Depression and Physician-Aid-in-Dying.

In this paper, I address the question of whether it is ever permissible to grant a request for physician-aid-in-dying (PAD) from an individual suffering from treatment-resistant depression. I assume for the sake of argument that PAD is sometimes permissible. There are three requirements for PAD: suffering, prognosis, and competence. First, an individual must be suffering from an illness or injury which is sufficient to cause serious, ongoing hardship. Second, one must have exhausted effective treatment options, and one's prospects for recovery must be poor. Third, the individual must be judged competent to request PAD. I argue that many cases of treatment-resistant depression meet the first two requirements. Thus, the key question concerns the third. I consider four features of depression that might compromise a person's decision-making capacity. Ultimately, I conclude that PAD requests from depressed patients can be permissibly granted in some circumstances.

Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy.

Visceral myopathy with abnormal intestinal and bladder peristalsis includes a clinical spectrum with megacystis-microcolon intestinal hypoperistalsis syndrome and chronic intestinal pseudo-obstruction. The vast majority of cases are caused by dominant variants in ACTG2; however, the overall genetic architecture of visceral myopathy has not been well-characterized. We ascertained 53 families, with visceral myopathy based on megacystis, functional bladder/gastrointestinal obstruction, or microcolon. A combination of targeted ACTG2 sequencing and exome sequencing was used. We report a molecular diagnostic rate of 64% (34/53), of which 97% (33/34) is attributed to ACTG2. Strikingly, missense mutations in five conserved arginine residues involving CpG dinucleotides accounted for 49% (26/53) of disease in the cohort. As a group, the ACTG2-negative cases had a more favorable clinical outcome and more restricted disease. Within the ACTG2-positive group, poor outcomes (characterized by total parenteral nutrition dependence, death, or transplantation) were invariably due to one of the arginine missense alleles. Analysis of specific residues suggests a severity spectrum of p.Arg178>p.Arg257>p.Arg40 along with other less-frequently reported sites p.Arg63 and p.Arg211. These results provide genotype-phenotype correlation for ACTG2-related disease and demonstrate the importance of arginine missense changes in visceral myopathy.

Nothing about Us without Us: Inclusion and IRB Review of Mental Health Research Protocols.

Research on mental health and illness presents a variety of unique ethical challenges. This article argues that institutional review boards (IRBs) can improve their reviews of such research by including the perspectives of individuals with the condition under study either as members of the IRB or as consultants thereto. Several reasons for including the perspectives of these individuals are advanced, with the discussion organized around a hypothetical case study involving the assessment of a novel talk-therapy modality. Having made this case, the article goes on to explain how to implement the idea by building on a recent proposal by Rebecca Dresser, who argues in a number of publications for the inclusion of former research participants in the IRB review process. Finally, concerns about protecting reviewer and consultant confidentiality are addressed.

An Argument for Reinterpreting the Benign Behavioral Intervention Exemption.

Recent changes to the Common Rule have helped reduce regulatory burden on researchers conducting minimal risk research. However, in this paper, I propose a way of minimizing burden further within the existing confines of the current regulations. I focus my discussion on the newly created "benign behavioral interventions" category of exempt research, arguing that this exemption from the federal regulations governing research with human subjects should be more expansively interpreted by the Secretary's Advisory Committee on Human Research Protections (SACHRP) than is currently the case. Specifically, I argue against the restriction, advocated by SACHRP, that the exemption exclude "physical (bodily) tasks" unless they are "incidental to the behavioral intervention." This restriction, I argue, is problematically vague and does no significant moral work. Acceptance of my proposed reinterpretation of "benign behavioral interventions" would, I hope, result in a significant reduction in regulatory burden for minimal risk research.

A New Multisystem Disorder Caused by the Gαs Mutation p.F376V.

CONTEXT: The α subunit of the stimulatory G protein (Gαs) links numerous receptors to adenylyl cyclase. Gαs, encoded by GNAS, is expressed predominantly from the maternal allele in certain tissues. Thus, maternal heterozygous loss-of-function mutations cause hormonal resistance, as in pseudohypoparathyroidism type Ia, whereas somatic gain-of-function mutations cause hormone-independent endocrine stimulation, as in McCune-Albright syndrome. OBJECTIVE: We report two unrelated boys presenting with a new combination of clinical findings that suggest both gain and loss of Gαs function. DESIGN AND SETTING: Clinical features were studied and sequencing of GNAS was performed. Signaling capacities of wild-type and mutant Gαs were determined in the presence of different G protein-coupled receptors (GPCRs) under basal and agonist-stimulated conditions. RESULTS: Both unrelated patients presented with unexplained hyponatremia in infancy, followed by severe early onset gonadotrophin-independent precocious puberty and skeletal abnormalities. An identical heterozygous de novo variant (c.1136T>G; p.F376V) was found on the maternal GNAS allele in both patients; this resulted in a clinical phenotype that differed from known Gαs-related diseases and suggested gain of function at the vasopressin 2 receptor (V2R) and lutropin/choriogonadotropin receptor (LHCGR), yet increased serum PTH concentrations indicative of impaired proximal tubular PTH1 receptor (PTH1R) function. In vitro studies demonstrated that Gαs-F376V enhanced ligand-independent signaling at the PTH1R, LHCGR, and V2R and, at the same time, blunted ligand-dependent responses. Structural homology modeling suggested mutation-induced modifications at the C-terminal α5 helix of Gαs that are relevant for interaction with GPCRs and signal transduction. CONCLUSIONS: The Gαs p.F376V mutation causes a previously unrecognized multisystem disorder.