Publications by authors named "Katherine Wood"

96 Publications

The Role of the U5 snRNP in Genetic Disorders and Cancer.

Front Genet 2021 28;12:636620. Epub 2021 Jan 28.

Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, United Kingdom.

Pre-mRNA splicing is performed by the spliceosome, a dynamic macromolecular complex consisting of five small uridine-rich ribonucleoprotein complexes (the U1, U2, U4, U5, and U6 snRNPs) and numerous auxiliary splicing factors. A plethora of human disorders are caused by genetic variants affecting the function and/or expression of splicing factors, including the core snRNP proteins. Variants in the genes encoding proteins of the U5 snRNP cause two distinct and tissue-specific human disease phenotypes - variants in , , and are associated with retinitis pigmentosa (RP), while variants in and cause the craniofacial disorders mandibulofacial dysostosis Guion-Almeida type (MFDGA) and Burn-McKeown syndrome (BMKS), respectively. Furthermore, recurrent somatic mutations or changes in the expression levels of a number of U5 snRNP proteins (, , , , and ) have been associated with human cancers. How and why variants in ubiquitously expressed spliceosome proteins required for pre-mRNA splicing in all human cells result in tissue-restricted disease phenotypes is not clear. Additionally, why variants in different, yet interacting, proteins making up the same core spliceosome snRNP result in completely distinct disease outcomes - RP, craniofacial defects or cancer - is unclear. In this review, we define the roles of different U5 snRNP proteins in RP, craniofacial disorders and cancer, including how disease-associated genetic variants affect pre-mRNA splicing and the proposed disease mechanisms. We then propose potential hypotheses for how U5 snRNP variants cause tissue specificity resulting in the restricted and distinct human disorders.
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http://dx.doi.org/10.3389/fgene.2021.636620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876476PMC
January 2021

Complete sternal-sparing left ventricular assist device implantation is associated with improved postoperative mobility.

Interact Cardiovasc Thorac Surg 2021 Feb 4. Epub 2021 Feb 4.

Division of Cardiac Surgery, Department of Surgery, University of Rochester, Rochester, NY, USA.

Left ventricular assist device (LVAD) implantation via a complete sternal-sparing (CSS) technique is gaining interest due to several potential benefits. We hypothesized that the CSS approach for HeartMate 3 (HM3) LVAD implantation improves postoperative mobility and physical independence compared to full sternotomy (FS). We retrospectively reviewed patients who were implanted with a commercial HM3 at our institution from September 2017 to August 2018. The Activity Measure for Post-Acute Care short forms and Functional Independence Measure scores were used to assess the patient's physical limitations postoperatively. A total of 43 patients were included in the study: 27 (63%) CSS patients and 16 (37%) FS patients. At postoperative day 3, the CSS cohort demonstrated improved mobility based on Activity Measure for Post-Acute Care scores compared to the FS group; 40% of the CSS cohort versus 67% of the FS cohort remained 100% impaired. The CSS cohort also demonstrated greater postoperative independence in the Functional Independence Measure sit-to-stand metric with 78% of the CSS cohort achieving modified or complete independence by postoperative day 15 compared to only 21% of the FS patients. These early data suggest that the CSS approach for HM3 LVAD implantation improves postoperative mobility and functional independence compared to FS.
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http://dx.doi.org/10.1093/icvts/ivab017DOI Listing
February 2021

Long-term renal function after venoarterial extracorporeal membrane oxygenation.

J Card Surg 2021 Mar 8;36(3):815-820. Epub 2021 Jan 8.

Division of Cardiac Surgery, University of Rochester Medical Center, Rochester, New York, USA.

Background: The utilization of venoarterial extracorporeal membrane oxygenation (VA-ECMO) as a life-supporting therapy has increased exponentially over the last decade. As more patients receive and survive ECMO, there are a number of unanswered clinical questions about their long-term prognosis and organ function including the need for long-term dialysis.

Methods: We aimed to utilize over 208 patient-years of follow-up data from our large institutional cohort of VA-ECMO patients to determine the incidence of requiring VA-ECMO support on the need for renal replacement therapy after discharge (LT-dialysis). This retrospective review included all adult VA-ECMO patients at our institution from January 2014 to October 2018 (N = 283).

Results: Out of the 99 (35%) survivors, 88 (89%) did not require LT-dialysis of any duration after discharge from the index hospitalization. Patients who required VA-ECMO for decompensated cardiogenic shock were more likely to need LT-dialysis (p = .034), and those who required renal replacement therapy during VA-ECMO (N = 27) also had a higher incidence of LT-dialysis (33%).

Conclusion: Overall, these data suggest there is a low incidence of long-term dialysis dependence among survivors of VA-ECMO support. Worries about the potential long-term detrimental effect of VA-ECMO should not preclude patients from receiving this life-saving support.
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http://dx.doi.org/10.1111/jocs.15277DOI Listing
March 2021

Structural and electronic studies of substituted m-terphenyl lithium complexes.

Dalton Trans 2021 Jan 21;50(2):722-728. Epub 2020 Dec 21.

School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.

The effect of para-substitution upon the structural and electronic properties of a series of m-terphenyl lithium complexes [R-Ar-Li] (R = t-Bu 1, SiMe2, H 3, Cl 4, CF5; where R-Ar = 2,6-{2,6-Xyl}-4-R-CH and 2,6-Xyl = 2,6-MeCH) has been investigated. X-ray crystallography reveals the complexes to be structurally similar, with little variation in C-M-C bond lengths and angles across the series. However, in-depth NMR spectroscopic studies reveal notable electronic differences, showing a linear correlation between the Li{H} NMR chemical shifts of the para-substituted complexes and their Hammett constants. The flanking methyl protons exhibit a similar electronic shift in the H NMR spectra, which has been rationalised by the presence of through-space LiH interactions, as evidenced by two-dimensional Li-H heteronuclear Overhauser spectroscopy (HOESY). In both cases, electron-withdrawing substituents are found to cause an upfield peak shift. A computational analysis is employed to account for these trends.
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http://dx.doi.org/10.1039/d0dt03972aDOI Listing
January 2021

Patient-Reported Outcomes Measurement Information System (PROMIS) in Left Ventricular Assist Devices.

Ann Thorac Surg 2020 Dec 1. Epub 2020 Dec 1.

Division of Cardiac Surgery. Electronic address:

Background: Appropriate collection of quality of life (QOL) measurements for left ventricular assist device (LVAD) patients is challenging. Patient-Reported Outcomes Measurement Information System (PROMIS) is a popular tool that has been validated across multiple disciplines, but its applicability to the LVAD population remains unknown.

Methods: This single-center, retrospective review included LVAD patients that completed a PROMIS assessment and Kansas City Cardiomyopathy Questionnaire (KCCQ-12) survey at clinical encounters postoperatively. Patients completed computer adaptive PROMIS assessments for physical function, pain interference and depression. All PROMIS domains are designed to follow a normal distribution (mean T-score 50, standard deviation 10) in the general population. Assessments were aggregated over time and correlation between the KCCQ-12 summary score and each PROMIS domain was assessed individually.

Results: A total of 178 LVAD patients were included in the study. The median time between LVAD implantation and PRO collection was 16.5 [interquartile range, 7.9-37.8] months. Patients typically had worse physical function (T-score 38.8 [33.6-44.2]) but comparable pain (51.1 [38.7-59.2]) and depression (49.9 [41.7-57.5]) as the general population. The KCCQ-12 was more strongly correlated to PROMIS physical function (Spearman's ρ = 0.746) than pain (ρ = -0.539) or depression (ρ = -0.591).

Conclusions: PROMIS provides a robust QOL data collection system that can be implemented in a clinical setting without imposing a significant burden. Using this more holistic system may allow for better patient-centered care in order to address QOL limitations imposed by LVAD support that are not directly related to heart failure symptoms.
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http://dx.doi.org/10.1016/j.athoracsur.2020.11.011DOI Listing
December 2020

Xanthine Oxidase Drives Hemolysis and Vascular Malfunction in Sickle Cell Disease.

Arterioscler Thromb Vasc Biol 2020 Dec 3:ATVBAHA120315081. Epub 2020 Dec 3.

Department of Pharmacology and Chemical Biology, University of Pittsburgh, PA. (H.M.S., D.A.V., A.C.S.).

Objective: Chronic hemolysis is a hallmark of sickle cell disease (SCD) and a driver of vasculopathy; however, the mechanisms contributing to hemolysis remain incompletely understood. Although XO (xanthine oxidase) activity has been shown to be elevated in SCD, its role remains unknown. XO binds endothelium and generates oxidants as a byproduct of hypoxanthine and xanthine catabolism. We hypothesized that XO inhibition decreases oxidant production leading to less hemolysis. Approach and Results: Wild-type mice were bone marrow transplanted with control (AA) or sickle (SS) Townes bone marrow. After 12 weeks, mice were treated with 10 mg/kg per day of febuxostat (Uloric), Food and Drug Administration-approved XO inhibitor, for 10 weeks. Hematologic analysis demonstrated increased hematocrit, cellular hemoglobin, and red blood cells, with no change in reticulocyte percentage. Significant decreases in cell-free hemoglobin and increases in haptoglobin suggest XO inhibition decreased hemolysis. Myographic studies demonstrated improved pulmonary vascular dilation and blunted constriction, indicating improved pulmonary vasoreactivity, whereas pulmonary pressure and cardiac function were unaffected. The role of hepatic XO in SCD was evaluated by bone marrow transplanting hepatocyte-specific XO knockout mice with SS Townes bone marrow. However, hepatocyte-specific XO knockout, which results in >50% diminution in circulating XO, did not affect hemolysis levels or vascular function, suggesting hepatocyte-derived elevation of circulating XO is not the driver of hemolysis in SCD.

Conclusions: Ten weeks of febuxostat treatment significantly decreased hemolysis and improved pulmonary vasoreactivity in a mouse model of SCD. Although hepatic XO accounts for >50% of circulating XO, it is not the source of XO driving hemolysis in SCD.
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http://dx.doi.org/10.1161/ATVBAHA.120.315081DOI Listing
December 2020

Family Satisfaction: Differences Between Nursing Homes and Residential Care Facilities.

J Appl Gerontol 2020 Nov 22:733464820971520. Epub 2020 Nov 22.

Miami University, Oxford, OH, USA.

This study compared differences in overall family satisfaction, specific satisfaction domains, and correlates of satisfaction between nursing homes (NHs) and residential care facilities (RCFs), using data from the 2016 Ohio Long-Term Care Family Satisfaction Survey. Satisfaction was higher for RCFs overall and within nearly every domain, with the largest difference observed in the domain. In both facility types, higher satisfaction was associated with male respondents, older respondent age, White race, less-frequent visitation, longer anticipated length of stay, less help provided during visits, smaller facilities, lower Medicaid-reliant resident percentage, and nonprofit status. Resident age, visitation frequency, perceived assistance required, and kinship tie were differentially related to satisfaction between facility types. NH administrators should focus on the environment and the moving in process. All administrators should address how residents spend time and should be aware that residents' and their family members' characteristics may affect satisfaction levels.
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http://dx.doi.org/10.1177/0733464820971520DOI Listing
November 2020

Minimally invasive off-pump surgical pulmonary embolectomy for improved patient-centred care.

Eur J Cardiothorac Surg 2020 Nov 22. Epub 2020 Nov 22.

Division of Cardiac Surgery, University of Rochester Medical Center, Rochester, NY, USA.

We present a complicated case of massive pulmonary embolism occurring 11 weeks after a craniotomy in a patient with multiple high-risk comorbidities. The patient underwent successful pulmonary artery surgical embolectomy via left mini-thoracotomy incision on peripheral venoarterial extracorporeal membrane oxygenation support. For this patient, avoiding a sternotomy allowed for greatly decreased postoperative morbidity and the use of venoarterial extracorporeal membrane oxygenation allowed for the avoidance of intraoperative anticoagulation. This case demonstrates the feasibility of off-pump surgical pulmonary embolectomy via left mini-thoracotomy as a treatment strategy for appropriate patients to improve patient-centred care.
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http://dx.doi.org/10.1093/ejcts/ezaa380DOI Listing
November 2020

An exploratory test of a couples-based condom-use intervention designed to promote pleasurable and safer penile-vaginal sex among university students.

J Am Coll Health 2020 Nov 5:1-8. Epub 2020 Nov 5.

Kinsey Institute for Research in Sex, Gender, and Reproduction, Indiana University, Bloomington, Indiana, USA.

Objective: Dual use of male condoms and female contraceptives is widely advocated for unplanned pregnancy prevention, yet college students often neglect condoms. This feasibility and acceptability study assessed the efficacy of a self-guided home-based condom-promotion intervention among college students in heterosexual relationships. Fifty-nine couples who had been together at least 30 days and had penile-vaginal sex at least twice weekly. Assessments were done at baseline and 6 months later. Outcomes were frequency of condom-unprotected penile-vaginal sex and four psychosocial mediators of condom use. Frequency of unprotected penile-vaginal sex decreased over time. Several corresponding psychosocial mediators showed change, particularly among women. Using actor-partner interdependence modeling, men's increase in condom use was associated with an increase in women's sexual pleasure. Findings support implementation of a brief, self-guided, home-based condom-use intervention that could lower incidence of unplanned pregnancy and STIs among heterosexually active college students.
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http://dx.doi.org/10.1080/07448481.2020.1818753DOI Listing
November 2020

Early B-cell Factor 3-Related Genetic Disease Can Mimic Urofacial Syndrome.

Kidney Int Rep 2020 Oct 14;5(10):1823-1827. Epub 2020 Jul 14.

Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.

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http://dx.doi.org/10.1016/j.ekir.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569699PMC
October 2020

In vitro characterization of hierarchical 3D scaffolds produced by combining additive manufacturing and thermally induced phase separation.

J Biomater Sci Polym Ed 2020 Nov 9:1-23. Epub 2020 Nov 9.

Department of Biology, Miami University, Oxford, OH, USA.

This paper reports on the hybrid process we have used for producing hierarchical scaffolds made of poly(lactic-co-glycolic) acid (PLGA) and nanohydroxyapatite (nHA), analyzes their internal structures scanning electron microscopy, and presents the results of our proliferation of MC3T3-E1 cells and alkaline phosphatase activity (ALP) for 0 and 21 days. These scaffolds were produced by combining additive manufacturing (AM) and thermally induced phase separation (TIPS) techniques. Slow cooling at a rate of 1.5 °C/min during the TIPS process was used to enable a uniform temperature throughout the scaffolds, and therefore, a relatively uniform pore size range. We produced ten different scaffold compositions and topologies in this study. These scaffolds had macrochannels with diameters of ∼300 µm, ∼380 µm, and ∼460 µm, generated by the extraction of embedded porous 3D-plotted polyethylene glycol (PEG) matrices. The other experimental factors included different TIPS temperatures (-20 °C, -10 °C, and 0 °C), as well as varying PLGA concentrations (8%, 10%, and 12% w/v) and nHA content (0%, 10%, and 20% w/w). Our results indicated that almost all these macro/microporous scaffolds supported cell growth over the period of 21 days. Nevertheless, significant differences were observed among some scaffolds in terms of their support of cell proliferation and differentiation. This paper presents the results of our cell culture for 0 and 21 days. Our optimal scaffold with a porosity of ∼90%, a modulus of ∼5.2 MPa, and a nHA content of 20% showed a cell adhesion of ∼29% on day 0 and maintained cell proliferation and ALP activity over the 21-day culture. Hence, the use of additive manufacturing and designed experiments to optimize the scaffold fabrication parameters resulted in superior mechanical properties that most other studies using TIPS.
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http://dx.doi.org/10.1080/09205063.2020.1841535DOI Listing
November 2020

The use of hydroxocobalamin for vasoplegic syndrome in left ventricular assist device patients.

Clin Case Rep 2020 Sep 26;8(9):1722-1727. Epub 2020 Jun 26.

Division of Cardiac Surgery University of Rochester Medical Center Rochester NY USA.

We demonstrate evidence supporting the efficacy of hydroxocobalamin in reducing vasopressor requirements for LVAD patients with refractory vasoplegia. Further study is needed to substantiate these findings and determine its optimal use in practice.
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http://dx.doi.org/10.1002/ccr3.2967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495745PMC
September 2020

Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.

PLoS One 2020 31;15(7):e0233582. Epub 2020 Jul 31.

Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.

The craniofacial developmental disorder Burn-McKeown Syndrome (BMKS) is caused by biallelic variants in the pre-messenger RNA splicing factor gene TXNL4A/DIB1. The majority of affected individuals with BMKS have a 34 base pair deletion in the promoter region of one allele of TXNL4A combined with a loss-of-function variant on the other allele, resulting in reduced TXNL4A expression. However, it is unclear how reduced expression of this ubiquitously expressed spliceosome protein results in craniofacial defects during development. Here we reprogrammed peripheral mononuclear blood cells from a BMKS patient and her unaffected mother into induced pluripotent stem cells (iPSCs) and differentiated the iPSCs into induced neural crest cells (iNCCs), the key cell type required for correct craniofacial development. BMKS patient-derived iPSCs proliferated more slowly than both mother- and unrelated control-derived iPSCs, and RNA-Seq analysis revealed significant differences in gene expression and alternative splicing. Patient iPSCs displayed defective differentiation into iNCCs compared to maternal and unrelated control iPSCs, in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT). RNA-Seq analysis of differentiated iNCCs revealed widespread gene expression changes and mis-splicing in genes relevant to craniofacial and embryonic development that highlight a dampened response to WNT signalling, the key pathway activated during iNCC differentiation. Furthermore, we identified the mis-splicing of TCF7L2 exon 4, a key gene in the WNT pathway, as a potential cause of the downregulated WNT response in patient cells. Additionally, mis-spliced genes shared common sequence properties such as length, branch point to 3' splice site (BPS-3'SS) distance and splice site strengths, suggesting that splicing of particular subsets of genes is particularly sensitive to changes in TXNL4A expression. Together, these data provide the first insight into how reduced TXNL4A expression in BMKS patients might compromise splicing and NCC function, resulting in defective craniofacial development in the embryo.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233582PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394406PMC
September 2020

Surgical Pulmonary Embolectomy With No Systemic Anticoagulation for Patient With Recent Stroke.

Ann Thorac Surg 2020 12 28;110(6):e493-e495. Epub 2020 May 28.

Division of Cardiac Surgery, Department of Surgery, University of Rochester Medical Center, Rochester, New York. Electronic address:

We present the successful use of surgical embolectomy (SE) without systemic anticoagulation to treat a complicated case of pulmonary embolism. The patient presented with an embolic cerebrovascular accident and subsequently developed a massive pulmonary embolism. Because of the risk of hemorrhagic transformation, the decision was made to proceed with emergent SE on venoarterial extracorporeal membrane oxygenation support without anticoagulation. The surgery was performed without complication. The potential to perform SE without anticoagulation could potentially decrease the incidence of surgical bleeding and make SE a therapeutic option for patients with contraindications to anticoagulation. Further research is needed to substantiate the efficacy of this treatment strategy.
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http://dx.doi.org/10.1016/j.athoracsur.2020.04.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669635PMC
December 2020

Predicting Survival After Extracorporeal Membrane Oxygenation by Using Machine Learning.

Ann Thorac Surg 2020 10 23;110(4):1193-1200. Epub 2020 May 23.

Division of Cardiac Surgery, University of Rochester Medical Center, Rochester, New York. Electronic address:

Background: Venoarterial (VA) extracorporeal membrane oxygenation (ECMO) undoubtedly saves many lives, but it is associated with a high degree of patient morbidity, mortality, and resource use. This study aimed to develop a machine learning algorithm to augment clinical decision making related to VA-ECMO.

Methods: Patients supported by VA-ECMO at a single institution from May 2011 to October 2018 were retrospectively reviewed. Laboratory values from only the initial 48 hours of VA-ECMO support were used. Data were split into 70% for training, 15% for validation, and 15% withheld for testing. Feature importance was estimated, and dimensionality reduction techniques were used. A deep neural network was trained to predict survival to discharge, and the final model was assessed using the independent testing cohort. Model performance was compared with that of the SAVE (Survival After Veno-arterial ECMO) score by using a receiver operator characteristic curve.

Results: Of the 282 eligible adult patients who were undergoing VA-ECMO, 117 (41%) survived to discharge. A total of 1.96 million laboratory values were extracted from the electronic medical record, from which 270 different summary variables were derived for each patient. The most important variables in predicting the primary outcome included lactate, age, total bilirubin, and creatinine. For the testing cohort, the final model achieved 82% overall accuracy and a greater area under the curve than the SAVE score (0.92 vs 0.65; P = .01) in predicting survival to discharge.

Conclusions: This proof of concept study demonstrates the potential for machine learning models to augment clinical decision making for patients undergoing VA-ECMO. Further development with multi-institutional data is warranted.
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http://dx.doi.org/10.1016/j.athoracsur.2020.03.128DOI Listing
October 2020

MELD-XI is predictive of mortality in venoarterial extracorporeal membrane oxygenation.

J Card Surg 2020 Jun 27;35(6):1275-1282. Epub 2020 Apr 27.

Division of Cardiac Surgery, University of Rochester Medical Center, Rochester, New York.

Background: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a life-saving method of supporting critically ill patients. However, it is expensive and associated with high morbidity and mortality, making early predictive outcome modeling extremely valuable. The model for end-stage liver disease-excluding international normalized ratio (MELD-XI) scoring system has been shown to have prognostic value in other critically ill patient populations.

Materials And Methods: A single-center retrospective review was performed for all adult patients managed on VA-ECMO from May 2011 to January 2018 (n = 247). Patients were included in the study if MELD-XI scores could be calculated during the first 48 hours on ECMO (n = 187). Receiver operating characteristic curve analysis was performed for MELD-XI in regard to in-hospital mortality.

Results: Of the 187 patients, 74 (40%) patients had MELD-XI less than 14 (low-risk) and 113 (60%) had a MELD-XI of 14 or greater (high-risk). The cohorts did not differ significantly in terms of patient characteristics or indication for ECMO. The high-risk MELD-XI group had significantly greater mortality during index hospitalization compared to the low-risk group (74% vs 39%; P < .0001). Quartile stratification demonstrated progressively worse prognosis associated with higher MELD-XI scores; the fourth quartile showed a ninefold increased risk of mortality compared to the first quartile (P < .001). The AUC for predicting index hospitalization mortality was 0.69 (95% CI, 0.62-0.77) with a Youden index (J) of 0.36 and optimized cutoff of 12.98.

Conclusions: These findings suggest that the MELD-XI scoring system can be applied to the VA-ECMO patient population early in their course of ECMO as a prognostic tool to aid in complex clinical decision making.
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http://dx.doi.org/10.1111/jocs.14578DOI Listing
June 2020

EFTUD2 missense variants disrupt protein function and splicing in mandibulofacial dysostosis Guion-Almeida type.

Hum Mutat 2020 Aug 3;41(8):1372-1382. Epub 2020 May 3.

Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

Pathogenic variants in the core spliceosome U5 small nuclear ribonucleoprotein gene EFTUD2/SNU114 cause the craniofacial disorder mandibulofacial dysostosis Guion-Almeida type (MFDGA). MFDGA-associated variants in EFTUD2 comprise large deletions encompassing EFTUD2, intragenic deletions and single nucleotide truncating or missense variants. These variants are predicted to result in haploinsufficiency by loss-of-function of the variant allele. While the contribution of deletions within EFTUD2 to allele loss-of-function are self-evident, the mechanisms by which missense variants are disease-causing have not been characterized functionally. Combining bioinformatics software prediction, yeast functional growth assays, and a minigene (MG) splicing assay, we have characterized how MFDGA missense variants result in EFTUD2 loss-of-function. Only four of 19 assessed missense variants cause EFTUD2 loss-of-function through altered protein function when modeled in yeast. Of the remaining 15 missense variants, five altered the normal splicing pattern of EFTUD2 pre-messenger RNA predominantly through exon skipping or cryptic splice site activation, leading to the introduction of a premature termination codon. Comparison of bioinformatic predictors for each missense variant revealed a disparity amongst different software packages and, in many cases, an inability to correctly predict changes in splicing subsequently determined by MG interrogation. This study highlights the need for laboratory-based validation of bioinformatic predictions for EFTUD2 missense variants.
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http://dx.doi.org/10.1002/humu.24027DOI Listing
August 2020

Association of previous cardiac surgery with outcomes in left ventricular assist device patients.

Interact Cardiovasc Thorac Surg 2020 07;31(1):1-8

Division of Cardiac Surgery, Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA.

Objectives: History of prior cardiac surgery has traditionally been considered a risk factor for subsequent cardiac procedures. The aim of this study was to investigate the outcomes of patients implanted with a left ventricular assist device via redo sternotomy.

Methods: Prospectively collected data were reviewed for all patients implanted with a continuous-flow left ventricular assist device at a single institution from December 2006 through June 2018. Patients were separated into 2 cohorts: those with a history of prior cardiac surgery (redo sternotomy) and those undergoing primary sternotomy at the time of left ventricular assist device implantation. The primary outcome was overall survival.

Results: Of the 321 patients included in the study, 77 (24%) were implanted via redo sternotomy and 244 (76%) via primary sternotomy. The redo sternotomy cohort was generally older (59 ± 10 vs 57 ± 12 years, P = 0.050) and had a higher incidence of ischaemic disease (70% vs 49%, P = 0.002). The Kaplan-Meier survival analysis demonstrated that overall survival was not significantly different between the redo sternotomy and primary sternotomy groups (6-month survival: 86% vs 92%; 5-year survival: 53% vs 51%; log-rank P = 0.590 for overall difference during follow-up). The propensity score analysis consistently showed that redo sternotomy was not significantly associated with mortality risk (hazard ratio 1.19, 95% confidence interval 0.73-1.93; P = 0.488). Redo sternotomy patients were more likely to require rehospitalization during their first year postoperatively (P = 0.020) and spent less time out of the hospital during the first year (P = 0.046).

Conclusions: The redo sternotomy cohort represents a more technically challenging patient population, but overall survival similar to that of primary sternotomy patients can be achieved.
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http://dx.doi.org/10.1093/icvts/ivaa055DOI Listing
July 2020

Long-term ungrounded cable support for short-to-shield syndrome.

Clin Case Rep 2020 Mar 7;8(3):512-515. Epub 2020 Feb 7.

University of Rochester Medical Center Rochester NY USA.

Short-to-shield (STS) is a potential complication for left ventricular assist device (LVAD) patients supported by the HeartMate II (HMII) pump. This phenomenon occurs when a damaged internal wire within the driveline makes contact with the surrounding sheath, resulting in insufficient power delivery to the motor when connected to a grounded power base unit (PBU). An ungrounded cable can be used to negate these effects, but the long-term safety of this treatment strategy is unknown. In this case series, we present our institutional experience treating 17 STS patients with an ungrounded cable. In total, we present 4922 patient-days (13.4 patient-years) of ungrounded cable support after primary STS treatment. There were no deaths or complications related to STS. These data suggest that the long-term use of an ungrounded cable is a reasonable treatment option for patients who cannot or do not wish to undergo pump exchange or splice repair.
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http://dx.doi.org/10.1002/ccr3.2583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069869PMC
March 2020

Ulcer metastasis? Anatomical locations of recurrence for patients in diabetic foot remission.

J Foot Ankle Res 2020 13;13. Epub 2020 Jan 13.

4Keck School of Medicine, University of Southern California, California, Los Angeles USA.

Background: The "cancer analogy" is powerful for communicating risk to and organizing care for patients with diabetic foot syndrome. One potentially underappreciated similarity between cancer and foot ulcers is that both can recur at anatomical locations distinct from the primary occurrence, albeit with different physiological mechanisms. Few studies have characterized the location of diabetic foot ulcer recurrence, and these have been limited by considering only the first recurrent wound following a recent-healed wound. We therefore characterized the anatomical locations at which diabetic foot ulcers are likely to recur considering multiple wounds during follow-up and the locations of all prior wounds documented in the participant's history.

Methods: We completed a secondary analysis of existing data from a 129 participant multi-center study of participants in diabetic foot remission. The primary outcome was plantar foot ulceration, and each participant was followed for 34 weeks or until withdrawing consent, allowing characterization of all wounds occurring. We stratified the anatomical locations of wounds prior to the trial by the following outcome categories during the trial: no recurrence, recurrence to the same anatomical location, recurrence to a different anatomical location on the same foot, and recurrence to the contralateral foot.

Results: A large percentage (48%) of wounds recurred to the contralateral foot, and the proportion of subsequent foot ulcer to the contralateral limb was largely unaffected by the anatomical location of foot ulcer prior to the study. Only 17% of prior diabetic foot ulcers were followed by recurrence to the same anatomical location. Rates of recurrence remained high during treatment of a wound (0.41 foot ulcer/ulcer-year). Participants had documented wounds to 2.2 distinct anatomical locations on average, and more than 60% of participants had wounds to more than one plantar location by the end of the study.

Conclusions: Given the significant morbidity, mortality, and resource utilization associated with foot ulcer recidivism, quality and evidenced-based preventive care is essential. Our results better characterize the burden of recurrence and to what anatomy recurrence is most likely. These insights may benefit providers and patients alike for the provision of high-quality preventive care thereby resulting in reduced morbidity, mortality, and cost.

Trial Registration: The study providing the data for this secondary analysis was registered on ClinicalTrials.gov (NCT02647346) on January 6, 2016. The study was retrospectively registered.
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http://dx.doi.org/10.1186/s13047-020-0369-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958592PMC
November 2020

Complete Sternal-Sparing Approach Improves Outcomes for Left Ventricular Assist Device Implantation in Patients With History of Prior Sternotomy.

Innovations (Phila) 2020 Jan/Feb;15(1):51-56. Epub 2020 Jan 5.

6923 Division of Cardiac Surgery, Department of Surgery, University of Rochester, Rochester, NY, USA.

Objective: Early reports of less invasive techniques for left ventricular assist device (LVAD) implantation have demonstrated promising results. We sought to investigate the safety and feasibility of implementing the complete sternal-sparing (CSS) approach for LVAD implantation in patients with a history of prior cardiac operation.

Methods: This was a retrospective review of prospectively collected data for all patients implanted with a fully magnetically levitated LVAD from April 2017 through December 2018. Patients were dichotomized based on surgical approach: CSS or full median sternotomy (FS). Perioperative complications and overall survival were compared between cohorts.

Results: Of the 29 eligible patients, 15 (52%) were implanted via the CSS approach and 14 (48%) via FS. Preoperative characteristics were similar between cohorts. Overall survival to discharge was 93% for CSS compared to 71% for FS ( = 0.169). The CSS cohort demonstrated fewer postoperative complications, including fewer cases of severe right ventricular failure ( = 0.006) and less blood product utilization ( = 0.015). Median hospital length of stay was significantly shorter for the CSS cohort (median 13 vs 32.5 days, = 0.016). Neither cohort had any 30-day readmissions.

Conclusions: Early data suggest that the CSS technique is a safe and effective technique for patients with a history of prior sternotomy. Further studies are needed to validate this single-center experience.
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http://dx.doi.org/10.1177/1556984519886282DOI Listing
December 2020

Extracorporeal life support to ventricular assist device: potential benefits of sternal-sparing approach.

J Thorac Dis 2019 Nov;11(11):4790-4797

Division of Cardiac Surgery, University of Rochester Medical Center, Rochester, NY, USA.

Background: Advancements in left ventricular assist device (LVAD) technology have improved long-term survival for properly selected patients with advanced heart failure. However, the subset of patients in critical cardiogenic shock remain difficult to treat with persistently high patient morbidity and mortality. The goal of this study is to describe our institutional experience utilizing extracorporeal membrane oxygenation (ECMO) as a bridge to LVAD for patients in cardiogenic shock comparing the less invasive complete sternal-sparing (CSS) surgical technique to median sternotomy.

Methods: Data was collected as a single center retrospective review of patients implanted with a continuous-flow LVAD directly off ECMO from 2012 to 2018. Patients were stratified by LVAD surgical technique. The primary outcome was survival to discharge. Secondary outcomes included postoperative complications, resource utilization and survival at 6-months.

Results: Of the 37 patients implanted directly off ECMO, 26 (70%) patients were implanted via median sternotomy and 11 (30%) patients by the CSS approach. Median time on ECMO support was 8 days (range, 2-29 days). Preoperative characteristics were similar between groups. Survival to discharge was 78% overall (73% 91% CSS, P=0.391). The CSS cohort had fewer postoperative complications, including fewer transfusions (P=0.044) and trend towards less right ventricular (RV) failure (62% 27% CSS, P=0.079). Both cohorts required similar median length of stay (LOS) in the intensive care unit (ICU) (11 12 days, P=0.695) and similar overall hospital LOS (34 22 days, P=0.242). Overall survival was 74% at six months (68% 89% CSS, P=0.386).

Conclusions: VA ECMO can be used effectively as a bridge-to-LVAD for patients in cardiogenic shock. The less invasive CSS approach demonstrates potential advantages to median sternotomy. Further study is needed to better understand the benefits of less invasive surgical techniques.
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http://dx.doi.org/10.21037/jtd.2019.10.21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940249PMC
November 2019

Now or never: noticing occurs early in sustained inattentional blindness.

R Soc Open Sci 2019 Nov 20;6(11):191333. Epub 2019 Nov 20.

Department of Psychology, University of Illinois, 603 E. Daniel Street, Champaign, IL 61820, USA.

People can show sustained inattentional blindness for unexpected objects visible for seconds or even minutes. Would such objects eventually be noticed given enough time, with the likelihood of noticing accumulating while the unexpected object is visible? Or, is there a narrow window around onset or offset when an object is most likely to be detected, with the chances of noticing dropping outside of that window? Across three experiments (total 's = 283, 756, 488) exploring the temporal dynamics of noticing in sustained inattentional blindness, subjects who noticed the unexpected object did so soon after it onset. Doubling or even tripling the time when the unexpected object was visible barely affected the likelihood of noticing it and had no impact on how accurately subjects reported its features. When people notice an unexpected object in these sustained inattentional blindness tasks, they do so soon after the unexpected object onsets.
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http://dx.doi.org/10.1098/rsos.191333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894580PMC
November 2019

Sickle cell disease: at the crossroads of pulmonary hypertension and diastolic heart failure.

Heart 2020 04 10;106(8):562-568. Epub 2019 Dec 10.

Division of Pulmonary, Allergy and Critical Care Medicine in the Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Sickle cell disease (SCD) is caused by a single point mutation in the gene that codes for beta globin synthesis, causing haemoglobin polymerisation, red blood cell stiffening and haemolysis under low oxygen and pH conditions. Downstream effects include widespread vasculopathy due to recurring vaso-occlusive events and haemolytic anaemia, affecting all organ systems. Cardiopulmonary complications are the leading cause of death in patients with SCD, primarily resulting from diastolic heart failure (HF) and/or pulmonary hypertension (PH). HF in SCD often features biventricular cardiac hypertrophy and left ventricular (LV) diastolic dysfunction. Among HF cases in the general population, approximately half occur with preserved ejection fraction (HFpEF). The insidious evolution of HFpEF differs from the relatively acute evolution of HF with reduced ejection fraction. The PH of SCD has diverse origins, which can be pulmonary arterial (precapillary), pulmonary venous (postcapillary) or pulmonary thromboembolic. It is also appreciated that patients with SCD can develop both precapillary and postcapillary PH, with elevations in LV diastolic pressures, as well as elevations in transpulmonary pressure gradient and pulmonary vascular resistance. Regardless of the cause of PH in SCD, its presence significantly reduces functional capacity and increases mortality. PH that occurs in the presence of HFpEF is usually of postcapillary origin. This review aims to assemble what has been learnt from clinical and animal studies about the manifestation of PH-HFpEF in SCD, specifically the contributions of LV diastolic dysfunction and myocardial fibrosis, in an attempt to gain an understanding of its evolution.
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http://dx.doi.org/10.1136/heartjnl-2019-314810DOI Listing
April 2020

Smooth muscle cytochrome b5 reductase 3 deficiency accelerates pulmonary hypertension development in sickle cell mice.

Blood Adv 2019 12;3(23):4104-4116

Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, Department of Medicine.

Pulmonary and systemic vasculopathies are significant risk factors for early morbidity and death in patients with sickle cell disease (SCD). An underlying mechanism of SCD vasculopathy is vascular smooth muscle (VSM) nitric oxide (NO) resistance, which is mediated by NO scavenging reactions with plasma hemoglobin (Hb) and reactive oxygen species that can oxidize soluble guanylyl cyclase (sGC), the NO receptor. Prior studies show that cytochrome b5 reductase 3 (CYB5R3), known as methemoglobin reductase in erythrocytes, functions in VSM as an sGC heme iron reductase critical for reducing and sensitizing sGC to NO and generating cyclic guanosine monophosphate for vasodilation. Therefore, we hypothesized that VSM CYB5R3 deficiency accelerates development of pulmonary hypertension (PH) in SCD. Bone marrow transplant was used to create SCD chimeric mice with background smooth muscle cell (SMC)-specific tamoxifen-inducible Cyb5r3 knockout (SMC R3 KO) and wild-type (WT) control. Three weeks after completing tamoxifen treatment, we observed 60% knockdown of pulmonary arterial SMC CYB5R3, 5 to 6 mm Hg elevated right-ventricular (RV) maximum systolic pressure (RVmaxSP) and biventricular hypertrophy in SS chimeras with SMC R3 KO (SS/R3KD) relative to WT (SS/R3WT). RV contractility, heart rate, hematological parameters, and cell-free Hb were similar between groups. When identically generated SS/R3 chimeras were studied 12 weeks after completing tamoxifen treatment, RVmaxSP in SS/R3KD had not increased further, but RV hypertrophy relative to SS/R3WT persisted. These are the first studies to establish involvement of SMC CYB5R3 in SCD-associated development of PH, which can exist in mice by 5 weeks of SMC CYB5R3 protein deficiency.
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http://dx.doi.org/10.1182/bloodadvances.2019000621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963246PMC
December 2019

Stability of spontaneous, correlated activity in mouse auditory cortex.

PLoS Comput Biol 2019 12 9;15(12):e1007360. Epub 2019 Dec 9.

Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Neural systems can be modeled as complex networks in which neural elements are represented as nodes linked to one another through structural or functional connections. The resulting network can be analyzed using mathematical tools from network science and graph theory to quantify the system's topological organization and to better understand its function. Here, we used two-photon calcium imaging to record spontaneous activity from the same set of cells in mouse auditory cortex over the course of several weeks. We reconstruct functional networks in which cells are linked to one another by edges weighted according to the correlation of their fluorescence traces. We show that the networks exhibit modular structure across multiple topological scales and that these multi-scale modules unfold as part of a hierarchy. We also show that, on average, network architecture becomes increasingly dissimilar over time, with similarity decaying monotonically with the distance (in time) between sessions. Finally, we show that a small fraction of cells maintain strongly-correlated activity over multiple days, forming a stable temporal core surrounded by a fluctuating and variable periphery. Our work indicates a framework for studying spontaneous activity measured by two-photon calcium imaging using computational methods and graphical models from network science. The methods are flexible and easily extended to additional datasets, opening the possibility of studying cellular level network organization of neural systems and how that organization is modulated by stimuli or altered in models of disease.
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http://dx.doi.org/10.1371/journal.pcbi.1007360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6968873PMC
December 2019

Free-Wilson Analysis of Comprehensive Data on Phosphoinositide-3-kinase (PI3K) Inhibitors Reveals Importance of -Methylation for PI3Kδ Activity.

J Med Chem 2019 11 6;62(22):10402-10422. Epub 2019 Nov 6.

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Phosphoinositide-3-kinase δ (PI3Kδ) is a critical regulator of cell growth and transformation and has been explored as a therapeutic target for a range of diseases. Through the exploration of the thienopyrimidine scaffold, we have identified a ligand-efficient methylation that leads to remarkable selectivity for PI3Kδ over the closely related isoforms. Interrogation through the Free-Wilson analysis highlights the innate selectivity the thienopyrimidine scaffold has for PI3Kδ and provides a predictive model for the activity against the PI3K isoforms.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01499DOI Listing
November 2019

Implantation of a fully magnetically levitated left ventricular assist device using a sternal-sparing surgical technique.

J Heart Lung Transplant 2020 01 25;39(1):37-44. Epub 2019 Sep 25.

Divisions of Cardiac Surgery.

Background: Left ventricular assist devices (LVADs) have improved outcomes for selected patients with advanced heart failure, but alternative optimal surgical techniques remain to be defined. We aim to describe our initial experience in using a sternal-sparing (SS) technique for implantation of a magnetically levitated LVAD, the HeartMate 3 (HM3) pump.

Methods: This retrospective, single-center study included consecutive patients implanted with the HM3 LVAD between September 2015 and September 2018. Patients were compared based on surgical approach: SS or traditional sternotomy (TS). The primary outcome was overall survival at 6 months. Secondary outcomes included peri-operative complications, blood product utilization, and hospital readmissions.

Results: Of 105 patients implanted with the HM3 LVAD, 41 (39%) were implanted via SS and 64 (61%) via TS approach. There were no intraoperative conversions. The SS patients were younger; otherwise, all other characteristics were similar between cohorts. The SS cohort demonstrated a significantly lower incidence of severe right ventricular failure (7% vs 28%, p = 0.012), fewer blood-product transfusions (41% vs 86%, p < 0.001), and shorter index hospital length of stay (15.5 vs 21 days, p = 0.018). Six-month survival was 93% for the SS cohort.

Conclusions: In this single-center observational study, we have demonstrated that the SS approach may be a safe and effective surgical technique for implantation of the HM3 LVAD in well-selected patients. The potential benefits compared with TS require further inquiry.
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http://dx.doi.org/10.1016/j.healun.2019.09.012DOI Listing
January 2020

Venoarterial-Extracorporeal Membrane Oxygenation Without Routine Systemic Anticoagulation Decreases Adverse Events.

Ann Thorac Surg 2020 05 26;109(5):1458-1466. Epub 2019 Sep 26.

Division of Cardiac Surgery, University of Rochester Medical Center, Rochester, New York. Electronic address:

Background: Despite limited evidence, systemic anticoagulation is the current standard of care for patients supported on venoarterial-extracorporeal membrane oxygenation (VA-ECMO). We hypothesized that not anticoagulating patients on VA-ECMO would decrease complications.

Methods: We retrospectively reviewed adult patients supported on VA-ECMO at our institution. Patients were stratified based on anticoagulation strategy. The primary outcome was a composite of hemorrhagic and thrombotic complications. Secondary outcomes included blood product use, incidence of heparin-induced thrombocytopenia (HIT), hospital length of stay, and in-hospital mortality.

Results: From May 2011 through January 2018, there were 203 eligible patients supported on VA-ECMO, 35% (75 patients) were not anticoagulated. Overall complication rates were significantly lower for the no anticoagulation group (57% versus 76%; P = .007) including a trend toward fewer hemorrhagic complications (53% versus 63%; P = .178) without increased risk of thrombosis (13% versus 21%; P = .147). The anticoagulated group required more transfusions of packed red blood cells (12.8 versus 1.09; P = .002) and platelets (3.0 versus 1.3; P = .009) and showed a higher incidence of HIT (8% versus 0%; P = .015). No difference was found in overall mortality (72% versus 62%; P = .165).

Conclusions: The absence of routine systemic anticoagulation for patients supported on VA-ECMO is not associated with higher mortality, pump failure, or thrombotic complications. Patients had a lower requirement for blood product transfusions, and there was no incidence of HIT. Patients supported on VA-ECMO without other indications for anticoagulation can be treated without systemic anticoagulation during their VA-ECMO course.
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http://dx.doi.org/10.1016/j.athoracsur.2019.08.040DOI Listing
May 2020

Decoding the role of SOD2 in sickle cell disease.

Blood Adv 2019 09;3(17):2679-2687

Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute.

Sickle cell disease (SCD) is an inherited hemoglobinopathy caused by a single point mutation in the β-globin gene. As a consequence, deoxygenated hemoglobin polymerizes triggering red blood cell sickling and hemolysis, vaso-occlusion, and ischemia/reperfusion. Allied to these pathologies is the overproduction of reactive oxygen species driven by hemoglobin Fenton chemistry and peroxidase reactions as well as by secondary activation of vascular oxidases, including NAD(P)H oxidase and xanthine oxidase. In addition, hypoxia, produced by sickle red blood cell occlusion, disrupts mitochondrial metabolism and generates excess superoxide through electron leak from the mitochondrial respiratory chain. Superoxide dismutase 2 (SOD2) is a mitochondrial-specific antioxidant enzyme that dismutates superoxide to hydrogen peroxide, which is then converted to water by catalase and glutathione peroxidase. In SCD, the antioxidant defense system is significantly diminished through decreased expression and activity levels of antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase. From a translational perspective, genetic variants including a missense variant in SOD2 (valine to alanine at position 16) are present in 45% of people with African ancestry and are associated with increased sickle complications. While it is known that there is an imbalance between oxidative species and antioxidant defenses in SCD, much more investigation is warranted. This review summarizes our current understanding of antioxidant defense systems in SCD, particularly focused on SOD2, and provides insight into challenges and opportunities as the field moves forward.
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http://dx.doi.org/10.1182/bloodadvances.2019000527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737422PMC
September 2019