Advance Medical Decision-Making Differs Across First- and Third-Person Perspectives.

BACKGROUND: Advance healthcare decision-making presumes that a prior treatment preference expressed with sufficient mental capacity ("T1 preference") should trump a contrary preference expressed after significant cognitive decline ("T2 preference"). This assumption is much debated in normative bioethics, but little is known about lay judgments in this domain. This study investigated participants' judgments about which preference should be followed, and whether these judgments differed depending on a first-person (deciding for one's future self) versus third-person (deciding for a friend or stranger) perspective. METHODS: A vignette-based survey was conducted (N = 1445 US Americans; gender-balanced sample), in a 3 (relationship: self, best friend, stranger) × 2 (T1 preference: treat, do not treat) × 2 (T2 contrary preference: ambiguous, unambiguous) design. RESULTS: Participants were more likely to defer to the incapacitated T2 preference of a third-party, while being more likely to insist on following their own T1 capacitated preference. Further, participants were more likely to conclude that others with substantial cognitive decline were still their "true selves," which correlated with increased deference to their T2 preferences. CONCLUSIONS: These findings add to the growing evidence that lay intuitions concerning the ethical entitlement to have decisions respected are not only a function of cognition, as would be expected under many traditional bioethical accounts, but also depend on the relationship of the decision to the decision-maker's true self.

Too Important for the Bureaucrats: Rethinking Risk and Regulatory Presumptions in Times of Crisis.

The posture of American regulation of medicine is negative-we assume that a new drug is unsafe and ineffective until it is proven safe and effective.1 This regulatory posture is a heuristic normative principle, a specific instance of the so-called precautionary principle in public health law.2 It is defensible, if debatable, in many ordinary circumstances.3 But like many normative heuristics, this negative posture may compel suboptimal decision-making in emergencies, where context-specific decisions must be made and a range of unique values may apply.

Safety and toxicology assessment of sodium nitrite administered by intramuscular injection.

Intramuscular (IM) injection of nitrite (1-10 mg/kg) confers survival benefit and protects against lung injury after exposure to chlorine gas in preclinical models. Herein, we evaluated safety/toxicity parameters after single, and repeated (once daily for 7 days) IM injection of nitrite in male and female Sprague Dawley rats and Beagle dogs. The repeat dose studies were performed in compliance with the Federal Drug Administration's (FDA) Good Laboratory Practices Code of Federal Regulations (21 CFR Part 58). Parameters evaluated consisted of survival, clinical observations, body weights, clinical pathology, plasma drug levels, methemoglobin and macroscopic and microscopic pathology. In rats and dogs, single doses of ≥100 mg/kg and 60 mg/kg resulted in death and moribundity, while repeated administration of ≤30 or ≤ 10 mg/kg/day, respectively, was well tolerated. Therefore, the maximum tolerated dose following repeated administration in rats and dogs were determined to be 30 mg/kg/day and 10 mg/kg/day, respectively. Effects at doses below the maximum tolerated dose (MTD) were limited to emesis (in dogs only) and methemoglobinemia (in both species) with clinical signs (e.g. blue discoloration of lips) being dose-dependent, transient and reversible. These signs were not considered adverse, therefore the No Observed Adverse Effect Level (NOAEL) for both rats and dogs was 10 mg/kg/day in males (highest dose tested for dogs), and 3 mg/kg/day in females. Toxicokinetic assessment of plasma nitrite showed no difference between male and females, with Cmax occurring between 5 mins and 0.5 h (rats) or 0.25 h (dogs). In summary, IM nitrite was well tolerated in rats and dogs at doses previously shown to confer protection against chlorine gas toxicity.

Understanding the Perspectives of Seniors on Dementia and Decision-Making.

BACKGROUND: The legal doctrine of capacity, which governs legally-authorized intervention in the decision-making of persons with dementia, has been subject to recent scholarly criticism and reform efforts. Such efforts require a coherent normative theory of when and how intervention in the decision-making of those with dementia is appropriate. This mixed-methods study sought to understand the perspectives of seniors on this normative question. METHODS: A survey, including closed- and open-ended questions and conversational interviews, was conducted. RESULTS: Quantitative results of 236 seniors were heterogeneous but showed important patterns. Qualitative results from survey data and interviews of 25 seniors presented 6 key themes: (1) a difficulty of giving concrete answers; (2) reliance on professional opinions; (3) concern for personal identity; (4) fear of abuse; (5) trust of family; and (6) fear of dementia. CONCLUSIONS: The study suggests support among seniors for: (1) a model of "supported decision-making" rather than "surrogate decision-making;" (2) a presumption that in order to preclude a person with dementia from making more "personal" decisions a more heightened showing of incapacity is required; and (3) a shift to a model of capacity as based more on features such as long term memory and relationships rather than cognitive functions or values. In reforming our understandings of capacity, ethicists and practitioners will have to navigate tensions found in the qualitative data, including: (1) between participants' fear of abuse and their expressions of trust in family members to decide when intervention is appropriate; and (2) between expressions of confidence in medical professionals' ability to tell participants when they are no longer able to make decisions and participants' own understanding of the question in terms of the philosophical construct of personal identity.

An adenovirus-based vaccine with a double-stranded RNA adjuvant protects mice and ferrets against H5N1 avian influenza in oral delivery models.

An oral gene-based avian influenza vaccine would allow rapid development and simplified distribution, but efficacy has previously been difficult to achieve by the oral route. This study assessed protection against avian influenza virus challenge using a chimeric adenovirus vector expressing hemagglutinin and a double-stranded RNA adjuvant. Immunized ferrets and mice were protected upon lethal challenge. Further, ferrets immunized by the peroral route induced cross-clade neutralizing antibodies, and the antibodies were selective against hemagglutinin, not the vector. Similarly, experiments in mice demonstrated selective immune responses against HA with peroral delivery and the ability to circumvent preexisting vector immunity.

PET imaging a MPTP-induced mouse model of Parkinson's disease using the fluoropropyl-dihydrotetrabenazine analog [18F]-DTBZ (AV-133).

Parkinson's disease (PD) is characterized by the loss of dopamine-producing neurons in the nigrostriatal system. Numerous researchers in the past have attempted to track the progression of dopaminergic depletion in PD. We applied a quantitative non-invasive PET imaging technique to follow this degeneration process in an MPTP-induced mouse model of PD. The VMAT2 ligand (18)F-DTBZ (AV-133) was used as a radioactive tracer in our imaging experiments to monitor the changes of the dopaminergic system. Intraperitoneal administrations of MPTP (a neurotoxin) were delivered to mice at regular intervals to induce lesions consistent with PD. Our results indicate a significant decline in the levels of striatal dopamine and its metabolites (DOPAC and HVA) following MPTP treatment as determined by HPLC method. Images obtained by positron emission tomography revealed uptake of (18)F-DTBZ analog in the mouse striatum. However, reduction in radioligand binding was evident in the striatum of MPTP lesioned animals as compared with the control group. Immunohistochemical analysis further confirmed PET imaging results and indicated the progressive loss of dopaminergic neurons in treated animals compared with the control counterparts. In conclusion, our findings suggest that MPTP induced PD in mouse model is appropriate to follow the degeneration of dopaminergic system and that (18)F-DTBZ analog is a potentially sensitive radiotracer that can used to diagnose changes associated with PD by PET imaging modality.