Transition to secondary progressive multiple sclerosis: The consequences for patients and healthcare systems, a healthcare professional survey.

BACKGROUND AND AIMS: Transition to secondary progressive multiple sclerosis (SPMS) from relapsing-remitting MS (RRMS) is an expected part of the disease trajectory for most patients. However, the transition is challenging to identify due to the gradual nature of progression, and the complications of superimposed relapses, comorbidities, and natural variability in symptoms. This healthcare professional (HCP) survey sought to characterize the transition to and management of SPMS in UK clinical practice. METHODS: Telephone interviews with 20 neurologists and MS specialist nurses from England and Scotland gathered quantitative and qualitative responses. Numerical analyses and theoretical thematic methods were used to identify key emerging themes. RESULTS: The burden SPMS imposes on patients and caregivers was a major theme; discharge from specialist services is common, leading to a sense of abandonment. Respondents acknowledged substantial hesitancy toward identifying SPMS, predominantly due to restricted options of licensed and reimbursed disease-modifying therapies (DMTs) for SPMS compared with RRMS. Currently, HCPs continue DMTs under a label of RRMS, even after recognition of progression. This survey identified MS to be unusual in comparison with other disease areas in that reimbursement guidelines have a direct impact on clinicians' decisions around disease staging. Respondents suggested reimbursed DMTs proven to slow disability progression in SPMS will create a step-change in identifying SPMS, providing rationale to acknowledge progression earlier while removing key obstacles to identification. To aid this change, respondents identified a need for SPMS-specific diagnostic guidance, despite substantial divergence in implementation of current guidance. CONCLUSIONS: In contrast to the current heterogeneity, a more structured and standardized approach to the identification of SPMS, along with guidelines on treatment, will ensure patients can maximally benefit as treatment options for SPMS evolve.

Fragment-Based Identification of Ligands for Bromodomain-Containing Factor 3 of Trypanosoma cruzi.

The Trypanosoma cruzi (T. cruzi) parasite is the cause of Chagas disease, a neglected disease endemic in South America. The life cycle of the T. cruzi parasite is complex and includes transitions between distinct life stages. This change in phenotype (without a change in genotype) could be controlled by epigenetic regulation, and might involve the bromodomain-containing factors 1-5 (TcBDF1-5). However, little is known about the function of the TcBDF1-5. Here we describe a fragment-based approach to identify ligands for T. cruzi bromodomain-containing factor 3 (TcBDF3). We expressed a soluble construct of TcBDF3 in E. coli, and used this to develop a range of biophysical assays for this protein. Fragment screening identified 12 compounds that bind to the TcBDF3 bromodomain. On the basis of this screen, we developed functional ligands containing a fluorescence or 19F reporter group, and a photo-crosslinking probe for TcBDF3. These tool compounds will be invaluable in future studies on the function of TcBDF3 and will provide insight into the biology of T. cruzi.