Benefits and Sustainability of a Learning Collaborative for Implementation of Treat‐to‐Target in Rheumatoid Arthritis: Results of a Cluster‐Randomized Controlled Phase II Clinical Trial

Objective

We conducted a 2‐phase randomized controlled trial of a learning collaborative to facilitate implementation of treat‐to‐target (T2T) to manage rheumatoid arthritis (RA). We found substantial improvement in implementation of T2T in phase I. Here, we report on a second 9 months (phase II), where we examined the maintenance of response in phase I and predictors of greater improvement in T2T adherence.

Methods

We recruited patients from 11 rheumatology sites and randomized them to either receive the learning collaborative during phase I or to a wait‐list control group that received the learning collaborative intervention during phase II. The outcome was change in T2T implementation score (0–100, where 100 = best) from pre‐ to postintervention. The T2T implementation score was defined as a percent of components documented in visit notes. Analyses examined the extent to which the phase‐I intervention teams sustained improvement in T2T, as well as predictors of T2T improvement.

Results

The analysis included 636 RA patients. At baseline, the mean T2T implementation score was 11% in phase I intervention sites and 13% in phase II sites. After the intervention, T2T implementation score improved to 57% in the phase I intervention sites and to 58% in the phase II sites. Intervention sites from phase I sustained the improvement during the phase II (52%). Predictors of greater T2T improvement included having only rheumatologist providers at the site, academic affiliation of the site, having fewer providers per site, and the rheumatologist provider being a trainee.

Conclusion

Improvement in T2T remained relatively stable over a postintervention period.

     

Integration of Ultrasound in Undergraduate Medical Education at the California Medical Schools

Since the first medical student ultrasound electives became available more than a decade ago, ultrasound in undergraduate medical education has gained increasing popularity. More than a dozen medical schools have fully integrated ultrasound education in their curricula, with several dozen more institutions planning to follow suit. Starting in June 2012, a working group of emergency ultrasound faculty at the California medical schools began to meet to discuss barriers as well as innovative approaches to implementing ultrasound education in undergraduate medical education. It became clear that an ongoing collaborative could be formed to discuss barriers, exchange ideas, and lend support for this initiative. The group, termed Ultrasound in Medical Education, California (UMeCali), was formed with 2 main goals: to exchange ideas and resources in facilitating ultrasound education and to develop a white paper to discuss our experiences. Five common themes integral to successful ultrasound education in undergraduate medical education are discussed in this article: (1) initiating an ultrasound education program; (2) the role of medical student involvement; (3) integration of ultrasound in the preclinical years; (4) developing longitudinal ultrasound education; and (5) addressing competency.     

Platelet‐rich plasma counteracts detrimental effect of high‐glucose concentrations on mesenchymal stem cells from Bichat fat pad

Diabetic patients display increased risk of periodontitis and failure in bone augmentation procedures. Mesenchymal stem cells (MSCs) and platelet‐rich plasma (PRP) represent a relevant advantage in tissue repair process and regenerative medicine. We isolated MSCs from Bichat's buccal fat pad (BFP) and measured the effects of glucose and PRP on cell number and osteogenic differentiation potential. Cells were cultured in the presence of 5.5‐mM glucose (low glucose [LG]) or 25‐mM glucose (high glucose [HG]). BFP–MSC number was significantly lower when cells were cultured in HG compared with those in LG. Following osteogenic differentiation procedures, calcium accumulation, alkaline phosphatase activity, and expression of osteogenic markers were significantly lower in HG compared with LG. Exposure of BFP–MSC to PRP significantly increased cell number and osteogenic differentiation potential, reaching comparable levels in LG and in HG. Thus, high‐glucose concentrations impair BFP–MSC growth and osteogenic differentiation. However, these detrimental effects are largely counteracted by PRP.     

IL-1 is required for tumor invasiveness and angiogenesis

Here, we describe that microenvironmental IL-1 beta and, to a lesser extent, IL-1 alpha are required for in vivo angiogenesis and invasiveness of different tumor cells. In IL-1 beta knockout (KO) mice, local tumor or lung metastases of B16 melanoma cells were not observed compared with WT mice. Angiogenesis was assessed by the recruitment of blood vessel networks into Matrigel plugs containing B16 melanoma cells; vascularization of the plugs was present in WT mice, but was absent in IL-1 beta KO mice. The addition of exogenous IL-1 into B16-containing Matrigel plugs in IL-1 beta KO mice partially restored the angiogenic response. Moreover, the incorporation of IL-1 receptor antagonist to B16-containing plugs in WT mice inhibited the ingrowth of blood vessel networks into Matrigel plugs. In IL-1 alpha KO mice, local tumor development and induction of an angiogenic response in Matrigel plugs was less pronounced than in WT mice, but significantly higher than in IL-1 beta KO mice. These effects of host-derived IL-1 alpha and IL-1 beta were not restricted to the melanoma model, but were also observed in DA/3 mammary and prostate cancer cell models. In addition to the in vivo findings, IL-1 contributed to the production of vascular endothelial cell growth factor and tumor necrosis factor in cocultures of peritoneal macrophages and tumor cells. Host-derived IL-1 seems to control tumor angiogenesis and invasiveness. Furthermore, the anti-angiogenic effects of IL-1 receptor antagonist, shown here, suggest a possible therapeutic role in cancer, in addition to its current use in rheumatoid arthritis.     

Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene

The product of the SLC40A1 gene, ferroportin 1, is a main iron export protein. Pathogenic mutations in ferroportin 1 lead to an autosomal dominant hereditary iron overload syndrome characterized by high serum ferritin concentration, normal transferrin saturation, iron accumulation predominantly in macrophages, and marginal anemia. Iron overload occurs in both the African and the African-American populations, but a possible genetic basis has not been established. We analyzed the ferroportin 1 gene in 19 unrelated patients from southern Africa (N = 15) and the United States (N = 4) presenting with primary iron overload. We found a new c. 744 C-->T (Q248H) mutation in the SLC40A1 gene in 4 of these patients (3 Africans and 1 African-American). Among 22 first degree family members, 10 of whom were Q248H heterozygotes, the mutation was associated with a trend to higher serum ferritin to amino aspartate transferase ratios (means of 14.8 versus 4.3 microg/U; P = 0.1) and lower hemoglobin concentrations (means of 11.8 versus 13.2 g/dL; P = 0.1). The ratio corrects serum ferritin concentration for alcohol-induced hepatocellular damage. We also found heterozygosity for the Q248H mutation in 7 of 51 (14%) southern African community control participants selected because they had a serum ferritin concentration below 400 microg/L and in 5 of 100 (5%) anonymous African-Americans, but we did not find the change in 300 Caucasians with normal iron status and 25 Caucasians with non-HFE iron overload. The hemoglobin concentration was significantly lower in the African community controls with the Q248H mutation than in those without it. We conclude that the Q248H mutation is a common polymorphism in the ferroportin 1 gene in African populations that may be associated with mild anemia and a tendency to iron loading.     

CD8+ T‐cell responses to Theileria parva are preferentially directed to a single dominant antigen: Implications for parasite strain‐specific immunity

Although immunodominance of CD8⁺ T‐cell responses is a well‐recognised feature of viral infections, its role in responses to more antigenically complex pathogens is less clear. In previous studies we have observed that CD8⁺ T‐cell responses to Theileria parva exhibit different patterns of parasite strain specificity in cattle of different MHC genotypes. In the current study, we demonstrated that animals homozygous for the A10 and A18 MHC haplotypes have detectable responses to only one of 5 T. parva antigens. Over 60% of the responding T cells from the A18⁺ and A10⁺ animals recognised defined epitopes in the Tp1 and Tp2 antigens, respectively. Comparison of T‐cell receptor β chain expression profiles of CD8⁺ T‐cell lines and CD8⁺ T cells harvested ex vivo confirmed that the composition of the T‐cell lines was representative of the in vivo memory CD8⁺ T‐cell populations. Analysis of the Tp1 and Tp2 antigens revealed sequence polymorphism, which was reflected by differential recognition by T‐cell lines. In conclusion, we have demonstrated a profound immunodominance in the CD8⁺ T‐cell response to T. parva, which we propose is a major determinant of the parasite strain specificity of the response and hence immune protection.