Sex differences in cognition, emotional reactivity, and motor ability in gonadally-intact middle-aged marmosets (Callithrix jacchus)

Sex differences in cognition are well documented. Women outperform men on measures of perceptual speed and verbal abilities, while men outperform women on tests of spatial processing. Robust sex differences also exist in stress responses. However, it is unclear how these sex differences change over time and whether males and females follow different trajectories of age-related cognitive decline. Studies in nonhuman primate models can help resolve this issue. The common marmoset (Callithrix jacchus) is a New World primate with a short lifespan that can perform complex cognitive tasks in computerized settings that are comparable to those used with humans. The present study is part of a longitudinal project aimed at determining whether males and females follow different trajectories of cognitive aging. This report focuses on sex differences at study entry. Thirteen marmosets (7 females), aged 4-6 years were tested on a comprehensive battery of tasks assessing cognitive function, motor skills and emotional reactivity. For cognition, monkeys were initially trained on a simple visual discrimination problem, followed by reversal learning using the Cambridge Neuropsychological Test Automated Battery (CANTAB). They also performed the Hill-and-Valley task as a measure of fine motor skills. To assess emotional reactivity, each marmoset was separated from their colony for 7 hours. Behavioral assessments, which involved recording the occurrence of approximately 25 behaviors, occurred a total of 6 times: immediately before separation, 3 times during separation, immediately after separation, and 24-hr later. No sex difference was found for simple discrimination, but males tended to perform better than females on the reversal learning task. No sex difference was observed in motor skills. During separation from the colony, females were more reactive than males, as indicated by more agitated locomotion, and vocalizations. Together, these findings expand upon previous studies and demonstrate sex differences in reversal learning and emotional reactivity in gonadally-intact middle-aged marmosets. As the study progresses, we should be able to determine the neural correlates of these sex differences and how they may change with aging. Supported by NIH grant AG04626

Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II\ue2\u80\u93IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56\uc2\ub76 [SEM 4\uc2\ub75] vs 68\uc2\ub73 [4\uc2\ub75]; rank-based treatment difference \ue2\u88\u9211\uc2\ub77, 95% CI \ue2\u88\u9224\uc2\ub73 to 0\uc2\ub796; p=0\uc2\ub70698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals