Faculty Bibliography

Background: Patients treated with cytotoxic chemotherapies and/or autologous stem-cell transplantation (ASCT) are at risk for therapy-related myeloid neoplasms (tMN). As these agents yield increased mutation burden in relapsed malignancies and leave evidence of exposure via mutational signatures, we studied the genomic and temporal relationship between chemo exposure and progression of clonal hematopoiesis (CH) to tMN.
Method(s): We analyzed 32 tMN whole genomes (WG) from 31 patients [27 acute myeloid leukemias (AML), 4 myelodysplastic syndromes]. For 7 patients with tMN post-high-dose melphalan/ASCT, we investigated the presence of antecedent CH using targeted sequencing (MSK-IMPACT; Bolton et al. Nat Gen 2020) on pre-melphalan blood mononuclear cells, granulocytes, or CD34+ apheresis samples.
Result(s): TMN was diagnosed a median of 4.2 years (IQR, 2.6-6.6) following primary treatment. When compared to data from 200 de novo AML from TCGA (NEJM, 2013), tMNs had fewer mutations in FLT3 (9.7% v 28.0%; p = 0.028) and NPM1 (3.2% v 27.0%; p = 0.003). TP53 loss was enriched in tMNs (25.8% v 10.5%; p = 0.035 ). Mutational signature analysis revealed 5 known single base substitution (SBS) signatures in tMN: the hematopoietic stem-cell (SBS-HSC), aging (SBS1), melphalan (SBS-MM1), and platinum signatures (E-SBS1, E-SBS20) (Rustad et al. Nat Comm 2020, Pich et al. Nat Gen 2019). Complex structural variants (SV), defined as >=3 breakpoint pairs involved in simultaneous copy number changes (Rustad et al. Blood Can Disc 2020), were observed in 7 tMNs; including chromothripsis in 6 tumors (19.4%), chromoplexy in 2 (6.5%), templated insertion in 1 (3.2%), and unspecified complex SV in 2 (6.5%). Chromothripsis has not been previously reported in de novo AML and, in 4 cases, involved chromosome 19 with hyper-amplification of the SMARCA4 locus (>=5 copies). CH variants that became clonal in tumor were seen in 5/7 pre-melphalan/ASCT samples and included mutations in TP53, RUNX1, NCOR1, NF1, CREBBP, DNMT3A, and PPM1D. Chemotherapy introduces hundreds of mutations, leaving each exposed cell with a unique catalogue (i.e., barcode). In fact, TMNs with evidence of chemo signatures had a higher mutation burden (median 1574 single nucleotide variants) than those without (median 938; p = 0.004). Detection of chemo signatures in bulk genome sequencing relies on one cell, with its catalogue of mutations, to expand to clonal dominance (Fig 1a, Landau et al. Nat Comm 2020). Given the long latency between exposure and tMN diagnosis, this single-cell expansion model was expected for all samples exposed to melphalan or platinum-based regimens (i.e., agents with a measurable signature). Strikingly, all patients with pre-tMN platinum exposure (n=7) had evidence of platinum SBS signatures whereas only 2 of 7 patients with prior melphalan/ASCT had a melphalan signature (SBS-MM1). As all platinum-exposed tMN had mutational evidence of exposure, a CH clone must have existed prior to exposure, supporting a single-cell expansion model. Absence of a chemo signature for 5/7 post-melphalan/ASCT tumors despite exposure implies tumor progression driven either by multiple clones in parallel (Fig 1b) or by an unexposed clone. As latency largely excludes the former, this suggests pre-tMN CH clones were re-infused during SCT, thus avoiding chemo exposure (Fig 1c). This is supported by two lines of evidence: 1) tMNs from 2 patients exposed to sequential platinum and melphalan/ASCT had platinum but not melphalan signatures confirming single-cell expansion of the pre-tMN CH clone post-platinum but with escape from exposure to melphalan in the ASCT (Fig 1d); 2) targeted sequencing of pre-tMN samples from melphalan/ASCT patients identified tMN genomic mutations at the CH level in 5/7 cases, including in all 3 tested apheresis samples - one of which (TP53) expanded to dominance without a melphalan signature.
Conclusion(s): WG sequencing identified novel features of tMN revealing the key driver role of complex SV. Mutational signature analyses and targeted sequencing of pre-tMN samples can increase our understanding of tMN pathogenesis and demonstrate that tMNs arising post-ASCT are often driven by CH clones that re-engraft after escaping melphalan exposure. This mode of expansion suggests that a permissive, immunosuppressed, post-transplant environment might play a more important role than chemotherapy-induced mutagenesis in tMN pathogenesis. [Formula presented] Disclosures: Diamond: Sanofi: Honoraria; Medscape: Honoraria. Watts: Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding. Kazandjian: Arcellx: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bradley: AbbVie: Consultancy, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bolli: Amgen: Honoraria; Takeda: Honoraria; Janssen: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria. Papaemmanuil: Isabl Technologies: Divested equity in a private or publicly-traded company in the past 24 months; Kyowa Hakko Kirin Pharma: Consultancy. Scordo: Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; i3 Health: Other: Speaker; Omeros Corporation: Consultancy; Angiocrine Bioscience: Consultancy, Research Funding; McKinsey & Company: Consultancy. Lahoud: MorphoSys: Membership on an entity's Board of Directors or advisory committees. Stein: Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Genentech: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Syndax Pharmaceuticals: Consultancy; PinotBio: Consultancy; Daiichi Sankyo: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy. Sauter: Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Celgene: Consultancy, Research Funding; Genmab: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Hassoun: Celgene, Takeda, Janssen: Research Funding. Mailankody: Bristol Myers Squibb/Juno: Research Funding; Physician Education Resource: Honoraria; Plexus Communications: Honoraria; Takeda Oncology: Research Funding; Jansen Oncology: Research Funding; Fate Therapeutics: Research Funding; Allogene Therapeutics: Research Funding; Legend Biotech: Consultancy; Evicore: Consultancy. Korde: Medimmune: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Hultcrantz: Daiichi Sankyo: Research Funding; Intellisphere LLC: Consultancy; Curio Science LLC: Consultancy; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding. Shah: Bristol Myers Squibb: Research Funding; Janssen: Research Funding. Shah: Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Park: Servier: Consultancy; Affyimmune: Consultancy; Autolus: Consultancy; Minerva: Consultancy; PrecisionBio: Consultancy; BMS: Consultancy; Novartis: Consultancy; Kura Oncology: Consultancy; Curocel: Consultancy; Artiva: Consultancy; Innate Pharma: Consultancy; Intellia: Consultancy; Amgen: Consultancy; Kite Pharma: Consultancy. Landau: Genzyme: Honoraria; Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Sekeres: BMS: Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Ho: Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees. Roshal: Celgene: Other: Provision of services; Auron Therapeutics: Other: Ownership / Equity interests; Provision of services; Physicians' Education Resource: Other: Provision of services. Lesokhin: pfizer: Consultancy, Research Funding; Janssen: Honoraria, Research Funding; Iteos: Consultancy; Serametrix, Inc: Patents & Royalties; Genetech: Research Funding; Trillium Therapeutics: Consultancy; bristol myers squibb: Research Funding; Behringer Ingelheim: Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Landgren: Janssen: Other: IDMC; Janssen: Research Funding; Amgen: Honoraria; Celgene: Research Funding; Janssen: Honoraria; Amgen: Research Funding; Takeda: Other: IDMC; GSK: Honoraria. Maura: OncLive: Honoraria; Medscape: Consultancy, Honoraria.
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Despite recent therapeutic advances in the management of non-Hodgkin lymphoma (NHL), up to 50% of patients with diffuse large B-cell lymphoma (DLBCL) relapse after first line therapy, and for DLBCL patients who relapse within 12 months after subsequent stem cell transplant (SCT), the median overall survival (OS) is 6.3 months. Recently, chimeric antigen receptor (CAR) T-cell therapy has shown remarkable activity in relapsed DLBCL with complete response (CR) rate of 40% and 54% for the two of the FDA-approved CAR T-cell products, tisagenlecleucel and axicabtagene ciloleucel, respectively. However, at a median follow-up of 18 months, only 36% of patients treated with tisagenlecleucel remained in CR; with longer follow-up for axicabtagene ciloleucel the median progression free survival (PFS) was 5.9 months. Immune escape and immune evasion are primary mechanisms of CAR-T resistance; clearly improvements are needed to increase response rate and cure. While CRISPR-based loss-of-function screens have shown promise for high-throughput identification of genes that modulate T-cell response, these methods have been limited thus far to negative regulators of T-cell functions, and raise safety concerns due to the permanent nature of genome modification. Here we identify positive T-cell regulators via overexpression of ~12,000 barcoded human open reading frames (ORFs). Using this genome-scale ORF screen, we found modulator genes which increased primary human CD4+ and CD8+ T-cell proliferation, including activation markers like CD25 and CD40L, and secretion of key cytokines like interleukin-2 and interferon-gamma. In addition, we developed a single-cell genomics method (OverCITE-seq) for high-throughput quantification of the transcriptome and surface proteome in ORF-engineered T-cells. The top-ranked ORF, lymphotoxin beta receptor (LTBR), is typically expressed in a subset of myeloid cells but absent in lymphocytes. When expressed in T-cells, LTBR induces a profound transcriptional remodelling, resulting in increased resistance to exhaustion and activation-induced apoptosis, as well as upregulation of a plethora of proinflammatory cytokines, co-stimulatory molecules and antigen presentation machinery. In order to investigate the mechanism of action of LTBR, we developed an epistasis assay which allows for simultaneous gene knockout and LTBR overexpression in primary T cells. Thus, LTBR appears to induce both canonical and non-canonical NFkB pathways - but the phenotype observed in T cells is dependent only on the former. Finally, we co-expressed several top-ranked genes, including LTBR, with FDA approved CD19-targeting CARs utilizing either 4-1BB or CD28 co-stimulatory domains. In line with previous results, co-expression of top-ranked ORFs increased proinflammatory cytokine secretion and cytotoxicity against CD19+ positive cancer cell lines. This functional improvement was also observed when top-ranked ORFs and CARs were delivered to T cells isolated from DLBCL patients as shown in Figure 1. Our results provide several strategies for improving next generation CAR T-cell therapies via induction of new synthetic cell programs which may optimize immune activation and enhance the efficacy of these important therapies, a high priority for patients with relapsed and refractory DLBCL and other lymphomas. [Formula presented] Disclosures: Mimitou: Immunai: Current Employment. Smibert: Immunai: Current Employment. Diefenbach: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; IMab: Research Funding; Gilead: Current equity holder in publicly-traded company; Celgene: Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; MEI: Consultancy, Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; Incyte: Research Funding; Trillium: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Sanjana: Qiagen: Consultancy; Vertex: Consultancy.
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Coronavirus disease 2019 (COVID-19) was first identified at the end of 2019 as a cluster of pneumonia cases in Wuhan, China. By February 2020, this virus quickly spread, becoming a global pandemic. The spectrum of symptomatic infection severity can range from mild, severe, and critical disease. Many correlated comorbidities were established, including smoking, socioeconomic background, gender (male prevalence), hypertension, obesity, cardiovascular disease, chronic lung disease, diabetes mellitus, cancer, and chronic kidney disease. In an extensive literature search, post-COVID-19 necrotizing Staphylococcus aureus pneumonia with pneumothorax has not been recorded. We present a case about a 62-year-old male who presented with symptoms of COVID-19 with many underlying comorbidities, including hypertension and hyperlipidemia. He was on ventilatory support during his first week in the hospital and then received supplemental oxygenation as he recovered from his COVID-19 pneumonia. Nearly a month and a half after his initial presentation, he quickly decompensated and was started on supplemental oxygen and the necessary treatments. It was then, with the aid of lab work and imaging, that we determined that he had developed necrotizing Staphylococcus aureus pneumonia with pneumothorax. He was adequately treated, and once he was stable, he was discharged home and was told to continue his therapy.

BACKGROUND:Lack of training is currently the most common barrier to implementation of point-of-care ultrasound (POCUS) use in clinical practice, and in-person POCUS continuing medical education (CME) courses have been paramount in improving this training gap. Due to travel restrictions and physical distancing requirements during the COVID-19 pandemic, most in-person POCUS training courses were cancelled. Though tele-ultrasound technology has existed for several years, use of tele-ultrasound technology to deliver hands-on training during a POCUS CME course has not been previously described. METHODS:We conducted a retrospective observational study comparing educational outcomes, course evaluations, and learner and faculty feedback from in-person versus tele-ultrasound POCUS courses. The same POCUS educational curriculum was delivered to learners by the two course formats. Data from the most recent pre-pandemic in-person course were compared to tele-ultrasound courses during the COVID-19 pandemic. RESULTS:Pre- and post-course knowledge test scores of learners from the in-person (n = 88) and tele-ultrasound course (n = 52) were compared. Though mean pre-course knowledge test scores were higher among learners of the tele-ultrasound versus in-person course (78% vs. 71%; p = 0.001), there was no significant difference in the post-course test scores between learners of the two course formats (89% vs. 87%; p = 0.069). Both learners and faculty rated the tele-ultrasound course highly (4.6-5.0 on a 5-point scale) for effectiveness of virtual lectures, tele-ultrasound hands-on scanning sessions, and course administration. Faculty generally expressed less satisfaction with their ability to engage with learners, troubleshoot image acquisition, and provide feedback during the tele-ultrasound course but felt learners completed the tele-ultrasound course with a better basic POCUS skillset. CONCLUSIONS:Compared to a traditional in-person course, tele-ultrasound POCUS CME courses appeared to be as effective for improving POCUS knowledge post-course and fulfilling learning objectives. Our findings can serve as a roadmap for educators seeking guidance on development of a tele-ultrasound POCUS training course whose demand will likely persist beyond the COVID-19 pandemic.

Objective/UNASSIGNED:The widespread deployment of electronic health records (EHRs) has introduced new sources of error and inefficiencies to the process of ordering medications in the hospital setting. Existing work identifies orders that require pharmacy intervention by comparing them to a patient's medical records. In this work, we develop a machine learning model for identifying medication orders requiring intervention using only provider behavior and other contextual features that may reflect these new sources of inefficiencies. Materials and Methods/UNASSIGNED:Data on providers' actions in the EHR system and pharmacy orders were collected over a 2-week period in a major metropolitan hospital system. A classification model was then built to identify orders requiring pharmacist intervention. We tune the model to the context in which it would be deployed and evaluate global and local feature importance. Results/UNASSIGNED:The resultant model had an area under the receiver-operator characteristic curve of 0.91 and an area under the precision-recall curve of 0.44. Conclusions/UNASSIGNED:Providers' actions can serve as useful predictors in identifying medication orders that require pharmacy intervention. Careful model tuning for the clinical context in which the model is deployed can help to create an effective tool for improving health outcomes without using sensitive patient data.

Background: Forensic odontology, a branch of dentistry includes identification of individuals in various crime scenes, natural calamities, and mass disasters. The identification is possible because every individual body is unique and so is our tongue due to its morphological variations. The primary objective of the study was to assess the morphological features of the tongue and its use in sex determination.
Method(s): The study included a sample size of 100 individuals (50 males and 50 females) in the age range of 20-50 years old. Photographs were taken of front and side view of the tongue; visual inspection was done and lastly impressions of the tongue were made with help of alginate and then poured with the help of dental stone. IBM SPSS statistics 20.0 (IBM Corporation, Armonk, NY, USA) was used for the analyses of the data. Microsoft word and Excel were used to generate graphs, tables etc. Females presented with triangular shape, presence of shallow fissures more commonly and a sharp lingual apex of tongue. Males presented with rectangular shape, presence of deep fissure/absence of fissures more commonly and septate/ sharp lingual apex of the tongue.
Conclusion(s): Tongue exhibits various unique characteristics and can be used in sex determination.
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Introduction: Critically-ill patients with COVID-19 often require long-term enteral access due to prolonged ventilator support and slow recovery from neurologic injury. The outcomes of hospitalized patients with SARS-CoV-2 who received gastrostomy tubes (GTs) are unknown and limited guidance exists on how to safely triage GT placement in this population. The Enteral Access Team (EAT) is a multidisciplinary team led by an attending gastroenterologist (GI) hospitalist with advanced practice providers who collaborate with Palliative Care, Geriatrics, Speech-Language Pathology, and Nutrition to reduce unnecessary feeding tube placements at the end-of-life. The EAT reviews the appropriateness of GT placement and triages each case to the indicated procedural service. The EAT's multidisciplinary approach was applied for patients with COVID-19.
Method(s): We performed a retrospective study of 135 hospitalized patients with positive PCR tests for SARS-CoV-2 who received GTs between 3/2020 and 4/2021. The GTs were placed by 3 services (gastroenterology, interventional radiology and surgery) at 3 hospitals within 1 health system in New York. One of the hospitals employed the multidisciplinary EAT approach to its triage of GT placement. Outcomes were compared between the EAT site and control sites where GT placement was decided through direct consultation by the primary team with one of the procedural services.
Result(s): Demographics for the two groups, including overall numbers of COVID-19 admissions, can be seen in Table 1. At the EAT site (n =43) 5% of patients expired prior to discharge following GT placement compared with 25% at the control sites (P <0.05). Patients at the EAT site were older with a mean age of 70 years compared to the control sites with a mean age of 63 years (P=0.01). There was no significant difference in the percentage of COVID-19 patients who received GTs, length-ofstay, or time from gastrostomy to discharge or death. Multivariable analysis showed the odds of in hospital mortality were 10.1 times greater with the standard workflow than with the EAT workflow (OR 10.1, [95% CI: 1.7-60.6], P <0.05).
Conclusion(s): The EAT's novel multidisciplinary team-based approach helps to appropriately select hospitalized patients with SARs-CoV-2 for long-term enteral access leading to reduced in-hospital mortality following GT placement. Additionally, this approach may help to mediate the national shortage of GTs and reduce the risk of exposure to providers involved in GT placement

Introduction: The objective structured clinical examination (OSCE) is a common educational strategy to assess interpersonal skills and knowledge gaps, and we have previously shown its benefits in inflammatory bowel disease (IBD) education. As a result of the COVID-19 pandemic, there has been explosive growth in telehealth. Currently, we lack methods to teach and evaluate trainees' related skillset and no telehealth-specific milestones exist. We assessed the telehealth proficiency of gastroenterology (GI) fellows as part of an annual IBD OSCE over Zoom (Z-OSCE).
Method(s): Seven GI fellows from four programs participated in Z-OSCE featuring four clinical scenarios. We used previously validated OSCE checklists to assess the fellows' performance in IBDspecific cases. Telehealth communication skills were also assessed. One of the scenarios required the trainees to conduct a televisit focusing on preventative care for a Crohn's disease patient based on the ACG guideline. Checklists were scored on a 3-point Likert scale by the Standardized Patient (SP).
Result(s): The telehealth behavioral anchored checklist items included: maintaining proper computer etiquette, use of non-verbal communication and positioning to optimize the encounter, optimized technical aspects, and exhibiting comfort and confidence with the virtual platform. In these domains 5 or 6 (out of 7) fellows received 3 points. In contrast less than half of the fellows asked questions of the SP to make sure they understood or acknowledged emotion, and 3 out 7 fellows did not make appropriate eye contact. Despite high performance in the telehealth aspects of the encounter, the SP did not fully recommend fellows for their communication skills without reservations to friends/ family, with all fellows receiving 2 points.
Conclusion(s): Telehealth has quickly become a fixture of our profession, and merits educational opportunities and assessment to improve clinicians' competency, as it will likely outlast the COVID- 19 pandemic. To our knowledge, this is the first OSCE designed to assess telehealth performance in the delivery of IBD care. Z-OSCEs can play a unique role in simulating realistic telehealth visits and this pilot program helps us identify future educational needs. Assessment of fellows' performance during this virtual program can provide an opportunity for learning, growth and reflection as well as prepare trainees for future patient encounters

Introduction: The objective structured clinical examination (OSCE) has been shown to not only assess but also improve the performance of trainees. Our group has previously demonstrated the benefits of OSCEs to assess gastroenterology (GI) fellows. We have successfully assessed performance across numerous milestones. Typically, OSCEs are held in person, however the COVID-19 pandemic has precipitated the need for virtual learning. We accordingly transitioned to a virtual zoom OSCE (Z-OSCE) and evaluated trainees' perception of this program.
Method(s): Fourteen first- and second-year GI fellows from five programs across multiple states participated in a four-station virtual OSCE on Zoom. Afterwards, participants answered a survey to share their perspectives and provide feedback. Learners were asked to rate the usefulness of the virtual OSCE and compare it to other in-person and virtual educational modalities. These questions were rated on a 10-point Likert scale (Figure 1). Additionally, free-text responses regarding any aspect of the OSCE were evaluated for comments on the virtual format.
Result(s): In comparing the usefulness of the virtual OSCE to other in-person modalities, trainees rated it a mean of 7.15 (range 5-10), and 31% of respondents rated it a 9 or 10. Trainees rated the virtual OSCE compared to other virtual learning modalities a mean of 8.15 (range 5-10), and 43% rated it 9 or 10. When asked whether they would recommend this OSCE as a training tool, the trainees gave a mean recommendation of 7.77 (range 5-10), and 38% gave a 9 or 10. General feedback regarding the nature of the OSCE noted the virtual format worked well, orientation to the format was important and could be improved by providing it in an email beforehand.
Conclusion(s): Virtual learning has been necessary during the COVID-19 pandemic, and it is crucial to evaluate the value of the novel Z-OSCE. Participants found the virtual OSCE may be more useful than in-person learning modalities and it compared favorably to other virtual learning modalities. One benefit of this modality was the easier inclusion of fellows from geographically disparate areas negating the need to travel for this program, a benefit given lack of universal access to simulation using standardized patients. To improve future exams, orientation prior to the day of the OSCE may improve trainees' experiences.

In 2021, Delta has become the predominant SARS-CoV-2 variant worldwide. While vaccines effectively prevent COVID-19 hospitalization and death, vaccine breakthrough infections increasingly occur. The precise role of clinical and genomic determinants in Delta infections is not known, and whether they contribute to increased rates of breakthrough infections compared to unvaccinated controls. Here, we show a steep and near complete replacement of circulating variants with Delta between May and August 2021 in metropolitan New York. We observed an increase of the Delta sublineage AY.25, its spike mutation S112L, and nsp12 mutation F192V in breakthroughs. Delta infections were associated with younger age and lower hospitalization rates than Alpha. Delta breakthroughs increased significantly with time since vaccination, and, after adjusting for confounders, they rose at similar rates as in unvaccinated individuals. Our data indicate a limited impact of vaccine escape in favor of Delta's increased epidemic growth in times of waning vaccine protection.