Publications by authors named "Stephen Kelly"

168 Publications

Targeting synovial fibroblast proliferation in rheumatoid arthritis (TRAFIC): an open-label, dose-finding, phase 1b trial.

Lancet Rheumatol 2021 May 9;3(5):e337-e346. Epub 2021 Mar 9.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

Background: Current rheumatoid arthritis therapies target immune inflammation and are subject to ceiling effects. Seliciclib is an orally available cyclin-dependent kinase inhibitor that suppresses proliferation of synovial fibroblasts-cells not yet targeted in rheumatoid arthritis. Part 1 of this phase 1b/2a trial aimed to establish the maximum tolerated dose of seliciclib in patients with active rheumatoid arthritis despite ongoing treatment with TNF inhibitors, and to evaluate safety and pharmacokinetics.

Methods: Phase 1b of the TRAFIC study was a non-randomised, open-label, dose-finding trial done in rheumatology departments in five UK National Health Service hospitals. Eligible patients (aged ≥18 years) fulfilled the 1987 American College of Rheumatology (ACR) or the 2010 ACR-European League Against Rheumatism classification criteria for rheumatoid arthritis and had moderate to severe disease activity (a Disease Activity Score for 28 joints [DAS28] of ≥3·2) despite stable treatment with anti-TNF therapy for at least 3 months before enrolment. Participants were recruited sequentially to a maximum of seven cohorts of three participants each, designated to receive seliciclib 200 mg, 400 mg, 600 mg, 800 mg, or 1000 mg administered in 200 mg oral capsules. Sequential cohorts received doses determined by a restricted, one-stage Bayesian continual reassessment model, which determined the maximum tolerated dose (the primary outcome) based on a target dose-limiting toxicity rate of 35%. Seliciclib maximum concentration (C) and area under the plasma concentration time curve 0-6 h (AUC) were measured. This study is registered with ISRCTN, ISRCTN36667085.

Findings: Between Oct 8, 2015, and Aug 15, 2017, 37 patients were screened and 15 were enrolled to five cohorts and received seliciclib, after which the trial steering committee and the data monitoring committee determined that the maximum tolerated dose could be defined. In addition to a TNF inhibitor, ten (67%) enrolled patients were taking conventional synthetic disease modifying antirheumatic drugs. The maximum tolerated dose of seliciclib was 400 mg, with an estimated dose-limiting toxicity probability of 0·35 (90% posterior probability interval 0·18-0·52). Two serious adverse events occurred (one acute kidney injury in a patient receiving the 600 mg dose and one drug-induced liver injury in a patient receiving the 400 mg dose), both considered to be related to seliciclib and consistent with its known safety profile. 65 non-serious adverse events occurred during the trial, 50 of which were considered to be treatment related. Most treatment-related adverse events were mild; 20 of the treatment-related non-serious adverse events contributed to dose-limiting toxicities. There were no deaths. Average C and AUC were two-times higher in participants developing dose-limiting toxicities.

Interpretation: The maximum tolerated dose of seliciclib has been defined for rheumatoid arthritis refractory to TNF blockade. No unexpected safety concerns were identified to preclude ongoing clinical evaluation in a formal efficacy trial.

Funding: UK Medical Research Council, Cyclacel, Research into Inflammatory Arthritis Centre (Versus Arthritis), and the National Institute of Health Research Newcastle and Birmingham Biomedical Research Centres and Clinical Research Facilities.
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http://dx.doi.org/10.1016/S2665-9913(21)00061-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062952PMC
May 2021

Microbiology of a NaCl stalactite 'salticle' formed within Triassic halite.

Environ Microbiol 2021 Apr 13. Epub 2021 Apr 13.

Biofilm Research Group, School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK.

Large regions of Earth's surface are underlain by salt deposits that evaporated from ancient oceans and are populated by extreme halophilic microbes. Some of these halophiles may have been preserved over geological timescales within hypersaline fluid inclusions, but ingresses of water and/or anthropogenic activities can lead to the formation of alternative habitats, including NaCl stalactites or speleothems. While the microbiology of ancient evaporites has been well-studied, the ecology of these recently formed structures is less-well understood. Here, the microbiology of a NaCl stalactite ('salticle') in a Triassic halite mine is characterised. The specific aims were to: determine the presence of fluid inclusions; determine the microbial structure of the salticle compared with a nearby brine-pool and surficial soil; and characterise the ecophysiological capabilities of this unique ecosystem. The salticle contained fluid inclusions, and their microbiome was composed of Euryarchaetota, Proteobacteria, and Actinobacteria, with Haloarchaea in greater abundance than brine-pool or soil microbiomes. The salticle metagenome exhibited a greater abundance of genes involved in osmoregulation, anaerobic respiration, UV resistance, oxidative stress, and stress-protein synthesis relative to the soil microbiome. We discuss the potential astrobiological implications of salticles as enclosed salt-saturated habitats that are protected from ionising radiation and have a stable water-activity. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/1462-2920.15524DOI Listing
April 2021

Antibiotic Therapy and the Gut Microbiome: Investigating the Effect of Delivery Route on Gut Pathogens.

ACS Infect Dis 2021 Apr 12. Epub 2021 Apr 12.

School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast, U.K., BT9 7BL.

The contribution of the gut microbiome to human health has long been established, with normal gut microbiota conferring protection against invasive pathogens. Antibiotics can disrupt the microbial balance of the gut, resulting in disease and the development of antimicrobial resistance. The effect of antibiotic administration route on gut dysbiosis remains under-studied to date, with conflicting evidence on the differential effects of oral and parenteral delivery. We have profiled the rat gut microbiome following treatment with commonly prescribed antibiotics (amoxicillin and levofloxacin), via either oral or intravenous administration. Fecal pellets were collected over a 13-day period and bacterial populations were analyzed by 16S rRNA gene sequencing. Significant dysbiosis was observed in all treatment groups, regardless of administration route. More profound dysbiotic effects were observed following amoxicillin treatment than those with levofloxacin, with population richness and diversity significantly reduced, regardless of delivery route. The effect on specific taxonomic groups was assessed, revealing significant disruption following treatment with both antibiotics. Enrichment of a number of groups containing known gut pathogens was observed, in particular, with amoxicillin, such as the family Enterobacteriaceae. Depletion of other commensal groups was also observed. The degree of dysbiosis was significantly reduced toward the end of the sampling period, as bacterial populations began to return to pretreatment composition. Richness and diversity levels appeared to return to pretreatment levels more quickly in intravenous groups, suggesting convenient parenteral delivery systems may have a role to play in reducing longer term gut dysbiosis in the treatment of infection.
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http://dx.doi.org/10.1021/acsinfecdis.1c00081DOI Listing
April 2021

Electrochemical quantification of d-glucose during the production of bioethanol from thermo-mechanically pre-treated wheat straw.

Electrochem commun 2021 Mar;124:106942

Department of Chemical Engineering, The University of Hull, Cottingham Road, Kingston-upon-Hull HU6 7RX, United Kingdom.

Mechanical pre-treatment (disc refining) of wheat straw, at both atmospheric and elevated pressure, is shown to be an efficient process to access fermentable monosaccharides, with the potential to integrate within the infrastructure of existing first-generation bioethanol plants. The mild, enzymatic degradation of this sustainable lignocellulosic biomass affords 0.10-0.13 g/g (dry weight) of d-glucose quantifiable voltammetrically in real time, over a two hundred-fold range in experimental laboratory scales (25 mL to 5.0 L), with pressure disc refining of the wheat straw enabling almost twice the amount of d-glucose to be generated during the hydrolysis stage than experiments using atmospheric refining (0.06-0.09 g/g dry weight). Fermentation of the resulting hydrolysate affords 0.08-0.10 g/g (dry weight) of ethanol over similar scales, with ethanol productivity at 37 mg/(L h). These results demonstrate that minimal cellulose decomposition occurs during pressure refining of wheat straw, in contrast to hemicellulose, and suggest that the development of green, mechanochemical processes for the scalable and cost-effective manufacture of second-generation bioethanol requires improved cellulose decomposition.
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http://dx.doi.org/10.1016/j.elecom.2021.106942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976448PMC
March 2021

Electrochemically Induced Mesomorphism Switching in a Chlorpromazine Hydrochloride Lyotropic Liquid Crystal.

ACS Omega 2021 Feb 5;6(7):4630-4640. Epub 2021 Feb 5.

Department of Physical Sciences (Chemistry), University of Hull, Cottingham Road, Kingston-upon-Hull HU6 7RX, Humberside, United Kingdom.

The discovery of electrochemical switching of the L phase of chlorpromazine hydrochloride in water is reported. The phase is characterized using polarizing microscopy, X-ray scattering, rheological measurements, and microelectrode voltammetry. Fast, heterogeneous oxidation of the lyotropic liquid crystal is shown to cause a phase change resulting from the disordering of the structural order in a stepwise process. The underlying molecular dynamics is considered to be a cooperative effect of both increasing electrostatic interactions and an unfolding of the monomers from "butterfly"-shaped in the reduced form to planar in the oxidized form.
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http://dx.doi.org/10.1021/acsomega.0c05284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905802PMC
February 2021

The LaserFIB: new application opportunities combining a high-performance FIB-SEM with femtosecond laser processing in an integrated second chamber.

Appl Microsc 2020 Oct 26;50(1):24. Epub 2020 Oct 26.

ZEISS Research Microscopy Solutions, Carl-Zeiss-Straße 22, 73447, Oberkochen, Germany.

The development of the femtosecond laser (fs laser) with its ability to provide extremely rapid athermal ablation of materials has initiated a renaissance in materials science. Sample milling rates for the fs laser are orders of magnitude greater than that of traditional focused ion beam (FIB) sources currently used. In combination with minimal surface post-processing requirements, this technology is proving to be a game changer for materials research. The development of a femtosecond laser attached to a focused ion beam scanning electron microscope (LaserFIB) enables numerous new capabilities, including access to deeply buried structures as well as the production of extremely large trenches, cross sections, pillars and TEM H-bars, all while preserving microstructure and avoiding or reducing FIB polishing. Several high impact applications are now possible due to this technology in the fields of crystallography, electronics, mechanical engineering, battery research and materials sample preparation. This review article summarizes the current opportunities for this new technology focusing on the materials science megatrends of engineering materials, energy materials and electronics.
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http://dx.doi.org/10.1186/s42649-020-00044-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818346PMC
October 2020

Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial.

Lancet 2021 01;397(10271):305-317

Centre for Experimental Medicine and Rheumatology, Queen Mary University of London, London, UK; Department of Rheumatology, Mile End Hospital, Barts Health NHS Trust, London, UK. Electronic address:

Background: Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis, 40% of patients show poor clinical response, which is mechanistically still unexplained. Because more than 50% of patients with rheumatoid arthritis have low or absent CD20 B cells-the target for rituximab-in the main disease tissue (joint synovium), we hypothesised that, in these patients, the IL-6 receptor inhibitor tocilizumab would be more effective. The aim of this trial was to compare the effect of tocilizumab with rituximab in patients with rheumatoid arthritis who had an inadequate response to anti-tumour necrosis factor (TNF) stratified for synovial B-cell status.

Methods: This study was a 48-week, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial (rituximab vs tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis; R4RA) done in 19 centres across five European countries (the UK, Belgium, Italy, Portugal, and Spain). Patients aged 18 years or older who fulfilled the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for rheumatoid arthritis and were eligible for treatment with rituximab therapy according to UK National Institute for Health and Care Excellence guidelines were eligible for inclusion in the trial. To inform balanced stratification, following a baseline synovial biopsy, patients were classified histologically as B-cell poor or rich. Patients were then randomly assigned (1:1) centrally in block sizes of six and four to receive two 1000 mg rituximab infusions at an interval of 2 weeks (rituximab group) or 8 mg/kg tocilizumab infusions at 4-week intervals (tocilizumab group). To enhance the accuracy of the stratification of B-cell poor and B-cell rich patients, baseline synovial biopsies from all participants were subjected to RNA sequencing and reclassified by B-cell molecular signature. The study was powered to test the superiority of tocilizumab over rituximab in the B-cell poor population at 16 weeks. The primary endpoint was defined as a 50% improvement in Clinical Disease Activity Index (CDAI50%) from baseline. The trial is registered on the ISRCTN database, ISRCTN97443826, and EudraCT, 2012-002535-28.

Findings: Between Feb 28, 2013, and Jan 17, 2019, 164 patients were classified histologically and were randomly assigned to the rituximab group (83 [51%]) or the tocilizumab group (81 [49%]). In patients histologically classified as B-cell poor, there was no statistically significant difference in CDAI50% between the rituximab group (17 [45%] of 38 patients) and the tocilizumab group (23 [56%] of 41 patients; difference 11% [95% CI -11 to 33], p=0·31). However, in the synovial biopsies classified as B-cell poor with RNA sequencing the tocilizumab group had a significantly higher response rate compared with the rituximab group for CDAI50% (rituximab group 12 [36%] of 33 patients vs tocilizumab group 20 [63%] of 32 patients; difference 26% [2 to 50], p=0·035). Occurrence of adverse events (rituximab group 76 [70%] of 108 patients vs tocilizumab group 94 [80%] of 117 patients; difference 10% [-1 to 21) and serious adverse events (rituximab group 8 [7%] of 108 vs tocilizumab group 12 [10%] of 117; difference 3% [-5 to 10]) were not significantly different between treatment groups.

Interpretation: The results suggest that RNA sequencing-based stratification of rheumatoid arthritis synovial tissue showed stronger associations with clinical responses compared with histopathological classification. Additionally, for patients with low or absent B-cell lineage expression signature in synovial tissue tocilizumab is more effective than rituximab. Replication of the results and validation of the RNA sequencing-based classification in independent cohorts is required before making treatment recommendations for clinical practice.

Funding: Efficacy and Mechanism Evaluation programme from the UK National Institute for Health Research.
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http://dx.doi.org/10.1016/S0140-6736(20)32341-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829614PMC
January 2021

Factors associated with non-attendance in the Irish national diabetic retinopathy screening programme (INDEAR study report no. 2).

Acta Diabetol 2021 May 23;58(5):643-650. Epub 2021 Jan 23.

Mater Retina Research Group, Mater Misericordiae University Hospital, Dublin, Ireland.

Aims: We aimed to determine the patient and screening-level factors that are associated with non-attendance in the Irish National Diabetic Retinal screening programme (Diabetic RetinaScreen). To accomplish this, we modelled a selection of predictors derived from the historical screening records of patients with diabetes.

Methods: In this cohort study, appointment data from the national diabetic retinopathy screening programme (RetinaScreen) were extracted and augmented using publicly available meteorological and geospatial data. A total of 653,969 appointments from 158,655 patients were included for analysis. Mixed-effects models (univariable and multivariable) were used to estimate the influence of several variables on non-attendance to screening appointments.

Results: All variables considered for analysis were statistically significant. Variables of note, with meaningful effect, were age (OR: 1.23 per decade away from 70; 95% CI: [1.22-1.24]), type 2 diabetes (OR: 1.10; 95% CI: [1.06-1.14]) and socio-economic deprivation (OR: 1.12; 95% CI: [1.09-1.16]). A majority (52%) of missed appointments were from patients who had missed three or more appointments.

Conclusions: This study is the first to outline factors that are associated with non-attendance within the Irish national diabetic retinopathy screening service. In particular, when corrected for age and other factors, patients with type 2 diabetes had higher rates of non-attendance. Additionally, this is the first study of any diabetic screening programme to demonstrate that weather may influence attendance. This research provides unique insight to guide the implementation of an optimal and cost-effective intervention strategy to improve attendance.
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http://dx.doi.org/10.1007/s00592-021-01671-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076137PMC
May 2021

Characterization of ionic liquid cytotoxicity mechanisms in human keratinocytes compared with conventional biocides.

Chemosphere 2021 May 31;270:129432. Epub 2020 Dec 31.

School of Pharmacy, Queens University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK. Electronic address:

The ability to chemically modify ionic liquids (ILs) has led to an expansion in interest in their use in a diversity of applications, not least as antimicrobials and biocides. Relatively little is known about cytotoxicity mechanisms of ILs in comparison to other biocides currently in widespread use, as well as their practical significance for the ecological environment and human health. Using NCTC 2544 and HaCat human keratinocyte cells, this study aimed to characterize cytotoxicity rates and mechanisms of a range of ILs. Using both lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) based cytotoxicity assays, it was confirmed that at biocide-relevant concentrations, ILs with longer alkyl chains exhibited greater biocidal activity than those with shorter alkyl chains, with comparable activity to the commonly used biocides chlorhexidine, benzalkonium chloride and cetylpyridinium chloride, at relevant in-use biocide concentrations. Mode of cell death, measured using fluorescence-activated cell sorting (FACS) and caspase 3/7 activity, determined necrosis to be the primary cytotoxic mechanism at higher concentrations of the biocides stated above, and with ILs [CMIM]Cl and [Cquin]Br, with apoptosis observed at borderline necrotic concentrations. Perhaps most interestingly, modification of anion had a significant effect on cytotoxicity. The use of N[SOCF] as an anion to [CMIM] attenuated cytotoxicity 10-fold in comparison to other anions, suggesting cytotoxicity may also be a tuneable property when using ILs as biocides.
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http://dx.doi.org/10.1016/j.chemosphere.2020.129432DOI Listing
May 2021

Directly Compressed Tablets: A Novel Drug-Containing Reservoir Combined with Hydrogel-Forming Microneedle Arrays for Transdermal Drug Delivery.

Adv Healthc Mater 2021 02 14;10(3):e2001256. Epub 2020 Dec 14.

School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Ireland.

Microneedle (MN) patches consist of a hydrogel-forming MN array and a drug-containing reservoir. Drug-containing reservoirs documented in the literature include polymeric films and lyophilized wafers. While effective, both reservoir formulations are aqueous based, and so degradation can occur during formulation and drying for drugs inherently unstable in aqueous media. The preparation and characterization of novel, nonaqueous-based, directly compressed tablets (DCTs) for use in combination with hydrogel-forming MN arrays are described for the first time. In this work, a range of drug molecules are investigated. Precipitation of amoxicillin (AMX) and primaquine (PQ) in conventional hydrogel-forming MN arrays leads to use of poly(vinyl alcohol)-based MN arrays. Following in vitro permeation studies, in vivo pharmacokinetic studies are conducted in rats with MN patches containing AMX, levodopa/carbidopa (LD/CD), and levofloxacin (LVX). Therapeutically relevant concentrations of AMX (≥2 µg mL ), LD (≥0.5 µg mL ), and LVX (≥0.2 µg mL ) are successfully achieved at 1, 2, and 1 h, respectively. Thus, the use of DCTs offers promise to expand the range of drug molecules that can be delivered transdermally using MN patches.
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http://dx.doi.org/10.1002/adhm.202001256DOI Listing
February 2021

IL-23 skin and joint profiling in psoriatic arthritis: novel perspectives in understanding clinical responses to IL-23 inhibitors.

Ann Rheum Dis 2020 Nov 26. Epub 2020 Nov 26.

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

Objectives: To determine the relationship between synovial versus skin transcriptional/histological profiles in patients with active psoriatic arthritis (PsA) and explore mechanistic links between diseased tissue pathology and clinical outcomes.

Methods: Twenty-seven active PsA patients were enrolled in an observational/open-label study and underwent biopsies of synovium and paired lesional/non-lesional skin before starting anti-tumour necrosis factor (TNF) (if biologic-naïve) or ustekinumab (if anti-TNF inadequate responders). Molecular analysis of 80-inflammation-related genes and protein levels for interleukin (IL)-23p40/IL-23p19/IL-23R were assessed by real-time-PCR and immunohistochemistry, respectively.

Results: At baseline, all patients had persistent active disease as per inclusion criteria. At primary end-point (16-weeks post-treatment), skin responses favoured ustekinumab, while joint responses favoured anti-TNF therapies. Principal component analysis revealed distinct clustering of synovial tissue gene expression away from the matched skin. While and were homogeneously expressed in lesional skin, their expression was extremely heterogeneous in paired synovial tissues. Here, IL-23 transcriptomic/protein expression was strongly linked to patients with high-grade synovitis who, however, were not distinguishable by conventional clinimetric measures.

Conclusions: PsA synovial tissue shows a heterogeneous IL-23 axis profile when compared with matched skin. Synovial molecular pathology may help to identify among clinically indistinguishable patients those with a greater probability of responding to IL-23 inhibitors.
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http://dx.doi.org/10.1136/annrheumdis-2020-218186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053336PMC
November 2020

Evolution of the Epigenetic Landscape in Childhood B Acute Lymphoblastic Leukemia and Its Role in Drug Resistance.

Cancer Res 2020 12 16;80(23):5189-5202. Epub 2020 Oct 16.

Perlmutter Cancer Center, NYU Langone Health, New York, New York.

Although B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy in children and while highly curable, it remains a leading cause of cancer-related mortality. The outgrowth of tumor subclones carrying mutations in genes responsible for resistance to therapy has led to a Darwinian model of clonal selection. Previous work has indicated that alterations in the epigenome might contribute to clonal selection, yet the extent to which the chromatin state is altered under the selective pressures of therapy is unknown. To address this, we performed chromatin immunoprecipitation, gene expression analysis, and enhanced reduced representation bisulfite sequencing on a cohort of paired diagnosis and relapse samples from individual patients who all but one relapsed within 36 months of initial diagnosis. The chromatin state at diagnosis varied widely among patients, while the majority of peaks remained stable between diagnosis and relapse. Yet a significant fraction was either lost or newly gained, with some patients showing few differences and others showing massive changes of the epigenetic state. Evolution of the epigenome was associated with pathways previously linked to therapy resistance as well as novel candidate pathways through alterations in pyrimidine biosynthesis and downregulation of polycomb repressive complex 2 targets. Three novel, relapse-specific superenhancers were shared by a majority of patients including one associated with S100A8, the top upregulated gene seen at relapse in childhood B-ALL. Overall, our results support a role of the epigenome in clonal evolution and uncover new candidate pathways associated with relapse. SIGNIFICANCE: This study suggests a major role for epigenetic mechanisms in driving clonal evolution in B-ALL and identifies novel pathways associated with drug resistance.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1145DOI Listing
December 2020

Prevalence and predictors of oral to intravenous antibiotic switch among adult emergency department patients with acute bacterial skin and skin structure infections: a pilot, prospective cohort study.

BMJ Open 2020 08 30;10(8):e034057. Epub 2020 Aug 30.

Emergency Care Research Unit, Royal College of Surgeons Ireland, Dublin, Ireland

Objective: To determine the prevalence and predictors of oral to intravenous antibiotic switch among adult emergency department (ED) patients with acute bacterial skin and skin structure infections (ABSSSIs).

Design: Multicentre, pilot cohort study.

Setting: Three urban EDs in Dublin, Ireland.

Participants: Consecutive ED patients aged >16 years old with ABSSSIs between March 2015 and September 2016.

Intervention: Oral flucloxacillin 500 mg-1 g four times a day (alternative in penicillin allergy).

Primary And Secondary Outcome Measures: The primary outcome was to determine the prevalence and predictors of oral to intravenous antibiotic switch. Secondary outcomes were to determine the prevalence and predictors of receiving an extended course of oral antibiotic treatment and measurement of interobserver reliability for clinical predictors at enrolment.

Results: Overall, 159 patients were enrolled of which eight were lost to follow-up and five were excluded. The majority of patients were male (65.1%) and <50 years of age (58.2%). Oral to intravenous antibiotic switch occurred in 13 patients (8.9%; 95% CI 4.8% to 14.7%). Increased lesion size (OR 1.74; 95% CI 1.09 to 2.79), white cell count (OR 1.32; 95% CI 1.05 to 1.67), athlete's foot (OR 8.00; 95% CI 2.31 to 27.71) and fungal nail infections (OR 7.25; 95% CI 1.99 to 26.35) were associated with oral to intravenous antibiotic switch. 24.8% (95% CI 18.1% to 33.0%) of patients received an extended course of oral antibiotic treatment.

Conclusion: The prevalence of oral to intravenous antibiotic switch in this pilot study is 8.9% (95% CI 4.8% to 14.7%). We identify the predictors of oral to intravenous switch worthy of future investigation.

Trial Registration Number: NCT02230813.
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http://dx.doi.org/10.1136/bmjopen-2019-034057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462158PMC
August 2020

Interannual monsoon wind variability as a key driver of East African small pelagic fisheries.

Sci Rep 2020 08 6;10(1):13247. Epub 2020 Aug 6.

National Oceanography Centre, Southampton, SO14 3ZH, UK.

Small pelagic fisheries provide food security, livelihood support and economic stability for East African coastal communities-a region of least developed countries. Using remotely- sensed and field observations together with modelling, we address the biophysical drivers of this important resource. We show that annual variations of fisheries yield parallel those of chlorophyll-a (an index of phytoplankton biomass). While enhanced phytoplankton biomass during the Northeast monsoon is triggered by wind-driven upwelling, during the Southeast monsoon, it is driven by two current induced mechanisms: coastal "dynamic uplift" upwelling; and westward advection of nutrients. This biological response to the Southeast monsoon is greater than that to the Northeast monsoon. For years unaffected by strong El-Niño/La-Niña events, the Southeast monsoon wind strength over the south tropical Indian Ocean is the main driver of year-to-year variability. This has important implications for the predictability of fisheries yield, its response to climate change, policy and resource management.
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http://dx.doi.org/10.1038/s41598-020-70275-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413268PMC
August 2020

Biocatalysis in seawater: Investigating a halotolerant ω-transaminase capable of converting furfural in a seawater reaction medium.

Eng Life Sci 2019 Oct 23;19(10):721-725. Epub 2019 Aug 23.

School of Pharmacy Queen's University Belfast Belfast UK.

The increasing demand for freshwater and the continued depletion of available resources has led to a deepening global water crisis. Significant water consumption required by many biotechnological processes contributes to both the environmental and economic cost of this problem. Relatively few biocatalytic processes have been developed to utilize the more abundant supply of seawater, with seawater composition and salinity limiting its use with many mesophilic enzymes. We recently reported a salt tolerant ω-transaminase enzyme, Ad2-TAm, isolated from the genome of a halophilic bacterium, sp. CSM-2, from a Triassic period salt mine. In this study we aimed to demonstrate its applicability to biocatalytic reactions carried out in a seawater-based medium. Ad2-TAm was examined for its ability to aminate the industrially relevant substrate, furfural, in both seawater and freshwater-based reaction systems. Furfural was aminated with 53.6% conversion in a buffered seawater system, displaying improved function versus freshwater. Ad2-TAm outperformed the commonly employed commercial ω-TAms from and , both of which showed decreased conversion in seawater. Given the increasingly precarious availability of global freshwater, such applications of enzymes from halophiles have the ability to reduce demand for freshwater in large-scale industrial processes, delivering considerable environmental and economic benefits.
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http://dx.doi.org/10.1002/elsc.201900053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999519PMC
October 2019

Treatment-resistant synovitis and radiographic progression are increased in elderly-onset rheumatoid arthritis patients: findings from a prospective observational longitudinal early arthritis cohort study.

Semin Arthritis Rheum 2020 08 15;50(4):735-743. Epub 2020 May 15.

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Electronic address:

Background: Clinical outcomes in elderly-onset rheumatoid arthritis (EORA), starting after the age of 60, are conflicting. Thus, we aimed to investigate in a unique biopsy-driven, treatment-naïve early arthritis cohort, the relationship between synovial pathobiology of elderly- (EORA) and younger-onset rheumatoid arthritis (YORA) patients through clinical, imaging and treatment response outcome-measures.

Methods: Patients (n = 140) with early RA (<12months) starting before (YORA, n = 99) or after (EORA, n = 41) age 60 had an ultrasound-guided synovial biopsy prior to conventional immunosuppressive therapy and after 6 months. Clinical, ultrasound and radiographic data were collected prospectively and compared between groups and against immunohistological features. Using multivariate logistic regression, we determined predictors of clinical response (disease activity score-28-erythrocyte sedimentation rate [DAS28-ESR]<3.2) at 6 months and radiographic progression (≥1-unit-increase in Sharp van der Heijde [SvdH] score) at 12 months.

Results: EORA patients were more frequently male and presented most commonly with an abrupt, polymyalgia rheumatica-like onset and extra-articular features. Both before and after treatment, DAS28-ESR was similar but ultrasound synovial-thickening (p<0.05) and power-Doppler (p<0.01) synovitis and SvdH (p<0.001) scores were higher in EORA patients. EORA was independently associated with poor treatment response at 6 months (OR=0.28, p = 0.047) and radiographic progression at 12 months (OR=4.08, p = 0.029). Synovial pathotype, synovitis scores and cellular infiltration were similar before treatment, but a pauci-immune-fibroid pathotype tended to be more common in YORA at 6 months (p = 0.093). Moreover, YORA patients had a marked improvement of all synovitis parameters (p<0.001), whereas EORA presented only mild decreases in synovitis (p<0.05), sublining macrophage (p<0.05) and T cell scores (p<0.05), with no significant changes in lining macrophages, B cells or plasma cells.

Conclusion: Early EORA presents differently and has a worse overall prognosis than YORA, with poorer clinical, histological, ultrasonographic and radiographic outcomes.
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http://dx.doi.org/10.1016/j.semarthrit.2020.03.018DOI Listing
August 2020

A Pauci-Immune Synovial Pathotype Predicts Inadequate Response to TNFα-Blockade in Rheumatoid Arthritis Patients.

Front Immunol 2020 5;11:845. Epub 2020 May 5.

Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom.

To assess whether the histopathological features of the synovium before starting treatment with the TNFi certolizumab-pegol could predict clinical outcome and examine the modulation of histopathology by treatment. Thirty-seven RA patients fulfilling UK NICE guidelines for biologic therapy were enrolled at Barts Health NHS trust and underwent synovial sampling of an actively inflamed joint using ultrasound-guided needle biopsy before commencing certolizumab-pegol and after 12-weeks. At 12-weeks, patients were categorized as responders if they had a DAS28 fall >1.2. A minimum of 6 samples was collected for histological analysis. Based on H&E and immunohistochemistry (IHC) staining for CD3 (T cells), CD20 (B cells), CD138 (plasma cells), and CD68 (macrophages) patients were categorized into three distinct synovial pathotypes (lympho-myeloid, diffuse-myeloid, and pauci-immune). At baseline, as per inclusion criteria, DAS28 mean was 6.4 ± 0.9. 94.6% of the synovial tissue was retrieved from the wrist or a metacarpophalangeal joint. Histological pathotypes were distributed as follows: 58% lympho-myeloid, 19.4% diffuse-myeloid, and 22.6% pauci-immune. Patients with a pauci-immune pathotype had lower levels of CRP but higher VAS fatigue compared to lympho- and diffuse-myeloid. Based on DAS28 fall >1.2, 67.6% of patients were deemed as responders and 32.4% as non-responders. However, by categorizing patients according to the baseline synovial pathotype, we demonstrated that a significantly higher number of patients with a lympho-myeloid and diffuse-myeloid pathotype in comparison with pauci-immune pathotype [83.3% (15/18), 83.3 % (5/6) vs. 28.6% (2/7), = 0.022) achieved clinical response to certolizumab-pegol. Furthermore, we observed a significantly higher level of post-treatment tender joint count and VAS scores for pain, fatigue and global health in pauci-immune in comparison with lympho- and diffuse-myeloid patients but no differences in the number of swollen joints, ESR and CRP. Finally, we confirmed a significant fall in the number of CD68+ sublining macrophages post-treatment in responders and a correlation between the reduction in the CD20+ B-cells score and the improvement in the DAS28 at 12-weeks. The analysis of the synovial histopathology may be a helpful tool to identify among clinically indistinguishable patients those with lower probability of response to TNFα-blockade.
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http://dx.doi.org/10.3389/fimmu.2020.00845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214807PMC
March 2021

Phases of match-play in professional Australian Football: Distribution of physical and technical performance.

J Sports Sci 2020 Jul 28;38(14):1682-1689. Epub 2020 Apr 28.

Sport & Exercise Discipline Group, Faculty of Health, University of Technology Sydney (UTS) , Sydney, Australia.

The current study aimed to describe the distribution of physical and technical performance during the different phases of play in professional Australian Football. The phases of play (offence, defence, contested play, umpire stoppages, set shots and goal resets) were manually coded from video footage for a single team competing in 18 matches in the Australian Football League. Measures of physical performance including total distance (m), average speed (m · min), low-speed running (LSR, <14.4 km h), high-speed running (HSR, >14.4 km h), accelerations (2.78 m · s) and decelerations (-2.78 m · s) were derived from each phase of play via global positioning system (GPS) devices. Technical skill data including tackles, handballs and kicks were obtained from a commercial statistics provider and derived from each phase of play. Linear mixed-effects models and effect sizes were used to assess and reflect the differences in physical and technical performance between the six phases of play. Activity and recovery cycles, defined as periods where the ball was in or out of play were also described using mean and 95% confidence intervals. The analysis showed that several similarities existed between offence and defence for physical performance metrics. Contested play involved the highest total distance, LSR, accelerations, decelerations and tackles compared to all other phases. Offence and defence involved the highest average speed and HSR running distances. Handballs and kicks were highest during offence, while tackles were highest during contested play, followed by defence. Activity and recovery cycles involved mean durations of ~110 and ~39 s and average speeds of ~160 and ~84 m · min, respectively. The integration of video, GPS and technical skill data can be used to investigate specific phases of Australian Football match-play and subsequently guide match analysis and training design.
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http://dx.doi.org/10.1080/02640414.2020.1754726DOI Listing
July 2020

Transaminases for industrial biocatalysis: novel enzyme discovery.

Appl Microbiol Biotechnol 2020 Jun 16;104(11):4781-4794. Epub 2020 Apr 16.

School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL, Northern Ireland.

Transaminases (TAms) are important enzymes for the production of chiral amines for the pharmaceutical and fine chemical industries. Novel TAms for use in these industries have been discovered using a range of approaches, including activity-guided methods and homologous sequence searches from cultured microorganisms to searches using key motifs and metagenomic mining of environmental DNA libraries. This mini-review focuses on the methods used for TAm discovery over the past two decades, analyzing the changing trends in the field and highlighting the advantages and drawbacks of the respective approaches used. This review will also discuss the role of protein engineering in the development of novel TAms and explore possible directions for future TAm discovery for application in industrial biocatalysis. KEY POINTS: • The past two decades of TAm enzyme discovery approaches are explored. • TAm sequences are phylogenetically analyzed and compared to other discovery methods. • Benefits and drawbacks of discovery approaches for novel biocatalysts are discussed. • The role of protein engineering and future discovery directions is highlighted.
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http://dx.doi.org/10.1007/s00253-020-10585-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228992PMC
June 2020

Regular Solution Theory for Polymer Permeation Transients: A Toolkit for Understanding Experimental Waveshapes.

Langmuir 2020 May 4;36(18):5003-5020. Epub 2020 May 4.

Aura Innovation Centre, Bridgehead Business Park, Meadow Road, Hessle HU13 0GD, United Kingdom.

The accurate measurement of permeation is important at the product design stage for a variety of industries as diverse as conveyance methods for oil and gas produced fluids, such as mixtures of carbon dioxide, methane, hydrogen sulfide, water, and hydrocarbons, and in polymer-lined, unbonded flexible risers and flow lines through connectors and valves, hydrogen and methane gas carrying domestic lines, hydrogen storage tanks, sulfur hexafluoride circuit breakers for high power-carrying lines, oxygen through display technology, and drug delivery. It would also be appropriate to monitor the permeation rate through the polymer, composite, and elastomeric layers during the in-service times where applications allow. In the future, any alteration in the short term and long-term transport rates could be analyzed in terms of an initial alteration or degradation of the polymeric materials and, in some cases, metallic components. Crucially, such measurements would serve as an early warning system of any change in a polymeric material that could result in the loss of function of the fluid of a gas containing barrier material. Most experimental determinations are made through recording flux transients (varying flux) through permeation cells in which a polymer membrane or film separates a donor compartment (usually an infinite supply) and an acceptor compartment and in which membrane transport is considered to be slow. Treatment of the resulting experimental data is usually, but not always, undertaken through comparison with a steady-state model based on Fickian diffusion through the membrane, so as to extract the membrane permeability, the diffusion coefficient of the permeant, and the solubility of the permeant in the membrane phase. However, in spite of these measurements being undertaken routinely using closed cell manometric or continuous flow methods, there is a lack of literature in which experimental flux transients are provided, and in several cases, it is clear that the experimental data do not conform to the expected model of slow, Fickian diffusion through the membrane, even though experiments are performed at temperatures much higher than the glass transition temperature of the polymer membrane. In this paper, we first re-examine the classical model for an infinite source and extend it to account for (1) molecular interactions between membrane and permeant, using regular solution theory, (2) slow transport in the acceptor phase, and (3) slow kinetics across the membrane|acceptor interface. We demonstrate that all three aspects can cause permeation flux transients to exhibit unusual, nonclassical waveshapes, which have nevertheless been experimentally realized without rationalization. This enables the development of an algorithmic toolkit for the interpretation of permeation flux transients, so as to provide reliable and accurate data analysis for experimentalists.
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http://dx.doi.org/10.1021/acs.langmuir.0c00589DOI Listing
May 2020

Progression from ocular hypertension to visual field loss in the English hospital eye service.

Br J Ophthalmol 2020 10 25;104(10):1406-1411. Epub 2020 Mar 25.

Division of Optometry and Visual Science, School of Health Sciences, City, University of London, London, UK

Background: There are more than one million National Health Service visits in England and Wales each year for patients with glaucoma or ocular hypertension (OHT). With the ageing population and an increase in optometric testing, the economic burden of glaucoma-related visits is predicted to increase. We examined the conversion rates of OHT to primary open-angle glaucoma (POAG) in England and assessed factors associated with risk of conversion.

Methods: Electronic medical records of 45 309 patients from five regionally different glaucoma clinics in England were retrospectively examined. Conversion to POAG from OHT was defined by deterioration in visual field (two consecutive tests classified as stage 1 or worse as per the glaucoma staging system 2). Cox proportional hazards models were used to examine factors (age, sex, treatment status and baseline intraocular pressure (IOP)) associated with conversion.

Results: The cumulative risk of conversion to POAG was 17.5% (95% CI 15.4% to 19.6%) at 5 years. Older age (HR 1.35 per decade, 95% CI 1.22 to 1.50, p<0.001) was associated with a higher risk of conversion. IOP-lowering therapy (HR 0.45, 95% CI 0.35 to 0.57, p<0.001) was associated with a lower risk of conversion. Predicted 5-year conversion rates for treated and untreated groups were 14.0% and 26.9%, respectively.

Conclusion: Less than one-fifth of OHT patients managed in glaucoma clinics in the UK converted to POAG over a 5-year period, suggesting many patients may require less intensive follow-up. Our study provides real-world evidence for the efficacy of current management (including IOP-lowering treatment) at reducing risk of conversion.
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http://dx.doi.org/10.1136/bjophthalmol-2019-315052DOI Listing
October 2020

Metformin to reduce metabolic complications and inflammation in patients on systemic glucocorticoid therapy: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial.

Lancet Diabetes Endocrinol 2020 04 25;8(4):278-291. Epub 2020 Feb 25.

Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. Electronic address:

Background: An urgent need to reduce the metabolic side-effects of glucocorticoid overexposure has been recognised, as glucocorticoid excess can lead to Cushing's syndrome, which is associated with high morbidity. We aimed to evaluate the potential of metformin to reverse such effects while sparing the anti-inflammatory benefits of glucocorticoids.

Methods: We did a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial involving four hospitals in the UK. Patients without diabetes were eligible if they were between the ages of 18 and 75 years with an inflammatory disease treated with continuous prednisolone (≥20 mg/day for ≥4 weeks and remaining on ≥10 mg/day for the subsequent 12 weeks, or its cumulative dose-equivalent). Eligible patients were randomly allocated (1:1) to either the metformin or placebo groups, using a computer-generated randomisation table stratified according to age and BMI. Metformin and placebo were administered orally for 12 weeks in escalating doses: 850 mg/day for the first 5 days, 850 mg twice a day for the next 5 days, and 850 mg three times a day subsequently. The primary outcome was the between-group difference in visceral-to-subcutaneous fat area ratio over 12 weeks, assessed by CT. Secondary outcomes included changes in metabolic, bone, cardiovascular, and inflammatory parameters over 12 weeks. Our analysis followed a modified intention-to-treat principle for the primary outcome. This study is registered with ClinicalTrials.gov, NCT01319994.

Findings: Between July 17, 2012, and Jan 14, 2014, 849 patients were assessed for study eligibility, of which 53 were randomly assigned to receive either metformin (n=26) or placebo (n=27) for 12 weeks. 19 patients in the metformin group and 21 in the placebo group were eligible for the primary outcome analysis. Both groups received an equivalent cumulative dose of glucocorticoids (1860 mg prednisolone-equivalent [IQR 1060-2810] in the metformin group vs 1770 mg [1020-2356] in the placebo group); p=0·76). No change in the visceral-to-subcutaneous fat area ratio between the treatment groups was observed (0·11, 95% CI -0·02 to 0·24; p=0·09), but patients in the metformin group lost truncal subcutaneous fat compared with the placebo group (-3835 mm, 95% CI -6781 to -888; p=0·01). Improvements in markers of carbohydrate, lipid, liver, and bone metabolism were observed in the metformin group compared with the placebo group. Additionally, those in the metformin group had improved fibrinolysis, carotid intima-media thickness, inflammatory parameters, and clinical markers of disease activity. The frequency of pneumonia (one event in the metformin group vs seven in the placebo group; p=0·01), overall rate of moderate-to-severe infections (two vs 11; p=0·001), and all-cause hospital admissions due to adverse events (one vs nine; p=0·001) were lower in the metformin group than in the placebo group. Patients in the metformin group had more events of diarrhoea than the placebo group (18 events vs eight; p=0·01).

Interpretation: No significant changes in the visceral-to-subcutaneous fat area ratio between the treatment groups were observed; however, metformin administration did improve some of the metabolic profile and clinical outcomes for glucocorticoid-treated patients with inflammatory disease, which warrants further investigation.

Funding: Barts Charity and Merck Serono.
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http://dx.doi.org/10.1016/S2213-8587(20)30021-8DOI Listing
April 2020

Profiling the microbial community of a Triassic halite deposit in Northern Ireland: an environment with significant potential for biodiscovery.

FEMS Microbiol Lett 2019 11;366(22)

Biofilm Research Group, School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK.

Kilroot salt mine, a Triassic halite deposit located in County Antrim, Northern Ireland, is the only permanent hypersaline environment on the island of Ireland. In this study, the microbiome of this unstudied environment was profiled for the first time using conventional and enhanced culturing techniques, and culture independent metagenomic approaches. Using both conventional isolation plates and iChip devices, 89 halophilic archaeal isolates from six known genera, and 55 halophilic or halotolerant bacterial isolates from 18 genera were obtained, based on 16S rRNA gene sequencing. The archaeal isolates were similar to those previously isolated from other ancient halite deposits, and as expected, numerous genera were identified in the metagenome which were not represented among the culturable isolates. Preliminary screening of a selection of isolates from this environment identified antimicrobial activities against a panel of clinically important bacterial pathogens from 15 of the bacterial isolates and one of the archaea. This, alongside previous studies reporting the discovery of novel biocatalysts from the Kilroot mine microbiome, suggests that this environment may be a new, untapped source of of chemical diversity with high biodiscovery potential.
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http://dx.doi.org/10.1093/femsle/fnz242DOI Listing
November 2019

Gut Check Time: Antibiotic Delivery Strategies to Reduce Antimicrobial Resistance.

Trends Biotechnol 2020 04 19;38(4):447-462. Epub 2019 Nov 19.

School of Pharmacy, Queen's University Belfast, Belfast, Northern Ireland. Electronic address:

Antimicrobial resistance (AMR) has developed into a huge threat to global health, and reducing it is an urgent priority for public health authorities. The importance of a healthy and balanced gut microbiome has been identified as a key protective factor against AMR development, but this can be significantly affected by antibiotic therapy, resulting in dysbiosis and reduction of taxonomic richness. The way in which antibiotics are administered could form an important part of future antimicrobial stewardship strategies, where drug delivery is ideally placed to play a key role in the fight against AMR. This review focuses on drug delivery strategies for antibiotic administration, including avoidance of the gut microbiome and targeted delivery approaches, which may reduce AMR.
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http://dx.doi.org/10.1016/j.tibtech.2019.10.008DOI Listing
April 2020

Revisiting multifocal breast cancer: a clonality study of ductal carcinoma using whole exome sequencing.

Hum Pathol 2019 12 6;94:71-77. Epub 2019 Nov 6.

New York University Medical Center. Electronic address:

Multifocal breast cancer (MFBC), ductal type, has been hypothesized to arise by one of two mechanisms: either through intramammary/intralymphatic spread from a single index tumor (MBC-1), or as multiple independent tumors with each focus carrying its corresponding ductal carcinoma in-situ (MBC-2). In order to improve our understanding of MFBC pathogenesis, we employed laser capture microdissection coupled with whole-exome sequencing to study clonal origin in MFBC. We selected three cases of MBC-1 (C1 to C3) and MBC-2 (C4 to C6) and analyzed three foci from each case. MBC-1 cases were histologically similar and showed a strong predilection for satellite foci, vascular invasion and nodal metastasis when compared to MBC-2. Our bioinformatics approach provided strong evidence for clonal relationships in MBC-1, as demonstrated by distinct clusters of genes conserved across all tumor foci. Conversely, no gene clusters were shared across all the foci in MBC-2, suggesting multiple independent tumors. These findings provide further support for the two distinct pathogenetic mechanisms in MFBC.
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http://dx.doi.org/10.1016/j.humpath.2019.08.021DOI Listing
December 2019

Synovial tissue signatures enhance clinical classification and prognostic/treatment response algorithms in early inflammatory arthritis and predict requirement for subsequent biological therapy: results from the pathobiology of early arthritis cohort (PEAC).

Ann Rheum Dis 2019 12 2;78(12):1642-1652. Epub 2019 Oct 2.

Experimental Medicine and Rheumatology, William Harvey Research Institute, London, UK

Objective: To establish whether synovial pathobiology improves current clinical classification and prognostic algorithms in early inflammatory arthritis and identify predictors of subsequent biological therapy requirement.

Methods: 200 treatment-naïve patients with early arthritis were classified as fulfilling RA1987 American College of Rheumatology (ACR) criteria (RA1987) or as undifferentiated arthritis (UA) and patients with UA further classified into those fulfilling RA2010 ACR/European League Against Rheumatism (EULAR) criteria. Treatment requirements at 12 months (Conventional Synthetic Disease Modifying Antirheumatic Drugs (csDMARDs) vs biologics vs no-csDMARDs treatment) were determined. Synovial tissue was retrieved by minimally invasive, ultrasound-guided biopsy and underwent processing for immunohistochemical (IHC) and molecular characterisation. Samples were analysed for macrophage, plasma-cell and B-cells and T-cells markers, pathotype classification (lympho-myeloid, diffuse-myeloid or pauci-immune) by IHC and gene expression profiling by Nanostring.

Results: 128/200 patients were classified as RA1987, 25 as RA2010 and 47 as UA. Patients classified as RA1987 criteria had significantly higher levels of disease activity, histological synovitis, degree of immune cell infiltration and differential upregulation of genes involved in B and T cell activation/function compared with RA2010 or UA, which shared similar clinical and pathobiological features. At 12-month follow-up, a significantly higher proportion of patients classified as lympho-myeloid pathotype required biological therapy. Performance of a clinical prediction model for biological therapy requirement was improved by the integration of synovial pathobiological markers from 78.8% to 89%-90%.

Conclusion: The capacity to refine early clinical classification criteria through synovial pathobiological markers offers the potential to predict disease outcome and stratify therapeutic intervention to patients most in need.
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http://dx.doi.org/10.1136/annrheumdis-2019-215751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900253PMC
December 2019

Auditing service delivery in glaucoma clinics using visual field records: a feasibility study.

BMJ Open Ophthalmol 2019 15;4(1):e000352. Epub 2019 Aug 15.

Division of Optometry and Visual Science, School of Health Sciences, City, University of London, London, UK.

Objective: This study aimed to demonstrate that large-scale visual field (VF) data can be extracted from electronic medical records (EMRs) and to assess the feasibility of calculating metrics from these data that could be used to audit aspects of service delivery of glaucoma care.

Method And Analysis: Humphrey visual field analyser (HFA) data were extracted from Medisoft EMRs from five regionally different clinics in England in November 2015, resulting in 602 439 records from 73 994 people. Target patients were defined as people in glaucoma clinics with measurable and sustained VF loss in at least one eye (HFA mean deviation (MD) outside normal limits ≥2 VFs). Metrics for VF reliability, stage of VF loss at presentation, speed of MD loss, predicted loss of sight years (bilateral VF impairment) and frequency of VFs were calculated.

Results: One-third of people (34.8%) in the EMRs had measurable and repeatable VF loss and were subject to analyses (n=25 760 patients). Median (IQR) age and presenting MD in these patients were 71 (61, 78) years and -6 (-10, -4) dB, respectively. In 19 264 patients with >4 years follow-up, median (IQR) MD loss was -0.2 (-0.8, 0.3) dB/year and median (IQR) intervals between VF examinations was 11 (8, 16) months. Metrics predicting loss of sight years and reliability of examinations varied between centres (p<0.001).

Conclusion: This study illustrates the feasibility of assessing aspects of health service delivery in glaucoma clinics through analysis of VF databases. Proposed metrics could be useful for blindness prevention from glaucoma in secondary care centres.
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http://dx.doi.org/10.1136/bmjophth-2019-000352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711463PMC
August 2019

Individualized pattern recognition for detecting mind wandering from EEG during live lectures.

PLoS One 2019 12;14(9):e0222276. Epub 2019 Sep 12.

Department of Surgery, McMaster University, Hamilton, Ontario, Canada.

Neural Correlates Of Mind Wandering: The ability to detect mind wandering as it occurs is an important step towards improving our understanding of this phenomenon and studying its effects on learning and performance. Current detection methods typically rely on observable behaviour in laboratory settings, which do not capture the underlying neural processes and may not translate well into real-world settings. We address both of these issues by recording electroencephalography (EEG) simultaneously from 15 participants during live lectures on research in orthopedic surgery. We performed traditional group-level analysis and found neural correlates of mind wandering during live lectures that are similar to those found in some laboratory studies, including a decrease in occipitoparietal alpha power and frontal, temporal, and occipital beta power. However, individual-level analysis of these same data revealed that patterns of brain activity associated with mind wandering were more broadly distributed and highly individualized than revealed in the group-level analysis.

Mind Wandering Detection: To apply these findings to mind wandering detection, we used a data-driven method known as common spatial patterns to discover scalp topologies for each individual that reflects their differences in brain activity when mind wandering versus attending to lectures. This approach avoids reliance on known neural correlates primarily established through group-level statistics. Using this method for individual-level machine learning of mind wandering from EEG, we were able to achieve an average detection accuracy of 80-83%.

Conclusions: Modelling mind wandering at the individual level may reveal important details about its neural correlates that are not reflected when using traditional observational and statistical methods. Using machine learning techniques for this purpose can provide new insight into the varieties of neural activity involved in mind wandering, while also enabling real-time detection of mind wandering in naturalistic settings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222276PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742406PMC
March 2020

Molecular Portraits of Early Rheumatoid Arthritis Identify Clinical and Treatment Response Phenotypes.

Cell Rep 2019 08;28(9):2455-2470.e5

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Electronic address:

There is a current imperative to unravel the hierarchy of molecular pathways that drive the transition of early to established disease in rheumatoid arthritis (RA). Herein, we report a comprehensive RNA sequencing analysis of the molecular pathways that drive early RA progression in the disease tissue (synovium), comparing matched peripheral blood RNA-seq in a large cohort of early treatment-naive patients, namely, the Pathobiology of Early Arthritis Cohort (PEAC). We developed a data exploration website (https://peac.hpc.qmul.ac.uk/) to dissect gene signatures across synovial and blood compartments, integrated with deep phenotypic profiling. We identified transcriptional subgroups in synovium linked to three distinct pathotypes: fibroblastic pauci-immune pathotype, macrophage-rich diffuse-myeloid pathotype, and a lympho-myeloid pathotype characterized by infiltration of lymphocytes and myeloid cells. This is suggestive of divergent pathogenic pathways or activation disease states. Pro-myeloid inflammatory synovial gene signatures correlated with clinical response to initial drug therapy, whereas plasma cell genes identified a poor prognosis subgroup with progressive structural damage.
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http://dx.doi.org/10.1016/j.celrep.2019.07.091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718830PMC
August 2019

Efficacy, Safety, and Sample Quality of Ultrasound-Guided Synovial Needle Biopsy in Clinical Practice and Research: A Prospective Observational Study.

Arthritis Care Res (Hoboken) 2020 10;72(10):1497-1505

Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, and Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon Academic Medical Centre, Lisbon, Portugal.

Objective: To study the efficacy, tolerability, safety, and sampling variation of ultrasound (US)-guided synovial biopsies performed in clinical practice and research.

Methods: We included all patients who had a US-guided synovial needle biopsy from November 2013 to January 2018. Patients were evaluated for procedure safety and tolerability. Usefulness of synovial biopsy was considered based on contribution for achieving the proposed aims. We analyzed samples for presence and quality of synovial tissue, synovitis score/grade, and pathotype. Variation across patients, samples, section levels, and sampling order was assessed.

Results: A total of 64 US-guided synovial biopsies were performed (n = 52 in clinical practice, n = 12 in research). Patient tolerability (70% no/mild discomfort) was remarkably high. There was no significant aggravation of symptoms or US synovitis in the biopsied joint. Procedures were overall safe, with few minor, 2 moderate, and no major adverse events. Usefulness of US-guided synovial biopsies was high, both in clinical practice (37% direct diagnostic impact, 100% positive/95% negative predictive values for infection) and in research (92% success). Synovial tissue was retrieved in 88% of biopsies, with a median of 75% gradable samples. There was significant variation in sample quality and synovitis features across patients and samples, but not between different section levels. Samples collected later in the procedure had a lower frequency of synovial tissue and were poorly concordant in pathotype with those collected earlier.

Conclusion: US-guided synovial needle biopsy is an effective, safe, and well-tolerated means to collect good quality synovial tissue for clinical and research purposes. Samples collected for different aims should be retrieved in parallel, rather than sequentially.
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http://dx.doi.org/10.1002/acr.24050DOI Listing
October 2020