"One Degree of Separation": A Mixed-Methods Evaluation of Canadian Mental Health Care User and Provider Experiences With Remote Care During COVID-19.

OBJECTIVES: The COVID-19 pandemic has contributed to a shift from in-person to remote mental health care. While remote care methods have long existed, their widespread use is unprecedented. There is little research about mental health care user and provider experiences with this transition, and no published studies to date have compared satisfaction between these groups. METHODS: Canadian mental health care users (n = 332) and providers (n = 107) completed an online self-report survey from October 2020 to February 2021 hosted by the Canadian Biomarker Integration Network in Depression. Using a mixed-methods approach, participants were asked about their use of remote care, including satisfaction, barriers to use, helpful and unhelpful factors, and suggestions for improvement. RESULTS: Overall, 59% to 63% of health care users and 59% of health care providers were satisfied with remote care. Users reported the greatest satisfaction with the convenience of remote care, while providers were most satisfied with the speed of provision of care; all groups were least satisfied with therapeutic rapport. Health care providers were less satisfied with the user-friendliness of remote care (P < 0.001) than users, while health care users were less satisfied than providers with continuity of care (P < 0.001). The use of a video-based platform was associated with remote care satisfaction among health care users (P < 0.02), and qualitative responses support the importance of visual cues in maintaining therapeutic rapport remotely. The majority of users (55%) and providers (87%) reported a likelihood of using remote care after the pandemic. CONCLUSIONS: Remote mental health care is generally accepted by both users and providers, and the majority would consider using remote care following the pandemic. Suggestions for improvement include greater use of video, increased attention to body language and eye contact, consistency with in-person care, as well as increased provider training and administrative support.

Febrile temperature facilitates hERG/IKr degradation through an altered K(+) dependence.

BACKGROUND: Dysfunction of the rapidly activating delayed rectifier K(+) channel (IKr) encoded by the human ether-à-go-go-related gene (hERG) is the primary cause of acquired long QT syndrome (LQTS). Fever has been reported to trigger LQTS in various conditions. OBJECTIVE: We aim to clarify the effect and underlying mechanisms of febrile temperature on hERG expressed in HEK cells, IKr in neonatal rat ventricular myocytes, and the QT interval in rabbits. METHODS: Western blot analysis was used to determine the expression of hERG channel protein in stably transfected HEK 293 cells. Immunocytochemistry was used to visualize the localization of hERG channels. The whole-cell patch clamp technique was used to record hERG K(+) current (IhERG) in hERG expressing HEK 293 cells, as well as IKr, transient outward K(+) current (Ito), and L-type Ca(2+) current (ICa) in neonatal rat ventricular myocytes. Electrocardiographic recordings were performed in an in vivo rabbit model. RESULTS: Compared with culture at 37°C, culture at 40°C reduced the mature hERG expression and IhERG in an extracellular K(+) concentration-dependent manner. Point mutations that remove the K(+) dependence of hERG-S624T and F627Y-also abolished the febrile temperature-induced hERG reduction. In neonatal rat ventricular myocytes, febrile temperature prolonged the action potential duration and selectively reduced IKr in a manner similar to low K(+) culture. In an in vivo rabbit model, fever and hypokalemia synergistically prolonged the QT interval. CONCLUSION: Febrile temperature facilitates the development of LQTS by expediting hERG degradation through altered K(+) dependence.

Regulation of the human ether-a-go-go-related gene (hERG) potassium channel by Nedd4 family interacting proteins (Ndfips).

The cardiac electrical disorder long QT syndrome (LQTS) pre-disposes affected individuals to ventricular arrhythmias and sudden death. Dysfunction of the human ether-a-go-go-related gene (hERG)-encoded rapidly activating delayed rectifier K(+) channel (IKr) is a major cause of LQTS. The expression of hERG channels is controlled by anterograde trafficking of newly synthesized channels to and retrograde degradation of existing channels from the plasma membrane. We have previously shown that the E3 ubiquitin (Ub) ligase Nedd4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2) targets the PY motif of hERG channels to initiate channel degradation. Although both immature and mature hERG channels contain the PY motif, Nedd4-2 selectively mediates the degradation of mature hERG channels. In the present study, we demonstrate that Nedd4-2 is directed to specific cellular compartments by the Nedd4 family interacting proteins, Nedd4 family-interacting protein 1 (Ndfip1) and Ndfip2. Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2. These findings extend our understanding of hERG channel regulation and provide information which may be useful for the rescue of impaired hERG function in LQTS.

Rab11-dependent Recycling of the Human Ether-a-go-go-related Gene (hERG) Channel.

The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr). A reduction in the hERG current causes long QT syndrome, which predisposes affected individuals to ventricular arrhythmias and sudden death. We reported previously that hERG channels in the plasma membrane undergo vigorous internalization under low K(+) conditions. In the present study, we addressed whether hERG internalization occurs under normal K(+) conditions and whether/how internalized channels are recycled back to the plasma membrane. Using patch clamp, Western blot, and confocal imaging analyses, we demonstrated that internalized hERG channels can effectively recycle back to the plasma membrane. Low K(+)-enhanced hERG internalization is accompanied by an increased rate of hERG recovery in the plasma membrane upon reculture following proteinase K-mediated clearance of cell-surface proteins. The increased recovery rate is not due to enhanced protein synthesis, as hERG mRNA expression was not altered by low K(+) exposure, and the increased recovery was observed in the presence of the protein biosynthesis inhibitor cycloheximide. GTPase Rab11, but not Rab4, is involved in the recycling of hERG channels. Interfering with Rab11 function not only delayed hERG recovery in cells after exposure to low K(+) medium but also decreased hERG expression and function in cells under normal culture conditions. We concluded that the recycling pathway plays an important role in the homeostasis of plasma membrane-bound hERG channels.

Muscarinic receptor activation increases hERG channel expression through phosphorylation of ubiquitin ligase Nedd4-2.

The human ether-à-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel, which is important for cardiac repolarization. Reduction of hERG current due to genetic mutations or drug interferences causes long QT syndrome, leading to cardiac arrhythmias and sudden death. To date, there is no effective therapeutic method to restore or enhance hERG channel function. Using cell biology and electrophysiological methods, we found that the muscarinic receptor agonist carbachol increased the expression and function of hERG, but not ether-à-go-go or Kv1.5 channels stably expressed in human embryonic kidney cells. The carbachol-mediated increase in hERG expression was abolished by the selective M3 antagonist 4-DAMP (1,1-dimethyl-4-diphenylacetoxypiperidinium iodide) but not by the M2 antagonist AF-DX 116 (11[[2-[(diethylamino)methyl]-1-piperidinyl]-acetyl]-5,11-dihydro-6H-pyrido[2,3-b] [1,4]benzodiazepine-6-one). Treatment of cells with carbachol reduced the hERG-ubiquitin interaction and slowed the rate of hERG degradation. We previously showed that the E3 ubiquitin ligase Nedd4-2 mediates degradation of hERG channels. Here, we found that disrupting the Nedd4-2 binding domain in hERG completely eliminated the effect of carbachol on hERG channels. Carbachol treatment enhanced the phosphorylation level, but not the total level, of Nedd4-2. Blockade of the protein kinase C (PKC) pathway abolished the carbachol-induced enhancement of hERG channels. Our data suggest that muscarinic activation increases hERG channel expression by phosphorylating Nedd4-2 via the PKC pathway.