Publications by authors named "Jonathan Li"

303 Publications

Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections.

Immunity 2021 Apr 22. Epub 2021 Apr 22.

Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.

A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections.
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http://dx.doi.org/10.1016/j.immuni.2021.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080416PMC
April 2021

SARS-CoV-2 Sequence Characteristics of COVID-19 Persistence and Reinfection.

Clin Infect Dis 2021 Apr 27. Epub 2021 Apr 27.

Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Background: Both SARS-CoV-2 reinfection and persistent infection have been reported, but sequence characteristics in these scenarios have not been described. We assessed published cases of SARS-CoV-2 reinfection and persistence, characterizing the hallmarks of reinfecting sequences and the rate of viral evolution in persistent infection.

Methods: A systematic review of PubMed was conducted to identify cases of SARS-CoV-2 reinfection and persistence with available sequences. Nucleotide and amino acid changes in the reinfecting sequence were compared to both the initial and contemporaneous community variants. Time-measured phylogenetic reconstruction was performed to compare intra-host viral evolution in persistent SARS-CoV-2 to community-driven evolution.

Results: Twenty reinfection and nine persistent infection cases were identified. Reports of reinfection cases spanned a broad distribution of ages, baseline health status, reinfection severity, and occurred as early as 1.5 months or >8 months after the initial infection. The reinfecting viral sequences had a median of 17.5 nucleotide changes with enrichment in the ORF8 and N genes. The number of changes did not differ by the severity of reinfection and reinfecting variants were similar to the contemporaneous sequences circulating in the community. Patients with persistent COVID-19 demonstrated more rapid accumulation of sequence changes than seen with community-driven evolution with continued evolution during convalescent plasma or monoclonal antibody treatment.

Conclusions: Reinfecting SARS-CoV-2 viral genomes largely mirror contemporaneous circulating sequences in that geographic region, while persistent COVID-19 has been largely described in immunosuppressed individuals and is associated with accelerated viral evolution.
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http://dx.doi.org/10.1093/cid/ciab380DOI Listing
April 2021

Transcription factors regulated by cAMP in smooth muscle of the myometrium at human parturition.

Biochem Soc Trans 2021 Apr;49(2):997-1011

Division of Reproductive and Developmental Biology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW10 9NH, U.K.

Cyclic adenosine monophosphate (cAMP) contributes to maintenance of a quiescent (relaxed) state in the myometrium (i.e. uterine smooth muscle) during pregnancy, which most commonly has been attributed to activation of protein kinase A (PKA). PKA-mediated phosphorylation of cytosolic contractile apparatus components in myometrial smooth muscle cells (mSMCs) are known to promote relaxation. Additionally, PKA also regulates nuclear transcription factor (TF) activity to control expression of genes important to the labour process; these are mostly involved in actin-myosin interactions, cell-to-cell connectivity and inflammation, all of which influence mSMC transition from a quiescent to a contractile (pro-labour) phenotype. This review focuses on the evidence that cAMP modulates the activity of TFs linked to pro-labour gene expression, predominantly cAMP response element (CRE) binding TFs, nuclear factor κB (NF-κB), activator protein 1 (AP-1) family and progesterone receptors (PRs). This review also considers the more recently described exchange protein directly activated by cAMP (EPAC) that may oppose the pro-quiescent effects of PKA, as well as explores findings from other cell types that have the potential to be of novel relevance to cAMP action on TF function in the myometrium.
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http://dx.doi.org/10.1042/BST20201173DOI Listing
April 2021

Unified model of short- and long-term HIV viral rebound for clinical trial planning.

J R Soc Interface 2021 04 14;18(177):20201015. Epub 2021 Apr 14.

Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA.

Antiretroviral therapy (ART) effectively controls HIV infection, suppressing HIV viral loads. Typically suspension of therapy is rapidly followed by rebound of viral loads to high, pre-therapy levels. Indeed, a recent study showed that approximately 90% of treatment interruption study participants show viral rebound within at most a few months of therapy suspension, but the remaining 10%, showed viral rebound some months, or years, after ART suspension. Some may even never rebound. We investigate and compare branching process models aimed at gaining insight into these viral dynamics. Specifically, we provide a theory that explains both short- and long-term viral rebounds, and post-treatment control, via a multitype branching process with time-inhomogeneous rates, validated with data from Li (Li 2016 , 343-353. (doi:10.1097/QAD.0000000000000953)). We discuss the associated biological interpretation and implications of our best-fit model. To test the effectiveness of an experimental intervention in delaying or preventing rebound, the standard practice is to suspend therapy and monitor the study participants for rebound. We close with a discussion of an important application of our modelling in the design of such clinical trials.
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http://dx.doi.org/10.1098/rsif.2020.1015DOI Listing
April 2021

SARS-CoV-2 evolution in an immunocompromised host reveals shared neutralization escape mechanisms.

Cell 2021 May 16;184(10):2605-2617.e18. Epub 2021 Mar 16.

Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Massachusetts Consortium on Pathogen Readiness, Boston, MA, USA. Electronic address:

Many individuals mount nearly identical antibody responses to SARS-CoV-2. To gain insight into how the viral spike (S) protein receptor-binding domain (RBD) might evolve in response to common antibody responses, we studied mutations occurring during virus evolution in a persistently infected immunocompromised individual. We use antibody Fab/RBD structures to predict, and pseudotypes to confirm, that mutations found in late-stage evolved S variants confer resistance to a common class of SARS-CoV-2 neutralizing antibodies we isolated from a healthy COVID-19 convalescent donor. Resistance extends to the polyclonal serum immunoglobulins of four out of four healthy convalescent donors we tested and to monoclonal antibodies in clinical use. We further show that affinity maturation is unimportant for wild-type virus neutralization but is critical to neutralization breadth. Because the mutations we studied foreshadowed emerging variants that are now circulating across the globe, our results have implications to the long-term efficacy of S-directed countermeasures.
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http://dx.doi.org/10.1016/j.cell.2021.03.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962548PMC
May 2021

Sexually dimorphic placental responses to maternal SARS-CoV-2 infection.

bioRxiv 2021 Mar 29. Epub 2021 Mar 29.

There is a persistent male bias in the prevalence and severity of COVID-19 disease. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of disease in adults, and play a key role in the placental anti-viral response. Moreover, the interferon response has been shown to alter Fc-receptor expression, and therefore may impact placental antibody transfer. Here we examined the intersection of viral-induced placental interferon responses, maternal-fetal antibody transfer, and fetal sex. Placental interferon stimulated genes (ISGs), Fc-receptor expression, and SARS-CoV-2 antibody transfer were interrogated in 68 pregnancies. Sexually dimorphic placental expression of ISGs, interleukin-10, and Fc receptors was observed following maternal SARS-CoV-2 infection, with upregulation in males. Reduced maternal SARS-CoV-2-specific antibody titers and impaired placental antibody transfer were noted in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.
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http://dx.doi.org/10.1101/2021.03.29.437516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020979PMC
March 2021

Expansion of Cytotoxic CD4+ T cells in the lungs in severe COVID-19.

medRxiv 2021 Mar 26. Epub 2021 Mar 26.

The contributions of T cells infiltrating the lungs to SARS-CoV-2 clearance and disease progression are poorly understood. Although studies of CD8+ T cells in bronchoalveolar lavage and blood have suggested that these cells are exhausted in severe COVID-19, CD4+ T cells have not been systematically interrogated within the lung parenchyma. We establish here that cytotoxic CD4+ T cells (CD4+CTLs) are prominently expanded in the COVID-19 lung infiltrate. CD4+CTL numbers in the lung increase with disease severity and progression is accompanied by widespread HLA-DR expression on lung epithelial and endothelial cells, increased apoptosis of epithelial cells and tissue remodeling. Based on quantitative evidence for re-activation in the lung milieu, CD4+ CTLs are as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19.

In Brief: In severe COVID-19 cytotoxic CD4+ T cells accumulate in draining lymph nodes and in the lungs during the resolving phase of the disease. Re-activated cytotoxic CD4+ T cells and cytotoxic CD8+ T cells are present in roughly equivalent numbers in the lungs at this stage and these cells likely collaborate to eliminate virally infected cells and potentially induce fibrosis. A large fraction of epithelial and endothelial cells in the lung express HLA class II in COVID-19 and there is temporal convergence between CD4+CTL accumulation and apoptosis in the lung.

Highlights: In severe COVID-19, activated CD4+ CTLs accumulate in the lungs late in diseaseThese cells likely participate in SARS-CoV-2 clearance, collaborating with CD8+ T cells many of which exhibit an exhausted phenotypeT cells likely contribute to the late exacerbation of inflammationCD4+CTLs have been linked to fibrosis in many disorders and could also be responsible for the eventual induction of fibrosis in a subset of COVID-19 patients.

Summary: The contributions of T cells infiltrating the lungs to SARS-CoV-2 clearance and disease progression are poorly understood. Although studies of CD8+ T cells in bronchoalveolar lavage and blood have suggested that these cells are exhausted in severe COVID-19, CD4+ T cells have not been systematically interrogated within the lung parenchyma. We establish here that cytotoxic CD4+ T cells (CD4+CTLs) are prominently expanded in the COVID-19 lung infiltrate. CD4+CTL numbers in the lung increase with disease severity and progression is accompanied by widespread HLA-DR expression on lung epithelial and endothelial cells, increased apoptosis of epithelial cells and tissue remodeling. Based on quantitative evidence for re-activation in the lung milieu, CD4+ CTLs are as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19.
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http://dx.doi.org/10.1101/2021.03.23.21253885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010762PMC
March 2021

Type I, II, and III interferon signatures correspond to COVID-19 disease severity.

medRxiv 2021 Mar 12. Epub 2021 Mar 12.

We analyzed the plasma levels of interferons and cytokines, and the expression of interferon-stimulated genes in peripheral blood mononuclear cells in COVID-19 patients with different disease severity. Mild patients exhibited transient type I interferon responses, while ICU patients had prolonged type I interferon responses with hyper-inflammation mediated by interferon regulatory factor 1. Type II interferon responses were compromised in ICU patients. Type III interferon responses were induced in the early phase of SARS-CoV-2 infection, even in convalescent patients. These results highlight the importance of type I and III interferon responses during the early phase of infection in controlling COVID-19 progression.
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http://dx.doi.org/10.1101/2021.03.10.21253317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987053PMC
March 2021

Single-cell immunophenotyping of the fetal immune response to maternal SARS-CoV-2 infection in late gestation.

Res Sq 2021 Mar 16. Epub 2021 Mar 16.

During the COVID-19 pandemic, thousands of pregnant women have been infected with SARS-CoV-2. The implications of maternal SARS-CoV-2 infection on fetal and childhood well-being are unknown. We aimed to characterize the fetal immune response to maternal SARS-CoV-2 infection. We performed single-cell RNA sequencing and T-cell receptor (TCR) sequencing on cord blood mononuclear cells (CBMC) from newborns of mothers infected with SARS-CoV-2 in the third-trimester (cases) or without SARS-CoV-2 infection. We identified widespread gene expression changes in CBMC from cases, including upregulation of interferon-stimulated genes and Major Histocompatibility Complex genes in CD14 + monocytes; transcriptional changes suggestive of activation of plasmacytoid dendritic cells, and activation and exhaustion of NK cells and CD8 + T-cells. Lastly, we observed fetal TCR repertoire expansion in cases. As none of the infants were infected with SARS-CoV-2, our results suggest that SARS-CoV-2 maternal infection might modulate the fetal immune system in the absence of vertical transmission.
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http://dx.doi.org/10.21203/rs.3.rs-311000/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987103PMC
March 2021

Recent trends in premature mortality and health disparities attributable to ambient PM exposure in China: 2005-2017.

Environ Pollut 2021 Jun 9;279:116882. Epub 2021 Mar 9.

School of Information Engineering, China University of Geosciences, Beijing, 100083, China.

In the past decade, particulate matter with aerodynamic diameter less than 2.5 μm (PM) has reached unprecedented levels in China and posed a significant threat to public health. Exploring the long-term trajectory of the PM attributable health burden and corresponding disparities across populations in China yields insights for policymakers regarding the effectiveness of efforts to reduce air pollution exposure. Therefore, we examine how the magnitude and equity of the PM-related public health burden has changed nationally, and between provinces, as economic growth and pollution levels varied during 2005-2017. We derive long-term PM exposures in China from satellite-based observations and chemical transport models, and estimate attributable premature mortality using the Global Exposure Mortality Model (GEMM). We characterize national and interprovincial inequality in health outcomes using environmental Lorenz curves and Gini coefficients over the study period. PM exposure is linked to 1.8 (95% CI: 1.6, 2.0) million premature deaths over China in 2017, increasing by 31% from 2005. Approximately 70% of PM attributable deaths were caused by stroke and IHD (ischemic heart disease), though COPD (chronic obstructive pulmonary disease) and LRI (lower respiratory infection) disproportionately affected poorer provinces. While most economic gains and PM-related deaths were concentrated in a few provinces, both gains and deaths became more equitably distributed across provinces over time. As a nation, however, trends toward equality were more recent and less clear cut across causes of death. The rise in premature mortality is due primarily to population growth and baseline risks of stroke and IHD. This rising health burden could be alleviated through policies to prevent pollution, exposure, and disease. More targeted programs may be warranted for poorer provinces with a disproportionate share of PM-related premature deaths due to COPD and LRI.
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http://dx.doi.org/10.1016/j.envpol.2021.116882DOI Listing
June 2021

Ultrasensitive Measurement of Both SARS-CoV-2 RNA and Antibodies from Saliva.

Anal Chem 2021 04 23;93(13):5365-5370. Epub 2021 Mar 23.

Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, United States.

Tests for COVID-19 generally measure SARS-CoV-2 viral RNA from nasal swabs or antibodies against the virus from blood. It has been shown, however, that both viral particles and antibodies against those particles are present in saliva, which is more accessible than both swabs and blood. We present methods for highly sensitive measurements of both viral RNA and antibodies from the same saliva sample. We developed an efficient saliva RNA extraction method and combined it with an ultrasensitive antibody test based on single molecule array (Simoa) technology. We apply our test to the saliva of patients who presented to the hospital with COVID-19 symptoms, some of whom tested positive with a conventional RT-qPCR nasopharyngeal swab test. We demonstrate that combining viral RNA detection by RT-qPCR with antibody detection by Simoa identifies more patients as infected than either method alone. Our results demonstrate the utility of combining viral RNA and antibody testing from saliva, a single easily accessible biofluid.
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http://dx.doi.org/10.1021/acs.analchem.1c00515DOI Listing
April 2021

Minimally Invasive Paraesophageal Hernia Repair in the Elderly: Is Age Really Just a Number?

J Laparoendosc Adv Surg Tech A 2021 Mar 11. Epub 2021 Mar 11.

Division of Minimally Invasive Surgery, Center for the Future of Surgery, University of California San Diego, San Diego, California, USA.

Paraesophageal hernias readily affect the elderly with a median age of presentation between 65 and 75 years. Laparoscopic paraesophageal hernia repair (PEHR) is a technically challenging operation with potential for dire complications. Advanced age and medical comorbidities may heighten perioperative risk and limit surgical candidacy, potentially refusing patients an opportunity toward symptom resolution. Given the increased prevalence in the elderly and associated surgical risks, we aim to assess age as an independent risk factor for perioperative morbidity and mortality after PEHR. A retrospective analysis using a prospectively maintained database assessed patients undergoing PEHR from 2007 to 2018. Patients were stratified by age: Group A (age <65 years), Group B (65≤ age <80 years), and Group C (age ≥80 years). Patient demographics, preoperative symptoms, postoperative outcomes, and mortality rate were analyzed. Barium esophagram was performed on symptomatic postsurgical patients. Recurrence was confirmed radiologically. In total, 143 patients underwent laparoscopic (94.4%) or robotic-assisted (5.6%) PEHR. Average age per group was Group A ( = 49) 55.4 years (standard deviation [SD] ±8.91), Group B ( = 76) 71.4 years (SD ±4.40), and Group C ( = 17) 84.1 (years) (SD ±3.37). Group C had significantly higher rates of nonelective surgery ( = .018), preoperative weight loss ( = .014), hypertension ( = .031), ischemic heart disease ( = .001), and cancer ( = .039); preoperative body mass index was significantly lower ( = .048). Charlson comorbidity index differences between groups were significant (2.00 versus 3.61 versus 5.28,  < .001). Median follow-up was 426 days (6-3199). Symptom improvement was seen in 78.3% of patients. Recurrence and reoperation rates were not significantly different between groups. No differences were seen in mortality, length of stay, or postoperative complications between groups. PEHR in elderly patients proved to be safe and effective. Avoidance of emergent intervention may be achieved through a judicious elective approach to this anatomic problem. Symptom resolution and quality-of-life improvement can be safely achieved with surgical repair in this patient population, demonstrating that age is truly just a number for PEHR.
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http://dx.doi.org/10.1089/lap.2020.0792DOI Listing
March 2021

Impact of pre-existing drug resistance on risk of virological failure in South Africa.

J Antimicrob Chemother 2021 May;76(6):1558-1563

Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Objectives: There is conflicting evidence on the impact of pre-existing HIV drug resistance mutations (DRMs) in patients infected with non-B subtype virus.

Methods: We performed a case-cohort substudy of the AIDS Drug Resistance Surveillance Study, which enrolled South African patients initiating first-line efavirenz/emtricitabine/tenofovir. Pre-ART DRMs were detected by Illumina sequencing of HIV pol and DRMs present at <20% of the viral population were labelled as minority variants (MVs). Weighted Cox proportional hazards models estimated the association between pre-ART DRMs and risk of virological failure (VF), defined as confirmed HIV-1 RNA ≥1000 copies/mL after ≥5 months of ART.

Results: The evaluable population included 178 participants from a randomly selected subcohort (16 with VF, 162 without VF) and 83 additional participants with VF. In the subcohort, 16% of participants harboured ≥1 majority DRM. The presence of any majority DRM was associated with a 3-fold greater risk of VF (P = 0.002), which increased to 9.2-fold (P < 0.001) in those with <2 active drugs. Thirteen percent of participants harboured MV DRMs in the absence of majority DRMs. Presence of MVs alone had no significant impact on the risk of VF. Inclusion of pre-ART MVs with majority DRMs improved the sensitivity but reduced the specificity of predicting VF.

Conclusions: In a South African cohort, the presence of majority DRMs increased the risk of VF, especially for participants receiving <2 active drugs. The detection of drug-resistant MVs alone did not predict an increased risk of VF, but their inclusion with majority DRMs affected the sensitivity/specificity of predicting VF.
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http://dx.doi.org/10.1093/jac/dkab062DOI Listing
May 2021

Viral Rebound Kinetics Correlate with Distinct HIV Antibody Features.

mBio 2021 03 9;12(2). Epub 2021 Mar 9.

Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA

Plasma viremia reoccurs in most HIV-infected individuals once antiretroviral therapy (ART) is interrupted. The kinetics of viral rebound, specifically the time until plasma virus becomes detectable, differ quite substantially between individuals, and associations with virological and immunological factors have been suggested. Standard clinical measures, like CD4 T-cell counts and plasma HIV RNA levels, however, are poor predictive markers. Antibody features, including Fc functionality and Fc glycosylation have been identified as sensitive surrogates for disease activity in multiple diseases. Here, we analyzed HIV-specific antibody quantities and qualitative differences like antibody-mediated functions, Fc gamma receptor (FcγR) binding, and IgG Fc glycosylation as well as cytokine profiles and cellular HIV DNA and RNA levels in 23 ART-suppressed individuals prior to undergoing an analytical ART interruption (ATI). We found that antibodies with distinct functional properties and Fc glycan signatures separated individuals into early and delayed viral rebounders (≤4 weeks versus >4 weeks) and tracked with levels of inflammatory cytokines and transcriptional activity of the viral reservoir. Specifically, individuals with early viral rebound exhibited higher levels of total HIV-specific IgGs carrying inflammatory Fc glycans, while delayed rebounders showed an enrichment of highly functional antibodies. Overall, only four features, including enhanced antibody-mediated NK cell activation in delayed rebounders, were necessary to discriminate the groups. These data suggest that antibody features can be used as sensitive indicators of HIV disease activity and could be included in future ATI studies. Plasma viremia reoccurs in most HIV-infected individuals once antiretroviral therapy is interrupted, and interindividual differences in the kinetics of viral rebound have been associated with virological and immunological factors. Antibody features, including Fc functionality and Fc glycosylation, have been identified as sensitive surrogates for disease activity in multiple diseases. Here, we systematically analyzed HIV-specific antibody quantities and qualitative differences in 23 ART-suppressed individuals prior to undergoing an analytical ART interruption (ATI). We found that antibodies with distinct functional properties and Fc glycan signatures separated individuals into early and delayed viral rebounders and tracked with levels of inflammatory cytokines and transcriptional activity of the viral reservoir. These data suggest that antibody features can be used as sensitive indicators of HIV disease activity and could be included in future HIV eradication studies.
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http://dx.doi.org/10.1128/mBio.00170-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092214PMC
March 2021

SARS-CoV-2 Viremia is Associated with Distinct Proteomic Pathways and Predicts COVID-19 Outcomes.

medRxiv 2021 Feb 26. Epub 2021 Feb 26.

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) plasma viremia has been associated with severe disease and death in coronavirus disease 2019 (COVID-19) in small-scale cohort studies. The mechanisms behind this association remain elusive.

Methods: We evaluated the relationship between SARS-CoV-2 viremia, disease outcome, inflammatory and proteomic profiles in a cohort of COVID-19 emergency department participants. SARS-CoV-2 viral load was measured using qRT-PCR based platform. Proteomic data were generated with Proximity Extension Assay (PEA) using the Olink platform.

Results: Three hundred participants with nucleic acid test-confirmed COVID-19 were included in this study. Levels of plasma SARS-CoV-2 viremia at the time of presentation predicted adverse disease outcomes, with an adjusted odds ratio (aOR) of 10.6 (95% confidence interval [CI] 4.4, 25.5, P<0.001) for severe disease (mechanical ventilation and/or 28-day mortality) and aOR of 3.9 (95%CI 1.5, 10.1, P=0.006) for 28-day mortality. Proteomic analyses revealed prominent proteomic pathways associated with SARS-CoV-2 viremia, including upregulation of SARS-CoV-2 entry factors (ACE2, CTSL, FURIN), heightened markers of tissue damage to the lungs, gastrointestinal tract, endothelium/vasculature and alterations in coagulation pathways.

Conclusions: These results highlight the cascade of vascular and tissue damage associated with SARS-CoV-2 plasma viremia that underlies its ability to predict COVID-19 disease outcomes.
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http://dx.doi.org/10.1101/2021.02.24.21252357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924277PMC
February 2021

Leclercia adecarboxylata urinary tract infection in a patient with bladder cancer and recurrent hematuria.

Urol Case Rep 2021 May 27;36:101579. Epub 2021 Jan 27.

Department of Urology, Geisinger, Danville, PA, USA.

is an rare human pathogen, mostly affecting immunocompromised individuals or as one microbe in polymicrobial infections in immunocompetent patients. is rarely isolated from the urinary tract. We describe a case of pan-sensitive isolated from a polymicrobial urinary tract infection from an immunocompetent older adult with recently diagnosed bladder cancer.
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http://dx.doi.org/10.1016/j.eucr.2021.101579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889819PMC
May 2021

Drug resistance mutations in HIV provirus are associated with defective proviral genomes with hypermutation.

AIDS 2021 Jun;35(7):1015-1020

Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School.

Background: HIV proviral sequencing overcomes the limit of plasma viral load requirement by detecting all the 'archived mutations', but the clinical relevance remains to be evaluated.

Methods: We included 25 participants with available proviral sequences (both intact and defective sequences available) and utilized the genotypic sensitivity score (GSS) to evaluate the level of resistance in their provirus and plasma virus. Defective sequences were further categorized as sequences with and without hypermutations. Personalized GSS score and total GSS score were calculated to evaluate the level of resistance to a whole panel of antiretroviral therapies and to certain antiretroviral therapy that a participant was using. The rate of sequences with drug resistance mutations (DRMs) within each sequence compartment (intact, defective and plasma viral sequences) was calculated for each participant.

Results: Defective proviral sequences harbored more DRMs than other sequence compartments, with a median DRM rate of 0.25 compared with intact sequences (0.0, P = 0.014) and plasma sequences (0.095, P = 0.30). Defective sequences with hypermutations were the major source of DRMs, with a median DRM rate of 1.0 compared with defective sequences without hypermutations (0.042, P < 0.001). Certain Apolipoprotein B Editing Complex 3-related DRMs including reverse transcriptase gene mutations M184I, E138K, M230I, G190E and protease gene mutations M46I, D30N were enriched in hypermutated sequences but not in intact sequences or plasma sequences. All the hypermutated sequences had premature stop codons due to Apolipoprotein B Editing Complex 3.

Conclusion: Proviral sequencing may overestimate DRMs as a result of hypermutations. Removing hypermutated sequences is essential in the interpretation of proviral drug resistance testing.
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http://dx.doi.org/10.1097/QAD.0000000000002850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102365PMC
June 2021

Phospholipid Metabolism Is Associated with Time to HIV Rebound upon Treatment Interruption.

mBio 2021 02 23;12(1). Epub 2021 Feb 23.

The Wistar Institute, Philadelphia, Pennsylvania, USA

Lipids are biologically active molecules involved in a variety of cellular processes and immunological functions, including inflammation. It was recently shown that phospholipids and their derivatives, lysophospholipids, can reactivate latent (dormant) tumor cells, causing cancer recurrence. However, the potential link between lipids and HIV latency, persistence, and viral rebound after cessation of antiretroviral therapy (ART) has never been investigated. We explored the links between plasma lipids and the burden of HIV during ART. We profiled the circulating lipidome from plasma samples from 24 chronically HIV-infected individuals on suppressive ART who subsequently underwent an analytic treatment interruption (ATI) without concurrent immunotherapies. The pre-ATI viral burden was estimated as time-to-viral-rebound and viral load set points post-ATI. We found that higher pre-ATI levels of lysophospholipids, including the proinflammatory lysophosphatidylcholine, were associated with faster time-to-viral-rebound and higher viral set points upon ART cessation. Furthermore, higher pre-ATI levels of the proinflammatory by-product of intestinal lysophosphatidylcholine metabolism, trimethylamine--oxide (TMAO), were also linked to faster viral rebound post-ART. Finally, pre-ATI levels of several phosphatidylcholine species (lysophosphatidylcholine precursors) correlated strongly with higher pre-ATI levels of HIV DNA in peripheral CD4 T cells. Our proof-of-concept data point to phospholipids and lysophospholipids as plausible proinflammatory contributors to HIV persistence and rapid post-ART HIV rebound. The potential interplay between phospholipid metabolism and both the establishment and maintenance of HIV latent reservoirs during and after ART warrants further investigation. The likelihood of HIV rebound after stopping antiretroviral therapy (ART) is a combination of the size of HIV reservoirs that persist despite ART and the host immunological and inflammatory factors that control these reservoirs. Therefore, there is a need to comprehensively understand these host factors to develop a strategy to cure HIV infection and prevent viral rebound post-ART. Lipids are important biologically active molecules that are known to mediate several cellular functions, including reactivating latent tumor cells; however, their role in HIV latency, persistence, and post-ART rebound has never been investigated. We observed significant links between higher levels of the proinflammatory lysophosphatidylcholine and its intestinal metabolic by-product, trimethylamine--oxide, and both faster time-to-viral-rebound and higher viral load set point post-ART. These data highlight the need for further studies to understand the potential contribution of phosphatidylcholine and lysophosphatidylcholine metabolism in shaping host immunological and inflammatory milieu during and after ART.
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http://dx.doi.org/10.1128/mBio.03444-20DOI Listing
February 2021

Saliva as a testing specimen with or without pooling for SARS-CoV-2 detection by multiplex RT-PCR test.

PLoS One 2021 23;16(2):e0243183. Epub 2021 Feb 23.

DiaCarta Inc., Richmond, California, United States of America.

Background: Sensitive and high throughput molecular detection assays are essential during the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The vast majority of the SARS-CoV-2 molecular assays use nasopharyngeal swab (NPS) or oropharyngeal swab (OPS) specimens collected from suspected individuals. However, using NPS or OPS as specimens has apparent drawbacks, e.g. the collection procedures for NPS or OPS specimens can be uncomfortable to some people and may cause sneezing and coughing which in turn generate droplets and/or aerosol particles that are of risk to healthcare workers, requiring heavy use of personal protective equipment. There have been recent studies indicating that self-collected saliva specimens can be used for molecular detection of SARS-CoV-2 and provides more comfort and ease of use for the patients. Here we report the performance of QuantiVirus™ SARS-CoV-2 test using saliva as the testing specimens with or without pooling.

Methods: Development and validation studies were conducted following FDA-EUA and molecular assay validation guidelines. Using SeraCare Accuplex SARS-CoV-2 reference panel, the limit of detection (LOD) and clinical performance studies were performed with the QuantiVirus™ SARS-CoV-2 test. For clinical evaluation, 85 known positive and 90 known negative clinical NPS samples were tested. Additionally, twenty paired NPS and saliva samples collected from recovering COVID-19 patients were tested and the results were further compared to that of the Abbott m2000 SARS-CoV-2 PCR assay. Results of community collected 389 saliva samples for COVID-19 screening by QuantiVirus™ SARS-CoV-2 test were also obtained and analyzed. Additionally, testing of pooled saliva samples was evaluated.

Results: The LOD for the QuantiVirus™ SARS-CoV-2 test was confirmed to be 100-200 copies/mL. The clinical performance studies using contrived saliva samples indicated that the positive percentage agreement (PPA) of the QuantiVirus™ SARS-CoV-2 test is 100% at 1xLOD, 1.5xLOD and 2.5xLOD. No cross-reactivity was observed for the QuantiVirus™ SARS-CoV-2 test with common respiratory pathogens. Testing of clinical samples showed a positive percentage agreement (PPA) of 100% (95% CI: 94.6% to 100%) and a negative percentage agreement (NPA) of 98.9% (95% CI: 93.1% to 99.9%). QuantiVirus™ SARS CoV-2 test had 80% concordance rate and no significant difference (p = 0.13) between paired saliva and NPS specimens by Wilcoxon matched pairs signed rank test. Positive test rate was 1.79% for 389 saliva specimens collected from local communities for COVID-19 screening. Preliminary data showed that saliva sample pooling up to 6 samples (1:6 pooling) for SARS-CoV-2 detection is feasible (sensitivity 94.8% and specificity 100%).

Conclusion: The studies demonstrated that the QuantiVirus™ SARS-CoV-2 test has a LOD of 200 copies/mL in contrived saliva samples. The clinical performance of saliva-based testing is comparable to that of NPS-based testing. Pooling of saliva specimens for SARS-CoV-2 detection is feasible. Saliva based and high-throughput QuantiVirus™ SARS-CoV-2 test offers a highly desirable testing platform during the ongoing COVID-19 pandemic.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243183PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901781PMC
March 2021

The Search for an HIV Cure: Where Do We Go From Here?

J Infect Dis 2021 Feb;223(Supplement_1):1-3

Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Since the first case of an HIV sterilizing cure was published, remarkable progress has been made in our understanding of the mechanisms behind HIV persistence. However, our goal of achieving a safe and broadly-available treatment for sustained HIV remission has proven elusive. In this supplement, we provide a series of articles reviewing the technical hurdles facing the field, key assays to measure HIV persistence and the next-generation of therapeutics for HIV remission.
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http://dx.doi.org/10.1093/infdis/jiaa738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883020PMC
February 2021

Challenges and Promise of Human Immunodeficiency Virus Remission.

J Infect Dis 2021 Feb;223(Supplement_1):4-12

Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Antiretroviral therapy effectively controls human immunodeficiency virus (HIV) replication but it is unable to fully eradicate the HIV reservoir and treatment must be life-long. Progress toward a strategy for HIV remission will require overcoming key hurdles to fill gaps in our understanding of HIV persistence, but the identification of individuals who have attained sterilizing or functional HIV cure show that such a goal is achievable. In this review, we first outline challenges in targeting the HIV reservoir, including difficulties identifying HIV-infected cells, ongoing work elucidating the complex intracellular environment that contribute to HIV latency, and barriers to reactivating and clearing the HIV reservoir. We then review reported cases of HIV sterilizing cure and explore natural models of HIV remission and the promise that such HIV spontaneous and posttreatment controllers may hold in our search for a broadly-applicable strategy for the millions of patients living with HIV.
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http://dx.doi.org/10.1093/infdis/jiaa568DOI Listing
February 2021

Uncovering Ways that Emerging SARS-CoV-2 Lineages May Increase Transmissibility.

J Infect Dis 2021 Feb 13. Epub 2021 Feb 13.

Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School.

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http://dx.doi.org/10.1093/infdis/jiab083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928799PMC
February 2021

Bioinformatic Approaches to Validation and Functional Analysis of 3D Lung Cancer Models.

Cancers (Basel) 2021 Feb 9;13(4). Epub 2021 Feb 9.

Department of Surgery, University of California, San Francisco, CA 94143, USA.

3D models of cancer have the potential to improve basic, translational, and clinical studies. Patient-derived xenografts, spheroids, and organoids are broad categories of 3D models of cancer, and to date, these 3D models of cancer have been established for a variety of cancer types. In lung cancer, for example, 3D models offer a promising new avenue to gain novel insights into lung tumor biology and improve outcomes for patients afflicted with the number one cancer killer worldwide. However, the adoption and utility of these 3D models of cancer vary, and demonstrating the fidelity of these models is a critical first step before seeking meaningful applications. Here, we review use cases of current 3D lung cancer models and bioinformatic approaches to assessing model fidelity. Bioinformatics approaches play a key role in both validating 3D lung cancer models and high dimensional functional analyses to support downstream applications.
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http://dx.doi.org/10.3390/cancers13040701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915264PMC
February 2021

Prospective mapping of viral mutations that escape antibodies used to treat COVID-19.

Science 2021 02 25;371(6531):850-854. Epub 2021 Jan 25.

Basic Sciences and Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

Antibodies are a potential therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the risk of the virus evolving to escape them remains unclear. Here we map how all mutations to the receptor binding domain (RBD) of SARS-CoV-2 affect binding by the antibodies in the REGN-COV2 cocktail and the antibody LY-CoV016. These complete maps uncover a single amino acid mutation that fully escapes the REGN-COV2 cocktail, which consists of two antibodies, REGN10933 and REGN10987, targeting distinct structural epitopes. The maps also identify viral mutations that are selected in a persistently infected patient treated with REGN-COV2 and during in vitro viral escape selections. Finally, the maps reveal that mutations escaping the individual antibodies are already present in circulating SARS-CoV-2 strains. These complete escape maps enable interpretation of the consequences of mutations observed during viral surveillance.
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http://dx.doi.org/10.1126/science.abf9302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963219PMC
February 2021

Participant Perspectives and Experiences Entering an Intensively Monitored Antiretroviral Pause: Results from the AIDS Clinical Trials Group A5345 Biomarker Study.

AIDS Res Hum Retroviruses 2021 Feb 16. Epub 2021 Feb 16.

UNC Gillings School of Global Public Health, Chapel Hill, North Carolina, USA.

The AIDS Clinical Trials Group (ACTG) A5345 study included an intensively monitored antiretroviral pause (IMAP), during which a cohort of participants temporarily stopped antiretroviral treatment during chronic HIV infection. We surveyed participant perceptions and understanding of A5345 using a cross-sectional sociobehavioral questionnaire. Participants completed the baseline questionnaire either before or after initiating the study's IMAP. Questionnaire responses were linked to existing demographic data. Quantitative responses were analyzed overall and stratified by IMAP status. Open-ended responses were analyzed using conventional content analysis. Thirty-two participants completed the baseline sociobehavioral questionnaire. Half ( = 16) completed it before (i.e., pre-IMAP initiation group) and half ( = 16) after IMAP initiation (i.e., post-IMAP initiation group). Eight pre-IMAP initiation respondents (50%) and 11 post-IMAP respondents (69%) responded "yes" when asked if they perceived any direct benefits from participating in A5345. Perceived societal-level benefits included furthering HIV cure-related research and helping the HIV community. Perceived personal-level benefits included the opportunity to learn about the body's response to IMAP and financial compensation. The majority of respondents-13 from each group (81% of each)-reported risks from participation, for example, viral load becoming detectable. A5345 participants perceived both societal- and personal-level benefits of study participation. While the majority of survey respondents perceived participatory risks, nearly one in five did not. Key messages pertaining to study-related risks and benefits may need to be clarified or reiterated periodically throughout follow-up in HIV cure-related studies with IMAPs. Clinical Trail Registration Number: NCT03001128.
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http://dx.doi.org/10.1089/AID.2020.0222DOI Listing
February 2021

Innate lymphoid cells and disease tolerance in SARS-CoV-2 infection.

medRxiv 2021 Jan 15. Epub 2021 Jan 15.

Background: Risk of severe coronavirus disease 2019 (COVID-19) increases with age, is greater in males, and is associated with decreased numbers of blood lymphoid cells. Though the reasons for these robust associations are unclear, effects of age and sex on innate and adaptive lymphoid subsets, including on homeostatic innate lymphoid cells (ILCs) implicated in disease tolerance, may underlie the effects of age and sex on COVID-19 morbidity and mortality.

Methods: Flow cytometry was used to quantitate subsets of blood lymphoid cells from people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comparing those hospitalized with severe COVID-19 (n=40) and those treated as outpatients for less severe disease (n=51). 86 healthy individuals served as controls. The relationship between abundance of specific blood lymphoid cell types, age, sex, hospitalization, duration of hospitalization, and elevation of blood markers for systemic inflammation, was determined using multiple regression.

Results: After accounting for effects of age and sex, hospitalization for COVID-19 was associated with 1.78-fold fewer ILCs (95%CI: 2.34-1.36; p = 4.55 x 10 ) and 2.31-fold fewer CD16 natural killer (NK) cells (95%CI: 3.1-1.71; p = 1.04 x 10 ), when compared to uninfected controls. Among people infected with SARS-CoV-2, the odds ratio for hospitalization, adjusted for age, sex, and duration of symptoms, was 0.413 (95%CI: 0.197-0.724; p = 0.00691) for every 2-fold increase in ILCs. In addition, higher ILC abundance was associated with less time spent in the hospital and lower levels of blood markers associated with COVID-19 severity: each two-fold increase in ILC abundance was associated with a 9.38 day decrease in duration of hospital stay (95% CI: 15.76-3.01; p= 0.0054), and decrease in blood C-reactive protein (CRP) by 46.29 mg/L (95% CI: 71.34-21.24; p = 6.25 x 10 ), erythrocyte sedimentation rate (ESR) by 11.04 mm/h (95% CI: 21.94-0.13; p = 0.047), and the fibrin degradation product D-dimer by 1098.52 ng/mL (95% CI: 1932.84-264.19; p = 0.011).

Conclusions: Both ILCs and NK cells were depleted in the blood of people hospitalized for severe COVID-19, but, among lymphoid cell subsets, only ILC abundance was independently associated with the need for hospitalization, duration of hospital stay, and severity of inflammation. These results indicate that, by promoting disease tolerance, homeostatic ILCs protect against morbidity and mortality in SARS-CoV-2 infection, and suggest that reduction in the number of ILCs with age and in males accounts for the increased risk of severe COVID-19 in these demographic groups.
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http://dx.doi.org/10.1101/2021.01.14.21249839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814851PMC
January 2021

Improving care for patients with atrial fibrillation through the use of a personal electrocardiogram.

J Am Assoc Nurse Pract 2021 Jan 12. Epub 2021 Jan 12.

Department of Cardiology, Southwest Medical, Part of OptumCare Las Vegas, Nevada, University of Nevada, School of Nursing, Las Vegas, Nevada.

Background: Atrial fibrillation (AF) is the most common arrhythmia affecting more than six million people in the United States. The economic burden is estimated to be >$6 billion annually with catastrophic events dramatically increasing expenditure. When patients experience symptoms, they commonly present to an acute care facility; this can be costly and anxiety provoking.

Local Problem: Same-day access issues prohibit patients from communicating directly with their cardiology provider, forcing them to use resources and increasing psychological burden.

Methods: A convenience sample, made up of 43 patients, was given a KardiaMobile device. Eligible patients had ≥2 AF-related emergency department (ED) or urgent care (UC) visits over 12 months, needed rate control with medication titration, or were monitored for AF reoccurrence after reestablishing sinus rhythm.

Interventions: Patients emailed recordings daily and when experiencing symptoms. The recordings were reviewed by a nurse practitioner (NP); abnormal readings were followed by a phone call, telehealth, or in-person visit.

Results: An independently designed survey was conducted online; almost all respondents (97%) found value in the project and the device. Virtually all respondents (97%) felt that the program improved access. A majority (86%) reported decreased anxiety. Had the respondents not been in the program, 34% indicated that they would have presented to an ED and 25% would have presented to an UC, realizing a cost savings of $81,950 in reduced ED visits alone.

Conclusion: A personal electrocardiogram, with NP oversight, to manage AF is cost-effective and reduces unnecessary resource utilization. It is patient centered, improves access, and empowers patients to manage their symptoms.
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http://dx.doi.org/10.1097/JXX.0000000000000550DOI Listing
January 2021

Error detection and classification in patient-specific IMRT QA with dual neural networks.

Med Phys 2020 Oct 13;47(10):4711-4720. Epub 2020 Aug 13.

Department of Radiation Oncology, University of Florida, Gainesville, FL, USA.

Purpose: Despite being the standard metric in patient-specific quality assurance (QA) for intensity-modulated radiotherapy (IMRT), gamma analysis has two shortcomings: (a) it lacks sensitivity to small but clinically relevant errors (b) it does not provide efficient means to classify the error sources. The purpose of this work is to propose a dual neural network method to achieve simultaneous error detection and classification in patient-specific IMRT QA.

Methods: For a pair of dose distributions, we extracted the dose difference histogram (DDH) for the low dose gradient region and two signed distance-to-agreement (sDTA) maps (one in x direction and one in y direction) for the high dose gradient region. An artificial neural network (ANN) and a convolutional neural network (CNN) were designed to analyze the DDH and the two sDTA maps, respectively. The ANN was trained to detect and classify six classes of dosimetric errors: incorrect multileaf collimator (MLC) transmission (±1%) and four types of monitor unit (MU) scaling errors (±1% and ±2%). The CNN was trained to detect and classify seven classes of spatial errors: incorrect effective source size, 1 mm MLC leaf bank overtravel or undertravel, 2 mm single MLC leaf overtravel or undertravel, and device misalignment errors (1 mm in x- or y direction). An in-house planar dose calculation software was used to simulate measurements with errors and noise introduced. Both networks were trained and validated with 13 IMRT plans (totaling 88 fields). A fivefold cross-validation technique was used to evaluate their accuracy.

Results: Distinct features were found in the DDH and the sDTA maps. The ANN perfectly identified all four types of MU scaling errors and the specific accuracies for the classes of no error, MLC transmission increase, MLC transmission decrease were 98.9%, 96.6%, and 94.3%, respectively. For the CNN, the largest confusion occurred between the 1-mm-MLC bank overtravel class and the 1-mm-device alignment error in x-direction class, which brought the specific accuracies down to 90.9% and 92.0%, respectively. The specific accuracy for the 2-mm-single MLC leaf undertravel class was 93.2% as it misclassified 5.7% of the class as being error free (false negative). Otherwise, the specific accuracy was above 95%. The overall accuracies across the fivefold were 98.3 ± 0.7% and 95.6% ± 1.5% for the ANN and the CNN, respectively.

Conclusions: Both the DDH and the sDTA maps are suitable features for error classification in IMRT QA. The proposed dual neural network method achieved simultaneous error detection and classification with excellent accuracy. It could be used in complement with the gamma analysis to potentially shift the IMRT QA paradigm from passive pass/fail analysis to active error detection and root cause identification.
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http://dx.doi.org/10.1002/mp.14416DOI Listing
October 2020

Hospital-Based Donor Recruitment and Predonation Serologic Testing for COVID-19 Convalescent Plasma.

Am J Clin Pathol 2021 Mar;155(4):515-521

Department of Laboratory Medicine.

Objectives: Serologic testing for antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in potential donors of coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) may not be performed until after blood donation. A hospital-based recruitment program for CCP may be an efficient way to identify potential donors prospectively.

Methods: Patients who recovered from known or suspected COVID-19 were identified and recruited through medical record searches and public appeals in March and April 2020. Participants were screened with a modified donor history questionnaire and, if eligible, were asked for consent and tested for SARS-CoV-2 antibodies (IgG and IgM). Participants positive for SARS-CoV-2 IgG were referred for CCP collection.

Results: Of 179 patients screened, 128 completed serologic testing and 89 were referred for CCP donation. IgG antibodies to SARS-CoV-2 were detected in 23 of 51 participants with suspected COVID-19 and 66 of 77 participants with self-reported COVID-19 confirmed by polymerase chain reaction (PCR). The anti-SARS-CoV-2 IgG level met the US Food and Drug Administration criteria for "high-titer" CCP in 39% of participants confirmed by PCR, as measured by the Ortho VITROS IgG assay. A wide range of SARS-CoV-2 IgG levels were observed.

Conclusions: A hospital-based CCP donor recruitment program can prospectively identify potential CCP donors. Variability in SARS-CoV-2 IgG levels has implications for the selection of CCP units for transfusion.
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http://dx.doi.org/10.1093/ajcp/aqaa268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929413PMC
March 2021

Development and Preliminary Clinical Activity of PD-1-Guided CTLA-4 Blocking Bispecific DART Molecule.

Cell Rep Med 2020 Dec 22;1(9):100163. Epub 2020 Dec 22.

MacroGenics, Rockville, MD, USA.

Combination immunotherapy with antibodies directed against PD-1 and CTLA-4 shows improved clinical benefit across cancer indications compared to single agents, albeit with increased toxicity. Leveraging the observation that PD-1 and CTLA-4 are co-expressed by tumor-infiltrating lymphocytes, an investigational PD-1 x CTLA-4 bispecific DART molecule, MGD019, is engineered to maximize checkpoint blockade in the tumor microenvironment via enhanced CTLA-4 blockade in a PD-1-binding-dependent manner. , MGD019 mediates the combinatorial blockade of PD-1 and CTLA-4, confirming dual inhibition via a single molecule. MGD019 is well tolerated in non-human primates, with evidence of both PD-1 and CTLA-4 blockade, including increases in Ki67CD8 and ICOSCD4 T cells, respectively. In the ongoing MGD019 first-in-human study enrolling patients with advanced solid tumors (NCT03761017), an analysis undertaken following the dose escalation phase revealed acceptable safety, pharmacodynamic evidence of combinatorial blockade, and objective responses in multiple tumor types typically unresponsive to checkpoint inhibitor therapy.
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http://dx.doi.org/10.1016/j.xcrm.2020.100163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762776PMC
December 2020