Design Principles for Product-Service-Software-System Innovation for Healthcare Manufacturers

Healthcare equipment manufacturers face the challenge of service innovation while simultaneously ensuring profitability and sustainability. However, service innovation fostered by digitalization seems promising to overcome these challenges through an innovative service offering leading towards Product-Service-Software-Systems (PSSS). In addition, the role of service design could be leveraged to create these new services successfully. Thus, this study contributes by further complementing service design and service innovation research with a design science approach. We present how a healthcare manufacturer can drive a transition to digital servitization by utilizing six design principles to offer PSSS innovation

ORF6 and ORF61 Expressing MVA Vaccines Impair Early but Not Late Latency in Murine Gammaherpesvirus MHV-68 Infection

Gammaherpesviruses (gamma HV) are important pathogens causing persistent infections which lead to several malignancies in immunocompromised patients. Murine gamma HV 68 (MHV-68), a homolog to human EBV and KSHV, has been employed as a classical pathogen to investigate the molecular pathogenicity of gamma HV infections. gamma HV express distinct antigens during lytic or latent infection and antigen-specific T cells have a significant role in controlling the acute and latent viral infection, although the quality of anti-viral T cell responses required for protective immunity is not well-understood. We have generated recombinant modified vaccinia virus Ankara (recMVA) vaccines via MVA-BAC homologous recombination technology expressing MHV-68 ORF6 and ORF61 antigens encoding both MHC class I and II-restricted epitopes. After vaccination, we examined T cell responses before and after MHV-68 infection to determine their involvement in latent virus control. We show recognition of recMVA- and MHV-68-infected APC by ORF6 and ORF61 epitope-specific T cell lines in vitro. The recMVA vaccines efficiently induced MHV-68-specific CD8+ and CD4+ T cell responses after a single immunization and more pronounced after homologous prime/boost vaccination in mice. Moreover, we exhibit protective capacity of prophylactic recMVA vaccination during early latency at day 17 after intranasal challenge with MHV-68, but failed to protect from latency at day 45. Further T cell analysis indicated that T cell exhaustion was not responsible for the lack of protection by recMVA vaccination in long-termlatency at day 45. The data support further efforts aiming at improved vaccine development against gamma HV infections with special focus on targeting protective CD4+ T cell responses

Differential Regulation of Inducible Nitric Oxide Synthase Production in Bovine and Caprine Macrophages

Inducible nitric oxide synthase (iNOS) regulation in human and murine macrophages in vitro differs considerably. In this study, expression of macrophage iNOS in ruminants was addressed. Nitric oxide (NO) output by cattle and goat macrophages was as different as that by human and mouse macrophages. Bovine macrophages activated by heated Salmonella dublin or lipopolysaccharide (LPS) expressed high levels of iNOS mRNA, protein, and enzyme activity. Analogously cultured caprine macrophages did not respond to these and other activators by NO generation and iNOS expression. The lack of response was not due to general unresponsiveness to stimuli. Caprine iNOS mRNA was induced by stimulation of caprine macrophages with LPS, as shown by reverse transcription polymerase chain reaction. The level of mRNA expression in activated goat macrophages was lower than in resting bovine macrophages. A caprine 372-bp iNOS mRNA fragment that was sequenced closely resembled the bovine counterpart. This points to species-specific iNOS gene regulation

Differential Regulation of Inducible Nitric Oxide Synthase Production in Bovine and Caprine Macrophages

Inducible nitric oxide synthase (iNOS) regulation in human and murine macrophages in vitro differs considerably. In this study, expression of macrophage iNOS in ruminants was addressed. Nitric oxide (NO) output by cattle and goat macrophages was as different as that by human and mouse macrophages. Bovine macrophages activated by heated Salmonella dublin or lipopolysaccharide (LPS) expressed high levels of iNOS mRNA, protein, and enzyme activity. Analogously cultured caprine macrophages did not respond to these and other activators by NO generation and iNOS expression. The lack of response was not due to general unresponsiveness to stimuli. Caprine iNOS mRNA was induced by stimulation of caprine macrophages with LPS, as shown by reverse transcription polymerase chain reaction. The level of mRNA expression in activated goat macrophages was lower than in resting bovine macrophages. A caprine 372-bp iNOS mRNA fragment that was sequenced closely resembled the bovine counterpart. This points to species-specific iNOS gene regulatio

Perturbation of Lytic and Latent Gammaherpesvirus Infection in the Absence of the Inhibitory Receptor CEACAM1

Control of gammaherpesvirus infections requires a complex, well orchestrated immune response regulated by positive and negative co-signaling molecules. While the impact of co-stimulatory molecules has been addressed in various studies, the role of co-inhibitory receptors has not been tested. The ITIM-bearing CEACAM1 is an inhibitory receptor expressed by a variety of immune cells, including B, T and NK cells. Using Ceacam1−/− mice, we analyzed the in vivo function of CEACAM1 during acute and latent murine gammaherpesvirus 68 (MHV-68) infection. During acute lytic replication, we observed lower virus titers in the lungs of Ceacam1−/− mice than in WT mice. In contrast, during latency amplification, Ceacam1−/− mice displayed increased splenomegaly and a higher latent viral load in the spleen. Analysis of the immune response revealed increased virus-specific antibody levels in Ceacam1−/− mice, while the magnitude of the T cell-mediated antiviral immune response was reduced. These findings suggest that inhibitory receptors can modulate the efficacy of immune responses against gammaherpesvirus infections

Cold Spray metal powder deposition with 9 %Cr-steel applied for the HCPB First Wall fabrication: Proof of concept and options for ODS steel processing

At the KIT a hybrid manufacturing concept for nuclear fusion First Walls is developed combining aspects of conventional and Additive Manufacturing (AM) technologies. The state of the art for ITER does not cover all specifications of a DEMO relevant First Wall. Thus, additional R&D-work has been initiated in terms of manufacturing. The AM technology basis used in the presented process combination is Cold Spray metal powder deposition applied in alternation with machining including the feature of filling grooves temporarily with a water-soluble granulate for creation of closed channels and cavities. Thus, the technology provides the option to manufacture shells with a thin gas tight membrane on top of previously machined structures. This membrane is used as pressure seal and makes the joining of shells by Hot Isostatic Pressing (HIP) into one monolithic body possible. This paper describes the manufacturing process and recalls differences and common aspects with regard to conventional concepts of First Wall manufacturing. The achievement of Technology Readiness Level TRL 3 by mechanical qualification and comparison of the results to other HIP joint experiments is also demonstrated. Finally, an outlook is given concerning integration options of the technology into manufacturing of shells with cooling channel structures using Oxide Dispersion Strengthened (ODS) materials