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1. Overview of the First Shared Task on Clinical Text Generation: RRG24 and 'Discharge Me!'

Author

Xu, Justin, Chen, Zhihong, Johnston, Andrew, Blankemeier, Louis, Varma, Maya, Hom, Jason, Collins, William J., Modi, Ankit, Lloyd, Robert, Hopkins, Benjamin, Langlotz, Curtis, and Delbrouck, Jean-Benoit

Subjects
Computer Science - Computation and Language
Abstract

Recent developments in natural language generation have tremendous implications for healthcare. For instance, state-of-the-art systems could automate the generation of sections in clinical reports to alleviate physician workload and streamline hospital documentation. To explore these applications, we present a shared task consisting of two subtasks: (1) Radiology Report Generation (RRG24) and (2) Discharge Summary Generation ("Discharge Me!"). RRG24 involves generating the 'Findings' and 'Impression' sections of radiology reports given chest X-rays. "Discharge Me!" involves generating the 'Brief Hospital Course' and 'Discharge Instructions' sections of discharge summaries for patients admitted through the emergency department. "Discharge Me!" submissions were subsequently reviewed by a team of clinicians. Both tasks emphasize the goal of reducing clinician burnout and repetitive workloads by generating documentation. We received 201 submissions from across 8 teams for RRG24, and 211 submissions from across 16 teams for "Discharge Me!"., Comment: ACL Proceedings. BioNLP workshop

Published
2024
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6. Author Correction: A local tumor microenvironment acquired super-enhancer induces an oncogenic driver in colorectal carcinoma

Author

Zhou, Royce W., Xu, Jia, Martin, Tiphaine C., Zachem, Alexis L., He, John, Ozturk, Sait, Demircioglu, Deniz, Bansal, Ankita, Trotta, Andrew P., Giotti, Bruno, Gryder, Berkley, Shen, Yao, Wu, Xuewei, Carcamo, Saul, Bosch, Kaitlyn, Hopkins, Benjamin, Tsankov, Alexander, Steinhagen, Randolph, Jones, Drew R., Asara, John, Chipuk, Jerry E., Brody, Rachel, Itzkowitz, Steven, Chio, Iok In Christine, Hasson, Dan, Bernstein, Emily, and Parsons, Ramon E.

Published
2023
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9. Epinephrine inhibits PI3Kα via the Hippo kinases

Author

Lin, Ting-Yu, Ramsamooj, Shakti, Perrier, Tiffany, Liberatore, Katarina, Lantier, Louise, Vasan, Neil, Karukurichi, Kannan, Hwang, Seo-Kyoung, Kesicki, Edward A., Kastenhuber, Edward R., Wiederhold, Thorsten, Yaron, Tomer M., Huntsman, Emily M., Zhu, Mengmeng, Ma, Yilun, Paddock, Marcia N., Zhang, Guoan, Hopkins, Benjamin D., McGuinness, Owen, Schwartz, Robert E., Ersoy, Baran A., Cantley, Lewis C., Johnson, Jared L., and Goncalves, Marcus D.

Published
2023
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11. Inhibitors of cullin-RING E3 ubiquitin ligase 4 with antitumor potential

Author

Wu, Kenneth, Huynh, Khoi Q, Lu, Iris, Moustakim, Moses, Miao, Haibin, Yu, Clinton, Haeusgen, Matthew J, Hopkins, Benjamin D, Huang, Lan, Zheng, Ning, Sanchez, Roberto, DeVita, Robert J, and Pan, Zhen-Qiang

Subjects
Cancer, Animals, Antineoplastic Agents, Apoptosis, Biomarkers, Tumor, Cell Proliferation, Enzyme Inhibitors, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Myeloid, Acute, Mice, Mice, Inbred BALB C, Mice, Nude, Tumor Cells, Cultured, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination, Xenograft Model Antitumor Assays, protein degradation, E3 CRL4, cullin4, small-molecule inhibitors, tumor inhibition
Abstract

Cullin-RING (really intersting new gene) E3 ubiquitin ligases (CRLs) are the largest E3 family and direct numerous protein substrates for proteasomal degradation, thereby impacting a myriad of physiological and pathological processes including cancer. To date, there are no reported small-molecule inhibitors of the catalytic activity of CRLs. Here, we describe high-throughput screening and medicinal chemistry optimization efforts that led to the identification of two compounds, 33-11 and KH-4-43, which inhibit E3 CRL4 and exhibit antitumor potential. These compounds bind to CRL4's core catalytic complex, inhibit CRL4-mediated ubiquitination, and cause stabilization of CRL4's substrate CDT1 in cells. Treatment with 33-11 or KH-4-43 in a panel of 36 tumor cell lines revealed cytotoxicity. The antitumor activity was validated by the ability of the compounds to suppress the growth of human tumor xenografts in mice. Mechanistically, the compounds' cytotoxicity was linked to aberrant accumulation of CDT1 that is known to trigger apoptosis. Moreover, a subset of tumor cells was found to express cullin4 proteins at levels as much as 70-fold lower than those in other tumor lines. The low-cullin4-expressing tumor cells appeared to exhibit increased sensitivity to 33-11/KH-4-43, raising a provocative hypothesis for the role of low E3 abundance as a cancer vulnerability.

Published
2021

14. An atlas of substrate specificities for the human serine/threonine kinome

Author

Johnson, Jared L., Yaron, Tomer M., Huntsman, Emily M., Kerelsky, Alexander, Song, Junho, Regev, Amit, Lin, Ting-Yu, Liberatore, Katarina, Cizin, Daniel M., Cohen, Benjamin M., Vasan, Neil, Ma, Yilun, Krismer, Konstantin, Robles, Jaylissa Torres, van de Kooij, Bert, van Vlimmeren, Anne E., Andrée-Busch, Nicole, Käufer, Norbert F., Dorovkov, Maxim V., Ryazanov, Alexey G., Takagi, Yuichiro, Kastenhuber, Edward R., Goncalves, Marcus D., Hopkins, Benjamin D., Elemento, Olivier, Taatjes, Dylan J., Maucuer, Alexandre, Yamashita, Akio, Degterev, Alexei, Uduman, Mohamed, Lu, Jingyi, Landry, Sean D., Zhang, Bin, Cossentino, Ian, Linding, Rune, Blenis, John, Hornbeck, Peter V., Turk, Benjamin E., Yaffe, Michael B., and Cantley, Lewis C.

Published
2023
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15. CD44 alternative splicing is a sensor of intragenic DNA methylation in tumors

Author

Batsché, Eric, Mauger, Oriane, Kornobis, Etienne, Hopkins, Benjamin, Hanmer-Lloyd, Charlotte, and Muchardt, Christian

Subjects
Quantitative Biology - Genomics
Abstract

DNA methylation (meDNA) is a suspected modulator of alternative splicing, while splicing in turn is involved in tumour formations nearly as frequently as DNA mutations. Yet, the impact of meDNA on tumorigenesis via its effect on splicing has not been thoroughly explored. Here, we find that HCT116 colon carcinoma cells inactivated for the DNA methylases DNMT1 and DNMT3b undergo a partial epithelial to mesenchymal transition (EMT) associated with alternative splicing of the CD44 transmembrane receptor. The skipping of CD44 variant exons is in part explained by altered expression or splicing of splicing and chromatin factors. A direct effect of meDNA on alternative splicing was sustained by transient depletion of DNMT1 and the methyl-binding genes MBD1, MBD2, and MBD3. Yet, local changes in intragenic meDNA also altered recruitment of MBD1 protein and of the chromatin factor HP1$\gamma$ known to alter transcriptional pausing and alternative splicing decisions. We further tested if meDNA level has sufficiently strong direct impact on the outcome of alternative splicing to have a predictive value in the MCF10A model for breast cancer progression and in patients with acute lymphoblastic leukemia (B ALL). We found that a small number of differentially spliced genes mostly involved in splicing and signal transduction is systematically correlated with local meDNA. Altogether, our observations suggest that, although DNA methylation has multiple avenues to alternative splicing, its indirect effect may be also mediated through alternative splicing isoforms of these sensors of meDNA.

Published
2019

16. PI3K drives the de novo synthesis of coenzyme A from vitamin B5

Author

Dibble, Christian C., Barritt, Samuel A., Perry, Grace E., Lien, Evan C., Geck, Renee C., DuBois-Coyne, Sarah E., Bartee, David, Zengeya, Thomas T., Cohen, Emily B., Yuan, Min, Hopkins, Benjamin D., Meier, Jordan L., Clohessy, John G., Asara, John M., Cantley, Lewis C., and Toker, Alex

Published
2022
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17. Patient-Derived In Vitro and In Vivo Models of Cancer

Author

Claridge, Sally E., Cavallo, Julie-Ann, Hopkins, Benjamin D., Crusio, Wim E., Series Editor, Dong, Haidong, Series Editor, Radeke, Heinfried H., Series Editor, Rezaei, Nima, Series Editor, Steinlein, Ortrud, Series Editor, Xiao, Junjie, Series Editor, and Laganà, Alessandro, editor

Published
2022
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18. Gender-associated gene expression and chromatin accessibility of human urothelium

Author

Hopkins, Benjamin Charles, Knowles, Margaret, and Burns, Julie

Subjects
616.99
Abstract

Bladder cancer is 7th most common type of cancer in the UK, and presents up to 4 times more often men than in women, even when adjusting for environmental factors such as smoking and occupation. Bladder cancer also has the highest rates of mutations in chromatin modifier genes compared to any other cancer type. Despite this, studies regarding the epigenome of bladder and bladder cancer are lacking. This study considers the genome-wide transcriptional and chromatin accessibility landscape of healthy urothelium, and aims to identify gender-associated differences promoting the gender biases observed in bladder cancer. The study is the first to establish reliable protocols for chromatin immunoprecipitation (ChIP) of histone marks, and an assay for transposase-accessible chromatin followed by next generation sequencing (ATAC-seq) in normal urothelium, and the first to carry out transcriptional profiling on normal human urothelial cells (NHUC). Affymetrix HTA2.0 microarrays using three models of healthy urothelium [NHUC, immortalised NHUC (TERT-NHUC), and uncultured healthy urothelial cells (UHUC)], showed that although the majority of differentially expressed (DE) genes between genders are located on the sex chromosomes, five autosomal genes are upregulated in female NHUC that are associated with invasive bladder tumours, inflammation, and hypoxia. Furthermore, each gender showed different transcriptomic perturbations in response to common mutations in a cohort of 102 stage Ta grade 2 tumours, including in tumours with mutations in the X-linked histone demethylase KDM6A where females had DE of chromatin regulatory genes but males did not. ATAC-seq in two male and two female TERT-NHUC lines showed a genome-wide increase in chromatin accessibility in males, which could be seen by increased signal at individual loci and a greater number of overall peaks. Although this difference did not correlate with increased transcriptional activity, cell proliferation, or cell-cycle stage, it did correlate with a global increase of the activating histone marks H3K4me3 and H3K27ac, but not the heterochromatin marker H3K27me3. A reliable ChIP protocol with validated controls was developed for the histone marks H3K4me1, H3K4me3, H3K27ac, and H3K27me3, and provides a foundation for future epigenetic research in bladder cancer. The results of this study suggest that, although variation between individual donors is greater than between gender groups, future research in bladder should consider genders separately. For instance, therapeutic efforts aimed at targeting chromatin architecture, such as HDAC inhibition, may be more effective in females, particularly when they have acquired mutations in KDM6A.

Published
2019

23. A local tumor microenvironment acquired super-enhancer induces an oncogenic driver in colorectal carcinoma

Author

Zhou, Royce W., Xu, Jia, Martin, Tiphaine C., Zachem, Alexis L., He, John, Ozturk, Sait, Demircioglu, Deniz, Bansal, Ankita, Trotta, Andrew P., Giotti, Bruno, Gryder, Berkley, Shen, Yao, Wu, Xuewei, Carcamo, Saul, Bosch, Kaitlyn, Hopkins, Benjamin, Tsankov, Alexander, Steinhagen, Randolph, Jones, Drew R., Asara, John, Chipuk, Jerry E., Brody, Rachel, Itzkowitz, Steven, Chio, Iok In Christine, Hasson, Dan, Bernstein, Emily, and Parsons, Ramon E.

Published
2022
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24. The sexually selected ejaculate

Author

Hopkins, Benjamin, Wigby, Stuart, Pizzari, Tommaso, and Sepil, Irem

Subjects
613.9
Abstract

The ejaculate is composed of many different parts: proteins, lipids, and much else travels alongside sperm. With so many elements comes the problem of composition. Does the mix matter for male reproductive success? To what extent is the composition fixed? What happens when males lose control over the composition? It is with these questions that this thesis is principally concerned. I start by testing whether males alter ejaculate composition in relation to the intensity of male-male competition. I find that divergent allocation rules govern the transfer of sperm and seminal fluid proteins ('SFPs'). While the allocation of both responds to competition, only SFP allocation responds to its intensity. I further show that variation between SFPs in their responsiveness leads to differentially-composed seminal fluid. The resulting ejaculate compositions are each accompanied by distinct costs and benefits for male reproductive performance, some of which appear specific to seminal fluid. I next demonstrate that loss of BMP-regulated secretions from a seminal fluid-contributing cell-type ('secondary cells') imparts a syndrome of dysregulation on male and female reproductive performance. Within this, males lose the ability to reduce female receptivity to remating, but gain an advantage in defensive sperm competition. Through a systematic dissection of different episodes influencing sperm competition outcome, I find that loss of these secretions influences sperm entry into storage and potentially enhances their resistance to displacement. In the following two chapters I show that loss of BMP-regulated secondary cell secretions and the keystone SFP sex peptide affects seminal fluid transfer to females. In both cases, I find clear signals of between-SFP dependencies in the regulation of SFP transfer, which collectively highlight novel mechanisms of seminal fluid organisation. I argue that these organising mechanisms may be used to a male's advantage to exercise fine-scale, real-time control over the transfer of ready-made seminal fluid.

Published
2018

26. Pre-operative stereotactic radiosurgery and peri-operative dexamethasone for resectable brain metastases: a two-arm pilot study evaluating clinical outcomes and immunological correlates.

Author

Jansen, Caroline S., Pagadala, Meghana S., Cardenas, Maria A., Prabhu, Roshan S., Goyal, Subir, Zhou, Chengjing, Chappa, Prasanthi, Vo, BaoHan T., Ye, Chengyu, Hopkins, Benjamin, Zhong, Jim, Klie, Adam, Daniels, Taylor, Admassu, Maedot, Green, India, Pfister, Neil T., Neill, Stewart G., Switchenko, Jeffrey M., Prokhnevska, Nataliya, and Hoang, Kimberly B.

Subjects
ANTIGEN presenting cells, STEREOTACTIC radiosurgery, BRAIN metastasis, TREATMENT effectiveness, DISEASE relapse, T cells
Abstract

Enhancing the efficacy of immunotherapy in brain metastases (BrM) requires an improved understanding of the immune composition of BrM and how this is affected by radiation and dexamethasone. Our two-arm pilot study (NCT04895592) allocated 26 patients with BrM to either low (Arm A) or high (Arm B) dose peri-operative dexamethasone followed by pre-operative stereotactic radiosurgery (pSRS) and resection (n= 13 per arm). The primary endpoint, a safety analysis at 4 months, was met. The secondary clinical endpoints of overall survival, distant brain failure, leptomeningeal disease and local recurrence at 12-months were 66%, 37.3%, 6%, and 0% respectively and were not significantly different between arms (p= 0.7739, p= 0.3884, p= 0.3469). Immunological data from two large retrospective BrM datasets and confirmed by correlates from both arms of this pSRS prospective trial revealed that BrM CD8 T cells were composed of predominantly PD1+ TCF1+ stem-like and PD1+ TCF1-TIM3+ effector-like cells. Clustering of TCF1+ CD8 T cells with antigen presenting cells in immune niches was prognostic for local control, even without pSRS. Following pSRS, CD8 T cell and immune niche density were transiently reduced compared to untreated BrM, followed by a rebound 6+ days post pSRS with an increased frequency of TCF1- effector-like cells. In sum, pSRS is safe and therapeutically beneficial, and these data provide a framework for how pSRS may be leveraged to maximize intracranial CD8 T cell responses. Radiation and steroid dosing can affect the immune composition of brain metastasis (BM). The authors have designed a pilot study of pre-operative stereotactic radiosurgery with low or high dose of peri-operative dexamethasone for resectable brain metastases, here reporting clinical outcomes and characterization of intratumor TCF1+ CD8+ stem-like T cell immune niches in the brain. [ABSTRACT FROM AUTHOR]

Published
2024
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27. Navigating Choppy Water: Flexibility Ripple Effects in the COVID-19 Pandemic and the Future of Remote and Hybrid Working.

Author

Wheatley, Daniel, Broome, Matthew R., Dobbins, Tony, Hopkins, Benjamin, and Powell, Owen

Subjects
FLEXIBLE work arrangements, TELECOMMUTING, COVID-19 pandemic, WELL-being, FOCUS groups
Abstract

This article investigates the challenges of navigating the adoption of remote and hybrid working for large organizations with diverse functions. Focus groups with employees of the UK business of a multinational organization identify conceptual contributions to the sociology of work and employment and empirical findings in the context of the COVID-19 pandemic that inform future policy and practice. Location-based flexible working has a potential unintended 'ripple' effect wherein application of individual-level flexibility has wider-reaching consequences throughout the organization. Findings emphasize that organizations need to recognize and respond to new realities of location-based flexibility. Management must navigate potential 'ripples' in the development of flexible working policies and practice, shaped by various tensions, including an overarching autonomy–control paradox. This requires a coordinated approach centred on 'inclusive flexibility' and 'responsible autonomy' that involves moving away from one-size-fits-all strategies towards a tailored approach offering employees choice, agency and voice in decision-making, while accommodating different stakeholder needs. [ABSTRACT FROM AUTHOR]

Published
2024
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28. Medical News, Products & Information.

Author

Hopkins, Benjamin

Subjects
*IMMUNIZATION, *MEDICAL informatics, *CHILD psychopathology, *OCCUPATIONAL roles, *HEALTH, *INFLUENZA vaccines, *ELECTRONIC cigarettes, *INFORMATION resources, *INFLUENZA, *VACCINATION coverage, *ELECTIONS, *DRUG approval, *PHARMACEUTICAL industry, *MANUFACTURING industries, *POLIOMYELITIS vaccines, *MEASLES vaccines, *GENETIC testing, *CHILDREN
Abstract

The article discusses a concerning decline in childhood vaccination rates, which could lead to a resurgence of vaccine-preventable diseases such as measles and varicella. Topics discussed include the impact of the COVID-19 pandemic on vaccination coverage, the importance of early genetic testing for neurodevelopmental disorders, and recent advancements in treatments for conditions like Rett syndrome and metachromatic leukodystrophy.

Published
2024

29. Navigating toward Neonatology: Neonatal Bacterial Meningitis.

Author

Hopkins, Benjamin and Khashu, Minesh

Subjects
*BACTERIAL meningitis, *RISK assessment, *NEONATOLOGY, *DISEASE duration, *INFECTION control, *AMPICILLIN, *DISEASES, *GENTAMICIN, *STREPTOCOCCAL diseases, *EARLY diagnosis, *LENGTH of stay in hospitals, *DISEASE risk factors, *CHILDREN
Abstract

The article focuses on neonatal bacterial meningitis, a life-threatening infection with high mortality and morbidity rates in neonates. Topics discussed include the leading causes of meningitis, particularly Group B Streptococcus, risk factors associated with infection, and the critical importance of early diagnosis and treatment.

Published
2024

30. 421 GPT-4 Artificial Intelligence Model Outperforms ChatGPT, Medical Students, and Neurosurgery Residents on Neurosurgery Written Board-Like Questions

Author

Guerra, Gage, primary, Hofmann, Hayden, additional, Sobhani, Sina, additional, Hofmann, Grady, additional, Gomez, David, additional, Soroudi, Daniel, additional, Hopkins, Benjamin, additional, Dallas, Jonathan, additional, Pangal, Dhiraj J., additional, Cheok, Stephanie, additional, Nguyen, Vincent, additional, Mack, William J., additional, and Zada, Gabriel, additional

Published
2024
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37. The PI3K Pathway in Human Disease

Author

Fruman, David A, Chiu, Honyin, Hopkins, Benjamin D, Bagrodia, Shubha, Cantley, Lewis C, and Abraham, Robert T

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Animals, Cell Physiological Phenomena, Humans, Immune System, Neoplasms, Phosphatidylinositol 3-Kinases, Signal Transduction, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.

Published
2017

40. The Cardiac Corner: Vocal Cord Injury after Surgery.

Author

Wernovsky, Gil, Desai, Manan, and Hopkins, Benjamin

Subjects
VOCAL cord injuries, MYOCARDIAL infarction, RECURRENT laryngeal nerve, CARDIOPULMONARY bypass, ENDOTRACHEAL tubes, SURGICAL complications, VOCAL cord diseases, BRONCHOSCOPY, DISEASE relapse, CARDIAC surgery, PARALYSIS, CHILDREN
Abstract

The article examines the challenges and advancements in managing left recurrent laryngeal nerve injuries following neonatal cardiac surgery. Topics include the risk of recurrent laryngeal nerve damage during cardiac procedures, changes in diagnosing and managing left vocal cord paralysis, and the embryological connections between heart development and nerve supply.

Published
2024

41. Navigating toward Neonatology: Brachial Plexus Injury.

Author

Hopkins, Benjamin and Pramanik, Arun

Subjects
*PHYSICAL diagnosis, *NEONATOLOGY, *MEDICAL fellowships, *MEDICAL technology, *BIRTH injuries, *NURSING interventions, *PROFESSIONS, *SIMULATION methods in education, *MEDICAL students, *SPIRITUALITY, *ABILITY, *STUDENT attitudes, *BRACHIAL plexus, *HEALTH care teams, *TRAINING, *DISEASE risk factors, DEVELOPING countries
Abstract

The article offers information on navigating towards neonatology and discusses brachial plexus injuries. Topics include the Sunderland classification for brachial plexus injuries, risk factors for neonatal brachial plexus injury, and the presentation and symptoms of different subgroups of brachial plexus injuries.

Published
2024

47. Outpatient telemedicine in neurosurgery: 15,677 consecutive encounters in a comparative analysis of its effectiveness and impact on the surgical conversion rate

Author

Hopkins, Benjamin S., primary, Cloney, Michael B., additional, Texakalidis, Pavlos, additional, Karras, Constantine L., additional, El Tecle, Najib, additional, Swong, Kevin, additional, Ganju, Aruna, additional, Stricsek, Geoffrey, additional, Wolinksy, Jean-Paul, additional, Potts, Matthew B., additional, Jahromi, Babak S., additional, Koski, Tyler, additional, and Dahdaleh, Nader S., additional

Published
2023
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