Mitochondrial cytochrome P450 1B1 is involved in pregnenolone synthesis in human brain cells.

Neurosteroids, which are steroids synthesized by the nervous system, can exert neuromodulatory and neuroprotective effects via genomic and nongenomic pathways. The neurosteroid and major steroid precursor pregnenolone has therapeutical potential in various diseases, such as psychiatric and pain disorders, and may play important roles in myelination, neuroinflammation, neurotransmission, and neuroplasticity. Although pregnenolone is synthesized by CYP11A1 in peripheral steroidogenic organs, our recent study showed that pregnenolone must be synthesized by another mitochondrial cytochrome P450 (CYP450) enzyme other than CYP11A1 in human glial cells. Therefore, we sought to identify the CYP450 responsible for pregnenolone production in the human brain. Upon screening for CYP450s expressed in the human brain that have mitochondrial localization, we identified three enzyme candidates: CYP27A1, CYP1A1, and CYP1B1. We found that inhibition of CYP27A1 through inhibitors and siRNA knockdown did not negatively affect pregnenolone synthesis in human glial cells. Meanwhile, treatment of human glial cells with CYP1A1/CYP1B1 inhibitors significantly reduced pregnenolone production in the presence of 22(R)-hydroxycholesterol. We performed siRNA knockdown of CYP1A1 or CYP1B1 in human glial cells and found that only CYP1B1 knockdown significantly decreased pregnenolone production. Furthermore, overexpression of mitochondria-targeted CYP1B1 significantly increased pregnenolone production under basal conditions and in the presence of hydroxycholesterols and low-density lipoprotein. Inhibition of CYP1A1 and/or CYP1B1 via inhibitors or siRNA knockdown did not significantly reduce pregnenolone synthesis in human adrenal cortical cells, implying that CYP1B1 is not a major pregnenolone-producing enzyme in the periphery. These data suggest that mitochondrial CYP1B1 is involved in pregnenolone synthesis in human glial cells.

The neurosteroid pregnenolone is synthesized by a mitochondrial P450 enzyme other than CYP11A1 in human glial cells.

Neurosteroids, modulators of neuronal and glial cell functions, are synthesized in the nervous system from cholesterol. In peripheral steroidogenic tissues, cholesterol is converted to the major steroid precursor pregnenolone by the CYP11A1 enzyme. Although pregnenolone is one of the most abundant neurosteroids in the brain, expression of CYP11A1 is difficult to detect. We found that human glial cells produced pregnenolone, detectable by mass spectrometry and ELISA, despite the absence of observable immunoreactive CYP11A1 protein. Unlike testicular and adrenal cortical cells, pregnenolone production in glial cells was not inhibited by CYP11A1 inhibitors DL-aminoglutethimide and ketoconazole. Furthermore, addition of hydroxycholesterols increased pregnenolone synthesis, suggesting desmolase activity that was not blocked by DL-aminoglutethimide or ketoconazole. We explored three different possibilities for an alternative pathway for glial cell pregnenolone synthesis: (1) regulation by reactive oxygen species, (2) metabolism via a different CYP11A1 isoform, and (3) metabolism via another CYP450 enzyme. First, we found oxidants and antioxidants had no significant effects on pregnenolone synthesis, suggesting it is not regulated by reactive oxygen species. Second, overexpression of CYP11A1 isoform b did not alter synthesis, indicating use of another CYP11A1 isoform is unlikely. Finally, we show nitric oxide and iron chelators deferoxamine and deferiprone significantly inhibited pregnenolone production, indicating involvement of another CYP450 enzyme. Ultimately, knockdown of endoplasmic reticulum cofactor NADPH-cytochrome P450 reductase had no effect, while knockdown of mitochondrial CYP450 cofactor ferredoxin reductase inhibited pregnenolone production. These data suggest that pregnenolone is synthesized by a mitochondrial cytochrome P450 enzyme other than CYP11A1 in human glial cells.

Neurosteroidogenic enzymes: CYP11A1 in the central nervous system.

Neurosteroids, steroid hormones synthesized locally in the nervous system, have important neuromodulatory and neuroprotective effects in the central nervous system. Progress in neurosteroid research has led to the successful translation of allopregnanolone into an approved therapy for postpartum depression. However, there is insufficient evidence to support the assumption that steroidogenesis is exactly the same between the nervous system and the periphery. This review focuses on CYP11A1, the only enzyme currently known to catalyze the first reaction in steroidogenesis to produce pregnenolone, the precursor to all other steroids. Although CYP11A1 mRNA has been found in brain of many mammals, the presence of CYP11A1 protein has been difficult to detect, particularly in humans. Here, we highlight the discrepancies in the current evidence for CYP11A1 in the central nervous system and propose new directions for understanding neurosteroidogenesis, which will be crucial for developing neurosteroid-based therapies for the future.

Sex effects on clinical features in LRRK2 G2385R carriers and non-carriers in Parkinson's disease.

BACKGROUND: Differences of genotypes between male and female have been studied in Parkinson's disease (PD), but limited research has focused on the comparison between sexes with LRRK2 G2385 variant. OBJECTIVE: The aim of this study was to explore sex effects in the same genetic subtype and role of leucine-rich repeat kinase 2 (LRRK2) G2385R variants in the same sex in PD. METHODS: 613 PD patients were recruited from the Movement Disorders Clinic in Ruijin Hospital. We did not include healthy controls in this study. The data collected includes demographic information, disease history, scores of motor and non-motor symptoms scales, midbrain transcranial sonography and DNA. Binary logistic regression analysis was performed to evaluate the association between clinical features and sex in LRRK2 G2385R carriers and non-carriers, as well as the association between the clinical features and LRRK2 G2385R variants in male and female sex. RESULTS: Sex distribution is similar in LRRK2 G2385R carriers and non-carriers. In male sex, LRRK2 G2385R carriers showed lower risk in cognitive impairment compared with non-carriers (OR = 0.301, p = 0.003, 95%CI 0.135-0.668). In female sex, LRRK2 G2385R carriers showed lower risk in autonomic dysfunction compared with non-carrier (OR = 0.401, p = 0.040, 95%CI 0.167-0.960). In LRRK2 G2385R non-carriers, female sex showed lower risk of impairment in activity of daily living (OR = 0.610, p = 0.021, 95%CI 0.400-0.928), excessive daytime sleepiness (OR = 0.555, p = 0.007, 95%CI 0.361-0.853), substantia nigra hyperechogenicity (OR = 0.448, p = 0.019, 95%CI 0.228-0.878), autonomic dysfunction frequency (OR = 0.626, p = 0.016, 95%CI 0.428-0.917) and higher risk in mood disorders (OR = 1.691, p = 0.022, 95%CI 1.078-2.654) compared with male. In LRRK2 G2385R carriers, female sex showed a lower risk of autonomic dysfunction (OR = 0.294, p = 0.024, 95%CI 0.102-0.849) compared with male. CONCLUSION: In contrast to male PD patients, a more benign disease course was observed in female in both LRRK2 G2385R carriers and non-carriers. However, sex differences were less notable in PD with LRRK2 G2385R variants.

Fast QLB algorithm and hypothesis tests in logistic model for ophthalmologic bilateral correlated data.

In ophthalmologic or otolaryngologic studies, bilateral correlated data often arise when observations involving paired organs (e.g., eyes, ears) are measured from each subject. Based on Donner's model , in this paper, we focus on investigating the relationship between the disease probability and covariates (such as ages, weights, gender, and so on) via the logistic regression for the analysis of bilateral correlated data. We first propose a new minorization-maximization (MM) algorithm and a fast quadratic lower bound (QLB) algorithm to calculate the maximum likelihood estimates of the vector of regression coefficients, and then develop three large-sample tests (i.e., the likelihood ratio test, Wald test, and score test) to test if covariates have a significant impact on the disease probability. Simulation studies are conducted to evaluate the performance of the proposed fast QLB algorithm and three testing methods. A real ophthalmologic data set in Iran is used to illustrate the proposed methods.

Midbrain/pons area ratio and clinical features predict the prognosis of progressive Supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a rare movement disorder with poor prognosis. This retrospective study aimed to characterize the natural history of PSP and to find predictors of shorter survival and faster decline of activity of daily living. METHOD: All patients recruited fulfilled the movement disorder society (MDS) clinical diagnostic criteria for PSP (MDS-PSP criteria) for probable and possible PSP with median 12 years. Data were obtained including age, sex, date of onset, age at onset (AAO), symptoms reported at first visit and follow-up, date of death and date of institutionalization. Magnetic resonance imaging was collected at the first visit. Endpoints were death and institutionalization. Kaplan-Meier method and Cox proportional hazard model were used to explore factors associated with early death and institutionalization. RESULTS: Fifty-nine patients fulfilling MDS-PSP criteria were enrolled in our study. Nineteen patients (32.2%) had died and 31 patients (52.5%) were institutionalized by the end of the follow-up. Predictors associated with poorer survival were late-onset PSP and decreased M/P area ratio. Predictors associated with earlier institutionalization were older AAO and decreased M/P area ratio. CONCLUSION: Older AAO and decreased M/P area ratio were predictors for earlier dearth and institutionalization in PSP. The neuroimaging biomarker M/P area ratio was a predictor for prognosis in PSP.

Serum soluble lymphocyte activation gene-3 as a diagnostic biomarker in Parkinson's disease: A pilot multicenter study.

OBJECTIVE: Lymphocyte activation gene-3 (LAG-3) could mediate pathological α-synuclein transmission in neurodegeneration and may be involved in the pathogenesis of Parkinson's disease (PD). The aim of the present study was to explore soluble LAG-3 (sLAG-3) as a potential diagnostic biomarker for PD. METHODS: Serum sLAG-3 concentrations were measured by a quantitative ELISA for patients with PD, essential tremor (ET) and age- and sex-matched controls. The relationships between sLAG-3 and clinical phenotype were assessed via correlation analysis and logistic regression. RESULTS: Serum sLAG-3 levels in patients with PD were significantly higher than those in ET patients and age- and sex-matched controls. The area under the curve of serum sLAG-3 in differentiating PD from age- and sex-matched controls was 0.82. Serum sLAG-3 was associated with non-motor symptoms and excessive daytime sleep. CONCLUSION: sLAG-3 is a candidate novel biomarker for PD. © 2018 International Parkinson and Movement Disorder Society.

Electro-Mechanical Ionic Channel Modeling for Uterine Contractions and Oxytocin Effect during Pregnancy.

Uterine contractions during normal pregnancy and preterm birth are an important physiological activity. Although the cause of preterm labor is usually unknown, preterm birth creates very serious health concerns in many cases. Therefore, understanding normal birth and predicting preterm birth can help both newborn babies and their families. In our previous work, we developed a multiscale dynamic electrophysiology model of uterine contractions. In this paper, we mainly focus on the cellular level and use electromyography (EMG) and cell force generation methods to construct a new ionic channel model and a corresponding mechanical force model. Specifically, the ionic channel model takes into consideration the knowledge of individual ionic channels, which include the electrochemical and bioelectrical characteristics of individual myocytes. We develop a new sodium channel and a new potassium channel based on the experimental data from the human myometrium and the average correlations are 0.9946 and 0.9945, respectively. The model is able to generate the single spike, plateau type and bursting type of action potentials. Moreover, we incorporate the effect of oxytocin on changing the properties of the L-type and T-type calcium channels and further influencing the output action potentials. In addition, we develop a mechanical force model based on the new ionic channel model that describes the detailed ionic dynamics. Our model produces cellular mechanical force that propagates to the tissue level. We illustrate the relationship between the cellular mechanical force and the intracellular ionic dynamics and discuss the relationship between the application of oxytocin and the output mechanical force. We also propose a simplified version of the model to enable large scale simulations using sensitivity analysis method. Our results show that the model is able to reproduce the bioelectrical and electromechanical characteristics of uterine contractions during pregnancy.

Shanghai cognitive intervention of mild cognitive impairment for delaying progress with longitudinal evaluation-a prospective, randomized controlled study (SIMPLE): rationale, design, and methodology.

BACKGROUND: Mild cognitive impairment is an early stage of Alzheimer's disease. Increasing evidence has indicated that cognitive training could improve cognitive abilities of MCI patients in multiple cognitive domains, making it a promising therapeutic approach for MCI. However, the effect of long-time training has not been widely explored. It is also necessary to evaluate the extent how it could reduce the convertion rate from MCI to AD. METHODS/DESIGN: The SIMPLE study is a multicenter, randomized, single-blind prospective clinical trial assessing the effects of computerized cognitive training on different cognitive domains in MCI patients. It is carried out in 7 centers in China. The study population includes patients aged 50-85, and they are randomly allocated to the training or control group. The primary outcome is to compare the conversion rate of MCI within 36-month follow-up. Structural and functional MRI will be used to interpret the effect of cognitive training. The cognitive training comprises a variety of games related with cognitive domains such as attention, memory, visualspatial ability and executive function. We cautiously set 50% reduction in the rate of conversion as estimated effect. With 80-90% statistical power and 12% as the overall probability of conversion within the study period, 600-800 patients are finally required in the study. The first patent has been recruited in April 2017. DISCUSSION: Previous studies suggested the benefit of cognitive training for MCI, but neither long-time nor Chinese culture were investigated. The SIMPLE designs and utilizes an improved computerized cognitive training approach and assesses its effects on MCI progress. In addition, neural activities explaining the effects on cognition function changes will be revealed, which could in turn to imply more useful therapeutic approaches. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03119051.

Prevalence and risk factors for depression and anxiety in Chinese patients with Parkinson disease.

BACKGROUND: Anxiety and depression are common in Parkinson disease and both are important determinants of quality of life in patients. Several risk factors are identified but few research have investigated general and Parkinson's disease (PD)-specific factors comprehensively. The aim of this work was to explore PD-specific and -non-specific risk factors for PD with depression or anxiety. METHODS: A cross-sectional survey was performed in 403 patients with PD. Multivariate logistic analysis was used to investigate the prevalence and risk factors for the depression and anxiety in PD. The data of patients included demographic information, medicine history, disease duration, age at onset (AAO), family history, anti-parkinsonism drug, modified Hoehn and Yahr staging (H-Y) stage, scales of motor and non-motor symptoms and substantia nigra (SN) echogenic areas. RESULTS: 403 PD patients were recruited in the study. Depression and anxiety were present in 11.17% and 25.81% respectively. Marital status, tumor, higher Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) II score, dyskinesia, higher Hamilton Anxiety Rating Scale (HARS) score and lower the Parkinson's disease sleep scale (PDSS) score were associated with depression in PD. female gender, higher rapid eye movement behavior disorder Questionnaire-Hong Kong (RBD-HK) score, higher Hamilton Deprssion Rating Scale (HAMD) score, higher the scale for outcomes in PD for autonomic symptoms (SCOPA-AUT)score and larger SN echogenic areas were associated with anxiety. Neither depression nor anxiety was related to any anti-parkinsonism drugs. CONCLUSIONS: The prevalence of depression and anxiety in the current PD patients was 11.17% and 25.81% respectively. Disease of tumor, currently having no partner, severer motor function, dyskinesia, poorer sleep quality and anxiety were risk factors for PD with depression. Female, depression, rapid eye movement behavior disorder (RBD), autonomic dysfunction and larger SN area were risk factors for PD with anxiety.

Performance of International Classification of Disease-10 codes in detecting emergency department patients with opioid misuse.

BACKGROUND AND AIMS: Accurate case discovery is critical for disease surveillance, resource allocation and research. International Classification of Disease (ICD) diagnosis codes are commonly used for this purpose. We aimed to determine the sensitivity, specificity and positive predictive value (PPV) of ICD-10 codes for opioid misuse case discovery in the emergency department (ED) setting. DESIGN AND SETTING: Retrospective cohort study of ED encounters from January 2018 to December 2020 at an urban academic hospital in the United States. A sample of ED encounters enriched for opioid misuse was developed by oversampling ED encounters with positive urine opiate screens or pre-existing opioid-related diagnosis codes in addition to other opioid misuse risk factors. CASES: A total of 1200 randomly selected encounters were annotated by research staff for the presence of opioid misuse within health record documentation using a 5-point scale for likelihood of opioid misuse and dichotomized into cohorts of opioid misuse and no opioid misuse. MEASUREMENTS: Using manual annotation as ground truth, the sensitivity and specificity of ICD-10 codes entered during the encounter were determined with PPV adjusted for oversampled data. Metrics were also determined by disposition subgroup: discharged home or admitted. FINDINGS: There were 541 encounters annotated as opioid misuse and 617 with no opioid misuse. The majority were males (54.4%), average age was 47 years and 68.5% were discharged directly from the ED. The sensitivity of ICD-10 codes was 0.56 (95% confidence interval [CI], 0.51-0.60), specificity 0.99 (95% CI, 0.97-0.99) and adjusted PPV 0.78 (95% CI, 0.65-0.92). The sensitivity was higher for patients discharged from the ED (0.65; 95% CI, 0.60-0.69) than those admitted (0.31; 95% CI, 0.24-0.39). CONCLUSIONS: International Classification of Disease-10 codes appear to have low sensitivity but high specificity and positive predictive value in detecting opioid misuse among emergency department patients in the United States.

Translocator protein in the rise and fall of central nervous system neurons.

Translocator protein (TSPO), a 18 kDa protein found in the outer mitochondrial membrane, has historically been associated with the transport of cholesterol in highly steroidogenic tissues though it is found in all cells throughout the mammalian body. TSPO has also been associated with molecular transport, oxidative stress, apoptosis, and energy metabolism. TSPO levels are typically low in the central nervous system (CNS), but a significant upregulation is observed in activated microglia during neuroinflammation. However, there are also a few specific regions that have been reported to have higher TSPO levels than the rest of the brain under normal conditions. These include the dentate gyrus of the hippocampus, the olfactory bulb, the subventricular zone, the choroid plexus, and the cerebellum. These areas are also all associated with adult neurogenesis, yet there is no explanation of TSPO's function in these cells. Current studies have investigated the role of TSPO in microglia during neuron degeneration, but TSPO's role in the rest of the neuron lifecycle remains to be elucidated. This review aims to discuss the known functions of TSPO and its potential role in the lifecycle of neurons within the CNS.

The complete mitochondrial genome of Batocera rubus Linnaeus, 1785 (Coleoptera: Cerambycidae).

Batocera rubus severely impacts on the health of banyan trees. In this study, the whole mitochondrial genome for B. rubus was found to be 16,158 bp with a GC content of 23.9%, including 39.1% A, 37.0% T, 14.8% C, and 9.1% G. This genome contains 13 protein-coding genes, 22 tRNAs, and two rRNAs. Phylogenetic analysis revealed that B. rubus is close to Batocera celebiana. This study provides valuable information that can help improve the classification and phylogeny of B. rubus and facilitate further evolutionary studies.

The complete mitochondrial genome of Tenebroides mauritanicus Linnaeus, 1758 (Coleoptera: Trogossitidae).

Tenebroides mauritanicus Linnaeus, 1758 (Coleoptera: Trogossitidae) is a storage pest that feeds mainly on soybean and corn. In this study, we sequenced the entire mitochondrial genome of Tenebroides mauritanicus (GenBank accession number: OM161967). The total length of the mitochondrial genome is 15,696 bp, GC content is 29.65%, and the contents of each base is 38.37% A, 18.35% C, 11.30% G and 31.98% T, respectively. The genome encodes 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs) and 2 ribosomal RNA genes (rRNAs). Phylogenetic analysis showed that Tenebroides mauritanicus is clustered with Byturus ochraceus. This study provides a piece of valuable genomic information for the population genetics, phylogeny, and molecular taxonomy of Tenebroides mauritanicus.

Noninvasive electrophysiological imaging identifies 4D uterine peristalsis patterns in subjects with normal menstrual cycles and patients with endometriosis.

Throughout the menstrual cycle, spontaneous mild contractions in the inner layer of the uterine smooth muscle cause uterine peristalsis, which plays a critical role in normal menstruation and fertility. Disruptions in peristalsis patterns may occur in women experiencing subfertility, abnormal uterine bleeding, ovulatory dysfunction, endometriosis, and other disorders. However, current tools to measure uterine peristalsis in humans have limitations that hamper their research or clinical utilities. Here, we describe an electrophysiological imaging system to noninvasively quantify the four-dimensional (4D) electrical activation pattern during human uterine peristalsis with high spatial and temporal resolution and coverage. We longitudinally imaged 4968 uterine peristalses in 17 participants with normal gynecologic anatomy and physiology over 34 hours and 679 peristalses in 5 participants with endometriosis over 12.5 hours throughout the menstrual cycle. Our data provide quantitative evidence that uterine peristalsis changes in frequency, direction, duration, magnitude, and power throughout the menstrual cycle and is disrupted in endometriosis patients. Moreover, our data suggest that disrupted uterine peristalsis contributes to excess retrograde menstruation and infertility in patients with endometriosis and potentially contributes to infertility in this cohort.

Objective Sleep Duration and All-Cause Mortality Among People With Obstructive Sleep Apnea.

Importance: The association between sleep duration and all-cause mortality remains unclear among people with obstructive sleep apnea (OSA). Objective: To explore whether there is an association between sleep duration and all-cause mortality among people with OSA. Design, Setting, and Participants: This cohort study investigated participants with OSA from the Sleep Heart Health Study (SHHS) in which participants were enrolled between 1995 and 1998 with questionnaires and polysomnography (PSG) assessment and followed up for a median of 11.8 years. SHHS was a multicenter community-based study; 2574 participants with OSA defined by apnea-hypopnea index (AHI) greater than or equal to 15 from SHHS were found; all of them had all-cause mortality data and were included in the study. Data were analyzed from November 2022 to October 2023. Exposures: Participants were divided into 4 groups with objective sleep duration of (1) at least 7 hours, (2) 6 to less than 7 hours, (3) 5 to less than 6 hours, and (4) less than 5 hours, which was determined by total sleep time on PSG at baseline. Main Outcomes and Measures: All-cause mortality was defined as deaths from any cause and its risk was compared among 4 OSA groups using Cox regression models. Results: A total of 2574 participants with OSA were included (1628 [63.2%] men and 946 [36.8%] women; mean [SD] age, 65.4 [10.7] years; 211 [8.2%] Black, 2230 [86.6%] White, 133 [5.2%] other race). Overall, 688 all-cause deaths were observed in participants. Compared with the group sleeping at least 7 hours, the groups sleeping 6 to less than 7 hours (hazard ratio [HR], 1.53 [95% CI, 1.13-2.07]), 5 to less than 6 hours (HR, 1.40 [95% CI, 1.03-1.90]), and less than 5 hours (HR, 1.64 [95% CI, 1.20-2.24]) had significantly higher risks of all-cause mortality independent of AHI. Sensitivity analyses were performed among participants with available data of positive airway pressure treatment during follow-up and the finding was mostly consistent, albeit the HR for the group of 5 to less than 6 hours was not statistically significant. Conclusions and Relevance: In this cohort study of 2574 participants with OSA, those with shorter objective sleep duration had higher risk of all-cause mortality independent of AHI compared with those sleeping at least 7 hours. Further studies would be needed to investigate health benefits of extending sleep length among people with OSA with short sleep duration.

Analysis of Airway Thickening and Serum Cytokines in COPD Patients with Frequent Exacerbations: A Heart of the Matter.

Background: Differences in lung function for Chronic Obstructive Pulmonary Disease (COPD) cause bias in the findings when identifying frequent exacerbator phenotype-related causes. The aim of this study was to determine whether computed tomographic (CT) biomarkers and circulating inflammatory biomarkers were associated with the COPD frequent exacerbator phenotype after eliminating the differences in lung function between a frequent exacerbator (FE) group and a non-frequent exacerbator (NFE) group. Methods: A total of 212 patients with stable COPD were divided into a FE group (n=106) and a NFE group (n=106) according to their exacerbation history. These patients were assessed by spirometry, quantitative CT measurements and blood sample measurements during their stable phase. Univariate and multivariate logistic regression were used to assess the association between airway thickening or serum cytokines and the COPD frequent exacerbator phenotype. Receiver operating characteristic (ROC) curves were calculated for Pi10, WA%, IL-1ß and IL-4 to identify frequent exacerbators. Results: Compared with NFE group, FE group had a greater inner perimeter wall thickness of a 10 mm diameter bronchiole (Pi10), a greater airway wall area percentage (WA%) and higher concentrations of IL-1ß and IL-4 (p<0.001). After adjusting for sex, age, BMI, FEV1%pred and smoking pack-years, Pi10, WA%, IL-ß and IL-4 were independently associated with a frequent exacerbator phenotype (p<0.001). Additionally, there was an increase in the odds ratio of the frequent exacerbator phenotype with increasing Pi10, WA%, IL-4, and IL-1ß (p for trend <0.001). The ROC curve demonstrated that IL-1ß had a significantly larger calculated area under the curve (p < 0.05) than Pi10, WA% and IL-4. Conclusion: Pi10, WA%, IL-4, and IL-1ß were independently associated with the frequent exacerbator phenotype among patients with stable COPD, suggesting that chronic airway and systemic inflammation contribute to the frequent exacerbator phenotype. Trial Registration: This trial was registered in Chinese Clinical Trial Registry (https://www.chictr.org.cn). Its registration number is ChiCTR2000038700, and date of registration is September 29, 2020.

Noninvasive electromyometrial imaging of human uterine maturation during term labor.

Electromyometrial imaging (EMMI) was recently developed to image the three-dimensional (3D) uterine electrical activation during contractions noninvasively and accurately in sheep. Herein we describe the development and application of a human EMMI system to image and evaluate 3D uterine electrical activation patterns at high spatial and temporal resolution during human term labor. We demonstrate the successful integration of the human EMMI system during subjects' clinical visits to generate noninvasively the uterine surface electrical potential maps, electrograms, and activation sequence through an inverse solution using up to 192 electrodes distributed around the abdomen surface. Quantitative indices, including the uterine activation curve, are developed and defined to characterize uterine surface contraction patterns. We thus show that the human EMMI system can provide detailed 3D images and quantification of uterine contractions as well as novel insights into the role of human uterine maturation during labor progression.