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The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessively inherited disease that has undergone extensive phenotypic expansion since being first described in patients with fevers, recurrent strokes, livedo racemosa, and polyarteritis nodosa in 2014. It is now recognized that patients may develop multisystem disease that spans multiple medical subspecialties. Here, we describe the findings from a large single center longitudinal cohort of 60 patients, the broad phenotypic presentation, as well as highlight the cohort's experience with hematopoietic cell transplantation and COVID-19. Disease manifestations could be separated into three major phenotypes: inflammatory/vascular, immune dysregulatory, and hematologic, however, most patients presented with significant overlap between these three phenotype groups. The cardinal features of the inflammatory/vascular group included cutaneous manifestations and stroke. Evidence of immune dysregulation was commonly observed, including hypogammaglobulinemia, absent to low class-switched memory B cells, and inadequate response to vaccination. Despite these findings, infectious complications were exceedingly rare in this cohort. Hematologic findings including pure red cell aplasia (PRCA), immune-mediated neutropenia, and pancytopenia were observed in half of patients. We significantly extended our experience using anti-TNF agents, with no strokes observed in 2026 patient months on TNF inhibitors. Meanwhile, hematologic and immune features had a more varied response to anti-TNF therapy. Six patients received a total of 10 allogeneic hematopoietic cell transplant (HCT) procedures, with secondary graft failure necessitating repeat HCTs in three patients, as well as unplanned donor cell infusions to avoid graft rejection. All transplanted patients had been on anti-TNF agents prior to HCT and received varying degrees of reduced-intensity or non-myeloablative conditioning. All transplanted patients are still alive and have discontinued anti-TNF therapy. The long-term follow up afforded by this large single-center study underscores the clinical heterogeneity of DADA2 and the potential for phenotypes to evolve in any individual patient.
Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS
(2021)
BACKGROUND
Biallelic loss-of-function variants in NCF1 lead to reactive oxygen species deficiency and chronic granulomatous disease (CGD). Heterozygosity for the p.Arg90His variant in NCF1 has been associated with susceptibility to systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome in adult patients. This study demonstrates the association of the homozygous p.Arg90His variant with interferonopathy with features of autoinflammation and autoimmunity in a pediatric patient.
CASE PRESENTATION
A 5-year old female of Indian ancestry with early-onset recurrent fever and headache, and persistently elevated antinuclear, anti-Ro, and anti-La antibodies was found to carry the homozygous p.Arg90His variant in NCF1 through exome sequencing. Her unaffected parents and three other siblings were carriers for the mutant allele. Because the presence of two NCF1 pseudogenes, this variant was confirmed by independent genotyping methods. Her intracellular neutrophil oxidative burst and NCF1 expression levels were normal, and no clinical features of CGD were apparent. Gene expression analysis in peripheral blood detected an interferon gene expression signature, which was further supported by cytokine analyses of supernatants of cultured patient's cells. These findings suggested that her inflammatory disease is at least in part mediated by type I interferons. While her fever episodes responded well to systemic steroids, treatment with the JAK inhibitor tofacitinib resulted in decreased serum ferritin levels and reduced frequency of fevers.
CONCLUSION
Homozygosity for p.Arg90His in NCF1 should be considered contributory in young patients with an atypical systemic inflammatory antecedent phenotype that may evolve into autoimmunity later in life. The complex genomic organization of NCF1 poses a difficulty for high-throughput genotyping techniques and variants in this gene should be carefully evaluated when using the next generation and Sanger sequencing technologies. The p.Arg90His variant is found at a variable allele frequency in different populations, and is higher in people of South East Asian ancestry. In complex genetic diseases such as SLE, other rare and common susceptibility alleles might be necessary for the full disease expressivity.
Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage-sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi-faceted complications due to haploinsufficiency of BPTF.
This article provides insights into the modalities of business-model change and innovation. On the basis of an analysis of empirical data of small and medium enterprises, a transition from wine production centrism to its expanded use in hospitality and tourism is explored. Previous research on wine tourism and hospitality predominantly focuses on a destination perspective, neglecting the organizational winery perspective. The article deploys a mixed methods approach, combining netnography and a content analysis for data collection with grounded research and clustering for theory building. The sample size included 885 German wineries. Data stemmed from two distinct sources (websites and a secondary publication in form of a wine guide) and has been analyzed through a two-step clustering algorithm as well as a Principal Component Analysis (PCA). The two-step clustering algorithm resulted in nine different business models while the PCA analysis grouped the variables into the following two categories: basic winery business model (BM) and BM extension into hospitality and tourism, thereby validating the difference between the two constructs. The results point to the diverse nature of business model extensions of wineries in tourism and hospitality, depending on their organizational type and size. This study offers a classification of small and medium sized enterprise’s strategic business model expansion, and explores the expansion of the wine industry through wine hospitality and tourism services, starting with the winery organizational perspective, which has not been done before.
The purpose of this paper is to examine the impact that various types of business model extensions (hospitality and tourism, online sales platforms, and sustainability) have on the winery business. The research is based on company data and online observations of N = 886 German wineries and deploys a content analysis, netnography, and structural equation modeling (SEM) in order to test the hypothesis on business model extensions of wineries, which have been set forth in the previous literature. The findings indicate that business model extensions related to online sales platforms have a positive impact on winery business size. These results mean that developing online sales platforms enlarges the winery BM (business model) size and type (manager-run, state-owned, or cooperatives). The paper presents in detail the impact of winery BM extensions on winery BM model type and size, thereby contributing to the literature on business model innovation.
This study set out to uncover brand positioning configurations by presenting state-of-the-art brand management literature and applying a novel, mixed-methods approach to examine the under-researched wine industry transformation towards open innovation in branding. German winery brands were analyzed using a multimethod approach leaning on a novel netnographic methodology and multiple sources. The sample included 572 wineries from all 13 German wine regions with website text data and online review text data from each winery. The study identified nine prime words used to describe both brand identity as well as wine brand image. It revealed word–price clusters of brand identity and image. The results offer insights into communication and pricing opportunities for wine brand identity as well as image, thereby contributing to open brand innovation.
The article improves understanding on leveraging new technology for DT (digital transformation) of grape harvest in SME wineries. It provides evidence on technologies used and workplace types deployed in grape harvesting, as well as strategic paths in deploying new technology, thereby contributing to the literature on networked sensing and seizing capabilities in the wine industry 4.0. The research approach is explorative and qualitative drawing on 31 interviews with wine industry 4.0 experts and managers, mostly owners of SMEs: wineries, wine software and wine machinery enterprises. Resulting findings serve as a roadmap for digital transformation of grape harvest process in SME wineries explaining technologies and work roles necessary for DWT (digital workplace transformation), as well as strategic paths of deployment of novel grape harvest technology. Previous research on the wine industry 4.0 has focused on BMI, while this research expands the focus to include a wider concept of technology adoption strategy as well as DWT. The research identifies two types of factors impacting the strategic deployment of grape harvest technology: pull factors, also termed servitization factors, as well as push factors, termed also digital transformation factors.
The purpose of this study is to research the antecedents of the sustainable travel decision-making of European travelers and thereby identify important lessons for the transition towards sustainable travel and tourism. The study is based on data collected through a representative survey, conducted in five European countries, with a sample of n = 5024 respondents. The results of descriptive statistics, EFA (Exploratory Factor Analysis) and FA (Factor Analysis) are presented in order to explore sustainable travel decision-making through environmental (policy-related and personal) attitudes and travel mode decision priorities in the European context. Furthermore, the study provides new evidence regarding the under-researched phenomenon of the attitude–behavior gap by presenting a model for the sustainability-oriented decision-making of travelers, including attitudes and travel mode priorities as antecedents. The results confirm the existence of moral licensing in travel decision-making, thereby extending the relevance of this theory into travel and tourism, which has not been done before. The denial of environmental issues is also being researched as regards its interaction with positive environmental attitudes, environmental travel mode priorities and non-environmental travel priorities, thereby advancing our understanding of the interplay between these categories. The interplay between the four categories furthers our understanding of the perplexity of travelers in terms of sustainable travel decision-making.
The reported research examines the impact of product portfolio labeling strategies on brand reputation and equity. A netnographic approach allowed to observe winery portfolio labeling approaches and create a typology of winery labeling strategies. Expert evaluation served to assess the dependent variable brand equity by deploying a regression analysis. For the observed wine industry, being part of the food industry, creating consistent and recognizable brands has a direct relevance for reducing (sustainability-related) food information overload and thereby building sustainable brand equity. The results uncover the relative importance of each of the six identified labeling strategies as well as their impact on reputation and brand equity creation. The results point to the need to establish a consistent, strategically founded product communication. Such an approach, with a positive effect on reputation building can serve to build sustainable brand equity. “Stuck in the middle”-type strategies apparently diminish winery brand equity exploitation. The findings contribute to the knowledge on food labels in product communication strategies and their impact on organizational brand equity, thereby having high relevance for the implementation of environmental certification initiatives in an organizational context. The article deploys a novel research approach in an under-researched area to provide new insights for further research as well as implications for practice.
The article explores SME (Small and Medium Sized Enterprises) brand strategies as a means to position and successfully engage in competitive markets. A derived typology of brand strategy types deals with social profiling and sheds light on brand strategy internalization of two current managerial paradigms—sustainability and co-creation. N = 895 German SME wineries were examined, leaning on a netnographic analysis of predominantly websites and social media interactions. A two-step clustering method thereby identified eight winery SME brand strategy types. The importance of sustainability across the identified eight brand strategy types is significant. Co-creation turned out to be a key profiling trait characterizing one brand strategy type. The typology illustrates strategic richness, with brand strategies leaning predominantly on traditional values, on sustainability, on external reputation, or on more innovative customer centric concepts such as co-creation. Hereby, the typology and the identified brand levers invite to strategically design brand management, governance, and sustainability. Wineries which focus on traditional positioning and legitimacy were found to be cautious in deploying co-creation through social media. Winery brands that are characterized by engagement in digital co-creation apparently either tend to expand their scope or partially combine it with traditional values, making them the most diverse type identified. Sustainability obviously needs to be addressed by all brand strategies. Despite industry and country focus, the analyses illustrate the relevance of socially-oriented profiling and highlights that sustainability has reached a status of a fundamental business approach still allowing to differentiate thereon. Furthermore, the business models of the SMEs need to deliver communicated values.
‚Making Media‘
(2021)
Die Kommunikation der Gegenwart ist dominant digital geleitet. Die Benutzung der Zeichen ist hier an mediale Artefakte gebunden, denen dabei das Kriterium des Mikroformatischen sowohl im Hinblick auf ihre Objektivationen als auch in Hinsicht auf ihre Inhalte zukommt. Der Beitrag nimmt diese Beobachtung zum Ausgang, um am Beispiel von WhatsApp eine Kommunikationspraktik medienästhetisch zu betrachten, die ihrerseits vehement die Gegenwärtigkeit der Kommunikation bestimmt.
The aim of this study was to investigate employees’ self-reported creativity before and after vacation and to examine the impact of recovery experiences (detachment, relaxation, mastery, meaning, autonomy, affiliation) on changes in creativity. The DRAMMA model of Newman et al. provides the theoretical background of our approach. Longitudinal data was assessed with four repeated measurements. The study encompassed data from 274 white-collar workers. Analyses showed that employees subjectively perceive their creativity to benefit not immediately after their vacation but 2 weeks later. Detachment was significantly related to lower creativity within persons, while mastery experiences explained differences in creativity between persons. This study provides a detailed picture of changes in creativity around vacations.
In this study, we investigate the thermo-mechanical relaxation and crystallization behavior of polyethylene using mesoscale molecular dynamics simulations. Our models specifically mimic constraints that occur in real-life polymer processing: After strong uniaxial stretching of the melt, we quench and release the polymer chains at different loading conditions. These conditions allow for free or hindered shrinkage, respectively. We present the shrinkage and swelling behavior as well as the crystallization kinetics over up to 600 ns simulation time. We are able to precisely evaluate how the interplay of chain length, temperature, local entanglements and orientation of chain segments influences crystallization and relaxation behavior. From our models, we determine the temperature dependent crystallization rate of polyethylene, including crystallization onset temperature.
Introduction: Chronic pain is a frequent severe disease and often associated with anxiety, depression, insomnia, disability, and reduced quality of life. This maladaptive condition is further characterized by sensory loss, hyperalgesia, and allodynia. Blue light has been hypothesized to modulate sensory neurons and thereby influence nociception.
Objectives: Here, we compared the effects of blue light vs red light and thermal control on pain sensation in a human experimental pain model.
Methods: Pain, hyperalgesia, and allodynia were induced in 30 healthy volunteers through high-density transcutaneous electrical stimulation. Subsequently, blue light, red light, or thermal control treatment was applied in a cross-over design. The nonvisual effects of the respective light treatments were examined using a well-established quantitative sensory testing protocol. Somatosensory parameters as well as pain intensity and quality were scored.
Results: Blue light substantially reduced spontaneous pain as assessed by numeric rating scale pain scoring. Similarly, pain quality was significantly altered as assessed by the German counterpart of the McGill Pain Questionnaire. Furthermore, blue light showed antihyperalgesic, antiallodynic, and antihypesthesic effects in contrast to red light or thermal control treatment.
Conclusion: Blue-light phototherapy ameliorates pain intensity and quality in a human experimental pain model and reveals antihyperalgesic, antiallodynic, and antihypesthesic effects. Therefore, blue-light phototherapy may be a novel approach to treat pain in multiple conditions.