Joint Design with Providers of Clinical Decision Support for Value-Based Advanced Shoulder Imaging.

BACKGROUND: Provider orders for inappropriate advanced imaging, while rarely altering patient management, contribute enough to the strain on available health care resources, and therefore the United States Congress established the Appropriate Use Criteria Program. OBJECTIVES: To examine whether co-designing clinical decision support (CDS) with referring providers will reduce barriers to adoption and facilitate more appropriate shoulder ultrasound (US) over magnetic resonance imaging (MRI) in diagnosing Veteran shoulder pain, given similar efficacies and only 5% MRI follow-up rate after shoulder US. METHODS: We used a theory-driven, convergent parallel mixed-methods approach to prospectively (1) determine medical providers' reasons for selecting MRI over US in diagnosing shoulder pain and identify barriers to ordering US, (2) co-design CDS, informed by provider interviews, to prompt appropriate US use, and (3) assess CDS impact on shoulder imaging use. CDS effectiveness in guiding appropriate shoulder imaging was evaluated through monthly monitoring of ordering data at our quaternary care Veterans Hospital. Key outcome measures were appropriate MRI/US use rates and transition to ordering US by both musculoskeletal specialist and generalist providers. We assessed differences in ordering using a generalized estimating equations logistic regression model. We compared continuous measures using mixed effects analysis of variance with log-transformed data. RESULTS: During December 2016 to March 2018, 569 (395 MRI, 174 US) shoulder advanced imaging examinations were ordered by 111 providers. CDS "co-designed" in collaboration with providers increased US from 17% (58/335) to 50% (116/234) of all orders (p < 0.001), with concomitant decrease in MRI. Ordering appropriateness more than doubled from 31% (105/335) to 67% (157/234) following CDS (p < 0.001). Interviews confirmed that generalist providers want help in appropriately ordering advanced imaging. CONCLUSION: Partnering with medical providers to co-design CDS reduced barriers and prompted appropriate transition to US from MRI for shoulder pain diagnosis, promoting evidence-based practice. This approach can inform the development and implementation of other forms of CDS.

Anti-tumor and immunomodulatory activity of resveratrol in vitro and its potential for combining with cancer immunotherapy.

We evaluated the anti-tumor effect of Resveratrol (RV) on M21 and NXS2 tumor cell lines and its immunosuppressive activity on human and murine immune cells to determine the potential for combining RV and immunotherapy. In vitro, concentrations of RV≥25 mcM, inhibited cell proliferation, blocked DNA synthesis and induced G1 phase arrest in tumor and immune cells. RV at 12-50 mcM inhibited antibody dependent cell mediated cytotoxicity (ADCC) of tumor cells facilitated by the hu14.18-IL2 immunocytokine (IC). The in vivo anti-tumor and immunomodulating activity of RV given systemically were assessed in mice. Results showed that this RV regimen inhibited the growth of NXS2 tumors in vivo but did not appear to interfere with blood cell count, splenocyte or macrophage function. Thus, RV may be a candidate for combining with immunotherapy.

Anti-tumour synergy of cytotoxic chemotherapy and anti-CD40 plus CpG-ODN immunotherapy through repolarization of tumour-associated macrophages.

We studied the effectiveness of monoclonal anti-CD40 + cytosine-phosphate-guanosine-containing oligodeoxynucleotide 1826 (CpG-ODN) immunotherapy (IT) in mice treated with multidrug chemotherapy (CT) consisting of vincristine, cyclophosphamide and doxorubicin. Combining CT with IT led to synergistic anti-tumour effects in C57BL/6 mice with established B16 melanoma or 9464D neuroblastoma. CT suppressed the functions of T cells and natural killer (NK) cells, but primed naïve peritoneal macrophages (Mφ) to in vitro stimulation with lipopolysaccharide (LPS), resulting in augmented nitric oxide (NO) production. IT, given after CT, did not restore the responsiveness of T cells and NK cells, but further activated Mφ to secrete NO, interferon-γ (IFN-γ) and interleukin (IL)-12p40 and to suppress the proliferation of tumour cells in vitro. These functional changes were accompanied by immunophenotype alterations on Mφ, including the up-regulation of Gr-1. CD11b(+) F4/80(+) Mφ comprised the major population of B16 tumour-infiltrating leucocytes. CT + IT treatment up-regulated molecules associated with the M1 effector Mφ phenotype [CD40, CD80, CD86, major histocompatibility complex (MHC) class II, IFN-γ, tumour necrosis factor-α (TNF-α) and IL-12] and down-regulated molecules associated with the M2 inhibitory Mφ phenotype (IL-4Rα, B7-H1, IL-4 and IL-10) on the tumour-associated Mφ compared with untreated controls. Together, the results show that CT and anti-CD40 + CpG-ODN IT synergize in the induction of anti-tumour effects which are associated with the phenotypic repolarization of tumour-associated Mφ.