Cardiorespiratory fitness in patients with rheumatoid arthritis is associated with the patient global assessment but not with objective measurements of disease activity.

Objective: Patients with rheumatoid arthritis (RA) suffer from more cardiovascular disease (CVD), and develop cardiovascular risk factors at an earlier age than the general population. Cardiorespiratory fitness (CRF) is an important predictor of cardiovascular health. There are few data regarding CRF of RA patients, measured as peak oxygen uptake (VO2peak) by the gold standard method; cardiopulmonary exercise testing. We compared CRF in RA patients to those from a healthy population, and investigated if risk factors for CVD and RA-specific variables including subjective and objective disease activity measures were associated with CRF in RA patients. Methods: VO2peak tests of RA patients (n=93) were compared to those of an age-matched and gender-matched healthy population (n=4631) from the Nord-Trøndelag Health Study. Predictors of VO2peak were found using Lasso (least absolute shrinkage and selection operator) regression, followed by standardised multiple linear regression. Results: Women with RA ≥40 years and men with RA aged 40-49 years or 60-69 years had up to 20% lower CRF than the healthy population in the same age groups. By relative importance, body mass index (standardised coefficient=-0.25, p<0.001), physical activity level (coefficient=0.21, p<0.001), patient global assessment (PGA; coefficient=-0.14, p=0.006), systolic blood pressure (coefficient=-0.12, p=0.016), resting heart rate (coefficient=-0.11, p=0.032) and smoking (coefficient=-0.10, p=0.046) were significant predictors of CRF (R2=0.82, gender-adjusted and age-adjusted). Conclusion: CRF in RA patients was lower than in a healthy population. CRF was associated with common risk factors for CVD and the PGA score. Focusing on fitness in RA patients may improve cardiovascular health.

What will it take? Pathways, time and funding: Australian medical students' perspective on clinician-scientist training.

BACKGROUND: Clinician-scientists are in decline worldwide. They represent a unique niche in medicine by bridging the gap between scientific discovery and patient care. A national, integrated approach to training clinician-scientists, typically programs that comprise a comprehensive MD-PhD pathway, are customary. Such a pathway is lacking in Australia. The objective was to gather perceptions from Australian medical students on factors they perceive would influence their decision to pursue clinician-scientist training. METHODS: A cross-sectional mixed methods design used quantitative and qualitative questions in an online self-report survey with medical students from a four-year MD program. Quantitative measures comprised scaled response questions regarding prior experience and current involvement in research, and short- and long-term opinions about factors that influence their decisions to undertake a research higher degree (RHD) during medical school. Qualitative questions gathered broader perceptions of what a career pathway as a clinician-scientist would include and what factors are most conducive to a medical student's commitment to MD-PhD training. RESULTS: Respondents (N = 418; 51% female) indicated Time, Funding and Pathway as the major themes arising from the qualitative data, highlighting negative perceptions rather than possible benefits to RHD training. The lack of an evident Pathway was inter-related to Time and Funding. Themes were supported by the quantitative data. Sixty percent of students have previous research experience of varying forms, and 90% report a current interest, mainly to improve their career prospects. CONCLUSIONS: The data emphasise the need for an MD-PhD pathway in Australia. A model that provides an early, integrated, and exclusive approach to research training pathways across all stages of medical education is suggested as the best way to rejuvenate the clinician-scientist. A national pathway that addresses factors influencing career decision making throughout the medical education continuum should include an appropriate funding structure, and provide early and continuing advice and mentoring. It should be flexible, gender equitable, and include post-graduate training. The implications of implementing MD-PhD programs represent a substantial investment. However this should not be a deterrent to Australia's commitment to an MD-PhD pathway, but rather a challenge to help ensure our future healthcare is guided by highly trained and competent clinician-scientists.

Interleukin-1ß produced in response to islet autoantigen presentation differentiates T-helper 17 cells at the expense of regulatory T-cells: Implications for the timing of tolerizing immunotherapy.

OBJECTIVE: The effectiveness of tolerizing immunotherapeutic strategies, such as anti-CD40L or dendritic cells (DCs), is greater when administered to young nonobese diabetic (NOD) mice than at peak insulitis. RelB(lo) DCs, generated in the presence of an nuclear factor-κB inhibitor, induce T-regulatory (Treg) cells and suppress inflammation in a model of rheumatoid arthritis. Interleukin (IL)-1ß is overexpressed in humans and mice at risk of type 1 diabetes, dysregulates Treg cells, and accelerates diabetes in NOD mice. We investigated the relationship between IL-1ß production and the response to RelB(lo) DCs in the prediabetic period. RESEARCH DESIGN AND METHODS: We injected RelB(lo) DCs subcutaneously into 4- or 14-week-old NOD mice and tracked the incidence of diabetes and effect on Treg cell function. We measured the expression of proinflammatory cytokines by stimulated splenocytes and unstimulated islets from mice of different ages and strains and proliferative and cytokine responses of T effectors to Treg in vitro. RESULTS: Tolerizing RelB(lo) DCs significantly inhibited diabetes progression when administered to 4-week-old but not 14-week-old mice. IL-1ß production by NOD splenocytes and mRNA expression by islets increased from 6 to 16 weeks of age when major histocompatibility complex (MHC)-restricted islet antigen presentation to autoreactive T-cells occurred. IL-1 reduced the capacity of Treg cells to suppress effector cells and promoted their conversion to Th17 cells. RelB(lo) DCs exacerbated the IL-1-dependent decline in Treg function and promoted Th17 conversion. CONCLUSIONS: IL-1ß, generated by islet-autoreactive cells in MHC-susceptible mice, accelerates diabetes by differentiating Th17 at the expense of Treg. Tolerizing DC therapies can regulate islet autoantigen priming and prevent diabetes, but progression past the IL-1ß/IL-17 checkpoint signals the need for other strategies.