Publications by authors named "Grace Kim"

419 Publications

US general surgical trainee performance for representative global surgery procedures.

Am J Surg 2021 Jun 9. Epub 2021 Jun 9.

Center for Surgical Training and Research, Department of Surgery, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Background: Many US general surgery residents are interested in global surgery, but their competence with key procedures is unknown.

Methods: Using a registry managed by the Society for Improving Medical Professional Learning (SIMPL), we extracted longitudinal operative performance ratings data for a national cohort of US general surgery residents. Operative performance at the time of graduation was estimated via a Bayesian generalized linear mixed model.

Results: Operative performance ratings for 12,976 procedures performed by 1584 residents in 52 general surgery programs were analyzed. These spanned 17 of 31 (55%) procedures deemed important for global surgical practice. For these procedures, the probability of a graduating resident being deemed competent to perform a procedure was 0.95 (95% confidence interval 0.86-1.00) but was less than 0.9 for 3 observed procedures.

Conclusion: Our results highlight gaps in the preparedness of US general surgery trainees to perform procedures deemed most important for global surgery settings.
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http://dx.doi.org/10.1016/j.amjsurg.2021.05.016DOI Listing
June 2021

Tipping the Scales With Zebrafish to Understand Adaptive Tumor Immunity.

Front Cell Dev Biol 2021 20;9:660969. Epub 2021 May 20.

Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA, United States.

The future of improved immunotherapy against cancer depends on an in-depth understanding of the dynamic interactions between the immune system and tumors. Over the past two decades, the zebrafish has served as a valuable model system to provide fresh insights into both the development of the immune system and the etiologies of many different cancers. This well-established foundation of knowledge combined with the imaging and genetic capacities of the zebrafish provides a new frontier in cancer immunology research. In this review, we provide an overview of the development of the zebrafish immune system along with a side-by-side comparison of its human counterpart. We then introduce components of the adaptive immune system with a focus on their roles in the tumor microenvironment (TME) of teleosts. In addition, we summarize zebrafish models developed for the study of cancer and adaptive immunity along with other available tools and technology afforded by this experimental system. Finally, we discuss some recent research conducted using the zebrafish to investigate adaptive immune cell-tumor interactions. Without a doubt, the zebrafish will arise as one of the driving forces to help expand the knowledge of tumor immunity and facilitate the development of improved anti-cancer immunotherapy in the foreseeable future.
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http://dx.doi.org/10.3389/fcell.2021.660969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173129PMC
May 2021

Association of the Irregular 3-Dimensional Shape of White Matter Hyperintensities with Cognitive Function.

Eur Neurol 2021 Jun 2:1-8. Epub 2021 Jun 2.

Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.

Introduction: The irregular shapes of white matter hyperintensities (WMHs) are associated with poor cognitive function, diabetes, or lacunes. However, the association between the WMH shape and dementia remains understudied. We investigated the association between the calculated shape index of WMH and the diagnosis of dementia and cognitive function.

Methods: The inverse sphericity index (ISIWMH) and volume of WMHs (VOLWMH) were compared among 82 participants with normal cognition, 82 with Alzheimer's dementia (AD), and 82 with subcortical vascular dementia (SVD). We examined the associations of ISIWMH and VOLWMH with the modified Hachinski Ischemic Score (mHIS), diagnosis of AD and SVD, and cognitive test scores, using linear, multinomial, or hierarchical linear regression models.

Results: The mHIS was associated with both ISIWMH (β = 0.326, p < 0.001) and VOLWMH (β = 0.299, p < 0.001). Both ISIWMH and VOLWMH were associated with the SVD diagnosis (odds ratio [OR] = 2.685, p = 0.002, ISIWMH; OR = 2.597, p = 0.005, VOLWMH), but not with AD. The SVD diagnosis was better explained when the multinomial regression model included both ISIWMH and VOLWMH instead of VOLWMH alone (χ2 = 20.768, df = 2, p < 0.001). The Trail Making Test-D (TMT-D) scores of the SVD patients were associated with both ISIWMH (β = 0.308) and VOLWMH (β = 0.293).

Conclusion: An irregular WMH shape may be associated with the high cerebrovascular component of cognitive impairment and the diagnosis and low cognitive flexibility of SVD, which may improve the prediction of SVD diagnosis when used in combination with WMH volume.
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http://dx.doi.org/10.1159/000515836DOI Listing
June 2021

Durable virological response and functional cure of chronic hepatitis D after long-term peginterferon therapy.

Aliment Pharmacol Ther 2021 May 28. Epub 2021 May 28.

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

Background: Hepatitis delta virus (HDV) infection is the most aggressive form of chronic viral hepatitis. Response rates to therapy with 1- to 2-year courses of pegylated interferon alpha (peginterferon) treatment are suboptimal.

Aims: To evaluate the long-term outcomes of patients with chronic hepatitis D after an extended course of peginterferon.

Methods: Patients were followed after completion of trial NCT00023322 and classified based on virological response defined as loss of detectable serum HDV RNA at last follow-up. During extended follow-up, survival and liver-related events were recorded.

Results: All 12 patients who received more than 6 months of peginterferon in the original study were included in this analysis. The cohort was mostly white (83%) and male (92%) and ranged in age from 18 to 58 years (mean = 42.6). Most patients had advanced but compensated liver disease at baseline, a median HBV DNA level of 536 IU per mL and median HDV RNA level of 6.86 log genome equivalents per mL. The treatment duration averaged 6.1 years (range 0.8-14.3) with a total follow-up of 8.8 years (range 1.7-17.6). At last follow-up, seven (58%) patients had durable undetectable HDV RNA in serum, and four (33%) cleared HBsAg. Overall, one of seven (14%) responders died or had a liver-related event vs four of five (80%) non-responders.

Conclusions: With further follow-up, an extended course of peginterferon therapy was found to result in sustained clearance of HDV RNA and favourable clinical outcomes in more than half of patients and loss of HBsAg in a third.
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http://dx.doi.org/10.1111/apt.16408DOI Listing
May 2021

NKTR-358: A novel regulatory T-cell stimulator that selectively stimulates expansion and suppressive function of regulatory T cells for the treatment of autoimmune and inflammatory diseases.

J Transl Autoimmun 2021 6;4:100103. Epub 2021 May 6.

Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA.

Impaired interleukin-2 (IL-2) production and regulatory T-cell dysfunction have been implicated as immunological mechanisms central to the pathogenesis of multiple autoimmune and inflammatory diseases. NKTR-358, a novel regulatory T-cell stimulator, is an investigational therapeutic that selectively restores regulatory T-cell homeostasis in these diseases. We investigated NKTR-358's selectivity for regulatory T-cells, receptor-binding properties, vo and pharmacodynamics, ability to suppress conventional T-cell proliferation in mice and non-human primates, and functional activity in a murine model of systemic lupus erythematosus. NKTR-358 demonstrated decreased affinity for IL-2Rα, IL-2Rβ, and IL-2Rαβ compared with recombinant human IL-2 (rhIL-2). A single dose of NKTR-358 in cynomolgus monkeys produced a greater than 15-fold increase in regulatory T-cells, and the increase lasted until day 14, while daily rhIL-2 administration for 5 days only elicited a 3-fold increase, which lasted until day 7. Repeated dosing of NKTR-358 over 6 months in cynomolgus monkeys elicited cyclical, robust increases in regulatory T-cells with no loss in drug activity over the course of treatment. Regulatory T-cells isolated from NKTR-358-treated mice displayed a sustained, higher suppression of conventional T-cell proliferation than regulatory T-cells isolated from vehicle-treated mice. NKTR-358 treatment in a mouse model (MRL/MpJ-Fas) of systemic lupus erythematosus for 12 weeks maintained elevated regulatory T-cells for the treatment duration and ameliorated disease progression. Together, these results suggest that NKTR-358 has the ability to elicit sustained and preferential proliferation and activation of regulatory T-cells without corresponding effects on conventional T-cells, with improved pharmacokinetics compared with rhIL-2.
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http://dx.doi.org/10.1016/j.jtauto.2021.100103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141531PMC
May 2021

Flipping the feedback script: Using a bottom-up feedback tool in surgical education.

Am J Surg 2021 May 10. Epub 2021 May 10.

Department of Surgery, University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI, 48109, USA. Electronic address:

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http://dx.doi.org/10.1016/j.amjsurg.2021.04.027DOI Listing
May 2021

Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children with Monogenic Cholestasis.

J Pediatr Gastroenterol Nutr 2021 Jun 3. Epub 2021 Jun 3.

Texas Children's Hospital, Baylor College of Medicine, Houston TX University of California, San Francisco, San Francisco CA King's College London, London UK Arbor Research Collaborative for Health, Ann Arbor MI University of Michigan Hospitals and Health Centers, Ann Arbor MI UPMC Children's Hospital of Pittsburgh, Pittsburgh PA Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago IL Cincinnati Children's Hospital Medical Center, Cincinnati OH Johns Hopkins Medicine, Baltimore MD Indiana University-Riley Hospital for Children, Indianapolis IN Seattle Children's Hospital, Seattle WA Emory University School of Medicine, Atlanta GA Washington University, St. Louis Children's Hospital, St. Louis MO University of Colorado School of Medicine, Children's Hospital Colorado, Aurora CO Children's Hospital Los Angeles, University of Southern California, Los Angeles CA The Children's Hospital of Philadelphia, Philadelphia PA Hospital for Sick Children, University of Toronto, Toronto ON.

Objectives: To advance our understanding of monogenic forms of intrahepatic cholestasis.

Methods: Analyses included participants with pathogenic biallelic mutations in ABCB11 (bile salt export pump; BSEP) or ATP8B1 (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in ABCB4 (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between 11/2007-12/2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data.

Results: Ninety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including 4 monoallelic) deficiency were analyzed. Thirty-five had surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported.

Conclusions: In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require study of larger cohorts.

An infographic is available for this article at: http://links.lww.com/MPG/C343.
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http://dx.doi.org/10.1097/MPG.0000000000003153DOI Listing
June 2021

Single-cell transcriptome analysis defines heterogeneity of the murine pancreatic ductal tree.

Elife 2021 May 19;10. Epub 2021 May 19.

Diabetes Center, University of California, San Francisco, San Francisco, United States.

To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA-sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, and intrapancreatic bile duct cells. We describe an epithelial-mesenchymal transitory axis in our three pancreatic duct subpopulations and identify osteopontin as a regulator of this fate decision as well as human duct cell dedifferentiation. Our results further identify functional heterogeneity within pancreatic duct subpopulations by elucidating a role for geminin in accumulation of DNA damage in the setting of chronic pancreatitis. Our findings implicate diverse functional roles for subpopulations of pancreatic duct cells in maintenance of duct cell identity and disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.
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http://dx.doi.org/10.7554/eLife.67776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184217PMC
May 2021

DRscDB: A single-cell RNA-seq resource for data mining and data comparison across species.

Comput Struct Biotechnol J 2021 11;19:2018-2026. Epub 2021 Apr 11.

Department of Genetics, Blavatnik Institute, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.

With the advent of single-cell RNA sequencing (scRNA-seq) technologies, there has been a spike in studies involving scRNA-seq of several tissues across diverse species including . Although a few databases exist for users to query genes of interest within the scRNA-seq studies, search tools that enable users to find orthologous genes and their cell type-specific expression patterns across species are limited. Here, we built a new search database, DRscDB (https://www.flyrnai.org/tools/single_cell/web/), to address this need. DRscDB serves as a comprehensive repository for published scRNA-seq datasets for and relevant datasets from human and other model organisms. DRscDB is based on manual curation of scRNA-seq studies of various tissue types and their corresponding analogous tissues in vertebrates including zebrafish, mouse, and human. Of note, our search database provides most of the literature-derived marker genes, thus preserving the original analysis of the published scRNA-seq datasets. Finally, DRscDB serves as a web-based user interface that allows users to mine gene expression data from scRNA-seq studies and perform cell cluster enrichment analyses pertaining to various scRNA-seq studies, both within and across species.
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http://dx.doi.org/10.1016/j.csbj.2021.04.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085783PMC
April 2021

Combined clinic and home-based therapeutic approach for the treatment of bilateral radial deficiency for a young child with Holt-Oram syndrome: A case report.

J Hand Ther 2021 Mar 6. Epub 2021 Mar 6.

NYU Langone Health Rusk Rehabilitation, New York, NY, USA. Electronic address:

Background: Holt-Oram syndrome (HOS) is a rare, genetic condition characterized by the combination of congenital heart defect and hypoplasia in one or both upper extremities. Children with HOS commonly present with varied joint and limb involvement including radial longitudinal deficiency impacting hand function. Evidence-based guidelines regarding orthotic wear and therapeutic techniques are lacking.

Purpose: The aim of this case report was to present the results of a long-term occupational therapy program for a patient with HOS pre and postpollicization.

Study Design: Case report.

Methods: A 4-month-old patient with bilateral radial longitudinal deficiencies began outpatient occupational therapy for custom orthosis fabrication and treatment which included long term clinic and home-based intervention. Techniques included passive range of motion, orthosis wear, therapeutic taping, and modified constraint induced movement therapy. Longitudinal assessment of musculoskeletal alignment and functional hand use was performed using goniometry for passive and active range of motion, the Assisting Hand Assessment (AHA), and The Thumb Grasp and Pinch Assessment (T-GAP).

Results: Improvement in passive and active range of motion was achieved as well as improved activity level function as measured by the AHA and T-GAP postpollicization and intervention.

Conclusions: A combined clinic and home-based therapeutic approach can be effective for children with HOS to improve alignment and function pre and postpollicization to further enhance hand function. Comprehensive, long-term assessment is necessary to fully evaluate and communicate improvement.
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http://dx.doi.org/10.1016/j.jht.2021.03.003DOI Listing
March 2021

Evaluation of a novel particle-based multi-analyte technology for the detection of anti-fibrillarin antibodies.

Immunol Res 2021 Apr 28. Epub 2021 Apr 28.

Immunologia E Allergologia, Ospedale S. Maria degli Angeli, Pordenone, Italy.

Systemic sclerosis (SSc) is a heterogeneous autoimmune disease associated with several anti-nuclear antibodies (ANA), including those in the classification criteria (anti-centromere, anti-topoisomerase I (Scl-70), anti-RNA Pol III). However, the presence of less common antibodies such as anti-fibrillarin (U3-RNP) that generate a clumpy nucleolar pattern by HEp-2 indirect immunofluorescence assay (IFA, ICAP AC-9) are considered disease specific and are with clinical subsets of SSc, therefore playing a role in diagnosis and prognosis. A specific and sensitive anti-fibrillarin assay would be an important addition to serological diagnosis and evaluation of SSc. The goal of this study was to evaluate a new particle-based multi-analyte technology (PMAT) for the measurement of anti-fibrillarin antibodies. A total of 149 patient samples were collected including 47 samples from France (Lyon and Paris, n = 32) and Italy (Careggi Hospital, Florence, n = 15) selected based on AC-9 HEp-2 IFA staining (> 1:640, clumpy nucleolar pattern) and 102 non-SSc controls (inflammatory bowel disease (IBD) n = 20, Sjögren's syndrome (SjS) n = 20, infectious disease (ID) n = 7, systemic lupus erythematosus (SLE) n = 17, rheumatoid arthritis (RA) n = 17, and healthy individuals (HI) n = 21). All samples were tested on the anti-fibrillarin PMAT assay (research use only, Inova Diagnostics, USA). Additionally, the 47 anti-fibrillarin positive samples were also tested on PMAT assays for detecting other autoantibodies in ANA-associated rheumatic diseases (AARD). Anti-fibrillarin antibody data performed by fluorescence enzyme immunoassay (FEIA, Thermo Fisher, Germany) was available for 34 samples. The anti-fibrillarin PMAT assay was positive in 31/32 (96.9%, France) and 12/15 (80.0%, Italy) of samples preselected based on the AC-9 IIF pattern (difference p = 0.09). Collectively, the PMAT assay showed 91.5% (95% confidence interval (CI): 80.1-96.6%) sensitivity with 100.0% (95% CI: 96.4-100.0%) specificity in non-SSc controls. Strong agreement was found between PMAT and FEIA with 100.0% positive qualitative agreement (34/34) and quantitative agreement (Spearman's rho = 0.89, 95% CI: 0.77.9-0.95%, p < 0.0001). Although most anti-fibrillarin positive samples were mono-specific (69.8%), some expressed additional antibodies (namely Scl-70, centromere, dsDNA, Ro52, Ro60, SS-B, Ribo-P, DFS70, and EJ). In conclusion, this first study on anti-fibrillarin antibodies measured using a novel PMAT assay shows promising results where the new PMAT assay had high level of agreement to FEIA for the detection of anti-fibrillarin antibodies. The availability of novel AFA assays such as PMAT might facilitate the clinical deployment, additional studies, standardization efforts, and potentially consideration of AFA for next generations of the classification criteria.
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http://dx.doi.org/10.1007/s12026-021-09197-1DOI Listing
April 2021

Vulvar apocrine hidradenocarcinoma arising in a hidradenoma papilliferum-A case report.

J Cutan Pathol 2021 Apr 28. Epub 2021 Apr 28.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

Hidradenoma papilliferum (HP) is a benign adnexal neoplasm of the vulva that typically presents as a unilateral, flesh-colored papule in the labium majus in middle-aged Caucasian women. It is considered to be a close counterpart of the intraductal papilloma of the breast. Malignant transformation is rare with few reports in the literature. We present a case of vulvar mammary-type apocrine hidradenocarcinoma arising in an HP.
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http://dx.doi.org/10.1111/cup.14033DOI Listing
April 2021

Towards a More Standardized Approach to Pathologic Reporting of Pancreatoduodenectomy Specimens for Pancreatic Ductal Adenocarcinoma: Cross-continental and Cross-specialty Survey From the Pancreatobiliary Pathology Society Grossing Working Group.

Am J Surg Pathol 2021 Apr 23. Epub 2021 Apr 23.

Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL Department of Pathology, Rogel Cancer Center, University of Michigan, Ann Arbor, MI Department of Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY Department of Pathology and Research Center for Translational Medicine (KUTTAM), Koç University, Istanbul, Turkey Department of Pathology, University of California San Francisco, San Francisco, CA.

In recent literature and international meetings held, it has become clear that there are significant differences regarding the definition of what constitutes as margins and how best to document the pathologic findings in pancreatic ductal adenocarcinoma. To capture the current practice, Pancreatobiliary Pathology Society (PBPS) Grossing Working Group conducted an international multispecialty survey encompassing 25 statements, regarding pathologic examination and reporting of pancreatic ductal adenocarcinoma, particularly in pancreatoduodenectomy specimens. The survey results highlighted several discordances; however, consensus/high concordance was reached for the following: (1) the pancreatic neck margin should be entirely submitted en face, and if tumor on the slide, then it is considered equivalent to R1; (2) uncinate margin should be submitted entirely and perpendicularly sectioned, and tumor distance from the uncinate margin should be reported; (3) all other surfaces (including vascular groove, posterior surface, and anterior surface) should be examined and documented; (4) carcinoma involving separately submitted celiac axis specimen should be staged as pT4. Although no consensus was achieved regarding what constitutes R1 versus R0, most participants agreed that ink on tumor or at and within 1 mm to the tumor is equivalent to R1 only in areas designated as a margin, not surface. In conclusion, this survey raises the awareness of the discordances and serves as a starting point towards further standardization of the pancreatoduodenectomy grossing and reporting protocols.
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http://dx.doi.org/10.1097/PAS.0000000000001723DOI Listing
April 2021

Pediatric Thoracolumbar Spinal Injuries in United States Trauma Centers.

Pediatr Emerg Care 2021 Apr 9. Epub 2021 Apr 9.

From the *Division of Pediatric Emergency Medicine, Rainbow Babies & Children's Hospital †Division of Pediatric Hospital Medicine, Rainbow Babies & Children's Hospital, University Hospitals Cleveland Medical Center ‡Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH.

Objectives: Injuries are the leading cause of morbidity and mortality in children ages 1 to 18 years. There are limited studies about pediatric thoracolumbar (TL) spinal injuries; the purpose of this study was to characterize TL spinal injuries among pediatric patients evaluated in US trauma centers.

Methods: This was a retrospective cohort study of the National Trauma Data Bank. Patients aged 1 to 18 years with a thoracic or lumbar spinal injury sustained by blunt trauma during calendar years 2011 through 2016 were included. Cervical spinal injuries, death before arrival, or penetrating trauma were excluded. The data was abstracted, and missing data was addressed by imputations. Data was analyzed using descriptive statistics and multinomial logistic regressions.

Results: A total of 20,062 patients were included in the study. Thoracolumbar spinal injuries were more commonly sustained by 16- to 17-year-olds (45.7%), boys (56.6%), and White (74.8%). The injuries were often from a motor vehicle collision (MVC) (55.2%) and resulted in a bone injury (82.3%). Mechanism of injury and age were significant in predicting injury type. A fall was more likely than MVC to result in disc injury (odds ratio [OR], 1.70; 95% confidence interval [CI], 1.24-2.33), strain injury (OR, 1.18; 95% CI, 1.05-1.34), or cord injury (OR, 1.27; 95% CI, 1.12-1.45). Younger children were more likely than adolescents to present with disc injury (OR, 2.79; 95% CI, 1.75-4.45), cord injury (OR, 1.46; 95% CI, 1.18-1.81), or strain injury (OR, 1.37; 95% CI, 1.09-1.72).

Conclusions: To our knowledge, this is the largest pediatric TL spinal study. Clinicians should consider TL spinal injuries when adolescents present after an MVC, and specifically, TL spinal cord injuries when young children present after a fall. Additionally, pediatric TL spinal injury prevention should highlight motor vehicle and fall safety.
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http://dx.doi.org/10.1097/PEC.0000000000002427DOI Listing
April 2021

Associations between childhood family emotional health, fronto-limbic grey matter volume, and saliva 5mC in young adulthood.

Clin Epigenetics 2021 Mar 31;13(1):68. Epub 2021 Mar 31.

Genomics Program, College of Public Health, University of South Florida, 3720 Spectrum Blvd., Suite 304, Tampa, FL, USA.

Background: Poor family emotional health (FEH) during childhood is prevalent and impactful, and likely confers similar neurodevelopmental risks as other adverse social environments. Pointed FEH study efforts are underdeveloped, and the mechanisms by which poor FEH are biologically embedded are unclear. The current exploratory study examined whether variability in 5-methyl-cytosine (5mC) and fronto-limbic grey matter volume may represent pathways through which FEH may become biologically embedded.

Results: In 98 university students aged 18-22 years, retrospective self-reported childhood FEH was associated with right hemisphere hippocampus (b = 10.4, p = 0.005), left hemisphere amygdala (b = 5.3, p = 0.009), and right hemisphere amygdala (b = 5.8, p = 0.016) volumes. After pre-processing and filtering to 5mC probes correlated between saliva and brain, analyses showed that childhood FEH was associated with 49 5mC principal components (module eigengenes; MEs) (p = 3 × 10 to 0.047). Saliva-derived 5mC MEs partially mediated the association between FEH and right hippocampal volume (Burlywood ME indirect effect b = - 111, p = 0.014), and fully mediated the FEH and right amygdala volume relationship (Pink4 ME indirect effect b = - 48, p = 0.026). Modules were enriched with probes falling in genes with immune, central nervous system (CNS), cellular development/differentiation, and metabolic functions.

Conclusions: Findings extend work highlighting neurodevelopmental variability associated with adverse social environment exposure during childhood by specifically implicating poor FEH, while informing a mechanism of biological embedding. FEH-associated epigenetic signatures could function as proxies of altered fronto-limbic grey matter volume associated with poor childhood FEH and inform further investigation into primarily affected tissues such as endocrine, immune, and CNS cell types.
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http://dx.doi.org/10.1186/s13148-021-01056-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010979PMC
March 2021

The value of imaging and clinical outcomes in a phase II clinical trial of a lysophosphatidic acid receptor antagonist in idiopathic pulmonary fibrosis.

Ther Adv Respir Dis 2021 Jan-Dec;15:17534666211004238

Bristol Myers Squibb, Princeton, NJ, USA.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease characterized by worsening dyspnea and lung function and has a median survival of 2-3 years. Forced vital capacity (FVC) is the primary endpoint used most commonly in IPF clinical trials as it is the best surrogate for mortality. This study assessed quantitative scores from high-resolution computed tomography (HRCT) developed by machine learning as a secondary efficacy endpoint in a 26-week phase II study of BMS-986020 - an LPA receptor antagonist - in patients with IPF.

Methods: HRCT scans from 96% (137/142) of randomized subjects were utilized. Quantitative lung fibrosis (QLF) scores were calculated from the HRCT images. QLF improvement was defined as ⩾2% reduction in QLF score from baseline to week 26.

Results: In the placebo arm, 5% of patients demonstrated an improvement in QLF score at week 26 compared with 15% and 27% of patients in the BMS-986020 600 mg once daily (QD) and twice daily (BID) arms, respectively [ placebo:  = 0.08 (600 mg QD);  = 0.0098 (600 mg BID)]. Significant correlations were found between changes in QLF and changes in percent predicted FVC, diffusing capacity for carbon monoxide (DLCO), and shortness of breath at week 26 ( = -0.41,  = -0.22, and  = 0.27, respectively; all  < 0.01).

Conclusions: This study demonstrated the utility of quantitative HRCT as an efficacy endpoint for IPF in a double-blind, placebo-controlled clinical trial setting.
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http://dx.doi.org/10.1177/17534666211004238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013716PMC
March 2021

A study design for statistical learning technique to predict radiological progression with an application of idiopathic pulmonary fibrosis using chest CT images.

Contemp Clin Trials 2021 May 19;104:106333. Epub 2021 Mar 19.

Biostatistics, Fielding School of Public Health, University of California, Los Angeles, United States of America.

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by an unpredictable decline in lung function. Predicting IPF progression from the early changes in lung function tests have known to be a challenge due to acute exacerbation. Although it is unpredictable, the neighboring regions of fibrotic reticulation increase during IPF's progression. With this clinical information, quantitative characteristics of high-resolution computed tomography (HRCT) and a statistical learning paradigm, the aim is to build a model to predict IPF progression.

Design: A paired set of anonymized 193 HRCT images from IPF subjects with 6-12 month intervals were collected retrospectively. The study was conducted in two parts: (1) Part A collects the ground truth in small regions of interest (ROIs) with labels of "expected to progress" or "expected to be stable" at baseline HRCT and develop a statistical learning model to classify voxels in the ROIs. (2) Part B uses the voxel-level classifier from Part A to produce whole-lung level scores of a single-scan total probability's (STP) baseline.

Methods: Using annotated ROIs from 71 subjects' HRCT scans in Part A, we applied Quantum Particle Swarm Optimization-Random Forest (QPSO-RF) to build the classifier. Then, 122 subjects' HRCT scans were used to test the prediction. Using Spearman rank correlations and survival analyses, we ascertained STP associations with 6-12 month changes in quantitative lung fibrosis and forced vital capacity.

Conclusion: This study can serve as a reference for collecting ground truth, and developing statistical learning techniques to predict progression in medical imaging.
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http://dx.doi.org/10.1016/j.cct.2021.106333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204677PMC
May 2021

Comprehensive genetic analysis of adhesin proteins and their role in virulence of Candida albicans.

Genetics 2021 Feb;217(2)

Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON NIG 2W1, Canada.

Candida albicans is a microbial fungus that exists as a commensal member of the human microbiome and an opportunistic pathogen. Cell surface-associated adhesin proteins play a crucial role in C. albicans' ability to undergo cellular morphogenesis, develop robust biofilms, colonize, and cause infection in a host. However, a comprehensive analysis of the role and relationships between these adhesins has not been explored. We previously established a CRISPR-based platform for efficient generation of single- and double-gene deletions in C. albicans, which was used to construct a library of 144 mutants, comprising 12 unique adhesin genes deleted singly, and every possible combination of double deletions. Here, we exploit this adhesin mutant library to explore the role of adhesin proteins in C. albicans virulence. We perform a comprehensive, high-throughput screen of this library, using Caenorhabditis elegans as a simplified model host system, which identified mutants critical for virulence and significant genetic interactions. We perform follow-up analysis to assess the ability of high- and low-virulence strains to undergo cellular morphogenesis and form biofilms in vitro, as well as to colonize the C. elegans host. We further perform genetic interaction analysis to identify novel significant negative genetic interactions between adhesin mutants, whereby combinatorial perturbation of these genes significantly impairs virulence, more than expected based on virulence of the single mutant constituent strains. Together, this study yields important new insight into the role of adhesins, singly and in combinations, in mediating diverse facets of virulence of this critical fungal pathogen.
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http://dx.doi.org/10.1093/genetics/iyab003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045720PMC
February 2021

The roles of racial discrimination and English in civic outcomes for Asian Americans and Pacific Islanders.

Cultur Divers Ethnic Minor Psychol 2021 Mar 15. Epub 2021 Mar 15.

Department of Curriculum and Instruction.

Asian Americans and Pacific Islanders (AAPIs) on average report higher rates of racial discrimination and lower levels of English proficiency than other racial and ethnic groups. Less clear is how these factors may shape AAPIs' civic outcomes. The current study explored the roles of racial discrimination and English proficiency in AAPIs' civic satisfaction and civic engagement. Using data from a quality-of-life survey of 2,463 AAPIs from five ethnic subgroups in a large southwestern city, we analyzed (a) whether racial discrimination was associated with lower civic satisfaction but higher civic engagement and (b) whether English proficiency is associated with higher civic satisfaction and civic engagement. Multivariate regression results indicated that racial discrimination was associated with lower levels of civic satisfaction for four AAPI groups (Asian Indian, Korean, Filipino, and Vietnamese) but not with higher civic engagement. English proficiency was not consistently associated with civic satisfaction or engagement across AAPI groups. Examining racial discrimination along civic outcomes brings attention to an important dimension of AAPIs' well-being and lived experiences. Although English proficiency was not associated with civic engagement, the findings on racial discrimination have implications for civic programs, services, and policies that are important for promoting a more inclusive democracy. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/cdp0000443DOI Listing
March 2021

Construction and validation of a cerebral white matter hyperintensity probability map of older Koreans.

Neuroimage Clin 2021 4;30:102607. Epub 2021 Mar 4.

Department of Brain and Cognitive Science, Seoul National University College of Natural Sciences, Seoul, South Korea; Department of Neuropsychiatry, Seoul National University Bundang Hospital, Gyeonggido, South Korea; Department of Psychiatry, Seoul National University, College of Medicine, Seoul, South Korea. Electronic address:

Background And Purpose: Although two white matter hyperintensity (WMH) probability maps of healthy older adults already exist, they have several limitations in representing the distribution of WMH in healthy older adults, especially Asian older adults. We constructed and validated a WMH probability map (WPM) of healthy older Koreans and examined the age-associated differences of WMH.

Methods: We constructed WPM using development dataset that consisted of high-resolution 3D fluid-attenuated inversion recovery images of 5 age groups (60-64 years, 65-69 years, 70-74 years, 75-79 years, and 80+ years). Each age group included 30 age-matched men and women each. We tested the validity of the WPM by comparing WMH ages estimated by the WPM and the chronological ages of 30 healthy controls, 30 hypertension patients, and 30 S patients.

Results: Older age groups showed a higher volume of WMH in both hemispheres (p < 0.001). About 90% of the WMH were periventricular in all age groups. With advancing age, the peak of the distance histogram from the ventricular wall of the periventricular WMH shifted away from the ventricular wall, while that of deep WMH shifted toward the ventricular wall. The estimated WMH ages were comparable to the chronological ages in the healthy controls, while being higher than the chronological ages in hypertension and stroke patients.

Conclusions: This WPM may serve as a standard atlas in research on WMH of older adults, especially Asians.
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http://dx.doi.org/10.1016/j.nicl.2021.102607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972979PMC
March 2021

Middle Cranial Fossa Approach to Repair Tegmen Dehiscence Using Self-setting Calcium Phosphate Cement: A Retrospective Case Review.

Otol Neurotol 2021 07;42(6):931-937

Department of Otolaryngology, Head and Neck Surgery, Sir Charles Gairdner Hospital, Perth.

Objectives: To review the outcomes of repairing tegmen dehiscence using the middle cranial fossa approach with a self-setting bone cement.

Study Design: Retrospective case series.

Setting: Two academic tertiary hospitals.

Patients: All patients presenting for surgical repair of tegmen dehiscence and with postoperative follow-up for at least 6 months between October 2015 and July 2019.

Intervention: Surgical repair using a middle cranial fossa approach using a layered reconstruction with temporalis fascia and self-setting calcium phosphate bone cement.

Main Outcome Measures: Perioperative complications, recurrence of presenting symptoms/disease, hearing, and facial nerve grade.

Results: The cohort consisted of 22 patients with 23 tegmen dehiscence repairs (1 sequential bilateral repair). There were 16 males and 6 females with an average age at operation of 52.6 years. Repairs were left sided in 9, right sided in 12 patients, and bilateral in 1 patient. No patients had recurrence of presenting symptoms or disease at most recent follow-up. Preoperative hearing was maintained in all patients. Two patients (9% of repairs) experienced delayed partial temporary facial nerve weakness House-Brackman grade 2 and 4 which had recovered by 8 weeks postoperative.

Conclusion: We demonstrate a technique for repairing tegmen dehiscence of the middle cranial fossa floor that has excellent postoperative outcomes. We highlight potential technical challenges in this approach as well as the need for counseling for potential partial transient facial nerve dysfunction.
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http://dx.doi.org/10.1097/MAO.0000000000003110DOI Listing
July 2021

New-Onset of Inflammatory Bowel Disease in a Patient Treated With Teprotumumab for Thyroid Associated Ophthalmopathy.

Ophthalmic Plast Reconstr Surg 2021 Mar 8. Epub 2021 Mar 8.

Department of Ophthalmology, University of California, San Francisco, San Francisco Division of Endocrinology, Department of Medicine, Stanford University School of Medicine, Stanford Department of Gastroenterology, University of California, San Francisco, San Francisco Department of Pathology, University of California, San Francisco, San Francisco, California, U.S.A.

A patient with thyroid-associated ophthalmopathy was treated with teprotumumab and developed symptoms concerning for inflammatory bowel disease after her sixth infusion. Colonoscopy was performed, and mucosal biopsies identified evidence of active colitis consistent with a diagnosis of ulcerative colitis. Despite treatment with budesonide and mesalamine, the patient continued to be symptomatic one and a half months after cessation of teprotumumab and required infliximab to achieve good control of her inflammatory bowel disease. This case represents the first report of new-onset inflammatory bowel disease arising during treatment with teprotumumab.
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http://dx.doi.org/10.1097/IOP.0000000000001943DOI Listing
March 2021

Reproducibility of lung nodule radiomic features: Multivariable and univariable investigations that account for interactions between CT acquisition and reconstruction parameters.

Med Phys 2021 Mar 11. Epub 2021 Mar 11.

Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Purpose: Recent studies have demonstrated a lack of reproducibility of radiomic features in response to variations in CT parameters. In addition, reproducibility of radiomic features has not been well established in clinical datasets. We aimed to investigate the effects of a wide range of CT acquisition and reconstruction parameters on radiomic features in a realistic setting using clinical low dose lung cancer screening cases. We performed univariable and multivariable explorations to consider the effects of individual parameters and the simultaneous interactions between three different acquisition/reconstruction parameters of radiation dose level, reconstructed slice thickness, and kernel.

Method: A cohort of 89 lung cancer screening patients were collected that each had a solid lung nodule >4mm diameter. A computational pipeline was used to perform a simulation of dose reduction of the raw projection data, collected from patient scans. This was followed by reconstruction of raw data with weighted filter back projection (wFBP) algorithm and automatic lung nodule detection and segmentation using a computer-aided detection tool. For each patient, 36 different image datasets were created corresponding to dose levels of 100%, 50%, 25%, and 10% of the original dose level, three slice thicknesses of 0.6 mm, 1 mm, and 2 mm, as well as three reconstruction kernels of smooth, medium, and sharp. For each nodule, 226 well-known radiomic features were calculated at each image condition. The reproducibility of radiomic features was first evaluated by measuring the intercondition agreement of the feature values among the 36 image conditions. Then in a series of univariable analyses, the impact of individual CT parameters was assessed by selecting subsets of conditions with one varying and two constant CT parameters. In each subset, intraparameter agreements were assessed. Overall concordance correlation coefficient (OCCC) served as the measure of agreement. An OCCC ≥ 0.9 implied strong agreement and reproducibility of radiomic features in intercondition or intraparameter comparisons. Furthermore, the interaction of CT parameters in impacting radiomic feature values was investigated via ANOVA.

Results: All included radiomic features lacked intercondition reproducibility (OCCC < 0.9) among all the 36 conditions. Out of 226 radiomic features analyzed, only 17 and 18 features were considered reproducible (OCCC ≥ 0.9) to dose and kernel variation, respectively, within the corresponding condition subsets. Slice thickness demonstrated the largest impact on radiomic feature values where only one to five features were reproducible at a few condition subsets. ANOVA revealed significant interactions (P < 0.05) between CT parameters affecting the variability of >50% of radiomic features.

Conclusion: We systematically explored the multidimensional space of CT parameters in affecting lung nodule radiomic features. Univariable and multivariable analyses of this study not only showed the lack of reproducibility of the majority of radiomic features but also revealed existing interactions among CT parameters, meaning that the effect of individual CT parameters on radiomic features can be conditional upon other CT acquisition and reconstruction parameters. Our findings advise on careful radiomic feature selection and attention to the inclusion criteria for CT image acquisition protocols within the datasets of radiomic studies.
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http://dx.doi.org/10.1002/mp.14830DOI Listing
March 2021

Lysosomal retargeting of Myoferlin mitigates membrane stress to enable pancreatic cancer growth.

Nat Cell Biol 2021 03 8;23(3):232-242. Epub 2021 Mar 8.

Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.

Lysosomes must maintain the integrity of their limiting membrane to ensure efficient fusion with incoming organelles and degradation of substrates within their lumen. Pancreatic cancer cells upregulate lysosomal biogenesis to enhance nutrient recycling and stress resistance, but it is unknown whether dedicated programmes for maintaining the integrity of the lysosome membrane facilitate pancreatic cancer growth. Using proteomic-based organelle profiling, we identify the Ferlin family plasma membrane repair factor Myoferlin as selectively and highly enriched on the membrane of pancreatic cancer lysosomes. Mechanistically, lysosomal localization of Myoferlin is necessary and sufficient for the maintenance of lysosome health and provides an early acting protective system against membrane damage that is independent of the endosomal sorting complex required for transport (ESCRT)-mediated repair network. Myoferlin is upregulated in human pancreatic cancer, predicts poor survival and its ablation severely impairs lysosome function and tumour growth in vivo. Thus, retargeting of plasma membrane repair factors enhances the pro-oncogenic activities of the lysosome.
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http://dx.doi.org/10.1038/s41556-021-00644-7DOI Listing
March 2021

The impact of psychopathology, social adversity and stress-relevant DNA methylation on prospective risk for post-traumatic stress: A machine learning approach.

J Affect Disord 2021 03 24;282:894-905. Epub 2020 Dec 24.

Genomics Program, College of Public Health, University of South Florida, Tampa, FL, United States. Electronic address:

Background: A range of factors have been identified that contribute to greater incidence, severity, and prolonged course of post-traumatic stress disorder (PTSD), including: comorbid and/or prior psychopathology; social adversity such as low socioeconomic position, perceived discrimination, and isolation; and biological factors such as genomic variation at glucocorticoid receptor regulatory network (GRRN) genes. This complex etiology and clinical course make identification of people at higher risk of PTSD challenging. Here we leverage machine learning (ML) approaches to identify a core set of factors that may together predispose persons to PTSD.

Methods: We used multiple ML approaches to assess the relationship among DNA methylation (DNAm) at GRRN genes, prior psychopathology, social adversity, and prospective risk for PTS severity (PTSS).

Results: ML models predicted prospective risk of PTSS with high accuracy. The Gradient Boost approach was the top-performing model with mean absolute error of 0.135, mean square error of 0.047, root mean square error of 0.217, and R of 95.29%. Prior PTSS ranked highest in predicting the prospective risk of PTSS, accounting for >88% of the prediction. The top ranked GRRN CpG site was cg05616442, in AKT1, and the top ranked social adversity feature was loneliness.

Conclusion: Multiple factors including prior PTSS, social adversity, and DNAm play a role in predicting prospective risk of PTSS. ML models identified factors accounting for increased PTSS risk with high accuracy, which may help to target risk factors that reduce the likelihood or course of PTSD, potentially pointing to approaches that can lead to early intervention.

Limitation: One of the limitations of this study is small sample size.
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http://dx.doi.org/10.1016/j.jad.2020.12.076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942200PMC
March 2021

Every 2-month belatacept maintenance therapy in kidney transplant recipients greater than 1-year posttransplant: A randomized, noninferiority trial.

Am J Transplant 2021 Feb 14. Epub 2021 Feb 14.

Emory Transplant Center, Atlanta, Georgia, USA.

Belatacept results in improved kidney transplant outcomes, but utilization has been limited by logistical barriers related to monthly (q1m) intravenous infusions. Every 2-month (q2m) belatacept has potential to increase utilization, therefore we conducted a randomized noninferiority trial in low immunologic risk renal transplant recipients greater than 1-year posttransplant. Patients on belatacept were randomly assigned to q1m or q2m therapy. The primary objective was a noninferiority comparison of renal function (eGFR) at 12 months with a noninferiority margin (NIM) of 6.0 ml/min/1.73 m . One hundred and sixty-six participants were randomized to q1m (n = 82) or q2m (n = 84) belatacept, 163 patients received treatment, and 76 q1m and 77 q2m subjects completed the 12-month study period. Every 2-month belatacept was noninferior to q1m, as the difference in mean eGFR adjusted for baseline renal function did not exceed the NIM. Two-month dosing was safe and well tolerated, with no patient deaths or graft losses. Four rejection episodes and three cases of donor-specific antibodies (DSAs) occurred among q2m subjects; however, only one rejection and one instance of DSA were observed in subjects adherent to the study protocol. Every 2-month belatacept therapy may facilitate long-term utilization of costimulation blockade, but future multicenter studies with long-term follow-up will further elucidate immunologic risk. (ClinicalTrials.gov NCT02560558).
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http://dx.doi.org/10.1111/ajt.16538DOI Listing
February 2021

End-to-end domain knowledge-assisted automatic diagnosis of idiopathic pulmonary fibrosis (IPF) using computed tomography (CT).

Med Phys 2021 May 19;48(5):2458-2467. Epub 2021 Mar 19.

Department of Biostatistics, University of California, Los Angeles, CA, 90024, USA.

Purpose: Domain knowledge (DK) acquired from prior studies is important for medical diagnosis. This paper leverages the population-level DK using an optimality design criterion to train a deep learning model in an end-to-end manner. In this study, the problem of interest is at the patient level to diagnose a subject with idiopathic pulmonary fibrosis (IPF) among subjects with interstitial lung disease (ILD) using a computed tomography (CT). IPF diagnosis is a complicated process with multidisciplinary discussion with experts and is subject to interobserver variability, even for experienced radiologists. To this end, we propose a new statistical method to construct a time/memory-efficient IPF diagnosis model using axial chest CT and DK, along with an optimality design criterion via a DK-enhanced loss function of deep learning.

Methods: Four state-of-the-art two-dimensional convolutional neural network (2D-CNN) architectures (MobileNet, VGG16, ResNet-50, and DenseNet-121) and one baseline 2D-CNN are implemented to automatically diagnose IPF among ILD patients. Axial lung CT images are retrospectively acquired from 389 IPF patients and 700 non-IPF ILD patients in five multicenter clinical trials. To enrich the sample size and boost model performance, we sample 20 three-slice samples (triplets) from each CT scan, where these three slices are randomly selected from the top, middle, and bottom of both lungs respectively. Model performance is evaluated using a fivefold cross-validation, where each fold was stratified using a fixed proportion of IPF vs non-IPF.

Results: Using DK-enhanced loss function increases the model performance of the baseline CNN model from 0.77 to 0.89 in terms of study-wise accuracy. Four other well-developed models reach satisfactory model performance with an overall accuracy >0.95 but the benefits brought on by the DK-enhanced loss function is not noticeable.

Conclusions: We believe this is the first attempt that (a) uses population-level DK with an optimal design criterion to train deep learning-based diagnostic models in an end-to-end manner and (b) focuses on patient-level IPF diagnosis. Further evaluation of using population-level DK on prospective studies is warranted and is underway.
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http://dx.doi.org/10.1002/mp.14754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141000PMC
May 2021

Tocilizumab Prevents Progression of Early Systemic Sclerosis-Associated Interstitial Lung Disease.

Arthritis Rheumatol 2021 Feb 3. Epub 2021 Feb 3.

University of Michigan, Ann Arbor.

Objective: Tocilizumab (TCZ) has demonstrated lung function preservation in 2 randomized controlled trials in early systemic sclerosis (SSc). This effect has yet to be characterized in terms of radiographically evident quantitative lung involvement. We undertook this study to assess the impact of TCZ on lung function preservation in a post hoc analysis, stratifying treatment arms according to the degree of lung involvement.

Methods: The focuSSced trial was a phase III randomized placebo-controlled trial of TCZ in patients with SSc and progressive skin disease. Participants underwent baseline and serial spirometry along with high-resolution chest computed tomography at baseline and at week 48. Quantitative interstitial lung disease (QILD) and fibrosis scores were assessed by computer software. We classified QILD into the following categories of lung involvement: mild (>5-10%), moderate (>10-20%), and severe (>20%).

Results: Of 210 participants recruited for the trial, 136 patients (65%) had ILD. The majority of these patients (77%) had moderate-to-severe involvement (defined as >10% lung involvement). The TCZ arm demonstrated preservation of forced vital capacity percent predicted (FVC%) over 48 weeks (least squares mean change in FVC% = -0.1) compared to placebo (-6.3%). For mild, moderate, and severe QILD, the mean ± SD change in FVC% in the TCZ arm at 48 weeks were -4.1 ± 2.5% (n = 11), 0.7 ± 1.9% (n =19), and 2.1 ± 1.6% (n = 26), respectively, and in the placebo group were -10.0 ± 2.6% (n = 11), -5.7 ± 1.6% (n = 26), and -6.7 ± 2.0% (n = 16), respectively. Similar treatment-related preservation findings were seen independent of fibrosis severity.

Conclusion: TCZ in early SSc-associated ILD with progressive skin disease stabilized FVC% over 48 weeks, independent of the extent of radiographically evident QILD.
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http://dx.doi.org/10.1002/art.41668DOI Listing
February 2021

Endovascular Removal of Thrombus and Right Heart Masses Using the AngioVac System: Results of 234 Patients from the Prospective, Multicenter Registry of AngioVac Procedures in Detail (RAPID).

J Vasc Interv Radiol 2021 04 29;32(4):549-557.e3. Epub 2021 Jan 29.

Division of Vascular Surgery, Eastern Virginia Medical School, Norfolk, Virginia.

Purpose: To assess device and procedural safety and technical success associated with the use of the AngioVac System to remove vascular thrombi and cardiac masses.

Materials And Methods: The Registry of AngioVac Procedures in Detail (RAPID) study prospectively collected data for 234 patients receiving treatment with AngioVac at 21 sites between March 2016 and August 2019: 84 (35.9%) with caval thromboemboli (CTEs), 113 (48.3%) with right heart masses (RHMs), 20 (8.5%) with catheter-related thrombi (CRTs), and 4 (1.7%) with pulmonary emboli (PEs). Thirteen patients had a combination of procedures during the same admission.

Results: Using the AngioVac system, 70%-100% thrombus or mass removal was achieved in 73.6% of patients with CTEs, 58.5% of patients with RHMs, 60% of patients with CRTs, and 57.1% of patients with PEs. Extracorporeal bypass time was < 1 hour for 176 (75.2%) procedures. Estimated blood loss was < 250 mL for 179 procedures (76.5%). Mean hemoglobin decreased from 10.4 g/dL ± 2.9 preoperatively to 9.4 g/dL ± 2.6 postoperatively. Transfusions were administered in 59 procedures (25.2%) with 47 transfusions (78.2%) being ≤ 2 U. There were 36 procedure-related complications, including 1 death.

Conclusions: The RAPID registry data demonstrate that the AngioVac System can be safely and effectively used to remove vascular thrombi and cardiac masses across a broad range of patient populations. The limited use of the device to remove pulmonary emboli in the present series precludes recommending the use of the AngioVac device for this indication.
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http://dx.doi.org/10.1016/j.jvir.2020.09.012DOI Listing
April 2021