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Aim: To evaluate the association between sarcopenic obesity and the decline in estimated GFR in people with type 2 diabetes., Methods: We enrolled 745 people with type 2 diabetes (mean age 64.6 years, 53.6% men). Body composition was evaluated using dual-energy X-ray absorptiometry. Skeletal muscle index, calculated as appendicular non-fat mass (kg) divided by height squared (m 2 ), was used to determine sarcopenia. Sarcopenic obesity was defined as the coexistence of sarcopenia and a ratio of android to gynoid fat mass greater than the median values in each gender. The association of sarcopenic obesity both with the annual rate of decline in estimated GFR and a >30% decline in estimated GFR was evaluated using multivariate linear regression models and Cox proportional hazard models, respectively., Results: Participants with sarcopenic obesity were at an increased risk of a high annual rate of decline in estimated GFR, even after adjustment for the confounding variables (standardized β = -0.228, P <0.001). Sarcopenic obesity was also significantly associated with risk of a >30% decline in estimated GFR (hazard ratio 4.52, 95% CI 2.16-9.47; P < 0.01) in multivariate model., Conclusions: Sarcopenic obesity evaluated by dual energy X-ray absorptiometry is associated with a faster decline in renal function in people with type 2 diabetes., (© 2019 Diabetes UK.)

Background: Supragastric belching (SGB) may play a role in the pathophysiology of proton pump inhibitors (PPIs)-refractoriness in gastroesophageal reflux disease (GERD). SGB may be present in up to 40% of reflux symptoms in PPI-refractory GERD. Most reports on SGB have come from Western countries, and little is known about the prevalence and relevance of SGB in Asian refractory GERD patients. This study aimed at comparing the role of SGB in GERD patients in Japan and the UK., Methods: We re-analyzed impedance-pH monitoring tracings from patients who were referred to tertiary centers in Japan and the UK due to PPI-refractory reflux symptoms. The prevalence of excessive SGB and the impact of SGB on reflux symptoms were compared between the two countries., Results: Impedance-pH tracings from124 Japanese and 83 British patients were re-analyzed. Japanese patients were significantly younger and had smaller body mass index than the British (P < 0.001). Japanese patients had significantly lower prevalence of excessive SGB (18.5%) than the UK (36.1%) irrespective of reflux phenotype (P = 0.006). Logistic regression analysis showed that the geographical/cultural difference was the only factor associated with the different prevalence of SGB (odds ratio; 2.91, 95% CI 1.09-7.73, P = 0.032). SGB were related to typical reflux symptoms very rarely in Japan [0% (0-4.9)] compared to the UK [35% (0-54.1)] (P = 0.071)., Conclusions: The prevalence of SGB and their impact on reflux symptoms is significantly lower in Japan compared to the UK. The difference is not related to reflux parameters but might come from ethnic/cultural factors to be further characterized.

The native distribution of the yellow-legged hornet, Vespa velutina, is throughout East Asia. Around 15 years ago this species was accidentally introduced into South Korea and France, where it became established and then spread into neighbouring countries. Previous mitochondrial DNA studies showed that the South Korean, Japanese, and French populations all originated from Eastern China. Recently, the hornet has invaded Iki Island, Japan and Jersey Island, UK. In this study, we analyze the complete mitochondrial DNA sequence of V. velutina to trace the origin of these two populations. The mitochondrial DNA haplotypes (COI, Cytb, and 16S rRNA) of V. velutina in Iki Island matched the unique haplotype present in China, South Korea, and Japan, while the haplotype from Jersey Island matched that of V. velutina found in France and China. These findings were supported by data from the complete mitochondrial DNA sequence of V. velutina from Iki Island, which was consistent with the sequence from South Korea and Tsushima, whereas V. velutina in Jersey was most similar to the French population.

Purpose: This study aimed to investigate the attitudes of speech-language pathology--related specialists (SPs) and speech-language pathology (SLP) students toward stuttering. Furthermore, we identified the factors that influence changes in the attitudes of SLP students and SPs in various countries. Method: Using a search formula, the PubMed and ScienceDirect databases were used to conduct primary and secondary screening for analysis. All previous studies included in the systematic review focused on SPs or SLP students and were published in English. Studies were collected and screened independently by the first and second authors and then discussed between them. Twenty-two studies with varying research designs and sample sizes were included in the systematic review. Finally, information on authors, publishing year, participant, country or region, assessment materials, and the results were extracted and organized before analysis. Results: Twenty-two articles from eight countries and one region (Middle East) were extracted. The results showed that SLP students and SPs in different countries have different attitudes toward stuttering depending on their education, experience, geographic location, cultural status, and societal development, but stereotypes of people who stutter (PWS) persist (e.g., nervous), and the attitudes toward the clinics appear to be more negative in Western countries. Conclusions: Negative attitudes toward PWS remain among both SLP students and SPs. Thus, the factors that may influence the attitudes of SLP students and SPs should be taken into account in academic and clinical education in fluency disorders, and the education content must be structured to improve the quality of education and the attitude toward PWS. [ABSTRACT FROM AUTHOR]

Objective: Immune–metabolic interactions may have causal and therapeutic impacts on abdominal aortic aneurysms (AAAs). However, due to the lack of research on the relationship between immune–metabolic interactions and AAAs, further exploration of the mechanism faces challenges. Methods: A two-sample, two-step mediation analysis with Mendelian randomization (MR) based on genome-wide association studies (GWASs) was performed to determine the causal associations among blood immune cell signatures, metabolites, and AAAs. The stability, heterogeneity, and pleiotropy of the results were verified using a multivariate sensitivity analysis. Results: After multiple two-sample MRs using the AAA data from two large-scale GWAS databases, we determined that the human leukocyte antigen-DR (HLA-DR) levels on HLA-DR + natural killer (NK) cells (HLA-DR/NK) were associated with the causal effect of an AAA, with consistent results in the two databases (FinnGen: odds ratio (OR) = 1.054, 95% confidence interval (CI): 1.003–1.067, p-value = 0.036; UK Biobank: OR = 1.149, 95% CI: 1.046–1.261, p-value = 0.004). The metabolites associated with the risk of developing an AAA were enriched to find a specific metabolic model. We also found that the ratio of adenosine 5′-monophosphate (AMP) to threonine could act as a potential mediator between the HLA/NK and an AAA, with a direct effect (beta effect = 0.0496) and an indirect effect (beta effect = 0.0029). The mediation proportion was 5.56%. Conclusions: Our study found that an up-regulation of HLA-DR on HLA-DR/NK cells can increase the risk of an AAA via improvements in the AMP-to-threonine ratio, thus providing a potential new biomarker for the prediction and treatment of AAAs. [ABSTRACT FROM AUTHOR]

Background: Emerging evidence suggests that remnant cholesterol (RC) is strongly associated with an increased incidence of cardiometabolic diseases (CMD). However, the causality have not been confirmed. We aimed to evaluate the causal associations of RC with CMD and the relative risk factors using two-sample Mendelian randomization (MR) methods. Methods: Summary-level statistics of RC, CMD, and cardiometabolic risk factors were obtained from the published data from individuals with a predominantly European ancestry mainly from the UK Biobank and the FinnGen biobank. Univariable and multivariable MR analyses were used to evaluate the causal relationships between RC and CMD. A bidirectional MR analysis was performed to estimate the causality between RC and cardiometabolic risk factors. The main MR method was conducted using the inverse-variance weighted method. Results: Univariable MR analyses showed that genetically predicted RC was causally associated with higher risk of ischemic heart disease, myocardial infarction, atrial fibrillation and flutter, peripheral artery disease, and non-rheumatic valve diseases (all P < 0.05). Multivariable MR analyses provided compelling evidence of the harmful effects of RC on the risk of ischemic heart disease (P < 0.05). Bidirectional MR analysis demonstrated that RC was bidirectionally causally linked to total cholesterol, triglycerides, low-density lipoprotein cholesterol, hypercholesterolemia (all P < 0.05). However, no genetic association was found between RC and metabolic disorders or the other cardiometabolic risk factors. Conclusions: This MR study demonstrates that genetically driven RC increases the risk of several CMD and cardiometabolic risk factors, suggesting that targeted RC-lowering therapies may be effective for the primary prevention of CMD. [ABSTRACT FROM AUTHOR]

There are high levels of work disability, absenteeism (sick leave) and presenteeism (reduced productivity) amongst people with inflammatory arthritis. WORKWELL is a multi-centre, randomised controlled trial of job retention vocational rehabilitation for employed people with inflammatory arthritis. The trial tested the effectiveness and cost-effectiveness of the WORKWELL programme compared to the receipt of written self-help information only. Both arms continued to receive usual care. In March 2020, due to the COVID-19 pandemic, the WORKWELL trial paused to recruitment and intervention delivery. To successfully re-start, protocol amendments were rapidly submitted and changes to existing trial procedures were made. The WORKWELL protocol was adapted in response to both the practical issues likely faced by many clinical research studies active across NHS sites during the pandemic and additional trial-specific challenges. A key eligibility criterion for the trial required participants to be in paid work for at least 15 h per week. However, UK national lockdowns led to a substantial proportion of the workforce suddenly being furloughed or unable to work, and many people with arthritis taking immunosuppressive medications were asked to shield themselves. Thus, the number of eligible participants was reduced. Those continuing to work were harder to identify, as hospital clinics moved to remote delivery, and also to then screen, consent and treat, as the hospital research staff and clinical therapists were re-deployed. New recruitment and consent strategies were applied, and where sites had reduced capacity, responsibilities were absorbed by the trial management team. Remote intervention delivery and electronic data capture were also implemented. By rapidly adapting the WORKWELL protocol and procedures, the trial successfully reopened to recruitment in July 2020, only 4 months after the trial pause. We were able to achieve recruitment figures above the pre-COVID target and maintain a high retention rate. In addition, we found many of the protocol changes beneficial, as these streamlined trial procedures, thus improving efficiency. It is likely that many strategies implemented in response to the pandemic may become standard practice in future research within trials of a similar design and methodology. Trial registration: ClinicalTrials.gov NCT03942783. Retrospectively registered on 08 May 2019. ISRCTN Registry ISRCTN61762297. Retrospectively registered on 13 May 2019. [ABSTRACT FROM AUTHOR]

Smart meters (SM) with wireless capabilities are one of the most meaningful applications of the Internet of Things. Standards like Zigbee have found a niche in transmitting data on energy usage to the user and the supplier wirelessly via these meters and communication hubs. There are still certain difficulties, notably in delivering wireless connectivity to meters situated in difficult-to-reach locations such as basements or deep indoors. To solve this issue, this paper investigates the usage of mesh networks at 868 MHz, particularly to increase coverage, and proposes an additional mounted antenna to significantly increase outside coverage while providing the necessary coverage extension for hard-to-reach indoor locations. Extensive measurements were made in Newbury in both suburban and open environments for validation and delivery of a simple statistical model for the 868 MHz band in United Kingdom conurbations. Results presented in this paper estimate that mesh networks at 868 MHz can accommodate large areas constituting several SMs with the proposed coverage extension method. With our findings and proposed methods on mesh connectivity, only 1% of UK premises will require mesh radios to achieve the desired coverage. [ABSTRACT FROM AUTHOR]

Background: Neonatal diabetes mellitus (NDM) is a rare (1:90,000 newborns) but potentially devastating metabolic disorder characterized by hyperglycemia combined with low levels of insulin. Dominantly-acting insulin (INS) gene mutations cause permanent NDM through single amino acid changes in the protein sequence leading to protein misfolding, which is retained within the endoplasmic reticulum (ER), causing ER stress and β-cell apoptosis. Over 90 dominantly-acting INS gene mutations have been identified in individuals with permanent NDM. Patients and Methods: The study included 70 infants diagnosed with NDM in the first year of life between May 2008 and May 2021 at the Vietnam National Children's Hospital. Sequencing analysis of all the genes known to cause NDM was performed at the Exeter Genomic Laboratory, UK. Clinical characteristics, molecular genetics, and annual data relating to glycemic control (HbA1c) and severe hypoglycemia of those with INS mutations were collected. The main outcomes of interest were HbA1c, daily insulin dose, growth, and cognitive/motor development. Results: Fifty-five of 70 infants (78.5%) with NDM harbored a mutation in a known disease-causing gene and of these, 10 had six different de novo heterozygous INS mutations. Mean gestational age was 38.1 ± 2.5 weeks and mean birth weight was 2.8 ± 0.5 g. They presented with NDM at 20 ± 17 weeks of age; 6/10 had diabetic ketoacidosis with pH 7.13 ± 0.26; plasma glucose level 32.6 ± 14.3 mmol/l and HbA1C 81 ± 15% mmol/mol. After 5.5 ± 4.8 years of insulin treatment, 9/10 have normal development with a developmental quotient of 80-100% and HbA1C 64 ± 7.3 mmol/mol, 9/10 have normal height, weight, and BMI on follow-up. Conclusions: We report a series of Vietnamese NDM cases with dominant INS mutations. INS mutations are the third commonest cause of permanent NDM. We recommend screening of the INS gene in all children diagnosed with diabetes in the first year of life. [ABSTRACT FROM AUTHOR]

Background: Electronic devices use has been reported to be associated with depression. However, limited effort has been provided to elucidate the associations between electronic devices use and mental traits in interaction with genetic factors.Methods: We first conducted an observational study consisting of 138 976-383 742 participants for TV watching, 29 636-38 599 participants for computer using and 118 61-330 985 participants for computer playing in the UK Biobank cohort. A linear regression model was used to evaluate the associations between common mental traits and electronic devices use. Subsequently, a genome-wide gene-environment interaction study (GWEIS) was performed by PLINK2.0 to estimate the interaction effects of genes and electronic devices use on the risks of the four mental traits.Results: In the UK Biobank cohort, significant associations were observed between electronic devices use and mental traits (all P < 1.0 × 10-9 ), including depression score (B = 0.094 for TV watching), anxiety score (B = 0.051 for TV watching), cigarette smoking (B = 0.046 for computer using) and alcohol drinking (B = 0.010 for computer playing). GWEIS identified multiple mental traits associated loci, interacting with electronic devices use, such as DCDC2 (rs115986722, P = 4.10 × 10-10 ) for anxiety score and TV watching, PRKCE (rs56181965, P = 9.64 × 10-10 ) for smoking and computer using and FRMD4A (rs56227933, P = 7.42 × 10-11 ) for depression score and computer playing.Conclusions: Our findings suggested that electronic devices use was associated with common mental traits and provided new clues for understanding genetic architecture of mental traits. [ABSTRACT FROM AUTHOR]

Background: Body mass index (BMI), waist and hip circumference are strongly correlated and do not reflect body composition. A Body Shape Index (ABSI) and Hip Index (HI) define waist and hip size among individuals with the same weight and height and would thus reflect body density. We examined differences in body composition between body-shape phenotypes defined with ABSI and HI and used this information to propose explanations for associations between body-shape phenotypes and colon cancer risk.Methods: We used data from the UK Biobank Resource for 15,520 men, 16,548 women with dual-emission X-ray absorptiometry (DXA) measurements; 3997 men, 4402 women with magnetic resonance imaging (MRI) measurements; 200,289 men, 230,326 women followed-up for colon cancer. We defined body-shape phenotypes as: large-ABSI-small-HI ("apple"), small-ABSI-large-HI ("pear"), small-ABSI-small-HI ("slim"), large-ABSI-large-HI ("wide"). We evaluated differences in body composition in linear models and associations with colon cancer risk in Cox proportional hazards models adjusted for confounders and explored heterogeneity by BMI.Results: Among individuals with the same height and weight, visceral adipose tissue (VAT) was lowest for "pear" and highest for "apple", while abdominal subcutaneous adipose tissue (ASAT) was lowest for "slim" and highest for "wide" phenotype. In the gynoid region, differences between "apple" and "pear" phenotypes were accounted for mainly by fat mass in women but by lean mass in men. In men, lean mass was inversely associated with waist size, while the pattern of gynoid fat resembled ASAT in women. Lean and fat mass were higher for higher BMI, but not hand grip strength. Compared to normal weight "pear", the risk of colon cancer in men (1029 cases) was higher for "apple" phenotype for normal weight (hazard ratio HR = 1.77; 95% confidence interval: 1.16-2.69) and comparably for overweight and obese, higher for "wide" phenotype for overweight (HR = 1.60; 1.14-2.24) and comparably for obese, but higher for "slim" phenotype only for obese (HR = 1.98; 1.35-2.88). Associations with colon cancer risk in women (889 cases) were weaker.Conclusions: ABSI-by-HI body-shape phenotypes provide information for body composition. Colon cancer risk in men appears related to ASAT quantity for "slim" and "wide" but to factors determining VAT accumulation for "apple" phenotype. [ABSTRACT FROM AUTHOR]

The diagnosis of Mild Cognitive Impairment (MCI) characterises patients at risk of dementia and may provide an opportunity for disease-modifying interventions. Identifying persons with MCI (PwMCI) from adults of a similar age without cognitive complaints is a significant challenge. The main aims of this study were to determine whether generic speech differences were evident between PwMCI and healthy controls (HC), whether such differences were identifiable in responses to recent or remote memory questions, and to determine which speech variables showed the clearest between-group differences. This study analysed recordings of 8 PwMCI (5 females, 3 males) and 14 HC of a similar age (8 females, 6 males). Participants were recorded interacting with an intelligent virtual agent: a computer-generated talking head on a computer screen which asks pre-recorded questions when prompted by the interviewee through pressing the next key on a computer keyboard. Responses to recent and remote memory questions were analysed. Mann–Whitney U tests were used to test for statistically significant differences between PwMCI and HC on each of 12 speech variables, relating to temporal characteristics, number of words produced and pitch. It was found that compared to HC, PwMCI produce speech for less time and in shorter chunks, they pause more often and for longer, take longer to begin speaking and produce fewer words in their answers. It was also found that the PwMCI and HC were more alike when responding to remote memory questions than when responding to recent memory questions. These findings show great promise and suggest that detailed speech analysis can make an important contribution to diagnostic and stratification systems in patients with memory complaints. [ABSTRACT FROM AUTHOR]

Janus kinase (JAK) Inhibitors are the latest drug class of disease-modifying medication to emerge for the treatment of rheumatoid arthritis (RA). They are a small molecule-targeted treatment and are the first oral option to compare favourably to existing biologic disease-modifying anti-rheumatic drugs (DMARDs). Tofacitinib, baricitinib and upadacitinib are the first 3 JAK inhibitors to become commercially available in the field and are the core focus of this review. To date, they have demonstrated comparable efficacy to tumour necrosis factor (TNF) inhibitors in terms of American College of Rheumatology (ACR) response rates and disease activity (DAS28) scores with similar cost to the benchmark adalimumab. This narrative review article aims to synthesise and distil the key available trial data on JAK inhibitor efficacy and safety, along with their place in the ACR and European League Against Rheumatism (EULAR) guidelines for RA. The novel mechanism of action of the JAK/STAT pathway is highlighted along with the potential effects of modulating each pathway. The rapid onset of action, role in attenuation of central pain processing and effect on structural damage and radiographic progression are also all examined in detail. We also explore the latest meta-analyses and comparative performance of each of the 3 available JAKs in an effort to determine which is most efficacious and which has the most favourable safety profile. Post marketing concerns regarding thromboembolism risk and herpes zoster infection are also discussed. Additionally, we review the cost-benefit analyses of the available JAK inhibitors and address some of the pharmacoeconomic considerations for real-world practice in the UK and US by detailing the raw acquisition cost and the value they provide in comparison to the benchmark biologic adalimumab and the anchor DMARD methotrexate. [ABSTRACT FROM AUTHOR]

Background Immunoglobulin-G4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory condition that can affect multiple organs. Despite growing interest in this condition, the natural history and management of IgG4-RD remain poorly understood. Aim To describe the clinical characteristics, treatment and outcomes of IgG4-RD in a multi-ethnic UK cohort, and investigate its possible association with malignancy. Design Retrospective analysis of case-note and electronic data. Methods Cases were identified from sub-specialty cohorts and a systematic search of an NHS trust histopathology database using 'IgG4' or 'inflammatory pseudotumour' as search terms. Electronic records, imaging and histopathology reports were reviewed. Results In total, 66 identified cases of IgG4-RD showed a similar multi-ethnic spread to the local population of North West London. The median age was 59 years and 71% of patients were male. Presenting symptoms relating to mass effect of a lesion were present in 48% of cases and the mean number of organs involved was 2.4. Total of 10 patients had reported malignancies with 6 of these being haematological. 83% of those treated with steroids had good initial response; however, 50% had relapsing-remitting disease. Rituximab was administered in 11 cases and all achieved an initial serological response. Despite this, seven patients subsequently relapsed after a mean duration of 11 months and four progressed despite treatment. Conclusions We report a large UK-based cohort of IgG4-RD that shows no clear ethnic predisposition and a wide range of affected organs. We discuss the use of serum IgG4 concentrations as a disease marker in IgG4-RD, the association with malignant disease and outcomes according to differing treatment regimens. [ABSTRACT FROM AUTHOR]

The current paradigm in the management of rheumatoid arthritis (RA) is to treat patients in the early stage of the disease (ERA). Previous meta-analysis-based mixed treatment comparisons (MTCs), aimed to identify the most effective drugs in ERA, are biased by the wide "window" of early definition, ranging from 6 months to 2 years. The aim of this study was to estimate through a Bayesian Network Meta-Analysis which biologics or small molecules are more likely to achieve a 1-year good clinical response in ERA patients with disease duration < 1 year. According to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, randomized controlled trials (RCTs) of biologic agents and small molecules in combination with MTX to treat patients affected with ERA lasting < 1 year were searched through MEDLINE, EMBASE, Cochrane Library, and Clinicaltrials.gov between 1990 and September 2017. The outcome of interest was the achievement of American College of Rheumatology (ACR) 50 and ACR 70 response at 1 year. WinBUGS 1.4 software (MRC Biostatistics Unit, Cambridge, UK) was used to perform the analyses, using a fixed effect model. Fourteen studies were included in the analysis. Tofacitinib (64.83%) followed by Etanercept (23.26%) were the drugs with the highest probability of achieving ACR50 response. Rituximab showed the highest probability of inducing ACR70 response (52.81%) followed by Etanercept (26.85%). This is the first MTC involving only RCTs on ERA patients with disease duration < 1 year. Tofacitinib and rituximab were the drugs ranked first in inducing 1-year ACR50 and ACR70 response, respectively. [ABSTRACT FROM AUTHOR]

The article discusses a guideline for the management of systemic lupus erythematosus (SLE) in adults issued by the British Society for Rheumatology. The guideline includes the incidence of SLE in different ancestries and the relapse and remission of the disease. It provides recommendations for the diagnosis, assessment and monitoring of SLE and discusses the effectiveness and side effects of drugs for the disease.

Background: CT-P13 subcutaneous (SC)-the first and only SC version of infliximab-is approved by the European Medicines Agency for the treatment of rheumatoid arthritis (RA). This new mode of infliximab administration will allow patients to self-inject at home, significantly reducing the number of outpatient visits and costs of intravenous (IV) administration. This paper describes the economic impact of introducing CT-P13 SC to the market from the UK societal perspective., Objective: The budget impact analysis was conducted to assess the financial impact of the adoption of CT-P13 SC over a 5-year period., Methods: A prevalence-based budget impact model was developed incorporating epidemiological data, administration cost data, and market share data. The analysis compared a "world with" CT-P13 SC scenario to a "world without" CT-P13 SC. A sensitivity analysis included dose escalation up to 4.1 mg/kg to reflect the real-world care delivery setting., Results: Compared to the "world without" scenario, the introduction of CT-P13 SC resulted in cost savings of ₤69.3 million in the UK over a 5-year period. In the scenario analysis, the saving increased to ₤173.5 million over 5 years., Conclusion: Use of CT-P13 SC may lead to substantial cost savings for the UK society., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The UK Association of Clinical Embryologists held a workshop on Culture Systems for assisted conception in Sheffield on 22 May 2013. The meeting was organised in the light of the availability of numerous commercial products for the culture of human preimplantation embryos in vitro and the absence of data comparing the performance of these products. Expert opinions were presented, along with survey data provided by participating IVF Centres. The workshop highlighted the lack of a sound evidence base to support the selection of any one commercial product over another, and raised concerns over the lack of information defining precisely the composition of media, and the potential for adverse long-term effects of such products following their use in assisted conception. [ABSTRACT FROM AUTHOR]

Objective Anti-tumor necrosis factor (anti-TNF) therapies are highly effective in rheumatoid arthritis (RA) and psoriatic arthritis (PsA), but a significant number of patients exhibit only a partial or no therapeutic response. Inflammation alters local and systemic metabolism, and TNF plays a role in this. We undertook this study to determine if the patient's metabolic fingerprint prior to therapy could predict responses to anti-TNF agents. Methods Urine was collected from 16 RA patients and 20 PsA patients before and during therapy with infliximab or etanercept. Urine metabolic profiles were assessed using nuclear magnetic resonance spectroscopy. Discriminating metabolites were identified, and the relationship between metabolic profiles and clinical outcomes was assessed. Results Baseline urine metabolic profiles discriminated between RA patients who did or did not have a good response to anti-TNF therapy according to European League Against Rheumatism criteria, with a sensitivity of 88.9% and a specificity of 85.7%, with several metabolites contributing (in particular histamine, glutamine, xanthurenic acid, and ethanolamine). There was a correlation between baseline metabolic profiles and the magnitude of change in the Disease Activity Score in 28 joints from baseline to 12 months in RA patients ( P = 0.04). In both RA and PsA, urinary metabolic profiles changed between baseline and 12 weeks of anti-TNF therapy. Within the responders, urinary metabolite changes distinguished between etanercept and infliximab treatment. Conclusion The clear relationship between urine metabolic profiles of RA patients at baseline and their response to anti-TNF therapy may allow development of novel approaches to the optimization of therapy. Differences in metabolic profiles during treatment with infliximab and etanercept in RA and PsA may reflect distinct mechanisms of action. [ABSTRACT FROM AUTHOR]

Objective. Rituximab (RTX), a B-cell depleting mAb, has been reported to cause pulmonary toxicity in many patients. As the use of this biologic is increasing, we have undertaken a systematic review of the literature to gauge the nature and extent of non-infection-related RTX-induced lung disease.Methods. A systematic literature review was undertaken to document all reported cases of RTX-associated interstitial lung disease (RTX-ILD), evaluating the epidemiological, clinical, radiological, histopathological, laboratory and management data from the available primary sources. The search was conducted using PubMed, the Cochrane Library and EMBASE up to June 2010 using the terms RTX in the advanced search option without limitations and all relevant publications reviewed manually. In addition, unpublished data from the Food and Drug Administration, the European Medicines Agency and the manufacturer (Roche) were evaluated to complement this search. Identified articles were included if they displayed a potential relationship between the administration of RTX and ILD following exclusion of other likely causes.Results. A total of 121 cases of potential RTX-ILD were identified from 21 clinical studies/trials, 30 case reports and 10 case series. The most common indication for RTX was diffuse large B-cell lymphoma. RTX-ILD occurred more frequently in male patients and was most common during the fifth and sixth decades of life. In most cases, RTX was part of combination chemotherapy, but in 30 (24.7%) cases it was given as monotherapy. The mean and median number of cycles of RTX before disease onset was four, but cases following the first cycle or as late as the 12th cycle were also identified. The mean time of onset, from the last RTX infusion until symptom development or relevant abnormal radiological change was 30 days (range 0–158 days). Abnormal radiological findings were similar in all patients, with diffuse bilateral lung infiltrates apparent on chest radiographs and/or thoracic CT. Hypoxaemia was seen in all cases and pulmonary function tests were uniformly abnormal with a characteristic diffusion capacity deficit and restrictive ventilatory pattern. RTX-ILD was fatal in 18 cases.Conclusion. ILD is a rare but potentially fatal complication of RTX therapy. This diagnosis should be considered in any patient who develops respiratory symptoms or new radiographic changes while receiving this biologic agent. [ABSTRACT FROM PUBLISHER]

Objective. Lung disease is commonly encountered in rheumatological practice either as a manifestation of the underlying condition or as a consequence of using disease-modifying therapies. This has been particularly apparent with the TNF-α antagonists and exacerbations of interstitial lung disease (ILD). In view of this, we undertook a review of the current literature to identify non-infectious pulmonary complications associated with the newer biologic agents used for the treatment of rheumatic conditions.Methods. A systematic literature review (SLR) was conducted using PubMed, the Cochrane Library and EMBASE for reviews, meta-analyses, clinical studies and randomized controlled trials, case studies and series, published up to June 2010 using the terms rituximab (RTX), certolizumab, golimumab (GOL), tocilizumab (TCZ) and abatacept in the advanced search option without limitations. In addition, abstracts from International Rheumatology conferences and unpublished data from the Food and Drug Administration, the European Medicines Agency and drug manufacturers were used to complement our search. References were reviewed manually and only those articles that suggested a potential relationship between the biological agent and lung toxicity, following exclusion of other causes, were included.Results. Reported non-infectious pulmonary adverse events with TCZ included a fatal exacerbation of RA-associated ILD, new-onset ILD, idiopathic pulmonary fibrosis and allergic pneumonitis, as well as three cases of microbiological culture-negative pneumonia. Although RTX had a higher incidence of pulmonary toxicity, only 7 of the 121 cases reported involved rheumatological diseases. GOL treatment was associated with four cases of non-infectious pulmonary toxicity and two cases of pneumonia with negative microbiological studies. There were no episodes of pulmonary toxicity identified for either certolizumab or abatacept.Conclusion. Our results highlight an association between the use of newer biologic agents (TCZ, RTX and GOL) and the development of non-infectious parenchymal lung disease in patients with RA. Post-marketing surveillance and biologic registries will be critical for detecting further cases of ILD and improving our understanding of the pathophysiology of this process. As the use of these drugs increases, clinicians must remain vigilant for potential pulmonary complications and exercise caution in prescribing biologic therapies, particularly to rheumatological patients with pre-existing ILD. [ABSTRACT FROM PUBLISHER]

Objective Rituximab appears to be effective in many studies of systemic lupus erythematosus (SLE), with variable initial clinical response and time to relapse. However, results of a randomized controlled trial of rituximab were negative. This study was undertaken to evaluate the effectiveness of rituximab in SLE, using highly sensitive flow cytometry (HSFC), which can define B cell numbers 50-100 times lower than conventional techniques and predicts responses in rheumatoid arthritis. Methods Thirty-nine patients with active SLE were started on a standard regimen of rituximab with intravenous and oral steroids. Clinical response and relapse were defined using the British Isles Lupus Assessment Group (BILAG) index with criteria for major clinical response, partial clinical response, and nonresponse. HSFC, including analysis of B cell subsets, was performed. Results There was a significant reduction from baseline in global BILAG score at all time points analyzed ( P < 0.0001), and major clinical response and partial clinical response rates were 51% and 31%, respectively. Time to relapse was highly variable. Fifty percent of the patients relapsed after 6-18 months (earlier relapse); the remainder relapsed at a slower rate (later relapse). B cell depletion and repopulation were variable and were predictive of these clinical outcomes. There was a persistent B cell presence in 21 patients after 2 infusions of rituximab, which included all 7 patients with no response ( P = 0.012 versus patients with complete depletion of B cells). Memory B cell ( P = 0.02) and plasmablast ( P < 0.001) repopulation after 26 weeks was markedly faster in patients with earlier relapse versus patients with later relapse. Conclusion Our findings indicate that rituximab is effective in SLE, and clinical responses are supported by close correlation with B cell numbers. HSFC is a valuable tool in the assessment and prediction of response in SLE. [ABSTRACT FROM AUTHOR]

In this study, previously unreported cohort characteristics and seizure patterns for canine epilepsy were identified from a series of UK-based epileptic dogs containing 1260 cases from 79 known pedigree breeds and a group of crossbreed dogs. [ABSTRACT FROM AUTHOR]

Chatzidionysiou K, van Vollenhoven RF (Karolinska Institutet, Stockholm, Sweden). When to initiate and discontinue biologic treatments for rheumatoid arthritis (Review). J Intern Med 2011; : 614-625. The introduction of biologic therapies heralded a new era in the treatment for chronic inflammatory autoimmune diseases of which rheumatoid arthritis is one of the most prevalent. From a scientific point of view, these therapies demonstrated that the targeting of individual cytokines or cell-surface markers is a very effective approach. For the physician, the appropriate selection of patients in whom these therapies should be initiated is critical, as is the even more contentious issue of whether these therapies can or should be discontinued in selected patients with excellent clinical responses. Whereas the former issue has been addressed in a large number of clinical trials and observational studies, the latter remains poorly investigated and is currently the subject of further study. [ABSTRACT FROM AUTHOR]

Objective. To assess the risk of adverse events (AEs) in patients with RA treated with tocilizumab, an IL-6 receptor antibody, in published randomized controlled trials (RCTs).Methods. A systematic literature search was conducted using the Cochrane library, PUBMED and EMBASE for all RCTs (of the use of tocilizumab for RA) until September 2009. Fixed effect meta-analyses were conducted to compare the incidence of AEs after treatment with tocilizumab 8 and 4 mg/kg in combination with MTX, and 8 mg/kg tocilizumab monotherapy, with controls. Pooled summary odds ratios (ORs) were calculated using the Mantel–Haenszel method.Results. Six trials were analysed (four trials included 8 mg/kg tocilizumab and MTX combination therapy, three of which also assessed the 4 mg/kg dose). Three studies assessed tocilizumab monotherapy at 8 mg/kg. Pooled ORs revealed statistical significance for an increased risk of AEs in the 8 mg/kg combination group compared with controls (OR = 1.53; 95% CI 1.26, 1.86). The risk of infection was significantly higher in the 8 mg/kg combination group compared with controls (OR = 1.30; 95% CI 1.07, 1.58). No increased incidence of malignancy, tuberculosis reactivation or hepatitis was seen.Conclusion. Tocilizumab in combination with MTX as a treatment for RA is associated with a small but significantly increased risk of AEs, which is comparable with that of other biologics. Vigilance for untoward effects is, therefore, imperative in any patient treated with these immuno-suppressive agents. [ABSTRACT FROM PUBLISHER]

OBJECTIVE: Most cases of autoimmune pancreatitis (AIP) have been reported from Japan. We present data on a UK series, including clinical and radiological features at presentation, and longitudinal response to immunosuppression. METHODS: Over an 18-month period, all patients diagnosed in our center with AIP were studied. Endoscopic biliary stenting was performed as required, and patients were treated with prednisolone, with response assessed longitudinally. In cases of disease relapse following steroid reduction, azathioprine was instituted. RESULTS: Eleven patients met diagnostic criteria for AIP. Diffuse pancreatic enlargement was seen in eight patients (73%), and pancreatic duct strictures in all. Seven patients required biliary stents. Extrapancreatic involvement occurred in all, including intrahepatic stricturing and renal disease. Eight weeks after starting steroids, the median serum bilirubin level had fallen from 38 μmol/L to 11 μmol/L ( P= 0.001), and ALT from 97 IU/L to 39 IU/L ( P= 0.002). Stents were removed in all cases, with no recurrence of jaundice. Improvements in mass lesions and pancreaticobiliary stricturing occurred in all patients. During a median 18-month follow-up, six patients relapsed, four of whom responded to azathioprine. Two patients discontinued steroids and remained well. CONCLUSIONS: Extrapancreatic disease was an important feature of AIP in this UK series. Initial response to immunosuppressive therapy was excellent, but disease relapse was common. Optimal long-term management remains to be established. [ABSTRACT FROM AUTHOR]

One hundred and thirty five isolates of Rhizoctonia solani were obtained from British potato crops between 2001 and 2003. Isolates were assigned to anastomosis group (AG) using conventional PCR assays for AG2-1 or AG3 or through the observation of hyphal interactions, where appropriate. A previously published primer set was modified in this study to enhance specificity for AG3PT. Most of the isolates (92·6%) belonged to AG3PT whilst some (6·7%) belonged to AG2-1. Only one isolate recovered (0·7%) belonged to AG5. Isolates of AG2-1 were diverse, with variation in both the length of the rDNA intergenic spacer 1 (IGS1) region and the categories of hyphal interaction observed between pairings of AG2-1 isolates. No variation in the length of the rDNA IGS1 region was observed amongst the AG3 isolates collected. Tests carried out on potato stems with a sub-set of the isolates revealed a wide range of aggressiveness amongst AG2-1 isolates. Sequencing of the rDNA internal transcribed spacer (ITS) region of the AG2-1 isolates and construction of a neighbour joining tree with other AG2-1 sequences available indicated that AG2-1 isolates with the short IGS1 region were closely related. This is the first investigation which provides evidence of the relative AG composition of R. solani populations causing disease in potato crops in Great Britain. [ABSTRACT FROM AUTHOR]

Authors from the UK studied the effect of nephroureterectomy on the GFR; they found that this operation had a profound effect on the future estimated GFR, and that the effect was compounded in those with risk factors for renal impairments. OBJECTIVE To determine the effect of nephroureterectomy (NU) on the glomerular filtration rate (GFR), and to determine whether the estimated GFR after NU is influenced by age and other factors associated with renal impairment. PATIENTS AND METHODS We retrospectively identified 131 patients who had had a NU at either of two UK institutions. Their serum creatinine levels were recorded before and after NU, along with comorbidity data, and from this their GFR before and after NU was estimated using the Modification of Diet in Renal Disease Study Group equation. RESULTS At a median follow-up of 5 years there was an 18% deterioration in estimated GFR in the 131 patients. The percentage deterioration in estimated GFR was greater in those aged ≥ 70 years than in those aged <70 years (20% vs 15% deterioration). Those with more risk factors for renal impairment had a greater percentage deterioration in estimated GFR than those with no such risk factors. CONCLUSIONS This study shows that NU has a profound effect on future estimated GFR, an effect that is further compounded in those with risk factors for renal impairment. This study therefore provides both the patient and the urologist with an idea of potential future renal function after NU and contributes greatly to preoperative counselling. [ABSTRACT FROM AUTHOR]

Studies knowledge creation and value in the British Army. Use of Nonaka's four modes and five-phase model; Review of a model of the way that knowledge is created; Assumption that although individual officers and soldiers tend to develop new knowledge, the Army as an entity plays a critical role in articulating and amplifying that knowledge; Application of the theoretical frameworks to different operational models for facilitating the dynamic creation of knowledge.

The article presents information on the automated instruments used for immunoassay in Great Britain. In the early days, cost and unreliability contributed to the limited use of such instruments. At that time, commercial systems were semi-automated which helped in automation of repetitive steps. Fully automated systems were developed in 1994. New technological innovations made it possible to control various immunoassay steps so that shorter incubation times and smaller sample volumes can be used.

This article examines the origins and potential effects of the liberalising reform agenda in Japanese secondary education in the light of experiences in the UK with policies such as local school management and school choice. The analysis is based on extensive interviews conducted with Japanese policy-makers, school heads and Prefectural administrators in 1997 in Tokyo and Osaka. The research was part of a joint Anglo-Japanese study, supported by the Japanese Embassy in London, and the analysis here highlights issues of national perspective which emerged in the collaboration between English and Japanese researchers observing reforms in each other's countries. The paper argues that the reform agenda in Japan has two strands. These involve both a necessary diversification of curriculum and pedagogic practices, and an administrative shift towards deregulation and school competition which may undermine some of the traditional strengths of Japanese secondary schooling. [ABSTRACT FROM AUTHOR]

BACKGROUND Many children treated for cancer are at risk of infertility, but for girls and prepubertal boys, all fertility preservation techniques remain experimental. We have assessed UK practice relating to information provision about the effects of cancer treatment on fertility and options for fertility preservation. METHODS Paediatric oncologists prospectively completed a data form for each new patient registered over a 12 month period. RESULTS Data were available on 1030 patients (68% of total registered). The effect of cancer treatment on fertility was discussed with 63% of patients. Of these, 61% were judged to be at high or medium risk of fertility problems. Discussions took place more commonly with boys than girls; the commonest reason for discussion not occurring was young age. The majority (83%) of post-pubertal boys assessed as high/medium risk of infertility were referred for semen cryopreservation. This rate fell to 39% of those in early puberty. Only 1% (n=4) of girls were referred to an assisted conception unit. CONCLUSIONS These data indicate a high awareness of the potential adverse effects of therapy on fertility among UK paediatric oncologists. High referral rates for older boys indicate that current guidelines are followed, but there is a need for fertility preservation techniques for girls and younger boys. [ABSTRACT FROM AUTHOR]