The relationship of cardiovascular disease risk, clozapine antipsychotic use and cognitive function in a large Chinese schizophrenia cohort.

OBJECTIVE: This study explores the intricate relationship between clozapine use, cardiovascular disease (CVD) risk, and cognitive function in patients with schizophrenia (SCZ). METHODS: A cohort comprising 765 patients was stratified based on clozapine usage. Data on demographics, clinical characteristics, and glycolipid metabolism were collected. The Framingham Risk Score and vascular age were calculated using gender-specific Cox regression calculators. Cognitive function was assessed with the Repeatable Battery for Assessment of Neuropsychological Status. RESULTS: Among the patients, 34.6 % were clozapine users. Clozapine users exhibited lower systolic blood pressure, high-density lipoprotein cholesterol and total cholesterol (all ps < 0.05). Furthermore, clozapine users exhibited higher PANSS scores, along with lower scores in RBANS scores (all ps < 0.05). Correlation analysis revealed positive correlation between CVD risk in non-clozapine users and negative symptom scores (r = 0.074, p = 0.043), and negative correlation with positive symptom scores and RBANS scores (r = -0.121, p = 0.001; r = -0.091, p = 0.028). Multivariate stepwise regression analysis indicated that attention scores as predictive factors for increased CVD risk in clozapine users (B = -0.08, 95 %CI = -0.11 to -0.03, p = 0.003). CONCLUSIONS: Patients with SCZ using clozapine exhibit more severe clinical symptoms and cognitive impairments. Attention emerges as a predictor for increased CVD risk in clozapine users.

Olanzapine-Induced Weight Gain and Glycolipid Metabolism Aberrations in First-Episode and Antipsychotic-Naïve Schizophrenia Patients: A Longitudinal Study.

OBJECTIVE: Limited research has delved into the comprehensive impact of monotherapy on weight and glycolipid metabolism in schizophrenia (SCZ) patients. Our study aims to longitudinally investigate the multidimensional effects of olanzapine (OLA) monotherapy on weight and glycolipid metabolism in first-episode and antipsychotic-naïve (FEAN) SCZ patients. METHODS: A total of 74 FEAN-SCZ patients were recruited, as well as 58 sex- and age-matched healthy controls. Eligible patients underwent a 4-week OLA treatment regimen, with weight assessments conducted at baseline and week 4. Moreover, lipid profiles and fasting plasma glucose (FPG) were measured at baseline and week 4. Insulin, leptin (LEP), and adiponectin (APN) levels were determined using enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: At baseline, FEAN-SCZ patients showed elevated levels of insulin, low-density lipoprotein (LDL), impaired insulin sensitivity, and reduced levels of APN compared to the healthy controls. Following 4-week OLA treatment, patients showed an increase in body mass index (BMI) of 0.96 kg/m2. Additionally, FPG, quantitative insulin sensitivity check index (QUICKI), HOMA-insulin sensitivity index (HOMA-ISI), and fasting plasma glucose to insulin ratio (G/I) displayed significant decreases, while insulin, HOMA-IR, and LEP levels showed significant increases. Stepwise regression analysis revealed that baseline FPG independently predicted the change in BMI after 4 weeks of OLA treatment. CONCLUSION: FEAN-SCZ patients exhibited pre-existing alterations in glucose homeostasis. After 4 weeks of OLA treatment, SCZ patients experienced significant weight gain, deteriorating insulin resistance, and increased LEP levels. In addition, baseline FPG emerged as a predictor of BMI changes after 4 weeks of OLA treatment.

SENP3 sensitizes macrophages to ferroptosis via de-SUMOylation of FSP1.

Ferroptosis, driven by an imbalance in redox homeostasis, has recently been identified to regulate macrophage function and inflammatory responses. SENP3 is a redox-sensitive de-SUMOylation protease that plays an important role in macrophage function. However, doubt remains on whether SENP3 and SUMOylation regulate macrophage ferroptosis. For the first time, the results of our study suggest that SENP3 sensitizes macrophages to RSL3-induced ferroptosis. We showed that SENP3 promotes the ferroptosis of M2 macrophages to decrease M2 macrophage proportion in vivo. Mechanistically, we identified the ferroptosis repressor FSP1 as a substrate for SUMOylation and confirmed that SUMOylation takes place mainly at its K162 site. We found that SENP3 sensitizes macrophages to ferroptosis by interacting with and de-SUMOylating FSP1 at the K162 site. In summary, our study describes a novel type of posttranslational modification for FSP1 and advances our knowledge of the biological functions of SENP3 and SUMOylation in macrophage ferroptosis.

Early Drain Removal Versus Routine Drain Removal After Pancreaticoduodenectomy and/or Distal Pancreatectomy: A Meta-Analysis and Systematic Review.

BACKGROUND: Early drain removal (EDR) has been widely accepted, but not been routinely used in patients after pancreaticoduodenectomy (PD) and distal pancreatectomy (DP). This study aimed to evaluate the safety and benefits of EDR versus routine drain removal (RDR) after PD or DP. METHODS: A systematic search was conducted on medical search engines from January 1, 2008 to November 1, 2023, for articles that compared EDR versus RDR after PD or DP. The primary outcome was clinically relevant postoperative pancreatic fistula (CR-POPF). Further analysis of studies including patients with low-drain fluid amylase (low-DFA) on postoperative day 1 and defining EDR timing as within 3 days was also performed. RESULTS: Four randomized controlled trials (RCTs) and eleven non-RCTs with a total of 9465 patients were included in this analysis. For the primary outcome, the EDR group had a significantly lower rate of CR-POPF (OR 0.23; p < 0.001). For the secondary outcomes, a lower incidence was observed in delayed gastric emptying (OR 0.63, p = 0.02), Clavien-Dindo III-V complications (OR 0.48, p < 0.001), postoperative hemorrhage (OR 0.55, p = 0.02), reoperation (OR 0.57, p < 0.001), readmission (OR 0.70, p = 0.003) and length of stay (MD -2.04, p < 0.001) in EDR. Consistent outcomes were observed in the subgroup analysis of low-DFA patients and definite EDR timing, except for postoperative hemorrhage in EDR. CONCLUSION: EDR after PD or DP is beneficial and safe, reducing the incidence of CR-POPF and other postoperative complications. Further prospective studies and RCTs are required to validate this finding.

A nomogram for prediction of early mortality in patients undergoing cardiac surgery for infective endocarditis: a retrospective single-center study.

OBJECTIVE: Despite advancements in surgical techniques, operations for infective endocarditis (IE) remain associated with relatively high mortality. The aim of this study was to develop a nomogram model to predict the early postoperative mortality in patients undergoing cardiac surgery for infective endocarditis based on the preoperative clinical features. METHODS: We retrospectively analyzed the clinical data of 357 patients with IE who underwent surgeries at our center between January 2007 and June 2023. Independent risk factors for early postoperative mortality were identified using univariate and multivariate logistic regression models. Based on these factors, a predictive model was developed and presented in a nomogram. The performance of the nomogram was evaluated through the receiver operating characteristic (ROC) curve, calibration plot, and decision curve analysis (DCA). Internal validation was performed utilizing the bootstrapping method. RESULTS: The nomogram included nine predictors: age, stroke, pulmonary embolism, albumin level, cardiac function class IV, antibotic use <4weeks, vegetation size ≥1.5 cm, perivalvular abscess and preoperative dialysis. The area under the ROC curve (AUC) of the model was 0.88 (95%CI:0.80-0.96). The calibration plot indicated strong prediction consistency of the nomogram with satisfactory Hosmer-Lemeshow test results (χ2 = 13.490, p = 0.142). Decision curve analysis indicated that the nomogram model provided greater clinical net benefits compared to "operate-all" or "operate-none" strategies. CONCLUSIONS: The innovative nomogram model offers cardiovascular surgeons a tool to predict the risk of early postoperative mortality in patients undergoing IE operations. This model can serve as a valuable reference for preoperative decision-making and can enhance the clinical outcomes of IE patients.

The development and validation of automated machine learning models for predicting lymph node metastasis in Siewert type II T1 adenocarcinoma of the esophagogastric junction.

Background: Lymph node metastasis (LNM) is considered an essential prognosis factor for adenocarcinoma of the esophagogastric junction (AEG), which also affects the treatment strategies of AEG. We aimed to evaluate automated machine learning (AutoML) algorithms for predicting LNM in Siewert type II T1 AEG. Methods: A total of 878 patients with Siewert type II T1 AEG were selected from the Surveillance, Epidemiology, and End Results (SEER) database to develop the LNM predictive models. The patients from two hospitals in Suzhou were collected as the test set. We applied five machine learning algorithms to develop the LNM prediction models. The performance of predictive models was assessed using various metrics including accuracy, sensitivity, specificity, the area under the curve (AUC), and receiver operating characteristic (ROC) curve. Results: Patients with LNM exhibited a higher proportion of male individuals, a poor degree of differentiation, and submucosal infiltration, with statistical differences. The deep learning (DL) model demonstrated relatively good accuracy (0.713) and sensitivity (0.868) among the five models. Moreover, the DL model achieved the highest AUC (0.781) and sensitivity (1.000) in the test set. Conclusion: The DL model showed good predictive performance among five AutoML models, indicating the advantage of AutoML in modeling LNM prediction in patients with Siewert type II T1 AEG.

Comparative analysis of robotically-assisted versus conventional sternotomy approach in left atrial-myxoma resection: A single-center retrospective observational study.

BACKGROUND: Minimally invasive surgery has emerged as a favorable alternative to conventional surgery for various cardiac conditions. This study aimed to compare the perioperative outcomes and follow-up results of the robotic approach versus the sternotomy approach for left atrial myxoma (LAM) resection. METHOD: We retrospectively analyzed the perioperative outcomes and follow-up results of 94 patients who underwent left atrial myxoma resection using either the sternotomy approach (n = 64) or the robotic approach (n = 30) at our center between January 2017 and April 2023. Multiple linear regressions were employed to examine the actual impact of the surgical approach on perioperative outcomes while controlling for potential confounding factors. RESULTS: There were no in-hospital deaths or follow-up deaths in the robotic group. Univariate analyses revealed that robotic LAM resection had a longer cardiopulmonary bypass (CPB) time (99.93 ± 22.30 vs. 76.28 ± 24.92, P < 0.001), longer aortic clamping time (57.80 ± 20.27 vs. 47.89 ± 18.10, P = 0.019), reduced postoperative drainage (P < 0.001), shorter mechanical ventilation time (P = 0.005), shorter postoperative bed-stay time (P < 0.001), shorter postoperative hospitalization time (P = 0.040), and higher hospital costs (P = 0.001) compared to the sternotomy group. After adjusting for baseline characteristics in a multiple regression model, a longer CPB time (B = 28.328; CI, 18.609-38.047; P < 0.001), longer aortic clamping time (B = 11.856; CI, 4.069-19.644; P = 0.003), reduced postoperative drainage (B = -200.224; CI, -254.962- -145.486; P < 0.001), shorter mechanical ventilation time (B = -3.429; CI, -6.562- -0.295; P = 0.032), shorter postoperative bed-stay time (B = -2.230; CI, -3.267- -1.193; P < 0.001), shorter postoperative hospitalization time (B = -1.998; CI, -3.747- -0.250; P = 0.026), and higher hospital costs (B = 2096.866, P = 0.002) were found in the robotic group. Furthermore, the robotic group exhibited a faster return to exercise compared to the sternotomy group (Log-Rank χ2 = 34.527, P < 0.001). CONCLUSION: Both the robotic and sternotomy approaches are viable and safe options for LAM resection. However, despite the higher costs, longer CPB time, and longer aortic clamping time associated with robotic LAM resection, this technique was correlated with reduced postoperative drainage and faster postoperative recovery compared to the sternotomy technique.

Effects and mechanisms of bisphenols exposure on neurodegenerative diseases risk: A systemic review.

Environmental bisphenols (BPs) pose a global threat to human health because of their extensive use as additives in plastic products. BP residues are increasing in various environmental media (i.e., water, soil, and indoor dust) and biological and human samples (i.e., serum and brain). Both epidemiological and animal studies have determined an association between exposure to BPs and an increased risk of neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis), including cognitive abnormalities and behavioral disturbances. Hence, understanding the biological responses to different BPs is essential for prevention, and treatment. This study provides an overview of the underlying pathogenic molecular mechanisms as a valuable basis for understanding neurodegenerative disease responses to BPs, including accumulation of misfolded proteins, reduction of tyrosine hydroxylase and dopamine, abnormal hormone signaling, neuronal death, oxidative stress, calcium homeostasis, and inflammation. These findings provide new insights into the neurotoxic potential of BPs and ultimately contribute to a comprehensive health risk evaluation.

Synthesis and Characterization of DOPO-Containing Poly(2,6-dimethyl-1,4-phenylene oxide)s by Oxidative Coupling Polymerization.

A set of polyphenylene oxides incorporating DOPO (9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide) functionality, denoted as DOPO-R-PPO, was synthesized by copolymerization of 2,6-dimethylphenol (2,6-DMP) with various DOPO-substituted tetramethyl bisphenol monomers. In the initial step, a Friedel-Crafts acylation reaction was employed to react 2,6-DMP with different acyl chlorides, leading to the formation of ketone derivatives substituted with 2,6-dimethylphenyl groups. Subsequently, the ketones, along with DOPO and 2,6-DMP, underwent a condensation reaction to yield a series of DOPO-substituted bisphenol derivatives. Finally, polymerizations of 2,6-dimethylphenol with these DOPO-substituted bisphenols were carried out in organic solvents using copper(I) bromide/N-butyldimethylamine catalysts (CuBr/DMBA) under a continuous flow of oxygen, yielding telechelic PPO oligomers with DOPO moieties incorporated into the polymer backbone. The chemical structures of the synthesized compounds were characterized using various analytical techniques, including Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (1H NMR), phosphorus nuclear magnetic resonance (31P NMR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). When compared to conventional poly(2,6-dimethyl-1,4-phenylene oxide)s with a similar molecular weight range, all DOPO-PPOs exhibited higher glass transition temperatures, enhanced thermal degradability, and increased char yield formation at 800 °C without compromising solubility in organic solvents.

Associations between Catechol-O-methyltransferase (COMT) polymorphisms and cognitive impairments, psychiatric symptoms and tardive dyskinesia in schizophrenia.

INTRODUCTION: Catechol-O-methyltransferase (COMT) is a crucial enzyme involved in dopamine metabolism and has been implicated in the etiology of tardive dyskinesia (TD). We aimed to investigate the associations between COMT gene polymorphisms and the occurrence and severity of TD in a Chinese population, as well as the impact on the psychiatric symptoms and cognitive impairments observed in TD patients. METHODS: A total of 216 chronic schizophrenia patients, including 59 TD patients and 157 NTD patients, were recruited for this study. Three SNPs of the COMT gene (rs4680, rs165599 and rs4818) were selected and genotyped using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). TD severity, psychopathology and cognitive functioning were assessed using the Abnormal Involuntary Movement Scale (AIMS), the Positive and Negative Syndrome Scale (PANSS) and the Repeated Battery for Assessment of Neuropsychological Status (RBANS), respectively. RESULTS: In TD patients, total AIMs scores were higher in carriers of the rs4680 AA genotype than in carriers of the AG and GG genotypes (p = 0.01, 0.006), carriers of the rs4818 GC and CC genotypes had higher orofacial scores than in GG genotypes (p = 0.032, 0.002). In male TD patients, carriers of the rs165599 GA genotype scored lower in the extremities and trunk scores than AA genotype carriers (p = 0.015). Moreover, in male TD patients, COMT rs4818 was associated with cognition, since the C allele carriers had significantly higher immediate memory (p = 0.043) and verbal function (p = 0.040) scores than the G allele carriers. In addition, rs165599 genotype interacted with TD diagnosis on depressed factor (p = 0.031). CONCLUSION: Within the Chinese population, COMT gene polymorphisms could potentially serve as biomarkers for the symptoms and prognosis of TD patients.

A Dual-Mechanism Targeted Bioorthogonal Prodrug Therapy.

Bioorthogonal prodrug therapies offer an intriguing two-component system that features enhanced circulating stability and controlled activation on demand. Current strategies often deliver either the prodrug or its complementary activator to the tumor with a monomechanism targeted mechanism, which cannot achieve the desired antitumor efficacy and safety profile. The orchestration of two distinct and orthogonal mechanisms should overcome the hierarchical heterogeneity of solid tumors to improve the delivery efficiency of both components simultaneously for bio-orthogonal prodrug therapies. We herein developed a dual-mechanism targeted bioorthogonal prodrug therapy by integrating two orthogonal, receptor-independent tumor-targeting strategies. We first employed the endogenous albumin transport system to generate the in situ albumin-bound, bioorthogonal-caged doxorubicin prodrug with extended plasma circulation and selective accumulation at the tumor site. We then employed enzyme-instructed self-assembly (EISA) to specifically enrich the bioorthogonal activators within tumor cells. As each targeted delivery mode induced an intrinsic pharmacokinetic profile, further optimization of the administration sequence according to their pharmacokinetics allowed the spatiotemporally controlled prodrug activation on-target and on-demand. Taken together, by orchestrating two discrete and receptor-independent targeting strategies, we developed an all-small-molecule based bioorthogonal prodrug system for dual-mechanism targeted anticancer therapies to maximize therapeutic efficacy and minimize adverse drug reactions for chemotherapeutic agents.

Genetic Susceptibility to Tardive Dyskinesia and Cognitive Impairments in Chinese Han Schizophrenia: Role of Oxidative Stress-Related and Adenosine Receptor Genes.

Objective: Tardive dyskinesia (TD) is a severe rhythmic movement disorder caused by long-term antipsychotic medication in chronic patients with schizophrenia (SCZ). We aimed to investigate the association between polymorphisms in oxidative stress-related genes (GSTM1, SOD2, NOS1, and NOS3) and adenosine receptor gene (ADORA2A), as well as their interactions, with the occurrence and severity of TD, and cognitive impairments in a Chinese Han population of SCZ patients. Methods: Two hundred and sixteen SCZ patients were recruited and divided into TD group (n=157) and non-TD group (n=59). DNA extraction was performed by a high-salt method, followed by SNP genotyping using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The severity of TD, psychopathology and cognitive functioning were assessed using the Abnormal Involuntary Movement Scale (AIMS), the Positive and Negative Syndrome Scale (PANSS) and the Repeated Battery for Assessment of Neuropsychological Status (RBANS), respectively. Results: The combination of GSTM1-rs738491, NOS1-rs738409 and ADORA2A-rs229883 was identified as the best three-point model to predict TD occurrence (p=0.01). Additionally, GSTM-rs738491 CC or NOS3-rs1800779 AG genotypes may be protective factors for psychiatric symptoms in TD patients. TD patients carrying the NOS1-rs738409 AG or ADORA2A-rs229883 TT genotypes exhibited poorer cognitive performance. Conclusion: Our findings suggest that the interaction of oxidative stress-related genes and adenosine receptor gene may play a role in the susceptibility and severity of TD in Chinese Han SCZ patient. Furthermore, these genes may also affect the psychiatric symptoms and cognitive function of TD patients.

Associations between polymorphisms in the cannabinoid receptor 1 gene, cognitive impairments and tardive dyskinesia in a Chinese population with schizophrenia.

OBJECTIVE: Tardive dyskinesia (TD) is a medically induced movement disorder that occurs as a result of long-term use of antipsychotic medications, commonly seen in patients with schizophrenia (SCZ). The study aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) of the CNR1 gene, TD and cognitive impairments in a Chinese population with SCZ. METHODS: A total of 216 SCZ patients were recruited. The participants were divided into TD and without TD (WTD) groups using the Schooler-Kane International Diagnostic Criteria. The severity of TD was assessed using the Abnormal Involuntary Movement Scale (AIMS). Cognitive function was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS) scale. Hardy-Weinberg equilibrium tests, chained disequilibrium analyses and haplotype analyses were performed using SHE-sis software. To explore the main effects of TD diagnosis, genotype and cognitive function, as well as interaction effects, analysis of covariance (ANCOVA) was employed. RESULTS: The prevalence of TD was approximately 27.3%. Significant differences were observed in the rs806368 CT genotype and rs806370 TC genotype within the hypercongenic pattern between the male TD and WTD groups (OR = 2.508, 95% CI: 1.055-5.961, p = 0.037; OR = 2.552, 95% CI: 1.073-6.069, p = 0.034). Among TD patients, those carrying the rs806368 CC genotype exhibited higher limb trunk scores (p < 0.05). Moreover, there was a statistically significant difference in visuospatial/construction between the TD and WTD groups (p = 0.04), and a borderline significant difference in visuospatial/construction when considering the interaction between TD diagnosis and genotype at the rs806368 locus (p = 0.05). CONCLUSION: CNR1 rs806368 and rs806370 polymorphisms may play a role in TD susceptibility. Additionally, CNR1 gene polymorphisms were associated with the severity of involuntary movements and cognitive impairments in TD patients.

Clinical Characteristics and Surgical Outcomes of Right Heart Myxoma and Its Comparison with Left Heart Myxoma: A Single-Center Retrospective Study.

BACKGROUND: Cardiac myxomas are commonly located in the left atrium but rarely affect the right side of the heart. We retrospectively analyzed 28 patients receiving surgical treatment for right heart myxomas at our center and aimed to summarize the clinical features and surgical outcomes of right heart myxomas. METHODS: Between May 2001 and June 2022, 244 patients with sporadic cardiac myxomas underwent complete surgical resection. Twenty-eight patients (28/244, 11.48%) were right heart myxomas. Among the 28 right heart myxoma cases, 25 underwent median sternotomy and 3 underwent robotic or total thoracoscopic procedures. The clinical features, operative information, and follow-up data of right heart myxoma were comprehensively reviewed, and clinical characteristics between right heart myxoma and left heart myxoma were also compared. RESULTS: A significant difference was noted in sex between right heart myxoma and left heart myxoma (P <.05). Right heart myxoma had a higher asymptomatic rate (17.86% vs. 3.70%, P =.007) and a lower embolization rate (3.57% vs. 30.09%, P =.003) than left heart myxoma. The most common attachment site of right heart myxoma is the atrial septum. The mean operative duration and cardiopulmonary bypass time of right heart myxoma resection were 207.71 ± 53.40 minutes and 63.86 ± 29.73 minutes, respectively, with an in-hospital mortality rate of 3.57%. During the follow-up, 2 patients died of noncardiac causes. The overall 1-, 2-, and 5-year actuarial survival rates after right heart myxoma resection were 95.8%, 90.8%, and 84.7%, respectively. CONCLUSIONS: As a rare cardiac tumor, the clinical characteristics of right heart myxoma are different from typical left heart myxoma in some aspects, such as sex, asymptomatic rate, and embolization rate. Prompt surgical resection of right heart myxoma gives excellent early and midterm results.

Histamine H1 receptor antagonist attenuates catecholamine surge and organ injury after severe burns.

Severe burns induce a catecholamine surge, causing severe damage to the organism and raising the possibility of multisystem organ failure. Few strategies are generally acceptable to reduce catecholamine surge and organ injury post-burn. We have previously shown that histamine can amplify the catecholamine surge. In addition, promethazine, a first-generation histamine H1 receptor antagonist, alleviates catecholamine surge and organ injury after severe burns in rats. However, evidence is lacking on whether promethazine benefits patients after severe burns. Currently, sedation and analgesia (such as midazolam and fentanyl) are commonly required for patients after severe burns. It remains unclear if patients after severe burns derive clinical benefit from histamine H1 receptor antagonists combined with sedation and analgesia. This study investigates the therapeutic effect of promethazine on patients after severe burns. Moreover, we test the therapeutic effect of cetirizine, a second-generation histamine H1 receptor antagonist, combined with sedation and analgesia in rats after severe burns. We find that promethazine-pethidine treatment shows a tendency for a lower level of total bilirubin than midazolam-fentanyl in patients 7-day after severe burn. Our study confirms that cetirizine combined with midazolam and fentanyl reduces catecholamine surge and liver and lung damage after severe burns in rats; the effects are better than midazolam and fentanyl treatment. In summary, for the first time, we suggest that histamine H1 receptor antagonist has the potential clinical value of reducing liver injury in patients after severe burns. In addition, we reveal that cetirizine combined with midazolam and fentanyl may be an ideal strategy for treating severe burns.

A comparison of total thoracoscopic versus robotic approach for cardiac myxoma resection: a single-center retrospective study.

Advances in instrumentation and technique have facilitated minimally invasive surgeries for cardiac myxoma treatment. This study aims to compare the clinical outcomes between the thoracoscopic and robotic approaches for myxoma resection. Intraoperative data and postoperative data of 46 patients who underwent either thoracoscopic (n = 15) or robotic (n = 31) cardiac myxoma resection in our center between July 2013 and September 2022 were retrospectively compared. There was no in-hospital death in either group. Meanwhile, the operative time and cardiopulmonary bypass time were significantly shorter in the robotic group than in thoracoscopic group (P = 0.015 and P = 0.035, respectively). Furthermore, shorter ICU stays (P = 0.006), shorter postoperative mechanical ventilation time (P = 0.035) and less thoracic drainage (P = 0.040) were observed in the robotic group. However, the operating room costs and total hospital costs were both significantly lower in thoracoscopic group (P = 0.004 and P = 0.007, respectively). There was no significant difference between two groups regarding the incidence of postoperative complications (P > 0.05). Lastly, a faster return to exercise was noted in robotic group than in thoracoscopic group (Log-Rank χ2 = 4.094, P = 0.043). Both approaches can be safe and feasible for myxoma resection. However, regardless of higher expenses, the robotic myxoma resection approach provides shorter operation time, less postoperative thoracic drainage, and faster recovery than total thoracoscopic technique.

Discovery and characterization of a novel cGAS covalent inhibitor for the treatment of inflammatory bowel disease.

Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, acts as a nucleotidyl transferase that catalyzes ATP and GTP to form cyclic GMP-AMP (cGAMP) and plays a critical role in innate immunity. Hyperactivation of cGAS-STING signaling contributes to hyperinflammatory responses. Therefore, cGAS is considered a promising target for the treatment of inflammatory diseases. Herein, we report the discovery and identification of several novel types of cGAS inhibitors by pyrophosphatase (PPiase)-coupled activity assays. Among these inhibitors, 1-(1-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)prop-2-yn-1-one (compound 3) displayed the highest potency and selectivity at the cellular level. Compound 3 exhibited better inhibitory activity and pathway selectivity than RU.521, which is a selective cGAS inhibitor with anti-inflammatory effects in vitro and in vivo. Thermostability analysis, nuclear magnetic resonance and isothermal titration calorimetry assays confirmed that compound 3 directly binds to the cGAS protein. Mass spectrometry and mutation analysis revealed that compound 3 covalently binds to Cys419 of cGAS. Notably, compound 3 demonstrated promising therapeutic efficacy in a dextran sulfate sodium (DSS)-induced mouse colitis model. These results collectively suggest that compound 3 will be useful for understanding the biological function of cGAS and has the potential to be further developed for inflammatory disease therapies.

Discovery and identification of a novel small molecule BCL-2 inhibitor that binds to the BH4 domain.

The B-cell lymphoma 2 (BCL-2) protein family plays a pivotal role in regulating the apoptosis process. BCL-2, as an antiapoptotic protein in this family, mediates apoptosis resistance and is an ideal target for cell death strategies in cancer therapy. Traditional treatment modalities target BCL-2 by occupying the hydrophobic pocket formed by BCL-2 homology (BH) domains 1-3, while in recent years, the BH4 domain of BCL-2 has also been considered an attractive novel target. Herein, we describe the discovery and identification of DC-B01, a novel BCL-2 inhibitor targeting the BH4 domain, through virtual screening combined with biophysical and biochemical methods. Our results from surface plasmon resonance and cellular thermal shift assay confirmed that the BH4 domain is responsible for the interaction between BCL-2 and DC-B01. As evidenced by further cell-based experiments, DC-B01 induced cell killing in a BCL-2-dependent manner and triggered apoptosis via the mitochondria-mediated pathway. DC-B01 disrupted the BCL-2/c-Myc interaction and consequently suppressed the transcriptional activity of c-Myc. Moreover, DC-B01 inhibited tumor growth in vivo in a BCL­2­dependent manner. Collectively, these results indicate that DC-B01 is a promising BCL-2 BH4 domain inhibitor with the potential for further development.

Maize plant detection using UAV-based RGB imaging and YOLOv5.

In recent years, computer vision (CV) has made enormous progress and is providing great possibilities in analyzing images for object detection, especially with the application of machine learning (ML). Unmanned Aerial Vehicle (UAV) based high-resolution images allow to apply CV and ML methods for the detection of plants or their organs of interest. Thus, this study presents a practical workflow based on the You Only Look Once version 5 (YOLOv5) and UAV images to detect maize plants for counting their numbers in contrasting development stages, including the application of a semi-auto-labeling method based on the Segment Anything Model (SAM) to reduce the burden of labeling. Results showed that the trained model achieved a mean average precision (mAP@0.5) of 0.828 and 0.863 for the 3-leaf stage and 7-leaf stage, respectively. YOLOv5 achieved the best performance under the conditions of overgrown weeds, leaf occlusion, and blurry images, suggesting that YOLOv5 plays a practical role in obtaining excellent performance under realistic field conditions. Furthermore, introducing image-rotation augmentation and low noise weight enhanced model accuracy, with an increase of 0.024 and 0.016 mAP@0.5, respectively, compared to the original model of the 3-leaf stage. This work provides a practical reference for applying lightweight ML and deep learning methods to UAV images for automated object detection and characterization of plant growth under realistic environments.

Lactylation of PKM2 Suppresses Inflammatory Metabolic Adaptation in Pro-inflammatory Macrophages.

Emerging evidence suggests that metabolic adaptation is a vital hallmark and prerequisite for macrophage phenotype transition. Pyruvate kinase M2 (PKM2) is an essential molecular determinant of metabolic adaptions in pro-inflammatory macrophages. Post-translational modifications play a central role in the regulation of PKM2. However, doubt remains on whether lactylation in PKM2 exists and how lactylation modulates the function of PKM2. For the first time, our study reports that lactate inhibits the Warburg effect by activating PKM2, promoting the transition of pro-inflammatory macrophages towards a reparative phenotype. We identify PKM2 as a lactylation substrate and confirm that lactylation occurs mainly at the K62 site. We find that lactate increases the lactylation level of PKM2, which inhibits its tetramer-to-dimer transition, promoting its pyruvate kinase activity and reducing nuclear distribution. In short, our study reports a novel post-translational modification type in PKM2 and clarifies its potential role in regulating inflammatory metabolic adaptation in pro-inflammatory macrophages.