Adenosine metabolic signature in circulating CD4+ T cells predicts remission in rheumatoid arthritis

\ua9 Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Objectives Long-term outcomes in rheumatoid arthritis (RA) depend on early and effective disease control. Methotrexate (MTX) remains the first-line disease modifying therapy, however there are no biomarkers with which to identify those most likely to achieve remission. To address this unmet need we explored metabolic pathways involved in MTX mechanism of action within circulating CD4+T cells in a cohort of treatment naive patients with early RA. Methods Purified CD4+T cells were isolated from peripheral blood of 68 patients with early RA commencing MTX. The expression of a range of putative MTX metabolism and mechanism of action targets were explored by flow-cytometry and transcriptional analysis. From these data significant predictors of Disease Activity Score 28-C reactive protein (DAS28-CRP) remission (<2.4 at 6 months) were determined by logistic regression (clinical; flow-cytometry data) and linear modelling (gene expression data). Results Low baseline DAS28-CRP was associated with remission at 6 months (p=0.02). Expression of the ectonucleotidase CD39, involved in ATP-ADP conversion during adenosine synthesis, was higher on CD4+CD25 High regulatory T cells at baseline in those achieving remission (molecules of equivalent fluorescence 1264 vs 847; p=0.007). Expression of other adenosine signalling elements in CD4+T cells were also upregulated at baseline in patients achieving remission: AMPD1 (p<0.001), ADORA2b (p=0.039) and ADORA3 (p=0.047). When combined into a single predictive metric, a combination of these variables outperformed baseline DAS28-CRP in prediction of early remission (area under the curve 0.92 vs 0.67, p=0.001) Conclusions Adenosine signalling is important in the achievement of early remission with MTX in RA and biomarkers of adenosine activity may hold utility for the stratification of therapy in early disease

The demand for sports and exercise: Results from an illustrative survey

Funding from the Department of Health policy research programme was used in this study.There is a paucity of empirical evidence on the extent to which price and perceived benefits affect the level of participation in sports and exercise. Using an illustrative sample of 60 adults at Brunel University, West London, we investigate the determinants of demand for sports and exercise. The data were collected through face-to-face interviews that covered indicators of sports and exercise behaviour; money/time price and perceived benefits of participation; and socio- economic/demographic details. Count, linear and probit regression models were fitted as appropriate. Seventy eight per cent of the sample participated in sports and exercise and spent an average of £27 per month and an average of 20 min travelling per occasion of sports and exercise. The demand for sport and exercise was negatively associated with time (travel or access time) and ‘variable’ price and positively correlated with ‘fixed’ price. Demand was price inelastic, except in the case of meeting the UK government’s recommended level of participation, which is time price elastic (elasticity = −2.2). The implications of data from a larger nationally representative sample as well as the role of economic incentives in influencing uptake of sports and exercise are discussed.This article is available through the Brunel Open Access Publishing Fund

Development of a decision support tool to facilitate primary care management of patients with abnormal liver function tests without clinically apparent liver disease [HTA03/38/02]. Abnormal Liver Function Investigations Evaluation (ALFIE)

Liver function tests (LFTs) are routinely performed in primary care, and are often the gateway to further invasive and/or expensive investigations. Little is known of the consequences in people with an initial abnormal liver function (ALF) test in primary care and with no obvious liver disease. Further investigations may be dangerous for the patient and expensive for Health Services. The aims of this study are to determine the natural history of abnormalities in LFTs before overt liver disease presents in the population and identify those who require minimal further investigations with the potential for reduction in NHS costs

Hepatic breast cancer dissemination after an iatrogenic hepatic laceration during talc pleurodesis: a case report

<p>Abstract</p> <p>Background</p> <p>Talc pleurodesis is an effective treatment for malignant pleural effusion. We present a case of an asymptomatic hepatic laceration that occurred during pleurodesis in a breast cancer patient and led to hepatic tumor dissemination.</p> <p>Discussion</p> <p>Pleurodesis is a relatively safe procedure, although previous studies have described malignant invasion of scar tissue.</p> <p>Conclusion</p> <p>To our knowledge, this is the first case report of tumor spread due to a liver puncture during talc pleurodesis in a breast cancer patient.</p

Should patients with abnormal liver function tests in primary care be tested for chronic viral hepatitis: cost minimisation analysis based on a comprehensively tested cohort

Background Liver function tests (LFTs) are ordered in large numbers in primary care, and the Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS) study was set up to assess their usefulness in patients with no pre-existing or self-evident liver disease. All patients were tested for chronic viral hepatitis thereby providing an opportunity to compare various strategies for detection of this serious treatable disease. Methods This study uses data from the BALLETS cohort to compare various testing strategies for viral hepatitis in patients who had received an abnormal LFT result. The aim was to inform a strategy for identification of patients with chronic viral hepatitis. We used a cost-minimisation analysis to define a base case and then calculated the incremental cost per case detected to inform a strategy that could guide testing for chronic viral hepatitis. Results Of the 1,236 study patients with an abnormal LFT, 13 had chronic viral hepatitis (nine hepatitis B and four hepatitis C). The strategy advocated by the current guidelines (repeating the LFT with a view to testing for specific disease if it remained abnormal) was less efficient (more expensive per case detected) than a simple policy of testing all patients for viral hepatitis without repeating LFTs. A more selective strategy of viral testing all patients for viral hepatitis if they were born in countries where viral hepatitis was prevalent provided high efficiency with little loss of sensitivity. A notably high alanine aminotransferase (ALT) level (greater than twice the upper limit of normal) on the initial ALT test had high predictive value, but was insensitive, missing half the cases of viral infection. Conclusions Based on this analysis and on widely accepted clinical principles, a "fast and frugal" heuristic was produced to guide general practitioners with respect to diagnosing cases of viral hepatitis in asymptomatic patients with abnormal LFTs. It recommends testing all patients where a clear clinical indication of infection is present (e.g. evidence of intravenous drug use), followed by testing all patients who originated from countries where viral hepatitis is prevalent, and finally testing those who have a notably raised ALT level (more than twice the upper limit of normal). Patients not picked up by this efficient algorithm had a risk of chronic viral hepatitis that is lower than the general population

Forest Plant and Bird Communities in the Lau Group, Fiji

We examined species composition of forest and bird communities in relation to environmental and human disturbance gradients on Lakeba (55.9 km²), Nayau (18.4 km²), and Aiwa Levu (1.2 km²), islands in the Lau Group of Fiji, West Polynesia. The unique avifauna of West Polynesia (Fiji, Tonga, Samoa) has been subjected to prehistoric human-caused extinctions but little was previously known about this topic in the Lau Group. We expected that the degree of human disturbance would be a strong determinant of tree species composition and habitat quality for surviving landbirds, while island area would be unrelated to bird diversity.All trees > 5 cm diameter were measured and identified in 23 forest plots of 500 m² each. We recognized four forest species assemblages differentiated by composition and structure: coastal forest, dominated by widely distributed species, and three forest types with differences related more to disturbance history (stages of secondary succession following clearing or selective logging) than to environmental gradients (elevation, slope, rockiness). Our point counts (73 locations in 1 or 2 seasons) recorded 18 of the 24 species of landbirds that exist on the three islands. The relative abundance and species richness of birds were greatest in the forested habitats least disturbed by people. These differences were due mostly to increased numbers of columbid frugivores and passerine insectivores in forests on Lakeba and Aiwa Levu. Considering only forested habitats, the relative abundance and species richness of birds were greater on the small but completely forested (and uninhabited) island of Aiwa Levu than on the much larger island of Lakeba.Forest disturbance history is more important than island area in structuring both tree and landbird communities on remote Pacific islands. Even very small islands may be suitable for conservation reserves if they are protected from human disturbance

Optimal functional outcome measures for assessing treatment for Dupuytren's disease: A systematic review and recommendations for future practice

This article is available through the Brunel Open Access Publishing Fund. Copyright © 2013 Ball et al.; licensee BioMed Central Ltd.Background: Dupuytren's disease of the hand is a common condition affecting the palmar fascia, resulting in progressive flexion deformities of the digits and hence limitation of hand function. The optimal treatment remains unclear as outcomes studies have used a variety of measures for assessment. Methods: A literature search was performed for all publications describing surgical treatment, percutaneous needle aponeurotomy or collagenase injection for primary or recurrent Dupuytren’s disease where outcomes had been monitored using functional measures. Results: Ninety-one studies met the inclusion criteria. Twenty-two studies reported outcomes using patient reported outcome measures (PROMs) ranging from validated questionnaires to self-reported measures for return to work and self-rated disability. The Disability of Arm, Shoulder and Hand (DASH) score was the most utilised patient-reported function measure (n=11). Patient satisfaction was reported by eighteen studies but no single method was used consistently. Range of movement was the most frequent physical measure and was reported in all 91 studies. However, the methods of measurement and reporting varied, with seventeen different techniques being used. Other physical measures included grip and pinch strength and sensibility, again with variations in measurement protocols. The mean follow-up time ranged from 2 weeks to 17 years. Conclusions: There is little consistency in the reporting of outcomes for interventions in patients with Dupuytren’s disease, making it impossible to compare the efficacy of different treatment modalities. Although there are limitations to the existing generic patient reported outcomes measures, a combination of these together with a disease-specific questionnaire, and physical measures of active and passive individual joint Range of movement (ROM), grip and sensibility using standardised protocols should be used for future outcomes studies. As Dupuytren’s disease tends to recur following treatment as well as extend to involve other areas of the hand, follow-up times should be standardised and designed to capture both short and long term outcomes

CD27 distinguishes two phases in bone marrow infiltration of splenic marginal zone lymphoma

Aims: To investigate CD27 expression in splenic marginal zone lymphoma (SMZL), an indolent low-grade B-cell lymphoma with constant involvement of the bone marrow, especially with an intrasinusoidal pattern. It is not clear if the neoplastic clone is composed of virgin or somatically mutated B cells. CD27 is reported to be a hallmark of memory B cells. Methods and results: We evaluated 64 bone marrow biopsy specimens (BMBs) from 36 patients with SMZL for the expression of CD27. For comparison, splenectomy specimens of patients with traumatic splenic rupture or with SMZL were used. All BMBs showed lymphomatous infiltration. When located in the marrow sinusoids, neoplastic cells were CD27- in all cases and therefore corresponded to naive B cells. In nodular/interstitial infiltration, the cells were CD27+ and therefore corresponded to memory B cells. No difference in immunohistochemical expression of B and T antibodies was found between intrasinusoidal and interstitial/nodular infiltration. CD27 was constantly expressed in the splenic marginal zone of normal spleen, surgically removed for trauma, and in seven out of 10 spleens with SMZL. Conclusion: We propose the existence of two different phases of neoplastic progression with, first, expansion of a virgin B clone in the bone marrow and, following exposure to antigen, a re-colonization of the bone marrow

Unpacking the relationships between impulsivity, neighborhood disadvantage, and adolescent violence : an application of a neighborhood-based group decomposition

The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007–2013)/ERC Grant Agreement no. 615159 (ERC Consolidator Grant DEPRIVEDHOODS, Socio-spatial inequality, deprived neighbourhoods, and neighbourhood effects); and from the Marie Curie programme under the European Union’s Seventh Framework Programme (FP/2007–2013)/Career Integration Grant no. PCIG10-GA-2011-303728 (CIG Grant NBHCHOICE, Neighbourhood choice, neighbourhood sorting, and neighbourhood effects).Scholars have become increasingly interested in how social environments condition the relationships between individual risk-factors and adolescent behavior. An appreciable portion of this literature is concerned with the relationship between impulsivity and delinquency across neighborhood settings. The present article builds upon this growing body of research by considering the more nuanced pathways through which neighborhood disadvantage shapes the development of impulsivity and provides a situational context for impulsive tendencies to manifest in violent and aggressive behaviors. Using a sample of 12,935 adolescent from the National Longitudinal Study of Adolescent to Adult Health (Add Health) (mean age = 15.3, 51% female; 20% Black, 17% Hispanic), we demonstrate the extent to which variation in the association between impulsivity and delinquency across neighborhoods can be attributed to (1) differences in mean-levels of impulsivity and violence and (2) differences in coefficients across neighborhoods. The results of a series of multivariate regression models indicate that impulsivity is positively associated with self-reported violence, and that this relationship is strongest among youth living in disadvantaged neighborhoods. The moderating effect of neighborhood disadvantage can be attributed primarily to the stronger effect of impulsivity on violence in these areas, while differences in average levels of violence and impulsivity account for a smaller, yet nontrivial portion of the observed relationship. These results indicate that the differential effect of impulsivity on violence can be attributed to both developmental processes that lead to the greater concentration of violent and impulsive adolescents in economically deprived neighborhoods as well as the greater likelihood of impulsive adolescents engaging in violence when they reside in economically disadvantaged communities.Publisher PDFPeer reviewe

Origin of reduced magnetization and domain formation in small magnetite nanoparticles

The structural, chemical, and magnetic properties of magnetite nanoparticles are compared. Aberration corrected scanning transmission electron microscopy reveals the prevalence of antiphase boundaries in nanoparticles that have significantly reduced magnetization, relative to the bulk. Atomistic magnetic modelling of nanoparticles with and without these defects reveals the origin of the reduced moment. Strong antiferromagnetic interactions across antiphase boundaries support multiple magnetic domains even in particles as small as 12–14 nm