Border-zone cardiomyocytes and macrophages contribute to remodeling of the extracellular matrix to promote cardiomyocyte invasion during zebrafish cardiac regeneration.

Despite numerous advances in our understanding of zebrafish cardiac regeneration, an aspect that remains less studied is how regenerating cardiomyocytes invade, and eventually replace, the collagen-containing fibrotic tissue following injury. Here, we provide an in-depth analysis of the process of cardiomyocyte invasion using live-imaging and histological approaches. We observed close interactions between protruding cardiomyocytes and macrophages at the wound border zone, and macrophage-deficient irf8 mutant zebrafish exhibited defects in extracellular matrix (ECM) remodeling and cardiomyocyte protrusion into the injured area. Using a resident macrophage ablation model, we show that defects in ECM remodeling at the border zone and subsequent cardiomyocyte protrusion can be partly attributed to a population of resident macrophages. Single-cell RNA-sequencing analysis of cells at the wound border revealed a population of cardiomyocytes and macrophages with fibroblast-like gene expression signatures, including the expression of genes encoding ECM structural proteins and ECM-remodeling proteins. The expression of mmp14b , which encodes a membrane-anchored matrix metalloproteinase, was restricted to cells in the border zone, including cardiomyocytes, macrophages, fibroblasts, and endocardial/endothelial cells. Genetic deletion of mmp14b led to a decrease in 1) macrophage recruitment to the border zone, 2) collagen degradation at the border zone, and 3) subsequent cardiomyocyte invasion. Furthermore, cardiomyocyte-specific overexpression of mmp14b was sufficient to enhance cardiomyocyte invasion into the injured tissue and along the apical surface of the wound. Altogether, our data shed important insights into the process of cardiomyocyte invasion of the collagen-containing injured tissue during cardiac regeneration. They further suggest that cardiomyocytes and resident macrophages contribute to ECM remodeling at the border zone to promote cardiomyocyte replenishment of the fibrotic injured tissue.

Biogenesis of Rab14-positive endosome buds at Golgi-endosome contacts by the RhoBTB3-SHIP164-Vps26B complex.

Early endosomes (EEs) are crucial in cargo sorting within vesicular trafficking. While cargoes destined for degradation are retained in EEs and eventually transported to lysosomes, recycled cargoes for the plasma membrane (PM) or the Golgi undergo segregation into specialized membrane structures known as EE buds during cargo sorting. Despite this significance, the molecular basis of the membrane expansion during EE bud formation has been poorly understood. In this study, we identify a protein complex comprising SHIP164, an ATPase RhoBTB3, and a retromer subunit Vps26B, which promotes the formation of EE buds at Golgi-EE contacts. Our findings reveal that Vps26B acts as a novel Rab14 effector, and Rab14 activity regulates the association of SHIP164 with EEs. Depletion of SHIP164 leads to enlarged Rab14+ EEs without buds, a phenotype rescued by wild-type SHIP164 but not the lipid transfer-defective mutants. Suppression of RhoBTB3 or Vps26B mirrors the effects of SHIP164 depletion. Together, we propose a lipid transport-dependent pathway mediated by the RhoBTB3-SHIP164-Vps26B complex at Golgi-EE contacts, which is essential for EE budding.

Opioid-Sparing Anesthesia Versus Opioid-Free Anesthesia for the Prevention of Postoperative Nausea and Vomiting after Laparoscopic Bariatric Surgery: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Patients who undergo laparoscopic bariatric surgery (LBS) are susceptible to postoperative nausea and vomiting (PONV). Opioid-free anesthesia (OFA) or opioid-sparing anesthesia (OSA) protocols have been proposed as solutions; however, differences between the 2 alternative opioid protocols for anesthesia maintenance in obese patients remain uncertain. A network meta-analysis was conducted to compare the impacts of OFA and OSA on PONV. METHODS: Systematic searches were conducted using Embase, PubMed, MEDLINE, and Cochrane Library databases to identify randomized controlled trials (RCTs) comparing OFA and OSA strategies. After screening according to the inclusion and exclusion criteria, we used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the credibility of the evidence. The main concern of this review was the difference between OFA and OSA in reducing PONV. The primary outcome was any PONV occurrence within 24 hours. Secondary outcomes included postoperative pain intensity, opioid consumption, opioid-related adverse events, and length of hospital stay. RESULTS: Fifteen RCTs involving 1310 patients were identified for a network meta-analysis from 1776 articles that compared OFA, OSA, and traditional opioid-based anesthesia (OBA) strategies in LBS. Twelve RCTs (80%) with 922 participants (70%) were eligible for the occurrence of PONV. These included 199 (22%) patients who received OFA and 476 (52%) and 247 (27%) patients who received OSA and OBA, respectively. OFA was more effective at reducing PONV (relative risks [RR], 0.6, 95% confidence interval [CI], 0.5-0.9, moderate-quality evidence) compared to OSA. No differences were observed in postoperative pain control or opioid consumption between the OFA and OSA strategies (very low-to high-quality evidence). Notably, OFA is associated with a higher risk of bradycardia than OSA (RR, 2.6, 95% CI, 1.2-5.9, moderate-quality evidence). CONCLUSIONS: OFA is more effective than OSA in reducing the occurrence of PONV during the early postoperative period of LBS, although it may associate with an increased risk of bradycardia. Patients who received either opioid-alternative strategy demonstrated similar effects in reducing postoperative opioid consumption and alleviating pain intensity.

Oral health self-management barriers among rural older adults in Guangxi, China: A qualitative study.

BACKGROUND: Objective: To understand the barriers associated with self-management of oral health among rural older adults in Guangxi, and to explore the high incidence of oral problems. This information will assist in the formulation of relevant strategies to solve the oral health problems in this population. METHODS: Taking a phenomenological approach, the current status of, and barriers to, oral health self-management in rural older adults from different regions of Guangxi were explored. Participants were purposively selected and interviewed face-to-face. RESULTS: The interviews yielded four overarching themes and six corresponding sub-themes pertaining to barriers in oral health self-management. These included: (1) Older adults' understanding of oral health and disease, perceptions of oral health and their oral health behaviours; (2) Problems in accessing oral health information; (3) Role of family support; and (4) Barriers to healthcare that included access to dental services, oral treatment experience and financial burden of access to dental care. CONCLUSION: Rural older adults in Guangxi face oral health self-management barriers. Improving access to oral healthcare services and changing existing oral health perceptions and habits may assist them in overcoming self-management challenges.

A p21-ATD mouse model for monitoring and eliminating senescent cells and its application in liver regeneration post injury.

Cellular senescence associates with pathological aging and tissue dysfunctions. Studies utilizing mouse models for cell lineage tracings have emphasized the importance of senescence heterogeneity in different organs and cell types. Here, we constructed a p21- (Akaluc - tdTomato - Diphtheria Toxin Receptor [DTR]) (ATD) mouse model to specifically study the undefined mechanism for p21-expressing senescent cells in the aged and liver injury animals. The successful expressions of these genes enabled in vitro flow cytometric sorting, in vivo tracing, and elimination of p21-expressing senescent cells. During the natural aging process, p21-expressing cells were found in various tissues of p21-ATD mice. Eliminating p21-expressing cells in the aged p21-ATD mice recovered their multiple biological functions. p21-ATD/Fah-/- mice, bred from p21-ATD mice and fumarylacetoacetate hydrolase (Fah)-/- mice of liver injury, showed that the majority of their senescent hepatocytes were the phenotype of p21+ rather than p16+. Furthermore, eliminating the p21-expressing hepatocytes significantly promoted the engraftment of grafted hepatocytes and facilitated liver repopulation, resulting in significant recovery from liver injury. Our p21-ATD mouse model serves as an optimal model for studying the pattern and function of p21-expressing senescent cells under the physical and pathological conditions during aging.

Effectiveness of Maze IV procedure versus thoracoscopic ablation for atrial fibrillation: a propensity score-matched analysis.

Background: Thoracoscopic ablation (TA) has emerged as a promising treatment for atrial fibrillation (AF), with the Cox-Maze IV Procedure (CMP-IV) as the current gold-standard intervention. This study aims to evaluate and compare the outcomes of TA and CMP-IV in treating AF. Methods: Patients with AF underwent either CMP-IV or TA through a left-side chest approach. The CMP-IV entailed bi-atrium ablation, whereas the TA involved creating three circular plus three linear ablations in the left atrium. We analyzed baseline characteristics, perioperative outcomes and recurrence rates using propensity score matching (PSM) at a 1:1 ratio, to ensure comparability between the two treatment groups. Results: A total of 459 patients underwent either CMP-IV (n=93) or TA via left chest (n=366) and 174 patients were deemed eligible for 1:1 PSM. The TA group experienced significantly shorter intensive care unit (ICU) and hospital stays. The mean follow-up period was 31.5±22.1 months. Pre- and post-matching analysis showed that CMP-IV had a higher rate of freedom from recurrence compared to TA, particularly in non-paroxysmal AF patients. Multivariable Cox regression analysis revealed that CMP-IV was associated with a reduced risk of recurrence, while an increased left atrial size emerged as an independent predictor of postoperative recurrence, regardless of the use of CMP-IV or TA. Conclusions: Our study suggests that while the therapeutic efficacy of TA for "lone" AF may fall short of the classic CMP-IV, its less invasive nature results in significantly shorter ICU and hospital stays. To enhance patient outcomes following TA, it is essential to improve the quality of ablation, refine the ablation route, and focus on careful patient selection.

Pulmonary succinate receptor 1 elevation in high-fat diet mice exacerbates lipopolysaccharides-induced acute lung injury via sensing succinate.

BACKGROUND: Individuals with obesity have higher level of circulating succinate, which acts as a signaling factor that initiates inflammation. It is obscure whether succinate and succinate receptor 1 (SUCNR1) are involved in the process of obesity aggravating acute lung injury (ALI). METHODS: The lung tissue and blood samples from patients with obesity who underwent lung wedgectomy or segmental resection were collected. Six-week-old male C57BL/6J mice were fed a high-fat diet for 12 weeks to induce obesity and lipopolysaccharides (LPS) were injected intratracheally (100 µg, 1 mg/ml) for 24 h to establish an ALI model. The pulmonary SUCNR1 expression and succinate level were measured. Exogenous succinate was supplemented to assess whether succinate exacerbated the LPS-induced lung injury. We next examined the cellular localization of pulmonary SUCNR1. Furthermore, the role of the succinate-SUCNR1 pathway in LPS-induced inflammatory responses in MH-s macrophages and obese mice was investigated. RESULT: The pulmonary SUCNR1 expression and serum succinate level were significantly increased in patients with obesity and in HFD mice. Exogenous succinate supplementation significantly increased the severity of ALI and inflammatory response. SUCNR1 was mainly expressed on lung macrophages. In LPS-stimulated MH-s cells, knockdown of SUCNR1 expression significantly inhibited pro-inflammatory cytokines' expression, the increase of hypoxia-inducible factor-1α (HIF-1α) expression, inhibitory κB-α (IκB-α) phosphorylation, p65 phosphorylation and p65 translocation to nucleus. In obese mice, SUCNR1 inhibition significantly alleviated LPS-induced lung injury and decreased the HIF-1α expression and IκB-α phosphorylation. CONCLUSION: The high expression of pulmonary SUCNR1 and serum succinate accumulation at least partly participate in the process of obesity aggravating LPS-induced lung injury.

Effect of different targets of goal-directed fluid therapy on intraoperative hypotension and fluid infusion in robot-assisted laparoscopic gynecological surgery: a randomized non-inferiority trial.

Carotid corrected flow time (FTc) and tidal volume challenge pulse pressure variation (VtPPV) are useful clinical parameters for assessing volume status and fluid responsiveness in robot-assisted surgery, but their usefulness as goal-directed fluid therapy (GDFT) targets is unclear. We investigated whether FTc or VtPPV as targets are inferior to PPV in GDFT. This single-center, prospective, randomized, non-inferiority study included 133 women undergoing robot-assisted laparoscopic gynecological surgery in the modified head-down lithotomy position. Patients were equally divided into three groups, and the GDFT protocol was guided by FTc, VtPPV, or PPV during surgery. Primary outcomes were non-inferiority of the time-weighted average of hypotension, intraoperative fluid volume, and urine output. Secondary outcomes were optic nerve sheath diameter (ONSD) pre- and post-operatively and creatinine and blood urea nitrogen preoperatively and on day 1 post-operatively. No significant differences were observed in intraoperative hypotension index, infusion and urine volumes, and ONSD post-operatively between the FTc and VtPPV groups and the PPV group. No differences in serum creatinine and urea nitrogen levels were identified between the FTc and VtPPV groups preoperatively, but on day 1 post-operatively, the urea nitrogen level in the FTc group was higher than that in the PPV group (4.09 ± 1.28 vs. 3.0 ± 1.1 mmol/L, 1.08 [0.59, 1.58], p < 0.0001), and the difference from the preoperative value was smaller than that in the PPV group (- 2 [- 2.97, 1.43] vs. - 1.34 [- 1.9, - 0.67], p = 0.004). FTc- or VtPPV-guided protocols are not inferior to that of PPV in GDFT during robot-assisted laparoscopic surgery in the modified head-down lithotomy position.Trial registration: Chinese Clinical Trial Registry (ChiCTR2200064419).

Obesity-induced downregulation of miR-192 exacerbates lipopolysaccharide-induced acute lung injury by promoting macrophage activation.

BACKGROUND: Macrophage activation may play a crucial role in the increased susceptibility of obese individuals to acute lung injury (ALI). Dysregulation of miRNA, which is involved in various inflammatory diseases, is often observed in obesity. This study aimed to investigate the role of miR-192 in lipopolysaccharide (LPS)-induced ALI in obese mice and its mechanism of dysregulation in obesity. METHODS: Human lung tissues were obtained from obese patients (BMI ≥ 30.0 kg/m2) and control patients (BMI 18.5-24.9 kg/m2). An obese mouse model was established by feeding a high-fat diet (HFD), followed by intratracheal instillation of LPS to induce ALI. Pulmonary macrophages of obese mice were depleted through intratracheal instillation of clodronate liposomes. The expression of miR-192 was examined in lung tissues, primary alveolar macrophages (AMs), and the mouse alveolar macrophage cell line (MH-S) using RT-qPCR. m6A quantification and RIP assays helped determine the cause of miR-192 dysregulation. miR-192 agomir and antagomir were used to investigate its function in mice and MH-S cells. Bioinformatics and dual-luciferase reporter gene assays were used to explore the downstream targets of miR-192. RESULTS: In obese mice, depletion of macrophages significantly alleviated lung tissue inflammation and injury, regardless of LPS challenge. miR-192 expression in lung tissues and alveolar macrophages was diminished during obesity and further decreased with LPS stimulation. Obesity-induced overexpression of FTO decreased the m6A modification of pri-miR-192, inhibiting the generation of miR-192. In vitro, inhibition of miR-192 enhanced LPS-induced polarization of M1 macrophages and activation of the AKT/ NF-κB inflammatory pathway, while overexpression of miR-192 suppressed these reactions. BIG1 was confirmed as a target gene of miR-192, and its overexpression offset the protective effects of miR-192. In vivo, when miR-192 was overexpressed in obese mice, the activation of pulmonary macrophages and the extent of lung injury were significantly improved upon LPS challenge. CONCLUSIONS: Our study indicates that obesity-induced downregulation of miR-192 expression exacerbates LPS-induced ALI by promoting macrophage activation. Targeting macrophages and miR-192 may provide new therapeutic avenues for obesity-associated ALI.

Microarray analysis identifies lncFirre as a potential regulator of obesity-related acute lung injury.

AIMS: The inflammatory response in acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is heightened in obesity. The aim of this study was to investigate whether lncRNAs are involved in the effects of obesity on acute lung injury and to find possible effector lncRNAs. MAIN METHODS: Microarray analysis was used to assess the transcriptional profiles of lncRNAs and mRNAs in lung tissues from normal (CON), high-fat diet induced obese (DIO), and obese ALI mice (DIO-ALI). GO and KEGG analyses were employed to explore the biological functions of differentially expressed genes. A lncRNA-mRNA co-expression network was constructed to identify specific lncRNA. Lung tissues and peripheral blood samples from patients with obesity and healthy lean donors were utilized to confirm the expression characteristics of lncFirre through qRT-PCR. lncFirre was knocked down in MH-S macrophages to explore its function. ELISA and Griess reagent kit were used to detect PGE2 and NO. Flow cytometry was used to detect macrophages polarization. KEY FINDINGS: There were 475 lncRNAs and 404 mRNAs differentially expressed between DIO and CON, while 1348 lncRNAs and 1349 mRNAs between DIO-ALI and DIO. Obesity increased lncFirre expression in both mice and patients, and PA elevated lncFirre in MH-S. PA exacerbated the inflammation and proinflammatory polarization of MH-S induced by LPS. LncFirre knockdown inhibited the secretion of PGE2 and NO, M1 differentiation while promoted the M2 differentiation in PA and LPS co-challenged MH-S. SIGNIFICANCE: Interfering with lncFirre effectively inhibit inflammation in MH-S, lncFirre can serve as a promising target for treating obesity-related ALI.

Clinical significance of platelet mononuclear cell aggregates in patients with sepsis and acute respiratory distress syndrome.

BACKGROUND: The diagnosis of sepsis combined with acute respiratory distress syndrome (ARDS) has increased owing to the enhanced awareness among medical professionals and the continuous development of modern medical technologies, while early diagnosis of ARDS still lacks specific biomarkers. One of the main pathogenic mechanisms of sepsis-associated ARDS involves the actions of various pathological injuries and inflammatory factors, such as platelet and white blood cells activation, leading to an increase of surface adhesion molecules. These adhesion molecules further form platelet-white blood cell aggregates, including platelet-mononuclear cell aggregates (PMAs). PMAs has been identified as one of the markers of platelet activation, here we hypothesize that PMAs might play a potential biomarker for the early diagnosis of this complication. AIM: To investigate the expression of PMAs in the serum of patients with sepsis complicated by ARDS and its clinical significance. METHODS: We selected 72 hospitalized patients diagnosed with sepsis as the study population between March 2019 and March 2022. Among them, 30 patients with sepsis and ARDS formed the study group, while 42 sepsis patients without ARDS comprised the control group. After diagnosis, venous blood samples were immediately collected from all patients. Flow cytometry was employed to analyze the expression of PMAs, platelet neutrophil aggregates (PNAs), and platelet aggregates (PLyAs) in the serum. Additionally, the Acute Physiology and Chronic Health Evaluation (APACHE) II score was calculated for each patient, and receiver operating characteristic curves were generated to assess diagnostic value. RESULTS: The study found that the levels of PNAs and PLyAs in the serum of the study group were higher than those in the control group, but the difference was not statistically significant (P > 0.05). However, the expression of PMAs in the serum of the study group was significantly upregulated (P < 0.05) and positively correlated with the APACHE II score (r = 0.671, P < 0.05). When using PMAs as a diagnostic indicator, the area under the curve value was 0.957, indicating a high diagnostic value (P < 0.05). Furthermore, the optimal cutoff value was 8.418%, with a diagnostic sensitivity of 0.819 and specificity of 0.947. CONCLUSION: In summary, the serum levels of PMAs significantly increase in patients with sepsis and ARDS. Therefore, serum PMAs have the potential to become a new biomarker for clinically diagnosing sepsis complicated by ARDS.

Mechanism of action and treatment of type I interferon in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) caused by HBV, HCV infection, and other factors is one of the most common malignancies in the world. Although, percutaneous treatments such as surgery, ethanol injection, radiofrequency ablation, and transcatheter treatments such as arterial chemoembolization are useful for local tumor control, they are not sufficient to improve the prognosis of patients with HCC. External interferon agents that induce interferon-related genes or type I interferon in combination with other drugs can reduce the recurrence rate and improve survival in HCC patients after surgery. Therefore, in this review, we focus on recent advances in the mechanism of action of type I interferons, emerging therapies, and potential therapeutic strategies for the treatment of HCC using IFNs (AU)

"One-Pot" Method Preparation of Dendritic Mesoporous Silica-Loaded Matrine Nanopesticide for Noninvasive Administration Control of Monochamus alternatus: The Vector Insect of Bursapherenchus xylophophilus.

Monochamus alternatus is an important stem-boring pest in forestry. However, the complex living environment of Monochamus alternatus creates a natural barrier to chemical control, resulting in a very limited control effect by traditional insecticidal pesticides. In this study, a stable pesticide dendritic mesoporous silica-loaded matrine nanopesticide (MAT@DMSNs) was designed by encapsulating the plant-derived pesticide matrine (MAT) in dendritic mesoporous silica nanoparticles (DMSNs). The results showed that MAT@DMSNs, sustainable nanobiopesticides with high drug loading capacity (80%) were successfully constructed. The release efficiency of DMSNs at alkaline pH was slightly higher than that at acidic pH, and the cumulative release rate of MAT was about 60% within 25 days. In addition, the study on the toxicity mechanism of MAT@DMSNs showed MAT@DMSNs were more effective than MAT and MAT (0.3% aqueous solutions) in touch and stomach toxicity, which might be closely related to their good dispersibility and permeability. Furthermore, MAT@DMSNs are also involved in water transport in trees, which can further transport the plant-derived insecticides to the target site and improve its insecticidal effect. Meanwhile, in addition, the use of essential oil bark penetrants in combination with MAT@DMSNs effectively avoids the physical damage to pines caused by traditional trunk injections and the development of new pests and diseases induced by the traditional trunk injection method, which provides a new idea for the application of biopesticides in the control of stem-boring pests in forestry.

Association Between the Blood Glucose Value at PACU Discharge and Postoperative Hypoglycemia in Nondiabetic Patients With Hyperglycemia After Hysteroscopic Surgery: A Retrospective Cohort Study.

PURPOSE: The target glycemic control for nondiabetic patients in the postanesthesia care unit (PACU) after hysteroscopic surgery remains unclear. Our goal is to determine the optimal level of glycemic control by finding the relationship between blood glucose level (BGL) leaving the PACU and postoperative hypoglycemia in nondiabetic patients. DESIGN: This retrospective cohort study was conducted at a comprehensive tertiary hospital in Chongqing, China between June 2018 and December 2020. METHODS: The target independent and dependent variables were BGL leaving the PACU and postoperative hypoglycemia, respectively. The primary outcome was the incidence of hypoglycemia. Logistic regression was used to explore the association between discharge BGL and hypoglycemia. The optimal glycemic control range was determined by using the receiver operating characteristic (ROC) curve. FINDINGS: Prior to insulin use, BGL in the insulin-using subgroup might be as high as 20 mmol/L. Hypoglycemia was related to the BGL while leaving the PACU (odds ratio (OR) 0.37 [95% confidence interval (CI) 0.22 to 0.65]). The best cut-off value (12.95 mmol/L) was determined by fitting the ROC curve. CONCLUSIONS: If severe hyperglycemia develops during hysteroscopic surgery in individuals with 5% glucose as the mediator of uterine distention, the recommendation is to maintain blood glucose above 12.95 mmol/L when treated with insulin.

Retrospective computed tomography assessment of chemotherapy-related pneumonia with severity screening in pediatric acute lymphoblastic leukemia by radiological imaging.

Objectives: To evaluate the radiological imaging-guided severity along the pneumonia course and evaluate the chest computed tomography (CT) findings of chemotherapy-related pneumonia in children with acute lymphoblastic leukemia (ALL). Materials and methods: A retrospective database review of children with ALL was conducted from March 2016 to August 2021 to identify cases with CT images who developed pneumonia during the chemotherapy course. A total of 51 children with ALL developed pneumonia were ultimately included (31 boys and 20 girls, mean age: 6 ± 4 years [standard deviation]). Each child's demographics, medical records, and laboratory results were collected. The CT images were then reviewed and the radiologic severity index (RSI) was calculated based on the regional opacity and implicated volume. A t-test, U test, Pearson's Chi-square test, and Fisher's exact test were performed to compare the clinical or radiologic features between the severe and moderate cases. The linear regression models were employed to analyze the correlation of RSIs with other clinical features. Results: Eleven children (22 %, 11/51) displayed severe phenotypes associated with respiratory failure. The ground glass opacity (GGO) frequently appeared (65 % of CT images). The baseline RSI was positively associated with the lowest lymphocyte (p = .003), neutrophil (p = .01) counts, and the highest C-reactive protein level (p = .04). The peak RSI may predict severe phenotypes at a cutoff of 4.5 (AUC 0.76 [0.61, 0.91]) with 73 % sensitivity and 63 % specificity. Conclusion: The chest CT images of children with chemotherapy-related pneumonia displayed clinically related baseline RSI and a peak RSI of >4.5 of 36 predicted severe phenotypes.

Comparative efficacy and tolerability of different anesthetics in electroconvulsive therapy for major depressive disorder: A systematic review and network meta-analysis.

Electroconvulsive therapy (ECT) is one of the most effective treatments for major depressive disorder. Modern ECT is conducted with anesthesia, however, the optimal anesthetic agent for ECT is yet to be understood. This study is aimed to compare the effects of different anesthetic agents on antidepressant efficacy and tolerability in depressed individuals undergoing ECT. We searched MEDLINE, EMBASE, the CENTRAL and PsycINFO for randomized controlled trials from database inception until Nov 13, 2022 (PROSPERO: CRD42022375407). Global and local inconsistencies, heterogeneity and publication bias were assessed. Rankings were calculated with the surface under the cumulative ranking curve. A total of 33 studies involving 1898 patients were enrolled. Remission rates were higher for ketamine anesthesia as compared to adjunctive ketamine and propofol. In terms of ranking, ketamine was found to be first in terms of response/remission rates and depressive scores after the 1st, 3rd and 6th ECT and at the end of ECT session, while a higher incidence of adverse events was also observed. No significant advantage of any anesthetic was revealed for the cognitive function after ECT. In summary, based on current evidence, no specific anesthetic is recommended for ECT anesthesia. However, despite more side effects, ketamine monoanesthesia seems to reveal a potential benefit in improving antidepressant efficacy of ECT, and further studies are needed to investigate the relationship between anesthetic agents and the therapeutic effect of ECT.

Mitochondrial-to-nuclear communications through multiple routes regulate cardiomyocyte proliferation.

The regenerative capacity of the adult mammalian heart remains a formidable challenge in biological research. Despite extensive investigations into the loss of regenerative potential during evolution and development, unlocking the mechanisms governing cardiomyocyte proliferation remains elusive. Two recent groundbreaking studies have provided fresh perspectives on mitochondrial-to-nuclear communication, shedding light on novel factors that regulate cardiomyocyte proliferation. The studies identified two mitochondrial processes, fatty acid oxidation and protein translation, as key players in restricting cardiomyocyte proliferation. Inhibition of these processes led to increased cell cycle activity in cardiomyocytes, mediated by reduction in H3k4me3 levels through accumulated α-ketoglutarate (αKG), and activation of the mitochondrial unfolded protein response (UPRmt), respectively. In this research highlight, we discuss the novel insights into mitochondrial-to-nuclear communication presented in these studies, the broad implications in cardiomyocyte biology and cardiovascular diseases, as well as the intriguing scientific questions inspired by the studies that may facilitate future investigations into the detailed molecular mechanisms of cardiomyocyte metabolism, proliferation, and mitochondrial-to-nuclear communications.

High-density lipoprotein cholesterol is associated with lowered cognitive recovery among acute ischemic stroke patients with mild cognitive impairment.

High-density lipoprotein (HDL) has been documented to be related to mild cognitive impairment (MCI) and dementia occurrence; however, the underlying basis behind this association remains unclear. We aimed to elucidate this basis by examining the association between HDL levels and cognitive improvements after 6 months, among acute ischemic stroke (AIS) patients with MCI. Five hundred fifty-eight AIS and MCI patients from the NICE study were enrolled, and divided into four groups, according to their baseline HDL quartiles; median HDL was 1.12 mmol/L (interquartile range 0.96-1.34 mmol/L). The primary outcome examined was the extent of cognitive improvement, defined as ΔMoCA (Montreal Cognitive Assessment) ≥ 2, while the secondary outcome was cognitive deterioration, defined as ΔADAS-cog (Alzheimer's Disease Assessment Scale-Cognitive Subscale) ≥ 4 or ΔMMSE (Mini-Mental State Examination) ≤ - 3, at 6-months post-AIS. We found that 314 (56.27%), 49 (8.78%), and 31 (5.56%) patients had ΔMoCA ≥ 2, ΔADAS-cog ≥ 4, and ΔMMSE ≤ - 3, respectively. Furthermore, cognitive improvement negatively correlated to HDL levels, with the lowest being present among patients in quartiles 4 (Q4; adjusted OR = 0.44, 95% CI 0.25-0.78, P = 0.0050) and Q3 (OR = 0.38, CI 0.23-0.65, P = 0.0004), compared to Q2 (OR = 0.57, CI 0.34-0.96, P = 0.0331). Q2 patients also had positive correlations with ΔADAS-cog ≥ 4 (OR = 5.18, CI 1.55-17.29, P = 0.0074). However, no association between HDL and ΔMMSE ≤ - 3 was observed, nor with LDL and any cognitive changes. Additionally, restricted cubic spline analysis found a nonlinear relationship between HDL and cognitive improvements. All these findings suggested that low plasma HDL was positively associated with improved cognitive functioning among AIS patients with MCI after 6 months.

Whole-brain in vivo base editing reverses behavioral changes in Mef2c-mutant mice.

Whole-brain genome editing to correct single-base mutations and reduce or reverse behavioral changes in animal models of autism spectrum disorder (ASD) has not yet been achieved. We developed an apolipoprotein B messenger RNA-editing enzyme, catalytic polypeptide-embedded cytosine base editor (AeCBE) system for converting C·G to T·A base pairs. We demonstrate its effectiveness by targeting AeCBE to an ASD-associated mutation of the MEF2C gene (c.104T>C, p.L35P) in vivo in mice. We first constructed Mef2cL35P heterozygous mice. Male heterozygous mice exhibited hyperactivity, repetitive behavior and social abnormalities. We then programmed AeCBE to edit the mutated C·G base pairs of Mef2c in the mouse brain through the intravenous injection of blood-brain barrier-crossing adeno-associated virus. This treatment successfully restored Mef2c protein levels in several brain regions and reversed the behavioral abnormalities in Mef2c-mutant mice. Our work presents an in vivo base-editing paradigm that could potentially correct single-base genetic mutations in the brain.