17 results on '"Engelthaler, David M."'
Search Results
2. Genomic surveillance and pathogen intelligence
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Engelthaler, David M., primary
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- 2024
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3. Sequencing by binding rivals SMOR error-corrected sequencing by synthesis technology for accurate detection and quantification of minor (< 0.1%) subpopulation variants.
- Author
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Allender, Christopher J., Wike, Candice L., Porter, W. Tanner, Ellis, Dean, Lemmer, Darrin, Pond, Stephanie J. K., and Engelthaler, David M.
- Subjects
WHOLE genome sequencing ,ERROR rates ,SINGLE molecules ,NUCLEOTIDE sequencing ,BASIC needs - Abstract
Background: Detecting very minor (< 1%) subpopulations using next-generation sequencing is a critical need for multiple applications, including the detection of drug resistant pathogens and somatic variant detection in oncology. A recently available sequencing approach termed 'sequencing by binding (SBB)' claims to have higher base calling accuracy data "out of the box." This paper evaluates the utility of using SBB for the detection of ultra-rare drug resistant subpopulations in Mycobacterium tuberculosis (Mtb) using a targeted amplicon assay and compares the performance of SBB to single molecule overlapping reads (SMOR) error corrected sequencing by synthesis (SBS) data. Results: SBS displayed an elevated error rate when compared to SMOR error-corrected SBS and SBB techniques. SMOR error-corrected SBS and SBB technologies performed similarly within the linear range studies and error rate studies. Conclusions: With lower sequencing error rates within SBB sequencing, this technique looks promising for both targeted and unbiased whole genome sequencing, leading to the identification of minor (< 1%) subpopulations without the need for error correction methods. [ABSTRACT FROM AUTHOR]
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- 2024
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4. A framework for integrating wastewater-based epidemiology and public health.
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Brosky, Hanna, Prasek, Sarah M., Innes, Gabriel K., Pepper, Ian L., Miranda, Jasmine, Brierley, Paul E., Slinski, Stephanie L., Polashenski, Lois, Betancourt, Walter Q., Gronbach, Katie, Gomez, Diana, Neupane, Reshma, Johnson, Jasmine, Weiss, Joli, Yaglom, Hayley D., Engelthaler, David M., Hepp, Crystal M., Crank, Katherine, Gerrity, Daniel, and Stewart, Jill R.
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- 2024
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5. Discovery and Repurposing of Pharmaceutical Agents as Antifungals:In vivoactivity againstCoccidioides
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Mead, Heather L., primary, Valentine, Michael, additional, Yin, Holly, additional, Thompson, George R., additional, Keim, Paul, additional, Engelthaler, David M., additional, and Barker, Bridget M., additional
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- 2024
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6. Large Clusters of Invasive emm49 Group A Streptococcus Identified Within Arizona Health Care Facilities Through Statewide Genomic Surveillance System, 2019–2021
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Yaglom, Hayley D, primary, Bhattarai, Rachana, additional, Lemmer, Darrin, additional, Rust, Laura, additional, Ridenour, Chase, additional, Chorbi, Kaitlyn, additional, Kim, Elizabeth, additional, Centner, Heather, additional, Sheridan, Krystal, additional, Jasso-Selles, Daniel, additional, Erickson, Daryn E, additional, French, Chris, additional, Bowers, Jolene R, additional, Valentine, Michael, additional, Francis, Drew, additional, Hepp, Crystal M, additional, Brady, Shane, additional, Komatsu, Kenneth K, additional, and Engelthaler, David M, additional
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- 2024
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7. Lyssa excreta: Defining parameters for fecal samples as a rabies virus surveillance method
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Walker, Faith M., primary, Upton, Jordyn R., additional, Erickson, Daryn, additional, Barrand, Zachary A., additional, Brock, Breezy, additional, Valentine, Michael, additional, Federman, Emma L., additional, Froehlich, Emma M., additional, Van Pelt, Lolita, additional, Hastings, Lias, additional, Sanchez, Daniel E., additional, Bergman, David L., additional, Engelthaler, David M., additional, and Hepp, Crystal M., additional
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- 2024
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8. DETECTION OF SARS-COV-2 IN A SQUIRREL MONKEY (SAIMIRI SCIUREUS): A ONE HEALTH INVESTIGATION AND RESPONSE.
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Yaglom, Hayley D., Roth, Alexis, Alvarez, Carolina, Corbus, Elaine, Ghai, Ria R., Ferguson, Sylvia, Ritter, Jana M., Hecht, Gavriella, Rekant, Steven, Engelthaler, David M., Venkat, Heather, and Tygielski, Sue
- Abstract
Through collaborative efforts, One Health partners have responded to outbreaks of COVID-19 among animals, including those in human care at zoos. Zoos have been faced with numerous challenges, including the susceptibility of many mammalian species, and therefore the need to heighten biosecurity measures rapidly. Robust One Health collaborations already exist in Arizona to address endemic and emerging zoonoses, but these have rarely included zoos. The pandemic shed light on this, and Arizona subsequently expanded its SARS-CoV-2 surveillance efforts to include zoo animals. Testing and epidemiologic support was provided to expedite the detection of and response to zoonotic SARS-CoV-2 infection in zoo animals, as well as to understand possible transmission events. Resulting from this program, SARS-CoV-2 was detected from a rectal swab collected from an 8-yr-old squirrel monkey (Saimiri sciureus) from a zoo in Southern Arizona. The animal had rapidly become ill with nonrespiratory symptoms and died in July 2022. Genomic sequencing from the swab revealed mutations consistent with the Omicron (BA.2) lineage. An epidemiologic investigation identified an animal caretaker in close proximity to the affected squirrel monkey who tested positive for COVID-19 the same day the squirrel monkey died. Critical One Health partners provided support to the zoo through engagement of local, state, and federal agencies. Necropsy and pathologic evaluation showed significant necrotizing colitis; the overall clinical and histopathological findings did not implicate SARS-CoV-2 infection alone as a causal or contributing factor in the squirrel monkey's illness and death. This report documents the first identification of SARS-CoV-2 in a squirrel monkey and highlights a successful and timely One Health investigation conducted through multisectoral collaboration. [ABSTRACT FROM AUTHOR]
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- 2024
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9. Investigation of SARS-CoV-2 Infection among Companion Animals in Households with Confirmed Human COVID-19 Cases.
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Venkat, Heather, Yaglom, Hayley D., Hecht, Gavriella, Goedderz, Andrew, Ely, Jennifer L., Sprenkle, Michael, Martins, Taylor, Jasso-Selles, Daniel, Lemmer, Darrin, Gesimondo, Jordan, Ruberto, Irene, Komatsu, Kenneth, and Engelthaler, David M.
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PETS ,COVID-19 pandemic ,WHOLE genome sequencing ,SARS-CoV-2 ,VIRAL transmission ,HOUSEHOLDS - Abstract
We aimed to characterize SARS-CoV-2 infection in companion animals living in households with COVID-19-positive people and understand the dynamics surrounding how these animals become infected. Public health investigators contacted households with at least one confirmed, symptomatic person with COVID-19 for study recruitment. Blood, nasal, and rectal swab specimens were collected from pet dogs and cats and a questionnaire was completed. Specimens were tested for SARS-CoV-2 by RT-PCR, and for neutralizing antibodies; genomic sequencing was performed on viral-positive samples. A total of 36.4% of 110 pets enrolled had evidence of infection with SARS-CoV-2. Pets were more likely to test positive if the pet was immunocompromised, and if more than one person in the home was positive for COVID-19. Among 12 multi-pet households where at least one pet was positive, 10 had at least one other pet test positive. Whole-genome sequencing revealed the genomes of viral lineages circulating in the community during the time of sample collection. Our findings suggest a high likelihood of viral transmission in households with multiple pets and when pets had very close interactions with symptomatic humans. Further surveillance studies are needed to characterize how new variants impact animals and to understand opportunities for infection and spillover in susceptible species. [ABSTRACT FROM AUTHOR]
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- 2024
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10. Understanding the exposure risk of aerosolized Coccidioides in a Valley fever endemic metropolis.
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Porter, W. Tanner, Gade, Lalitha, Montfort, Parker, Mihaljevic, Joseph R., Bowers, Jolene R., Willman, Andrew, Klimowski, Brian A., LaFleur, Bonnie J., Sunenshine, Rebecca H., Collins, Jennifer, Adame, Guillermo, Brady, Shane, Komatsu, Kenneth K., Williams, Samantha, Toda, Mitsuru, Chiller, Tom, Litvintseva, Anastasia P., and Engelthaler, David M.
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COCCIDIOIDOMYCOSIS ,RISK exposure ,AIR sampling ,METROPOLIS ,METROPOLITAN areas - Abstract
Coccidioides is the fungal causative agent of Valley fever, a primarily pulmonary disease caused by inhalation of fungal arthroconidia, or spores. Although Coccidioides has been an established pathogen for 120 years and is responsible for hundreds of thousands of infections per year, little is known about when and where infectious Coccidioides arthroconidia are present within the ambient air in endemic regions. Long-term air sampling programs provide a means to investigate these characteristics across space and time. Here we present data from > 18 months of collections from 11 air sampling sites across the Phoenix, Arizona, metropolitan area. Overall, prevalence was highly variable across space and time with no obvious spatial or temporal correlations. Several high prevalence periods were identified at select sites, with no obvious spatial or temporal associations. Comparing these data with weather and environmental factor data, wind gusts and temperature were positively associated with Coccidioides detection, while soil moisture was negatively associated with Coccidioides detection. These results provide critical insights into the frequency and distribution of airborne arthroconidia and the associated risk of inhalation and potential disease that is present across space and time in a highly endemic locale. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Novel Presentation of Coccidioidomycosis with Myriad Free-Floating Proteinaceous Spheres in the Pericardial Sac of a Southern Sea Otter (Enhydra lutris nereis).
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Harris, Heather S., Harris, Michael D., Thompson III, George R., Engelthaler, David M., Montfort, Parker L., Leviner, Alexis L., and Miller, Melissa A.
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A southern sea otter (Enhydra lutris nereis) stranded dead in central California, USA, with a distended pericardial sac containing thousands of free-floating proteinaceous masses. Serology, fungal culture, PCR, and sequencing confirmed the etiology of this novel lesion as Coccidioides immitis. Range expansion of this zoonotic pathogen is predicted with climate change. [ABSTRACT FROM AUTHOR]
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- 2024
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12. In vitro small molecule screening to inform novel candidates for use in fluconazole combination therapy in vivo against Coccidioides .
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Mead HL, Valentine M, Yin H, Thompson Iii GR, Keim P, Engelthaler DM, and Barker BM
- Abstract
Identifying improved treatments for severe and refractory coccidioidomycosis (Valley fever) is needed. This endemic fungal disease is common in North and South America, and cases have increased substantially over the last 30 years. The current standard of care, oral daily fluconazole, often fails to completely eradicate Coccidioides infection; however, the high cost of identifying new compounds effective in treating Valley fever is a barrier to improving treatment. Therefore, repurposing existing pharmaceutical agents in combination with fluconazole therapy is an attractive option. We screened the Library of Pharmacologically Active Compounds (LOPAC) small molecule library for compounds that inhibited fungal growth in vitro and determined IC
50 values for a subset of compounds. Based on these findings, we tested a small subset of these agents to validate the screen, as well as to test the performance of fluconazole in a combination therapy approach, as compared with fluconazole alone, in a murine model. We observed that combination therapy of tamoxifen:fluconazole and sertraline:fluconazole significantly reduced the burden of live fungus in the lung compared with fluconazole alone, and we observed reduced or nonexistent dissemination. These results suggest that tamoxifen and sertraline may be repurposed as adjunctive agents in the treatment of this important fungal disease., Importance: Developing new drugs, especially for regional orphan diseases, such as Valley Fever, is a slow and costly endeavor. However, there is a wealth of FDA-approved drugs available for repurposing, offering a more economical and expedited approach to improve treatment. Those existing compounds with antifungal properties can become novel therapies with relative ease: a considerable advantage for patients in need of alternative treatment. Despite the scope of remaining tasks, our comprehensive screening of potential candidates has revealed promising combinations for further exploration. This effort outlines a practical pipeline for Valley fever drug screening and identifies viable drug combinations that could impact patients more rapidly than single drug development pathways.- Published
- 2024
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13. The Hidden Epidemic of Isoniazid-Resistant Tuberculosis in South Africa.
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Klopper M, van der Merwe CJ, van der Heijden YF, Folkerts M, Loubser J, Streicher EM, Mekler K, Hayes C, Engelthaler DM, Metcalfe JZ, and Warren RM
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Background: Isoniazid-resistant tuberculosis (Hr-TB) is often overlooked in diagnostic algorithms due to reliance on first-line molecular assays testing only for rifampicin resistance., Objectives: To determine the prevalence, outcomes and molecular mechanisms associated with Hr-TB in the Eastern Cape, South Africa., Methods: Between April 2016 and October 2017, sputum samples were collected from patients with rifampin-susceptible TB at baseline and at weeks 7 and 23 of drug-susceptible TB treatment. We performed isoniazid phenotypic and genotypic drug susceptibility testing, FluorotypeMTBDR, Sanger sequencing, targeted next-generation sequencing (tNGS), and whole genome sequencing., Results: We analysed baseline isolates from 766 patients with rifampin-susceptible TB. Of 89 patients (11.7%) found to have Hr-TB, 39 (44%) had canonical katG or inhA promoter mutations; 35 (39%) had non-canonical katG mutations (including 5 with underlying large deletions); 4 (5%) had mutations in other candidate genes associated with isoniazid resistance. For 11 (12.4%), no cause of resistance was found., Conclusions: Among patients with rifampin-susceptible TB diagnosed using first-line molecular TB assays, there is a high prevalence of Hr-TB. Phenotypic DST remains the gold standard. To improve performance of genetic-based phenotyping tests, all isoniazid resistance associated regions should be included, and such tests should have the ability to identify underlying mutations.
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- 2024
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14. Drug resistance and epidemiological success of modern Mycobacterium tuberculosis lineages in western India.
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Dixit A, Ektefaie Y, Kagal A, Freschi L, Karyakarte R, Lokhande R, Groschel M, Tornheim JA, Gupte N, Pradhan NN, Paradkar MS, Deshmukh S, Kadam D, Schito M, Engelthaler DM, Gupta A, Golub J, Mave V, and Farhat M
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Background: Transmission is contributing to the slow decline of tuberculosis (TB) incidence globally. Drivers of TB transmission in India, the country estimated to carry a quarter of the World's burden, are not well studied. We conducted a genomic epidemiology study to compare epidemiological success, host factors and drug resistance (DR) among the four major Mycobacterium tuberculosis (Mtb) lineages (L1-4) circulating in Pune, India., Methods: We performed whole-genome sequencing (WGS) of Mtb sputum culture-positive isolates from participants in two prospective cohort studies and predicted genotypic susceptibility using a validated random forest model. We used maximum likelihood estimation to build phylogenies. We compared lineage specific phylogenetic and time-scaled metrics to assess epidemiological success., Results: Of the 642 isolates that underwent WGS, 612 met sequence quality criteria. Most isolates belonged to L3 (44.6%). The majority (61.1%) of multidrug-resistant isolates belonged to L2 (P < 0.001). In molecular dating, L2 demonstrated a higher rate and more recent resistance acquisition. We measured higher clustering, and time-scaled haplotypic density (THD) for L4 and L2 compared to L3 and/or L1 suggesting higher epidemiological success. L4 demonstrated higher THD and clustering (OR 5.1 (95% CI 2.3-12.3) in multivariate models controlling for host factors and DR., Conclusion: L2 shows a higher frequency of DR and both L2 and L4 demonstrate evidence of higher epidemiological success than L3 or L1 in the study setting. Our findings highlight the need for contact tracing around TB cases, and heightened surveillance of TB DR in India., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)
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- 2024
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15. Sequencing by Binding rivals error-corrected Sequencing by Synthesis technology for accurate detection and quantification of minor (<0.1%) subpopulation variants.
- Author
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Allender CJ, Wike C, Ellis D, Lemmer D, Porter T, Pond SJK, and Engelthaler DM
- Abstract
Detecting very minor (< 1%) subpopulations using next-generation sequencing is a critical need for multiple applications including detection of drug resistant pathogens and somatic variant detection in oncology. To enable these applications, wet lab enhancements and bioinformatic error correction methods have been developed for 'sequencing by synthesis' technology to reduce its inherent sequencing error rate. A recently available sequencing approach termed 'sequencing by binding' claims to have higher base calling accuracy data "out of the box." This paper evaluates the utility of using 'sequencing by binding' for the detection of ultra-rare subpopulations down to 0.001%., Competing Interests: Competing interests: Pacific Biosciences provided early access to the SBB sequencing reagents and platform, as well as technician and data analysis support (see Acknowledgements). The authors declare no other competing interests for this study.
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- 2024
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16. Pan-Enterovirus Characterization Reveals Cryptic Circulation of Clinically Relevant Subtypes in Arizona Wastewater.
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Erickson DE, Simmons KM, Barrand ZA, Ridenour CL, Hawkinson PB, Lemke L, Sellner SP, Brock BN, Rivas AN, Sheridan K, Lemmer D, Yaglom HD, Porter WT, Belanger M, Torrey RM, Stills AJR, McCormack K, Black M, Holmes W, Rostain D, Mikus J, Sotelo K, Haq E, Neupane R, Weiss J, Johnson J, Collins C, Avalle S, White C, Howard BJ, Maltinsky SA, Whealy RN, Gordon NB, Sahl JW, Pearson T, Fofanov VY, Furstenau T, Driebe EM, Caporaso JG, Barber J, Terriquez J, Engelthaler DM, and Hepp CM
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Background: Most seasonally circulating enteroviruses result in asymptomatic or mildly symptomatic infections. In rare cases, however, infection with some subtypes can result in paralysis or death. Of the 300 subtypes known, only poliovirus is reportable, limiting our understanding of the distribution of other enteroviruses that can cause clinical disease., Objective: The overarching objectives of this study were to: 1) describe the distribution of enteroviruses in Arizona during the late summer and fall of 2022, the time of year when they are thought to be most abundant, and 2) demonstrate the utility of viral pan-assay approaches for semi-agnostic discovery that can be followed up by more targeted assays and phylogenomics., Methods: This study utilizes pooled nasal samples collected from school-aged children and long-term care facility residents, and wastewater from multiple locations in Arizona during July-October of 2022. We used PCR to amplify and sequence a region common to all enteroviruses, followed by species-level bioinformatic characterization using the QIIME 2 platform. For Enterovirus-D68 (EV-D68), detection was carried out using RT-qPCR, followed by confirmation using near-complete whole EV-D68 genome sequencing using a newly designed tiled amplicon approach., Results: In the late summer and early fall of 2022, multiple enterovirus species were identified in Arizona wastewater, with Coxsackievirus A6, EV-D68, and Coxsackievirus A19 composing 86% of the characterized reads sequenced. While EV-D68 was not identified in pooled human nasal samples, and the only reported acute flaccid myelitis case in Arizona did not test positive for the virus, an in-depth analysis of EV-D68 in wastewater revealed that the virus was circulating from August through mid-October. A phylogenetic analysis on this relatively limited dataset revealed just a few importations into the state, with a single clade indicating local circulation., Significance: This study further supports the utility of wastewater-based epidemiology to identify potential public health threats. Our further investigations into EV-D68 shows how these data might help inform healthcare diagnoses for children presenting with concerning neurological symptoms.
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- 2024
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17. Large Clusters of Invasive emm49 Group A Streptococcus Identified within and across Arizona Healthcare Facilities through Statewide Genomic Surveillance System, 2019-2021.
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Yaglom HD, Bhattarai R, Lemmer D, Rust L, Ridenour C, Chorbi K, Kim E, Centner H, Sheridan K, Jasso-Selles D, Erickson DE, French C, Bowers JR, Valentine M, Francis D, Hepp CM, Brady S, Komatsu KK, and Engelthaler DM
- Abstract
A statewide genomic surveillance system for invasive Group A Streptococcus was implemented in Arizona in June 2019, resulting in 1,046 isolates being submitted for genomic analysis to characterize emm-types and identify transmission clusters. Eleven of the 32 identified distinct emm-types comprised >80% of samples, with 29.7% of all isolates being typed as emm49 (and its genetic derivative emm151). Phylogenetic analysis initially identified an emm49 genomic cluster of four isolates that rapidly expanded over subsequent months (June 2019-February 2020). Public health investigations identified epidemiologic links with three different long-term care facilities, resulting in specific interventions. Unbiased genomic surveillance allowed for identification and response to clusters that would have otherwise remained undetected., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2024
- Full Text
- View/download PDF
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