Expert opinion on the long-term use of cladribine tablets for multiple sclerosis: Systematic literature review of real-world evidence

Background: Treatment with cladribine tablets (CladT), an immune reconstitution therapy for relapsing multiple sclerosis (RMS), involves two short courses of treatment in Year 1 and Year 2. Most patients achieve sustained efficacy with CladT, but a small proportion may experience new disease activity (DA). Following completion of the indicated dose, physicians may have questions relating to the long-term management of these patients. Since the EU approval of CladT over 5 years ago, real-world evidence (RWE) is increasing and may provide some insights and guidance for clinical practice. We describe a systematic literature review (SLR) of RWE and provide expert opinions relating to six questions regarding the long-term use of CladT.Methods: Pertinent clinical questions were developed by a steering committee (SC) of 14 international multiple sclerosis (MS) experts regarding breakthrough DA in Year 1, new DA after 2 years or more of treatment, long-term management of stable patients, and whether additional courses of CladT may be required or safe. An SLR was performed in EMBASE and PubMed using the population, intervention, comparators, outcomes, study design (PICOS) framework to identify relevant studies within the last 15 years. Searches of key congress pro-ceedings for the last 2-3 years were also performed. Following review of the results and RWE, the SC drafted and agreed on expert opinion statements for each question. Results: A total of 35 publications reporting RWE for CladT were included in this review. In the real world, breakthrough DA in Year 1 is of low incidence (1.1-21.9%) but can occur, particularly in patients switching from anti-lymphocyte trafficking agents. In most patients, this DA did not lead to treatment discontinuation. Reported rates of DA after the full therapeutic effect of CladT has been achieved (end of Year 2, 3 or 4) range from 12.0 to 18.7% in the few studies identified. No RWE was identified to support management decisions for stable patients in Year 5 or later. Views among the group were also diverse on this question and voting on expert opinion statements was required. Only two studies reported the administration of additional courses of CladT, but detailed safety outcomes were not provided. Conclusions: RWE for the long-term use of CladT in the treatment of RMS is increasing, however, gaps in knowledge remain. Where possible, the RWE identified through the SLR informed expert statements, but, where RWE is still lacking, these were based solely on experiences and opinion, providing some guidance on topics and questions that occur in daily clinical practice. More real-world studies with longer-term follow-up periods are needed and highly anticipated

A Model for Solving the Optimal Water Allocation Problem in River Basins with Network Flow Programming When Introducing Non-Linearities

[EN] The allocation of water resources between different users is a traditional problem in many river basins. The objective is to obtain the optimal resource distribution and the associated circulating flows through the system. Network flow programming is a common technique for solving this problem. This optimisation procedure has been used many times for developing applications for concrete water systems, as well as for developing complete decision support systems. As long as many aspects of a river basin are not purely linear, the study of non-linearities will also be of great importance in water resources systems optimisation. This paper presents a generalised model for solving the optimal allocation of water resources in schemes where the objectives are minimising the demand deficits, complying with the required flows in the river and storing water in reservoirs. Evaporation from reservoirs and returns from demands are considered, and an iterative methodology is followed to solve these two non-network constraints. The model was applied to the Duero River basin (Spain). Three different network flow algorithms (Out-of-Kilter, RELAX-IVand NETFLO) were used to solve the allocation problem. Certain convergence issues were detected during the iterative process. There is a need to relate the data from the studied systems with the convergence criterion to be able to find the convergence criterion which yields the best results possible without requiring a long calculation time.We thank the Spanish Ministry of Economy and Competitivity (Comision Interministerial de Ciencia y Tecnologia, CICYT) for funding the projects INTEGRAME (contract CGL2009-11798) and SCARCE (program Consolider-Ingenio 2010, project CSD2009-00065). We also thank the European Commission (Directorate-General for Research & Innovation) for funding the project DROUGHT-R&SPI (program FP7-ENV-2011, project 282769). And last, but not least, to the Fundacion Instituto Euromediterraneo del Agua with the project "Estudio de Adaptaciones varias del modelo de optimizacion de gestiones de recursos hidricos Optiges".Haro Monteagudo, D.; Paredes Arquiola, J.; Solera Solera, A.; Andreu Álvarez, J. (2012). A Model for Solving the Optimal Water Allocation Problem in River Basins with Network Flow Programming When Introducing Non-Linearities. Water Resources Management. 26(14):4059-4071. https://doi.org/10.1007/s11269-012-0129-7S405940712614Ahuja R, Magnanti T, Orlin J (1993) Network flows: theory, algorithms and applications. Prentice Hall, New YorkAndreu J, Capilla J, Sanchís E (1996) AQUATOOL, a generalized decision-support system for water resources planning and operational management. 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J Water Resour Plan Manag 124:69–78Harou JJ, Medellín-Azuara J, Zhu T et al (2010) Economic consequences of optimized water management for a prolonged, severe drought in California. Water Resour Res 46:W05522Hsu N, Cheng K (2002) Network Flow Optimization Model for Basin-Scale Water Supply Planning. J Water Resour Plan Manag 128:102–112Ilich N (1993) Improvement of the return flow allocation in the Water Resources Management Model of Alberta Environment. Can J Civ Eng 20:613–621Ilich N (2009) Limitations of network flow algorithms in river basin modeling. J Water Resour Plan Manag 135:48–55Kennington JL, Helgason RV (1980) Algorithms for network programming. John Wiley and Sons, New YorkKhaliquzzaman, Chander S (1997) Network flow programming model for multireservoir sizing. J Water Resour Plan Manag 123:15–21Kuczera G (1989) Fast Multireservoir Mulltiperiod Linear Programming Models. Water Resour Res 25:169–176Kuczera G (1993) Network linear programming codes for water-supply headworks modeling. J Water Resour Plan Manag 119:412–417Labadie J (2004) Optimal operation of multireservoir systems: state-of-the-art review. J Water Resour Plan Manag 130:93–111Labadie J (2006) MODSIM: river basin management decision support system. In: Singh W, Frevert D (eds) Watershed models. CRC, Boca Raton, pp 569–592Labadie J, Baldo M, Larson R (2000) MODSIM: decision support system for river basin management. Documentation and user manual. Dept. Of Civil Engineering, CSU, Fort CollinsManca A, Sechi G, Zuddas P (2010) Water supply network optimisation using equal flow algorithms. Water Resour Manag 24:3665–3678MMA (2000) Libro blanco del agua en España. Ministerio de Medio Ambiente, Secretaría general Técnica, Centro de PublicacionesMMA (2008) Confederación Hidrográfica del Duero. Memoria 2008. http://www.chduero.es/Inicio/Publicaciones/tabid/159/Default.aspx . 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Iron deposition and inflammation in multiple sclerosis. Which one comes first?

Whether iron deposition is an epiphenomenon of the multiple sclerosis (MS) disease process or may play a primary role in triggering inflammation and disease development remains unclear at this time, and should be studied at the early stages of disease pathogenesis. However, it is difficult to study the relationship between iron deposition and inflammation in early MS due to the delay between the onset of symptoms and diagnosis, and the poor availability of tissue specimens. In a recent article published in BMC Neuroscience, Williams et al. investigated the relationship between inflammation and iron deposition using an original animal model labeled as "cerebral experimental autoimmune encephalomyelitis", which develops CNS perivascular iron deposits. However, the relative contribution of iron deposition vs. inflammation in the pathogenesis and progression of MS remains unknown. Further studies should establish the association between inflammation, reduced blood flow, iron deposition, microglia activation and neurodegeneration. Creating a representative animal model that can study independently such relationship will be the key factor in this endeavor

Hsp90 middle domain phosphorylation initiates a complex conformational program to recruit the ATPase-stimulating cochaperone Aha1

Complex conformational dynamics are essential for function of the dimeric molecular cha- perone heat shock protein 90 (Hsp90), including transient, ATP-biased N-domain dimer- ization that is necessary to attain ATPase competence. The intrinsic, but weak, ATP hydrolyzing activity of human Hsp90 is markedly enhanced by the co-chaperone Aha1. However, the cellular concentration of Aha1 is substoichiometric relative to Hsp90. Here we report that initial recruitment of this cochaperone to Hsp90 is markedly enhanced by phosphorylation of a highly conserved tyrosine (Y313 in Hsp90α) in the Hsp90 middle domain. Importantly, phosphomimetic mutation of Y313 promotes formation of a transient complex in which both N- and C-domains of Aha1 bind to distinct surfaces of the middle domains of opposing Hsp90 protomers prior to ATP-directed N-domain dimerization. Thus, Y313 represents a phosphorylation-sensitive conformational switch, engaged early after client loading, that affects both local and long-range conformational dynamics to facilitate initial recruitment of Aha1 to Hsp90

Natalizumab, Fingolimod and Dimethyl Fumarate Use and Pregnancy-Related Relapse and Disability in Women With Multiple Sclerosis

To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort

Restrained Th17 response and myeloid cell infiltration into the central nervous system by human decidua-derived mesenchymal stem cells during experimental autoimmune encephalomyelitis

Background: Multiple sclerosis is a widespread inflammatory demyelinating disease. Several immunomodulatory therapies are available, including interferon-β, glatiramer acetate, natalizumab, fingolimod, and mitoxantrone. Although useful to delay disease progression, they do not provide a definitive cure and are associated with some undesirable side-effects. Accordingly, the search for new therapeutic methods constitutes an active investigation field. The use of mesenchymal stem cells (MSCs) to modify the disease course is currently the subject of intense interest. Decidua-derived MSCs (DMSCs) are a cell population obtained from human placental extraembryonic membranes able to differentiate into the three germ layers. This study explores the therapeutic potential of DMSCs. Methods: We used the experimental autoimmune encephalomyelitis (EAE) animal model to evaluate the effect of DMSCs on clinical signs of the disease and on the presence of inflammatory infiltrates in the central nervous system. We also compared the inflammatory profile of spleen T cells from DMSC-treated mice with that of EAE control animals, and the influence of DMSCs on the in vitro definition of the Th17 phenotype. Furthermore, we analyzed the effects on the presence of some critical cell types in central nervous system infiltrates. Results: Preventive intraperitoneal injection of DMSCs resulted in a significant delay of external signs of EAE. In addition, treatment of animals already presenting with moderate symptoms resulted in mild EAE with reduced disease scores. Besides decreased inflammatory infiltration, diminished percentages of CD4+IL17+, CD11b+Ly6G+ and CD11b+Ly6C+ cells were found in infiltrates of treated animals. Early immune response was mitigated, with spleen cells of DMSC-treated mice displaying low proliferative response to antigen, decreased production of interleukin (IL)-17, and increased production of the anti-inflammatory cytokines IL-4 and IL-10. Moreover, lower RORγT and higher GATA-3 expression levels were detected in DMSC-treated mice. DMSCs also showed a detrimental influence on the in vitro definition of the Th17 phenotype. Conclusions: DMSCs modulated the clinical course of EAE, modified the frequency and cell composition of the central nervous system infiltrates during the disease, and mediated an impairment of Th17 phenotype establishment in favor of the Th2 subtype. These results suggest that DMSCs might provide a new cell-based therapy for the control of multiple sclerosis.This work was sponsored by grants from Acción Estratégica en Salud (PI13/00297 and PI11/00581), the Neurosciences and Aging Foundation, the Francisco Soria Melguizo Foundation, Octopharma, and Parkinson Madrid (PI2012/0032).S

Venous hemodynamics in neurological disorders: an analytical review with hydrodynamic analysis.

Venous abnormalities contribute to the pathophysiology of several neurological conditions. This paper reviews the literature regarding venous abnormalities in multiple sclerosis (MS), leukoaraiosis, and normal-pressure hydrocephalus (NPH). The review is supplemented with hydrodynamic analysis to assess the effects on cerebrospinal fluid (CSF) dynamics and cerebral blood flow (CBF) of venous hypertension in general, and chronic cerebrospinal venous insufficiency (CCSVI) in particular.CCSVI-like venous anomalies seem unlikely to account for reduced CBF in patients with MS, thus other mechanisms must be at work, which increase the hydraulic resistance of the cerebral vascular bed in MS. Similarly, hydrodynamic changes appear to be responsible for reduced CBF in leukoaraiosis. The hydrodynamic properties of the periventricular veins make these vessels particularly vulnerable to ischemia and plaque formation.Venous hypertension in the dural sinuses can alter intracranial compliance. Consequently, venous hypertension may change the CSF dynamics, affecting the intracranial windkessel mechanism. MS and NPH appear to share some similar characteristics, with both conditions exhibiting increased CSF pulsatility in the aqueduct of Sylvius.CCSVI appears to be a real phenomenon associated with MS, which causes venous hypertension in the dural sinuses. However, the role of CCSVI in the pathophysiology of MS remains unclear

Keys to success of a community of clinical practice in primary care : a qualitative evaluation of the ECOPIH project

The current reality of primary care (PC) makes it essential to have telemedicine systems available to facilitate communication between care levels. Communities of practice have great potential in terms of care and education, and that is why the Online Communication Tool between Primary and Hospital Care was created. This tool enables PC and non-GP specialist care (SC) professionals to raise clinical cases for consultation and to share information. The objective of this article is to explore healthcare professionals' views on communities of clinical practice (CoCPs) and the changes that need to be made in an uncontrolled real-life setting after more than two years of use. A descriptive-interpretative qualitative study was conducted on a total of 29 healthcare professionals who were users and non-users of a CoCP using 2 focus groups, 3 triangular groups and 5 individual interviews. There were 18 women, 21 physicians and 8 nurses. Of the interviewees, 21 were PC professionals, 24 were users of a CoCP and 7 held managerial positions. For a system of communication between PC and SC to become a tool that is habitually used and very useful, the interviewees considered that it would have to be able to find quick, effective solutions to the queries raised, based on up-to-date information that is directly applicable to daily clinical practice. Contact should be virtual - and probably collaborative - via a platform integrated into their habitual workstations and led by PC professionals. Organisational changes should be implemented to enable users to have more time in their working day to spend on the tool, and professionals should have a proactive attitude in order to make the most if its potential. It is also important to make certain technological changes, basically aimed at improving the tool's accessibility, by integrating it into habitual clinical workstations. The collaborative tool that provides reliable, up-to-date information that is highly transferrable to clinical practice is valued for its effectiveness, efficiency and educational capacity. In order to make the most of its potential in terms of care and education, organisational changes and techniques are required to foster greater use. The online version of this article (10.1186/s12875-018-0739-0) contains supplementary material, which is available to authorized users