Publications by authors named "David Murray"

709 Publications

MASS-FIX for the detection of monoclonal proteins and light chain N-glycosylation in routine clinical practice: a cross-sectional study of 6315 patients.

Blood Cancer J 2021 Mar 4;11(3):50. Epub 2021 Mar 4.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Immunoenrichment-based matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), termed MASS-FIX, offers several advantages over immunofixation for the detection and isotyping of serum monoclonal protein, including superior sensitivity and specificity, the ability to differentiate therapeutic monoclonal antibodies, and the rapid identification of light chain (LC) N-glycosylation. We identified 6315 patients with MASS-FIX performed at our institution since 2018. Of these, 4118 patients (65%) with a wide array of plasma cell disorders (PCD), including rare monoclonal gammopathies of clinical significance, had a positive MASS-FIX. Two-hundred twenty-one (5%) of the MASS-FIX positive patients had evidence of LC N-glycosylation, which was more commonly identified in IgM heavy chain isotype, kappa LC isotype, and in diagnoses of immunoglobulin light chain (AL) amyloidosis and cold agglutinin disease (CAD) compared to other PCD. This cross-sectional study describes the largest cohort of patients to undergo MASS-FIX in routine clinical practice. Our findings demonstrate the widespread utility of this assay, and confirm that LC N-glycosylation should prompt suspicion for AL amyloidosis and CAD in the appropriate clinical context.
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http://dx.doi.org/10.1038/s41408-021-00444-0DOI Listing
March 2021

Synthesis of redox-active fluorinated 5-hydroxytryptophans as molecular reporters for biological electron transfer.

Chem Commun (Camb) 2021 Feb 24. Epub 2021 Feb 24.

Department of Chemistry, East Carolina University, Greenville, NC, USA.

Fluorinated 5-hydroxytryptophans (Fn-5HOWs) were synthesized in gram scale quantities and incorporated into a β-hairpin peptide and the protein azurin. The redox-active Fn-5HOWs exhibit unique radical spectroscopic signatures that expand the function of 5HOW as probes for biological electron transfer.
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http://dx.doi.org/10.1039/d1cc00187fDOI Listing
February 2021

Citric acid functionalized nitinol stent surface promotes endothelial cell healing.

J Biomed Mater Res A 2021 Feb 24. Epub 2021 Feb 24.

Department of Chemical Sciences, Bernal Institute, University of Limerick, Limerick, Ireland.

While drug-eluting stents containing anti-proliferative agents inhibit proliferation of smooth muscle cells (SMCs), they also delay the regrowth of the endothelial cells which can result in subsequent development of restenosis. Acidic extracellular environments promote cell anchorage and migration by inducing conformational change in integrins, the main cell adhesion proteins. This study addresses the feasibility of a citric acid (CA) functionalized nitinol stent for improving vascular biocompatibility, specifically enhancing endothelialization. CA functionalized nitinol vascular stents are compared to commercial bare metal (Zilver Flex) and paclitaxel eluting stents (Zilver PTX) in terms of re-endothelialization. To study the effect of stent coatings, a stent conditioned media methodology was developed in an attempt to represent in vivo conditions. Overall, distinct advantages of the CA functionalized nitinol stent over commercial Zilver PTX DES and Zilver Flex BMS stents in terms of endothelial cell adhesion, migration, and proliferation are reported. These novel findings indicate the potential of a CA functionalized stent to serve as a bioactive and therapeutic surface for re-endothelialization, perhaps in combination with a SMC proliferation inhibitor coating, to prevent restenosis.
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http://dx.doi.org/10.1002/jbm.a.37150DOI Listing
February 2021

Disease monitoring with quantitative serum IgA levels provides a more reliable response assessment in multiple myeloma patients.

Leukemia 2021 Feb 23. Epub 2021 Feb 23.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Unlike IgG monoclonal proteins (MCPs), IgA MCP quantification is unreliable due to beta-migration of IgA MCPs on serum protein electrophoresis (SPEP). The utility of nephelometric quantitative IgA (qIgA) to monitor IgA multiple myeloma (MM) is unclear. We retrospectively studied disease response kinetics using qIgA versus MCPs by SPEP, and developed and validated novel qIgA disease assessment criteria in 491 IgA MM patients. The SPEP MCP nadir occurred a median of 41 (IQR 0-102) days before the qIgA. The median time to achieve a partial response (PR) was shorter using standard IMWG versus qIgA response criteria (32 vs 58 days, p < 0.001). Stratification by qIgA criteria, unlike IMWG criteria, led to clear separation of the progression-free survival curves of patients achieving a PR or very good PR. There was a consistent trend toward earlier detection of disease progression using qIgA versus IMWG progression criteria. In conclusion, monitoring IgA MM using MCP-based IMWG criteria may be falsely reassuring, given that MCP levels on SPEP decrease faster than qIgA levels. The qIgA response criteria more accurately stratify patients based on the progression risk and may detect disease progression earlier, which may lead to more consistent measurement of trial endpoints and improved patient outcomes.
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http://dx.doi.org/10.1038/s41375-021-01180-xDOI Listing
February 2021

Meiosis and beyond - understanding the mechanistic and evolutionary processes shaping the germline genome.

Biol Rev Camb Philos Soc 2021 Jan 1. Epub 2021 Jan 1.

School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, U.K.

The separation of germ cell populations from the soma is part of the evolutionary transition to multicellularity. Only genetic information present in the germ cells will be inherited by future generations, and any molecular processes affecting the germline genome are therefore likely to be passed on. Despite its prevalence across taxonomic kingdoms, we are only starting to understand details of the underlying micro-evolutionary processes occurring at the germline genome level. These include segregation, recombination, mutation and selection and can occur at any stage during germline differentiation and mitotic germline proliferation to meiosis and post-meiotic gamete maturation. Selection acting on germ cells at any stage from the diploid germ cell to the haploid gametes may cause significant deviations from Mendelian inheritance and may be more widespread than previously assumed. The mechanisms that affect and potentially alter the genomic sequence and allele frequencies in the germline are pivotal to our understanding of heritability. With the rise of new sequencing technologies, we are now able to address some of these unanswered questions. In this review, we comment on the most recent developments in this field and identify current gaps in our knowledge.
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http://dx.doi.org/10.1111/brv.12680DOI Listing
January 2021

HDAC inhibition prevents transgene expression downregulation and loss-of-function in T-cell-receptor-transduced T cells.

Mol Ther Oncolytics 2021 Mar 26;20:352-363. Epub 2021 Jan 26.

Department of Surgery, Loyola University Chicago, 2160 S. 1st Avenue, Maywood, IL 60153, USA.

T cells that are gene-modified with tumor-specific T cell receptors are a promising treatment for metastatic melanoma patients. In a clinical trial, we treated seven metastatic melanoma patients with autologous T cells transduced to express a tyrosinase-reactive T cell receptor (TCR) (TIL 1383I) and a truncated CD34 molecule as a selection marker. We followed transgene expression in the TCR-transduced T cells after infusion and observed that both lentiviral- and retroviral-transduced T cells lost transgene expression over time, so that by 4 weeks post-transfer, few T cells expressed either lentiviral or retroviral transgenes. Transgene expression was reactivated by stimulation with anti-CD3/anti-CD28 beads and cytokines. TCR-transduced T cell lentiviral and retroviral transgene expression was also downregulated when T cells were cultured without cytokines. Transduced T cells cultured with interleukin (IL)-15 maintained transgene expression. Culturing gene-modified T cells in the presence of histone deacetylase (HDAC) inhibitors maintained transgene expression and functional TCR-transduced T cell responses to tumor. These results implicate epigenetic processes in the loss of transgene expression in lentiviral- and retroviral-transduced T cells.
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http://dx.doi.org/10.1016/j.omto.2021.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878989PMC
March 2021

The effect of age on the outcomes of cementless mobile bearing unicompartmental knee replacements.

Knee Surg Sports Traumatol Arthrosc 2021 Feb 12. Epub 2021 Feb 12.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Nuffield Orthopaedic Centre, Oxford, OX3 7LD, UK.

Purpose: Unicompartmental Knee Replacements (UKR) are being performed in patients with increasing demands and life expectancies with surgical concerns that cemented fixation will not last. Cementless fixation may offer a solution, but the results in different age groups have not been assessed. The effect of age at surgery on the outcomes of cementless UKRs was investigated.

Methods: A prospective cohort of 1000 medial cementless mobile bearing UKR were analysed. Patients were categorised into four age groups (< 55, 55 to < 65, 65 to < 75 and ≥ 75 years). Implant survival was assessed using endpoints reoperation, revision and major revision requiring revision knee replacement components. Functional outcomes were assessed.

Results: 10 year cumulative revision rate for the < 55, 55 to < 65, 65 to < 75 and ≥ 75 groups were 2.1% (CI 0.6-6.1), 1.8% (CI 0.6-5.3), 3.2% (CI 1.5-6.5) and 4.1% (1.7-9.6) with no differences between groups (p = 0.52). Two of the 22 revisions were considered major. The 10 year cumulative reoperation rates were 4.5% (CI 2.0-10.0), 3.0% (CI 1.3-6.5), 3.8% (CI 2.0-7.1) and 4.1% (CI 1.7-9.6) with no differences between groups (p = 0.81). The 10 year median Oxford Knee Scores were 42.5, 46.5, 45 and 42.5, respectively. The 10 year median Objective American Knee Society Scores were 95 for all age groups.

Conclusion: The cementless mobile bearing UKR has low reoperation and revision rates and similar functional outcomes in all age groups. Cementless UKR should be used in all age groups and age should not be considered a contraindication.

Level Of Evidence: III.
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http://dx.doi.org/10.1007/s00167-020-06428-0DOI Listing
February 2021

Mass spectrometry for the evaluation of monoclonal proteins in multiple myeloma and related disorders: an International Myeloma Working Group Mass Spectrometry Committee Report.

Blood Cancer J 2021 Feb 1;11(2):24. Epub 2021 Feb 1.

Department of Hematology, Cedars-Sinai Outpatient Cancer Center, Los Angeles, CA, USA.

Plasma cell disorders (PCDs) are identified in the clinical lab by detecting the monoclonal immunoglobulin (M-protein) which they produce. Traditionally, serum protein electrophoresis methods have been utilized to detect and isotype M-proteins. Increasing demands to detect low-level disease and new therapeutic monoclonal immunoglobulin treatments have stretched the electrophoretic methods to their analytical limits. Newer techniques based on mass spectrometry (MS) are emerging which have improved clinical and analytical performance. MS is gaining traction into clinical laboratories, and has replaced immunofixation electrophoresis (IFE) in routine practice at one institution. The International Myeloma Working Group (IMWG) Mass Spectrometry Committee reviewed the literature in order to summarize current data and to make recommendations regarding the role of mass spectrometric methods in diagnosing and monitoring patients with myeloma and related disorders. Current literature demonstrates that immune-enrichment of immunoglobulins coupled to intact light chain MALDI-TOF MS has clinical characteristics equivalent in performance to IFE with added benefits of detecting additional risk factors for PCDs, differentiating M-protein from therapeutic antibodies, and is a suitable replacement for IFE for diagnosing and monitoring multiple myeloma and related PCDs. In this paper we discuss the IMWG recommendations for the use of MS in PCDs.
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http://dx.doi.org/10.1038/s41408-021-00408-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873248PMC
February 2021

In from the cold: M-protein light chain glycosylation is positively associated with cold agglutinin titer levels.

Transfusion 2021 Jan 27. Epub 2021 Jan 27.

Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, Minnesota.

Background: Primary cold agglutinin disease (CAD) is a monoclonal antibody (M-protein) and complement-mediated chronic hemolytic disease process. Antibody glycosylation can play a role in both antibody half-life and complement fixation. Recently, M-protein light chain (LC) glycosylation has been shown to be associated with AL amyloidosis. We hypothesized that M-protein LC glycosylation is also associated with cold agglutinin (CA) titers and CA-mediated hemolysis.

Study Design And Methods: A cross-sectional study of patients undergoing CA titer evaluation underwent mass spectrometric analysis for M-proteins and M-protein LC glycosylation. A subset of serum samples also underwent evaluation for the ability to trigger cold hemolysis in vitro. M-protein and M-protein LC glycosylation rates were compared across CA titer groups, clinical diagnosis, direct antiglobulin testing (DAT) results, and cold in vitro hemolysis rates.

Results: Both M-protein and M-protein LC glycosylation rates significantly differed across CA titer groups with the highest rates in those with elevated CA titers. M-protein LC glycosylation occurred almost exclusively on IgM kappa M-proteins and was significantly associated with positive DAT results and a clinical diagnosis of CAD. Cold in vitro hemolysis was demonstrated in two patients who both had a CA titer of more than 512 but there was no significant association with CA titer group or M-protein LC glycosylation status.

Conclusion: M-protein LC glycosylation is significantly associated with higher CA titer levels. Given the role that antibody glycosylation can play in antibody half-life and complement fixation, further studies are needed to clarify the effects of LC glycosylation within the context of CAD.
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http://dx.doi.org/10.1111/trf.16279DOI Listing
January 2021

Successful heart transplantation in a patient who recovered from COVID-19.

J Card Surg 2021 Mar 15;36(3):1148-1149. Epub 2021 Jan 15.

Division of Cardiothoracic Surgery, Department of Surgery, University of Wisconsin, Madison, Wisconsin, USA.

Coronavirus disease-2019 has created unprecedented challenges for society, and specifically the medical community. While the pandemic continues to unfold, the transplant community has had to pivot to keep recipients, donors, and institutional transplant teams safe given the unique circumstances inherent to solid organ transplantation.
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http://dx.doi.org/10.1111/jocs.15331DOI Listing
March 2021

Systematic review and meta-analysis of bearing dislocation in lateral meniscal bearing unicompartmental knee replacement: Domed versus flat tibial surface.

Knee 2021 Jan 7;28:214-228. Epub 2021 Jan 7.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK; Nuffield Orthopaedic Centre, Oxford, UK.

Background: Bearing dislocation is a problem following mobile bearing Oxford lateral Unicompartmental Knee Replacement (UKR). Therefore, the design of the tibial component was changed from a flat tibial surface to a domed tibial surface with a biconcave bearing to increase bearing entrapment. This systematic review compared the dislocation and revision rates of the two designs.

Methods: Two authors independently searched MEDLINE, EMBASE and ISI Web of Science, reference lists of retrieved articles, and the internet. Randomised, cohort, case-control and case studies of adult patients with lateral knee osteoarthritis treated with flat or domed Oxford lateral UKR and their outcomes were included. The overall dislocation rate and the annual revision rate (per 100 component years) were determined.

Results: Nine studies (937 knees) met the inclusion criteria (3 flat, 6 domed). Four studies (all domed) had a low risk of bias and five had a high risk (3 flat, 2 domed), so data should be interpreted with caution. The bearing dislocation rate decreased from 17% (flat) to 3.7% (domed). Dislocations occurred on average at 16 months and medial dislocations were most common. The revision rate excluding dislocation decreased from 1.1%pa to 0.7%pa. PROSPERO registration: CRD42019139250.

Conclusion: Modifying the tibial component from a flat to a domed shape decreased the bearing dislocation rate to 3.7% and increased the 10 year survival rate excluding dislocation to 93%. The dislocation rate is still relatively high so bearing stability should be assessed intra-operatively and if unacceptable, a fixed bearing version of the Oxford lateral tibial component can be inserted.
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http://dx.doi.org/10.1016/j.knee.2020.10.013DOI Listing
January 2021

Monitoring Ravulizumab effect on complement assays.

J Immunol Methods 2021 Mar 13;490:112944. Epub 2020 Dec 13.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America.

Ravulizumab is a new C5 inhibitor therapeutic monoclonal antibody with a longer half-life than eculizumab. Monitoring complete complement blockade by eculizumab has allowed personalized therapy in specific settings. Similar action is expected with ravulizumab. Ravulizumab has 4 different amino acids from eculizumab, which allow greater affinity for the FcRn immunoglobulin receptor and change the affinity of the molecule for C5. Here we investigate if clinical lab tests traditionally used to monitor complement blockade for eculizumab are appropriate for monitoring complement blockade caused by ravulizumab. De-identified serum samples with known normal complement activity were spiked with increasing amounts of ravulizumab, from zero to 1000 μg/mL. Measurement of classical pathway function (CH50) and C5 function using a liposome method (Wako Diagnostics) showed >50% complement inhibition starting with 50 μg/mL of ravulizumab, but inhibition >95% of complement activity was not achieved, with residual measurements of 11% at 700 μg/mL. In contrast, measurement of alternative pathway function using an ELISA (AH50, Wieslab) showed alternative pathway function inhibition of 80% at 50 μg/mL of ravulizumab and > 95% at 200 μg/mL, which is consistent with expected therapeutic concentrations of ravulizumab >175 μg/mL. If replicated in patient sera, AH50 could be a suitable therapeutic monitoring tool.
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http://dx.doi.org/10.1016/j.jim.2020.112944DOI Listing
March 2021

Do TUNEL and Other Apoptosis Assays Detect Cell Death in Preclinical Studies?

Int J Mol Sci 2020 Nov 29;21(23). Epub 2020 Nov 29.

Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada.

The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay detects DNA breakage by labeling the free 3'-hydroxyl termini. Given that genomic DNA breaks arise during early and late stages of apoptosis, TUNEL staining continues to be widely used as a measure of apoptotic cell death. The advantages of the assay include its relative ease of performance and the broad availability of TUNEL assay kits for various applications, such as single-cell analysis of apoptosis in cell cultures and tissue samples. However, as briefly discussed herein, aside from some concerns relating to the specificity of the TUNEL assay itself, it was demonstrated some twenty years ago that the early stages of apoptosis, detected by TUNEL, can be reversed. More recently, compelling evidence from different biological systems has revealed that cells can recover from even late stage apoptosis through a process called anastasis. Specifically, such recovery has been observed in cells exhibiting caspase activation, genomic DNA breakage, phosphatidylserine externalization, and formation of apoptotic bodies. Furthermore, there is solid evidence demonstrating that apoptotic cells can promote neighboring tumor cell repopulation (e.g., through caspase-3-mediated secretion of prostaglandin E) and confer resistance to anticancer therapy. Accordingly, caution should be exercised in the interpretation of results obtained by the TUNEL and other apoptosis assays (e.g., caspase activation) in terms of apoptotic cell demise.
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http://dx.doi.org/10.3390/ijms21239090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730366PMC
November 2020

Targeting the RhoGEF βPIX/COOL-1 in Glioblastoma: Proof of Concept Studies.

Cancers (Basel) 2020 Nov 26;12(12). Epub 2020 Nov 26.

Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.

Glioblastoma (GBM), a highly invasive and vascular malignancy is shown to rapidly develop resistance and evolve to a more invasive phenotype following bevacizumab (Bev) therapy. Rho Guanine Nucleotide Exchange Factor proteins (RhoGEFs) are mediators of key components in Bev resistance pathways, GBM and Bev-induced invasion. To identify GEFs with enhanced mRNA expression in the leading edge of GBM tumours, a cohort of GEFs was assessed using a clinical dataset. The GEF βPix/COOL-1 was identified, and the functional effect of gene depletion assessed using 3D-boyden chamber, proliferation, and colony formation assays in GBM cells. Anti-angiogenic effects were assessed in endothelial cells using tube formation and wound healing assays. In vivo effects of βPix/COOL-1-siRNA delivered via RGD-Nanoparticle in combination with Bev was studied in an invasive model of GBM. We found that siRNA-mediated knockdown of βPix/COOL-1 in vitro decreased cell invasion, proliferation and increased apoptosis in GBM cell lines. Moreover βPix/COOL-1 mediated endothelial cell migration in vitro. Mice treated with βPix/COOL-1 siRNA-loaded RGD-Nanoparticle and Bev demonstrated a trend towards improved median survival compared with Bev monotherapy. Our hypothesis generating study suggests that the RhoGEF βPix/COOL-1 may represent a target of vulnerability in GBM, in particular to improve Bev efficacy.
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http://dx.doi.org/10.3390/cancers12123531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761123PMC
November 2020

Reply.

Authors:
David Murray

J Vasc Surg 2020 12;72(6):2213-2214

Department of Vascular Surgery, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, United Kingdom.

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http://dx.doi.org/10.1016/j.jvs.2020.06.010DOI Listing
December 2020

Implications of detecting serum monoclonal protein by MASS-fix following stem cell transplantation in multiple myeloma.

Br J Haematol 2020 Nov 20. Epub 2020 Nov 20.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

Measurable residual disease (MRD) assessment by marrow-based next-generation flow cytometry (NGF) following autologous stem cell transplantation (ASCT) may lead to false-negative results due to patchy marrow involvement and extramedullary disease in patients with multiple myeloma. We assessed the value of simultaneous MRD evaluation with NGF and serum matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MASS-FIX). Of all 61 complete responders who were NGF-negative for MRD, around day-100 post ASCT, 59% were MASS-FIX-positive. At median follow-up of 26 months, 69% of MASS-FIX(+)/NGF(-) patients were alive and progression-free versus 96% of MASS-FIX(-)/NGF(-) patients, P = 0·02. MASS-FIX, a simple peripheral blood-based assay complements marrow-based NGF to accurately prognosticate patients with myeloma.
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http://dx.doi.org/10.1111/bjh.17195DOI Listing
November 2020

Development of a patient-reported outcome measure (PROM) and change measure for use in early recovery following hip or knee replacement.

J Patient Rep Outcomes 2020 Nov 7;4(1):91. Epub 2020 Nov 7.

Nuffield Department of Population Health, University of Oxford, Headington, Oxford, OX37LF, England.

Background: Hip and knee replacement are effective procedures for end-stage arthritis that has not responded to medical management. However, until now, there have been no validated, patient-reported tools to measure early recovery in this growing patient population. The process of development and psychometric evaluation of the Oxford Arthroplasty Early Recovery Score (OARS), a 14-item patient-reported outcome measure (PROM) measuring health status, and the Oxford Arthroplasty Early Change Score (OACS) a 14-item measure to assess change during the first 6 weeks following surgery is reported.

Patients And Methods: A five-phased, best practice, iterative approach was used. From a literature based starting point, qualitative interviews with orthopaedic healthcare professionals, were then performed ascertaining if and how clinicians would use such a PROM and change measure. Analysis of in-depth patient-interviews in phase one identified important patient-reported factors in early recovery which were used to provide questionnaire themes. In Phase two, candidate items from Phase One interviews were generated and pilot questionnaires developed and tested. Exploratory factor analysis with item reduction and final testing of the questionnaires was performed in phase three. Phase Four involved validation testing.

Results: Qualitative interviews (n = 22) with orthopaedic healthcare professionals, helped determine views of potential users, and guide structure. In Phase One, factors from patient interviews (n = 30) were used to find questionnaire themes and generate items. Pilot questionnaires were developed and tested in Phase Two. Items were refined in the context of cognitive debrief interviews (n = 34) for potential inclusion in the final tools. Final testing of questionnaire properties with item reduction (n = 168) was carried out in phase three. Validation of the OARS and OACS was performed in phase four. Both measures were administered to consecutive patients (n = 155) in an independent cohort. Validity and reliability were assessed. Psychometric testing showed positive results, in terms of internal consistency and sensitivity to change, content validity and relevance to patients and clinicians. In addition, these measures have been found to be acceptable to patients throughout early recovery with validation across the 6 week period.

Conclusions: These brief, easy-to-use tools could be of great use in assessing recovery pathways and interventions in arthroplasty surgery.
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http://dx.doi.org/10.1186/s41687-020-00262-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648815PMC
November 2020

Liquid Chromatography-Tandem Mass Spectrometry-Based α1-Antitrypsin (AAT) Testing.

Am J Clin Pathol 2020 Oct 21. Epub 2020 Oct 21.

Department of Laboratory Medicine and Pathology.

Objectives: Failure to produce sufficient quantities of functional α1-antitrypsin (AAT) can result in AAT deficiency (AATD) and significant comorbidities. Laboratory testing plays a vital role in AATD, with diagnosis requiring documentation of both a low AAT level and a mutated allele. This retrospective evaluation examines the efficacy of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) (proteotyping)-based algorithm for AATD detection.

Methods: A 16-month retrospective data analysis was performed on two cohorts: 5,474 samples tested with the proteotype-based algorithm and 16,147 samples directly tested by isoelectric focusing (IEF) phenotyping.

Results: LC-MS/MS reduced the rate of IEF testing by 97%. The 3% of cases reflexed to IEF resulted in 12 (0.2%) additional phenotype findings. Retrospectively applying the proteotype-based algorithm to the IEF cohort demonstrated a 99.9% sensitivity for the detection of deficiency-associated phenotypes. Most deficiency phenotypes missed by the proteotyping algorithm would come from heterozygous patients with an F, I, or P paired to an S or Z. In all of these cases, patient AAT levels were greater than 70 mg/dL, above the threshold for AAT augmentation therapy.

Conclusions: The proteotype algorithm is a sensitive and cost-effective approach for the diagnosis of clinical AAT deficiency.
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http://dx.doi.org/10.1093/ajcp/aqaa149DOI Listing
October 2020

Development of novel methods for non-canonical myeloma protein analysis with an innovative adaptation of immunofixation electrophoresis, native top-down mass spectrometry, and middle-down de novo sequencing.

Clin Chem Lab Med 2020 Oct 20. Epub 2020 Oct 20.

Proteomics Center of Excellence & Departments of Chemistry and Molecular Biology,Northwestern University, Evanston, IL, USA.

Objectives: Multiple myeloma (MM) is a malignant plasma cell neoplasm, requiring the integration of clinical examination, laboratory and radiological investigations for diagnosis. Detection and isotypic identification of the monoclonal protein(s) and measurement of other relevant biomarkers in serum and urine are pivotal analyses. However, occasionally this approach fails to characterize complex protein signatures. Here we describe the development and application of next generation mass spectrometry (MS) techniques, and a novel adaptation of immunofixation, to interrogate non-canonical monoclonal immunoproteins.

Methods: Immunoprecipitation immunofixation (IP-IFE) was performed on a Sebia Hydrasys Scan2. Middle-down de novo sequencing and native MS were performed with multiple instruments (21T FT-ICR, Q Exactive HF, Orbitrap Fusion Lumos, and Orbitrap Eclipse). Post-acquisition data analysis was performed using Xcalibur Qual Browser, ProSight Lite, and TDValidator.

Results: We adapted a novel variation of immunofixation electrophoresis (IFE) with an antibody-specific immunosubtraction step, providing insight into the clonal signature of gamma-zone monoclonal immunoglobulin (M-protein) species. We developed and applied advanced mass spectrometric techniques such as middle-down de novo sequencing to attain in-depth characterization of the primary sequence of an M-protein. Quaternary structures of M-proteins were elucidated by native MS, revealing a previously unprecedented non-covalently associated hetero-tetrameric immunoglobulin.

Conclusions: Next generation proteomic solutions offer great potential for characterizing complex protein structures and may eventually replace current electrophoretic approaches for the identification and quantification of M-proteins. They can also contribute to greater understanding of MM pathogenesis, enabling classification of patients into new subtypes, improved risk stratification and the potential to inform decisions on future personalized treatment modalities.
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http://dx.doi.org/10.1515/cclm-2020-1072DOI Listing
October 2020

The effect of obesity on revision rate in unicompartmental knee arthroplasty: a systematic review and meta-analysis.

Knee Surg Sports Traumatol Arthrosc 2020 Oct 16. Epub 2020 Oct 16.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Windmill Road, Oxford, OX3 7LD, UK.

The number of patients with knee osteoarthritis, the proportion that is obese and the number undergoing unicompartmental knee arthroplasty (UKA) are all increasing. The primary aim of this systematic review was to determine the effects of obesity on outcomes in UKA. A systematic review was performed using PRISMA guidelines and the primary outcome was revision rate per 100 observed component years, with a BMI of ≥ 30 used to define obesity. The MINORS criteria and OCEBM criteria were used to assess risk of bias and level of evidence, respectively. 9 studies were included in the analysis. In total there were 4621 knees that underwent UKA. The mean age in included studies was reported to be 63 years (mean range 59.5-72 years old)) and range of follow up was 2-18 years. Four studies were OCEBM level 2b and the average MINORS score was 13. The mean revision rate in obese patients (BMI > 30) was 0.33% pa (95% CI - 3.16 to 2.5) higher than in non-obese patients, however this was not statistically significant (p = 0.82). This meta-analysis concludes that there is no significant difference in outcomes between obese and non-obese patients undergoing UKA. There is currently no evidence that obesity should be considered a definite contraindication to UKA. Further studies are needed to increase the numbers in meta-analysis to explore activity levels, surgeon's operative data, implant design and perioperative complications and revision in more depth.Level of evidence Level III.
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http://dx.doi.org/10.1007/s00167-020-06297-7DOI Listing
October 2020

Low polyethylene creep and wear following mobile-bearing unicompartmental knee replacement.

Knee Surg Sports Traumatol Arthrosc 2020 Sep 17. Epub 2020 Sep 17.

Oxford Orthopaedic Engineering Centre, NDORMS, University of Oxford, Oxford, UK.

Purpose: The Oxford unicompartmental knee replacement (UKR) has a fully congruent mobile bearing to minimise wear. However, with younger higher demand patients, wear remains a concern. The aim of this study was to quantify the wear rate of Phase 3 Oxford UKR bearings over the course of 5 years and to identify the factors that influence it.

Methods: 40 medial Oxford UKRs recruited for a randomised study of cemented and cementless fixation were studied with Radiostereometric analysis (RSA) at 1 week, 3 months, 6 months, 1 year, 2 years, and 5 years post-operatively and bearing thickness was calculated. Penetration, defined as the change in thickness compared to the 1-week measurement, was determined. Creep (early penetration) and wear (late penetration at a constant rate) were calculated. The influence of demographic factors, Oxford Knee Score (OKS), Tegner score, fixation and bearing overhang (determined by RSA) on wear was analysed.

Results: After 6 months the penetration rate was constant, indicating that wear alone was occurring. The wear rate was 0.07 mm/year (SD 0.03). The creep was 0.06 mm with about 95% occurring during the first 3 months. There was no significant relationship between fixation (cemented/cementless), age, component size, OKS and Tegner score with wear rate. Increasing BMI was associated with decreasing wear (p = 0.042). 37/40 bearings overhung the tibia to some extent and 23/40 overhung the tibia medially. An increase in the area of overhang (p = 0.036), amount of medial overhang (p = 0.028) and distance between the bearing and tibial wall (p = 0.019) were associated with increased wear. Bearings that did not overhang (0.06 mm/year) had less wear (p = 0.025) than those that did (0.08 mm/year). There was no relationship (p = 0.6) between the femoral contact area and wear.

Conclusion: During the first three to six months after implantation, the bearing becomes 0.06 mm thinner due to creep. The combined wear rate of the upper and lower surfaces of the bearing is constant (0.07 mm/year). The wear is lower if the bearing does not overhang the tibia so surgeons should aim for the bearing to be close to the tibial wall. The orientation of the femoral component does not influence wear.

Level Of Evidence: Retrospective Study, Level III.
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http://dx.doi.org/10.1007/s00167-020-06243-7DOI Listing
September 2020

Additions to the "Martian Flora": new botanical records from the Mars Desert Research Station, Utah.

Biodivers Data J 2020 18;8:e55063. Epub 2020 Aug 18.

Mars Society, Lakewood, United States of America Mars Society Lakewood United States of America.

The Mars Desert Research Station (MDRS) is a Mars-simulation campus set in a Martian planetary analogue in southern Utah. Despite a long history of astrobiology research, collections-based taxonomic inventories of the macro-level biodiversity around the station are relatively new. This study serves to add to the initial vascular plant list published for the station in 2016, where 39 species were recorded for MDRS. Here we report 40 new species, two new taxa recorded only to genus and two species re-identified from our 2016 fieldwork, bringing the total number of taxa in the "Martian" flora to 79 species and two taxa recorded to genus.
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http://dx.doi.org/10.3897/BDJ.8.e55063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447676PMC
August 2020

Free Light Chain Assay Drift: Potential for Misdiagnosis?

J Appl Lab Med 2020 11;5(6):1411-1413

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1093/jalm/jfaa093DOI Listing
November 2020

Cellular Responses to Platinum-Based Anticancer Drugs and UVC: Role of p53 and Implications for Cancer Therapy.

Int J Mol Sci 2020 Aug 11;21(16). Epub 2020 Aug 11.

Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada.

Chemotherapy is intended to induce cancer cell death through apoptosis and other avenues. Unfortunately, as discussed in this article, moderate doses of genotoxic drugs such as cisplatin typical of those achieved in the clinic often invoke a cytostatic/dormancy rather than cytotoxic/apoptosis response in solid tumour-derived cell lines. This is commonly manifested by an extended apoptotic threshold, with extensive apoptosis only being seen after very high/supralethal doses of such agents. The dormancy response can be associated with senescence-like features, polyploidy and/or multinucleation, depending in part on the p53 status of the cells. In most solid tumour-derived cells, dormancy represents a long-term survival mechanism, ultimately contributing to disease recurrence. This review highlights the nonlinearity of key aspects of the molecular and cellular responses to bulky DNA lesions in human cells treated with chemotherapeutic drugs (e.g., cisplatin) or ultraviolet light-C (a widely used tool for unraveling details of the DNA damage-response) as a function of the level of genotoxic stress. Such data highlight the growing realization that targeting dormant cancer cells, which frequently emerge following conventional anticancer treatments, may represent a novel strategy to prevent or, at least, significantly suppress cancer recurrence.
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http://dx.doi.org/10.3390/ijms21165766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461110PMC
August 2020

The Mid- to Long-Term Outcomes of the Lateral Domed Oxford Unicompartmental Knee Replacement: An Analysis From the National Joint Registry for England, Wales, Northern Ireland, and the Isle of Man.

J Arthroplasty 2021 Jan 17;36(1):107-111. Epub 2020 Jul 17.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Nuffield Orthopaedic Centre, Oxford, United Kingdom.

Background: Lateral unicompartmental knee replacement (UKR) is an alternative to total knee replacement for isolated lateral unicompartmental knee arthritis. The geometry and mechanics of the lateral compartment differ to the medial compartment with the Lateral Domed Oxford UKR designed to address this. We used the National Joint Registry (NJR) data to report the mid- to long-term outcomes of this device.

Methods: We performed a retrospective observational study using NJR data on 992 Lateral Domed Oxford UKRs implanted between 1st January 2005 and 31st December 2017. Outcomes of interest were implant survival and revision indications.

Results: The 10 year cumulative implant survival rates were 88.6% (CI 85.3-91.2). When compared with <55 year age group, the 55-64, 65-74 and ≥75 groups had significantly lower revision rates (hazard ratio (HR) = 0.56 (CI 0.32-0.98, P = .04), HR 0.40 (CI 0.22-0.72, P = .003), and HR 0.27 (CI 0.12-0.58, P = .001), respectively). The obese group had significantly (P = .04) increased revision risk compared with normal BMI (HR 2.33, CI 1.06-5.12). The commonest reasons for revision surgery were dislocation (n = 23, 2.3%), pain (n = 15, 1.5%), and aseptic loosening (n = 14, 1.4%).

Conclusion: The Lateral Domed Oxford UKR provides a good option for isolated lateral compartment osteoarthritis. However, dislocation of the mobile bearing remains a problem, occurring in 2.3% of the patients and accounting for 30% of the revisions. To help prevent dislocation, it is now possible to assess bearing stability intraoperatively and if very unstable to implant a compatible fixed bearing tibial component, without the need for further bone preparation.
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http://dx.doi.org/10.1016/j.arth.2020.07.031DOI Listing
January 2021

Automation and validation of a MALDI-TOF MS (Mass-Fix) replacement of immunofixation electrophoresis in the clinical lab.

Clin Chem Lab Med 2020 Aug 3;59(1):155-163. Epub 2020 Aug 3.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Objectives: A matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) method (Mass-Fix) as a replacement for gel-based immunofixation (IFE) has been recently described. To utilize Mass-Fix clinically, a validated automated method was required. Our aim was to automate the pre-analytical processing, improve positive specimen identification and ergonomics, reduce paper data storage and increase resource utilization without increasing turnaround time.

Methods: Serum samples were batched and loaded onto a liquid handler along with reagents and a barcoded sample plate. The pre-analytical steps included: (1) Plating immunopurification beads. (2) Adding 10 μl of serum. (3) Bead washing. (4) Eluting the immunoglobulins (Igs), and reducing to separate the heavy and light Ig chains. The resulting plate was transferred to a second low-volume liquid handler for MALDI plate spotting. MALDI-TOF mass spectra were collected. Integrated in-house developed software was utilized for sample tracking, driving data acquisition, data analysis, history tracking, and result reporting. A total of 1,029 residual serum samples were run using the automated system and results were compared to prior electrophoretic results.

Results: The automated Mass-Fix method was capable of meeting the validation requirements of concordance with IFE, limit of detection (LOD), sample stability and reproducibility with a low repeat rate. Automation and integrated software allowed a single user to process 320 samples in an 8 h shift. Software display facilitated identification of monoclonal proteins. Additionally, the process maintains positive specimen identification, reduces manual pipetting, allows for paper free tracking, and does not significantly impact turnaround time (TAT).

Conclusions: Mass-Fix is ready for implementation in a high-throughput clinical laboratory.
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http://dx.doi.org/10.1515/cclm-2020-0581DOI Listing
August 2020

Delayed knee flexion is a safe and effective pathway for Total Knee Replacement.

Physiotherapy 2020 09 8;108:45. Epub 2020 Jun 8.

Clinical Director, Professor of Physiotherapy, Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7HE, UK.

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http://dx.doi.org/10.1016/j.physio.2020.05.002DOI Listing
September 2020

Association of α 1 Antitrypsin Phenotype and Development of Advanced Liver Disease and Pulmonary Complications Before and After Liver Transplantation.

Transplantation 2020 Jul 6. Epub 2020 Jul 6.

William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic College of Medicine, 200 1 street, SW, Rochester, MN 55902.

Objective: The role of MZ phenotype of α 1 antitrypsin (α1AT) deficiency as a potential cofactor in advanced liver disease arising from other primary etiologies is not widely understood. In the general population, MZ phenotype accounts for 2-4% in Europe and 2-7.1% in North America. The aim of this study was to determine the prevalence of the MZ phenotype among various etiologies of cirrhosis in the U.S. in the modern era and its impact on pulmonary function before and after liver transplantation.

Methods: This retrospective study included adult patients with cirrhosis who underwent liver transplantation at Mayo Clinic. Participants' data including etiology of cirrhosis, MELD-Na score, α1AT phenotype, liver decompensation events and pulmonary outcomes was determined by retrospective review of the liver transplantation database.

Results: 130/1341 adult patients with cirrhosis (9.7%) were α1AT MZ carriers. When comparing the distribution of PI MZ among different etiologies, the prevalence of MZ was significantly increased in NASH, ALD, and cryptogenic cirrhosis compared to other etiologies. 37/171 with NASH (22%), 37/187 with ALD (20%), and 9/39 with cryptogenic cirrhosis (23.1%) were identified as PI MZ, while in other subgroups; we detected 18/320 with viral hepatitis, and 11/339 with PBC/PSC. Also, MZ patients were more likely to develop preoperative COPD, and postoperative pulmonary hypertension and pulmonary embolism than MM patients.

Conclusion: The rates of preoperative and postoperative pulmonary complications were found to be higher in PI MZ patients than in PI MM patients. The MZ phenotype was significantly enriched in NASH, ALD and cryptogenic cirrhosis.
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http://dx.doi.org/10.1097/TP.0000000000003390DOI Listing
July 2020

Oxford domed lateral unicompartmental knee arthroplasty.

Bone Joint J 2020 Aug;102-B(8):1033-1040

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, UK.

Aims: To report mid- to long-term results of Oxford mobile bearing domed lateral unicompartmental knee arthroplasty (UKA), and determine the effect of potential contraindications on outcome.

Methods: A total of 325 consecutive domed lateral UKAs undertaken for the recommended indications were included, and their functional and survival outcomes were assessed. The effects of age, weight, activity, and the presence of full-thickness erosions of cartilage in the patellofemoral joint on outcome were evaluated.

Results: Median follow-up was seven years (3 to 14), and mean age at surgery was 65 years (39 to 90). Median Oxford Knee Score (OKS) was 43 (interquartile range (IQR) 37 to 47), with 260 (80%) achieving a good or excellent score (OKS > 34). Revisions occurred in 34 (10%); 14 (4%) were for dislocation, of which 12 had no recurrence following insertion of a new bearing, and 12 (4%) were revised for medial osteoarthritis (OA). Ten-year survival was 85% (95% confidence interval (CI) 79 to 90, at risk 72). Age, weight, activity, and patellofemoral erosions did not have a significant effect on the clinical outcome or survival.

Conclusion: Domed lateral UKA provides a good alternative to total knee arthroplasty (TKA) in the management of lateral compartment OA. Although dislocation is relatively easy to treat successfully, the dislocation rate of 4% is high. It is recommended that the stability of the bearing is assessed intraoperatively. If the bearing can easily be displaced, the fixed rather than the mobile bearing version of the Oxford lateral tibial component should be inserted instead. Younger age, heavier weight, high activity, and patellofemoral erosions did not detrimentally affect outcome, so should not be considered contraindications. Cite this article: 2020;102-B(8):1033-1040.
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http://dx.doi.org/10.1302/0301-620X.102B8.BJJ-2019-1330.R2DOI Listing
August 2020

A study from The Mayo Clinic evaluated long-term outcomes of kidney transplantation in patients with immunoglobulin light chain amyloidosis.

Kidney Int 2021 03 23;99(3):707-715. Epub 2020 Jul 23.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA; Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

Longer survival using modern therapies has increased the number of patients with immunoglobulin light-chain amyloidosis receiving kidney transplantation. We evaluated 60 patients with immunoglobulin light chain amyloidosis who underwent kidney transplantation based on their hematologic response for outcomes of death, graft failure, and complications. Patient hematologic responses (light-chain in blood or urine) prior to kidney transplantation were three patients had no response, five had a partial response, six had a very good partial response, 37 had a complete response, and nine were treatment-naive patients (never treated for this disorder). After transplantation, seven of nine treatment-naive patients achieved a complete response. The median follow-up for the entire transplant cohort was 61 months. The estimated median overall survival from the time of kidney transplantation was 123 months for the entire group. Median overall survival was not reached for the very good partial response plus complete response groups, it was 47 months for no response plus partial response groups, and 117 months for the treatment-naive group (all significantly different). Median overall survival of very good partial response was 81 months, while the median was not reached in the complete response group (no significant difference). The time to amyloid recurrence was significantly longer in complete response compared to very good partial response (median 181 vs 81 months). Death-censored graft survival at one- and five-years was 98.3%, and 95.8%, respectively for all groups. Of the 60 patients, three had allograft failure, 19 died with a functioning graft, and 13 had an amyloid recurrence. Thus, outcomes after kidney transplant in patients with immunoglobulin light-chain amyloidosis seem acceptable if a very good partial response or complete response is achieved either before or after transplantation.
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http://dx.doi.org/10.1016/j.kint.2020.06.036DOI Listing
March 2021