Modes of Aβ toxicity in Alzheimer’s disease

Alzheimer’s disease (AD) is reaching epidemic proportions, yet a cure is not yet available. While the genetic causes of the rare familial inherited forms of AD are understood, the causes of the sporadic forms of the disease are not. Histopathologically, these two forms of AD are indistinguishable: they are characterized by amyloid-β (Aβ) peptide-containing amyloid plaques and tau-containing neurofibrillary tangles. In this review we compare AD to frontotemporal dementia (FTD), a subset of which is characterized by tau deposition in the absence of overt plaques. A host of transgenic animal AD models have been established through the expression of human proteins with pathogenic mutations previously identified in familial AD and FTD. Determining how these mutant proteins cause disease in vivo should contribute to an understanding of the causes of the more frequent sporadic forms. We discuss the insight transgenic animal models have provided into Aβ and tau toxicity, also with regards to mitochondrial function and the crucial role tau plays in mediating Aβ toxicity. We also discuss the role of miRNAs in mediating the toxic effects of the Aβ peptide

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Dosing transcranial magnetic stimulation in major depressive disorder: Relations between number of treatment sessions and effectiveness in a large patient registry

Background: The number of sessions in an acute TMS course for major depressive disorder (MDD) is greater than in the earlier randomized controlled trials. Objective: To compare clinical outcomes in groups that received differing numbers of TMS sessions. Methods: From a registry sample (N = 13,732), data were extracted for 7215 patients treated for MDD with PHQ-9 assessments before and after their TMS course. Groups were defined by number of acute course treatment sessions: 1–19 (N = 658), 20–29 (N = 616), 30–35 (N = 1375), 36 (N = 3591), 37–41 (N = 626), or >41 (N = 349) and compared in clinical outcomes at endpoint and at fixed intervals (after 10, 20, 30, and 36 sessions). The impact of additional treatments beyond 36 sessions was also examined. Results: Groups that received fewer than 30 sessions had inferior endpoint outcomes than all other groups. PHQ-9 symptom reduction was greatest in the group that ended treatment at 36 sessions. The extended treatment groups (>36 sessions) differed from all other groups by manifesting less antidepressant response early in the course and had a slower but steady rate of improvement over time. Extending treatment beyond 36 sessions was associated with further improvement without evidence of a plateau. Conclusions: In real-world practice, there are strong relations between the number of TMS sessions in a course and the magnitude of symptom reduction. Courses with less than 30 sessions are associated with diminished benefit. Patients with longer than standard courses typically show less initial improvement and a more gradual trajectory, but meaningful benefit accrues with treatment beyond 36 sessions

Stakeholder expectations of future policy implementation compared to formal policy trajectories: scenarios for agricultural food systems in the Mekong delta

The development of a coherent and coordinated policy for the management of large socio-agricultural systems, such as the Mekong delta in southern Vietnam, is reliant on aligning the development, delivery, and implementation of policy on national to local scales. Effective decision making is linked to a coherent, broadly-shared vision of the strategic management of socio-agricultural systems. However, when policies are ambiguous, and at worst contradictory, long-term management and planning can consequently suffer. These potential adverse impacts may be compounded if stakeholders have divergent visions of the current and future states of socio-agricultural systems. Herein we used a transferable, scenario-based methodology which uses a standard quadrant matrix in order to explore both anticipated and idealized future states. Our case study was the Mekong delta. The scenario matrix was based upon two key strategic choices (axis) for the delta, derived from analysis of policy documents, literature, stakeholder engagement, and land use models. These are: (i) who will run agriculture in the future, agri-business or the established commune system; and (ii) to what degree sustainability will be incorporated into production. During a workshop meeting, stakeholders identified that agri-business will dominate future agricultural production in the delta but showed a clear concern that sustainability might consequently be undermined despite policy claims of the contrary. As such, our study highlights an important gap between national expectations and regional perspectives. Our results suggest that the new development plans for the Mekong delta (which comprise a new Master Plan and a new 5-year socio-economic development plan), which emphasize agro-business development, should adopt approaches that address concerns of sustainability as well as a more streamlined policy formulation and implementation that accounts for stakeholder concerns at both provincial and national levels

Identifying effect modifiers of CAR-T cell therapeutic efficacy : a systematic review and individual patient data meta-analysis protocol

Background: Chimeric antigen receptor T cell therapy (CAR-T) represents a promising and exciting new therapy for hematologic malignancies, where prognosis for relapsed/refractory patients remains poor. Encouraging results from clinical trials have often been tempered by heterogeneity in response to treatment among patients, as well as safety concerns including cytokine release syndrome. The identification of specific patient or treatment-specific factors underlying this heterogeneity may provide the key to the long-term sustainability of this complex and expensive therapy. An individual patient data meta-analysis (IPMDA) may provide potential explanations for the high degree of heterogeneity. Therefore, our objective is to perform a systematic review and IPDMA of CAR-T cell therapy in patients with hematologic malignancies to explore potential effect modifiers of CAR-T cell therapy. Methods and analysis: We will search MEDLINE, Embase, and the Cochrane Central Register of Controlled Clinical Trials. Studies will be screened in duplicate at the abstract level, then at the full-text level by two independent reviewers. We will include any prospective clinical trial of CAR-T cell therapy in patients with hematologic malignancies. Our primary outcome is complete response, while secondary outcomes of interest include overall response, progression-free survival, overall survival, and safety. IPD will be collected from each included trial and, in the case of missing data, corresponding authors/study sponsors will be contacted. Standard aggregate meta-analyses will be performed, followed by the IPD meta-analysis using a one-stage approach. A modified Institute of Health Economics tool will be used to evaluate the risk of bias of included studies. Ethics and dissemination: Identifying characteristics that may act as modifiers of CAR-T cell efficacy is of paramount importance and can help shape future clinical trials in the field. Results from this study will be submitted for publication in a peer-reviewed scientific journal, presented at relevant conferences and shared with relevant stakeholders.Medicine, Faculty ofNon UBCMedicine, Department ofReviewedFacultyResearche

Mendelian disorders and multifactorial traits: the big divide or one for all?

For the past century, Mendelian and multifactorial traits have existed at opposite ends of the disease spectrum in humans. Furthermore, the recent emphasis on genome-wide association studies for uncovering variants that underlie common diseases has risked deepening the divide - or has it? Four experienced human geneticists express their views on the changing landscape of human disease studies and the impact of new technologies and study designs on the age-old aim of connecting a genomic variant with its phenotypic consequences