Improving Clinician Performance in Classifying EEG Patterns on the Ictal-Interictal Injury Continuum Using Interpretable Machine Learning.

BACKGROUND: In intensive care units (ICUs), critically ill patients are monitored with electroencephalography (EEG) to prevent serious brain injury. EEG monitoring is constrained by clinician availability, and EEG interpretation can be subjective and prone to interobserver variability. Automated deep-learning systems for EEG could reduce human bias and accelerate the diagnostic process. However, existing uninterpretable (black-box) deep-learning models are untrustworthy, difficult to troubleshoot, and lack accountability in real-world applications, leading to a lack of both trust and adoption by clinicians. METHODS: We developed an interpretable deep-learning system that accurately classifies six patterns of potentially harmful EEG activity - seizure, lateralized periodic discharges (LPDs), generalized periodic discharges (GPDs), lateralized rhythmic delta activity (LRDA), generalized rhythmic delta activity (GRDA), and other patterns - while providing faithful case-based explanations of its predictions. The model was trained on 50,697 total 50-second continuous EEG samples collected from 2711 patients in the ICU between July 2006 and March 2020 at Massachusetts General Hospital. EEG samples were labeled as one of the six EEG patterns by 124 domain experts and trained annotators. To evaluate the model, we asked eight medical professionals with relevant backgrounds to classify 100 EEG samples into the six pattern categories - once with and once without artificial intelligence (AI) assistance - and we assessed the assistive power of this interpretable system by comparing the diagnostic accuracy of the two methods. The model's discriminatory performance was evaluated with area under the receiver-operating characteristic curve (AUROC) and area under the precision-recall curve. The model's interpretability was measured with task-specific neighborhood agreement statistics that interrogated the similarities of samples and features. In a separate analysis, the latent space of the neural network was visualized by using dimension reduction techniques to examine whether the ictal-interictal injury continuum hypothesis, which asserts that seizures and seizure-like patterns of brain activity lie along a spectrum, is supported by data. RESULTS: The performance of all users significantly improved when provided with AI assistance. Mean user diagnostic accuracy improved from 47 to 71% (P<0.04). The model achieved AUROCs of 0.87, 0.93, 0.96, 0.92, 0.93, and 0.80 for the classes seizure, LPD, GPD, LRDA, GRDA, and other patterns, respectively. This performance was significantly higher than that of a corresponding uninterpretable black-box model (with P<0.0001). Videos traversing the ictal-interictal injury manifold from dimension reduction (a two-dimensional representation of the original high-dimensional feature space) give insight into the layout of EEG patterns within the network's latent space and illuminate relationships between EEG patterns that were previously hypothesized but had not yet been shown explicitly. These results indicate that the ictal-interictal injury continuum hypothesis is supported by data. CONCLUSIONS: Users showed significant pattern classification accuracy improvement with the assistance of this interpretable deep-learning model. The interpretable design facilitates effective human-AI collaboration; this system may improve diagnosis and patient care in clinical settings. The model may also provide a better understanding of how EEG patterns relate to each other along the ictal-interictal injury continuum. (Funded by the National Science Foundation, National Institutes of Health, and others.).

Effect of Chinese quince proanthocyanidins on the inhibition of heterocyclic amines and quality of fried chicken meatballs and tofu.

Heterocyclic amines (HCAs) have potential carcinogenic and mutagenic activity and are generated in cooked protein-rich foods. Adding proanthocyanidins (PAs) to these foods before frying is an effective way to reduce HCAs. In this study, polymeric PAs (PPA) and ultrasound-assisted acid-catalyzed/catechin nucleophilic depolymerized PAs (UAPA, a type of oligomeric PA) were prepared from Chinese quince fruits (CQF). Different levels of PPA and UAPA (0.05%, 0.1%, and 0.15%) were added to chicken meatballs and tofu; then these foods were fried, and the content of HCAs in them after frying was investigated. The results showed that PPA and, particularly, UAPA significantly inhibited the formation of HCAs in fried meatballs and tofu, and this inhibition was dose-dependent. The inhibition of HCAs by both PPA and UAPA was stronger in the chicken meatballs than in fried tofu. The level of total HCAs was significantly reduced by 57.84% (from 11.93 to 5.03 ng/g) after treatment of meatballs with 0.15% UAPA, with inhibition rates of 78.94%, 50.37%, and 17.81% for norharman, harman, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), respectively. Of note, there was a negative correlation between water, lipid, protein, creatine, and glucose content and HCA content in the crust, interior, and whole (crust-plus-interior) measurements of all fried samples. Interestingly, PPA and UAPA were found more effective in inhibiting HCAs in the exterior crust than in the interior of the fried chicken meatballs. These results provide evidence that further studies on the reduction of the formation of harmful HCAs in fried foods by adding CQF PAs could be valuable to the fried food industry. PRACTICAL APPLICATION: Chinese quince proanthocyanidins treatments significantly inhibited the generation of heterocyclic amines (HCAs) in chicken meatballs and tofu when deep-fried. These results suggest that Chinese quince proanthocyanidins can be used as natural food additive for reducing HCAs in fried foods, laying the foundation for using Chinese quince fruit proanthocyanidins for HCA inhibition in the food industry.

A randomized controlled educational pilot trial of interictal epileptiform discharge identification for neurology residents.

OBJECTIVE: To assess the effectiveness of an educational program leveraging technology-enhanced learning and retrieval practice to teach trainees how to correctly identify interictal epileptiform discharges (IEDs). METHODS: This was a bi-institutional prospective randomized controlled educational trial involving junior neurology residents. The intervention consisted of three video tutorials focused on the six IFCN criteria for IED identification and rating 500 candidate IEDs with instant feedback either on a web browser (intervention 1) or an iOS app (intervention 2). The control group underwent no educational intervention ("inactive control"). All residents completed a survey and a test at the onset and offset of the study. Performance metrics were calculated for each participant. RESULTS: Twenty-one residents completed the study: control (n = 8); intervention 1 (n = 6); intervention 2 (n = 7). All but two had no prior EEG experience. Intervention 1 residents improved from baseline (mean) in multiple metrics including AUC (.74; .85; p < .05), sensitivity (.53; .75; p < .05), and level of confidence (LOC) in identifying IEDs/committing patients to therapy (1.33; 2.33; p < .05). Intervention 2 residents improved in multiple metrics including AUC (.81; .86; p < .05) and LOC in identifying IEDs (2.00; 3.14; p < .05) and spike-wave discharges (2.00; 3.14; p < .05). Controls had no significant improvements in any measure. SIGNIFICANCE: This program led to significant subjective and objective improvements in IED identification. Rating candidate IEDs with instant feedback on a web browser (intervention 1) generated greater objective improvement in comparison to rating candidate IEDs on an iOS app (intervention 2). This program can complement trainee education concerning IED identification.

Modified Chinese quince oligomeric proanthocyanidin protects deep-frying oil quality by inhibiting oxidation.

Chinese quince (Chaenomeles sinensis) fruit is an underutilized resource, rich in proanthocyanidins with antioxidant ability but poor lipid solubility. In this study, a novel modified oligomeric proanthocyanidin (MOPA) was prepared, which exhibited favorable lipid solubility (354.52 mg/100 g). It showed higher radical scavenging abilities than commercial antioxidant-BHA (butylated hydroxyanisole), both at 0.4-0.5 mg/mL. The addition of MOPA (0.04 %wt.) significantly increased the oxidative stability index of the soybean oil from 5.52 to 8.03 h, which was slightly lower than that of BHA (8.35 h). Analysis of the physicochemical properties and composition of oil during deep-frying showed that MOPA demonstrated significant antioxidant effects and effectively restricted the oil oxidation. This inhibition also delays the formation of heterocyclic amines (HAs) in fried food, thereby reducing the migration of HAs from food to deep-frying oil. Therefore, MOPA is a promising novel liposoluble antioxidant for protecting the quality of deep-frying oil.

Efficacy and safety of the orthopaedic manipulation techniques of the Lin School of Lingnan Region in the treatment of adolescent idiopathic scoliosis: protocol of a participant-and-assessor-blinded randomized controlled study.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is the most common developmental spine disorder among children. It is characterized by a lateral deviation of the spine that gives rise to the distinctive "S" or "C" shaped bending of the spine. The Lin School of Lingnan Region (LSLR), one of the prominent schools for bare-handed orthopaedic manipulation in southern China, provides preliminary evidences that the orthopaedic manipulation techniques help to correct deviations of the spine. Previous research found that Orthopaedic Manipulation Techniques of LSLR (OMT-LSLR) could reduce the Cobb's angles in patients with AIS. Therefore, the current study aims to investigate the effectiveness and safety of the OMT-LSLR in treating teenagers with AIS. METHODS: In this participant-and-assessor-blinded randomized controlled clinical trial, 50 participants identified AIS without surgical indications will be recruited and randomized into two groups to receive physiotherapy scoliosis-specific exercises training with either orthopaedic manipulation or sham manipulation treatment for 16 weeks, followed by post-treatment visits at week 24. Primary outcome measure is the change of Scoliosis Research Society-22 (SRS-22) questionnaire score. Secondary outcome measures include Traditional Chinese version of Spinal Appearance Questionnaire (TC-SAQ) score, Italian Spine Youth Quality of Life (ISYQOL) score, the change of Cobb's angle measured by Xray, and the change of Cobb's angle, spinal rotation and muscle volume measured by three-dimensional (3D) ultrasound. The trial will be conducted at the Chinese University of Hong Kong Chinese Medicine Specialty Clinic cum Clinical Teaching and Research Centre in Hong Kong (CUHK-CMSCTRC). DISCUSSION: The results of this study will establish comprehensive clinical evidence about the efficacy and safety of the Orthopaedic Manipulation Techniques of the Lin School of Lingnan Region in the Treatment of Adolescent Idiopathic Scoliosis. One of the characteristics of this trial is that it is a participant-and-assessor-blinded randomized controlled clinical trial with sham manipulation. The study would also apply three-dimensional (3D) ultrasound technology to investigate the relationship between the change of the muscle volume and the spinal curve. TRIAL REGISTRATION: The trial is registered on ClinicalTrials.gov (Identifier: NCT05639023 ) on December 6, 2022.

A Bibliometric and Visual Analysis of Single Nucleotide Polymorphism Studies in Depression.

BACKGROUND: Genetic polymorphism has been proven to have an important association with depression, which can influence the risk of developing depression, the efficacy of medications, and adverse effects via metabolic and neurological pathways. Nonetheless, aspects of the association between single nucleotide polymorphisms and depression have not been systematically investigated by bibliometric analysis. OBJECTIVE: The aim of this study was to analyze the current status and trends of single nucleotide polymorphism research on depression through bibliometric and visual analysis. METHODS: The Web of Science Core Collection was used to retrieve 10,043 articles that were published between 1998 and 2021. CiteSpace (6.1 R4) was used to perform collaborative network analysis, co-citation analysis, co-occurrence analysis, and citation burst detection. RESULTS: The most productive and co-cited journals were the Journal of Affective Disorders and Biological Psychiatry, respectively, and an analysis of the references showed that the most recent research focused on the largest thematic cluster, "5-HT", reflecting the important research base in this area. "CYP2D6" has been in the spotlight since its emergence in 2009 and has become a research hotspot since its outbreak in 2019. However, "BDNF ", "COMT ", "older adults", "loci", and "DNA methylation" are also the new frontier of research, and some of them are currently in the process of exploration. CONCLUSION: These findings offer a useful perspective on existing research and potential future approaches in the study of the association between single nucleotide polymorphisms and depression, which may assist researchers in selecting appropriate collaborators or journals.

Spectral Flow Cytometry Analysis of Resident Tissue Macrophages.

Spectral flow cytometry improves flow cytometry panels by resolving the full emission spectra of individual fluorophores, allowing greater flexibility to incorporate more fluorochromes when designing multicolor panels. Additionally, the spectral approach captures the autofluorescence of a sample or cell population (e.g., macrophages, which are highly autofluorescent) that can be considered during unmixing for improved downstream analyses. As the increased complexity of macrophage heterogeneity unravels in the scientific community, it is crucial to obtain high-dimensional data at the single-cell level to resolve these populations.

iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer.

Microglia are specialized brain-resident macrophages that arise from primitive macrophages colonizing the embryonic brain1. Microglia contribute to multiple aspects of brain development, but their precise roles in the early human brain remain poorly understood owing to limited access to relevant tissues2-6. The generation of brain organoids from human induced pluripotent stem cells recapitulates some key features of human embryonic brain development7-10. However, current approaches do not incorporate microglia or address their role in organoid maturation11-21. Here we generated microglia-sufficient brain organoids by coculturing brain organoids with primitive-like macrophages generated from the same human induced pluripotent stem cells (iMac)22. In organoid cocultures, iMac differentiated into cells with microglia-like phenotypes and functions (iMicro) and modulated neuronal progenitor cell (NPC) differentiation, limiting NPC proliferation and promoting axonogenesis. Mechanistically, iMicro contained high levels of PLIN2+ lipid droplets that exported cholesterol and its esters, which were taken up by NPCs in the organoids. We also detected PLIN2+ lipid droplet-loaded microglia in mouse and human embryonic brains. Overall, our approach substantially advances current human brain organoid approaches by incorporating microglial cells, as illustrated by the discovery of a key pathway of lipid-mediated crosstalk between microglia and NPCs that leads to improved neurogenesis.

Dendritic cell type 3 arises from Ly6C+ monocyte-dendritic cell progenitors.

Conventional dendritic cells (cDCs) are professional antigen-presenting cells that control the adaptive immune response. Their subsets and developmental origins have been intensively investigated but are still not fully understood as their phenotypes, especially in the DC2 lineage and the recently described human DC3s, overlap with monocytes. Here, using LEGENDScreen to profile DC vs. monocyte lineages, we found sustained expression of FLT3 and CD45RB through the whole DC lineage, allowing DCs and their precursors to be distinguished from monocytes. Using fate mapping models, single-cell RNA sequencing and adoptive transfer, we identified a lineage of murine CD16/32+CD172a+ DC3, distinct from DC2, arising from Ly6C+ monocyte-DC progenitors (MDPs) through Lyz2+Ly6C+CD11c- pro-DC3s, whereas DC2s develop from common DC progenitors (CDPs) through CD7+Ly6C+CD11c+ pre-DC2s. Corresponding DC subsets, developmental stages, and lineages exist in humans. These findings reveal DC3 as a DC lineage phenotypically related to but developmentally different from monocytes and DC2s.

Individuals with chronic epilepsy have elevated P-wave heterogeneity comparable to patients with atrial fibrillation.

OBJECTIVE: Identification of epilepsy patients with elevated risk for atrial fibrillation (AF) is critical given the heightened morbidity and premature mortality associated with this arrhythmia. Epilepsy is a worldwide health problem affecting nearly 3.4 million people in the United States alone. The potential for increased risk for AF in patients with epilepsy is not well appreciated, despite recent evidence from a national survey of 1.4 million hospitalizations indicating that AF is the most common arrhythmia in people with epilepsy. METHODS: We analyzed inter-lead heterogeneity of P-wave morphology, a marker reflecting arrhythmogenic nonuniformities of activation/conduction in atrial tissue. The study groups consisted of 96 patients with epilepsy and 44 consecutive patients with AF in sinus rhythm before clinically indicated ablation. Individuals without cardiovascular or neurological conditions (n = 77) were also assessed. We calculated P-wave heterogeneity (PWH) by second central moment analysis of simultaneous beats from leads II, III, and aVR ("atrial dedicated leads") from standard 12-lead electrocardiography (ECG) recordings from admission day to the epilepsy monitoring unit (EMU). RESULTS: Female patients composed 62.5%, 59.6%, and 57.1% of the epilepsy, AF, and control subjects, respectively. The AF cohort was older (66 ± 1.1 years) than the epilepsy group (44 ± 1.8 years, p < .001). The level of PWH was greater in the epilepsy group than in the control group (67 ± 2.6 vs. 57 ± 2.5 µV, p = .046) and reached levels observed in AF patients (67 ± 2.6 vs. 68 ± 4.9 µV, p = .99). In multiple linear regression analysis, PWH levels in individuals with epilepsy were mainly correlated with the PR interval and could be related to sympathetic tone. Epilepsy remained associated with PWH after adjustments for cardiac risk factors, age, and sex. SIGNIFICANCE: Patients with chronic epilepsy have increased PWH comparable to levels observed in patients with AF, while being ~20 years younger, suggesting an acceleration in structural change and/or cardiac electrical instability. These observations are consistent with emerging evidence of an "epileptic heart" condition.

Interaction between Chinese quince fruit proanthocyanidins and bovine serum albumin: Antioxidant activity, thermal stability and heterocyclic amine inhibition.

Heterocyclic amines (HCAs) are carcinogenic and mutagenic substances produced in fried meat. Adding natural antioxidants (e.g., proanthocyanidins (PAs)) is a common method to reduce HCAs; however, the interaction between the PAs and protein can affect the inhibitory efficacy of PAs on the formation of HCAs. In this study, two PAs (F1 and F2) with different degrees of polymerization (DP) were extracted from Chinese quince fruits. These were combined with bovine serum albumin (BSA). The thermal stability, antioxidant capacity and HCAs inhibition of all four (F1, F2, F1-BSA, F2-BSA) were compared. The results showed that F1 and F2 interact with BSA to form complexes. Circular dichroism spectra indicate that complexes had fewer α-helices and more ß-sheets, ß-turns and random coils than BSA. Molecular docking studies indicated that hydrogen bonds and hydrophobic interactions are the forces holding the complexes together. The thermal stabilities of F1 and, particularly, F2 were stronger than those of F1-BSA and F2-BSA. Interestingly, F1-BSA and F2-BSA showed increased antioxidant activity with increasing temperature. F1-BSA's and F2-BSA's HCAs inhibition was stronger than F1 and F2, reaching 72.06 % and 76.3 %, respectively, for norharman. This suggests that PAs can be used as natural antioxidants for reducing the HCAs in fried foods.

Guidelines for mouse and human DC functional assays.

This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various non-lymphoid tissues. Recent studies have provided evidence for an increasing number of phenotypically distinct conventional DC (cDC) subsets that on one hand exhibit a certain functional plasticity, but on the other hand are characterized by their tissue- and context-dependent functional specialization. Here, we describe a selection of assays for the functional characterization of mouse and human cDC. The first two protocols illustrate analysis of cDC endocytosis and metabolism, followed by guidelines for transcriptomic and proteomic characterization of cDC populations. Then, a larger group of assays describes the characterization of cDC migration in vitro, ex vivo, and in vivo. The final guidelines measure cDC inflammasome and antigen (cross)-presentation activity. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.

Joint population pharmacokinetic modeling of venlafaxine and O-desmethyl venlafaxine in healthy volunteers and patients to evaluate the impact of morbidity and concomitant medication.

Introduction: Venlafaxine (VEN) is a widely used dual selective serotonin/noradrenaline reuptake inhibitor indicated for depression and anxiety. It undergoes first-pass metabolism to its active metabolite, O-desmethyl venlafaxine (ODV). The aim of the present study was to develop a joint population pharmacokinetic (PPK) model to characterize their pharmacokinetic characters simultaneously. Methods: Plasma concentrations with demographic and clinical data were derived from a bioequivalence study in 24 healthy subjects and a naturalistic TDM setting containing 127 psychiatric patients. A parent-metabolite PPK modeling was performed with NONMEM software using a non-linear mixed effect modeling approach. Goodness of fit plots and normalized prediction distribution error method were used for model validation. Results and conclusion: Concentrations of VEN and ODV were well described with a one-compartment model incorporating first-pass metabolism. The first-pass metabolism was modeled as a first-order conversion. The morbid state and concomitant amisulpride were identified as two significant covariates affecting the clearance of VEN and ODV, which may account for some of the variations in exposure. This model may contribute to the precision medication in clinical practice and may inspire other drugs with pre-system metabolism.

Population pharmacokinetics and dosing optimization of olanzapine in Chinese paediatric patients: Based on the impact of sex and concomitant valproate on clearance.

WHAT IS KNOWN AND OBJECTIVE: Olanzapine is an atypical antipsychotic drug used for mental disorders. There are limited studies providing sufficient pharmacokinetic data, thus the variability of concentrations of olanzapine used in Chinese paediatric patients aged 10 to 17 years remains to be evaluated. METHODS: Therapeutic drug monitoring data were collected from 151 paediatric patients aged 10 to 17 years who received olanzapine. The model was developed with a NONMEM software program. The final model validation and evaluation were assessed by bootstrap, diagnostic scatter plots, and normalized prediction distribution error (NPDE). Regimens of different dosages were simulated to reach the target concentration levels of 20 ng/ml, by using the final model with typical parameters. RESULTS: The one-compartment model was considered the best fit for the data. Typical estimates of the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) in the final model were 0.142 h-1 , 15.4 L/h, and 322 L, respectively. Sex and concomitant valproate (VPA) were included as significant predictors of olanzapine clearance, which was described by the following equation: CL/F = 15.4 × (1 + 0.546 × SEX) × (1 + 0.264 × VPA). Results of Monte-Carlo simulation suggested that male paediatric patients with concomitant VPA were advised to take no less than 15 mg per day of olanzapine orally, and in female paediatric patients with concomitant VPA, a dosing regimen of 10 mg may be sufficient to achieve the therapeutic range of olanzapine. WHAT IS NEW AND CONCLUSION: Our results identified concomitant valproate and sex as significant covariates in olanzapine population pharmacokinetics. Our model may be a useful tool for recommending dosage adjustments for physicians. The pharmacokinetics of olanzapine in patients aged 10 to 17 years was generally similar to that of adults and the elderly.

Pharmacokinetics of immediate and sustained-release formulations of paroxetine: Population pharmacokinetic approach to guide paroxetine personalized therapy in chinese psychotic patients.

Paroxetine is one of the most potent selective serotonin reuptake inhibitors (SSRIs) approved for treating depression, panic disorder, and obsessive-compulsive disorder. There is evidence linking genetic polymorphisms and nonlinear metabolism to the Paroxetine's pharmacokinetic (PK) variability. The purpose of the present study was to develop a population PK (PPK) model of paroxetine in Chinese patients, which was used to define the paroxetine's PK parameters and quantify the effect of clinical and baseline demographic factors on these PK characteristics. The study included 184 inpatients with psychosis (103 females and 81 males), with a total of 372 serum concentrations of paroxetine for PPK analyses. The total daily dosage ranged from 20 to 75 mg. One compartment model could fit the PKs characterize of paroxetine. Covariate analysis revealed that dose, formulation, and sex had a significant effect on the PK parameters of paroxetine; however, there was no evident genetic influence of CYP2D6 enzymes on paroxetine concentrations in Chinese patients. The study determined that the population's apparent distribution volume (V/F) and apparent clearance (CL/F), respectively, were 8850 and 21.2 L/h. The CL/F decreased 1-2-fold for each 10 mg dose increase, whereas the different formulations caused a decrease in V/F of 66.6%. Sex was found to affect bioavailability (F), which decreased F by 47.5%. Females had higher F values than males. This PPK model described data from patients with psychosis who received paroxetine immediate-release tablets (IR-T) and/or sustained-release tablets (SR-T). Paroxetine trough concentrations and relative bioavailability were different between formulations and sex. The altered serum concentrations of paroxetine resulting from individual variants and additive effects need to be considered, to optimize the dosage regimen for individual patients.

Acute symptomatic seizures and status epilepticus in older adults: A narrative review focusing on management and outcomes.

A clear narrative of acute symptomatic seizures (ASyS) in older adults is lacking. Older adults (≥60 years) have the highest incidence of seizures of all age groups and necessitate a tailored approach. ASyS has a bimodal peak in infancy and old age (82.3-123.2/100,000/year after 65 years of age). ASyS can represent half of the new-onset seizures in older adults and can progress to acute symptomatic status epilepticus (ASySE) in 52-72% of the patients. Common etiologies for ASyS in older adults include acute stroke and metabolic disturbances. For ASySE, common etiologies are acute stroke and anoxic brain injury (ABI). Initial testing for ASyS should be consistent with the most common and urgent etiologies. A 20-min electroencephalogram (EEG) is less sensitive in older adults than in younger adults and might not help predict chronic epilepsy. The prolonged postictal phase is an additional challenge for acute management. Studies note that 30% of older adults with ASyS subsequently develop epilepsy. The risk of wrongly equating ASyS as the first seizure of epilepsy is higher in older adults due to the increased long-term challenges with chronic anti-seizure medication (ASM) treatment. Specific challenges to managing ASyS in older adults are related to their chronic comorbidities and polypharmacy. It is unclear if the prognosis of ASyS is dependent on the underlying etiology. Short-term mortality is 1.6 to 3.6 times higher than younger adults. ASySE has high short-term mortality, especially when it is secondary to acute stroke. An acute symptomatic etiology of ASySE had five times increased risk of short-term mortality compared to other types of etiology.

Population pharmacokinetics model for escitalopram in Chinese psychiatric patients: effect of CYP2C19 and age.

Objective: To establish a population pharmacokinetic model in Chinese psychiatric patients to characterize escitalopram pharmacokinetic profile to identify factors influencing drug exposure, and through simulation to compare the results with the established therapeutic reference range. Methods: Demographic information, dosing regimen, CYP2C19 genotype, concomitant medications, and liver and kidney function indicators were retrospectively collected for inpatients taking escitalopram with therapeutic drug monitoring from 2018 to 2021. Nonlinear mixed-effects modeling was used to model the pharmacokinetic characteristics of escitalopram. Goodness-of-fit plots, bootstrapping, and normalized prediction distribution errors were used to evaluate the model. Simulation for different dosing regimens was based on the final estimations. Results: The study comprised 106 patients and 337 measurements of serum sample. A structural model with one compartment with first-order absorption and elimination described the data adequately. The population-estimated apparent volume of distribution and apparent clearance were 815 and 16.3 L/h, respectively. Age and CYP2C19 phenotype had a significant effect on the apparent clearance (CL/F). CL/F of escitalopram decreased with increased age, and CL/F of poor metabolizer patients was significantly lower than in extensive and immediate metabolizer patients. The final model-based simulation showed that the daily dose of adolescents with poor metabolizer might be as high as 15 mg or 20 mg and referring to the therapeutic range for adults may result in overdose and a high risk of adverse effects in older patients. Conclusion: A population pharmacokinetics model of escitalopram was successfully created for the Chinese population. Depending on the age of the patients, CYP2C19 genotype and serum drug concentrations throughout treatment are required for adequate individualization of dosing regimens. When developing a regimen for older patients, especially those who are poor metabolizers, vigilance is required.

Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration.

Brain macrophage populations include parenchymal microglia, border-associated macrophages, and recruited monocyte-derived cells; together, they control brain development and homeostasis but are also implicated in aging pathogenesis and neurodegeneration. The phenotypes, localization, and functions of each population in different contexts have yet to be resolved. We generated a murine brain myeloid scRNA-seq integration to systematically delineate brain macrophage populations. We show that the previously identified disease-associated microglia (DAM) population detected in murine Alzheimer's disease models actually comprises two ontogenetically and functionally distinct cell lineages: embryonically derived triggering receptor expressed on myeloid cells 2 (TREM2)-dependent DAM expressing a neuroprotective signature and monocyte-derived TREM2-expressing disease inflammatory macrophages (DIMs) accumulating in the brain during aging. These two distinct populations appear to also be conserved in the human brain. Herein, we generate an ontogeny-resolved model of brain myeloid cell heterogeneity in development, homeostasis, and disease and identify cellular targets for the treatment of neurodegeneration.

ISM1 protects lung homeostasis via cell-surface GRP78-mediated alveolar macrophage apoptosis.

Alveolar macrophages (AMs) are critical for lung immune defense and homeostasis. They are orchestrators of chronic obstructive pulmonary disease (COPD), with their number significantly increased and functions altered in COPD. However, it is unclear how AM number and function are controlled in a healthy lung and if changes in AMs without environmental assault are sufficient to trigger lung inflammation and COPD. We report here that absence of isthmin 1 (ISM1) in mice (Ism1-/- ) leads to increase in both AM number and functional heterogeneity, with enduring lung inflammation, progressive emphysema, and significant lung function decline, phenotypes similar to human COPD. We reveal that ISM1 is a lung resident anti-inflammatory protein that selectively triggers the apoptosis of AMs that harbor high levels of its receptor cell-surface GRP78 (csGRP78). csGRP78 is present at a heterogeneous level in the AMs of a healthy lung, but csGRP78high AMs are expanded in Ism1-/- mice, cigarette smoke (CS)-induced COPD mice, and human COPD lung, making these cells the prime targets of ISM1-mediated apoptosis. We show that csGRP78high AMs mostly express MMP-12, hence proinflammatory. Intratracheal delivery of recombinant ISM1 (rISM1) depleted csGRP78high AMs in both Ism1-/- and CS-induced COPD mice, blocked emphysema development, and preserved lung function. Consistently, ISM1 expression in human lungs positively correlates with AM apoptosis, suggesting similar function of ISM1-csGRP78 in human lungs. Our findings reveal that AM apoptosis regulation is an important physiological mechanism for maintaining lung homeostasis and demonstrate the potential of pulmonary-delivered rISM1 to target csGRP78 as a therapeutic strategy for COPD.

Proteomics and weighted gene correlated network analysis reveal glutamatergic synapse signaling in diazepam treatment of alcohol withdrawal.

Background: Alcohol use disorder (AUD) is characterized by chronic excessive alcohol consumption, often alternating with periods of abstinence known as alcohol withdrawal syndrome (AWS). Diazepam is the preferred benzodiazepine for treatment of alcohol withdrawal syndrome under most circumstances, but the specific mechanism underlying the treatment needs further research. Methods: We constructed an animal model of two-bottle choices and chronic intermittent ethanol exposure. LC-MS/MS proteomic analysis based on the label-free and intensity-based quantification approach was used to detect the protein profile of the whole brain. Weighted gene correlated network analysis was applied for scale-free network topology analysis. We established a protein-protein interaction network based on the Search Tool for the Retrieval of Interacting Genes (STRING) database and Cytoscape software and identified hub proteins by CytoHubba and MCODE plugins of Cytoscape. The online tool Targetscan identified miRNA-mRNA pair interactions. Results: Seven hub proteins (Dlg3, Dlg4, Shank3, Grin2b, Camk2b, Camk2a and Syngap1) were implicated in alcohol withdrawal syndrome or diazepam treatment. In enrichment analysis, glutamatergic synapses were considered the most important pathway related to alcohol use disorder. Decreased glutamatergic synapses were observed in the late stage of withdrawal, as a protective mechanism that attenuated withdrawal-induced excitotoxicity. Diazepam treatment during withdrawal increased glutamatergic synapses, alleviating withdrawal-induced synapse inhibition. Conclusion: Glutamatergic synapses are considered the most important pathway related to alcohol use disorder that may be a potential molecular target for new interventional strategies.