Publications by authors named "Yizhe Xu"

21 Publications

  • Page 1 of 1

Does Non-Neurologic Multiorgan Dysfunction After Out-of-Hospital Cardiac Arrest among Children Admitted in Coma Predict Outcome 1 Year Later?

J Pediatr Intensive Care 2021 Sep 11;10(3):188-196. Epub 2020 Sep 11.

Department of Pediatrics, Washington Permanente Medical Group, Spokane, Washington, United States.

In this article, we investigated whether non-neurologic multiorgan dysfunction syndrome (MODS) following out-of-hospital cardiac arrest (OHCA) predicts poor 12-month survival. We conducted a secondary data analysis of therapeutic hypothermia after pediatric cardiac arrest out-of-hospital randomized trial involving children who remained unconscious and intubated after OHCA (  = 237). Associations between MODS and 12-month outcomes were assessed using multivariable logistic regression. Non-neurologic MODS was present in 95% of patients and sensitive (97%; 95% confidence interval [CI]: 93-99%) for 12-month survival but had poor specificity (10%; 95% CI: 4-21%). Development of non-neurologic MODS is not helpful to predict long-term neurologic outcome or survival after OHCA.
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http://dx.doi.org/10.1055/s-0040-1715850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354356PMC
September 2021

Patient Selection for Intensive Blood Pressure Management Based on Benefit and Adverse Events.

J Am Coll Cardiol 2021 04;77(16):1977-1990

Division of General Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.

Background: Intensive systolic blood pressure (SBP) treatment prevents cardiovascular disease (CVD) events in patients with high CVD risk on average, though benefits likely vary among patients.

Objectives: The aim of this study was to predict the magnitude of benefit (reduced CVD and all-cause mortality risk) along with adverse event (AE) risk from intensive versus standard SBP treatment.

Methods: This was a secondary analysis of SPRINT (Systolic Blood Pressure Intervention Trial). Separate benefit outcomes were the first occurrence of: 1) a CVD composite of acute myocardial infarction or other acute coronary syndrome, stroke, heart failure, or CVD death; and 2) all-cause mortality. Treatment-related AEs of interest included hypotension, syncope, bradycardia, electrolyte abnormalities, injurious falls, and acute kidney injury. Modified elastic net Cox regression was used to predict absolute risk for each outcome and absolute risk differences on the basis of 36 baseline variables available at the point of care with intensive versus standard treatment.

Results: Among 8,828 SPRINT participants (mean age 67.9 years, 35% women), 600 CVD composite events, 363 all-cause deaths, and 481 treatment-related AEs occurred over a median follow-up period of 3.26 years. Individual participant risks were predicted for the CVD composite (C index = 0.71), all-cause mortality (C index = 0.75), and treatment-related AEs (C index = 0.69). Higher baseline CVD risk was associated with greater benefit (i.e., larger absolute CVD risk reduction). Predicted CVD benefit and predicted increased treatment-related AE risk were correlated (Spearman correlation coefficient = -0.72), and 95% of participants who fell into the highest tertile of predicted benefit also had high or moderate predicted increases in treatment-related AE risk. Few were predicted as high benefit with low AE risk (1.8%) or low benefit with high AE risk (1.5%). Similar results were obtained for all-cause mortality.

Conclusions: SPRINT participants with higher baseline predicted CVD risk gained greater absolute benefit from intensive treatment. Participants with high predicted benefit were also most likely to experience treatment-related AEs, but AEs were generally mild and transient. Patients should be prioritized for intensive SBP treatment on the basis of higher predicted benefit. (Systolic Blood Pressure Intervention Trial [SPRINT]; NCT01206062).
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http://dx.doi.org/10.1016/j.jacc.2021.02.058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068761PMC
April 2021

Estimating the optimal individualized treatment rule from a cost-effectiveness perspective.

Biometrics 2020 Nov 20. Epub 2020 Nov 20.

Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.

Optimal individualized treatment rules (ITRs) provide customized treatment recommendations based on subject characteristics to maximize clinical benefit in accordance with the objectives in precision medicine. As a result, there is growing interest in developing statistical tools for estimating optimal ITRs in evidence-based research. In health economic perspectives, policy makers consider the tradeoff between health gains and incremental costs of interventions to set priorities and allocate resources. However, most work on ITRs has focused on maximizing the effectiveness of treatment without considering costs. In this paper, we jointly consider the impact of effectiveness and cost on treatment decisions and define ITRs under a composite-outcome setting, so that we identify the most cost-effective ITR that accounts for individual-level heterogeneity through direct optimization. In particular, we propose a decision-tree-based statistical learning algorithm that uses a net-monetary-benefit-based reward to provide nonparametric estimations of the optimal ITR. We provide several approaches to estimating the reward underlying the ITR as a function of subject characteristics. We present the strengths and weaknesses of each approach and provide practical guidelines by comparing their performance in simulation studies. We illustrate the top-performing approach from our simulations by evaluating the projected 15-year personalized cost-effectiveness of the intensive blood pressure control of the Systolic Blood Pressure Intervention Trial (SPRINT) study.
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http://dx.doi.org/10.1111/biom.13406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134511PMC
November 2020

Empirical evidence of disease activity thresholds used to indicate need for major therapeutic change in US veterans with rheumatoid arthritis.

Arthritis Res Ther 2020 10 22;22(1):253. Epub 2020 Oct 22.

Salt Lake City VA Medical Center and University of Utah, Salt Lake City, UT, USA.

Background: A previous analysis of the Veterans Affairs Rheumatoid Arthritis (VARA) registry showed that more than half of the patients with rheumatoid arthritis (RA) did not receive a major therapeutic change (MTC) despite moderate or severe disease activity. We aimed to empirically determine disease activity thresholds associated with a decision by rheumatologists and nurse practitioners to institute a MTC in patients with RA and to report the impact of that change on RA disease activity.

Methods: We analyzed data from the VARA registry between January 1, 2006, and September 30, 2017. Eligible patients had a visit with 3 disease activity measures (DAMs) recorded: Disease Activity Score for 28 joints (DAS28), Clinical Disease Activity Index (CDAI), and Routine Assessment of Patient Index Data 3 (RAPID3). The Youden Index was used to identify disease activity thresholds that best discriminated rheumatologist/nurse practitioner decision to initiate MTC. Clinical outcome was 20% improvement in the American College of Rheumatology criteria (ACR20 response). The effect of MTC on ACR20 response was presented as crude descriptive statistics and evaluated using G-computation for marginal and conditional effects with established disease activity level combined with an empirical threshold from Youden analysis.

Results: The study population comprised 1776 patients (12,094 visits: 3077 with MTC, 9017 without MTC). Empirical thresholds (95% bootstrap confidence interval with 1000 replications) for MTC were 4.03 (3.70-4.36) for DAS28, 12.9 (10.4-15.4) for CDAI, and 3.81 (3.32-4.30) for RAPID3. Visits with MTC had increased likelihood of ACR20 response: risk ratios for ACR20 response for visits with MTC vs without MTC ranged 1.2-2.6 across DAMs; risk differences ranged 0.2-14.5%.

Conclusions: MTC was associated with clinical improvement across all DAMs with the greatest change in patients with RA disease activity above the Youden threshold identified in this work.

Trial Registration: VARA Registry, https://www.hsrd.

Research: va.gov/research/abstracts.cfm?Project_ID=2141698764.
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http://dx.doi.org/10.1186/s13075-020-02346-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579862PMC
October 2020

Tonifying kidney therapy for stable chronic obstructive pulmonary disease: a systematic review.

J Tradit Chin Med 2020 04;40(2):188-196

Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China.

Objective: To evaluate the efficacy and safety of tonifying kidney therapy (Bushen, TK) for stable chronic obstructive pulmonary disease (COPD).

Methods: Randomized controlled trials (RCTs) of TK use for treatment of stable COPD were searched in four databases including PubMed, the Cochrane Library, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure Database from inception to December 2017. Two reviewers independently screened the literature, extracted the data, and assessed the risk of bias in the included studies. RevMan 5.3 software was used for the Meta-analysis.

Results: Eight RCTs involving 809 patients with stable COPD were included. Compared with the conventional Western Medicine (CWM) group, the TK group (TK combined with CWM) showed significant improvements in the effectiveness rates (RR = 1.37, 95% CI 1.22 to 1.53, P < 0.000 01) and 6-min walk distance in meters (MD 11.92, 95% CI 3.52 to 20.32, P = 0.005), this study also showed that the TK group can decrease The Traditional Chinese Medicine Syndrome Score (MD -8.01, 95% CI -12.89 to -3.13, P = 0.001). The lung function [forced expiratory volume in one second% (FEV1%), FEV1/forced vital capacity] showed no difference between the TK and control groups.

Conclusion: For patients with stable COPD, TK can improve the clinical effectiveness and exercise capacity but fail to improve the patient's symptoms. Because of the low methodological quality of the included trials, additional high-quality and large-scale RCTs are required.
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April 2020

Traction Time, Force and Postoperative Nerve Block Significantly Influence the Development and Duration of Neuropathy Following Hip Arthroscopy.

Arthroscopy 2019 10;35(10):2825-2831

Department of Orthopaedic Surgery, University of Utah, Salt Lake City, Utah, U.S.A.. Electronic address:

Purpose: To (1) evaluate the individual and combined effects of traction time and traction force on postoperative neuropathy following hip arthroscopy, (2) determine if perioperative fascia iliaca block has an effect on the risk of this neuropathy, and (3) identify if the these items had a significant association with the presence, location, and/or duration of postoperative numbness.

Methods: Between February 2015 and December 2016, a consecutive cohort of hip arthroscopy patients was prospectively enrolled. Traction time, force, and postoperative nerve block administration were recorded. The location and duration of numbness were assessed at postoperative clinic visits. Numbness location was classified into regions: 1, groin; 2, lateral thigh; 3, medial thigh; 4, dorsal foot; and 5,preoperative thigh or radiculopathic numbness.

Results: A total of 156 primary hip arthroscopy patients were analyzed, 99 (63%) women and 57 (37%) men. Mean traction time was 46.5 ± 20.3 minutes. Seventy-four patients (47%) reported numbness with an average duration of 157.5 ± 116.2 days. Postoperative fascia iliaca nerve block was a significant predictor of medial thigh numbness (odds ratio, 3.36; 95% confidence interval, 1.46-7.76; P = .04). Neither traction time nor force were associated with generalized numbness (P = .85 and P = .40, respectively). However, among those who experienced numbness, traction time and force were greater in patients with combined groin and lateral thigh numbness compared with those with isolated lateral thigh or medial thigh numbness (P = .001 and P = .005, respectively).

Conclusions: Postoperative neuropathy is a well-documented complication following hip arthroscopy. Concomitant pudendal and lateral femoral cutaneous nerve palsy may be related to increased traction force and time, even in the setting of low intraoperative traction time (<1 hour). Isolated medial thigh numbness is significantly associated with postoperative fascia iliaca blockade.

Level Of Evidence: IV, case series.
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http://dx.doi.org/10.1016/j.arthro.2019.03.062DOI Listing
October 2019

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Nat Genet 2019 10 2;51(10):1459-1474. Epub 2019 Oct 2.

Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
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http://dx.doi.org/10.1038/s41588-019-0504-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858555PMC
October 2019

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.

Nat Commun 2019 09 11;10(1):4130. Epub 2019 Sep 11.

Department of Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT, USA.

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
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http://dx.doi.org/10.1038/s41467-019-11576-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739370PMC
September 2019

A catalog of genetic loci associated with kidney function from analyses of a million individuals.

Nat Genet 2019 06 31;51(6):957-972. Epub 2019 May 31.

Diabetes and Cardiovascular Disease-Genetic Epidemiology, Department of Clincial Sciences in Malmö, Lund University, Malmö, Sweden.

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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http://dx.doi.org/10.1038/s41588-019-0407-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698888PMC
June 2019

Comparison of Direct Surgical Costs for Proximal Row Carpectomy and Four-Corner Arthrodesis.

J Wrist Surg 2019 Feb 16;8(1):66-71. Epub 2018 Nov 16.

Department of Orthopaedics, University of Utah, Salt Lake City, Utah.

 Proximal row carpectomy (PRC) and four-corner arthrodesis (FCA) are common treatments for stage II scapholunate advanced collapse (SLAC) and scaphoid nonunion advanced collapse (SNAC) wrists, with similar functional and patient-reported outcomes reported in the peer-reviewed literature.  Study questions included (1) whether surgical encounter total direct costs (SETDCs) differ between PRC and FCA, and (2) whether SETDC differs by method of fixation for FCA.  Consecutive adult patients (≥ 18 years) undergoing PRC and FCA between July 2011 and May 2017 at a single tertiary care academic institution were identified. Patients undergoing additional simultaneous procedures were excluded. Using our institution's information technology value tools, we extracted prospectively collected cost data for each surgical encounter. SETDCs were compared between PRC and FCA, and between FCA subgroups (screws, plating, or staples).  Of 42 included patients, mean age was similar between the 23 PRC and 19 FCA patients (51.2 vs. 54.5 years, respectively). SETDCs were significantly greater for FCA than PRC by 425%. FCA involved significantly greater facility costs (2.3-fold), supply costs (10-fold), and operative time (121 vs. 57 minutes). Implant costs were absent for PRC, which were responsible for 55% of the SETDC for FCA. Compared with compression screws, plating and staple fixation were significantly more costly (70% and 240% greater, respectively).  SETDCs were 425% greater for FCA than PRC. Implant costs for FCA alone were 130% greater than the entire surgical encounter for PRC. For FCA, SETDC varied depending on the method of fixation.  This is a level III, cost analysis study.
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http://dx.doi.org/10.1055/s-0038-1675791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358450PMC
February 2019

Short-Term Particulate Air Pollution Exposure is Associated with Increased Severity of Respiratory and Quality of Life Symptoms in Patients with Fibrotic Sarcoidosis.

Int J Environ Res Public Health 2018 05 26;15(6). Epub 2018 May 26.

Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45219, USA.

This study aimed to determine if short-term exposure to particulate matter (PM) and ozone (O₃) is associated with increased symptoms or lung function decline in fibrotic sarcoidosis. Sixteen patients with fibrotic sarcoidosis complicated by frequent exacerbations completed pulmonary function testing and questionnaires every three months for one year. We compared 7-, 10-, and 14-day average levels of PM and O₃ estimated at patient residences to spirometry (forced expiratory volume in 1 s (FEV1), to forced vital capacity (FVC), episodes of FEV1 decline > 10%) and questionnaire outcomes (Leicester cough questionnaire (LCQ), Saint George Respiratory Questionnaire (SGRQ), and King's Sarcoidosis Questionnaire (KSQ)) using generalized linear mixed effect models. PM level averaged over 14 days was associated with lower KSQ general health status (score change -6.60 per interquartile range (IQR) PM increase). PM level averaged over 10 and 14 days was associated with lower KSQ lung specific health status (score change -6.93 and -6.91, respectively). PM levels were not associated with FEV₁, FVC, episodes of FEV₁ decline > 10%, or respiratory symptoms measured by SGRQ or LCQ. Ozone exposure was not associated with any health outcomes. In this small cohort of patients with fibrotic sarcoidosis, PM exposure was associated with increased severity of respiratory and quality of life symptoms.
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http://dx.doi.org/10.3390/ijerph15061077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025101PMC
May 2018

Evaluation of Factors Driving Cost Variation for Distal Radius Fracture Open Reduction Internal Fixation.

J Hand Surg Am 2018 07 31;43(7):606-614.e1. Epub 2018 May 31.

Department of Orthopaedics, University of Utah, Salt Lake City, UT.

Purpose: Distal radius fracture open reduction and internal fixation (ORIF) represents a considerable cost burden to the health care system. We aimed to elucidate demographic-, injury-, and treatment-specific factors influencing surgical encounter costs for distal radius ORIF.

Methods: We retrospectively reviewed adult patients treated with isolated distal radius ORIF between November 2014 and October 2016 at a single tertiary academic medical center. Using our institution's information technology value tools-which allow for comprehensive payment and cost data collection and analysis on an item-level basis-we determined relative costs (RC) for each factor potentially influencing total direct costs (TDC) for distal radius ORIF using univariate and multivariable gamma regression analyses.

Results: Of the included 108 patients, implants and facility utilization costs were responsible for 48.3% and 37.9% of TDC, respectively. Factors associated with increased TDC include plate manufacturer (RC 1.52 for the most vs least expensive manufacturer), number of screws (RC 1.03 per screw) and distal radius plates used (RC 1.67 per additional plate), surgery setting (RC 1.32 for main hospital vs ambulatory surgery center), treating service (RC 1.40 for trauma vs hand surgeons), and surgical time (RC 1.04 for every 10 min of additional surgical time). Open fracture was associated with increased costs (RC 1.55 vs closed fracture), whereas other estimates of fracture severity were nonsignificant. In the multivariable model controlling for injury-specific factors, variables including implant manufacturer, and number of distal radius plates and screws used, remained as significant drivers of TDC.

Conclusions: Substantial variations in surgical direct costs for distal radius ORIF exist, and implant choice is the predominant driver. Cost reductions may be expected through judicious use of additional plates and screws, if hospital systems use bargaining power to reduce implant costs, and by efficiently completing surgeries.

Clinical Relevance: This study identifies modifiable factors that may lead to cost reduction for distal radius ORIF.
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http://dx.doi.org/10.1016/j.jhsa.2018.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035098PMC
July 2018

Cost Implications of Varying the Surgical Technique, Surgical Setting, and Anesthesia Type for Carpal Tunnel Release Surgery.

J Hand Surg Am 2018 Nov 18;43(11):971-977.e1. Epub 2018 May 18.

Department of Orthopaedics, University of Utah, Salt Lake City, UT.

Purpose: Carpal tunnel release (CTR) is a common surgical procedure, representing a financial burden to the health care system. The purpose of this study was to test whether the choice of CTR technique (open carpal tunnel release [OCTR] vs endoscopic carpal tunnel release [ECTR]), surgical setting (operating room vs procedure room [PR]), and anesthetic type (local, monitored anesthesia care [MAC], Bier block, general) affected costs or payments.

Methods: Consecutive adult patients undergoing isolated unilateral CTR between July 2014, and October 2017, at a single academic medical center were identified. Patients undergoing ECTR converted to OCTR, revision surgery, or additional procedures were excluded. Using our institution's information technology value tools, we calculated total direct costs (TDCs), total combined payment (TCP), hospital payment, surgeon payment, and anesthesia payment for each surgical encounter. Cost data were normalized using each participant's surgical encounter cost divided by the average cost in the data set and compared across 8 groups (defined by surgery type, operation location, and anesthesia type).

Results: Of 479 included patients, the mean age was 55.3 ± 16.1 years, and 68% were female. Payer mix included commercial (45%), Medicare (37%), Medicaid (13%), workers' compensation (2%), self-pay (1%), and other (3%) insurance types. The TDC and TCP both differed significantly between each CTR group, and OCTR in the PR under local anesthesia was the lowest. The OCTR/local/operating room, OCTR/MAC/operating room, and ECTR/operating room, were associated with 6.3-fold, 11.0-fold, and 12.4-16.6-fold greater TDC than OCTR/local/PR, respectively.

Conclusions: Performing OCTR under local anesthetic in the PR setting significantly minimizes direct surgical encounter costs relative to other surgical methods (ECTR), anesthetic methods (Bier block, MAC, general), and surgical settings (operating room).

Clinical Relevance: This study identifies modifiable factors that may lead to cost reductions for CTR surgery.
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http://dx.doi.org/10.1016/j.jhsa.2018.03.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218304PMC
November 2018

Operative Time and Flap Failure in Unilateral and Bilateral Free Flap Breast Reconstruction.

J Reconstr Microsurg 2018 Jul 16;34(6):428-435. Epub 2018 Feb 16.

Division of Plastic and Reconstructive Surgery, University of Utah, Salt Lake City, Utah.

Background:  There is an increasing trend toward bilateral breast reconstruction. Using the National Surgical Quality Improvement Program (NSQIP) database, we sought to understand the association between unilateral and bilateral free flap breast reconstruction and operative time and flap failure.

Methods:  We selected a cohort of patients undergoing free flap breast reconstruction using the 2005 to 2010 NSQIP database. Cases were divided into unilateral and bilateral reconstruction. Subgroup analyses were performed dividing cases into delayed and immediate reconstruction. The effect of patient characteristics including age, body mass index (BMI), history of diabetes, and the American Society of Anesthesiologists' classification on operative time and flap failure was examined using univariable and multivariable regression models. Rates and odds ratios (OR) were reported using the multivariable gamma and logistic regression models, respectively.

Results:  There were 691 free flap breast reconstructions performed in the cohort and 29.1% were bilateral cases. There was a 78-minute increase in the median operative time when comparing unilateral and bilateral reconstruction ( = 0.005). Patients undergoing bilateral reconstructions were generally younger and had fewer comorbidities compared with unilateral reconstructions. There was no significant association between bilateral reconstruction and flap failure. Immediate bilateral reconstructions had a significant increase in median operative time compared with immediate unilateral reconstructions (563 versus 480 minutes,  = 0.002) but no significant increase in operative time was noted when comparing delayed unilateral and delayed bilateral reconstructions. Prolonged operative time was associated with flap failure after adjusting for age and BMI (OR 1.17,  < 0.001).

Conclusions:  Bilateral free flap breast reconstruction can be performed safely despite an increase in operative time when compared with unilateral reconstruction.
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http://dx.doi.org/10.1055/s-0038-1627445DOI Listing
July 2018

Variation in Adolescent Idiopathic Scoliosis Surgery: Implications for Improving Healthcare Value.

J Pediatr 2018 04;195:213-219.e3

Department of Orthopedic Surgery, University of Utah School of Medicine, Salt Lake City, UT.

Objectives: To investigate the variation in care and cost of spinal fusion for adolescent idiopathic scoliosis (AIS), and to identify opportunities for improving healthcare value.

Study Design: Retrospective cohort study from the Pediatric Health Information Systems database, including children 11-18 years of age with AIS who underwent spinal fusion surgery between 2004 and 2015. Multivariable regression was used to evaluate the relationships between hospital cost, patient outcomes, and resource use.

Results: There were 16 992 cases of AIS surgery identified. There was marked variation across hospitals in rates of intensive care unit admission (0.5%-99.2%), blood transfusions (0%-100%), surgical complications (1.8%-32.3%), and total hospital costs ($31 278-$90 379). Hospital cost was 32% higher at hospitals that most frequently admitted patients to the intensive care unit (P = .009), and 8% higher for each additional 25 operative cases per hospital (P = .003). Hospital duration of stay was shorter for patients admitted to hospitals with highest intensive care unit admission rates and higher surgical volumes. There was no association between cost and duration of stay, 30-day readmission, or surgical complications. The largest contribution to hospital charges was supplies (55%). Review of a single hospital's detailed cost accounting system also found supplies to be the greatest single contributor to cost, the majority of which were for spinal implants, accounting for 39% of total hospital costs.

Conclusions: The greatest contribution to AIS surgery cost was supplies, the majority of which is likely attributed to spinal implant costs. Opportunities for improving healthcare value should focus on controlling costs of spinal instrumentation, and improving quality of care with standardized treatment protocols.
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http://dx.doi.org/10.1016/j.jpeds.2017.12.031DOI Listing
April 2018

Contemporary management of high-grade renal trauma: Results from the American Association for the Surgery of Trauma Genitourinary Trauma study.

J Trauma Acute Care Surg 2018 03;84(3):418-425

From the Division of Urology, Department of Surgery (S.K., J.M.H., J.B.M.), Division of Epidemiology, Department of Internal Medicine (Y.X., A.P.P.), Department of Surgery (R.N.), University of Utah, Salt Lake City, Utah; Department of Urology (J.P.), Department of Surgery (C.M.D.), University of Wisconsin, Milwaukee, Wisconsin; Division of Acute Care Surgery (C.M.B., K.M.), Loma Linda University Medical Center, Loma Linda, California; Division of Trauma and Surgical Critical Care (B.J.M., S.M.), Intermountain Medical Center, Murray, Utah; Division of Trauma and Surgical Critical Care (B.P.S.), Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Urology (I.S., S.P.E.), Hennepin County Medical Center, University of Minnesota, Minneapolis, Minnesota; Department of Surgery (E.S.D.), Division of Trauma, Acute Care Surgery, and Surgical Critical Care, Department of Surgery (S.Z.), University of California Davis Medical Center, Sacramento, California; Department of Urology (P.B.T., B.A.E.), University of Iowa, Iowa City, Iowa; Department of Urology (N.B., B.N.B.), University of California-San Francisco, San Francisco, California; Department of Urology (B.M., R.A.S.), Detroit Medical Center, Detroit, Miami; Medical City Plano (M.M.C.), Plano, Texas; Department of Urology (T.H., F.N.B.), Oakland University William Beaumont School of Medicine, Royal Oak, Michigan; Department of Surgery (J.F.K.), East Texas Medical Center, Tyler, Texas; and Division of Trauma, Department of Surgery (R.A.), Brigham and Women's Hospital, Boston, Massachusetts.

Background: The rarity of renal trauma limits its study and the strength of evidence-based guidelines. Although management of renal injuries has shifted toward a nonoperative approach, nephrectomy remains the most common intervention for high-grade renal trauma (HGRT). We aimed to describe the contemporary management of HGRT in the United States and also evaluate clinical factors associated with nephrectomy after HGRT.

Methods: From 2014 to 2017, data on HGRT (American Association for the Surgery of Trauma grades III-V) were collected from 14 participating Level-1 trauma centers. Data were gathered on demographics, injury characteristics, management, and short-term outcomes. Management was classified into three groups-expectant, conservative/minimally invasive, and open operative. Descriptive statistics were used to report management of renal trauma. Univariate and multivariate logistic mixed effect models with clustering by facility were used to look at associations between proposed risk factors and nephrectomy.

Results: A total of 431 adult HGRT were recorded; 79% were male, and mechanism of injury was blunt in 71%. Injuries were graded as III, IV, and V in 236 (55%), 142 (33%), and 53 (12%), respectively. Laparotomy was performed in 169 (39%) patients. Overall, 300 (70%) patients were managed expectantly and 47 (11%) underwent conservative/minimally invasive management. Eighty-four (19%) underwent renal-related open operative management with 55 (67%) of them undergoing nephrectomy. Nephrectomy rates were 15% and 62% for grades IV and V, respectively. Penetrating injuries had significantly higher American Association for the Surgery of Trauma grades and higher rates of nephrectomy. In multivariable analysis, only renal injury grade and penetrating mechanism of injury were significantly associated with undergoing nephrectomy.

Conclusion: Expectant and conservative management is currently utilized in 80% of HGRT; however, the rate of nephrectomy remains high. Clinical factors, such as surrogates of hemodynamic instability and metabolic acidosis, are associated with nephrectomy for HGRT; however, higher renal injury grade and penetrating trauma remain the strongest associations.

Level Of Evidence: Prognostic/epidemiologic study, level III; Therapeutic study, level IV.
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http://dx.doi.org/10.1097/TA.0000000000001796DOI Listing
March 2018

Impact of removed tumor volume and location on patient outcome in glioblastoma.

J Neurooncol 2017 Oct 6;135(1):161-171. Epub 2017 Jul 6.

Department of Neurosurgery, Clinical Neuroscience Center, University of Utah, Fifth Floor, 175 North Medical Drive, Salt Lake City, UT, 84132, USA.

Glioblastoma is an aggressive primary brain tumor with devastatingly poor prognosis. Multiple studies have shown the benefit of wider extent of resection (EOR) on patient overall survival (OS) and worsened survival with larger preoperative tumor volumes. However, the concomitant impact of postoperative tumor volume and eloquent location on OS has yet to be fully evaluated. We performed a retrospective chart review of adult patients treated for glioblastoma from January 2006 through December 2011. Adherence to standardized postoperative chemoradiation protocols was used as an inclusion criterion. Detailed volumetric and location analysis was performed on immediate preoperative and immediate postoperative magnetic resonance imaging. Cox proportional hazard modeling approach was employed to explore the modifying effects of EOR and eloquent location after adjusting for various confounders and associated characteristics, such as preoperative tumor volume and demographics. Of the 471 screened patients, 141 were excluded because they did not meet all inclusion criteria. The mean (±SD) age of the remaining 330 patients (60.6% male) was 58.9 ± 12.9 years; the mean preoperative and postoperative Karnofsky performance scores (KPSs) were 76.2 ± 10.3 and 80.0 ± 16.6, respectively. Preoperative tumor volume averaged 33.2 ± 29.0 ml, postoperative residual was 4.0 ± 8.1 ml, and average EOR was 88.6 ± 17.6%. The observed average follow-up was 17.6 ± 15.7 months, and mean OS was 16.7 ± 14.4 months. Survival analysis showed significantly shorter survival for patients with lesions in periventricular (16.8 ± 1.7 vs. 21.5 ± 1.4 mo, p = 0.03), deep nuclei/basal ganglia (11.6 ± 1.7 vs. 20.6 ± 1.2, p = 0.002), and multifocal (12.0 ± 1.4 vs. 21.3 ± 1.3 months, p = 0.0001) locations, but no significant influence on survival was seen for eloquent cortex sites (p = 0.14, range 0.07-0.9 for all individual locations). OS significantly improved with EOR in univariate analysis, averaging 22.3, 19.7, and 13.2 months for >90, 80-90, and 70-80% resection, respectively. Survival was 22.8, 19.0, and 12.7 months for 0, 0-5, and 5-10 ml postoperative residual, respectively. A hazard model showed that larger preoperative tumor volume [hazard ratio (HR) 1.05, 95% CI 1.02-1.07], greater age (HR 1.02, 95% CI 1.01-1.03), multifocality (HR 1.44, 95% CI 1.01-2.04), and deep nuclei/basal ganglia (HR 2.05, CI 1.27-3.3) were the most predictive of poor survival after adjusting for KPS and tumor location. There was a negligible but significant interaction between EOR and preoperative tumor volume (HR 0.9995, 95% CI 0.9993-0.9998), but EOR alone did not correlate with OS after adjusting for other factors. The interaction between EOR and preoperative tumor volume represented tumor volume removed during surgery. In conclusion, EOR alone was not an important predictor of outcome during GBM treatment once preoperative tumor volume, age, and deep nuclei/basal ganglia location were factored. Instead, the interaction between EOR and preoperative volume, representing reduced disease burden, was an important predictor of reducing OS. Removal of tumor from eloquent cortex did not impact postoperative KPS. These results suggest aggressive surgical treatment to reduce postoperative residual while maintaining postoperative KPS may aid patient survival outcomes for a given tumor size and location.
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http://dx.doi.org/10.1007/s11060-017-2562-1DOI Listing
October 2017

Icariin alters the expression of glucocorticoid receptor, FKBP5 and SGK1 in rat brains following exposure to chronic mild stress.

Int J Mol Med 2016 Jul 17;38(1):337-44. Epub 2016 May 17.

Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China.

Icariin, a flavonoid and a major constituent of Herba Epimedii, has been previously demonstrated to possess potential antidepressant-like effects. In the present study, we established a rat model of depression induced by unpredictable chronic mild stress (CMS) in order to examine the effects of icariin treatment. The rats were allocated into the control group or one of the treatment groups [exposure to CMS plus oral administration of saline, icariin (20 or 40 mg/kg) or fluoxetine (10mg/kg)]. We examined the therapeutic effects of icariin administration on depression‑like behaviors (with a sucrose preference test), on the mRNA and protein expression of glucocorticoid receptor (GR), FK506 binding protein 5 (FKBP5) and serum- and glucocorticoid-inducible kinase 1 (SGK1), as well as on the distribution of GR (in the cytoplasm and nucleus) in both the hippocampus and the prefrontal cortex following exposure to CMS. Our results revealed that the oral administration of icariin (20 and 40 mg/kg) for 35 consecutive days attenuated the development of depression-like behaviors induced by exposure to CMS. The increased mRNA expression of GR and SGK1 in the prefrontal cortex was reversed by icariin treatment. Moreover, the CMS-induced increases in the levels of cytosolic GR and SGK1 were partially restored by icariin administration in both the hippocampus and the prefrontal cortex, particularly in the hippocampus. Icariin also partially reversed the upregulated epxression of nuclear GR in the prefrontal cortex and that of FKBP5 in the hippocampus. On the whole, our findings indicate that icariin may have therapeutic applications as a potential antidepressant with multiple targets in both the hippocampus and prefrontal cortex. It exerts antidepressant-like effects by restoring the negative feedback regulation of the hypothalamic-pituitary-adrenal axis, which is at least partially attributed to normalization of the distribution of GR, and decreases in the expression levels of FKBP5 and SGK1.
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http://dx.doi.org/10.3892/ijmm.2016.2591DOI Listing
July 2016

Hyaluronan ameliorates LPS-induced acute lung injury in mice via Toll-like receptor (TLR) 4-dependent signaling pathways.

Int Immunopharmacol 2015 Oct 28;28(2):1050-8. Epub 2015 Aug 28.

Department of Integrative Medicine, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai 200040, China. Electronic address:

Toll-like receptor-4 (TLR4) signaling has been implicated in innate immunity and acute inflammation following acute lung injury (ALI). As such, modulating inflammatory response through TLR4 represents an attractive therapeutic approach to treat ALI. Increasing evidence demonstrates that hyaluronan (HA) can modulate TLR4 activation and has shown early promise as a therapeutic agent in ALI. However, the mechanism associated with HA has not been fully elucidated. In the current study, we sought to determine the effects of HA on lipopolysaccharide (LPS)-induced inflammatory response and gain insights into the mechanism of action in mice with intratracheal instillation of LPS. Our results demonstrate that in contrast to mice challenged with LPS, pretreatment with HA significantly inhibited inflammatory cell recruitment, attenuated lung injury and suppressed the level of cytokine/chemokine in bronchial alveolar lavage fluid (BALF). Investigation of the mechanism responsible for inhibition of LPS activation showed HA treatment significantly inhibited the nuclear translocation of NF-κB p65 and protein expression of myeloid differentiation primary response protein (MyD88) and TIR-domain-containing adapter-inducing interferon-β (TRIF) and p38 MAPK, JNK and ERK activation in lung tissue. Furthermore, we compared the protection effect of HA in TLR4-deficient mice with those of genetically matched wild type (WT) mice in an acute model of lung injury. However, in TLR4-deficient mice, HA pretreatment before LPS instillation fail to affect the LPS response. Therefore, our findings suggest that HA pretreatment attenuated LPS-induced ALI and the anti-inflammatory function of HA was partial dependent on TLR4, which shed new light on potential elements that regulate the lung injury response.
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http://dx.doi.org/10.1016/j.intimp.2015.08.021DOI Listing
October 2015

Icariin attenuates social defeat-induced down-regulation of glucocorticoid receptor in mice.

Pharmacol Biochem Behav 2011 Apr 20;98(2):273-8. Epub 2011 Jan 20.

Department of Integrative Medicine, Huashan Hospital, Fudan University, Middle, Urumqi Road 12#, Shanghai, 200040, China.

Icariin is a major constituent of flavonoids isolated from the herb Epimedium. It displays antidepressant-like activity in mice behavioral despair models and chronic mild stress models. In this study, a chronic social defeat protocol is used as a mouse model for depression, and the social avoidance effects of icariin administration are investigated. The data indicate that social defeat significantly reduces mice social interaction time and that icariin administered at 25 mg/kg and 50 mg/kg for 28 consecutive days produce remarkable increases in social interaction time. Impaired glucocorticoid receptor (GR) function is related to depression and normalization of GR function is closely associated with the recovery from depression. In this study, GR binding affinity and protein expression were evaluated by radioactive ligand and western blot, respectively. Our results demonstrate that both GR binding affinity and protein expression in the social defeat model are remarkably decreased and that icariin administration attenuates social defeat-induced GR down-regulation. In the present study, our data also show that icariin administration significantly inhibits social defeat-induced increases of corticosterone and IL-6 levels. The potential mechanisms of icariin induced GR modulation, such as effects on HPA-axis function, proinflammatory signaling pathway and membrane steroid transporters, need further study.
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http://dx.doi.org/10.1016/j.pbb.2011.01.008DOI Listing
April 2011

In vivo and in vitro anti-inflammatory effects of a novel derivative of icariin.

Immunopharmacol Immunotoxicol 2011 Mar 25;33(1):49-54. Epub 2010 Mar 25.

Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China.

Icariin is the major active constituent of Epimedii Herba. Our recent study showed that icariin displayed anti-inflammatory potential. One novel derivate of icariin is 3,5,7-Trihydroxy-4'-methoxy-8-(3-hydroxy-3-methylbutyl)-flavone (ICT). Little is known about ICT's pharmacological activities. In our study, the anti-inflammatory properties of ICT were evaluated. Murine RAW264.7 cells and C57BL/6J mice stimulated by lipopolysaccharide (LPS) was used as in vitro and in vivo inflammatory model, respectively. Our data showed that ICT (1-100 μg/mL) significantly inhibited LPS-induced tumor necrosis factor-α (TNF-α), nitric oxide (NO), prostaglandin E2 (PGE2) production in vitro. These effects did not depend on cytotoxicity. The in vivo assay displayed that pretreatment of C57BL/6J mice with ICT (25-100 mg/kg, by gavage) for 3 days decreased LPS-induced serum levels of TNF-α, PGE2, and neutrophils CD11b expression dose-dependently. Furthermore, our data suggested that ICT reduced NO and PGE2 levels by inhibiting inducible NO synthase and cyclooxygenase-2 protein expression. To our knowledge, it is the first time that the anti-inflammatory effects of ICT have been evaluated.
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http://dx.doi.org/10.3109/08923971003725144DOI Listing
March 2011
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