Publications by authors named "John Barnard"

150 Publications

Does Medicaid Cover Penile Prosthesis Surgery? A State-by-State Analysis.

J Sex Med 2021 08 8;18(8):1455-1460. Epub 2021 Jul 8.

University of California, Irvine School of Medicine, Department of Urology, Orange, CA, USA.

Background: Malleable [MPP] and inflatable [IPP] penile prosthesis surgery for the management of erectile dysfunction is a reliable treatment option with high success rates and excellent patient satisfaction; however, Medicaid coverage transparency is poor leaving a knowledge gap in this population.

Aim: The present study seeks to assess Medicaid coverage for MPP and IPP by state as evidenced by inclusion in publicly available physician fee schedules.

Methods: State Medicaid websites were utilized to access public physician fee schedules. Individual search queries were performed for CPT codes 54400 and 54405 which represent insertion of MPP and IPP, respectively. Data were recorded for each device, including the coverage status, physician fees, and the presence of clear documentation of a prior authorization requirement.

Outcomes: Medicaid physician fee schedules were accessible for 49 out of 50 US states, and 28 states reported coverage for at least one type of penile prosthesis.

Results: Two states reported coverage for MPP only, one state reported coverage for IPP only, and 24 states reported coverage for both devices. One state reported that it did not cover either device, but listed coverage for a self-contained IPP (CPT 54401) only. Mean physician reimbursement was $477.15 (290.82-$1175.50) for MPP placement and $691.76 (421.68-$1794.27) for IPP. Eleven states documented prior authorization requirements within their fee schedules, while the remaining 17 states did not. Criteria for approval for prior authorization were not clearly stated in any fee schedule.

Clinical Implications: Efforts to clearly document approval criteria and educate Men's Health providers on available coverage could result in a significant improvement in sexual satisfaction in the Medicaid population.

Strengths And Limitations: Graphical representation of states offering Medicaid penile prosthetic coverage and physician reimbursement ranges are provided with comparison to Medicare rates. Limitations include heterogeneity in fee schedules, lack of prior authorization requirement details, inability to correlate to successful claims data, and the evolving nature of Medicaid coverage for the given procedures.

Conclusions: Medicaid coverage exists for penile prosthetic surgery in 28 states, although often with significant, non-transparent prior authorization criteria. Barnard JT, Grimaud L, Yafi FA. Does Medicaid Cover Penile Prosthesis Surgery? A State-by-State Analysis. J Sex Med 2021;18:1455-1460.
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http://dx.doi.org/10.1016/j.jsxm.2021.05.010DOI Listing
August 2021

Genetic variant in 3' untranslated region of the mouse gene regulates inflammasome activity.

Elife 2021 07 1;10. Epub 2021 Jul 1.

Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, United States.

Quantitative trait locus mapping for interleukin-1β release after inflammasome priming and activation was performed on bone-marrow-derived macrophages (BMDM) from an AKRxDBA/2 mouse strain intercross. The strongest associated locus mapped very close to the gene on chromosome 7, which codes for the inflammasome adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC). The DBA/2 and AKR genes only differ at a single-nucleotide polymorphism (SNP) in their 3' untranslated region (UTR). DBA/2 vs. AKR BMDM had increased levels of mRNA expression and ASC protein, and increased inflammasome speck formation, which was associated with increased mRNA stability without an increased transcription rate. CRISPR/Cas9 gene editing was performed on DBA/2 embryonic stem cells to change the 3'UTR SNP from the DBA/2 to the AKR allele. This single base change significantly reduced expression and inflammasome activity after cells were differentiated into macrophages due to reduced mRNA stability.
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http://dx.doi.org/10.7554/eLife.68203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248980PMC
July 2021

Technological Advances in Penile Implant Surgery.

J Sex Med 2021 07 25;18(7):1158-1166. Epub 2021 Jun 25.

Department of Urology, University of California Irvine, CA, USA. Electronic address:

Background: During the last century, surgical management of erectile dysfunction has evolved from an experimental concept to a core treatment modality with widespread use among the men's health community. Over time, innovations in materials, mechanical design elements, device coatings, and surgical technique have provided patients with low-risk, reliable, and reproducible erectile function with high satisfaction rates.

Aim: To provide a foundation for future innovation by improving understanding of historical penile prosthetics and the rationale behind incremental technological improvements for the contemporary Men's Health physician.

Methods: Literature review was conducted to generate a comprehensive review of historical technological innovations in penile implant surgery. Companies with FDA approved penile prosthetics in use in the United States were contacted for information regarding technological innovations in the past and future devices in development. A separate literature review was performed to identify any significant future device design elements being tested, even in the ex vivo setting, which may have future clinical applications.

Outcomes: Technological innovations in penile implant surgery were described.

Results: Current options for the prosthetic surgeon include malleable penile prostheses (MPP), self-contained (2-piece) inflatable penile prostheses, and multicomponent (3-piece) inflatable penile prostheses. Current MPPs consist of a synthetic coated solid core which allow for manipulation of the penis for concealability while maintaining sufficient axial rigidity to achieve penetration when desired. Multi-component (3-Piece) IPPs currently include the Coloplast Titan and Boston Scientific/AMS 700 which consist of a fluid reservoir, intrascrotal pump, and intracavernosal cylinders. The devices have undergone numerous design updates to the cylinders, pump, reservoir, tubing, and external coatings to increase reliability and decrease short- and long-term complications.

Clinical Implications: Future innovations in penile prosthetic surgery seek to broaden the indications and applicability to the transgender community and improve both safety and functionality for patient and partner.

Strengths & Limitations: The review is limited primarily to penile prosthetics approved for current or historical clinical use in the United States and may not be representative of the global prosthetic environment. Additionally, the research and development of future innovations, particularly those provided by device manufacturers, is likely limited by non-disclosure to maintain a competitive advantage.

Conclusions: Penile prosthetic surgery will undoubtedly remain integral to the treatment of erectile dysfunction, and education regarding the current state of technological innovation will empower the prosthetic surgeon and biomedical engineering community to improve contemporary patient care and drive the development of the next generation of implantable penile prosthetics. Barnard JT, Cakir OO, Ralph D, et al. Technological Advances in Penile Implant Surgery. J Sex Med 2021;18:1158-1166.
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http://dx.doi.org/10.1016/j.jsxm.2021.04.011DOI Listing
July 2021

Increased Incidence of Venous Thromboembolism with Cancer Immunotherapy.

Med (N Y) 2021 Apr 12;2(4):423-434. Epub 2021 Mar 12.

Department of Hematology & Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.

Background: Cancer immunotherapy is associated with several immune-related adverse events, but the relationship between immunotherapy and venous thromboembolism has not been thoroughly studied.

Methods: We conducted a retrospective cohort study of 1,686 patients who received immunotherapy for a variety of malignancies to determine the incidence of venous thromboembolism and the impact of venous thromboembolism on survival. To examine the potential role of inflammation in venous thromboembolism, we also profiled immune cells and plasma cytokines in blood samples obtained prior to initiation of immunotherapy in a sub-cohort of patients treated on clinical trials who subsequently did (N = 15), or did not (N = 10) develop venous thromboembolism.

Findings: Venous thromboembolism occurred while on immunotherapy in 404/1686 patients (24%) and was associated with decreased overall survival [HR=1.22 (95% CI 1.06-1.41), p<0.008]. Patients that developed venous thromboembolism had significantly higher pretreatment levels of myeloid-derived suppressor cells (5.382 ± 0.873 vs. 3.341 ± 0.3402, mean ± SEM; p=0.0045), interleukin 8 (221.2 ± 37.53 vs. 111.6 ± 25.36, mean ± SEM; p=0.016), and soluble vascular cell adhesion protein 1 (1210 ± 120.6 vs. 895.5 ± 53.34, mean ± SEM; p=0.0385).

Conclusions: These findings demonstrate that venous thromboembolism is an underappreciated and important immune-related adverse event associated with cancer immunotherapy, and may implicate an interleukin 8 and myeloid-derived suppressor cell-driven pathway in pathogenesis.
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http://dx.doi.org/10.1016/j.medj.2021.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143033PMC
April 2021

Evaporation and propagation of liquid drop streams at vacuum pressures: Experiments and modeling.

Phys Rev E 2021 Apr;103(4-1):043105

Los Alamos, National Laboratory, Los Alamos, New Mexico 87545, USA.

Evaporation of streams of liquid droplets in environments at vacuum pressures below the vapor pressure has not been widely studied. Here, experiments and simulations are reported that quantify the change in droplet diameter when a steady stream of ≈100 μm diameter drops is injected into a chamber initially evacuated to <10^{-8}bar. In experiments, droplets fall through the center of a 0.8 m long liquid nitrogen cooled shroud, simulating infinity radiation and vapor mass flux boundary conditions. Experimentally measured changes in drop diameters vary from ≈0 to 6 μm when the initial vapor pressure is increased from 10^{-6} to 10^{-3} bar by heating the liquid. Measured diameter changes are predicted by a model based on the Hertz-Knudsen equation. One uncertainty in the calculation is the "sticking coefficient" β. Assuming a constant β for all conditions studied here, predicted diameter changes best match measurements with β≈0.3. This value falls within the range of β reported in the literature for organic liquids. Finally, at the higher vapor pressure conditions considered here, the drop stream disperses transverse to the main flow direction. This spread is attributed to forces imparted by an absolute pressure gradient produced by the evaporating stream.
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http://dx.doi.org/10.1103/PhysRevE.103.043105DOI Listing
April 2021

NHLBI-CMREF Workshop Report on Pulmonary Vascular Disease Classification: JACC State-of-the-Art Review.

J Am Coll Cardiol 2021 Apr;77(16):2040-2052

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

The National Heart, Lung, and Blood Institute and the Cardiovascular Medical Research and Education Fund held a workshop on the application of pulmonary vascular disease omics data to the understanding, prevention, and treatment of pulmonary vascular disease. Experts in pulmonary vascular disease, omics, and data analytics met to identify knowledge gaps and formulate ideas for future research priorities in pulmonary vascular disease in line with National Heart, Lung, and Blood Institute Strategic Vision goals. The group identified opportunities to develop analytic approaches to multiomic datasets, to identify molecular pathways in pulmonary vascular disease pathobiology, and to link novel phenotypes to meaningful clinical outcomes. The committee suggested support for interdisciplinary research teams to develop and validate analytic methods, a national effort to coordinate biosamples and data, a consortium of preclinical investigators to expedite target evaluation and drug development, longitudinal assessment of molecular biomarkers in clinical trials, and a task force to develop a master clinical trials protocol for pulmonary vascular disease.
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http://dx.doi.org/10.1016/j.jacc.2021.02.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065203PMC
April 2021

Type 2 Diabetes Subtype Responsive to ACCORD Intensive Glycemia Treatment.

Diabetes Care 2021 Apr 16. Epub 2021 Apr 16.

Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH

Objective: Current type 2 diabetes (T2D) management contraindicates intensive glycemia treatment in patients with high cardiovascular disease (CVD) risk and is partially motivated by evidence of harms in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Heterogeneity in response to intensive glycemia treatment has been observed, suggesting potential benefit for some individuals.

Research Design And Methods: ACCORD was a randomized controlled trial that investigated whether intensively treating glycemia in individuals with T2D would reduce CVD outcomes. Using a novel approach to cluster HbA trajectories, we identified groups in the intensive glycemia arm with modified CVD risk. Genome-wide analysis and polygenic score (PS) were developed to predict group membership. Mendelian randomization was performed to infer causality.

Results: We identified four clinical groupings in the intensive glycemia arm, and clinical group 4 (C4) displayed fewer CVD (hazard ratio [HR] 0.34; 2.01 × 10) and microvascular outcomes (HR 0.86; 0.015) than those receiving standard treatment. A single-nucleotide polymorphism, rs220721, in reached suggestive significance in C4 ( 4.34 10). PS predicted C4 with high accuracy (area under the receiver operating characteristic curve 0.98), and this predicted C4 displayed reduced CVD risk with intensive versus standard glycemia treatment (HR 0.53; 4.02 × 10), but not reduced risk of microvascular outcomes ( 0.05). Mendelian randomization indicated causality between PS, on-trial HbA, and reduction in CVD outcomes ( 0.05).

Conclusions: We found evidence of a T2D clinical group in ACCORD that benefited from intensive glycemia treatment, and membership in this group could be predicted using genetic variants. This study generates new hypotheses with implications for precision medicine in T2D and represents an important development in this landmark clinical trial warranting further investigation.
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http://dx.doi.org/10.2337/dc20-2700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247498PMC
April 2021

COVID-19 and Cardiovascular Disease: From Bench to Bedside.

Circ Res 2021 04 15;128(8):1214-1236. Epub 2021 Apr 15.

Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.L.).

A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection worldwide. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.
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http://dx.doi.org/10.1161/CIRCRESAHA.121.317997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048382PMC
April 2021

Current practices regarding corporotomy localization during penoscrotal inflatable penile implant surgery: a multicenter cohort study.

Int J Impot Res 2021 Apr 12. Epub 2021 Apr 12.

Jessa Hospital, Hasselt, Belgium.

Literature concerning corporotomy location in multicomponent inflatable penile prosthetic surgery via a penoscrotal approach is scarce if not nonexistent. Aim of our study was to report practices in low-, moderate-, and high-volume penile implant centers regarding corporotomy location and evaluate its potential impact on intraoperative and short-term postoperative complications. Data from 18 (13 European and 5 American) implant centers were collected retrospectively between September 1st, 2018 and August 31st, 2019. Variables included: intraoperative proximal and distal corpus cavernosum length measurement, total corporal length measurement, total penile implant cylinder length, and length of rear tip extenders. Eight hundred and nine virgin penile implant cases were included in the analysis. Mean age of participants was 61.5 ± 9.6 years old. In total, 299 AMS 700™ (Boston Scientific, USA) and 510 Coloplast Titan® (Minneapolis, MN USA) devices were implanted. The mean proximal/distal corporal measurement ratio during corporotomy was 0.93 ± 0.29 while no statistical difference was found among low-, moderate-, and high-volume penile implant centers. A statistically significant correlation between lower proximal/distal measurement ratio and higher age (p = 0.0013), lower BMI (p < 0.0001), lower use of rear tip extenders (RTE) (p = 0.04), lower RTE length (p < 0.0001), and absence of diabetes (p = 0.0004) was reported. In a 3-month follow up period, 49 complications and 37 revision procedures were reported. This is the first study reporting the current practices regarding corporotomy location during IPP placement in a multicenter cohort, particularly when including such a high number of patients. Nevertheless, the retrospective design and the short follow up period limits the study outcomes. Corporotomy location during penoscrotal IPP implantation does not correlate with intraoperative or short-term postoperative complication rates. Future studies with longer follow up are needed in order to evaluate the association of corporotomy location with long-term complications.
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http://dx.doi.org/10.1038/s41443-021-00431-wDOI Listing
April 2021

Robust, flexible, and scalable tests for Hardy-Weinberg equilibrium across diverse ancestries.

Genetics 2021 May;218(1)

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.
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http://dx.doi.org/10.1093/genetics/iyab044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128395PMC
May 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Atrial fibrillation rhythm is associated with marked changes in metabolic and myofibrillar protein expression in left atrial appendage.

Pflugers Arch 2021 03 16;473(3):461-475. Epub 2021 Jan 16.

Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, 9500 Euclid Avenue, M/S ND50, Cleveland, OH, 44195, USA.

Atrial fibrillation (AF) is strongly associated with risk of stroke and heart failure. AF promotes atrial remodeling that increases risk of stroke due to left atrial thrombogenesis, and increases energy demand to support high rate electrical activity and muscle contraction. While many transcriptomic studies have assessed AF-related changes in mRNA abundance, fewer studies have assessed proteomic changes. We performed a proteomic analysis on left atrial appendage (LAA) tissues from 12 patients with a history of AF undergoing elective surgery; atrial rhythm was documented at time of surgery. Proteomic analysis was performed using liquid chromatography with mass spectrometry (LC/MS-MS). Data-dependent analysis identified 3090 unique proteins, with 408 differentially expressed between sinus rhythm and AF. Ingenuity Pathway Analysis of differentially expressed proteins identified mitochondrial dysfunction, oxidative phosphorylation, and sirtuin signaling among the most affected pathways. Increased abundance of electron transport chain (ETC) proteins in AF was accompanied by decreased expression of ETC complex assembly factors, tricarboxylic acid cycle proteins, and other key metabolic modulators. Discordant changes were also evident in the contractile unit with both up and downregulation of key components. Similar pathways were affected in a comparison of patients with a history of persistent vs. paroxysmal AF, presenting for surgery in sinus rhythm. Together, these data suggest that while the LAA attempts to meet the energetic demands of AF, an uncoordinated response may reduce ATP availability, contribute to tissue contractile and electrophysiologic heterogeneity, and promote a progression of AF from paroxysmal episodes to development of a substrate amenable to persistent arrhythmia.
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http://dx.doi.org/10.1007/s00424-021-02514-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940600PMC
March 2021

Validation of International Working Group response criteria in higher-risk myelodysplastic syndromes: A report on behalf of the MDS Clinical Research Consortium.

Cancer Med 2021 01 22;10(2):447-453. Epub 2020 Dec 22.

Leukemia Program, Cleveland Clinic, Cleveland, OH, USA.

The utility of the International Working Group (IWG) 2006 response criteria for myelodysplastic syndromes (MDS) as a surrogate endpoint for outcomes is unclear. We assessed the validity of the IWG 2006 response criteria in a large cohort of higher-risk MDS patients (pts) treated at centers from the MDS Clinical Research Consortium. The best overall response rate (ORR) by IWG 2006 criteria to first-line therapy among 597 evaluable pts was 38% and include complete response (CR) 16%, marrow CR (mCR) 2%, partial response (PR) 10%, hematological improvement (HI) 10%, stable disease (SD) 33%, and progressive disease (PD) 24%. CR was associated with a better overall survival (OS) compared to all other response groups (P < 0.001). Among 470 pts treated with hypomethylating agent (HMA) as first-line therapy, the overall Response Rate, defined as HI or better was 39%. The median OS from time of best response was 21 mo, 8 mo, 14 mo, 12 mo, 13 mo, and 8 mo for CR, mCR, PR, HI, SD, and PD, respectively (P < 0.001). We validated those results in a separate cohort of 539 higher-risk MDS pts treated at Moffitt Cancer Center who received first-line HMA therapy, particularly addressing the value of mCR and mCR+HI. mCR alone without HI, SD, and PD outcomes were inferior to CR, PR, mCR+HI, and HI. In conclusion, CR by IWG 2006 response criteria can be used as a surrogate endpoint for OS in higher-risk MDS pts. Any response associated with restoration of effective hematopoiesis is associated with better outcome.
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http://dx.doi.org/10.1002/cam4.3608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877342PMC
January 2021

Characterization of heterogeneous primary human cartilage-derived cell population using non-invasive live-cell phase-contrast time-lapse imaging.

Cytotherapy 2021 Jun 20;23(6):488-499. Epub 2020 Oct 20.

Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA; Department of Orthopedic Surgery, Cleveland Clinic, Cleveland, Ohio, USA.

Reliable and reproducible cell therapy strategies to treat osteoarthritis demand an improved characterization of the cell and heterogeneous cell population resident in native cartilage tissue. Using live-cell phase-contrast time-lapse imaging (PC-TLI), this study investigates the morphological attributes and biological performance of the three primary biological objects enzymatically isolated from primary human cartilage: connective tissue progenitors (CTPs), non-progenitors (NPs) and multi-cellular structures (MCSs). The authors' results demonstrated that CTPs were smaller in size in comparison to NPs (P < 0.001). NPs remained part of the adhered cell population throughout the cell culture period. Both NPs and CTP progeny on day 8 increased in size and decreased in circularity in comparison to their counterparts on day 1, although the percent change was considerably less in CTP progeny (P < 0.001). PC-TLI analyses indicated three colony types: single-CTP-derived (29%), multiple-CTP-derived (26%) and MCS-derived (45%), with large heterogeneity with respect to cell morphology, proliferation rate and cell density. On average, clonal (CL) (P = 0.009) and MCS (P = 0.001) colonies exhibited higher cell density (cells per colony area) than multi-clonal (MC) colonies; however, it is interesting to note that the behavior of CL (less cells per colony and less colony area) and MCS (high cells per colony and high colony area) colonies was quite different. Overall effective proliferation rate (EPR) of the CTPs that formed CL colonies was higher than the EPR of CTPs that formed MC colonies (P = 0.02), most likely due to CTPs with varying EPR that formed the MC colonies. Finally, the authors demonstrated that lag time before first cell division of a CTP (early attribute) could potentially help predict its proliferation rate long-term. Quantitative morphological characterization using non-invasive PC-TLI serves as a reliable and reproducible technique to understand cell heterogeneity. Size and circularity parameters can be used to distinguish CTP from NP populations. Morphological cell and colony features can also be used to reliably and reproducibly identify CTP subpopulations with preferred proliferation and differentiation potentials in an effort to improve cell manufacturing and therapeutic outcomes.
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http://dx.doi.org/10.1016/j.jcyt.2020.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053735PMC
June 2021

Computerized Adaptive Tests: Efficient and Precise Assessment of the Patient-Centered Impact of Diabetic Retinopathy.

Transl Vis Sci Technol 2020 06 3;9(7). Epub 2020 Jun 3.

Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

Purpose: Evaluate efficiency, precision, and validity of RetCAT, which comprises ten diabetic retinopathy (DR) quality of life (QoL) computerized adaptive tests (CATs).

Methods: In this cross-sectional clinical study, 183 English and/or Mandarin-speaking participants with DR (mean age ± standard deviation [SD] 56.4 ± 11.9 years; 38% proliferative DR [worse eye]) were recruited from retinal clinics in Singapore. Participants answered the RetCAT tests (Symptoms, Activity Limitation, Mobility, Emotional, Health Concerns, Social, Convenience, Economic, Driving, and Lighting), which were capped at seven items each, and other questionnaires, and underwent eye tests. Our primary evaluation focused on RetCAT efficiency (i.e. standard error of measurement [SEM] ± SD achieved and time needed to complete each CAT). Secondary evaluations included an assessment of RetCAT's test precision and validity.

Results: Mean SEM across all RetCAT tests was 0.351, ranging from 0.272 ± 0.130 for Economic to 0.484 ± 0.130 for Emotional. Four tests (Mobility, Social, Convenience, and Driving) had a high level of measurement error. The median time to take each RetCAT test was 1.79 minutes, ranging from 1.12 (IQR [interquartile range] 1.63) for Driving to 3.28 (IQR 2.52) for Activity Limitation. Test precision was highest for participants at the most impaired end of the spectrum. Most RetCAT tests displayed expected correlations with other scales (convergent/divergent validity) and were sensitive to DR and/or vision impairment severity levels (criterion validity).

Conclusions: RetCAT can provide efficient, precise, and valid measurement of DR-related QoL impact. Future application of RetCAT will employ a stopping rule based on SE rather than number of items to ensure that all tests can detect meaningful differences in person abilities. Responsiveness of RetCAT to treatment interventions must also be determined.

Translational Relevance: RetCAT may be useful for measuring the patient-centered impact of DR severity and disease progression and evaluating the effectiveness of new therapies.
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http://dx.doi.org/10.1167/tvst.9.7.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414626PMC
June 2020

SARS-CoV-2 and ACE2: The biology and clinical data settling the ARB and ACEI controversy.

EBioMedicine 2020 Aug 6;58:102907. Epub 2020 Aug 6.

Heart, Vascular and Thoracic Institute, United States; Cleveland Clinic Lerner College of Medicine, United States; Case Western Reserve University, United States.

Background: SARS-CoV-2 enters cells by binding of its spike protein to angiotensin-converting enzyme 2 (ACE2). Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) have been reported to increase ACE2 expression in animal models, and worse outcomes are reported in patients with co-morbidities commonly treated with these agents, leading to controversy during the COVID-19 pandemic over whether these drugs might be helpful or harmful.

Methods: Animal, in vitro and clinical data relevant to the biology of the renin-angiotensin system (RAS), its interaction with the kallikrein-kinin system (KKS) and SARS-CoV-2, and clinical studies were reviewed.

Findings And Interpretation: SARS-CoV-2 hijacks ACE2to invade and damage cells, downregulating ACE2, reducing its protective effects and exacerbating injurious Ang II effects. However, retrospective observational studies do not show higher risk of infection with ACEI or ARB use. Nevertheless, study of the RAS and KKS in the setting of coronaviral infection may yield therapeutic targets.
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http://dx.doi.org/10.1016/j.ebiom.2020.102907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415847PMC
August 2020

Machine Learning of 12-Lead QRS Waveforms to Identify Cardiac Resynchronization Therapy Patients With Differential Outcomes.

Circ Arrhythm Electrophysiol 2020 07 14;13(7):e008210. Epub 2020 Jun 14.

Cleveland Clinic Lerner College of Medicine (A.K.F., N.V., M.J.N., E.Z.G., R.A.G., J.B., M.K.C.), Case Western Reserve University, Cleveland, OH.

Background: Cardiac resynchronization therapy (CRT) improves heart failure outcomes but has significant nonresponse rates, highlighting limitations in ECG selection criteria: QRS duration (QRSd) ≥150 ms and subjective labeling of left bundle branch block (LBBB). We explored unsupervised machine learning of ECG waveforms to identify CRT subgroups that may differentiate outcomes beyond QRSd and LBBB.

Methods: We retrospectively analyzed 946 CRT patients with conduction delay. Principal component analysis (PCA) dimensionality reduction obtained a 2-dimensional representation of preCRT 12-lead QRS waveforms. -means clustering of the 2-dimensional PCA representation of 12-lead QRS waveforms identified 2 patient subgroups (QRS PCA groups). Vectorcardiographic QRS area was also calculated. We examined following 2 primary outcomes: (1) composite end point of death, left ventricular assist device, or heart transplant, and (2) degree of echocardiographic left ventricular ejection fraction (LVEF) change after CRT.

Results: Compared with QRS PCA Group 2 (=425), Group 1 (=521) had lower risk for reaching the composite end point (HR, 0.44 [95% CI, 0.38-0.53]; <0.001) and experienced greater mean LVEF improvement (11.1±11.7% versus 4.8±9.7%; <0.001), even among patients with LBBB with QRSd ≥150 ms (HR, 0.42 [95% CI, 0.30-0.57]; <0.001; mean LVEF change 12.5±11.8% versus 7.3±8.1%; =0.001). QRS area also stratified outcomes but had significant differences from QRS PCA groups. A stratification scheme combining QRS area and QRS PCA group identified patients with LBBB with similar outcomes to non-LBBB patients (HR, 1.32 [95% CI, 0.93-1.62]; difference in mean LVEF change: 0.8% [95% CI, -2.1% to 3.7%]). The stratification scheme also identified patients with LBBB with QRSd <150 ms with comparable outcomes to patients with LBBB with QRSd ≥150 ms (HR, 0.93 [95% CI, 0.67-1.29]; difference in mean LVEF change: -0.2% [95% CI, -2.7% to 3.0%]).

Conclusions: Unsupervised machine learning of ECG waveforms identified CRT subgroups with relevance beyond LBBB and QRSd. This method may assist in objective classification of bundle branch block morphology in CRT.
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http://dx.doi.org/10.1161/CIRCEP.119.008210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901121PMC
July 2020

Hypomethylating Agent Therapy in Myelodysplastic Syndromes With Chromosome 3 Abnormalities.

Clin Lymphoma Myeloma Leuk 2020 09 20;20(9):e597-e605. Epub 2020 Mar 20.

Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. Electronic address:

Background: Abnormalities of chromosome 3 in myelodysplastic syndromes (MDS), that is, inversion 3 (inv[3]), translocation 3q (t[3q]), or deletion 3q (del[3q]), are defined as poor-risk karyotypes in the Revised International Prognostic Scoring System (IPSS-R). The objective of this study was to further define the outcomes of patients with MDS with chromosome 3 abnormalities and address the impact of hypomethylating agent (HMA) therapy on this patient subset.

Patients And Methods: Through the MDS Clinical Research Consortium, we identified 411 patients with chromosome 3 abnormalities and MDS or oligoblastic acute myeloid leukemia (20%-30% blasts).

Results: Specific chromosome 3 aberrations and cytogenetic complexity were predictive of survival; patients with t(3q) and isolated chromosome 3 had improved overall survival (OS), albeit still poor, whereas patients with complex cytogenetics, including those with 3p abnormalities, had inferior OS. Overall response rates to HMAs among this patient population were similar to those of patients with nonchromosome 3-MDS (52%, with a 25% complete remission rate), although with higher response rates in decitabine-treated patients (69% vs. 45%, P = .008). HMA therapy improved the OS of patients with higher-risk MDS compared with intensive chemotherapy (median OS of 15.5 vs. 8.2 months; P  =  .017). This improvement remained significant in multivariate analyses (hazard ratio, 0.60; P  =  .018); however, there were no chromosome 3 aberrations among this subgroup predictive of improved response rates to or survival from HMAs.

Conclusion: Patients with MDS with chromosome 3 abnormalities represent a cytogenetic cohort with poor OS, and there is an urgent need for novel therapeutic strategies.
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http://dx.doi.org/10.1016/j.clml.2020.03.005DOI Listing
September 2020

Spontaneous Urethral Laceration in a Patient Experiencing Acute Ulcerative Colitis Flare.

Case Rep Urol 2020 5;2020:9285071. Epub 2020 Feb 5.

West Virginia University Health Science Center, USA.

Spontaneous urethral laceration in the female without associated external trauma is an exceedingly rare phenomenon. Most cases are related to childbirth or the presence of a concomitant pelvic fracture or penetrating injury. Herein, we present a novel case of spontaneous urethral laceration in a female which happened to occur during an acute flare of her previously diagnosed ulcerative colitis. The diagnosis of spontaneous urethral laceration is rare, and underlying etiology is often uncertain.
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http://dx.doi.org/10.1155/2020/9285071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025027PMC
February 2020

Genetic Susceptibility for Atrial Fibrillation in Patients Undergoing Atrial Fibrillation Ablation.

Circ Arrhythm Electrophysiol 2020 03 14;13(3):e007676. Epub 2020 Feb 14.

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.B.S., C.S., L.L.R., D.M.C., J.M., Z.Y., Q.W., T.I., P.W., G.M.).

Background: Ablation is a widely used therapy for atrial fibrillation (AF); however, arrhythmia recurrence and repeat procedures are common. Studies examining surrogate markers of genetic susceptibility to AF, such as family history and individual AF susceptibility alleles, suggest these may be associated with recurrence outcomes. Accordingly, the aim of this study was to test the association between AF genetic susceptibility and recurrence after ablation using a comprehensive polygenic risk score for AF.

Methods: Ten centers from the AF Genetics Consortium identified patients who had undergone de novo AF ablation. AF genetic susceptibility was measured using a previously described polygenic risk score (N=929 single-nucleotide polymorphisms) and tested for an association with clinical characteristics and time-to-recurrence with a 3 month blanking period. Recurrence was defined as >30 seconds of AF, atrial flutter, or atrial tachycardia. Multivariable analysis adjusted for age, sex, height, body mass index, persistent AF, hypertension, coronary disease, left atrial size, left ventricular ejection fraction, and year of ablation.

Results: Four thousand two hundred seventy-six patients were eligible for analysis of baseline characteristics and 3259 for recurrence outcomes. The overall arrhythmia recurrence rate between 3 and 12 months was 44% (1443/3259). Patients with higher AF genetic susceptibility were younger (<0.001) and had fewer clinical risk factors for AF (=0.001). Persistent AF (hazard ratio [HR], 1.39 [95% CI, 1.22-1.58]; <0.001), left atrial size (per cm: HR, 1.32 [95% CI, 1.19-1.46]; <0.001), and left ventricular ejection fraction (per 10%: HR, 0.88 [95% CI, 0.80-0.97]; =0.008) were associated with increased risk of recurrence. In univariate analysis, higher AF genetic susceptibility trended towards a higher risk of recurrence (HR, 1.08 [95% CI, 0.99-1.18]; =0.07), which became less significant in multivariable analysis (HR, 1.06 [95% CI, 0.98-1.15]; =0.13).

Conclusions: Higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors but not recurrence. Arrhythmia recurrence after AF ablation may represent a genetically different phenotype compared to AF susceptibility.
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http://dx.doi.org/10.1161/CIRCEP.119.007676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080569PMC
March 2020

Traumatic Bladder Ruptures: A Ten-Year Review at a Level 1 Trauma Center.

Adv Urol 2019 12;2019:2614586. Epub 2019 Dec 12.

West Virginia University Hospitals, Department of Urology, Morgantown, USA.

Bladder rupture occurs in only 1.6% of blunt abdominopelvic trauma cases. Although rare, bladder rupture can result in significant morbidity if undiagnosed or inappropriately managed. AUA Urotrauma Guidelines suggest that urethral catheter drainage is a standard of care for both extraperitoneal and intraperitoneal bladder rupture regardless of the need for surgical repair. However, no specific guidance is given regarding the length of catheterization. The present study seeks to summarize contemporary management of bladder trauma at our tertiary care center, assess the impact of length of catheterization on bladder injuries and complications, and develop a protocol for management of bladder injuries from time of injury to catheter removal. A retrospective review was performed on 34,413 blunt trauma cases to identify traumatic bladder ruptures over the past 10 years (January 2008-January 2018) at our tertiary care facility. Patient data were collected including age, gender, BMI, mechanism of injury, and type of injury. The primary treatment modality (surgical repair vs. catheter drainage only), length of catheterization, and post-injury complications were also assessed. Review of our institutional trauma database identified 44 patients with bladder trauma. Mean age was 41 years, mean BMI was 24.8 kg/m, 95% were Caucasian, and 55% were female. Motor vehicle collision (MVC) was the most common mechanism, representing 45% of total injuries. Other mechanisms included falls (20%) and all-terrain vehicle (ATV) accidents (13.6%). 31 patients had extraperitoneal injury, and 13 were intraperitoneal. Pelvic fractures were present in 93%, and 39% had additional solid organ injuries. Formal cystogram was performed in 59% on presentation, and mean time to cystogram was 4 hours. Gross hematuria was noted in 95% of cases. Operative management was performed for all intraperitoneal injuries and 35.5% of extraperitoneal cases. Bladder closure in operative cases was typically performed in 2 layers with absorbable suture in a running fashion. The intraperitoneal and extraperitoneal injuries managed operatively were compared, and length of catheterization (28 d vs. 22 d, =0.46), time from injury to normal fluorocystogram (19.8 d vs. 20.7 d, =0.80), and time from injury to repair (4.3 vs. 60.5 h, =0.23) were not statistically different between cohorts. Patients whose catheter remained in place for greater than 14 days had prolonged time to initial cystogram (26.6 d vs. 11.5 d) compared with those whose foley catheter was removed within 14 days. The complication rate was 21% for catheters left more than 14 days while patients whose catheter remained less than 14 days experienced no complications. The present study provides a 10-year retrospective review characterizing the presentation, management, and follow-up of bladder trauma patients at our level 1 trauma center. Based on our findings, we have developed an institutional protocol which now includes recommendations regarding length of catheterization after traumatic bladder rupture. By providing specific guidelines for initial follow-up cystogram and foley removal, we hope to decrease patient morbidity from prolonged catheterization. Further study will seek to allow multidisciplinary trauma teams to standardize management, streamline care, and minimize complications for patients presenting with traumatic bladder injuries.
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http://dx.doi.org/10.1155/2019/2614586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930775PMC
December 2019

Genomic Biomarkers to Predict Resistance to Hypomethylating Agents in Patients With Myelodysplastic Syndromes Using Artificial Intelligence.

JCO Precis Oncol 2019 20;3. Epub 2019 Sep 20.

Cleveland Clinic, Cleveland, OH.

Purpose: We developed an unbiased framework to study the association of several mutations in predicting resistance to hypomethylating agents (HMAs) in patients with myelodysplastic syndromes (MDS), analogous to consumer and commercial recommender systems in which customers who bought products A and B are likely to buy C: patients who have a mutation in gene A and gene B are likely to respond or not respond to HMAs.

Methods: We screened a cohort of 433 patients with MDS who received HMAs for the presence of common myeloid mutations in 29 genes that were obtained before the patients started therapy. The association between mutations and response was evaluated by the Apriori market basket analysis algorithm. Rules with the highest confidence (confidence that the association exists) and the highest lift (strength of the association) were chosen. We validated our biomarkers in samples from patients enrolled in the S1117 trial.

Results: Among 433 patients, 193 (45%) received azacitidine, 176 (40%) received decitabine, and 64 (15%) received HMA alone or in combination. The median age was 70 years (range, 31 to 100 years), and 28% were female. The median number of mutations per sample was three (range, zero to nine), and 176 patients (41%) had three or more mutations per sample. Association rules identified several genomic combinations as being highly associated with no response. These molecular signatures were present in 30% of patients with three or more mutations/sample with an accuracy rate of 87% in the training cohort and 93% in the validation cohort.

Conclusion: Genomic biomarkers can identify, with high accuracy, approximately one third of patients with MDS who will not respond to HMAs. This study highlights the importance of machine learning technologies such as the recommender system algorithm in translating genomic data into useful clinical tools.
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http://dx.doi.org/10.1200/po.19.00119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818517PMC
September 2019

Insights From Atrial Fibrillation Genomics: From Bedside to Bench and Back Again.

Cardiol Rev 2019 Nov/Dec;27(6):302-307

Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.

From the bedside of patients contributing samples to large genome-wide association studies for atrial fibrillation (AF), over 100 AF risk loci have been identified. The top locus is near a gene implicated in pulmonary vein formation; the ostia of the pulmonary veins harbor initiating triggers of AF, and isolation of these areas is the cornerstone of ablation therapies for AF. Transcriptomic studies suggest that AF is associated with impaired or overwhelmed responses to cell stress. A dual risk model proposes that in genetically-susceptible individuals, inadequate transcriptional responses to stress predispose to AF in later life. Drugs targeting metabolic, oxidative, or protein handling stress may be novel upstream agents to bring back to the bedside for study in the prevention of AF.
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http://dx.doi.org/10.1097/CRD.0000000000000267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421131PMC
February 2020

Locally Recurrent Leiomyoma of the Bladder Refractory to Visually Complete Transurethral Resection: An Indication for Cystoprostatectomy.

Case Rep Urol 2019 25;2019:1086575. Epub 2019 Aug 25.

West Virginia University, Department of Urology, Morgantown, WV, USA.

Leiomyomas are benign smooth muscle tumors that have low malignant potential (0.1%) and can arise in nearly any area of the body. Genitourinary involvement is very rare and represents only 0.05% of all bladder tumors (Mendes et al., 2017; GÖK, 2017). The most common presenting symptoms of bladder leiomyomas are obstructive voiding (49%), irritative voiding (38%), and hematuria (11%) (Goluboff et al., 1994). Treatment involves complete excision, in this case transurethral resection (TUR), and generally results in complete cure with no recurrences noted in the 250 cases reported in the literature for open resection and 18% recurrence rates after TUR which were successfully treated with a repeat TUR in all cases. Herein, we report a case of leiomyoma of the bladder which was refractory to four visually complete transurethral resections and ultimately required radical cystoprostatectomy with ileal conduit urinary diversion.
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http://dx.doi.org/10.1155/2019/1086575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732623PMC
August 2019

Proteomic Investigations of Autism Brain Identify Known and Novel Pathogenetic Processes.

Sci Rep 2019 09 11;9(1):13118. Epub 2019 Sep 11.

Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, 44195, USA.

Autism Spectrum Disorder (ASD) is a set of heterogeneous neurodevelopmental conditions defined by impairments in social communication and restricted, repetitive behaviors, interests or activities. Only a minority of ASD cases are determined to have a definitive etiology and the pathogenesis of most ASD is poorly understood. We hypothesized that a global analysis of the proteomes of human ASD vs. control brain, heretofore not done, would provide important data with which to better understand the underlying neurobiology of autism. In this study, we characterized the proteomes of two brain regions, Brodmann area 19 (BA19) and posterior inferior cerebellum (CB), from carefully selected idiopathic ASD cases and matched controls using label-free HPLC-tandem mass spectrometry. The data revealed marked differences between ASD and control brain proteomes for both brain regions. Unlike earlier transcriptomic analyses using frontal and temporal cortex, however, our proteomic analysis did not support ASD attenuating regional gene expression differences. Bioinformatic analyses of the differentially expressed proteins between cases and controls highlighted canonical pathways involving glutamate receptor signaling and glutathione-mediated detoxification in both BA19 and CB; other pathways such as Sertoli cell signaling and fatty acid oxidation were specifically enriched in BA19 or CB, respectively. Network analysis of both regions of ASD brain showed up-regulation of multiple pre- and post-synaptic membrane or scaffolding proteins including glutamatergic ion channels and related proteins, up-regulation of proteins involved in intracellular calcium signaling, and down-regulation of neurofilament proteins, with DLG4 and MAPT as major hub proteins in BA19 and CB protein interaction networks, respectively. Upstream regulator analysis suggests neurodegeneration-associated proteins drive the differential protein expression for ASD in both BA19 and CB. Overall, the proteomic data provide support for shared dysregulated pathways and upstream regulators for two brain regions in human ASD brain, suggesting a common ASD pathophysiology that has distinctive regional expression.
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http://dx.doi.org/10.1038/s41598-019-49533-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739414PMC
September 2019

Use of Cadaveric Pericardial Tissue in the Surgical Treatment of Neurogenic Bladder.

Case Rep Urol 2019 15;2019:6182397. Epub 2019 Jul 15.

West Virginia University School of Medicine, Morgantown, WV 26506, USA.

The surgical treatments for neurogenic bladder are extremely variable. The lack of specific treatment guidelines makes this disease process even more challenging to treat. We present a case of a 55-year-old female with neurogenic bladder secondary to spinal cord injury (SCI). Her incontinence was conservatively managed with indwelling Foley drainage. Despite continued upsizing of the Foley catheters, the patient continued to have urinary leakage. The patient subsequently underwent a transvaginal bladder neck closure (BNC) with suprapubic bladder neck diversion (SPC). The urethra was successfully closed and uniquely supported with the use of cadaveric pericardial tissue (CPT). This surgical approach of neurogenic bladder provides durable continence with short operative times, minimal patient morbidity, decreased hospital length, and low risk of progressive renal dysfunction. BNC with SPC can provide an excellent management solution for neurogenic bladder from spinal cord injury refractory to conservative management.
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http://dx.doi.org/10.1155/2019/6182397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662501PMC
July 2019

Machine Learning Prediction of Response to Cardiac Resynchronization Therapy: Improvement Versus Current Guidelines.

Circ Arrhythm Electrophysiol 2019 07 20;12(7):e007316. Epub 2019 Jun 20.

Department of Cardiovascular Medicine, Heart and Vascular Institute (J.R., D.P., S.T., K.M.T., N.V., M.J.N., E.Z.G., R.A.G., M.K.C.), Cleveland Clinic, OH.

Background: Cardiac resynchronization therapy (CRT) has significant nonresponse rates. We assessed whether machine learning (ML) could predict CRT response beyond current guidelines.

Methods: We analyzed CRT patients from Cleveland Clinic and Johns Hopkins. A training cohort was created from all Johns Hopkins patients and an equal number of randomly sampled Cleveland Clinic patients. All remaining patients comprised the testing cohort. Response was defined as ≥10% increase in left ventricular ejection fraction. ML models were developed to predict CRT response using different combinations of classification algorithms and clinical variable sets on the training cohort. The model with the highest area under the curve was evaluated on the testing cohort. Probability of response was used to predict survival free from a composite end point of death, heart transplant, or placement of left ventricular assist device. Predictions were compared with current guidelines.

Results: Nine hundred twenty-five patients were included. On the training cohort (n=470: 235, Johns Hopkins; 235, Cleveland Clinic), the best ML model was a naive Bayes classifier including 9 variables (QRS morphology, QRS duration, New York Heart Association classification, left ventricular ejection fraction and end-diastolic diameter, sex, ischemic cardiomyopathy, atrial fibrillation, and epicardial left ventricular lead). On the testing cohort (n=455, Cleveland Clinic), ML demonstrated better response prediction than guidelines (area under the curve, 0.70 versus 0.65; P=0.012) and greater discrimination of event-free survival (concordance index, 0.61 versus 0.56; P<0.001). The fourth quartile of the ML model had the greatest risk of reaching the composite end point, whereas the first quartile had the least (hazard ratio, 0.34; P<0.001).

Conclusions: ML with 9 variables incrementally improved prediction of echocardiographic CRT response and survival beyond guidelines. Performance was not improved by incorporating more variables. The model offers potential for improved shared decision-making in CRT (online calculator: http://riskcalc.org:3838/CRTResponseScore ). Significant remaining limitations confirm the need to identify better variables to predict CRT response.
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http://dx.doi.org/10.1161/CIRCEP.119.007316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588175PMC
July 2019

Nonnucleoside Reverse Transcriptase Inhibitor Hypersusceptibility and Resistance by Mutation of Residue 181 in HIV-1 Reverse Transcriptase.

Antimicrob Agents Chemother 2019 08 25;63(8). Epub 2019 Jul 25.

Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

Substitutions at residue Y181 in HIV-1 reverse transcriptase (RT), in particular, Y181C, Y181I, and Y181V, are associated with nonnucleoside RT inhibitor (NNRTI) cross-resistance. In this study, we used kinetic and thermodynamic approaches, in addition to molecular modeling, to gain insight into the mechanisms by which these substitutions confer resistance to nevirapine (NVP), efavirenz (EFV), and rilpivirine (RPV). Using pre-steady-state kinetics, we found that the dissociation constant ( ) values for inhibitor binding to the Y181C and Y181I RT-template/primer (T/P) complexes were significantly reduced. In the presence of saturating concentrations of inhibitor, the Y181C RT-T/P complex incorporated the next correct deoxynucleoside triphosphate (dNTP) more efficiently than the wild-type (WT) complex, and this phenotype correlated with decreased mobility of the RT on the T/P substrate. Interestingly, we found that the Y181F substitution in RT-which represents a transitional mutation between Y181 and Y181I/V, or a partial revertant-conferred hypersusceptibility to EFV and RPV at both the virus and enzyme levels. EFV and RPV bound more tightly to Y181F RT-T/P. Furthermore, inhibitor-bound Y181F RT-T/P was less efficient than the WT complex in incorporating the next correct dNTP, and this could be attributed to increased mobility of Y181F RT on the T/P substrate. Collectively, our data highlight the key role that Y181 in RT plays in NNRTI binding.
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http://dx.doi.org/10.1128/AAC.00676-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658764PMC
August 2019

Relationship of auditory electrophysiological responses to magnetic resonance spectroscopy metabolites in Early Phase Psychosis.

Int J Psychophysiol 2019 11 23;145:15-22. Epub 2019 May 23.

Department of Psychiatry, Prevention and the Recovery Center for Early Psychosis, Indiana University School of Medicine, Indianapolis, IN, United States of America.

Both auditory evoked responses and metabolites measured by magnetic resonance spectroscopy (MRS) are altered in schizophrenia and other psychotic disorders, but the relationship between electrophysiological and metabolic changes are not well characterized. We examined the relation of MRS metabolites to cognitive and electrophysiological measures in individuals during the early phase of psychosis (EPP) and in healthy control subjects. The mismatch negativity (MMN) of the auditory event-related potential to duration deviant tones and the auditory steady response (ASSR) to 40 Hz stimulation were assessed. MRS was used to quantify glutamate+glutamine (Glx), N-Acetylasparate (NAA), creatine (Cre), myo-inositol (Ins) and choline (Cho) at a voxel placed medially in the frontal cortex. MMN amplitude and ASSR power did not differ between groups. The MRS metabolites Glx, Cre and Cho were elevated in the psychosis group. Partial least squares analysis in the patient group indicated that elevated levels of MRS metabolites were associated with reduced MMN amplitude and increased 40 Hz ASSR power. There were no correlations between the neurobiological measures and clinical measures. These data suggest that elevated neurometabolites early in psychosis are accompanied by altered auditory neurotransmission, possibly indicative of a neuroinflammatory or excitotoxic disturbance which disrupts a wide range of metabolic processes in the cortex.
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http://dx.doi.org/10.1016/j.ijpsycho.2019.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791740PMC
November 2019
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