Publications by authors named "Peter Taylor"

731 Publications

Neutralizing monoclonal antibodies for treatment of COVID-19.

Nat Rev Immunol 2021 Apr 19. Epub 2021 Apr 19.

Baylor University Medical Center, Dallas, TX, USA.

Several neutralizing monoclonal antibodies (mAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and are now under evaluation in clinical trials. With the US Food and Drug Administration recently granting emergency use authorizations for neutralizing mAbs in non-hospitalized patients with mild-to-moderate COVID-19, there is an urgent need to discuss the broader potential of these novel therapies and to develop strategies to deploy them effectively in clinical practice, given limited initial availability. Here, we review the precedent for passive immunization and lessons learned from using antibody therapies for viral infections such as respiratory syncytial virus, Ebola virus and SARS-CoV infections. We then focus on the deployment of convalescent plasma and neutralizing mAbs for treatment of SARS-CoV-2. We review specific clinical questions, including the rationale for stratification of patients, potential biomarkers, known risk factors and temporal considerations for optimal clinical use. To answer these questions, there is a need to understand factors such as the kinetics of viral load and its correlation with clinical outcomes, endogenous antibody responses, pharmacokinetic properties of neutralizing mAbs and the potential benefit of combining antibodies to defend against emerging viral variants.
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http://dx.doi.org/10.1038/s41577-021-00542-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054133PMC
April 2021

Liothyronine and Levothyroxine Prescribing in England: A Comprehensive Survey and Evaluation.

Int J Clin Pract 2021 Apr 16:e14228. Epub 2021 Apr 16.

The School of Medicine, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, England, UK.

Introduction: The approach to thyroid hormone replacement varies across centres but the extent and determinants of variation is unclear. We evaluated geographical variation in levothyroxine (LT4) and liothyronine (LT3) prescribing across General Practices in England and analysed the relationship of prescribing patterns to clinical and socioeconomic factors.

Methods: Data was downloaded from the NHS monthly General Practice Prescribing Data in England for the period 2011-2020.

Results: The study covered a population of 19.4 million women over 30 years of age, attending 6,660 GP practices and being provided with 33.7 million prescriptions of LT4 and LT3 at a total cost of £90million / year. Overall, 0.5% of levothyroxine treated patients continue to receive liothyronine. All Clinical Commission Groups (CCGs) in England continue to have at least one liothyronine prescribing practice and 48.5% of English general practices prescribed liothyronine in 2019-20. Factors strongly influencing more levothyroxine prescribing (model accounted for 62% of variance) were the CCG to which the practice belonged and the proportion of people with diabetes registered on the practice list plus antidepressant prescribing, with socioeconomic disadvantage associated with less levothyroxine prescribing. For liothyronine prescribing (model accounted for 17% of variance), factors that were associated with increased levels of liothyronine prescribing were antidepressant prescribing and % of type 2 diabetes mellitus individuals achieving HbA1c control of 58mmol/mol or less. Factors that were associated with reduced levels of liothyronine prescribing included smoking and higher obesity rates.

Conclusion: In spite of strenuous attempts to limit prescribing of liothyronine in general practice a significant number of patients continue to receive this therapy, although there is significant geographical variation in the prescribing of this as for levothyroxine, with specific general practice and CCG related factors influencing prescribing of both levothyroxine and liothyronine across England.
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http://dx.doi.org/10.1111/ijcp.14228DOI Listing
April 2021

Safe Blues: The case for virtual safe virus spread in the long-term fight against epidemics.

Patterns (N Y) 2021 Mar 12;2(3):100220. Epub 2021 Mar 12.

Department of Industrial Engineering and Operations Research, Columbia University, New York, NY 10027, USA.

Viral spread is a complicated function of biological properties, the environment, preventative measures such as sanitation and masks, and the rate at which individuals come within physical proximity. It is these last two elements that governments can control through social-distancing directives. However, infection measurements are almost always delayed, making real-time estimation nearly impossible. Safe Blues is one way of addressing the problem caused by this time lag via online measurements combined with machine learning methods that exploit the relationship between counts of multiple forms of the Safe Blues strands and the progress of the actual epidemic. The Safe Blues protocols and techniques have been developed together with an experimental minimal viable product, presented as an app on Android devices with a server backend. Following initial exploration via simulation experiments, we are now preparing for a university-wide experiment of Safe Blues.
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http://dx.doi.org/10.1016/j.patter.2021.100220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961183PMC
March 2021

Guiding principles for rewilding.

Conserv Biol 2021 Mar 16. Epub 2021 Mar 16.

German Centre for Integrative Biodiversity Research (iDiv) andMartin Luther University Halle-Wittenberg, Germany.

There has been much recent interest in the concept of rewilding as a tool for nature conservation, but also confusion over the idea, which has in turn limited its utility. We outline a unified definition and a series of ten guiding principles for rewilding, drawing on a global advisory group of rewilding experts. These were developed through a survey of 59 rewilding pioneers, a summary of key organisations' rewilding visions, and academic/practitioner workshops involving over 100 participants from around the world. The resulting principles are intended to clarify the concept of rewilding and to improve its effectiveness as a tool to achieve global conservation targets including actions of the UN Decade on Ecosystem Restoration and post-2020 Global Biodiversity Framework. As such we note the potential contribution of other related conservation approaches such as the IUCN CEM NbS programme. The guiding principles developed here state implicitly that rewilding sits upon a continuum of scale, connectivity, and level of human influence, and aims to restore ecosystem structure and functions to achieve a self-sustaining autonomous nature. We suggest that differences in rewilding perspectives lie largely in the extent to which this is seen as achievable, and ultimately, in those interventions which are necessary, feasible or acceptable. An understanding of the contextual setting of rewilding projects is often the key to success, and careful site-specific interpretations will be most successful at achieving the aims of rewilding. Article impact statement: Rewilding is on a continuum of scale, connectivity, and human influence and aims to restore ecosystems to achieve self-sustaining nature. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/cobi.13730DOI Listing
March 2021

A randomized, placebo-controlled experimental medicine study of RIPK1 inhibitor GSK2982772 in patients with moderate to severe rheumatoid arthritis.

Arthritis Res Ther 2021 03 16;23(1):85. Epub 2021 Mar 16.

GlaxoSmithKline Medicine Research Center, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.

Background: Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of inflammation through cell death and proinflammatory cytokine production. This multicenter, randomized, double-blind (sponsor-unblinded), placebo-controlled, experimental medicine study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in moderate to severe rheumatoid arthritis (RA).

Methods: Patients with moderate to severe RA who had received ≥12 weeks' stable-dose conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy were randomized (2:1) to GSK2982772 60 mg or placebo orally 2 or 3 times daily for 84 days. Safety, PK, disease activity, joint damage, and pharmacodynamic (PD) biomarkers were assessed at days 43 and 85.

Results: A total of 52 patients were randomized (placebo, 18; GSK2982772, 34). Adverse events (AEs) were reported in 13 (72%) in patients in the placebo group (n = 3 b.i.d; n = 10 t.i.d.) and 20 (61%) in the GSK2982772 group (n = 3 b.i.d; n = 17 t.i.d.). All treatment-related AEs were mild/moderate, except one severe case of alopecia areata at day 49 and retinal vein thrombosis at day 66 (which led to withdrawal from the study) in patients receiving GSK2982772 t.i.d. Disease Activity Score in 28 Joints-C-reactive protein (DAS28-CRP) scores, ACR20/50/70 response, and rates of low disease activity and remission were similar between placebo and GSK2982772 arms.

Conclusions: These results suggest that inhibition of RIPK1 activity at the GSK2982772 exposure levels evaluated do not translate into meaningful clinical improvement of RA.

Trial Registration: ClinicalTrials.gov Identifier: NCT02858492 . Registered 8 August 2016.
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http://dx.doi.org/10.1186/s13075-021-02468-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962407PMC
March 2021

The Co-occurrence of Self-Harm and Aggression: A Cognitive-Emotional Model of Dual-Harm.

Front Psychol 2021 25;12:586135. Epub 2021 Feb 25.

Division of Psychology and Mental Health, School of Health Sciences, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom.

There is growing evidence that some individuals engage in both self-harm and aggression during the course of their lifetime. The co-occurrence of self-harm and aggression is termed dual-harm. Individuals who engage in dual-harm may represent a high-risk group with unique characteristics and pattern of harmful behaviours. Nevertheless, there is an absence of clinical guidelines for the treatment and prevention of dual-harm and a lack of agreed theoretical framework that accounts for why people may engage in this behaviour. The present work aimed to address this gap in the literature by providing a narrative review of previous research of self-harm, aggression and dual-harm, and through doing so, presenting an evidence-based theory of dual-harm - the cognitive-emotional model of dual-harm. This model draws from previous studies and theories, including the General Aggression Model, diathesis-stress models and emotional dysregulation theories. The cognitive-emotional model highlights the potential distal, proximal and feedback processes of dual-harm, the role of personality style and the possible emotional regulation and interpersonal functions of this behaviour. In line with our theory, various clinical and research implications for dual-harm are suggested, including hypotheses to be tested by future studies.
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http://dx.doi.org/10.3389/fpsyg.2021.586135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946988PMC
February 2021

Reformulating the relationship between cognitive analytic therapy and research: Navigating the landscape and exploring new directions.

Psychol Psychother 2021 Mar;94 Suppl 1:1-7

Division of Psychology and Mental Health, School of Health Sciences, Manchester Academic Health Sciences Centre, University of Manchester, UK.

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http://dx.doi.org/10.1111/papt.12292DOI Listing
March 2021

Treatment Satisfaction, Patient Preferences, and the Impact of Suboptimal Disease Control in a Large International Rheumatoid Arthritis Cohort: SENSE Study.

Patient Prefer Adherence 2021 17;15:359-373. Epub 2021 Feb 17.

Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Background: Patients' needs and perspectives are important determinants of treatment success in rheumatoid arthritis (RA). Assessing patients' perspectives can help identify unmet needs and enhance the understanding of treatment benefits.

Objective: The SENSE study assessed the impact of inadequate response to disease-modifying antirheumatic drugs (DMARDs) on treatment satisfaction, disease outcomes, and patient perspectives related to RA disease management.

Methods: SENSE was a noninterventional, cross-sectional study conducted in 18 countries across Europe, Asia, and South America. Adult patients with poorly controlled RA of moderate/high disease activity were eligible. Patient satisfaction was assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM v1.4). Treatment adherence, healthcare resource utilization (HRU), quality of life (QoL), work ability, digital health literacy (DHL), patient preference information, and treatment strategy were also assessed.

Results: A total of 1624 patients were included in the study: most were female (84.2%) and middle-aged, and mean disease duration was 10.5 years. Mean TSQM global satisfaction subscore was 60.9, with only 13.5% of patients reporting good treatment satisfaction (TSQM global ≥80). The strongest predictor of good treatment satisfaction was treatment with advanced therapies. Most patients (87.4%) reported good treatment adherence. In general, patients had impaired QoL and work ability, high HRU, and 67.4% had poor DHL. Leading treatment expectations were "general improvement of arthritis" and "less joint pain". Most patients preferred oral RA medications (60.7%) and rapid (≤1 week) onset of action (71.1%). "Increased risk for malignancies" and "increased risk for cardiovascular disease" were the least acceptable side effects. Despite suboptimal control, advanced therapies were only used in a minority of patients, and DMARD switches were planned for only half of the patients.

Conclusion: Suboptimal disease control negatively impacts treatment satisfaction, work ability, QoL, and HRU. Data collected on patient perspectives may inform shared decision-making and optimize treat-to-target strategies for improving patient outcomes in RA.
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http://dx.doi.org/10.2147/PPA.S289692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900444PMC
February 2021

A phase III randomized study of apremilast, an oral phosphodiesterase 4 inhibitor, for active ankylosing spondylitis.

J Rheumatol 2021 Feb 15. Epub 2021 Feb 15.

Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom; Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands; Amsterdam University Medical Centre & Zuyderland Medical Centre, Heerlen, The Netherlands; Celgene Corporation, Summit, New Jersey, USA; Amgen Inc., Thousand Oaks, California, USA; Division of Rheumatology, Department of Internal Medicine, Maastricht University Medical Centre, and Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands. This study was funded by Celgene. Amgen Inc. acquired the worldwide rights to Otezla® (apremilast) on November 21, 2019. P.C. Taylor has received grant/research support from Celgene. D. van der Heijde has served as a consultant for AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda and UCB Pharma, and is a director of Imaging Rheumatology BV. R. Landewé has served as a consultant for AbbVie, Eli Lilly, Galapagos, Gilead, Merck, Novartis, Pfizer and UCB Pharma and received an honorarium from Celgene for reading films for this study. S. McCue is a former employee of Celgene. S. Cheng is an employee of Amgen Inc. and a former employee of Celgene. A. Boonen has received grant/research support from Celgene. Address correspondence to Dr. P.C. Taylor, Norman Collisson Professor of Musculoskeletal Sciences, Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Windmill Road Headington, Oxford, OX3 7LD, UK; Tel.: 01865 227323; E-mail:

Objective: To evaluate the efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with active ankylosing spondylitis (AS).

Methods: This phase III, multicenter, double-blind, placebo-controlled study (NCT01583374) randomized patients with active AS (1:1:1) to placebo, apremilast 20 mg twice daily, or apremilast 30 mg twice daily for 24 weeks, followed by a long-term extension phase (up to 5 years). The primary endpoint was assessment of the SpondyloArthritis International Society 20 (ASAS 20) response at Week 16. The impact of treatment on radiographic outcomes after 104 weeks was assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS).

Results: In total, 490 patients with active AS were randomized in the study (placebo: n=164; apremilast 20 mg twice daily: n=163; apremilast 30 mg twice daily: n=163). The primary endpoint of ASAS 20 response at Week 16 was not met (placebo: 37%; apremilast 20 mg twice daily: 35%; apremilast 30 mg twice daily: 33%; p=0.44 vs placebo). At Week 104, mean (SD) changes from baseline in mSASSS were 0.83 (3.6), 0.98 (2.2), and 0.57 (1.9) in patients initially randomized to placebo, apremilast 20 mg twice daily, and apremilast 30 mg twice daily, respectively. The most frequently reported adverse events through Week 104 were diarrhea, nasopharyngitis, upper respiratory infection, and nausea.

Conclusion: No clinical benefit was observed with apremilast treatment in patients with active AS. The safety and tolerability of apremilast were consistent with its known profile.
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http://dx.doi.org/10.3899/jrheum.201088DOI Listing
February 2021

The Key Comorbidities in Patients with Rheumatoid Arthritis: A Narrative Review.

J Clin Med 2021 Feb 1;10(3). Epub 2021 Feb 1.

St. Joseph's Health Care, Schulich School of Medicine, University of Western Ontario, London, ON N6A 5C1, Canada.

Comorbidities in patients with rheumatoid arthritis (RA) are often associated with poor health outcomes and increased mortality. Treatment decisions should take into account these comorbidities due to known or suspected associations with certain drug classes. In clinical practice, it is critical to balance potential treatment benefit against the possible risks for comorbidities as well as the articular manifestations of RA. This review summarises the current literature relating to prevalence and risk factors for the important comorbidities of cardiovascular disease, infections, lymphomas and nonmelanoma skin cancers in patients with RA. The impact on patient outcomes and the interplay between these comorbidities and the therapeutic options currently available, including tumour necrosis factor inhibitors and newer biological therapies, are also explored. As newer RA therapies are developed, and patients gain wider and earlier access to advanced therapies, in part due to the emergence of biosimilars, it is important to consider the prevention or treatment of comorbidities as part of the overall management of RA.
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http://dx.doi.org/10.3390/jcm10030509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867048PMC
February 2021

Altered structural connectome in non-lesional newly diagnosed focal epilepsy: Relation to pharmacoresistance.

Neuroimage Clin 2021 19;29:102564. Epub 2021 Jan 19.

Department of Pharmacology & Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK; Department of Neuroradiology, The Walton Centre NHS Foundation Trust, Liverpool, UK.

Despite an expanding literature on brain alterations in patients with longstanding epilepsy, few neuroimaging studies investigate patients with newly diagnosed focal epilepsy (NDfE). Understanding brain network impairments at diagnosis is necessary to elucidate whether or not brain abnormalities are principally due to the chronicity of the disorder and to develop prognostic markers of treatment outcome. Most adults with NDfE do not have MRI-identifiable lesions and the reasons for seizure onset and refractoriness are unknown. We applied structural connectomics to T1-weighted and multi-shell diffusion MRI data with generalized q-sampling image reconstruction using Network Based Statistics (NBS). We scanned 27 patients within an average of 3.7 (SD = 2.9) months of diagnosis and anti-epileptic drug treatment outcomes were collected 24 months after diagnosis. Seven patients were excluded due to lesional NDfE and outcome data was available in 17 patients. Compared to 29 healthy controls, patients with non-lesional NDfE had connectomes with significantly decreased quantitative anisotropy in edges connecting right temporal, frontal and thalamic nodes and increased diffusivity in edges between bilateral temporal, frontal, occipital and parietal nodes. Compared to controls, patients with persistent seizures showed the largest effect size (|d|>=1) for decreased anisotropy in right parietal edges and increased diffusivity in edges between left thalamus and left parietal nodes. Compared to controls, patients who were rendered seizure-free showed the largest effect size for decreased anisotropy in the edge connecting the left thalamus and right temporal nodes and increased diffusivity in edges connecting right frontal nodes. As demonstrated by large effect sizes, connectomes with decreased anisotropy (edge between right frontal and left insular nodes) and increased diffusivity (edge between right thalamus and left parietal nodes) were found in patients with persistent seizures compared to patients who became seizure-free. Patients who had persistent seizures showed larger effect sizes in all network metrics than patients who became seizure-free when compared to each other and compared to controls. Furthermore, patients with focal-to-bilateral tonic-clonic seizures (FBTCS, N = 11) had decreased quantitative anisotropy in a bilateral network involving edges between temporal, parietal and frontal nodes with greater effect sizes than those of patients without FBTCS (N = 9). NBS findings between patients and controls indicated that structural network changes are not necessarily a consequence of longstanding refractory epilepsy and instead are present at the time of diagnosis. Computed effect sizes suggest that there may be structural network MRI-markers of future pharmacoresistance and seizure severity in patients with a new diagnosis of focal epilepsy.
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http://dx.doi.org/10.1016/j.nicl.2021.102564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841400PMC
January 2021

TLR expression profiles are a function of disease status in rheumatoid arthritis and experimental arthritis.

J Autoimmun 2021 Mar 22;118:102597. Epub 2021 Jan 22.

Kennedy Institute for Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford, OX3 7FY, UK.

The role of the innate immune system has been established in the initiation and perpetuation of inflammatory disease, but less attention has been paid to its role in the resolution of inflammation and return to homeostasis. Toll-like receptor (TLR) expression profiles were analysed in tissues with differing disease status in rheumatoid arthritis (RA), ankylosing spondylitis (AS), and in experimental arthritis. TLR gene expression was measured in whole blood and monocytes, before and after TNF blockade. In RA and osteoarthritis synovia, the expression of TLRs was quantified by standard curve qPCR. In addition, four distinct stages of disease were defined and validated in collagen-induced arthritis (CIA), the gold standard animal model for RA - pre-onset, early disease, late disease and immunised mice that were resistant to the development of disease. TLR expression was measured in spleens, lymph nodes, blood cells, liver and the paws (inflamed and unaffected). In RA whole blood, the expression of TLR1, 4 and 6 was significantly reduced by TNF blockade but the differences in TLR expression profiles between responders and non-responders were less pronounced than the differences between RA and AS patients. In RA non-responders, monocytes had greater TLR2 expression prior to therapy compared to responders. The expression of TLR1, 2, 4 and 8 was higher in RA synovium compared to control OA synovium. Circulating cytokine levels in CIA resistant mice were similar to naïve mice, but anti-collagen antibodies were similar to arthritic mice. Distinct profiles of inflammatory gene expression were mapped in paws and organs with differing disease status. TLR expression in arthritic paws tended to be similar in early and late disease, with TLR1 and 2 moderately higher in late disease. TLR expression in unaffected paws varied according to gene and disease status but was generally lower in resistant paws. Disease status-specific profiles of TLR expression were observed in spleens, lymph nodes, blood cells and the liver. Notably, TLR2 expression rose then fell in the transition from naïve to pre-onset to early arthritis. TLR gene expression profiles are strongly associated with disease status. In particular, increased expression in the blood precedes clinical manifestation.
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http://dx.doi.org/10.1016/j.jaut.2021.102597DOI Listing
March 2021

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

Focal to bilateral tonic-clonic seizures are associated with widespread network abnormality in temporal lobe epilepsy.

Epilepsia 2021 Mar 21;62(3):729-741. Epub 2021 Jan 21.

Computational Neuroscience, Neurology, and Psychiatry Lab, Interdisciplinary Computing and Complex BioSystems Research Group, School of Computing, Newcastle University, Newcastle Upon Tyne, UK.

Objective: Our objective was to identify whether the whole-brain structural network alterations in patients with temporal lobe epilepsy (TLE) and focal to bilateral tonic-clonic seizures (FBTCS) differ from alterations in patients without FBTCS.

Methods: We dichotomized a cohort of 83 drug-resistant patients with TLE into those with and without FBTCS and compared each group to 29 healthy controls. For each subject, we used diffusion-weighted magnetic resonance imaging to construct whole-brain structural networks. First, we measured the extent of alterations by performing FBTCS-negative (FBTCS-) versus control and FBTCS-positive (FBTCS+) versus control comparisons, thereby delineating altered subnetworks of the whole-brain structural network. Second, by standardizing each patient's networks using control networks, we measured the subject-specific abnormality at every brain region in the network, thereby quantifying the spatial localization and the amount of abnormality in every patient.

Results: Both FBTCS+ and FBTCS- patient groups had altered subnetworks with reduced fractional anisotropy and increased mean diffusivity compared to controls. The altered subnetwork in FBTCS+ patients was more widespread than in FBTCS- patients (441 connections altered at t > 3, p < .001 in FBTCS+ compared to 21 connections altered at t > 3, p = .01 in FBTCS-). Significantly greater abnormalities-aggregated over the entire brain network as well as assessed at the resolution of individual brain areas-were present in FBTCS+ patients (p < .001, d = .82, 95% confidence interval = .32-1.3). In contrast, the fewer abnormalities present in FBTCS- patients were mainly localized to the temporal and frontal areas.

Significance: The whole-brain structural network is altered to a greater and more widespread extent in patients with TLE and FBTCS. We suggest that these abnormal networks may serve as an underlying structural basis or consequence of the greater seizure spread observed in FBTCS.
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http://dx.doi.org/10.1111/epi.16819DOI Listing
March 2021

Focal to bilateral tonic-clonic seizures are associated with widespread network abnormality in temporal lobe epilepsy.

Epilepsia 2021 Mar 21;62(3):729-741. Epub 2021 Jan 21.

Computational Neuroscience, Neurology, and Psychiatry Lab, Interdisciplinary Computing and Complex BioSystems Research Group, School of Computing, Newcastle University, Newcastle Upon Tyne, UK.

Objective: Our objective was to identify whether the whole-brain structural network alterations in patients with temporal lobe epilepsy (TLE) and focal to bilateral tonic-clonic seizures (FBTCS) differ from alterations in patients without FBTCS.

Methods: We dichotomized a cohort of 83 drug-resistant patients with TLE into those with and without FBTCS and compared each group to 29 healthy controls. For each subject, we used diffusion-weighted magnetic resonance imaging to construct whole-brain structural networks. First, we measured the extent of alterations by performing FBTCS-negative (FBTCS-) versus control and FBTCS-positive (FBTCS+) versus control comparisons, thereby delineating altered subnetworks of the whole-brain structural network. Second, by standardizing each patient's networks using control networks, we measured the subject-specific abnormality at every brain region in the network, thereby quantifying the spatial localization and the amount of abnormality in every patient.

Results: Both FBTCS+ and FBTCS- patient groups had altered subnetworks with reduced fractional anisotropy and increased mean diffusivity compared to controls. The altered subnetwork in FBTCS+ patients was more widespread than in FBTCS- patients (441 connections altered at t > 3, p < .001 in FBTCS+ compared to 21 connections altered at t > 3, p = .01 in FBTCS-). Significantly greater abnormalities-aggregated over the entire brain network as well as assessed at the resolution of individual brain areas-were present in FBTCS+ patients (p < .001, d = .82, 95% confidence interval = .32-1.3). In contrast, the fewer abnormalities present in FBTCS- patients were mainly localized to the temporal and frontal areas.

Significance: The whole-brain structural network is altered to a greater and more widespread extent in patients with TLE and FBTCS. We suggest that these abnormal networks may serve as an underlying structural basis or consequence of the greater seizure spread observed in FBTCS.
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http://dx.doi.org/10.1111/epi.16819DOI Listing
March 2021

The Jak/STAT pathway: A focus on pain in rheumatoid arthritis.

Semin Arthritis Rheum 2021 Feb 18;51(1):278-284. Epub 2020 Dec 18.

Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Avenue, Tucson, AZ 85718, USA. Electronic address:

Pain is a manifestation of rheumatoid arthritis (RA) that is mediated by inflammatory and non-inflammatory mechanisms and negatively affects quality of life. Recent findings from a Phase 3 clinical trial showed that patients with RA who were treated with a Janus kinase 1 (Jak1) and Janus kinase 2 (Jak2) inhibitor achieved significantly greater improvements in pain than those treated with a tumor necrosis factor blocker; both treatments resulted in similar changes in standard clinical measures and markers of inflammation. These findings suggest that Jak1 and Jak2 inhibition may relieve pain in RA caused by inflammatory and non-inflammatory mechanisms and are consistent with the overarching involvement of the Jak-signal transducer and activator of transcription (Jak/STAT) pathway in mediating the action, expression, and regulation of a multitude of pro- and anti-inflammatory cytokines. In this review, we provide an overview of pain in RA, the underlying importance of cytokines regulated directly or indirectly by the Jak/STAT pathway, and therapeutic targeting of the Jak/STAT pathway in RA. As highlighted herein, multiple cytokines directly or indirectly regulated by the Jak/STAT pathway play important roles in mediating various mechanisms underlying pain in RA. Having a better understanding of these mechanisms may help clinicians make treatment decisions that optimize the control of inflammation and pain.
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http://dx.doi.org/10.1016/j.semarthrit.2020.10.008DOI Listing
February 2021

Trends in costs and prescribing for liothyronine and levothyroxine in England and wales 2011-2020.

Clin Endocrinol (Oxf) 2021 Jan 7. Epub 2021 Jan 7.

The School of Medicine and Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.

Introduction: Recent prescribing policies in England and Wales have imposed significant restrictions on liothyronine prescribing in general practice driven by the prohibitive costs and uncertain benefits of liothyronine in the management of hypothyroidism. However, the impact of these policies on liothyronine usage and costs is still unclear.

Methods: Data were downloaded from the NHS monthly General Practice Prescribing Data in England and from the Comparative Analysis System for Prescribing Audit (CASPA) in Wales for 2011-2020. Trends over the period in amount and costs of levothyroxine and liothyronine prescribing were analysed.

Results: The total medication costs per year for England Wales for hypothyroidism rose from £60.8 million to £129.8 million in 2015-16 and have since reduced to £88.4 million. Levothyroxine prescriptions have been growing above the population growth rate at 0.7%/annum in England and 1.1% in Wales. The costs/patient/year for liothyronine rose from £550 to £3000 in 2015-16 and has since fallen to £2500. Use of liothyronine as a percentage of levothyroxine started to fall in 2015-16 at 7%/annum in England and 3% in Wales. Nevertheless, 0.5% of levothyroxine-treated patients continue to receive liothyronine. All Clinical Commission Groups (CCGs) in England continue to have at least one liothyronine prescribing practice and 48.5% of English general practices prescribed liothyronine in 2019-20.

Conclusion: In spite of strenuous attempts to limit prescribing of liothyronine in general practice, a significant number of patients continue to receive this therapy. The price differential of liothyronine vs levothyroxine should be examined again in light of the continuing use of liothyronine.
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http://dx.doi.org/10.1111/cen.14414DOI Listing
January 2021

Antibody Dynamics for Plasmodium vivax Malaria: A Mathematical Model.

Bull Math Biol 2021 Jan 2;83(1). Epub 2021 Jan 2.

School of Mathematics and Statistics, The University of Melbourne, Melbourne, Australia.

Malaria is a mosquito-borne disease that, despite intensive control and mitigation initiatives, continues to pose an enormous public health burden. Plasmodium vivax is one of the principal causes of malaria in humans. Antibodies, which play a fundamental role in the host response to P. vivax, are acquired through exposure to the parasite. Here, we introduce a stochastic, within-host model of antibody responses to P. vivax for an individual in a general transmission setting. We begin by developing an epidemiological framework accounting for P. vivax infections resulting from new mosquito bites (primary infections), as well as the activation of dormant-liver stages known as hypnozoites (relapses). By constructing an infinite server queue, we obtain analytic results for the distribution of relapses in a general transmission setting. We then consider a simple model of antibody kinetics, whereby antibodies are boosted with each infection, but are subject to decay over time. By embedding this model for antibody kinetics in the epidemiological framework using a generalised shot noise process, we derive analytic expressions governing the distribution of antibody levels for a single individual in a general transmission setting. Our work provides a means to explore exposure-dependent antibody dynamics for P. vivax, with the potential to address key questions in the context of serological surveillance and acquired immunity.
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http://dx.doi.org/10.1007/s11538-020-00837-5DOI Listing
January 2021

Structural Brain Network Abnormalities and the Probability of Seizure Recurrence After Epilepsy Surgery.

Neurology 2021 02 22;96(5):e758-e771. Epub 2020 Dec 22.

From the Translational and Clinical Research Institute (N.S.), Faculty of Medical Sciences, and Computational Neuroscience, Neurology, and Psychiatry Lab (N.S., Y.W., N.M.d.S., P.N.T.), Interdisciplinary Computing and Complex BioSystems Group, School of Computing, Newcastle University, Newcastle Upon Tyne; NIHR University College London Hospitals Biomedical Research Centre (Y.W., A.M., A.W.M., J.d.T., S.B.V., G.P.W., J.S.D., P.N.T.), UCL Institute of Neurology, Queen Square; Centre for Medical Image Computing (S.B.V.), University College London; Epilepsy Society MRI Unit (S.B.V., G.P.W., J.S.D), Chalfont St Peter, UK; and Department of Medicine (G.P.W.,), Division of Neurology, Queen's University, Kingston, Ontario, Canada.

Objective: We assessed preoperative structural brain networks and clinical characteristics of patients with drug-resistant temporal lobe epilepsy (TLE) to identify correlates of postsurgical seizure recurrences.

Methods: We examined data from 51 patients with TLE who underwent anterior temporal lobe resection (ATLR) and 29 healthy controls. For each patient, using the preoperative structural, diffusion, and postoperative structural MRI, we generated 2 networks: presurgery network and surgically spared network. Standardizing these networks with respect to controls, we determined the number of abnormal nodes before surgery and expected to be spared by surgery. We incorporated these 2 abnormality measures and 13 commonly acquired clinical data from each patient into a robust machine learning framework to estimate patient-specific chances of seizures persisting after surgery.

Results: Patients with more abnormal nodes had a lower chance of complete seizure freedom at 1 year and, even if seizure-free at 1 year, were more likely to relapse within 5 years. The number of abnormal nodes was greater and their locations more widespread in the surgically spared networks of patients with poor outcome than in patients with good outcome. We achieved an area under the curve of 0.84 ± 0.06 and specificity of 0.89 ± 0.09 in predicting unsuccessful seizure outcomes (International League Against Epilepsy [ILAE] 3-5) as opposed to complete seizure freedom (ILAE 1) at 1 year. Moreover, the model-predicted likelihood of seizure relapse was significantly correlated with the grade of surgical outcome at year 1 and associated with relapses up to 5 years after surgery.

Conclusion: Node abnormality offers a personalized, noninvasive marker that can be combined with clinical data to better estimate the chances of seizure freedom at 1 year and subsequent relapse up to 5 years after ATLR.

Classification Of Evidence: This study provides Class II evidence that node abnormality predicts postsurgical seizure recurrence.
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http://dx.doi.org/10.1212/WNL.0000000000011315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884990PMC
February 2021

Effects of Thyroid Status on Regional Brain Volumes: A Diagnostic and Genetic Imaging Study in UK Biobank.

J Clin Endocrinol Metab 2021 Mar;106(3):688-696

Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff, UK.

Background: Thyroid hormone is essential for optimal human neurodevelopment and may modify the risk of attention-deficit/hyperactivity disorder (ADHD). However, the brain structures involved are unknown and it is unclear if the adult brain is also susceptible to changes in thyroid status.

Methods: We used International Classification of Disease-10 codes, polygenic thyroid scores at different thresholds of association with thyroid traits (PT-values), and image-derived phenotypes in UK Biobank (n = 18 825) to investigate the effects of a recorded diagnosis of thyroid disease and genetic risk for thyroid status on cerebellar and subcortical gray matter volume. Regional genetic pleiotropy between thyroid status and ADHD was explored using the GWAS-pairwise method.

Results: A recorded diagnosis of hypothyroidism (n = 419) was associated with significant reductions in total cerebellar and pallidum gray matter volumes (β [95% CI] = -0.14[-0.23, -0.06], P = 0.0005 and β [95%CI] = -0.12 [-0.20, -0.04], P = 0.0042, respectively), mediated in part by increases in body mass index. While we found no evidence for total cerebellar volume alterations with increased polygenic scores for any thyroid trait, opposing influences of increased polygenic scores for hypo- and hyperthyroidism were found in the pallidum (PT < 1e-3: β [95% CI] = -0.02 [-0.03, -0.01], P = 0.0003 and PT < 1e-7: β [95% CI] = 0.02 [0.01, 0.03], P = 0.0003, respectively). Neither hypo- nor hyperthyroidism showed evidence of regional genetic pleiotropy with ADHD.

Conclusions: Thyroid status affects gray matter volume in adults, particularly at the level of the cerebellum and pallidum, with potential implications for the regulation of motor, cognitive, and affective function.
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http://dx.doi.org/10.1210/clinem/dgaa903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947746PMC
March 2021

Evolving the comprehensive management of rheumatoid arthritis: identification of unmet needs and development of practical and educational tools.

Clin Exp Rheumatol 2020 Nov-Dec;38(6):1056-1067. Epub 2020 Nov 17.

University of Twente, Faculty of Behavioural, Management and Social Sciences, Enschede, The Netherlands.

Objectives: Despite availability of efficacious treatments, unmet needs still exist, preventing optimal and comprehensive management of rheumatoid arthritis (RA). Evolving the management of RA (eRA) is a European-wide educational initiative aiming to support improved patient care through practical and educational tools addressing specific unmet needs.

Methods: A multidisciplinary Steering Committee (17 members, 12 countries) identified unmet needs within the management of RA and prioritised those with the greatest impact on patient outcomes. Practical educational tools addressing priority needs were then developed for dissemination and implementation by the rheumatology community across Europe.

Results: Five areas of priority need were identified: increasing early recognition of RA and treatment initiation; treating RA to target; optimal, holistic approach to selection of treatment strategy, including shared decision-making; improving identification and management of comorbidities; and non-pharmacological patient management. A suite of 14 eRA tools included educational slides, best-practice guidance, self‑assessment questionnaires, clinical checklists, a multidisciplinary team training exercise, an interactive patient infographic, and case scenarios. By April 2020, rheumatology professionals in 17 countries had been actively engaged in the eRA programme; in 11 countries, eRA tools were selected by national leaders in rheumatology and translated for local dissemination. A web platform, with country-specific pages, was developed to support access to the translated tools (https://www.evolvingthemanagementofra.com/).

Conclusions: The eRA programme supports comprehensive management of RA across Europe through development and dissemination of practical educational tools. The eRA tools address priority needs and are available free of charge to the rheumatology community.
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December 2020

Genetic origins and diversity of bushpigs from Madagascar (Potamochoerus larvatus, family Suidae).

Sci Rep 2020 11 26;10(1):20629. Epub 2020 Nov 26.

Sydney School of Veterinary Science, Faculty of Science, The University of Sydney, Sydney, NSW, 2006, Australia.

The island of Madagascar, situated off the southeast coast of Africa, shows the first evidence of human presence ~ 10,000 years ago; however, other archaeological data indicates a settlement of the modern peoples of the island distinctly more recent, perhaps > 1500 years ago. Bushpigs of the genus Potamochoerus (family Suidae), are today widely distributed in Madagascar and presumed to have been introduced from Africa at some stage by human immigrants to the island. However, disparities about their origins in Madagascar have been presented in the literature, including the possibility of endemic subspecies, and few empirical data are available. Furthermore, the separation of bushpigs in Madagascar from their mainland relatives may have favoured the evolution of a different repertoire of immune genes first due to a founder effect and then as a response to distinct pathogens compared to their ancestors. Molecular analysis confirmed the species status of the bushpig in Madagascar as P. larvatus, likely introduced from the central region of southern Africa, with no genetic evidence for the recognition of eastern and western subspecies as suggested from previous cranial morphology examination. Investigation of the immunologically important SLA-DQB1 peptide-binding region showed a different immune repertoire of bushpigs in Madagascar compared to those on the African mainland, with seventeen exon-2 haplotypes unique to bushpigs in Madagascar (2/28 haplotypes shared). This suggests that the MHC diversity of the Madagascar populations may have enabled Malagasy bushpigs to adapt to new environments.
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http://dx.doi.org/10.1038/s41598-020-77279-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693328PMC
November 2020

Multivariate white matter alterations are associated with epilepsy duration.

Eur J Neurosci 2021 Apr 11;53(8):2788-2803. Epub 2020 Dec 11.

CNNP Lab, Interdisciplinary Computing and Complex BioSystems Group, School of Computing, Newcastle University, Newcastle upon Tyne, UK.

Previous studies investigating associations between white matter alterations and duration of temporal lobe epilepsy (TLE) have shown differing results, and were typically limited to univariate analyses of tracts in isolation. In this study, we apply a multivariate measure (the Mahalanobis distance), which captures the distinct ways white matter may differ in individual patients, and relate this to epilepsy duration. Diffusion MRI, from a cohort of 94 subjects (28 healthy controls, 33 left-TLE and 33 right-TLE), was used to assess the association between tract fractional anisotropy (FA) and epilepsy duration. Using ten white matter tracts, we analysed associations using the traditional univariate analysis (z-scores) and a complementary multivariate approach (Mahalanobis distance), incorporating multiple white matter tracts into a single unified analysis. For patients with right-TLE, FA was not significantly associated with epilepsy duration for any tract studied in isolation. For patients with left-TLE, the FA of two limbic tracts (ipsilateral fornix, contralateral cingulum gyrus) were significantly negatively associated with epilepsy duration (Bonferonni corrected p < .05). Using a multivariate approach we found significant ipsilateral positive associations with duration in both left, and right-TLE cohorts (left-TLE: Spearman's ρ = 0.487, right-TLE: Spearman's ρ = 0.422). Extrapolating our multivariate results to duration equals zero (i.e., at onset) we found no significant difference between patients and controls. Associations using the multivariate approach were more robust than univariate methods. The multivariate Mahalanobis distance measure provides non-overlapping and more robust results than traditional univariate analyses. Future studies should consider adopting both frameworks into their analysis in order to ascertain a more complete understanding of epilepsy progression, regardless of laterality.
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http://dx.doi.org/10.1111/ejn.15055DOI Listing
April 2021

Efficacy of baricitinib in patients with moderate-to-severe rheumatoid arthritis with 3 years of treatment: results from a long-term study.

Rheumatology (Oxford) 2020 Nov 17. Epub 2020 Nov 17.

Cochin Hospital, Paris, France.

Objective: To evaluate the long-term efficacy of once-daily baricitinib 4 mg in patients with active RA who were either naïve to DMARDs or who had inadequate response (IR) to MTX.

Methods: Analyses of data from two completed 52-week, phase III studies, RA-BEGIN (DMARD-naïve) and RA-BEAM (MTX-IR), and one ongoing long-term extension (LTE) study (RA-BEYOND) were performed (148 total weeks). At week 52, DMARD-naïve patients treated with MTX monotherapy or baricitinib 4 mg+MTX in RA-BEGIN were switched to open-label baricitinib 4 mg monotherapy; MTX-IR patients treated with adalimumab (+MTX) in RA-BEAM were switched to open-label baricitinib 4 mg (+MTX) in the LTE. Patients who received placebo (+MTX) were switched to baricitinib 4 mg (+MTX) at week 24. Low disease activity (LDA) [Simple Disease Activity Index (SDAI) ≤11], clinical remission (SDAI ≤ 3.3), and physical functioning [Health Assessment Questionnaire Disability Index (HAQ-DI) ≤ 0.5] were assessed. Data were assessed using a non-responder imputation.

Results: At week 148, SDAI LDA was achieved in up to 61% of DMARD-naïve patients and 59% of MTX-IR patients initially treated with baricitinib, and SDAI remission was achieved in up to 34% of DMARD-naïve patients and 24% of MTX-IR patients; HAQ-DI ≤ 0.5 was reached in up to 48% of DMARD-naïve patients and 38% of MTX-IR patients initially treated with baricitinib. Over 148 weeks, 3.6% and 10.7% of MTX-IR patients discontinued across treatment groups due to lack of efficacy or due to adverse events, respectively; discontinuation rates were similar in the DMARD-naïve population.

Conclusion: Treatment with baricitinib 4 mg demonstrated efficacy for up to 3 years and was well tolerated.
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http://dx.doi.org/10.1093/rheumatology/keaa576DOI Listing
November 2020

Update on the diagnosis and management of early rheumatoid arthritis.

Authors:
Peter C Taylor

Clin Med (Lond) 2020 Nov;20(6):561-564

Norman Collisson professor of musculoskeletal sciences, University of Oxford, Oxford, UK

The clinical spectrum of rheumatoid arthritis (RA) presentation is heterogeneous, with wide variation in age of onset, degree of joint involvement and severity. Delayed rheumatological referral is associated with less favourable long-term outcomes. Multidisciplinary teamwork is key to the success of a holistic approach to patient care and addressing issues that are important to the person. Pharmacological treatment of early RA aims to optimally suppress the inflammatory component of the disease with an ideal treatment target of remission. The overarching aim of management of early RA is to achieve a quality of life that permits the individual to pursue normal work, domestic and social activity.
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http://dx.doi.org/10.7861/clinmed.2020-0727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687323PMC
November 2020

Independent components of human brain morphology.

Neuroimage 2021 02 10;226:117546. Epub 2020 Nov 10.

Institute of Physics, Federal University of Rio de Janeiro, Brazil.

Quantification of brain morphology has become an important cornerstone in understanding brain structure. Measures of cortical morphology such as thickness and surface area are frequently used to compare groups of subjects or characterise longitudinal changes. However, such measures are often treated as independent from each other. A recently described scaling law, derived from a statistical physics model of cortical folding, demonstrates that there is a tight covariance between three commonly used cortical morphology measures: cortical thickness, total surface area, and exposed surface area. We show that assuming the independence of cortical morphology measures can hide features and potentially lead to misinterpretations. Using the scaling law, we account for the covariance between cortical morphology measures and derive novel independent measures of cortical morphology. By applying these new measures, we show that new information can be gained; in our example we show that distinct morphological alterations underlie healthy ageing compared to temporal lobe epilepsy, even on the coarse level of a whole hemisphere. We thus provide a conceptual framework for characterising cortical morphology in a statistically valid and interpretable manner, based on theoretical reasoning about the shape of the cortex.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836233PMC
February 2021

Synovial fluid fingerprinting in end-stage knee osteoarthritis: a novel biomarker concept.

Bone Joint Res 2020 Sep 12;9(9):623-632. Epub 2020 Oct 12.

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

Aims: The lack of disease-modifying treatments for osteoarthritis (OA) is linked to a shortage of suitable biomarkers. This study combines multi-molecule synovial fluid analysis with machine learning to produce an accurate diagnostic biomarker model for end-stage knee OA (esOA).

Methods: Synovial fluid (SF) from patients with esOA, non-OA knee injury, and inflammatory knee arthritis were analyzed for 35 potential markers using immunoassays. Partial least square discriminant analysis (PLS-DA) was used to derive a biomarker model for cohort classification. The ability of the biomarker model to diagnose esOA was validated by identical wide-spectrum SF analysis of a test cohort of ten patients with esOA.

Results: PLS-DA produced a streamlined biomarker model with excellent sensitivity (95%), specificity (98.4%), and reliability (97.4%). The eight-biomarker model produced a fingerprint for esOA comprising type IIA procollagen N-terminal propeptide (PIIANP), tissue inhibitor of metalloproteinase (TIMP)-1, a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4), monocyte chemoattractant protein (MCP)-1, interferon-γ-inducible protein-10 (IP-10), and transforming growth factor (TGF)-β3. Receiver operating characteristic (ROC) analysis demonstrated excellent discriminatory accuracy: area under the curve (AUC) being 0.970 for esOA, 0.957 for knee injury, and 1 for inflammatory arthritis. All ten validation test patients were classified correctly as esOA (accuracy 100%; reliability 100%) by the biomarker model.

Conclusion: SF analysis coupled with machine learning produced a partially validated biomarker model with cohort-specific fingerprints that accurately and reliably discriminated esOA from knee injury and inflammatory arthritis with almost 100% efficacy. The presented findings and approach represent a new biomarker concept and potential diagnostic tool to stage disease in therapy trials and monitor the efficacy of such interventions.Cite this article: 2020;9(9):623-632.
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http://dx.doi.org/10.1302/2046-3758.99.BJR-2019-0192.R1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548522PMC
September 2020

The impact of endoscopic transsphenoidal pituitary adenoma surgery on endocrine function: a single-centre study.

Acta Neurochir (Wien) 2021 02 21;163(2):391-398. Epub 2020 Oct 21.

Department of Neurosurgery, University Hospital of Wales, Cardiff, Wales, CF14 4XW, UK.

Introduction: The outcome for pituitary endocrine function following endoscopic transsphenoidal surgery remains unclear. This study aims to evaluate endocrine outcomes following endoscopic surgery in order to provide a benchmark to assist in the counselling of patients perioperatively.

Methods: A prospectively held pituitary database was retrospectively analysed for all adult pituitary adenoma patients undergoing endoscopic surgery from May 2011 to May 2017. All operations were performed by a single neurosurgeon at a regional centre for pituitary surgery. Functioning and non-functioning adenomas were included. Hormonal status was assessed at most recent follow-up.

Results: One hundred forty-five patients (69 M, 76 F) were included in the study with a median age of 52 years. Median follow-up was 52 months. Eighty-eight patients (61%) were not taking any hormone replacement medications, whilst 57 patients (39%) required hormone replacement therapy (HRT) preoperatively. Preoperatively, 29 patients (20%) had hypothalamo-pituitary-adrenal (HPA) axis dysfunction, 39 patients (27%) had thyroid axis dysfunction, 11 males (16%) and 7 females (9%) had gonadal axis dysfunction, and one patient had preoperative diabetes insipidus. Postoperatively, 26 patients (18%) had a new deficiency in pituitary function, whilst 6 patients (11%) were able to cease HRT. Nineteen patients (13%) had new HPA axis deterioration, 12 (8%) had new thyroid axis dysfunction, 8 males (11%) and 4 females (5%) had gonadal axis deterioration, and 6 patients (4%) had new diabetes insipidus (DI).

Conclusions: The ability to restore pituitary function following endoscopic surgery remains limited, whilst new deficits still occur. It is essential that patients are counselled accordingly as hormonal replacement therapy can have a significant impact on quality of life. Larger longer-term collaborative studies of endocrine outcome in endoscopic pituitary surgery are needed.
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http://dx.doi.org/10.1007/s00701-020-04609-xDOI Listing
February 2021

Removal of Interictal MEG-Derived Network Hubs Is Associated With Postoperative Seizure Freedom.

Front Neurol 2020 24;11:563847. Epub 2020 Sep 24.

Interdisciplinary Computing and Complex BioSystems Group, CNNP Lab, School of Computing, Newcastle University, Newcastle upon Tyne, United Kingdom.

To investigate whether MEG network connectivity was associated with epilepsy duration, to identify functional brain network hubs in patients with refractory focal epilepsy, and assess if their surgical removal was associated with post-operative seizure freedom. We studied 31 patients with drug refractory focal epilepsy who underwent resting state magnetoencephalography (MEG), and structural magnetic resonance imaging (MRI) as part of pre-surgical evaluation. Using the structural MRI, we generated 114 cortical regions of interest, performed surface reconstruction and MEG source localization. Representative source localized signals for each region were correlated with each other to generate a functional brain network. We repeated this procedure across three randomly chosen one-minute epochs. Network hubs were defined as those with the highest intra-hemispheric mean correlations. Post-operative MRI identified regions that were surgically removed. Greater mean MEG network connectivity was associated with a longer duration of epilepsy. Patients who were seizure free after surgery had more hubs surgically removed than patients who were not seizure free (AUC = 0.76, = 0.01) consistently across three randomly chosen time segments. Our results support a growing literature implicating network hub involvement in focal epilepsy, the removal of which by surgery is associated with greater chance of post-operative seizure freedom.
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http://dx.doi.org/10.3389/fneur.2020.563847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543719PMC
September 2020

Expulsion at home for early medical abortion: A systematic review with meta-analyses.

Acta Obstet Gynecol Scand 2021 04 28;100(4):727-735. Epub 2020 Nov 28.

Sexual and Reproductive Health Services, NHS Lothian, Edinburgh, Scotland.

Introduction: The safety and acceptability of medical abortion using mifepristone and misoprostol at home at ≤9  weeks' gestation is well established. However, the upper gestational limit at which the procedure remains safe and acceptable at home is not known. To inform a national guideline on abortion care we conducted a systematic review to determine what gestational limit for expulsion at home offers the best balance of benefits and harms for women who are having medical abortion.

Material And Methods: We searched Embase, MEDLINE, Cochrane Library, Cinahl Plus and Web-of-Science on 2 January 2020 for prospective and retrospective cohort studies with ≥50 women per gestational age group, published in English from 1995 onwards, that included women undergoing medical abortion and compared home expulsion of pregnancies of ≤9  weeks' gestational age with pregnancies of 9 -10  weeks or >10  weeks' gestational age, or compared the latter two gestational age groups. We assessed risk-of-bias using the Newcastle-Ottowa scale. All outcomes were meta-analyzed as risk ratios (RR) using the Mantel-Haenszel method. The certainty of the evidence was assessed using GRADE.

Results: Six studies (n = 3381) were included. The "need for emergency care/admission to hospital" (RR = 0.79, 95% confidence interval [CI] 0.45-1.4), "hemorrhage requiring transfusion/≥500 mL blood loss" (RR = 0.62, 95% CI 0.11-3.55), patient satisfaction (RR = 0.99, 95% CI 0.95-1.03), pain (RR = 0.91, 95% CI 0.82-1.02), and "complete abortion without the need for surgical intervention" (RR = 1.03, 95% CI 1-1.05) did not differ statistically significantly between the ≤9 and >9  weeks' gestation groups. The rates of vomiting (RR = 0.8, 95% CI 0.69-0.93) and diarrhea (RR = 0.85, 95% CI 0.73-0.99) were statistically significantly lower in the ≤9  weeks group but these differences were not considered clinically important. We found no studies comparing pregnancies of 9 -10  weeks' gestation with pregnancies of >10  weeks' gestation. The certainty of this evidence was predominantly low and mainly compromised by low event rates and loss to follow up.

Conclusions: Women who are having a medical abortion and will be taking mifepristone up to and including 10  weeks' gestation should be offered the option of expulsion at home after they have taken the misoprostol. Further research needs to determine whether the gestational limit for home expulsion can be extended beyond 10  weeks.
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http://dx.doi.org/10.1111/aogs.14025DOI Listing
April 2021