Publications by authors named "Michael J Peluso"

68 Publications

SARS-CoV-2 antibody magnitude and detectability are driven by disease severity, timing, and assay.

Sci Adv 2021 Jul 30;7(31). Epub 2021 Jul 30.

Vitalant Research Institute, San Francisco, CA, USA.

Interpretation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serosurveillance studies is limited by poorly defined performance of antibody assays over time in individuals with different clinical presentations. We measured antibody responses in plasma samples from 128 individuals over 160 days using 14 assays. We found a consistent and strong effect of disease severity on antibody magnitude, driven by fever, cough, hospitalization, and oxygen requirement. Responses to spike protein versus nucleocapsid had consistently higher correlation with neutralization. Assays varied substantially in sensitivity during early convalescence and time to seroreversion. Variability was dramatic for individuals with mild infection, who had consistently lower antibody titers, with sensitivities at 6 months ranging from 33 to 98% for commercial assays. Thus, the ability to detect previous infection by SARS-CoV-2 is highly dependent on infection severity, timing, and the assay used. These findings have important implications for the design and interpretation of SARS-CoV-2 serosurveillance studies.
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http://dx.doi.org/10.1126/sciadv.abh3409DOI Listing
July 2021

Genetic regulation of nonsense-mediated decay underlies association with risk of severe COVID-19.

medRxiv 2021 Jul 13. Epub 2021 Jul 13.

Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76 variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay of . We suggest that genetically-regulated loss of expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of the risk haplotypes.
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http://dx.doi.org/10.1101/2021.07.09.21260221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288155PMC
July 2021

Global health education in China's medical schools: A national cross-sectional study.

Med Teach 2021 Jul 14:1-6. Epub 2021 Jul 14.

Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.

Introduction: Despite China's large and growing global presence, data about global health (GH) education (GHE) in China's medical schools are limited. We aimed to describe GHE in these schools and determine whether some may teach GH concepts without labeling them as such.

Methods: In 2019, 161 Chinese medical schools eligible for accreditation by the Ministry of Education were invited to complete a questionnaire as part of a national survey. Data were analyzed using descriptive analyses, Chi-square tests, Fisher exact tests, and logit models.

Results: Approximately 57% of schools completed the survey ( = 93). 33 (35.5%) indicated that GHE was included in the curriculum. Although the majority of responding schools reported the absence of GH in the curriculum, GH topics were identified at many institutions. Schools affiliated with the central government or an aspiring world-class university were more likely to report the inclusion of GHE and offered more opportunities at international away sites.

Conclusions: Chinese medical schools are frequently teaching GH topics, but may not label the instruction as such. Policy-makers and educators should be equipped with a global perspective to facilitate GHE at China's medical schools and take measures to address differences between schools.
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http://dx.doi.org/10.1080/0142159X.2021.1947478DOI Listing
July 2021

Citywide serosurveillance of the initial SARS-CoV-2 outbreak in San Francisco using electronic health records.

Nat Commun 2021 06 11;12(1):3566. Epub 2021 Jun 11.

University of California San Francisco, San Francisco, CA, USA.

Serosurveillance provides a unique opportunity to quantify the proportion of the population that has been exposed to pathogens. Here, we developed and piloted Serosurveillance for Continuous, ActionabLe Epidemiologic Intelligence of Transmission (SCALE-IT), a platform through which we systematically tested remnant samples from routine blood draws in two major hospital networks in San Francisco for SARS-CoV-2 antibodies during the early months of the pandemic. Importantly, SCALE-IT allows for algorithmic sample selection and rich data on covariates by leveraging electronic health record data. We estimated overall seroprevalence at 4.2%, corresponding to a case ascertainment rate of only 4.9%, and identified important heterogeneities by neighborhood, homelessness status, and race/ethnicity. Neighborhood seroprevalence estimates from SCALE-IT were comparable to local community-based surveys, while providing results encompassing the entire city that have been previously unavailable. Leveraging this hybrid serosurveillance approach has strong potential for application beyond this local context and for diseases other than SARS-CoV-2.
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http://dx.doi.org/10.1038/s41467-021-23651-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195995PMC
June 2021

TNF-alpha inhibition in the setting of undiagnosed HIV infection: a call for enhanced screening guidelines.

AIDS 2021 Jun 10. Epub 2021 Jun 10.

Department of Medicine, University of California, San Francisco, CA, USA Division of Hospital Medicine, University of California, San Francisco, CA, USA Department of Pathology, University of California, San Francisco, CA, USA Division of Gastroenterology, University of California, San Francisco, CA, USA Division of Infectious Diseases, University of California, San Francisco, CA, USA Division of Experimental Medicine, University of California, San Francisco, CA, USA Division of HIV, Infectious Diseases, and Global Medicine University of California, San Francisco, CA, USA.

Background: Despite the risks of immunosuppression, recommendations regarding screening for HIV infection prior to initiation of biologic therapies targeting common rheumatologic disorders, including inflammatory bowel disease (IBD) and inflammatory arthritides, are limited. Few cases of patients started on biologics while living with undiagnosed HIV infection have been reported.

Methods: We report 3 cases of patients initiated on biologics in the absence of recent or concurrent HIV screening who developed refractory disease or unanticipated complications and were later found to have undiagnosed chronic HIV infection.

Results: In Case 1, a 53-year-old man who has sex with men (MSM) with negative HIV testing two years prior presented with presumed rheumatoid arthritis. He did not respond to methotrexate (MTX), so adalimumab (ADA) was started. HIV testing to evaluate persistent symptoms was positive 9 months later; CD4+ T cell count was 800 cells/uL. Antiretroviral therapy (ART) resulted in resolution of symptoms, which were attributed to HIV-associated arthropathy. In Case 2, a 55-year-old woman with injection drug use in remission and no prior HIV testing presented with hidradenitis suppurativa (HS). She started infliximab (IFX) and MTX therapy with good response. After she developed weight loss and lymphopenia, an HIV test was positive; CD4+ T cell count was 334 cells/uL. Biologic HS therapy was discontinued, with subsequent poor HS control. In Case 3, a 32-year-old MSM with no prior HIV testing presented with presumed IBD; IFX and steroids were started. Symptoms progressed despite IBD-directed therapy, and he was diagnosed with extensive Kaposi Sarcoma (KS) with visceral and cutaneous involvement, likely exacerbated by immunosuppression. HIV testing was positive; CD4+ T cell count was 250 cells/uL. KS initially worsened due to ART-associated immune reconstitution inflammatory syndrome. He is now improving with systemic chemotherapy and ART. HIV-associated KS is presumed to be the underlying diagnosis.

Conclusion: All three patients had elevated risk for HIV infection, and two had final diagnoses attributed to chronic HIV infection, not warranting therapeutic immunosuppression. Screening for HIV infection prior to initiation of biologic therapy should be incorporated into clinical practice guidelines.
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http://dx.doi.org/10.1097/QAD.0000000000002985DOI Listing
June 2021

Universal Polymerase Chain Reaction and Antibody Testing Demonstrate Little to No Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 in a Rural Community.

Open Forum Infect Dis 2021 Jan 30;8(1):ofaa531. Epub 2020 Oct 30.

University of California San Francisco, San Francisco, California, USA.

Background: Limited systematic surveillance for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the early months of the US epidemic curtailed accurate appraisal of transmission intensity. Our objective was to perform case detection of an entire rural community to quantify SARS-CoV-2 transmission using polymerase chain reaction (PCR) and antibody testing.

Methods: We conducted a cross-sectional survey of SARS-CoV-2 infection in the rural town of Bolinas, California (population 1620), 4 weeks after shelter-in-place orders. Participants were tested between April 20 and 24, 2020. Prevalence by PCR and seroprevalence from 2 forms of antibody testing were performed in parallel (Abbott ARCHITECT immunoglobulin [Ig]G and in-house IgG enzyme-linked immunosorbent assay).

Results: Of 1891 participants, 1312 were confirmed Bolinas residents (>80% community ascertainment). Zero participants were PCR positive. Assuming 80% sensitivity, it would have been unlikely to observe these results ( < .05) if there were >3 active infections in the community. Based on antibody results, estimated prevalence of prior infection was 0.16% (95% credible interval [CrI], 0.02%-0.46%). The positive predictive value (PPV) of a positive result on both tests was 99.11% (95% CrI, 95.75%-99.94%), compared with PPV 44.19%-63.32% (95% CrI, 3.25%-98.64%) if 1 test was utilized.

Conclusions: Four weeks after shelter-in-place, SARS-CoV-2 infection in a rural Northern California community was extremely rare. In this low-prevalence setting, use of 2 antibody tests increased seroprevalence estimate precision. This was one of the first community-wide studies to successfully implement synchronous PCR and antibody testing, particularly in a rural setting. Widespread testing remains an underpinning of effective disease control in conjunction with consistent uptake of public health measures.
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http://dx.doi.org/10.1093/ofid/ofaa531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665736PMC
January 2021

multiSero: open multiplex-ELISA platform for analyzing antibody responses to SARS-CoV-2 infection.

medRxiv 2021 May 11. Epub 2021 May 11.

Serology has provided valuable diagnostic and epidemiological data on antibody responses to SARS-CoV-2 in diverse patient cohorts. Deployment of high content, multiplex serology platforms across the world, including in low and medium income countries, can accelerate longitudinal epidemiological surveys. Here we report multiSero, an open platform to enable multiplex serology with up to 48 antigens in a 96-well format. The platform consists of three components: ELISA-array of printed proteins, a commercial or home-built plate reader, and modular python software for automated analysis (pysero). We validate the platform by comparing antibody titers against the SARS-CoV-2 Spike, receptor binding domain (RBD), and nucleocapsid (N) in 114 sera from COVID-19 positive individuals and 87 pre-pandemic COVID-19 negative sera. We report data with both a commercial plate reader and an inexpensive, open plate reader (nautilus). Receiver operating characteristic (ROC) analysis of classification with single antigens shows that Spike and RBD classify positive and negative sera with the highest sensitivity at a given specificity. The platform distinguished positive sera from negative sera when the reactivity of the sera was equivalent to the binding of 1 ng mL RBD-specific monoclonal antibody. We developed normalization and classification methods to pool antibody responses from multiple antigens and multiple experiments. Our results demonstrate a performant and accessible pipeline for multiplexed ELISA ready for multiple applications, including serosurveillance, identification of viral proteins that elicit antibody responses, differential diagnosis of circulating pathogens, and immune responses to vaccines.
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http://dx.doi.org/10.1101/2021.05.07.21249238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132273PMC
May 2021

SARS-CoV-2 seroprevalence, and IgG concentration and pseudovirus neutralising antibody titres after infection, compared by HIV status: a matched case-control observational study.

Lancet HIV 2021 06 29;8(6):e334-e341. Epub 2021 Apr 29.

Division of HIV, Infectious Diseases, and Global Medicine, University of California, San Francisco, San Francisco, CA, USA.

Background: Most cohorts show similar or lower COVID-19 incidence among people living with HIV compared with the general population. However, incidence might be affected by lower testing rates among vulnerable populations. We aimed to compare SARS-CoV-2 IgG seroprevalence, disease severity, and neutralising antibody activity after infection among people with and without HIV receiving care in a county hospital system over a 3-month period.

Methods: In this matched case-control observational study, remnant serum samples were collected between Aug 1 and Oct 31, 2020, from all people living with HIV who underwent routine outpatient laboratory testing in a municipal health-care system (San Francisco General Hospital, CA, USA). Samples from people living with HIV were date of collection-matched (same day) and age-matched (±5 years) to samples from randomly selected adults (aged 18 years or older) without HIV receiving care for chronic conditions at the same hospital. We compared seroprevalence by HIV status via mixed-effects logistic regression models, accounting for the matched structure of the data (random effects for the matched group), adjusting for age, sex, race or ethnicity, and clinical factors (ie, history of cardiovascular or pulmonary disease, and type 2 diabetes). Severe COVID-19 was assessed in participants with past SARS-CoV-2 (IgG or PCR) infection by chart review and compared with multivariable mixed-effects logistic regression, adjusting for age and sex. SARS-CoV-2 IgG, neutralising antibody titres, and antibody avidity were measured in serum of participants with previous positive PCR tests and compared with multivariable mixed-effects models, adjusting for age, sex, and time since PCR-confirmed SARS-CoV-2 infection.

Findings: 1138 samples from 955 people living with HIV and 1118 samples from 1062 people without HIV were tested. SARS-CoV-2 IgG seroprevalence was 3·7% (95% CI 2·4 to 5·0) among people with HIV compared with 7·4% (5·7 to 9·2) among people without HIV (adjusted odds ratio 0·50, 95% CI 0·30 to 0·83). Among 31 people with HIV and 70 people without HIV who had evidence of past infection, the odds of severe COVID-19 were 5·52 (95% CI 1·01 to 64·48) times higher among people living with HIV. Adjusting for time since PCR-confirmed infection, SARS-CoV-2 IgG concentrations were lower (percentage change -53%, 95% CI -4 to -76), pseudovirus neutralising antibody titres were lower (-67%, -25 to -86), and avidity was similar (7%, -73 to 87) among people living with HIV compared with those without HIV.

Interpretation: Although fewer infections were detected by SARS-CoV-2 IgG testing among people living with HIV than among those without HIV, people with HIV had more cases of severe COVID-19. Among people living with HIV with past SARS-CoV-2 infection, lower IgG concentrations and pseudovirus neutralising antibody titres might reflect a diminished serological response to infection, and the similar avidity could be driven by similar time since infection.

Funding: US National Institute of Allergy and Infectious Diseases, US National Institutes of Health.
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http://dx.doi.org/10.1016/S2352-3018(21)00072-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084354PMC
June 2021

Engineering luminescent biosensors for point-of-care SARS-CoV-2 antibody detection.

Nat Biotechnol 2021 Mar 25. Epub 2021 Mar 25.

Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.

Current serology tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies mainly take the form of enzyme-linked immunosorbent assays, chemiluminescent microparticle immunoassays or lateral flow assays, which are either laborious, expensive or lacking sufficient sensitivity and scalability. Here we present the development and validation of a rapid, low-cost, solution-based assay to detect antibodies in serum, plasma, whole blood and to a lesser extent saliva, using rationally designed split luciferase antibody biosensors. This new assay, which generates quantitative results in 30 min, substantially reduces the complexity and improves the scalability of coronavirus disease 2019 (COVID-19) antibody tests. This assay is well-suited for point-of-care, broad population testing, and applications in low-resource settings, for monitoring host humoral responses to vaccination or viral infection.
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http://dx.doi.org/10.1038/s41587-021-00878-8DOI Listing
March 2021

Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19.

medRxiv 2021 Mar 12. Epub 2021 Mar 12.

Background: As the coronavirus disease 2019 (COVID-19) pandemic continues and millions remain vulnerable to infection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), attention has turned to characterizing post-acute sequelae of SARS-CoV-2 infection (PASC).

Methods: From April 21 to December 31, 2020, we assembled a cohort of consecutive volunteers who a) had documented history of SARS-CoV-2 RNA-positivity; b) were ≥ 2 weeks past onset of COVID-19 symptoms or, if asymptomatic, first test for SARS-CoV-2; and c) were able to travel to our site in San Francisco. Participants learned about the study by being identified on medical center-based registries and being notified or by responding to advertisements. At 4-month intervals, we asked participants about physical symptoms that were new or worse compared to the period prior to COVID-19, mental health symptoms and quality of life. We described 4 time periods: 1) acute illness (0-3 weeks), 2) early recovery (3-10 weeks), 3) late recovery 1 (12-20 weeks), and 4) late recovery 2 (28-36 weeks). Blood and oral specimens were collected at each visit.

Results: We have, to date, enrolled 179 adults. During acute SARS-CoV-2 infection, 10 had been asymptomatic, 125 symptomatic but not hospitalized, and 44 symptomatic and hospitalized. In the acute phase, the most common symptoms were fatigue, fever, myalgia, cough and anosmia/dysgeusia. During the post-acute phase, fatigue, shortness of breath, concentration problems, headaches, trouble sleeping and anosmia/dysgeusia were the most commonly reported symptoms, but a variety of others were endorsed by at least some participants. Some experienced symptoms of depression, anxiety, and post-traumatic stress, as well as difficulties with ambulation and performance of usual activities. The median visual analogue scale value rating of general health was lower at 4 and 8 months (80, interquartile range [IQR]: 70-90; and 80, IQR 75-90) compared to prior to COVID-19 (85; IQR 75-90). Biospecimens were collected at nearly 600 participant-visits.

Conclusion: Among a cohort of participants enrolled in the post-acute phase of SARS-CoV-2 infection, we found many with persistent physical symptoms through 8 months following onset of COVID-19 with an impact on self-rated overall health. The presence of participants with and without symptoms and ample biological specimens will facilitate study of PASC pathogenesis. Similar evaluations in a population-representative sample will be needed to estimate the population-level prevalence of PASC.
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http://dx.doi.org/10.1101/2021.03.11.21252311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987054PMC
March 2021

Characterizing the COVID-19 illness experience to inform the study of post-acute sequalae and recovery: a qualitative study.

medRxiv 2021 Mar 12. Epub 2021 Mar 12.

Center for AIDS Prevention Studies, University of California, San Francisco, San Francisco, CA.

We aimed to characterize the variability in the illness experience and recovery process from COVID-19. We conducted in-depth individual interviews with participants enrolled in the Long-term Immunological Impact of Novel Coronavirus (LIINC) cohort study in San Francisco, California from June through October of 2020. Participants were adults who had a previously confirmed positive SARV-CoV-2 nucleic acid amplification test result, had recovered or were recovering from acute infection, and underwent serial evaluations at our clinical research center. We purposefully sampled 24 English- and Spanish-speaking adults with asymptomatic, mild and severe symptomatic infection, including those who were hospitalized, and those with HIV co-infection. Half of our sample (50.0%) identified as Latinx/Hispanic and most of the participants were men (62.5%). We used thematic analysis to characterize the illness experience, recovery process, and mental health impact of experiencing COVID-19 and present clinical data for each participant. Emergent themes were: (1) across symptom profiles and severity, experiencing COVID-19 was associated with psychological distress, (2) among participants with symptomatic infection, the illness experience was characterized by uncertainty in terms of managing symptoms and recovery, and (3) despite wide-ranging illness experiences, participants shared many common characteristics, including health information-seeking behavior facilitated by access to medical care, and uncertainty regarding the course of their illness and recovery. COVID-19 was associated with elevated levels of psychological distress, regardless of symptoms.
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http://dx.doi.org/10.1101/2021.03.10.21253330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987040PMC
March 2021

Ethical and practical considerations for mitigating risks to sexual partners during analytical treatment interruptions in HIV cure-related research.

HIV Res Clin Pract 2021 Feb 24;22(1):14-30. Epub 2021 Mar 24.

Division of HIV, Infectious Diseases and Global Medicine, University of California, San Francisco, CA, USA.

Background: Analytical treatment interruptions (ATIs) in HIV cure-related research can result in trial participants becoming viremic with HIV, placing HIV-negative sexual partners at elevated risk of acquiring HIV.

Objective: Our study aimed to generate ethical and practical considerations for designing and implementing appropriate risk mitigation strategies to reduce unintended HIV transmission events during ATIs.

Methods: We conducted 21 in-depth interviews with five types of informants: bioethicists, community members, biomedical HIV cure researchers, socio-behavioral scientists/epidemiologists, and HIV care providers. We used conventional content analysis to analyze the data and generate considerations.

Results: Key findings include: 1) Ethical permissibility of ATI trials depends on due diligence and informed consent to mitigate risks to participants and their sexual partners; 2) Participants should receive adequate support and/or counseling if they choose to disclose ATI participation to their partners; 3) Measures to protect sexual partners of trial participants from HIV transmission during ATIs should include referral to and/or provision of pre-exposure prophylaxis, as well as other available means of preventing HIV transmission; 4) There is uncertainty regarding the appropriate management of emerging sexually transmitted infections during ATI trials and possible protection measures for multiple and/or anonymous partners of ATI trial participants.

Conclusion: While there is no way to completely eliminate the risk of HIV transmission to sexual partners during ATIs, HIV cure trialists and sponsors should consider the ethical concerns related to the sexual partners of ATI participants. Doing so is essential to ensuring the welfare of participants, their partners and the trustworthiness of research.
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http://dx.doi.org/10.1080/25787489.2021.1902116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272285PMC
February 2021

Long-Term SARS-CoV-2-Specific Immune and Inflammatory Responses Across a Clinically Diverse Cohort of Individuals Recovering from COVID-19.

medRxiv 2021 Mar 1. Epub 2021 Mar 1.

A detailed understanding of long-term SARS-CoV-2-specific T cell responses and their relationship to humoral immunity and markers of inflammation in diverse groups of individuals representing the spectrum of COVID-19 illness and recovery is urgently needed. Data are also lacking as to whether and how adaptive immune and inflammatory responses differ in individuals that experience persistent symptomatic sequelae months following acute infection compared to those with complete, rapid recovery. We measured SARS-CoV-2-specific T cell responses, soluble markers of inflammation, and antibody levels and neutralization capacity longitudinally up to 9 months following infection in a diverse group of 70 individuals with PCR-confirmed SARS-CoV-2 infection. The participants had varying degrees of initial disease severity and were enrolled in the northern California Long-term Impact of Infection with Novel Coronavirus (LIINC) cohort. Adaptive T cell responses remained remarkably stable in all participants across disease severity during the entire study interval. Whereas the magnitude of the early CD4+ T cell immune response is determined by the severity of initial infection (participants requiring hospitalization or intensive care), pre-existing lung disease was significantly associated with higher long-term SARS-CoV2-specific CD8+ T cell responses, independent of initial disease severity or age. Neutralizing antibody levels were strongly correlated with SARS-CoV-2-specific CD4+ T but not CD8+ T cell responses. Importantly, we did not identify substantial differences in long-term virus-specific T cell or antibody responses between participants with and without COVID-19-related symptoms that persist months after initial infection.
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http://dx.doi.org/10.1101/2021.02.26.21252308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941662PMC
March 2021

SARS-CoV-2 antibody magnitude and detectability are driven by disease severity, timing, and assay.

medRxiv 2021 Mar 5. Epub 2021 Mar 5.

Serosurveillance studies are critical for estimating SARS-CoV-2 transmission and immunity, but interpretation of results is currently limited by poorly defined variability in the performance of antibody assays to detect seroreactivity over time in individuals with different clinical presentations. We measured longitudinal antibody responses to SARS-CoV-2 in plasma samples from a diverse cohort of 128 individuals over 160 days using 14 binding and neutralization assays. For all assays, we found a consistent and strong effect of disease severity on antibody magnitude, with fever, cough, hospitalization, and oxygen requirement explaining much of this variation. We found that binding assays measuring responses to spike protein had consistently higher correlation with neutralization than those measuring responses to nucleocapsid, regardless of assay format and sample timing. However, assays varied substantially with respect to sensitivity during early convalescence and in time to seroreversion. Variations in sensitivity and durability were particularly dramatic for individuals with mild infection, who had consistently lower antibody titers and represent the majority of the infected population, with sensitivities often differing substantially from reported test characteristics (e.g., amongst commercial assays, sensitivity at 6 months ranged from 33% for ARCHITECT IgG to 98% for VITROS Total Ig). Thus, the ability to detect previous infection by SARS-CoV-2 is highly dependent on the severity of the initial infection, timing relative to infection, and the assay used. These findings have important implications for the design and interpretation of SARS-CoV-2 serosurveillance studies.
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http://dx.doi.org/10.1101/2021.03.03.21251639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941652PMC
March 2021

Characterization and Biomarker Analyses of Post-COVID-19 Complications and Neurological Manifestations.

Cells 2021 02 13;10(2). Epub 2021 Feb 13.

Department of Laboratory Medicine, San Francisco VA Health Care System, San Francisco, CA 94121, USA.

As the SARS-CoV-2 pandemic continues, reports have demonstrated neurologic sequelae following COVID-19 recovery. Mechanisms to explain long-term neurological sequelae are unknown and need to be identified. Plasma from 24 individuals recovering from COVID-19 at 1 to 3 months after initial infection were collected for cytokine and antibody levels and neuronal-enriched extracellular vesicle (nEV) protein cargo analyses. Plasma cytokine IL-4 was increased in all COVID-19 participants. Volunteers with self-reported neurological problems (nCoV, = 8) had a positive correlation of IL6 with age or severity of the sequalae, at least one co-morbidity and increased SARS-CoV-2 antibody compared to those COVID-19 individuals without neurological issues (CoV, = 16). Protein markers of neuronal dysfunction including amyloid beta, neurofilament light, neurogranin, total tau, and p-T181-tau were all significantly increased in the nEVs of all participants recovering from COVID-19 compared to historic controls. This study suggests ongoing peripheral and neuroinflammation after COVID-19 infection that may influence neurological sequelae by altering nEV proteins. Individuals recovering from COVID-19 may have occult neural damage while those with demonstrative neurological symptoms additionally had more severe infection. Longitudinal studies to monitor plasma biomarkers and nEV cargo are warranted to assess persistent neurodegeneration and systemic effects.
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http://dx.doi.org/10.3390/cells10020386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918597PMC
February 2021

Citywide serosurveillance of the initial SARS-CoV-2 outbreak in San Francisco.

Res Sq 2021 Feb 4. Epub 2021 Feb 4.

Serosurveillance provides a unique opportunity to quantify the proportion of the population that has been exposed to pathogens. Here, we developed and piloted (SCALE-IT), a platform through which we systematically tested remnant samples from routine blood draws in two major hospital networks in San Francisco for SARS-CoV-2 antibodies during the early months of the pandemic. Importantly, SCALE-IT allows for algorithmic sample selection and rich data on covariates by leveraging electronic medical record data. We estimated overall seroprevalence at 4.2%, corresponding to a case ascertainment rate of only 4.9%, and identified important heterogeneities by neighborhood, homelessness status, and race/ethnicity. Neighborhood seroprevalence estimates from SCALE-IT were comparable to local community-based surveys, while providing results encompassing the entire city that have been previously unavailable. Leveraging this hybrid serosurveillance approach has strong potential for application beyond this local context and for diseases other than SARS-CoV-2.
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http://dx.doi.org/10.21203/rs.3.rs-180966/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872360PMC
February 2021

Persistent COVID-19-associated neurocognitive symptoms in non-hospitalized patients.

J Neurovirol 2021 02 2;27(1):191-195. Epub 2021 Feb 2.

Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, CA, USA.

As cases of coronavirus disease 2019 (COVID-19) mount worldwide, attention is needed on potential long-term neurologic impacts for the majority of patients who experience mild to moderate illness managed as outpatients. To date, there has not been discussion of persistent neurocognitive deficits in patients with milder COVID-19. We present two cases of non-hospitalized patients recovering from COVID-19 with persistent neurocognitive symptoms. Commonly used cognitive screens were normal, while more detailed testing revealed working memory and executive functioning deficits. An observational cohort study of individuals recovering from COVID-19 (14 or more days following symptom onset) identified that among the first 100 individuals enrolled, 14 were non-hospitalized patients reporting persistent cognitive issues. These 14 participants had a median age of 39 years (interquartile range: 35-56), and cognitive symptoms were present for at least a median of 98 days (interquartile range: 71-120 following acute COVID-19 symptoms); no participants with follow-up evaluation reported symptom resolution. We discuss potential mechanisms to be explored in future studies, including direct viral effects, indirect consequences of immune activation, and immune dysregulation causing auto-antibody production.
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http://dx.doi.org/10.1007/s13365-021-00954-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852463PMC
February 2021

Genome-wide DNA methylation profiling of peripheral blood reveals an epigenetic signature associated with severe COVID-19.

J Leukoc Biol 2021 07 19;110(1):21-26. Epub 2021 Jan 19.

Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.

The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly pathogenic RNA virus causing coronavirus disease 2019 (COVID-19) in humans. Although most patients with COVID-19 have mild illness and may be asymptomatic, some will develop severe pneumonia, acute respiratory distress syndrome, multi-organ failure, and death. RNA viruses such as SARS-CoV-2 are capable of hijacking the epigenetic landscape of host immune cells to evade antiviral defense. Yet, there remain considerable gaps in our understanding of immune cell epigenetic changes associated with severe SARS-CoV-2 infection pathology. Here, we examined genome-wide DNA methylation (DNAm) profiles of peripheral blood mononuclear cells from 9 terminally-ill, critical COVID-19 patients with confirmed SARS-CoV-2 plasma viremia compared with uninfected, hospitalized influenza, untreated primary HIV infection, and mild/moderate COVID-19 HIV coinfected individuals. Cell-type deconvolution analyses confirmed lymphopenia in severe COVID-19 and revealed a high percentage of estimated neutrophils suggesting perturbations to DNAm associated with granulopoiesis. We observed a distinct DNAm signature of severe COVID-19 characterized by hypermethylation of IFN-related genes and hypomethylation of inflammatory genes, reinforcing observations in infection models and single-cell transcriptional studies of severe COVID-19. Epigenetic clock analyses revealed severe COVID-19 was associated with an increased DNAm age and elevated mortality risk according to GrimAge, further validating the epigenetic clock as a predictor of disease and mortality risk. Our epigenetic results reveal a discovery DNAm signature of severe COVID-19 in blood potentially useful for corroborating clinical assessments, informing pathogenic mechanisms, and revealing new therapeutic targets against SARS-CoV-2.
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http://dx.doi.org/10.1002/JLB.5HI0720-466RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013321PMC
July 2021

Re-examining the HIV 'functional cure' oxymoron: Time for precise terminology?

J Virus Erad 2020 Nov 14;6(4):100017. Epub 2020 Oct 14.

Division of HIV, Infectious Diseases and Global Medicine, University of California, San Francisco, CA, USA.

For over a decade, the binary concepts of 'sterilizing' 'functional' cure have provided an organizing framework for the field of HIV cure-related research. In this article, we examine how the expression 'functional cure' is employed within the field, published literature, and community understanding of HIV cure research. In our synthesis of the different meanings attributed to 'functional cure' within contemporary biomedical discourse, we argue that employing the 'functional cure' terminology poses a series of problems. The expression itself is contradictory and inconsistently used across a wide array of HIV cure research initiatives. Further, the meaning and acceptability of 'functional cure' within communities of people living with and affected by HIV is highly variable. After drawing lessons from other fields, such as cancer and infectious hepatitis cure research, we summarize our considerations and propose alternative language that may more aptly describe the scientific objectives in question. We call for closer attention to language used to describe HIV cure-related research, and for continued, significant, and strategic engagement to ensure acceptable and more precise terminology.
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http://dx.doi.org/10.1016/j.jve.2020.100017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646673PMC
November 2020

Clinical outcomes and features of COVID-19 in patients with primary immunodeficiencies in New York City.

J Allergy Clin Immunol Pract 2021 01 8;9(1):490-493.e2. Epub 2020 Oct 8.

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2020.09.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543763PMC
January 2021

Clinical features, diagnostics, and outcomes of patients presenting with acute respiratory illness: A retrospective cohort study of patients with and without COVID-19.

EClinicalMedicine 2020 Oct 26;27:100518. Epub 2020 Aug 26.

Division of Hospital Medicine, University of California, San Francisco, CA, USA.

Background: Most data on the clinical presentation, diagnostics, and outcomes of patients with COVID-19 have been presented as case series without comparison to patients with other acute respiratory illnesses.

Methods: We examined emergency department patients between February 3 and March 31, 2020 with an acute respiratory illness who were tested for SARS-CoV-2. We determined COVID-19 status by PCR and metagenomic next generation sequencing (mNGS). We compared clinical presentation, diagnostics, treatment, and outcomes.

Findings: Among 316 patients, 33 tested positive for SARS-CoV-2; 31 without COVID-19 tested positive for another respiratory virus. Among patients with additional viral testing (27/33), no SARS-CoV-2 co-infections were identified. Compared to those who tested negative, patients with COVID-19 reported longer symptoms duration (median 7d vs. 3d,  < 0.001). Patients with COVID-19 were more often hospitalized (79% vs. 56%,  = 0.014). When hospitalized, patients with COVID-19 had longer hospitalizations (median 10.7d vs. 4.7d,  < 0.001) and more often developed ARDS (23% vs. 3%,  < 0.001). Most comorbidities, medications, symptoms, vital signs, laboratories, treatments, and outcomes did not differ by COVID-19 status.

Interpretation: While we found differences in clinical features of COVID-19 compared to other acute respiratory illnesses, there was significant overlap in presentation and comorbidities. Patients with COVID-19 were more likely to be admitted to the hospital, have longer hospitalizations and develop ARDS, and were unlikely to have co-existent viral infections.

Funding: National Center for Advancing Translational Sciences, National Heart Lung Blood Institute, National Institute of Allergy and Infectious Diseases, Chan Zuckerberg Biohub, Chan Zuckerberg Initiative.
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http://dx.doi.org/10.1016/j.eclinm.2020.100518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447618PMC
October 2020

Distinct viral reservoirs in individuals with spontaneous control of HIV-1.

Nature 2020 09 26;585(7824):261-267. Epub 2020 Aug 26.

Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.

Sustained, drug-free control of HIV-1 replication is naturally achieved in less than 0.5% of infected individuals (here termed 'elite controllers'), despite the presence of a replication-competent viral reservoir. Inducing such an ability to spontaneously maintain undetectable plasma viraemia is a major objective of HIV-1 cure research, but the characteristics of proviral reservoirs in elite controllers remain to be determined. Here, using next-generation sequencing of near-full-length single HIV-1 genomes and corresponding chromosomal integration sites, we show that the proviral reservoirs of elite controllers frequently consist of oligoclonal to near-monoclonal clusters of intact proviral sequences. In contrast to individuals treated with long-term antiretroviral therapy, intact proviral sequences from elite controllers were integrated at highly distinct sites in the human genome and were preferentially located in centromeric satellite DNA or in Krüppel-associated box domain-containing zinc finger genes on chromosome 19, both of which are associated with heterochromatin features. Moreover, the integration sites of intact proviral sequences from elite controllers showed an increased distance to transcriptional start sites and accessible chromatin of the host genome and were enriched in repressive chromatin marks. These data suggest that a distinct configuration of the proviral reservoir represents a structural correlate of natural viral control, and that the quality, rather than the quantity, of viral reservoirs can be an important distinguishing feature for a functional cure of HIV-1 infection. Moreover, in one elite controller, we were unable to detect intact proviral sequences despite analysing more than 1.5 billion peripheral blood mononuclear cells, which raises the possibility that a sterilizing cure of HIV-1 infection, which has previously been observed only following allogeneic haematopoietic stem cell transplantation, may be feasible in rare instances.
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http://dx.doi.org/10.1038/s41586-020-2651-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837306PMC
September 2020

Operationalizing Human Immunodeficiency Virus Cure-related Trials with Analytic Treatment Interruptions During the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Pandemic: A Collaborative Approach.

Clin Infect Dis 2021 05;72(10):1843-1849

Center for AIDS Prevention Studies, University of California, San Francisco, San Francisco, California, USA.

Efforts to recognize and minimize the risk to study participants will be necessary to safely and ethically resume scientific research in the context of the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. These efforts are uniquely challenging in the context of human immunodeficiency virus (HIV) cure clinical trials, which often involve complex experimental therapy regimens and perhaps analytic treatment interruption, in which participants pause antiretroviral therapy. In this viewpoint, we discuss our approach to reopening an HIV cure trial in this context, with a focus on key considerations regarding study design, informed consent and participant education, and study implementation. These recommendations might be informative to other groups seeking to resume HIV cure research in settings similar to ours.
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http://dx.doi.org/10.1093/cid/ciaa1260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499539PMC
May 2021

Engineering luminescent biosensors for point-of-care SARS-CoV-2 antibody detection.

medRxiv 2020 Aug 21. Epub 2020 Aug 21.

Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, 94158, USA.

Current serology tests for SARS-CoV-2 antibodies mainly take the form of enzyme-linked immunosorbent assays or lateral flow assays, with the former being laborious and the latter being expensive and often lacking sufficient sensitivity and scalability. Here we present the development and validation of a rapid, low-cost solution-based assay to detect antibodies in serum, plasma, whole blood, and saliva, using rationally designed split luciferase antibody biosensors (spLUC). This new assay, which generates quantitative results in as short as 5 minutes, substantially reduces the complexity and improves the scalability of COVID-19 antibody tests for point-of-care and broad population testing.
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http://dx.doi.org/10.1101/2020.08.17.20176925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444307PMC
August 2020

Universal PCR and antibody testing demonstrate little to no transmission of SARS-CoV-2 in a rural community.

medRxiv 2020 Aug 17. Epub 2020 Aug 17.

University Of California San Francisco, San Francisco, CA, USA.

Background: The absence of systematic surveillance for SARS-CoV-2 has curtailed accurate appraisal of transmission intensity. Our objective was to perform case detection of an entire rural community to quantify SARS-CoV-2 transmission using PCR and antibody testing.

Methods: We conducted a cross-sectional survey of the prevalence and cumulative incidence of SARS-CoV-2 infection in the rural town of Bolinas, California (population 1,620), four weeks following shelter-in-place orders. Residents and county essential workers were tested between April 20th-24th, 2020. Prevalence by PCR and seroprevalence combining data from two forms of antibody testing were performed in parallel (Abbott ARCHITECT IgG to nucleocapsid protein and in-house IgG ELISA to the receptor binding domain).

Results: Of 1,891 participants, 1,312 were confirmed Bolinas residents (>80% community ascertainment). Zero participants were PCR positive. Assuming 80% sensitivity, it would have been unlikely to observe these results (p<0.05) if there were >3 active infections in the community. Based on antibody results, estimated prevalence of prior infection was 0.16% (95% CrI: 0.02%, 0.46%). Seroprevalence estimates using only one of the two tests would have been higher, with greater uncertainty. The positive predictive value (PPV) of a positive result on both tests was 99.11% (95% CrI: 95.75%, 99.94%), compared to PPV 44.19%-63.32% (95% CrI range 3.25%-98.64%) if only one test was utilized.

Conclusions: Four weeks following shelter-in-place, active and prior SARS-CoV-2 infection in a rural Northern California community was extremely rare. In this low prevalence setting, use of two antibody tests increased the PPV and precision of seroprevalence estimates.
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http://dx.doi.org/10.1101/2020.08.15.20175786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444294PMC
August 2020

Clinical Outcomes and Immunologic Characteristics of Coronavirus Disease 2019 in People With Human Immunodeficiency Virus.

J Infect Dis 2021 02;223(3):403-408

Icahn School of Medicine at Mount Sinai, New York, New York, USA.

We performed a retrospective study of coronavirus disease 2019 (COVID-19) in people with human immunodeficiency virus (PWH). PWH with COVID-19 demonstrated severe lymphopenia and decreased CD4+ T cell counts. Levels of inflammatory markers, including C-reactive protein, fibrinogen, D-dimer, interleukin 6, interleukin 8, and tumor necrosis factor α were commonly elevated. In all, 19 of 72 hospitalized individuals (26.4%) died and 53 (73.6%) recovered. PWH who died had higher levels of inflammatory markers and more severe lymphopenia than those who recovered. These findings suggest that PWH remain at risk for severe manifestations of COVID-19 despite antiretroviral therapy and that those with increased markers of inflammation and immune dysregulation are at risk for worse outcomes.
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http://dx.doi.org/10.1093/infdis/jiaa380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337732PMC
February 2021

Clinical features, diagnostics, and outcomes of patients presenting with acute respiratory illness: a comparison of patients with and without COVID-19.

medRxiv 2020 May 6. Epub 2020 May 6.

Background: Emerging data on the clinical presentation, diagnostics, and outcomes of patients with COVID-19 have largely been presented as case series. Few studies have compared these clinical features and outcomes of COVID-19 to other acute respiratory illnesses.

Methods: We examined all patients presenting to an emergency department in San Francisco, California between February 3 and March 31, 2020 with an acute respiratory illness who were tested for SARS-CoV-2. We determined COVID-19 status by PCR and metagenomic next generation sequencing (mNGS). We compared demographics, comorbidities, symptoms, vital signs, and laboratory results including viral diagnostics using PCR and mNGS. Among those hospitalized, we determined differences in treatment (antibiotics, antivirals, respiratory support) and outcomes (ICU admission, ICU interventions, acute respiratory distress syndrome, cardiac injury).

Findings: In a cohort of 316 patients, 33 (10%) tested positive for SARS-CoV-2; 31 patients, all without COVID-19, tested positive for another respiratory virus (16%). Among patients with additional viral testing, no co-infections with SARS-CoV-2 were identified by PCR or mNGS. Patients with COVID-19 reported longer symptoms duration (median 7 vs. 3 days), and were more likely to report fever (82% vs. 44%), fatigue (85% vs. 50%), and myalgias (61% vs 27%); p<0.001 for all comparisons. Lymphopenia (55% vs 34%, p=0.018) and bilateral opacities on initial chest radiograph (55% vs. 24%, p=0.001) were more common in patients with COVID-19. Patients with COVID-19 were more often hospitalized (79% vs. 56%, p=0.014). Of 186 hospitalized patients, patients with COVID-19 had longer hospitalizations (median 10.7d vs. 4.7d, p<0.001) and were more likely to develop ARDS (23% vs. 3%, p<0.001). Most comorbidities, home medications, signs and symptoms, vital signs, laboratory results, treatment, and outcomes did not differ by COVID-19 status.

Interpretation: While we found differences in clinical features of COVID-19 compared to other acute respiratory illnesses, there was significant overlap in presentation and comorbidities. Patients with COVID-19 were more likely to be admitted to the hospital, have longer hospitalizations and develop ARDS, and were unlikely to have co-existent viral infections. These findings enhance understanding of the clinical characteristics of COVID-19 in comparison to other acute respiratory illnesses.  .
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http://dx.doi.org/10.1101/2020.05.02.20082461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273256PMC
May 2020

Opportunistic coinfection with and associated with idelalisib treatment in a patient with chronic lymphocytic leukaemia.

BMJ Case Rep 2020 Apr 29;13(4). Epub 2020 Apr 29.

Division of Infectious Diseases, University of California San Francisco, San Francisco, California, USA.

We describe a case of opportunistic coinfections with and following treatment with idelalisib, a phosphoinositide 3-kinase inhibitor, for chronic lymphocytic leukaemia. This is the first case of pulmonary coccidioidomycosis reported in association with idelalisib. We review challenges related to diagnosis of opportunistic infections in this context. This report illustrates (1) the uncommon occurrence of two opportunistic infections concurrently or in rapid succession, (2) the importance of maintaining a broad differential diagnosis in the setting of an atypical imaging finding, slow clinical response or when immunomodulatory drugs are used, and (3) the challenges associated with non-invasive serological testing in individuals with haematological malignancy on immunomodulatory therapy.
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http://dx.doi.org/10.1136/bcr-2019-234113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213705PMC
April 2020
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