Adoption of biosimilar infliximab for rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel diseases in the EU5: A budget impact analysis using a Delphi panel

Introduction: Introducing biosimilar infliximab for the treatment in rheumatology (rheumatoid arthritis and ankylosing spondylitis) and inflammatory bowel disease (Crohn's disease and ulcerative colitis) may reduce treatment costs associated with biologics. This study aimed to investigate the budget impact of adopting biosimilar infliximab in five European countries, considering that the budget impact includes the adoption of biosimilar infliximab and the availability of biologic alternatives such as vedolizumab, biosimilar etanercept, biosimilar rituximab, and other relevant factors. Methods: An existing budget impact model was adapted to forecast the budget impact in the UK, Germany, France, Spain, and Italy. Epidemiological parameters were derived from published literature reviewed in July 2015. Current market shares of biologics were derived from Therapy Watch (2012/2013 data). Respondents in a Delphi panel, conducted in 2015 and consisting of several leading rheumatologists and gastroenterologists from different nationalities, were asked to forecast uptake of biosimilar infliximab and estimate the proportion of patients eligible for a particular type of biological treatment, including biosimilar infliximab. Scenario analyses assessed the influence of various factors, including price reductions, on the budget. Results: Uptake of biosimilar infliximab was particularly expected for naïve patients; switching patients that already received other biologics was not expected much. Market shares after 5 years of biosimilar infliximab were ~2% in rheumatology in all five countries and in gastroenterology ranged from 4% in France to over 30% in Italy. Except for France, budgets were expected to decrease for rheumatologic diseases. For gastroenterology, budgets were expected to decrease in Spain and Italy. Budgets were expected to increase substantially in the UK and Germany, due to the introduction of vedolizumab in the studied period. In France, budget was expected to slightly increase for ankylosing spondylitis, Crohn's Disease, and ulcerative collitis. Savings in budget were expected in all countries, for all diseases, when larger price discounts on biosimilar infliximab were used. Discussion and Conclusion: This study has shown that only when price reductions are large en

PrimPol bypasses UV photoproducts during eukaryotic chromosomal DNA replication

DNA damage can stall the DNA replication machinery, leading to genomic instability. Thus, numerous mechanisms exist to complete genome duplication in the absence of a pristine DNA template, but identification of the enzymes involved remains incomplete. Here, we establish that Primase-Polymerase (PrimPol; CCDC111), an archaeal-eukaryotic primase (AEP) in eukaryotic cells, is involved in chromosomal DNA replication. PrimPol is required for replication fork progression on ultraviolet (UV) lightdamaged DNA templates, possibly mediated by its ability to catalyze translesion synthesis (TLS) of these lesions. This PrimPol UV lesion bypass pathway is not epistatic with the Pol h-dependent pathway and, as a consequence, protects xeroderma pigmentosum variant (XP-V) patient cells from UV-induced cytotoxicity. In addition, we establish that PrimPol is also required for efficient replication fork progression during an unperturbed S phase. These and other findings indicate that PrimPol is an important player in replication fork progression in eukaryotic cells

Economic evaluation of apixaban for the prevention of stroke in non-valvular atrial fibrillation in the Netherlands

BACKGROUND: Stroke prevention is the main goal of treating patients with atrial fibrillation (AF). Vitamin-K antagonists (VKAs) present an effective treatment in stroke prevention, however, the risk of bleeding and the requirement for regular coagulation monitoring are limiting their use. Apixaban is a novel oral anticoagulant associated with significantly lower hazard rates for stroke, major bleedings and treatment discontinuations, compared to VKAs.OBJECTIVE: To estimate the cost-effectiveness of apixaban compared to VKAs in non-valvular AF patients in the Netherlands.METHODS: Previously published lifetime Markov model using efficacy data from the ARISTOTLE and the AVERROES trial was modified to reflect the use of oral anticoagulants in the Netherlands. Dutch specific costs, baseline population stroke risk and coagulation monitoring levels were incorporated. Univariate, probabilistic sensitivity and scenario analyses on the impact of different coagulation monitoring levels were performed on the incremental cost-effectiveness ratio (ICER).RESULTS: Treatment with apixaban compared to VKAs resulted in an ICER of €10,576 per quality adjusted life year (QALY). Those findings correspond with lower number of strokes and bleedings associated with the use of apixaban compared to VKAs. Univariate sensitivity analyses revealed model sensitivity to the absolute stroke risk with apixaban and treatment discontinuations risks with apixaban and VKAs. The probability that apixaban is cost-effective at a willingness-to-pay threshold of €20,000/QALY was 68%. Results of the scenario analyses on the impact of different coagulation monitoring levels were quite robust.CONCLUSIONS: In patients with non-valvular AF, apixaban is likely to be a cost-effective alternative to VKAs in the Netherlands.</p

The cost-effectiveness and monetary benefits of dabigatran in the prevention of arterial thromboembolism for patients with non-valvular atrial fibrillation in the Netherlands

BACKGROUND: Atrial fibrillation (AF) causes a significant health and economic burden to the Dutch society. Dabigatran was proven to have at least similar efficacy and a similar or better safety profile when compared to vitamin K antagonists (VKAs) in preventing arterial thromboembolism in patients with AF. OBJECTIVE: To evaluate the cost-effectiveness and monetary benefit of dabigatran versus VKAs in Dutch patients with non-valvular AF. Value-based pricing considerations and corresponding negotiations on dabigatran will be explicitly considered. METHODS: The base case economic analysis was conducted from the societal perspective. Health effects and costs were analysed using a Markov model. The main model inputs were derived from the RE-LY trial and Dutch observational data. Univariate, probabilistic sensitivity, and various scenario analyses were performed. RESULTS: Dabigatran was cost saving compared to VKAs. A total of 4,552 QALYs were gained and €13,892,288 was saved in a cohort of 10,000 AF patients. The economic value of dabigatran was strongly related to the costs of VKA control that are averted. Notably, dabigatran was cost saving compared to VKAs if annual costs of VKA control exceeded €159 per person or dabigatran costs were below €2.81 per day. CONCLUSION: Dabigatran was cost saving compared to VKAs for the prevention of atrial thromboembolism in patients with non-valvular AF in the Netherlands. This result appeared robust in the sensitivity analysis. Furthermore, volume based reduction of the price in the Netherlands will further increase the monetary benefits of dabigatran

The Peptidoglycan-Binding Protein SjcF1 Influences Septal Junction Function and Channel Formation in the Filamentous Cyanobacterium Anabaena

Filamentous, heterocyst-forming cyanobacteria exchange nutrients and regulators between cells for diazotrophic growth. Two alternative modes of exchange have been discussed involving transport either through the periplasm or through septal junctions linking adjacent cells. Septal junctions and channels in the septal peptidoglycan are likely filled with septal junction complexes. While possible proteinaceous factors involved in septal junction formation, SepJ (FraG), FraC, and FraD, have been identified, little is known about peptidoglycan channel formation and septal junction complex anchoring to the peptidoglycan. We describe a factor, SjcF1, involved in regulation of septal junction channel formation in the heterocyst-forming cyanobacterium Anabaena sp. strain PCC 7120. SjcF1 interacts with the peptidoglycan layer through two peptidoglycan-binding domains and is localized throughout the cell periphery but at higher levels in the intercellular septa. A strain with an insertion in sjcF1 was not affected in peptidoglycan synthesis but showed an altered morphology of the septal peptidoglycan channels, which were significantly wider in the mutant than in the wild type. The mutant was impaired in intercellular exchange of a fluorescent probe to a similar extent as a sepJ deletion mutant. SjcF1 additionally bears an SH3 domain for protein-protein interactions. SH3 binding domains were identified in SepJ and FraC, and evidence for interaction of SjcF1 with both SepJ and FraC was obtained. SjcF1 represents a novel protein involved in structuring the peptidoglycan layer, which links peptidoglycan channel formation to septal junction complex function in multicellular cyanobacteria. Nonetheless, based on its subcellular distribution, this might not be the only function of SjcF1.Peer reviewe

Correction:Cost-effectiveness of apixaban compared to other anticoagulants in patients with atrial fibrillation in the real-world and trial settings

[This corrects the article DOI: 10.1371/journal.pone.0222658.]

Promoting Client Participation and Constructing Decisions in Mental Health Rehabilitation Meetings

The chapter analyzes practices by which support workers promote client participation in mental health rehabilitation meetings at the Clubhouse. While promoting client participation, the support workers also need to ascertain that at least some decisions get constructed during the meetings. This combination of goals—promoting participation and constructing decisions—leads to a series of dilemmatic practices, the dynamics of which the chapter focuses on analyzing. The support workers may treat clients’ turns retrospectively as proposals, even if the status of these turns as such is ambiguous. In the face of a lack of recipient uptake, the support workers may remind the clients about their epistemic access to the content of the proposal or pursue their agreement or commitment to the idea. These practices involve the support workers carrying primary responsibility over the unfolding of interaction, which is argued to compromise the jointness of the decision-making outcome.The chapter analyzes practices by which support workers promote client participation in mental health rehabilitation meetings at the Clubhouse. While promoting client participation, the support workers also need to ascertain that at least some decisions get constructed during the meetings. This combination of goals—promoting participation and constructing decisions—leads to a series of dilemmatic practices, the dynamics of which the chapter focuses on analyzing. The support workers may treat clients’ turns retrospectively as proposals, even if the status of these turns as such is ambiguous. In the face of a lack of recipient uptake, the support workers may remind the clients about their epistemic access to the content of the proposal or pursue their agreement or commitment to the idea. These practices involve the support workers carrying primary responsibility over the unfolding of interaction, which is argued to compromise the jointness of the decision-making outcome.Peer reviewe

Co-constructing desired activities : Small-scale activity decisions in occupational therapy

Social inclusion and exclusion are buzzwords in today’s political discourse. While there are many causes of social exclusion, one of the factors repeatedly shown to lead to social exclusion is mental illness, which may hinder people in developing themselves in accordance with their wishes and abilities. Participation is a key dimension of social inclusion—and one that we particularly seek to increase understanding of in this volume. We focus on participation taking place in face-to-face social encounters, seeking to get to the root of the preconditions and consequences of participation by unraveling the interactional processes that underlie what makes it possible. We presuppose that participation in any social or societal sphere presupposes social interaction, which in turn requires the capacity to coordinate with and make sense of others’ actions. Thus, drawing on joint decision-making as a specific arena of social interaction, where the participants’ collaborative management of the turn-by-turn sequential unfolding of interaction can have tangible consequences for the participants’ social and economic circumstances, we seek to increase understanding of the specific vulnerabilities that individuals with mental illness have in this context.In occupational therapy, a therapist and client engage in shared activities that they perform collaboratively during therapeutic sessions. An important part of this joint performance involves providing the client with the opportunity to make short-term decisions on the activities they wish to perform. Analyzing 15 occupational therapy encounters at psychiatric outpatient clinics, in the chapter I explore the functions of these small-scale decisions. The analysis demonstrates that therapists (1) make room for the client’s proposals by shaping the activity context and (2) make proposals themselves on the ways the performance should be accomplished. To summarize, clients are given decision-making power over the content of the activity, whereas therapists use their decision-making power to assist the client’s performance. The analysis shows how small-scale decisions can be employed to construct the occupational performance as shared endeavors and to position the clients as active subjects rather than objects of the professionals’ performance.Peer reviewe