Publications by authors named "Chris Burns"

49 Publications

National control laboratory independent lot testing of COVID-19 vaccines: the UK experience.

NPJ Vaccines 2021 Aug 12;6(1):100. Epub 2021 Aug 12.

The National Institute for Biological Standards and Control, a Centre of the Medicines and Healthcare products Regulatory Agency, Division of Biotherapeutics, Hertfordshire, United Kingdom.

The past 18 months have seen an unprecedented approach to vaccine development in the global effort against the COVID-19 pandemic. The process from discovery research, through clinical trials and regulatory approval often takes more than 10 years. However, the critical need to expedite vaccine availability in the pandemic has meant that new approaches to development, manufacturing, and regulation have been required: this has necessitated many stages of product development, clinical trials, and manufacturing to be undertaken in parallel at a global level. Through the development of these innovative products, the world has the best chance of finding individual, or combinations of, vaccines that will provide adequate protection for the world's population. Despite the huge scientific and regulatory achievements and significant investment to accelerate vaccine availability, it is essential that safety measures are not compromised. Here we focus on the post regulatory approval testing by independent laboratories that provides an additional assurance of the safety and quality of a product, with an emphasis on the UK experience through the National Institute for Biological Standards and Control (NIBSC), an expert centre of the UK's Medicines and Healthcare products Regulatory Agency (MHRA).
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http://dx.doi.org/10.1038/s41541-021-00368-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360948PMC
August 2021

Challenges in Measuring AMH in the Clinical Setting.

Front Endocrinol (Lausanne) 2021 24;12:691432. Epub 2021 May 24.

Discipline of Obstetrics & Gynaecology, School of Women's & Children's Health, University of New South Wales, Sydney, NSW, Australia.

Serum anti-Mullerian hormone (AMH) is a widely used marker of functional ovarian reserve in the assessment and treatment of infertility. It is used to determine dosing of gonadotropins used for superovulation prior to fertilization, as well as to determine the degree of damage to ovarian reserve by cytotoxic treatments such as chemotherapy. AMH is also now used to predict proximity to menopause and potentially provides a sensitive and specific test for polycystic ovarian syndrome. Twenty one different AMH immunoassay platforms/methods are now commercially available. Of those compared, the random-access platforms are the most reliable. However, to date there has not been an agreed common international AMH reference preparation to standardize calibration between the various immunoassays. Recently, a purified human AMH preparation (code 16/190) has been investigated by the World Health Organization as a potential international reference preparation. However, this was only partially successful as commutability between it and serum samples was observed only in some but not all immunoassay methods. Development of a second generation reference preparation with wider commutability is proposed.
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http://dx.doi.org/10.3389/fendo.2021.691432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183164PMC
May 2021

Therapeutic targets in lung tissue remodelling and fibrosis.

Pharmacol Ther 2021 09 25;225:107839. Epub 2021 Mar 25.

Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia. Electronic address:

Structural changes involving tissue remodelling and fibrosis are major features of many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Abnormal deposition of extracellular matrix (ECM) proteins is a key factor in the development of tissue remodelling that results in symptoms and impaired lung function in these diseases. Tissue remodelling in the lungs is complex and differs between compartments. Some pathways are common but tissue remodelling around the airways and in the parenchyma have different morphologies. Hence it is critical to evaluate both common fibrotic pathways and those that are specific to different compartments; thereby expanding the understanding of the pathogenesis of fibrosis and remodelling in the airways and parenchyma in asthma, COPD and IPF with a view to developing therapeutic strategies for each. Here we review the current understanding of remodelling features and underlying mechanisms in these major respiratory diseases. The differences and similarities of remodelling are used to highlight potential common therapeutic targets and strategies. One central pathway in remodelling processes involves transforming growth factor (TGF)-β induced fibroblast activation and myofibroblast differentiation that increases ECM production. The current treatments and clinical trials targeting remodelling are described, as well as potential future directions. These endeavours are indicative of the renewed effort and optimism for drug discovery targeting tissue remodelling and fibrosis.
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http://dx.doi.org/10.1016/j.pharmthera.2021.107839DOI Listing
September 2021

Maintaining 'standards' for biosimilar monoclonal antibodies.

Nat Biotechnol 2021 03;39(3):276-280

National Institute for Biological Standards and Control (NIBSC), South Mimms, United Kingdom.

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http://dx.doi.org/10.1038/s41587-021-00848-0DOI Listing
March 2021

Assessing health literacy among adult outpatients attending allied health clinics in western sydney: A cross-sectional survey using a multidimensional instrument.

Health Promot J Austr 2021 Jan 11. Epub 2021 Jan 11.

Westmead Hospital, Western Sydney Local Health District, Sydney, Australia.

Issue Addressed: Low health literacy disproportionately affects adults from culturally and linguistically diverse backgrounds. This study investigated the health literacy of adults attending outpatient allied health services in western Sydney, a highly diverse region in Sydney with residents from a range of cultural and linguistic backgrounds.

Methods: A cross-sectional survey was undertaken between March and April 2017 using the Health Literacy Questionnaire (HLQ). Participants, aged over 18 years and with a primary language of English, Arabic, Chinese or Hindi, were recruited from outpatient allied health clinics at Westmead Hospital. Means (standard deviation) for each of the nine HLQ domains were calculated and associations with demographic variables were investigated using analysis of variance (ANOVA).

Results: Two hundred and thirty people were included with mean age of 45.1 years (SD = 19.0), the majority were female (75.5%), over half were born overseas (55.7%) and 77.6% reported speaking English at home. The highest mean score on a HLQ domain (out of 5) was "Understanding health information well enough to know what to do" (M = 4.19; SD = 0.67), and the lowest mean score (out of 4) was "Appraisal of health information" (M = 2.97; SD = 0.54). Participants who did not speak English at home had significantly lower scores on seven of the nine HLQ domains.

Conclusions: Important health literacy strengths and limitations of a diverse sample of adults attending outpatient allied health services in western Sydney were identified. Findings should be considered in the light of the cross-sectional survey methodology with non-random sampling.

So What: Data will inform future interventions to improve health literacy and health outcomes among vulnerable population groups in western Sydney.
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http://dx.doi.org/10.1002/hpja.456DOI Listing
January 2021

Establishment of a WHO Reference Reagent for anti-Mullerian hormone.

Reprod Biol Endocrinol 2020 Aug 15;18(1):86. Epub 2020 Aug 15.

Biotherapeutics Division, National Institute for Biological Standards and Control, South Mimms, Potters Bar, Hertfordshire, UK.

Background: There is a need for a reference material to support the development and ensure the quality of immunoassays for human AMH. A batch of ampoules, coded 16/190, containing lyophilised recombinant AMH was evaluated in a WHO Collaborative Study. The aims of the study were to determine the AMH content in terms of the calibration of each immunoassay method, to predict long-term stability and to assess the suitability of the preparation to calibrate AMH immunoassays.

Methods: Study participants were asked to report the AMH content of specific dilutions of coded ampoules of 16/190 and a comparator preparation containing approximately half the AMH content. In each assay, participants also reported the AMH content of 22 patient samples to assess commutability. A robust all-laboratory geometric mean of the content estimates was determined using the laboratory geometric mean estimates. Commutability was assessed using a difference in bias approach. Stability was predicted by the measurement of thermally accelerated degradation samples.

Results: Seven laboratories performed twenty-one immunoassay method-platform combinations, sixteen of which provided data which met the validity criteria, giving a consensus geometric mean estimate of AMH content of 511 ng/ampoule (95% CI, 426-612, n = 16, GCV 42%) and a robust geometric mean of 489 ng/ampoule. By contrast, the GCV% for the all-laboratory geometric mean of the relative content estimates for the comparator sample to 16/190 was 12%. Commutability was assessed using 20 of the 22 representative patient samples. Of the valid assays, 16/190 was within the limits of acceptable commutability for 6 methods, partially commutable for a further 3 methods and non-commutable when measured by 7 methods. The preparation was predicted to be highly stable when stored at - 20 °C.

Conclusion: The majority of methods met the validity criteria. Content estimates showed a high between-method variability, yet assays exhibited a similar proportionality of response as demonstrated using the comparator sample. 16/190 was commutable in some but not all methods. On the basis of these results, it was agreed by the WHO Expert Committee on Biological Standardization to establish 16/190 as a WHO Reference Reagent for AMH with a content defined by consensus immunoassay of 489 ng/ampoule.
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http://dx.doi.org/10.1186/s12958-020-00641-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429692PMC
August 2020

IFCC Working Group Recommendations for Correction of Bias Caused by Noncommutability of a Certified Reference Material Used in the Calibration Hierarchy of an End-User Measurement Procedure.

Clin Chem 2020 06;66(6):769-778

Centers for Disease Control and Prevention, Atlanta, GA.

Establishing metrological traceability to an assigned value of a matrix-based certified reference material (CRM) that has been validated to be commutable among available end-user measurement procedures (MPs) is central to producing equivalent results for the measurand in clinical samples (CSs) irrespective of the clinical laboratory MPs used. When a CRM is not commutable with CSs, the bias due to noncommutability will be propagated to the CS results causing incorrect metrological traceability to the CRM and nonequivalent CS results among different MPs. In a commutability assessment, a conclusion that a CRM is commutable or noncommutable for use with a specific MP is made when the difference in bias between the CRM and CSs meets or does not meet a criterion for that specific MP when compared to other MPs. A conclusion regarding commutability or noncommutability requires that the magnitude of the difference in bias observed in the commutability assessment remains unchanged over time. This conclusion requires the CRM to be stable and no substantive changes in the MPs. These conditions should be periodically reverified. If an available CRM is determined to be noncommutable for a specific MP, that CRM can be used in the calibration hierarchy for that MP when an appropriately validated MP-specific correction for the noncommutability bias is included. We describe with examples how a MP-specific correction and its uncertainty can be developed and applied in a calibration hierarchy to achieve metrological traceability of results for CSs to the CRM's assigned value.
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http://dx.doi.org/10.1093/clinchem/hvaa048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551486PMC
June 2020

Development and evaluation of a health literacy training program for allied health professionals: A pre-post study assessing impact and implementation outcomes.

Health Promot J Austr 2021 Feb 26;32 Suppl 1:88-97. Epub 2020 May 26.

Western Sydney Local Health District, Sydney, Australia.

Issue Addressed: We developed and evaluated a health literacy training program for allied health professionals, and explored the feasibility of a train-the-trainer model to support dissemination.

Methods: The program combined didactic and experiential teaching methods and behaviour change techniques, with a focus on teach-back and developing easy-to-understand written materials. Outcomes included participant reactions, confidence (range: 6-30), behavioural intentions (range: 6-42), and dissemination of training content. Implementation outcomes were evaluated using the Normalization MeAsure Development (NoMAD) tool, assessing the constructs of coherence (range: 4-20), cognitive participation (range: 4-20), collective action (range: 7-35) and reflexive monitoring (range: 5-25).

Results: Of the 29 allied health professionals who participated, 90% rated the program as 'excellent'/'very good', and 97% said the information was 'extremely'/'very' helpful for their everyday practice. We observed increases in confidence (mean difference [MD] = 6.3, standard deviation [SD] = 2.7, t  = 11.87, P < .001) and intentions (MD = 3.6, SD = 8.1, t  = 2.2, P = .04) related to health literacy practices after 6 weeks. Improved confidence was retained over 6 months (MD = 7.1, SD = 5.2, t  = 5.96, P < .001). After 6 months, 95% of participants (n = 19) reported using teach-back and 50% (n = 10) reported having used a readability formula. Eight-five per cent of participants (17/20) had trained others in health literacy, reaching n = 201 allied health professionals and students. NoMAD scores were highest in relation to cognitive participation (/20) (M = 18.2, SD = 2.1) and lowest in relation to collective action (/35) (M = 25.4, SD = 3.0).

Conclusions: A train-the-trainer model appears to be a feasible method to disseminate health literacy training, but additional work may be needed to improve the collective work done to enable health literacy practices in real-world clinical contexts.

So What: Staff training is particularly important in highly diverse areas where patients are disproportionately affected by low health literacy.
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http://dx.doi.org/10.1002/hpja.350DOI Listing
February 2021

Human iPSC-Derived Neural Crest Stem Cells Exhibit Low Immunogenicity.

Mol Ther Methods Clin Dev 2020 Mar 13;16:161-171. Epub 2020 Jan 13.

Endocrinology Section, Biotherapeutics, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, Potters Bar EN6 3QG, UK.

Recent clinical trials are evaluating induced pluripotent stem cells (iPSCs) as a cellular therapy in the field of regenerative medicine. The widespread clinical utility of iPSCs is expected to be realized using allogeneic cells that have undergone thorough safety evaluations, including assessment of their immunogenicity. IPSC-derived neural crest stem cells (NCSCs) have significant potential in regenerative medicine; however, their application in cellular therapy has not been widely studied to date, and no reports on their potential immunogenicity have been published so far. In this study, we have assessed the expression of immune-related antigens in iPSC-NCSCs, including human leukocyte antigen (HLA) class I and II and co-stimulatory molecules. To investigate functional immunogenicity, we used iPSC-NCSCs as stimulator cells in a one-way mixed lymphocyte reaction. In these experiments, iPSC-NCSCs did not stimulate detectable proliferation of CD3 and CD3CD8 T cells or induce cytokine production. We show that this was not a result of any immunosuppressive features of iPSC-NCSCs, but rather more consistent with their non-immunogenic molecular phenotype. These results are encouraging for the potential future use of iPSC-NCSCs as a cellular therapy.
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http://dx.doi.org/10.1016/j.omtm.2019.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005462PMC
March 2020

The first World Health Organization International Standard for in vitro biological activity of darbepoetin.

Biologicals 2020 Jan 18;63:33-38. Epub 2019 Dec 18.

National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Hertfordshire, EN6 3QG, UK.

The expiry of patents protecting the manufacture and sale of therapeutic darbepoetin products is expected to lead to the emergence of biosimilar products. In response to this, the first World Health Organization (WHO) International Standard (IS) for darbepoetin has been developed. A lyophilized preparation of darbepoetin, coded 17/204, was evaluated in an international collaborative study, the results of which suggest that the candidate preparation is suitable to serve as an IS. This material defines the International Unit (IU) of in vitro biological activity of darbepoetin and should be used to calibrate of in vitro potency assays of darbepoetin preparations. It is envisaged that widespread use of the IS will promote the consistency and harmonization of darbepoetin in vitro bioassay measurements in laboratories worldwide. Each ampoule contains 100,000 IU of darbepoetin activity. The IU is not intended to revise product labelling or dosing requirements, decisions regarding which lie solely with the regulatory authority. Additionally, the IS is not intended to define the specific activity of darbepoetin, as this may differ between products in the future. Finally, the IS is not intended to serve any regulatory role in defining biosimilarity (i.e. as a reference medicinal product).
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http://dx.doi.org/10.1016/j.biologicals.2019.12.004DOI Listing
January 2020

Continued provision of WHO International Standards for total and free PSA: Content and commutability of replacement preparations.

Clin Biochem 2019 Sep 8;71:58-66. Epub 2019 Jul 8.

Biotherapeutics Group, National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3QG, United Kingdom. Electronic address:

Objectives: Replacements are required for the WHO International Standards (IS) for free PSA, coded 96/668 and total PSA (90:10), coded 96/670, which were established in 1999 to support efforts to harmonise PSA assays and address non-equimolarity. An important consideration is that the introduction of the replacements should have minimal impact on PSA measurements.

Design And Methods: We report the development of a replacement strategy, informed by field assessment of preparations through an external quality assessment scheme and the subsequent evaluation of the candidate ISs in worldwide collaborative studies.

Results: By immunoassay, data from participants confirmed the value assigned to the current standards. Robust geometric mean estimates of the free PSA content of the candidate replacement for 96/668 coded 17/102 was 0.533 μg/ampoule (n = 21). The ratio of the content estimates of 17/102:96/668 was 0.516 (GCV 12.5%, n = 21). Robust geometric mean estimates of the total PSA content of the candidate replacement for 96/670, coded 17/100, was 0.505 μg/ampoule (n = 22). The ratio of the content estimates of 17/100:96/670 was 0.490 (GCV 5.3%, n = 22). Through concomitant measurement of a panel of 15 representative patient samples, the candidate ISs were shown to exhibit commutability with patient samples that was comparable with that of the current ISs.

Conclusion: On the basis of these results, the preparations coded 17/102 and 17/100 were established by the WHO Expert Committee on Biological Standardization as the 2nd ISs for free and total PSA (PSA-ACT+free PSA) respectively, with assigned contents of 0.53 μg/ampoule and 0.50 μg/ampoule.
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http://dx.doi.org/10.1016/j.clinbiochem.2019.07.007DOI Listing
September 2019

Applying the science of measurement to biology: Why bother?

PLoS Biol 2019 06 20;17(6):e3000338. Epub 2019 Jun 20.

National Institute of Biological Standards and Control, South Mimms, Potters Bar, Hertfordshire, United Kingdom.

Both basic and translational research are continuously evolving, but the principles that underpin research integrity remain constant. These include rational, hypothesis-driven, and adequately planned and controlled science, which is carried out openly, honestly, and ethically. An important component of this should be minimising experimental irreproducibility. Biological systems, in particular, are inherently variable due to the nature of cells and tissues, as well as the complex molecules within them. As a result, it is important to understand and identify sources of variability and to strive to minimise their influence. In many instances, the application of metrology (the science of measurement) can play an important role in ensuring good quality research, even within biological systems that aren't always amenable to many of the metrological concepts applied in other fields. Here, we introduce the basic concepts of metrology in relation to biological systems and promote the application of these principles to help avoid potentially costly mistakes in both basic and translational research. We also call on funders to encourage the uptake of metrological principles, as well as provide funding and support for later engagement with regulatory bodies.
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http://dx.doi.org/10.1371/journal.pbio.3000338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605671PMC
June 2019

Development of a stable chemically cross-linked erythropoietin dimer for use in the quality control of erythropoietin therapeutic products.

Anal Bioanal Chem 2019 May 10;411(13):2755-2758. Epub 2019 Apr 10.

National Institute for Biological Standards & Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, UK.

Erythropoietin (EPO) is a glycoprotein hormone which promotes red cell replenishment and is also a global biotherapeutic medicine widely used to treat anaemia resulting, for example, from chemotherapy. Requirements of the European Pharmacopoeia stipulate that the level of dimer must be quantified in clinical EPO products (with a limit of 2%). Quantification is hampered by the lack of reference preparations containing stable measurable levels of EPO dimer, but the reproducible generation of a stable dimerised EPO preparation is challenging. We describe here the development of a lyophilised, chemically cross-linked EPO preparation, which has good stability and may be used for calibration and system suitability assurance for the size exclusion chromatographic separation of EPO preparations. Graphical abstract.
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http://dx.doi.org/10.1007/s00216-019-01768-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522647PMC
May 2019

Concise Review: Exploring Immunomodulatory Features of Mesenchymal Stromal Cells in Humanized Mouse Models.

Stem Cells 2019 03 21;37(3):298-305. Epub 2018 Dec 21.

Endocrinology Section, Biotherapeutics, National Institute for Biological Standards and Control, South Mimms, United Kingdom.

With their immunosuppressive features, human mesenchymal stromal cells (MSCs), sometimes also termed as mesenchymal stem cells, hold great potential as a cell-based therapy for various immune-mediated diseases. Indeed, MSCs have already been approved as a treatment for graft versus host disease. However, contradictory data from clinical trials and lack of conclusive proof of efficacy hinder the progress toward wider clinical use of MSCs and highlight the need for more relevant disease models. Humanized mice are increasingly used as models to study immune-mediated disease, as they simulate human immunobiology more closely than conventional murine models. With further advances in their resemblance to human immunobiology, it is very likely that humanized mice will be used more commonly as models to investigate MSCs with regard to their therapeutic safety and their immunomodulatory effect and its underlying mechanisms. Recent studies that explore the immunosuppressive features of MSCs in humanized mouse models will be discussed in this review. Stem Cells 2019;37:298-305.
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http://dx.doi.org/10.1002/stem.2948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446739PMC
March 2019

Towards international standardization of immunoassays for Müllerian inhibiting substance/anti-Müllerian hormone.

Reprod Biomed Online 2018 Nov 5;37(5):631-640. Epub 2018 Sep 5.

Biotherapeutics Division, NIBSC, South Mimms, Potters Bar Hertfordshire, UK.

Research Question: Is formulated and lyophilized, recombinant human Müllerian inhibiting substance, also known as anti-Müllerian hormone (AMH), suitable for the preparation of a WHO international standard to calibrate AMH immunoassays?

Design: The AMH content of a trial preparation, coded SS-581, was determined by five laboratories using seven immunoassay methods. Participants were requested to report the content of the preparation in terms of their method calibrators through the measurement of a minimum of five concentrations in the linear part of the dose-response curve. Participants were also asked to measure, concomitantly, a panel of six serum samples containing AMH at concentrations of 0.1-13.0 ng/ml.

Results: Across all assays, including two automated assays in development, the geometric mean content was 361.76 ng/ampoule with a geometric coefficient of variation (GCV%) of 39.95%. When measured by immunoassays that were commercially available at the time of the study, the mean content was 423.08 ng/ampoule, with a GCV% of 26.67%. The inter-method geometric means of five serum samples with an AMH concentration >0.3 ng/ml and measured concomitantly with dilutions of SS-581 varied with a range of GCV% of 14.90-22.35%, which may reflect the use of serum sample value transfer to calibrate current immunoassays, some of which use non-human AMH calibrators. The AMH in trial preparation SS-581 was shown to be biologically active in the Müllerian duct regression assay.

Conclusions: A reference material prepared using human recombinant AMH is a promising candidate for the preparation of an international standard for AMH for immunoassays calibrated to recombinant human AMH.
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http://dx.doi.org/10.1016/j.rbmo.2018.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302068PMC
November 2018

An examination of the effect of open versus paywalled access publication on the disseminative impact and citation count of publications in intensive care medicine and anesthesia.

J Crit Care 2018 08 18;46:88-93. Epub 2018 May 18.

Department of Anesthesia, BreastCheck & Cork University Hospital, Wilton Road, Cork, Ireland.

Purpose: We aimed to assess the impact of open access (OA) versus paywalled access (PA) publication on Altmetric Attention Scores (AAS) and whether AAS correlates with future citation count access in the context of intensive care medicine (ICM) and anesthesia.

Methods: 1854 and 2935 publications, in the year 2015, were identified in ICM and anesthesia respectively, using a Pubmed search. The mean AAS was measured for each article.

Results: More ICM articles were OA, compared to of anesthesia articles (38.9% v 35.0% p = 0.02). The mean AAS for OA ICM publications was significantly higher than that of PA ICM publications (17.34 vs 8.45, p < 0.01), however, this was not observed when examined in a fixed follow up time frame. AAS appear to correlate with future citation counts.

Conclusions: ICM publications that are available as OA in the medium term result in higher AAS when compared to PA publications, this phenomenon was not observed in anesthesia. AAS correlate with future citation counts, however, a larger study is required to confirm this.
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http://dx.doi.org/10.1016/j.jcrc.2018.05.008DOI Listing
August 2018

Quantification of Müllerian Inhibiting Substance/Anti-Müllerian Hormone polypeptide by isotope dilution mass spectrometry.

Anal Biochem 2018 11 6;560:50-55. Epub 2018 May 6.

National Institute for Biological Standards and Control, South Mimms, Potters Bar, EN6 3QG, UK.

Measurement of serum concentrations of Müllerian inhibiting substance (MIS), also known as anti-Müllerian Hormone (AMH) by immunoassay is gaining clinical acceptance and widespread use for the diagnosis of ovarian conditions and for prediction of the response to ovarian stimulation protocols as part of assisted reproductive therapies. Provision of an International Standard to harmonize immunoassay methods is required. It is desirable for the content of a future International Standard to be assigned in mass units for consistency with the units reported by current methods. Isotope dilution mass spectrometry (IDMS), a physicochemical method with traceability to the SI (Système International d'Unités) unit of mass, is a candidate approach to provide orthogonal data to support this mass assignment. Here, we report on the development of an IDMS method for quantitation of AMH using three peptides from different regions of the AMH monomer as surrogates for the measurement of AMH. We show the sensitivity and linearity of the standard peptides and demonstrate the reproducibility and consistency of the measurement amongst the three peptides for determining the AMH content in buffered preparations and in trial preparations of recombinant AMH, lyophilised in the presence of an excess of bovine casein.
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http://dx.doi.org/10.1016/j.ab.2018.05.006DOI Listing
November 2018

TANK-Binding Kinase 1-Dependent Responses in Health and Autoimmunity.

Front Immunol 2018 6;9:434. Epub 2018 Mar 6.

Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

The pathogenesis of autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is driven by genetic predisposition and environmental triggers that lead to dysregulated immune responses. These include the generation of pathogenic autoantibodies and aberrant production of inflammatory cytokines. Current therapies for RA and other autoimmune diseases reduce inflammation by targeting inflammatory mediators, most of which are innate response cytokines, resulting in generalized immunosuppression. Overall, this strategy has been very successful, but not all patients respond, responses can diminish over time and numerous side effects can occur. Therapies that target the germinal center (GC) reaction and/or antibody-secreting plasma cells (PC) potentially provide a novel approach. TANK-binding kinase 1 (TBK1) is an IKK-related serine/threonine kinase best characterized for its involvement in innate antiviral responses through the induction of type I interferons. TBK1 is also gaining attention for its roles in humoral immune responses. In this review, we discuss the role of TBK1 in immunological pathways involved in the development and maintenance of antibody responses, with particular emphasis on its potential relevance in the pathogenesis of humoral autoimmunity. First, we review the role of TBK1 in the induction of type I IFNs. Second, we highlight how TBK1 mediates inducible T cell co-stimulator signaling to the GC T follicular B helper population. Third, we discuss emerging evidence on the contribution of TBK1 to autophagic pathways and the potential implications for immune cell function. Finally, we discuss the therapeutic potential of TBK1 inhibition in autoimmunity.
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http://dx.doi.org/10.3389/fimmu.2018.00434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845716PMC
June 2019

IFCC Working Group Recommendations for Assessing Commutability Part 2: Using the Difference in Bias between a Reference Material and Clinical Samples.

Clin Chem 2018 03 18;64(3):455-464. Epub 2018 Jan 18.

Department of Pathology, Virginia Commonwealth University, Richmond, VA.

A process is described to assess the commutability of a reference material (RM) intended for use as a calibrator, trueness control, or external quality assessment sample based on the difference in bias between an RM and clinical samples (CSs) measured using 2 different measurement procedures (MPs). This difference in bias is compared with a criterion based on a medically relevant difference between an RM and CS results to make a conclusion regarding commutability. When more than 2 MPs are included, the commutability is assessed pairwise for all combinations of 2 MPs. This approach allows the same criterion to be used for all combinations of MPs included in the assessment. The assessment is based on an error model that allows estimation of various random and systematic sources of error, including those from sample-specific effects of interfering substances. An advantage of this approach is that the difference in bias between an RM and the average bias of CSs at the concentration (i.e., amount of substance present or quantity value) of the RM is determined and its uncertainty estimated. An RM is considered fit for purpose for those MPs for which commutability is demonstrated.
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http://dx.doi.org/10.1373/clinchem.2017.277541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835923PMC
March 2018

IFCC Working Group Recommendations for Assessing Commutability Part 3: Using the Calibration Effectiveness of a Reference Material.

Clin Chem 2018 03 18;64(3):465-474. Epub 2018 Jan 18.

Department of Pathology, Virginia Commonwealth University, Richmond, VA.

A process is described to assess the commutability of a reference material (RM) intended for use as a calibrator based on its ability to fulfill its intended use in a calibration traceability scheme to produce equivalent clinical sample (CS) results among different measurement procedures (MPs) for the same measurand. Three sources of systematic error are elucidated in the context of creating the calibration model for translating MP signals to measurand amounts: calibration fit, calibrator level trueness, and commutability. An example set of 40 CS results from 7 MPs is used to illustrate estimation of bias and variability for each MP. The candidate RM is then used to recalibrate each MP, and its effectiveness in reducing the systematic error among the MPs within an acceptable level of equivalence based on medical requirements confirms its commutability for those MPs. The RM is declared noncommutable for MPs for which, after recalibration, the CS results do not agree with those from other MPs. When a lack of agreement is found, other potential causes, including lack of calibration fit, should be investigated before concluding the RM is noncommutable. The RM is considered fit for purpose for those MPs where commutability is demonstrated.
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http://dx.doi.org/10.1373/clinchem.2017.277558DOI Listing
March 2018

IFCC Working Group Recommendations for Assessing Commutability Part 1: General Experimental Design.

Clin Chem 2018 03 18;64(3):447-454. Epub 2018 Jan 18.

Centers for Disease Control and Prevention, Atlanta, GA.

Commutability is a property of a reference material (RM) that relates to the closeness of agreement between results for an RM and results for clinical samples (CSs) when measured by ≥2 measurement procedures (MPs). Commutability of RMs used in a calibration traceability scheme is an essential property for them to be fit for purpose. Similarly, commutability of trueness controls or external quality assessment samples is essential when those materials are used to assess trueness of results for CSs. This report is part 1 of a 3-part series describing how to assess commutability of RMs. Part 1 defines commutability and addresses critical components of the experimental design for commutability assessment, including selection of individual CSs, use of pooled CSs, qualification of MPs for inclusion, establishing criteria for the determination that an RM is commutable, generalization of commutability conclusions to future measurements made with the MPs included in the assessment, and information regarding commutability to be included in the certificate for an RM. Parts 2 and 3 in the series present 2 different statistical approaches to commutability assessment that use fixed criteria related to the medical decisions that will be made using the laboratory test results.
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http://dx.doi.org/10.1373/clinchem.2017.277525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832613PMC
March 2018

Implementing a Reference Measurement System for C-Peptide: Successes and Lessons Learned.

Clin Chem 2017 Sep 23;63(9):1447-1456. Epub 2017 Jun 23.

National Institute for Biological Standards and Control, South Mimms, UK.

Background: Assessment of endogenous insulin secretion by measuring C-peptide concentrations is widely accepted. Recent studies have shown that preservation of even small amounts of endogenous C-peptide production in patients with type 1 diabetes reduces risks for diabetic complications. Harmonization of C-peptide results will facilitate comparison of data from different research studies and later among clinical laboratory results at different sites using different assay methods.

Content: This review provides an overview of the general process of harmonization and standardization and the challenges encountered with implementing a reference measurement system for C-peptide.

Summary: Efforts to harmonize C-peptide results are described, including those by the National Institute of Diabetes and Digestive and Kidney Diseases-led C-peptide Standardization Committee in the US, activities in Japan, efforts by the National Institute for Biological Standards and Control in the UK, as well as activities led by the Bureau International des Poids et Mesures and the National Metrology Institute in China. A traceability scheme is proposed along with the next steps for implementation. Suggestions are made for better collaboration to optimize the harmonization process for other measurands.
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http://dx.doi.org/10.1373/clinchem.2016.269274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575958PMC
September 2017

Preparation, calibration and evaluation of the First International Standard for human C-peptide.

Clin Chem Lab Med 2017 Jul;55(8):1224-1233

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Background: Measurement of C-peptide by immunoassay contributes to the diagnosis of a number of disorders related to β cell function. Stocks of the current international reference reagent (IRR) for C-peptide, used to calibrate these immunoassays, are exhausted, and this report summarises the international study to establish a replacement World Health Organization (WHO) international standard (IS) to maintain the availability of a globally available reference material and support efforts to standardise C-peptide assays.

Methods: The study was conducted in three phases; phase I involved the assignment of a value to a primary calibrant in mass units by amino acid analysis and phase II applied this value to the calibration of a candidate standard, 13/146, by reversed phase high-performance liquid chromatography (RP-HPLC) assay. In phase III, the candidate standard was compared to the first IRR by current immunoassays to assess its suitability to serve as an IS.

Results: Calibration of the candidate standard by RP-HPLC gave a final estimated content of 8.64 μg/ampoule with expanded uncertainty of 8.21-9.07 μg/ampoule (95% confidence; k=2.45). The candidate standard also appears sufficiently stable to serve as an IS, based on HPLC analysis of accelerated thermal degradation samples of 13/146, and was also shown to have appropriate immunological activity. A difference in bias approach was used to assess the commutability of 13/146 with human serum and urine samples. With the exception of two laboratories, the candidate standard demonstrated commutability with respect to the serum and urine samples included in this study.

Conclusions: The candidate standard, 13/146, is suitable to serve as the First International Standard for human C-peptide, and it has been formally adopted by the Expert Committee on Biological Standardisation of the WHO.
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http://dx.doi.org/10.1515/cclm-2017-0029DOI Listing
July 2017

Developing the WorkingWell mobile app to promote job tenure for individuals with serious mental illnesses.

Psychiatr Rehabil J 2017 09 20;40(3):276-282. Epub 2016 Jun 20.

Dartmouth Psychiatric Research Center, Center for Technology & Behavioral Health, The Geisel School of Medicine.

Objective: Individuals living with serious mental illnesses are key stakeholders in user experience design and the development of the mobile app to enhance on-the-job follow-along support. In this study, Individual Placement and Support (IPS) consumers identify challenges in sustaining employment, provide data regarding their use of technology, and suggest technology-based solutions for coping on the job to inform app development.

Method: Focus groups were conducted in 3 agencies providing IPS services to examine consumers' perspectives on supported employment, work, and their preferences for technology-based supports. Qualitative data were coded thematically in a multistep, collaborate approach to ensure trustworthiness. Survey data were collected to describe participants and their current technology use; these data were analyzed descriptively.

Results: A total of 25 IPS consumers reported work challenges related to interpersonal relationships and social situations; job characteristics, tasks, and expectations; illness- and treatment-related issues; lifestyle/wellness and conditions apart from work; and motivation. The majority owned mobile phones, felt comfortable using technology, and could see how technology-based tools could help sustain employment. Participants highlighted the potential benefits of technology-based supports for work challenges, and underscored the potential for independence and empowerment as a consequence.

Conclusions And Implications For Practice: Study findings suggest the value of a mobile app that is innovative, easy to access, self-directed, and individually tailored to enhance IPS follow-along support. The app, if proven effective, will provide an empowering set of tools designed with input from individuals with serious mental illnesses, and integrated into a single, accessible interface. (PsycINFO Database Record
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http://dx.doi.org/10.1037/prj0000201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480984PMC
September 2017

Quality and Batch-to-Batch Consistency of Original and Biosimilar Epoetin Products.

J Pharm Sci 2016 Feb 9;105(2):542-550. Epub 2016 Jan 9.

Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, 3584 CG Utrecht, the Netherlands. Electronic address:

Comprehensive physicochemical characterization and biological assays are essential parts in assessing quality attributes of biologicals. Here, we compared the quality of different marketed recombinant human erythropoietin (epoetin) products: originators, Eprex and NeoRecormon as well as 2 biosimilars, Retacrit and Binocrit. In addition, assessment of batch-to-batch variability was included by collecting 2 or more batches of each product. Common assays which included sodium dodecyl sulfate-polyacrylamide gel electrophoresis, high-performance size-exclusion chromatography, asymmetrical flow field-flow fractionation, capillary zone electrophoresis, and potency testing were used. Of the tested products and among batches of single products, variations in epoetin content, isoform profiles, and potency were found. Ultimately, this study demonstrated the high quality of epoetin products with some degree of variation among products and batches, confirming the "similar but not identical" paradigm of biologicals.
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http://dx.doi.org/10.1016/j.xphs.2015.10.019DOI Listing
February 2016

Changes in microRNA expression during differentiation of embryonic and induced pluripotent stem cells to definitive endoderm.

Gene Expr Patterns 2015 Sep-Nov;19(1-2):70-82. Epub 2015 Aug 13.

Endocrinology Section, Biotherapeutics Department, National Institute of Biological Standards and Control, Blanche Lane, South Mimms, Hertfordshire, EN6 3QG, UK. Electronic address:

Pluripotent stem cells, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have the potential to treat type 1 diabetes through cell replacement therapy. However, the protocols used to generate insulin-expressing cells in vitro frequently result in cells which have an immature phenotype and are functionally restricted. MicroRNAs (miRNAs) are now known to be important in cell fate specification, and a unique miRNA signature characterises pancreatic development at the definitive endoderm stage. Several studies have described differences in miRNA expression between ESCs and iPSCs. Here we have used microarray analysis both to identify miRNAs up- or down-regulated upon endoderm formation, and also miRNAs differentially expressed between ESCs and iPSCs. Several miRNAs fulfilling both these criteria were identified, suggesting that differences in the expression of these miRNAs may affect the ability of pluripotent stem cells to differentiate into definitive endoderm. The expression of these miRNAs was validated by qRT-PCR, and the relationship between one of these miRNAs, miR-151a-5p, and its predicted target gene, SOX17, was investigated by luciferase assay, and suggested an interaction between miR-151a-5p and this key transcription factor. In conclusion, these findings demonstrate a unique miRNA expression pattern for definitive endoderm derived from both embryonic and induced pluripotent stem cells.
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http://dx.doi.org/10.1016/j.gep.2015.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6101203PMC
September 2016

Systematic Screening Identifies Dual PI3K and mTOR Inhibition as a Conserved Therapeutic Vulnerability in Osteosarcoma.

Clin Cancer Res 2015 Jul 10;21(14):3216-29. Epub 2015 Apr 10.

St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia. ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.

Purpose: Osteosarcoma is the most common cancer of bone occurring mostly in teenagers. Despite rapid advances in our knowledge of the genetics and cell biology of osteosarcoma, significant improvements in patient survival have not been observed. The identification of effective therapeutics has been largely empirically based. The identification of new therapies and therapeutic targets are urgently needed to enable improved outcomes for osteosarcoma patients.

Experimental Design: We have used genetically engineered murine models of human osteosarcoma in a systematic, genome-wide screen to identify new candidate therapeutic targets. We performed a genome-wide siRNA screen, with or without doxorubicin. In parallel, a screen of therapeutically relevant small molecules was conducted on primary murine- and primary human osteosarcoma-derived cell cultures. All results were validated across independent cell cultures and across human and mouse osteosarcoma.

Results: The results from the genetic and chemical screens significantly overlapped, with a profound enrichment of pathways regulated by PI3K and mTOR pathways. Drugs that concurrently target both PI3K and mTOR were effective at inducing apoptosis in primary osteosarcoma cell cultures in vitro in both human and mouse osteosarcoma, whereas specific PI3K or mTOR inhibitors were not effective. The results were confirmed with siRNA and small molecule approaches. Rationale combinations of specific PI3K and mTOR inhibitors could recapitulate the effect on osteosarcoma cell cultures.

Conclusions: The approaches described here have identified dual inhibition of the PI3K-mTOR pathway as a sensitive, druggable target in osteosarcoma, and provide rationale for translational studies with these agents.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-3026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506243PMC
July 2015

The role of microRNAs in the pancreatic differentiation of pluripotent stem cells.

Microrna 2014 ;3(1):54-63

Endocrinology Section, Biotherapeutics Department, National Institute of Biological Standards and Control, Blanche Lane, South Mimms, Hertfordshire, EN6 3QG, UK.

The generation of β-cells in vitro is an attractive option for cell therapy treatments for type 1 diabetes and also for the development of more accurate disease models. A number of studies have demonstrated that insulin-expressing cells can be generated by the in vitro differentiation of human pluripotent stem cells. However, to date, these differentiation protocols are often inefficient, time-consuming and highly variable. In many cases, this is a result of an incomplete understanding of the regulatory processes involved in the differentiation of human pluripotent stem cells. One such process is the control of gene expression by microRNAs (miRNAs). Given that miRNAs have the potential to influence cell fate, we present in this short review the evidence that a further understanding of the role of miRNAs in pancreatic development and function may be important in the on-going quest to generate insulin-secreting cells from pluripotent stem cells.
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http://dx.doi.org/10.2174/2211536603666140522003220DOI Listing
March 2015

Applications of cell-based bioassays measuring the induced expression of endogenous genes.

Bioanalysis 2014 Jun;6(11):1563-74

Biotherapeutics Group, National Institute of Biological Standards & Control, Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, UK.

Cell-based bioassays are used to determine the biological activity of complex biotherapeutic products, to assign potency and to assure the quality and consistency of the manufacturing process. Clinically, these assays are used to assess bioactivity in patient samples, particularly for the detection of antidrug neutralizing antibodies. Owing to their versatility, cellular assays that measure endogenous gene expression by quantitative reverse transcription PCR offer a rapid and automatable alternative to assays measuring functional, late-stage responses. Notably, detection of immediate early gene expression represents a direct response of the cell to receptor ligation by the biotherapeutic. We review current developments in the use of this approach and demonstrate its application to the detection of receptor-binding autoantibodies using, as a case study, the detection of autoantibodies to the thyroid-stimulating hormone receptor.
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http://dx.doi.org/10.4155/bio.14.98DOI Listing
June 2014

Standardization of therapeutic, urinary gonadotrophins: an update on the use and availability of International Standards for Menotrophin.

Biologicals 2013 Nov 21;41(6):435-8. Epub 2013 Sep 21.

Endocrinology Section, Biotherapeutics Group, National Institute of Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3QG, UK. Electronic address:

The potencies of therapeutic preparations of gonadotrophins of human, urinary origin, which comprise a heterogenous mix of isoforms with follicle-stimulating hormone (FSH) and luteinizing hormone (LH) bioactivities, are standardized by WHO International Standards (IS). We report here, the evaluation, through an international collaborative study, of a candidate preparation, coded 10/286, to replace the 4th IS, 98/704, for human, urinary FSH and LH (Menotrophin) which has been used for many years for the potency assignment of therapeutic preparations using bioassays. The mean FSH and LH bioactivities of 10/286, determined by in vivo bioassays in terms of 98/704, were 183 IU per ampoule (95% confidence limits 165-202) and 177 IU per ampoule (95% confidence limits 159-197), respectively.
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http://dx.doi.org/10.1016/j.biologicals.2013.08.004DOI Listing
November 2013
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