respiratory tract infection (LRTI) and pneumonia among US older adults. Design: Prospective, open cohort study following participants from 2016 to 2019. We conducted analyses in a self-matched framework, comparing outcomes during participants' follow-up periods before and after receipt of PCV13. Setting: Kaiser Permanente Southern California (KPSC) integrated healthcare delivery system. Participants: Adults aged [≥]65 years who received PCV13 between 2016-2019. Exposures: Receipt of PCV13 at ages [≥]65 years, concordant with ACIP guidelines. Main outcomes and measures: We estimated the adjusted hazards ratio (aHR) for first LRTI and pneumonia episodes during each respiratory season, comparing PCV13-exposed and PCV13-unexposed time at risk for each participant using a self-matched inference framework. We computed aHR estimates using Cox proportional hazards models. We defined vaccine effectiveness (VE) as (1-aHR)*100%. We also estimated PCV13-attributable absolute reductions in incidence of LRTI and pneumonia. Results: Observations were available both before and after PCV13 receipt for 42,700 participants. Among these individuals, 1,419 experienced LRTI and 969 experienced pneumonia over approximately 26,000 combined years of follow-up before PCV13 receipt; 3,849 experienced LRTI and 2,727 experienced pneumonia over approximately 74,000 combined years of follow-up after PCV13 receipt. In adjusted analyses, VE was 9.5% (95% confidence interval: 2.2% to 16.3%) against all-cause medically-attended LRTI and 8.8% (-0.2% to 17.0%) against all-cause medically-attended pneumonia. In contrast, we did not identify evidence of protection against LRTI and pneumonia following receipt of 23-valent pneumococcal polysaccharide vaccine. We estimated that PCV13 prevented 0.7 (0.2 to 1.4) and 0.5 (0.0 to 1.0) cases of LRTI and pneumonia, respectively, per 100 vaccinated persons annually. Over a five-year time horizon, one case of LRTI and pneumonia, respectively, was prevented for every 27 (14 to 116) and 42 (-97 to 268) individuals receiving PCV13. Conclusions and relevance: PCV13 vaccination among older adults reduced the burden of medically-attended respiratory illness in this population.","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76890893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-06-22DOI: 10.1101/2021.06.21.449240
G. Nagaraj, V. Shamanna, V. Govindan, Steffi Rose, D. Sravani, K. P. Akshata, M. Shincy, V. T. Venkatesha, M. Abrudan, S. Argimón, M. Kekre, A. Underwood, D. Aanensen, K. Ravikumar, Khalil Harry Dawn Ben Nicole Sophia Pilar Johan Fabian Al Abudahab Harste Muddyman Taylor Wheeler David Dona, Khalil AbuDahab, Harry Harste, Dawn Muddyman, Ben Taylor, Nicole Wheeler, S. David, P. Donado-Godoy, J. Bernal, A. Arévalo, M. F. Valencia, Erik C D Osma Castro, K. N. Ravishankar, I. Okeke, A. Oaikhena, A. O. Afolayan, Jolaade J. Ajiboye, E. E. Odih, C. Carlos, Marietta L Lagrada, P. K. Macaranas, Agnettah M. Olorosa, June M. Gayeta, Elmer M Herrera
summary We report insights into genome sequences of Indian K. pneumoniae isolates, highlighting the presence of high-risk international clones and genetic pools different from those predominating in other regions. Identification of multidrug-resistant and hypervirulent K. pneumoniae elicits public health concerns. Background Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a threat to public health in India due to its high dissemination, mortality, and limited treatment options. Its genomic variability is reflected in the diversity of sequence types, virulence factors, and antimicrobial resistance (AMR) mechanisms. This study aims to characterize the clonal relationships and genetic mechanisms of resistance and virulence in CRKP isolates in India. Materials and Methods We characterized 344 retrospective K. pneumoniae clinical isolates collected from 8 centers across India collected in 2013-2019. Susceptibility to antibiotics was tested with VITEK 2. Capsular types, MLST, virulence genes, AMR determinants, plasmid replicon types, and a single-nucleotide polymorphism (SNP) phylogeny were inferred from their whole genome sequences. Results Phylogenetic analysis of the 325 Klebsiella isolates that passed QC revealed 3 groups: K. pneumoniae sensu stricto (n=307), K. quasipneumoniae (n=17), and K. varicolla (n=1). Sequencing and capsular diversity analysis of the 307 K. pneumoniae sensu stricto isolates revealed 28 sequence types, 26 K-locus types, and 11 O-locus types, with ST231, KL51, and O1V2 being predominant. blaOXA-48-like and blaNDM-1/5 were present in 73.2% and 24.4% of isolates respectively. The major plasmid replicon types associated with carbapenase genes were IncF (51.0%), and Col group (35.0%). Conclusion Our study documents for the first time the genetic diversity of K- and O-antigens circulating in India. The results demonstrate the practical applicability of genomic surveillance and its utility in tracking the population dynamics of CRKP. It alerts us to the urgency for longitudinal surveillance of these virulent and transmissible lineages. Funding This work was supported by Official Development Assistance (ODA) funding from the National Institute of Health Research [grant number 16_136_111]. This research was commissioned by the National Institute of Health Research using Official Development Assistance (ODA) funding. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. Conflict of Interest The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
{"title":"High-Resolution Genomic Profiling of Carbapenem-Resistant Klebsiella pneumoniae Isolates: A Multicentric Retrospective Indian Study","authors":"G. Nagaraj, V. Shamanna, V. Govindan, Steffi Rose, D. Sravani, K. P. Akshata, M. Shincy, V. T. Venkatesha, M. Abrudan, S. Argimón, M. Kekre, A. Underwood, D. Aanensen, K. Ravikumar, Khalil Harry Dawn Ben Nicole Sophia Pilar Johan Fabian Al Abudahab Harste Muddyman Taylor Wheeler David Dona, Khalil AbuDahab, Harry Harste, Dawn Muddyman, Ben Taylor, Nicole Wheeler, S. David, P. Donado-Godoy, J. Bernal, A. Arévalo, M. F. Valencia, Erik C D Osma Castro, K. N. Ravishankar, I. Okeke, A. Oaikhena, A. O. Afolayan, Jolaade J. Ajiboye, E. E. Odih, C. Carlos, Marietta L Lagrada, P. K. Macaranas, Agnettah M. Olorosa, June M. Gayeta, Elmer M Herrera","doi":"10.1101/2021.06.21.449240","DOIUrl":"https://doi.org/10.1101/2021.06.21.449240","url":null,"abstract":"summary We report insights into genome sequences of Indian K. pneumoniae isolates, highlighting the presence of high-risk international clones and genetic pools different from those predominating in other regions. Identification of multidrug-resistant and hypervirulent K. pneumoniae elicits public health concerns. Background Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a threat to public health in India due to its high dissemination, mortality, and limited treatment options. Its genomic variability is reflected in the diversity of sequence types, virulence factors, and antimicrobial resistance (AMR) mechanisms. This study aims to characterize the clonal relationships and genetic mechanisms of resistance and virulence in CRKP isolates in India. Materials and Methods We characterized 344 retrospective K. pneumoniae clinical isolates collected from 8 centers across India collected in 2013-2019. Susceptibility to antibiotics was tested with VITEK 2. Capsular types, MLST, virulence genes, AMR determinants, plasmid replicon types, and a single-nucleotide polymorphism (SNP) phylogeny were inferred from their whole genome sequences. Results Phylogenetic analysis of the 325 Klebsiella isolates that passed QC revealed 3 groups: K. pneumoniae sensu stricto (n=307), K. quasipneumoniae (n=17), and K. varicolla (n=1). Sequencing and capsular diversity analysis of the 307 K. pneumoniae sensu stricto isolates revealed 28 sequence types, 26 K-locus types, and 11 O-locus types, with ST231, KL51, and O1V2 being predominant. blaOXA-48-like and blaNDM-1/5 were present in 73.2% and 24.4% of isolates respectively. The major plasmid replicon types associated with carbapenase genes were IncF (51.0%), and Col group (35.0%). Conclusion Our study documents for the first time the genetic diversity of K- and O-antigens circulating in India. The results demonstrate the practical applicability of genomic surveillance and its utility in tracking the population dynamics of CRKP. It alerts us to the urgency for longitudinal surveillance of these virulent and transmissible lineages. Funding This work was supported by Official Development Assistance (ODA) funding from the National Institute of Health Research [grant number 16_136_111]. This research was commissioned by the National Institute of Health Research using Official Development Assistance (ODA) funding. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. Conflict of Interest The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":"22 1","pages":"S300 - S307"},"PeriodicalIF":0.0,"publicationDate":"2021-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81635634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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