Can machine learning predict late seizures after intracerebral hemorrhages? Evidence from real-world data.

INTRODUCTION: Intracerebral hemorrhage represents 15 % of all strokes and it is associated with a high risk of post-stroke epilepsy. However, there are no reliable methods to accurately predict those at higher risk for developing seizures despite their importance in planning treatments, allocating resources, and advancing post-stroke seizure research. Existing risk models have limitations and have not taken advantage of readily available real-world data and artificial intelligence. This study aims to evaluate the performance of Machine-learning-based models to predict post-stroke seizures at 1 year and 5 years after an intracerebral hemorrhage in unselected patients across multiple healthcare organizations. DESIGN/METHODS: We identified patients with intracerebral hemorrhage (ICH) without a prior diagnosis of seizures from 2015 until inception (11/01/22) in the TriNetX Diamond Network, using the International Classification of Diseases, Tenth Revision (ICD-10) I61 (I61.0, I61.1, I61.2, I61.3, I61.4, I61.5, I61.6, I61.8, and I61.9). The outcome of interest was any ICD-10 diagnosis of seizures (G40/G41) at 1 year and 5 years following the first occurrence of the diagnosis of intracerebral hemorrhage. We applied a conventional logistic regression and a Light Gradient Boosted Machine (LGBM) algorithm, and the performance of the model was assessed using the area under the receiver operating characteristics (AUROC), the area under the precision-recall curve (AUPRC), the F1 statistic, model accuracy, balanced-accuracy, precision, and recall, with and without seizure medication use in the models. RESULTS: A total of 85,679 patients had an ICD-10 code of intracerebral hemorrhage and no prior diagnosis of seizures, constituting our study cohort. Seizures were present in 4.57 % and 6.27 % of patients within 1 and 5 years after ICH, respectively. At 1-year, the AUROC, AUPRC, F1 statistic, accuracy, balanced-accuracy, precision, and recall were respectively 0.7051 (standard error: 0.0132), 0.1143 (0.0068), 0.1479 (0.0055), 0.6708 (0.0076), 0.6491 (0.0114), 0.0839 (0.0032), and 0.6253 (0.0216). Corresponding metrics at 5 years were 0.694 (0.009), 0.1431 (0.0039), 0.1859 (0.0064), 0.6603 (0.0059), 0.6408 (0.0119), 0.1094 (0.0037) and 0.6186 (0.0264). These numerical values indicate that the statistical models fit the data very well. CONCLUSION: Machine learning models applied to electronic health records can improve the prediction of post-hemorrhagic stroke epilepsy, presenting a real opportunity to incorporate risk assessments into clinical decision-making in post-stroke care clinical care and improve patients' selection for post-stroke epilepsy research.

Simple Ge/Si bilayer junction-based doping-less tunnel field-effect transistor.

Tunnel field-effect transistors (TFETs) have garnered great interest as an option for the replacement of metal-oxide-semiconductor field-effect transistors owing to their extremely low off-current and fast switching suitable for low-power-consumption applications. However, conventional doped TFETs have the disadvantage of introducing undesirable random dopant fluctuation (RDF) events, which cause a large variance in the threshold voltage and ambipolar leakage current at negative gate voltages. In this study, a simple approach for charge plasma-based doping-less TFETs (DL-TFETs), including the Ge/Si bilayer frame, which affects the RDF and low on-current issues, was developed by the commercially available Silvaco Atlas device simulator. The use of the Ge/Si bilayer enhances the on-current and point subthreshold swing to 1.4 × 10-6A and 16.6 mV dec-1, respectively. In addition, the dependencies of the Ge/Si junction boundary position and Ge content were examined systematically to attain a firm understanding of the electrical features in DL-TFETs.

NFAT5 Deficiency Alleviates Formalin-Induced Inflammatory Pain Through mTOR.

Nuclear factor of activated T cells (NFAT5) is a well-known transcription factor that regulates the expression of genes involved in osmotic stress. However, the role of NFAT5 in inflammatory pain remains unknown. Here, we studied the function of NFAT5 in inflammatory pain using NFAT5-heterozygous (Het) mice. To study inflammatory pain, we injected 10 µL of 2% formalin into the right hind paws of mice and monitored pain behaviors, such as licking, lifting, and flinching, for 60 min. After the first 15 min (phase I), there were no significant differences in pain behaviors between wild-type (WT) and NFAT5-Het mice. However, from 15-60 min (phase II), NFAT5-Het mice displayed significantly fewer pain behaviors compared to WT mice. Further, the expression levels of inflammatory-pain-related factors, including c-Fos, phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated n-methyl-D-aspartate receptor subunit 2B (p-NR2B), were significantly elevated in the spinal dorsal neurons of formalin-treated WT mice but was not elevated in NFAT5-Het mice. Similarly, c-Fos, p-ERK, and p-NR2B levels were significantly higher in glutamate-treated PC12 neuronal cells but were not affected by Nfat5 silencing in glutamate-treated PC12 cells. Altogether, our findings suggest that NFAT5 deficiency may mitigate formalin-induced inflammatory pain by upregulating mammalian target of rapamycin (mTOR) expression and downregulating its downstream factors in spinal dorsal neurons. Therefore, NFAT5 is a potential therapeutic target for the treatment of inflammatory pain.

Development and Validation of a Short-Form Internet Overuse Screening Questionnaire for Adults.

AIMS: The aim of the current study was to develop and validate a short-form of the internet overuse screening questionnaire (IOS-Qs). METHODS: A total of 571 adults were recruited from a representative, stratified, and multistage cluster sample. Among participants, 188 and 383 were used in the development and validation of the IOS-Qs, respectively. RESULTS: Experts' ratings and Rasch model analyses led to the selection of 8 items from the IOS-Qs; latent-class analysis using these 8 items revealed an estimated prevalence of 8.6% (33 out of 383) of problematic internet over-users. Problematic internet over-users were positively associated with a 1-year prevalence rate of any mental disorder (OR 3.08, p = 0.008), mood disorder (OR 7.11, p = 0.003), and depressive disorder (OR 5.22, p = 0.016). The receiver operating characteristic curves identified an optimal cutoff score of 9.5 for differentiating problematic internet over-users from unproblematic internet users with 94% sensitivity and 94% specificity. CONCLUSION: The results suggest that the IOS-Qs was valid, and items including social isolation were crucial to the brief distinction of at-risk internet users. Because of its brevity, the questionnaire can be effectively administered as a large-scale survey.

BMAL1 Suppresses Proliferation, Migration, and Invasion of U87MG Cells by Downregulating Cyclin B1, Phospho-AKT, and Metalloproteinase-9.

Several studies have shown that brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1), an important molecule for maintaining circadian rhythms, inhibits the growth and metastasis of tumor cells in several types of cancer, including lung, colon, and breast cancer. However, its role in glioblastoma has not yet been established. Here, we addressed the function of BMAL1 in U87MG glioblastoma cells with two approaches-loss and gain of function. In the loss of function experiments, cell proliferation in U87MG cells transfected with small interfering RNA (siRNA) targeting BMAL1 was increased by approximately 24% (small interfering (si)-NC 0.91 ± 0.00 vs. si-BMAL1 1.129 ± 0.08) via upregulation of cyclin B1. In addition, cell migration and invasion of BMAL1 siRNA-treated glioblastoma cells were elevated by approximately 20% (si-NC 51.00 ± 1.53 vs. si-BMAL161.33 ± 0.88) and 209% (si-NC 21.28 ± 1.37 vs. si-BMAL1 44.47 ± 3.48), respectively, through the accumulation of phosphorylated-AKT (p-AKT) and matrix metalloproteinase (MMP)-9. Gain of function experiments revealed that adenovirus-mediated ectopic expression of BMAL1 in U87MG cells resulted in a 19% (Adenovirus (Ad)-vector 0.94± 0.03 vs. Ad-BMAL1 0.76 ± 0.03) decrease in cell proliferation compared with the control via downregulation of cyclin B1 and increased early and late apoptosis due to changes in the levels of BCL2-associated X protein (BAX), B-cell lymphoma 2 (BCL-2), and cleaved caspase-3. Likewise, cell migration and invasion were attenuated by approximately 24% (Ad-vector 55.00 ± 0.00 vs. Ad-BMAL1 41.83 ± 2.90) and 49% (Ad-vector 70.01 ± 1.24 vs. Ad-BMAL1 35.55 ± 1.78), respectively, in BMAL1-overexpressing U87MG cells following downregulation of p-AKT and MMP-9. Taken together, our results suggest that BMAL1 acts as an anti-cancer gene by altering the proliferation, migration, and invasion of glioblastoma cells. Therefore, the BMAL1 gene could be a potential therapeutic target in the treatment of glioblastoma.

Foxp3 plasmid-encapsulated PLGA nanoparticles attenuate pain behavior in rats with spinal nerve ligation.

Microglia play a critical role in neuropathic pain. Since upregulated Foxp3 in microglia enhances tissue repair by resolving neuroinflammation in excitotoxin-induced neuronal death, it may attenuate neuropathic pain in a similar manner. Therefore, this study tests whether Foxp3 introduced with poly (D, L-lactic-co-glycolic acid) (PLGA) nanoparticles (Foxp3 NPs) can alleviate neuropathic pain by inhibiting microglia activity. The prepared Foxp3 NPs had an anti-inflammatory effect on lipopolysaccharide-stimulated BV2 cells in vitro, and localized to spinal microglia in vivo. Further, the Foxp3 NPs significantly attenuated pain behavior induced by spinal nerve ligation in rats for 7 days by suppressing microglial activity, followed by the downregulation of pro-nociceptive genes and the upregulation of anti-nociceptive genes in the spinal dorsal horn. Collectively, these data suggest that Foxp3 NPs effectively relieve neuropathic pain in animals by reducing microglia activity and subsequent modulation of neuroinflammation, and may be of therapeutic value in the treatment of neuropathic pain.

Evans Blue Reduces Neuropathic Pain Behavior by Inhibiting Spinal ATP Release.

Upon peripheral nerve injury, vesicular ATP is released from damaged primary afferent neurons. This extracellular ATP subsequently activates purinergic receptors of the spinal cord, which play a critical role in neuropathic pain. As an inhibitor of the vesicular nucleotide transporter (VNUT), Evans blue (EB) inhibits the vesicular storage and release of ATP in neurons. Thus, we tested whether EB could attenuate neuropathic pain behavior induced by spinal nerve ligation (SNL) in rats by targeting VNUT. An intrathecal injection of EB efficiently attenuated mechanical allodynia for five days in a dose-dependent manner and enhanced locomotive activity in an SNL rat model. Immunohistochemical analysis showed that EB was found in VNUT immunoreactivity on neurons in the dorsal root ganglion and the spinal dorsal horn. The level of ATP in cerebrospinal fluid in rats with SNL-induced neuropathic pain decreased upon administration of EB. Interestingly, EB blocked ATP release from neurons, but not glial cells in vitro. Eventually, the loss of ATP decreased microglial activity in the ipsilateral dorsal horn of the spinal cord, followed by a reduction in reactive oxygen species and proinflammatory mediators, such as interleukin (IL)-1ß and IL-6. Finally, a similar analgesic effect of EB was demonstrated in rats with monoiodoacetate-induced osteoarthritis (OA) pain. Taken together, these data demonstrate that EB prevents ATP release in the spinal dorsal horn and reduces the ATP/purinergic receptor-induced activation of spinal microglia followed by a decline in algogenic substances, thereby relieving neuropathic pain in rats with SNL.

Primary cilia modulate TLR4-mediated inflammatory responses in hippocampal neurons.

BACKGROUND: The primary cilium is an organelle that can act as a master regulator of cellular signaling. Despite the presence of primary cilia in hippocampal neurons, their function is not fully understood. Recent studies have demonstrated that the primary cilium influences interleukin (IL)-1ß-induced NF-κB signaling, ultimately mediating the inflammatory response. We, therefore, investigated ciliary function and NF-κB signaling in lipopolysaccharide (LPS)-induced neuroinflammation in conjunction with ciliary length analysis. METHODS: Since TLR4/NF-κB signaling is a well-known inflammatory pathway, we measured ciliary length and inflammatory mediators in wild type (WT) and TLR4-/- mice injected with LPS. Next, to exclude the effects of microglial TLR4, we examined the ciliary length, ciliary components, inflammatory cytokine, and mediators in HT22 hippocampal neuronal cells. RESULTS: Primary ciliary length decreased in hippocampal pyramidal neurons after intracerebroventricular injection of LPS in WT mice, whereas it increased in TLR4-/- mice. LPS treatment decreased primary ciliary length, activated NF-κB signaling, and increased Cox2 and iNOS levels in HT22 hippocampal neurons. In contrast, silencing Kif3a, a key protein component of cilia, increased ARL13B ciliary protein levels and suppressed NF-κB signaling and expression of inflammatory mediators. CONCLUSIONS: These data suggest that LPS-induced NF-κB signaling and inflammatory mediator expression are modulated by cilia and that the blockade of primary cilium formation by Kif3a siRNA regulates TLR4-induced NF-κB signaling. We propose that primary cilia are critical for regulating NF-κB signaling events in neuroinflammation and in the innate immune response.

Internet Game Addiction, Depression, and Escape From Negative Emotions in Adulthood: A Nationwide Community Sample of Korea.

The aim of this study was to investigate the association between adult Internet game addiction (IGA) and mental disorders. A total of 1401 adults aged between 18 and 74 years participated in this study. The IGA group had significantly younger patients, and it showed a higher proportion of unmarried and unemployed adults, and higher rates of suicidal ideation, plan, and attempt than the non-IGA group. Multivariate logistic regression indicated that IGA was significantly associated with major depressive disorder, dysthymia, and depressive disorders adjusting for all variables. The Patient Health Questionnaire-9 score was significantly higher in the IGA group than in the non-IGA group for both young adults and middle groups. "Escape from negative emotions like nervousness, sadness, and anger" was the only significant item associated with depression among symptoms of IGA. This study suggests that adults with IGA and depression may use Internet games to escape from negative emotions.

Plasma glial cell line-derived neurotrophic factor in patients with major depressive disorder: a preliminary study.

BACKGROUND: Some clinical studies have reported reduced peripheral glial cell line-derived neurotrophic factor (GDNF) level in elderly patients with major depressive disorder (MDD). We verified whether a reduction in plasma GDNF level was associated with MDD. METHOD: Plasma GDNF level was measured in 23 healthy control subjects and 23 MDD patients before and after 6 weeks of treatment. RESULTS: Plasma GDNF level in MDD patients at baseline did not differ from that in healthy controls. Plasma GDNF in MDD patients did not differ significantly from baseline to the end of treatment. GDNF level was significantly lower in recurrent-episode MDD patients than in first-episode patients before and after treatment. CONCLUSIONS: Our findings revealed significantly lower plasma GDNF level in recurrent-episode MDD patients, although plasma GDNF levels in MDD patients and healthy controls did not differ significantly. The discrepancy between our study and previous studies might arise from differences in the recurrence of depression or the ages of the MDD patients.

The inhibitory effects of bupivacaine, levobupivacaine, and ropivacaine on K2P (two-pore domain potassium) channel TREK-1.

PURPOSE: Bupivacaine, levobupivacaine, and ropivacaine are amide local anesthetics. Levobupivacaine and ropivacaine are stereoisomers of bupivacaine and were developed to circumvent the bupivacaine's severe toxicity. The recently characterized background potassium channel, K(2P) TREK-1, is a well-known target for various local anesthetics. The purpose of study is to investigate the differences in inhibitory potency and stereoselectivity among bupivacaine, levobupivacaine, and ropivacaine on K(2P) TREK-1 channels overexpressed in COS-7 cells. METHODS: We investigated the effects of bupivacaine, levobupivacaine, and ropivacaine (10, 50, 100, 200, and 400 µM) on TREK-1 channels expressed in COS-7 cells by using the whole cell patch clamp technique with a voltage ramp protocol ranging from -100 to 100 mV for 200 ms from a holding potential of -70 mV. RESULTS: Bupivacaine, levobupivacaine, and ropivacaine showed reversible inhibition of TREK-1 channels in a concentration-dependent manner. The half-maximal inhibitory concentrations (IC(50)) of bupivacaine, levobupivacaine, and ropivacaine were 95.4 ± 14.6, 126.1 ± 24.5, and 402.7 ± 31.8 µM, respectively. IC(50) values indicated a rank order of potency (bupivacaine > levobupivacaine > ropivacaine) with stereoselectivity. Hill coefficients were 0.84, 0.93, and 0.89 for bupivacaine, levobupivacaine, and ropivacaine, respectively. CONCLUSION: Inhibitory effects on TREK-1 channels by bupivacaine, levobupivacaine, and ropivacaine demonstrated stereoselectivity: bupivacaine was more potent than levobupivacaine and ropivacaine. Inhibition of TREK-1 channels and consecutive depolarization of the cell membrane by bupivacaine, levobupivacaine, and ropivacaine may contribute to the blockade of neuronal conduction and side effects.

Effects of Preoperative Glucocorticoid Use on Patients Undergoing Single-Level Lumbar Fusions: A Retrospective Propensity Score-Matched Registry Study.

Objective Spinal fusions are gaining popularity as a means of treating spinal deformity and instability from a range of pathologies. The prevalence of glucocorticoid use has also increased in recent decades, and their systemic effects are well-documented. Although commonly used in the preoperative period, the effects of steroids on outcomes among patients undergoing spinal fusions are inadequately described. This study compares the odds of developing complications among patients who underwent single-level lumbar fusions with and without preoperative glucocorticoid use in hopes of establishing more evidence-based parameters for guiding preoperative steroid use. Methods The TriNetX multi-institutional electronic health record database was used to perform a retrospective, propensity score-matched analysis of clinical outcomes of two cohorts of patients who underwent posterior or posterolateral single-level lumbar fusions with and without interbody fusion, those who used glucocorticoids for at least one week within a year of fusion and those who did not. The outcomes of interest were examined within 30 days of the operation and included death, reoperation, deep or superficial surgical site infection (SSI), pneumonia, reintubation, ventilator dependence, tracheostomy, acute kidney injury (AKI), renal insufficiency, pulmonary embolism (PE) or deep venous thrombosis (DVT), urinary tract infection (UTI), emergency department (ED) visit, sepsis, and myocardial infarction (MI). Results The odds of developing pneumonia within 30 days of spinal fusion in the cohort that used glucocorticoids within one year of operation compared to the cohort without glucocorticoid use was 0.67 (p≤0.001, 95% CI: 0.59-0.69). The odds of requiring a tracheostomy within 30 days of spinal fusion in the cohort that used glucocorticoids within one year of operation compared to the cohort without glucocorticoid use was 0.39 (p≤0.001, 95% CI: 0.26-0.60). The odds of reoperation, deep and superficial SSI, and ED visits within 30 days of operation were significantly higher for the same glucocorticoid-receiving cohort, with odds ratios of 1.4 (p=0.003, 95% CI: 1.11-1.65), 1.86 (p≤0.001, 95% CI: 1.31-2.63), 2.28 (p≤0.001, 95% CI: 1.57-3.31), and 1.25 (p≤0.001, 95% CI: 1.17-1.33), respectively. After propensity score-matching, there was no significant difference between the odds of death, DVT, PE, MI, UTI, AKI, sepsis, reintubation, and ventilator dependence between the two cohorts. Conclusion In support of much of the current literature regarding preoperative glucocorticoid use and rates of complications, patients who underwent a single-level lumbar fusion and have used glucocorticoids for at least a week within a year of operation experienced significantly higher odds of reoperation, deep and superficial SSI, and ED visits. However, these patients using glucocorticoids were also found to have lower odds of developing pneumonia, renal insufficiency, and tracheostomy requirement than those who did not use steroids within a year of surgery.

Exploring the Ramifications of Delayed Hospital Discharges: Impacts on Patients, Physicians, and Healthcare Systems.

Prolonged hospital stays can significantly impede patients' recovery, negatively affecting anything from physical health via issues like hospital-acquired infections and increased complications due to immobility to psychological health. Several studies investigated the psychosocial impact of prolonged hospital stays, revealing a variety of patient perspectives, such as feeling uncertain and frustrated about their conditions, which can erode their trust in healthcare providers. Delayed discharges not only affect patients but also have multifaceted effects on healthcare providers, potentially reducing physician efficiency and contributing to higher rates of burnout among healthcare professionals. This article investigates the consequences of delayed versus early discharge on physicians, patients, and the overall hospital system. We conducted an extensive search through PubMed and Google Scholar using the keywords "delayed discharge," "hospital discharge," and "bed blocking" to identify all the recent studies highlighting the dynamics of patient discharge. Our results support the hypothesis that reducing delayed discharge rates will not only improve patient outcomes but also have widespread fiscal impacts. This review also outlines measures to reduce delayed discharges, ultimately leading to a significant enhancement in the healthcare system.

Non-volatile reconfigurable spin logic functions in a two-channel Hall bar by spin-orbit torque-based magnetic domains and directional read current.

A long-standing goal of CMOS-based logic devices is to meet the needs of key markets, including ultralow-power operation and high operation speed, along with the continuing miniaturization of the architecture. However, despite significant progress in their development, conventional CMOS-based devices still suffer from drawbacks such as introducing large unintended leakage currents and volatile behavior. Thus, reconfigurable logic gates based on magnetic domain (MD) have emerged as a highly promising option because they offer fast operation speeds, nonvolatility, and diverse logic functions in a single-device configuration. Here, we address multiple reconfigurable MD logic gates in a single two-channel Hall bar device by varying the voltage-driven read-current directions and selecting a non-inverting or inverting comparator in W/CoFeB/MgO/Ta stacks. The non-volatile MD switching behavior induced by spin-orbit torque significantly affects our logic gate functions, which are not necessarily synchronized to a single clock. By adapting MD switching by spin-orbit torque and anomalous Hall effect voltage outputs, we identified eight reconfigurable logic gates, including AND, NAND, NOR, OR, INH, Converse INH, Converse IMP, and IMP, in a single device. These experimental findings represent a significant step forward in a wide range of MD-based logic applications in the near future.

Near-real-time global gridded daily CO2 emissions 2021.

We present a near-real-time global gridded daily CO2 emissions dataset (GRACED) throughout 2021. GRACED provides gridded CO2 emissions at a 0.1° × 0.1° spatial resolution and 1-day temporal resolution from cement production and fossil fuel combustion over seven sectors, including industry, power, residential consumption, ground transportation, international aviation, domestic aviation, and international shipping. GRACED is prepared from the near-real-time daily national CO2 emissions estimates (Carbon Monitor), multi-source spatial activity data emissions and satellite NO2 data for time variations of those spatial activity data. GRACED provides the most timely overview of emissions distribution changes, which enables more accurate and timely identification of when and where fossil CO2 emissions have rebounded and decreased. Uncertainty analysis of GRACED gives a grid-level two-sigma uncertainty of value of ±19.9% in 2021, indicating the reliability of GRACED was not sacrificed for the sake of higher spatiotemporal resolution that GRACED provides. Continuing to update GRACED in a timely manner could help policymakers monitor energy and climate policies' effectiveness and make adjustments quickly.

Imiquimod enhances excitability of dorsal root ganglion neurons by inhibiting background (K(2P)) and voltage-gated (K(v)1.1 and K(v)1.2) potassium channels.

BACKGROUND: Imiquimod (IQ) is known as an agonist of Toll-like receptor 7 (TLR7) and is widely used to treat various infectious skin diseases. However, it causes severe itching sensation as its side effect. The precise mechanism of how IQ causes itching sensation is unknown. A recent report suggested a molecular target of IQ as TLR7 expressed in dorsal root ganglion (DRG) neurons. However, we recently proposed a TLR7-independent mechanism, in which the activation of TLR7 is not required for the action of IQ in DRG neurons. To resolve this controversy regarding the involvement of TLR7 and to address the exact molecular identity of itching sensation by IQ, we investigated the possible molecular target of IQ in DRG neurons. FINDINGS: When IQ was applied to DRG neurons, we observed an increase in action potential (AP) duration and membrane resistance both in wild type and TLR7-deficient mice. Based on these results, we tested whether the treatment of IQ has an effect on the activity of K(+) channels, K(v)1.1 and K(v)1.2 (voltage-gated K(+) channels) and TREK1 and TRAAK (K(2P) channels). IQ effectively reduced the currents mediated by both K(+) channels in a dose-dependent manner, acting as an antagonist at TREK1 and TRAAK and as a partial antagonist at K(v)1.1 and K(v)1.2. CONCLUSIONS: Our results demonstrate that IQ blocks the voltage-gated K(+) channels to increase AP duration and K(2P) channels to increase membrane resistance, which are critical for the membrane excitability of DRG neurons. Therefore, we propose that IQ enhances the excitability of DRG neurons by blocking multiple potassium channels and causing pruritus.

Economic burden of depression in South Korea.

BACKGROUND: A recent national survey in South Korea indicated that the 12-month prevalence rate of major depressive disorder was 2.5%. Depressive disorders may lead to disability, premature death, and severe suffering of patients and their families. This study estimates the economic burden of depression in Korea from a societal perspective. METHODS: Annual direct healthcare costs associated with depression were calculated based on the National Health Insurance database. Annual direct non-healthcare costs were estimated for transport. Annual indirect costs were estimated for the following components of productivity loss due to illness such as morbidity (absenteeism and presenteeism) and premature mortality. Indirect costs were estimated using the large national psychiatric epidemiological surveys in Korea. The human capital approach was used to estimate indirect costs. RESULT: The total cost of depression was estimated to be $4,049 million, of which $152.6 million represents a direct healthcare cost. Total direct non-healthcare costs were estimated to be $15.9 million. Indirect costs were estimated at $3,880.5 million. The morbidity cost was $2,958.9 million and the mortality cost was $921.6 million. The morbidity cost was identified as the largest component of overall cost. CONCLUSION: Depression is a considerable burden on both society and the individual, especially in terms of incapacity to work. The Korean society should increase the public health effort to prevent and detect depression in order to ensure that appropriate treatment is provided. Such actions will lead to a significant reduction in the total burden resulting from depression.

Identification and characterization of triamcinolone acetonide, a microglial-activation inhibitor.

Recent studies show that necrotic neuronal cells (NNC) activate microglia, thereby leading to neuronal cell death. This suggests that chemicals that inhibit microglia activation may be used as neuroprotective drugs. In this context, we screened a chemical library for inhibitors of microglia activation. Using a screening system based on a nitrite assay, we isolated two chemicals that inhibit nitric oxide (NO) release from activated microglia: triamcinolone acetonide (TA) and amcinonide. The half-maximal inhibitory concentrations (IC50) of TA and amcinonide for NO release inhibition were 1.78 nM and 3.38 nM, respectively. These chemicals also inhibited NNC-induced expression of the proinflammatory genes iNOS, TNF-α, and IL-1ß in glial cells. A study based on a luciferase assay revealed that TA attenuated NNC-induced microglia activation by blocking the NF-κB signaling pathway. In addition, TA protected cortical neurons in coculture with microglia from LPS/IFN-γ-induced neuronal cell death. In conclusion, TA may inhibit microglia activation and may protect neuronal cells from death induced by microglial activation.

SARS-CoV-2 spike protein induces cognitive deficit and anxiety-like behavior in mouse via non-cell autonomous hippocampal neuronal death.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is accompanied by chronic neurological sequelae such as cognitive decline and mood disorder, but the underlying mechanisms have not yet been elucidated. We explored the possibility that the brain-infiltrating SARS-CoV-2 spike protein contributes to the development of neurological symptoms observed in COVID-19 patients in this study. Our behavioral study showed that administration of SARS-CoV-2 spike protein S1 subunit (S1 protein) to mouse hippocampus induced cognitive deficit and anxiety-like behavior in vivo. These neurological symptoms were accompanied by neuronal cell death in the dorsal and ventral hippocampus as well as glial cell activation. Interestingly, the S1 protein did not directly induce hippocampal cell death in vitro. Rather, it exerted neurotoxicity via glial cell activation, partially through interleukin-1ß induction. In conclusion, our data suggest a novel pathogenic mechanism for the COVID-19-associated neurological symptoms that involves glia activation and non-cell autonomous hippocampal neuronal death by the brain-infiltrating S1 protein.

Up-regulation of CPNE1 Appears to Enhance Cancer Progression in HER2-positive and Luminal A Breast Cancer Cells.

BACKGROUND/AIM: Copine 1 (CPNE1) is a calciumdependent phospholipid protein that has been shown to regulate the AKT serine/threonine kinase 1 (AKT) signaling pathway to mediate its function in various cell types. However, little is known about the physiological function of this protein in breast cancer cells. We aimed to investigate the prognostic and therapeutic value of CPNE1 in erb-b2 receptor tyrosine kinase 2 [human epidermal growth factor receptor 2 (HER2)]-positive and luminal A subtypes of breast cancer. MATERIALS AND METHODS: Western blotting, cell viability, wound-healing and invasion assays were performed on SK-BR3 and MCF-7 breast cancer cells with forced overexpression of CPNE1. CPNE1 immunohistochemical (IHC) staining and bioinformatics analysis were performed on specimens from patients with breast cancer and compared to normal breast samples. RESULTS: CPNE1 overexpression promoted AKT activation, and increased cell viability and cell motility in SK-BR3 and MCF-7 breast cancer cells. In addition, invasive capabilities of SK-BR3 cells were increased by the overexpression of CPNE1. The expression levels of CPNE1 were higher in HER2-positive and luminal A subtypes of human breast cancer tissues compared with those in adjacent normal tissues. Furthermore, CPNE1 expression was increased in RNA microarray analysis of samples from patients with breast cancer compared to normal breast samples. CONCLUSION: CPNE1 may play a key role in the pathophysiology of HER2-positive and luminal A subtypes of breast cancer.