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Abstract Background Hereditary anemias are a group of genetic diseases prevalent worldwide and pose a significant health burden on patients and societies. The clinical phenotype of hereditary anemias varies from compensated hemolysis to life-threatening anemia. They can be roughly categorized into three broad categories: hemoglobinopathies, membranopathies, and enzymopathies. Traditional therapeutic approaches like blood transfusions, iron chelation, and splenectomy are witnessing a paradigm shift with the advent of targeted treatments. However, access to these treatments remains limited due to lacking or imprecise diagnoses. The primary objective of the study is to establish accurate diagnoses for patients with hereditary anemias, enabling optimal management. As a secondary objective, the study aims to enhance our diagnostic capabilities. Results The DAHEAN study is a nationwide cohort study that collects advanced phenotypic and genotypic data from patients suspected of having hereditary anemias from all pediatric and hematological departments in Denmark. The study deliberates monthly by a multidisciplinary anemia board involving experts from across Denmark. So far, fifty-seven patients have been thoroughly evaluated, and several have been given diagnoses not before seen in Denmark. Conclusions The DAHEAN study and infrastructure harness recent advancements in diagnostic tools to offer precise diagnoses and improved management strategies for patients with hereditary anemias.

BackgroundThis study examines the humoral and cellular response in multiple sclerosis (MS) patients on anti-CD20 therapy before and after the 1st to 4th BNT162b2 mRNA SARS-CoV-2 vaccination and the relationship with breakthrough infection.MethodsParticipants with McDonald 2017 MS that were treated with ocrelizumab were included. The study duration was throughout the COVID-19 pandemic until four months after fourth mRNA SARS-CoV-2 vaccination (BNT162b2). Longitudinal blood samples were analysed for: IgG antibodies of SARS-CoV-2 spike anti-receptor binding domain (anti-RBD), nucleocapsid IgG antibodies (anti-N) and activation induced marker expressing CD4+, CD8+ T-cells and concentration of ocrelizumab and anti-drug antibodies. Incidences of breakthrough infection were confirmed with SARS-CoV-2 PCR tests.ResultsThe rate of anti-RBD positive participants increased substantially between the third and fourth vaccination from 22.2% to 55.9% (median 54.7 BAU/mL; IQR: 14.5 – 221.2 BAU/mL and 607.7 BAU/mL; IQR: 29.4 – 784.6 BAU/mL, respectively). Within the same period 75% of participants experienced breakthrough infection. The fourth vaccination resulted in an additional increase in seropositive individuals (64.3%) (median 541.8 BAU/mL (IQR: 19.1-1007 BAU/mL). Breakthrough infection did not influence the cellular response without a significant change after the fourth vaccination. During the study period two participants had detectable anti-N, both after the fourth vaccination. No correlation was found between serum concentration of ocrelizumab and the humoral and cellular response.DiscussionLow levels or absence of specific anti-RBD following vaccination, with a significant increase after breakthrough infections and boosted by the fourth vaccination. T-cell reactivity remained sustained and unaffected by breakthrough infections.

In this interview-based article, Professor Christian Nielsen summons two of the latest decades’ biggest management thinkers, the two inventors of the Business Model Canvas, Alex Osterwalder and Yves Pigneur, for a conversation about the current challenges for companies in doing business model innovation. According to Alex and Yves, companies face two major challenges. First, companies have inadequate governance structures for allowing innovators to do decent work, and second, the old guard knows jack shit about innovation. Unfortunately, it is precisely the old guard sitting with the management reigns at this time. Our conversation identifies three enablers to help overcome these challenges. First, the enabler is about ensuring leadership commitment and allocating management time to innovation. The second enabler is the ability to kill ideas. This is important, because every company needs to focus its innovation efforts, besides ensuring that budgets and resources are channeled in the most fruitful directions. The third enabler is building an innovation culture that coexists with an exploitation culture and where innovators can thrive. In successful companies, innovators are not pirates; they are highly esteemed contributors to corporate success. Finally, we get a sneak peek at their current work focus.

Abstract Background Patients with the rare disease; Hereditary haemorrhagic telangiectasia (HHT) often bleed from telangiectatic lesions in mucosal surfaces. Studies suggest that impaired platelet function may also play a role in their bleeding tendency. The aim of the present study was to investigate whether HHT-patients with epistaxis have impaired platelet function. Method We conducted a case–control study based on a sample size calculation and included 22 HHT-patients (inclusion criteria: epistaxis severity score ≥ 4, no intake of medicine affecting platelet function the last 5 days, HHT-type 1 or 2, age ≥ 18 years) and 20 controls. We assessed the platelet function with standard haemostasis parameters, flow cytometry (platelet function and micro aggregation), rotational thromboelastometry and Platelet Function Analyzer 200. Results We found no significant difference in mean platelet volume and immature platelet fraction and no difference in platelet activation as measured by exposure of CD62P, CD63P and PAC1 binding. Nor did we find a significant difference in platelet aggregation response in HHT-patients compared with the control group for all agonists (thrombin receptor activating peptide, adenosine diphosphate and collagen-related peptide). The PFA-200 analysis was without difference between the two groups and thromboelastometry showed no impairment of global haemostasis. Conclusion Reduced platelet function is unlikely to contribute to the frequent and long bleeding episodes that HHT-patients suffer from. We propose that further studies should focus on whether patients with HHT have hypercoagulability.

Objective: Shared decision making (SDM) and use of patient decision aids (PtDAs) are key components in patient-centered care in relapsed ovarian cancer. This paper describes the development and implementation process of PtDAs into a clinical routine in three departments. Methods: Two PtDAs were developed in collaboration between patients and clinicians. Acceptability and usability of the PtDAs were tested on clinicians and patients using items from the internationally validated questionnaire “Preparation for Decision Making Scale”. Results: Ten patients and 15 clinicians participated in the study. Most patients indicated that PtDAs would be helpful as preparation for the decision-making process with the clinicians. Ten (75%) of the clinicians responded that the PtDAs helped the patients to understand the benefits and disadvantages of each treatment option. Generally, the clinicians indicated that they would use SDM if they had a PtDA tailored to the clinical situation. Conclusions: Two PtDAs were systematically developed, tested, and implemented thereby supporting an SDM intervention. The PtDAs are still in use at the participating departments. Innovation: This study was successful in reusing a generic template for a patient decision aid (PtDA) developed at one institution and implemented in two other institutions. This was guided by a well-described systematic development process for PtDAs.

This article proposes a conceptual framework for analysing future business model innovation scenarios. It also introduces the special issue “The Future of Business Model Innovation: Core Themes and Pivotal Technologies.” Drawing on existing knowledge, the article identifies two key dimensions that will shape the boundaries and directions of business model innovation in the near to mid-term future. Thus, this article frames the contributions of the special issue to provide a starting point for academics and practitioners seeking to engage in the field.

The area of interest is future business model innovation in Society 5.0. This is important as the transition from Society 4.0 to Society 5.0 is happening at an exponential pace driven by the Metaverse. Thus, the research question is: how should companies think and do business model innovation in the Society 5.0 / Metaverse space? The method is conceptual, where the business model characteristics of Society 1.0 to 4.0 are empirically stated for inductive arguments for equivalent characteristics of Society 5.0. This is framed with Society 5.0 theory, Metaverse theory, and Osterwalder and Pigneur’s nine business model building blocks from their iconic Business Model Canvas (BMC). The contribution is a framework cross-tabulating Society 1.0 to Society 5.0 with the nine BMC elements. Finally, a discussion is provided with findings and implications for managers regarding business model innovation, new businesses, outcome logic, ecospheres, and currencies.

FOREWORD TO THE JOURNAL OF BUSINESS MODELS SPECIAL ISSUE

Business regulation is the norms, standards, principles and rules, and their enforcement governs commerce. Firms need to be aware of the potential impacts of regulation on their business models, anticipate changes in the regulatory landscape, and adapt their business models accordingly. This article surveys seven archetypes of regulation and, from that, identifies six key regulatory trajectories affecting business model innovation. The article offers a 2-by-2 model to assist managers in coping with business model innovation reactions to both negative and positive regulatory effects.

Digital transformation is the process that a company must undertake to connect its operational model with all stakeholders to respond to ongoing market effective changes in technological trends and to create the conditions for anticipating future trends. This article introduces and explains the digital transformation canvas’s components and tools, intending to provide a starting point for developing a digital transformation strategy and a plan of action to achieve this.

Objective: Patients with relapsed ovarian cancer are offered multiple treatment options. To match treatment with the individual patient's life situation and preferences, healthcare professionals can apply shared decision making (SDM) including patient decision aids (PtDAs).This study aimed to evaluate the implementation of two different PtDAs in consultations with patients suffering from relapsed ovarian cancer. Methods: We analyzed the following data before and after implementation of the PtDAs: 1) observed SDM using the OPTION instrument, 2) physician treatment recommendations, and 3) patients' and physicians' evaluations of SDM in consultations using the CollaboRATE, SDM-Q-9, and SDM-Q-Doc. Results: Significant improvement in observed SDM was found after the implementation (p = 0.002). Improvement of SDM was detected in consultations conducted by physicians reporting more than two hours of SDM-training (p < 0.001), but not when physicians reported less than two hours of SDM-training.No before/after differences in treatment recommendations and in patients' and physicians' evaluations were found. Conclusion: Implementation of PtDAs improved the level of observed SDM. Training of physicians in SDM is necessary for improved SDM practice. Innovation: Discussing oncological treatment options with the use of PtDAs is not standard practice in Denmark. The present study is one of the first Danish studies focusing on how to implement SDM and PtDAs in oncological consultations.

Abstract Introduction Immunoglobulin G subclass measurements are important for the diagnostic work‐up of immunodeficiencies and immunoglobulin G4 (IgG4) related diseases. It is currently unknown whether a single sampling is truly representative for an individual's IgG subclass concentrations. This study aimed to investigate whether IgG and IgG subclass concentrations in healthy individuals are stable over time. Method With a span of median 42 weeks, four samples from each of 54 (34M, 20F) healthy adult volunteers (24–66 years) were analyzed for IgG and IgG1–4 using turbidimetry. Concentrations were compared within and between individuals. Results IgG and IgG subclass concentrations followed either a normal (IgG, IgG1, and IgG3) or log normal (IgG2 and IgG4) distribution. Immunoglobulin 4 demonstrated by far the widest range of concentrations between individuals (670‐fold: 0.004–2.68 g/L). Immunoglobulin G subclass variations within individuals were expressed as pooled standard deviations (PSD). These ranged from 0.056 (IgG4) to 0.955 g/L (IgG) and correlated with mean concentration of IgG or the particular IgG subclass. As a consequence, the relative PSDs (i.e., PSD divided by mean IgG or IgG subclass concentration) fell within a narrow range: 5.82%–10.1%. Based on these numbers, the 95%‐upper one‐sided confidence limits for intraindividual IgG and IgG subclass variation was calculated to range from 9.82% (IgG2) to 16.9% (IgG4). Conclusion The study documents that IgG or IgG subclass concentrations within healthy individuals are very stable over at least 42 weeks. The expected variation for IgG4 concentrations at a 95% confidence level does not exceed ±16.9%.

The absence of people (employees) from the business model literature is at odds with their pivotal contribution to the value creation, delivery and capture process. As a resource that management is continually challenged to grow, their success in doing so has been identified as an outcome falling within the scope of Integrated Reporting, an approach currently touted as the new corporate reporting. This short paper suggests a number of employee attributes that might be documented in such reports.

Reducing the treatment duration for chronic hepatitis C could be an important tool in the effort to reach the elimination goals set by the World Health Organization. The current challenge is to predict the target group who will achieve sustained virological response at week 12 (SVR12) with shorter treatment duration. The aim of this exploratory study was to characterize immune subsets with focus on inhibitory receptors in patients who experienced SVR12 or virological relapse following four weeks treatment with glecaprevir/pibrentasvir with or without ribavirin. A total of 32 patients were included in this study of whom 21 achieved SVR12 and 11 had virological relapse. All available samples at baseline (n = 31) and end of treatment (EOT) (n = 30) were processed for flow cytometric analysis in order to measure the expression of PD-1, 2B4, BY55, CTLA-4, TIM-3 and LAG-3 on 12 distinct T cell subsets. At baseline, patients with SVR12 (n=21) had numerically lower frequencies of inhibitory receptors for 83% (60/72) of the investigated T-cell subtypes. The most significant difference observed between the two groups was a lower frequency of stem cell-like memory T-cells CD4+PD1+ in the SVR group (p = 0.007). Furthermore, we observed a significant positive correlation between baseline viral load and the expression of PD-1 on the total CD8+ T-cells and effector memory T-cells CD4+ and CD8+ for patients with virological relapse. This study suggests a measurable immunologic phenotype at baseline of patients achieving SVR12 after short treatment compared to patients with virological relapse.

Several antirheumatic drugs lower the cardiovascular risk among rheumatoid arthritis patients. It is, however, unknown whether inhibition of platelet function contributes to this risk reduction. Only few studies have investigated the potential role of platelets as a target of antirheumatic drugs. In this study, platelet function was tested in vitro in samples from 24 healthy individuals spiked with antirheumatic drugs in clinically relevant concentrations or vehicle. Platelet aggregation was tested with 96-well light transmission aggregometry (LTA), and when an effect ≥20% compared to vehicle was observed, flow cytometric platelet aggregation and activation were evaluated and closure time was measured by Platelet Function Analyzer (PFA-200). When evaluated by LTA, teriflunomide (the active metabolite of leflunomide), tocilizumab, and prednisolone reduced ADP- and collagen-induced platelet aggregation ≥20%, while adalimumab increased TRAP-induced platelet aggregation ≥20%. Using flow cytometry, agonist-induced platelet aggregation with teriflunomide or vehicle was mean ± standard deviation (SD); 30.7% ± 5.8 vs. 41.7% ± 6.5, p = 0.02 using ADP, and 34.7% ± 13.9 vs. 55.8% ± 3.9, p = 0.01 using collagen. Results indicate that teriflunomide, prednisolone, and tocilizumab inhibit, and adalimumab increases platelet aggregation. The study suggests that the majority of antirheumatic drugs mainly reduced cardiovascular risk through indirect effects (e.g., reducing inflammation).

Abstract This case suggests a mechanistic rationale for the clinical efficacy of intravenous immunoglobulins (IVIG) in treating CD40 ligand (CD40L) deficiency associated neutropenia as it is the first reported instance of free and cell‐bound antineutrophil antibodies in a case of CD40L deficiency, accompanied by a prolonged and clinically severe neutropenia.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has become a treatment option for fit patients with mantle cell lymphoma (MCL). However, these patients often relapse within few years, potentially caused by contaminating lymphoma cells within the reinfused stem cell product (SCP). Studies have shown that measurable residual disease, also termed minimal residual disease (MRD), following ASCT predicts shorter survival. Using next-generation sequencing, we explore whether the diagnostic MCL clonotype is present within the infused SCP. MRD was detected in 4/17 of the SCPs, ranging 4–568 clonal cells/100,000 cells. With a median survival of 17 months, 3/4 of patients with MRD+ graft succumbed from MCL relapse versus 2/13 in the MRD– fraction. Patients receiving MRD+ grafts had increased risk of mortality, and thus screening of SCPs may be important for clinical decision-making.

Purpose: We illustrate how cross-disciplinarity in business model research (multi-, inter- and transdisciplinarity) can help scholars overcome silo-building and span disciplinary boundaries. The seven articles contained in the special issue ‘Fostering Cross-Disciplinarity in Business Model Research’ are summarised, and the authors’ perspectives on the phenomena studied as well as the theories and methods adopted are portrayed. Methodology: We provide literature-based definitions of cross-disciplinary research modes and discuss their potential for business model research informed by insights from the seven special issue articles. Findings: There is much variety regarding the theories applied in business model research. These include design, imprinting, information asymmetry, paradox theories and many more. This variety illustrates that traditional domains, such as organisation, management and entrepreneurship studies, can be extended in creative ways, and hence can be equipped to deal with emerging and complex issues such as sustainability, circular economy, data management and base-of-thepyramid entrepreneurship. Interdisciplinarity seems to be well developed regarding the use of theories, but more must follow in terms of research methods and collaboration formats. Research Implications and Limitations: The common understanding of the potential and importance of cross-disciplinarity can be considered the major implication of this special issue. Beyond this, further critical reflection is required. Important questions remain open, primarily regarding research methods and collaboration formats. This editorial article reflects the perspectives of both the guest editors and the authors in this special issue. The presented understandings of cross-disciplinary business model research and implications for its future are of a preliminary nature. Originality and Value: Business model research is growing rapidly and scholars from various fields contribute to expanding our knowledge. An explicit focus on the potential of multi-, inter- and transdisciplinary research approaches is missing so far.

Abstract Background Atypical hemolytic uremic syndrome (aHUS) is a disorder of the microvasculature with hemolytic anemia, thrombocytopenia and acute kidney injury. Nowadays, aHUS is successfully treated with eculizumab, a humanized, chimeric IgG2/4 kappa antibody, which binds human complement C5 and blocks generation of C5a and membrane-attack-complex. Case presentation A 25-year-old woman with end stage renal disease due to relapsing atypical hemolytic uremic syndrome had a relapse of the disease during pregnancy. She was treated with eculizumab. We measured reduced formation of the membrane-attack complex in newborn’s umbilical cord vein blood using the sensitive and specific Palarasah-Nielsen-ELISA. Conclusions Eculizumab treatment of the mother with end stage renal disease may cause reduced innate immunity which could render newborns more susceptible to infections.

Background: Pneumococcal prime-boost vaccination is recommended for solid organ transplant recipients and candidates. The long-term durability of the antibody (AB) response is unknown. The same applies to a dose-dependent immune response. Methods: We studied the durability of the vaccine response after 18 months in kidney transplant recipients (KTRs) and patients on the kidney transplant waiting list (WLPs). Both groups received either a normal dose (ND) or a double dose (DD) of the 13-valent pneumococcal conjugate vaccine and the 23-valent pneumococcal polysaccharide vaccine. The average pneumococcal AB geometric mean concentration (GMC) was evaluated. A level ≥ 1 mg/L was considered protective against invasive pneumococcal disease (IPD). Results: Sixty WLPs and 70 KTRs were included. The proportion of participants protected declined from 52% to 33% in WLPs and from 29% to 16% in KTRs, with the previously significant dose-effect in WLPs no longer present (40% DD vs. 27% ND; p = 0.273). Average pneumococcal AB GMCs remained significantly above baseline levels (all groups p ≤ 0.001). Drug-induced immunosuppression diminished the vaccine dose-effect. Conclusions: At follow-up, the pneumococcal prime-boost vaccination still provided significantly elevated average pneumococcal AB GMCs in both populations. Though the proportion of participants protected against IPD in WLP-DD and WLP-ND were statistically comparable, a DD may still be recommended for WLPs (EudraCT: 2016-004123-23).

Objectives To correlate the level of fibrocytes in peripheral blood, synovial tissue and in vitro culture in rheumatoid arthritis (RA) with changes in disease activity, imaging and pulmonary function.Methods Twenty patients with early RA (ERA) and 20 patients with long-standing RA (LRA) were enrolled in a 6-month prospective study. Sixteen patients undergoing wrist arthroscopy were healthy controls. Patients with RA underwent pulmonary function tests, ultrasound and synovial ultrasound-guided needle biopsy of the same wrist at baseline and 6 months. Wrist MRI was performed at baseline (all) and 6 months (ERA). Circulating fibrocytes were measured by flow cytometry, in vitro by the number of monocytes that were differentiated to fibrocytes and in synovial biopsies by counting in histological sections.Results Fibrocytes were primarily located around vessels and in the subintimal area in the synovium. Fibrocyte levels did not decline during the trial despite effective RA treatment. In the ERA group, increased synovitis assessed by ultrasound was moderate and strongly correlated with an increase in circulating and synovial fibrocyte levels, respectively. Increased synovitis assessed by MRI during the trial in the ERA group was moderately correlated with both increased numbers of circulating and cultured fibrocytes. Absolute diffusion capacity level was overall weakly negatively correlated with the level of circulating and synovial fibrocytes. The decline in diffusion capacity during the trial was moderately correlated with increased levels of synovial fibrocytes.Conclusion Our findings suggest that fibrocytes are involved in RA pathogenesis, both in the synovium and the reduction in lung function seen in a part of patients with RA.Trial registration number NCT02652299.

The aim of this work is to investigate the alignment of preparers’ and users’ perceptions of the BM and its constitutive elements. Results show that, while both categories assign great importance to this concept, different conceptions of the purpose and the components of a BM emerge.

It is not only new trends and technologies that are currently disrupting and changing the way we do and think business. Global geopolitical stability is deteriorating, leading to rising uncertainty for international trade. Climate change is fostering the need for inclusiveness in business and for an increase in sustainability to the zero-impact level. In addition, we face exogenous shocks such as the COVID-19 pandemic. Although none of these factors are unforeseen, their magnitude and recurrence have provided a platform for a massive refocusing of business and research priorities since the beginning of 2020. Therefore, the fifth stage of business model research will be known as “the role of business models in times of uncertainty”. In this paper we discuss the role of business models in times of uncertainty and provide new venues for further research and progression of business models as we know them.

Purpose: We discuss traditional assumptions about value creation and confront these with current views on sustainable value creation (SVC). Against this backdrop, the articles contained in the special issue ‘Sustainable Value Creation Through Business Models’ are introduced, and their contributions to the exploration of SVC are highlighted.* Methodology: Assumptions about value creation are summarised and turned into an initial theoretical framework concerning the what, who and how of value creation. This framework is used to structure and discuss current views on SVC that have been presented in the sustainable business model (SBM) litterature. Findings: The proposed framework identifies cornerstones for theorising about SVC in regard to the what, who and how of value creation. A main finding is that, although value creation and SVC are widely discussed in the literature, there are huge gaps in terms of the who, what and how of value creation, particularly in the SBM field. Research implications and limitations: The major implication is that the SBM discourse still lacks clear SVC concepts, and closing this gap may enable the creation of a new multi- and interdisciplinary research programme. A major limitation of this paper is the mainly theoretical and preliminary nature of the presented discussion and framework. Originality and value: There is a surprising dearth of definitions and concepts of value creation in both the traditional business model and SBM research. The originality and value of this paper lie in its potential to stimulate further research on the theoretical foundations of SVC. Various theoretical propositions are developed, including notions such as stakeholder-responsive and relational interpretations of value creation.

Results from previous studies regarding platelet function in liver cirrhosis are discordant. The aim was to investigate platelet activation and platelet aggregation in patients with alcoholic liver cirrhosis. We included 27 patients with alcoholic liver cirrhosis and 22 healthy individuals. A recently established flow cytometric approach was used to measure platelet activation and platelet aggregation independent of sample platelet count. Platelet aggregation was further investigated using light transmission aggregometry (LTA) (for platelet count >100 × 109/L). Platelet agonists were adenosine diphosphate, thrombin receptor-activating peptide, arachidonic acid, collagen, and collagen-related peptide. Patients had lower median platelet count than healthy individuals, 125 × 109/L (interquartile range [IQR] 90˗185) versus 240 × 109 (IQR 204˗285), p < 0.001. Platelet activation levels in stimulated samples were lower in patients versus healthy individuals, e.g., after collagen-related peptide stimulation, the median percentage of platelets positive for activated glycoprotein IIb/IIIa was 85% (IQR 70–94) in patients versus 97% (IQR 94–99) in healthy individuals, p < 0.001; lower platelet activation capacity being associated with low platelet count and Child–Pugh class B/C cirrhosis. Flow cytometric platelet aggregation was reduced in patients for collagen-related peptide and for adenosine diphosphate, e.g., platelet aggregation (mean ± standard deviation) was 57% ± 4 in patients versus 70% ± 1 in healthy individuals for collagen-related peptide, p = 0.01. Light LTA showed reduced collagen-induced platelet aggregation in some patients compared with healthy individuals. In conclusion, platelet function was reduced in some patients with alcoholic liver cirrhosis and the severity was associated with platelet count and severity of liver cirrhosis.

Abstract Background Understanding what influences people to seek help can inform interventions to promote earlier diagnosis of cancer, and ultimately better cancer survival. We aimed to examine relationships between negative cancer beliefs, recognition of cancer symptoms and how long people think they would take to go to the doctor with possible cancer symptoms (anticipated patient intervals). Methods Telephone interviews of 20,814 individuals (50+) in the United Kingdom, Australia, Canada, Denmark, Norway and Sweden were carried out using the Awareness and Beliefs about Cancer Measure (ABC). ABC included items on cancer beliefs, recognition of cancer symptoms and anticipated time to help-seeking for cough and rectal bleeding. The anticipated time to help-seeking was dichotomised as over one month for persistent cough and over one week for rectal bleeding. Results Not recognising persistent cough/hoarseness and unexplained bleeding as cancer symptoms increased the likelihood of a longer anticipated patient interval for persistent cough (OR = 1.66; 95%CI = 1.47–1.87) and rectal bleeding (OR = 1.90; 95%CI = 1.58–2.30), respectively. Endorsing four or more out of six negative beliefs about cancer increased the likelihood of longer anticipated patient intervals for persistent cough and rectal bleeding (OR = 2.18; 95%CI = 1.71–2.78 and OR = 1.97; 95%CI = 1.51–2.57). Many negative beliefs about cancer moderated the relationship between not recognising unexplained bleeding as a cancer symptom and longer anticipated patient interval for rectal bleeding (p = 0.005). Conclusions Intervention studies should address both negative beliefs about cancer and knowledge of symptoms to optimise the effect.

Abstract Background Interstitial lung disease (ILD) can be a severe extra-articular disease manifestation in Rheumatoid Arthritis (RA). A potential role of fibrocytes in RA associated ILD (RA-ILD) has not previously been described. We present a modified faster method for measuring circulating fibrocytes, without intracellular staining. The results are compared to the traditional culture method, where the number of monocytes that differentiate into mature fibrocytes in vitro are counted. The results are following compared to disease activity in patients with severe asthma, ILD, RA (without diagnosed ILD) and RA with verified ILD (RA-ILD). Method CD45+ CD34+ CD11b+ (7-AAD− CD3− CD19− CD294−) cells were isolated by cell sorting and stained for pro-collagen type 1. Thirty-nine patients (10 RA, 9 ILD and 10 with severe asthma, 10 with RA-ILD) and 10 healthy controls (HC) were included. Current medication, disease activity, pulmonary function test and radiographic data were collected. Circulating fibrocytes were quantified by flow cytometry. Peripheral blood mononuclear cells were isolated and cultured for 5 days and the numbers of mature fibrocytes were counted. Results 90.2% (mean, SD = 1.5%) of the sorted cells were pro-collagen type 1 positive and thereby fulfilled the criteria for being circulating fibrocytes. The ILD and RA-ILD groups had increased levels of circulating fibrocytes compared to HC (p

Abstract Background The International Cancer Benchmarking Partnership aims to study international differences in cancer survival and the possible causes. Participating countries are Australia, Canada, Norway, Sweden, Denmark and the UK and a particular focus area is differences in awareness and beliefs about cancer. In this connection, the Awareness and Beliefs about Cancer (ABC) measure has been translated into multiple languages. The aim of this study is to appraise the translation process and measurement properties of the Danish version of the ABC measure. Methods The translation process included forward and backward translations and a pilot-test. Data quality was assessed using survey data from 3000 Danish respondents and content validity indexes were calculated based on judgments from ten academic researchers. Construct validity was determined by a confirmative factor analysis (CFA) and exploratory factor analyses (EFA) using survey data and a known group comparison analysis including 56 persons. Test-retest reliability was assessed based on responses from 123 person whom completed the interview twice with an interval of 2–3 weeks. Results The translation process resulted in a Danish ABC measure conceptually equivalent to the English ABC measure. Data quality was acceptable in relation to non-response to individual items which was maximum 0.3%, but the percentage of respondents answering ‘don’t know’ was above 3% for 16 out of 48 items. Content validity indexes showed that items adequately reflected and represented the constructs to be measured (item content validity indexes: 0.9–1.0; construct content validity indexes: 0.8–1.0). The hypothesised factor structure could not be replicated by a CFA, but EFA on each individual subscale showed that six out of seven subscales were unidimensional. The ABC measure discriminated well between non-medical academics and medical academics, but had some difficulties in discriminating between educational groups. Test–retest reliability was moderate to substantial for most items. Conclusions The Danish ABC measure is a useful measurement that is accepted and understood by the target group and with accepted measurement criteria for content validity and test-retest reliability. Future studies may further explore the factorial structure of the ABC measure and should focus on improving the response categories.

This chapter applies the lens of emergentism and emergent properties to the understanding of value propositions, value creation, value delivery and value realization. It argues that none of the building blocks typically asserted with business models are of any value without the underlying intellectual capital to apply them and furthers this understanding through a series of case examples. This chapter enhances our understanding of the role of intellectual capital in the value creation of business models and argues that intellectual capital is the foundation of business models.

The adoption of a performative approach promises to enrich research enquiries pursued in the business model field. Such an approach has demonstrated its purchase in other business and management disciplines, including accounting, and has contributed to the wider exploration of social science methodology by their respective research communities.

[This corrects the article DOI: 10.1371/journal.pone.0171723.].

While the business model has become a popular concept in many academic disciplines, it has not been invited into the accounting sphere. A new development, Integrated Reporting, promises to challenge this, but unfortunately its conceptualisation of the concept is flawed. Can the accountancy profession grasp value propositions to customers?

This article provides a research program for the field of business models. It focusses specifically on 4th stage research, which is concerned with the performative notions of business models to which six conceptual avenues for further research are depicted.

Purpose: The purpose of the article is to de ne what scalable business models are. Central to the contemporary understanding of business models is the value proposition towards the customer and the hypotheses generated about delivering value to the customer which become a good foundation for a long-term pro table business. However, the main message of this article is that while providing a good value proposition may help the rm ‘get by’, the really successful businesses of today are those able to reach the sweet-spot of business model scalability. Design/Methodology/Approach: The article is based on a ve-year longitudinal action research project of over 90 companies that participated in the International Center for Innovation project aimed at building 10 global network-based business models. Findings: This article introduces and discusses the term scalability from a company-level perspective. It il- lustrates how managers should be using this term for the bene t of their business by focusing on business models capable of achieving exponentially increasing returns to scale, thus ful lling the objective of making it applicable for business decisions and not merely an abstract economical concept. The article nds ve pat- terns of business model scalability that all companies, regardless of industrial a liation, can use to their advantage. Especially the role of stakeholders in the business model is highlighted in achieving scalability. Research limitations/implications: Limitations relating to qualitative research con ne the generalisation of the ndings. The implication of this research is that achieving scalability is not solely a matter of digitalizing business models. Rather, there are a number of speci c business model con gurations that support scalability and the mechanisms to do this are not merely characterized as digital. Practical implications: This article provides managers with a concrete roadmap for how to work towards busi- ness model scalability including suggested managerial processes and how to facilitate these. Originality/Value: The power of business models lies in their ability to visualize and clarify how rms’ may con gure their value creation processes. Among the key aspects of business model thinking are a focus on what the customer values, how this value is best delivered to the customer and how strategic partners are leveraged in this value creation, delivery and realization exercise. This paper couples these advantages with a structure for identifying scalability, and hence stronger business models.

Opioids are increasingly used for treatment of chronic pain. However, they are only effective in a subset of patients and have multiple side effects. Thus, studies using biomarkers for response are highly warranted. The current study prospectively examined 63 opioid-naïve patients initiating opioid use for diverse types of chronic pain at five European centers. Quantitative sensory testing, electroencephalography (EEG) recordings, and assessment of pain catastrophizing were performed prior to treatment. The co-primary outcomes were change from baseline in ratings of chronic pain and quality of life after 14 days of opioid treatment. Secondary outcomes included patient's global impression of clinical change and side effects. Logistic regression models adjusted for age and sex were used to identify biomarkers predictive for successful treatment, defined as at least a 30% reduction in average pain intensity or an improvement in quality of life of at least 10 scale points. Fifty-nine patients (94%) completed the study. The mean age was 55 ± 16 years and 69% were females. Pain reduction was predicted by cold pain intensity (OR: 0.69; P = 0.01), pain catastrophizing (OR: 0.82; P = 0.03), relative delta (OR: 0.76; P = 0.03) and beta EEG activity (OR: 1.18; P = 0.04) induced by experimental cold pain. None of the study variables were related to improvement in quality of life. For the first time, individual pain processing characteristics have been linked to opioid response in a mixed chronic pain population. This has the potential to personalize treatment of chronic pain and restrict opioid use to patients with high likelihood for response.

One of the hallmarks of Celiac disease (CD) is intraepithelial lymphocytosis in the small intestine. Until now, investigations to characterize the T cell subpopulations within the epithelial layer have not discriminated between the heterodimeric co-receptor molecule, CD8αβ, and the possibly immunoregulatory CD8αα homodimer molecule. Besides TCRαβ+ CD4+ cells, no other phenotypes have been shown to be gluten-reactive. Using flow cytometry on lymphocytes from duodenal biopsies, we determined that the number of B cells (CD3- CD19+) and the number of CD3+ CD4- CD8- double-negative (DN) T cells were elevated 6-7 fold in children with CD. We next isolated and quantified intraepithelial lymphocytes (IELs) from biopsies obtained from patients (both children and adults) with CD, potential CD and non-CD controls. Flow cytometric analysis of the duodenal T cell subpopulations was performed including the markers TCRαβ, TCRγδ, CD4, CD8α and CD8β. Proportions of γδ T cells and CD8αβ+ cells among IELs were increased in CD patients, whereas proportions of CD4+ CD8αα+ and CD4+ single-positive T cells were decreased. Additionally, two gluten-reactive T cell lines (TCLs) derived from CD biopsies were analyzed for changes in proportions of T cell subsets before and after gluten stimulation. In a proliferation assay, dividing cells were tracked with carboxyfluorescein succinimidyl ester (CFSE), and both αβ and γδ T cells proliferated in response to gluten. Changes in duodenal T cell subpopulations in potential CD patients followed the same pattern as for CD patients, but with less pronounced effect.

Objectives: In an explorative epigenome-wide association study (EWAS) to search for gene independent, differentially methylated DNA positions (DMPs) and regions (DMRs) associated with rheumatoid arthritis (RA) by studying monozygotic (MZ) twin pairs discordant for rheumatoid arthritis.Methods: Genomic DNA was isolated from whole blood samples from 28 monozygotic (MZ) twin pairs discordant for RA. DNA methylation was measured using the HumanMethylation450 BeadChips. Smoking, anti-cyclic citrullinated peptide antibodies and immunosuppressive treatment were included as covariates. Pathway analysis was performed using GREAT.Results: Smoking was significantly associated with hypomethylation of a DMR overlapping the promoter region of the RNF5 and the AGPAT1, which are implicated in inflammation and autoimmunity, whereas DMARD treatment induced hypermethylation of the same region. Additionally, the promotor region of both S100A6 and EFCAB4B were hypomethylated and both genes have previously been associated with RA. We replicated several candidate genes identified in a previous EWAS in treatment naïve RA singletons. Gene set analysis indicated the involvement of immunologic signatures and cancer-related pathways in RA.Conclusion: We identified several differentially methylated regions associated with RA which may represent environmental effects or consequences of the disease and plausible biological pathways pertinent to the pathogenesis of rheumatoid arthritis

The presence of unique carbohydrate structures in the glycocalyx/mucous layer of the intestine may be involved in a susceptibility to celiac disease (CD) by serving as attachment sites for bacteria. This host-microbiota interaction may influence the development of CD and possibly other diseases with autoimmune components. We examined duodenal biopsies from a total of 30 children, of which 10 had both celiac disease (CD) and type 1 diabetes (T1D); 10 had CD alone; and 10 were suspected of having gastrointestinal disease, but had normal duodenal histology (non-CD controls). Patients with both CD and T1D were examined before and after remission following a gluten-free diet. We performed lectin histochemistry using peanut agglutinin (PNA) and Ulex europaeus agglutinin (UEA) staining for Gal-β(1,3)-GalNAc and Fucα1-2Gal-R, respectively, of the glycocalyx/mucous layer. The staining was scored based on dissemination of stained structures on a scale from 0 to 3. Evaluation of the scores revealed no difference between biopsies obtained before and after remission in the group of children with both CD and T1D. A comparison of this pre-remission group with the children who had CD alone or the non-CD controls also showed no significant differences. Based on our material, we found no indication that the presence of Gal-β(1,3)-GalNAc or Fucα1-2Gal-R is involved in the susceptibility to CD, or that the disease process affects the expression of these carbohydrates.

Purpose: The paper proposes a research design recipe capable of leading to future business model taxonomies and discusses the potential benefits and implications of achieving this goal. Design/Methodology/Approach: The paper provides a review of relevant scholarly literature about business models to clarify the subject as well as highlighting the importance of past studies of business model classifications. In addition it reviews the scholarly literature on relevant methodological approaches, such as cluster analysis and latent class analysis, for constructing a business model taxonomy. The two literature streams combined to form the basis for the suggested recipe. Findings: The paper highlights the need for further large-scale empirical studies leading to a potential business model taxonomy, a topic that is currently under-exposed even though its merits are highlighted continuously in the contemporary literature. However, the research stream in relation to a business model taxonomy also needs a sound starting point in order to ensure valid and reliable outcomes. In this paper a research design for conducting such studies is presented and obstacles, which need to be overcome to ensure the quality of business model taxonomy studies in the future are identified. Originality/Value: The paper highlights the benefits and potential implications of designing business model taxonomy studies and makes the case for ensuring the quality of future studies relating to e.g. performance. Reviewing the literature on both business models and methodological theories achieves this.

Leading on from the bestselling 2010 book Business Model Generation (VPD), Alexander Osterwalder and Yves Pigneur, this time flanked by Greg Bernarda, Alan Smith and Trish Papadakos, set out to further the intricate link between business models and value propositions in the 2014 publication Value Proposition Design (VPD). This is a Book Review on the new publication.

This paper is based on a study of 755 Danish SMEs and further in-depth case studies of 12 of these. Its objective was to identify a model of components and relationships among the very best, most efficient, high-performing SMEs. We call these Kickass Companies. The result is a model made up of six interrelated dimensions, which together illustrate what makes up a Kickass Company: • You need willpower • You need to be there for your customers • You strive to be the best • Success is a “we thing” • You need to be able to accelerate • Use motivating KPIs Following these six dimensions might not be a guarantee of success, and not all components will be implementable in all types of companies. However, the empirical evidence here suggests that, if companies think along these lines of doing business, their probability of success will be higher than otherwise.

Purpose: Existing frameworks for understanding and analyzing the value configuration and structuring of partnerships in relation such network-based business models are found to be inferior. The purpose of this paper is therefore to broaden our understanding of how business models may change over time and how the role of strategic partners may differ over time too. Design/methodology/approach: A longitudinal case study spanning over years and mobilising multiple qualitative methods such as interviews, observation and participative observation forms the basis of the data collection. Findings: This paper illustrates how a network-based business model arises and evolves and how the forces of a network structure impact the development of its partner relationships. The contribution of this article is to understanding how partners positioned around a business model can be organized into a network-based business model that generates additional value for the core business model and for both the partners and the customers. Research limitations/implications: The results should be taken with caution as they are based on the case study of a single network-based business model. Practical implications: Managers can gain insight into barriers and enablers relating to different types of loose organisations and how to best manage such relationships and interactions Originality/value: This study adds value to the existing literature by reflecting the dynamics created in the interactions between a business model’s strategic partners and how a how a business model can evolve in a series of distinct phases

“Our business mission is to create an open source journal that is free of the ties that come along with a publisher. In turn we wish to develop a new type of profitable business model for an academic journal that sends more of the total value created back to the academic community and the strategic partners that enable its existence. This is a very clear value proposition.”

BackgroundRheumatoid arthritis (RA) is an autoimmune disease with a complex origin. Previous studies have reported heritability estimates on RA at about 60%. Only 16% of the genetic background of the disease has been disclosed so far. The purpose of the present investigation was to provide an optimized estimate on the heritability of RA and to study the recurrence risk in a nationwide Caucasian twin population.Methods and findingsIn a mail survey addressed to 56.707 twin individuals, RA was reported by 479 individuals, mean age 52 (range 16-73). Respondents underwent an interview and clinical examination. Ascertainment probability was 80%. RA was confirmed in 162 twin individuals yielding a prevalence at 0.37% (95% CI 0.31-0.43). The mean discordance time was 19 years (range 0-57). The concordance was 9.1% (95% CI 1.9 to 24.3) in MZ, 6.4% (95% CI 2.1 to 14.3) in DZss. The increased relative risk of attracting RA conditioned on having an affected cotwin compared to the background population risk was 24.6 to 35.4 in MZ twins and 17.3 to 31.6 in DZss twins. The correlation coefficients were 0.60 (0.33 to 0.78) in monozygotic (MZ) and 0.55 (0.33 to 0.72) in dizygotic same sexed (DZss) pairs. Twelve percent (95% CI 0-76%) of the phenotypic variance in the liability to RA was due to additive genetic effects, 50% (95% CI 0-72%) to shared environmental effects and 38% (95% CI 17-61%) to non-shared environmental effects.ConclusionsThis study emphasizes that family factors are important for the development of RA. Although genetic effectors are important, shared and non-shared environmental triggers and/or epigenetic stochastic events seem to be even more significant. However, it should be borne in mind that the genetic and non-genetic components may not be the same across disease subsets.

The complement system is an important part of our immune system, and complement defects lead generally to increased susceptibility to infections and autoimmune diseases. We have studied the role of complement activity in relation with chronic rhinosinusitis (CRS), and more specifically studied whether complement defects collectively predispose individuals for CRS or affect CRS severity. The participants comprised 87 CRS patients randomly selected from the general population, and a control group of 150 healthy blood donors. The CRS patients were diagnosed according to the European Position Paper on Rhinosinusitis and nasal Polyps criteria, and severity was evaluated by the Sino-nasal Outcome Test-22. Serum samples were analysed by ELISA for activity of the respective pathways of complement, and subsequently for serum levels of relevant components. We found that the frequency of complement defects was significantly higher among CRS patients than among healthy control subjects. A majority of Mannan-binding lectin deficient CRS patients was observed. The presence of complement defects had no influence on the severity of subjective symptoms. Our studies show that defects in the complement system collectively may play an immunological role related to the development of CRS. However, an association between severity of symptoms and presence of complement defects could not be demonstrated.