Publications by authors named "Lucy Li"

71 Publications

Estimation of secondary household attack rates for emergent spike L452R SARS-CoV-2 variants detected by genomic surveillance at a community-based testing site in San Francisco.

Clin Infect Dis 2021 Mar 31. Epub 2021 Mar 31.

Department of Biochemistry and Biophysics, University of California San Francisco, CA, USA.

Background: Sequencing of the SARS-CoV-2 viral genome from patient samples is an important epidemiological tool for monitoring and responding to the pandemic, including the emergence of new mutations in specific communities.

Methods: SARS-CoV-2genomicsequencesweregeneratedfrompositivesamplescollected,alongwithepidemiologicalmetadata,atawalk-up, rapid testing site in the Mission District of San Francisco, California during November 22-December 1, 2020 and January 10-29, 2021. Secondary household attack rates and mean sample viral load were estimated and compared across observed variants.

Results: A total of 12,124 tests were performed yielding 1,099 positives. From these, 928 high quality genomes were generated. Certain viral lineages bearing spike mutations, defined in part by L452R, S13I, and W152C, comprised 54.4% of the total sequences from January, compared to 15.7% in November. Household contacts exposed to the "California" or "West Coast" variants (B.1.427 and B.1.429) were at higher risk of infection compared to household contacts exposed to lineages lacking these variants (0.36 vs 0.29, RR=1.28; 95% CI:1.00-1.64). The reproductive number was estimated to be modestly higher than other lineages spreading in California during the second half of 2020. Viral loads were similar among persons infected with West Coast versus non-West Coast strains, as was the proportion of individuals with symptoms (60.9% vs 64.3%).

Conclusions: The increase in prevalence, relative household attack rates, and reproductive number are consistent with a modest transmissibility increase of the West Coast variants.
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http://dx.doi.org/10.1093/cid/ciab283DOI Listing
March 2021

Estimation of secondary household attack rates for emergent SARS-CoV-2 variants detected by genomic surveillance at a community-based testing site in San Francisco.

medRxiv 2021 Mar 3. Epub 2021 Mar 3.

Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Background: Sequencing of the SARS-CoV-2 viral genome from patient samples is an important epidemiological tool for monitoring and responding to the pandemic, including the emergence of new mutations in specific communities.

Methods: SARS-CoV-2 genomic sequences were generated from positive samples collected, along with epidemiological metadata, at a walk-up, rapid testing site in the Mission District of San Francisco, California during November 22-December 2, 2020 and January 10-29, 2021. Secondary household attack rates and mean sample viral load were estimated and compared across observed variants.

Results: A total of 12,124 tests were performed yielding 1,099 positives. From these, 811 high quality genomes were generated. Certain viral lineages bearing spike mutations, defined in part by L452R, S13I, and W152C, comprised 54.9% of the total sequences from January, compared to 15.7% in November. Household contacts exposed to "West Coast" variants were at higher risk of infection compared to household contacts exposed to lineages lacking these variants (0.357 vs 0.294, RR=1.29; 95% CI:1.01-1.64). The reproductive number was estimated to be modestly higher than other lineages spreading in California during the second half of 2020. Viral loads were similar among persons infected with West Coast versus non-West Coast strains, as was the proportion of individuals with symptoms (60.9% vs 64.1%).

Conclusions: The increase in prevalence, relative household attack rates, and reproductive number are consistent with a modest transmissibility increase of the West Coast variants; however, additional laboratory and epidemiological studies are required to better understand differences between these variants.

Summary: We observed a growing prevalence and elevated attack rate for "West Coast" SARS-CoV-2 variants in a community testing setting in San Francisco during January 2021, suggesting its modestly higher transmissibility.
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http://dx.doi.org/10.1101/2021.03.01.21252705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941666PMC
March 2021

Adoptive T cell immunotherapy for medullary thyroid carcinoma targeting GDNF family receptor alpha 4.

Mol Ther Oncolytics 2021 Mar 26;20:387-398. Epub 2021 Jan 26.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Metastatic medullary thyroid cancer (MTC) is a rare but often aggressive thyroid malignancy with a 5-year survival rate of less than 40% and few effective therapeutic options. Adoptive T cell immunotherapy using chimeric antigen receptor (CAR)-modified T cells (CAR Ts) is showing encouraging results in the treatment of cancer, but development is challenged by the availability of suitable target antigens. We identified glial-derived neurotrophic factor (GDNF) family receptor alpha 4 (GFRα4) as a putative antigen target for CAR-based therapy of MTC. We show that GFRα4 is highly expressed in MTC, in parafollicular cells within the thyroid from which MTC originates, and in normal thymus. We isolated two single-chain variable fragments (scFvs) targeting GFRα4 isoforms a and b by antibody phage display. CARs bearing the CD3ζ and the CD137 costimulatory domains were constructed using these GFRα4-specific scFvs. GFRα4-specific CAR Ts trigger antigen-dependent cytotoxicity and cytokine production , and they are able to eliminate tumors derived from the MTC TT cell line in an immunodeficient mouse xenograft model of MTC. These data demonstrate the feasibility of targeting GFRα4 by CAR T and support this antigen as a promising target for adoptive T cell immunotherapy and other antibody-based therapies for MTC.
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http://dx.doi.org/10.1016/j.omto.2021.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879023PMC
March 2021

The Legacy of Leadership: Our Commitment to Future Generations of Family Medicine Leaders.

Fam Med 2021 Jan;53(1):78-79

John Peter Smith Family Medicine Residency, Ft Worth, TX.

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http://dx.doi.org/10.22454/FamMed.2021.869496DOI Listing
January 2021

A minimal model for household-based testing and tracing in epidemics.

Phys Biol 2021 Jan 12. Epub 2021 Jan 12.

Jikoji Zen Center, Los Gatos, California, UNITED STATES.

In a previous work [Huber et al. A minimal model for household effects in epidemics. Physical Biology, 17(6):065010], we discussed virus transmission dynamics modified by a uniform clustering of contacts in the population: close contacts within households and more distant contacts between households. In this paper, we discuss testing and tracing in such a stratified population. We propose a minimal tracing strategy consisting of random testing of the entire population plus full testing of the households of those persons found positive. We provide estimates of testing frequency for this strategy to work.
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http://dx.doi.org/10.1088/1478-3975/abdacdDOI Listing
January 2021

Rash, Diaphoresis, Anorexia, and Loss of Motor Skills in a 10-month-old Boy.

Pediatr Rev 2021 Jan;42(1):38-40

Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1542/pir.2020-0024DOI Listing
January 2021

Upper airway gene expression reveals suppressed immune responses to SARS-CoV-2 compared with other respiratory viruses.

Nat Commun 2020 11 17;11(1):5854. Epub 2020 Nov 17.

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

SARS-CoV-2 infection is characterized by peak viral load in the upper airway prior to or at the time of symptom onset, an unusual feature that has enabled widespread transmission of the virus and precipitated a global pandemic. How SARS-CoV-2 is able to achieve high titer in the absence of symptoms remains unclear. Here, we examine the upper airway host transcriptional response in patients with COVID-19 (n = 93), other viral (n = 41) or non-viral (n = 100) acute respiratory illnesses (ARIs). Compared with other viral ARIs, COVID-19 is characterized by a pronounced interferon response but attenuated activation of other innate immune pathways, including toll-like receptor, interleukin and chemokine signaling. The IL-1 and NLRP3 inflammasome pathways are markedly less responsive to SARS-CoV-2, commensurate with a signature of diminished neutrophil and macrophage recruitment. This pattern resembles previously described distinctions between symptomatic and asymptomatic viral infections and may partly explain the propensity for pre-symptomatic transmission in COVID-19. We further use machine learning to build 27-, 10- and 3-gene classifiers that differentiate COVID-19 from other ARIs with AUROCs of 0.981, 0.954 and 0.885, respectively. Classifier performance is stable across a wide range of viral load, suggesting utility in mitigating false positive or false negative results of direct SARS-CoV-2 tests.
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http://dx.doi.org/10.1038/s41467-020-19587-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673985PMC
November 2020

Conventional T cell therapies pave the way for novel Treg therapeutics.

Cell Immunol 2021 Jan 12;359:104234. Epub 2020 Oct 12.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Approaches to harness the immune system to alleviate disease have become remarkably sophisticated since the crude, yet impressively-effective, attempts using live bacteria in the late 1800s. Recent evidence that engineered T cell therapy can deliver durable results in patients with cancer has spurred frenzied development in the field of T cell therapy. The myriad approaches include an innumerable variety of synthetic transgenes, multiplex gene-editing, and broader application to diseases beyond cancer. In this article, we review the preclinical studies and over a decade of clinical experience with engineered conventional T cells that have paved the way for translating engineered regulatory T cell therapies.
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http://dx.doi.org/10.1016/j.cellimm.2020.104234DOI Listing
January 2021

A minimal model for household effects in epidemics.

Phys Biol 2020 10 21;17(6):065010. Epub 2020 Oct 21.

Chan Zuckerberg Biohub, San Francisco, CA 94158, United States of America.

Shelter-in-place and other confinement strategies implemented in the current COVID-19 pandemic have created stratified patterns of contacts between people: close contacts within households and more distant contacts between the households. The epidemic transmission dynamics is significantly modified as a consequence. We introduce a minimal model that incorporates these household effects in the framework of mean-field theory and numerical simulations. We show that the reproduction number R depends on the household size in a surprising way: linearly for relatively small households, and as a square root of size for larger households. We discuss the implications of the findings for the lockdown, test, tracing, and isolation policies.
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http://dx.doi.org/10.1088/1478-3975/abb209DOI Listing
October 2020

Coblation of paediatric cystic laryngeal lymphovascular malformations: a safe and effective alternative to tracheostomy.

BMJ Case Rep 2020 Sep 29;13(9). Epub 2020 Sep 29.

Department of Paediatric Otolaryngology, NHS Lothian, Edinburgh, UK.

We describe the case of a 12-hour-old, full-term newborn girl referred to the Ear, Nose and Throat emergency team with increased work of breathing and stridor present at birth. Flexible nasendoscopy revealed a cystic laryngeal lesion obstructing the glottis that prompted securing of the airway with intubation and transfer to a tertiary paediatric centre. On further investigation with MRI and direct visualisation, the lesion was identified as a mixed macro/microcystic laryngeal lymphovascular malformation. The patient successfully underwent a series of microlaryngo-bronchoscopy and coblations of the laryngeal lesion with the aim of avoiding a tracheostomy. We describe the presentation, diagnosis and management of this rare condition in a paediatric case, along with a literature review of the subject.
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http://dx.doi.org/10.1136/bcr-2020-235596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526315PMC
September 2020

Infant spinal anesthesia reduces postoperative pain scores and pain medication consumption in infants undergoing inguinal herniorrhaphy.

J Pediatr Surg 2020 12 22;55(12):2840-2843. Epub 2020 Aug 22.

Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jpedsurg.2020.08.011DOI Listing
December 2020

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 Infectious Diseases, 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

Microbe-Metabolite Associations Linked to the Rebounding Murine Gut Microbiome Postcolonization with Vancomycin-Resistant Enterococcus faecium.

mSystems 2020 Aug 18;5(4). Epub 2020 Aug 18.

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia.

Vancomycin-resistant (VREfm) is an emerging antibiotic-resistant pathogen. Strain-level investigations are beginning to reveal the molecular mechanisms used by VREfm to colonize regions of the human bowel. However, the role of commensal bacteria during VREfm colonization, in particular following antibiotic treatment, remains largely unknown. We employed amplicon 16S rRNA gene sequencing and metabolomics in a murine model system to try and investigate functional roles of the gut microbiome during VREfm colonization. First-order taxonomic shifts between and within the gut microbial community composition were detected both in response to pretreatment using ceftriaxone and to subsequent VREfm challenge. Using neural networking approaches to find cooccurrence profiles of bacteria and metabolites, we detected key metabolome features associated with butyric acid during and after VREfm colonization. These metabolite features were associated with , indicative of a transition toward a preantibiotic naive microbiome. This study shows the impacts of antibiotics on the gut ecosystem and the progression of the microbiome in response to colonization with VREfm. Our results offer insights toward identifying potential nonantibiotic alternatives to eliminate VREfm through metabolic reengineering to preferentially select for This study demonstrates the importance and power of linking bacterial composition profiling with metabolomics to find the interactions between commensal gut bacteria and a specific pathogen. Knowledge from this research will inform gut microbiome engineering strategies, with the aim of translating observations from animal models to human-relevant therapeutic applications.
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http://dx.doi.org/10.1128/mSystems.00452-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438022PMC
August 2020

High Incidence of Burst Suppression during Propofol Sedation for Outpatient Colonoscopy: Lessons Learned from Neuromonitoring.

Anesthesiol Res Pract 2020 19;2020:7246570. Epub 2020 Jun 19.

Department of Anesthesiology, Division of Neurological Anesthesia, Thomas Jefferson University, 111 S. 11 Street, Philadelphia, PA 19107, USA.

Background: Although anesthesia providers may plan for moderate sedation, the depth of sedation is rarely quantified. Using processed electroencephalography (EEG) to assess the depth of sedation, this study investigates the incidence of general anesthesia with variable burst suppression in patients receiving propofol for outpatient colonoscopy. The lessons learned from neuromonitoring can then be used to guide institutional best sedation practice.

Methods: This was a prospective observational study of 119 outpatients undergoing colonoscopy at Thomas Jefferson University Hospital (TJUH). Propofol was administered by CRNAs under anesthesiologists' supervision. The Patient State Index (PSi™) generated by the Masimo SedLine® Brain Root Function monitor (Masimo Corp., Irvine, CA) was used to assess the depth of sedation. PSi data correlating to general anesthesia with variable burst suppression were confirmed by neuroelectrophysiologists' interpretation of unprocessed EEG.

Results: PSi values of <50 consistent with general anesthesia were attained in 118/119 (99.1%) patients. Of these patients, 33 (27.7%) attained PSi values <25 consistent with variable burst suppression. The 118 patients that reached PSi <50 spent a significantly greater percentage (53.1% vs. 42%) of their case at PSi levels <50 compared to PSi levels >50 (=0.001). Mean total propofol dose was significantly correlated to patient PSi during periods of PSi <25 (=0.406, =0.021).

Conclusion: Although providers planned for moderate to deep sedation, processed EEG showed patients were under general anesthesia, often with burst suppression. Anesthesiologists and endoscopists may utilize processed EEG to recognize their institutional practice patterns of procedural sedation with propofol and improve upon it.
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http://dx.doi.org/10.1155/2020/7246570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321500PMC
June 2020

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

Upper airway gene expression differentiates COVID-19 from other acute respiratory illnesses and reveals suppression of innate immune responses by SARS-CoV-2.

medRxiv 2020 May 19. Epub 2020 May 19.

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

We studied the host transcriptional response to SARS-CoV-2 by performing metagenomic sequencing of upper airway samples in 238 patients with COVID-19, other viral or non-viral acute respiratory illnesses (ARIs). Compared to other viral ARIs, COVID-19 was characterized by a diminished innate immune response, with reduced expression of genes involved in toll-like receptor and interleukin signaling, chemokine binding, neutrophil degranulation and interactions with lymphoid cells. Patients with COVID-19 also exhibited significantly reduced proportions of neutrophils and macrophages, and increased proportions of goblet, dendritic and B-cells, compared to other viral ARIs. Using machine learning, we built 26-, 10- and 3-gene classifiers that differentiated COVID-19 from other acute respiratory illnesses with AUCs of 0.980, 0.950 and 0.871, respectively. Classifier performance was stable at low viral loads, suggesting utility in settings where direct detection of viral nucleic acid may be unsuccessful. Taken together, our results illuminate unique aspects of the host transcriptional response to SARS-CoV-2 in comparison to other respiratory viruses and demonstrate the feasibility of COVID-19 diagnostics based on patient gene expression.
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http://dx.doi.org/10.1101/2020.05.18.20105171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273244PMC
May 2020

Interrogating the impact of KIR ligand mismatch in engraftment following HLA-disparate stem cell transplantation.

Bone Marrow Transplant 2020 12 27;55(12):2294-2297. Epub 2020 May 27.

Stem Cell Transplant Program, University Hospitals Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH, 44106, USA.

The effects of donor-derived natural killer (NK) cell alloreactivity on disease relapse and transplant-related mortality following allogeneic stem cell transplantation have been described while the impact of recipient-derived NK cell alloreactivity on donor engraftment is not well known. Epitopes of HLA Class I molecules act as ligands for NK cell killer immunoglobulin-like receptors (KIR) regulating their cytotoxicity. As such, NK cell alloreactivity is predictable from KIR ligand mismatches between donors and recipients. We analyzed the impact of KIR ligand mismatch (KIR-L-MM) on donor engraftment in 70 cord blood transplants (CBT) and 26 haploidentical transplants (HaploSCT). In CBT, host-versus-graft-directed KIR-L-MM predicted primary graft failure; an effect not mitigated by use of ATG. This trend was most significant with HLA-C KIR-L-MM. In addition, graft-versus-host-directed KIR-L-MM predicted the dominant cord blood unit in double CBT. In the limited HaploSCT cohort, host-versus-graft-directed KIR-L-MM did not predict graft failure. Time to neutrophil engraftment was unaffected by KIR-L-MM in either CBT or HaploSCT. The direction of KIR-L mismatch may be a parameter to consider when selecting CBT units to ensure successful engraftment. The role of KIR-L-MM in CBT and HaploSCT engraftment merits further exploration in a large transplant database.
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http://dx.doi.org/10.1038/s41409-020-0957-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685980PMC
December 2020

Cryptococcus neoformans Evades Pulmonary Immunity by Modulating Xylose Precursor Transport.

Infect Immun 2020 07 21;88(8). Epub 2020 Jul 21.

Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA

is a fungal pathogen that kills almost 200,000 people each year and is distinguished by abundant and unique surface glycan structures that are rich in xylose. A mutant strain of that cannot transport xylose precursors into the secretory compartment is severely attenuated in virulence in mice yet surprisingly is not cleared. We found that this strain failed to induce the nonprotective T helper cell type 2 (Th2) responses characteristic of wild-type infection, instead promoting sustained interleukin 12p40 (IL-12p40) induction and increased IL-17A (IL-17) production. It also stimulated dendritic cells to release high levels of proinflammatory cytokines, a behavior we linked to xylose expression. We further discovered that inducible bronchus-associated lymphoid tissue (iBALT) forms in response to infection with either wild-type cryptococci or the mutant strain with reduced surface xylose; although iBALT formation is slowed in the latter case, the tissue is better organized. Finally, our temporal studies suggest that lymphoid structures in the lung restrict the spread of mutant fungi for at least 18 weeks after infection, which is in contrast to ineffective control of the pathogen after infection with wild-type cells. These studies demonstrate the role of xylose in modulation of host response to a fungal pathogen and show that cryptococcal infection triggers iBALT formation.
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http://dx.doi.org/10.1128/IAI.00288-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375766PMC
July 2020

Two cases of imported respiratory diphtheria in Edinburgh, Scotland, October 2019.

Epidemiol Infect 2020 05 15;148:e143. Epub 2020 May 15.

Health Protection Team, NHS Lothian, Edinburgh, Scotland.

We report two cases of respiratory toxigenic Corynebacterium diphtheriae infection in fully vaccinated UK born adults following travel to Tunisia in October 2019. Both patients were successfully treated with antibiotics and neither received diphtheria antitoxin. Contact tracing was performed following a risk assessment but no additional cases were identified. This report highlights the importance of maintaining a high index of suspicion for re-emerging infections in patients with a history of travel to high-risk areas outside Europe.
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http://dx.doi.org/10.1017/S0950268820001028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374812PMC
May 2020

Wound botulism presenting as dysphagia to an ENT ward.

BMJ Case Rep 2020 Feb 11;13(2). Epub 2020 Feb 11.

Department of Otolaryngology, Queen Elizabeth University Hospital, Glasgow, UK.

A 44-year-old man with a background of heroin injection drug use was referred to the ear, nose and throat team with a sore throat and dysphagia. He was treated with intravenous antibiotics and steroids for suspected uvulitis. He developed progressive bulbar weakness and symmetrical descending weakness of the upper extremities over a 12-hour period and was intubated prior to transfer to the intensive care unit.Botulinum heptavalent antitoxin was administered, and subsequent PCR assay confirmed neurotoxin B from his most recent injection site. He was found unconscious on the ward 3 days following extubation. Postmortem confirmed he died from heroin intoxication.This case highlights the importance of considering wound botulism in injection drug users presenting with unexplained weakness, particularly of the lower cranial nerves. Botulism is not characteristically associated with signs of localised or systemic infection in contrary to other bacterial complications of injection drug use.
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http://dx.doi.org/10.1136/bcr-2019-232367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021180PMC
February 2020

Prophylactic Intravitreal Bevacizumab After Plaque Radiotherapy for Uveal Melanoma: Analysis of Visual Acuity, Tumor Response, and Radiation Complications in 1131 Eyes Based on Patient Age.

Asia Pac J Ophthalmol (Phila) 2020 Jan-Feb;9(1):29-38

From the Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, 840 Walnut Street, 14th Floor, Philadelphia, PA.

Purpose: The aim of this study was to determine the impact of age on radiation complications after plaque radiotherapy and prophylactic intravitreal bevacizumab for uveal melanoma.

Design: Retrospective cohort study.

Methods: Retrospective single-center study of plaque-irradiated uveal melanoma with prophylactic intravitreal bevacizumab at 4-month intervals from July 2000 to January 2018.

Results: Of 1131 eyes in 1131 patients, age was <50 years (n = 231), 50 to 70 years (n = 657), or >70 years (n = 243). Comparison by age category (<50 vs 50-70 vs >70 years) revealed the oldest group presenting with greatest tumor basal diameter (11.3 vs 11.3 vs 12.1 mm, P = 0.03) and worst visual acuity (20/40 vs 20/40 vs 20/50, P = 0.02). After plaque (mean follow-up 40 vs 42 vs 32 months, P < 0.001), radiation complications were most common in the youngest age group, including maculopathy (48% vs 39% vs 28%, P < 0.001), extramacular retinopathy (30% vs 25% vs 16%, P = 0.002), and papillopathy (21% vs 18% vs 12%, P = 0.03). The youngest age group had the highest Kaplan-Meier estimated 48-month cumulative probability for radiation maculopathy (62% vs 46% vs 47%, P = 0.001), extramacular retinopathy (36% vs 34% vs 29%, P = 0.03), and papillopathy (29% vs 26% vs 22%, P = 0.13). On subanalysis, the youngest age group had increased 48-month risk of developing radiation maculopathy when compared with the middle [hazard ratio (HR) = 1.5, P = 0.001] and older (HR = 1.6, P = 0.005) age groups and increased 48-month risk of developing extramacular radiation retinopathy compared with the older age group (HR = 1.5, P = 0.04).

Conclusions: After plaque radiotherapy for uveal melanoma and prophylactic intravitreal bevacizumab at 4-month intervals, patients younger than 50 years old have an increased 48-month risk of radiation maculopathy.
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http://dx.doi.org/10.1097/APO.0000000000000271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004475PMC
October 2020

5-fluorocytosine resistance is associated with hypermutation and alterations in capsule biosynthesis in Cryptococcus.

Nat Commun 2020 01 8;11(1):127. Epub 2020 Jan 8.

Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.

Patients infected with the fungal pathogen Cryptococcus are most effectively treated with a combination of 5-fluorocytosine (5FC) and amphotericin B. 5FC acts as a prodrug, which is converted into toxic 5-fluorouracil (5FU) upon uptake into fungal cells. However, the pathogen frequently develops resistance through unclear mechanisms. Here we show that resistance to 5FC in Cryptococcus deuterogattii is acquired more frequently in isolates with defects in DNA mismatch repair that confer an elevated mutation rate. We use whole genome sequencing of 16 independent isolates to identify mutations associated with 5FC resistance in vitro. We find mutations in known resistance genes (FUR1 and FCY2) and in a gene UXS1, previously shown to encode an enzyme that converts UDP-glucuronic acid to UDP-xylose for capsule biosynthesis, but not known to play a role in 5FC metabolism. Mutations in UXS1 lead to accumulation of UDP-glucuronic acid and alterations in nucleotide metabolism, which appear to suppress toxicity of both 5FC and its toxic derivative 5FU.
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http://dx.doi.org/10.1038/s41467-019-13890-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949227PMC
January 2020

Unbiased Metagenomic Sequencing for Pediatric Meningitis in Bangladesh Reveals Neuroinvasive Chikungunya Virus Outbreak and Other Unrealized Pathogens.

mBio 2019 12 17;10(6). Epub 2019 Dec 17.

Department of Biochemistry and Biophysics, University of California, San Francisco, California, USA

The burden of meningitis in low-and-middle-income countries remains significant, but the infectious causes remain largely unknown, impeding institution of evidence-based treatment and prevention decisions. We conducted a validation and application study of unbiased metagenomic next-generation sequencing (mNGS) to elucidate etiologies of meningitis in Bangladesh. This RNA mNGS study was performed on cerebrospinal fluid (CSF) specimens from patients admitted in the largest pediatric hospital, a World Health Organization sentinel site, with known neurologic infections ( = 36), with idiopathic meningitis ( = 25), and with no infection ( = 30), and six environmental samples, collected between 2012 and 2018. We used the IDseq bioinformatics pipeline and machine learning to identify potentially pathogenic microbes, which we then confirmed orthogonally and followed up through phone/home visits. In samples with known etiology and without infections, there was 83% concordance between mNGS and conventional testing. In idiopathic cases, mNGS identified a potential bacterial or viral etiology in 40%. There were three instances of neuroinvasive Chikungunya virus (CHIKV), whose genomes were >99% identical to each other and to a Bangladeshi strain only previously recognized to cause febrile illness in 2017. CHIKV-specific qPCR of all remaining stored CSF samples from children who presented with idiopathic meningitis in 2017 ( = 472) revealed 17 additional CHIKV meningitis cases, exposing an unrecognized meningitis outbreak. Orthogonal molecular confirmation, case-based clinical data, and patient follow-up substantiated the findings. Case-control CSF mNGS surveys can complement conventional diagnostic methods to identify etiologies of meningitis, conduct surveillance, and predict outbreaks. The improved patient- and population-level data can inform evidence-based policy decisions. Globally, there are an estimated 10.6 million cases of meningitis and 288,000 deaths every year, with the vast majority occurring in low- and middle-income countries. In addition, many survivors suffer from long-term neurological sequelae. Most laboratories assay only for common bacterial etiologies using culture and directed PCR, and the majority of meningitis cases lack microbiological diagnoses, impeding institution of evidence-based treatment and prevention strategies. We report here the results of a validation and application study of using unbiased metagenomic sequencing to determine etiologies of idiopathic (of unknown cause) cases. This included CSF from patients with known neurologic infections, with idiopathic meningitis, and without infection admitted in the largest children's hospital of Bangladesh and environmental samples. Using mNGS and machine learning, we identified and confirmed an etiology (viral or bacterial) in 40% of idiopathic cases. We detected three instances of Chikungunya virus (CHIKV) that were >99% identical to each other and to a strain previously recognized to cause systemic illness only in 2017. CHIKV qPCR of all remaining stored 472 CSF samples from children who presented with idiopathic meningitis in 2017 at the same hospital uncovered an unrecognized CHIKV meningitis outbreak. CSF mNGS can complement conventional diagnostic methods to identify etiologies of meningitis, and the improved patient- and population-level data can inform better policy decisions.
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http://dx.doi.org/10.1128/mBio.02877-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918088PMC
December 2019

A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis.

Nat Chem Biol 2019 11 7;15(11):1057-1066. Epub 2019 Oct 7.

Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

Activating the intrinsic apoptosis pathway with small molecules is now a clinically validated approach to cancer therapy. In contrast, blocking apoptosis to prevent the death of healthy cells in disease settings has not been achieved. Caspases have been favored, but they act too late in apoptosis to provide long-term protection. The critical step in committing a cell to death is activation of BAK or BAX, pro-death BCL-2 proteins mediating mitochondrial damage. Apoptosis cannot proceed in their absence. Here we show that WEHI-9625, a novel tricyclic sulfone small molecule, binds to VDAC2 and promotes its ability to inhibit apoptosis driven by mouse BAK. In contrast to caspase inhibitors, WEHI-9625 blocks apoptosis before mitochondrial damage, preserving cellular function and long-term clonogenic potential. Our findings expand on the key role of VDAC2 in regulating apoptosis and demonstrate that blocking apoptosis at an early stage is both advantageous and pharmacologically tractable.
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http://dx.doi.org/10.1038/s41589-019-0365-8DOI Listing
November 2019

Investigating Transfusion-related Sepsis Using Culture-Independent Metagenomic Sequencing.

Clin Infect Dis 2020 Aug;71(5):1179-1185

Chan Zuckerberg Biohub, San Francisco, California, USA.

Background: Transfusion-related sepsis remains an important hospital infection control challenge. Investigation of septic transfusion events is often restricted by the limitations of bacterial culture in terms of time requirements and low yield in the setting of prior antibiotic administration.

Methods: In 3 gram-negative septic transfusion cases, we performed metagenomic next-generation sequencing (mNGS) of direct clinical blood specimens in addition to standard culture-based approaches utilized for infection control investigations. Pathogen detection leveraged IDSeq, a new open-access microbial bioinformatics portal. Phylogenetic analysis was performed to assess microbial genetic relatedness and understand transmission events.

Results: mNGS of direct clinical blood specimens afforded precision detection of pathogens responsible for each case of transfusion-related sepsis and enabled discovery of a novel Acinetobacter species in a platelet product that had become contaminated despite photochemical pathogen reduction. In each case, longitudinal assessment of pathogen burden elucidated the temporal sequence of events associated with each transfusion-transmitted infection. We found that informative data could be obtained from culture-independent mNGS of residual platelet products and leftover blood specimens that were either unsuitable or unavailable for culture or that failed to grow due to prior antibiotic administration. We additionally developed methods to enhance accuracy for detecting transfusion-associated pathogens that share taxonomic similarity to contaminants commonly found in mNGS library preparations.

Conclusions: Culture-independent mNGS of blood products afforded rapid and precise assessment of pathogen identity, abundance, and genetic relatedness. Together, these challenging cases demonstrated the potential for metagenomics to advance existing methods for investigating transfusion-transmitted infections.
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http://dx.doi.org/10.1093/cid/ciz960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442849PMC
August 2020

Unstable chromosome rearrangements in cause phenotype switching associated with persistent infections.

Proc Natl Acad Sci U S A 2019 10 16;116(40):20135-20140. Epub 2019 Sep 16.

Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, 3000, Australia;

small-colony variants (SCVs) are associated with unusually chronic and persistent infections despite active antibiotic treatment. The molecular basis for this clinically important phenomenon is poorly understood, hampered by the instability of the SCV phenotype. Here we investigated the genetic basis for an unstable SCV that arose spontaneously while studying rifampicin resistance. This SCV showed no nucleotide differences across its genome compared with a normal-colony variant (NCV) revertant, yet the SCV presented the hallmarks of linked to persistent infection: down-regulation of virulence genes and reduced hemolysis and neutrophil chemotaxis, while exhibiting increased survival in blood and ability to invade host cells. Further genome analysis revealed chromosome structural variation uniquely associated with the SCV. These variations included an asymmetric inversion across half of the chromosome via recombination between type I restriction modification system (T1RMS) genes, and the activation of a conserved prophage harboring the immune evasion cluster (IEC). Phenotypic reversion to the wild-type-like NCV state correlated with reversal of the chromosomal inversion (CI) and with prophage stabilization. Further analysis of 29 complete genomes showed strong signatures of recombination between genes, suggesting that analogous CI has repeatedly occurred during evolution. Using qPCR and long-read amplicon deep sequencing, we detected subpopulations with T1RMS rearrangements causing CIs and prophage activation across major lineages. Here, we have discovered a previously unrecognized and widespread mechanism of reversible genomic instability in associated with SCV generation and persistent infections.
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http://dx.doi.org/10.1073/pnas.1904861116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778178PMC
October 2019

The significance of vascular loops in the internal auditory meatus: a true incidental imaging finding?

Eur Arch Otorhinolaryngol 2019 Dec 5;276(12):3275-3280. Epub 2019 Sep 5.

Department of Otolaryngology, Queen Elizabeth University Hospital, 1345 Govan Road, Glasgow, G51 4TF, UK.

Purpose: To determine the clinical significance of vascular loops (VL) in the internal auditory meatus (IAM) and cerebellopontine angle (CPA).

Methods: We carried out a retrospective case series in a tertiary referral centre. Out of 6978 patients undergoing magnetic resonance imaging (MRI) of the IAM for unilateral cochleovestibular symptoms we identified the ones with VLs and reviewed their medical notes. We performed a statistical correlation between the laterality of the VL in the IAM/ CPA as graded according to the Chavda classification (type 1 in the CPA, type 2 extending in the IAM, type 3 extending to the distal IAM end), the laterality of symptoms and the patient's age.

Results: A total of 77 VL were identified in 64 patients (0.9%); 39 patients had the VL on the same side of the main symptom, while 25 patients had the VL on the contralateral side. There were 37 Type 1 loops, 29 Type 2 loops and 11 Type 3 loops. The comparison between the grading of the VL and the laterality of symptoms did not reach the level of significance (p = 0.321). There was also no association between the presence of the loop and the patients' age (p = 0.5). All patients were reassured and discharged without any representation in three years follow-up.

Conclusions: We did not identify any significant correlation between the laterality of VLs and the laterality of symptoms, irrespective of the grading of the loop or the patients' age. Such VLs should be considered an incidental rather than causal findings.
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http://dx.doi.org/10.1007/s00405-019-05615-1DOI Listing
December 2019

Sentinel Case of in the Western United States Following Prolonged Occult Colonization in a Returned Traveler from India.

Microb Drug Resist 2019 Jun;25(5):677-680

2 Chan Zuckerberg Biohub, San Francisco, California.

is an emerging multidrug-resistant yeast with high mortality. We report the sentinel case on the United States West Coast in a patient who relocated from India. We identified close phylogenetic relatedness to the South Asia clade and Y132F and S639Y mutations potentially explaining antifungal resistance.
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http://dx.doi.org/10.1089/mdr.2018.0408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555181PMC
June 2019

: Clinical Characteristics and Draft Genome of an Emerging Pathogen in Native and Prosthetic Valve Endocarditis.

Open Forum Infect Dis 2019 Apr 15;6(4):ofz134. Epub 2019 Mar 15.

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

is a new species in the family Flavobacteriaceae that was recently described in 3 cases of native valve infective endocarditis. We report the first case of prosthetic valve endocarditis, provide the first draft genome of this species, and review the microbiologic characteristics of this emerging pathogen.
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http://dx.doi.org/10.1093/ofid/ofz134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475584PMC
April 2019