STRENGTHS AND WEAKNESSES OF (INTER)NATIONAL BRANDS: IKEA, L’ORÉAL, STARBUCKS AND FORD, BASED ON THE OPINION OF CONSUMERS

In our everyday lives the presence of global brands is indisputable, as we decorate our homes with furnishings, purchase cosmetics to reverse the time, use services to make our everyday lives more enjoyable and purchase cars, all of which are available in several countries. It is also true that we typically buy and use those products and services that contribute to our personal appearance and to the development of our personality. In addition, the country of origin of a given product/brand also plays an important role in our purchasing decision. There are products/brands that we immediately associate with a particular country and nation, but there are countries to which we cannot associate any product or brand. This paper analyses the consumer opinions of international brands that are strongly associated with a particular country. The objectives of the analyses are the following: to identify (1) the strengths - (2) weaknesses of IKEA, L’Oréal, Starbucks and Ford, (3) to identify those factors, based on the results, that have an important role in case of two (inter)national brands at least, even though they represent different products/services, and finally, (4) to describe the opinion of the participants. JEL Classification: M3

Hosting Multinationals: Economic and Fiscal Implications

Switzerland is a prime location for both domestically owned as well as foreign-owned multinational enterprises (MNEs). In this paper, we review the literature on MNE activity with respect to its main fundamental (non-policy) drivers, the non-fiscal consequences of MNEs for various economic aggregates, and the fiscal implications associated with the operation of foreign affiliate networks. In particular, the paper puts emphasis on the fiscal implications of hosting MNEs and their relation to the current tax environment in Switzerland

Insulin-induced vascular redox dysregulation in human atherosclerosis is ameliorated by dipeptidyl peptidase 4 inhibition

Recent clinical trials have revealed that aggressive insulin treatment has a neutral effect on cardiovascular risk in patients with diabetes despite improved glycemic control, which may suggest confounding direct effects of insulin on the human vasculature. We studied 580 patients with coronary atherosclerosis undergoing coronary artery bypass surgery (CABG), finding that high endogenous insulin was associated with reduced nitric oxide (NO) bioavailability ex vivo in vessels obtained during surgery. Ex vivo experiments with human internal mammary arteries and saphenous veins obtained from 94 patients undergoing CABG revealed that both long-acting insulin analogs and human insulin triggered abnormal responses of post-insulin receptor substrate 1 downstream signaling ex vivo, independently of systemic insulin resistance status. These abnormal responses led to reduced NO bioavailability, activation of NADPH oxidases, and uncoupling of endothelial NO synthase. Treatment with an oral dipeptidyl peptidase 4 inhibitor (DPP4i) in vivo or DPP4i administered to vessels ex vivo restored physiological insulin signaling, reversed vascular insulin responses, reduced vascular oxidative stress, and improved endothelial function in humans. The detrimental effects of insulin on vascular redox state and endothelial function as well as the insulin-sensitizing effect of DPP4i were also validated in high-fat diet-fed ApoE(-/-) mice treated with DPP4i. High plasma DPP4 activity and high insulin were additively related with higher cardiac mortality in patients with coronary atherosclerosis undergoing CABG. These findings may explain the inability of aggressive insulin treatment to improve cardiovascular outcomes, raising the question whether vascular insulin sensitization with DPP4i should precede initiation of insulin treatment and continue as part of a long-term combination therapy

Mapping atopic dermatitis and anti-IL-22 response signatures to Type 2-low severe neutrophilic asthma

BACKGROUND: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases.OBJECTIVE: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti-IL-22 (fezakinumab [FZ]) is enriched in severe asthma.METHODS: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies. Differentially expressed genes from lesional skin from therapeutic superresponders before and after 12 weeks of FZ treatment defined the FZ-response signature. Gene set variation analysis was used to produce enrichment scores of AD and FZ-response signatures in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes asthma cohort.RESULTS: The AD disease signature (112 upregulated genes) encompassing inflammatory, T-cell, T H2, and T H17/T H22 pathways was enriched in the blood and sputum of patients with asthma with increasing severity. Patients with asthma with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (P &lt; .05). The FZ-response signature (296 downregulated genes) was enriched in asthmatic blood (P &lt; .05) and particularly in neutrophilic and mixed granulocytic sputum (P &lt; .05). These data were confirmed in sputum of the Airway Disease Endotyping for Personalized Therapeutics cohort. IL-22 mRNA across tissues did not correlate with FZ-response enrichment scores, but this response signature correlated with T H22/IL-22 pathways. CONCLUSIONS: The FZ-response signature in AD identifies severe neutrophilic asthmatic patients as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases.</p

Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma

Background: Patients with severe asthma may have a greater risk of dying from COVID-19 disease. Angiotensin converting enzyme-2 (ACE2) and the enzyme proteases, transmembrane protease serine 2 (TMPRSS2) and FURIN, are needed for viral attachment and invasion into host cells. Methods: We examined microarray mRNA expression of ACE2, TMPRSS2 and FURIN in sputum, bronchial brushing and bronchial biopsies of the European U-BIOPRED cohort. Clinical parameters and molecular phenotypes, including asthma severity, sputum inflammatory cells, lung functions, oral corticosteroid (OCS) use, and transcriptomic-associated clusters, were examined in relation to gene expression levels. Results: ACE2 levels were significantly increased in sputum of severe asthma compared to mild-moderate asthma. In multivariate analyses, sputum ACE2 levels were positively associated with OCS use and male gender. Sputum FURIN levels were significantly related to neutrophils (%) and the presence of severe asthma. In bronchial brushing samples, TMPRSS2 levels were positively associated with male gender and body mass index, whereas FURIN levels with male gender and blood neutrophils. In bronchial biopsies, TMPRSS2 levels were positively related to blood neutrophils. The neutrophilic molecular phenotype characterised by high inflammasome activation expressed significantly higher FURIN levels in sputum than the eosinophilic Type 2-high or the pauci-granulocytic oxidative phosphorylation phenotypes. Conclusion: Levels of ACE2 and FURIN may differ by clinical or molecular phenotypes of asthma. Sputum FURIN expression levels were strongly associated with neutrophilic inflammation and with inflammasome activation. This might indicate the potential for a greater morbidity and mortality outcome from SARS-CoV-2 infection in neutrophilic severe asthma.</p

Correction to: Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma (Respiratory Research, (2021), 22, 1, (10), 10.1186/s12931-020-01605-8)

An amendment to this paper has been published and can be accessed via the original article.</p

Mapping atopic dermatitis and anti-IL-22 response signatures to Type 2-low severe neutrophilic asthma.

BACKGROUND Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases. OBJECTIVE To determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma (SA) and whether a transcriptomic signature for AD patients who respond clinically to anti-IL-22 (Fezakinumab, FZ) is enriched in SA. METHODS An AD disease signature was obtained from analysis of differentially expressed genes (DEGs) between AD lesional and non-lesional skin biopsies. DEGs from lesional skin from therapeutic super-responders before and after 12 weeks FZ treatment defined the FZ-response signature. Gene Set Variation Analysis (GSVA) was used to produce enrichment scores (ES) of AD and FZ-response signatures in the U-BIOPRED asthma cohort. RESULTS The AD disease signature (112 up-regulated genes) encompassing inflammatory, T-cell, Th2 and Th17/Th22 pathways was enriched in the blood and sputum of asthmatics with increasing severity. Asthmatics with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (p<0.05). The FZ-response signature (296 down-regulated genes) was enriched in asthmatic blood (p<0.05) and particularly in neutrophilic and mixed granulocytic sputum (p<0.05). These data were confirmed in sputum of the ADEPT (Airway Disease Endotyping for Personalized Therapeutics) cohort. IL-22 mRNA across tissues did not correlate with FZ-response ES, but this response signature correlated with Th22/IL-22 pathways. CONCLUSIONS The FZ-response signature in AD identifies severe neutrophilic asthmatics as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases

Association of differential mast cell activation with granulocytic inflammation in severe asthma

Rationale: mast cells (MCs) play a role in inflammation and both innate and adaptive immunity, but their involvement in severe asthma (SA) remains undefined. Objectives: we investigated the phenotypic characteristics of the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) asthma cohort by applying published MC activation signatures to the sputum cell transcriptome. Methods: eighty-four participants with SA, 20 with mild/moderate asthma (MMA), and 16 healthy participants without asthma were studied. We calculated enrichment scores (ESs) for nine MC activation signatures by asthma severity, sputum granulocyte status, and three previously defined sputum molecular phenotypes or transcriptome-associated clusters (TACs) 1, 2, and 3 using gene set variation analysis. Measurements and Main Results: MC signatures except unstimulated, repeated FceR1-stimulated and IFN-g–stimulated signatures were enriched in SA. A FceR1-IgE–stimulated and a single-cell signature from asthmatic bronchial biopsies were highly enriched in eosinophilic asthma and in the TAC1 molecular phenotype. Subjects with a high ES for these signatures had elevated sputum amounts of similar genes and pathways. IL-33– and LPS-stimulated MC signatures had greater ES in neutrophilic and mixed granulocytic asthma and in the TAC2 molecular phenotype. These subjects exhibited neutrophil, NF-kB (nuclear factor-kB), and IL-1b/TNF-a (tumor necrosis factor-a) pathway activation. The IFN-g–stimulated signature had the greatest ES in TAC2 and TAC3 that was associated with responses to viral infection. Similar results were obtained in an independent ADEPT (Airway Disease Endotyping for Personalized Therapeutics) asthma cohort. Conclusions: gene signatures of MC activation allow the detection of SA phenotypes and indicate that MCs can be induced to take on distinct transcriptional phenotypes associated with specific clinical phenotypes. IL-33–stimulated MC signature was associated with severe neutrophilic asthma, whereas IgE-activated MC was associated with an eosinophilic phenotype.</p