Two double-blind, randomized, placebo-controlled feasibility trials of minocycline in ALS were conducted. In Trial 1, 19 subjects received 200 mg/day or placebo for 6 months; there were no significant differences in adverse events (AE). In Trial 2, 23 subjects received up to 400 mg/day in an 8-month crossover trial. The mean tolerated dose was 387 mg/day, there was a trend toward more gastrointestinal AE (p = 0.057), and blood urea nitrogen and liver enzymes became elevated (p < 0.05). Using these data, the authors have designed and launched a phase III trial.

ObjectivesTo estimate patient-acceptable symptom state (PASS) cut-points for myasthenia gravis (MG) health scales.MethodsWe conducted an electronic survey that included the Myasthenia Gravis Impairment Index (MGII), EuroQol 5-Dimension (EQ5D) and a simple PASS question. PASS anchored thresholds were estimated for the MGII questionnaire through receiver operating characteristic curves. We used the MGII PASS cut-point in a validation cohort of 257 patients to estimate PASS thresholds for other clinically relevant health scales such as the quantitative myasthenia gravis score (QMGS), MG activities of daily living (MG-ADL), Myasthenia gravis composite (MGC) and myasthenia quality of life (MG-QoL15) scale.ResultsOne hundred twenty-four of approximately 250 invited patients answered the electronic survey (49% response rate), and 80 considered their current symptom state acceptable (PASS-positive). These had lower MGII scores than PASS-negative patients (7.76 ± 9.37 vs 25.0 ± 13.7, p < 0.0001) and better EQ5D scores (0.86 ± 0.17 vs 0.69 ± 0.18, p < 0.0001). The MGII questionnaire threshold for PASS was ≤10 points. Using this threshold in an independent dataset of 257 patients, all patients in remission or minimal manifestation status were PASS-positive. In addition, some patients in Classes I, II and IIIA also achieved PASS status. PASS thresholds for the QMGS, MG-ADL, MGC and MG-QoL15 were ≤7, 2, 3 and 8 points, respectively.ConclusionsWe have estimated thresholds for commonly-used myasthenia health scales reflecting patient-acceptable states in myasthenia patients. These thresholds indicate a global state—“being well” —rather than a change in scores —or “being better.” Therefore, PASS thresholds can be used as secondary endpoints for myasthenia research.

A key step in generating planar cell polarity (PCP) is the formation of restricted junctional domains containing Frizzled/Dishevelled/Diego (Fz/Dsh/Dgo) or Van Gogh/Prickle (Vang/Pk) complexes within the same cell, stabilized via Flamingo (Fmi) across cell membranes. Although models have been proposed for how these complexes acquire and maintain their polarized localization, the machinery involved in moving core PCP proteins around cells remains unknown. We describe the AP-1 adaptor complex and Arf1 as major regulators of PCP protein trafficking in vivo. AP-1 and Arf1 disruption affects the accumulation of Fz/Fmi and Vang/Fmi complexes in the proximo–distal axis, producing severe PCP phenotypes. Using novel tools, we demonstrate a direct and specific Arf1 involvement in Fz trafficking in vivo. Moreover, we uncover a conserved Arf1 PCP function in vertebrates. Our data support a model whereby the trafficking machinery plays an important part during PCP establishment, promoting formation of polarized PCP-core complexes in vivo.

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a chloride and bicarbonate channel in secretory epithelia with a critical role in maintaining fluid homeostasis. Mutations in CFTR are associated with Cystic Fibrosis (CF), the most common lethal autosomal recessive disorder in Caucasians. While remarkable treatment advances have been made recently in the form of modulator drugs directly rescuing CFTR dysfunction, there is still considerable scope for improvement of therapeutic effectiveness. Here, we report the application of a high-throughput screening variant of the Mammalian Membrane Two-Hybrid (MaMTH-HTS) to map the protein-protein interactions of wild-type (wt) and mutant CFTR (F508del), in an effort to better understand CF cellular effects and identify new drug targets for patient-specific treatments. Combined with functional validation in multiple disease models, we have uncovered candidate proteins with potential roles in CFTR function/CF pathophysiology, including Fibrinogen Like 2 (FGL2), which we demonstrate in patient-derived intestinal organoids has a significant effect on CFTR functional expression.

Background and purpose Defining refractory myasthenia gravis is important, as this can drive clinical decision making, for example, by escalating treatments in refractory individuals. There are several definitions of refractory myasthenia, and their performances have not been compared. Having valid and reliable criteria can help select patients in whom more aggressive treatments may be needed. Methods We applied five different refractory myasthenia criteria (Drachman, Mantegazza, Suh, the International Consensus Guideline (ICG), and the randomised controlled trial of eculizumab in refractory, anti‐acetylcholine receptor positive, generalised myasthenia gravis (REGAIN), to a cohort of 237 patients. We compared the proportion of refractory patients among different criteria and their scores on disease severity, fatigue, and quality‐of‐life (QoL) scales. We also assessed the agreement for each criterion between two trained assessors. Results The Drachman, Mantegazza, and Suh criteria resulted in high proportions of refractory individuals (40.1%, 39.2%, and 38.8%, respectively), compared with the ICG and REGAIN criteria (9.7% and 3.0%, respectively). Refractory patients by the ICG and REGAIN criteria had worse disease severity, QoL, and fatigue scores, compared with patients classified as refractory by other criteria. All criteria had high agreement between raters (between 70% and 100%). Conclusions There is high variability in the proportion of refractory myasthenia gravis patients depending on the criteria used, with ICG and REGAIN criteria capturing patients with worse disease severity. This reflects conceptual differences as to what refractory means. Further multicenter studies are needed to determine appropriate criteria for refractory myasthenia gravis.

Background There is limited data regarding gender differences in quality of life between women and men with Neurofibromatosis type 1. We aimed to study differences in quality of life domains between women and men with Neurofibromatosis type 1 living in Canada. Methods This is a cross sectional study of adults with Neurofibromatosis type 1 attending a tertiary NF centre at Toronto General Hospital between January 2016 to December 2017. Demographic and clinical data were collected. We compared scores of generic measures (SF-36, EQ-5D-5L, pain interference) and a disease-specific measure (PedsQL-NF1 module) between women and men. We also assessed the relationship between disease visibility scored by an examiner (Ablon’s visibility index) and self-reported perceived physical appearance, stratified by gender. Results One hundred and sixty-two participants were enrolled, 92 females and 70 males. Ablon’s index score 1 was in 43% and score 2 in 44%, while only 13% of patients had a score 3. Women had worse scores on the total PedsQL-NF1 scales, and also in the perceived physical appearance, anxiety and emotional health domains. In women, there was a low but significant correlation between Ablon’s index and perceived physical appearance (r = − 0.27, p = 0.01, ANOVA p < 0.001). In men, there was no difference in self-reported physical appearance by Ablon’s index. There were no differences between men and women in the SF-36 or EQ-5D-5L scores. Conclusion Women with NF1 reported worse NF1-related quality of life than men, with worse perceived physical appearance, anxiety, and mental health. Perceived physical appearance does not always correlate to disease visibility; therefore, healthcare providers should inquire about body image, physical appearance concerns, and mental health, especially among women with NF1.

Background: We aimed to determine the safety and tolerance of higher rates of infusion of intravenous immunoglobulin (IVIG) in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Methods: Patients began infusions with 10% IVIG at the standard rate of 0.08 mL/ kg/min. If tolerated, infusion rates were incrementally increased to 0.14 mL/kg/min. We considered the frequency of infusions with adverse events (AEs) as the primary outcome. Results: Nineteen of 25 patients safely tolerated the maximum rate of 0.14 mL/kg/ min. We observed 25 treatment-related AEs (TAEs) over 13 infusions at standard or transitional rates, across seven patients. We observed no TAEs associated with the maximum infusion rate. Conclusions: We found that 10% IVIG can be safely administered at a high infusion rate (0.14 ml/kg/min) in most CIDP patients, reducing the treatment time and burden on healthcare resources.

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