Neurofilament Light Chain in Adult and Pediatric Multiple Sclerosis:A Promising Biomarker to Better Characterize Disease Activity and Personalize MS Treatment

Many biological markers have been explored in multiple sclerosis (MS) to better quantify disease burden and better evaluate response to treatments, beyond clinical and MRI data. Among these, neurofilament light chain (Nf-L), although non-specific for this disease and found to be increased in other neurological conditions, has been shown to be the most promising biomarker for assessing axonal damage in MS, with a definite role in predicting the development of MS in patients at the first neurological episode suggestive of MS, and also in a preclinical phase. There is strong evidence that Nf-L levels are increased more in relapsing versus stable MS patients, and that they predict future disease evolution (relapses, progression, MRI measures of activity/progression) in MS patients, providing information on response to therapy, helping to anticipate clinical decisions in patients with an apparently stable evolution, and identifying patient non-responders to disease-modifying treatments. Moreover, Nf-L can contribute to the better understanding of the mechanisms of demyelination and axonal damage in adult and pediatric MS. A fundamental requirement for its clinical use is the accurate standardization of normal values, corrected for confounding factors, in particular age, sex, body mass index, and presence of comorbidities. In this review, a guide is provided to update clinicians on the use of Nf-L in clinical activity.</p

Business Model Adaptation: Evidence of Lean Experimentation in Digital Startups

Digital startups frequently adapt their business model, but in doing so they face resource scarcity and need to “make-do” in validating and implementing their design changes at a practical level. We thus argue that digital startups employ a Lean Experimental approach when adapting their BM to contextual conditions. By means of an exploratory multiple-case study on Digital startups, this research investigates the factors driving the deployment of an experimental approach and proposing some factors that may drive differences in its application. Results suggest that most startups dealing with BM adaptation engage in experimentation practices that can be identified with the Lean Startup Approaches (LSAs), although with different extents of application. In this sense, startups move from scarce resource availability in resembling selected elements of the framework, whereas those with higher resource availability seem to be more prone to adopting LSAs in a structured and customized way at the organizational level

What happens after market validation? Experimentation for scaling in technology-based startups

Scaling is one of the most critical phases in the lifecycle of technology-based startups: failure to scale often translates into failure to survive. Entrepreneurial experimentation has emerged as a method to reduce the likelihood of startup failure by anticipating market information. However, previous studies only described experimentation as the means to achieve market validation during the early stages of a startup's lifecycle. In our study, we have inductively investigated experimentation in technology-based startups after they had achieved market validation, conducting a comparative multiple-case study on four technology-based startups operating as digital platforms for financial and marketing services. Our findings conclude that technology-based startups continue to experiment extensively as they scale up. We present a process model of how experimentation for scaling focuses on probing for new customer segments, experimenting on customer relationships and channels, whilst carefully pacing and prioritizing experiments, and selecting the relevant growth metrics to monitor. Our study thus extends the current understanding of entrepreneurial experimentation beyond the accomplishment of market validation to the phase of scaling. This article also provides practical guidelines for technology entrepreneurs to direct their efforts towards experimentation during the challenging scaling phase

MxA mRNA quantification and disability progression in interferon beta-treated Multiple Sclerosis patients

Even though anti-interferon beta (IFNβ) antibodies are the main determinants of IFNβ bioactivity loss and Myxovirus-resistance protein A (MxA) is the most established marker of IFNβ biological activity in IFNβ-treated multiple sclerosis patients, their usefulness in the routine clinical practice is still debated. Therefore, 118 multiple sclerosis patients naïve for treatment were enrolled for a 3-year longitudinal observational study mimicking the conditions of a real-world setting. In order to evaluate the kinetics of bioactivity loss in blood samples obtained every 6 months after therapy initiation, MxA and interferon receptor isoform/subunit mRNA were quantified by real-time PCR, anti-IFNβ binding antibodies were detected by radioimmunoprecipitation, and neutralizing antibodies by cytopathic effect inhibition assay. Clinical measures of disease activity and disability progression were also obtained at all time points. We found that, at the individual-patient level, the response to IFNβ therapy was extremely heterogeneous, including patients with stable or transitory, early or late loss of IFNβ bioactivity, and patients with samples lacking MxA mRNA induction in spite of absence of antibodies. No interferon receptor isoform alterations that could explain these findings were found. At the group level, none of these biological features correlated with the measures of clinical disease activity or progression. However, when MxA mRNA was evaluated not at the single time point as a dichotomic marker (induced vs. non-induced), but as the mean of its values measured over the 6-to-24 month period, the increasing average MxA predicted a decreasing risk of short-term disability progression, independently from the presence of relapses. Therefore, a more bioactive treatment, even if unable to suppress relapses, reduces their severity by an amount that is proportional to MxA levels. Together with its feasibility in the routine laboratory setting, these data warrant the quantification of MxA mRNA as a primary tool for a routine monitoring of IFNβ therapy

Patients with paediatric-onset multiple sclerosis are at higher risk of cognitive impairment in adulthood: an Italian collaborative study

Background: Patients with paediatric-onset multiple sclerosis (POMS) could be at an increased risk for cognitive impairment (CI), given the potential harmful effects of disease activity in neurodevelopment. However, there is scarce information on their long-term cognitive outcomes. Objective: To compare the prevalence and profile of CI between adults with a history of POMS and those with classic, adult-onset multiple sclerosis (AOMS). Methods: Cognitive performance was assessed through the Brief Repeatable Battery (BRB) and the Stroop Test in consecutive patients referred to six Italian MS centres. CI was defined as impairment in ⩾2 cognitive domains. Results: In all, 119 patients with POMS and 712 with AOMS were included in this analysis. The prevalence of CI was 48.0% in AOMS, 44.5% in POMS; with similar neuropsychological profile between the two groups. However, when adjusting for current age, we found a significantly increased risk for CI (odds ratio (OR) = 1.71; p = 0.02) and for impairment in information processing speed (OR = 1.86; p < 0.01) in patients with POMS. A higher Expanded Disability Status Scale (EDSS) was also identified in POMS (p = 0.03) compared with AOMS patients.The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This study was in part financed through an FISM (Italian Federation of Multiple Sclerosis) research grant

The still under-investigated role of cognitive deficits in PML diagnosis

Background: Despite cognitive deficits frequently represent the first clinical manifestations of Progressive Multifocal Leukoencephalopathy (PML) in Natalizumab-treated MS patients, the importance of cognitive deficits in PML diagnosis is still under-investigated. The aim of the current study is to investigate the cognitive deficits at PML diagnosis in a group of Italian patients with PML. Methods: Thirty-four PML patients were included in the study. The demographic and clinical data, the lesion load and localization, and the longitudinal clinical course was compared between patients with (n = 13) and without (n = 15) cognitive deficit upon PML suspicion (the remaining six patients were asymptomatic). Clinical presentation of cognitive symptoms was described in detail. Result: After symptoms detection, the time to diagnosis resulted to be shorter for patients presenting with cognitive than for patients with non cognitive onset (p = 0.03). Within patients with cognitive onset, six patients were presenting with language and/or reading difficulties (46.15%); five patients with memory difficulties (38.4%); three patients with apraxia (23.1%); two patients with disorientation (15.3%); two patients with neglect (15.3%); one patients with object agnosia (7.7%), one patient with perseveration (7.7%) and one patient with dementia (7.7%). Frontal lesions were less frequent (p = 0.03), whereas temporal lesions were slightly more frequent (p = 0.06) in patients with cognitive deficits. The longitudinal PML course seemed to be more severe in cognitive than in non cognitive patients (F = 2.73, p = 0.03), but differences disappeared (F = 1.24, p = 0.29) when balancing for the incidence of immune reconstitution syndrome and for other treatments for PML (steroids, plasma exchange (PLEX) and other therapies (Mefloquine, Mirtazapine, Maraviroc). Conclusion: Cognitive deficits at PML onset manifest with symptoms which are absolutely rare in MS. Their appearance in MS patients should strongly suggest PML. Clinicians should be sensitive to the importance of formal neuropsychological evaluation, with particular focus on executive function, which are not easily detected without a formal assessment

Understanding corporate entrepreneurship in the digital age: a review and research agenda

In a digital world increasingly characterized by new business opportunities and challenges driven by the proliferation of pervasive digital technologies, companies are more than ever called to act entrepreneurially. This scenario has raised important questions at the intersection of corporate entrepreneurship (CE) and digital technologies, as we currently lack a comprehensive understanding on the implications of digital technologies in CE strategy, related antecedents, processes, and outcomes. To fill this gap, our study takes stock of the extant literature on CE in the digital age. Through a review of 54 studies, we craft an integrative framework of CE in the digital age, articulated across six building blocks. Building on the proposed framework, we elaborate a research agenda for future research

Unpacking the Digital Transformation in an Incumbent Context: The Role of Digital Skills

Digital technologies entail novel opportunities for incumbent organizations. However, the possibilities offered by digital technologies need to come together with skilled employees and executives to reveal the transformational implications of digital technologies for incumbent organizations. Despite the contemporary significance, extant literature lacks guidance for digital skills enhancement in incumbents, i.e., assess and develop digital skills in incumbents. Moreover, existing literature on digital skills focuses mainly on the educational context while leaving less explored the incumbent context. Thus, this study explores how incumbents assess and develop digital skills within their organizations through an in-depth case study of a utility company. Specifically, we shed lights on organizational mechanisms (i.e. top management support; company population engagement and human resources function intervention) that can facilitate the development and integration of digital skills in incumbent organizations. We also document organizational characteristics (i.e. time availability and recognition) and individual characteristics (i.e. individual digital skills and willingness) that can enable a group of individuals to facilitate digital transformation and initiate corporate entrepreneurship initiatives in the digital age in incumbent organizations. This study therefore contributes to digital skills, digital transformation, and corporate entrepreneurship literatures and offers practical implications for incumbents

Pharmacokinetics and pharmacodynamics of natalizumab in pediatric patients with RRMS

This phase I study investigated pharmacokinetic (PK) and pharmacodynamic (PD) profiles of natalizumab in pediatric patients with relapsing-remitting MS (RRMS)