Evaluating the efficacy and safety of perianal injection of liposomal ropivacaine HR18034 for postoperative analgesia following hemorrhoidectomy: A multicenter, randomized, double-blind, controlled phase II clinical trial.

STUDY OBJECTIVE: HR18034, composed of the ropivacaine encapsulated in multi-lamellar, concentric circular structure liposomes as the major component and a small amount of free ropivacaine, has performed well in animal experiments and phase I clinical trials. This trial was to investigate the efficacy, safety, pharmacokinetic profile and the minimum effective dose of HR18034 for postoperative analgesia after hemorrhoidectomy compared with ropivacaine. DESIGN: A multicenter, randomized, double-blind trial. SETTING: 19 medical centers in China. PATIENTS: 85 patients undergoing hemorrhoidectomy between October 2022 to November 2022. INTERVENTIONS: Patients were randomly divided into HR 18034 190 mg group, 285 mg group, 380 mg group and ropivacaine 75 mg group, receiving single local anesthetic perianal injection for postoperative analgesia. MEASUREMENTS: The primary outcome was the area under the resting state NRS score -time curve within 72 h after injection. The second outcomes included the proportion of patients without pain, the proportion of patients not requiring rescue analgesia, cumulative morphine consumption for rescue analgesia, etc. Safety was evaluated by adverse events incidence and plasma ropivacaine concentrations were measured to explore the pharmacokinetic characteristics of HR18034. MAIN RESULTS: The areas under the NRS score (at rest and moving states)-time curve were significantly lower in HR 18034 380 mg group than ropivacaine 75 mg at 24 h, 48 h, and 72 h after administration. However, this superiority was not observed in HR18034 190 mg group and 285 mg group. There was no difference in cumulative morphine consumption for rescue analgesia between HR 18034 groups and ropivacaine group. CONCLUSIONS: HR 18034 380 mg showed superior analgesic efficacy and equivalent safety compared to ropivacaine 75 mg after hemorrhoidectomy, thus preliminarily determined as minimum effective dose.

miR-29a-5p rescues depressive-like behaviors in a CUMS-induced mouse model by facilitating microglia M2-polarization in the prefrontal cortex via TMEM33 suppression.

BACKGROUND: Depression accounts for a high proportion of neuropsychiatric disorders and is associated with abnormal states of neurons in specific brain regions. Microglia play a pivotal role in the inflammatory state during depression development; however, the exact mechanism underlying chronic mood states remains unknown. Thus, the present study aimed to determine whether microRNAs (miRNAs) alleviate stress-induced depression-like behavior in mice by regulating the expression levels of their target genes, explore the role of neuroinflammation induced by microglial activation in the pathogenesis and progression of depression, and determine whether the role of the miR-29a-5p/transmembrane protein 33 (TMEM33) axis. METHODS: In this study, chronic unpredictable mild stress (CUMS) mouse depression model, various behavioral tests, western blotting, dual-luciferase reporter assay, enzyme-linked immunosorbent assay, real-time quantitative reverse transcription PCR, immunofluorescence and lentivirus-mediated gene transfer were used. RESULTS: After exposure to the CUMS paradigm, miR-29a-5p was significantly down-regulated. This downregulation subsequently promoted the polarization of microglia M1 by upregulating the expression of TMEM33, resulting in enhanced inflammatory chemokines affecting neurons. Conversely, the upregulation of miR-29a-5p within the prefrontal cortex (PFC) suppressed TMEM33 expression, facilitated microglia M2-polarization, and ameliorated depressive-like behavior. LIMITATIONS: Only rodent models of depression were used, and human samples were not included. CONCLUSIONS: The results of this study suggest that miR-29a-5p deficits within the PFC mediate microglial anomalies and contribute to depressive-like behaviors. miR-29a-5p and TMEM33 may, therefore, serve as potential therapeutic targets for the treatment of depression.

Santacruzamate A Alleviates Pain and Pain-Related Adverse Emotions through the Inhibition of Microglial Activation in the Anterior Cingulate Cortex.

Chronic pain is a complex disease. It seriously affects patients' quality of life and imposes a significant economic burden on society. Santacruzamate A (SCA) is a natural product isolated from marine cyanobacteria in Panama. In this study, we first demonstrated that SCA could alleviate chronic inflammatory pain, pain-related anxiety, and depression emotions induced by complete Freund's adjuvant in mice while inhibiting microglial activation in the anterior cingulate cortex. Moreover, SCA treatment attenuated lipopolysaccharide (LPS)-induced inflammatory response by downregulating interleukin 1ß and 6 (IL-1ß and IL-6) and tumor necrosis factor-α (TNF-α) levels in BV2 cells. Furthermore, we found that SCA could bind to soluble epoxide hydrolase (sEH) through molecular docking technology, and the thermal stability of sEH was enhanced after binding of SCA to the sEH protein. Meanwhile, we identified that SCA could reduce the sEH enzyme activity and inhibit sEH protein overexpression in the LPS stimulation model. The results indicated that SCA could alleviate the development of inflammation by inhibiting the enzyme activity and expression of sEH to further reduce chronic inflammatory pain. Our study suggested that SCA could be a potential drug for treating chronic inflammatory pain.

Linderane Attenuates Complete Freund's Adjuvant-Induced Pain and Anxiety in Mice by Restoring Anterior Cingulate Cortex Microglia M2 Polarization through Activating Cannabinoid 2 Receptor.

Chronic pain is a common condition that causes negative emotions as the disease progresses. The anterior cingulate cortex (ACC) is a key region in the integration of nociceptive perception and emotional response in chronic pain. Linderane (LDR) is an active ingredient from Linderae radix, a traditional Chinese medicine with anti-inflammatory, analgesic, and antibacterial properties. In this study, the analgesic and antianxiety effects of LDR were evaluated using a complete Freund's adjuvant (CFA)-induced inflammatory pain model in C57BL/6 male mice. Mechanical and thermal pain sensitivity were measured through plantar mechanical analgesia and hot plate apparatus, and anxiety-like behavior was evaluated by open field and elevated plus maze tests. The results showed that LDR-alleviated CFA-induced pain and anxiety, reduced the release of inflammatory cytokines, and inhibited ACC microglial activation. Target prediction, molecular docking, and cellular thermal shift assay demonstrated that LDR could bind to the cannabinoid 2 receptor (CB2R), a key component of the endocannabinoid system with an important role in regulating pain and related emotions. Moreover, both the analgesic effect of LDR and its regulation of microglia polarization were reversed by a CB2R antagonist (SR144528) treatment. Therefore, our results suggested that LDR exerted analgesic effects by regulating microglial polarization in ACC via CB2R activation.

Perioperative intravenous infusion of dexmedetomidine for alleviating postpartum depression after cesarean section: A meta-analysis and systematic review.

The efficacy of perioperative dexmedetomidine (DEX) infusion as a precaution against postpartum depression (PPD) in women undergoing cesarean section has not been substantiated systematically. A literature search for RCTs on DEX against PPD was retrieved in the following databases from inception to January 3, 2024: PubMed, Embase, Web of Science, the Cochrane Library, CNKI, Wanfang, CBM, VIP, etc. A total of 13 RCTs with 1711 participants were included. Meta-analysis was performed by RevMan5.3 and Stata16 using a random-effects model. EPDS scores were significantly decreased in the DEX group within one week or over one week postpartum compared to the control group (SMD = -1.25, 95 %CI: -1.73 to -0.77; SMD = -1.08, 95 %CI: -1.43 to -0.73). The prevalence of PPD was significantly inferior to the control at both time points (RR = 0.36, 95 %CI: 0.24 to 0.54; RR = 0.39, 95 %CI: 0.26 to 0.57). Univariate meta-regression suggested that age influenced the heterogeneity of the EPDS scores (P = 0.039), and DEX infusion dose was a potential moderator (P = 0.074). The subgroup analysis results of PPD scores at both time points were consistent, showing that: ① Mothers younger than 30 years old had better sensitivity to DEX for treating PPD. ② The anti-PPD efficacy of continuous infusion of DEX by PCIA was superior to both single infusion and combined infusion. ③ DEX showed a better anti-PPD effect when the total infusion dose was ≤ 2 µg/kg. Moreover, DEX improved analgesia and sleep quality, provided appropriate sedation, and reduced the incidence of nausea, vomiting, and chills. The current evidence confirmed the prophylaxis and superiority of DEX for PPD. More high-quality, large-scale RCTs are required for verifying the reliability and formulating administration methods.

Influenza A Virus PB1-F2 Induces Affective Disorder by Interfering Synaptic Plasticity in Hippocampal Dentate Gyrus.

Influenza A virus (IAV) infection, which leads to millions of new cases annually, affects many tissues and organs of the human body, including the central nervous system (CNS). The incidence of affective disorders has increased after the flu pandemic; however, the potential mechanism has not been elucidated. PB1-F2, a key virulence molecule of various influenza virus strains, has been shown to inhibit cell proliferation and induce host inflammation; however, its role in the CNS has not been studied. In this study, we constructed and injected PB1-F2 into the hippocampal dentate gyrus (DG), a region closely associated with newborn neurons and neural development, to evaluate its influence on negative affective behaviors and learning performance in mice. We observed anxiety- and depression-like behaviors, but not learning impairment, in mice injected with PB1-F2. Furthermore, pull-down and mass spectrometry analyses identified several potential PB1-F2 binding proteins, and enrichment analysis suggested that the most affected function was neural development. Morphological and western blot studies revealed that PB1-F2 inhibited cell proliferation and oligodendrocyte development, impaired myelin formation, and interfered with synaptic plasticity in DG. Taken together, our results demonstrated that PB1-F2 induces affective disorders by inhibiting oligodendrocyte development and regulating synaptic plasticity in the DG after IAV infection, which lays the foundation for developing future cures of affective disorders after IAV infection.

Effect of Dexmedetomidine on Postpartum Depression in Women With Prenatal Depression: A Randomized Clinical Trial.

Importance: Postpartum depression (PPD) is emerging as a major public health problem worldwide. Although the particular period and context in which PPD occurs provides an opportunity for preventive interventions, there is still a lack of pharmacologic prevention strategies for PPD. Objective: To assess the efficacy and safety of dexmedetomidine for prevention of PPD among women with prenatal depression undergoing cesarean delivery. Design, Setting, and Participants: This randomized clinical trial enrolled 338 women who screened positive for prenatal depression at 2 hospitals in Hunan, China from March 28, 2022, to April 16, 2023. Women with an Edinburgh Postnatal Depression Scale score of more than 9 who were 18 years of age or older and were scheduled for elective cesarean delivery were eligible. Interventions: Eligible participants were randomly assigned in a 1:1 ratio to either the dexmedetomidine group or the control group via centrally computer-generated group randomization. Dexmedetomidine, 0.5 µg/kg and 0.9% saline were intravenously infused for 10 minutes after delivery in the dexmedetomidine and control groups, respectively. After infusion, sufentanil or dexmedetomidine plus sufentanil was administered via patient-controlled intravenous analgesia for 48 hours in the control group and dexmedetomidine group, respectively. Main Outcomes and Measures: The primary outcome was positive PPD screening results at 7 and 42 days post partum, defined as a postpartum Edinburgh Postnatal Depression Scale score of more than 9. Analysis was on an intention-to-treat basis. Results: All 338 participants were female, with a mean (SD) age of 31.5 (4.1) years. Positive PPD screening incidence at 7 and 42 days post partum in the dexmedetomidine group vs the control group was significantly decreased (day 7, 21 of 167 [12.6%] vs 53 of 165 [32.1%]; risk ratio, 0.39 [95% CI, 0.25-0.62]; P < .001; day 42, 19 of 167 [11.4%] vs 50 of 165 [30.3%]; risk ratio, 0.38 [95% CI, 0.23-0.61]; P < .001). The dexmedetomidine group showed no significant difference in adverse events vs the control group (46 of 169 [27.2%] vs 33 of 169 [19.5%]; P = .10), but the incidence of hypotension increased (31 of 169 [18.3%] vs 16 of 169 [9.5%]; risk ratio, 2.15 [95% CI, 1.13-4.10]; P = .02). Conclusions and Relevance: Dexmedetomidine administration in the early postpartum period significantly reduced the incidence of a positive PPD screening and maintained a favorable safety profile. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2200057213.

Narirutin Attenuates Cerebral Ischemia-Reperfusion Injury by Suppressing the TXNIP/NLRP3 Pathway.

Narirutin (Nar) is a flavonoid that is abundantly present in citrus fruits and has attracted considerable attention because of its diverse pharmacological activities and low toxicity. Here, we evaluated the preventive effects of Nar in middle cerebral artery occlusion/reperfusion (MCAO/R)-injured mice and oxygen-glucose deprivation/reperfusion (OGD/R)-injured bEnd.3 cells. Pretreatment with Nar (150 mg/kg) for 7 days effectively reduced infarct volume, improved neurological deficits, and significantly inhibited neuronal death in the hippocampus and cortex in MCAO/R-injured mice. Moreover, anti-apoptotic effects of Nar (50 µM) were observed in OGD/R-injured bEnd.3 cells. In addition, Nar pre-administration regulated blood-brain barrier function by increasing tight junction-related protein expression after MCAO/R and OGD/R injury. Nar also inhibited NOD-like receptor protein 3 (NLRP3) inflammasome activation by reducing the expression of thioredoxin-interacting protein (TXNIP) in vivo and in vitro. Taken together, these results provide new evidence for the use of Nar in the prevention and treatment of ischemic stroke.

A novel endomorphin-2/salmon calcitonin hybrid peptide with enhancing anti-allodynic and anti-anxiety effects.

Pain, a worldwide problem with a high incidence and complex pathogenesis, has attracted the attention of pharmaceutical enterprises for the development of safer and more effective drugs. Extensive experimental and clinical evidence has demonstrated the analgesic effects of two endogenous peptides: endomorphin-2 (EM-2) and salmon calcitonin (sCT). However, EM-2 has limitations, such as poor ability to cross the blood-brain barrier (BBB) and little therapeutic effect in chronic pain due to rapid in vivo proteolysis. Herein, we propose the design of a novel hybrid peptide TEM2CT by combining EM-2, sCT16-21, and the cell-penetrating peptide HIV-1 trans-activator protein (TAT) with the aim of enhancing their analgesic effects. TEM2CT treatment attenuated nociceptive behavior in both acute and chronic pain mouse models, exhibiting increased anti-allodynic and anti-anxiety effects compared to sCT treatment. Furthermore, TEM2CT also regulated the excitability of pyramidal neurons in the anterior cingulate cortex (ACC) in spared nerve injury (SNI) model mice. The improved efficacy of this hybrid peptide provides a promising strategy for developing analgesic drugs.

Photic sensitization is mediated by cortico-accumbens pathway in rats with trigeminal neuropathic pain.

Exposure to light stimuli may trigger or exacerbate perception of pain, also known as a common yet debilitating symptom of photophobia in patient with chronic orofacial pain. Mechanism underlying this phenomenon of photic sensitization in neuropathic condition remains elusive. Here, we found that rats developed hypersensitivity to normal light illumination after establishment of chronic constriction injury of infraorbital nerve (ION-CCI) model, which can be attenuated by blocking the exposure of photic stimulation. Additionally, this behavioral phenotype of light-sensitivity impairment was associated with overexpression of anterior cingulate cortex (ACC) c-fos positive neurons, enhancement of neural excitability in the ACC neurons and its excitatory synaptic transmission between nucleus accumbens (NAc). Optogenetic and chemogenic silencing of ACC-NAc pathway improved trigeminal sensitization in responses to light stimuli by decreasing spontaneous pain-like episodes in ION-CCI animals. In contrast, selective activation of ACC-to-NAc circuits enhanced photic hypersensitivity in dark environment. Thus, our data provided novel role of ACC and its projection to NAc in bidirectional modulation of photic sensation, which may contribute to the understanding of photic allodynia in trigeminal neuropathic pain status.

Preemptive QP001, a fast-acting meloxicam formulation, provides analgesia and reduces opioid consumption following abdominal surgery: a randomized controlled trial.

BACKGROUND: QP001, a novel meloxicam formulation, has been developed to manage moderate to severe postoperative pain. This study aimed to evaluate the efficacy and safety of QP001 injections for moderate to severe pain following abdominal surgery. METHOD: This prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial enlisted patients experiencing moderate to severe pain following abdominal surgery. These patients were randomized to receive either QP001 injections (30 mg or 60 mg) or a placebo pre-surgery. The primary efficacy endpoint was the total morphine consumption within 24 h after the first administration. RESULTS: A total of 108 patients were enrolled, and 106 patients completed the study. The total morphine consumption in the QP001 30 mg group and 60 mg group, versus placebo group, were significantly lower over the following 24 h (5.11[5.46] vs 8.86[7.67], P = 0.011; 3.11[3.08] vs 8.86[7.67], P < 0.001), respectively. The total morphine consumption in the QP001 30 mg and 60 mg groups, versus placebo group, was also significantly decreased over the following 48 h, including the 24-48 h period (P ≤ 0.001). The QP001 30 mg and 60 mg groups, versus placebo, showed a significant decrease in the area under the curve for pain intensity-time as well as a significant decrease in the effective pressing times of the analgesic pump over the 24 h and 48 h periods (P < 0.05). The QP001 groups, versus placebo, show no significant different in Adverse Events or Adverse Drug Reactions (P > 0.05). CONCLUSION: Preoperative/preemptive QP001 provides analgesia and reduces opioid consumption in patients with moderate to severe pain following abdominal surgery, while maintaining a favorable safety profile.

Predicting efficacy of sub-anesthetic ketamine/esketamine i.v. dose during course of cesarean section for PPD prevention, utilizing traditional logistic regression and machine learning models.

OBJECTIVE: Increasing researches supported that intravenous ketamine/esketamine during the perioperative period of cesarean section could prevent postpartum depression(PPD). With the effective rate ranging from 87.2 % to 95.5 % in PPD, ketamine/esketamine's responsiveness was individualized. To optimize ketamine dose/form based on puerpera prenatal characteristics, reducing adverse events and improving the total efficacy rate, prediction models were developed to predict ketamine/esketamine's efficacy. METHOD: Based on two randomized controlled trials, 12 prenatal features of 507 women administered the ketamine/esketamine intervention were collected. Traditional logistics regression, SVM, random forest, KNN and XGBoost prediction models were established with prenatal features and dosage regimen as predictors. RESULTS: According to the logistic regression model (ain = 0.10, aout = 0.15, area under the receiver operating characteristic curve, AUC = 0.728), prenatal Edinburgh Postnatal Depression Scale (EPDS) score ≥ 10, thoughts of self-injury and bad mood during pregnancy were associated with poorer ketamine efficacy in PPD prevention, whilst a high dose of esketamine (0.25 mg/kg loading dose+2 mg/kg PCIA) was the most effective dosage regimen and esketamine was more recommended rather than ketamine in PPD. The AUCvalidation set of KNN and XGBoost model were 0.815 and 0.651, respectively. CONCLUSION: Logistic regression and machine learning algorithm, especially the KNN model, could predict the effectiveness of ketamine/esketamine iv. during the course of cesarean section for PPD prevention. An individualized preventative strategy could be developed after entering puerpera clinical features into the model, possessing great clinical practice value in reducing PPD incidence.

Praeruptorin C alleviates cognitive impairment in type 2 diabetic mice through restoring PI3K/AKT/GSK3ß pathway.

Diabetic encephalopathy is a common consequence of diabetes mellitus that causes cognitive dysfunction and neuropsychiatric disorders. Praeruptorin C (Pra-C) from the traditional Chinese medicinal herb Peucedanum praeruptorum Dunn. is a potential antioxidant and neuroprotective agent. This study was conducted to investigate the molecular mechanisms underlying the effect of Pra-C on diabetic cognitive impairment. A novel object recognition test and the Morris water maze test were performed to assess the behavioral performance of mice. Electrophysiological recordings were made to monitor synaptic plasticity in the hippocampus. A protein-protein interaction network of putative Pra-C targets was constructed, and molecular docking simulations were performed to predict the potential mechanisms of the action of Pra-C. Protein expression levels were detected by western blotting. Pra-C administration significantly lowered body weight and fasting blood glucose levels and alleviated learning and memory deficits in type 2 diabetic mice. Network pharmacology and molecular docking results suggested that Pra-C affects the PI3K/AKT/GSK3ß signaling pathway. Western blot analysis confirmed significant increases in phosphorylated PI3K, AKT, and GSK3ß levels in vivo and in vitro upon Pra-C administration. Pra-C alleviated cognitive impairment in type 2 diabetic mice by activating PI3K/AKT/GSK3ß pathway.

Correlations between GRIN2B and GRIN3A gene polymorphisms and postpartum depressive symptoms in Chinese parturients undergoing cesarean section: A prospective cohort study.

OBJECTIVE: To investigate the association of postpartum depressive symptoms (PDS) and self-harm ideation with n-methyl-d-aspartate (NMDA) receptor GRIN2B and GRIN3A gene polymorphisms and other risk factors in women undergoing cesarean section. METHODS: A total of 362 parturients undergoing cesarean section under lumbar anesthesia were selected and their postpartum depression level was assessed by the Edinburgh Postpartum Depression Scale (EPDS) at 42 days postpartum, with an EPDS score of 9/10 as the cut-off value. Three GRIN2B SNP loci (rs1805476, rs3026174, rs4522263) and five GRIN3A SNP loci (rs1983812, rs2050639, rs2050641, rs3739722, rs10989563) were selected for genotype detection. The role of each SNP, linkage disequilibrium and haplotypes in the development of postpartum depression was analyzed. Logistic regression analysis was performed for related risk factors. RESULTS: PDS incidence was 16.85%, and self-harm ideation incidence was 13.54%. Univariate analysis showed that GRIN2B rs1805476, rs3026174 and rs4522263 gene polymorphisms were associated with PDS (p < 0.05), with GRIN2B rs4522263 gene also associated with maternal self-harm ideation. GRIN3A rs1983812, rs2050639, rest rs2050641, rs3739722 and rs10989563 alleles were not associated with PDS. Logistic regression analysis indicated that high pregnancy stress, as well as rs1805476 and rs4522263 alleles were PDS risk factors following cesarean delivery. GRIN2B (TTG p = 0.002) and GRIN3A (TGTTC p = 0.002) haplotypes were associated with the lower PDS incidence and higher PDS incidence respectively. CONCLUSION: GRIN2B rs1805476 GG genotype, rs4522263 CC genotype and high stress during pregnancy were risk factors for PDS, whilst a significantly higher incidence of self-harm ideation was evident in parturients carrying GRIN2B rs4522263 CC genotype.

Carnosic acid inhibits NLRP3 inflammasome activation by targeting both priming and assembly steps.

Carnosic acid (CA) is a polyphenolic diterpene from rosemary extract with anti-tumor and anti-inflammatory activities. Numerous reports have focused on its anti-tumor ability, while the exact mechanisms underlying its anti-inflammation remains unclear. Here, we have identified that CA is a potent inhibitor of NLRP3 inflammasome in vitro and in vivo. CA not only reduces NLRP3 expression by blocking NF-κB activation, but also inhibits NLRP3 inflammasome assembly and activation by suppressing mitochondrial ROS production and interrupting NLRP3-NEK7 interaction. Furthermore, in mouse models, CA alleviates lipopolysaccharide-induced acute systemic inflammation and MSU-induced peritonitis via NLRP3. Taken together, our data demonstrated the inhibitory effect of CA on NLRP3 inflammasome and pointed out the potential application of CA in the treatment of NLRP3-driven diseases.

An optimization for postpartum depression risk assessment and preventive intervention strategy based machine learning approaches.

BACKGROUND: Postpartum depression (PPD) is one of the most common psychiatric disorders for women after delivery. The establishment of an effective PPD prediction model helps to distinguish high-risk groups, and verifying whether such high-risk groups can benefit from drug intervention is very important for clinical guidance. METHODS: We collected data of parturients that underwent a cesarean delivery. The Control group was divided into a training cohort and a testing cohort. Six different ML models were constructed and we compared their prediction performance in the testing cohort. For model interpretation, we introduced SHapley Additive exPlanations (SHAP). Then, training cohort, ketamine group and dexmedetomidine (DEX) group were classified as high or low risk for PPD by the model. A 1:1 propensity score matching (PSM) was performed to compare the incidence of PPD between two groups in different risk cohorts. RESULTS: Extreme gradient enhancement (XGB) had the best recognition effect, with an area under the receiver operating characteristic curve (AUROC) of 0.789 (95 % CI 0.742-0.836) in the training cohort and 0.744 (95 % CI 0.655-0.823) in the testing cohort, respectively. A threshold of 21.5 % PPD risk probability was determined. After PSM, the results showed that the incidence of PPD in the two intervention groups was significantly different from the control group in the high-risk cohort (P < 0.001) but not in the low-risk cohort (P > 0.001). CONCLUSION: Our study demonstrated that the XGB algorithm provided a more accurate in prediction of PPD risk, and it was beneficial to receive early intervention for the high-risk groups distinguished by the model.

Efficacy and safety of remimazolam besylate in bronchoscopy for adults: A multicenter, randomized, double-blind, positive-controlled clinical study.

Background: With the development of fiberoptic bronchoscopy in the diagnosis and treatment of various pulmonary diseases, the anesthesia/sedation requirements are becoming more demanding, posing great challenges for patient safety while ensuring a smooth examination/surgery process. Remimazolam, a brand-new ultra-short-acting anesthetic, may compensate for the shortcomings of current anesthetic/sedation strategies in bronchoscopy. Methods: This study was a prospective, multicenter, randomized, double-blind, parallel positive controlled phase 3 clinical trial. Subjects were randomized to receive 0.2 mg/kg remimazolam besylate or 2 mg/kg propofol during bronchoscopy to evaluate the efficacy and safety of remimazolam. Results: A total of 154 subjects were successfully sedated in both the remimazolam group and the propofol group, with a success rate of 99.4% (95%CI of the adjusted difference -6.7 × 10%-6% to -5.1 × 10%-6%). The sedative effect of remimazolam was noninferior to that of propofol based on the prespecified noninferiority margin of -5%. Compared with the propofol group, the time of loss of consciousness in the remimazolam group (median 61 vs. 48s, p < 0.001), the time from the end of study drug administration to complete awakening (median 17.60 vs. 12.80 min, p < 0.001), the time from the end of bronchoscopy to complete awakening (median 11.00 vs. 7.00 min, p < 0.001), the time from the end of study drug administration to removal of monitoring (median 19.50 vs. 14.50 min, p < 0.001), and the time from the end of bronchoscopy to removal of monitoring (median 12.70 vs. 8.60 min, p < 0.001) were slightly longer. The incidence of Adverse Events in the remimazolam group and the propofol group (74.8% vs. 77.4%, p = 0.59) was not statistically significant, and none of them had Serious Adverse Events. The incidence of hypotension (13.5% vs. 29.7%, p < 0.001), hypotension requiring treatment (1.9% vs. 7.7%, p = 0.017), and injection pain (0.6% vs. 16.8%, p < 0.001) were significantly lower in the remimazolam group than in the propofol group. Conclusion: Moderate sedation with 0.2 mg/kg remimazolam besylate is effective and safe during bronchoscopy. The incidence of hypotension and injection pain was less than with propofol, but the time to loss of consciousness and recovery were slightly longer. Clinical Trial Registration: clinicaltrials.gov, ChiCTR2000039753.

Establishment and assessment of postoperative cognitive impairment in intermittent hypoxia rats. / é—´æ­‡æ€§ç¼ºæ°§å¤§é¼ æœ¯åŽè®¤çŸ¥åŠŸèƒ½æŸä¼¤æ¨¡åž‹çš„å»ºç«‹.

OBJECTIVES: Obstructive sleep apnea hypopnea syndrome (OSAHS) is a chronic disease characterized by repeated episodes of apnea or hypopnea, accompanied by intermittent awakening and sleep disturbances. The incidence of OSAHS is increasing and has become a serious disease. In recent years, more and more evidence shows that OSAHS is closely related to postoperative neurocognitive disorders, and the preparation of models of postoperative cognitive impairment in intermittent hypoxia animals is an important way to study its pathogenesis and intervention targets. This study aims to explore the establishment and evaluation of the animal model of postoperative cognitive impairment in intermittent hypoxia rats. METHODS: A total of 108 male SD rats were randomly divided into 8 groups: a control group (C group, n=27), a surgery group (S group, n=27), an intermittent hypoxia 7 d group (H1 group, n=9), an intermittent hypoxia 14 d group (H2 group, n=9), an intermittent hypoxia 21 d group (H3 group, n=9), an intermittent hypoxia 7 d operation group (O1 group, n=9), an intermittent hypoxia 14 d operation group (O2 group, n=9), and an intermittent hypoxia 21 d operation group (O3 group, n=9). The rats in the H1, H2 and H3 group treated with intermittent hypoxia for 7, 14, and 21 d, respectively. The rats in the O1, O2 and O3 groups received left lateral hepatic lobectomy after 7, 14, and 21 d intermittent hypoxia, respectively. The rats in each group were subjected to open field test, new object recognition test, and Barnes Maze test. The expression of IL-1ß mRNA in hippocampus of rats was detected at the 1st day after the surgery. RESULTS: Compared with the C, S, and H2 groups, the discrimination index in novel object recognition test 6 h and 1 d after the surgery of the O2 group was significantly lower (P<0.05), the latency and errors in Barnes maze at the 1st day and 2nd day after the surgery were increased significantly (P<0.05) and the expression of IL-1ß mRNA in hippocampus was significantly increased at the 1st day after the operation (P<0.05). However, there was no difference in the preference index in NORT 6 h and 1 d after the surgery, the latency and errors in Barnes maze and the expression of IL-1ß mRNA in hippocampus between the O1 group and the H1 group, the H3 group and the O3 group (all P>0.05). CONCLUSIONS: The rate with intermittent hypoxia 14 d pretreatment with anesthesia and laparotomy could be established the animal model of postoperative cognitive impairment.

Safety, Pharmacokinetics/Pharmacodynamics, and Absolute Bioavailability of Dexmedetomidine Hydrochloride Nasal Spray in Healthy Subjects: A Randomized, Parallel, Escalating Dose Study.

Background: The present study evaluated the safety, pharmacokinetics/pharmacodynamics (PK/PD), and absolute bioavailability (Fabs) of Dex nasal spray in healthy adult subjects, which serves as a bridge for the subsequent study in children. Methods: Part 1: a double-blind, placebo-controlled, single ascending dose study was performed on 48 subjects. For 20-/40-µg groups, every 6/2 subjects received either Dex/placebo nasal spray or Dex/placebo injection in two periods. In total, 12/4 subjects each received 100 µg Dex/placebo nasal spray. Part 2: a randomized, double-blind, placebo-controlled study; 12/4 subjects received 150 µg Dex/placebo nasal spray. Part 3: a randomized, open, self-crossover study; 12 subjects received 20 µg and 100 µg Dex nasal spray in two periods alternately. The method of administration was optimized in Part 2 and Part 3. Results: In part 1, Dex nasal spray was well tolerated up to the maximum dose of 100 µg, whereas the Fabs was tolerated to only 28.9%-32.3%. In Part 2 and Part 3, the optimized nasal spray method was adopted to promote the Fabs of Dex nasal spray to 74.1%-89.0%. A severe adverse event was found in Part 2. In Part 3 (100 µg), the Ramsay score increased the most and lasted the longest, whereas the BIS score decreased most significantly. Conclusion: Using the optimized nasal spray method, a single dose of 20/100 µg of the test drug was safe and tolerable, and 100 µg may have approached or reached the plateau of sedation. In addition, it is found that the optimized method can greatly improve the bioavailability of the test drug, leading to its higher reference value.

A single intravenous administration of a sub-anesthetic ketamine dose during the perioperative period of cesarean section for preventing postpartum depression: A meta-analysis.

The feasibility of intravenous ketamine administration during the perioperative period of cesarean section to prevent postpartum depression (PPD) has not been determined by meta-analysis. To evaluate the efficacy, safety and dose of prophylactic ketamine in offsetting PPD, we retrieved the following databases in English or Chinese from inception to December 2020: Pubmed, Embase, Web of Science, The Cochrane Library, CNKI, VIP and Wanfang. A total of 10 studies (9 RCTs and 1 retrospective study) were included with 2087 cases. Meta-analysis showed that in ketamine group, the score and the prevalence of PPD within 1 week postpartum were significantly reduced, whereas PPD score after 4 weeks postpartum showed no superiority. There was no significant difference in terms of total adverse events rate, although vomiting occurred more frequently in the ketamine group. In addition, we found that ketamine efficacy emerged at 0.5 mg/kg. By meta-regression, we observed that: (1) Age and BMI are negatively associated with mood response to ketamine. (2) An analgesic pump containing ketamine for continuous 48 h postpartum administration was more efficacious than an intravenous injection of ketamine during cesarean section. Current evidence shows ketamine could be efficacious and safe in the prophylactic management of PPD in women having a cesarean section.