Late-onset chylothorax after lung cancer surgery: clinical characteristics, management, and prevention.

BACKGROUND: The clinical characteristics and management of late-onset chylothorax after lung cancer surgery remained unknown. Here we aimed to provide evidence on the management of late-onset chylothorax by analysis of several cases with the largest sample size. METHODS: We retrospectively collected clinical data of patients who developed late-onset chylothorax after lung cancer surgery and were re-admitted by a single surgeon in our center from 2016 to 2022. The clinical characteristics and management for these patients were analysed. The role of Hem-o-lok clipping after lymphadenectomy in preventing late-onset chylothorax was further explored by comparing the surgical outcomes between treated group and control group. RESULT: A total of six patients who were re-admitted for late-onset chylothorax after lung cancer surgery were included for analysis. The mean age of them was 60.7 years old. The symptom of late-onset chylothorax was mainly dyspnea and cough and the diagnosis was all made by Sudan III staining between postoperative day 17 to 42. All patients were firstly treated with thoracocentesis and low-fat diet with intravenous nutrition. Four patients were successfully managed with low-fat diet and thoracocentesis, while the other two patients were further managed with pleurodesis with 50% glucose fluid solution. We found a significantly decreased risk of late-onset chylothorax in the treated group with improved procedure of applying Hem-o-lok clipping after lymphadenectomy than in the control group (0% versus 2.6%, P < 0.01). CONCLUSION: Late-onset chylothorax after lung cancer surgery was a rare and negligible complication, which may usually be managed by non-surgical methods. Hem-o-lok clipping during lymphadenectomy seemed to be an effective method to prevent late-onset chylothorax after lung cancer surgery.

The relationship between childhood trauma and mental health status among Chinese vocational high school adolescents: the mediating effect of poor self-control and internet addiction.

BACKGROUND: Mental health problems among adolescents are a common concern globally. However, its relationship with childhood trauma is not clearly understood from the existing studies. Therefore, this study aims to explore the relationships among childhood trauma, mental health, self-control, and internet addiction in Chinese vocational high school students. METHODS: A cross-sectional survey was conducted among vocational high school students in China from October 2020 to December 2020. Standardized questionnaires were used to collect basic information regarding childhood trauma, self-control, psychological state, and social demographics. A structural equation model was used to study the relationships among internet addiction, self-control, childhood trauma, and mental health. RESULTS: A total of 3368 individuals participated in the study. The results revealed the mediating effects of poor self-control and internet addiction on the association between childhood trauma and mental health. CONCLUSIONS: Internet addiction and low self-control play mediating roles in childhood trauma and mental health. Clarifying these relationships will help formulate better-targeted interventions to improve the mental health of Chinese vocational high school students and aid in interventions to treat and prevent mental health problems.

Olanzapine enhances early brain maturation through activation of the NODAL/FOXH1 axis.

The portrayed effects of olanzapine on brain development and neuronal response remain unclear under the genetic background of Homo sapiens. Here, we constructed therapeutic-dosage olanzapine-treated cerebral organoid (CO) models using induced pluripotent stem cells from human samples. We found that the activation of NODAL/FOXH1 axis mediated the early response to olanzapine up to day 15, which subsequently caused thicker cortical-like structures, cell identity maturation, higher stemness of neural progenitor cells (NPCs), and mature neuronal firing of early neurons in day 24. Transcriptomics and targeted metabolomics confirmed the upregulation of neurodevelopmental-related terms and glutamate production on day 24. Gene enrichment of transcriptomics into large-scale genome-wide association studies (GWAS) showed possible relationships with intelligence, major depressive disorder, schizophrenia. We did not observe the negative effects of in-utero exposure to olanzapine in mice. Collectively, we tended to conclude that olanzapine treatment had beneficial effects instead of harmful on early brain development.

Acceptability and usability of a WeChat-based intervention for depression in China: A mixed-methods study.

Background: As research on the use of mobile technology to deliver mental health support grows, the research from China is still very limited. How to design an acceptable and usable mobile mental health service model suitable for China's social and cultural environment remains to be studied. Objective: To understand the acceptability and usability of a WeChat-based intervention among Chinese patients with depression, and to provide insights to promote future development of user-centered mobile mental health services design. Methods: The research team developed a multi-theoretical intervention that includes seven modules: recovery lessons, recovery journal, coaching sessions, mindfulness, personalized support, regular assessments and feedback collection. Forty-two patients diagnosed with depressive disorder were recruited, with a mixed sample of patients who were using an antidepressant medication (n = 29) and patients who were not using an antidepressant medication (n = 13). A single-arm mixed-methods study was conducted to understand engagement, satisfaction, usability and potential clinical effectiveness of the intervention. Results: There was a retention rate of 83.33% - 22 participants who used an antidepressant medication and 13 participants who did not use an antidepressant medication completed the final assessments. The median (upper quartile-lower quartile) of the completed 60 recovery journals and 7 coaching sessions was 56 (59-46) and 6 (7-4) times, respectively. Participants' satisfaction regarding their recovery progress, and on perceived helpfulness on different modules were high. The overall score of the user version of the Mobile Application Rating Scale was 4.23 (SD 0.44, range 1-5), indicating high acceptability and usability. Qualitative feedback identified three key themes: an efficient access to professional help, a personalized source of social support, and a facilitator of cognitive and behavioral change. Conclusions: This study demonstrated that a WeChat-based intervention for depression was acceptable, and has the potential to promote personal recovery. More studies are needed to understand the efficacy and implementation of this model in real world.

Clinical characteristics of 217 Chinese cases with depersonalization/derealization disorder.

Depersonalization/derealization disorder (DPD) is a prevalent yet inadequately understood clinical condition characterized by a recurrent or persistent sense of unreality. This study aims to provide insight into DPD through descriptive and comparative analyses involving a large group of Chinese participants. The socio-demographic details (age, gender proportion, education, occupational status, marital status), depersonalized and dissociative symptom characteristics (symptomatic factors or subscales of the Cambridge Depersonalization Scale and the Dissociative Experiences Scale), development trajectory (age of onset, potential precipitating factors, course characteristics), treatment history (duration of delayed healthcare attendance, duration of delayed diagnosis, previous diagnoses), and adverse childhood experiences of the DPD patients are presented. Comparisons of anxiety and depressive symptoms, alongside psychosocial functioning, between DPD participants and those diagnosed with generalized anxiety disorder, bipolar disorders, and major depressive disorder were conducted. The analysis highlights a higher male preponderance and early onset of DPD, symptomatology marked by derealization, notable impairment in psychosocial functioning, and prolonged periods of delayed healthcare attendance and diagnosis associated with symptom severity. Furthermore, noteworthy relationships between adverse childhood experiences and symptom levels were identified. The findings substantiate the view that DPD is a serious but neglected mental disorder, urging initiatives to improve the current condition of DPD patients.

Human umbilical cord-derived mesenchymal stem cells alleviate valproate-induced immune stress and social deficiency in rats.

Introduction: Autism spectrum disorders (ASD) are a set of heterogeneous neurodevelopmental disorders characterized by impaired social interactions and stereotypic behaviors. Current clinical care is palliative at the most and there remains huge unmet medical need to fully address the core symptoms of ASD. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are emerging as a promising candidate for ASD treatment, but the precise mechanism remains controversial. Methods: In vitro studies we performed the transwell migration assay to explore the interaction between hUC-MSCs and the primary-cultured cortical neurons. Then we determined the therapeutic effects of intravenous administration of hUC-MSCs in rats challenged with valproic acid (VPA) during gestation, a well-defined rat model of autism. Results: Our studies showed that hUC-MSCs promoted the growth of primary-cultured cortical neurons. Furthermore, our results demonstrated that hUC-MSCs significantly alleviated microglial activation in the brain, especially in the anterior cingulate cortex, and effectively improved the sociability of the VPA-exposed rats. Discussion: These results offer valuable insights for clinical translation and further research on the mechanisms of hUC-MSCs in psychiatric disorders characterized by microglial activation, particularly in cases of autism, shall be warranted.

Differences in cognitive impairment and its correlation with circulating cell-free mitochondrial DNA in medication-free depression and bipolar depression patients.

OBJECTIVE: This study aimed to investigate whether there are differences in cognitive impairment between medication-free patients with bipolar depression (BD) and major depressive disorder (MDD) and whether these differences are related to circulating cell-free mtDNA (ccf-mtDNA). METHODS: For this cross-sectional study, 76 outpatients with BD, 86 outpatients with MDD and 70 healthy controls (HCs) were enrolled. Sociodemographic and clinical data were collected. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Stroop Color-Word Test were used to assess cognitive function. Plasma ccf-mtDNA levels were measured via qPCR. RESULTS: BD and MDD patients had similar scores for immediate memory, language, attention, delayed memory, the RBANS total score, Stroop color, Stroop word, and Stroop total score, which were significantly lower than the HCs. The visuospatial/constructive scores of the BD patients were significantly lower than those of the HCs (p < 0.001) and MDD patients (p = 0.008), but there was no difference between the HCs and MDD patients. The ccf-mtDNA levels in the BD and MDD patient groups were significantly higher than those in the HC group, and those in the MDD group were higher than those in the BD group (p = 0.016). Multiple stepwise regression analysis showed that ccf-mtDNA was negatively correlated with language in patients with depression (t = -2.11, p = 0.039). CONCLUSION: There were differences in specific cognitive dimensions between patients with BD and MDD. Increased ccf-mtDNA levels were found in BD and MDD patients, suggesting ccf-mtDNA may be involved in the pathophysiology of MDD and BD.

The epigenetic mechanism of metabolic risk in bipolar disorder.

Bipolar disorder (BD) is a complex and severe mental illness that causes significant suffering to patients. In addition to the burden of depressive and manic symptoms, patients with BD are at an increased risk for metabolic syndrome (MetS). MetS includes factors associated with an increased risk of atherosclerotic cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM), which may increase the mortality rate of patients with BD. Several studies have suggested a link between BD and MetS, which may be explained at an epigenetic level. We have focused on epigenetic mechanisms to review the causes of metabolic risk in BD.

N-3 PUFA supplementation alleviates anxiety symptoms by manipulating erythrocyte fatty acid levels in depression.

PURPOSE: Major depressive disorder (MDD) is frequently accompanied by the symptoms of clinical anxiety. Since our previous research has found that n-3 PUFA supplementation alleviates anxiety in MDD, this study was aimed to further explore whether n-3 PUFA supplementation improves anxiety symptoms in depression by directly manipulating fatty acid levels. METHODS: A secondary analysis of biomarker data (erythrocyte fatty acid composition) collected as part of the randomized clinical trial which investigated the adjunctive effect of n-3 PUFAs was conducted on 72 venlafaxine-treated outpatients with first-diagnosed, drug-naïve depression. All participants with longitudinal biomarker data were included in the association analysis to determine how n-3 PUFA supplementation influences fatty acid composition and alleviates anxiety symptoms in depression. RESULTS: Decreases of the C20:3n6 were found in all participants at both follow-up time points (χ2 = 96.36, p = 0.000). The n-3 index (χ2 = 10.59, p = 0.001), EPA (χ2 = 24.31, p = 0.000), and C22:5n3/C20:5n3 ratio (χ2 = 10.71, p = 0.001) were increased, while C22:4n6 (χ2 = 7.703, p = 0.006) was decreased in n-3 PUFA group compared to the placebo group. The improvement in anxiety symptoms positively correlates with the extent of reduction of C16:0, C18:0, and total fatty acid levels as well as D5 desaturase activity (p < 0.05). CONCLUSION: These data suggest that the anxiolytic effect exerted by n-3 PUFAs in first-diagnosed, drug-naïve depression is manipulated by erythrocyte fatty acid levels. Saturated fatty acid levels have an important role in predicting the severity of anxiety symptoms.

CD24 promotes metastasis and chemoresistance by directly targeting Arf6-ERK pathway in esophageal squamous cell carcinoma.

Increasing evidence suggests the importance of CD24 in tumor progression, but its role and mechanism in esophageal squamous cell carcinoma (ESCC) remain unclear. The present study aims to explore the potential of CD24 as a novel predictive biomarker in ESCC, as well as its mechanism and therapeutic implications in metastasis and 5-FU chemoresistance. By using tissue microarray and immunohistochemistry, we found that CD24 expression was higher in ESCC tumor tissues than paired non-tumor tissues, further indicating that CD24 was markedly associated with poor prognosis. CD24 significantly promoted metastasis and 5-FU chemoresistance in vitro and in vivo. Mechanistically, CD24 competes with GIT2 to bind to Arf6, and stabilizes Arf6-GTP to activate the subsequent ERK pathway, thus promoting cancer progression. In addition, a significant positive correlation between CD24 and p-ERK was observed in clinical ESCC tissues. In summary, this study not only reveals CD24 as a regulatory factor for Arf6 activity, but also uncovers CD24-Arf6-ERK signaling axis as a novel mechanism of ESCC progression. Our findings suggest CD24 as a promising biomarker and therapeutic target in ESCC.

Does strategic coupling of TNCs affect their exit from host regions: Empirical analysis of the exit of Taiwanese enterprises from mainland China.

This study aims to investigate the temporal and spatial attributes of the exit of Taiwanese enterprises from mainland China between 2001 and 2021, by applying enterprise database data. Furthermore, the influence of strategic coupling on Taiwanese enterprises' exit from mainland China was also investigated. The following are the key findings: The spatial distribution pattern of the exit rate of Taiwanese enterprises in mainland China varied at different phases. In contrast, the inland regions of the country's central and western zones, which are characterized by comparatively less developed economies, maintained consistently high exit rates, whereas the eastern coastal region retained a low exit rate. Particularly, the relationship between Taiwanese enterprises and the invested areas changed from Captive coupling to Cooperative coupling and subsequently to Absorptive Coupling. Similarly, the coupling modes significantly influenced the exit of Taiwanese enterprises from mainland China. Moreover, the COVID-19 pandemic has contributed to the backward connection of Taiwanese corporations, which have become more reliant on the mainland China market and local suppliers than earlier. Taiwan-favoring policies and the regional innovation environment have consequently emerged as the primary locational advantages for retaining Taiwanese enterprises in the aftermath of the global financial crisis. Therefore, the aforementioned factors may help to reduce the Taiwanese enterprises' exit from mainland China and possess valuable policy implications for Taiwan investment zones in mainland China.

Metabolic profiling of lumateperone in vitro and in vivo by UPLC-Q Exactive Orbitrap HRMS, and its pharmacokinetic study in rat plasma by LC-MS/MS.

Lumateperone is a novel agent approved by FDA for treatment of schizophrenia in adults. To elucidate the species differences in the of biotransformation of lumateperone and its pharmacokinetic (PK) characteristics in rats, the metabolite identification of lumateperone was carried out in rat, dog and human liver microsomes, and rat plasma after oral administration using UPLC-Q Exactive Orbitrap high-resolution mass spectrometry HRMS. Furtherly, the PK characteristics of lumateperone and its N-demethylated metabolite (M3) in rat plasma were investigated using a validated LC-MS/MS method following intravenous and oral administration. Fourteen phase I metabolites were found in liver microsomes and ten of them were observed in rat plasma. N-demethylation, carbonylation, dehydrogenation, and piperazine ring cleavage were main metabolic pathway of lumateperone. No unique metabolites were formed in human liver microsomes. After rapid absorption in rats, lumateperone was quickly metabolized and eliminated with bioavailability of less than 5%. The exposure level of M3 was about 1.5-fold higher than that of lumateperone in rat plasma. Lumatperone underwent extensive metabolism and was absorbed rapidly in rats. Metabolite M3 had equivalent or slightly higher exposure levels than lumateperone. This study provides essential PK information to facilitate further pharmacodynamic researches of lumateperone.

Determining of 18 amino acids in plasma of pregnant women with sleep disorders by UHPLC-MS/MS.

Many pregnant women experience sleep disorders, and amino acid levels could play a crucial role in affecting maternal sleep. To explore this potential relationship, an accurate and effective UHPLC-MS/MS method has been developed to monitor 18 amino acids in the plasma samples of pregnant women. This method aims to assess how plasma amino acid levels might be linked to sleep disorders during pregnancy. Plasma samples were precipitated with acetonitrile containing 0.2% formic acid. We used 5% seralbumin as the surrogate matrix to establish quantitative curves for amino acid determination in human plasma. The method was validated in both the surrogate matrix and human plasma. The optimized UHPLC-MS/MS method was validated, showing that that the analytes had comparable recovery and negligible matrix effects in both 5% seralbumin and human plasma. The linearity, lower limit of quantification, precision, accuracy, and stability all met the acceptance criteria. The validated method was successfully applied to determination of the plasma levels of 18 amino acids in pregnant women with or without sleep disorders, indicating that alanine, lysine, tryptophan, glutamic acid, and phenylalanine levels had significant changes which may be related to sleep disorders during early pregnancy. An accurate, reliable, and efficient UHPLC-MS/MS method was successfully developed and support to find the specific amino acids as potential biomarkers for sleep disorders in pregnant women.

Impact of sequential (first- to third-generation) EGFR-TKI treatment on corrected QT interval in NSCLC patients.

Objective: To evaluate the impact of sequential (first- to third-generation) epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment on top-corrected QT interval (top-QTc) in non-small cell lung cancer (NSCLC) patients. Methods: We retrospectively reviewed the medical records of NSCLC patients undergoing sequential EGFR-TKI treatment at Shanghai Chest Hospital between October 2016 and August 2021. The heart rate (HR), top-QT interval, and top-QTc of their ECGs were extracted from the institutional database and analyzed. Logistic regression was performed to identify predictors for top-QTc prolongation. Results: Overall, 228 patients were enrolled. Compared with baseline (median, 368 ms, same below), both first-generation (376 ms vs. 368 ms, p < 0.001) and sequential third-generation EGFR-TKIs (376 ms vs. 368 ms, p = 0.002) prolonged top-QT interval to a similar extent (p = 0.635). Top-QTc (438 ms vs. 423 ms, p < 0.001) and HR (81 bpm vs.79 bpm, p = 0.008) increased after first-generation EGFR-TKI treatment. Further top-QTc prolongation (453 ms vs. 438 ms, p < 0.001) and HR increase (88 bpm vs. 81 bpm, p < 0.001) occurred after treatment advanced. Notably, as HR elevated during treatment, top-QT interval paradoxically increased rather than decreased, and the top-QTc increased rather than slightly fluctuated. Moreover, such phenomena were more significant after treatment advanced. After adjusting for confounding factors, pericardial effusion and lower serum potassium levels were independent predictors of additional QTc prolongation during sequential third-generation EGFR-TKI treatment. Conclusion: First-generation EGFR-TKI could prolong top-QTc, and sequential third-generation EGFR-TKI induced further prolongation. Top-QT interval paradoxically increased and top-QTc significantly increased as HR elevated, which was more significant after sequential EGFR-TKI treatment. Pericardial effusion and lower serum potassium levels were independent predictors of additional QTc prolongation after sequential EGFR-TKI treatment.

Association among abnormal glycolipids, reproductive hormones, and cognitive dysfunction in female patients with bipolar disorder.

BACKGROUND: Patients with bipolar disorder (BD) show abnormalities in glucolipid metabolism and reproductive hormone levels, which are of concern in women with BD. This study was dedicated to investigating the glucolipid and reproductive hormone levels of female patients, and to preliminarily investigating their relationships with cognition. METHODS: A total of 58 unmedicated female BD patients, 61 stable-medicated female BD patients, and 63 healthy controls (HC) were recruited in this study. Serum glycolipid indexes and reproductive hormones were measured. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Stroop Color-Word Test (Stroop test). RESULTS: Patients with BD showed significant cognitive impairment (p < 0.05), which was not affected by medication. Triglycerides (TG), luteinizing hormone (LH), and high-density lipoprotein cholesterol (HDL-c) were altered in stable-medicated BD patients. In addition, regression analysis showed that progesterone (PRGE) and prolactin (PRL) were negatively associated with cognitive performance in stable-medicated BD patients. CONCLUSIONS: Female BD patients may have cognitive deficits and abnormal levels of glycolipids and reproductive hormones. And abnormal levels of glycolipids and reproductive hormones may be associated with cognitive dysfunction in female BD patients.

Effects of intermittent overload doses of oral vitamin D3 on serum 25(OH)D concentrations and the incidence rates of fractures, falls, and mortality in elderly individuals: A systematic review and meta-analysis.

Vitamin D is commonly used to prevent and treat osteoporosis, with studies indicating its potential to reduce fractures, falls, and mortality. However, meta-analyses present inconsistent findings regarding its efficacy, particularly reflecting significant variability in data and outcomes related to various dosing regimens. In this meta-analysis, we assessed the impact of high-dose intermittent oral administration of vitamin D3 on serum 25(OH)D levels, fractures, falls, and mortality among elderly individuals. We included 14 randomized controlled trials (RCTs) and employed Review Manager 5.4 for statistical analysis. Our findings indicate that intermittent monthly administration of vitamin D3 (over 800 IU per day) significantly raised serum 25(OH)D levels at all timepoints after six months, maintaining levels above 75 nmol/L throughout the year. This regimen showed no increase in all-cause mortality, with a risk ratio (95% CI) of 0.95 (0.87-1.04). Likewise, it did not significantly reduce the risks of falls and fractures, with risk ratios of 1.02 (0.98-1.05) and 0.95 (0.87-1.04) respectively. Although one-year intermittent administration significantly increased the concentration of 25(OH)D in serum, further research is needed to determine if this method would increase the incidence of falls. Therefore, it is not recommended at this stage due to the lack of demonstrated safety in additional relevant RCTs. This study had been registered at PROSPERO (CRD42022363229).

Intervertebral disc injury triggers neurogenic inflammation of adjacent healthy discs.

BACKGROUND CONTEXT: Intervertebral disc degeneration is common and may play an important role in low back pain, but it is not well-understood. Previous studies have shown that the outer layer of the annulus fibrosus of a healthy disc is innervated by nociceptive nerve fibers. In the process of disc degeneration, it can grow into the inner annulus fibrosus or nucleus pulposus and release neuropeptides. Disc degeneration is associated with inflammation that produces inflammatory factors and potentiates nociceptor sensitization. Subsequently neurogenic inflammation is induced by neuropeptide release from activated primary afferent terminals. Because the innervation of a lumbar disc comes from multisegmental dorsal root ganglion neurons, does neurogenic inflammation in a degenerative disc initiate neurogenic inflammation in neighboring healthy discs by antidromic activity? PURPOSE: This study was based on animal experiments in Sprague-Dawley rats to investigate the role of neurogenic inflammation in adjacent healthy disc degeneration induced by disc injury. STUDY DESIGN: This was an experimental study. METHODS: Seventy-five 12-week-old, male Sprague-Dawley rats were allocated to 3 groups (sham group, disc injury group and disc injury+TrkA antagonist group). The disc injury group was punctured in the tail disc between the eighth and ninth coccygeal vertebrae (Co8-9) to establish an animal model of tail intervertebral disc degeneration. The sham group underwent only skin puncture and the disc injury+TrkA antagonist group was intraperitoneally injected with GW441756 two days before disc puncture. The outcome measure included quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: Disc injury induced an increase in aggrecan, NGF, TrkA, CGRP, SP, IL-1ß, and IL-6 mRNA levels in the injured (Co8-9) and adjacent discs (Co7-8), which reached a peak on day 1, then gradually decreased, and returned to normal on day 14. After intraperitoneal injection of GW441756 prior to puncture, the mRNA levels of the above indicators were down-regulated in Co7-8 and Co8-9 intervertebral discs on the 1st and 7th days. The protein content of the above indicators in Co7-8 and Co8-9 intervertebral discs showed roughly the same trend as mRNA levels. CONCLUSIONS: Degeneration of one disc can induce neurogenic inflammation of adjacent healthy discs in a rat model. CLINICAL SIGNIFICANCE: This model supports a key role of neurogenic inflammation in disc degeneration, and may play a role in the experience of low back pain.

Effect of propranolol on pharmacokinetics of clozapine in schizophrenic patients: a meta-analysis.

PURPOSE: Clozapine is the effective therapy for treatment-refractory schizophrenia. However, the use of clozapine is limited by its adverse effects. As propranolol is frequently used for the prevention and treatment of clozapine-induced tachycardia, we performed a meta-analysis to evaluate the effects of propranolol on steady state pharmacokinetics of clozapine in schizophrenic patients. METHODS: We included 16 retrospective studies on the effects of propranolol on steady state pharmacokinetics of clozapine in schizophrenic patients, with data from both generic and brand name treatment phases in eight clozapine bioequivalence studies conducted in a single center in China from 2018 to 2022. Review Manager 5.4 was used for meta-analysis of the included studies. RESULTS: The SMDs with 95% CIs of AUC0-12, Cmax,ss, C, and C were calculated to be 0.44 (0.23, 0.64), 0.40 (0.20, 0.61), 0.43 (0.22, 0.63), and 0.44 (0.23, 0.64), respectively. These findings proved that combination with propranolol would increase the systemic exposure of clozapine. T1/2 of clozapine was significantly longer in the presence of propranolol than in the absence of propranolol (SMD = 0.32, 95% CI [0.12, 0.52], p = 0.002). There was no statistically significant difference for T of clozapine in the presence or absence of propranolol (SMD = - 0.05, 95% CI [- 0.25, 0.15], p = 0.63). CONCLUSION: The combination with propranolol could significantly increase systemic exposure and extended T1/2 of clozapine, and thus need to be considered in prescribing decisions.

Association of childhood trauma, social support, cognition, and suicidality in females with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a severe mental disorder with heavy disease burden. Females with BD are special populations who suffer a lot from childhood trauma, social support, cognitive deficits, and suicidality. In this study, the relationship among childhood trauma, social support, and clinical symptoms of BD was investigated and the risk factors for suicidality were explored in female patients with BD. METHODS: This study included 57 drug-naive female BD patients, 64 female BD patients with long-term medication, and 50 age-matched female healthy controls. Childhood trauma, social support, clinical symptoms, cognition, and suicidality (suicide ideation, suicide plan, suicide attempt, suicide frequency) were measured with scales. RESULTS: Compared with healthy controls, females with BD showed higher levels of childhood trauma and suicidality, and lower levels of social support and cognitive deficits. In the drug-naïve BD group, social support mediated the relationship between childhood trauma and insomnia symptoms (indirect effect: ab = 0.025). In the BD with long-term medication group, mania symptom was associated with suicide plan (OR = 1.127, p = 0.030), childhood trauma was associated with suicide attempt (OR = 1.088, p = 0.018), and years of education (OR = 0.773, p = 0.028), childhood trauma (OR = 1.059, p = 0.009), and delayed memory (OR= 1.091, p= 0.016) was associated with suicide frequency (OR = 1.091, p = 0.016). CONCLUSIONS: This study provides initial evidence that social support partially explains the relationship between childhood trauma and clinical symptoms in females with BD. Additionally, mania symptoms, childhood trauma, and delayed memory were risk factors for suicidality. Interventions providing social support and improving cognitive function may be beneficial for females with BD who are exposed to childhood trauma and with high suicide risk.

Increased circulating cell-free mitochondrial DNA in plasma of first-diagnosed drug-naïve bipolar disorder patients: A case-control and 4-week follow-up study.

BACKGROUND: The study of clinical biological indicators in bipolar disorder (BD) is important. In recent years, basic experiments have associated the pathophysiological mechanism of BD is related to mitochondrial dysfunction, but few clinical studies have confirmed this finding. OBJECT: The present study aimed to evaluate whether plasma circulating cell-free mitochondrial DNA (ccf-mtDNA) levels, which can represent the degree of mitochondrial damage in vivo, are altered in patients with BD in early onset and during treatment compared with controls. METHOD: A total of 75 first-diagnosed drug-naive patients with BD and 60 HCs were recruited and followed up for 1 month. The clinical symptoms were assessed using HAMD, HAMA, and YMRS, and ccf-mtDNA levels were measured by qPCR before and after drug treatment in BD. RESULT: (1) The plasma ccf-mtDNA levels in first-diagnosed drug-naive patients with BD increased compared with those in HCs (p = 0.001). (2) Drug treatment for 1 month can decrease the expression of ccf-mtDNA in BD (p < 0.001). (3) No significant correlation was observed between the changes in ccf-mtDNA levels and the improvement of clinical symptoms in BD after drug treatment. CONCLUSION: The plasma ccf-mtDNA level was increased in BD, and decreased after pharmacological treatment. These outcomes suggested that plasma ccf-mtDNA level is likely to be sensitive to the drug response in BD, and mitochondrial pathway is a potential target for further therapy.