Claire Gorman

Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept.The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013-003413-18).Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for eligibility and, of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo. During the treatment period, seven (6%) of 110 participants in the abatacept group and 30 (29%) of 103 participants in the placebo group met the primary endpoint. At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92·8% (SE 2·6) in the abatacept group and 69·2% (4·7) in the placebo group. Kaplan-Meier arthritis-free survival plots over 24 months favoured abatacept (log-rank test p=0·044). The difference in restricted mean survival time between groups was 53 days (95% CI 28-78; p<0·0001) at 12 months and 99 days (95% CI 38-161; p=0·0016) at 24 months in favour of abatacept. During treatment, abatacept was associated with improvements in pain scores, functional wellbeing, and quality-of-life measurements, as well as low scores of subclinical synovitis by ultrasonography, compared with placebo. However, the effects were not sustained at 24 months. Seven serious adverse events occurred in the abatacept group and 11 in the placebo group, including one death in each group deemed unrelated to treatment.Therapeutic intervention during the at-risk phase of rheumatoid arthritis is feasible, with acceptable safety profiles. T-cell co-stimulation modulation with abatacept for 12 months reduces progression to rheumatoid arthritis, with evidence of sustained efficacy beyond the treatment period, and with no new safety signals.Bristol Myers Squibb.

Whilst many physiological functions of nitric oxide (NO) have been revealed so far, recent evidence proposes an essential role for NO in T lymphocyte activation and signal transduction. NO acts as a second messenger, activating soluble guanyl cyclase and participating in signal transduction pathways involving cyclic GMP. NO modulates mitochondrial events that are involved in apoptosis and regulates mitochondrial biogenesis in many cell types, including lymphocytes. Several studies undertaken on patients with RA and SLE have documented increased endogenous NO synthesis, although the effects of NO may be distinct. Here, we discuss recent evidence that NO contributes to T cell dysfunction in both SLE and RA by altering multiple signaling pathways in T cells. Although NO may play a physiological role in lymphocyte cell signaling, its overproduction may perturb T cell activation, differentiation and effector responses, each of which may contribute in different ways to the pathogenesis of autoimmunity.

BackgroundDespite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status.MethodsSTRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)–European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU).FindingsBetween June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47–2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53).InterpretationIn this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response.FundingUK Medical Research Council and Versus Arthritis.

TCRzeta (CD247) functions as an amplification module in the TCR signaling cascade and is essential for assembly and surface expression of the TCR/CD3 complex. The TCRzeta-chain is down-regulated in many chronic infectious and inflammatory diseases, including systemic lupus erythematosus (SLE). It is unclear whether reduced TCRzeta expression is a cause or a consequence of chronic inflammatory responses. We have addressed this question by adopting a combined genetic and functional approach. We analyzed TCRzeta protein expression using a FACS-based expression index and documented considerable, but longitudinally stable, variation in TCRzeta expression in healthy individuals. The variation in TCRzeta expression was associated with polymorphisms in the CD3Z 3'-untranslated region (UTR) in SLE patients and healthy controls. Detailed mapping of the 3'-UTR revealed that the minor alleles of two single nucleotide polymorphisms (SNPs) in strong disequilibrium (rs1052230 and rs1052231) were the causal variants associated with low TCRzeta expression (p=0.015). Using allelic imbalance analysis, the minor alleles of these 3'-UTR SNPs were associated with one-third of the level of mRNA compared with the major allele. A family-based association analysis showed that the haplotype carrying the low-expression variants predisposes to SLE (p=0.033). This suggests that a genetically determined reduction in TCRzeta expression has functional consequences manifested by systemic autoimmunity.

Experimental and clinical evidence for T cell involvement in the pathology of rheumatoid arthritis (RA) is compelling, and points to a local dysregulation of T cell function in the inflamed joint. Nitric oxide (NO) has been shown to regulate T cell function under physiological conditions, but overproduction of NO may contribute to lymphocyte dysfunction characteristic of RA. Several investigations in patients with RA have documented evidence of increased NO synthesis, but these studies have focused largely on macrophage-derived NO and its impact on innate immune and inflammatory responses. In this study, we set out to explore the contribution that T cells make to NO production. We find that T cells from RA patients produce >2.5 times more NO than healthy donor T cells (p<0.001). Although NO is an important physiological mediator of mitochondrial biogenesis, mitochondrial mass is similar in RA and control T cells. In contrast, increased NO production is associated with increased cytoplasmic Ca(2+) concentrations in RA T cells (p<0.001). In vitro treatment of human peripheral blood lymphocytes, or Jurkat cells with TNF increases NO production (p=0.006 and p=0.001, respectively), whilst infliximab treatment in RA patients decreases T cell derived NO production within 6 weeks of the first infusion (p=0.005). Together, these data indicate that TNF induced NO production in T lymphocytes may contribute to perturbations of immune homeostasis in RA.

Although neuropathic pain is known to negatively affect cognition, the neural mechanisms involved are poorly understood. Chronic pain is associated with changes in synaptic plasticity in the brain which may impact on cognitive functioning. The aim of this study was to model neuropathic pain in mid-aged rats using spinal nerve ligation (SNL). Following establishment of allodynia and hyperalgesia, behaviour was assessed in a battery of cognitive tests. Expression of the presynaptic protein, synaptophysin, and its colocalisation with the vesicular GABA and glutamate transporters (vGAT and vGLUT, respectively), was investigated in the medial prefrontal cortex (mPFC) and hippocampus.Nine month old male Sprague Dawley rats underwent L5-L6 spinal nerve ligation or a sham procedure. Mechanical and cold allodynia and thermal hyperalgesia were assessed using von Frey, acetone and Hargreaves tests, respectively. Cognition was assessed in the novel-object recognition, air-puff passive avoidance and Morris water maze behavioural tasks. Immunohistochemistry was used to examine the expression of synaptophysin in the mPFC and CA1 region of the hippocampus and double labelling of synaptophysin and the vesicular transporters vGAT and vGlut was used to investigate the distribution of synaptophysin on GABAergic and glutamatergic neurons.SNL rats displayed impaired performance in the novel-object recognition task. Passive-avoidance responding, and spatial learning and memory in the Morris water maze, were unaffected by SNL surgery. However, in the water maze reversal task, pain-related impairments were evident during training and probe trials. SNL surgery was not associated with any differences in the expression of synaptophysin or its colocalisation with vGAT or vGLUT in the mPFC or the hippocampal CA1 region.These results suggest that the SNL model of neuropathic pain is associated with deficits in recognition memory and cognitive flexibility, but these deficits are not associated with altered synaptophysin expression or distribution in the mPFC and CA1.Cognitive complaints are common amongst chronic pain patients. Here we modelled cognitive impairment in a well-established animal model of neuropathic pain and investigated the neural mechanisms involved. A better understanding of this phenomenon is an important prerequisite for the development of improved treatment of patients affected.

Conradina verticillata Jennison, commonly known as Cumberland Rosemary, is an endangered plant from the mint family Lamiaceae. This species is a flowering, perennial shrub found only in a few counties in Kentucky and Tennessee. Although the odorants responsible for Cumberland Rosemary's unique aroma have not been previously characterized, in this study, a total of 32 odorants were identified using gas chromatography-olfactometry (GC-O) and gas chromatography-mass spectrometry (GC-MS). Odorant flavor dilution (FD) factors were determined through the application of aroma extract dilution analysis (AEDA). Seven odorants with FD factors ≥64 were quantitated by stable isotope dilution assays (SIDA), and their odor activity values (OAV) were calculated. Odorants with OAV ≥1 included 1-octen-3-one (earthy-mushroom, OAV 2,900,000), 1,8-cineole (eucalyptus, OAV 510,000), borneol (earthy, OAV 10,000), bornyl acetate (earthy-fruity, OAV 3,700), eugenol (spicy, OAV 2,200), menthone (mint, OAV 130), and camphor (herbaceous, OAV 72). Sensory analysis revealed that an odor simulation model based on the quantitative data was a close match to the aroma of the plant. Omission studies determined that 1-octen-3-one, 1,8-cineole, and eugenol were the key odorants critical to Cumberland Rosemary's distinct aroma profile. The stereochemistry of selected odorants was also determined by chiral chromatography. This study established a foundation for future experiments on the aroma chemistry of C. verticillata and the other six members of the Conradina genus.

The CD20 cell marker appears early in the process of B cell development. In this review we focus on the results of attempts to utilize B cell depletion based on the use of a chimeric monoclonal antibody (MAb) specific for human CD20, rituximab, for the treatment of patients with autoimmune diseases. In 1997, rituximab was approved for the treatment of low-grade B cell non-Hodgkin's lymphoma. Following these encouraging results, rituximab started to be used experimentally in other diseases presumed to be due to B cell pathology. The first autoimmune disease to be treated effectively was chronic idiopathic thrombocytopaenia. More recent success has been demonstrated in patients with rheumatoid arthritis and systemic lupus erythematosus.

Abstract The T-cell receptor ζ (TCRζ) chain is a master sensor and regulator of lymphocyte responses. Loss of TCRζ expression has been documented in infectious, inflammatory, and malignant diseases, suggesting that it may serve to limit T-cell reactivity and effector responses at sites of tissue damage. These observations prompted us to explore the relationship between TCRζ expression and effector function in T cells. We report here that TCRζdim lymphocytes are enriched for antigen-experienced cells refractory to TCR-induced proliferation. Compared to their TCRζbright counterparts, TCRζdim cells share characteristics of differentiated effector T cells but use accessory pathways for transducing signals for inflammatory cytokine gene expression and cell contact-dependent pathways to activate monocytes. TCRζdim T cells accumulate in inflamed tissues in vivo and have intrinsic migratory activity in vitro. Whilst blocking leukocyte trafficking with anti-TNF therapy in vivo is associated with the accumulation of TCRζdim T cells in peripheral blood, this T-cell subset retains the capacity to migrate in vitro. Taken together, the functional properties of TCRζdim T cells make them promising cellular targets for the treatment of chronic inflammatory disease.

Rheumatoid arthritis (RA) is the prototype chronic inflammatory arthropathy; its precise aetiology is unknown. Over recent years, a number of crucial advances in our understanding of the disease have had a major impact on the treatment of patients with RA.

The T-cell receptor zeta (TCR zeta)-chain is a master sensor and regulator of lymphocyte responses. Loss of TCR zeta-chain expression has been documented during infectious and inflammatory diseases and defines a population of effector T cells (TCR zeta(dim) T cells) that migrate to inflamed tissues. We assessed the expression and functional correlates of circulating TCR zeta(dim) T cells in coronary artery disease.We examined the expression of TCR zeta-chain by flow cytometry in 140 subjects. Increased peripheral blood CD4(+) TCR zeta(dim) T cells were found in patients with acute coronary syndromes (ACS, n=66; median 5.3%, interquartile 2.6 to 9.1% of total CD4(+) T cells; P<0.0001) compared to chronic stable angina (CSA, n=32; 1.6%; 1.0 to 4.1%) and controls (n=42; 1.5%; 0.5 to 2.9%). Such increase was significantly greater in ACS patients with elevated levels of C-reactive protein, and it persisted after the acute event. Moreover, TCR zeta(dim) cells were also more represented within CD8(+) T cell, NK, and CD4(+)CD28(null) T cell subsets in ACS compared to CSA and controls. Finally, CD4(+) and CD8(+) TCR zeta(dim) T cells isolated from ACS displayed an enhanced transendothelial migratory capacity.TCR zeta(dim) T cells, an effector T-cell subset with transendothelial migratory ability, are increased in ACS, and may be implicated in coronary instability.

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In this article, we aim to conceptualize and formalize the construct of resilience using the tools of active inference, a new physics-based modeling approach apt for the description and analysis of complex adaptive systems. We intend this as a first step toward a computational model of resilient systems. We begin by offering a conceptual analysis of resilience, to clarify its meaning, as established in the literature. We examine an orthogonal, threefold distinction between meanings of the word "resilience": (i) inertia, or the ability to resist change (ii) elasticity, or the ability to bounce back from a perturbation, and (iii) plasticity, or the ability to flexibly expand the repertoire of adaptive states. We then situate all three senses of resilience within active inference. We map resilience as inertia onto high precision beliefs, resilience as elasticity onto relaxation back to characteristic (i.e., attracting) states, and resilience as plasticity onto functional redundancy and structural degeneracy.

B cell dysfunction and pathogenic autoantibody formation are thought to be critical in the pathogenesis of systemic lupus erythematosus (SLE). In this review we will summarize the results of attempts to utilize B cell depletion, based on the use of a chimeric monoclonal antibody (MAb) specific for human CD20, rituximab, for the treatment of patients with SLE.

Rheumatologists increasingly perform ultrasound (US) imaging to aid diagnosis and management decisions. There is a need to determine the role of US in facilitating early diagnosis of inflammatory arthritis. This study describes the impact of US use by rheumatologists on diagnosis and management of inflammatory arthritis in routine UK clinical practice.We conducted a prospective study in four secondary care rheumatology clinics, each with one consultant who routinely used US and one who did not. Consenting patients aged > 18, newly referred with suspected inflammatory arthritis were included. Data were collected both retrospectively from medical records and via a prospectively-completed physician questionnaire on US use. Analyses were stratified by US/non-US groups and by sub-population of rheumatoid arthritis (RA)-diagnosed patients.258 patients were included; 134 US and 124 non-US. 42% (56/134) of US and 47% (58/124) of non-US were diagnosed with RA. Results described for US and non-US cohorts, respectively as follows. The proportion of patients diagnosed at their first clinic visit was 37% vs 19% overall (p = 0.004) and 41% vs 19% in RA-diagnosed patients (p = 0.01). The median time to diagnosis (months) was 0.85 vs 2.00 (overall, p = 0.0046) and 0.23 vs 1.38 (RA-diagnosed, p = 0.0016). Median time (months) to initiation on a DMARD (where initiated) was 0.62 vs 1.41 (overall, p = 0.0048) and 0.46 vs 1.81 (RA-diagnosed, p = 0.0007).In patients with suspected inflammatory arthritis, routine US use in newly referred patients seems to be associated with significantly earlier diagnosis and DMARD initiation.

One billion people live in informal settlements worldwide. The complex and multilayered spaces that characterize this unplanned form of urbanization pose a challenge to traditional approaches to mapping and morphological analysis. This study proposes a methodology to study the morphological properties of informal settlements based on terrestrial LiDAR (Light Detection and Ranging) data collected in Rocinha, the largest favela in Rio de Janeiro, Brazil. To measure the morphology of the informal settlement, we propose a series of five metrics related to the geometric characteristics of streets: street width, street elevation, facade heterogeneity, facade density, and street canyon. Our analysis operates at two resolutions, including a global analysis focused on comparing different favela streets to one another and a local analysis unpacking the variation of morphological metrics within streets. We show that our methodology reveals meaningful differences and commonalities in terms of the global morphological characteristics across streets and their local variations, which align with the historical evidence of the favela’s development. Finally, we create morphological maps at high spatial resolution from LiDAR data to inform urban planning assessments of concerns related to crowding, structural safety, air quality, and accessibility in the favela. The methods for this study are automated and can be easily scaled to analyze entire informal settlements, leveraging the increasing availability of inexpensive LiDAR scanners on portable devices such as cellphones.

The TCR complex is a multisubunit complex, comprising at least eight transmembrane units. The clonotypic TCR alpha and beta chains are responsible for antigen recognition, whilst the invariant chains of the CD3 complex (delta, epsilon and gamma) and two zeta (zeta) polypeptides couple antigen recognition to downstream signal transduction pathways. TCRzeta (CD247) functions as an amplification module in the TCR signalling cascade and is also essential for the assembly and surface expression of the TCR/CD3 complex. Loss of TCRzeta expression is common in chronic infectious and inflammatory diseases, as well as in cancer. Previous work has indicated that TCRzeta(low)-expressing cells phenotypically resemble antigen-experienced effector T cells. Here, we describe the derivation of a flow cytometry-based TCRzeta expression index for the purpose of more precisely defining TCRzeta expression, in addition to utilising a simple transmigration assay in the demonstration that TCRzeta(dim) T cells have intrinsic migratory properties that may explain their accumulation at sites of inflammation.

In this case, we describe an unusual presentation of a young woman with a rash typical of morphoea (confirmed on biopsy), who went on to develop myositis in an atypical distribution. Although the association of myositis with diffuse systemic sclerosis is well described, the link with localised scleroderma (morphoea) and myositis has not been described.

<h3>Background</h3> Rheumatologists are increasingly performing ultrasound (US) imaging in the clinic as an additional tool to aid patient diagnosis and management decisions. The National Institute for Clinical Excellence (NICE) has recognised the importance of early detection of persistent synovitis and initiation of disease-modifying anti-rheumatic drugs (DMARDs), which have beneficial effects on long-term patient outcomes. The recent NICE appraisal on RA management highlights the need to determine the role of imaging in assisting with early diagnosis and whether the added cost is justified by better outcomes¹. <h3>Objectives</h3> To describe the impact of US use by rheumatologists on the diagnosis and management of RA patients in routine UK clinical practice when compared to those not using US. <h3>Methods</h3> A prospective, non-interventional, multi-centre study was conducted within 4 secondary care rheumatology clinics. Eligible centres were those that had one consultant using US to aid diagnosis and management and one consultant who did not. Patients aged &gt; 18, newly referred to the rheumatology clinic with suspected inflammatory arthritis were included. Data were collected on demographics, investigations (such as US, MRI, blood tests), diagnosis, subsequent management, and for patients diagnosed with RA, outcomes at 1 year. <h3>Results</h3> 258 patients were included across 4 centres<b>.</b> Of these, 134 were diagnosed and managed by clinicians routinely using US and 124 by clinicians not routinely using US. Mean age was 51.28 (SD 15.75) years in the US group and 53.12 (SD 17.34) in the non-US group. The percentage of males in the US and non-US groups was 31% and 35%, respectively. 42% (56/134) of the US and 47% (58/124) of the non-US group had a diagnosis of RA. A significantly greater proportion of patients in the US group received a formal diagnosis at their 1st clinic visit (36% v 19%, respectively, Fisher's exact test p=0.002). A similar difference was observed for patients with a diagnosis of RA (46% v 19%, respectively, Fisher's exact test p=0.003). Where patients had a diagnosis of RA, there was a significant difference in the time to diagnosis (1.27 v 1.94 months in US and non-US group, T test<b>,</b> p=0.043). For those initiated on a DMARD, there was a significant difference in time to initiation (1.45 v 2.38 months in US (n=54) and non-US group (n=55), T test p=0.02). <h3>Conclusions</h3> This study shows that routine use of US in newly referred patients is associated with an earlier diagnosis and earlier DMARD initiation in patients with RA. Whilst earlier diagnosis and treatment is known to lead to better outcomes², a large prospective study is required to explore the long-term clinical impact and cost-effectiveness of wider routine use of US by rheumatologists in the UK NHS. <h3>References</h3> NICE CG79: Rheumatoid arthritis: The management of rheumatoid arthritis in adults. M. van der Linden et al. Long-term Impact of Delay in Assessment of Early Arthritis Patients. Arthritis &amp; Rheumatism; Online: August 18, 2010 <h3>Acknowledgements</h3> This study was sponsored by AbbVie. pH associates, a company specialising in real world evaluation, supported Abbott and the authors to develop the protocol, conduct the study and analyse the results. <h3>Disclosure of Interest</h3> None Declared

week after the last dose of IV CYC patients were commenced on oral immunosuppression using azathioprine or cyclophosphamide. The effectiveness of the regime was demonstrated by a significant reduction in anti-double-stranded DNA (dsDNA) antibody titre and oral prednisolone dose. Only two patients developed ESRF requiring continuous peritoneal dialysis. No patients developed a significant decline in their neutrophil count 10 days after receiving low-dose IV CYC, and only one patient suffered severe sepsis. This retrospective study suggested that low-dose CYC was well tolerated and beneficial in the short term. A larger retrospective study came to essentially the same conclusion. Ninety patients with a number of different autoimmune disorders were treated with low-dose IV CYC. Of these 90 patients, 43 had lupus nephritis. Patients were treated with weekly infusions of 500 mg CYC for a median of six pulses per patient. If complete remission was achieved, patients were commenced on azathioprine; if partial remission was achieved, patients were given IV CYC 500 mg every month. Follow-up was for a median of 56 months. Results from this study revealed that 33/43 patients (75%) with lupus nephritis achieved complete or partial remission. A significant reduction of patients’ erythrocyte sedimentation rate (ESR), anti-dsDNA antibody titre and proteinuria was observed. Only 7.8% of patients had serious infections during the follow-up period. No cases of premature ovarian failure were seen in 40 pre-menopausal women [10]. The impressive safety profile of the low-dose IV CYC regime was supported in a study of 37 patients with neuropsychiatric SLE: only 5.4% of patients developed herpes zoster and no patients developed leucopenia, cystitis or amenorrhoea [11].

Achieving equity in education outcomes for Aboriginal and Torres Strait Islander students continues to be a key focus for educators across the country. Reports into Indigenous Education frequently cite the need for teachers to have the knowledge and practice required to effectively teach Aboriginal and Torres Strait Islander students who are learning English as an additional language or dialect (EAL/D).

Experimental and clinical evidence for T-cell involvement in the pathogenesis of rheumatoid arthritis (RA) is compelling, and points to a local dysregulation of T-cell function in the inflamed joint. Nitric oxide (NO) has been shown to regulate T-cell function under physiological conditions, but overproduction of NO may contribute to lymphocyte dysfunction in RA. NO has recently been recognized as a key signaling intermediate for T-cell activation and mitochondrial biogenesis. NO is synthesized from L-arginine by NO synthetases (NOS). Three distinct isoforms of NOS are known, including neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS) enzymes. We previously detected the expression of eNOS and nNOS and the absence of iNOS in human PBL, while during inflammation macrophages and monocytes express iNOS. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown origin characterized by the involvement of multiple organs. Several studies carried out on patients with both RA and SLE have documented increased endogenous NO synthesis, but its contribution to T-lymphocyte mitochondrial biogenesis and T-cell dysregulation is not known. We investigated the role of NO in T-cell mitochondrial biogenesis in RA and SLE. The mitochondrial mass, NO production and cytoplasmic Ca2+ levels were measured by flow cytometry. Mitochondria were visualized using transmission electron microscope. T cells from RA patients produce >2.5 times more NO than T cells from healthy donors (P < 0.001). Unexpectedly, the mitochondrial mass was found to be similar in RA and control T cells (P = 0.65), whilst increased NO production was associated with increased cytoplasmic Ca2+ concentrations in RA T cells (P < 0.001). We observed that T-cell NO production decreased in most RA patients following anti-TNF treatment. Although lupus T cells produced comparable amounts of NO to normal T cells, lupus monocytes produced twice as much NO as normal monocytes (P = 0.015). We also observed increased mitochondrial mass (47.7 ± 2.8%; P = 0.00017) and increased cytoplasmic (38 ± 6.4%; P = 0.0023) Ca2+ content in T cells from SLE patients when compared with control donors. Electron microscopy revealed that T cells of lupus patients contained 8.76 ± 1 mitochondria, while control donors contained 3.18 ± 0.28 mitochondria per cell (P = 0.0009). In addition, lupus lymphocytes harbor several-fold enlarged mega-mitochondria. These data suggest that monocytes are the primary source of NO in SLE, while T lymphocytes are the primary source of NO in RA. Although the iNOS pathway is not as rapid as eNOS or nNOS, it is thought to be capable of generating much larger quantities of NO (nanomolar range) than the constitutive NOS isoforms (picomolar range), explaining the differences in T-cell mitochondrial biogenesis in SLE and RA. Since mitochondria can take up, store and release Ca2+, increased mitochondrial mass may account for altered Ca2+ handling in SLE. Furthermore increased NO production may contribute to T-cell dysfunction in both SLE and RA.

In this paper, we aim to conceptualize and formalize the construct of resilience using the tools of active inference, a new physics-based modeling approach apt for the description and analysis of complex adaptive systems. We intend this as a first step towards a computational model of resilient systems. We begin by offering a conceptual analysis of resilience, to clarify its meaning, as established in the literature. We examine an orthogonal, threefold distinction between meanings of the word “resilience”: (i) inertia, or the ability to resist change (ii) elasticity, or the ability to bounce back from a perturbation, and (iii) plasticity, or the ability to flexibly expand the repertoire of adaptive states. We then situate all three senses of resilience within active inference. We map resilience as inertia onto high precision beliefs, resilience as elasticity onto relaxation back to characteristic (i.e., attracting) states, and resilience as plasticity onto functional redundancy and structural degeneracy.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by destruction of cartilage and bone. The destructive lesions result from both immune responses and non-antigen-specific inflammatory processes. Little is known about the primary cause of RA. Although the primacy of T-cell-related events early in the disease remains debated, strong evidence indicates that autoantigen recognition by specific T cells is crucial to the pathophysiology of rheumatoid synovitis. We will discuss evolving concepts about T-cell involvement in RA and the roles for various T cell subsets in the development of joint abnormalities. The hypothesis that RA is a T-cell driven disease was put forward when studies of RA synovium showed numerous T cells carrying activation markers. These T cells were found to participate in the complex network of cell- and mediator-driven events leading to joint destruction. Conceivably, these T cells may be stimulated by an autoantigen (whether specific to the joints or ubiquitous), a highly conserved foreign protein cross-reacting with its human homolog, or a neo-antigen expressed as a result of posttranslational events. For many years, animal models have provided valuable evidence supporting a role for T cells in RA. We will review three murine models of arthritis caused by different mechanisms. In collagen-induced arthritis, the immune response to a joint antigen is mediated by pathogenic Th1 cells that elicit severe inflammatory synovitis. Spontaneous arthritis in K/BxN T-cell-receptor transgenic mice is related to an adaptive immune response against a ubiquitous protein whose end-stage effector mechanisms are heavily dependent on the innate immune system. In the SKG model of autoimmune inflammatory arthritis, a point mutation in the gene encoding a key signal-transduction molecule in T cells causes defective T cell selection in the thymus, which releases polyclonal autoreactive T cells. Studies in these and other animal models have established that a variety of T-cell subsets whose roles vary with cell location and disease stage can contribute to synovitis. Finally, in addition to direct autoimmune attack by effector T cells, arthritis may result from defective homeostatic control of immunity by regulatory T cells.

Rheumatoid arthritis is a chronic inflammatory autoimmune disease in which, although the exact etiology is unknown, the contribution from genetic factors is approximately 60%. major histocompatibility complex alleles make the largest contribution to this genetic effect. The remainder is probably made up of an, as yet undefined, number of genes (∼50–200) with low disease penetrance. Recent advances in genetic technology are now enabling us to start to identify some of these more moderate risk-conferring candidate genes. Evidence from functional studies of such genes is beginning to provide insight into the exact nature of the pathways and processes involved in disease susceptibility and expression. In this review, we will discuss how a growing number of genetic polymorphisms might underpin the immunological and molecular anomalies characteristic of rheumatoid arthritis. Specifically, we will focus on one particular pathway, T-cell activation, with an emphasis on the genetic polymorphism that influences antigen presentation and recognition in antigen-presenting cells, as well as those genes that influence the thresholds of antigen-receptor signaling in T lymphocytes.

cells. We aimed to test the hypothesis that the association between CD3Z genotype and TCRchain expression defined in patients with SLE could also be confirmed in healthy donors and patients with RA. Methods: We initially established a FACS-based TCRexpression index reflecting 1) constitutive expression of TCRin TCR� pos T cells and 2) the number of TCR� dim T cells expressed as a ratio of TCR� bright/dim events. Using this composite index, we compared TCRexpression in CD3 þ , CD4 þ , CD8 þ and CD56 þ lymphocyte subsets from 45 healthy donors genotyped for the CD3Z7 and CD3Z8 SNPs. TCRexpression was also analysed in 36 patients with severe RA requiring anti-TNFtherapy. Genotyping was performed by PCR-RFLP. Results: TCRexpression was reduced in all T cell subsets in donors carrying one copy of the minor allele of both SNPs; this association was true for both TCRexpression indices. Analysis of the 36 RA patients revealed that 36% carried at least 1 copy of the minor alleles of both SNPs compared to frequencies of 15% (for CD3Z7) and 17% (for CD3Z8) in a cohort of 962 healthy controls. Conclusions: These data suggest that variation in expression of TCRis linked to polymorphisms in the 3'UTR of the human CD3Z gene and that minor alleles of the CD3Z gene may be a marker for severe RA. As the 3'UTR of mRNA plays a key role in post-transcriptional gene regulation by affecting mRNA stability, it is feasible that reduced TCRexpression may occur via impaired TCRmRNA stability. These findings could have important implications for understanding the genetic basis of the immune response.

<h3></h3> COVID-19 has had a significant impact on specialty training. All training days were cancelled and the majority of trainees were redeployed to general medicine. By early May 2020, there was a shift in the focus back towards specialty training as COVID-19 related hospital admissions continued to decrease. With the help of the team from King's College London, a remote rheumatology training programme was developed and accessible to trainees from four different regions – South London, North West London, North East/North Central London and Kent/Surrey/Sussex. The collaboration between different regions gave access to a greater pool of speakers and reduced the administrative workload. Subsequent collaboration with the British Society for Rheumatology facilitated the delivery of the webinars on a national level, supporting other regions that had not yet set up any remote training. Feedback was particularly important for this innovative programme in order to understand how this experience could be optimised for trainees. There were no additional difficulties related to the training taking place online, with one trainee responding that it was 'very easy to log on'. There was also positive feedback regarding the recording – '[it] was great to have a link to the recording to watch it later'. By having a shared vision for change, we were able to work across regions and organisations, delivering a high quality training programme on a national scale, benefitting a greater number of trainees. Remote training has the additional benefit of removing the need to travel between hospitals. Therefore, there may be a push towards blended learning (a combination of online and face-to-face learning) in the future. Using a robust feedback mechanism, we are confident that the programme will continue to improve as it evolves alongside the pandemic, aiming to at least in part, satisfy the speciality rheumatology training needs within our regions.

Background: Parents of children with high weight are often the target of blame and shaming. However, this form of stigma, termed weight stigma by association, is poorly understood.Objective: To investigate the sources, forms, and impacts of weight stigma by association among mothers of children with overweight or obesity. Methods: Mothers of 5 to 16-year-old children (N=34; 54% non-Hispanic White) participated in semi-structured interviews. A coding scheme was developed using the constant comparative method and reliably applied to interview transcripts. Mothers’ self-reported sociodemographic information, and height and weight were measured.Results: Family members were a common source of negative comments to parents about children’s weight; these comments were often critical of mothers’ parenting and caused hurt feelings and family estrangement. Many mothers also reported negative feelings about their children’s physicians due to interactions about their children’s weight. Almost all mothers expressed guilt and sadness for not parenting differently; many internalized beliefs that they were bad parents because of their children’s weight. Conclusion: Mothers of children with overweight and obesity are frequently the target of weight stigma by association. Additional research is needed to elucidate the impacts of this form of stigma on parents’ health, the parent/child relationship, and children’s health.

One billion people live in informal settlements worldwide. The complex and multilayered spaces that characterize this unplanned form of urbanization pose a challenge to traditional approaches to mapping and morphological analysis. This study proposes a methodology to study the morphological properties of informal settlements based on terrestrial LiDAR (Light Detection and Ranging) data collected in Rocinha, the largest favela in Rio de Janeiro, Brazil. Our analysis operates at two resolutions, including a \emph{global} analysis focused on comparing different streets of the favela to one another, and a \emph{local} analysis unpacking the variation of morphological metrics within streets. We show that our methodology reveals meaningful differences and commonalities both in terms of the global morphological characteristics across streets and their local distributions. Finally, we create morphological maps at high spatial resolution from LiDAR data, which can inform urban planning assessments of concerns related to crowding, structural safety, air quality, and accessibility in the favela. The methods for this study are automated and can be easily scaled to analyze entire informal settlements, leveraging the increasing availability of inexpensive LiDAR scanners on portable devices such as cellphones.