Recommendations by the ClinGen Rett/Angelman-like Expert Panel for Gene-specific Variant Interpretation Methods

The genes MECP2, CDKL5, FOXG1, UBE3A, SLC9A6, and TCF4 present unique challenges for current ACMG/AMP variant interpretation guidelines. To address those challenges, the Rett and Angelman-like Disorders Variant Curation Expert Panel (Rett/AS VCEP) drafted gene-specific modifications. A pilot study was conducted to test the clarity and accuracy of using the customized variant interpretation criteria. Multiple curators obtained the same interpretation for 78 out of the 87 variants (~90%), indicating appropriate usage of the modified guidelines the majority of times by all the curators. The classification of 13 variants changed using these criteria specifications compared to when the variants were originally curated and as present in ClinVar. Many of these changes were due to internal data shared from laboratory members however some changes were because of changes in strength of criteria. There were no two step classification changes and only 1 clinically relevant change (Likely pathogenic to VUS). The Rett/AS VCEP hopes that these gene-specific variant curation rules and the assertions provided help clinicians, clinical laboratories, and others interpret variants in these genes but also other fully penetrant, early-onset genes associated with rare disorders.

Ethical Issues

The implementation of advance directives to withhold food and water by mouth faces significantly more challenges than VSED by persons with decision-making capacity, though with sufficient care and attention, many of these can be resolved. Reduced awareness may leave the person with little understanding of her directive or no awareness at all. In severe dementia, is behavioral expression of a simple desire for food or drink a relevant change of mind about the directive, or by then does the person no longer have the capacity to make such a change? How relevant is the moral distress that caregivers and health care agents will often experience when implementing the person’s directive, or when they are unable to get it implemented? Patients in severe dementia also may be relatively content, with little pain and suffering—is the deterioration itself, without pain and suffering, a legitimate reason for implementing a VSED directive?

Rescaling Retail and Consumption in the Contemporary Barcelona Area

Consumption is one of the less know variable in urban studies. The article presents a general overview of Catalan and Barcelona study case, summarizing almost thirty years of research, with the goal to isolate the main contemporary trends of retail and consumption in the area. The recent economic processes in the Catalan context are analyzed in the first place. At the same scale, the level of analysis is again recentered on the changes into the metropolitan and regional Barcelona, focussing in the perspective of the old slogan of Catalonia-city. The necessity of the restructuration of the scale of the analysis is proposed. After, the lens is adjusted to the city of Barcelona case, focussing on the relevant change in his traditional centrality. Finally some future trends are advanced.

Frailty and Forgiveness

My aim in this chapter is to characterize the change of heart that plays a role in forgiveness—in giving up warranted blaming reactive attitudes. I present this in the context of developing a Kantian account of what forgiveness is and why we need it, drawing on his moral psychology to characterize the relevant change of heart. I appeal in particular to Kant’s account of human frailty and its relation to his account of human evil. I argue that it is frail and flawed agents who lack an entirely fixed and stable character for whom forgiveness is a live option and a need. For such agents, there may be space to interpret us in the light of better willing than our wrongdoing indicates.

Peers as Culturally Relevant Change Agents

As the United States’ school-age population has become increasingly diverse, it is critical that the curricula, instruction, assessments, and interventions in schools are culturally relevant, reflecting the values and lived experiences of children and families. In this chapter, we posit that peer-mediated interventions are viable strategies that can be used to improve the cultural relevance of interventions in schools. After reviewing culturally relevant school-based service delivery, we offer four reasons supporting the use of peers as culturally relevant change agents: (a) communal orientation, (b) preference for racial/ethnic match, (c) overcoming cultural mismatches in schools, and (d) near peer modeling.