The Mechanistic Target Of Rapamycin Complex 1 (mTORC1) pathway controls several aspects of neuronal development. Mutations in regulators of mTORC1, such as Tsc1 and Tsc2, lead to neurodevelopmental disorders associated with autism, intellectual disabilities and epilepsy. The correct development of inhibitory interneurons is crucial for functional circuits. In particular, the axonal arborisation and synapse density of parvalbumin (PV)-positive GABAergic interneurons change in the postnatal brain. How and whether mTORC1 signaling affects PV cell development is unknown. Here, we show that Tsc1 haploinsufficiency causes a premature increase in terminal axonal branching and bouton density formed by mutant PV cells, followed by a loss of perisomatic innervation in adult mice. PV cell-restricted Tsc1 haploinsufficient and knockout mice show deficits in social behavior. Finally, we identify a sensitive period during the third postnatal week during which treatment with the mTOR inhibitor Rapamycin rescues deficits in both PV cell innervation and social behavior in adult conditional haploinsufficient mice. Our findings reveal a role of mTORC1 signaling in the regulation of the developmental time course and maintenance of cortical PV cell connectivity and support a mechanistic basis for the targeted rescue of autism-related behaviors in disorders associated with deregulated mTORC1 signaling.
The artificial pancreas combines a hormone infusion pump with a continuous glucose monitoring device, supported by a dosing algorithm currently installed on the pump. It allows for dynamic infusions of insulin (and possibly other hormones such as glucagon) tailored to patient needs. For patients with type 1 diabetes the artificial pancreas has been shown to prevent more effectively hypoglycaemic events and hyperglycaemia than insulin pump therapy and has the potential to simplify care. However, the potential ethical issues associated with the upcoming integration of the artificial pancreas into clinical practice have not yet been discussed. Our objective was to identify and articulate ethical issues associated with artificial pancreas use for patients, healthcare professionals, industry and policymakers. We performed a literature review to identify clinical, psychosocial and technical issues raised by the artificial pancreas and subsequently analysed them through a common bioethics framework. We identified five sensitive domains of ethical issues. Patient confidentiality and safety can be jeopardized by the artificial pancreas' vulnerability to security breaches or unauthorized data sharing. Public and private coverage of the artificial pancreas could be cost-effective and warranted. Patient selection criteria need to ensure equitable access and sensitivity to patient-reported outcomes. Patient coaching and support by healthcare professionals or industry representatives could help foster realistic expectations in patients. Finally, the artificial pancreas increases the visibility of diabetes and could generate issues related to personal identity and patient agency. The timely consideration of these issues will optimize the technological development and clinical uptake of the artificial pancreas.
Aim To identify the expectations of a diversified sample of informed adults with type 1 diabetes on their prospective use of a hybrid closed-loop system. Methods Semi-structured interviews were conducted with 16 adults with type 1 diabetes who shared their expectations on an experimental hybrid closed-loop system after receiving information on its design, functioning and capability. The sample had equal representation of genders and diabetes management methods and was diversified according to age, education and occupation when possible. Qualitative content analysis of the interview transcripts with MaxQDA was used to identify expected benefits, expected inconveniences and concerns, expected improvements to design and functionalities, and interest and trust in the system. Results Participants expected benefits regarding diabetes management, clinical outcomes, psychosocial aspects of their lives, nutrition and meals, and physical activity. Participants expected inconveniences or shared concerns regarding wearability, costs and technical limitations. According to participants, improvements could be made to the system's physical appearance, practical convenience, functionalities, and software integration. Overall, 12 participants would use the system. While participants' trust could be immediate or grow over time, it could ultimately be conditional on the system's performance. Conclusion Prospective users' general enthusiasm and trust foster the clinical and commercial success of hybrid closedloop systems. However, poor user satisfaction caused by unrealistic expectations and plausible inconveniences and concerns may limit this success. Providing prospective users with comprehensive information while validating their understanding could mitigate unrealistic expectations. Improvements to design and coverage policies could favour uptake.
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