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Article: On the Origins of Omicron's Unique Spike Gene Insertion.

Venkatakrishnan, A J / Anand, Praveen / Lenehan, Patrick J / Suratekar, Rohit / Raghunathan, Bharathwaj / Niesen, Michiel J M / Soundararajan, Venky

Vaccines

2022 Volume 10, Issue 9

Abstract: The emergence of a heavily mutated SARS-CoV-2 variant (Omicron; Pango lineage B.1.1.529 and BA sublineages) and its rapid spread to over 75 countries raised a global public health alarm. Characterizing the mutational profile of Omicron is necessary to ... ...

Abstract	The emergence of a heavily mutated SARS-CoV-2 variant (Omicron; Pango lineage B.1.1.529 and BA sublineages) and its rapid spread to over 75 countries raised a global public health alarm. Characterizing the mutational profile of Omicron is necessary to interpret its clinical phenotypes which are shared with or distinctive from those of other SARS-CoV-2 variants. We compared the mutations of the initially circulating Omicron variant (now known as BA.1) with prior variants of concern (Alpha, Beta, Gamma, and Delta), variants of interest (Lambda, Mu, Eta, Iota, and Kappa), and ~1500 SARS-CoV-2 lineages constituting ~5.8 million SARS-CoV-2 genomes. Omicron's Spike protein harbors 26 amino acid mutations (23 substitutions, 2 deletions, and 1 insertion) that are distinct compared to other variants of concern. While the substitution and deletion mutations appeared in previous SARS-CoV-2 lineages, the insertion mutation (ins214EPE) was not previously observed in any other SARS-CoV-2 lineage. Here, we consider and discuss various mechanisms through which the nucleotide sequence encoding for ins214EPE could have been acquired, including local duplication, polymerase slippage, and template switching. Although we are not able to definitively determine the mechanism, we highlight the plausibility of template switching. Analysis of the homology of the inserted nucleotide sequence and flanking regions suggests that this template-switching event could have involved the genomes of SARS-CoV-2 variants (e.g., the B.1.1 strain), other human coronaviruses that infect the same host cells as SARS-CoV-2 (e.g., HCoV-OC43 or HCoV-229E), or a human transcript expressed in a host cell that was infected by the Omicron precursor.
Language	English
Publishing date	2022-09-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines10091509
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Article: Genetic alteration of human MYH6 is mimicked by SARS-CoV-2 polyprotein: mapping viral variants of cardiac interest.

Anand, Praveen / Lenehan, Patrick J / Niesen, Michiel / Yoo, Unice / Patwardhan, Dhruti / Montorzi, Marcelo / Venkatakrishnan, A J / Soundararajan, Venky

Cell death discovery

2022 Volume 8, Issue 1, Page(s) 124

Abstract: Acute cardiac injury has been observed in a subset of COVID-19 patients, but the molecular basis for this clinical phenotype is unknown. It has been hypothesized that molecular mimicry may play a role in triggering an autoimmune inflammatory reaction in ... ...

Abstract	Acute cardiac injury has been observed in a subset of COVID-19 patients, but the molecular basis for this clinical phenotype is unknown. It has been hypothesized that molecular mimicry may play a role in triggering an autoimmune inflammatory reaction in some individuals after SARS-CoV-2 infection. Here we investigate if linear peptides contained in proteins that are primarily expressed in the heart also occur in the SARS-CoV-2 proteome. Specifically, we compared the library of 136,704 8-mer peptides from 144 human proteins (including splicing variants) to 9926 8-mers from all the viral proteins in the reference SARS-CoV-2 proteome. No 8-mers were exactly identical between the reference human proteome and the reference SARS-CoV-2 proteome. However, there were 45 8-mers that differed by only one amino acid when compared to the reference SARS-CoV-2 proteome. Interestingly, analysis of protein-coding mutations from 141,456 individuals showed that one of these 8-mers from the SARS-CoV-2 Replicase polyprotein 1a/1ab (KIALKGGK) is identical to an MYH6 peptide encoded by the c.5410 C > A (Q1804K) genetic variation, which has been observed at low prevalence in Africans/African Americans (0.08%), East Asians (0.3%), South Asians (0.06%), and Latino/Admixed Americans (0.003%). Furthermore, analysis of 4.85 million SARS-CoV-2 genomes from over 200 countries shows that viral evolution has already resulted in 20 additional 8-mer peptides that are identical to human heart-enriched proteins encoded by reference sequences or genetic variants. Whether such mimicry contributes to cardiac inflammation during or after COVID-19 illness warrants further experimental evaluation. We suggest that SARS-CoV-2 variants harboring peptides identical to human cardiac proteins should be investigated as "viral variants of cardiac interest".
Language	English
Publishing date	2022-03-21
Publishing country	United States
Document type	Journal Article
ISSN	2058-7716
ISSN	2058-7716
DOI	10.1038/s41420-022-00914-9
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Article ; Online: Paediatric safety assessment of BNT162b2 vaccination in a multistate hospital-based electronic health record system in the USA: a retrospective analysis.

Matson, Robert P / Niesen, Michiel J M / Levy, Emily R / Opp, Derek N / Lenehan, Patrick J / Donadio, Greg / O'Horo, John C / Venkatakrishnan, A J / Badley, Andrew D / Soundararajan, Venky

The Lancet. Digital health

2023 Volume 5, Issue 4, Page(s) e206–e216

Abstract: Background: The emergency use authorisation of BNT162b2 (tozinameran; Comirnaty, Pfizer-BioNTech) for children aged 5-17 years has resulted in rapid vaccination in the paediatric population. However, there are few studies of adverse events associated ... ...

Abstract	Background: The emergency use authorisation of BNT162b2 (tozinameran; Comirnaty, Pfizer-BioNTech) for children aged 5-17 years has resulted in rapid vaccination in the paediatric population. However, there are few studies of adverse events associated with vaccination in children. The aim of this study was to systematically assess the adverse events of two-dose BNT162b2 vaccination in the paediatric population. Methods: We conducted a retrospective analysis of patient electronic health records (EHRs) of children aged 5-17 years who received the primary two-dose series of the BNT162b2 vaccine between Jan 5, 2021, and Aug 5, 2022, at the Mayo Clinic Health System (MN, FL, AZ, IA, and WI), USA. Using natural language processing, we automatically curated adverse events reported by physicians in EHR clinical notes before and after vaccination. To determine significant adverse events after BNT162b2 vaccination, we calculated risk differences, which was defined as the percentage difference between the rate of children with an adverse event after a vaccine dose and the baseline rate of children with an adverse event before vaccination. 95% CIs and p values were calculated using the Miettinen and Nurminen score method. Findings: 56 436 individuals aged 5-17 years (20 227 aged 5-11 years and 36 209 aged 12-17 years) with EHRs in the Mayo Clinic Health Systems were included in the study. Overall, the reporting of adverse events remained low in passive surveillance. Serious adverse events were rare after the first and second doses of BNT162b2, with rates of anaphylaxis (six [0·01%] of 56 436), myocarditis (five [0·01%]), and pericarditis (three [0·01%]) consistent with previous studies. Among the 20 227 5-11-year-olds, there were increased risks of fatigue (58 after second dose vs 41 before first dose; risk difference [RD] Interpretation: Overall, this data suggests that vaccination with BNT162b2 in the paediatric population is generally safe and well-tolerated. Further research is warranted to investigate the basis for the increased risk of myocarditis in adolescent males. Additionally, further studies are needed to confirm whether the findings in our study population apply to the whole vaccinated paediatric population. Funding: nference.
MeSH term(s)	Adolescent ; Child ; Humans ; Male ; BNT162 Vaccine/adverse effects ; Electronic Health Records ; Hospitals ; Myocarditis ; Retrospective Studies ; United States/epidemiology ; Vaccination ; COVID-19/prevention & control
Chemical Substances	BNT162 Vaccine
Language	English
Publishing date	2023-03-24
Publishing country	England
Document type	Journal Article
ISSN	2589-7500
ISSN (online)	2589-7500
DOI	10.1016/S2589-7500(22)00253-9
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Article ; Online: Correction: PD-1 blockade and CDK4/6 inhibition augment nonoverlapping features of T cell activation in cancer.

Ali, Lestat R / Garrido-Castro, Ana C / Lenehan, Patrick J / Bollenrucher, Naima / Stump, Courtney T / Dougan, Michael / Goel, Shom / Shapiro, Geoffrey I / Tolaney, Sara M / Dougan, Stephanie K

The Journal of experimental medicine

2023 Volume 220, Issue 9

Language	English
Publishing date	2023-08-24
Publishing country	United States
Document type	Published Erratum
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.2022072908182023c
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Article ; Online: PD-1 blockade and CDK4/6 inhibition augment nonoverlapping features of T cell activation in cancer.

Ali, Lestat R / Garrido-Castro, Ana C / Lenehan, Patrick J / Bollenrucher, Naima / Stump, Courtney T / Dougan, Michael / Goel, Shom / Shapiro, Geoffrey I / Tolaney, Sara M / Dougan, Stephanie K

The Journal of experimental medicine

2023 Volume 220, Issue 4

Abstract: We performed single-cell RNA-sequencing and T cell receptor clonotype tracking of breast and ovarian cancer patients treated with the CDK4/6 inhibitor ribociclib and PD-1 blockade. We highlight evidence of two orthogonal treatment-associated phenomena: ... ...

Abstract	We performed single-cell RNA-sequencing and T cell receptor clonotype tracking of breast and ovarian cancer patients treated with the CDK4/6 inhibitor ribociclib and PD-1 blockade. We highlight evidence of two orthogonal treatment-associated phenomena: expansion of T cell effector populations and promotion of T cell memory formation. Augmentation of the antitumor memory pool by ribociclib boosts the efficacy of subsequent PD-1 blockade in mouse models of melanoma and breast cancer, pointing toward sequential therapy as a potentially safe and synergistic strategy in patients.
MeSH term(s)	Animals ; Mice ; Programmed Cell Death 1 Receptor ; Aminopyridines/pharmacology ; Purines ; Melanoma
Chemical Substances	ribociclib (TK8ERE8P56) ; Programmed Cell Death 1 Receptor ; Aminopyridines ; Purines
Language	English
Publishing date	2023-01-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20220729
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Ua VI Zs.107: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Type 2 immunity is maintained during cancer-associated adipose tissue wasting.

Lenehan, Patrick J / Cirella, Assunta / Uchida, Amiko M / Crowley, Stephanie J / Sharova, Tatyana / Boland, Genevieve / Dougan, Michael / Dougan, Stephanie K / Heckler, Max

Immunotherapy advances

2021 Volume 1, Issue 1, Page(s) ltab011

Abstract: Objectives: Cachexia is a systemic metabolic disorder characterized by loss of fat and muscle mass, which disproportionately impacts patients with gastrointestinal malignancies such as pancreatic cancer. While the immunologic shifts contributing to the ... ...

Abstract	Objectives: Cachexia is a systemic metabolic disorder characterized by loss of fat and muscle mass, which disproportionately impacts patients with gastrointestinal malignancies such as pancreatic cancer. While the immunologic shifts contributing to the development of other adipose tissue (AT) pathologies such as obesity have been well described, the immune microenvironment has not been studied in the context of cachexia. Methods: We performed bulk RNA-sequencing, cytokine arrays, and flow cytometry to characterize the immune landscape of visceral AT (VAT) in the setting of pancreatic and colorectal cancers. Results: The cachexia inducing factor IL-6 is strongly elevated in the wasting VAT of cancer bearing mice, but the regulatory type 2 immune landscape which characterizes healthy VAT is maintained. Pathologic skewing toward Th1 and Th17 inflammation is absent. Similarly, the VAT of patients with colorectal cancer is characterized by a Th2 signature with abundant IL-33 and eotaxin-2, albeit also with high levels of IL-6. Conclusions: Wasting AT during the development of cachexia may not undergo drastic changes in immune composition like those seen in obese AT. Our approach provides a framework for future immunologic analyses of cancer associated cachexia.
Language	English
Publishing date	2021-06-02
Publishing country	England
Document type	Journal Article
ISSN	2732-4303
ISSN (online)	2732-4303
DOI	10.1093/immadv/ltab011
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Article ; Online: Radiology report "disclaimers" increase the use of abdominal CT in the work-up of pediatric abdominal pain.

Alter, Scott M / Walsh, Brian / Lenehan, Patrick J / Shih, Richard D

The American journal of emergency medicine

2017 Volume 36, Issue 4, Page(s) 556–559

Abstract: Objective: Pediatric abdominal pain is commonly evaluated in the emergency department (ED) initially by ultrasonography (U/S). Radiology reports often include commentary about U/S limitations and possible need for additional testing or evaluation ... ...

Abstract	Objective: Pediatric abdominal pain is commonly evaluated in the emergency department (ED) initially by ultrasonography (U/S). Radiology reports often include commentary about U/S limitations and possible need for additional testing or evaluation independent of study interpretation. We sought to determine if presence of a "disclaimer" is associated with additional imaging. Methods: Design: Retrospective cohort. Setting: Community ED with volume of 85,000 annual visits. Population: Consecutive ED patients <21-years-old with appendix U/S over 12-months. Radiologist reports were assessed for disclaimers and if definitive diagnoses of appendicitis were made. The incidence of subsequent CT imaging was determined and group differences between categories were calculated. Results: 441 eligible patients were identified with average age 11.7years. Of all U/S studies, 26% were definitive for appendicitis and 74% were non-definitive. Disclaimers were included on 60% of all studies, including 13% of definitive studies and 76% of non-definitive studies. 25% of all studies including a disclaimer had follow-up CT versus 10% of studies without a disclaimer (15% difference; 95% CI: 9-21). For patients with definitive interpretations, 6% had follow-up CT with no significant difference between groups with or without a disclaimer. For patients with non-definitive studies, 26% with a disclaimer had follow-up CT scans versus 13% without a disclaimer (13% difference; 95% CI: 4-22). Conclusions: Appendix ultrasound interpretations often include a disclaimer, which leads to a 150% increase in follow-up CT imaging. We suggest that radiologists consider the impact of including such a disclaimer, knowing that this may contribute to possible unnecessary imaging.
MeSH term(s)	Abdominal Pain/diagnostic imaging ; Abdominal Pain/etiology ; Adolescent ; Appendicitis/diagnostic imaging ; Child ; Child, Preschool ; Diagnostic Imaging/standards ; Emergency Service, Hospital/statistics & numerical data ; Female ; Humans ; Infant ; Male ; Retrospective Studies ; Tomography, X-Ray Computed/utilization ; Ultrasonography ; Young Adult
Language	English
Publishing date	2017-09-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	605890-5
ISSN	1532-8171 ; 0735-6757
ISSN (online)	1532-8171
ISSN	0735-6757
DOI	10.1016/j.ajem.2017.09.016
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Article ; Online: Expanding repertoire of SARS-CoV-2 deletion mutations contributes to evolution of highly transmissible variants.

Venkatakrishnan, A J / Anand, Praveen / Lenehan, Patrick J / Ghosh, Pritha / Suratekar, Rohit / Silvert, Eli / Pawlowski, Colin / Siroha, Abhishek / Chowdhury, Dibyendu Roy / O'Horo, John C / Yao, Joseph D / Pritt, Bobbi S / Norgan, Andrew P / Hurt, Ryan T / Badley, Andrew D / Halamka, John / Soundararajan, Venky

Scientific reports

2023 Volume 13, Issue 1, Page(s) 257

Abstract: The emergence of highly transmissible SARS-CoV-2 variants and vaccine breakthrough infections globally mandated the characterization of the immuno-evasive features of SARS-CoV-2. Here, we systematically analyzed 2.13 million SARS-CoV-2 genomes from 188 ... ...

Abstract	The emergence of highly transmissible SARS-CoV-2 variants and vaccine breakthrough infections globally mandated the characterization of the immuno-evasive features of SARS-CoV-2. Here, we systematically analyzed 2.13 million SARS-CoV-2 genomes from 188 countries/territories (up to June 2021) and performed whole-genome viral sequencing from 102 COVID-19 patients, including 43 vaccine breakthrough infections. We identified 92 Spike protein mutations that increased in prevalence during at least one surge in SARS-CoV-2 test positivity in any country over a 3-month window. Deletions in the Spike protein N-terminal domain were highly enriched for these 'surge-associated mutations' (Odds Ratio = 14.19, 95% CI 6.15-32.75, p value = 3.41 × 10
MeSH term(s)	Humans ; SARS-CoV-2/genetics ; COVID-19/epidemiology ; COVID-19/genetics ; Spike Glycoprotein, Coronavirus/genetics ; Breakthrough Infections ; Mutation ; Sequence Deletion ; Vaccines
Chemical Substances	Spike Glycoprotein, Coronavirus ; Vaccines ; spike protein, SARS-CoV-2
Language	English
Publishing date	2023-01-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-26646-5
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Article: Ultrasound for Diagnosis of Appendicitis in a Community Hospital Emergency Department has a High Rate of Nondiagnostic Studies.

Alter, Scott M / Walsh, Brian / Lenehan, Patrick J / Shih, Richard D

The Journal of emergency medicine

2017 Volume 52, Issue 6, Page(s) 833–838

Abstract: Background: Radiation concerns are changing the way emergency physicians evaluate patients. This is especially prevalent in pediatrics, and exemplified by abdominal pain management. Large academic center-based studies suggest appendix ultrasound (U/S) ... ...

Abstract	Background: Radiation concerns are changing the way emergency physicians evaluate patients. This is especially prevalent in pediatrics, and exemplified by abdominal pain management. Large academic center-based studies suggest appendix ultrasound (U/S) is sensitive and specific for appendicitis, with low nondiagnostic rates. Objectives: We sought to determine the diagnostic rate of appendix U/S and incidence of follow-up computed tomography (CT) imaging for pediatric patients at a community hospital. Methods: Design: Retrospective cohort. Setting: Emergency department with 85,000 annual visits. Population: Patients younger than 21 years old that had an appendix U/S over a 12-month period. U/S were performed by technicians and interpreted by radiologists. Investigators classified readings as "diagnostic" ("positive" and "negative") or "non-diagnostic" ("borderline" and "appendix not visualized") and identified follow-up CT studies and interpretations. Results: There were 441 pediatric appendix U/S performed; 26% were diagnostic (14% positive for appendicitis, 12% negative) and 74% nondiagnostic (5% borderline, 69% appendix not visualized). Follow-up CT scans were obtained in 19% of all patients, including 8% with positive U/S, 4% negative, 32% borderline, and 22% not visualized. Follow-up CT was nearly four times more likely in the nondiagnostic group than the diagnostic group (23% vs. 6%, p < 0.0001). Conclusion: The utility of U/S to diagnose appendicitis at a community hospital is limited by a high rate of nondiagnostic studies. Some patients with diagnostic U/S even had follow-up CT imaging. To minimize radiation exposure in children, improvements should be made in the performance and acceptance of U/S as the primary modality of abdominal pain imaging at community hospitals.
Language	English
Publishing date	2017-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	605559-x
ISSN	0736-4679
ISSN	0736-4679
DOI	10.1016/j.jemermed.2017.01.003
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Article ; Online: Continuous genomic diversification of long polynucleotide fragments drives the emergence of new SARS-CoV-2 variants of concern.

Murugadoss, Karthik / Niesen, Michiel J M / Raghunathan, Bharathwaj / Lenehan, Patrick J / Ghosh, Pritha / Feener, Tyler / Anand, Praveen / Simsek, Safak / Suratekar, Rohit / Hughes, Travis K / Soundararajan, Venky

PNAS nexus

2022 Volume 1, Issue 1, Page(s) pgac018

Abstract: Highly transmissible or immuno-evasive SARS-CoV-2 variants have intermittently emerged, resulting in repeated COVID-19 surges. With over 6 million SARS-CoV-2 genomes sequenced, there is unprecedented data to decipher the evolution of fitter SARS-CoV-2 ... ...

Abstract	Highly transmissible or immuno-evasive SARS-CoV-2 variants have intermittently emerged, resulting in repeated COVID-19 surges. With over 6 million SARS-CoV-2 genomes sequenced, there is unprecedented data to decipher the evolution of fitter SARS-CoV-2 variants. Much attention has been directed to studying the functional importance of specific mutations in the Spike protein, but there is limited knowledge of genomic signatures shared by dominant variants. Here, we introduce a method to quantify the genome-wide distinctiveness of polynucleotide fragments (3- to 240-mers) that constitute SARS-CoV-2 sequences. Compared to standard phylogenetic metrics and mutational load, the new metric provides improved separation between Variants of Concern (VOCs; Reference = 89, IQR: 65-108; Alpha = 166, IQR: 149-181; Beta 131, IQR: 114-149; Gamma = 164, IQR: 150-178; Delta = 235, IQR: 217-255; and Omicron = 459, IQR: 395-521). Omicron's high genomic distinctiveness may confer an advantage over prior VOCs and the recently emerged and highly mutated B.1.640.2 (IHU) lineage. Evaluation of 883 lineages highlights that genomic distinctiveness has increased over time (
Language	English
Publishing date	2022-03-10
Publishing country	England
Document type	Journal Article
ISSN	2752-6542
ISSN (online)	2752-6542
DOI	10.1093/pnasnexus/pgac018
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