Complement C1q-mediated microglial synaptic elimination by enhancing desialylation underlies sevoflurane-induced developmental neurotoxicity.

BACKGROUND: Repeated neonatal sevoflurane exposures led to neurocognitive disorders in young mice. We aimed to assess the role of microglia and complement C1q in sevoflurane-induced neurotoxicity and explore the underlying mechanisms. METHODS: Neonatal mice were treated with sevoflurane on postnatal days 6, 8, and 10, and the Morris water maze was performed to assess cognitive functions. For mechanistic explorations, mice were treated with minocycline, C1q-antibody ANX005, and sialidase-inhibitor N-acetyl-2,3-dehydro-2-deoxyneuraminic acid (NADNA) before sevoflurane exposures. Western blotting, RT-qPCR, Golgi staining, 3D reconstruction and engulfment analysis, immunofluorescence, and microglial morphology analysis were performed. In vitro experiments were conducted in microglial cell line BV2 cells. RESULTS: Repeated neonatal sevoflurane exposures resulted in deficiencies in learning and cognition of young mice, accompanied by microglial activation and synapse loss. Sevoflurane enhanced microglia-mediated synapse elimination through C1q binding to synapses. Inhibition of microglial activation and phagocytosis with minocycline significantly reduced the loss of synapses. We further revealed the involvement of neuronal sialic acids in this process. The enhanced activity of sialidase by sevoflurane led to the loss of sialic acids, which facilitated C1q binding to synapses. Inhibition of C1q with ANX005 or inhibition of sialidase with NADNA significantly rescued microglia-mediated synapse loss and improved neurocognitive function. Sevoflurane enhanced the engulfment of BV2 cells, which was reversed by ANX005. CONCLUSIONS: Our findings demonstrated that C1q-mediated microglial synaptic elimination by enhancing desialylation contributed to sevoflurane-induced developmental neurotoxicity. Inhibition of C1q or sialidase may be a potential therapeutic strategy for this neurotoxicity.

iVR-fNIRS: studying brain functions in a fully immersive virtual environment.

Immersive virtual reality (iVR) employs head-mounted displays or cave-like environments to create a sensory-rich virtual experience that simulates the physical presence of a user in a digital space. The technology holds immense promise in neuroscience research and therapy. In particular, virtual reality (VR) technologies facilitate the development of diverse tasks and scenarios closely mirroring real-life situations to stimulate the brain within a controlled and secure setting. It also offers a cost-effective solution in providing a similar sense of interaction to users when conventional stimulation methods are limited or unfeasible. Although combining iVR with traditional brain imaging techniques may be difficult due to signal interference or instrumental issues, recent work has proposed the use of functional near infrared spectroscopy (fNIRS) in conjunction with iVR for versatile brain stimulation paradigms and flexible examination of brain responses. We present a comprehensive review of current research studies employing an iVR-fNIRS setup, covering device types, stimulation approaches, data analysis methods, and major scientific findings. The literature demonstrates a high potential for iVR-fNIRS to explore various types of cognitive, behavioral, and motor functions in a fully immersive VR (iVR) environment. Such studies should set a foundation for adaptive iVR programs for both training (e.g., in novel environments) and clinical therapeutics (e.g., pain, motor and sensory disorders and other psychiatric conditions).

Novel STAT3 oligonucleotide compounds suppress tumor growth and overcome the acquired resistance to sorafenib in hepatocellular carcinoma.

Signal transducer and activator of transcription 3 (STAT3) plays an important role in the occurrence and progression of tumors, leading to resistance and poor prognosis. Activation of STAT3 signaling is frequently detected in hepatocellular carcinoma (HCC), but potent and less toxic STAT3 inhibitors have not been discovered. Here, based on antisense technology, we designed a series of stabilized modified antisense oligonucleotides targeting STAT3 mRNA (STAT3 ASOs). Treatment with STAT3 ASOs decreased the STAT3 mRNA and protein levels in HCC cells. STAT3 ASOs significantly inhibited the proliferation, survival, migration, and invasion of cancer cells by specifically perturbing STAT3 signaling. Treatment with STAT3 ASOs decreased the tumor burden in an HCC xenograft model. Moreover, aberrant STAT3 signaling activation is one of multiple signaling pathways involved in sorafenib resistance in HCC. STAT3 ASOs effectively sensitized resistant HCC cell lines to sorafenib in vitro and improved the inhibitory potency of sorafenib in a resistant HCC xenograft model. The developed STAT3 ASOs enrich the tools capable of targeting STAT3 and modulating STAT3 activity, serve as a promising strategy for treating HCC and other STAT3-addicted tumors, and alleviate the acquired resistance to sorafenib in HCC patients. A series of novel STAT3 antisense oligonucleotide were designed and showed potent anti-cancer efficacy in hepatocellular carcinoma in vitro and in vivo by targeting STAT3 signaling. Moreover, the selected STAT3 ASOs enhance sorafenib sensitivity in resistant cell model and xenograft model.

Research progress of drug eluting balloon in arterial circulatory system.

The arterial circulatory system diseases are common in clinical practice, and their treatment options have been of great interest due to their high morbidity and mortality. Drug-eluting balloons, as a new type of endovascular interventional treatment option, can avoid the long-term implantation of metal stents and is a new type of angioplasty without stents, so drug-eluting balloons have better therapeutic effects in some arterial circulatory diseases and have been initially used in clinical practice. In this review, we first describe the development, process, and mechanism of drug-eluting balloons. Then we summarize the current studies on the application of drug-eluting balloons in coronary artery lesions, in-stent restenosis, and peripheral vascular disease. As well as the technical difficulties and complications in the application of drug-eluting balloons and possible management options, in order to provide ideas and help for future in-depth studies and provide new strategies for the treatment of more arterial system diseases.

Recurrent RhoGAP gene fusion CLDN18-ARHGAP26 promotes RHOA activation and focal adhesion kinase and YAP-TEAD signalling in diffuse gastric cancer.

OBJECTIVE: Genomic studies of gastric cancer have identified highly recurrent genomic alterations impacting RHO signalling, especially in the diffuse gastric cancer (DGC) histological subtype. Among these alterations are interchromosomal translations leading to the fusion of the adhesion protein CLDN18 and RHO regulator ARHGAP26. It remains unclear how these fusion constructs impact the activity of the RHO pathway and what is their broader impact on gastric cancer development. Herein, we developed a model to allow us to study the function of this fusion protein in the pathogenesis of DGC and to identify potential therapeutic targets for DGC tumours with these alterations. DESIGN: We built a transgenic mouse model with LSL-CLDN18-ARHGAP26 fusion engineered into the Col1A1 locus where its expression can be induced by Cre recombinase. Using organoids generated from this model, we evaluated its oncogenic activity and the biochemical effects of the fusion protein on the RHOA pathway and its downstream cell biological effects in the pathogenesis of DGC. RESULTS: We demonstrated that induction of CLDN18-ARHGAP26 expression in gastric organoids induced the formation of signet ring cells, characteristic features of DGC and was able to cooperatively transform gastric cells when combined with the loss of the tumour suppressor geneTrp53. CLDN18-ARHGAP26 promotes the activation of RHOA and downstream effector signalling. Molecularly, the fusion promotes activation of the focal adhesion kinase (FAK) and induction of the YAP pathway. A combination of FAK and YAP/TEAD inhibition can significantly block tumour growth. CONCLUSION: These results indicate that the CLDN18-ARHGAP26 fusion is a gain-of-function DGC oncogene that leads to activation of RHOA and activation of FAK and YAP signalling. These results argue for further evaluation of emerging FAK and YAP-TEAD inhibitors for these deadly cancers.

Piezoresistive Porous Composites with Triply Periodic Minimal Surface Structures Prepared by Self-Resistance Electric Heating and 3D Printing.

Three-dimensional flexible piezoresistive porous sensors are of interest in health diagnosis and wearable devices. In this study, conductive porous sensors with complex triply periodic minimal surface (TPMS) structures were fabricated using the 3D printed sacrificial mold and enhancement of MWCNTs. A new curing routine by the self-resistance electric heating was implemented. The porous sensors were designed with different pore sizes and unit cell types of the TPMS (Diamond (D), Gyroid (G), and I-WP (I)). The impact of pore characteristics and the hybrid fabrication technique on the compressive properties and piezoresistive response of the developed porous sensors was studied. The results indicate that the porous sensors cured by the self-resistance electric heating could render a uniform temperature distribution in the composites and reduce the voids in the walls, exhibiting a higher elastic modulus and a better piezoresistive response. Among these specimens, the specimen with the D-based structure cured by self-resistance electric heating showed the highest responsive strain (61%), with a corresponding resistance response value of 0.97, which increased by 10.26% compared to the specimen heated by the external heat sources. This study provides a new perspective on design and fabrication of porous materials with piezoresistive functionalities, particularly in the realm of flexible and portable piezoresistive sensors.

The combination of allantoin, bisabolol, D-panthenol and dipotassium glycyrrhizinate mitigates UVB-induced PGE2 synthesis by keratinocytes.

OBJECTIVE: Erythema, characterized by the redness of the skin, is a common skin reaction triggered by various endogenous and exogenous factors. This response is often a result of the activation of underlying inflammatory mechanisms within the skin. The objective of this study is to investigate the potential benefits of applying a combination of skincare ingredients, namely allantoin, bisabolol, D-panthenol and dipotassium glycyrrhizinate (AB5D), in the modulation of inflammatory factors associated with erythema. Additionally, the study aims to elucidate the mechanisms by which these ingredients exert their combined actions to alleviate erythema-associated inflammation. METHODS: Human epidermal keratinocytes were exposed to UVB and subsequently treated with AB5D. Transcriptomics profiling was performed to analyse the dose-response effect of AB5D treatment on keratinocytes. The quantitation of inflammatory mediators, including PGE2 , IL-1α, IL-6, IL-8, IL-1RA and TNFα, was performed on cultured media. Additionally, the oxygen radical absorbance capacity (ORAC) assay was carried out to evaluate the total antioxidant capacity of both individual ingredients and the AB5D combination. To assess the in-vitro antioxidant effects of AB5D against UVB-induced oxidative stress in hTERT keratinocytes, real-time quantitation of mitochondrial superoxide was measured through live-cell imaging. RESULTS: The application of AB5D to UVB-exposed keratinocytes downregulated gene sets associated with inflammatory responses, highlighting the anti-inflammatory properties of AB5D. Specifically, AB5D effectively reduced the production of PGE2 , leading to the downregulation of inflammatory cytokines. Moreover, our findings indicate that AB5D exhibits antioxidative capabilities, functioning as both an antioxidant agent and a regulator of antioxidant enzyme expression to counteract the detrimental effects of cellular oxidative stress. CONCLUSION: We demonstrated that AB5D can reduce UVB-induced PGE2 , IL-1α, IL-6, IL-8, IL-1RA and TNFα as well as mitochondrial superoxide. These findings suggest that AB5D may alleviate erythema by modulating inflammation via PGE2 and through antioxidation mechanisms.

L'érythème, caractérisé par une rougeur sur la peau, est une réaction cutanée fréquente déclenchée par divers facteurs endogènes et exogènes. Il s'agit d'une réponse qui résulte souvent de l'activation des mécanismes inflammatoires sous-jacents dans la peau. OBJECTIF: cette étude vise à étudier les bénéfices potentiels de l'application d'une association d'ingrédients de soins cutanés, à savoir l'allantoïne, le bisabolol, le D-panthénol et le glycyrrhizinate dipotassique (AB5D) dans la modulation des facteurs inflammatoires associés à l'érythème. En outre, l'étude vise à élucider les mécanismes par lesquels ces ingrédients exercent leurs actions combinées pour soulager l'inflammation associée à l'érythème. MÉTHODES: les kératinocytes épidermiques humains ont été exposés aux UVB et traités par la suite par AB5D. Un profilage transcriptomique a été effectué pour analyser l'effet dose-réponse du traitement par AB5D sur les kératinocytes. La quantification des médiateurs inflammatoires, y compris PGE2, IL-1α, IL-6, IL-8, IL-1RA et TNFα, a été effectuée sur des milieux de culture. En outre, le dosage de la capacité d'absorption des radicaux oxygénés (Oxygen Radical Absorbance Capacity, ORAC) a été effectué pour évaluer la capacité antioxydante totale des deux ingrédients individuels et de l'association AB5D. Pour évaluer les effets antioxydants in vitro de l'AB5D contre le stress oxydatif induit par les UVB dans les kératinocytes hTERT, on a mesuré la quantification en temps réel du superoxyde mitochondrial par des tests d'imagerie des cellules vivantes. RÉSULTATS: l'application de l'AB5D aux ensembles de gènes régulés à la baisse exposés aux kératinocytes UVB associés à des réponses inflammatoires, a mis en évidence les propriétés anti-inflammatoires de l'AB5D. Plus précisément, l'AB5D a efficacement réduit la production de PGE2, entraînant une régulation négative des cytokines inflammatoires. En outre, nos résultats indiquent que l'AB5D présente des capacités antioxydantes. Il fonctionne à la fois comme un agent antioxydant et comme un régulateur de l'expression enzymatique antioxydante pour contrer les effets néfastes du stress oxydatif cellulaire. CONCLUSION: nous avons montré que l'AB5D pouvait réduire la PGE2 induite par les UVB, l'IL-1α, l'IL-6, IL-8, IL-1RA et le TNFα, ainsi que le superoxyde mitochondrial. Ces résultats suggèrent que l'AB5D pourrait soulager l'érythème en modulant l'inflammation via la PGE2 et via des mécanismes d'antioxydation.

High-Density Dynamic Bonds Cross-Linked Hydrogel with Tissue Adhesion, Highly Efficient Self-Healing Behavior, and NIR Photothermal Antibacterial Ability as Dressing for Wound Repair.

Multifunctional hydrogels with tissue adhesion, self-healing behavior, and antibacterial properties have potential in wound healing applications. However, their inefficient self-healing behavior and antibacterial agents can cause long-term cytotoxicity and drug resistance, considerably limiting their clinical use. Herein, we reported a PDA@LA hydrogel constructed by introducing polydopamine nanoparticles (PDA-NPs) into a high-density dynamic bonds cross-linked lipoic acid (LA) hydrogel that was formed by the polymerization of LA. Because of its rich carboxyl groups, the LA hydrogel could adhere firmly to various tissues. Owing to the high-density dynamic bonds, the cut LA hydrogel exhibited highly inefficient self-healing behavior and recovered to its uncut state after self-healing for 10 min. After the introduction of the PDA-NPs, the hydrogel was able to heat up to more than 40 °C to kill approximately 100% of the Escherichia coli and Staphylococcus aureus under near-infrared (NIR) laser, thus resisting wound infections. Because no toxic antibacterial agent was used, the PDA@LA hydrogel caused mild long-term cytotoxicity or drug resistance. Consequently, the adhesive, highly efficient self-healing, and NIR photothermal antibacterial PDA@LA hydrogel exhibits considerable potential for clinical use.

Development and validation of a prognostic model for predicting post-discharge mortality risk in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI).

BACKGROUND: Accurately predicting post-discharge mortality risk in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) remains a complex and critical challenge. The primary objective of this study was to develop and validate a robust risk prediction model to assess the 12-month and 24-month mortality risk in STEMI patients after hospital discharge. METHODS: A retrospective study was conducted on 664 STEMI patients who underwent PPCI at Xiangtan Central Hospital Chest Pain Center between 2020 and 2022. The dataset was randomly divided into a training cohort (n = 464) and a validation cohort (n = 200) using a 7:3 ratio. The primary outcome was all-cause mortality following hospital discharge. The least absolute shrinkage and selection operator (LASSO) regression model was employed to identify the optimal predictive variables. Based on these variables, a regression model was constructed to determine the significant predictors of mortality. The performance of the model was evaluated using receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA). RESULTS: The prognostic model was developed based on the LASSO regression results and further validated using the independent validation cohort. LASSO regression identified five important predictors: age, Killip classification, B-type natriuretic peptide precursor (NTpro-BNP), left ventricular ejection fraction (LVEF), and the usage of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (ACEI/ARB/ARNI). The Harrell's concordance index (C-index) for the training and validation cohorts were 0.863 (95% CI: 0.792-0.934) and 0.888 (95% CI: 0.821-0.955), respectively. The area under the curve (AUC) for the training cohort at 12 months and 24 months was 0.785 (95% CI: 0.771-0.948) and 0.812 (95% CI: 0.772-0.940), respectively, while the corresponding values for the validation cohort were 0.864 (95% CI: 0.604-0.965) and 0.845 (95% CI: 0.705-0.951). These results confirm the stability and predictive accuracy of our model, demonstrating its reliable discriminative ability for post-discharge all-cause mortality risk. DCA analysis exhibited favorable net benefit of the nomogram. CONCLUSION: The developed nomogram shows potential as a tool for predicting post-discharge mortality in STEMI patients undergoing PPCI. However, its full utility awaits confirmation through broader external and temporal validation.

Effect of Iron Concentration on the Co-Production of Fucoxanthin and Fatty Acids in Conticribra weissflogii.

The production of fucoxanthin and fatty acids in Conticribra weissflogii has been examined, but there is still a lack of understanding regarding the impact of trace elements, including iron, on their co-production. To address this knowledge gap, this study investigated the effects of FeCl3·6H2O on the growth, fucoxanthin, and fatty acids of C. weissflogii. The findings revealed that the highest cell density (1.9 × 106 cells mL-1), cell dry weight (0.89 ± 0.15 g L-1), and total fatty acid concentration (83,318.13 µg g-1) were achieved at an iron concentration of 15.75 mg L-1, while the maximum carotenoid and fucoxanthin contents were obtained at an iron concentration of 3.15 mg L-1. The study demonstrated that the content of the active substance in C. weissflogii could be increased by adjusting the iron concentration, providing new information as to the more efficient co-production of fucoxanthin and fatty acids and offering experimental support for large-scale production.

The effect of sevoflurane exposure on cell-type-specific changes in the prefrontal cortex in young mice.

Sevoflurane, the predominant pediatric anesthetic, has been linked to neurotoxicity in young mice, although the underlying mechanisms remain unclear. This study focuses on investigating the impact of neonatal sevoflurane exposure on cell-type-specific alterations in the prefrontal cortex (PFC) of young mice. Neonatal mice were subjected to either control treatment (60% oxygen balanced with nitrogen) or sevoflurane anesthesia (3% sevoflurane in 60% oxygen balanced with nitrogen) for 2 hours on postnatal days (PNDs) 6, 8, and 10. Behavioral tests and single-nucleus RNA sequencing (snRNA-seq) of the PFC were conducted from PNDs 31 to 37. Mechanistic exploration included clustering analysis, identification of differentially expressed genes (DEGs), enrichment analyses, single-cell trajectory analysis, and genome-wide association studies (GWAS). Sevoflurane anesthesia resulted in sociability and cognition impairments in mice. Novel specific marker genes identified 8 distinct cell types in the PFC. Most DEGs between the control and sevoflurane groups were unique to specific cell types. Re-defining 15 glutamatergic neuron subclusters based on layer identity revealed their altered expression profiles. Notably, sevoflurane disrupted the trajectory from oligodendrocyte precursor cells (OPCs) to oligodendrocytes (OLs). Validation of disease-relevant candidate genes across the main cell types demonstrated their association with social dysfunction and working memory impairment. Behavioral results and snRNA-seq collectively elucidated the cellular atlas in the PFC of young male mice, providing a foundation for further mechanistic studies on developmental neurotoxicity induced by anesthesia.

Association of high-density lipoprotein cholesterol with all-cause and cause-specific mortality in a Chinese population of 3.3 million adults: a prospective cohort study.

Background: High-density lipoprotein cholesterol (HDL-C) has been inversely associated with cardiovascular disease (CVD) risk, but recent evidence suggests that extremely high levels of HDL-C are paradoxically related to increased CVD incidence and mortality. This study aimed to comprehensively examine the associations of HDL-C with all-cause and cause-specific mortality in a Chinese population. Methods: The China Health Evaluation And risk Reduction through nationwide Teamwork (ChinaHEART) project included 3,397,547 participants aged 35-75 years with a median follow-up of 3.9 years. Baseline HDL-C levels were measured, and mortality data was ascertained from the National Mortality Surveillance System and Vital Registration of Chinese Center for Disease Control and Prevention. Findings: This study found U-shaped associations of HDL-C with all-cause, cardiovascular and cancer mortality. When compared with the groups with the lowest risk, the adjusted hazard ratios (95% CIs) for HDL-C <30 mg/dL was 1.23 (1.17-1.29), 1.33 (1.23-1.45) and 1.18 (1.09-1.28) for all-cause, CVD and cancer mortality, respectively. For HDL-C >90 mg/dL, the corresponding HR (95% CIs) was 1.10 (1.05-1.15), 1.09 (1.01-1.18) and 1.11 (1.03-1.19). Similar U-shaped patterns were also found in associations of HDL-C with ischemic heart disease, ischemic stroke, and liver cancer. About 3.25% of all-cause mortality could be attributed to abnormal levels of HDL-C. The major contributor to mortality was ischemic heart disease (16.06 deaths per 100,000 persons, 95% UI: 10.30-22.67) for HDL-C <40 mg/dL and esophageal cancer (2.29 deaths per 100,000 persons, 95% UI: 0.57-4.77) for HDL-C >70 mg/dL. Interpretation: Both low and high HDL-C were associated with increased mortality risk. We recommended 50-79 mg/dL as the optimal range of HDL-C among Chinese adults. Individuals with dyslipidemia might benefit from proper management of both low and high HDL-C. Funding: The CAMS Innovation Fund for Medical Science (2021-1-I2M-011), the National High Level Hospital Clinical Research Funding (2022-GSP-GG-4), the Ministry of Finance of China and National Health Commission of China, and the 111 Project from the Ministry of Education of China (B16005), the Program for Guangdong Introducing Innovative and Enterpreneurial Teams (2019ZT08Y481), Sanming Project of Medicine in Shenzhen (SZSM201811096), the Young Talent Program of the Academician Fund, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen (YS-2022-006) and Guangdong Basic and Applied Basic Research Foundation (2023A1515010076 & 2021A1515220173).

Trends of mean systolic and diastolic blood pressure among adults in Shenzhen, China, 1997-2018: findings from three rounds of the population-based survey.

OBJECTIVE: To quantify the trends in systolic and diastolic blood pressure (BP) among adults in Shenzhen from 1997 to 2018. DESIGN: Cross-sectional study. SETTINGS: The data were collected from all districts in Shenzhen, China in the years of 1997, 2009 and 2018 by multistage cluster sampling procedure. PARTICIPANTS: Participants were residents aged 18-69 years in Shenzhen, China. A total of 26 621 people were included: 8266 people in 1997, 8599 people in 2009 and 9756 people in 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: All participants were surveyed about their sociodemographic and lifestyle information. BP was measured by trained physicians using a mercury sphygmomanometer. Hypertension was defined as systolic BP of at least 140 mm Hg and diastolic BP of at least 90 mm Hg, self-reported use of antihypertensive medications or both. Hypertension control was defined as systolic BP values of less than 140 mm Hg and diastolic BP values of less than 90 mm Hg. RESULT: Age-adjusted mean systolic BP increased from 117±16 mm Hg to 123±15 mm Hg (p<0.001) in males, and from 113±18 mm Hg to 115±16 mm Hg (p<0.001) in females from 1997 to 2018. Diastolic BP among males increased from 75 mm Hg (SD=11) to 79 mm Hg (SD=11) and increased from 71 mm Hg (SD=10) to 73 mm Hg (SD=10) among females between 1997 and 2018 (p<0.001). Rate of hypertension rose rapidly from 17.71% (95% CI: 16.60% to 18.90%) in 2009 to 24.01% (95% CI: 22.84% to 25.22%) in 2018 among males (p<0.001), whereas the prevalence among females remained stable at around 13.5% (p=0.98). Both awareness and treatment rates of hypertension among males and females showed a decreased trend between 2009 and 2018, while no significant changes were observed for control rates. CONCLUSIONS: The mean systolic BP and diastolic BP among adults in Shenzhen increased from 1997 to 2018, and no improvements in hypertension awareness, treatment and control rates were found.

Dexmedetomidine and acute kidney injury after non-cardiac surgery: A meta-analysis with trial sequential analysis.

BACKGROUND: Acute kidney injury (AKI) is a common complication after surgery and is associated with detrimental outcomes. This systematic review and meta-analysis evaluated perioperative dexmedetomidine on AKI and renal function after non-cardiac surgery. METHODS: PubMed, Embase, and Cochrane Library databases were searched until August 2023 for randomised trials comparing dexmedetomidine with normal saline on AKI and renal function in adults undergoing non-cardiac surgery. The primary outcome was the incidence of AKI (according to Kidney Disease Improving Global Outcomes or Acute Kidney Injury Network criteria). Meta-analysis was performed using a random-effect model. We conducted sensitivity analysis, trial sequential analysis (TSA), and Grading of Recommendations Assessment, Development and Evaluation level of evidence. RESULTS: Twenty-three trials involving 2440 patients were included. Dexmedetomidine administration, as compared to normal saline, significantly reduced the incidence of AKI (7.4% vs. 13.2%; risk ratio = 0.57, 95% CI = 0.40-0.83, P = 0.003, I2 = 0%; a high level of evidence); TSA and sensitivity analyses suggested the robustness of this outcome. For the renal function and inflammation parameters, dexmedetomidine decreased serum creatinine, blood urea nitrogen, cystatin C, tumour necrosis factor-α, and interleukin-6, and increased urine output and estimated glomerular filtration rate. Additionally, dexmedetomidine reduced postoperative nausea and vomiting and length of hospital stay. Dexmedetomidine was associated with an increased rate of bradycardia, but not hypotension. CONCLUSION: Dexmedetomidine administration reduced the incidence of AKI and improved renal function after non-cardiac surgery. Based on a high level of evidence, dexmedetomidine is recommended as a component of perioperative renoprotection. REGISTRATION: International Prospective Register of Systematic Reviews; Registration number: CRD42022299252.

Machines, mathematics, and modules: the potential to provide real-time metrics for pain under anesthesia.

The brain-based assessments under anesthesia have provided the ability to evaluate pain/nociception during surgery and the potential to prevent long-term evolution of chronic pain. Prior studies have shown that the functional near-infrared spectroscopy (fNIRS)-measured changes in cortical regions such as the primary somatosensory and the polar frontal cortices show consistent response to evoked and ongoing pain in awake, sedated, and anesthetized patients. We take this basic approach and integrate it into a potential framework that could provide real-time measures of pain/nociception during the peri-surgical period. This application could have significant implications for providing analgesia during surgery, a practice that currently lacks quantitative evidence to guide patient tailored pain management. Through a simple readout of "pain" or "no pain," the proposed system could diminish or eliminate levels of intraoperative, early post-operative, and potentially, the transition to chronic post-surgical pain. The system, when validated, could also be applied to measures of analgesic efficacy in the clinic.

Intradermal delivery of the antiretroviral drugs cabotegravir and rilpivirine by dissolving microarray patches: Investigation of lymphatic uptake.

The lymphatic system possesses the main viral replication sites in the body following viral infection. Unfortunately, current antiretroviral agents penetrate the lymph nodes insufficiently when administered orally and, therefore, cannot access the lymphatic system sufficiently to interrupt this viral replication. For this reason, novel drug delivery systems aimed at enhancing the lymphatic uptake of antiretroviral drugs are highly desirable. Dissolving polymeric microarray patches (MAPs) may help to target the lymph intradermally. MAPs are intradermal drug delivery systems used to deliver many types of compounds. The present work describes a novel work investigating the lymphatic uptake of two anti-HIV drugs: cabotegravir (CAB) and rilpivirine (RPV) when delivered intradermally using dissolving MAPs containing nanocrystals of both drugs. Maps were formulated using NCs obtained by solvent-free milling technique. The polymers used to prepare the NCs of both drugs were PVA 10 Kda and PVP 58 Kda. Both NCs were submitted to the lyophilization process and reconstituted with deionized water to form the first layer of drug casting. Backing layers were developed for short application times and effective skin deposition. In vivo biodistribution profiles of RPV and CAB after MAP skin application were investigated and compared with the commercial intramuscular injection using rats. After a single application of RPV MAPs, a higher concentration of RPV was delivered to the axillary lymph nodes (AL) (Cmax 2466 ng/g - Tmax 3 days) when compared with RPV IM injection (18 ng/g - Tmax 1 day), while CAB MAPs delivered slightly lower amounts of drug to the AL (5808 ng/g in 3 days) when compared with CAB IM injection (9225 ng/g in 10 days). However, CAB MAPs delivered 7726 ng/g (Tmax 7 days) to the external lumbar lymph nodes, which was statistically equivalent to IM delivery (Cmax 8282 ng/g - Tmax 7 days). This work provides strong evidence that MAPs were able to enhance the delivery of CAB and RPV to the lymphatic system compared to the IM delivery route.

Mogroside V alleviates the heat stress-induced disruption of the porcine oocyte in vitro maturation.

Heat stress (HS) is a stressor that negatively affect female reproduction. Specially, oocytes are very sensitive to HS. It has been demonstrated that some active compounds can protect oocyte from HS. We previously found that Mogroside V (MV), extracted from Siraitia grosvenorii (Luo Han Guo), can protect oocyte from many kinds of stresses. However, how MV alleviates HS-induced disruption of oocyte maturation remains unknown. In this study, we treated the HS-induced porcine oocytes with MV to examine their maturation and quality. Our findings demonstrate that MV can effectively alleviate HS-induced porcine oocyte abnormal cumulus cell expansion, decrease of first polar body extrusion rate, spindle assembly and chromosome separation abnormalities, indicating MV attenuates oocyte mature defects. We further observed that MV can effectively alleviate HS-induced cortical granule distribution abnormality and decrease of blastocyst formation rate after parthenogenesis activation. In addition, MV treatment reversed mitochondrial dysfunction and lipid droplet content decrease, reduced reactive oxygen species levels, early apoptosis and DNA damage in porcine oocytes after HS. Collectively, this study suggests that MV can effectively protect porcine oocytes from HS.

Effect of remimazolam on electroencephalogram burst suppression in elderly patients undergoing cardiac surgery: Protocol for a randomized controlled noninferiority trial.

Background: Postoperative delirium (POD) is a common complication following cardiac surgery and increases postoperative morbidity and mortality. Intraoperative electroencephalogram (EEG) burst suppression suggests excessively deep anesthesia and predicts POD. Use of remimazolam provides a stable hemodynamic status and an appropriate depth of anesthesia. We aim to assess remimazolam administered for anesthesia and sedation in elderly patients having cardiac surgery. Methods: This is a randomized controlled clinical trial with noninferiority design. A total of 260 elderly patients aged equal to or greater than 60 years undergoing cardiac surgery will be randomly allocated to receive remimazolam or propofol (1:1) for general anesthesia and postoperative sedation until extubation. The primary outcome is the cumulative time with EEG burst suppression which is obtained from the SedLine system. The noninferiority margin is 2.0 min. The secondary outcomes include the POD occurrence within the first 5 days postoperatively and the duration of perioperative hypotension. Discussion: This noninferiority trial is the first to evaluate the effect of perioperative remimazolam administration on EEG burst suppression, POD occurrence, and duration of hypotension in elderly patients who undergo cardiac surgery. Trial registration: Chinese Clinical Trial Registry (ChiCTR2200056353).

A nanoluciferase SFTSV for rapid screening antivirals and real-time visualization of virus infection in mice.

BACKGROUND: Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne pathogen that causes severe hemorrhagic fever in humans, but no FDA-approved specific antivirals or vaccines are available to treat or prevent SFTS. METHODS: The plasmids construction and transfection were performed to generate the recombinant SFTSV harboring the nanoluciferase gene (SFTSV-Nluc). Immunostaining plaque assay was performed to measure viral titers, and DNA electrophoresis and Sanger sequencing were performed to evaluate the genetic stability. Luciferase assay and quantitative RT-PCR were performed to evaluate the efficacy of antivirals in vitro. Bioluminescence imaging, titration of virus from excised organs, hematology, and histopathology and immunohistochemistry were performed to evaluate the efficacy of antivirals in vivo. FINDINGS: SFTSV-Nluc exhibited high genetic stability and replication kinetics similar to those of wild-type virus (SFTSVwt), then a rapid high-throughput screening system for identifying inhibitors to treat SFTS was developed, and a nucleoside analog, 4-FlU, was identified to effectively inhibit SFTSV in vitro. SFTSV-Nluc mimicked the replication characteristics and localization of SFTSVwt in counterpart model mice. Bioluminescence imaging of SFTSV-Nluc allowed real-time visualization and quantification of SFTSV replication in the mice. 4-FlU was demonstrated to inhibit the replication of SFTSV with more efficiency than T-705 and without obvious adverse effect in vivo. INTERPRETATION: The high-throughput screening system based on SFTSV-Nluc for use in vitro and in vivo revealed that a safe and effective antiviral nucleoside analog, 4-FlU, may be a basis for the strategic treatment of SFTSV and other bunyavirus infections, paving the way for the discovery of antivirals. FUNDING: This work was supported by grants from the National Key Research and Development Plan of China (2021YFC2300700 to L. Zhang, 2022YFC2303300 to L. Zhang), Strategic Priority Research Program of Chinese Academy of Sciences (XDB0490000 to L. Zhang), National Natural Science Foundation of China (31970165 to L. Zhang, U22A20379 to G. Xiao), the Science and Technology Commission of Shanghai Municipality (21S11903100 to Y. Xie), Hubei Natural Science Foundation for Distinguished Young Scholars (2022CFA099 to L. Zhang).

Ensure the accuracy and consistency of biochemical analyzer test results: Chemometrics for instrument and inter-instrument item comparison in Chinese hospital laboratory.

Biochemical analyzers are vital instruments that utilize the principle of photoelectric colorimetry to quantify a specific chemical composition in body fluids. This analysis provides critical data for the diagnosis, treatment, prognosis, and overall health status of various diseases in clinical practice. However, the performance of a biochemical analyzer can vary significantly between different brands or over time within the same brand. Therefore, it is imperative to regularly assess the performance of the analyzer to ensure consistent results for longitudinal studies and to maintain day-to-day data consistency. Additionally, when multiple analyzers are utilized, it is necessary to evaluate the performance of each instrument to ensure accurate results across multiple platforms. In this study, we developed and verified an experimental evaluation scheme for the analytical performance of the instrument, chemometrics for biochemical analyzers, utilizing national reference materials and patient sera as the experimental subjects. We evaluated the performance of the optical system, temperature control system, sample-adding system, and detection system to confirm the feasibility of this scheme. We also compared the analytical performance of different brands of biochemical analyzers for routine biochemical tests, such as liver function, kidney function, ion, blood lipids, blood glucose, and myocardial enzyme spectrum. Using the AU 5400 as a control and the ADVIA 2400 as the comparison system, the relative variation in inter-instrument comparison data was found to be acceptable at the clinical medicine decision level. In conclusion, the performance of a biochemical analyzer can vary significantly between different brands or over time within the same brand. Regular evaluations are necessary to ensure accurate and consistent results across different analyzers. This study provides a feasible scheme for evaluating the analytical performance of biochemical analyzers that can be used to ensure the accuracy and consistency of the results of different brands of automatic chemical analyzers in the laboratory.