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Patient-reported outcomes as early warning signs of flare following drug cessation in rheumatoid arthritis.
OBJECTIVES: Drug withdrawal in rheumatoid arthritis (RA) in remission can reduce toxicity, but with the risk of flare which requires close monitoring. We explored the potential of patient-reported outcomes (PROs) for flare detection among RA patients in sustained remission after conventional synthetic disease-modifying antirheumatic drug (csDMARD) cessation. METHODS: Four PROs (Factors that Limit sustAined Remission in rhEumatoid arthritis (FLARE-RA), EuroQol-5 Dimensions (EQ5D), Routine Assessment of Patient Index Data-3 (RAPID-3) and RA Flare Questionnaire (RA-FQ)) were captured at baseline and at sequential visits until time-of-flare or end of 6-month follow-up as part of the BIO-FLARE prospective cohort study. Flare was defined as any of (i) Disease Activity Score 28 (DAS28)-C reactive protein (CRP) ≥3.2 at any visit, (ii) DAS28-CRP≥2.4 on two visits within 2 weeks or (iii) resuming DMARD and/or steroid therapy despite DAS28-CRP<2.4. Cox regression models with time-varying covariates were fitted to evaluate associations between PRO changes and likelihood of flare. Receiver-operating characteristic (ROC) curves enabled discriminatory changes in each PRO to be compared as a means of identifying flare. RESULTS: 58/121 (47.9%) participants (70.1% females, mean age 64.8 years) experienced a flare. A 1-point change in each PRO score was strongly associated with flare development in the multivariate Cox regression model (p<0.001 in each case). ROC curve analysis confirmed that monitoring adverse changes in PROs from baseline offered robust discriminatory utility for identifying flare occurrence. This was most evident for RA-FQ and FLARE-RA (both areas under the curves 0.90, 95% CI 0.84 to 0.96; p=0.001); for example, an RA-FQ increment of ≥5.5 from baseline identified objective flare with positive and negative predictive values of 80% and 91%, respectively. CONCLUSIONS: Our data support the potential value of remote PRO monitoring of RA patients in drug-free remission to identify flare occurrence.
Automatically quantified follow-up imaging biomarkers predict clinical outcomes after acute ischemic stroke.
BACKGROUND: Follow-up infarct volume (FIV) is a proposed surrogate endpoint for proof-of-concept clinical studies in acute ischemic stroke (AIS). This study aimed to provide clinical validation of an automated FIV algorithm, demonstrating the association of imaging biomarkers with clinical outcomes to support the use of these imaging endpoints in clinical trials. METHODS: Data were gathered for adult AIS patients undergoing mechanical thrombectomy with follow-up imaging 12-96 h from initial assessment. Non-contrast computed tomography was used to quantify infarct volume. Image processing used the AI-powered software Brainomix 360 Stroke (Brainomix Ltd., Oxford, United Kingdom) and Brainomix core lab research software. Measures included total FIV and components-ischemic injury corrected FIV (cFIV), hemorrhagic transformation (HT), anatomical distortion (AD; a marker of edema) and infarct growth (IG). The primary clinical endpoint was modified Rankin Scale (mRS) at 90 days; secondary clinical endpoint was NIH Stroke Scale (NIHSS) score at 24 h. RESULTS: Of 986 patients, 843 (85.5%; median age 72 years, 56.7% male) had complete data and were included in the study analysis. Median baseline NIHSS score was 17 (IQR: 12-21). Median imaging follow-up time was 24 h (IQR 20-28). Median 24 h NIHSS score was 11 (5-17); 34% of patients had mRS 0-2 at 90 days. Median FIV was 30.2 mL (12.5-120.8 mL). FIV was significantly associated with 90-day mRS (concordance = 0.819, p
The unusual metabolism of germinal center B cells.
In the germinal center (GC), B cells undergo rounds of somatic hypermutation (SHM), proliferation, and positive selection to develop into high-affinity, long-lived plasma cells and memory B cells. It is well established that, upon activation, B cells significantly alter their metabolism, but until recently little was understood about their metabolism within the GC. In this review we discuss novel in vivo models in which GC B cell (GCBC) metabolism is disrupted; these have greatly increased our understanding of B cell metabolic phenotype. GCBCs are unusual in that, unlike almost all other rapidly proliferating immune cells, they use little glycolysis but prefer fatty acid oxidation (FAO) to fuel ATP synthesis, whilst preferentially utilizing glucose and amino acids as carbon and nitrogen sources for biosynthetic pathways.
Exploring the value of a well-established conditioned pain modulation paradigm in women: a Translational Research in Pelvic Pain (TRiPP) study.
BACKGROUND: Conditioned pain modulation (CPM) is considered a human proxy for descending inhibitory pain pathways. However, there is wide variation in the CPM response described in the literature and ongoing debate about its utility. METHODS: Here we explored CPM in women with (n = 59) and without (n = 26) chronic pelvic pain (CPP), aiming to determine the magnitude of effect and factors influencing variability in the CPM response. RESULTS: Using a pressure pain threshold test stimulus and ischaemic pressure cuff conditioning stimulus (CS), we found no significant difference in the mean CPM effect between CPP and control participants. Using a robust statistical method (+/-2 standard error of measurement) to further investigate CPM, there was no significant difference in the proportion exhibiting inhibition between controls and CPP participants (X2 = 0.003, p = 0.96). Notably, only 23.1% of our healthy controls demonstrated a "true" CPM effect (n = 4 inhibitory, n = 2 facilitatory). Despite a rich data set, we were unable to identify any single questionnaire, clinical or psychophysical covariate correlating with the CPM effect. CONCLUSIONS: Despite using one of the recommended CPM paradigms we were only able to demonstrate "true" CPM in 23.1% of control participants. Thus, the absence of differences between women with and without chronic pelvic pain must be interpreted with caution. Future studies using different CPM paradigms or larger sample sizes may find different results. Although CPM in chronic pain populations is of major theoretical mechanistic interest, the lack of an established assessment standard led us to question its added value in current clinical research.
The risk of revision surgery after trainee-led primary total hip replacement.
INTRODUCTION: The aim of this study was to determine the impact of operating surgeon grade and level of supervision on the incidence of one-year patient mortality and all-cause revision following elective primary total hip replacement (THR). METHODS: National Joint Registry data from 2005 to 2020 for a single University Teaching Hospital were used, with analysis performed on the 15-year dataset divided into 5-year block periods (B1, 2005-2010; B2, 2010-2015; B3, 2015-2020). Outcome measures were mortality and revision surgery at one year, in relation to lead surgeon grade, and level of supervision for trainee-led (TL) operations. RESULTS: A total of 9,999 eligible primary THRs were performed, of which 5,526 (55.3%) were consultant-led (CL), and 4,473 (44.7%) TL. Of TL, 2,404 (53.7%) were nonconsultant-supervised (TU) and 2,069 (46.3%) consultant-supervised (TS). The incidence of one-year patient mortality was 2.05% (n=205), and all-cause revision was 1.11% (n=111). There was no difference in one-year mortality between TL and CL operations (p=0.20, odds ratio (OR) 0.78, confidence interval (CI) 0.55-1.10). The incidence of one-year revision was not different for TL and CL operations (p=0.15, OR 1.37, CI 0.89-2.09). Overall, there was no temporal change for either outcome measure between TL or CL operations. A significant increase in revision within one-year was observed in B3 between TU compared with CL operations (p=0.005, OR 2.81, CI 1.35-5.87). CONCLUSIONS: We found no difference in overall one-year mortality or all-cause revision rate between TL and CL primary THR. Despite a reduction in unsupervised THR in the latest five-year period (2015-2020), unsupervised TL THR resulted in an increased risk of early revision.
Animal models of intestinal inflammation: clues to the pathogenesis of inflammatory bowel disease
In the last decade a number of models of chronic intestinal inflammation have been described that resemble aspects of the pathology found in patients with inflammatory bowel disease. Several themes have emerged from these studies that are of relevance to the pathogenesis of inflammatory bowel disease. Firstly, intestinal inflammation is a consequence of an aberrant chronic immune response triggered by enteric bacteria. Both innate and adaptive immune mechanisms can cause colitis and in many models there is evidence of differential activation of T helper 1 (Th1)-type cells. Targeting the Th1 pathway prevents experimental colitis and there is also evidence that this may be useful in Crohn's disease. Secondly, specialized populations of regulatory T cells have been shown to prevent colitis and in some systems cure it, suggesting immune responses in the intestine are subject to dominant T cell-mediated control. Here we focus on new insights into the pathogenesis and regulation of intestinal inflammation as revealed by model systems and how these may be harnessed for the treatment of IBD.
Homing of intestinal immune cells
The homing of immune cells into the intestinal mucosa, the gut-associated lymphoid tissue or the mesenteric lymph nodes involves a complex process of molecular events that is dependent on cell type and cell maturation. Key factors that collectively determine the homing of leukocytes and their interaction with resident endothelial, epithelial, stromal and immune cells are interactions between integrins or selectins with their tissue adhesion molecules as well as chemokine receptors and their ligands. The organization of the small and large intestinal tissue and the mucosa associated lymphoid tissue as well as the presence or absence of inflammatory stimuli influence the homing of intestinal immune cells. The homing pattern of intestinal dendritic cells and CD4+ T cells and its role for the pathogenesis and regulation of inflammatory bowel disease are discussed.
Blood pressure and its associations in 554 children and young people with CAH.
BACKGROUND: Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) affects approximately 1 in 15,000 individuals. We leveraged the power of multicentre registry data to assess the trend and predictors of blood pressure (BP) within children and young persons with 21OHD to inform monitoring strategies. METHOD: Data from the International CAH Registry in patients younger than 20 years was compared to normative values. Values of BP were modelled to create reference curves, multiple change point analysis applied to quantify the difference with normative data. Covariate adjustment was informed by a directed acyclic graph, prior to joint outcome regression modelling to accurately assess predictors of BP. RESULTS: A total of 6436 visits within 554 patients (52.5% females) showed BP-Standard deviation scores (SDS) were higher at younger ages. Patients under five years had systolic BP-SDS of 1.6 (Q1:0.6-Q3:2.7) decreasing to 1.0 (Q1:0.2-Q3:1.8) over five years, equating to 31.0% over the 95th centile decreasing to 15.0%. Higher doses of fludrocortisone were associated with a small increase in systolic BP equivalent to 1.2mmHg with every 100 micrograms extra fludrocortisone. Renin of 100µU/ml was associated with 4.6mmHg lower systolic BP than a renin of 1µU/ml, higher 17OH-progesterone and androstenedione also predicted lower systolic and diastolic BP (p<0.05). CONCLUSION: Higher BP in children with 21OHD is common and particularly pronounced at a younger age, but may not be attributable to excessive mineralocorticoid replacement. There is a need to improve our understanding of the determinants of this raised BP as well as its long-term effects.