Charles Chan

All Publications

• Medial and Lateral Posterior Tibial Slope in the Skeletally Immature: Variability Across Pediatric Ages Without a Consistent Trend. Journal of ISAKOS : joint disorders & orthopaedic sports medicine Okoro, S. I., Taylor, V., Troyer, S., Alayleh, A., Ellis, H. B., Yen, Y. M., Tompkins, M., Ganley, T., Chan, C., Shea, K. G. 2025: 100869

  Abstract

  Increased knee posterior tibial slope (PTS) angle elevates anterior cruciate ligament (ACL) strain and ACL injury risk. Adult biomechanical research indicates that decreasing the PTS may reduce ACL injuries. Younger patients have much higher risk of ACL injury than adults, with limited anatomic research on tibial slope. The purpose of this study is to evaluate the pediatric medial and lateral PTS in a larger cohort group than prior research.83 CT scans of the knee from children aged <2 to 11 were evaluated using OsiriX imaging software. The PTS was evaluated at two distinct points on sagittal CT sections: (1) At the medial and 2) lateral tibial plateaus, both aligned with the central part of the coronal view of the femoral condyles.The medial and lateral PTS demonstrated variability across ages <2 to 11, with mean values ranging from 3.6° ± 1.8° to 8.7° ± 5.3° for medial slopes and 5.1° ± 3.3° to 12.4° ± 3.6° for lateral slopes. The proportion of patients with at least one slope >10° peaked at age 8 (100%) and age 6 (67%). Simple linear regression revealed no statistically significant relationship between age and tibial slope for medial (coefficient of -0.07, p = 0.574, R2 = 0.004) or lateral slopes (coefficient of -0.08, p = 0.459, R2 = 0.007).Corrective osteotomy of increased PTS to lower the risk of ACL injury may be performed in high injury risk adult patients. However, such invasive procedures are not recommended for the skeletal immature because osteotomy in the growth plates in the proximal tibia could induce growth disturbance. In a unique skeletally immature patient with high risk of recurrent ACL injury, guided growth might be an option in high risk for lowering PTS in a controlled manner. As younger patients have some of the higher risks of primary and recurrent ACL injury, future research in this area may offer another approach to lower the risk of these injuries.Level III.

  View details for DOI 10.1016/j.jisako.2025.100869

  View details for PubMedID 40288755

• Osteopontin attenuates the foreign-body response to silicone implants. Nature biomedical engineering Griffin, M. F., Parker, J. B., Tevlin, R., Liang, N. E., Valencia, C., Morgan, A., Kuhnert, M., Downer, M., Meany, E. L., Guo, J. L., Henn, D., Navarro, R. S., Shefren, K., Nguyen, D., Gurtner, G. C., Heilshorn, S. C., Chan, C. K., Januszyk, M., Appel, E. A., Momeni, A., Wan, D. C., Longaker, M. T. 2025

  Abstract

  The inflammatory process resulting in the fibrotic encapsulation of implants has been well studied. However, how acellular dermal matrix (ADM) used in breast reconstruction elicits an attenuated foreign-body response (FBR) remains unclear. Here, by leveraging single-cell RNA-sequencing and proteomic data from pairs of fibrotically encapsulated specimens (bare silicone and silicone wrapped with ADM) collected from individuals undergoing breast reconstruction, we show that high levels of the extracellular-matrix protein osteopontin are associated with the use of ADM as a silicone wrapping. In mice with osteopontin knocked out, FBR attenuation by ADM-coated implants was abrogated. In wild-type mice, the sustained release of recombinant osteopontin from a hydrogel placed adjacent to a silicone implant attenuated the FBR in the absence of ADM. Our findings suggest strategies for the further minimization of the FBR.

  View details for DOI 10.1038/s41551-025-01361-4

  View details for PubMedID 40128393

  View details for PubMedCentralID 8081831

• Human skeletal development and regeneration are shaped by functional diversity of stem cells across skeletal sites. Cell stem cell Ambrosi, T. H., Taheri, S., Chen, K., Sinha, R., Wang, Y., Hunt, E. J., Goodnough, L. H., Murphy, M. P., Steininger, H. M., Hoover, M. Y., Felix, F., Weldon, K. C., Koepke, L. S., Sokol, J., Liu, D. D., Zhao, L., Conley, S. D., Lu, W. J., Morri, M., Neff, N. F., Van Rysselberghe, N. L., Wheeler, E. E., Wang, Y., Leach, J. K., Saiz, A., Wang, A., Yang, G. P., Goodman, S., Bishop, J. A., Gardner, M. J., Wan, D. C., Weissman, I. L., Longaker, M. T., Sahoo, D., Chan, C. K. 2025

  Abstract

  The skeleton is one of the most structurally and compositionally diverse organ systems in the human body, depending on unique cellular dynamisms. Here, we integrate prospective isolation of human skeletal stem cells (hSSCs; CD45-CD235a-TIE2-CD31-CD146-PDPN+CD73+CD164+) from ten skeletal sites with functional assays and single-cell RNA sequencing (scRNA-seq) analysis to identify chondrogenic, osteogenic, stromal, and fibrogenic subtypes of hSSCs during development and their linkage to skeletal phenotypes. We map the distinct composition of hSSC subtypes across multiple skeletal sites and demonstrate their unique in vivo clonal dynamics. We find that age-related changes in bone formation and regeneration disorders stem from a pathological fibroblastic shift in the hSSC pool. Utilizing a Boolean algorithm, we uncover gene regulatory networks that dictate differences in the ability of hSSCs to generate specific skeletal tissues. Importantly, hSSC lineage dynamics are pharmacologically malleable, providing a new strategy to treat aberrant hSSC diversity central to aging and skeletal maladies.

  View details for DOI 10.1016/j.stem.2025.02.013

  View details for PubMedID 40118065

• Elevated hematopoietic stem cell frequency in mouse alveolar bone marrow. Stem cell reports Niizuma, K., Morikawa, S., Gars, E., Xiang, J., Matsubara-Takahashi, T., Saito, R., Takematsu, E., Wang, Y., Xu, H., Wakimoto, A., Tan, T. K., Kubota, Y., Chan, C. K., Weissman, I. L., Nakagawa, T., Wilkinson, A. C., Nakauchi, H., Yamamoto, R. 2024: 102374

  Abstract

  Hematopoietic stem cells (HSCs) are crucial for maintaining hematopoietic homeostasis and are localized within distinct bone marrow (BM) niches. While BM niches are often considered similar across different skeletal sites, we discovered that the alveolar BM (al-BM) in the mandible harbors the highest frequency of immunophenotypic HSCs in nine different skeletal sites. Transplantation assays revealed significantly increased engraftment from al-BM compared to femur, tibia, or pelvis BM, likely due to a higher proportion of alveolar HSCs. Moreover, hematopoietic progenitor cells (c-Kit+ Sca-1+ Lin-) in al-BM exhibited increased quiescence and reduced apoptosis, indicating superior maintenance and survival characteristics. We also observed an enrichment of mesenchymal stromal cells and skeletal stem cells in al-BM, suggesting a more supportive microenvironment. These findings indicate that al-BM provides a unique microenvironment conducive to higher frequency of HSCs, offering new insights into site-specific hematopoiesis.

  View details for DOI 10.1016/j.stemcr.2024.11.004

  View details for PubMedID 39672154

• TGF-β Signaling Plays a Significant Role on the Skeletal Stem Cell and Tendon Enthesis Healing Diiorio, S., Titan, A., Davitt, M., Foster, D., Menon, S., Fox, P. M., Chan, C. K., Quarto, N., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2024: S402

  View details for Web of Science ID 001348680702290

• Wisp2 Promotes Aging of the Skeletal Stem Cell Lineage Chen, K., Weldon, K., Hunt, E., Morales, D., Chan, C. F., Ambrosi, T. OXFORD UNIV PRESS. 2024: 31

  View details for Web of Science ID 001361790800097

• Pre-Clinical Trail of Bone Morphogenetic Protein-2-Based Articular Cartilage Regenerative Therapy for Osteoarthritis Takematsu, E., Murphy, M., Wang, Y., Zhao, L., Longaker, M., Chan, C. F. OXFORD UNIV PRESS. 2024: 329

  View details for Web of Science ID 001361790802111

• Author Correction: Sexually dimorphic estrogen sensing in skeletal stem cells controls skeletal regeneration. Nature communications Andrew, T. W., Koepke, L. S., Wang, Y., Lopez, M., Steininger, H., Struck, D., Boyko, T., Ambrosi, T. H., Tong, X., Sun, Y., Gulati, G. S., Murphy, M. P., Marecic, O., Tevlin, R., Schallmoser, K., Strunk, D., Seita, J., Goodman, S. B., Yang, F., Longaker, M. T., Yang, G. P., Chan, C. K. 2024; 15 (1): 8030

  View details for DOI 10.1038/s41467-024-51829-1

  View details for PubMedID 39271692

• A maternal brain hormone that builds bone. Nature Babey, M. E., Krause, W. C., Chen, K., Herber, C. B., Torok, Z., Nikkanen, J., Rodriguez, R., Zhang, X., Castro-Navarro, F., Wang, Y., Wheeler, E. E., Villeda, S., Leach, J. K., Lane, N. E., Scheller, E. L., Chan, C. K., Ambrosi, T. H., Ingraham, H. A. 2024

  Abstract

  In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone loss1. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females. We began by showing that our previously reported female-specific, dense bone phenotype2 originates from a humoral factor that promotes bone mass and acts on skeletal stem cells to increase their frequency and osteochondrogenic potential. This circulatory factor was then identified as CCN3, a brain-derived hormone from ARCKISS1 neurons that is able to stimulate mouse and human skeletal stem cell activity, increase bone remodelling and accelerate fracture repair in young and old mice of both sexes. The role of CCN3 in normal female physiology was revealed after detecting a burst of CCN3 expression in ARCKISS1 neurons coincident with lactation. After reducing CCN3 in ARCKISS1 neurons, lactating mothers lost bone and failed to sustain their progeny when challenged with a low-calcium diet. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals.

  View details for DOI 10.1038/s41586-024-07634-3

  View details for PubMedID 38987585

  View details for PubMedCentralID 6329772

• Ultrasensitive and multiplexed tracking of single cells using whole-body PET/CT. Science advances Nguyen, H. T., Das, N., Ricks, M., Zhong, X., Takematsu, E., Wang, Y., Ruvalcaba, C., Mehadji, B., Roncali, E., Chan, C. K., Pratx, G. 2024; 10 (24): eadk5747

  Abstract

  In vivo molecular imaging tools are crucially important for elucidating how cells move through complex biological systems; however, achieving single-cell sensitivity over the entire body remains challenging. Here, we report a highly sensitive and multiplexed approach for tracking upward of 20 single cells simultaneously in the same subject using positron emission tomography (PET). The method relies on a statistical tracking algorithm (PEPT-EM) to achieve a sensitivity of 4 becquerel per cell and a streamlined workflow to reliably label single cells with over 50 becquerel per cell of 18F-fluorodeoxyglucose (FDG). To demonstrate the potential of the method, we tracked the fate of more than 70 melanoma cells after intracardiac injection and found they primarily arrested in the small capillaries of the pulmonary, musculoskeletal, and digestive organ systems. This study bolsters the evolving potential of PET in offering unmatched insights into the earliest phases of cell trafficking in physiological and pathological processes and in cell-based therapies.

  View details for DOI 10.1126/sciadv.adk5747

  View details for PubMedID 38875333

  View details for PubMedCentralID PMC11177933

• MRI Features That Contribute to Decision-Making for Treatment of Capitellar OCD Lesions: An Expert Consensus Using the Delphi Method. Orthopaedic journal of sports medicine Kostyun, R. O., Nguyen, J. C., Chhabra, B., Todd R Lawrence, J., Polousky, J. D., Saper, M., Uquillas, C., Nissen, C. W., Members of the ROCKET Group, Kostyun, R. O., Albright, J., Bae, D., Bohn, D., Chan, C., Crepeau, A., Edmonds, E., Fabricant, P., Ganley, T., Little, K., Lee Pace, J., Pacicca, D., Pennock, A., Saluan, P., Shea, K., Wall, E., Wilson, P., Nissen, C. W. 2024; 12 (6): 23259671241252813

  Abstract

  Background: Most healthcare providers utilize magnetic resonance imaging (MRI) to assist in diagnosing and treating osteochondritis dissecans (OCD) of the capitellum. However, consensus on imaging features that portend clinically relevant information in the care of these lesions has not been determined.Purpose: To conduct a survey on the MRI features of a capitellar OCD that are salient for clinical decision-making using a classic Delphi protocol.Study Design: A consensus statement.Methods: Invitations to participate were sent to 33 healthcare providers identified as capitellar OCD experts. A classic 3-round survey method was used to gather agreement and consensus on the level of importance for clinical decision-making on 33 MRI features. A concise list of features that guide decision-making on the stability of an OCD lesion and the ability of an OCD lesion to heal with nonoperative care was also identified. Agreement and consensus were determined a priori as ≥66%.Results: Of the 33 identified experts, 20 agreed to participate, and 17 (52%) completed all 3 rounds. Of the 33 MRI features evaluated, 17 reached agreement as important for clinical decision-making by the experts. Consensus was reached for a concise list of MRI features that were significant to decision-making (94%), suggestive of a stable lesion (100%), had the potential to heal with nonoperative treatment (94%), were suggestive of an unstable lesion (100%), and had low potential to heal with nonoperative treatment (88%).Conclusion: This 3-round Delphi process produced consensus on clinically relevant MRI features that contribute to clinical decision-making for capitellar OCD. The results of this study will be used as the basis for an interrater reliability assessment of the identified salient features, creating the foundation for developing a reliable MRI assessment tool rooted in clinical experiences. The development of a standardized assessment of capitellar OCD is intended to improve clinical practice and patient outcomes.

  View details for DOI 10.1177/23259671241252813

  View details for PubMedID 38845610

• Modeling the effects of treatment resistance and anticholinergic burden on cognitive function domains in patients with schizophrenia. Psychiatry research Chan, S. K., Pang, T. S., Tsui, H. K., Suen, Y. N., Yan, W. C., Tsui, C. F., Poon, L. T., Chan, C. W., Lo, A., Cheung, K. M., Hui, C. L., Chang, W. C., Lee, E. H., Chen, E. Y., Honer, W. G. 2024; 337: 115985

  Abstract

  The contribution of anticholinergic burden to cognitive function in patients with treatment resistant schizophrenia (TRS) is uncertain. This case-control study aims to comprehensively examine the association between treatment resistance and cognitive functions and the contribution of anticholinergic burden in patients with schizophrenia. Anticholinergic burden of all patients was calculated using the Anticholinergic Cognitive Burden scale. Exploratory Factor Analysis of 11 cognitive assessments identified four cognitive domains: verbal memory, attention and general cognitive functions, visual memory and processing speed, and executive function. Two structural equation models (SEM) examined the relationship of TRS and these cognitive functions with, and without considering anticholinergic burden. A total of 288 participants were included (TRS N=111, non-TRS N=177). Patients with TRS performed poorer than the non-TRS group only in the executive function domain. Anticholinergic burden contributed significantly to the attention and general cognitive functions, visual memory and processing speed, and executive function. The impact of TRS on executive function was no longer significant after adding anticholinergic burden to the SEM. Results suggested that anticholinergic burden contributes to a wide range of cognitive function impairment in patients with schizophrenia and is likely to be part of the apparent differences of cognitive function between TRS and non-TRS.

  View details for DOI 10.1016/j.psychres.2024.115985

  View details for PubMedID 38820652

• New evidence for the epigenetic regulation of skeletal stem cells. Science bulletin Zhao, L., Xiao, J., Chan, C. K. 2024

  View details for DOI 10.1016/j.scib.2024.04.025

  View details for PubMedID 38664096

• An organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome. Nature communications Liu, S., Ezran, C., Wang, M. F., Li, Z., Awayan, K., Long, J. Z., De Vlaminck, I., Wang, S., Epelbaum, J., Kuo, C. S., Terrien, J., Krasnow, M. A., Ferrell, J. E. 2024; 15 (1): 2188

  Abstract

  Hormones mediate long-range cell communication and play vital roles in physiology, metabolism, and health. Traditionally, endocrinologists have focused on one hormone or organ system at a time. Yet, hormone signaling by its very nature connects cells of different organs and involves crosstalk of different hormones. Here, we leverage the organism-wide single cell transcriptional atlas of a non-human primate, the mouse lemur (Microcebus murinus), to systematically map source and target cells for 84 classes of hormones. This work uncovers previously-uncharacterized sites of hormone regulation, and shows that the hormonal signaling network is densely connected, decentralized, and rich in feedback loops. Evolutionary comparisons of hormonal genes and their expression patterns show that mouse lemur better models human hormonal signaling than mouse, at both the genomic and transcriptomic levels, and reveal primate-specific rewiring of hormone-producing/target cells. This work complements the scale and resolution of classical endocrine studies and sheds light on primate hormone regulation.

  View details for DOI 10.1038/s41467-024-46070-9

  View details for PubMedID 38467625

  View details for PubMedCentralID 1540572

• Use of Peripheral Nerve Blocks Is Not Associated With Decreased Postoperative Opioid Prescription After ACL Reconstruction in Adolescents ORTHOPEDICS Kaur, J., Pham, N., Cahan, E., Halvorsen, K., Langner, J. L., Bryson, X. M., Chan, C. M., Vorhies, J. 2024; 47 (2): 83-88

  Abstract

  The rate of anterior cruciate ligament (ACL) injuries and reconstruction in pediatric patients is increasing. Perioperative peripheral nerve blocks (PNBs) are widely used for pain management in this population. We used a multi-state administrative claims database to describe the effect of PNB after ACL reconstruction on postoperative opioid consumption. We identified patients 10 to 18 years old undergoing primary ACL reconstruction between 2014 and 2016 in an administrative claims database. Patients filling an outpatient perioperative prescription for opioids with at least 1 year of follow-up were included. We stratified patients based on PNB. Our primary outcome was opioid prescription patterns (in morphine milligram equivalents [MMEs]) and incidence of opioid represcription. Of the 4459 cases, 2432 (54.5%) of the patients were given a PNB during ACL reconstruction while 2027 (45.5%) were not. Patients with PNB were prescribed more MMEs per day (76.1±41.7 vs 62.7±35.7 MMEs, P<.001), more pills (63.6±53.1 vs 54.4±40.6 pills, P<.001), higher MMEs per pill (10.0±9.5 vs 8.3±5.0 MMEs, P<.001), and more total MMEs (460.6±259.4 vs 355.7±215.1 MMEs, P<.001) than patients without PNB. Adjusting for prescription patterns and demographic variables with logistic regression, PNBs were associated with a 60% increase in the odds of opioid represcription within 30 days and a 32% increase in the odds of opioid represcription within 90 days. We demonstrated an increase in postoperative opioid prescription rates with PNB after ACL reconstruction. [Orthopedics. 2024;47(2):83-88.].

  View details for DOI 10.3928/01477447-20230616-05

  View details for Web of Science ID 001190541800001

  View details for PubMedID 37341565

• Synthetic BMP-2 Analog for Specific Targeting of the Skeletal Stem Cell Niche Takematsu, E., Zhao, L., Chan, C. OXFORD UNIV PRESS. 2023: 236-237

  View details for Web of Science ID 001266167001160

• In Vivo Tracking of Human Fetal Skeletal Stem Cell Lineage Dynamics at the Single Cell Level Ambrosi, T., Sinha, R., Chan, C. OXFORD UNIV PRESS. 2023: 318

  View details for Web of Science ID 001266167001417

• In Vivo Tracking of Human Fetal Skeletal Stem Cell Lineage Dynamics at the Single Cell Level Ambrosi, T., Sinha, R., Chan, C. OXFORD UNIV PRESS. 2023: 42

  View details for Web of Science ID 001266167000129

• Glucocorticoid-induced Reduction in Osteogenesis and Angiogenesis is Coupled through Altered Skeletal Stem Cell Lineage Dynamics Ambrosi, T., Wang, Y., Murphy, M., Chan, C., Lane, N. OXFORD UNIV PRESS. 2023: 7

  View details for Web of Science ID 001266167000019

• Intravenous Vitamin C for Patients Hospitalized With COVID-19: Two Harmonized Randomized Clinical Trials. JAMA LOVIT-COVID Investigators, o. b., Adhikari, N. K., Hashmi, M., Tirupakuzhi Vijayaraghavan, B. K., Haniffa, R., Beane, A., Webb, S. A., Angus, D. C., Gordon, A. C., Cook, D. J., Guyatt, G. H., Berry, L. R., Lorenzi, E., Mouncey, P. R., Au, C., Pinto, R., Menard, J., Sprague, S., Masse, M., Huang, D. T., Heyland, D. K., Nichol, A. D., McArthur, C. J., de Man, A., Al-Beidh, F., Annane, D., Anstey, M., Arabi, Y. M., Battista, M., Berry, S., Bhimani, Z., Bonten, M. J., Bradbury, C. A., Brant, E. B., Brunkhorst, F. M., Burrell, A., Buxton, M., Cecconi, M., Cheng, A. C., Cohen, D., Cove, M. E., Day, A. G., Derde, L. P., Detry, M. A., Estcourt, L. J., Fagbodun, E. O., Fitzgerald, M., Goossens, H., Green, C., Higgins, A. M., Hills, T. E., Ichihara, N., Jayakumar, D., Kanji, S., Khoso, M. N., Lawler, P. R., Lewis, R. J., Litton, E., Marshall, J. C., McAuley, D. F., McGlothlin, A., McGuinness, S. P., McQuilten, Z. K., McVerry, B. J., Murthy, S., Parke, R. L., Parker, J. C., Reyes, L. F., Rowan, K. M., Saito, H., Salahuddin, N., Santos, M. S., Saunders, C. T., Seymour, C. W., Shankar-Hari, M., Tolppa, T., Trapani, T., Turgeon, A. F., Turner, A. M., Udy, A. A., van de Veerdonk, F. L., Zarychanski, R., Lamontagne, F., Florescu, S., Stanciu, D., Zaharia, M., Kosa, A., Codreanu, D., Fareed, K., Kidwai, A., Kaye, C., Coutts, A., MacKay, L., Summers, C., Polgarova, P., Farahi, N., Fox, E., Sapsford, D., Bongaerts, K., Featherstone, P., Ng, A., McWilliam, S., Hawcutt, D., Rad, L., O'Malley, L., Whitbread, J., Jones, D., Dore, R., Saunderson, P., Kelsall, O., Cowley, N., Wild, L., Thrush, J., Wood, H., Austin, K., Donnelly, A., Kelly, M., Smyth, N., O'Kane, S., McClintock, D., Warnock, M., Campbell, R., McCallion, E., Azaiz, A., Charron, C., Godement, M., Geri, G., Vieillard-Baron, A., Johnson, P., McKenna, S., Hanley, J., Currie, A., Allen, B., McGoldrick, C., McMaster, M., Mani, A., Mathew, M., Kandeepan, R., Vignesh, C., Ramakrishnan, N., James, A., Elvira, E., Pratheema, R., Babu, S., Ebenezer, R., Krishnamoorthy, S., Ranganathan, L., Ganesan, M., Shree, M., Piva, S., Foca, E., Rizzoni, D., Boari, G., Marchesi, M., Butler, M., Cowdrey, K., Mason, B., Woolett, M., Duffy, E., Chen, Y., Nakamuro, H., O'Connor, C., West, L., El-Khawas, K., Richardson, A., Hill, D., Commons, R., Abdelkharim, H., Saxena, M., Muteithia, M., Dobell-Brown, K., Jha, R., Kalogirou, M., Ellis, C., Krishnamurthy, V., O'Connor, A., Thurairatnam, S., Mukherjee, D., Kaliappan, A., Vertue, M., Nicholson, A., Riches, J., Maloney, G., Kittridge, L., Solesbury, A., Ramos, A., Collins, D., Brickell, K., Reid, L., Smyth, M., Breen, P., Spain, S., Curley, G., McEvoy, N., Geoghegan, P., Clarke, J., Silversides, J., McGuigan, P., Ward, K., O'Neill, A., Finn, S., Wright, C., Green, J., Collins, E., Major, E., McAuley, J., Carter, A., Smith, J., Boschert, C., Slieker, K., Ewalds, E., Sanders, A., Wittenberg, W., Geurts, H., Poojara, L., Sara, T., Nand, K., Reeve, B., Dechert, W., Phillips, B., Oritz-Ruiz de Gordoa, L., Campbell, M., Dos Santos, F., Hansen, D., Mullan, D., Affleck, J., Shaikh, A., Murray, A., Ramanan, M., Frakking, T., Pinnell, J., Robinson, M., Gledhill, L., Wood, T., Sanghavi, R., Bhonagiri, D., Ford, M., Parikh, H. G., Avard, B., Nourse, M., McDonald, B., Edmunds, N., Hoiting, O., Peters, M., Rengers, E., Bindels, M., Evers, M., Prinssen, A., Morgan, M., Cole, J., Hill, H., Davies, M., Williams, A., Thomas, E., Davies, R., Wise, M., Law, D., Grimm, P., Soukup, J., Wetzold, R., Lobel, M., Starke, L., Lellouche, F., Lizotte, P., Auvet, A., Ravry, C., Creange, V., Boivin, A., Barreau, A., Vandewoestyne, S., Declercq, P., Marchalot, A., Saladin, C., Gelinotte, S., Eraldi, J., Bourgerol, F., Beuzelin, M., Jean-Philippe, R., Pourcine, F., Monchi, M., Pradel, G., Hausermann, M., Boudineau, M., Nguyen-Valat, T., Guitton, C., Marnai, R., Leroyer, M., Landais, M., Darreau, C., Saint Martin, M., Tirot, P., Chudeau, N., Brasselet, A., Volkov, L., Callahan, J., Meunier, J., Douillard, T., Le Basnier, E., Veillard, M., Vivier, D., Luis, D., Mercier, R., Sagnier, A., Verrier, N., Caplin, C., Richecoeu, J., Combaux, D., Siami, S., Aparicio, C., Vautier, S., Jeblaoui, A., Lemaire-Brunel, D., D'Aragon, F., Berard, D., Grondin-Beaudoin, B., Leclair, M., Lesur, O., Mayette, M., Poulin, Y., Quiroz-Martinez, H., St-Arnaud, C., Carbonneau, E., Bolduc, B., Belisle, J., Bouchard, M., Cote, L., Martineau, J., Naisby, A., Robert-Petit, L., Thibault, M., Leblond, J., Plantefeve, G., Leparco, C., Contou, D., Fartoukh, M., Courtin, L., Labbe, V., Voiriot, G., Salhi, S., Chasse, M., Pierre, A., Belisle, S., Carrier, F. M., Charbonney, E., Girard, M., Guimond, J., Halwagi, A., Kolan, C., Robillard, N., Boumahni, D., Benettaib, F., Cantin, M., Coutu-Beaudry, K., Ghamraoui, A., Lamothe, F., Lebrasseur, M., Prie, C., Salame, M., Archambault, P., Cote, E., Beaudoin, R., Noel-Hunter, M., Boutin, M., Couture, L., Sement, A., Gachet, A., Hanisch, A., Haffiane, A., Boivin, A., Barreau, A., Guerineau, E., Poupblanc, S., Egreteau, P. Y., Lefevre, M., Bocher, S., Le Loup, G., Le Guen, L., Carn, V., Bertel, M., Antcliffe, D., Templeton, M., Rojo, R., Coghlan, P., Smee, J., Barker, G., Finn, A., KreSS, G., Hoff, U., Hinrichs, C., Nee, J., Mackay, E., Cort, J., Whileman, A., Spencer, T., Spittle, N., Beavis, S., Padmakumar, A., Dale, K., Hawes, J., Moakes, E., Gascoyne, R., Pritchard, K., Stevenson, L., Cooke, J., Nemeth-Roszpopa, K., Adhikari, S., Gauli, B., Kunwar, P., Muller, G., Nay, M., Kamel, T., Benzekri, D., Jacquier, S., Runge, I., Mathonnet, A., Barbier, F., Bretagnol, A., Carter, J., Van Der Heyden, K., Mehrtens, J., Morris, A., Morgan, S., Burke, T., Mercier, E., Chartier, D., Salmon, C., Dequin, P., Garot, D., Quenot, J. 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N., Taqdees, H., Frey, C., Scano, R., McKee, M., Murphy, P., Thomas, M., Worner, R., Faulkner, B., Gendall, E., Hayes, K., Blakemore, H., Borislavova, B., Smith, K., Stephens, D., Deshpande, K., van Haren, F., Konecny, P., Inskip, D., Tung, R., Hayes, L., Murphy, L., Neill, A., Reidy, B., O'Dwyer, M., Ryan, D., Ainscough, K., Hamilton-Davies, C., Chan, C., Mfuko, C., Abbass, H., Mandadapu, V., Leaver, S., Patel, K., Farnell-Ward, S., Saluzzio, R., Rawlins, S., Sicat, C., Fernandes, E., De Keulenaer, B., Ferrier, J., Fysh, E., Davda, A., Al-Hazzani, W., Ligori, T., Soth, M., Clarke, F., Matic, K., Copland, M., Hoad, N., Sawyer, A., Banach, D., Fernandez de Pinedo Artaraz, Z., Cabreros, L., Latham, V., Wong, J., Gurung, A., Mohammed, A., Jepson, E., Kruisselbrink, R., Brochard, L., Burns, K., Sandhu, G., Khalid, I., White, I., Croft, M., Holland, N., Pereira, R., Frost, V., Wells, K., Chin, T., Aquino, M., Nair, P., Buscher, H., Reynolds, C., Campion, A., Hall, A., Santamaria, J., Haydon, T., Homes, J., Zaki, A., Johnson, D., Garrard, H., Juhaz, V., Brown, L., Pemberton, A., Roy, A., Rostron, A., Woods, L., Cornell, S., Amaral, A., Angriman, F., Cuthbertson, B., Fowler, R., Piquette, D., Scales, D., Tillman, B., Marinoff, N., Kaur, N., Adeel, Z., Kamra, M., Khan, H., Murali, D., Ruxandra, P., Sabananthan, T., Sugumaran, T., Garrett, P., Murray, L., Brailsford, J., Pillai, S., Harford, R., Ivatt, H., Evans, D., Richards, S., Roberts, E., Bowen, J., Ainsworth, J., Williams, M., Kuitunen, A., Karlsson, S., Vahtera, A., Kiiski, H., Ristimaki, S., Albrett, J., Jackson, C., Kirkham, S., Tamme, K., Reinhard, V., Ellervee, A., Poldots, L., Rennit, P., Svitskar, N., Chen, J., Miller, A., McCracken, P., Young, M., Board, J., Martin, E., Kasipandian, V., Patel, A., Allibone, S., Mary-Genetu, R., English, S., Seely, A., McIntyre, L., Watpool, I., Porteous, R., Miezitis, S., Haines, J., Brady, K., Vale, C., Shekar, K., Lavana, J., Parmar, D., Peake, S., Williams, P., Kurenda, C., Wijewardena, G., Hormis, A., Walker, R., Collier, D., Kimpton, S., Oakley, S., Graham, C., Maynard, V., Bhagani, S., De Neef, M., Garcia, S., Maharajh, A., Nandani, A., Dobson, J., Fernando, G., Eastgate, C., Gomez, K., Abdi, Z., Pakou, G., Tatham, K., Jhanji, S., Black, E., Dela Rosa, A., Howle, R., Baikady, R., Tully, R., Drummond, A., Dearden, J., Philbin, J., Munt, S., Gopal, S., Pooni, J., Ganguly, S., Smallwood, A., Metherell, S., Naeem, A., Fagan, L., Turner, E., Mariappa, V., Smith, J., Foulds, A., Revill, A., Bhattarai, B., Maharjan, S., Maharjan, R., Phuyal, A., Shrestha, N., Meijer, K., Postma, D., Thedinga, K., de Jonge, E., Wigbers, J., Del Prado, M., Cremer, O., Mulier, J., Rademaker, E., Peters, A., Romberg, B., Leavis, H., Schutgens, R., Troeman, D., van Opdorp, M., Besten, H., Brakke, K., Barber, R., Hilldrith, A., Sloan, A., Okubanjo, M., Francis, O., Barker, S., Butler, S., Hewitt, C., Lee, K., Tavares, S., Kluge, S., Nierhaus, A., Jarczak, D., Roedl, K., Kochanek, M., RueSS-Paterno, G., Mc-Kenzie, J., Eichenauer, D., Shimabukuro-Vornhagen, A., Gopel, S., Eisenbeis, S., Rissen, R., Conzelmann, N., Wilcox, E., Del Sorbo, L., Abdelhady, H., Romagnuolo, T., Simpson, S., Maiden, M., Horton, M., Trickey, J., Brohi, F., Jagannathan, V., Clark, M., Purvis, S., Wetherill, B., Dushianthan, A., Cusack, R., de Courcy-Golder, K., Salmon, K., Burnish, R., Smith, S., Jackson, S., Ruiz, W., Duke, Z., Johns, M., Male, M., Gladas, K., Virdee, S., Swabe, J., Tomlinson, H., Baker, A., Carter, M., Roberts, B., Greene, E., Rohde, G., Grunewaldt, A., Bojunga, J., Petros, S., Pasieka, B., Kunz, K., Laudi, S., Seidel, A., Ullmann, H., Schlegel, C., Weismann, D., Frey, A., Drayss, M., Goebeler, M. E., Flor, T., Fragner, G., Wahl, N., Totzke, J., Sayehli, C., Bewley, J., Sweet, K., Grimmer, L., Johnson, R., Wyatt, R., Morgan, K., Varghese, S., Willis, J., Stratton, E., Kyle, L., Putensen, D., Drury, K., Skorko, A., Dell, A., Wright, K., Webster, D., Corcoran, K., Kolovou, A., Efford, G., McCullagh, L., Bremmer, P., Ward, G., Bassford, C., Sligl, W., Baig, N., Rewa, O., Bagshaw, S., Markota, A., Kalamar, Z., Svensek, F., Marinsek, M., Fluher, J., Jerenec, K., Kit, B., Zivko, I., Linstrum, K., Basile, K., Stavor, D., Burbee, D., McNamara, A., Wunderley, R., Bensen, N., Richardson, A., Adams, P., Vita, T., Buhay, M., Scholl, D., Gilliam, M., Winters, J., Doherty, K., Berryman, E., Ghaffari, M., Marroquin, O., Quinn, K., Garrard, W., Kalchthaler, K., Beard, G., Skrtich, A., Bagavathy, K., Drapola, D., Wells, A., Bryan-Morris, K., Arnold, J., Reynolds, B., Hussain, M., Dunsavage, J., Saiyed, S., Hernandez, E., Goldman, J., Brown, C., Comp, S., Raczek, J., Morris, J., Vargas, J. J., Weiss, D., Hensley, J., Kochert, E., Wnuk, C., Nemeth, C., Mowery, B., Hutchinson, C., Winters, L., McAdams, D., Walker, G., Minnier, T., Wisniewski, M., Mayak, K., McCreary, E., Martin, E., Bariola, R., Viehman, A., Daley, J., Lopus, A., Schmidhofer, M., Ambrosino, R., Keen, S., Toffalo, S., Stambaugh, M., Trimmer, K., Perri, R., Casali, S., Medva, R., Massar, B., Beyerl, A., Burkey, J., Keeler, S., Lowery, M., Oncea, L., Daugherty, J., Sevilla, C., Woelke, A., Dice, J., Weber, L., Roth, J., Ferringer, C., Beer, D., Fesz, J., Carpio, L., Colin, G., Zinzoni, V., Maquigneau, N., Henri-Lagarrigue, M., Pouplet, C., Reill, L., Distler, M., Maselli, A., Martynoga, R., Trask, K., Butler, A., Newlands, J., Henderson, K., Attwood, B., Parsons, P., Campbell, B., Smith, A., Hakak, S., Murphy, A., Joyce, K., Page, V., Zhao, X., Oza, D., Abrahamson, G., Sheath, B., Ellis, C., Guanco, M., Hoxha, E., Hegazy, A., Nordin, N., Denham, L., Young, P., Lesona, E., Navarra, L., Delaney, K., Marmol, J., Latino, R., Qiu, S., Monaghan, M., Rhodes, J., Anderson, T., Morris, S., Madani, Y., Nayyar, V., Bowen, D., Kong, J., Monzon, A., Fuchs, R., Lambert, B., Tai, C., Thomas, A., Keen, A., Tierney, C., Omer, N., Bacon, G., Evans, A., Binnie, A., Powell, E., McMillan, A., Luk, T., Aref, N., Denmade, C., Sadera, G., Jacob, R., Jones, C., Hughes, D., Elgendy, A., Geng, W., Digby, S., Southern, D., Reddy, H., Hulse, S., Campbell, A., Garton, M., Watkins, C., Smuts, S., The, S., Smith, O., Harris, J., Quinn, A., Simpson, B., McMillan, C., Finch, C., Hill, C., Cooper, J., Brittain, M., Teo, H., Waddington, N., Budd, J., Small, C., O'Leary, R., Birch, J., Collins, E., Holland, A., Alexander, P., Felton, T., Ferguson, S., Sellers, K., Ward, L., Bentley, A., Fiouni, S., Yates, D., Birkinshaw, I., Kell, K., Scott, Z., Pearson, H., Wittekamp, B., Grady, B., Platenkamp, E., Hashmi, M., Ali, M., Hassan, N., Panjwani, A., Umrani, Z., Shaikh, M., Siddiqui, A., Ain, Q., Kanwal, D., van Bree, S., Bouw-Ruiter, M., Osinga, M., van Zanten, A., Adhikari, N. K., Annane, D., Battista, M., Cohen, D., Cook, D., Day, A., Guyatt, G., Heyland, D., Kanji, S., Tirupakuzhi Vijayaraghavan, B. K., Lamontagne, F., Masse, M., McGuinness, S., Menard, J., Parke, R., Pinto, R., Sprague, S., Bouffard, L., Gritsas, A., Buckingham, L., Tetu, A., Malenfant, F., Turcotte, P., Al-Beidh, F., Angus, D., Annane, D., Arabi, Y., Beane, A., Berry, S., Bhimani, Z., Bonten, M., Bradbury, C., Brunkhorst, F., Burrell, A., Buxton, M., Cecconi, M., Cheng, A., Cove, M., Derde, L., Escourt, L., Goossens, H., Gordon, A., Green, C., Haniffa, R., Hill, T., Huang, D., Ichihara, N., Lawler, P., Marshall, J., McArthur, C., McAuley, D., McGQuilten, Z., McVerry, B., Mouncey, P., Murthy, S., Nichol, A., Parker, J., Reyes, L. F., Rowan, K., Saito, H., Santos, M., Seymour, C., Shankar-Hari, M., Turgeon, A., Turner, A., Webb, S., Zarychanski, R., McEldrew, R., Kc, S., Tolppa, T., Rashan, S., Singh, V., van Bentum-Puijk, W., Brugman, C., Groeneveld, E., Jafarzadeh, M., Jongenelen, I., Keijzer-Timmers, N., Kester, E., Koelink, M., Okundaye, C., Parker, L., Patil, S., Peters, S., Rietveld, I., Sayada, S., Smit, A., van Amerongen, R., Vermont-van der Staaij, J., Doran, P., Anjum, A., Au, C., Lane, J., Fagboden, E., Barton, F., Charles, W., Miller, L., Parry-Billings, K., Peters, S., Richards-Belle, A., Saull, M., Sprinckmoller, S., Wiley, D., Darnell, R., Stronach, L., Wada, A., Beqaj, B., Forbes, A., Green, C., Heritier, S., Hills, T., McEldrew, B., McQuilten, Z., Trapani, T., Manoharan, V., Dondrop, A. M., Bin Hasan, M. S., Jayakumar, D., Kalla, I., Murray, L., Siika, W., Brunkhorst, F., Ehrmann, S., Povoa, P., Horvat, C., Doi, Y., Fujitani, S., Honda, H., Jindai, K., Kamata, K., Kato, H., Kunishima, H., Nakazono, K., Shintani, A., Yamagishi, Y., Yamashita, C., Beasley, R., Daneman, N., Fowler, R., McGloughlin, S., Paterson, D., Hullegie, S., Litton, E., Murphy, S., Venkatesh, B., de Jong, M., Uyeki, T., Baillie, K., Netea, M., Orr, K., Patanwala, A., Tong, S., Cooper, N., Galea, J., Ogungbenro, K., Patawala, A., Tong, S., Youngstein, T., Carrier, M., Fergusson, D., Goligher, E., Hunt, B., Kumar, A., Laffan, M., Lother, S., Middledorp, S., Neal, M., Stanworth, S., Anstey, M., de Man, A., Udy, A., Abraham, J., Arnold, D., Begin, P., Charlewood, R., Chasse, M., Cooper, J., Coyne, M., Daly, J., Estcourt, L., Gosbell, I., Harvala-Simmonds, H., Hills, T., MacLennan, S., McDyer, J., Menon, D., Pridee, N., Roberts, D., Thomas, H., Tinmouth, A., Triulzi, D., Walsh, T., Wood, E., Calfee, C., O'Kane, C., Shyamsundar, M., Sinha, P., Thompson, T., Young, I., Ferguson, N., Hodgson, C., Neto, A., Orford, N., Phua, J., Baron, R., Epelman, S., Ezekowitz, J., Frankfurter, C., Gommans, F., Kwan, Y., Kim, E., Leaf, D., Owen, D., Pollock, K., Puskarich, M., Vaduganathan, M., van Kimmenade, R., Harrison, D., Higgins, A., Lampro, L., Mason, A., Mila de la Fuente, G., Leffelaar, E., Schotsman, J., Boyd, C., Harland, C., Shearer, A., Wren, J., Clermont, G., Ricketts, D., Fazla, F., Muvindi, H., Ishani, P., Rashan, A., Udayanga, I., Detry, M., Fitzgerald, M., Lewis, R., McGlothlin, A., Saunders, C., Berry, L., Lorenzi, E. 2023

  Abstract

  Importance: The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain.Objective: To determine whether vitamin C improves outcomes for patients with COVID-19.Design, Setting, and Participants: Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents.Interventions: Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses).Main Outcomes and Measures: The primary outcome was a composite of organ support-free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from -1 organ support-free days for patients experiencing in-hospital death to 22 organ support-free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support-free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility.Results: Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support-free days was 7 (IQR, -1 to 17 days) for the vitamin C group vs 10 (IQR, -1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support-free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy.Conclusions and Relevance: In hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support-free days and hospital survival.Trial Registration: ClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP).

  View details for DOI 10.1001/jama.2023.21407

  View details for PubMedID 37877585

• Efficient and multiplexed tracking of single cells using whole-body PET/CT. bioRxiv : the preprint server for biology Nguyen, H. T., Das, N., Wang, Y., Ruvalcaba, C., Mehadji, B., Roncali, E., Chan, C. K., Pratx, G. 2023

  Abstract

  In vivo molecular imaging tools are crucially important for elucidating how cells move through complex biological systems, however, achieving single-cell sensitivity over the entire body remains challenging. Here, we report a highly sensitive and multiplexed approach for tracking upwards of 20 single cells simultaneously in the same subject using positron emission tomography (PET). The method relies on a new tracking algorithm (PEPT-EM) to push the cellular detection threshold to below 4 Bq/cell, and a streamlined workflow to reliably label single cells with over 50 Bq/cell of 18F-fluorodeoxyglucose (FDG). To demonstrate the potential of method, we tracked the fate of over 70 melanoma cells after intracardiac injection and found they primarily arrested in the small capillaries of the pulmonary, musculoskeletal, and digestive organ systems. This study bolsters the evolving potential of PET in offering unmatched insights into the earliest phases of cell trafficking in physiological and pathological processes and in cell-based therapies.

  View details for DOI 10.1101/2023.08.23.554536

  View details for PubMedID 37662335

  View details for PubMedCentralID PMC10473747

• TET1 regulates skeletal stem cell (SSC) mediated cartilage regeneration. Arthritis & rheumatology (Hoboken, N.J.) Pandey, A., Hoover, M., Singla, M., Bedi, Y., Storaci, H., Goodman, S. B., Chan, C., Bhutani, N. 2023

  Abstract

  Adult skeletal stem cells (SSC) give rise to chondrocytes, osteocytes and stromal cells as progeny have been shown to contribute to cartilage regeneration in Osteoarthritis (OA). Understanding extrinsic and intrinsic regulators of SSC fate and function can therefore identify putative candidate factors to enhance cartilage regeneration. This study explores how the DNA hydroxymethylase, TET1 regulates SSC function in OA.We investigated the differences in SSC lineage tree and differentiation potential in neonatal and adult Tet1 +/+ and Tet1-/- mice, with and without injury and upon OA induction and progression. Using RNA-seq, the transcriptomic differences between SSC and Bone, cartilage and stromal progenitor cells (BCSP) were identified in Tet1 +/+ mice and Tet1-/- mice.Loss of Tet1 skewed the SSC lineage tree by expanding the SSC pool and enhanced the chondrogenic potential of SSC and BCSP. Tet1 inhibition led to enhanced chondrogenesis in in human SSC and chondroprogenitors (CP) isolated from human cartilage. Importantly, TET1 inhibition in vivo in late stages of a mouse model of Osteoarthritis (OA) led to increased cartilage regeneration. Transcriptomic analyses of SSC and BCSP lacking Tet1 revealed pathway alterations in TGFβ signaling, melatonin degradation and cartilage development associated genes. Lastly, we report that use of hormone melatonin can dampen inflammation and improve cartilage health.While Tet1 is a broad epigenetic regulator, Melatonin can mimic the ability of TET1 inhibition to enhance the chondrogenic ability of skeletal stem cells. Melatonin administration has the potential to be an attractive stem cell based therapy for cartilage regeneration.

  View details for DOI 10.1002/art.42678

  View details for PubMedID 37610277

• Del1 Is a Growth Factor for Skeletal Progenitor Cells in the Fracture Callus. Biomolecules Sun, Y., Boyko, T., Marecic, O., Struck, D., Mann, R. K., Andrew, T. W., Lopez, M., Tong, X., Goodman, S. B., Yang, F., Longaker, M. T., Chan, C. K., Yang, G. P. 2023; 13 (8)

  Abstract

  Failure to properly form bone or integrate surgical implants can lead to morbidity and additional surgical interventions in a significant proportion of orthopedic surgeries. While the role of skeletal stem cells (SSCs) in bone formation and repair is well-established, very little is known about the factors that regulate the downstream Bone, Cartilage, Stromal, Progenitors (BCSPs). BCSPs, as transit amplifying progenitor cells, undergo multiple mitotic divisions to expand the pool of lineage committed progenitors allowing stem cells to preserve their self-renewal and stemness. Del1 is a protein widely expressed in the skeletal system, but its deletion led to minimal phenotype changes in the uninjured mouse. In this paper, we demonstrate that Del1 is a key regulator of BCSP expansion following injury. In Del1 knockout mice, there is a significant reduction in the number of BCSPs which leads to a smaller callus and decreased bone formation compared with wildtype (WT) littermates. Del1 serves to promote BCSP proliferation and prevent apoptosis in vivo and in vitro. Moreover, exogenous Del1 promotes proliferation of aged human BCSPs. Our results highlight the potential of Del1 as a therapeutic target for improving bone formation and implant success. Del1 injections may improve the success of orthopedic surgeries and fracture healing by enhancing the proliferation and survival of BCSPs, which are crucial for generating new bone tissue during the process of bone formation and repair.

  View details for DOI 10.3390/biom13081214

  View details for PubMedID 37627279

• Gla-domain mediated targeting of externalized phosphatidylserine for intracellular delivery. FASEB journal : official publication of the Federation of American Societies for Experimental Biology Hardy, J., Bauzon, M., Chan, C. K., Makela, A. V., Kanada, M., Schneider, D., Blankenberg, F., Contag, C. H., Hermiston, T. 2023; 37 (8): e23113

  Abstract

  Phosphatidylserine (PS) is a negatively charged phospholipid normally localized to the inner leaflet of the plasma membrane of cells but is externalized onto the cell surface during apoptosis as well as in malignant and infected cells. Consequently, PS may comprise an important molecular target in diagnostics, imaging, and targeted delivery of therapeutic agents. While an array of PS-binding molecules exist, their utility has been limited by their inability to internalize diagnostic or therapeutic payloads. We describe the generation, isolation, characterization, and utility of a PS-binding motif comprised of a carboxylated glutamic acid (GLA) residue domain that both recognizes and binds cell surface-exposed PS, and then unlike other PS-binding molecules is internalized into these cells. Internalization is independent of the traditional endosomal-lysosomal pathway, directly entering the cytosol of the target cell rapidly. We demonstrate that this PS recognition extends to stem cells and that GLA-domain-conjugated probes can be detected upon intravenous administration in animal models of infectious disease and cancer. GLA domain binding and internalization offer new opportunities for specifically targeting cells with surface-exposed PS for imaging and delivery of therapeutics.

  View details for DOI 10.1096/fj.202201250RRR

  View details for PubMedID 37486772

• Thumb Osteoarthritis: Stem Cell Activation, Niche Augmentation and Tissue Regeneration Murphy, M., Takematsu, E., Koepke, L., Tong, X., Butler, G., Ambrosi, T., Hoover, M., Wang, Y., Zhao, L., Wong, J., Reid, A., Longaker, M., Chan, C. MARY ANN LIEBERT, INC. 2023

  View details for Web of Science ID 001126807000330

• Purification and functional characterization of novel human skeletal stem cell lineages. Nature protocols Hoover, M. Y., Ambrosi, T. H., Steininger, H. M., Koepke, L. S., Wang, Y., Zhao, L., Murphy, M. P., Alam, A. A., Arouge, E. J., Butler, M. G., Takematsu, E., Stavitsky, S. P., Hu, S., Sahoo, D., Sinha, R., Morri, M., Neff, N., Bishop, J., Gardner, M., Goodman, S., Longaker, M., Chan, C. K. 2023

  Abstract

  Human skeletal stem cells (hSSCs) hold tremendous therapeutic potential for developing new clinical strategies to effectively combat congenital and age-related musculoskeletal disorders. Unfortunately, refined methodologies for the proper isolation of bona fide hSSCs and the development of functional assays that accurately recapitulate their physiology within the skeleton have been lacking. Bone marrow-derived mesenchymal stromal cells (BMSCs), commonly used to describe the source of precursors for osteoblasts, chondrocytes, adipocytes and stroma, have held great promise as the basis of various approaches for cell therapy. However, the reproducibility and clinical efficacy of these attempts have been obscured by the heterogeneous nature of BMSCs due to their isolation by plastic adherence techniques. To address these limitations, our group has refined the purity of individual progenitor populations that are encompassed by BMSCs by identifying defined populations of bona fide hSSCs and their downstream progenitors that strictly give rise to skeletally restricted cell lineages. Here, we describe an advanced flow cytometric approach that utilizes an extensive panel of eight cell surface markers to define hSSCs; bone, cartilage and stromal progenitors; and more differentiated unipotent subtypes, including an osteogenic subset and three chondroprogenitors. We provide detailed instructions for the FACS-based isolation of hSSCs from various tissue sources, in vitro and in vivo skeletogenic functional assays, human xenograft mouse models and single-cell RNA sequencing analysis. This application of hSSC isolation can be performed by any researcher with basic skills in biology and flow cytometry within 1-2 days. The downstream functional assays can be performed within a range of 1-2 months.

  View details for DOI 10.1038/s41596-023-00836-5

  View details for PubMedID 37316563

  View details for PubMedCentralID 6568007

• Optimizing Delivery of Therapeutic Growth Factors for Bone and Cartilage Regeneration. Gels (Basel, Switzerland) Takematsu, E., Murphy, M., Hou, S., Steininger, H., Alam, A., Ambrosi, T. H., Chan, C. K. 2023; 9 (5)

  Abstract

  Bone- and cartilage-related diseases, such as osteoporosis and osteoarthritis, affect millions of people worldwide, impairing their quality of life and increasing mortality. Osteoporosis significantly increases the bone fracture risk of the spine, hip, and wrist. For successful fracture treatment and to facilitate proper healing in the most complicated cases, one of the most promising methods is to deliver a therapeutic protein to accelerate bone regeneration. Similarly, in the setting of osteoarthritis, where degraded cartilage does not regenerate, therapeutic proteins hold great promise to promote new cartilage formation. For both osteoporosis and osteoarthritis treatments, targeted delivery of therapeutic growth factors, with the aid of hydrogels, to bone and cartilage is a key to advance the field of regenerative medicine. In this review article, we propose five important aspects of therapeutic growth factor delivery for bone and cartilage regeneration: (1) protection of protein growth factors from physical and enzymatic degradation, (2) targeted growth factor delivery, (3) controlling GF release kinetics, (4) long-term stability of regenerated tissues, and (5) osteoimmunomodulatory effects of therapeutic growth factors and carriers/scaffolds.

  View details for DOI 10.3390/gels9050377

  View details for PubMedID 37232969

• Canadian multidisciplinary expert consensus on the use of biologics in upper airways: a Delphi study. Journal of otolaryngology - head & neck surgery = Le Journal d'oto-rhino-laryngologie et de chirurgie cervico-faciale Thamboo, A. V., Lee, M., Bhutani, M., Chan, C., Chan, Y., Chapman, K. R., Chin, C. J., Connors, L., Dorscheid, D., Ellis, A. K., Gall, R. M., Godbout, K., Janjua, A., Javer, A., Kilty, S., Kim, H., Kirkpatrick, G., Lee, J. M., Leigh, R., Lemiere, C., Monteiro, E., Neighbour, H., Keith, P. K., Philteos, G., Quirt, J., Rotenberg, B., Ruiz, J. C., Scott, J. R., Sommer, D. D., Sowerby, L., Tewfik, M., Waserman, S., Witterick, I., Wright, E. D., Yamashita, C., Desrosiers, M. 2023; 52 (1): 30

  Abstract

  Chronic rhinosinusitis with nasal polyposis (CRSwNP) often coexists with lower airway disease. With the overlap between upper and lower airway disease, optimal management of the upper airways is undertaken in conjunction with that of the lower airways. Biologic therapy with targeted activity within the Type 2 inflammatory pathway can improve the clinical signs and symptoms of both upper and lower airway diseases. Knowledge gaps nevertheless exist in how best to approach patient care as a whole. There have been sixteen randomized, double-blind, placebo-controlled trails performed for CRSwNP targeted components of the Type 2 inflammatory pathway, notably interleukin (IL)-4, IL-5 and IL-13, IL- 5R, IL-33, and immunoglobulin (Ig)E. This white paper considers the perspectives of experts in various disciplines such as rhinology, allergy, and respirology across Canada, all of whom have unique and valuable insights to contribute on how to best approach patients with upper airway disease from a multidisciplinary perspective.A Delphi Method process was utilized involving three rounds of questionnaires in which the first two were completed individually online and the third was discussed on a virtual platform with all the panelists. A national multidisciplinary expert panel of 34 certified specialists was created, composed of 16 rhinologists, 7 allergists, and 11 respirologists who evaluated the 20 original statements on a scale of 1-9 and provided comments. All ratings were quantitively reviewed by mean, median, mode, range, standard deviation and inter-rater reliability. Consensus was defined by relative interrater reliability measures-kappa coefficient ([Formula: see text]) value > 0.61.After three rounds, a total of 22 statements achieved consensus. This white paper only contains the final agreed upon statements and clear rationale and support for the statements regarding the use of biologics in patients with upper airway disease.This white paper provides guidance to Canadian physicians on the use of biologic therapy for the management of upper airway disease from a multidisciplinary perspective, but the medical and surgical regimen should ultimately be individualized to the patient. As more biologics become available and additional trials are published we will provide updated versions of this white paper every few years.

  View details for DOI 10.1186/s40463-023-00626-9

  View details for PubMedID 37095527

  View details for PubMedCentralID 6340111

• Combination of Distinct Vascular Stem/Progenitor Cells for Neovascularization and Ischemic Rescue. Arteriosclerosis, thrombosis, and vascular biology Zhao, L., Lee, A. S., Sasagawa, K., Sokol, J., Wang, Y., Ransom, R. C., Zhao, X., Ma, C., Steininger, H. M., Koepke, L. S., Borrelli, M. R., Brewer, R. E., Lee, L. L., Huang, X., Ambrosi, T. H., Sinha, R., Hoover, M. Y., Seita, J., Weissman, I. L., Wu, J. C., Wan, D. C., Xiao, J., Longaker, M. T., Nguyen, P. K., Chan, C. K. 2023

  Abstract

  Peripheral vascular disease remains a leading cause of vascular morbidity and mortality worldwide despite advances in medical and surgical therapy. Besides traditional approaches, which can only restore blood flow to native arteries, an alternative approach is to enhance the growth of new vessels, thereby facilitating the physiological response to ischemia.The ActinCreER/R26VT2/GK3 Rainbow reporter mouse was used for unbiased in vivo survey of injury-responsive vasculogenic clonal formation. Prospective isolation and transplantation were used to determine vessel-forming capacity of different populations. Single-cell RNA-sequencing was used to characterize distinct vessel-forming populations and their interactions.Two populations of distinct vascular stem/progenitor cells (VSPCs) were identified from adipose-derived mesenchymal stromal cells: VSPC1 is CD45-Ter119-Tie2+PDGFRa-CD31+CD105highSca1low, which gives rise to stunted vessels (incomplete tubular structures) in a transplant setting, and VSPC2 which is CD45-Ter119-Tie2+PDGFRa+CD31-CD105lowSca1high and forms stunted vessels and fat. Interestingly, cotransplantation of VSPC1 and VSPC2 is required to form functional vessels that improve perfusion in the mouse hindlimb ischemia model. Similarly, VSPC1 and VSPC2 populations isolated from human adipose tissue could rescue the ischemic condition in mice.These findings suggest that autologous cotransplantation of synergistic VSPCs from nonessential adipose tissue can promote neovascularization and represents a promising treatment for ischemic disease.

  View details for DOI 10.1161/ATVBAHA.122.317943

  View details for PubMedID 37051932

• Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support-Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial. JAMA Writing Committee for the REMAP-CAP Investigators, Lawler, P. R., Derde, L. P., van de Veerdonk, F. L., McVerry, B. J., Huang, D. T., Berry, L. R., Lorenzi, E., van Kimmenade, R., Gommans, F., Vaduganathan, M., Leaf, D. E., Baron, R. M., Kim, E. Y., Frankfurter, C., Epelman, S., Kwan, Y., Grieve, R., O'Neill, S., Sadique, Z., Puskarich, M., Marshall, J. C., Higgins, A. M., Mouncey, P. R., Rowan, K. M., Al-Beidh, F., Annane, D., Arabi, Y. M., Au, C., Beane, A., van Bentum-Puijk, W., Bonten, M. J., Bradbury, C. A., Brunkhorst, F. M., Burrell, A., Buzgau, A., Buxton, M., Cecconi, M., Cheng, A. C., Cove, M., Detry, M. A., Estcourt, L. J., Ezekowitz, J., Fitzgerald, M., Gattas, D., Godoy, L. C., Goossens, H., Haniffa, R., Harrison, D. A., Hills, T., Horvat, C. 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S., Kalla, I., Kc, S., Murray, L., Siika, W., Ehrmann, S., Povoa, P., Girard, T., Doi, Y., Fujitani, S., Honda, H., Jindai, K., Kamata, K., Kato, H., Kunishima, H., Nakazono, K., Shintani, A., Yamagishi, Y., Yamashita, C., Beasley, R., Daneman, N., Fowler, R., McGloughlin, S., Paterson, D., Hullegie, S., Venkatesh, B., de Jong, M., Uyeki, T., Baillie, K., Hashmi, M., Netea, M., Orr, K., Patanwala, A., Tong, S., Cooper, N., Galea, J., Leavis, H., Ogungbenro, K., Patawala, A., Tong, S., Youngstein, T., Carrier, M., Fergusson, D., Goligher, E., Hunt, B., Kumar, A., Laffan, M., Lother, S., Middledorp, S., Neal, M., Stanworth, S., de Man, A., Masse, M., Abraham, J., Arnold, D., Begin, P., Charlewood, R., Chasse, M., Cooper, J., Coyne, M., Daly, J., Gosbell, I., Harvala-Simmonds, H., MacLennan, S., McDyer, J., Menon, D., Pridee, N., Roberts, D., Thomas, H., Tinmouth, A., Triulzi, D., Walsh, T., Wood, E., Calfee, C., O'Kane, C., Shyamsundar, M., Sinha, P., Thompson, T., Young, I., Ferguson, N., Hodgson, C., Neto, A., Orford, N., Phua, J., Lampro, L., Mason, A., Mila de la Fuente, G., Leffelaar, E., Schotsman, J., Boyd, C., Harland, C., Shearer, A., Wren, J., Clermont, G., Ricketts, D., Fazla, F., Muvindi, H., Ishani, P., Rashan, A., Udayanga, I. 2023; 329 (14): 1183-1196

  Abstract

  IMPORTANCE: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.Objective: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.DESIGN, SETTING, AND PARTICIPANTS: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022).INTERVENTIONS: Patients were randomized to receive open-label initiation of an ACE inhibitor (n=257), ARB (n=248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n=10), or no RAS inhibitor (control; n=264) for up to 10 days.MAIN OUTCOMES AND MEASURES: The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes.RESULTS: On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n=231), 8 (-1 to 17) in the ARB group (n=217), and 12 (0 to 17) in the control group (n=231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively).CONCLUSIONS AND RELEVANCE: In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.

  View details for DOI 10.1001/jama.2023.4480

  View details for PubMedID 37039790

• Denervation during mandibular distraction osteogenesis results in impaired bone formation. Scientific reports Tevlin, R., Griffin, M., Chen, K., Januszyk, M., Guardino, N., Spielman, A., Walters, S., Gold, G. E., Chan, C. K., Gurtner, G. C., Wan, D. C., Longaker, M. T. 2023; 13 (1): 2097

  Abstract

  Mandibular distraction osteogenesis (DO) is mediated by skeletal stem cells (SSCs) in mice, which enact bone regeneration via neural crest re-activation. As peripheral nerves are essential to progenitor function during development and in response to injury, we questioned if denervation impairs mandibular DO. C57Bl6 mice were divided into two groups: DO with a segmental defect in the inferior alveolar nerve (IAN) at the time of mandibular osteotomy ("DO Den") and DO with IAN intact ("DO Inn"). DO Den demonstrated significantly reduced histological and radiological osteogenesis relative to DO Inn. Denervation preceding DO results in reduced SSC amplification and osteogenic potential in mice. Single cell RNA sequencing analysis revealed that there was a predominance of innervated SSCs in clusters dominated by pathways related to bone formation. A rare human patient specimen was also analyzed and suggested that histological, radiological, and transcriptional alterations seen in mouse DO may be conserved in the setting of denervated human mandible distraction. Fibromodulin (FMOD) transcriptional and protein expression were reduced in denervated relative to innervated mouse and human mandible regenerate. Finally, when exogenous FMOD was added to DO-Den and DO-Inn SSCs undergoing in vitro osteogenic differentiation, the osteogenic potential of DO-Den SSCs was increased in comparison to control untreated DO-Den SSCs, modeling the superior osteogenic potential of DO-Inn SSCs.

  View details for DOI 10.1038/s41598-023-27921-9

  View details for PubMedID 36747028

• Intracompartmental Human Skeletal Stem Cell Diversity and Crosstalk Is Central To Long Bone Morphogenesis Ambrosi, T., Taheri, S., Felix, F., Sinha, R., Sahoo, D., Chan, C. WILEY. 2023: 304-305

  View details for Web of Science ID 001008985202148

• Opioid Represcriptions After ACL Reconstruction in Adolescents are Associated With Subsequent Opioid Use Disorder. Journal of pediatric orthopedics Cahan, E. M., Halvorsen, K. C., Pham, N. S., Kaur, J., Bryson, X. M., Chan, C. M., Vorhies, J. S. 2023

  Abstract

  INTRODUCTION: Postoperative opioid prescriptions may confer a risk for subsequent opioid use disorders (OUDs). For many children, postoperative analgesia is often the first opioid exposure. The rates of anterior cruciate ligament (ACL) reconstruction in pediatric populations are rising. Here, we use an administrative claims database to describe opioid prescription patterns after ACL reconstruction and their effect on subsequent risk of OUD.METHODS: Using International Classification of Diseases (ICD)-9, ICD-10, and CPT codes, we identified patients, with ages 10 to 18, undergoing primary ACL reconstruction between 2014 and 2016 with minimum 1 year follow-up in the Optum Clinformatics Data Mart, which is a nationally representative administrative claims database. Demographic variables and prescription patterns (in morphine milligram equivalents [MMEs]) were analyzed using univariate tests and multivariable logistic regression to determine any potential association with the appearance of anew an ICD-9 or ICD-10 code for OUD within 1 year of the initial procedure.RESULTS: A total of 4459 cases were included and 29 (0.7%) of these patients were diagnosed with an OUD within 1 year of surgery. Upon univariate analysis, opioid represcriptions within 6 weeks were significantly more common among patients with OUD; 27.6% vs. 9.7% of patients that did not develop a new diagnosis of OUD (P=0.005). Multivariable logistic regression indicated an independent significant relationship between total MMEs initially prescribed and the odds of a subsequent OUD diagnosis: for each additional 100 MMEs prescribed in total, the odds of OUD increased by 13% (P=0.002). Patients with a represcription within 6 weeks of surgery had an average increase in the odds of OUD by 161% (P=0.027).CONCLUSIONS: In this cohort of patient ages 10 to 18 undergoing primary isolated ACL reconstruction, we found substantial variability in opiate prescribing patterns and higher initial opioid prescription volume, as well as opioid represcription within 6 weeks were predictive of the subsequent development of OUD.LEVEL OF EVIDENCE: Level III.

  View details for DOI 10.1097/BPO.0000000000002340

  View details for PubMedID 36652547

• A seed-and-soil theory for blood ageing. Nature cell biology Ambrosi, T. H., Chan, C. K. 2023

  View details for DOI 10.1038/s41556-022-01062-z

  View details for PubMedID 36650380

• Hydra: Effective Runtime Network Verification Renganathan, S., Rubin, B., Kim, H., Ventre, P., Cascone, C., Moro, D., Chan, C., McKeown, N., Foster, N., ACM ASSOC COMPUTING MACHINERY. 2023: 182-194

  View details for DOI 10.1145/3603269.3604856

  View details for Web of Science ID 001116971100013

• Development and systematic characterization of GelMA/alginate/PEGDMA/xanthan gum hydrogel bioink system for extrusion bioprinting. Biomaterials Li, J., Moeinzadeh, S., Kim, C., Pan, C. C., Weale, G., Kim, S., Abrams, G., James, A. W., Choo, H., Chan, C., Yang, Y. P. 2022; 293: 121969

  Abstract

  Gelatin methacryloyl (GelMA)/alginate-based hydrogels have shown great promise in bioprinting, but their printability is limited at room temperature. In this paper, we present our development of a room temperature printable hydrogel bioink by introducing polyethylene glycol dimethacrylate (PEGDMA) and xanthan gum into the GelMA/alginate system. The inclusion of PEGDMA facilitates tuning of the hydrogel's mechanical property, while xanthan gum improves the viscosity of the hydrogel system and allows easy extrusion at room temperature. To fine-tune the mechanical and degradation properties, methacrylated xanthan gum was synthesized and chemically crosslinked to the system. We systematically characterized this hydrogel with attention to printability, strut size, mechanical property, degradation and cytocompatibility, and achieved a broad range of compression modulus (∼10-100 kPa) and degradation profile (100% degradation by 24 h-40% by 2 weeks). Moreover, xanthan gum demonstrated solubility in ionic solutions such as cell culture medium, which is essential for biocompatibility. Live/dead staining showed that cell viability in the printed hydrogels was over 90% for 7 days. Metabolic activity analysis demonstrated excellent cell proliferation and survival within 4 weeks of incubation. In summary, the newly developed hydrogel system has demonstrated distinct features including extrusion printability, widely tunable mechanical property and degradation, ionic solubility, and cytocompatibility. It offers great flexibility in bioprinting and tissue engineering.

  View details for DOI 10.1016/j.biomaterials.2022.121969

  View details for PubMedID 36566553

• Sexually dimorphic estrogen sensing in skeletal stem cells controls skeletal regeneration. Nature communications Andrew, T. W., Koepke, L. S., Wang, Y., Lopez, M., Steininger, H., Struck, D., Boyko, T., Ambrosi, T. H., Tong, X., Sun, Y., Gulati, G. S., Murphy, M. P., Marecic, O., Telvin, R., Schallmoser, K., Strunk, D., Seita, J., Goodman, S. B., Yang, F., Longaker, M. T., Yang, G. P., Chan, C. K. 2022; 13 (1): 6491

  Abstract

  Sexually dimorphic tissues are formed by cells that are regulated by sex hormones. While a number of systemic hormones and transcription factors are known to regulate proliferation and differentiation of osteoblasts and osteoclasts, the mechanisms that determine sexually dimorphic differences in bone regeneration are unclear. To explore how sex hormones regulate bone regeneration, we compared bone fracture repair between adult male and female mice. We found that skeletal stem cell (SSC) mediated regeneration in female mice is dependent on estrogen signaling but SSCs from male mice do not exhibit similar estrogen responsiveness. Mechanistically, we found that estrogen acts directly on the SSC lineage in mice and humans by up-regulating multiple skeletogenic pathways and is necessary for the stem cell's ability to self- renew and differentiate. Our results also suggest a clinically applicable strategy to accelerate bone healing using localized estrogen hormone therapy.

  View details for DOI 10.1038/s41467-022-34063-5

  View details for PubMedID 36310174

• Glucocorticoids Affect Bone Mass and Strength by Inhibiting Osteoprogenitor Cell Maturation Ambrosi, T., Murphy, M., Chan, C. F., Lane, N. WILEY. 2022: 2569

  View details for Web of Science ID 000877386503054

• Partial Tendon Injury at the Tendon-to-Bone Enthesis Activates Skeletal Stem Cells. Stem cells translational medicine Titan, A. L., Davitt, M., Foster, D., Salhotra, A., Menon, S., Chen, K., Fahy, E., Lopez, M., Jones, R. E., Baiu, I., Burcham, A., Januszyk, M., Gurtner, G., Fox, P., Chan, C., Quarto, N., Longaker, M. 2022

  Abstract

  The tendon enthesis plays a critical role in facilitating movement and reducing stress within joints. Partial enthesis injuries heal in a mechanically inferior manner and never achieve healthy tissue function. The cells responsible for tendon-to-bone healing remain incompletely characterized and their origin is unknown. Here, we evaluated the putative role of mouse skeletal stem cells (mSSCs) in the enthesis after partial-injury. We found that mSSCs were present at elevated levels within the enthesis following injury and that these cells downregulated TGFβ signaling pathway elements at both the RNA and protein levels. Exogenous application of TGFβ post-injury led to a reduced mSSC response and impaired healing, whereas treatment with a TGFβ inhibitor (SB43154) resulted in a more robust mSSC response. Collectively, these data suggest that mSSCs may augment tendon-to-bone healing by dampening the effects of TGFβ signaling within the mSSC niche.

  View details for DOI 10.1093/stcltm/szac027

  View details for PubMedID 35640155

• The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans. Science (New York, N.Y.) Jones, R. C., Karkanias, J., Krasnow, M. A., Pisco, A. O., Quake, S. R., Salzman, J., Yosef, N., Bulthaup, B., Brown, P., Harper, W., Hemenez, M., Ponnusamy, R., Salehi, A., Sanagavarapu, B. A., Spallino, E., Aaron, K. A., Concepcion, W., Gardner, J. M., Kelly, B., Neidlinger, N., Wang, Z., Crasta, S., Kolluru, S., Morri, M., Pisco, A. O., Tan, S. Y., Travaglini, K. J., Xu, C., Alcántara-Hernández, M., Almanzar, N., Antony, J., Beyersdorf, B., Burhan, D., Calcuttawala, K., Carter, M. M., Chan, C. K., Chang, C. A., Chang, S., Colville, A., Crasta, S., Culver, R. N., Cvijović, I., D'Amato, G., Ezran, C., Galdos, F. X., Gillich, A., Goodyer, W. R., Hang, Y., Hayashi, A., Houshdaran, S., Huang, X., Irwin, J. C., Jang, S., Juanico, J. V., Kershner, A. M., Kim, S., Kiss, B., Kolluru, S., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Li, B., Loeb, G. B., Lu, W. J., Mantri, S., Markovic, M., McAlpine, P. L., de Morree, A., Morri, M., Mrouj, K., Mukherjee, S., Muser, T., Neuhöfer, P., Nguyen, T. D., Perez, K., Phansalkar, R., Pisco, A. O., Puluca, N., Qi, Z., Rao, P., Raquer-McKay, H., Schaum, N., Scott, B., Seddighzadeh, B., Segal, J., Sen, S., Sikandar, S., Spencer, S. P., Steffes, L. C., Subramaniam, V. R., Swarup, A., Swift, M., Travaglini, K. J., Van Treuren, W., Trimm, E., Veizades, S., Vijayakumar, S., Vo, K. C., Vorperian, S. K., Wang, W., Weinstein, H. N., Winkler, J., Wu, T. T., Xie, J., Yung, A. R., Zhang, Y., Detweiler, A. M., Mekonen, H., Neff, N. F., Sit, R. V., Tan, M., Yan, J., Bean, G. R., Charu, V., Forgó, E., Martin, B. A., Ozawa, M. G., Silva, O., Tan, S. Y., Toland, A., Vemuri, V. N., Afik, S., Awayan, K., Botvinnik, O. B., Byrne, A., Chen, M., Dehghannasiri, R., Detweiler, A. M., Gayoso, A., Granados, A. A., Li, Q., Mahmoudabadi, G., McGeever, A., de Morree, A., Olivieri, J. E., Park, M., Pisco, A. O., Ravikumar, N., Salzman, J., Stanley, G., Swift, M., Tan, M., Tan, W., Tarashansky, A. J., Vanheusden, R., Vorperian, S. K., Wang, P., Wang, S., Xing, G., Xu, C., Yosef, N., Alcántara-Hernández, M., Antony, J., Chan, C. K., Chang, C. A., Colville, A., Crasta, S., Culver, R., Dethlefsen, L., Ezran, C., Gillich, A., Hang, Y., Ho, P. Y., Irwin, J. C., Jang, S., Kershner, A. M., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Liu, S., Loeb, G. B., Lu, W. J., Maltzman, J. S., Metzger, R. J., de Morree, A., Neuhöfer, P., Perez, K., Phansalkar, R., Qi, Z., Rao, P., Raquer-McKay, H., Sasagawa, K., Scott, B., Sinha, R., Song, H., Spencer, S. P., Swarup, A., Swift, M., Travaglini, K. J., Trimm, E., Veizades, S., Vijayakumar, S., Wang, B., Wang, W., Winkler, J., Xie, J., Yung, A. R., Artandi, S. E., Beachy, P. A., Clarke, M. F., Giudice, L. C., Huang, F. W., Huang, K. C., Idoyaga, J., Kim, S. K., Krasnow, M., Kuo, C. S., Nguyen, P., Quake, S. R., Rando, T. A., Red-Horse, K., Reiter, J., Relman, D. A., Sonnenburg, J. L., Wang, B., Wu, A., Wu, S. M., Wyss-Coray, T. 2022; 376 (6594): eabl4896

  Abstract

  Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.

  View details for DOI 10.1126/science.abl4896

  View details for PubMedID 35549404

• Human Coronary Plaque T Cells Are Clonal and Cross-React to Virus and Self. Circulation research Roy Chowdhury, R., D'Addabbo, J., Huang, X., Veizades, S., Sasagawa, K., Louis, D. M., Cheng, P., Sokol, J., Jensen, A., Tso, A., Shankar, V., Wendel, B. S., Bakerman, I., Liang, G., Koyano, T., Fong, R., Nau, A., Ahmad, H., Gopakumar, J. K., Wirka, R., Lee, A., Boyd, J., Woo, Y. J., Quertermous, T., Gulati, G., Jaiswal, S., Chien, Y. H., Chan, C., Davis, M. M., Nguyen, P. K. 2022: 101161CIRCRESAHA121320090

  Abstract

  Once considered primarily a disorder of lipid deposition, coronary artery disease is an incurable, life-threatening disease that is now also characterized by chronic inflammation notable for the buildup of atherosclerotic plaques containing immune cells in various states of activation and differentiation. Understanding how these immune cells contribute to disease progression may lead to the development of novel therapeutic strategies.We used single-cell technology and in vitro assays to interrogate the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity.In addition to macrophages, we found a high proportion of αβ T cells in the coronary plaques. Most of these T cells lack high expression of CCR7 and L-selectin, indicating that they are primarily antigen-experienced, memory cells. Notably, nearly one-third of these cells express the HLA-DRA surface marker, signifying activation through their TCRs (T-cell receptors). Consistent with this, TCR repertoire analysis confirmed the presence of activated αβ T cells (CD4

  View details for DOI 10.1161/CIRCRESAHA.121.320090

  View details for PubMedID 35430876

• REGENERATION OF CARTILAGE THOUGH ACTIVATION OF TISSUE RESIDENT SKELETAL STEM CELLS AND AUGMENTATION OF THE NICHE Murphy, M. P., Koepke, L. S., Lopez, M. T., Tong, X., Ambrosi, T. H., Gulati, G., Marecic, O., Wang, Y., Ransom, R. C., Hoover, M., Longaker, M. T., Chan, C. F. MARY ANN LIEBERT, INC. 2022: S375

  View details for Web of Science ID 000821187301490

• Publisher Correction: Cell types of origin of the cell-free transcriptome. Nature biotechnology Vorperian, S. K., Moufarrej, M. N., Tabula Sapiens Consortium, Quake, S. R., Jones, R. C., Karkanias, J., Krasnow, M., Pisco, A. O., Quake, S. R., Salzman, J., Yosef, N., Bulthaup, B., Brown, P., Harper, W., Hemenez, M., Ponnusamy, R., Salehi, A., Sanagavarapu, B. A., Spallino, E., Aaron, K. A., Concepcion, W., Gardner, J. M., Kelly, B., Neidlinger, N., Wang, Z., Crasta, S., Kolluru, S., Morri, M., Tan, S. Y., Travaglini, K. J., Xu, C., Alcantara-Hernandez, M., Almanzar, N., Antony, J., Beyersdorf, B., Burhan, D., Calcuttawala, K., Carter, M. M., Chan, C. K., Chang, C. A., Chang, S., Colville, A., Culver, R. N., Cvijovic, I., D'Amato, G., Ezran, C., Galdos, F. X., Gillich, A., Goodyer, W. R., Hang, Y., Hayashi, A., Houshdaran, S., Huang, X., Irwin, J. C., Jang, S., Juanico, J. V., Kershner, A. M., Kim, S., Kiss, B., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Li, B., Loeb, G. B., Lu, W., Mantri, S., Markovic, M., McAlpine, P. L., de Morree, A., Mrouj, K., Mukherjee, S., Muser, T., Neuhofer, P., Nguyen, T. D., Perez, K., Phansalkar, R., Puluca, N., Qi, Z., Rao, P., Raquer-McKay, H., Schaum, N., Scott, B., Seddighzadeh, B., Segal, J., Sen, S., Sikandar, S., Spencer, S. P., Steffes, L., Subramaniam, V. R., Swarup, A., Swift, M., Van Treuren, W., Trimm, E., Veizades, S., Vijayakumar, S., Vo, K. C., Vorperian, S. K., Wang, W., Weinstein, H. N., Winkler, J., Wu, T. T., Xie, J., Yung, A. R., Zhang, Y., Detweiler, A. M., Mekonen, H., Neff, N. F., Sit, R. V., Tan, M., Yan, J., Bean, G. R., Charu, V., Forgo, E., Martin, B. A., Ozawa, M. G., Silva, O., Toland, A., Vemuri, V. N., Afik, S., Awayan, K., Bierman, R., Botvinnik, O. B., Byrne, A., Chen, M., Dehghannasiri, R., Gayoso, A., Granados, A. A., Li, Q., Mahmoudabadi, G., McGeever, A., Olivieri, J. E., Park, M., Ravikumar, N., Stanley, G., Tan, W., Tarashansky, A. J., Vanheusden, R., Wang, P., Wang, S., Xing, G., Xu, C., Yosef, N., Culver, R., Dethlefsen, L., Ho, P., Liu, S., Maltzman, J. S., Metzger, R. J., Sasagawa, K., Sinha, R., Song, H., Wang, B., Artandi, S. E., Beachy, P. A., Clarke, M. F., Giudice, L. C., Huang, F. W., Huang, K. C., Idoyaga, J., Kim, S. K., Kuo, C. S., Nguyen, P., Rando, T. A., Red-Horse, K., Reiter, J., Relman, D. A., Sonnenburg, J. L., Wu, A., Wu, S. M., Wyss-Coray, T. 2022

  View details for DOI 10.1038/s41587-022-01293-3

  View details for PubMedID 35347330

• Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA REMAP-CAP Writing Committee for the REMAP-CAP Investigators, Bradbury, C. A., Lawler, P. R., Stanworth, S. J., McVerry, B. J., McQuilten, Z., Higgins, A. M., Mouncey, P. R., Al-Beidh, F., Rowan, K. M., Berry, L. R., Lorenzi, E., Zarychanski, R., Arabi, Y. M., Annane, D., Beane, A., van Bentum-Puijk, W., Bhimani, Z., Bihari, S., Bonten, M. J., Brunkhorst, F. M., Buzgau, A., Buxton, M., Carrier, M., Cheng, A. C., Cove, M., Detry, M. A., Estcourt, L. J., Fitzgerald, M., Girard, T. D., Goligher, E. C., Goossens, H., Haniffa, R., Hills, T., Huang, D. T., Horvat, C. M., Hunt, B. J., Ichihara, N., Lamontagne, F., Leavis, H. L., Linstrum, K. M., Litton, E., Marshall, J. C., McAuley, D. F., McGlothlin, A., McGuinness, S. P., Middeldorp, S., Montgomery, S. K., Morpeth, S. C., Murthy, S., Neal, M. D., Nichol, A. D., Parke, R. L., Parker, J. C., Reyes, L., Saito, H., Santos, M. S., Saunders, C. T., Serpa-Neto, A., Seymour, C. W., Shankar-Hari, M., Singh, V., Tolppa, T., Turgeon, A. F., Turner, A. M., van de Veerdonk, F. L., Green, C., Lewis, R. J., Angus, D. C., McArthur, C. J., Berry, S., Derde, L. P., Webb, S. A., Gordon, A. C., Florescu, S., Stanciu, D., Zaharia, M., Kosa, A., Codreanu, D., Kidwai, A., Masood, S., Kaye, C., Coutts, A., MacKay, L., Summers, C., Polgarova, P., Farahi, N., Fox, E., McWilliam, S., Hawcutt, D., Rad, L., O'Malley, L., Whitbread, J., Jones, D., Dore, R., Saunderson, P., Kelsall, O., Cowley, N., Wild, L., Thrush, J., Wood, H., Austin, K., Belteczki, J., Magyar, I., Fazekas, A., Kovacs, S., Szoke, V., Donnelly, A., Kelly, M., Smyth, N., O'Kane, S., McClintock, D., Warnock, M., Campbell, R., McCallion, E., Azaiz, A., Charron, C., Godement, M., Geri, G., Vieillard-Baron, A., Johnson, P., McKenna, S., Hanley, J., Currie, A., Allen, B., McGoldrick, C., McMaster, M., Mani, A., Mathew, M., Kandeepan, R., Vignesh, C., Tv, B., Ramakrishnan, N., James, A., Elvira, E., Jayakumar, D., Pratheema, R., Babu, S., Ebenezer, R., Krishnaoorthy, S., Ranganathan, L., Ganesan, M., Shree, M., Guilder, E., Butler, M., Cowdrey, K., Robertson, M., Ali, F., McMahon, E., Duffy, E., Chen, Y., Simmonds, C., McConnochie, R., O'Connor, C., El-Khawas, K., Richardson, A., Hill, D., Commons, R., Abdelkharim, H., Jha, R., Kalogirou, M., Ellis, C., Krishnamurthy, V., O'Connor, A., Thurairatnam, S., Mukherjee, D., Kaliappan, A., Vertue, M., Nicholson, A., Riches, J., Maloney, G., Kittridge, L., Solesbury, A., Ramos, A., Collins, D., Brickell, K., Reid, L., Smyth, M., Breen, P., Spain, S., Curley, G., McEvoy, N., Geoghegan, P., Clarke, J., Silversides, J., McGuigan, P., Ward, K., O'Neill, A., Finn, S., Wright, C., Green, J., Collins, E., Knott, C., Smith, J., Boschert, C., Slieker, K., Ewalds, E., Sanders, A., Wittenberg, W., Geurts, H., Reeve, B., Dechert, W., Phillips, B., Oritz-Ruiz de Gordoa, L., Affleck, J., Apte, Y., Subbanna, U., Bartholdy, R., Frakking, T., Pinnell, J., Robinson, M., Gledhill, L., Wood, T., Keat, K., Bhonagiri, D., Sanghavi, R., Nema, J., Ford, M., Parikh, H., Avard, B., Nourse, M., Hoiting, O., Peters, M., Rengers, E., Evers, M., Prinssen, A., Morgan, M., Cole, J., Hill, H., Davies, M., Williams, A., Thomas, E., Davies, R., Wise, M., Grimm, P., Soukup, J., Wetzold, R., Lobel, M., Starke, L., Lellouche, F., Lizotte, P., Declerq, P., Antoine, M., Stephanie, G., Jean-Pierre, E., Francois, B., Marion, B., Philippe, R., Pourcine, F., Monchi, M., Luis, D., Mercier, R., Sagnier, A., Verrier, N., Caplin, C., Richecoeu, J., Combaux, D., Siami, S., Aparicio, C., Vautier, S., Jeblaoui, A., Lemaire-Brunel, D., Carbonneau, F., Leblond, J., Plantefeve, G., Leparco, C., Contou, D., Fartoukh, M., Courtin, L., Labbe, V., Voiriot, G., Salhi, S., Chasse, M., Carrier, F., Boumahni, D., Benettaib, F., Ghamraoui, A., Sement, A., Gachet, A., Hanisch, A., Haffiane, A., Boivin, A., Barreau, A., Guerineau, E., Poupblanc, S., Egreteau, P., Lefevre, M., Bocher, S., Le Loup, G., Le Guen, L., Carn, V., Bertel, M., Antcliffe, D., Templeton, M., Rojo, R., Coghlan, P., Smee, J., Barker, G., Finn, A., KreSS, G., Hoff, U., Hinrichs, C., Nee, J., Mackay, E., Cort, J., Whileman, A., Spencer, T., Spittle, N., Beavis, S., Padmakumar, A., Dale, K., Hawes, J., Moakes, E., Gascoyne, R., Pritchard, K., Stevenson, L., Cooke, J., Nemeth-Roszpopa, K., Gauli, B., Bastola, S., Muller, G., Nay, M., Kamel, T., Benzekri, D., Jacquier, S., Runge, I., Mathonnet, A., Barbier, F., Bretagnol, A., Carter, J., Van Der Heyden, K., Mehrtens, J., Morris, A., Morgan, S., Burke, T., Mercier, E., Chartier, D., Salmon, C., Dequin, P., Garot, D., Bellemare, D., Cloutier, E., Daher, R., Costerousse, O., Boulanger, M., Couillard-Chenard, E., Francoeur, F., Francois, B., Gay, A., Anne-Laure, F., Ramali, M., Hc, O., Ghosh, A., Osagie, R., Arachchige, M., Hartley, M., Cheung, W., Kol, M., Wong, H., Shah, A., Wagh, A., Bamford, P., Reid, A., Cawley, K., Faulkner, M., Pickering, C., Raj, A., Tsinaslanidis, G., Khade, R., Agha, G., Sekiwala, R., Smith, T., Brewer, C., Gregory, J., Limb, J., Cowton, A., O'Brien, J., Postlethwaite, K., Malakouti, S., Music, E., Ricketts, D., King, A., Clermont, G., Bart, R., Mayr, F., Schoenling, A., Andreae, M., Shetty, V., Brant, E., Malley, B., Donadee, C., Sackrowitz, R., Weissman, A., Yealy, D., Barton, D., Talia, N., Nikitas, N., Wells, C., Lankester, L., McMillan, H., van den Oever, H., Kruisdijk-Gerritsen, A., Haidar, G., Bain, W., Barbash, I., Fitzpatrick, M., Franz, C., Kitsios, G., Moghbeli, K., Rosborough, B., Shah, F., Suber, T., Pulletz, M., Williams, P., Birch, J., Wiseman, S., Horton, S., Alegria, A., Turki, S., Elsefi, T., Crisp, N., Allen, L., Truman, N., Smith, M., Chukkambotla, S., Goddard, W., Duberley, S., Khan, M., Kazi, A., Simpson, J., Duke, G., Chan, P., Carter, B., Hunter, S., Voigt, I., Schueler, R., Blank, E., Huning, V., Steffen, M., Goralski, P., Regli, A., Pellicano, S., Palermo, A., Eroglu, E., Laver, R., Shrestha, T., Jin, X., French, C., Bates, S., Towns, M., Yang, Y., McGain, F., McCullagh, I., Cairns, T., Hanson, H., Patel, B., Clement, I., Evetts, G., Touma, O., Holland, S., Hodge, C., Taylor, H., Alderman, M., Barnes, N., Da Rocha, J., Smith, C., Brooks, N., Weerasinghe, T., Sinclair, J., Abusamra, Y., Doherty, R., Cudlipp, J., Singh, R., Yu, H., Daebis, A., Ng, C., Kendrick, S., Saran, A., Makky, A., Greener, D., Rowe-Leete, L., Edwards, A., Bland, Y., Dolman, R., Foster, T., Laffey, J., McNicholas, B., Scully, M., Casey, S., Kernan, M., Brennan, A., Rangan, R., Tully, R., Corbett, S., McCarthy, A., Duffy, O., Burke, D., Linnett, V., Sanderson, A., Ritzema, J., Wild, H., Lucas, R., Marriott, Y., Andric, Z., Cviljevic, S., Dimoti, R., Zapalac, M., Mirkovic, G., Khare, D., Pinder, M., Gopinath, A., Kannan, T., Dean, S., Vanmali, P., Depuydt, P., De Waele, J., De Bus, L., Fierens, J., Bracke, S., Vermassen, J., Vermeiren, D., Pugh, R., Lean, R., Qiu, X., Scanlan, J., Evans, A., Davies, G., Lewis, J., Plesnikova, Y., Khoud, A., Coetzee, S., Puxty, K., Cathcart, S., Rimmer, D., Bagot, C., Scott, K., Martin, L., Yusuff, H., Isgro, G., Brightling, C., Bourne, M., Craner, M., Boyles, R., 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J., Pereira, T. N., Ferreira, R. M., Bastos, J. M., Batista, T. 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  Abstract

  Importance: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain.Objective: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19.Design, Setting, and Participants: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021).Interventions: Patients were randomized to receive either open-label aspirin (n=565), a P2Y12 inhibitor (n=455), or no antiplatelet therapy (control; n=529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis.Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions.Results: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm).Conclusions and Relevance: Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days.Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

  View details for DOI 10.1001/jama.2022.2910

  View details for PubMedID 35315874

• Molecular hallmarks of heterochronic parabiosis at single-cell resolution. Nature Palovics, R., Keller, A., Schaum, N., Tan, W., Fehlmann, T., Borja, M., Kern, F., Bonanno, L., Calcuttawala, K., Webber, J., McGeever, A., Tabula Muris Consortium, Luo, J., Pisco, A. O., Karkanias, J., Neff, N. F., Darmanis, S., Quake, S. R., Wyss-Coray, T., Almanzar, N., Antony, J., Baghel, A. S., Bakerman, I., Bansal, I., Barres, B. A., Beachy, P. A., Berdnik, D., Bilen, B., Brownfield, D., Cain, C., Chan, C. K., Chen, M. B., Clarke, M. F., Conley, S. D., Demers, A., Demir, K., de Morree, A., Divita, T., du Bois, H., Ebadi, H., Espinoza, F. H., Fish, M., Gan, Q., George, B. M., Gillich, A., Gomez-Sjoberg, R., Green, F., Genetiano, G., Gu, X., Gulati, G. S., Hahn, O., Haney, M. S., Hang, Y., Harris, L., He, M., Hosseinzadeh, S., Huang, A., Huang, K. C., Iram, T., Isobe, T., Ives, F., Jones, R. C., Kao, K. S., Karnam, G., Kershner, A. M., Khoury, N., Kim, S. K., Kiss, B. M., Kong, W., Krasnow, M. A., Kumar, M. E., Kuo, C. S., Lam, J., Lee, D. P., Lee, S. E., Lehallier, B., Leventhal, O., Li, G., Li, Q., Liu, L., Lo, A., Lu, W., Lugo-Fagundo, M. F., Manjunath, A., May, A. P., Maynard, A., McKay, M., McNerney, M. W., Merrill, B., Metzger, R. J., Mignardi, M., Min, D., Nabhan, A. N., Ng, K. M., Nguyen, P. K., Noh, J., Nusse, R., Patkar, R., Peng, W. C., Penland, L., Pollard, K., Puccinelli, R., Qi, Z., Rando, T. A., Rulifson, E. J., Segal, J. M., Sikandar, S. S., Sinha, R., Sit, R. V., Sonnenburg, J., Staehli, D., Szade, K., Tan, M., Tato, C., Tellez, K., Torrez Dulgeroff, L. B., Travaglini, K. J., Tropini, C., Tsui, M., Waldburger, L., Wang, B. M., van Weele, L. J., Weinberg, K., Weissman, I. L., Wosczyna, M. N., Wu, S. M., Xiang, J., Xue, S., Yamauchi, K. A., Yang, A. C., Yerra, L. P., Youngyunpipatkul, J., Yu, B., Zanini, F., Zardeneta, M. E., Zee, A., Zhao, C., Zhang, F., Zhang, H., Zhang, M. J., Zhou, L., Zou, J. 2022

  Abstract

  The ability to slow or reverse biological ageing would have major implications for mitigating disease risk and maintaining vitality1. Although an increasing number of interventions show promise for rejuvenation2, their effectiveness on disparate cell types across the body and the molecular pathways susceptible to rejuvenation remain largely unexplored. Here we performed single-cell RNA sequencing on 20 organs to reveal cell-type-specific responses to young and aged blood in heterochronic parabiosis. Adipose mesenchymal stromal cells, haematopoietic stem cells and hepatocytes are among those cell types that are especially responsive. On the pathway level, young blood invokes new gene sets in addition to reversing established ageing patterns, with the global rescue of genes encoding electron transport chain subunits pinpointing a prominent role of mitochondrial function in parabiosis-mediated rejuvenation. We observed an almost universal loss of gene expression with age that is largely mimicked by parabiosis: aged blood reduces global gene expression, and young blood restores it in select cell types. Together, these data lay the groundwork for a systemic understanding of the interplay between blood-borne factors and cellular integrity.

  View details for DOI 10.1038/s41586-022-04461-2

  View details for PubMedID 35236985

• Cell types of origin of the cell-free transcriptome. Nature biotechnology Vorperian, S. K., Moufarrej, M. N., Tabula Sapiens Consortium, Quake, S. R., Jones, R. C., Karkanias, J., Krasnow, M., Pisco, A. O., Quake, S. R., Salzman, J., Yosef, N., Bulthaup, B., Brown, P., Harper, W., Hemenez, M., Ponnusamy, R., Salehi, A., Sanagavarapu, B. A., Spallino, E., Aaron, K. A., Concepcion, W., Gardner, J. M., Kelly, B., Neidlinger, N., Wang, Z., Crasta, S., Kolluru, S., Morri, M., Tan, S. Y., Travaglini, K. J., Xu, C., Alcantara-Hernandez, M., Almanzar, N., Antony, J., Beyersdorf, B., Burhan, D., Calcuttawala, K., Carter, M. M., Chan, C. K., Chang, C. A., Chang, S., Colville, A., Culver, R. N., Cvijovic, I., D'Amato, G., Ezran, C., Galdos, F. X., Gillich, A., Goodyer, W. R., Hang, Y., Hayashi, A., Houshdaran, S., Huang, X., Irwin, J. C., Jang, S., Juanico, J. V., Kershner, A. M., Kim, S., Kiss, B., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Li, B., Loeb, G. B., Lu, W., Mantri, S., Markovic, M., McAlpine, P. L., de Morree, A., Mrouj, K., Mukherjee, S., Muser, T., Neuhofer, P., Nguyen, T. D., Perez, K., Phansalkar, R., Puluca, N., Qi, Z., Rao, P., Raquer-McKay, H., Schaum, N., Scott, B., Seddighzadeh, B., Segal, J., Sen, S., Sikandar, S., Spencer, S. P., Steffes, L., Subramaniam, V. R., Swarup, A., Swift, M., Van Treuren, W., Trimm, E., Veizades, S., Vijayakumar, S., Vo, K. C., Vorperian, S. K., Wang, W., Weinstein, H. N., Winkler, J., Wu, T. T., Xie, J., Yung, A. R., Zhang, Y., Detweiler, A. M., Mekonen, H., Neff, N. F., Sit, R. V., Tan, M., Yan, J., Bean, G. R., Charu, V., Forgo, E., Martin, B. A., Ozawa, M. G., Silva, O., Toland, A., Vemuri, V. N., Afik, S., Awayan, K., Bierman, R., Botvinnik, O. B., Byrne, A., Chen, M., Dehghannasiri, R., Gayoso, A., Granados, A. A., Li, Q., Mahmoudabadi, G., McGeever, A., Olivieri, J. E., Park, M., Ravikumar, N., Stanley, G., Tan, W., Tarashansky, A. J., Vanheusden, R., Wang, P., Wang, S., Xing, G., Xu, C., Yosef, N., Culver, R., Dethlefsen, L., Ho, P., Liu, S., Maltzman, J. S., Metzger, R. J., Sasagawa, K., Sinha, R., Song, H., Wang, B., Artandi, S. E., Beachy, P. A., Clarke, M. F., Giudice, L. C., Huang, F. W., Huang, K. C., Idoyaga, J., Kim, S. K., Kuo, C. S., Nguyen, P., Rando, T. A., Red-Horse, K., Reiter, J., Relman, D. A., Sonnenburg, J. L., Wu, A., Wu, S. M., Wyss-Coray, T. 2022

  Abstract

  Cell-free RNA from liquid biopsies can be analyzed to determine disease tissue of origin. We extend this concept to identify cell types of origin using the Tabula Sapiens transcriptomic cell atlas as well as individual tissue transcriptomic cell atlases in combination with the Human Protein Atlas RNA consensus dataset. We define cell type signature scores, which allow the inference of cell types that contribute to cell-free RNA for a variety of diseases.

  View details for DOI 10.1038/s41587-021-01188-9

  View details for PubMedID 35132263

• Tractable Human Skeletal Stem Cell Diversity Shapes Bone Development and Regeneration Ambrosi, T., Taheri, S., Sinha, R., Goodnough, L., Steininger, H., Weissman, I., Longaker, M., Sahoo, D., Chan, C. WILEY. 2022: 266-267

  View details for Web of Science ID 000778074501234

• A Brain Dependent Osteogenic Factor Controls Peak Bone Mass Herber, C., Ambrosi, T., Morioka, K., Marcucio, R., Ventura, P., Villeda, S., Chan, C., Lane, N., Ingraham, H. WILEY. 2022: 191

  View details for Web of Science ID 000778074501002

• Cross-species comparisons reveal resistance of human skeletal stem cells to inhibition by non-steroidal anti-inflammatory drugs. Frontiers in endocrinology Goodnough, L. H., Ambrosi, T. H., Steininger, H. M., Butler, M. G., Hoover, M. Y., Choo, H., Van Rysselberghe, N. L., Bellino, M. J., Bishop, J. A., Gardner, M. J., Chan, C. K. 2022; 13: 924927

  Abstract

  Fracture healing is highly dependent on an early inflammatory response in which prostaglandin production by cyclo-oxygenases (COX) plays a crucial role. Current patient analgesia regimens favor opioids over Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) since the latter have been implicated in delayed fracture healing. While animal studies broadly support a deleterious role of NSAID treatment to bone-regenerative processes, data for human fracture healing remains contradictory. In this study, we prospectively isolated mouse and human skeletal stem cells (SSCs) from fractures and compared the effect of various NSAIDs on their function. We found that osteochondrogenic differentiation of COX2-expressing mouse SSCs was impaired by NSAID treatment. In contrast, human SSCs (hSSC) downregulated COX2 expression during differentiation and showed impaired osteogenic capacity if COX2 was lentivirally overexpressed. Accordingly, short- and long-term treatment of hSSCs with non-selective and selective COX2 inhibitors did not affect colony forming ability, chondrogenic, and osteogenic differentiation potential in vitro. When hSSCs were transplanted ectopically into NSG mice treated with Indomethacin, graft mineralization was unaltered compared to vehicle injected mice. Thus, our results might contribute to understanding species-specific differences in NSAID sensitivity during fracture healing and support emerging clinical data which conflicts with other earlier observations that NSAID administration for post-operative analgesia for treatment of bone fractures are unsafe for patients.

  View details for DOI 10.3389/fendo.2022.924927

  View details for PubMedID 36093067

• Aging of Skeletal Stem Cells. Advances in geriatric medicine and research Butler, M. G., Ambrosi, T. H., Murphy, M. P., Chan, C. K. 2022; 4 (2)

  Abstract

  The skeletal system is generated and maintained by its progenitors, skeletal stem cells (SSCs), across the duration of life. Gradual changes associated with aging result in significant differences in functionality of SSCs. Declines in bone and cartilage production, increase of bone marrow adipose tissue, compositional changes of cellular microenvironments, and subsequent deterioration of external and internal structures culminate in the aged and weakened skeleton. The features and mechanisms of skeletal aging, and of its stem and progenitor cells in particular, are topics of recent investigation. The discovery of functionally homogeneous SSC populations with a defined cell surface phenotype has allowed for closer inspection of aging in terms of its effects on transcriptional regulation, cell function, and identity. Here, we review the aspects of SSC aging on both micro- and macroscopic levels. Up-to-date knowledge of SSC biology and aging is presented, and directions for future research and potential therapies are discussed. The realm of SSC-mediated bone aging remains an important component of global health and a necessary facet in our understanding of human aging.

  View details for DOI 10.20900/agmr20220006

  View details for PubMedID 36037035

• Denervation During Mandibular Distraction Osteogenesis Results in Impaired Osteogenesis Tevlin, R., Januszyk, M., Griffin, M., Salhotra, A., Wan, D. C., Chan, C. F., Longaker, M. T. ELSEVIER SCIENCE INC. 2021: S196-S197

  View details for Web of Science ID 000718303100369

• Acellular Dermal Matrix Modulation of the Peri-Prosthetic Breast Microenvironment During Breast Reconstruction Tevlin, R., Januszyk, M., Griffin, M., Shefren, K., Chan, C. F., Momeni, A., Wan, D. C., Longaker, M. T. ELSEVIER SCIENCE INC. 2021: S195-S196

  View details for Web of Science ID 000718303100367

• Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA Writing Committee for the REMAP-CAP Investigators, Estcourt, L. J., Turgeon, A. F., McQuilten, Z. K., McVerry, B. J., Al-Beidh, F., Annane, D., Arabi, Y. M., Arnold, D. M., Beane, A., Begin, P., van Bentum-Puijk, W., Berry, L. R., Bhimani, Z., Birchall, J. E., Bonten, M. J., Bradbury, C. A., Brunkhorst, F. M., Buxton, M., Callum, J. L., Chasse, M., Cheng, A. C., Cove, M. E., Daly, J., Derde, L., Detry, M. A., De Jong, M., Evans, A., Fergusson, D. A., Fish, M., Fitzgerald, M., Foley, C., Goossens, H., Gordon, A. C., Gosbell, I. B., Green, C., Haniffa, R., Harvala, H., Higgins, A. M., Hills, T. E., Hoad, V. C., Horvat, C., Huang, D. T., Hudson, C. L., Ichihara, N., Laing, E., Lamikanra, A. A., Lamontagne, F., Lawler, P. R., Linstrum, K., Litton, E., Lorenzi, E., MacLennan, S., Marshall, J., McAuley, D. F., McDyer, J. F., McGlothlin, A., McGuinness, S., Miflin, G., Montgomery, S., Mouncey, P. R., Murthy, S., Nichol, A., Parke, R., Parker, J. C., Priddee, N., Purcell, D. F., Reyes, L. F., Richardson, P., Robitaille, N., Rowan, K. M., Rynne, J., Saito, H., Santos, M., Saunders, C. T., Serpa Neto, A., Seymour, C. W., Silversides, J. A., Tinmouth, A. A., Triulzi, D. J., Turner, A. M., van de Veerdonk, F., Walsh, T. S., Wood, E. M., Berry, S., Lewis, R. J., Menon, D. K., McArthur, C., Zarychanski, R., Angus, D. C., Webb, S. A., Roberts, D. J., Shankar-Hari, M., Abdelhady, H., Abdelrazik, M., Abdi, Z., Abdo, D., Abdulle, A., Abel, L., Abouzeenni, S., Abrahamson, G., Abusamra, Y., Adams, L., Adebambo, O., Ademokun, D., Adhikari, N., Affron, D., Aggarwal, A., Agno, R., Ahmad, H., Ahmad, N., Ahmed, S., Ainscough, K., Ainsworth, J., Airoldi, G., Aitken, L., Ajeneye, F., Akhtar, N., Akinwumiju, O., Al-Bayati, M., Albert, M., Alderman, M., Alegria, A., Alexander, B., Alexander, P. D., Alfonso, J., Ali, H., Ali, S., Allameddine, A., Allan, S., Allard, I., Allen, B., Allen, B., Allen, J., Allen, L., Allen, L., Allibone, S., Ambrosino, R., Amenyah, K., Ammoun, M., Anand, R., Anand, S. P., Andersen, K., Anderson, C., Anderson, K., Anderson, T., Andreae, M., Andrews, S., Andrikopoulos, G., Anjum, A., Anstey, M., Antar, M., Antcliffe, D., Anthony, A., Antoine, P., Anumakonda, V., Apostolides, G., Aravindan, L., Arbane, G., Arbon, E., Archer, S., Aref, N., Arias, A., Armali, C., Armer-Ducker, J., Armstrong, M., Armstrong-Fisher, S., Arnold, J., Arnott, S., Arroyo, A., Arsenault, V., Aryal, D., Asghar, A., Ashby, G., Asher, D., Ashford, B., Ashgar, S., Asif Ali, M., Aspinwall, A., Asquith, A., Atallah, T., Athay-Hunt, R., Attanayaka, U., Atugonza, R., Aube, M., Auclair, M., Austin, K., Austin, P., Awan, S., Bacon, G., Badhesha, H., Bagavathy, K., Baglole, D., Bagnas, C., Bagot, C., Bagshaw, S., Baig, N., Bailey, S., Baillie, K., Bain, W., Baines, S., Baird, A., Baker, C., Baker, E., Bakhtiari, P., Bakthavatsalam, D., Balaie, M., Bali, G., Balkee, S., Ballinger, A., Bamford, A., Bamford, P., Banerjee, M., Banks, L., Bannard-Smith, J., Banning, N., Bansal, B., Banthorpe, R., Barbash, I., Barber, A., Barber, R., Barbosa, M., Barillas, M., Bariola, R., Barker, G., Barnes, N., Barnett, M., Barnett, N., Baron, R., Bart, R., Bartholomew, J., Bartley, S., Barton, D., Barwell, J., Bashyal, A., Basile, K., Bass, F., Bassford, C., Bassi, P., Bassis, B., Bateman, I., Bates, M., Bates, S., Batty, D., Bauchmuller, K., Baughan, P., Baxter, L., Baylem, C., Bayliss, L., Bayne, M., Bays, E., Bazin, R., Beard, G., Beard, K., Beasley, R., Beaudin, L., Beaudoin, J., Beaudoin-Bussieres, G., Beddows, S., Bedford, C., Beer, D., Begum, S., Beharry, J., Bei Zhao, X., Belec, N., Bell, G., Bell, G., Bell, J., Bellemare, D., Benettaib, F., Beninato, A., Benlarbi, M., Bennett, A., Bennett, C., Bennett-Mills, C., Benoit, A., Benstead, J., Bentley, D., Berg, L., Bergin, C., Berscheid, C., Best-Lane, J., Bevan, E., Bewley, J., Beyerl, A., Bhagani, S., Bhandal, K., Biddie, S., Biemans, J., Bignell, K., Bihari, S., Bilodeau, M., Bilton, C., Binney, M. J., Binnie, A., Bion, J., Birch, C., Birch, J., Birchall, K., Birkinshaw, I., Bisa, R., Black, E., Blackledge, B., Blackmore, S., Blackwell, A., Blackwood, L., Bland, Y., Blanton, M., Blaxland, J., Blofield, D., Blom, M., Board, J., Bociek, A., Bodh, S., Boisclair, V., Bolton, S., Bolton, W., Bond, H., Bonner, S., Bonnert, W., Boorman, L., Booth, C., Borgatta, B., Borhani, C., Borkent, N., Borrell, R., Borrill, Z., Boshir, M., Bouchard, B., Boulanger, M., Boumahni, D., Bourassa, C., Bourne, M., Bourne, R., Boutin, D., Boutin, M., Bowen, D., Bowen, J., Bowler, H., Bowyer, G., Boyd, C., Boyd, C., Boyd, M., Boyer, L., Boyles, R., Bozovic, G., Brack, D., Brackstone, C., Bradburn, R., Bradley, B., Bradley, P., Bradshaw, S., Brailsford, J., Brailsford, S., Brant, E., Brazier, A., Bremmer, P., Brend, M., Brennan, V., Brett, S., Brewer, C., Brickell, K., Briggs, M., Brightling, C., Brillinger, N., Brimfield, L., Brisson, S., Brittin, T., Brochard, L., Broderick, A., Broggio, D., Brohi, F., Brookes, C., Brooks, N., Broom, R., Browett, M., Brown, C., Brown, E., Brown, L., Brown, M., Brown, R., Brown, W., Brulotte, M., Brunet, E., Brunskill, N., Bryan-Morris, K., Buchan, J., Buchanan, A., Buckmire, K., Budd, J., Bugden, P., Buhr, H., Bullock, L., Buonavoglia, V., Buoy, A., Burda, D., Burgess, P., Burkey, J., Burnish, R., Burns, D., Burns, K., Burns, S., Busby, A., Buscher, H., Butler, L., Butt, S., Byrne, R., Byworth, E., Cabrelli, L., Cabreros, L., Cairns, T., Caldwell, M., Calfee, C., Cambalova, L., Cameron, S., Campbell, A., Campbell, D., Campbell, H., Campbell, K., Campbell, L., Campbell, R., Campisi, J., Campos, S., Camsooksai, J., Canabarro, A., Carbonneau, E., Cardenas, N., Carlton, A., Carnegie, R., Carpenter, E., Carpio, L., Carr, S., Carrier, F. M., Carrier, M., Carrington, S., Carr-Wilkinson, J., Carter, D., Carter, M., Carter, S., Carter-Graham, S., Carveth-Marshall, C., Casali, S., Casey, R., Cathcart, S., Caulfield, J., Cavayas, A., Cawley, K., Cecconi, M., Centofanti, J., Chamara Warnapura, L., Chamberland, E., Chambers, E., Champanerkar, S., Chan, C., Chan, M., Chan, P., Chand, S., Chandler-Vizard, V., Chang, C., Channon, T., Chapman, M., Chapman, S., Chapple, L., Charles, B., Charlewood, R., Charlton, A., Charlton, S., Charlton, S., Charnock, S., Chauhan, V., Chavez, R., Cheadle, M., Cherian, S., Cherif, S., Cheung, B., Cheung, E., Chhablani, M., Chinn, K., Chiroma, V., Choquet, C., Chou, J. 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H., Crawford, A., Crawshaw, S., Creagh-Brown, B., Creighton, R., Cremer, O., Crisp, N., Croft, M., Cron, I., Crook, D., Croot, H., Crosby, M., Cross, S., Crumley, H., Cudlipp, J., Cuevas, O., Cullen, D., Cundall, M., Curley, D., Currie, A., Curtis, A., Curtis, B., Cusack, R., Cuthbertson, B., Cutler, S., D'Aragon, F., Da Rocha, J., Daebis, A., Daggett, P., Daher, R., Daigle, L., Dakers-Black, H., Daley, J., Dallas, N., Dalton, J., Daly, Z., Damhar, R., Daneman, N., Daniels, C., Dark, P., Darling, K., Darling, T., Darshana, S., Das, A., Daugherty, J., Davey, M., Davey, M., David, A., Davidson, N., Davies, A., Davies, C., Davies, E., Davies, G., Davies, J., Davies, J., Davies, L., Davies, M., Davies, M., Davies, R., Davis, A., Davison, S., Dawe, J., Dawe, L., Dawson, L. 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  Abstract

  Importance: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive.Objective: To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19.Design, Setting, and Participants: The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021.Interventions: The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL±150 mL) within 48 hours of randomization (n=1084) or no convalescent plasma (n=916).Main Outcomes and Measures: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events.Results: Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11 secondary outcomes. Serious adverse events were reported in 3.0% (32/1075) of participants in the convalescent plasma group and in 1.3% (12/905) of participants in the no convalescent plasma group.Conclusions and Relevance: Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support-free days.Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

  View details for DOI 10.1001/jama.2021.18178

  View details for PubMedID 34606578

• RNA splicing programs define tissue compartments and cell types at single cell resolution. eLife Olivieri, J. E., Dehghannasiri, R., Wang, P. L., Jang, S., de Morree, A., Tan, S. Y., Ming, J., Ruohao Wu, A., Tabula Sapiens Consortium, Quake, S. R., Krasnow, M. A., Salzman, J. 2021; 10

  Abstract

  The extent splicing is regulated at single-cell resolution has remained controversial due to both available data and methods to interpret it. We apply the SpliZ, a new statistical approach, to detect cell-type-specific splicing in >110K cells from 12 human tissues. Using 10x data for discovery, 9.1% of genes with computable SpliZ scores are cell-type-specifically spliced, including ubiquitously expressed genes MYL6 and RPS24. These results are validated with RNA FISH, single-cell PCR, and Smart-seq2. SpliZ analysis reveals 170 genes with regulated splicing during human spermatogenesis, including examples conserved in mouse and mouse lemur. The SpliZ allows model-based identification of subpopulations indistinguishable based on gene expression, illustrated by subpopulation-specific splicing of classical monocytes involving an ultraconserved exon in SAT1. Together, this analysis of differential splicing across multiple organs establishes that splicing is regulated cell-type-specifically.

  View details for DOI 10.7554/eLife.70692

  View details for PubMedID 34515025

• RNA splicing programs define tissue compartments and cell types at single-cell resolution ELIFE Olivieri, J., Dehghannasiri, R., Wang, P. L., Jang, S., de Morree, A., Tan, S. Y., Ming, J., Wu, A., Consortium, T., Quake, S. R., Krasnow, M. A., Salzman, J. 2021; 10

  View details for DOI 10.7554/eLife.70692.sa2

  View details for Web of Science ID 000715795700001

• Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. The New England journal of medicine REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, Goligher, E. C., Bradbury, C. A., McVerry, B. J., Lawler, P. R., Berger, J. S., Gong, M. N., Carrier, M., Reynolds, H. R., Kumar, A., Turgeon, A. F., Kornblith, L. Z., Kahn, S. R., Marshall, J. C., Kim, K. S., Houston, B. L., Derde, L. P., Cushman, M., Tritschler, T., Angus, D. C., Godoy, L. C., McQuilten, Z., Kirwan, B., Farkouh, M. E., Brooks, M. M., Lewis, R. J., Berry, L. R., Lorenzi, E., Gordon, A. C., Berry, S. M., McArthur, C. J., Neal, M. D., Hochman, J. S., Webb, S. A., Zarychanski, R., Ahuja, T., Al-Beidh, F., Annane, D., Arabi, Y. M., Aryal, D., Baumann Kreuziger, L., Beane, A., Bhimani, Z., Bihari, S., Billett, H. H., Bond, L., Bonten, M., Brunkhorst, F., Buxton, M., Buzgau, A., Castellucci, L. A., Chekuri, S., Chen, J., Cheng, A. 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  Abstract

  BACKGROUND: Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.METHODS: In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.RESULTS: The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis.CONCLUSIONS: In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.).

  View details for DOI 10.1056/NEJMoa2103417

  View details for PubMedID 34351722

• Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19. The New England journal of medicine ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, Lawler, P. R., Goligher, E. C., Berger, J. S., Neal, M. D., McVerry, B. J., Nicolau, J. C., Gong, M. N., Carrier, M., Rosenson, R. S., Reynolds, H. R., Turgeon, A. F., Escobedo, J., Huang, D. T., Bradbury, C. A., Houston, B. L., Kornblith, L. Z., Kumar, A., Kahn, S. R., Cushman, M., McQuilten, Z., Slutsky, A. S., Kim, K. S., Gordon, A. C., Kirwan, B., Brooks, M. M., Higgins, A. M., Lewis, R. J., Lorenzi, E., Berry, S. M., Berry, L. R., Angus, D. C., McArthur, C. J., Webb, S. A., Farkouh, M. E., Hochman, J. S., Zarychanski, R., Aday, A. W., Al-Beidh, F., Annane, D., Arabi, Y. M., Aryal, D., Baumann Kreuziger, L., Beane, A., Bhimani, Z., Bihari, S., Billett, H. H., Bond, L., Bonten, M., Brunkhorst, F., Buxton, M., Buzgau, A., Castellucci, L. A., Chekuri, S., Chen, J., Cheng, A. 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  Abstract

  BACKGROUND: Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.METHODS: In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.RESULTS: The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.CONCLUSIONS: In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT02735707, and NCT04359277.).

  View details for DOI 10.1056/NEJMoa2105911

  View details for PubMedID 34351721

• Skeletal stem and progenitor cells maintain cranial suture patency and prevent craniosynostosis. Nature communications Menon, S., Salhotra, A., Shailendra, S., Tevlin, R., Ransom, R. C., Januszyk, M., Chan, C. K., Behr, B., Wan, D. C., Longaker, M. T., Quarto, N. 2021; 12 (1): 4640

  Abstract

  Cranial sutures are major growth centers for the calvarial vault, and their premature fusion leads to a pathologic condition called craniosynostosis. This study investigates whether skeletal stem/progenitor cells are resident in the cranial sutures. Prospective isolation by FACS identifies this population with a significant difference in spatio-temporal representation between fusing versus patent sutures. Transcriptomic analysis highlights a distinct signature in cellsderived from the physiological closing PF suture, and scRNA sequencing identifies transcriptional heterogeneity among sutures. Wnt-signaling activation increases skeletal stem/progenitor cells in sutures, whereas its inhibition decreases. Crossing Axin2LacZ/+ mouse, endowing enhanced Wnt activation, to a Twist1+/- mouse model of coronal craniosynostosis enriches skeletal stem/progenitor cells in sutures restoring patency. Co-transplantation of these cells with Wnt3a prevents resynostosis following suturectomy in Twist1+/- mice. Our study reveals that decrease and/or imbalance of skeletal stem/progenitor cells representation within sutures may underlie craniosynostosis. These findings have translational implications toward therapeutic approaches for craniosynostosis.

  View details for DOI 10.1038/s41467-021-24801-6

  View details for PubMedID 34330896

• Distinct skeletal stem cell types orchestrate long bone skeletogenesis. eLife Ambrosi, T. H., Sinha, R., Steininger, H. M., Hoover, M. Y., Murphy, M. P., Koepke, L. S., Wang, Y., Lu, W., Morri, M., Neff, N. F., Weissman, I. L., Longaker, M. T., Chan, C. K. 2021; 10

  Abstract

  Skeletal stem and progenitor cell populations are crucial for bone physiology. Characterization of these cell types remains restricted to heterogenous bulk populations with limited information on whether they are unique or overlap with previously characterized cell types. Here we show, through comprehensive functional and single-cell transcriptomic analyses, that postnatal long bones of mice contain at least two types of bone progenitors with bona fide skeletal stem cell (SSC) characteristics. An early osteochondral SSC (ocSSC) facilitates long bone growth and repair, while a second type, a perivascular SSC (pvSSC), co-emerges with long bone marrow and contributes to shape the hematopoietic stem cell niche and regenerative demand. We establish that pvSSCs, but not ocSSCs, are the origin of bone marrow adipose tissue. Lastly, we also provide insight into residual SSC heterogeneity as well as potential crosstalk between the two spatially distinct cell populations. These findings comprehensively address previously unappreciated shortcomings of SSC research.

  View details for DOI 10.7554/eLife.66063

  View details for PubMedID 34280086

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A., Roche, L., Davies, E., Turner, K., Reschreiter, H., Camsooksai, J., Patch, S., Jenkins, S., Humphrey, C., Pogson, D., Rose, S., Daly, Z., Brimfield, L., Nown, A., Parekh, D., Bergin, C., Bates, M., McGhee, C., Lynch, D., Bhandal, K., Tsakiridou, K., Bamford, A., Cooper, L., Whitehouse, T., Veenith, T., Sim, M. A., Hay, S. K., Henderson, S., Nygren, M., Valentine, E., Katary, A., Bell, G., Wilcox, L., English, K., Adams, A., Phull, M., Zaidi, A., Pogreban, T., Rosaroso, L. P., Harvey, D., Lowe, B., Meredith, M., Ryan, L., Hormis, A., Walker, R., Collier, D., Kimpton, S., Oakley, S., Rooney, K., Rodden, N., Hughes, E., Thomson, N., McGlynn, D., Clark, C., Clark, P., Walden, A., Keating, L., Frise, M., Okeke, T., Jacques, N., Coles, H., Tilney, E., Vowell, E., Schuster-Bruce, M., Pitts, S., Miln, R., ADipHE, Purandare, L., Vamplew, L., Patel, B., Dempster, D., Gummadi, M., Dormand, N., Wang, S. F., Spivey, M., Bean, S., Burt, K., Moore, L., Day, C., Gibson, C., Gordon, E., Zitter, L., Keenan, S., Singh, J., Lynch, C., Roche, L., Mikusek, J., Deacon, B., Turner, K., Szakmany, T., Baker, E., Cherian, S., Hickey, J., Champanerkar, S., Aitken, L., Prosser, L. L., Mills, G. H., Raithatha, A., Bauchmuller, K., Ahmad, N., Wiles, M., Willson, J., Grecu, I., Martin, J., Brown, C. W., Arias, A., Bevan, E., Craven, T. H., Hope, D., Singleton, J., Clark, S., McCulloch, C., Welters, I. D., Hamilton, D. O., Williams, K., Waugh, V., Shaw, D., Mulla, S., Waite, A., Roman, J. F., Martinez, M. L., Puthucheary, Z., Martin, T., Santos, F., Uddin, R., Fernandez, M., Seidu, F., Somerville, A., Pakats, M. L., Dias, P., Begum, S., Shahid, T., Bhagani, S., De Neef, M., Filipe, H., Mingos, S., Maharajh, A., Pakou, G., Nandani, A., Tatham, K. C., Jhanji, S., Black, E., Rosa, A. D., Howle, R., Baikady, R. R., Tully, R. P., Drummond, A., Dearden, J., Philbin, J. E., Munt, S., Gopal, S., Pooni, J., Ganguly, S., Smallwood, A., Metherell, S., Vuylsteke, A., Chan, C., Victor, S., Matsa, R., Gellamucho, M., Davies, M., Creagh-Brown, B., Tooley, J., Montague, L., De Beaux, F., Bullman, L., Kerslake, I., Demetriou, C., Mitchard, S., Ramos, L., White, K., Reay, M., Jenkins, S., Tuckwell, C., Watts, A., Traverse, E., Jennings, S., Donnison, P., Johns, M., Casey, R., Mattocks, L., Salisbury, S., Dark, P., Harvey, A., Doonan, R., McMorrow, L., Knowles, K., Hulme, J., Kannan, S., Joseph, S., Kinney, F., Senya, H. J., Ratnam, V., Gill, M., Kirk, J., Shelton, S., Frey, C., Scano, R., McKee, M., Murphy, P., Thomas, M., Worner, R., Faulkner, B., Gendall, E., Hayes, K., Blakemore, H., Borislavova, B., Hamilton-Davies, C., Chan, C., Mfuko, C., Abbass, H., Mandadapu, V., Leaver, S., Patel, K., Farnell-Ward, S., Saluzzio, R. P., Rawlins, J., Gordon, A., Banach, D., de Pinedo Artaraz, Z. F., Cabreros, L., White, I., Croft, M., Holland, N., Pereira, R., Zaki, A., Johnson, D., Jackson, M., Garrard, H., Juhaz, V., Brown, L., Roy, A., Rostron, A., Woods, L., Cornell, S., Pillai, S., Harford, R., Ivatt, H., Evans, D., Richards, S., Roberts, E., Bowen, J., Ainsworth, J., Clark, T., Foulds, A., Atkins, S., Lee, K., Barber, R., Hilldrith, A., Hewitt, C., Phalod, G., Bremmer, P., Ward, G., Bassford, C., Brohi, F., Jagannathan, V., Clark, M., Purvis, S., Wetherill, B., Dushianthan, A., Cusack, R., de Courcy-Golder, K., Salmon, K., Burnish, R., Smith, S., Jackson, S., Ruiz, W., Duke, Z., Johns, M., Male, M., Gladas, K., Virdee, S., Swabe, J., Tomlinson, H., Attwood, B., Parsons, P., Campbell, B., Smith, A., Page, V. J., Zhao, X. B., Oza, D., Abrahamson, G., Sheath, B., Ellis, C., Rhodes, J., Anderson, T., Morris, S., Le Tai, C. X., Thomas, A., Keen, A., Tridente, A., Shuker, K., Anders, J., Greer, S., Scott, P., Millington, A., Buchanan, P., Kirk, J., Denmade, C., Sadera, G., Jacob, R., Jones, C., Hughes, D., Digby, S., Cowley, N., Wild, L., Thrush, J., Wood, H., Austin, K., Southern, D., Reddy, H., Hulse, S., Campbell, A., Garton, M., Watkins, C., Smuts, S., Quinn, A., Simpson, B., McMillan, C., Finch, C., Hill, C., Coope, J., Budd, J., Small, C., O'Leary, R., Birch, J., Collins, E., Alexander, P. D., Felton, T., Ferguson, S., Sellers, K., Bradley-Potts, J., Yates, D., Birkinshaw, I., Kell, K., Scott, Z., Pearson, H., Adams, P., Bain, W., Barbash, I., Brant, E., Fitzpatrick, M., Franz, C. A., Girard, T. D., Huang, D. T., Basile, K., Haidar, G., Hussain, M., Kitsios, G., Linstrum, K., Mayr, F. B., Malley, B., McCreary, E., McVerry, B. J., Moghbeli, K., Rosborough, B., Shah, F., Schoenling, A., Shetty, V. U., Vita, T., Weissman, A. 2021

  Abstract

  PURPOSE: To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19).METHODS: Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR>1 is favorable.RESULTS: We randomized 694 patients to receive lopinavir-ritonavir (n=255), hydroxychloroquine (n=50), combination therapy (n=27) or control (n=362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (-1 to 15), 0 (-1 to 9) and-1 (-1 to 7), respectively, compared to 6 (-1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥99.0%), and high probabilities of harm (98.0%, 99.9% and>99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively).CONCLUSION: Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy.

  View details for DOI 10.1007/s00134-021-06448-5

  View details for PubMedID 34251506

• Opiate prescribing patterns in the adolescent population following anterior cruciate ligament reconstruction. Journal of opioid management Karius, A., Cahan, E. M., Segovia, N. A., Fan, A., Chan, C. M. 2021; 17 (4): 321-325

  Abstract

  OBJECTIVE: We sought to determine prescribing patterns for opioid analgesia following anterior cruciate ligament (ACL) reconstruction among age- and gender-stratified adolescents in a nationally representative database.DESIGN: A retrospective study.SETTING: PearlDiver Patient Records.PATIENTS, PARTICIPANTS: Outpatient opioid claims within 30 days of surgery were extracted. The patients were defined into age groups 10-14 ("younger") and 15-19 ("older"). A total of 1,139 patients were included in this study (536 female and 603 males) with 108 patients in the 10-14 age category and 1,034 patients in the 15-19 category.MAIN OUTCOME MEASURE(S): The primary study outcome measures the average number of opioid pills administered, average total morphine milligram equivalents (MMEs) prescribed, and the average prescription strength (MMEs/pill).RESULTS: No difference was found in the average number of pills (p = 0.26) or normalized total MMEs (p = 0.312) prescribed by age group. Normalized total morphine equivalents per prescription was significantly lower in females than males (p = 0.005). Multivariate linear regression analysis demonstrated that increasing patient age was predictive of fewer total pills (p = 0.017), after accounting for gender.CONCLUSIONS: There are age- and gender-based disparities in prescription patterns for adolescent ACL reconstruction. Our findings indicate that patients in the older age group on average received fewer pills than the younger age group, which consequently trended toward receiving higher total MMEs prescribed. This suggests that surgeons may be inadvertently overprescribing in the younger cohort. Additional studies that account for concurrent factors should be conducted to observe potentially similar trends.

  View details for DOI 10.5055/jom.2021.0664

  View details for PubMedID 34533826

• Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 NEW ENGLAND JOURNAL OF MEDICINE Gordon, A. C., Al-Beidh, F., Rowan, K. M., Nichol, A. D., Arabi, Y. M., Annane, D., Beane, A., Van Bentum-Puijk, W., Berry, L. R., Bhimani, Z., Bonten, M. M., Bradbury, C. A., Brunkhorst, F. M., Buzgau, A., Cheng, A. C., Detry, M. A., Duffy, E. J., Estcourt, L. J., Fitzgerald, M., Goossens, H., Haniffa, R., Higgins, A. M., Hills, T. E., Horvat, C. M., Lamontagne, F., Lawler, P. R., Leavis, H. L., Linstrum, K. M., Litton, E., Lorenzi, E., Marshall, J. C., Mayr, F. B., McAuley, D. F., McGlothlin, A., McGuinness, S. P., McVerry, B. J., Montgomery, S. K., Morpeth, S. C., Murthy, S., Orr, K., Parke, R. L., Parker, J. C., Patanwala, A. E., Pettill, V., Rademaker, E., Santos, M. S., Saunders, C. T., Seymour, C. W., Shankar-Hari, M., Sligl, W. L., Turgeon, A. F., Turner, A. M., van de Veerdonk, F. L., Zarychanski, R., Green, C., Lewis, R. J., Angus, D. C., McArthur, C. J., Berry, S., Webb, S. A., Derde, L. G., REMAP-CAP Investigators 2021: 1491–1502

  Abstract

  The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both.Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists.In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).

  View details for DOI 10.1056/NEJMoa2100433

  View details for Web of Science ID 000640379800001

  View details for PubMedID 33631065

  View details for PubMedCentralID PMC7953461

• Skeletal Stem Cells as the Developmental Origin of Cellular Niches for Hematopoietic Stem and Progenitor Cells. Current topics in microbiology and immunology Ambrosi, T. H., Chan, C. K. 2021; 434: 1-31

  Abstract

  The skeletal system is a highly complex network of mesenchymal, hematopoietic, and vasculogenic stem cell lineages that coordinate the development and maintenance of defined microenvironments, so-called niches. Technological advancements in recent years have allowed for the dissection of crucial cell types as well as their autocrine and paracrine signals that regulate these niches during development, homeostasis, regeneration, and disease. Ingress of blood vessels and bone marrow hematopoiesis are initiated by skeletal stem cells (SSCs) and their more committed downstream lineage cell types that direct shape and form of skeletal elements. In this chapter, we focus on the role of SSCs as the developmental origin of niches for hematopoietic stem and progenitor cells. We discuss latest updates in the definition of SSCs, cellular processes establishing and maintaining niches, as well as alterations of stem cell microenvironments promoting malignancies. We conclude with an outlook on future studies that could take advantage of SSC-niche engineering as a basis for the development of new therapeutic tools to not only treat bone-related diseases but also maladies stemming from derailed niche dynamics altering hematopoietic output.

  View details for DOI 10.1007/978-3-030-86016-5_1

  View details for PubMedID 34850280

• Aged skeletal stem cells generate an inflammatory degenerative niche. Nature Ambrosi, T. H., Marecic, O., McArdle, A., Sinha, R., Gulati, G. S., Tong, X., Wang, Y., Steininger, H. M., Hoover, M. Y., Koepke, L. S., Murphy, M. P., Sokol, J., Seo, E. Y., Tevlin, R., Lopez, M., Brewer, R. E., Mascharak, S., Lu, L., Ajanaku, O., Conley, S. D., Seita, J., Morri, M., Neff, N. F., Sahoo, D., Yang, F., Weissman, I. L., Longaker, M. T., Chan, C. K. 2021

  Abstract

  Loss of skeletal integrity during ageing and disease is associated with an imbalance in the opposing actions of osteoblasts and osteoclasts1. Here we show that intrinsic ageing of skeletal stem cells (SSCs)2 in mice alters signalling in the bone marrow niche and skews the differentiation of bone and blood lineages, leading to fragile bones that regenerate poorly. Functionally, aged SSCs have a decreased bone- and cartilage-forming potential but produce more stromal lineages that express high levels of pro-inflammatory and pro-resorptive cytokines. Single-cell RNA-sequencing studies link the functional loss to a diminished transcriptomic diversity of SSCs in aged mice, which thereby contributes to the transformation of the bone marrow niche. Exposure to a youthful circulation through heterochronic parabiosis or systemic reconstitution with young haematopoietic stem cells did not reverse the diminished osteochondrogenic activity of aged SSCs, or improve bone mass or skeletal healing parameters in aged mice. Conversely, the aged SSC lineage promoted osteoclastic activity and myeloid skewing by haematopoietic stem and progenitor cells, suggesting that the ageing of SSCs is a driver of haematopoietic ageing. Deficient bone regeneration in aged mice could only be returned to youthful levels by applying a combinatorial treatment of BMP2 and a CSF1 antagonist locally to fractures, which reactivated aged SSCs and simultaneously ablated the inflammatory, pro-osteoclastic milieu. Our findings provide mechanistic insights into the complex, multifactorial mechanisms that underlie skeletal ageing and offer prospects for rejuvenating the aged skeletal system.

  View details for DOI 10.1038/s41586-021-03795-7

  View details for PubMedID 34381212

• Radial Width of the Lateral Meniscus at the Popliteal Hiatus: Relevance to Saucerization of Discoid Lateral Menisci. The American journal of sports medicine Gamble, J. G., Abdalla, A. B., Meadows, M. G., Rauer, T., Chan, C. M., Ganley, T. J., Tompkins, M., Shea, K. G., Gamble, J. G. 2021: 3635465211056661

  Abstract

  A discoid lateral meniscus (DLM) is a congenital anomaly of the knee in which the lateral meniscus has an "O" shape and contains irregular, abnormal collagenous tissue. A DLM can cause mechanical symptoms and pain. Treatment of a symptomatic DLM is arthroscopic saucerization to reshape the meniscus to a more normal contour. Enough tissue must be removed to eliminate mechanical symptoms but not too much to create instability. The residual width of the meniscus is crucial at the popliteus hiatus because here the peripheral rim is unattached at the capsule. Reports in the literature recommend a residual width of 6 to 8 mm.The purpose of this research was to determine the width of the lateral meniscus at the popliteal hiatus in normal specimens. Our null hypothesis was that a residual width of 6 to 8 mm will be sufficient to approximate normal anatomy.Cross-sectional study; Level of evidence, 3.We made direct measurements of the radial width of the lateral meniscus from the outer rim at the popliteal hiatus to the inner edge in 19 specimens (age, 2-120 months.) We measured one 4-year-old specimen with a bilateral complete DLM. We also measured 39 digital images of specimens (age, 1-132 months) using ImageJ. Finally, we made direct arthroscopic measurements of 8 skeletally mature specimens.The average width of specimens <3 years old was 5.5 mm. The average width of the 10-year-old specimens was 12 mm. The average width of the skeletally mature specimens was 16 mm. A 4-year-old DLM specimen measured 19 mm.We rejected our null hypothesis. Direct measurements suggest that a residual width of 6 to 8 mm is insufficient for children ≥8 years old. A width of at least a full centimeter approximates the normal for 8-year-olds and at least 15 mm for adolescents.

  View details for DOI 10.1177/03635465211056661

  View details for PubMedID 34780308

• Prrx1 Fibroblasts Represent a Pro-fibrotic Lineage in the Mouse Ventral Dermis. Cell reports Leavitt, T., Hu, M. S., Borrelli, M. R., Januszyk, M., Garcia, J. T., Ransom, R. C., Mascharak, S., desJardins-Park, H. E., Litzenburger, U. M., Walmsley, G. G., Marshall, C. D., Moore, A. L., Duoto, B., Adem, S., Foster, D. S., Salhotra, A., Shen, A. H., Griffin, M., Shen, E. Z., Barnes, L. A., Zielins, E. R., Maan, Z. N., Wei, Y., Chan, C. K., Wan, D. C., Lorenz, H. P., Chang, H. Y., Gurtner, G. C., Longaker, M. T. 2020; 33 (6): 108356

  Abstract

  Fibroblast heterogeneity has been shown within the unwounded mouse dorsal dermis, with fibroblast subpopulations being identified according to anatomical location and embryonic lineage. Using lineage tracing, we demonstrate that paired related homeobox 1 (Prrx1)-expressing fibroblasts are responsible for acute and chronic fibroses in the ventral dermis. Single-cell transcriptomics further corroborated the inherent fibrotic characteristics of Prrx1 fibroblasts during wound repair. In summary, we identify and characterize a fibroblast subpopulation in the mouse ventral dermis with intrinsic scar-forming potential.

  View details for DOI 10.1016/j.celrep.2020.108356

  View details for PubMedID 33176144

• Delayed Union of a Diaphyseal Forearm Fracture Associated With Impaired Osteogenic Differentiation of Prospectively Isolated Human Skeletal Stem Cells. JBMR plus Goodnough, L. H., Ambrosi, T. H., Steininger, H., DeBaun, M. R., Abrams, G. D., McAdams, T. R., Gardner, M. J., Chan, C. K., Bishop, J. A. 2020; 4 (10): e10398

  Abstract

  Delayed union or nonunion are relatively rare complications after fracture surgery, but when they do occur, they can result in substantial morbidity for the patient. In many cases, the etiology of impaired fracture healing is uncertain and attempts to determine the molecular basis for delayed union and nonunion formation have been limited. Prospectively isolating skeletal stem cells (SSCs) from fracture tissue samples at the time of surgical intervention represent a feasible methodology to determine a patient's biologic risk for compromised fracture healing. This report details a case in which functional in vitro readouts of SSCs derived from human fracture tissue at time of injury predicted a poor fracture healing outcome. This case suggests that it may be feasible to stratify a patient's fracture healing capacity and predict compromised fracture healing by prospectively isolating and analyzing SSCs during the index fracture surgery. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

  View details for DOI 10.1002/jbm4.10398

  View details for PubMedID 33103027

• Human skeletal stem cell aging AGING-US Ambrosi, T. H., Goodnough, L., Chan, C. F. 2020; 12 (17): 16669–71

  View details for Web of Science ID 000572850000003

• Human skeletal stem cell aging. Aging Ambrosi, T. H., Goodnough, L. H., Chan, C. K. 2020

  View details for DOI 10.18632/aging.104034

  View details for PubMedID 32929053

• Articular cartilage regeneration by activated skeletal stem cells. Nature medicine Murphy, M. P., Koepke, L. S., Lopez, M. T., Tong, X., Ambrosi, T. H., Gulati, G. S., Marecic, O., Wang, Y., Ransom, R. C., Hoover, M. Y., Steininger, H., Zhao, L., Walkiewicz, M. P., Quarto, N., Levi, B., Wan, D. C., Weissman, I. L., Goodman, S. B., Yang, F., Longaker, M. T., Chan, C. K. 2020

  Abstract

  Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of articular cartilage1. The etiology of OA is complex and involves a variety of factors, including genetic predisposition, acute injury and chronic inflammation2-4. Here we investigate the ability of resident skeletal stem-cell (SSC) populations to regenerate cartilage in relation to age, a possible contributor to the development of osteoarthritis5-7. We demonstrate that aging is associated with progressive loss of SSCs and diminished chondrogenesis in the joints of both mice and humans. However, a local expansion of SSCs could still be triggered in the chondral surface of adult limb joints in mice by stimulating a regenerative response using microfracture (MF) surgery. Although MF-activated SSCs tended to form fibrous tissues, localized co-delivery of BMP2 and soluble VEGFR1 (sVEGFR1), a VEGF receptor antagonist, in a hydrogel skewed differentiation of MF-activated SSCs toward articular cartilage. These data indicate that following MF, a resident stem-cell population can be induced to generate cartilage for treatment of localized chondral disease in OA.

  View details for DOI 10.1038/s41591-020-1013-2

  View details for PubMedID 32807933

• Relationship Between Dynamic Limb Symmetry And Subjective Limb Confidence Post ACL Reconstruction In Youth Athletes Morgan, J. J., Lyons, S. M., Chan, S. K., Chan, C. M., Shea, K. G., Kraus, E. A. LIPPINCOTT WILLIAMS & WILKINS. 2020: 2–3

  View details for Web of Science ID 000590026300006

• Geriatric fragility fractures are associated with a human skeletal stem cell defect. Aging cell Ambrosi, T. H., Goodnough, L. H., Steininger, H. M., Hoover, M. Y., Kim, E., Koepke, L. S., Marecic, O., Zhao, L., Seita, J., Bishop, J. A., Gardner, M. J., Chan, C. K. 2020: e13164

  Abstract

  Fragility fractures have a limited capacity to regenerate, and impaired fracture healing is a leading cause of morbidity in the elderly. The recent identification of a highly purified bona fide human skeletal stem cell (hSSC) and its committed downstream progenitor cell populations provides an opportunity for understanding the mechanism of age-related compromised fracture healing from the stem cell perspective. In this study, we tested whether hSSCs isolated from geriatric fractures demonstrate intrinsic functional defects that drive impaired healing. Using flow cytometry, we analyzed and isolated hSSCs from callus tissue of five different skeletal sites (n=61) of patients ranging from 13 to 94years of age for functional and molecular studies. We observed that fracture-activated amplification of hSSC populations was comparable at all ages. However, functional analysis of isolated stem cells revealed that advanced age significantly correlated with reduced osteochondrogenic potential but was not associated with decreased in vitro clonogenicity. hSSCs derived from women displayed an exacerbated functional decline with age relative to those of aged men. Transcriptomic comparisons revealed downregulation of skeletogenic pathways such as WNT and upregulation of senescence-related pathways in young versus older hSSCs. Strikingly, loss of Sirtuin1 expression played a major role in hSSC dysfunction but re-activation by trans-resveratrol or a small molecule compound restored in vitro differentiation potential. These are the first findings that characterize age-related defects in purified hSSCs from geriatric fractures. Our results provide a foundation for future investigations into the mechanism and reversibility of skeletal stem cell aging in humans.

  View details for DOI 10.1111/acel.13164

  View details for PubMedID 32537886

• Therapeutic modulation of phagocytosis in glioblastoma can activate both innate and adaptive antitumour immunity. Nature communications von Roemeling, C. A., Wang, Y., Qie, Y., Yuan, H., Zhao, H., Liu, X., Yang, Z., Yang, M., Deng, W., Bruno, K. A., Chan, C. K., Lee, A. S., Rosenfeld, S. S., Yun, K., Johnson, A. J., Mitchell, D. A., Jiang, W., Kim, B. Y. 2020; 11 (1): 1508

  Abstract

  Tumour cell phagocytosis by antigen presenting cells (APCs) is critical to the generation of antitumour immunity. However, cancer cells can evade phagocytosis by upregulating anti-phagocytosis molecule CD47. Here, we show that CD47 blockade alone is inefficient in stimulating glioma cell phagocytosis. However, combining CD47 blockade with temozolomide results in a significant pro-phagocytosis effect due to the latter's ability to induce endoplasmic reticulum stress response. Increased tumour cell phagocytosis subsequently enhances antigen cross-presentation and activation of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) in APCs, resulting in more efficient T cell priming. This bridging of innate and adaptive responses inhibits glioma growth, but also activates immune checkpoint. Sequential administration of an anti-PD1 antibody overcomes this potential adaptive resistance. Together, these findings reveal a dynamic relationship between innate and adaptive immune regulation in tumours and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses.

  View details for DOI 10.1038/s41467-020-15129-8

  View details for PubMedID 32198351

• Expansion of Bone Precursors through Jun as a Novel Treatment for Osteoporosis-Associated Fractures. Stem cell reports Lerbs, T., Cui, L., Muscat, C., Saleem, A., van Neste, C., Domizi, P., Chan, C., Wernig, G. 2020

  Abstract

  Osteoporosis and osteoporotic fractures lead to decreased life quality and high healthcare costs. Current treatments prevent losses in bone mass and fractures to some extent but have side effects. Therefore, better therapies are needed. This study investigated whether the transcriptionfactor Jun has a specific pro-osteogenic potency and whether modulating Jun could serve as a novel treatment for osteoporosis-associated fractures. We demonstrate that ectopically transplanted whole bones and distinct osteoprogenitors increase bone formation. Perinatal Jun induction disturbs growth plate architecture, causing a striking phenotype with shortened and thickened bones. Molecularly, Jun induces hedgehog signaling in skeletal stem cells. Therapeutically, Jun accelerates bone growth and healing in a drilling-defect model. Altogether, these results demonstrate that Jun drives bone formation by expanding osteoprogenitor populations and forcing them into the bone fate, providing a rationale for future clinical applications.

  View details for DOI 10.1016/j.stemcr.2020.02.009

  View details for PubMedID 32197115

• A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 2020

  Abstract

  Ageing is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death1. Despite rapid advances over recent years, many of the molecular and cellular processes that underlie the progressive loss of healthy physiology are poorly understood2. To gain a better insight into these processes, here we generate a single-cell transcriptomic atlas across the lifespan of Mus musculus that includes data from 23 tissues and organs. We found cell-specific changes occurring across multiple cell types and organs, as well as age-related changes in the cellular composition of different organs. Using single-cell transcriptomic data, we assessed cell-type-specific manifestations of different hallmarks of ageing-such as senescence3, genomic instability4 and changes in the immune system2. This transcriptomic atlas-which we denote Tabula Muris Senis, or 'Mouse Ageing Cell Atlas'-provides molecular information about how the most important hallmarks of ageing are reflected in a broad range of tissues and cell types.

  View details for DOI 10.1038/s41586-020-2496-1

  View details for PubMedID 32669714

• Ageing hallmarks exhibit organ-specific temporal signatures. Nature Schaum, N. n., Lehallier, B. n., Hahn, O. n., Pálovics, R. n., Hosseinzadeh, S. n., Lee, S. E., Sit, R. n., Lee, D. P., Losada, P. M., Zardeneta, M. E., Fehlmann, T. n., Webber, J. T., McGeever, A. n., Calcuttawala, K. n., Zhang, H. n., Berdnik, D. n., Mathur, V. n., Tan, W. n., Zee, A. n., Tan, M. n., Pisco, A. O., Karkanias, J. n., Neff, N. F., Keller, A. n., Darmanis, S. n., Quake, S. R., Wyss-Coray, T. n. 2020

  Abstract

  Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified-such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function1-these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus, and integrated these findings with data from the accompanying Tabula Muris Senis2-or 'Mouse Ageing Cell Atlas'-which follows on from the original Tabula Muris3. We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions-including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue-including plasma cells that express immunoglobulin J-which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age.

  View details for DOI 10.1038/s41586-020-2499-y

  View details for PubMedID 32669715

• Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. JAMA Angus, D. C., Derde, L. n., Al-Beidh, F. n., Annane, D. n., Arabi, Y. n., Beane, A. n., van Bentum-Puijk, W. n., Berry, L. n., Bhimani, Z. n., Bonten, M. n., Bradbury, C. n., Brunkhorst, F. n., Buxton, M. n., Buzgau, A. n., Cheng, A. C., de Jong, M. n., Detry, M. n., Estcourt, L. n., Fitzgerald, M. n., Goossens, H. n., Green, C. n., Haniffa, R. n., Higgins, A. M., Horvat, C. n., Hullegie, S. J., Kruger, P. n., Lamontagne, F. n., Lawler, P. R., Linstrum, K. n., Litton, E. n., Lorenzi, E. n., Marshall, J. n., McAuley, D. n., McGlothin, A. n., McGuinness, S. n., McVerry, B. n., Montgomery, S. n., Mouncey, P. n., Murthy, S. n., Nichol, A. n., Parke, R. n., Parker, J. n., Rowan, K. n., Sanil, A. n., Santos, M. n., Saunders, C. n., Seymour, C. n., Turner, A. n., van de Veerdonk, F. n., Venkatesh, B. n., Zarychanski, R. n., Berry, S. n., Lewis, R. J., McArthur, C. n., Webb, S. A., Gordon, A. 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P., Harvey, D. n., Lowe, B. n., Meredith, M. n., Ryan, L. n., Hormis, A. n., Walker, R. n., Collier, D. n., Kimpton, S. n., Oakley, S. n., Rooney, K. n., Rodden, N. n., Hughes, E. n., Thomson, N. n., McGlynn, D. n., Walden, A. n., Jacques, N. n., Coles, H. n., Tilney, E. n., Vowell, E. n., Schuster-Bruce, M. n., Pitts, S. n., Miln, R. n., Purandare, L. n., Vamplew, L. n., Spivey, M. n., Bean, S. n., Burt, K. n., Moore, L. n., Day, C. n., Gibson, C. n., Gordon, E. n., Zitter, L. n., Keenan, S. n., Baker, E. n., Cherian, S. n., Cutler, S. n., Roynon-Reed, A. n., Harrington, K. n., Raithatha, A. n., Bauchmuller, K. n., Ahmad, N. n., Grecu, I. n., Trodd, D. n., Martin, J. n., Wrey Brown, C. n., Arias, A. M., Craven, T. n., Hope, D. n., Singleton, J. n., Clark, S. n., Rae, N. n., Welters, I. n., Hamilton, D. O., Williams, K. n., Waugh, V. n., Shaw, D. n., Puthucheary, Z. n., Martin, T. n., Santos, F. n., Uddin, R. n., Somerville, A. n., Tatham, K. C., Jhanji, S. n., Black, E. n., Dela Rosa, A. n., Howle, R. n., Tully, R. n., Drummond, A. n., Dearden, J. n., Philbin, J. n., Munt, S. n., Vuylsteke, A. n., Chan, C. n., Victor, S. n., Matsa, R. n., Gellamucho, M. n., Creagh-Brown, B. n., Tooley, J. n., Montague, L. n., De Beaux, F. n., Bullman, L. n., Kersiake, I. n., Demetriou, C. n., Mitchard, S. n., Ramos, L. n., White, K. n., Donnison, P. n., Johns, M. n., Casey, R. n., Mattocks, L. n., Salisbury, S. n., Dark, P. n., Claxton, A. n., McLachlan, D. n., Slevin, K. n., Lee, S. n., Hulme, J. n., Joseph, S. n., Kinney, F. n., Senya, H. J., Oborska, A. n., Kayani, A. n., Hadebe, B. n., Orath Prabakaran, R. n., Nichols, L. n., Thomas, M. n., Worner, R. n., Faulkner, B. n., Gendall, E. n., Hayes, K. n., Hamilton-Davies, C. n., Chan, C. n., Mfuko, C. n., Abbass, H. n., Mandadapu, V. n., Leaver, S. n., Forton, D. n., Patel, K. n., Paramasivam, E. n., Powell, M. n., Gould, R. n., Wilby, E. n., Howcroft, C. n., Banach, D. n., Fernández de Pinedo Artaraz, Z. n., Cabreros, L. n., White, I. n., Croft, M. n., Holland, N. n., Pereira, R. n., Zaki, A. n., Johnson, D. n., Jackson, M. n., Garrard, H. n., Juhaz, V. n., Roy, A. n., Rostron, A. n., Woods, L. n., Cornell, S. n., Pillai, S. n., Harford, R. n., Rees, T. n., Ivatt, H. n., Sundara Raman, A. n., Davey, M. n., Lee, K. n., Barber, R. n., Chablani, M. n., Brohi, F. n., Jagannathan, V. n., Clark, M. n., Purvis, S. n., Wetherill, B. n., Dushianthan, A. n., Cusack, R. n., de Courcy-Golder, K. n., Smith, S. n., Jackson, S. n., Attwood, B. n., Parsons, P. n., Page, V. n., Zhao, X. B., Oza, D. n., Rhodes, J. n., Anderson, T. n., Morris, S. n., Xia Le Tai, C. n., Thomas, A. n., Keen, A. n., Digby, S. n., Cowley, N. n., Wild, L. n., Southern, D. n., Reddy, H. n., Campbell, A. n., Watkins, C. n., Smuts, S. n., Touma, O. n., Barnes, N. n., Alexander, P. n., Felton, T. n., Ferguson, S. n., Sellers, K. n., Bradley-Potts, J. n., Yates, D. n., Birkinshaw, I. n., Kell, K. n., Marshall, N. n., Carr-Knott, L. n. 2020; 324 (13): 1317–29

  Abstract

  Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.To determine whether hydrocortisone improves outcome for patients with severe COVID-19.An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively.Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.ClinicalTrials.gov Identifier: NCT02735707.

  View details for DOI 10.1001/jama.2020.17022

  View details for PubMedID 32876697

  View details for PubMedCentralID PMC7489418

• A Brain-Dependent Osteogenic Factor Dramatically Enhances the Capacity of Skeletal Stem Cells to form Bone in Female Mice Herber, C., Ventura, P., Villeda, S., Ingraham, H., Ambrosi, T., Chan, C., Lane, N. WILEY. 2019: 57

  View details for Web of Science ID 000508614700162

• A Brain-Dependent Osteogenic Factor Dramatically Enhances the Capacity of Skeletal Stem Cells to form Bone in Female Mice Herber, C., Ventura, P., Villeda, S., Ingraham, H., Ambrosi, T., Chan, C., Lane, N. WILEY. 2019: 57

  View details for Web of Science ID 000508356600162

• Role of the Skeletal Stem Cell in Achilles Tendon to Bone Interface Healing Titan, A. L., Jones, R., Salhotra, A., Robertson, K. S., Foster, D., Menon, S., Murphy, M., Lucero, G. V., Chan, C. K., Longaker, M. T. ELSEVIER SCIENCE INC. 2019: S228–S229

  View details for Web of Science ID 000492740900438

• A Revised Perspective of Skeletal Stem Cell Biology. Frontiers in cell and developmental biology Ambrosi, T. H., Longaker, M. T., Chan, C. K. 2019; 7: 189

  Abstract

  Bone-related maladies are a major health burden on modern society. Loss of skeletal integrity and regeneration capacity through aging, obesity, and disease follows from a detrimental shift in bone formation and resorption dynamics. Targeting tissue-resident adult stem cells offers a potentially innovative paradigm in the development of therapeutic strategies against organ dysfunction. While the essential role of skeletal stem cells (SSCs) for development, growth, and maintenance of the skeleton has been generally established, a common consensus on the exact identity and definition of a pure bona fide SSC population remains elusive. The controversies stem from conflicting results between different approaches and criteria for isolation, detection, and functional evaluation; along with the interchangeable usage of the terms SSC and "mesenchymal stromal/stem cell (MSC)". A great number of prospective bone-forming stem cell populations have been reported with various characteristic markers, often describing overlapping cell populations with widely unexplored heterogeneity, species specificity, and distribution at distinct skeletal sites, bone regions, and microenvironments, thereby creating confusion that may complicate future advances in the field. In this review, we examine the state-of-the-art knowledge of SSC biology and try to establish a common ground for the definition and terminology of specific bone-resident stem cells. We also discuss recent advances in the identification of highly purified SSCs, which will allow detailed interrogation of SSC diversity and regulation at the single-cell level.

  View details for DOI 10.3389/fcell.2019.00189

  View details for PubMedID 31572721

  View details for PubMedCentralID PMC6753172

• A Revised Perspective of Skeletal Stem Cell Biology FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY Ambrosi, T. H., Longaker, M. T., Chan, C. F. 2019; 7

  View details for DOI 10.3389/fcell.2019.00189

  View details for Web of Science ID 000485330300001

• Sport Participation and Specialization Characteristics Among Pediatric Soccer Athletes ORTHOPAEDIC JOURNAL OF SPORTS MEDICINE McLeod, T., Israel, M., Christino, M. A., Chung, J. S., McKay, S. D., Lang, P. J., Bell, D. R., Chan, C. M., Crepeau, A., Davis, E., Fletcher, A. L., Laniak, J., McCaffrey, K., Pacicca, D., Riederer, M., Rizzone, K., Rush, J. K., Zaslow, T., PRiSM Sports Specialization Res 2019; 7 (3): 2325967119832399

  Abstract

  Soccer is an increasingly popular sport for children and adolescents in the United States. Little is known about participation patterns related to sport specialization.To investigate soccer participation levels and sport specialization characteristics among youth soccer athletes.Cross-sectional study.Adolescent athletes aged between 12 and 18 years completed an online survey addressing participant demographics, sports and soccer participation history, and level of specialization. Descriptive analyses characterized participation, while chi-square and Kruskal-Wallis tests assessed the influence of specialization, sex, and grade on survey variables.Overall, 83.7% of 746 respondents participated in an organized soccer league outside of school, and 37% played in multiple leagues concurrently. Nearly three-quarters of respondents trained in soccer more than 8 months of the year, with those who participated in club soccer being more likely to train more than 8 months of the year. More respondents were classified as high specialization (37.5%), followed by moderate (35.6%) and low (28.6%) specialization. No differences between sexes were noted for level of specialization or quitting other sports to specialize in soccer, but male athletes were more likely to train more than 8 months per year compared with female athletes. Respondents in older grades (9th-10th and 11th-12th grades) were more likely to be highly specialized and quit other sports to focus on soccer. No differences between grade levels were found among respondents training more than 8 months per year.The study findings suggest that many youth soccer athletes participated in multiple teams or leagues at the same time and trained more than 8 months of the year. Characteristics including participation on a club team, level of specialization, and male sex were associated with a greater likelihood of exceeding the 8-month training recommendation.

  View details for DOI 10.1177/2325967119832399

  View details for Web of Science ID 000462590100001

  View details for PubMedID 30944839

  View details for PubMedCentralID PMC6437330

• A little bit faster: Lower extremity joint kinematics and kinetics as recreational runners achieve faster speeds (vol 71, pg 167, 2018) JOURNAL OF BIOMECHANICS Orendurff, M. S., Kobayashi, T., Tulchin-Francis, K., Tullock, A., Villarosa, C., Chan, C., Kraus, E., Strike, S. 2019; 82: 404

  View details for DOI 10.1016/j.jbiomech.2018.10.034

  View details for Web of Science ID 000456353700052

• Computer Navigation for Pediatric Femoral ACL Tunnel Placement. The Iowa orthopaedic journal Popkin, C. A., Chan, C. M., Nowell, J. A., Crowley, S. G., Wright, M. n., Ahmad, C. S. 2019; 39 (1): 121–29

  Abstract

  To compare accuracy, time and radiation exposure of pediatric femoral tunnel placement using computer navigation with a traditional freehand technique.A single all-epiphyseal femoral tunnel was placed in the distal femur of 20 Sawbones™ adolescent knee models. Ten tunnels were drilled using standard fluoroscopic guidance (FG). An additional 10 tunnels were drilled using 3D fluoroscopic computer navigation (CN). Both techniques aimed to match an exact point described by the quadrant system of Bernard. Time to perform the procedure was recorded as were number of single shot fluoroscopic images and approximate effective radiation doses.The deviation from ideal femoral tunnel position was on average 6.4 ± 4.2 mm for FG tunnels and 2.7 ± 3.1 mm for CN tunnels (p<0.05) . There was no violation of the femoral growth plate using either technique. The surgeon was exposed to 17 ± 5.3 and 3 ± 0.66 single fluoroscopy exposures for FG and CN guidance, respectively (p<0.05). However, the effective dose for the CN because of the acquisition of 3D images was 0.52±.003 mSv and for FG was only 0.09mSv ± .027 (p <0.001). CN however required on average 12.5 ± 3.4 min compared to 4.6 ± 1.7 for FG (p<0.05) to complete drilling of the tunnel.CN achieves a more accurate epiphyseal femoral ACL tunnel position but requires more time to complete and has a higher effective radiation dose than FG. Whether the CN ACL tunnels can translate to improved clinical outcomes is still unknown.Level of Evidence: V.

  View details for PubMedID 31413685

• Mechanoresponsive stem cells acquire neural crest fate in jaw regeneration NATURE Ransom, R. C., Carter, A. C., Salhotra, A., Leavitt, T., Marecic, O., Murphy, M. P., Lopez, M. L., Wei, Y., Marshall, C. D., Shen, E. Z., Jones, R., Sharir, A., Klein, O. D., Chan, C. F., Wan, D. C., Chang, H. Y., Longaker, M. T. 2018; 563 (7732): 514-+

  View details for DOI 10.1038/s41586-018-0650-9

  View details for Web of Science ID 000450960000045

• Corrigendum to "A little bit faster: Lower extremity joint kinematics and kinetics as recreational runners achieve faster speeds" [J. Biomech. 71 (2018) 167-175]. Journal of biomechanics Orendurff, M. S., Kobayashi, T., Tulchin-Francis, K., Tullock, A. M., Villarosa, C., Chan, C., Kraus, E., Strike, S. 2018

  View details for PubMedID 30442429

• THERAPEUTIC MODULATION OF THE PHAGOCYTIC AXIS SPARKS ANTI-TUMOR CD8 T CELL RESPONSES IN GLIOBLASTOMA von Roemeling, C., Qie, Y., Jiang, W., Chen, Y., Shih, K., Liu, X., Knight, J., Tian, R., Chan, C., Kim, B. OXFORD UNIV PRESS INC. 2018: 124

  View details for Web of Science ID 000460646300519

• Identification of the Human Skeletal Stem Cell CELL Chan, C. F., Gulati, G. S., Sinha, R., Tompkins, J., Lopez, M., Carter, A. C., Ransom, R. C., Reinisch, A., Wearda, T., Murphy, M., Brewer, R. E., Koepke, L. S., Marecic, O., Manjunath, A., Seo, E., Leavitt, T., Lu, W., Allison Nguyen, Conley, S. D., Salhotra, A., Ambrosi, T. H., Borrelli, M. R., Siebel, T., Chan, K., Schallmoser, K., Seita, J., Sahoo, D., Goodnough, H., Bishop, J., Gardner, M., Majeti, R., Wan, D. C., Goodman, S., Weissman, I. L., Chang, H. Y., Longaker, M. T. 2018; 175 (1): 43-+

  View details for DOI 10.1016/j.cell.2018.07.029

  View details for Web of Science ID 000445120000013

• THE LOWER EXTREMITY GRADING SYSTEM (LEGS) TO EVALUATE BASELINE LOWER EXTREMITY PERFORMANCE IN HIGH SCHOOL ATHLETES. International journal of sports physical therapy Smith, J., DePhillipo, N., Azizi, S., McCabe, A., Beverine, C., Orendurff, M., Pun, S., Chan, C. 2018; 13 (3): 401–9

  Abstract

  Background and Purpose: Lower extremity athletic injuries result in impairments in balance, power, and jump-landing mechanics. Unilateral injury has bilateral effects and the literature supports that it is important to assess neuromuscular impairments such as balance, power, and jumping mechanics following injury and for safe return to sport after injury rehabilitation. Currently, individual tests are established in the literature, but no combined approach or clinical tool exists for this purpose. The purpose of this study is to describe and provide the initial data for the Lower Extremity Grading System (LEGS), comprised of three neuromuscular components for use as a baseline pre-season assessment for high school athletes to assess lower extremity performance. Furthermore, this study focuses on the differences in baseline lower extremity performance outcomes between male and female soccer and basketball athletes.Methods: One hundred and eighty-five high school basketball, and soccer athletes (94 female, 91 male; mean age = 15.6±4.4) participated. The participants were administered the LEGS assessment during the preseason for their respective sports, which includes three component tests: (1) Y-balance test, (2) drop vertical jump test, (3) triple-crossover-hop-for-distance test. Participants' scores on each test were recorded, and then totaled to present an overall LEGS composite score. Participants' baseline LEGS scores were then analyzed according to sex and sport, and standard normal distribution was calculated for all scores to enable percentile rankings to be established.Results: Mean scores and standard deviation for each functional performance test are presented. Furthermore, a LEGS composite score combining the test scores was established and presented as a normal distribution curve allowing for further comparison and analysis. The mean LEGS composite score for males was 700.3 (±76.6), while the mean LEGS composite score for females was 587.4 (±51.6). Statistically different LEGS composite scores were found between males and females.Conclusion: The current findings present descriptive data for the utility of the LEGS as a neuromuscular baseline assessment before high school sports participation and/or as a tool for assessing return to sports after injury rehabilitation. The LEGS may augment current assessment tools and may serve as a composite score and combined approach to the assessment of lower extremity risk of injury and readiness to return to sports.Level of evidence: 3.

  View details for PubMedID 30038826

• THE LOWER EXTREMITY GRADING SYSTEM (LEGS) TO EVALUATE BASELINE LOWER EXTREMITY PERFORMANCE IN HIGH SCHOOL ATHLETES INTERNATIONAL JOURNAL OF SPORTS PHYSICAL THERAPY Smith, J., DePhillipo, N., Azizi, S., McCabe, A., Beverine, C., Orendurff, M., Pun, S., Chan, C. 2018; 13 (3): 401–9

  View details for DOI 10.26603/ijspt20180401

  View details for Web of Science ID 000442339400005

• MANAGEMENT OF OSTEOCHONDRITIS DISSECANS OF THE FEMORAL CONDYLE A Critical Analysis Review JBJS REVIEWS Chan, C., Richmond, C., Shea, K. G., Frick, S. L. 2018; 6 (3)

  View details for DOI 10.2106/JBJS.RVW.17.00005

  View details for Web of Science ID 000437210100005

• Prolonged survival of transplanted stem cells after ischaemic injury via the slow release of pro-survival peptides from a collagen matrix. Nature biomedical engineering Lee, A. S., Inayathullah, M., Lijkwan, M. A., Zhao, X., Sun, W., Park, S., Hong, W. X., Parekh, M. B., Malkovskiy, A. V., Lau, E., Qin, X., Pothineni, V. R., Sanchez-Freire, V., Zhang, W. Y., Kooreman, N. G., Ebert, A. D., Chan, C. K., Nguyen, P. K., Rajadas, J., Wu, J. C. 2018; 2 (2): 104-113

  Abstract

  Stem-cell-based therapies hold considerable promise for regenerative medicine. However, acute donor-cell death within several weeks after cell delivery remains a critical hurdle for clinical translation. Co-transplantation of stem cells with pro-survival factors can improve cell engraftment, but this strategy has been hampered by the typically short half-lives of the factors and by the use of Matrigel and other scaffolds that are not chemically defined. Here, we report a collagen-dendrimer biomaterial crosslinked with pro-survival peptide analogues that adheres to the extracellular matrix and slowly releases the peptides, significantly prolonging stem cell survival in mouse models of ischaemic injury. The biomaterial can serve as a generic delivery system to improve functional outcomes in cell-replacement therapy.

  View details for DOI 10.1038/s41551-018-0191-4

  View details for PubMedID 29721363

  View details for PubMedCentralID PMC5927627

• Management of Osteochondritis Dissecans of the Femoral Condyle: A Critical Analysis Review. JBJS reviews Chan, C. n., Richmond, C. n., Shea, K. G., Frick, S. L. 2018; 6 (3): e5

  View details for PubMedID 29557795

• A little bit faster: Lower extremity joint kinematics and kinetics as recreational runners achieve faster speeds. Journal of biomechanics Orendurff, M. S., Kobayashi, T. n., Tulchin-Francis, K. n., Tullock, A. M., Villarosa, C. n., Chan, C. n., Strike, S. n. 2018; 71: 167–75

  Abstract

  There appears a linear relationship between small increases in running speed and cardiovascular health benefits. Encouraging or coaching recreational runners to increase their running speed to derive these health benefits might be more effective if their joint level kinematic and kinetic strategy was understood. The aim of this investigation was to compare the peak sagittal plane motions, moments, and powers of the hip, knee and ankle at 85%, 100%, 115% and 130% of self-selected running speed. Overground running data were collected in 12 recreational runners (6 women, 6 men) with a full body marker set using a 12-camera Vicon MX system with an AMTI force plate. Kinematics and kinetics were analyzed with Vicon Nexus software. Participants chose to run at 2.6 ± 0.5 m/s (85%); 3.0 ± 0.5 m/s (100%); 3.3 ± 0.5 m/s (115%); and 3.7 ± 0.5 m/s (130%); these four speeds approximately correspond to 6:24-, 5:33-, 5:03-, and 4:30-min kilometer running paces. Running speed had a significant effect (P < 0.05) on peak kinematic and kinetic variables of the hips, knees and ankles, with peak sagittal hip moments invariant (P > 0.54) and the peak sagittal ankle power generation (P < 0.0001) the most highly responsive variable. The timing of the peak sagittal extensor moments and powers at the hip, knee and ankle were distributed across stance in a sequential manner. This study shows that running speed affects lower limb joint kinematics and kinetics and suggests that specific intersegmental kinetic strategies might exist across the narrow range of running speeds.

  View details for PubMedID 29472010

• Patellar Instability in the Skeletally Immature. Current reviews in musculoskeletal medicine Popkin, C. A., Bayomy, A. F., Trupia, E. P., Chan, C. M., Redler, L. H. 2018

  Abstract

  This review will focus on the evaluation and management of patellar instability in the developing patient.A large number of surgical techniques have been described to prevent recurrent patellofemoral instability in the pediatric population, including both proximal and distal realignment procedures. The wide variety of treatment options highlights the lack of agreement as to the best surgical approach. However, when a comprehensive exam and workup are paired with a surgical plan to address each of the identified abnormalities, outcomes are predictably good. Patellar instability is a common knee disorder in the skeletally immature patient that presents a unique set of challenges. Rates of re-dislocation in pediatric and adolescent patients are higher than in their adult counterparts. Careful consideration of the physeal and apophyseal anatomy is essential in these patients. While the majority of primary patellar instability events can be treated conservatively, multiple events often require surgical intervention.

  View details for PubMedID 29682681

• Rescue of Del1 Knock Out Phenotype in Bone Fracture Healing in Mice Boyko, T. V., Marecic, O., Lopez, M., Seo, E., Tong, X., Chan, C., Longaker, M. T., Yang, G. P. ELSEVIER SCIENCE INC. 2017: S89–S90

  View details for DOI 10.1016/j.jamcollsurg.2017.07.192

  View details for Web of Science ID 000413315300183

• Shifting Skeletal Stem Cell Dynamics Underlie Skeletal Aging in Mice Marecic, O., McArdle, A., Seo, E., Tevlin, R., Gulati, G. S., Murphy, M. P., Lopez, M., Weissman, I. L., Chan, C. K., Longaker, M. T. ELSEVIER SCIENCE INC. 2017: S166

  View details for DOI 10.1016/j.jamcollsurg.2017.07.374

  View details for Web of Science ID 000413315300353

• Cellular Mechanisms Underlying Regeneration in Mandibular Distraction Osteogenesis Ransom, R. C., Leavitt, T., Murphy, M. P., Marecic, O., Lopez, M., Marshall, C. D., Barnes, L. A., Wan, D. C., Chan, C. K., Longaker, M. T. ELSEVIER SCIENCE INC. 2017: E143–E144

  View details for DOI 10.1016/j.jamcollsurg.2017.07.914

  View details for Web of Science ID 000413319300350

• Activation of the Mouse Resident Skeletal Stem Cell for Articular Cartilage Repair Murphy, M. P., Lopez, M., Ransom, R. C., Marecic, O., Gulati, G. S., Chan, C. K., Longaker, M. T. ELSEVIER SCIENCE INC. 2017: S160

  View details for DOI 10.1016/j.jamcollsurg.2017.07.360

  View details for Web of Science ID 000413315300339

• Lessons from immuno-oncology: a new era for cancer nanomedicine? NATURE REVIEWS DRUG DISCOVERY Jiang, W., Yuan, H., Chan, C. K., von Roemeling, C. A., Yan, Z., Weissman, I. L., Kim, B. S. 2017; 16 (6): 369–70

  Abstract

  Despite a decade of intensive preclinical research, the translation of cancer nanomedicine to the clinic has been slow. Here, we discuss how recent lessons learned from the successes with immuno-oncology therapies could be applied to cancer nanomedicine and how this may help to overcome some of the key technical challenges in this field.

  View details for PubMedID 28303024

• Detection of Femoral Neck Fractures in Pediatric Patients With Femoral Shaft Fractures JOURNAL OF PEDIATRIC ORTHOPAEDICS Caldwell, L., Chan, C. M., Sanders, J. O., Gorczyca, J. T. 2017; 37 (3): E164-E167

  Abstract

  Ipsilateral femoral neck fractures occur in 1% to 9% of adult trauma patients with femoral shaft fractures making dedicated imaging important. This is not as clear in children. Our purpose is to establish the incidence of ipsilateral femoral neck fractures in children with femoral shaft fractures and to provide recommendations regarding diagnostic imaging protocols.A retrospective analysis of medical records was performed for pediatric patients (below 18 y) with femoral shaft fractures seen at our trauma center over a 10-year period. Mechanism of injury, associated injuries, procedures, and follow-up data were collected, and all radiographs reviewed. Exclusion criteria included peri-implant fractures or evidence of pathologic fracture. A similar retrospective analysis was performed in a cohort of adult patients.Of 267 pediatric patients with femoral shaft fractures, 2 patients (0.7%) had ipsilateral femoral neck fractures. One femoral neck fracture was detected on initial plain radiographs and the other on a pelvic computed tomography (CT) scan. Both of these fractures resulted from high-energy trauma, which accounted for 92 (42%) of pediatric femoral shaft fractures. The cohort of 100 adults aged 18 to 89 years with femoral shaft fractures revealed 6 adult patients (6%) with ipsilateral femoral neck fractures, all from high-energy trauma. High-energy trauma accounted for 85% of the adult femoral shaft fractures, and was more common than in the pediatric population (P<0.005). The difference in incidence of ipsilateral femoral neck fracture between the pediatric (0.7%) and the adult group (6%) was significant (P=0.007). No missed or delayed diagnoses were identified.The incidence of associated ipsilateral femoral neck fracture in pediatric patients with femoral shaft fracture is very low (0.7%). Most (58%) pediatric femur fractures are caused by low-energy trauma. We were unable to demonstrate a need for routine CT scanning of the femoral neck in children with femoral shaft fractures. Given the increased risks of radiation exposure with younger and smaller patients, it does not appear that routine CT scanning low-energy pediatric femoral shaft fractures to evaluate for femoral neck fractures is justified unless there is a high level of clinical suspicion.Level II.

  View details for DOI 10.1097/BPO.0000000000000800

  View details for Web of Science ID 000395941800004

• Discussion: Regeneration of Vascularized Corticocancellous Bone and Diploic Space Using Muscle- Derived Stem Cells: A Translational Biologic Alternative for Healing Critical Bone Defects PLASTIC AND RECONSTRUCTIVE SURGERY Murphy, M. P., Chan, C. K., Longaker, M. T. 2017; 139 (4): 906-907

  View details for DOI 10.1097/PRS.0000000000003210

  View details for PubMedID 28350669

• Pharmacological rescue of diabetic skeletal stem cell niches SCIENCE TRANSLATIONAL MEDICINE Tevlin, R., Seo, E., Marecic, O., McArdle, A., Tong, X., Zimdahl, B., Malkovskiy, A., Sinha, R., Gulati, G., Li, X., Wearda, T., Morganti, R., Lopez, M., Ransom, R. C., Duldulao, C. R., Rodrigues, M., Nguyen, A., Januszyk, M., Maan, Z., Paik, K., Yapa, K., Rajadas, J., Wan, D. C., Gurtner, G. C., Snyder, M., Beachy, P. A., Yang, F., Goodman, S. B., Weissman, I. L., Chan, C. F., Longaker, M. T. 2017; 9 (372)

  View details for DOI 10.1126/scitranslmed.aag2809

  View details for Web of Science ID 000394445700005

• Human Adipose-Derived Stromal Cell Isolation Methods and Use in Osteogenic and Adipogenic In Vivo Applications. Current protocols in stem cell biology Brett, E., Tevlin, R., McArdle, A., Seo, E. Y., Chan, C. K., Wan, D. C., Longaker, M. T. 2017; 43

  Abstract

  Adipose tissue represents an abundant and easily accessible source of multipotent cells, which may serve as excellent building blocks for tissue engineering. This article presents a newly described protocol for isolating adipose-derived stromal cells (ASCs) from human lipoaspirate, compared to the standard protocol for harvesting ASCs established in 2001. Human ASC isolation is performed using two methods, and resultant cells are compared through cell yield, cell viability, cell proliferation and regenerative potential. The osteogenic and adipogenic potential of ASCs isolated using both protocols are assessed invitro and gene expression analysis is performed. The focus of this series of protocols is the regenerative potential of both cell populations in vivo. As such, the two in vivo animal models described are fat graft retention (soft tissue reconstruction) and calvarial defect healing (bone regeneration). The techniques described comprise fat grafting with cell assisted lipotransfer, and calvarial defect creation healed with cell-seeded scaffolds. © 2017 by John Wiley & Sons, Inc.

  View details for PubMedID 29140567

• External Beam Radiation Therapy for the Treatment of Human Pluripotent Stem Cell-Derived Teratomas. Stem cells (Dayton, Ohio) Lee, A. S., Tang, C. n., Hong, W. X., Park, S. n., Bazalova, M. n., Nelson, G. n., Sanchez-Freire, V. n., Bakerman, I. n., Zhang, W. n., Neofytou, E. n., Connolly, A. J., Chan, C. K., Graves, E. E., Weissman, I. L., Nguyen, P. K., Wu, J. C. 2017

  Abstract

  Human pluripotent stem cells (hPSCs), including embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), have great potential as an unlimited donor source for cell-based therapeutics. The risk of teratoma formation from residual undifferentiated cells, however, remains a critical barrier to the clinical application of these cells. Herein we describe external beam radiation therapy (EBRT) as an attractive option for the treatment of this iatrogenic growth. We present the evidence that EBRT is effective in arresting growth of hESC-derived teratomas in vivo at day 28 post-implantation by utilizing a microCT irradiator capable of targeted treatment in small animals. Within several days of irradiation, teratomas derived from injection of undifferentiated hESCs and hiPSCs demonstrated complete growth arrest lasting several months. In addition, EBRT reduced re-seeding potential of teratoma cells during serial transplantation experiments, requiring irradiated teratomas to be seeded at 1x10(3) higher doses to form new teratomas. We demonstrate that radiation induces teratoma cell apoptosis, senescence, and growth arrest, similar to established radiobiology mechanisms. Taken together, these results provide proof of concept for the use of EBRT in the treatment of existing teratomas and highlight a strategy to increase the safety of stem cell-based therapies. This article is protected by copyright. All rights reserved.

  View details for PubMedID 28600830

• The Role of Skeletal Stem Cells in the Reconstruction of Bone Defects. The Journal of craniofacial surgery Murphy, M. P., Irizarry, D. n., Lopez, M. n., Moore, A. L., Ransom, R. C., Longaker, M. T., Wan, D. C., Chan, C. K. 2017; 28 (5): 1136–41

  Abstract

  Craniofacial surgery, since its inauguration, has been the culmination of collaborative efforts to solve complex congenital, dysplastic, oncological, and traumatic cranial bone defects. Now, 50 years on from the first craniofacial meeting, the collaborative efforts between surgeons, scientists, and bioengineers are further advancing craniofacial surgery with new discoveries in tissue regeneration. Recent advances in regenerative medicine and stem cell biology have transformed the authors' understanding of bone healing, the role of stem cells governing bone healing, and the effects of the niche environment and extracellular matrix on stem cell fate. This review aims at summarizing the advances within each of these fields.

  View details for PubMedID 28665863

• Lectins bring benefits to bones ELIFE Chan, C. F., Ransom, R. C., Longaker, M. T. 2016; 5

  Abstract

  The discovery that proteins called c-type lectins promote bone growth could lead to new treatments for age-related bone disorders.

  View details for PubMedID 27960074

• Immune Priming of the Tumor Microenvironment by Radiation TRENDS IN CANCER Jiang, W., Chan, C. K., Weissman, I. L., Kim, B. S., Hahn, S. M. 2016; 2 (11): 638–45

  Abstract

  Ionizing irradiation can induce a multitude of alterations within the tumor microenvironment. Unlike targeted therapies, radiation delivered to the tumor bed can prompt phenotypic changes in both normal stromal and cancer cells, leading to molecular and physiological alterations within the tumor microenvironment. These environmental modulations directly influence the degree of immunogenicity of the tumor microenvironment and may ultimately affect tumor responsiveness to cancer immunotherapies. Here we review the preclinical evidence for tumor microenvironment-mediated immune suppression and how radiation can modulate immune properties within a tumor. We then discuss the therapeutic opportunities for combining radiation with molecular agents to enhance tumor immunogenicity and how this represents a potential exciting strategy to complement immunotherapies including immune checkpoint blockers in cancer treatment.

  View details for PubMedID 28741502

• Computer Modeling Analysis of the Talar Dome as a Graft for the Humeral Head ARTHROSCOPY-THE JOURNAL OF ARTHROSCOPIC AND RELATED SURGERY Chan, C. M., LeVasseur, M. R., Lerner, A. L., Maloney, M. D., Voloshin, I. 2016; 32 (8): 1671-1675

  Abstract

  To study the degree of surface congruency between the talar dome and humeral head, to determine the size of graft harvestable from the talar dome, and to determine if there are surrogate markers that correspond to a higher degree of surface congruency.Computer models of 7 nonmatched humeral heads and 7 talar domes were generated by digital segmentation of magnetic resonance (MR) images. Modeled defect regions of each humeral head were then aligned with medial and lateral surfaces of each talar dome using software to maximally limit surface mismatch. Modeled defect sizes ranging from 24 × 10 mm to 30 × 10 mm were tested. Congruence match of <1 mm separation was then measured.The average surface match between randomly selected talar domes to humeral head surfaces was 87.2% when 1 mm was selected as the maximal acceptable congruence difference. Congruence match was not affected by graft size or laterality of talar dome as source of graft. Matching radius of curvature of talar dome to humeral head and height of donor to recipient correlated with improved congruence match. Under best match conditions, a maximal congruence match of 95.2% was achieved.The present study indicates that the talar dome can be a potential source of osteochondral allograft for Hill-Sachs lesions with a maximal defect size of 30 × 10 mm for a single graft. Larger graft sizes resulted in decreased success of actual graft harvest as a result of dimensional constraints of the talar dome. Additional studies are required to determine the biomechanical compatibility of this graft.The talar dome has a high degree of surface congruency in comparison with the humeral head though the maximal graft size harvestable limits its clinical applicability.

  View details for DOI 10.1016/j.arthro.2016.03.021

  View details for PubMedID 27177437

• Proceedings of the 8th Annual Conference on the Science of Dissemination and Implementation : Washington, DC, USA. 14-15 December 2015. Implementation science : IS Chambers, D., Simpson, L., Hill-Briggs, F., Neta, G., Vinson, C., Chambers, D., Beidas, R., Marcus, S., Aarons, G., Hoagwood, K., Schoenwald, S., Evans, A., Hurford, M., Rubin, R., Hadley, T., Barg, F., Walsh, L., Adams, D., Mandell, D., Martin, L., Mignogna, J., Mott, J., Hundt, N., Kauth, M., Kunik, M., Naik, A., Cully, J., McGuire, A., White, D., Bartholomew, T., McGrew, J., Luther, L., Rollins, A., Salyers, M., Cooper, B., Funaiole, A., Richards, J., Lee, A., Lapham, G., Caldeiro, R., Lozano, P., Gildred, T., Achtmeyer, C., Ludman, E., Addis, M., Marx, L., Bradley, K., VanDeinse, T., Wilson, A. B., Stacey, B., Powell, B., Bunger, A., Cuddeback, G., Barnett, M., Stadnick, N., Brookman-Frazee, L., Lau, A., Dorsey, S., Pullmann, M., Mitchell, S., Schwartz, R., Kirk, A., Dusek, K., Oros, M., Hosler, C., Gryczynski, J., Barbosa, C., Dunlap, L., Lounsbury, D., O’Grady, K., Brown, B., Damschroder, L., Waltz, T., Powell, B., Ritchie, M., Waltz, T., Atkins, D., Imel, Z. E., Xiao, B., Can, D., Georgiou, P., Narayanan, S., Berkel, C., Gallo, C., Sandler, I., Brown, C. H., Wolchik, S., Mauricio, A. M., Gallo, C., Brown, C. H., Mehrotra, S., Chandurkar, D., Bora, S., Das, A., Tripathi, A., Saggurti, N., Raj, A., Hughes, E., Jacobs, B., Kirkendall, E., Loeb, D., Trinkley, K., Yang, M., Sprowell, A., Nease, D., Lyon, A., Lewis, C., Boyd, M., Melvin, A., Nicodimos, S., Liu, F., Jungbluth, N., Lyon, A., Lewis, C., Boyd, M., Melvin, A., Nicodimos, S., Liu, F., Jungbluth, N., Flynn, A., Landis-Lewis, Z., Sales, A., Baloh, J., Ward, M., Zhu, X., Bennett, I., Unutzer, J., Mao, J., Proctor, E., Vredevoogd, M., Chan, Y. F., Williams, N., Green, P., Bernstein, S., Rosner, J. M., DeWitt, M., Tetrault, J., Dziura, J., Hsiao, A., Sussman, S., O’Connor, P., Toll, B., Jones, M., Gassaway, J., Tobin, J., Zatzick, D., Bradbury, A. R., Patrick-Miller, L., Egleston, B., Olopade, O. I., Hall, M. J., Daly, M. B., Fleisher, L., Grana, G., Ganschow, P., Fetzer, D., Brandt, A., Farengo-Clark, D., Forman, A., Gaber, R. S., Gulden, C., Horte, J., Long, J., Chambers, R. L., Lucas, T., Madaan, S., Mattie, K., McKenna, D., Montgomery, S., Nielsen, S., Powers, J., Rainey, K., Rybak, C., Savage, M., Seelaus, C., Stoll, J., Stopfer, J., Yao, S., Domchek, S., Hahn, E., Munoz-Plaza, C., Wang, J., Delgadillo, J. G., Mittman, B., Gould, M., Liang, S. (., Kegler, M. C., Cotter, M., Phillips, E., Hermstad, A., Morton, R., Beasley, D., Martinez, J., Riehman, K., Gustafson, D., Marsch, L., Mares, L., Quanbeck, A., McTavish, F., McDowell, H., Brown, R., Thomas, C., Glass, J., Isham, J., Shah, D., Liebschutz, J., Lasser, K., Watkins, K., Ober, A., Hunter, S., Lamp, K., Ewing, B., Iwelunmor, J., Gyamfi, J., Blackstone, S., Quakyi, N. K., Plange-Rhule, J., Ogedegbe, G., Kumar, P., Van Devanter, N., Nguyen, N., Nguyen, L., Nguyen, T., Phuong, N., Shelley, D., Rudge, S., Langlois, E., Tricco, A., Ball, S., Lambert-Kerzner, A., Sulc, C., Simmons, C., Shell-Boyd, J., Oestreich, T., O’Connor, A., Neely, E., McCreight, M., Labebue, A., DiFiore, D., Brostow, D., Ho, P. M., Aron, D., Harvey, J., McHugh, M., Scanlon, D., Lee, R., Soltero, E., Parker, N., McNeill, L., Ledoux, T., McIsaac, J. L., MacLeod, K., Ata, N., Jarvis, S., Kirk, S., Purtle, J., Dodson, E., Brownson, R., Mittman, B., Curran, G., Curran, G., Pyne, J., Aarons, G., Ehrhart, M., Torres, E., Miech, E., Miech, E., Stevens, K., Hamilton, A., Cohen, D., Padgett, D., Morshed, A., Patel, R., Prusaczyk, B., Aron, D. C., Gupta, D., Ball, S., Hand, R., Abram, J., Wolfram, T., Hastings, M., Moreland-Russell, S., Tabak, R., Ramsey, A., Baumann, A., Kryzer, E., Montgomery, K., Lewis, E., Padek, M., Powell, B., Brownson, R., Mamaril, C. B., Mays, G., Branham, K., Timsina, L., Mays, G., Hogg, R., Fagan, A., Shapiro, V., Brown, E., Haggerty, K., Hawkins, D., Oesterle, S., Hawkins, D., Catalano, R., McKay, V., Dolcini, M. M., Hoffer, L., Moin, T., Li, J., Duru, O. K., Ettner, S., Turk, N., Chan, C., Keckhafer, A., Luchs, R., Ho, S., Mangione, C., Selby, P., Zawertailo, L., Minian, N., Balliunas, D., Dragonetti, R., Hussain, S., Lecce, J., Chinman, M., Acosta, J., Ebener, P., Malone, P. S., Slaughter, M., Freedman, D., Flocke, S., Lee, E., Matlack, K., Trapl, E., Ohri-Vachaspati, P., Taggart, M., Borawski, E., Parrish, A., Harris, J., Kohn, M., Hammerback, K., McMillan, B., Hannon, P., Swindle, T., Curran, G., Whiteside-Mansell, L., Ward, W., Holt, C., Santos, S. L., Tagai, E., Scheirer, M. A., Carter, R., Bowie, J., Haider, M., Slade, J., Wang, M. Q., Masica, A., Ogola, G., Berryman, C., Richter, K., Shelton, R., Jandorf, L., Erwin, D., Truong, K., Javier, J. R., Coffey, D., Schrager, S. M., Palinkas, L., Miranda, J., Johnson, V., Hutcherson, V., Ellis, R., Kharmats, A., Marshall-King, S., LaPradd, M., Fonseca-Becker, F., Kepka, D., Bodson, J., Warner, E., Fowler, B., Shenkman, E., Hogan, W., Odedina, F., De Leon, J., Hooper, M., Carrasquillo, O., Reams, R., Hurt, M., Smith, S., Szapocznik, J., Nelson, D., Mandal, P., Teufel, J. 2016; 11 Suppl 2 (Suppl 2): 100

  Abstract

  A1 Introduction to the 8th Annual Conference on the Science of Dissemination and Implementation: Optimizing Personal and Population Health David Chambers, Lisa Simpson D1 Discussion forum: Population health D&I research Felicia Hill-Briggs D2 Discussion forum: Global health D&I research Gila Neta, Cynthia Vinson D3 Discussion forum: Precision medicine and D&I research David Chambers S1 Predictors of community therapists’ use of therapy techniques in a large public mental health system Rinad Beidas, Steven Marcus, Gregory Aarons, Kimberly Hoagwood, Sonja Schoenwald, Arthur Evans, Matthew Hurford, Ronnie Rubin, Trevor Hadley, Frances Barg, Lucia Walsh, Danielle Adams, David Mandell S2 Implementing brief cognitive behavioral therapy (CBT) in primary care: Clinicians' experiences from the field Lindsey Martin, Joseph Mignogna, Juliette Mott, Natalie Hundt, Michael Kauth, Mark Kunik, Aanand Naik, Jeffrey Cully S3 Clinician competence: Natural variation, factors affecting, and effect on patient outcomes Alan McGuire, Dominique White, Tom Bartholomew, John McGrew, Lauren Luther, Angie Rollins, Michelle Salyers S4 Exploring the multifaceted nature of sustainability in community-based prevention: A mixed-method approach Brittany Cooper, Angie Funaiole S5 Theory informed behavioral health integration in primary care: Mixed methods evaluation of the implementation of routine depression and alcohol screening and assessment Julie Richards, Amy Lee, Gwen Lapham, Ryan Caldeiro, Paula Lozano, Tory Gildred, Carol Achtmeyer, Evette Ludman, Megan Addis, Larry Marx, Katharine Bradley S6 Enhancing the evidence for specialty mental health probation through a hybrid efficacy and implementation study Tonya VanDeinse, Amy Blank Wilson, Burgin Stacey, Byron Powell, Alicia Bunger, Gary Cuddeback S7 Personalizing evidence-based child mental health care within a fiscally mandated policy reform Miya Barnett, Nicole Stadnick, Lauren Brookman-Frazee, Anna Lau S8 Leveraging an existing resource for technical assistance: Community-based supervisors in public mental health Shannon Dorsey, Michael Pullmann S9 SBIRT implementation for adolescents in urban federally qualified health centers: Implementation outcomes Shannon Mitchell, Robert Schwartz, Arethusa Kirk, Kristi Dusek, Marla Oros, Colleen Hosler, Jan Gryczynski, Carolina Barbosa, Laura Dunlap, David Lounsbury, Kevin O'Grady, Barry Brown S10 PANEL: Tailoring Implementation Strategies to Context - Expert recommendations for tailoring strategies to context Laura Damschroder, Thomas Waltz, Byron Powell S11 PANEL: Tailoring Implementation Strategies to Context - Extreme facilitation: Helping challenged healthcare settings implement complex programs Mona Ritchie S12 PANEL: Tailoring Implementation Strategies to Context - Using menu-based choice tasks to obtain expert recommendations for implementing three high-priority practices in the VA Thomas Waltz S13 PANEL: The Use of Technology to Improve Efficient Monitoring of Implementation of Evidence-based Programs - Siri, rate my therapist: Using technology to automate fidelity ratings of motivational interviewing David Atkins, Zac E. Imel, Bo Xiao, Doğan Can, Panayiotis Georgiou, Shrikanth Narayanan S14 PANEL: The Use of Technology to Improve Efficient Monitoring of Implementation of Evidence-based Programs - Identifying indicators of implementation quality for computer-based ratings Cady Berkel, Carlos Gallo, Irwin Sandler, C. Hendricks Brown, Sharlene Wolchik, Anne Marie Mauricio S15 PANEL: The Use of Technology to Improve Efficient Monitoring of Implementation of Evidence-based Programs - Improving implementation of behavioral interventions by monitoring emotion in spoken speech Carlos Gallo, C. Hendricks Brown, Sanjay Mehrotra S16 Scorecards and dashboards to assure data quality of health management information system (HMIS) using R Dharmendra Chandurkar, Siddhartha Bora, Arup Das, Anand Tripathi, Niranjan Saggurti, Anita Raj S17 A big data approach for discovering and implementing patient safety insights Eric Hughes, Brian Jacobs, Eric Kirkendall S18 Improving the efficacy of a depression registry for use in a collaborative care model Danielle Loeb, Katy Trinkley, Michael Yang, Andrew Sprowell, Donald Nease S19 Measurement feedback systems as a strategy to support implementation of measurement-based care in behavioral health Aaron Lyon, Cara Lewis, Meredith Boyd, Abigail Melvin, Semret Nicodimos, Freda Liu, Nathanial Jungbluth S20 PANEL: Implementation Science and Learning Health Systems: Intersections and Commonalities - Common loop assay: Methods of supporting learning collaboratives Allen Flynn S21 PANEL: Implementation Science and Learning Health Systems: Intersections and Commonalities - Innovating audit and feedback using message tailoring models for learning health systems Zach Landis-Lewis S22 PANEL: Implementation Science and Learning Health Systems: Intersections and Commonalities - Implementation science and learning health systems: Connecting the dots Anne Sales S23 Facilitation activities of Critical Access Hospitals during TeamSTEPPS implementation Jure Baloh, Marcia Ward, Xi Zhu S24 Organizational and social context of federally qualified health centers and variation in maternal depression outcomes Ian Bennett, Jurgen Unutzer, Johnny Mao, Enola Proctor, Mindy Vredevoogd, Ya-Fen Chan, Nathaniel Williams, Phillip Green S25 Decision support to enhance treatment of hospitalized smokers: A randomized trial Steven Bernstein, June-Marie Rosner, Michelle DeWitt, Jeanette Tetrault, James Dziura, Allen Hsiao, Scott Sussman, Patrick O’Connor, Benjamin Toll S26 PANEL: Developing Sustainable Strategies for the Implementation of Patient-Centered Care across Diverse US Healthcare Systems - A patient-centered approach to successful community transition after catastrophic injury Michael Jones, Julie Gassaway S27 PANEL: Developing Sustainable Strategies for the Implementation of Patient-Centered Care across Diverse US Healthcare Systems - Conducting PCOR to integrate mental health and cancer screening services in primary care Jonathan Tobin S28 PANEL: Developing Sustainable Strategies for the Implementation of Patient-Centered Care across Diverse US Healthcare Systems - A comparative effectiveness trial of optimal patient-centered care for US trauma care systems Douglas Zatzick S29 Preferences for in-person communication among patients in a multi-center randomized study of in-person versus telephone communication of genetic test results for cancer susceptibility Angela R Bradbury, Linda Patrick-Miller, Brian Egleston, Olufunmilayo I Olopade, Michael J Hall, Mary B Daly, Linda Fleisher, Generosa Grana, Pamela Ganschow, Dominique Fetzer, Amanda Brandt, Dana Farengo-Clark, Andrea Forman, Rikki S Gaber, Cassandra Gulden, Janice Horte, Jessica Long, Rachelle Lorenz Chambers, Terra Lucas, Shreshtha Madaan, Kristin Mattie, Danielle McKenna, Susan Montgomery, Sarah Nielsen, Jacquelyn Powers, Kim Rainey, Christina Rybak, Michelle Savage, Christina Seelaus, Jessica Stoll, Jill Stopfer, Shirley Yao and Susan Domchek S30 Working towards de-implementation: A mixed methods study in breast cancer surveillance care Erin Hahn, Corrine Munoz-Plaza, Jianjin Wang, Jazmine Garcia Delgadillo, Brian Mittman Michael Gould S31Integrating evidence-based practices for increasing cancer screenings in safety-net primary care systems: A multiple case study using the consolidated framework for implementation research Shuting (Lily) Liang, Michelle C. Kegler, Megan Cotter, Emily Phillips, April Hermstad, Rentonia Morton, Derrick Beasley, Jeremy Martinez, Kara Riehman S32 Observations from implementing an mHealth intervention in an FQHC David Gustafson, Lisa Marsch, Louise Mares, Andrew Quanbeck, Fiona McTavish, Helene McDowell, Randall Brown, Chantelle Thomas, Joseph Glass, Joseph Isham, Dhavan Shah S33 A multicomponent intervention to improve primary care provider adherence to chronic opioid therapy guidelines and reduce opioid misuse: A cluster randomized controlled trial protocol Jane Liebschutz, Karen Lasser S34 Implementing collaborative care for substance use disorders in primary care: Preliminary findings from the summit study Katherine Watkins, Allison Ober, Sarah Hunter, Karen Lamp, Brett Ewing S35 Sustaining a task-shifting strategy for blood pressure control in Ghana: A stakeholder analysis Juliet Iwelunmor, Joyce Gyamfi, Sarah Blackstone, Nana Kofi Quakyi, Jacob Plange-Rhule, Gbenga Ogedegbe S36 Contextual adaptation of the consolidated framework for implementation research (CFIR) in a tobacco cessation study in Vietnam Pritika Kumar, Nancy Van Devanter, Nam Nguyen, Linh Nguyen, Trang Nguyen, Nguyet Phuong, Donna Shelley S37 Evidence check: A knowledge brokering approach to systematic reviews for policy Sian Rudge S38 Using Evidence Synthesis to Strengthen Complex Health Systems in Low- and Middle-Income Countries Etienne Langlois S39 Does it matter: timeliness or accuracy of results? The choice of rapid reviews or systematic reviews to inform decision-making Andrea Tricco S40 Evaluation of the veterans choice program using lean six sigma at a VA medical center to identify benefits and overcome obstacles Sherry Ball, Anne Lambert-Kerzner, Christine Sulc, Carol Simmons, Jeneen Shell-Boyd, Taryn Oestreich, Ashley O'Connor, Emily Neely, Marina McCreight, Amy Labebue, Doreen DiFiore, Diana Brostow, P. Michael Ho, David Aron S41 The influence of local context on multi-stakeholder alliance quality improvement activities: A multiple case study Jillian Harvey, Megan McHugh, Dennis Scanlon S42 Increasing physical activity in early care and education: Sustainability via active garden education (SAGE) Rebecca Lee, Erica Soltero, Nathan Parker, Lorna McNeill, Tracey Ledoux S43 Marking a decade of policy implementation: The successes and continuing challenges of a provincial school food and nutrition policy in Canada Jessie-Lee McIsaac, Kate MacLeod, Nicole Ata, Sherry Jarvis, Sara Kirk S44 Use of research evidence among state legislators who prioritize mental health and substance abuse issues Jonathan Purtle, Elizabeth Dodson, Ross Brownson S45 PANEL: Effectiveness-Implementation Hybrid Designs: Clarifications, Refinements, and Additional Guidance Based on a Systematic Review and Reports from the Field - Hybrid type 1 designs Brian Mittman, Geoffrey Curran S46 PANEL: Effectiveness-Implementation Hybrid Designs: Clarifications, Refinements, and Additional Guidance Based on a Systematic Review and Reports from the Field - Hybrid type 2 designs Geoffrey Curran S47 PANEL: Effectiveness-Implementation Hybrid Designs: Clarifications, Refinements, and Additional Guidance Based on a Systematic Review and Reports from the Field - Hybrid type 3 designs Jeffrey Pyne S48 Linking team level implementation leadership and implementation climate to individual level attitudes, behaviors, and implementation outcomes Gregory Aarons, Mark Ehrhart, Elisa Torres S49 Pinpointing the specific elements of local context that matter most to implementation outcomes: Findings from qualitative comparative analysis in the RE-inspire study of VA acute stroke care Edward Miech S50 The GO score: A new context-sensitive instrument to measure group organization level for providing and improving care Edward Miech S51 A research network approach for boosting implementation and improvement Kathleen Stevens, I.S.R.N. Steering Council S52 PANEL: Qualitative methods in D&I Research: Value, rigor and challenge - The value of qualitative methods in implementation research Alison Hamilton S53 PANEL: Qualitative methods in D&I Research: Value, rigor and challenge - Learning evaluation: The role of qualitative methods in dissemination and implementation research Deborah Cohen S54 PANEL: Qualitative methods in D&I Research: Value, rigor and challenge - Qualitative methods in D&I research Deborah Padgett S55 PANEL: Maps & models: The promise of network science for clinical D&I - Hospital network of sharing patients with acute and chronic diseases in California Alexandra Morshed S56 PANEL: Maps & models: The promise of network science for clinical D&I - The use of social network analysis to identify dissemination targets and enhance D&I research study recruitment for pre-exposure prophylaxis for HIV (PrEP) among men who have sex with men Rupa Patel S57 PANEL: Maps & models: The promise of network science for clinical D&I - Network and organizational factors related to the adoption of patient navigation services among rural breast cancer care providers Beth Prusaczyk S58 A theory of de-implementation based on the theory of healthcare professionals’ behavior and intention (THPBI) and the becker model of unlearning David C. Aron, Divya Gupta, Sherry Ball S59 Observation of registered dietitian nutritionist-patient encounters by dietetic interns highlights low awareness and implementation of evidence-based nutrition practice guidelines Rosa Hand, Jenica Abram, Taylor Wolfram S60 Program sustainability action planning: Building capacity for program sustainability using the program sustainability assessment tool Molly Hastings, Sarah Moreland-Russell S61 A review of D&I study designs in published study protocols Rachel Tabak, Alex Ramsey, Ana Baumann, Emily Kryzer, Katherine Montgomery, Ericka Lewis, Margaret Padek, Byron Powell, Ross Brownson S62 PANEL: Geographic variation in the implementation of public health services: Economic, organizational, and network determinants - Model simulation techniques to estimate the cost of implementing foundational public health services Cezar Brian Mamaril, Glen Mays, Keith Branham, Lava Timsina S63 PANEL: Geographic variation in the implementation of public health services: Economic, organizational, and network determinants - Inter-organizational network effects on the implementation of public health services Glen Mays, Rachel Hogg S64 PANEL: Building capacity for implementation and dissemination of the communities that care prevention system at scale to promote evidence-based practices in behavioral health - Implementation fidelity, coalition functioning, and community prevention system transformation using communities that care Abigail Fagan, Valerie Shapiro, Eric Brown S65 PANEL: Building capacity for implementation and dissemination of the communities that care prevention system at scale to promote evidence-based practices in behavioral health - Expanding capacity for implementation of communities that care at scale using a web-based, video-assisted training system Kevin Haggerty, David Hawkins S66 PANEL: Building capacity for implementation and dissemination of the communities that care prevention system at scale to promote evidence-based practices in behavioral health - Effects of communities that care on reducing youth behavioral health problems Sabrina Oesterle, David Hawkins, Richard Catalano S68 When interventions end: the dynamics of intervention de-adoption and replacement Virginia McKay, M. Margaret Dolcini, Lee Hoffer S69 Results from next-d: can a disease specific health plan reduce incident diabetes development among a national sample of working-age adults with pre-diabetes? Tannaz Moin, Jinnan Li, O. Kenrik Duru, Susan Ettner, Norman Turk, Charles Chan, Abigail Keckhafer, Robert Luchs, Sam Ho, Carol Mangione S70 Implementing smoking cessation interventions in primary care settings (STOP): using the interactive systems framework Peter Selby, Laurie Zawertailo, Nadia Minian, Dolly Balliunas, Rosa Dragonetti, Sarwar Hussain, Julia Lecce S71 Testing the Getting To Outcomes implementation support intervention in prevention-oriented, community-based settings Matthew Chinman, Joie Acosta, Patricia Ebener, Patrick S Malone, Mary Slaughter S72 Examining the reach of a multi-component farmers’ market implementation approach among low-income consumers in an urban context Darcy Freedman, Susan Flocke, Eunlye Lee, Kristen Matlack, Erika Trapl, Punam Ohri-Vachaspati, Morgan Taggart, Elaine Borawski S73 Increasing implementation of evidence-based health promotion practices at large workplaces: The CEOs Challenge Amanda Parrish, Jeffrey Harris, Marlana Kohn, Kristen Hammerback, Becca McMillan, Peggy Hannon S74 A qualitative assessment of barriers to nutrition promotion and obesity prevention in childcare Taren Swindle, Geoffrey Curran, Leanne Whiteside-Mansell, Wendy Ward S75 Documenting institutionalization of a health communication intervention in African American churches Cheryl Holt, Sheri Lou Santos, Erin Tagai, Mary Ann Scheirer, Roxanne Carter, Janice Bowie, Muhiuddin Haider, Jimmie Slade, Min Qi Wang S76 Reduction in hospital utilization by underserved patients through use of a community-medical home Andrew Masica, Gerald Ogola, Candice Berryman, Kathleen Richter S77 Sustainability of evidence-based lay health advisor programs in African American communities: A mixed methods investigation of the National Witness Project Rachel Shelton, Lina Jandorf, Deborah Erwin S78 Predicting the long-term uninsured population and analyzing their gaps in physical access to healthcare in South Carolina Khoa Truong S79 Using an evidence-based parenting intervention in churches to prevent behavioral problems among Filipino youth: A randomized pilot study Joyce R. Javier, Dean Coffey, Sheree M. Schrager, Lawrence Palinkas, Jeanne Miranda S80 Sustainability of elementary school-based health centers in three health-disparate southern communities Veda Johnson, Valerie Hutcherson, Ruth Ellis S81 Childhood obesity prevention partnership in Louisville: creative opportunities to engage families in a multifaceted approach to obesity prevention Anna Kharmats, Sandra Marshall-King, Monica LaPradd, Fannie Fonseca-Becker S82 Improvements in cervical cancer prevention found after implementation of evidence-based Latina prevention care management program Deanna Kepka, Julia Bodson, Echo Warner, Brynn Fowler S83 The OneFlorida data trust: Achieving health equity through research & training capacity building Elizabeth Shenkman, William Hogan, Folakami Odedina, Jessica De Leon, Monica Hooper, Olveen Carrasquillo, Renee Reams, Myra Hurt, Steven Smith, Jose Szapocznik, David Nelson, Prabir Mandal S84 Disseminating and sustaining medical-legal partnerships: Shared value and social return on investment James Teufel

  View details for DOI 10.1186/s13012-016-0452-0

  View details for PubMedID 27490260

  View details for PubMedCentralID PMC4977475

• Detection of Femoral Neck Fractures in Pediatric Patients With Femoral Shaft Fractures. Journal of pediatric orthopedics Caldwell, L., Chan, C. M., Sanders, J. O., Gorczyca, J. T. 2016: -?

  Abstract

  Ipsilateral femoral neck fractures occur in 1% to 9% of adult trauma patients with femoral shaft fractures making dedicated imaging important. This is not as clear in children. Our purpose is to establish the incidence of ipsilateral femoral neck fractures in children with femoral shaft fractures and to provide recommendations regarding diagnostic imaging protocols.A retrospective analysis of medical records was performed for pediatric patients (below 18 y) with femoral shaft fractures seen at our trauma center over a 10-year period. Mechanism of injury, associated injuries, procedures, and follow-up data were collected, and all radiographs reviewed. Exclusion criteria included peri-implant fractures or evidence of pathologic fracture. A similar retrospective analysis was performed in a cohort of adult patients.Of 267 pediatric patients with femoral shaft fractures, 2 patients (0.7%) had ipsilateral femoral neck fractures. One femoral neck fracture was detected on initial plain radiographs and the other on a pelvic computed tomography (CT) scan. Both of these fractures resulted from high-energy trauma, which accounted for 92 (42%) of pediatric femoral shaft fractures. The cohort of 100 adults aged 18 to 89 years with femoral shaft fractures revealed 6 adult patients (6%) with ipsilateral femoral neck fractures, all from high-energy trauma. High-energy trauma accounted for 85% of the adult femoral shaft fractures, and was more common than in the pediatric population (P<0.005). The difference in incidence of ipsilateral femoral neck fracture between the pediatric (0.7%) and the adult group (6%) was significant (P=0.007). No missed or delayed diagnoses were identified.The incidence of associated ipsilateral femoral neck fracture in pediatric patients with femoral shaft fracture is very low (0.7%). Most (58%) pediatric femur fractures are caused by low-energy trauma. We were unable to demonstrate a need for routine CT scanning of the femoral neck in children with femoral shaft fractures. Given the increased risks of radiation exposure with younger and smaller patients, it does not appear that routine CT scanning low-energy pediatric femoral shaft fractures to evaluate for femoral neck fractures is justified unless there is a high level of clinical suspicion.Level II.

  View details for PubMedID 27261972

• Effect of Preoperative Indications Conference on Procedural Planning for Treatment of Scoliosis. Spine deformity Chan, C. M., Swindell, H. W., Matsumoto, H., Park, H. Y., Hyman, J. E., Vitale, M. G., Roye, D. P., Roye, B. D. 2016; 4 (1): 27-32

  Abstract

  This study determines the rate of change in the scoliosis surgery plan in cases presented in preoperative indications conference.To determine the effect of preoperative indications conference on the plan of surgery and to identify characteristics that increased the likelihood of change.Preoperative indications conferences are used as a teaching and planning tool. Levels of fusion, construct options, and necessity for osteotomies are often debated in the planning of scoliosis surgery.Scoliosis surgeries were presented at preoperative indications conference with four attending pediatric orthopedic surgeons present. The operative surgeon committed to a surgical plan before conference. A consensus-based plan was made without knowledge of the operative surgeon's preconference plan. Changes of plan were classified as major, minor, or no change.Of the 107 surgical plans, 50 were index surgeries, 13 were revisions, and 44 were scheduled growing rod lengthenings. There were two major changes, including a change to a growing construct from planned fusion, and a change in fusion levels in an adolescent idiopathic scoliosis (AIS) patient. There were 13 minor changes, which included changes in fusion levels (1 to 3; mean = 1.23) and the addition of an osteotomy. The rate of change was 28% for index surgeries and 7.69% for revisions. Of the 14 changes in the 50 index surgeries, there were 8 AIS, 3 cerebral palsy, 1 congenital scoliosis, 1 Ehlers-Danlos, and 1 patient with an undetermined neuromuscular condition. There was 1 change in 13 revision surgeries. There were no changes for growing rod lengthenings and no cancellations as a result of indications conference.Although revision scoliosis surgery is complex, index AIS/JIS surgery was most subject to the influence of indications conference. This likely reflects controversy around choosing levels of fusion.IV.

  View details for DOI 10.1016/j.jspd.2015.05.003

  View details for PubMedID 27852496

• Impairment in Fracture Healing in a Mouse Model of Type 2 Diabetes Is Driven by Skeletal Stem Cell Niche Dysregulation Tevlin, R., Seo, E., Mc Ardle, A., Tong, X., Januszyk, M., Yang, F., Gurtner, G. C., Chan, C. F., Weissman, I. L., Longaker, M. T. ELSEVIER SCIENCE INC. 2015: S115

  View details for DOI 10.1016/j.jamcollsurg.2015.07.268

  View details for Web of Science ID 000361119700230

• Effects of Varying Locations for Biceps Tendon Tenotomy and Superior Labral Integrity on Shoulder Stability in a Cadaveric Concavity-Compression Model ARTHROSCOPY-THE JOURNAL OF ARTHROSCOPIC AND RELATED SURGERY Chan, C. M., Behrend, C., Shields, E., Maloney, M. D., Voloshin, I. 2014; 30 (12): 1557-1561

  Abstract

  The purpose of this study was to examine the location of biceps tenotomy and the integrity of the superior labrum as they relate to superior glenohumeral joint stability in a cadaveric concavity-compression model.Eight cadaveric glenoid labrums were mounted individually onto a load cell with the corresponding humerus fixed to the loading arm in the hanging-arm position. All surrounding soft tissue was removed except the labrum and proximal stump of the long head of the biceps (LHB) tendon, simulating a biceps tenotomy. A compressive load of 22 N was applied across the glenohumeral joint. The humerus was then translated superiorly until it subluxated over the glenoid labrum. The force resisting superior translation was characterized for each of 50 cycles. Each specimen was tested under the following conditions: (1) with a 4 cm biceps stump after tenotomy, (2) with a 0 cm biceps stump, (3) after full detachment of the superior labrum, and (4) after repair of the labrum.Biceps tenotomy performed at the biceps-labral junction resulted in an average decrease in force required to superiorly subluxate the humeral head by 8.6% (P = .01) when compared with leaving 4 cm of biceps stump. Resection of the entire superior labrum resulted in a future decrease to 15.2% (P < .001) from baseline. Repair of the labrum resulted in restoration of stability with a mean of 101.1% (P = .82) and was not statistically different from baseline. The kinematics of the glenohumeral joint was affected by labral repair, with an earlier upslope on the force-to-displacement curve and alteration in the total energy required to cause subluxation of the humeral head noted.In this study, location of the biceps tenotomy and integrity of the superior labrum affected glenohumeral stability during axial loading in the hanging-arm position. Repair of the labrum restored stability for superior subluxation but also changed the kinematics of the subluxation event.Preservation of superior labrum after biceps tenotomy provides increased resistive force to superior translation in a unidirectional biomechanical model.

  View details for DOI 10.1016/j.arthro.2014.06.012

  View details for Web of Science ID 000345855700007

  View details for PubMedID 25129863

• Positive selection for bone morphogenetic protein receptor type-IB promotes differentiation and specification of human adipose-derived stromal cells toward an osteogenic lineage. Tissue engineering. Part A McArdle, A., Chung, M. T., Paik, K. J., Duldulao, C., Chan, C., Rennert, R., Walmsley, G. G., Senarath-Yapa, K., Hu, M., Seo, E., Lee, M., Wan, D. C., Longaker, M. T. 2014; 20 (21-22): 3031-3040

  Abstract

  Adipose tissue represents an abundant and easily accessible source of multipotent cells that may serve as an excellent building block for tissue engineering. However, adipose-derived stromal cells (ASCs) are a heterogeneous group and subpopulations may be identified with enhanced osteogenic potential.Human ASC subpopulations were prospectively isolated based on expression of bone morphogenetic protein receptor type-IB (BMPR-IB). Unsorted, BMPR-IB(+), and BMPR-IB(-) cells were analyzed for their osteogenic capacity through histological staining and gene expression. To evaluate their in vivo osteogenic potential, critical-sized calvarial defects were created in immunocompromised mice and treated with unsorted, BMPR-IB(+), or BMPR-IB(-) cells. Healing was assessed using microcomputed tomography and pentachrome staining of specimens at 8 weeks.Increased osteogenic differentiation was noted in the BMPR-IB(+) subpopulation, as demonstrated by alkaline phosphatase staining at day 7 and extracellular matrix mineralization with Alizarin red staining at day 14. This was also associated with increased expression for osteocalcin, a late marker of osteogenesis. Radiographic analysis demonstrated significantly enhanced healing of critical-sized calvarial defects treated with BMPR-IB(+) ASCs compared with unsorted or BMPR-IB(-) cells. This was confirmed through pentachrome staining, which revealed more robust bone regeneration in the BMPR-IB(+) group.BMPR-IB(+) human ASCs have an enhanced ability to form bone both in vitro and in vivo. These data suggest that positive selection for BMPR-IB(+) and manipulation of the BMP pathway in these cells may yield a highly osteogenic subpopulation of cells for bone tissue engineering.

  View details for DOI 10.1089/ten.TEA.2014.0101

  View details for PubMedID 24854876

• Impaired Angiogenesis: A Critical Contributor to Problematic Fracture Healing in Diabetes Tevlin, R., Mc Ardle, A., Senarath-Yapa, K., Rodrigues, M., Maan, Z. N., Li, S., Chan, C. K., Brunski, J., Gurtner, G. C. ELSEVIER SCIENCE INC. 2014: S83

  View details for DOI 10.1016/j.jamcollsurg.2014.07.196

  View details for Web of Science ID 000342420900168

• Diminished Recruitment of Resident Skeletal Progenitor Cells in Diabetic Fracture Healing Tevlin, R., Seo, E., McArdle, A., Marecic, O., Wearda, T., Senarath-Yapa, K., Zielins, E. R., Chan, C. K., Weissman, I. L., Longaker, M. T. ELSEVIER SCIENCE INC. 2014: S82

  View details for DOI 10.1016/j.jamcollsurg.2014.07.193

  View details for Web of Science ID 000342420900165

• Heterochronic Parabiosis Rejuvenates Aged Bones McArdle, A., Tevlin, R., Marecic, O., Wearda, T., Senarath-Yapa, K., Walmsley, G. G., Snyder, M. P., Weissman, I. L., Chan, C. K., Longaker, M. T. ELSEVIER SCIENCE INC. 2014: S82–S83

  View details for DOI 10.1016/j.jamcollsurg.2014.07.195

  View details for Web of Science ID 000342420900167

• Response of Skeletal Progenitor Cells to Fracture Injury in a Mouse Model Marecic, O., McArdle, A., Seo, E., Tevlin, R., Duldulao, C., Wearda, T., Chan, C., Weissman, I. L., Longaker, M. T. ELSEVIER SCIENCE INC. 2014: S86

  View details for DOI 10.1016/j.jamcollsurg.2014.07.204

  View details for Web of Science ID 000342420900176

• LOW DOSE RADIATION FROM CARDIAC COMPUTED TOMOGRAPHY IS ASSOCIATED WITH DNA DAMAGE AND CELLULAR DEATH Hong, W., Lee, W., Liang, G., Chan, C., Sanchez-Freire, V., Hu, S., Longaker, M. T., Wu, J., Nguyen, P. ELSEVIER SCIENCE INC. 2014: A1047

  View details for DOI 10.1016/S0735-1097(14)61047-0

  View details for Web of Science ID 000359579101705

• The Effect of Rod Diameter on Correction of Adolescent Idiopathic Scoliosis at Two Years Follow-Up JOURNAL OF PEDIATRIC ORTHOPAEDICS Prince, D. E., Matsumoto, H., Chan, C. M., Gomez, J. A., Hyman, J. E., Roye, D. P., Vitale, M. G. 2014; 34 (1): 22-28

  Abstract

  The review of multicenter national pediatric scoliosis database.The purpose of this study was to compare the radiographic outcomes of patients who underwent scoliosis surgery utilizing different rod diameter constructs by the posterior approach.Little attention has specifically been focused on the effect of rod diameter on correction of spinal deformity after posterior spinal instrumentation and fusion in children with adolescent idiopathic scoliosis (AIS).The review of national database comprised of 1125 patients, of which 352 patients had a minimum follow-up of 2 years. Of these, 163 patients received 5.5 mm and 189 patients received 6.35 mm diameter rods for posterior spinal instrumentation.The 6.35 mm rods were used more often for patients who were male, taller, heavier, with larger coronal curves, and more flexible curves. Larger diameter rods were also more likely to be stainless steel, implanted with an increased number of implants per level, and an increased number of pedicle screws used on the concavity of the curve. Univariate analysis of coronal curve showed a significant difference between 5.5 and 6.35 mm rods in correction (67.0% vs. 57.3%) at 2 years. Multivariate analysis revealed that the most significant factors affecting coronal curve correction at 2 years were rod diameter, the patient's preoperative coronal major curve and flexibility, and the implant density. In the sagittal plane, preoperative sagittal curve and rod diameter are the predictors of sagittal correction at 2 years.The study did not support our hypothesis that larger rods would be associated with a greater correction of frontal and sagittal plane in patients with AIS. In addition to rod diameter, implant density and the inherent flexibility and deformity of the patient were found to be influential factors contributing for the correction and maintenance of coronal and sagittal curves in AIS.

  View details for DOI 10.1097/BPO.0b013e318288b3c1

  View details for PubMedID 23863413

• Treatment of Idiopathic Pulmonary Fibrosis With Ambrisentan A Parallel, Randomized Trial ANNALS OF INTERNAL MEDICINE Raghu, G., Behr, J., Brown, K. K., Egan, J. J., Kawut, S. M., Flaherty, K. R., Martinez, F. J., Nathan, S. D., Wells, A. U., Collard, H. R., Costabel, U., Richeldi, L., de Andrade, J., Khalil, N., Morrison, L. D., Lederer, D. J., Shao, L., Li, X., Pedersen, P. S., Montgomery, A., Chien, J. W., O'Riordan, T. G., ARTEMIS-IPF Investigators 2013; 158 (9): 641-+

  Abstract

  Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor.To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression.Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300).Academic and private hospitals.Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans.Ambrisentan, 10 mg/d, or placebo.Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function.The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point.The study was terminated early.Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations.Gilead Sciences.

  View details for DOI 10.7326/0003-4819-158-9-201305070-00003

  View details for Web of Science ID 000319126900001

  View details for PubMedID 23648946

• Unilateral meniscomeniscal ligament. Orthopedics Chan, C. M., Goldblatt, J. P. 2012; 35 (12): e1815-7

  Abstract

  Four normal variants of meniscomeniscal ligaments have been previously reported in the anatomy, arthroscopy, and radiology literature. The anterior and posterior transverse meniscal ligaments are the 2 most commonly observed, with a reported frequency of 58% and 1% to 4%, respectively. The last 2 variants include the medial and lateral oblique meniscomeniscal ligaments and account for a combined frequency of 1% to 4%.This article describes 2 patients with unilateral meniscomeniscal ligaments observed on magnetic resonance imaging. One patient had a unilateral lateral meniscomeniscal ligament extending from the anterior horn of the lateral meniscus to the posterior horn of the lateral meniscus and underwent conservative management. The second patient had a unilateral medial meniscomeniscal ligament with a concomitant medial meniscus tear and underwent arthroscopic intervention. The ligament was stable intraoperatively and, therefore, was not resected. Both patients had resolution of their symptoms.These 2 variants are additions to the previously described 4 normal intermeniscal ligament variants. The functions of the 2 new variants described in this article are poorly understood but are thought to involve meniscal stability. Accurate descriptions of normal variants can lead to the proper management of anomalous rare structures and prevent false imaging interpretations because these structures can closely mimic a double posterior cruciate ligament sign. Furthermore, an understanding of the various normal variants of intermeniscal ligaments can prevent unnecessary surgery that could result in further iatrogenic meniscus injury.

  View details for DOI 10.3928/01477447-20121120-31

  View details for PubMedID 23218643

• Signal rewiring induced by EWS/FLI-1 in mouse and human mesenchymal stem cells Marques, M., Nieves, B., Chen, R., Vaka, D., Chan, C., Zheng, G., Chang, H., Weissman, I., Sweet-Cordero, A. AMER ASSOC CANCER RESEARCH. 2012

  View details for DOI 10.1158/1538-7445.AM2012-1427

  View details for Web of Science ID 000209701501448

• Minocycline-Induced Bone Discoloration JBJS Case Connector Chan, C. M., Hicks, D. G., Giordano, B. D. 2012; 2 (3)

  View details for DOI 10.2106/JBJS.CC.K.00153

• HIF-dependent over-expression of CUB domain-containing protein 1 stimulates migration in clear cell renal cell carcinoma Razorenova, O. V., Finger, E. C., Colavitti, R., Chernikova, S. B., Boiko, A. D., Chan, C. F., Krieg, A., Bedogni, B., LaGory, E., Weissman, I. L., Broome-Powell, M., Giaccia, A. J. AMER ASSOC CANCER RESEARCH. 2011

  View details for DOI 10.1158/1538-7445.AM2011-LB-357

  View details for Web of Science ID 000209701303365

• Identification and Isolation of the Hematopoietic Stem Cell Niche Initiating Cell Population 50th Annual Meeting of the American-Society-of-Hematology/ASH/ASCO Joint Symposium Chan, C., Chen, C., Kraft, D. L., Luppen, C., Kim, J., DeBoer, A., Wei, K. W., Weissman, I. L. AMER SOC HEMATOLOGY. 2008: 1223–23

  View details for Web of Science ID 000262104704192

• The CASE survey: Patient and physician perceptions regarding asthma medication use and associated oropharyngeal symptoms CANADIAN RESPIRATORY JOURNAL FitzGerald, J., Chan, C. N., Holroyde, M. C., Boulet, L. 2008; 15 (1): 27–32

  Abstract

  Oropharyngeal (OP) symptoms are common in asthma patients using inhaled corticosteroids (ICSs) alone and in combination with a long-acting beta(2)-agonist (LABA). Patterns of medication use, level of asthma control and association with OP symptoms are not often reported in a nonstudy setting.To determine the prevalence of OP symptoms among adult asthma patients using ICSs alone and an ICS plus a LABA; to investigate the relationships between medication use, asthma control and OP symptoms; and to assess family physicians' (FPs') perceptions of the prevalence and management of OP symptoms.A random telephone survey of 1003 asthma patients and 250 FPs treating asthma patients was conducted from February to March 2005 across Canada.Twenty-four per cent of patients experienced OP symptoms; 67% of them spoke to their FPs about the OP symptoms. Thirty-one per cent of patients who experienced OP symptoms stopped or reduced their dose of medication. OP symptoms were reported by 25% of patients using ICSs and 22% using an ICS plus a LABA. The incidence of OP symptoms was not affected by the choice of inhalation device (metered-dose inhaler versus dry powder inhaler) or the use of a spacer. Fifty-eight per cent of patients had uncontrolled asthma; patients achieving a lower level of general education were more likely to have poor control. Patients with uncontrolled asthma were more likely than those with controlled asthma to report OP symptoms (28% versus 18%, respectively; P<0.05). Eighty-nine per cent of FPs had patients who had reported OP symptoms to them. FPs estimated that 15% of their patients experienced OP symptoms and that compliance to treatment worsened in approximately 20% of them.The prevalence of OP symptoms in asthma patients using ICSs and an ICS plus a LABA is significant. OP symptoms were found to be associated with a reduced patient education level, with a likelihood of reducing or stopping medication, and with a less well-controlled asthma patient. While FPs recognized that a significant proportion of their asthma patients experience OP symptoms and that OP symptoms may affect compliance, they underestimated the prevalence of this problem.

  View details for DOI 10.1155/2008/593723

  View details for Web of Science ID 000254274400005

  View details for PubMedID 18292850

  View details for PubMedCentralID PMC2677852

• Predictors of a more favourable response to combined therapy with salmeterol and fluticasone as initial maintenance therapy in asthma RESPIRATORY MEDICINE Ernst, P., Franssen, E., Chanc, C. N., Okell, M., O'Byrne, P., Baie, T. 2008; 102 (1): 77–81

  Abstract

  Orally inhaled corticosteroids represent the usually recommended initial controller therapy for most patients with persistent asthma. Some patients might benefit from earlier use of a combination of an inhaled corticosteroid and an orally inhaled long-acting beta agonist, however. We wished to identify clinical characteristics of patients which would enable one to identify a sub-group of patients who would benefit most from initiating sustained controller therapy with combination therapy.We carried out a secondary analysis of five randomized clinical trials including 1606 subjects in order to examine whether differences in baseline characteristics of patients might predict a greater preferential response to combination therapy with salmeterol and fluticasone.Subjects whose asthma had been present for 10 or more years were 2.2 times more likely to achieve well-controlled asthma by 12 weeks on combination therapy, while subjects with a shorter duration of asthma were only 1.4 times as likely to achieve asthma control with combination therapy as opposed to inhaled corticosteroids alone. None of the other factors examined including symptom frequency or severity, rescue beta-agonist use, severity of lung function impairment or degree of reversibility, was able to distinguish subjects who would benefit preferentially from such combination therapy.Longer duration of asthma might be used to identify subjects who will benefit more from combined maintenance therapy with a long-acting beta agonist and an inhaled corticosteroid rather than an inhaled corticosteroid alone.

  View details for DOI 10.1016/j.rmed.2007.08.008

  View details for Web of Science ID 000252633500011

  View details for PubMedID 17904834

• Musashi1 antigen expression in human fetal germinal matrix development EXPERIMENTAL NEUROLOGY Chan, C., Moore, B. E., Cotman, C. W., Okano, H., Tavares, R., Hovanesian, V., Pinar, H., Johanson, C. E., Svendsen, C. N., Stopa, E. G. 2006; 201 (2): 515-518

  Abstract

  Musashi1 is a highly conserved protein found in neural progenitor cells. We examined the expression dynamics of Musashi1 in conjunction with other representative neural progenitor antigenic determinants (Ki-67 and nestin) during 8 different stages of the developing human fetal germinal matrix. Our results indicate that Musashi1 is a useful marker for immature cells in periventricular areas inhabited by stem cells, progenitor cells, and differentiating cells.

  View details for DOI 10.1016/j.expneurol.2006.04.023

  View details for Web of Science ID 000241393900025

  View details for PubMedID 16777095

• Acute and long-term clinical and angiographic outcome after S-Stent implantation: S-Stent multicenter safety and efficacy trial CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Chan, C., Lim, Y. L., Santoso, T., Tresukosol, D., Lim, Y. T., Sonoda, S., Fitzgerald, P. 2004; 62 (4): 439–44

  Abstract

  The purpose of this study is to demonstrate safety and effectiveness of the S-Stent in de novo coronary lesions treated with conventional percutaneous coronary balloon angioplasty. Between January 2000 and June 2001, 120 patients were prospectively enrolled at four study centers. Patients were treated with coronary stenting in a total of 137 lesions. Procedural success was achieved in 100% of 137 attempted lesions. Clinical success was 99.8%. In-hospital mortality was 0.8%; myocardial infarction occurred in 0.8% and stent thrombosis in 0.8%. After stent implantation, the minimal lumen diameter increased from 0.92 +/- 0.43 to 2.74 +/- 0.36 mm (P < 0.0001) and the percent diameter stenosis decreased from 68.0 +/- 16.2 to 4.5 +/- 12.0 (P < 0.0001). At 6-month follow-up, the percent diameter stenosis was 33.5 +/- 21.3 and the angiographic restenosis rate was 16.5%. Target lesion revascularization was required in 12 patients (10.1%). We conclude that the use of S-Stent for coronary intervention resulted in a high procedural success rate and low angiographic restenosis at 6 months after implantation.

  View details for DOI 10.1002/ccd.20066

  View details for Web of Science ID 000223181400004

  View details for PubMedID 15274151

• Six- and twelve-month results from first human experience using everolimus-eluting stents with bioabsorbable polymer CIRCULATION Grube, E., Sonoda, S., Ikeno, F., Honda, Y., Kar, S., Chan, C., Gerckens, U., Lansky, A. J., Fitzgerald, P. J. 2004; 109 (18): 2168-2171

  Abstract

  Everolimus, an active immunosuppressive and antiproliferative agent of the same family as sirolimus (rapamycin), has demonstrated significant reduction of neointimal proliferation in animal studies. The First Use To Underscore restenosis Reduction with Everolimus (FUTURE) I trial was the first in-human experience to evaluate the safety and efficacy of everolimus-eluting stents (EES), coated with a bioabsorbable polymer, compared with bare metal stents (BMS).FUTURE I was a prospective, single-blind, randomized trial that enrolled 42 patients with de novo coronary lesions (EES 27, BMS 15). Patient and lesion characteristics were comparable between the groups. Major adverse cardiac event rates were low at 30 days and 6 months, without any early or late stent thrombosis for either group (P=NS). Between 6 and 12 months, there were no additional reports of major adverse cardiac events. The 6-month angiographic in-stent restenosis rate was 0% versus 9.1% (1 patient) (P=NS), with an associated late loss of 0.11 mm versus 0.85 mm (P<0.001), and the in-segment restenosis rate was 4% (1 patient) and 9.1% (1 patient) (P=NS) for EES and BMS, respectively. Intravascular ultrasound analysis revealed a significant reduction of percent neointimal volume in EES compared with BMS (2.9+/-1.9 mm3/mm versus 22.4+/-9.4 mm3/mm, P<0.001). There was no late stent malapposition in either group. The safety and efficacy of the EES appeared to be sustained at 12 months.In this initial clinical experience, EES with bioabsorbable polymer demonstrated a safe and efficacious method to reduce in-stent neointimal hyperplasia and restenosis.

  View details for DOI 10.1161/01.CIR.0000128850.84227.FD

  View details for Web of Science ID 000221322600003

  View details for PubMedID 15123533

• An intravascular ultrasound analysis from FUTURE I, the first human experience using everolimus-eluting stents: Six- and 12-month results 53rd Annual Scientific Session of the American-College-of-Cardiology Sonoda, S., Grube, E., SHIMADA, Y., Hassan, A. H., Yock, P. G., Chan, C., Honda, H., Kar, S., Lansky, A. J., Fitzgerald, P. J., Honda, Y. ELSEVIER SCIENCE INC. 2004: 85A–86A

  View details for Web of Science ID 000189388500359

• Effect of everolimus-eluting stents in preventing neointimal hyperplasia: An intravascular ultrasound analysis from the FUTURE II trial 53rd Annual Scientific Session of the American-College-of-Cardiology Sonoda, S., Grube, E., SHIMADA, Y., Hassan, A. H., Honda, Y., Yock, P. G., Chan, C., Honda, H., Kar, S., Hauptmann, K. E., Storger, H., Lansky, A. J., Fitzgerald, P. J. ELSEVIER SCIENCE INC. 2004: 66A–66A

  View details for Web of Science ID 000189388500278