To introduce or not? Strategic analysis of hospital operations with telemedicine.

Despite its efficiency in reducing the impact of pandemics (e.g., the COVID-19), whether to introduce telemedicine as an additional way to serve chronically ill patients remains controversial for hospitals in many countries. This paper builds a stylized model to investigate a hospital's telemedicine strategy and the corresponding impacts on its operations regarding outpatient management of chronic diseases. We implement our analysis from three key concerns of the hospital in the presence of a pandemic: the differences in medical consumption and reimbursement between in-person and telemedicine modalities and the effort cost of infection reduction resulting from the pandemic. We find that in the absence of the pandemic, the hospital prefers to introduce telemedicine when the differences in medical consumption and reimbursement are both small. In the presence of the pandemic, we find that the introduction of telemedicine does not always benefit the hospital and that it is better not to introduce telemedicine in some cases since it may exacerbate the negative influence of the pandemic on the hospital's total costs. Furthermore, we surprisingly find that the hospital may set greater in-person capacity but less telemedicine capacity in response to the outbreak of the pandemic under certain conditions, which contradicts public beliefs. Finally, we show that social welfare can be improved by introducing telemedicine when the effort cost of infection reduction and the difference in reimbursement are both of moderate size. The condition under which social welfare is improved tightens with a greater difference in medical consumption.

Akt Regulates Sox10 Expression to Control Oligodendrocyte Differentiation via Phosphorylating FoxO1.

Sox10 is a well known factor to control oligodendrocyte (OL) differentiation, and its expression is regulated by Olig2. As an important protein kinase, Akt has been implicated in diseases with white matter abnormalities. To study whether and how Akt may regulate OL development, we generated OL lineage cell-specific Akt1/Akt2/Akt3 triple conditional knock-out (Akt cTKO) mice. Both male and female mice were used. These mutants exhibit a complete loss of mature OLs and unchanged apoptotic cell death in the CNS. We show that the deletion of Akt three isoforms causes downregulation of Sox10 and decreased levels of phosphorylated FoxO1 in the brain. In vitro analysis reveals that the expression of FoxO1 with mutations on phosphorylation sites for Akt significantly represses the Sox10 promoter activity, suggesting that phosphorylation of FoxO1 by Akt is important for Sox10 expression. We further demonstrate that mutant FoxO1 without Akt phosphorylation epitopes is enriched in the Sox10 promoter. Together, this study identifies a novel FoxO1 phosphorylation-dependent mechanism for Sox10 expression and OL differentiation.SIGNIFICANCE STATEMENT Dysfunction of Akt is associated with white matter diseases including the agenesis of the corpus callosum. However, it remains unknown whether Akt plays an important role in oligodendrocyte differentiation. To address this question, we generated oligodendrocyte lineage cell-specific Akt1/Akt2/Akt3 triple-conditional knock-out mice. Akt mutants exhibit deficient white matter development, loss of mature oligodendrocytes, absence of myelination, and unchanged apoptotic cell death in the CNS. We demonstrate that deletion of Akt three isoforms leads to downregulation of Sox10, and that phosphorylation of FoxO1 by Akt is critical for Sox10 expression. Together, these findings reveal a novel mechanism to regulate Sox10 expression. This study may provide insights into molecular mechanisms for neurodevelopmental diseases caused by dysfunction of protein kinases.

Loss of PP2A Disrupts the Retention of Radial Glial Progenitors in the Telencephalic Niche to Impair the Generation for Late-Born Neurons During Cortical Development†.

Telencephalic radial glial progenitors (RGPs) are retained in the ventricular zone (VZ), the niche for neural stem cells during cortical development. However, the underlying mechanism is not well understood. To study whether protein phosphatase 2A (PP2A) may regulate the above process, we generate Ppp2cα conditional knockout (cKO) mice, in which PP2A catalytic subunit α (PP2Acα) is inactivated in neural progenitor cells in the dorsal telencephalon. We show that RGPs are ectopically distributed in cortical areas outside of the VZ in Ppp2cα cKO embryos. Whereas deletion of PP2Acα does not affect the proliferation of RGPs, it significantly impairs the generation of late-born neurons. We find complete loss of apical adherens junctions (AJs) in the ventricular membrane in Ppp2cα cKO cortices. We observe abundant colocalization for N-cadherin and PP2Acα in control AJs. Moreover, in vitro analysis reveals direct interactions of N-cadherin to PP2Acα and to ß-catenin. Overall, this study not only uncovers a novel function of PP2Acα in retaining RGPs into the VZ but also demonstrates the impact of PP2A-dependent retention of RGPs on the generation for late-born neurons.

Increased Resting-State Functional Connectivity of the Hippocampus in Rats With Sepsis-Associated Encephalopathy.

Background: Sepsis-associated encephalopathy (SAE) has been identified as a frequent complication of sepsis, featured by an aberrant level of cognitive and affective functions. The present study is designed to explore the changes in functional connectivity (FC) of the hippocampus in rats with SAE utilizing resting-state functional magnetic resonance imaging (rs-fMRI). Methods: Sprague-Dawley rats were randomly assigned to the SAE and control groups. We acquired rs-fMRI data using a 7T MRI to evaluate hippocampal network functional differences between the two groups with a seed-based approach. Behavioral performance was assessed using the open field test and forced swimming test. Statistical analysis was undertaken to evaluate the correlation between the hippocampal FC and behavioral findings. Results: Compared with the control group, the SAE group showed increased FC between the bilateral hippocampus and thalamus, septum, bed nuclei stria terminalis (BNST), left primary forelimb somatosensory cortex (S1FL), primary motor cortex (M1), and inferior colliculus. Increased FC between the left hippocampus and thalamus, septum, BNST, left S1FL, and inferior colliculus was observed. While with the right hippocampus, FC in thalamus, septum, left S1FL and inferior colliculus was enhanced. Additionally, positive correlations were found between the hippocampal FC and the immobility time in the forced swimming test. Conclusion: Hippocampus-related brain networks have significant alterations in rats with SAE, and the elevated hippocampal resting-state FC was positively related to affective deficits. Changes in FC between the hippocampus and other brain regions could be a potential neuroimaging biomarker of cognitive or mental disorders triggered by SAE.

Neuron-specific deletion of presenilin enhancer2 causes progressive astrogliosis and age-related neurodegeneration in the cortex independent of the Notch signaling.

INTRODUCTION: Presenilin enhancer2 (Pen-2) is an essential subunit of γ-secretase, which is a key protease responsible for the cleavage of amyloid precursor protein (APP) and Notch. Mutations on Pen-2 cause familial Alzheimer disease (AD). However, it remains unknown whether Pen-2 regulates neuronal survival and neuroinflammation in the adult brain. METHODS: Forebrain neuron-specific Pen-2 conditional knockout (Pen-2 cKO) mice were generated for this study. Pen-2 cKO mice expressing Notch1 intracellular domain (NICD) conditionally in cortical neurons were also generated. RESULTS: Loss of Pen-2 causes astrogliosis followed by age-dependent cortical atrophy and neuronal loss. Loss of Pen-2 results in microgliosis and enhanced inflammatory responses in the cortex. Expression of NICD in Pen-2 cKO cortices ameliorates neither neurodegeneration nor neuroinflammation. CONCLUSIONS: Pen-2 is required for neuronal survival in the adult cerebral cortex. The Notch signaling may not be involved in neurodegeneration caused by loss of Pen-2.

Dexamethasone does not ameliorate gliosis in a mouse model of neurodegenerative disease.

Prolonged neuroinflammation is a driving force for neurodegenerative disease, and agents against inflammatory responses are regarded as potential treatment strategies. Here we aimed to evaluate the prevention effects on gliosis by dexamethasone (DEX), an anti-inflammation drug. We used DEX to treat the nicastrin conditional knockout (cKO) mouse, a neurodegenerative mouse model. DEX (10 mg/kg) was given to 2.5-month-old nicastrin cKO mice, which have not started to display neurodegeneration and gliosis, for 2 months. Immunohistochemistry (IHC) and Western blotting techniques were used to detect changes in neuroinflammatory responses. We found that activation of glial fibrillary acidic protein (GFAP) positive or ionized calcium binding adapter molecule1 (Iba1) positive cells was not inhibited in nicastrin cKO mice treated with DEX as compared to those treated with saline. These data suggest that DEX does not prevent or ameliorate gliosis in a neurodegenerative mouse model when given prior to neuronal or synaptic loss.