Rheumatoid arthritis - clinical aspects: 134. Predictors of Joint Damage in South Africans with Rheumatoid Arthritis

Background: Rheumatoid arthritis (RA) causes progressive joint damage and functional disability. Studies on factors affecting joint damage as clinical outcome are lacking in Africa. The aim of the present study was to identify predictors of joint damage in adult South Africans with established RA. Methods: A cross-sectional study of 100 black patients with RA of >5 years were assessed for joint damage using a validated clinical method, the RA articular damage (RAAD) score. Potential predictors of joint damage that were documented included socio-demographics, smoking, body mass index (BMI), disease duration, delay in disease modifying antirheumatic drug (DMARD) initiation, global disease activity as measured by the disease activity score (DAS28), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and autoantibody status. The predictive value of variables was assessed by univariate and stepwise multivariate regression analyses. A p value <0.05 was considered significant. Results: The mean (SD) age was 56 (9.8) years, disease duration 17.5 (8.5) years, educational level 7.5 (3.5) years and DMARD lag was 9 (8.8) years. Female to male ratio was 10:1. The mean (SD) DAS28 was 4.9 (1.5) and total RAAD score was 28.3 (12.8). The mean (SD) BMI was 27.2 kg/m2 (6.2) and 93% of patients were rheumatoid factor (RF) positive. More than 90% of patients received between 2 to 3 DMARDs. Significant univariate predictors of a poor RAAD score were increasing age (p = 0.001), lower education level (p = 0.019), longer disease duration (p < 0.001), longer DMARD lag (p = 0.014), lower BMI (p = 0.025), high RF titre (p < 0.001) and high ESR (p = 0.008). The multivariate regression analysis showed that the only independent significant predictors of a higher mean RAAD score were older age at disease onset (p = 0.04), disease duration (p < 0.001) and RF titre (p < 0.001). There was also a negative association between BMI and the mean total RAAD score (p = 0.049). Conclusions: Patients with longstanding established RA have more severe irreversible joint damage as measured by the clinical RAAD score, contrary to other studies in Africa. This is largely reflected by a delay in the initiation of early effective treatment. Independent of disease duration, older age at disease onset and a higher RF titre are strongly associated with more joint damage. The inverse association between BMI and articular damage in RA has been observed in several studies using radiographic damage scores. The mechanisms underlying this paradoxical association are still widely unknown but adipokines have recently been suggested to play a role. Disclosure statement: C.I. has received a research grant from the Connective Tissue Diseases Research Fund, University of the Witwatersrand. All other authors have declared no conflicts of interes

Rheumatoid arthritis - treatment: 180. Utility of Body Weight Classified Low-Dose Leflunomide in Japanese Rheumatoid Arthritis

Background: In Japan, more than 20 rheumatoid arthritis (RA) patients died of interstitial pneumonia (IP) caused by leflunomide (LEF) were reported, but many of them were considered as the victims of opportunistic infection currently. In this paper, efficacy and safety of low-dose LEF classified by body weight (BW) were studied. Methods: Fifty-nine RA patients were started to administrate LEF from July 2007 to July 2009. Among them, 25 patients were excluded because of the combination with tacrolimus, and medication modification within 3 months before LEF. Remaining 34 RA patients administered 20 to 50 mg/week of LEF were followed up for 1 year and enrolled in this study. Dose of LEF was classified by BW (50 mg/week for over 50 kg, 40 mg/week for 40 to 50 kg and 20 to 30 mg/week for under 40 kg). The average age and RA duration of enrolled patients were 55.5 years old and 10.2 years. Prednisolone (PSL), methotrexate (MTX) and etanercept were used in 23, 28 and 2 patients, respectively. In case of insufficient response or adverse effect, dosage change or discontinuance of LEF were considered. Failure was defined as dosages up of PSL and MTX, or dosages down or discontinuance of LEF. Last observation carried forward method was used for the evaluation of failed patients at 1 year. Results: At 1 year after LEF start, good/ moderate/ no response assessed by the European League Against Rheumatism (EULAR) response criteria using Disease Activity Score, including a 28-joint count (DAS28)-C reactive protein (CRP) were showed in 14/ 10/ 10 patients, respectively. The dosage changes of LEF at 1 year were dosage up: 10, same dosage: 5, dosage down: 8 and discontinuance: 11 patients. The survival rate of patients in this study was 23.5% (24 patients failed) but actual LEF continuous rate was 67.6% (11 patients discontinued) at 1 year. The major reason of failure was liver dysfunction, and pneumocystis pneumonia was occurred in 1 patient resulted in full recovery. One patient died of sepsis caused by decubitus ulcer infection. DAS28-CRP score was decreased from 3.9 to 2.7 significantly. Although CRP was decreased from 1.50 to 0.93 mg/dl, it wasn't significant. Matrix metalloproteinase (MMP)-3 was decreased from 220.0 to 174.2 ng/ml significantly. Glutamate pyruvate transaminase (GPT) was increased from 19 to 35 U/l and number of leukocyte was decreased from 7832 to 6271 significantly. DAS28-CRP, CRP, and MMP-3 were improved significantly with MTX, although they weren't without MTX. Increase of GPT and leukopenia were seen significantly with MTX, although they weren't without MTX. Conclusions: It was reported that the risks of IP caused by LEF in Japanese RA patients were past IP history, loading dose administration and low BW. Addition of low-dose LEF is a potent safe alternative for the patients showing unsatisfactory response to current medicines, but need to pay attention for liver function and infection caused by leukopenia, especially with MTX. Disclosure statement: The authors have declared no conflicts of interes

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Building bioinformatics solutions for biomarker identification

This thesis describes the design, implementation and application of bioinformatics systems to aid work in the field of biomarker discovery and diagnostic test development. The aim of the work was to develop a flexible data storage and analysis platform that would be capable of housing and working with data from a variety of modern biomarker analysis techniques. In order to achieve this aim, several tools were developed: a flexible database schema, taking ideas from the field of systems biology, was developed with the goal of being flexible enough to house information about experiments looking at targets such as genes, proteins and metabolites; and API was created to allow easy programmatic interaction with the database; and multivariate data analysis routines were prepared so that data imported into the database could be investigated. Together this toolset was named XPA [for ‘Cross Platform Analysis’]. The XPA system was tested by using it to house and analyse data from two different medical studies, one using quantitative PCR [qPCR] to observe gene expression changes in prostate cancer, and the second using surface enhanced laser desorption/ionisation mass spectrometry [SELDI MS] to generate protein profiles in sufferers of pre-eclampsia. In both studies XPA was used to develop multivariate classification models using partial least squares discriminant analysis [PLS-DA] and support vector machines [SVMs], with the aim of evaluating the data acquired for potential diagnostic use. The results showed the benefit of a tool such as XPA to the field of biomarker discovery

Scoping, options analysis and design of a ‘Climate Information and Services Programme’ for Africa (CIASA): Final report

There have been many initiatives to strengthen weather and climate information and services across Africa in the last decade or so, with numerous valuable outcomes. However, it is commonly observed that availability and uptake of information and services is still relatively low and that this represents a threat to social and economic development. The “mainstreaming” of weather and climate information into decision making is recognised to be a multi-disciplinary process involving components that include, inter alia, climate science and information services, translational science (developing appropriate communication approaches and delivery channels) as well as issues of governance to incentivise service delivery and use (as, for example, exists for weather services to the aviation sector). Considerable research has been conducted to improve capabilities in some aspects of these individual components, including pilot projects, generally of sub-national scale, to improve interaction and mutual understanding between climate information providers and users. The UN-led Global Framework for Climate Services (GFCS) is now providing important guidance for new programmes and fostering and promoting government recognition of the benefits of climate services. However, there has as yet been no major large scale Africa-focussed initiative to comprehensively address the various barriers to progress in an integrated way and to consider also their interactions and dependencies. There is a growing consensus that this lack of a holistic approach lies behind currently limited progress in uptake of weather and climate services. The need for an innovative, holistic approach forms the central motivation behind DFID’s consideration of a new intervention – Climate Information and Services for Africa (CIASA1). CIASA aims to achieve a step change in use of weather and climate information in Africa by addressing, at scale and in an integrated and coordinated way, the very diverse barriers to uptake and use of weather and climate services. Current planning is for a 4-year programme (as Phase 1 and including inception) disbursing £35 million to operational and research investments. It is anticipated that further phases of CIASA may follow. In November 2014 DFID procured a Met Office-led team to scope, analyse options and support design of the CIASA programme. The team comprised weather and climate experts from the UK and Africa as well as representatives from the World Meteorological Organisation (WMO), and experts in the fields of climate communication and development. This report presents the results of the scoping study and summarises DFID’s selection of preferred intervention options for Phase 1. The CIASA scoping comprised three main phases. Firstly, the Met Office-led Scoping Team developed a set of evidenced-based options for intervention themes and activities, working from DFID guidance in the scoping Terms of Reference and from the Inception meeting. Secondly, the Scoping Team worked together with DFID and other partners to refine the intervention options identified, develop a programme outline, raise options for a regional focus and to consider appropriate mechanisms of delivery and governance for the programme. In the third phase DFID conducted a formal appraisal, independent of the Scoping Team, to select preferred options for region, delivery and governance. Working on DFID selections, the Scoping Team then developed a draft framework for programme monitoring and evaluation

The effect of long-distance family migration and motherhood on partnered women's labour-market activity rates in Great Britain and the USA

Many studies of long-distance family migration demonstrate that female partners are often disenfranchised in the labour market. One factor that has not been fully considered is the role of children. Heterosexual couples may be more likely to migrate in favour of the male 'breadwinner's' career if the couple have children, or are planning to commence childrearing in the foreseeable future. However, little work seems to have examined this empirically. The authors focus on the influence of 'motherhood' in different national contexts, using comparable census microdata for Great Britain and the United States. They test whether apparent 'tied migration' effects may in fact be influenced by family decisions related to childbearing/childrearing, and two sets of modelling results are provided. First, they examine whether the effects of long-distance family migration on women's labour-market status is influenced by the presence or absence of children of different ages. Second, they conduct the same analysis for women who have a high-status occupation. The results demonstrate that women in families with young children are most likely to be out of employment after family migration. A smaller, but similar, tied-migration effect exists for families with older children and families with no children. The same pattern exists for women in high-status occupations. Tied migration appears to influence women's labour-market status equally in Great Britain and the United States, regardless of the presence or absence of children.</p