Survival analysis of mortality and development of lupus nephritis in patients with systemic lupus erythematosus up to 40-years of follow-up

OBJECTIVES: Patients with systemic lupus erythematosus (SLE) have increased mortality compared with age and sex-matched controls. Lupus nephritis (LN) is a severe manifestation of SLE and an important cause of death. We carried out a retrospective survival analysis to investigate factors that could influence risk of mortality and LN in a large multi-ethnic cohort of patients with SLE. METHODS: By careful review of medical records, we identified 496 patients with SLE for whom we had complete information regarding period of observation and occurrence of death and nephritis. Patients were stratified into groups according to sex, ethnicity, age at start of follow-up and time-period of diagnosis. Kaplan-Meier analysis was used to investigate differences between the groups. RESULTS: Of 496 patients in the study, 91(18.3%) died, 165(33.3%) developed LN and 33(6.7%) developed end-stage renal failure. There was no difference between men and women in either mortality or development of LN. Caucasian patients were significantly less likely to develop LN than other ethnic groups (p< 0.0001) but not less likely to die. Patients diagnosed before the median age of 28 years were significantly more likely to develop LN (p< 0.0001) but significantly less likely to die (p= 0.0039) during the period of observation. There has been a significant improvement in survival between patients diagnosed between 1978-1989 and those diagnosed between 2006-11 (p= 0.019). CONCLUSION: In our cohort, non-Caucasian ethnicity and younger age at diagnosis are associated with risk of developing LN. There is evidence of improvement in survival of patients with SLE over time

Pain management for chronic musculoskeletal conditions : the development of an evidence-based and theory-informed pain self-management course

Objective: To devise and test a self-management course for chronic pain patients based on evidence and underpinned by theory using the Medical Research Council (MRC) framework for developing complex interventions. Design: We used a mixed method approach. We conducted a systematic review of the effectiveness of components and characteristics of pain management courses. We then interviewed chronic pain patients who had attended pain and self-management courses. Behavioural change theories were mapped onto our findings and used to design the intervention. We then conducted a feasibility study to test the intervention. Setting: Primary care in the inner city of London, UK. Participants: Adults (18 years or older) with chronic musculoskeletal pain. Outcomes: Related disability, quality of life, coping, depression, anxiety, social integration and healthcare resource use. Results: The systematic reviews indicated that group-based courses with joint lay and healthcare professional leadership and that included a psychological component of short duration (<8 weeks) showed considerable promise. The qualitative research indicated that participants liked relaxation, valued social interaction and course location, and that timing and good tutoring were important determinants of attendance. We used behavioural change theories (social learning theory and cognitive behaviour approaches (CBA)) to inform course content. The course addressed: understanding and accepting pain, mood and pain, unhelpful thoughts and behaviour, problem solving, goal setting, action planning, movement, relaxation and social integration/reactivation. Attendance was 85%; we modified the recruitment of patients, the course and the training of facilitators as a result of testing. Conclusions: The MRC guidelines were helpful in developing this intervention. It was possible to train both lay and non-psychologists to facilitate the courses and deliver CBA. The course was feasible and well received

Effectiveness and cost-effectiveness of a novel, group self-management course for adults with chronic musculoskeletal pain: study protocol for a multicentre, randomised controlled trial (COPERS)

Introduction: Chronic musculoskeletal pain is a common condition that often responds poorly to treatment. Self-management courses have been advocated as a non-drug pain management technique, although evidence for their effectiveness is equivocal. We designed and piloted a self-management course based on evidence for effectiveness for specific course components and characteristics. Methods/analysis: COPERS (coping with persistent pain, effectiveness research into self-management) is a pragmatic randomised controlled trial testing the effectiveness and cost-effectiveness of an intensive, group, cognitive behavioural-based, theoretically informed and manualised self-management course for chronic pain patients against a control of best usual care: a pain education booklet and a relaxation CD. The course lasts for 15 h, spread over 3 days, with a –2 h follow-up session 2 weeks later. We aim to recruit 685 participants with chronic musculoskeletal pain from primary, intermediate and secondary care services in two UK regions. The study is powered to show a standardised mean difference of 0.3 in the primary outcome, pain-related disability. Secondary outcomes include generic health-related quality of life, healthcare utilisation, pain self-efficacy, coping, depression, anxiety and social engagement. Outcomes are measured at 6 and 12 months postrandomisation. Pain self-efficacy is measured at 3 months to assess whether change mediates clinical effect. Ethics/dissemination: Ethics approval was given by Cambridgeshire Ethics 11/EE/046. This trial will provide robust data on the effectiveness and cost-effectiveness of an evidence-based, group self-management programme for chronic musculoskeletal pain. The published outcomes will help to inform future policy and practice around such self-management courses, both nationally and internationally. Trial registration: ISRCTN24426731

Prevalence and impact of chronic widespread pain in the Bangladeshi and White populations of Tower Hamlets, East London

The prevalence and impact of chronic pain differ between ethnic groups. We report a study of the comparative prevalence and impact of chronic pain in Bangladeshi, British Bangladeshi and White British/Irish people. We posted a short questionnaire to a random sample of 4,480 patients registered with 16 general practices in the London Borough of Tower Hamlets and conducted a longer questionnaire with patients in the waiting areas at those practices. We distinguished between Bangladeshi participants who were born in the UK or had arrived in the UK at the age of 14 or under (British Bangladeshi) and those who arrived in UK at the age of over 14 (Bangladeshi). We obtained 1,223/4,480 (27 %) responses to the short survey and 600/637 (94 %) to the long survey. From the former, the prevalence of chronic pain in the White, British Bangladeshi and Bangladeshi groups was 55, 54 and 72 %, respectively. The corresponding figures from the long survey were 49, 45 and 70 %. Chronic widespread pain was commoner in the Bangladeshi (16 %) than in the White (10 %) or British Bangladeshi (9 %) groups. People with chronic pain experienced poorer quality of life (odds ratio for scoring best possible health vs. good health (or good vs. poor health) 5.6 (95 % confidence interval 3.4 to 9.8)), but we found no evidence of differences between ethnic groups in the impact of chronic pain on the quality of life. Chronic pain is commoner and, of greater severity, in Bangladeshis than in Whites. On most measures in this study, British Bangladeshis resembled the Whites more than the Bangladeshis

Extent of vascular plaque predicts future cardiovascular events in patients with systemic lupus erythematosus

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) have increased prevalence of clinical cardiovascular disease (CVD) and subclinical atherosclerosis. Although 30-40% of patients with SLE have vascular plaque on ultrasound scanning, this study is the first to consider the relationship between total burden of plaque and subsequent CVD risk. METHODS: One hundred patients with SLE and without any previous clinical CVD underwent vascular ultrasound scans of both carotid and both common femoral bifurcations between 2011 and 2013. Clinical, serological, demographic and treatment data were collected at baseline. Patients were followed till 2020 to identify those who developed new onset coronary disease or stroke. Statistical analysis to identify factors associated with increased risk of developing CVD events was carried out. RESULTS: Thirty-six patients had plaque at baseline. During follow-up five patients (all had baseline plaque) developed coronary disease and two, without baseline plaque, developed lacunar strokes. Mean (SD) age of these patients was 46.5 (4.5) years. Patients with three or more baseline bifurcations with plaque were 10 times more likely to develop CVD than those with 0-2 bifurcations with plaques (OR 9.9, p= 0.009). TPA > 16mm2 was associated with six-fold increased risk of CVD (OR = 6.44, p= 0.028). Patients with disease duration > 14 years were more likely than those with disease duration < 14 years to develop CVD (OR 8.3 p= 0.043). CONCLUSIONS: The number of bifurcations with plaque and TPA in patients with SLE may be valuable in assessing risk of CVD and deciding on clinical measures to reduce this risk

A novel expression system of domain I of human beta2 glycoprotein I in Escherichia coli

BACKGROUND: The antiphospholipid syndrome (APS), characterised by recurrent miscarriage and thrombosis, is a significant cause of morbidity and mortality. Domain I (DI) of human beta 2 glycoprotein I (β(2)GPI) is thought to contain crucial antibody binding epitopes for antiphospholipid antibodies (aPL), which are critical to the pathogenesis of APS. Expressing this protein in bacteria could facilitate studies investigating how this molecule interacts with aPL. METHODS: Using a computer programme called Juniper, sequentially overlapping primers were designed to be used in a recursive polymerase chain reaction (PCR) to produce a synthetic DI gene. Specifically Juniper incorporates 'major' codons preferred by bacteria altering 41 codons out of 61. This was cloned into the expression plasmid pET(26b) and expressed in BL21(DE3) Escherichia coli (E. coli). By virtue of a pelB leader sequence, periplasmic localisation of DI aided disulphide bond formation and toxicity was addressed by tightly regulating expression through the high stringency T7lac promoter. RESULTS: Purified, soluble his-tagged DI in yields of 750 μg/L bacterial culture was obtained and confirmed on Western blot. Expression using the native human cDNA sequence of DI in the same construct under identical conditions yielded significantly less DI compared to the recombinant optimised sequence. This constitutes the first description of prokaryotic expression of soluble DI of β(2)GPI. Binding to murine monoclonal antibodies that recognise conformationally restricted epitopes on the surface of DI and pathogenic human monoclonal IgG aPL was confirmed by direct and indirect immunoassay. Recombinant DI also bound a series of 21 polyclonal IgG samples derived from patients with APS. CONCLUSION: By producing a synthetic gene globally optimised for expression in E. coli, tightly regulating expression and utilising periplasmic product translocation, efficient, soluble E. coli expression of the eukaryotic protein DI of β(2)GPI is possible. This novel platform of expression utilising pan-gene prokaryote codon optimisation for DI production will aid future antigenic studies. Furthermore if DI or peptide derivatives of DI are eventually used in the therapeutic setting either as toleragen or as a competitive inhibitor of pathogenic aPL, then an E. coli production system may aid cost-effective production

Stable expression of a recombinant human antinucleosome antibody to investigate relationships between antibody sequence, binding properties, and pathogenicity

When purified under rigorous conditions, some murine anti-double-stranded-DNA (anti-dsDNA) antibodies actually bind chromatin rather than dsDNA. This suggests that they may actually be antinucleosome antibodies that only appear to bind dsDNA when they are incompletely dissociated from nucleosomes. Experiments in murine models suggest that antibody–nucleosome complexes may play a crucial role in the pathogenesis of glomerulonephritis in systemic lupus erythematosus. Some human monoclonal anti-DNA antibodies are pathogenic when administered to mice with severe combined immunodeficiency (SCID). Our objective was to achieve stable expression of sequence-altered variants of one such antibody, B3, in Chinese hamster ovary (CHO) cells. Purified antibodies secreted by these cells were tested to investigate whether B3 is actually an antinucleosome antibody. The pathogenic effects of the antibodies were tested by implanting CHO cells secreting them into SCID mice. Purified B3 does not bind to dsDNA unless supernatant from cultured cells is added, but does bind to nucleosomes. The strength of binding to dsDNA and nucleosomes is dependent on the sequence of the light chain. Mice that received CHO cells secreting wild-type B3 developed more proteinuria and died earlier than control mice that received nonsecreting CHO cells or mice that received B3 with a single light chain mutation. However, none of the mice had histological changes or deposition of human immunoglobulin G in the kidneys. Sequence changes may alter the pathogenicity of B3, but further studies using different techniques are needed to investigate this possibility

Developing targeted client communication messages to pregnant women in Bangladesh: a qualitative study

AbstractBackground:Timely and appropriate evidence-based practices during antenatal care improve maternal andneonatal health. There is a lack of information on how pregnant women and families perceive antenatal care inBangladesh. The aim of our study was to develop targeted client communication via text messages for increasingantenatal care utilization, as part of an implementation of an electronic registry for maternal and child health.Methods:Using a phenomenological approach, we conducted this qualitative study from May to June 2017 in two sub-districts of Chandpur district, Bangladesh. We selected study participants by purposive sampling. A total of 24 in-depthinterviews were conductedwithpregnantwomen(n= 10), lactating women (n=5),husbands(n= 5), and mothers-in-law(n= 4). The Health Belief Model (HBM) was used to guide the datacollection. Thematic analysis was carried out manuallyaccording to the HBM constructs. We used behavior change techniques to inform the development of targeted clientcommunication based on the thematic results.Results:Almost no respondents mentioned antenatal care as a preventive form of care, and only perceived it as necessary ifany complications developed during pregnancy. Knowledge of the content of antenatal care (ANC) and pregnancycomplications was low. Women reported avariety of reasons for not attending ANC, including the lack of information onthe timing of ANC; lack of decision-making power; long-distance to access care; being busy with household chores, and notbeing satisfied with the treatment by health care providers. Study participants recommended phone calls as their preferredcommunication strategy when asked to choose between thephone call and text message, but saw text messages as afeasible option. Based on the findings, we developed a library of 43 automatically customizable text messages to increaseANC utilization.Conclusions:Pregnant women and family members had limited knowledge about antenatal care and pregnancycomplications. Effective health information through text messages could increase awareness of antenatal careamong the pregnant women in Bangladesh. This study presents an example of designing targeted clientcommunication to increase antenatal care utilization within formal scientific frameworks, including a taxonomy ofbehavior change techniques.publishedVersio

An Electronic Registry for Improving the Quality of Antenatal Care in Rural Bangladesh (eRegMat): Protocol for a Cluster Randomized Controlled Trial

Background: Digital health interventions (DHIs) can alleviate several barriers to achieving better maternal and child health. The World Health Organization’s guideline recommendations for DHIs emphasize the need to integrate multiple DHIs for maximizing impact. The complex health system of Bangladesh provides a unique setting for evaluating and understanding the role of an electronic registry (eRegistry) for antenatal care, with multiple integrated DHIs for strengthening the health system as well as improving the quality and utilization of the public health care system. Objective: The aim of this study is to assess the effect of an eRegistry with DHIs compared with a simple digital data entry tool without DHIs in the community and frontline health facilities. Methods: The eRegMat is a cluster-randomized controlled trial conducted in the Matlab North and Matlab South subdistricts in the Chandpur district, Bangladesh, where health facilities are currently using the eRegistry for digital tracking of the health status of pregnant women longitudinally. The intervention arm received 3 superimposed data-driven DHIs: health worker clinical decision support, health worker feedback dashboards with action items, and targeted client communication to pregnant women. The primary outcomes are appropriate screening as well as management of hypertension during pregnancy and timely antenatal care attendance. The secondary outcomes include morbidity and mortality in the perinatal period as well as timely first antenatal care visit; successful referrals for anemia, diabetes, or hypertension during pregnancy; and facility delivery. Results: The eRegistry and DHIs were co-designed with end users between 2016 and 2018. The eRegistry was implemented in the study area in July 2018. Recruitment for the trial started in October 2018 and ended in June 2020, followed by an 8-month follow-up period to capture outcome data until February 2021. Trial results will be available for publication in June 2021. Conclusions: This trial allows the simultaneous assessment of multiple integrated DHIs for strengthening the health system and aims to provide evidence for its implementation. The study design and outcomes are geared toward informing the living review process of the guidelines for implementing DHIs.publishedVersio