Publications by authors named "David Elashoff"

370 Publications

Effect of 2 Interventions on Cervical Cancer Screening Guideline Adherence.

Am J Prev Med 2021 Feb 22. Epub 2021 Feb 22.

Department of Obstetrics & Gynecology, University of California, Irvine, California.

Introduction: This study sought to determine whether a provider mobile phone application, used with or without a patient educational tool accessed on a computer tablet, would promote adherence to guidelines for cervical cancer screening and management of abnormal cytology in young women.

Methods: The study was conducted as a prospective cohort study in which 14 Family Planning, Access, Care, and Treatment provider clinics were randomized to 1 of 2 arms: (1) provider mobile phone application only or (2) provider mobile phone application plus patient educational tool. The provider mobile phone application gave information to providers regarding cervical cancer screening and management of abnormal cytology. The patient educational tool accessed on a computer tablet was a patient-centered educational tool. Each arm was compared with clinic control groups (no intervention) in a 2:1 ratio (control:intervention). Claims data were used to calculate and compare 18-month cytology (Pap) and colposcopy rates before the intervention and during the 18 months using the Poisson mixed-effect regression model. A sensitivity analysis examined the differences in the rate of change between each arm and controls. The study took place between July 2015 and December 2016, and analysis was performed in 2019.

Results: The clinics randomized to the provider mobile phone application plus patient educational tool arm and their control group achieved similar 18-month Pap rates (0.52, 95% CI=0.37, 0.74 and 0.68, 95% CI=0.53, 0.86, respectively) as well as the provider mobile phone application arm and their control group (0.44, 95% CI=0.33, 0.58 and 0.41, 95% CI=0.34, 0.51; p-values >0.1). In the sensitivity analysis, the difference in the rate of change in Pap rates for the provider mobile phone application plus patient educational tool arm and their control group before and during the intervention was -0.22 and -0.09, respectively (p=0.02), but no differences were seen between the provider mobile phone application arm and their control group. No significant changes were observed for colposcopy rates.

Conclusions: Providing clinicians and patients with information on guidelines had no demonstrable effect on 18-month Pap and colposcopy rates in the regression model; however, results from the sensitivity analysis for the patient educational tool were encouraging.

Trial Registration: This study is registered at www.clinicaltrials.gov NCT02270021.
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http://dx.doi.org/10.1016/j.amepre.2020.11.015DOI Listing
February 2021

Identifying the Best Candidates for Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography as the Primary Staging Approach Among Men with High-risk Prostate Cancer and Negative Conventional Imaging.

Eur Urol Oncol 2021 Feb 15. Epub 2021 Feb 15.

Department of Radiation Oncology, UCLA Medical Center, Los Angeles, CA, USA. Electronic address:

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) is an emerging imaging modality with greater sensitivity and specificity over conventional imaging for prostate cancer (PCa) staging. Using data from two prospective trials (NCT03368547 and NCT04050215), we explored predictors of overall upstaging (nodal and metastatic) by PSMA PET/CT among patients with cN0M0 National Comprehensive Cancer Network high-risk PCa on conventional imaging (n = 213). Overall, 21.1%, 8.9%, and 23.9% of patients experienced nodal, metastatic, and overall upstaging, respectively, without histologic confirmation. On multivariable analysis, Gleason grade group (GG) and percent positive core (PPC) on systematic biopsy significantly predict overall upstaging (odds ratio [OR] 2.15, 95% confidence interval [CI] 1.33-3.45; p =  0.002; and OR 1.03, 95% CI 1.01-1.04; p <  0.001). Overall upstaging was significantly more frequent among men with GG 5 disease (33.0% vs. 17.6%; p =  0.0097) and PPC ≥50% (33.0% vs 15.0%; p =  0.0020). We constructed a nomogram that predicts overall upstaging using initial prostate-specific antigen, PPC, GG, and cT stage, with coefficients estimated from a standard logistic regression model (using maximum likelihood estimation). It is internally validated with a tenfold cross-validated area under the receiver operating characteristic curve estimated at 0.74 (95% CI 0.67-0.82). In our cohort, 90% of patients who had a nomogram-estimated risk below the cutoff of 22% for overall upstaging could have been spared PSMA PET/CT as our model correctly predicted no upstaging. In other words, the predictive model only missed 10% of patients who would otherwise have benefitted from PSMA PET/CT. PATIENT SUMMARY: We analyzed predictors of overall upstaging (lymph node or/and metastasis) by prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) from conventional imaging in men with high-risk prostate cancer undergoing initial staging deemed free of disease in the lymph nodes and distant metastasis by conventional imaging techniques. We found that the pathologic grade and disease burden in a prostate biopsy are associated with upstaging. We also developed a tool that predicts the probability of upstaging according to an individual patient's characteristics. Our study may help in defining patient groups who are most likely to benefit from the addition of a PSMA PET/CT scan.
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http://dx.doi.org/10.1016/j.euo.2021.01.006DOI Listing
February 2021

Understanding trajectories of underlying dimensions of posttraumatic psychopathology.

J Affect Disord 2021 Apr 5;284:75-84. Epub 2021 Feb 5.

School of Dentistry, UCLA, Los Angeles, CA, United States.

Background: Research suggests four modal trajectories of psychological symptoms after traumatic injury: Resilient, Chronic, Delayed Onset, Recovery. However, most studies focus on symptoms of psychiatric disorders (e.g., posttraumatic stress disorder, depression), which are limited by heterogeneity and symptom overlap. We examined trajectories of cross-cutting posttraumatic symptom dimensions following traumatic injury and predictors of trajectory membership.

Methods: In this longitudinal study of 427 predominantly Hispanic/Latino traumatic injury survivors, posttraumatic psychopathology symptoms were assessed during hospitalization and approximately one and five months post-trauma. Using latent class growth analysis, we estimated trajectories of several posttraumatic symptom dimensions: re-experiencing, avoidance, anxious arousal, numbing, dysphoric arousal, loss, and threat. We then examined sociodemographic and trauma-related characteristics (measured during hospitalization) as predictors of trajectory membership for each dimension.

Results: Four trajectories (Resilient, Chronic, Delayed Onset, Recovery) emerged for all dimensions except loss and threat, which manifested three trajectories (Resilient, Chronic, Delayed Onset). Across dimensions, membership in the Chronic (vs. Resilient) trajectory was consistently predicted by unemployment (7 of 7 dimensions), followed by older age (3/7), female sex (3/7), and assaultive trauma (2/7). For several dimensions, unemployment also distinguished between participants who presented with similar symptom levels days after trauma, but then diverged over time.

Limitations: Measures of posttraumatic symptom dimension constructs differed across assessments.

Conclusions: This study provides evidence of distinct trajectories across transdiagnostic symptom dimensions after traumatic injury. Employment status emerged as the most important predictor of trajectory membership. Research is needed to better understand the etiologies and consequences of these posttraumatic symptom dimension trajectories.
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http://dx.doi.org/10.1016/j.jad.2021.01.086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927420PMC
April 2021

The impact of monosodium glutamate on Ga-PSMA-11 biodistribution in men with prostate cancer: a prospective randomized, controlled, imaging study.

J Nucl Med 2021 Jan 28. Epub 2021 Jan 28.

University of California Los Angeles, United States.

The prostate-specific membrane antigen (PSMA) has been targeted for PET imaging and radioligand therapy (RLT) in patients with prostate cancer. Xerostomia is a common side effect of RLT due to high salivary gland uptake of PSMA-radioligands. Here we aimed to determine the impact of monosodium glutamate (MSG) administration on PSMA-radioligand biodistribution within healthy organs and tumor lesions by using Ga-PSMA-11 PET imaging. 16 men with prostate cancer were randomized (1:1) into oral ingestion and oral topical application ('swishing') arms. Each subject underwent two Ga-PSMA-11 PET/CT scans within 14 days under baseline and MSG conditions. Salivary glands and whole-body tumor lesions were segmented using qPSMA software. We quantified tracer uptake via mean and maximum standardized uptake values (SUVmean and SUV) and compared parameters within each patient. For the oral ingestion arm, salivary gland SUVmean/max decreased on average from Control to MSG scan by 45±15% ( = 0.004) and 53±11% (p<0.001), respectively. Tumor lesions SUVmean/ max also decreased by 38% (IQR -67%, -33%) and -52% (IQR -70%, -49%), respectively ( = 0.018). Swishing had no significant effect on Ga-PSMA-11 accumulation in normal organs or tumor lesions. Oral ingestion but not topical application of MSG reduced Ga-PSMA-11 uptake in salivary glands. Tumor uptake also declined, therefore, the clinical application of MSG is unlikely to be useful in the framework of RLT.
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http://dx.doi.org/10.2967/jnumed.120.257931DOI Listing
January 2021

Association Between the ACA Medicaid Expansions and Changes in Cardiovascular Risk Factors Among Low-Income Individuals.

J Gen Intern Med 2021 Jan 22. Epub 2021 Jan 22.

Department of Health Policy and Management, UCLA Fielding School of Public Health, Los Angeles, CA, USA.

Background: Evidence is limited as to whether the introduction of the Affordable Care Act (ACA)'s Medicaid expansions was associated with improvements in cardiovascular risk factors at the population level.

Objective: To examine the association between the ACA Medicaid expansions and changes in cardiovascular risk factors among low-income individuals during the first 3 years of the implementation of the ACA Medicaid expansions at the national level.

Design: A quasi-experimental difference-in-differences (DID) analysis to compare outcomes before (2005-2012) and after (2015-2016) the implementation of the ACA Medicaid expansions between individuals in states that expanded Medicaid and individuals in non-expansion states.

Participants: A nationally representative sample of individuals aged 19-64 years with family incomes below 138% of the federal poverty level from the 2005-2016 National Health and Nutrition Examination Survey (NHANES).

Intervention: ACA Medicaid expansions.

Main Measures: Cardiovascular risk factors included (1) systolic and diastolic blood pressure, (2) hemoglobin A1c (HbA1c) level, and (3) cholesterol levels (low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol).

Key Results: A total of 9177 low-income individuals were included in our analysis. We found that the ACA Medicaid expansions were associated with a lower systolic blood pressure (DID estimate, - 3.03 mmHg; 95% CI, - 5.33 mmHg to - 0.73 mmHg; P = 0.01; P = 0.03 after adjustment for multiple comparisons) and lower HbA1c level (DID estimate, - 0.14 percentage points [pp]; 95% CI, - 0.24 pp to - 0.03 pp; P = 0.01; P = 0.03 after adjustment for multiple comparisons). We found no evidence that diastolic blood pressure and cholesterol levels changed following the ACA Medicaid expansions.

Conclusion: Using the nationally representative data of individuals who were affected by the ACA, we found that the ACA Medicaid expansions were associated with a modest improvement in cardiovascular risk factors related to hypertension and diabetes during the first 3 years of implementation.
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http://dx.doi.org/10.1007/s11606-020-06417-6DOI Listing
January 2021

Tissue-specific endothelial cell heterogeneity contributes to unequal inflammatory responses.

Sci Rep 2021 Jan 21;11(1):1949. Epub 2021 Jan 21.

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, 1000 Veteran Avenue, Room 1-520, Los Angeles, CA, 90095, USA.

Endothelial cells (EC) coordinate vascular homeostasis and inflammation. In organ transplantation, EC are a direct alloimmune target. We posited that tissue specific heterogeneity of vascular EC may partly underlie the disparate organ-specific alloimmune risk. We examined the vascular endothelial response to inflammation across six primary endothelial beds from four major transplanted organs: the heart, lung, kidney and liver. First, we reanalyzed a public dataset of cardiac allograft rejection and found that endothelial inflammatory response genes were elevated in human cardiac allograft biopsies undergoing rejection compared with stable grafts. Next, the inducible inflammatory phenotypes of EC from heart, lung, kidney, and liver were characterized in vitro, focused on expression of adhesion molecules and chemokines, and recruitment of allogeneic peripheral blood mononuclear immune cells. Large vessel cardiac EC most highly upregulated VCAM-1, particularly compared with hepatic EC, supported greater leukocyte adhesion and had distinct chemokine profiles after stimulation with cytokines and complement. Differentially expressed gene candidates that are known regulators of cytokine signaling and inflammatory programming were verified in publicly available datasets of organ-specific endothelial transcriptomes. In summary, differential baseline expression of immune regulating genes may contribute to differential vascular inflammatory responses depending on organ.
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http://dx.doi.org/10.1038/s41598-020-80102-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820348PMC
January 2021

Using Wearable Sensor Technology to Measure Motion Complexity in Infants at High Familial Risk for Autism Spectrum Disorder.

Sensors (Basel) 2021 Jan 17;21(2). Epub 2021 Jan 17.

Department of Pediatrics, Keck School of Medicine, Division of Research on Children, Youth, and Families, Developmental Neuroscience and Neurogenetics Program, The Saban Research Institute, Children's Hospital Los Angeles, 4650 Sunset Blvd., MS #71, Los Angeles, CA 90027, USA.

Background: Motor dysfunction has been reported as one of the first signs of atypical development in infants at high familial risk for autism spectrum disorder (ASD) (HR infants). However, studies have shown inconsistent results regarding the nature of motor dysfunction and whether it can be predictive of later ASD diagnosis. This is likely because current standardized motor assessments may not identify subtle and specific motor impairments that precede clinically observable motor dysfunction. Quantitative measures of motor development may address these limitations by providing objective evaluation of subtle motor differences in infancy.

Methods: We used Opal wearable sensors to longitudinally evaluate full day motor activity in HR infants, and develop a measure of motion complexity. We focus on complexity of motion because optimal motion complexity is crucial to normal motor development and less complex behaviors might represent repetitive motor behaviors, a core diagnostic symptom of ASD. As proof of concept, the relationship of the motion complexity measure to developmental outcomes was examined in a small set of HR infants.

Results: HR infants with a later diagnosis of ASD show lower motion complexity compared to those that do not. There is a stronger correlation between motion complexity and ASD outcome compared to outcomes of cognitive ability and adaptive skills.

Conclusions: Objective measures of motor development are needed to identify characteristics of atypical infant motor function that are sensitive and specific markers of later ASD risk. Motion complexity could be used to track early infant motor development and to discriminate HR infants that go on to develop ASD.
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http://dx.doi.org/10.3390/s21020616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830886PMC
January 2021

Genetic Variants in Immune Related Genes as Predictors of Responsiveness to BCG Immunotherapy in Metastatic Melanoma Patients.

Cancers (Basel) 2020 Dec 30;13(1). Epub 2020 Dec 30.

Department of Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, CA 90404, USA.

Adjuvant immunotherapy in melanoma patients improves clinical outcomes. However, success is unpredictable due to inherited heterogeneity of immune responses. Inherent immune genes associated with single nucleotide polymorphisms (SNPs) may influence anti-tumor immune responses. We assessed the predictive ability of 26 immune-gene SNPs genomic panels for a clinical response to adjuvant BCG (Bacillus Calmette-Guérin) immunotherapy, using melanoma patient cohorts derived from three phase III multicenter clinical trials: AJCC (American Joint Committee on Cancer) stage IV patients given adjuvant BCG (; = 92), AJCC stage III patients given adjuvant BCG (; = 269), and AJCC stage III patients that are sentinel lymph node (SLN) positive receiving no immunotherapy (; = 80). The SNP panel analysis demonstrated that the responder patient group had an improved disease-free survival (DFS) (hazard ratio [HR] 1.84, 95% CI 1.09-3.13, = 0.021) in the pilot cohort. In the verification cohort, an improved overall survival (OS) (HR 1.67, 95% CI 1.07-2.67, = 0.025) was observed. No significant differences of SNPs were observed in DFS or OS in the control patient cohort. This study demonstrates that SNP immune genes can be utilized as a predictive tool for identifying melanoma patients that are inherently responsive to BCG and potentially other immunotherapies in the future.
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http://dx.doi.org/10.3390/cancers13010091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795941PMC
December 2020

Update from PSMA-SRT Trial NCT03582774: A Randomized Phase 3 Imaging Trial of Prostate-specific Membrane Antigen Positron Emission Tomography for Salvage Radiation Therapy for Prostate Cancer Recurrence Powered for Clinical Outcome.

Eur Urol Focus 2021 Mar 30;7(2):238-240. Epub 2020 Dec 30.

Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA; Institute of Urologic Oncology, University of California, Los Angeles, Los Angeles, CA, USA; Physics and Biology in Medicine Interdepartmental Graduate Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

The purpose of this randomized trial is to evaluate the success rate of salvage radiation therapy for recurrence of prostate cancer after radical prostatectomy, with and without planning based on prostate-specific membrane antigen positron emission tomography/computed tomography. Enrollment has been completed and patients are being followed for 5yr.
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http://dx.doi.org/10.1016/j.euf.2020.12.009DOI Listing
March 2021

A Systematic Review and Meta-analysis of Local Salvage Therapies After Radiotherapy for Prostate Cancer (MASTER).

Eur Urol 2020 Dec 10. Epub 2020 Dec 10.

Department of Radiation Oncology, University of California, Los Angeles, CA, USA; Department of Urology, University of California, Los Angeles, CA, USA. Electronic address:

Context: Management of locally recurrent prostate cancer after definitive radiotherapy remains controversial due to the perceived high rates of severe genitourinary (GU) and gastrointestinal (GI) toxicity associated with any local salvage modality.

Objective: To quantitatively compare the efficacy and toxicity of salvage radical prostatectomy (RP), high-intensity focused ultrasound (HIFU), cryotherapy, stereotactic body radiotherapy (SBRT), low-dose-rate (LDR) brachytherapy, and high-dose-rate (HDR) brachytherapy.

Evidence Acquisition: We performed a systematic review of PubMed, EMBASE, and MEDLINE. Two- and 5-yr recurrence-free survival (RFS) rates and crude incidences of severe GU and GI toxicity were extracted as endpoints of interest. Random-effect meta-analyses were conducted to characterize summary effect sizes and quantify heterogeneity. Estimates for each modality were then compared with RP after adjusting for individual study-level covariates using mixed-effect regression models, while allowing for differences in between-study variance across treatment modalities.

Evidence Synthesis: A total of 150 studies were included for analysis. There was significant heterogeneity between studies within each modality, and covariates differed between modalities, necessitating adjustment. Adjusted 5-yr RFS ranged from 50% after cryotherapy to 60% after HDR brachytherapy and SBRT, with no significant differences between any modality and RP. Severe GU toxicity was significantly lower with all three forms of radiotherapeutic salvage than with RP (adjusted rates of 20% after RP vs 5.6%, 9.6%, and 9.1% after SBRT, HDR brachytherapy, and LDR brachytherapy, respectively; p ≤ 0.001 for all). Severe GI toxicity was significantly lower with HDR salvage than with RP (adjusted rates 1.8% vs 0.0%, p < 0.01), with no other differences identified.

Conclusions: Large differences in 5-yr outcomes were not uncovered when comparing all salvage treatment modalities against RP. Reirradiation with SBRT, HDR brachytherapy, or LDR brachytherapy appears to result in less severe GU toxicity than RP, and reirradiation with HDR brachytherapy yields less severe GI toxicity than RP. Prospective studies of local salvage for radiorecurrent disease are warranted.

Patient Summary: In a large study-level meta-analysis, we looked at treatment outcomes and toxicity for men treated with a number of salvage treatments for radiorecurrent prostate cancer. We conclude that relapse-free survival at 5 years is equivalent among salvage modalities, but reirradiation may lead to lower toxicity.
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http://dx.doi.org/10.1016/j.eururo.2020.11.010DOI Listing
December 2020

Understanding the Heterogeneity of Obesity and the Relationship to the Brain-Gut Axis.

Nutrients 2020 Nov 30;12(12). Epub 2020 Nov 30.

Division of Hematology and Oncology, University of California, Los Angeles, CA 90095, USA.

Obesity is best understood as a multifactorial metabolic imbalances disorder. In a cross-sectional study, we aimed to explore sociodemographic and dietary determinants of obesity in relation to brain-gut homeostasis among overweight and obese individuals. Multivariate logistic regression models were used to examine obesity and its association with sociodemographic and dietary factors. Biological variables examined included the gut microbiome, fecal amino acid metabolites and brain structural volumes. Among 130 participants, there were higher odds of obesity if individuals were Hispanic (adjusted odds ratio (aOR) 1.56, = 0.014). Compared to non-Hispanics, Hispanics differed in gut microbial composition ( = 0.046) with lower microbial species richness (Chao1) ( = 0.032) and evenness (Shannon) ( = 0.0029). Fourteen of the twenty fecal amino acids including branch-chain- and aromatic- amino acids were increased among Hispanics ( < 0.05). Brain structural volumes in reward regions were decreased in Hispanics (pallidum, = 0.036; brainstem, = 0.011). Correlation patterns suggest complex brain-gut interactions differ by Hispanic ethnicity. In conclusion, Hispanics expressed a unique brain-gut microbial signature, which was associated with obesity despite sociodemographic and dietary differences. Addressing ethnic disparities guided by biologic phenotypes may unlock novel understanding of obesity heterogeneity and treatment strategies.
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http://dx.doi.org/10.3390/nu12123701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761087PMC
November 2020

Botulinum Toxin Type A for the Treatment of Post-traumatic Headache: A Randomized, Placebo-Controlled, Cross-over Study.

Mil Med 2020 Nov 26. Epub 2020 Nov 26.

Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.

Introduction: Botulinum toxin type A (BoNT/A) is an approved treatment for chronic migraine and has been shown to be effective in reducing number, days, and severity of headache in other headache disorders. Whether botulinum toxin is a safe and effective treatment specifically for post-traumatic headache (PTH), however, is unknown. This study sought to determine whether treatment with BoNT/A improved symptoms of PTH in military veterans.

Materials And Methods: Forty subjects with PTH were randomized to receive treatment of either BoNT/A or a saline placebo. Sixteen weeks post-treatment or at return to baseline headache severity, subjects were crossed over to receive treatment with the other medication than previously treated with in the first session. Subjects recorded number of headaches, number of headache days, and headache pain severity in daily diaries. Outcome measures included change in the weekly number of headaches, number of headache days per week, and headache pain severity compared to baseline, and the change in number of headaches and number of headaches days at baseline compared to the rating scores averaged across weeks 6-11.

Results: The number of headaches per week significantly decreased by 2.24 (43.3%) with BoNT/A treatment (P < .001) and significantly increased by 1.28 (35.1%) with placebo (P = .02) at the end of the 16 weeks and the difference between groups was also significant (P < .001). The number of headache days per week also significantly decreased by 2.24 (44.4%) at the end of 16 weeks with BoNT/A treatment (P < .001), was not significantly changed with placebo, and the difference between the two groups was significant (P < .001). Both the change in number of headaches and number of headache days averaged across weeks 6-11 compared to baseline were significantly decreased in the BoNT/A group (1.6 and 1.4, respectively) compared to a significant increase of 0.3 in number of weekly headaches and a nonsignificant decrease of 0.1 in number of headache days for the placebo group (P = .048 and P = .005, respectively). Headache pain severity was significantly reduced by 0.06 with botulinum toxin treatment (P = .02) and was not significantly increased by 0.04 in the placebo group with a significant difference between groups (P = .006).

Conclusions: Treatment with BoNT/A clinically and significantly improved the frequency and pain severity of PTH compared to placebo in military veterans. Limitations of the study include subject dropout, adherence to documenting variables daily in the dairy, and only one treatment of BoNT/A. Strengths include the cross-over study design, which demonstrated that BoNT/A was effective regardless of treatment order. This dataset is the first prospective study to evaluate BoNT/A as an intervention for symptoms of PTH and provides evidence that larger-scale and multiple treatment studies evaluating BoNT/A for this headache type are warranted.
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http://dx.doi.org/10.1093/milmed/usaa391DOI Listing
November 2020

Endothelin Type A Receptor Antibodies Are Associated With Angiotensin II Type 1 Receptor Antibodies, Vascular Inflammation, and Decline in Renal Function in Pediatric Kidney Transplantation.

Kidney Int Rep 2020 Nov 6;5(11):1925-1936. Epub 2020 Sep 6.

Division of Pediatric Nephrology, Department of Pediatrics, University of California Los Angeles, Los Angeles, California, USA.

Introduction: Autoantibody to angiotensin II type 1 receptor (AT1R-Ab) has been recognized as a non-human leukocyte antigen (HLA) antibody relevant in transplantation. Endothelin type A receptor antibody (ETAR-Ab) has been strongly associated with AT1R-Ab, but the data in kidney transplantation are scarce.

Methods: We examined the relationship of ETAR-Ab and AT1R-Ab with clinical outcomes, biopsy findings, inflammatory cytokines, and HLA donor-specific antibody (DSA) in a cohort of pediatric renal transplant recipients. Sixty-five patients were longitudinally monitored for ETAR-Ab, AT1R-Ab, HLA DSA, interleukin (IL)-8, tumor necrosis factor-α, IL-1β, interferon-γ, IL-17, IL-6, renal dysfunction, hypertension, rejection, and allograft loss during the first 2 years post-transplant.

Results: Fifteen patients (23%) had AT1R-Ab alone, 1 (2%) had ETAR-Ab alone, 23 (35%) had both ETAR-Ab and AT1R-Ab, and 26 (40%) were negative for both antibodies at all timepoints. Having both ETAR-Ab and AT1R-Ab was associated with >30% decline in estimated glomerular filtration rate ( = 0.024), arteritis ( = 0.016), and elevated IL-8 levels ( = 0.010), but not rejection, HLA DSA, or allograft loss. Having both antibodies resulted in greater increases in IL-8 compared with AT1R-Ab alone, even when controlled for additional clinical factors, including HLA DSA ( = 0.012).

Conclusion: Our study demonstrates that, in pediatric kidney transplantation, ETAR-Ab is highly associated with AT1R-Ab, but there are a subset of patients with AT1R-Ab alone. Having both antibodies is significantly associated with arteritis, elevated IL-8, and decline in renal function, and our results suggest possible interaction effects. Better understanding of this interaction may be informative in developing protocols for testing, treatment, and prevention of allograft injury.
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http://dx.doi.org/10.1016/j.ekir.2020.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609952PMC
November 2020

DNA Methylation Age Is More Closely Associated With Infection Risk Than Chronological Age in Kidney Transplant Recipients.

Transplant Direct 2020 Aug 15;6(8):e576. Epub 2020 Jul 15.

Division of General Internal Medicine and Health Services Research, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Older kidney transplant recipients demonstrate increased rates of infection but decreased rates of rejection compared with younger recipients, suggesting that older transplant patients are functionally overimmunosuppressed. We hypothesized that this is a consequence of reduction in immunological activity due to biological aging and that an immune biological age, as determined by DNA methylation (DNAm), would be associated more strongly with incidence of infection than chronological age.

Methods: DNAm analysis was performed on peripheral blood mononuclear cell collected from 60 kidney transplant recipients representing older (≥age 60 y) and younger (aged 30-59 y) patients 3 months after transplantation. DNAm age was calculated based on methylation status of a panel of CpG sites, which have been previously identified as indicative of biological age.

Results: Correlation was seen between chronological and DNAm age; however, there were many patients with significant differences (either acceleration or slowing) between DNAm age and chronological age. A statistically significant association was seen between increased DNAm age and incidence of infection in the first year after kidney transplantation, whereas no significant association was seen between chronological age and infection.

Conclusions: Assessment of DNAm age holds promise as an approach for patient evaluation and individualization of immune suppression regimens. This analysis may provide insights into the immunological mechanism behind increased incidence of infection observed in older transplant patients. The ability to measure biological age would allow for patient risk stratification and individualization of immunosuppression, improving outcomes for the growing numbers of older patients undergoing kidney transplantation.
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http://dx.doi.org/10.1097/TXD.0000000000001020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581059PMC
August 2020

Ultrasound and multi-biomarker disease activity score for assessing and predicting clinical response to tofacitinib treatment in patients with rheumatoid arthritis.

BMC Rheumatol 2020 19;4:55. Epub 2020 Oct 19.

Department of Rheumatology, UCLA-David Geffen School of Medicine, 1000 Veteran Blvd., RM 32-59, Los Angeles, CA 90095 USA.

Background: Musculoskeletal ultrasound (MSUS) and the multi-biomarker disease activity (MBDA) score are outcome measures that may aid in the management of rheumatoid arthritis (RA) patients. This study evaluated tofacitinib response by MSUS/MBDA scores and assessed whether baseline MSUS/MBDA scores or their early changes predict later clinical response.

Methods: Twenty-five RA patients treated with tofacitinib were assessed at baseline, 2, 6 and 12-weeks. Power doppler (PDUS) and gray scale (GSUS) ultrasound scores, MBDA score, clinical disease activity index (CDAI), and disease activity score (DAS28) were obtained. Pearson correlations and multiple linear regression models were used to evaluate associations and identify predictors of response to therapy.

Results: MSUS, MBDA scores, CDAI, and DAS28 improved significantly over 12 weeks ( < 0.0001). Baseline MSUS and MBDA score correlated with each other, and with 12-week changes in CDAI/DAS28 (r = 0.45-0.62,  < 0.05), except for GSUS with DAS28. Two-week change in MSUS correlated significantly with 12-week changes in CDAI/DAS28 (r = 0.42-0.57,  < 0.05), except for early change in PDUS with 12-week change in CDAI. Regression analysis demonstrated significant independent associations between baseline PDUS/MBDA score and 6-week change in CDAI/DAS28, with adjustment for baseline CDAI/DAS28 (all  < 0.05); and between baseline MBDA scores and 12-week change in DAS28 ( = 0.03).

Conclusions: RA patients treated with tofacitinib for 12 weeks demonstrated improvement by clinical, imaging, and biomarker end-points. Baseline PDUS and MBDA score were predictive of CDAI and DAS28 responses. This is the first study to evaluate early measurements of MSUS and MBDA score as predictors of clinical response in RA patients treated with tofacitinib.

Trial Registration: ClinicalTrials.gov NCT02321930 (registered 12/22/2014).
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http://dx.doi.org/10.1186/s41927-020-00153-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569763PMC
October 2020

Scalp EEG interictal high frequency oscillations as an objective biomarker of infantile spasms.

Clin Neurophysiol 2020 Nov 3;131(11):2527-2536. Epub 2020 Sep 3.

Division of Pediatric Neurology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine, Los Angeles, California, USA.

Objective: To investigate the diagnostic utility of high frequency oscillations (HFOs) via scalp electroencephalogram (EEG) in infantile spasms.

Methods: We retrospectively analyzed interictal slow-wave sleep EEGs sampled at 2,000 Hz recorded from 30 consecutive patients who were suspected of having infantile spasms. We measured the rate of HFOs (80-500 Hz) and the strength of the cross-frequency coupling between HFOs and slow-wave activity (SWA) at 3-4 Hz and 0.5-1 Hz as quantified with modulation indices (MIs).

Results: Twenty-three patients (77%) exhibited active spasms during the overnight EEG recording. Although the HFOs were detected in all children, increased HFO rate and MIs correlated with the presence of active spasms (p < 0.001 by HFO rate; p < 0.01 by MIs at 3-4 Hz; p = 0.02 by MIs at 0.5-1 Hz). The presence of active spasms was predicted by the logistic regression models incorporating HFO-related metrics (AUC: 0.80-0.98) better than that incorporating hypsarrhythmia (AUC: 0.61). The predictive performance of the best model remained favorable (87.5% accuracy) after a cross-validation procedure.

Conclusions: Increased rate of HFOs and coupling between HFOs and SWA are associated with active epileptic spasms.

Significance: Scalp-recorded HFOs may serve as an objective EEG biomarker for active epileptic spasms.
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http://dx.doi.org/10.1016/j.clinph.2020.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606823PMC
November 2020

Purification of HCC-specific extracellular vesicles on nanosubstrates for early HCC detection by digital scoring.

Nat Commun 2020 09 7;11(1):4489. Epub 2020 Sep 7.

California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, 90095, USA.

We report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific extracellular vesicle (EV) purification system for early detection of HCC by performing digital scoring on the purified EVs. Earlier detection of HCC creates more opportunities for curative therapeutic interventions. EVs are present in circulation at relatively early stages of disease, providing potential opportunities for HCC early detection. We develop an HCC EV purification system (i.e., EV Click Chips) by synergistically integrating covalent chemistry-mediated EV capture/release, multimarker antibody cocktails, nanostructured substrates, and microfluidic chaotic mixers. We then explore the translational potential of EV Click Chips using 158 plasma samples of HCC patients and control cohorts. The purified HCC EVs are subjected to reverse-transcription droplet digital PCR for quantification of 10 HCC-specific mRNA markers and computation of digital scoring. The HCC EV-derived molecular signatures exhibit great potential for noninvasive early detection of HCC from at-risk cirrhotic patients with an area under receiver operator characteristic curve of 0.93 (95% CI, 0.86 to 1.00; sensitivity = 94.4%, specificity = 88.5%).
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http://dx.doi.org/10.1038/s41467-020-18311-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477161PMC
September 2020

Major Lipids and Future Risk of Pneumonia: 20-Year Observation of the Atherosclerosis Risk in Communities (ARIC) Study Cohort.

Am J Med 2021 02 16;134(2):243-251.e2. Epub 2020 Aug 16.

Division of Rheumatology.

Background: Circulating lipids have been implicated as important modulators of immune response, and altered lipid levels correlate with the severity of infection. However, long-term prognostic implications of lipid levels regarding future infection risk remain unclear. The current project aims to explore whether baseline lipid levels are associated with risk of future serious infection, measured by hospitalization for pneumonia.

Methods: A retrospective analysis was performed in 13,478 participants selected from the Atherosclerosis Risk in Communities (ARIC) study, a large community-based longitudinal cohort in the United States with a median follow-up time of >20 years. First incident of hospitalization for pneumonia was identified through hospital discharge records. Cox proportional hazard models were used to assess the association of baseline major lipid levels (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], triglycerides) with time to first pneumonia hospitalization.

Results: A total of 1969 (14.61%) participants had a pneumonia hospitalization during a median follow-up time of 21.5 years. The hazard ratio (HR) for pneumonia hospitalization was 0.90 (95% confidence interval, 0.87-0.92) for every 10-mg/dL increase in baseline HDL-C, and 1.02 (95% confidence interval, 1.02-1.03) for every 10-mg/dL increase in baseline triglycerides. HDL-C and triglycerides both remained significant predictors of pneumonia hospitalization after multivariable adjustment. Such associations were not seen with baseline LDL-C or total cholesterol levels.

Conclusion: Lower baseline HDL-C and higher triglyceride levels were strongly associated with increased risk of long-term pneumonia hospitalization in a large longitudinal US cohort.
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http://dx.doi.org/10.1016/j.amjmed.2020.07.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870521PMC
February 2021

Sentinel joint scoring in rheumatoid arthritis: an individualized power Doppler assessment strategy.

Clin Rheumatol 2021 Mar 15;40(3):1077-1084. Epub 2020 Aug 15.

David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

Objective: Musculoskeletal ultrasound quantifies the total synovial inflammatory burden in rheumatoid arthritis (RA) but is time consuming when scanning numerous joints. This study evaluated a novel patient-centered method for constructing a longitudinal ultrasound score in RA patients.

Methods: Fifty-four RA patients starting intravenous tocilizumab were evaluated with power Doppler ultrasound (PDUS) of 34 joints and DAS28-ESR was assessed at baseline and weeks 4, 12, 16, and 24. The sentinel joint score (SJS) was derived from the reduced subset of joints with PDUS ≥ 1 at baseline. Total PDUS (tPDUS) score and US7 were also calculated. Changes in tPDUS and SJS were correlated. Effect sizes were calculated for tPDUS, SJS, and US7. The proportion of "flipped" joints without baseline PDUS signal that later developed PDUS signal was estimated.

Results: At baseline, 1236/1829 joints scanned (67.5%) did not have PDUS signal. The proportion of "flipped" joints at 24 weeks was 5.6% for ≥ 1, 2.9% for ≥ 2, and 1.0% for = 3 PD. tPDUS and SJS scores were highly correlated (r = 0.91 to 0.97). Overall the effect sizes for tPDUS, SJS, and US7 increased over 24 weeks, where SJS was the highest (SJS 1.00 4-week, 1.07 12-week, 1.26 24-week) and tPDUS and US7 were comparable (tPDUS 0.32 4-week, 0.52 12-week, 0.84 24-week; US7 0.23 4-week, 0.52 12-week, 0.74 24-week).

Conclusion: In RA patients starting a biologic, scanning only joints with baseline PDUS signal can substantially reduce the number of joints requiring follow-up scanning by 67.5% and improves feasibility. "Flipped" joints are infrequently seen after starting therapy.

Trial Registration: ClinicalTrials.gov NCT01717859 Key messages • Only a small percent of joints develop power Doppler signal after baseline scanning. • Changes in the SJS correlate well with changes in clinical activity measured by DAS28-ESR over time. • The SJS effect size is higher than total PDUS and US7 scores, and may improve examination feasibility.
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http://dx.doi.org/10.1007/s10067-020-05340-9DOI Listing
March 2021

The intraprostatic immune environment after stereotactic body radiotherapy is dominated by myeloid cells.

Prostate Cancer Prostatic Dis 2021 Mar 9;24(1):135-139. Epub 2020 Jul 9.

Radiation Oncology at UCLA, Los Angeles, CA, USA.

Background: Hundreds of ongoing clinical trials combine radiation therapy, mostly delivered as stereotactic body radiotherapy (SBRT), with immune checkpoint blockade. However, our understanding of the effect of radiotherapy on the intratumoral immune balance is inadequate, hindering the optimal design of trials that combine radiation therapy with immunotherapy. Our objective was to characterize the intratumoral immune balance of the malignant prostate after SBRT in patients.

Methods: Sixteen patients with high-risk, non-metastatic prostate cancer at comparable Gleason Grade disease underwent radical prostatectomy with (n = 9) or without (n = 7) neoadjuvant SBRT delivered in three fractions of 8 Gy over 5 days completed 2 weeks before surgery. Freshly resected prostate specimens were processed to obtain single-cell suspensions, and immune-phenotyped for major lymphoid and myeloid cell subsets by staining with two separate 14-antibody panels and multicolor flow cytometry analysis.

Results: Malignant prostates 2 weeks after SBRT had an immune infiltrate dominated by myeloid cells, whereas malignant prostates without preoperative treatment were more lymphoid-biased (myeloid CD45 cells 48.4 ± 19.7% vs. 25.4 ± 7.0%; adjusted p-value = 0.11; and CD45 lymphocytes 51.6 ± 19.7% vs. 74.5 ± 7.0%; p = 0.11; CD3 T cells 35.2 ± 23.8% vs. 60.9 ± 9.7%; p = 0.12; mean ± SD).

Conclusion: SBRT drives a significant lymphoid to myeloid shift in the prostate-tumor immune infiltrate. This may be of interest when combining SBRT with immunotherapies, particularly in prostate cancer.
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http://dx.doi.org/10.1038/s41391-020-0249-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794088PMC
March 2021

Phase 1 Trial of Stereotactic Body Radiation Therapy Neoadjuvant to Radical Prostatectomy for Patients With High-Risk Prostate Cancer.

Int J Radiat Oncol Biol Phys 2020 11 17;108(4):930-935. Epub 2020 Jun 17.

Department of Radiation Oncology, University of California Los Angeles, Los Angeles, California; Department of Urology, University of California Los Angeles, Los Angeles, California; Radiation Therapy Service, VA Greater Los Angeles Healthcare System, Los Angeles, California. Electronic address:

Purpose: This study aimed to evaluate the feasibility and safety of prostate stereotactic body radiation therapy (SBRT) neoadjuvant to radical prostatectomy (RP) in a phase 1 trial. The primary endpoint was treatment completion rate without severe acute surgical complications. Secondary endpoints included patient-reported quality of life and physician-reported toxicities.

Methods And Materials: Patients with nonmetastatic high-risk or locally advanced prostate cancer received 24 Gy in 3 fractions to the prostate and seminal vesicles over 5 days, completed 2 weeks before RP. Patients with pN1 disease were treated after multidisciplinary discussion and shared decision making. Patient-reported quality of life (International Prostate Symptom Score and Expanded Prostate Cancer Index Composite 26-item version questionnaires) and physician-reported toxicity (Common Terminology Criteria for Adverse Events, version 4.03) were assessed before SBRT, immediately before surgery, and at 3-month intervals for 1 year.

Results: Twelve patients were enrolled, and 11 completed treatment (1 patient had advanced disease on prostate-specific membrane antigen positron emission tomography after enrollment but before treatment). There were no significant surgical complications. After RP, 2 patients underwent additional radiation therapy to nodes with androgen suppression for pN1 disease. Median follow-up after completion of treatment was 20.1 months, with 9 of 11 patients having a follow-up period of >12 months. Two patients had biochemical recurrence (prostate-specific antigen ≥0.05) within the first 12 months, with an additional 2 patients found to have biochemical recurrence after the 12-month period. The highest Common Terminology Criteria for Adverse Events genitourinary grades were 0, 1, 2, and 3 (n = 1, 4, 4, and 2, respectively), and the highest gastrointestinal grades were 0, 1, and 2 (n = 9, 1, and 1, respectively). At 12 months, incontinence was the only grade ≥2 toxicity. One and 2 of 9 patients had grade 2 and 3 incontinence, respectively. On the Expanded Prostate Cancer Index Composite (26-item version), the mean/median changes in scores from baseline to 12 months were -32.8/-31.1 for urinary incontinence, -1.6/-6.2 for urinary irritative/obstructive, -2.1/0 for bowel, -34.4/-37.5 for sexual function, and -10.6/-2.5 for hormonal. The mean/median change in International Prostate Symptom Score from baseline to 12 months was 0.5/0.5.

Conclusions: RP after neoadjuvant SBRT appears to be feasible and safe at the dose tested. The severity of urinary incontinence may be higher than RP alone.
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http://dx.doi.org/10.1016/j.ijrobp.2020.06.010DOI Listing
November 2020

Myelin and Lipid Composition of the Corpus Callosum in Mucopolysaccharidosis Type I Mice.

Lipids 2020 11 14;55(6):627-637. Epub 2020 Jun 14.

Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA, 90502, USA.

Mucopolysaccharidosis type I (MPS I) is a lysosomal disease with progressive central nervous system involvement. This study examined the lipid, cholesterol, and myelin basic protein composition of white matter in the corpus callosum of MPS I mice. We studied 50 week-old, male MPS I mice and littermate, heterozygote controls (n = 12 per group). Male MPS I mice showed lower phosphatidylcholine and ether-linked phosphatidylcholine quantities than controls (p < 0.05). Twenty-two phospholipid or ceramide species showed significant differences in percent of total. Regarding specific lipid species, MPS I mice exhibited lower quantities of sphingomyelin 18:1, phosphatidylserine 38:3, and hexosylceramide d18:1(22:1) mH O than controls. Principal components analyses of polar, ceramide, and hexosylceramide lipids, respectively, showed some separation of MPS I and control mice. We found no significant differences in myelin gene expression, myelin basic protein, or total cholesterol in the MPS I mice versus heterozygous controls. There was a trend toward lower proteolipid protein-1 levels in MPS I mice (p = 0.06). MPS I mice show subtle changes in white matter composition, with an unknown impact on pathogenesis in this model.
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http://dx.doi.org/10.1002/lipd.12261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992919PMC
November 2020

Transcriptomic Heterogeneity of Gleason Grade Group 5 Prostate Cancer.

Eur Urol 2020 09 24;78(3):327-332. Epub 2020 May 24.

Department of Radiation Oncology, University of California, Los Angeles, CA, USA.

Gleason grade group (GG) 5 prostate cancer has been associated with an aggressive natural history, and retrospective data support a role for treatment intensification. However, clinical outcomes remain heterogeneous in this cohort, and intensified treatments carry an increased risk of adverse events. We sought to explore the transcriptomic heterogeneity of GG 5 tumors by querying transcriptomic data from the tumors of 2138 patients with GG 5 disease who underwent prostatectomy. Four distinct consensus clusters were identified with respect to differential transcriptional activation of hallmark pathways, with distinct molecular subtyping profiles and different average genomic risks (AGRs). One cluster, accounting for 325 tumors (15.2% of the population), was enriched for genes related to the cell cycle/proliferation, metabolic pathways, androgen response pathways, and DNA repair, and had a higher AGR than the other clusters (p < 0.001). This clustering, with an identification of a high genomic risk cluster, was subsequently validated in a separate cohort of 1921 patients as well as a third cohort of 201 patients. The latter cohort had outcomes available, and it was found that patients in the high genomic risk cluster had significantly worse distant metastasis-free survival than the other clusters. Tumors in this high genomic risk cluster of GG 5 disease may be particularly likely to benefit from treatment intensification. PATIENT SUMMARY: In this report, we examined differences in gene expression in tumors from men with Gleason grade group 5 prostate cancer. We identified significant diversity, with one specific subgroup of tumors associated with expression profiles that suggest a worse prognosis.
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http://dx.doi.org/10.1016/j.eururo.2020.05.009DOI Listing
September 2020

Dietary Protein, Fiber and Coffee Are Associated with Small Intestine Microbiome Composition and Diversity in Patients with Liver Cirrhosis.

Nutrients 2020 May 13;12(5). Epub 2020 May 13.

The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA.

The gut microbiome is a key factor in chronic liver disease progression. In prior research, we found that the duodenal microbiome was associated with sex, ethnicity, and cirrhosis complications. Here, we examined the association between diet and the duodenal microbiome in patients with liver cirrhosis. This study included 51 participants who completed a detailed food frequency questionnaire and donated duodenal biopsies for microbiome characterization by 16S ribosomal RNA gene sequencing. Data were analyzed for alpha diversity, beta diversity, and association of taxa abundance with diet quality and components using QIIME 2 pipelines. Diet quality was assessed through calculation of the Healthy Eating Index 2010. Participants with higher adherence to protein recommendations exhibited increased microbial richness and evenness ( = 0.03) and a different microbial profile compared to those with lower adherence ( = 0.03). and were increased in association with increased protein adherence. Fiber consumption was also associated with the duodenal microbial profile ( = 0.01), with several taxa exhibiting significantly decreased or increased abundance in association with fiber intake. Coffee drinking was associated with microbial richness and evenness ( = 0.001), and there was a dose-response association between coffee drinking and relative abundance of ( = 0.01). We conclude that protein, fiber, and coffee are associated with diversity and composition of the duodenal microbiome in liver cirrhosis.
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http://dx.doi.org/10.3390/nu12051395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285216PMC
May 2020

Quantitative Gait Analysis in Duplication 15q Syndrome and Nonsyndromic ASD.

Autism Res 2020 07 13;13(7):1102-1110. Epub 2020 Apr 13.

Semel Institute of Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

Motor impairments occur frequently in genetic syndromes highly penetrant for autism spectrum disorder (syndromic ASD) and in individuals with ASD without a genetic diagnosis (nonsyndromic ASD). In particular, abnormalities in gait in ASD have been linked to language delay, ASD severity, and likelihood of having a genetic disorder. Quantitative measures of motor function can improve our ability to evaluate motor differences in individuals with syndromic and nonsyndromic ASD with varying levels of intellectual disability and adaptive skills. To evaluate this methodology, we chose to use quantitative gait analysis to study duplication 15q syndrome (dup15q syndrome), a genetic disorder highly penetrant for motor delays, intellectual disability, and ASD. We evaluated quantitative gait variables in individuals with dup15q syndrome (n = 39) and nonsyndromic ASD (n = 21) and compared these data to a reference typically developing cohort. We found a gait pattern of slow pace, poor postural control, and large gait variability in dup15q syndrome. Our findings improve characterization of motor function in dup15q syndrome and nonsyndromic ASD. Quantitative gait analysis can be used as a translational method and can improve our identification of clinical endpoints to be used in treatment trials for these syndromes. Autism Res 2020, 13: 1102-1110. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Motor impairments, particularly abnormalities in walking, occur frequently in genetic syndromes highly penetrant for autism spectrum disorder (syndromic ASD). Here, using quantitative gait analysis, we find that individuals with duplication 15q syndrome have an atypical gait pattern that differentiates them from typically developing and nonsyndromic ASD individuals. Our findings improve motor characterization in dup15q syndrome and nonsyndromic ASD.
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http://dx.doi.org/10.1002/aur.2298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498372PMC
July 2020

Merkel Cell Carcinoma: A 28-Year Experience.

Otolaryngol Head Neck Surg 2020 08 31;163(2):364-371. Epub 2020 Mar 31.

Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Objective: To evaluate the management and recurrence outcomes of head and neck Merkel cell carcinoma (HN-MCC) at a single institution.

Study Design: A retrospective review of outcomes in patients with HN-MCC.

Setting: A tertiary center from May 1990 to December 2018.

Subjects And Methods: Electronic medical records of patients with HN-MCC were reviewed.

Results: Sixty cases were included, with 67% (40 of 60) males and a mean age of 73.3 years. Imaging had a moderate sensitivity and specificity for detection of occult disease when compared with histopathologic analysis. Forty-two percent (25 of 60) of patients underwent neck dissection, and 12% (7 of 60) had a sentinel lymph node biopsy (SLNB). There was a high rate of negative SLNB findings. The majority of patients were treated with surgery alone (29 of 60), followed by a cohort (21 of 60) treated with surgery plus adjuvant treatment, and 10 of 60 patients were treated with radiation therapy with or without chemotherapy. Recurrence-free survival was 50%, 45%, and 42% at 1, 2, and 5 years.

Conclusions: We report higher recurrence rates and higher negative SLNB result rates than other studies. Our results affirm that imaging may not be a substitute for SLNB and that it had an intermediate ability to identify the occult disease. Traditional predictors, including SLNB and cervical node pathology, may not identify patients at risk for recurrence in HN-MCC. We report similar recurrence rates in patients who had treatment of the cervical nodes by radiation therapy or neck dissection as compared with those who did not receive neck treatment.
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http://dx.doi.org/10.1177/0194599820913622DOI Listing
August 2020

Ultrasound detects synovitis in replaced and other surgically operated joints in rheumatoid arthritis patients.

BMC Rheumatol 2020 3;4. Epub 2020 Feb 3.

1Department of Medicine, Division of Rheumatology, University of California, Los Angeles, CA USA.

Background: Joint replacements continue to occur during a rheumatoid arthritis (RA) patient's lifetime despite significant advances in available treatment options. The purpose of this study was to examine and quantify synovitis in surgically operated joints by ultrasound (US) in RA patients starting a new therapeutic agent.

Methods: RA subjects were enrolled in either tocilizumab or tofacitinib open-label, investigator-initiated trials and were assessed by ultrasound. In a subset of RA patients with joint replacements and/or operations of joint areas (OJA; e.g. joint arthroscopies, fusions, and synovectomies), joint-level scores of synovitis were compared between replaced joints, OJAs, and native joints. Joint-level synovitis was measured by grayscale (GSUS (0-3)) and power Doppler (PDUS (0-3)) at baseline and follow-up (3-6 months). McNemar's test or Wilcoxon signed rank test utilized the mixed effects ordinal logistic regression models.

Results: Twenty RA patients had a total of 25 replaced joints and 24 OJA. All replaced joints had GSUS> 1 and 92% had PDUS> 1 at baseline, while OJA and native joints had lower evidence of GSUS> 1 (37.5, 38% respectively) and PDUS> 1 (45.8, 62% respectively). GSUS and PDUS semiquantitative scores improved significantly with treatment in replaced joints ( = 0.01,  = 0.007), and native joints ( < 0.001 both), but not OJA.

Conclusions: In RA, joint replacement does not eliminate or prevent ultrasound measured synovitis, where all replaced joints have some evidence of US synovitis. US can also act as a potential marker of response to therapy in replaced joints. Scoring US synovitis in replaced joints should be considered in ultrasound RA clinical trials.

Trial Registration: ClinicalTrials.gov NCT01717859 (registered 10/31/2012); ClinicalTrials.gov NCT02321930 (registered 12/22/2014).
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http://dx.doi.org/10.1186/s41927-019-0107-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996180PMC
February 2020

An IL-18-centered inflammatory network as a biomarker for cerebral white matter injury.

PLoS One 2020 24;15(1):e0227835. Epub 2020 Jan 24.

Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States of America.

Chronic systemic sterile inflammation is implicated in the pathogenesis of cerebrovascular disease and white matter injury. Non-invasive blood markers for risk stratification and dissection of inflammatory molecular substrates in vivo are lacking. We sought to identify whether an interconnected network of inflammatory biomarkers centered on IL-18 and all previously associated with white matter lesions could detect overt and antecedent white matter changes in two populations at risk for cerebral small vessel disease. In a cohort of 167 older adults (mean age: 76, SD 7.1, 83 females) that completed a cognitive battery, physical examination, and blood draw in parallel with MR imaging including DTI, we measured cerebral white matter hyperintensities (WMH) and free water (FW). Concurrently, serum levels of a biologic network of inflammation molecules including MPO, GDF-15, RAGE, ST2, IL-18, and MCP-1 were measured. The ability of a log-transformed population mean-adjusted inflammatory composite score (ICS) to associate with MR variables was demonstrated in an age and total intracranial volume adjusted model. In this cohort, ICS was significantly associated with WMH (β = 0.222, p = 0.013), FW (β = 0.3, p = 0.01), and with the number of vascular risk factor diagnoses (r = 0.36, p<0.001). In a second cohort of 131 subjects presenting for the evaluation of acute neurologic deficits concerning for stroke, we used serum levels of 11 inflammatory biomarkers in an unbiased principal component analysis which identified a single factor significantly associated with WMH. This single factor was strongly correlated with the six component ICS identified in the first cohort and was associated with WMH in a generalized linear regression model adjusted for age and gender (p = 0.027) but not acute stroke. A network of inflammatory molecules driven by IL-18 is associated with overt and antecedent white matter injury resulting from cerebrovascular disease and may be a promising peripheral biomarker for vascular white matter injury.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227835PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980497PMC
April 2020

Comparing NGS and NanoString platforms in peripheral blood mononuclear cell transcriptome profiling for advanced heart failure biomarker development.

J Biol Methods 2020 3;7(1):e123. Epub 2020 Jan 3.

David Geffen School of Medicine, University of California Los Angeles Medical Center, Los Angeles, CA 90095, USA.

In preparation to create a clinical assay that predicts 1-year survival status of advanced heart failure (AdHF) patients before surgical/interventional therapies and to select the appropriate clinical assay platform for the future assay, we compared the properties of next generation sequencing (NGS) used in the gene discovery phase to the NanoString platform used in the clinical assay development phase. In 25 AdHF patients in a tertiary academic medical center from 2015 to 2016, PBMC samples were collected and aliquoted for NGS RNA whole transcriptome sequencing and compared to 770 genes represented on NanoString's PanCancer IO 360 Gene Expression research panel. Prior to statistical analysis, NanoString and NGS expression values were log transformed. We computed Pearson correlation coefficients for each sample, comparing gene expression values between NanoString and NGS across the set of matched genes and for each of the matched genes across the set of samples. Genes were grouped by average NGS expression, and the NanoString-NGS correlation for each group was computed. Out of 770 genes from the NanoString panel, 734 overlapped between both platforms and showed high intrasample correlation. Within an individual sample, there was an expression-level dependent correlation between both platforms. The low- . intermediate/high-expression groups showed NGS average correlation 0.21 . 0.58-0.68, respectively, and NanoString average correlation 0.07-0.34 . 0.59-0.70, respectively. NanoString demonstrated high reproducibility ( > 0.99 for 100 ng input), sensitivity (probe counts between 100 and 500 detected and quantified), and robustness (similar gene signature scores across different RNA input concentrations, cartridges, and outcomes). Data from NGS and NanoString were highly correlated. These platforms play a meaningful, complementary role in the biomarker development process.
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http://dx.doi.org/10.14440/jbm.2020.300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974694PMC
January 2020

Receipt of Corrective Lenses and Academic Performance of Low-Income Students.

Acad Pediatr 2020 Sep - Oct;20(7):910-916. Epub 2020 Jan 9.

Department of Pediatrics and Children's Discovery & Innovation Institute, David Geffen School of Medicine at UCLA and UCLA Mattel Children's Hospital (RN Dudovitz, W Slusser, and PJ Chung); UCLA Fielding School of Public Health (W Slusser and PJ Chung); RAND Health, RAND Corporation (PJ Chung), Santa Monica, Calif. Dr Chung is now with the Health Systems Science, Kaiser Permanente School of Medicine and Pediatrics and Health Policy & Management, UCLA, Los Angeles, Calif.

Objective: Untreated vision problems are associated with poor school performance. Whether providing glasses alone improves performance, however, remains unknown. We sought to test whether receiving glasses was associated with improved school performance for low-income minority students in Los Angeles.

Methods: From 2017 to 2018, we analyzed achievement marks in mathematics and language arts from 406 first to fifth grade students attending 24 public elementary schools who received glasses through a free school-based vision program between February and May 2014, and 23,393 of their nonparticipating same-school, same-grade peers. We calculated students' percentile rank during each grading period in 1 year before and 2 years since they received glasses. Multilevel linear regressions tested whether percentile rank differed from baseline at each subsequent grading period. Models accounted for clustering at the school level and controlled for gender, grade level, and baseline class rank. Interaction terms tested whether associations differed by gender and class rank.

Results: Students increased 4.5 percentile points (P = .02) in language arts in the second year after receiving glasses. There was no change in math achievement overall; however, those with baseline performance in the bottom tercile had an immediate and sustained improvement of 10 to 24 percentile points from baseline (interaction term P < .001). Class rank for behavior marks decreased during the fourth grading period after receiving glasses but subsequently returned to baseline. There were no significant changes in work habits and no variation in results by gender.

Conclusions: Ensuring access to vision care may be a simple, scalable strategy to improve language arts performance for low-income minority children.
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http://dx.doi.org/10.1016/j.acap.2020.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343614PMC
January 2020