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Vaccine dose-response curves can follow both saturating and peaking shapes. Dose-response curves for adenoviral vector vaccines have not been systematically described. In this paper, we explore the dose-response shape of published adenoviral animal and human studies. Where data were informative, dose-response was approximately five times more likely to be peaking than saturating. There was evidence that host species and response type may be sufficient for prediction of dose-response curve shape. Dose-response curve shape prediction could decrease clinical trial costs, accelerating the development of life-saving vaccines.

Optimal vaccine dosing is important to ensure the greatest protection and safety. Analysis of dose-response data, from previous studies, may inform future studies to determine the optimal dose. Implementing more quantitative modelling approaches in vaccine dose finding have been recently suggested to accelerate vaccine development. Adenoviral vectored vaccines are in advanced stage of development for a variety of prophylactic and therapeutic indications, however dose-response has not yet been systematically determined. To further inform adenoviral vectored vaccines dose identification, historical dose-response data should be systematically reviewed. A systematic literature review was conducted to collate and describe the available dose-response studies for adenovirus vectored vaccines. Of 2787 papers identified by Medline search strategy, 35 were found to conform to pre-defined criteria. The majority of studies were in mice or humans and studied adenovirus serotype 5. Dose-response data were available for 12 different immunological responses. The majority of papers evaluated three dose levels, only two evaluated more than five dose levels. The most common dosing range was 10 7 -10 10 viral particles in mouse studies and 10 8 -10 11 viral particles in human studies. Data were available on adenovirus vaccine dose-response, primarily on adenovirus serotype 5 backbones and in mice and humans. These data could be used for quantitative adenoviral vectored vaccine dose optimisation analysis., Competing Interests: This work is partially funded by Vaccitech, a company that is developing novel adenoviral vector vaccines using the vectors ChAdOx1 and ChAdOx2.

Aim: To characterise the role of substitutes for receptor-activator nuclear factor kappa-B ligand (RANKL) in rheumatoid arthritis (RA) joint destruction., Methods: Synovial fluid (SF) macrophages isolated from the knee joint of RA patients were incubated with 25 ng/mL macrophage-colony stimulating factor (M-CSF) and 50 ng/mL LIGHT (lymphotoxin-like, exhibits inducible expression and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes) in the presence and absence of 25 ng/mL RANKL and 100 ng/mL osteoprotegerin (OPG) on glass coverslips and dentine slices. Osteoclastogenesis was assessed by the formation of multinucleated cells (MNCs) expressing tartrate-resistant acid phosphatase (TRAP) on coverslips and the extent of lacunar resorption pit formation on dentine slices. The concentration of LIGHT in RA and osteoarthritis (OA) synovial fluid was measured by an enzyme-linked immunosorbent assay (ELISA) and the expression of LIGHT in RA and OA synovium was determined by immunohistochemistry using an indirect immunoperoxidase technique., Results: In cultures of RA SF macrophages treated with LIGHT and M-CSF, there was significant formation of TRAP + MNCs on coverslips and extensive lacunar resorption pit formation on dentine slices. SF-macrophage-osteoclast differentiation was not inhibited by the addition of OPG, a decoy receptor for RANKL. Resorption pits were smaller and less confluent than in RANKL-treated cultures but the overall percentage area of the dentine slice resorbed was comparable in LIGHT- and RANKL-treated cultures. LIGHT significantly stimulated RANKL-induced lacunar resorption compared with RA SF macrophages treated with either RANKL or LIGHT alone. LIGHT was strongly expressed by synovial lining cells, subintimal macrophages and endothelial cells in RA synovium and the concentration of LIGHT was much higher in RA compared with OA SF., Conclusion: LIGHT is highly expressed in RA synovium and SF, stimulates RANKL-independent/dependent osteoclastogenesis from SF macrophages and may contribute to marginal erosion formation., Competing Interests: Conflict-of-interest statement: To the best of our knowledge, no conflict of interest exists.

Introduction: Cutting back on the staff and equipment and also reduction of costs and devices, balanced distribution of resources for optimal use and prevention of unreasonable costs for patients are some advantages of the fulfillment of referral system process. Accordingly the purpose of the present study is to determine factors affecting the fulfillment of referral system process from the viewpoints of clients of Isfahan's public hospitals so that health system could benefit its advantages., Methodology: The research is a descriptive-analytic survey and the population consisted of clients referring to public hospitals of Isfahan Province. Hospitals conforming to health network in cities of Falavarjan, ShahinShahr, Shahreza, Naein and some public hospitals of Isfahan city were selected for study. Cluster sampling was applied and at the end 400 subjects were selected by simple random sampling., Findings: Results showed that awareness and satisfaction in urban communities and motivation in rural are of higher levels. Regarding insurance status, those covered by Social Security have the most referrals to all levels and those covered by Health Service Insurance have more referral to the first level. The mean score of awareness of clients about referral system among the hospitals investigated shows a significant difference (p-value≤0.05)., Conclusion: Results indicate that from the viewpoints of urban clients, the rate of the awareness of and satisfaction with the way of offering health services at primary levels and from that of rural clients motivation affect the fulfillment of referral system process. Therefore improvement of these factors could make the system more efficient.