Publications by authors named "Paul Lin"

160 Publications

The PrEDICT-DGE score as a simple preoperative screening tool identifies patients at increased risk for delayed gastric emptying after pancreaticoduodenectomy.

HPB (Oxford) 2021 Jun 24. Epub 2021 Jun 24.

Department of Surgery, George Washington University, Washington, DC, USA.

Background: Morbidity after Pancreaticoduodenectomy (PD) has remained unchanged over the past decade. Delayed Gastric Emptying (DGE) is a major contributor with significant impact on healthcare-costs, quality of life and, for malignancies, even survival. We sought to develop a scoring system to aid in easy preoperative identification of patients at risk for DGE.

Methods: The ACS-NSQIP dataset from 2014 to 2018 was queried for patients undergoing PD with Whipple or pylorus preserving reconstruction. 15,154 patients were analyzed using multivariable logistic regression to identify risk factors for DGE, which were incorporated into a prediction model. Subgroup analysis of patients without SSI or fistula (primary DGE) was performed.

Results: We identified 9 factors independently associated with DGE to compile the PrEDICT-DGE score: Procedures (Concurrent adhesiolysis, feeding jejunostomy, vascular reconstruction with vein graft), Elderly (Age>70), Ductal stent (Lack of biliary stent), Invagination (Pancreatic reconstruction technique), COPD, Tobacco use, Disease, systemic (ASA>2), Gender (Male) and Erythrocytes (preoperative RBC-transfusion). PrEDICT-DGE scoring strongly correlated with actual DGE rates (R = 0.95) and predicted patients at low, intermediate, and high risk. Subgroup analysis of patients with primary DGE, retained all predictive factors, except for age>70 (p = 0.07) and ASA(p = 0.30).

Conclusion: PrEDICT-DGE scoring accurately identifies patients at high risk for DGE and can help guide perioperative management.
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http://dx.doi.org/10.1016/j.hpb.2021.06.417DOI Listing
June 2021

Generation of glucocorticoid-resistant SARS-CoV-2 T cells for adoptive cell therapy.

Cell Rep 2021 07 7;36(3):109432. Epub 2021 Jul 7.

Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Adoptive cell therapy with virus-specific T cells has been used successfully to treat life-threatening viral infections, supporting application of this approach to coronavirus disease 2019 (COVID-19). We expand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T cells from the peripheral blood of COVID-19-recovered donors and non-exposed controls using different culture conditions. We observe that the choice of cytokines modulates the expansion, phenotype, and hierarchy of antigenic recognition by SARS-CoV-2 T cells. Culture with interleukin (IL)-2/4/7, but not under other cytokine-driven conditions, results in more than 1,000-fold expansion in SARS-CoV-2 T cells with a retained phenotype, function, and hierarchy of antigenic recognition compared with baseline (pre-expansion) samples. Expanded cytotoxic T lymphocytes (CTLs) are directed against structural SARS-CoV-2 proteins, including the receptor-binding domain of Spike. SARS-CoV-2 T cells cannot be expanded efficiently from the peripheral blood of non-exposed controls. Because corticosteroids are used for management of severe COVID-19, we propose an efficient strategy to inactivate the glucocorticoid receptor gene (NR3C1) in SARS-CoV-2 CTLs using CRISPR-Cas9 gene editing.
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http://dx.doi.org/10.1016/j.celrep.2021.109432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260499PMC
July 2021

Mice with dysfunctional TGF-β signaling develop altered intestinal microbiome and colorectal cancer resistant to 5FU.

Biochim Biophys Acta Mol Basis Dis 2021 Oct 31;1867(10):166179. Epub 2021 May 31.

Center for Translational Medicine, Department of Surgery, The George Washington University, Washington, DC, USA; The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, NY, USA. Electronic address:

Emerging data show a rise in colorectal cancer (CRC) incidence in young men and women that is often chemoresistant. One potential risk factor is an alteration in the microbiome. Here, we investigated the role of TGF-β signaling on the intestinal microbiome and the efficacy of chemotherapy for CRC induced by azoxymethane and dextran sodium sulfate in mice. We used two genotypes of TGF-β-signaling-deficient mice (Smad4 and Smad4Sptbn1), which developed CRC with similar phenotypes and had similar alterations in the intestinal microbiome. Using these mice, we evaluated the intestinal microbiome and determined the effect of dysfunctional TGF-β signaling on the response to the chemotherapeutic agent 5-Fluoro-uracil (5FU) after induction of CRC. Using shotgun metagenomic sequencing, we determined gut microbiota composition in mice with CRC and found reduced amounts of beneficial species of Bacteroides and Parabacteroides in the mutants compared to the wild-type (WT) mice. Furthermore, the mutant mice with CRC were resistant to 5FU. Whereas the abundances of E. boltae, B.dorei, Lachnoclostridium sp., and Mordavella sp. were significantly reduced in mice with CRC, these species only recovered to basal amounts after 5FU treatment in WT mice, suggesting that the alterations in the intestinal microbiome resulting from compromised TGF-β signaling impaired the response to 5FU. These findings could have implications for inhibiting the TGF-β pathway in the treatment of CRC or other cancers.
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http://dx.doi.org/10.1016/j.bbadis.2021.166179DOI Listing
October 2021

Veridical Causal Inference using Propensity Score Methods for Comparative Effectiveness Research with Medical Claims.

Health Serv Outcomes Res Methodol 2021 Jun 20;21(2):206-228. Epub 2020 Oct 20.

Department of Biostatistics, School of Public Health, University of Michigan.

Medical insurance claims are becoming increasingly common data sources to answer a variety of questions in biomedical research. Although comprehensive in terms of longitudinal characterization of disease development and progression for a potentially large number of patients, population-based inference using these datasets require thoughtful modifications to sample selection and analytic strategies relative to other types of studies. Along with complex selection bias and missing data issues, claims-based studies are purely observational, which limits effective understanding and characterization of the treatment differences between groups being compared. All these issues contribute to a crisis in reproducibility and replication of comparative findings using medical claims. This paper offers practical guidance to the analytical process, demonstrates methods for estimating causal treatment effects with propensity score methods for several types of outcomes common to such studies, such as binary, count, time to event and longitudinally-varying measures, and also aims to increase transparency and reproducibility of reporting of results from these investigations. We provide an online version of the paper with readily implementable code for the entire analysis pipeline to serve as a guided tutorial for practitioners. The online version can be accessed at https://rydaro.github.io/. The analytic pipeline is illustrated using a sub-cohort of patients with advanced prostate cancer from the large Clinformatics TM Data Mart Database (OptumInsight, Eden Prairie, Minnesota), consisting of 73 million distinct private payer insurees from 2001-2016.
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http://dx.doi.org/10.1007/s10742-020-00222-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142944PMC
June 2021

Cardiovascular and metabolic morbidity following spinal cord injury.

Spine J 2021 May 21. Epub 2021 May 21.

Department of Physical Medicine and Rehabilitation, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.

Background Context: Individuals living with a spinal cord injury (SCI) are at heightened risk for a number of chronic health conditions such as secondary comorbidities that may develop or be influenced by the injury, the presence of impairment, and/or the process of aging.

Purpose: The objective of this study was to compare the incidence of and adjusted hazards for cardiovascular and metabolic (cardiometabolic) morbidities among adults following SCI compared to adults without SCIs.

Study Design/setting: Longitudinal cohort from a nationwide insurance claims database.

Patient Sample: Privately-insured beneficiaries were included if they had an ICD-9-CM diagnostic code for traumatic SCI (n=9,081). Adults without SCI were also included (n=1,474,232).

Outcome Measures And Methods: Incidence estimates of common cardiometabolic morbidities were compared at 4-years of enrollment. Survival models were used to quantify unadjusted and adjusted hazard ratios for incident cardiometabolic morbidities.

Results: Adults living with traumatic SCIs had a higher 5-year incidence of any cardiometabolic morbidities (56.2% vs. 36.4%) as compared to adults without SCI, and differences were to a clinically meaningful extent. Survival models demonstrated that adults with SCI had a greater hazard for any cardiometabolic morbidity (Hazard Ratio [HR]: 1.67; 95%CI: 1.58, 1.76) and all cardiometabolic disorders; this ranged from HR: 1.45 (1.32, 1.59) for non-alcoholic fatty liver disease to HR: 3.55 (3.36, 3.76) for heart failure.

Conclusions: Adults with SCIs have a significantly higher incidence of and risk for common cardiometabolic morbidities, as compared to adults without SCIs. Efforts are needed to facilitate the development of improved clinical screening algorithms and early interventions to reduce risk of cardiometabolic disease onset/progression in this vulnerable population.
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http://dx.doi.org/10.1016/j.spinee.2021.05.014DOI Listing
May 2021

Metabolic Reprogramming of GMP Grade Cord Tissue Derived Mesenchymal Stem Cells Enhances Their Suppressive Potential in GVHD.

Front Immunol 2021 4;12:631353. Epub 2021 May 4.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Acute graft-vs.-host (GVHD) disease remains a common complication of allogeneic stem cell transplantation with very poor outcomes once the disease becomes steroid refractory. Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for the treatment of GVHD, but so far this strategy has had equivocal clinical efficacy. Therapies using MSCs require optimization taking advantage of the plasticity of these cells in response to different microenvironments. In this study, we aimed to optimize cord blood tissue derived MSCs (CBti MSCs) by priming them using a regimen of inflammatory cytokines. This approach led to their metabolic reprogramming with enhancement of their glycolytic capacity. Metabolically reprogrammed CBti MSCs displayed a boosted immunosuppressive potential, with superior immunomodulatory and homing properties, even after cryopreservation and thawing. Mechanistically, primed CBti MSCs significantly interfered with glycolytic switching and mTOR signaling in T cells, suppressing T cell proliferation and ensuing polarizing toward T regulatory cells. Based on these data, we generated a Good Manufacturing Process (GMP) Laboratory protocol for the production and cryopreservation of primed CBti MSCs for clinical use. Following thawing, these cryopreserved GMP-compliant primed CBti MSCs significantly improved outcomes in a xenogenic mouse model of GVHD. Our data support the concept that metabolic profiling of MSCs can be used as a surrogate for their suppressive potential in conjunction with conventional functional methods to support their therapeutic use in GVHD or other autoimmune disorders.
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http://dx.doi.org/10.3389/fimmu.2021.631353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130860PMC
May 2021

Psychological, cardiometabolic, musculoskeletal morbidity and multimorbidity among adults with cerebral palsy and spina bifida: a retrospective cross-sectional study.

Am J Phys Med Rehabil 2021 May 17. Epub 2021 May 17.

Department of Physical Medicine and Rehabilitation, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA Institute for Healthcare Policy and Innovation, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA Department of Obstetrics and Gynecology, Michigan Medicine, University of Michigan Department of Emergency Medicine, Michigan Medicine, University of Michigan Department of Surgery, Michigan Medicine, University of Michigan Department of Family Medicine, Michigan Medicine, University of Michigan.

Background: Individuals living with cerebral palsy (CP) or spina bifida (SB) are at heightened risk for a number of chronic health conditions such as secondary comorbidities, that may develop or be influenced by the disability, the presence of impairment, and/or the process of aging. However, very little is known about the prevalence and/or risk of developing secondary-comorbidities among individuals living with CP or SB throughout adulthood. The objective of this study was to compare the prevalence of psychological, cardiometabolic, musculoskeletal morbidity, and multimorbidity among adults with and without CP or SB.

Methods: Privately-insured beneficiaries were included if they had an ICD-9-CM diagnostic code for CP or SB (n = 29,841). Adults without CP or SB were also included (n = 5,384,849). Prevalence estimates of common psychological, cardiometabolic, and musculoskeletal morbidity and multimorbidity (≥2 conditions) were compared.

Results: Adults living with CP or SB had a higher prevalence of all psychological disorders and psychological multimorbidity (14.6% vs 5.4%), all cardiometabolic disorders and cardiometabolic multimorbidity (22.4% vs. 15.0%), and all musculoskeletal disorders and musculoskeletal multimorbidity (12.2% vs. 5.4%), as compared to adults without CP or SB, and differences were to a clinically meaningful extent.

Conclusions: Adults with CP or SB have a significantly higher prevalence of common psychological, cardiometabolic, and musculoskeletal morbidity and multimorbidity, as compared to adults without CP or SB. Efforts are needed to facilitate the development of improved clinical screening algorithms and early interventions to reduce risk of disease onset/progression in these higher risk populations.
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http://dx.doi.org/10.1097/PHM.0000000000001787DOI Listing
May 2021

Letter to the Editor: Traumatic Spinal Cord Injury and Risk of Early and Late Onset Alzheimer's Disease and related Dementia: Large Longitudinal Study.

Arch Phys Med Rehabil 2021 Jul 18;102(7):1431-1432. Epub 2021 Mar 18.

Institute for Healthcare Policy and Innovation, and, Departments of Physical Medicine and Rehabilitation, Obstetrics and Gynecology, Emergency Medicine, Surgery, and Neurosurgery, Michigan Medicine, University of Michigan, Ann Arbor, MI.

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http://dx.doi.org/10.1016/j.apmr.2021.03.003DOI Listing
July 2021

GMP-Compliant Universal Antigen Presenting Cells (uAPC) Promote the Metabolic Fitness and Antitumor Activity of Armored Cord Blood CAR-NK Cells.

Front Immunol 2021 26;12:626098. Epub 2021 Feb 26.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Natural killer (NK) cells are innate lymphocytes recognized for their important role against tumor cells. NK cells expressing chimeric antigen receptors (CARs) have enhanced effector function against various type of cancer and are attractive contenders for the next generation of cancer immunotherapies. However, a number of factors have hindered the application of NK cells for cellular therapy, including their poor growth kinetics and relatively low starting percentages within the mononuclear cell fraction of peripheral blood or cord blood (CB). To overcome these limitations, we genetically-engineered human leukocyte antigen (HLA)-A and HLA-B K562 cells to enforce the expression of CD48, 4-1BBL, and membrane-bound IL-21 (mbIL21), creating a universal antigen presenting cell (uAPC) capable of stimulating their cognate receptors on NK cells. We have shown that uAPC can drive the expansion of both non-transduced (NT) and CAR-transduced CB derived NK cells by >900-fold in 2 weeks of co-culture with excellent purity (>99.9%) and without indications of senescence/exhaustion. We confirmed that uAPC-expanded research- and clinical-grade NT and CAR-transduced NK cells have higher metabolic fitness and display enhanced effector function against tumor targets compared to the corresponding cell fractions cultured without uAPCs. This novel approach allowed the expansion of highly pure GMP-grade CAR NK cells at optimal cell numbers to be used for adoptive CAR NK cell-based cancer immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2021.626098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952299PMC
February 2021

The Adolescent and Young Adult (AYA) Horizon Study: An AYA Cancer Survivorship Cohort.

Cancer Epidemiol Biomarkers Prev 2021 May 22;30(5):857-866. Epub 2021 Feb 22.

Division of Research, Kaiser Permanente Northern California, Oakland, California.

Background: In the United States, >45,000 adolescent and young adult (AYA) women are diagnosed with cancer annually. Reproductive issues are critically important to AYA cancer survivors, but insufficient information is available to address their concerns. The AYA Horizon Study was initiated to contribute high-quality, contemporary evidence on reproductive outcomes for female cancer survivors in the United States.

Methods: The study cohort includes women diagnosed with lymphoma, breast, melanoma, thyroid, or gynecologic cancer (the five most common cancers among women ages 15-39 years) at three study sites: the state of North Carolina and the Kaiser Permanente health systems in Northern and Southern California. Detailed information on cancer treatment, fertility procedures, and pregnancy (e.g., miscarriage, live birth) and birth (e.g., birth weight, gestational length) outcomes are leveraged from state cancer registries, health system databases and administrative insurance claims, national data on assisted reproductive technology procedures, vital records, and survey data.

Results: We identified a cohort of 11,072 female AYA cancer survivors that includes >1,200 African American women, >1,400 Asian women, >1,600 Medicaid enrollees, and >2,500 Hispanic women using existing data sources. Active response to the survey component was low overall ( = 1,679), and notably lower among minority groups compared with non-Hispanic white women.

Conclusions: Passive data collection through linkage reduces participant burden and prevents systematic cohort attrition or potential selection biases that can occur with active participation requirements.

Impact: The AYA Horizon study will inform survivorship planning as fertility and parenthood gain increasing recognition as key aspects of high-quality cancer care.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102328PMC
May 2021

Contemporary Management of Traumatic Duodenal Injuries.

Am Surg 2021 Feb 17:3134821995054. Epub 2021 Feb 17.

Center for Trauma and Critical Care, Department of Surgery, RinggoldID:43963George Washington University, Washington, DC, USA.

Background: Traumatic duodenal injury is a rare, potentially devastating condition with challenging management decisions. Contemporary literature on operative management of duodenal injury is lacking. The purpose of this study is to assess optimal management strategies based on outcomes of patients with traumatic duodenal injury at a single trauma center.

Methods: A retrospective study of patients with traumatic duodenal injury from 2013-2020 at a level 1 trauma center was performed. Patient demographics, grade of injury as noted on CT scan or intraoperatively, surgical procedure(s) performed, and resultant outcomes were extracted.

Results: After excluding one patient due to death on arrival, 23 patients met inclusion criteria. Injuries consisted of grade 1 (n = 7), grade 2 (n = 2), grade 3 (n = 12), and grade 5 (n = 2); there were no grade 4 injuries. Patients were predominantly male (83%) with a median age of 30 years old. Nineteen patients (82%) underwent surgery. Four of nine patients (44%) with grade 1/2 injuries had hematomas and were managed non-operatively. The remaining five patients (56%) with grade 1/2 injuries underwent operation, which included primary repair (n = 3), duodenal exclusion (n = 1), and periduodenal drainage (n = 1). Of 12 patients with grade 3 injury, 6 underwent primary repair and 6 underwent resection. Three patients who underwent primary repair and one who underwent resection developed a duodenal leak. All patients with grade 5 injury (n = 2) underwent pancreaticoduodenectomy.

Conclusion: Grade 1 and 2 duodenal hematomas can be managed non-operatively, while lacerations require operative repair. Outcomes may be better following resection in patients with grade 3 injury.
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http://dx.doi.org/10.1177/0003134821995054DOI Listing
February 2021

Traumatic Spinal Cord Injury and Risk of Early and Late Onset Alzheimer's Disease and Related Dementia: Large Longitudinal Study.

Arch Phys Med Rehabil 2021 06 27;102(6):1147-1154. Epub 2021 Jan 27.

Institute for Healthcare Policy and Innovation, Michigan Medicine, University of Michigan, Ann Arbor, MI; Department of Physical Medicine and Rehabilitation, Michigan Medicine, University of Michigan, Ann Arbor, MI; Department of Obstetrics and Gynecology, Michigan Medicine, University of Michigan, Ann Arbor, MI; Department of Emergency Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI; Department of Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI; Department of Neurosurgery, Michigan Medicine, University of Michigan, Ann Arbor, MI.

Objective: Traumatic spinal cord injury (TSCI) is a life altering event most often causing permanent physical disability. Little is known about the risk of developing Alzheimer disease and related dementia (ADRD) among middle-aged and older adults living with TSCI. Time to diagnosis of and adjusted hazard for ADRD was assessed.

Design: Cohort study.

Setting: Using 2007-2017 claims data from the Optum Clinformatics Data Mart, we identified adults (45+) with diagnosis of TSCI (n=7019). Adults without TSCI diagnosis were included as comparators (n=916,516). Using age, sex, race/ethnicity, cardiometabolic, psychological, and musculoskeletal chronic conditions, US Census division, and socioeconomic variables, we propensity score matched persons with and without TSCI (n=6083). Incidence estimates of ADRD were compared at 4 years of enrollment. Survival models were used to quantify unadjusted, fully adjusted, and propensity-matched unadjusted and adjusted hazard ratios (HRs) for incident ADRD.

Participants: Adults with and without TSCI (N=6083).

Intervention: Not applicable.

Main Outcomes Measures: Diagnosis of ADRD.

Results: Both middle-aged and older adults with TSCI had higher incident ADRD compared to those without TSCI (0.5% vs 0.2% and 11.7% vs 3.3% among 45-64 and 65+ y old unmatched cohorts, respectively) (0.5% vs 0.3% and 10.6% vs 6.2% among 45-64 and 65+ y old matched cohorts, respectively). Fully adjusted survival models indicated that adults with TSCI had a greater hazard for ADRD (among 45-64y old: unmatched HR: 3.19 [95% confidence interval, 95% CI, 2.30-4.44], matched HR: 1.93 [95% CI, 1.06-3.51]; among 65+ years old: unmatched HR: 1.90 [95% CI, 1.77-2.04], matched HR: 1.77 [1.55-2.02]).

Conclusions: Adults with TSCI are at a heightened risk for ADRD. Improved clinical screening and early interventions aiming to preserve cognitive function are of paramount importance for this patient cohort.
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http://dx.doi.org/10.1016/j.apmr.2020.12.019DOI Listing
June 2021

Musculoskeletal morbidity following spinal cord injury: A longitudinal cohort study of privately-insured beneficiaries.

Bone 2021 01 20;142:115700. Epub 2020 Oct 20.

Department of Physical Medicine and Rehabilitation, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA; Institute for Healthcare Policy and Innovation, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Background: People living with spinal cord injuries (SCIs) experience motor, sensory and autonomic impairments that cause musculoskeletal disorders following the injury and that progress throughout lifetime. The range and severity of issues are largely dependent on level and completeness of the injury and preserved function.

Objective: High risk of developing musculoskeletal morbidities among individuals after sustaining a traumatic SCI is well known in the clinical setting, however, there is a severe lack of evidence in literature. The objective of this study was to compare the incidence of and adjusted hazards for musculoskeletal morbidities among adults with and without SCIs.

Methods: Privately-insured beneficiaries were included if they had an ICD-9-CM diagnostic code for SCI (n = 9081). Adults without SCI were also included (n = 1,474,232). Incidence estimates of common musculoskeletal morbidities (e.g., osteoporosis, sarcopenia, osteoarthritis, fractures, etc.) were compared at 5-years of enrollment. Survival models were used to quantify unadjusted and adjusted hazard ratios for incident musculoskeletal morbidities.

Results: Adults living with traumatic SCIs had a higher incidence of any musculoskeletal morbidities (82.4% vs. 47.5%) as compared to adults without SCI, and differences were to a clinically meaningful extent. Survival models demonstrated that adults with SCI had a greater fully-adjusted hazard for any musculoskeletal morbidity (Hazard Ratio [HR]: 2.41; 95%CI: 2.30, 2.52), and all musculoskeletal disorders, and ranged from HR: 1.26 (1.14, 1.39) for rheumatoid arthritis to HR: 7.02 (6.58, 7.49) for pathologic fracture.

Conclusions: Adults with SCIs have a significantly higher incidence of and risk for common musculoskeletal morbidities, as compared to adults without SCIs. Efforts are needed to facilitate the development of improved clinical screening algorithms and early interventions to reduce risk of musculoskeletal disease onset/progression in this higher risk population.
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http://dx.doi.org/10.1016/j.bone.2020.115700DOI Listing
January 2021

Fertility clinic advertising in the United States: Is the Society for Assisted Reproductive Technology oversight of advertising policy effective?

Fertil Steril 2021 01 11;115(1):72-73. Epub 2020 Oct 11.

Seattle Reproductive Medicine, Seattle, Washington.

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http://dx.doi.org/10.1016/j.fertnstert.2020.09.002DOI Listing
January 2021

A highly sensitive and specific real-time quantitative PCR for BRAF V600E/K mutation screening.

Sci Rep 2020 10 9;10(1):16943. Epub 2020 Oct 9.

Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi, Taiwan.

Mutations that lead to constitutive activation of key regulators in cellular processes are one of the most important drivers behind vigorous growth of cancer cells, and are thus prime targets in cancer treatment. BRAF V600E mutation transduces strong growth and survival signals for cancer cells, and is widely present in various types of cancers including lung cancer. A combination of BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) has recently been approved and significantly improved the survival of patients with advanced NSCLC harboring BRAF V600E/K mutation. To improve the detection of BRAF V600E/K mutation and investigate the incidence and clinicopathological features of the mutation in lung cancer patients of southern Taiwan, a highly sensitive and specific real-time quantitative PCR (RT-qPCR) method, able to detect single-digit copies of mutant DNA, was established and compared with BRAF V600E-specific immunohistochemistry. Results showed that the BRAF V600E mutation was present at low frequency (0.65%, 2/306) in the studied patient group, and the detection sensitivity and specificity of the new RT-qPCR and V600E-specific immunohistochemistry both reached 100% and 97.6%, respectively. Screening the BRAF V600E/K mutation with the RT-qPCR and V600E-specific immunohistochemistry simultaneously could help improve detection accuracy.
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http://dx.doi.org/10.1038/s41598-020-72809-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547094PMC
October 2020

Generation of glucocorticoid resistant SARS-CoV-2 T-cells for adoptive cell therapy.

bioRxiv 2020 Sep 15. Epub 2020 Sep 15.

Adoptive cell therapy with viral-specific T cells has been successfully used to treat life-threatening viral infections, supporting the application of this approach against COVID-19. We expanded SARS-CoV-2 T-cells from the peripheral blood of COVID-19-recovered donors and non-exposed controls using different culture conditions. We observed that the choice of cytokines modulates the expansion, phenotype and hierarchy of antigenic recognition by SARS-CoV-2 T-cells. Culture with IL-2/4/7 but not other cytokine-driven conditions resulted in >1000 fold expansion in SARS-CoV-2 T-cells with a retained phenotype, function and hierarchy of antigenic recognition when compared to baseline (pre-expansion) samples. Expanded CTLs were directed against structural SARS-CoV-2 proteins, including the receptor-binding domain of Spike. SARS-CoV-2 T-cells could not be efficiently expanded from the peripheral blood of non-exposed controls. Since corticosteroids are used for the management of severe COVID-19, we developed an efficient strategy to inactivate the glucocorticoid receptor gene ( ) in SARS-CoV-2 CTLs using CRISPR-Cas9 gene editing.
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http://dx.doi.org/10.1101/2020.09.15.298547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523118PMC
September 2020

Theoretical Model for Delivery of Congenital Heart Surgery in the United States.

Ann Thorac Surg 2021 05 26;111(5):1628-1635. Epub 2020 Aug 26.

Division of Pediatric Cardiac Surgery and the Heart and Vascular Institute, The Cleveland Clinic, Cleveland, Ohio.

Background: Over 150 hospitals perform congenital heart surgery (CHS) in the United States. Many hospitals are close together, with a median patient travel distance of 38.5 miles. We began with a theoretical blank slate and used objective methodology guided by population density and volume thresholds to estimate the optimal number and locations of hospitals to provide CHS in the United States.

Methods: Guided by published data, we estimated the number of CHS operations in the United States in to be 32,500 per year. We distributed patients geographically based on population density. Metropolitan Statistical Areas (population centers and surrounding areas with close economic/social ties) were used as potential hospital locations. Patients were assigned to the closest hospital location such that all hospitals had a CHS volume of ≥300 operations.

Results: We estimated 57 hospitals could serve the contiguous United States. Median theoretical hospital volume after regionalization was 451 operations (interquartile range, 366-648). Median patient travel distance was 35.1 miles. Some patients (6396/31,895, 20%) traveled more than 100 miles.

Conclusions: Our model suggests the United States could be served by approximately 100 fewer CHS hospitals than currently exist. With hospitals optimally placed, patient travel burden would decrease. This model serves as a platform to improve care delivery by regionalization of CHS.
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http://dx.doi.org/10.1016/j.athoracsur.2020.06.057DOI Listing
May 2021

Psychological morbidity among adults with cerebral palsy and spina bifida.

Psychol Med 2021 03 27;51(4):694-701. Epub 2020 Jul 27.

Department of Physical Medicine and Rehabilitation, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.

Background: Very little is known about the risk of developing psychological morbidities among adults living with cerebral palsy (CP) or spina bifida (SB). The objective of this study was to compare the incidence of and adjusted hazards for psychological morbidities among adults with and without CP or SB.

Methods: Privately insured beneficiaries were included if they had an International Classification of Diseases, Ninth revision, Clinical Modification diagnostic code for CP or SB (n = 15 302). Adults without CP or SB were also included (n = 1 935 480). Incidence estimates of common psychological morbidities were compared at 4-years of enrollment. Survival models were used to quantify unadjusted and adjusted hazard ratios for incident psychological morbidities.

Results: Adults living with CP or SB had a higher 4-year incidence of any psychological morbidity (38.8% v. 24.2%) as compared to adults without CP or SB, and differences were to a clinically meaningful extent. Fully adjusted survival models demonstrated that adults with CP or SB had a greater hazard for any psychological morbidity [hazard ratio (HR): 1.60; 95% CI 1.55-1.65], and all but one psychological disorder (alcohol-related disorders), and ranged from HR: 1.32 (1.23, 1.42) for substance disorders, to HR: 4.12 (3.24, 5.25) for impulse control disorders.

Conclusions: Adults with CP or SB have a significantly higher incidence of and risk for common psychological morbidities, as compared to adults without CP or SB. Efforts are needed to facilitate the development of improved clinical screening algorithms and early interventions to reduce the risk of disease onset/progression in these higher-risk populations.
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http://dx.doi.org/10.1017/S0033291720001981DOI Listing
March 2021

Cardiometabolic Morbidity in Adults With Cerebral Palsy and Spina Bifida.

Am J Med 2020 12 17;133(12):e695-e705. Epub 2020 Jul 17.

Department of Physical Medicine and Rehabilitation.

Purpose: The purpose of this study was to compare the incidence of, and adjusted hazards for, cardiometabolic morbidities among adults with and without cerebral palsy or spina bifida.

Methods: Privately insured beneficiaries were included if they had an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic code for cerebral palsy or spina bifida (n = 15,302). Adults without cerebral palsy or spina bifida were also included (n = 1,935,480). Incidence estimates of common cardiometabolic morbidities were compared at 4 years of enrollment. Survival models were used to quantify unadjusted and adjusted hazard ratios (HRs) for incident cardiometabolic morbidities.

Results: Adults living with cerebral palsy or spina bifida had a higher 4-year incidence of any cardiometabolic morbidity (41.5% vs 30.6%) as compared to adults without cerebral palsy or spina bifida, and differences were to a clinically meaningful extent. Fully adjusted survival models demonstrated that adults with cerebral palsy or spina bifida had a greater hazard for any cardiometabolic morbidity (HR: 1.52; 95% confidence interval [CI]: 1.47, 1.57), and all but 1 cardiometabolic disorder (nonalcoholic fatty liver disease) and ranged from HR: 1.20 (1.15, 1.25) for hypercholesterolemia to HR: 1.86 (1.74, 1.98) for heart failure.

Conclusions: Adults with cerebral palsy or spina bifida have a significantly higher incidence of, and risk for, common cardiometabolic morbidities, as compared to adults without cerebral palsy or spina bifida. Efforts are needed to facilitate the development of improved clinical screening algorithms and early interventions to reduce risk of cardiometabolic disease onset and progression in these higher-risk populations.
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http://dx.doi.org/10.1016/j.amjmed.2020.05.032DOI Listing
December 2020

In vitro fertilization is safe for women undergoing the treatment after they deliver: a call to arms for the children, too!

Authors:
Paul C Lin

Fertil Steril 2020 03;113(3):544-545

Seattle Reproductive Medicine, Seattle, Washington.

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http://dx.doi.org/10.1016/j.fertnstert.2020.01.014DOI Listing
March 2020

Targeting the E3 Ubiquitin Ligase PJA1 Enhances Tumor-Suppressing TGFβ Signaling.

Cancer Res 2020 05 3;80(9):1819-1832. Epub 2020 Mar 3.

Center for Translational Medicine, Department of Surgery, George Washington University, Washington, D.C.

RING-finger E3 ligases are instrumental in the regulation of inflammatory cascades, apoptosis, and cancer. However, their roles are relatively unknown in TGFβ/SMAD signaling. SMAD3 and its adaptors, such as β2SP, are important mediators of TGFβ signaling and regulate gene expression to suppress stem cell-like phenotypes in diverse cancers, including hepatocellular carcinoma (HCC). Here, PJA1, an E3 ligase, promoted ubiquitination and degradation of phosphorylated SMAD3 and impaired a SMAD3/β2SP-dependent tumor-suppressing pathway in multiple HCC cell lines. In mice deficient for SMAD3 ( ), PJA1 overexpression promoted the transformation of liver stem cells. Analysis of genes regulated by PJA1 knockdown and TGFβ1 signaling revealed 1,584 co-upregulated genes and 1,280 co-downregulated genes, including many implicated in cancer. The E3 ligase inhibitor RTA405 enhanced SMAD3-regulated gene expression and reduced growth of HCC cells in culture and xenografts of HCC tumors, suggesting that inhibition of PJA1 may be beneficial in treating HCC or preventing HCC development in at-risk patients. These findings provide a novel mechanism regulating the tumor suppressor function of TGFβ in liver carcinogenesis.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704101PMC
May 2020

Opioid Fills for Lumbar Facet Radiofrequency Ablation Associated with New Persistent Opioid Use.

Anesthesiology 2020 05;132(5):1165-1174

From the Division of Pain Medicine, Department of Anesthesiology (D.L.S., S.M., A.A.S., C.M.B.) the Sections of Transplant Surgery (V.G.) Plastic Surgery (J.F.W.), University of Michigan Medical School, Ann Arbor, Michigan the School of Public Health (H.A-A.) the Institute for Healthcare Policy and Innovation (P.L.), University of Michigan, Ann Arbor, Michigan.

Background: Zygapophyseal (facet) joint interventions are the second most common interventional procedure in pain medicine. Opioid exposure after surgery is a significant risk factor for chronic opioid use. The aim of this study was to determine the incidence of new persistent use of opioids after lumbar facet radiofrequency ablation and to assess the effect of postprocedural opioid prescribing on the development of new persistent opioid use.

Methods: The authors conducted a retrospective cohort study using claims from the Clinformatics Data Mart Database (OptumInsight, USA) to identify opioid-naïve patients between 18 and 64 yr old who had lumbar radiofrequency ablation. Patients who had either subsequent radiofrequency ablation 15 to 180 days or subsequent surgery within 180 days after the primary procedure were excluded from the analysis. The primary outcome was new persistent opioid use, defined as opioid prescription fulfillment within the 8 to 90 and 91 to 180 day periods after radiofrequency ablation. The authors then assessed patient-level risk factors for new persistent opioid use.

Results: A total of 2,887 patients met the inclusion criteria. Of those patients, 2,277 (78.9%) had radiofrequency ablation without a perioperative opioid fill, and 610 (21.1%) patients had the procedure with a perioperative opioid fill. The unadjusted rate of new persistent opioid use was 5.6% (34 patients) in the group with a perioperative opioid fill versus 2.8% (63 patients) for those without an opioid fill. Periprocedural opioid prescription fill was independently associated with increased odds of new persistent use (adjusted odds ratio, 2.35; 95% CI, 1.51 to 3.66; P < 0.001).

Conclusions: Periprocedural opioid use after lumbar radiofrequency ablation was associated with new persistent use in previously opioid-naïve patients, suggesting that new exposure to opioids is an independent risk factor for persistent use in patients having radiofrequency ablation for chronic back pain. Opioid prescribing after radiofrequency ablation should be reevaluated and likely discontinued in this population.
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http://dx.doi.org/10.1097/ALN.0000000000003164DOI Listing
May 2020

Attending Specialization and 30-Day Outcomes Following Laparoscopic Bariatric Surgery: an Analysis of the ACS-MBSAQIP Database.

Obes Surg 2020 05;30(5):1827-1836

Department of Surgery, George Washington University, 2150 Pennsylvania Avenue, NW, Suite 6B, Washington, DC, 20037, USA.

Background: Surgeon and hospital volume are factors that have been shown to impact outcomes following bariatric surgery. Nevertheless, there is a paucity of literature investigating surgeon training on bariatric surgery outcomes. The purpose of our study was to determine if bariatric specialty training leads to improved short-term outcomes following laparoscopic bariatric surgery using the American College of Surgeons Metabolic and Bariatric Surgery Accreditation Quality Improvement Program (ACS-MBSAQIP) database.

Methods: All patients undergoing first-time, elective, laparoscopic bariatric surgery from 2015 to 2016 were identified within the ACS-MBSAQIP database. Patients were divided into two groups based on the type of bariatric procedure performed and the surgeon performing the procedure. Thirty-day outcomes were compared between the groups using multivariable logistic regression analysis.

Results: A total of 140,340 patients met inclusion criteria. Higher risk patients with more associated comorbidities underwent bariatric surgery by a metabolic and bariatric surgeon. After controlling for these differences, patients who underwent Roux-en-Y gastric bypass (RYGB) had similar 30-day irrespective of the surgeon performing the procedure while patients who underwent sleeve gastrectomy (SG) by a metabolic and bariatric surgeon (MBS) had improved 30-day outcomes.

Conclusion: Surgeon type is associated with 30-day morbidity and mortality outcomes for SG but not for RYGB. These differences in 30-day morbidity and mortality outcomes may be facilitated by institutional factors, surgeon experience, and participation in bariatric surgery accredited centers. Standardization of the perioperative process for both surgeons and institutions may improve 30-day morbidity and mortality outcomes for all patients who undergo laparoscopic bariatric surgery.
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http://dx.doi.org/10.1007/s11695-020-04402-wDOI Listing
May 2020

Mutated CEACAMs Disrupt Transforming Growth Factor Beta Signaling and Alter the Intestinal Microbiome to Promote Colorectal Carcinogenesis.

Gastroenterology 2020 01 1;158(1):238-252. Epub 2019 Oct 1.

Center for Translational Medicine, Department of Surgery, The George Washington University, Washington, DC; Department of Gastroenterology, Veterans Affairs Medical Center, Washington, DC. Electronic address:

Background & Aims: We studied interactions among proteins of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, which interact with microbes, and transforming growth factor beta (TGFB) signaling pathway, which is often altered in colorectal cancer cells. We investigated mechanisms by which CEACAM proteins inhibit TGFB signaling and alter the intestinal microbiome to promote colorectal carcinogenesis.

Methods: We collected data on DNA sequences, messenger RNA expression levels, and patient survival times from 456 colorectal adenocarcinoma cases, and a separate set of 594 samples of colorectal adenocarcinomas, in The Cancer Genome Atlas. We performed shotgun metagenomic sequencing analyses of feces from wild-type mice and mice with defects in TGFB signaling (Sptbn1 and Smad4/Sptbn1) to identify changes in microbiota composition before development of colon tumors. CEACAM protein and its mutants were overexpressed in SW480 and HCT116 colorectal cancer cell lines, which were analyzed by immunoblotting and proliferation and colony formation assays.

Results: In colorectal adenocarcinomas, high expression levels of genes encoding CEACAM proteins, especially CEACAM5, were associated with reduced survival times of patients. There was an inverse correlation between expression of CEACAM genes and expression of TGFB pathway genes (TGFBR1, TGFBR2, and SMAD3). In colorectal adenocarcinomas, we also found an inverse correlation between expression of genes in the TGFB signaling pathway and genes that regulate stem cell features of cells. We found mutations encoding L640I and A643T in the B3 domain of human CEACAM5 in colorectal adenocarcinomas; structural studies indicated that these mutations would alter the interaction between CEACAM5 and TGFBR1. Overexpression of these mutants in SW480 and HCT116 colorectal cancer cell lines increased their anchorage-independent growth and inhibited TGFB signaling to a greater extent than overexpression of wild-type CEACAM5, indicating that they are gain-of-function mutations. Compared with feces from wild-type mice, feces from mice with defects in TGFB signaling had increased abundance of bacterial species that have been associated with the development of colon tumors, including Clostridium septicum, and decreased amounts of beneficial bacteria, such as Bacteroides vulgatus and Parabacteroides distasonis.

Conclusion: We found expression of CEACAMs and genes that regulate stem cell features of cells to be increased in colorectal adenocarcinomas and inversely correlated with expression of TGFB pathway genes. We found colorectal adenocarcinomas to express mutant forms of CEACAM5 that inhibit TGFB signaling and increase proliferation and colony formation. We propose that CEACAM proteins disrupt TGFB signaling, which alters the composition of the intestinal microbiome to promote colorectal carcinogenesis.
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http://dx.doi.org/10.1053/j.gastro.2019.09.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7124154PMC
January 2020

The effect of bougie size and distance from the pylorus on dehydration after laparoscopic sleeve gastrectomy: an analysis of the ACS-MBSAQIP database.

Surg Obes Relat Dis 2019 Oct 24;15(10):1656-1661. Epub 2019 Aug 24.

Department of Surgery, The George Washington University, Washington, D.C.

Background: Dehydration is the most common cause of readmission after laparoscopic sleeve gastrectomy (SG). Bougie size and distance from the pylorus, both of which have been associated with rates of dehydration postoperatively, varies by surgeon and across institutions.

Objectives: To determine if there is an association between bougie size or distance from the pylorus on the rate of dehydration after laparoscopic SG.

Setting: American College of Surgeons Metabolic and Bariatric Surgery Accreditation Quality Improvement Program database.

Methods: All patients undergoing first-time, elective laparoscopic SG from 2015-2016 were identified. The association of bougie size and distance from the pylorus on the rate of dehydration within the first 30 days postoperatively was investigated.

Results: The inclusion criteria were met by 170,751 patients. The most commonly used bougie size was 36 Fr and the most common distance from the pylorus at which the gastric sleeve was started was 5 cm. Patients were divided into 4 groups based on bougie size and distance from the pylorus (Group 1: bougie size <36 Fr, pylorus distance <4 cm; Group 2: bougie size ≥36 Fr, pylorus distance <4 cm; Group 3: bougie size ≥36 Fr, pylorus distance ≥4 cm; and Group 4: bougie size <36 Fr, pylorus distance ≥4 cm). Patients in Group 4 were significantly less likely than any other group to experience dehydration-related complications.

Conclusion: Both distance from the pylorus and bougie size are significantly associated with dehydration-related complications after SG. Consideration should be made for standardizing these technical aspects of SG to help reduce the rate of postoperative dehydration and hospital readmission.
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http://dx.doi.org/10.1016/j.soard.2019.08.014DOI Listing
October 2019

Patterns of glucocorticoid prescribing and provider-level variation in a commercially insured incident rheumatoid arthritis population: A retrospective cohort study.

Semin Arthritis Rheum 2020 04 7;50(2):228-236. Epub 2019 Sep 7.

VA Center for Clinical Management Research, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA; Institute for Healthcare Policy and Innovation, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, MI, USA.

Objective: Glucocorticoids are common in RA management despite an unfavorable, exposure-dependent risk profile impacted by patient and provider-level factors. Existing work describing glucocorticoid use in RA is not generalizable and does not adequately examine provider factors. We aim to describe how providers prescribe glucocorticoids to commercially insured, newly diagnosed RA patients in the United States.

Methods: This was a retrospective cohort study which used the national Optum© administrative database. We identified 9221 adults ages 18-65 with RA diagnosed 2010-2014. We assessed glucocorticoid dispensing 3 months pre-diagnosis through 12months post-diagnosis ("study period"), cumulatively stratified by calendar quarter and prescriber specialty (rheumatologist, primary care, other). We examined prescribing variation among individual rheumatologists by dividing quarterly distribution of per-patient dose and days' supply into quartiles.

Results: 6717 (72.8%) patients filled ≥1 glucocorticoid prescription during the study period. 2890 (31.3%) patients received ≥3 months' supply, with median (IQR) daily dose 10 (6.6) mg/day and days' supply 189 (143) days. 52.6% of patients received glucocorticoids 1-3 months post-diagnosis; 29.2% received glucocorticoids 10-12 months post-diagnosis. Among glucocorticoid users post-diagnosis, quarterly median daily dose and days' supply were consistently ≥10 mg/day and ≥30 days, respectively. Rheumatologists prescribed most glucocorticoids, with median per-quarter daily dose and days' supply 10 mg/day and 43-60 days. Individual rheumatologists' prescribing varied widely across all quarters.

Conclusion: Among commercially insured incident RA patients, receipt of ≥10 mg/day prednisone equivalent for months is common, typically prescribed by rheumatologists, and persists a year post-diagnosis in 29.2% of patients. Glucocorticoid prescribing varies widely across rheumatologists. Further work is warranted to identify provider factors explaining variation in glucocorticoid prescribing, and assess how these affect health outcomes.
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http://dx.doi.org/10.1016/j.semarthrit.2019.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060094PMC
April 2020

Regionalization of Congenital Heart Surgery in the United States.

Semin Thorac Cardiovasc Surg 2020 10;32(1):128-137. Epub 2019 Sep 10.

Division of Pediatric Cardiac Surgery and the Heart and Vascular Institute, The Cleveland Clinic, Cleveland, Ohio.

The objective of this study is to simulate regionalization of congenital heart surgery (CHS) in the United States and assess the impact of such a system on travel distance and mortality. Patients ≤18 years of age who underwent CHS were identified in 2012 State Inpatient Databases. Operations were stratified by the Risk Adjustment for Congenital Heart Surgery, version 1 (RACHS-1) method, with high risk defined as RACHS-1 levels 4-6. Regionalization was simulated by progressive closure of hospitals, beginning with the lowest volume hospital. Patients were moved to the next closest hospital. Analyses were conducted (1) maintaining original hospital mortality rates and (2) estimating mortality rates based on predicted surgical volumes after absorbing moved patients. One hundred fifty-three hospitals from 36 states performed 1 or more operation (19,064 operations). With regionalization wherein, all hospitals performed >310 operations, 37 hospitals remained, from 12.5% to 17.4% fewer deaths occurred (83-116/666), and median patient travel distance increased from 38.5 to 69.6 miles (P < 0.01). When only high-risk operations were regionalized, 3.9-5.9% fewer deaths occurred (26-39/666), and the overall mortality rate did not change significantly. Regionalization of CHS in the United States to higher volume centers may reduce mortality with minimal increase in patient travel distance. Much of the mortality reduction may be missed if solely high-risk patients are regionalized.
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http://dx.doi.org/10.1053/j.semtcvs.2019.09.005DOI Listing
June 2020

MET exon 14 skipping mutations and gene amplification in a Taiwanese lung cancer population.

PLoS One 2019 1;14(8):e0220670. Epub 2019 Aug 1.

Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi branch, Taiwan.

Somatic mutations of MET gene are emerging as important driver mutations for lung cancers. To identify the common clinicopathological features of MET exon 14 skipping mutations and amplification and clarify whether the two MET gene alterations cause protein overexpression were investigated using 196 lung cancer samples of Taiwan through real time-qPCR/sequencing, fluorescence in situ hybridization, and immunohistochemistry. The two MET gene alterations are both present in low frequency, ~1%, in the studied lung cancer population of Taiwan. MET exon 14 skipping mutations were identified from two early-stage patients, who were both relatively advanced in age, and did not carry other driver mutations. One was an adenocarcinoma and the other was a rare carcinosarcoma. Three gene amplifications cases were identified. Neither of the two MET gene alterations would lead to protein overexpression; hence, direct detection in nucleic acid level would be a preferred and straightforward solution for the identification of skipping mutations. The presence of MET exon 14 mutations in minor histological types of lung cancers urge to extend screening scope of this mutation in lung cancer and treatment response evaluation in clinical trials. These would be important next steps for the success of MET target therapy in clinical practice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220670PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675391PMC
March 2020

Patient and Provider Variables Associated with Variation in the Systemic Treatment of Advanced Prostate Cancer.

Urol Pract 2019 Jul;6(4):234-242

Department of Biostatistics and Epidemiology, School of Public Health, University of Michigan.

Purpose: Six treatments have improved overall survival in men with metastatic castration-resistant prostate cancer (mCRPC), each differing in toxicities and cost. This study identified patient and provider factors associated with variation in treatment of men with mCRPC to identify potential barriers to treatments.

Methods: A claims database of commercially insured patients was used to identify patients with prostate cancer treated with abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, or radium-223 between 2010 and 2016. Multinomial and binomial logistic regressions were conducted to determine patient and provider factors associated with treatment patterns.

Results: Among 5,575 patients identified, patients with a household income >$99,000 were less likely to receive an expensive oral androgen signaling inhibitor (abiraterone or enzalutamide) as first-line treatment versus docetaxel compared to patients with a household income <$50,000 (odds ratio, OR, 0.66, 95% confidence interval, CI, 0.48-0.92). Patients who are Black (OR 1.43, 95% CI 1.02-2.01), live in the Pacific region versus the South Atlantic (OR 2.68, 95% CI 1.74-4.11), received treatment from a urologist versus a medical oncologist (OR 16.05, 95% CI 6.01-42.86), or had pre-existing heart failure (OR 1.69, 95% CI 1.18-2.42) were more likely to receive first-line oral androgen signaling inhibitors over docetaxel, independent of other factors on multivariable analysis.

Conclusion: Clinicians and policy makers should be aware of the potential barriers and provider factors that influence use of novel therapies among patients with advanced prostate cancer, including the paradoxical effect of income and the substantial effect of provider specialty on first-line treatment rendered to patients with mCRPC.
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http://dx.doi.org/10.1097/UPJ.0000000000000020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605774PMC
July 2019
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