State transitions of coupled Gi-protein: Insights into internal water channel dynamics within dopamine receptor D3 from in silico submolecular analyses.

Dopamine is a crucial neurotransmitter in the central nervous system (CNS) that facilitates communication among neurons. Activation of dopamine receptors in the CNS regulates key functions such as movement, cognition, and emotion. Disruption of these receptors can result in severe neurological diseases. Although recent research has elucidated the structure of D3R in complex with Gi-protein, revealing the binding and activation mechanisms, the precise conformational changes induced by G-protein activation and GDP/GTP exchange remain unclear. In this study, atomic-level long-term molecular dynamics (MD) simulations were employed to investigate the dynamics of D3R in complex with different states of Gi-protein and ß-arrestin. Our simulations revealed distinct molecular switches within D3R and fluctuations in the distance between Ras and helical domains of G-protein across different G-protein-D3R states. Notably, the D3R-GTP-Gi state exhibited increased activity compared with the D3R-empty-Gi state. Additionally, analyses of potential of mean force (PMF) and free energy landscapes for various systems revealed the formation of a continuous water channel exclusively in the D3R-Gi-GTP state. Furthermore, allosteric communication pathways were proposed for active D3R bound to Gi-protein. This study offers insights into the activation mechanism when Gi-protein interacts with active D3R, potentially aiding in developing selective drugs targeting the dopaminergic system.

Characterisation of Antimicrobial Resistance in Special-Fed Veal Production Environments.

INTRODUCTION: Antimicrobial resistance (AMR) is one of the leading public health threats globally. AMR genes can be transferred between bacteria through lateral gene transfer, and AMR organisms can spread through environments by contaminated water, agriculture and animals. Thus, widespread environmental dissemination of bacteria and lateral gene transfer facilitate AMR transmission pathways. Farm environments in dairy and calf production are known to harbour AMR bacteria that pose a risk for food contamination and to workers in direct or indirect contact with animals. Escherichia coli is present in farm environments and is known to participate in lateral gene transfer, providing a good marker of resistance genes in each environment. METHODS: In this study, E. coli from nine cohorts of calves was isolated at different time points from nine barns, nine trailers and one slaughterhouse environment in a single special-fed veal calf production facility. The antimicrobial susceptibility to 15 antimicrobials, classified as highly or critically important by the World Health Organization, was characterised for E. coli isolates using Kirby-Bauer disk diffusion. RESULTS: The highest proportion of isolates showing multidrug resistance was present in barn environments (51.7%), where calves were housed from their arrival at < 2 weeks of age until they were transported to slaughter. Additionally, 15 E. coli isolates were resistant to 11 of the 15 antimicrobials tested. Trailer and slaughterhouse environments had greater prevalence of resistance after accommodating calves, including resistance to third-generation cephalosporins. CONCLUSION: These data highlight the importance of calf environments in the dissemination of resistant bacteria and gives insight into where interventions could be most effective in combatting antimicrobial-resistant bacteria that could infect humans and livestock.

Evaluation of immune checkpoint inhibitors for colorectal cancer: A network meta­analysis.

Colorectal cancer (CRC) is challenging to treat due to its high metastatic rate. Recent strategies have focused on combining immune checkpoint inhibitors (ICIs) with other treatments. The aim of the present study was to conduct a network meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and adverse effects of different ICI treatments for CRC. A literature search for RCTs was conducted using PubMed, the Cochrane Library, Embase, ClinicalTrials.gov and Web of Science databases, covering the period from the inception of each database until April 2024. A total of 12 RCTs involving 2,050 participants were selected for inclusion in the analysis. The network meta-analysis employed the MetaInsight tool to assess multiple endpoints. The criteria for study selection were based on the Population, Intervention, Comparison, Outcome and Studies framework as follows: i) Population, patients with CRC; ii) intervention, studies using ICI to treat CRC; iii) comparison, active comparators, including placebo; iv) outcome, overall survival, progression-free survival, objective response rate and adverse events; and v) study design, RCTs. The results of the analysis revealed that programmed cell death-ligand 1 (PD-L1) inhibitors significantly improved overall survival time [mean difference (MD), 2.28 months; 95% confidence interval (CI), 0.44 to 4.11], while programmed cell death protein 1 (PD-1) inhibitors exhibited a superior progression-free survival time (MD, 4.79 months; 95% CI, 3.18 to 6.40) compared with active comparators. However, none of the ICI treatments had significant differences in odds ratios for the objective response rate and adverse events compared with active comparators. These findings indicate that treatment with PD-L1 and PD-1 inhibitors improved the overall survival time and delayed disease progression in patients with CRC. These findings offer valuable insights for future research aimed at improving CRC patient outcomes.

Achieving a 35-Plex Tandem Mass Tag Reagent Set through Deuterium Incorporation.

Mass spectrometry-based sample multiplexing with isobaric tags permits the development of high-throughput and precise quantitative biological assays with proteome-wide coverage and minimal missing values. Here, we nearly doubled the multiplexing capability of the TMTpro reagent set to a 35-plex through the incorporation of one deuterium isotope into the reporter group. Substituting deuterium frequently results in suboptimal peak coelution, which can compromise the accuracy of reporter ion-based quantification. To counteract the deuterium effect on quantitation, we implemented a strategy that necessitated the segregation of nondeuterium and deuterium-containing channels into distinct subplexes during normalization procedures, with reassembly through a common bridge channel. This multiplexing strategy of "design independent sub-plexes but acquire together" (DISAT) was used to compare protein expression differences between human cell lines and in a cysteine-profiling (i.e., chemoproteomics) experiment to identify compounds binding to cysteine-113 of Pin1.

Biomechanical analysis of four different meniscus suturing techniques for posterior meniscal root pull-out repair: A human cadaveric study.

Purpose: To compare the biomechanical properties of the slip-knot technique with three other transtibial pullout suture repair constructs for meniscal root tears. Method: Thirty-two fresh-frozen cadaveric menisci were randomly allocated to four meniscus-suture fixation constructs: Two simple-sutures (TSS), two slip-knot (TSK) sutures, two cinch-loop (TCL) sutures, and two modified Mason-Allen (TMMA) sutures. Cyclic loading from 5 to 20 N was conducted for 1000 cycles at 0.5 Hz, and then loaded to failure at 0.5 mm/s. Parametric data (displacement during cyclic loading, ultimate load, yield load, and displacement at failure) were analysed using a one-way analysis of variance (ANOVA), whereas nonparametric data (stiffness) were analysed using the Kruskal-Wallis test. Results: After 1000 cycles, the TCL construct significantly displaced the most (mean ± SD, 6.78 ± 1.32 mm; p < 0.001), followed by the TMMA (2.83 ± 0.90 mm), TSK (2.33 ± 0.57 mm), and TSS (2.03 ± 0.62 mm) groups. On ultimate failure load, there was no significant difference between the TSK group (123.48 ± 27.24 N, p > 0.05) and the other three groups (TSS, 94.65 ± 25.33 N; TMMA, 168.38 ± 23.24 N; TCL, 170.54 ± 57.32 N); however, it exhibited the least displacement (5.53 ± 1.25 mm) which was significantly shorter than those of the TCL (11.82 ± 4.25 mm, p < 0.001) and TMMA (9.53 ± 2.18 mm, p = 0.03) constructs. No significant difference in stiffness was observed among the four meniscus-suture constructs. Conclusion: The slip-knot technique has proven to be a simple, yet robust and stable meniscal root fixation option; moreover, it exhibited superiority over the more complex modified Mason-Allen suture construct in resisting displacement at the ultimate failure load. Level of Evidence: Not applicable.

Quantitative changes in platelet count in response to different pathogens: an analysis of patients with sepsis in both retrospective and prospective cohorts.

BACKGROUND: Thrombocytopenia is commonly observed in patients with sepsis and is an independent risk factor for poor prognosis. However, the changes of platelet count caused by different pathogens can vary significantly. Our study aims to evaluate the quantitative changes in platelet count in response to various pathogens. MATERIAL AND METHODS: We retrospectively analysed data of 3044 patients with sepsis from Medical Information Mart for Intensive Care (MIMIC, 2008-2019) database and prospectively collected data of 364 patients with sepsis from our local cohort of the Shandong Bloodstream Infection and Sepsis Collaboration Study (SBISC, 2020-2022). Propensity score matching (PSM) was employed to control for baseline differences in variables, except for the causative pathogen. RESULTS: Multivariate logistic analyses of both original and PSM populations identified Candida, Escherichia, Klebsiella, and Serratia species posing a higher risk for thrombocytopenia compared to others. Restricted cubic spline (RCS) curves showed L- or U-shaped associations between platelet count and 28-mortality with various cut-off values among different pathogens: ranging from 96 × 109/L in Candida species - 190 × 109/L in Klebsiella species. CONCLUSION: Our present findings indicate a pathogen-specific effect on platelet count, highlighting the importance of monitoring thrombocytopenia in patients infected with above microorganisms. Clinicians need to consider pathogen-specific thresholds when intervene on platelet count.

This study validated the differential incidence of thrombocytopenia among various pathogens within two distinct populations.Candida, Escherichia, Klebsiella, and Serratia species were identified as having a notably higher risk of causing thrombocytopenia compared to other pathogens.We observed L- or U-shaped relationships between platelet counts and 28-day mortality in Candida species, Enterococcus species, Escherichia species, Enterobacter species, Staphylococcus species, and Klebsiella species with platelet count cutoff values of 96 × 10⁹/L, 100 × 10⁹/L, 100 × 10⁹/L, 146 × 10⁹/L, 152 × 10⁹/L, and 190 × 10⁹/L, respectively.

Kinetics of Viral Shedding for Outbreak Surveillance of Emerging Infectious Diseases: Modeling Approach to SARS-CoV-2 Alpha and Omicron Infection.

BACKGROUND: Previous studies have highlighted the importance of viral shedding using cycle threshold (Ct) values obtained via reverse transcription polymerase chain reaction to understand the epidemic trajectories of SARS-CoV-2 infections. However, it is rare to elucidate the transition kinetics of Ct values from the asymptomatic or presymptomatic phase to the symptomatic phase before recovery using individual repeated Ct values. OBJECTIVE: This study proposes a novel Ct-enshrined compartment model to provide a series of quantitative measures for delineating the full trajectories of the dynamics of viral load from infection until recovery. METHODS: This Ct-enshrined compartment model was constructed by leveraging Ct-classified states within and between presymptomatic and symptomatic compartments before recovery or death among people with infections. A series of recovery indices were developed to assess the net kinetic movement of Ct-up toward and Ct-down off recovery. The model was applied to (1) a small-scale community-acquired Alpha variant outbreak under the "zero-COVID-19" policy without vaccines in May 2021 and (2) a large-scale community-acquired Omicron variant outbreak with high booster vaccination rates following the lifting of the "zero-COVID-19" policy in April 2022 in Taiwan. The model used Bayesian Markov chain Monte Carlo methods with the Metropolis-Hastings algorithm for parameter estimation. Sensitivity analyses were conducted by varying Ct cutoff values to assess the robustness of the model. RESULTS: The kinetic indicators revealed a marked difference in viral shedding dynamics between the Alpha and Omicron variants. The Alpha variant exhibited slower viral shedding and lower recovery rates, but the Omicron variant demonstrated swifter viral shedding and higher recovery rates. Specifically, the Alpha variant showed gradual Ct-up transitions and moderate recovery rates, yielding a presymptomatic recovery index slightly higher than 1 (1.10), whereas the Omicron variant had remarkable Ct-up transitions and significantly higher asymptomatic recovery rates, resulting in a presymptomatic recovery index much higher than 1 (152.5). Sensitivity analysis confirmed the robustness of the chosen Ct values of 18 and 25 across different recovery phases. Regarding the impact of vaccination, individuals without booster vaccination had a 19% higher presymptomatic incidence rate compared to those with booster vaccination. Breakthrough infections in boosted individuals initially showed similar Ct-up transition rates but higher rates in later stages compared to nonboosted individuals. Overall, booster vaccination improved recovery rates, particularly during the symptomatic phase, although recovery rates for persistent asymptomatic infection were similar regardless of vaccination status once the Ct level exceeded 25. CONCLUSIONS: The study provides new insights into dynamic Ct transitions, with the notable finding that Ct-up transitions toward recovery outpaced Ct-down and symptom-surfacing transitions during the presymptomatic phase. The Ct-up against Ct-down transition varies with variants and vaccination status. The proposed Ct-enshrined compartment model is useful for the surveillance of emerging infectious diseases in the future to prevent community-acquired outbreaks.

The role and mechanism of various trace elements in atherosclerosis.

Atherosclerosis is a slow and complex disease that involves various factors, including lipid metabolism disorders, oxygen-free radical production, inflammatory cell infiltration, platelet adhesion and aggregation, and local thrombosis. Trace elements play a crucial role in human health. Many trace elements, especially metallic ones, not only maintain the normal functions of organs but also participate in basic metabolic processes. The latest studies have revealed a close correlation between trace elements and the occurrence and progression of atherosclerosis. The imbalance of these trace elements can induce atherosclerosis or accelerate its progression through various mechanisms, which poses a significant threat to human health. Therefore, exploring the specific mechanism of trace elements on atherosclerosis is highly significant. In this review, we summarized the roles and mechanisms of iron, copper, zinc, magnesium, and selenium homeostasis and imbalance in atherosclerosis development, in order to identify novel targets and therapeutic strategies for treating atherosclerosis.

Rapid detection of tertiary butylated hydroquinone in food samples using Mn-MOF@f-CNF composite-modified screen-printed electrode.

Hydroquinone-based organic molecules are often used as unavoidable preservatives in the food industry. Among these additives, tertiary butylated hydroquinone (TBHQ) is widely employed as a preservative in various processed foods. However, the potential health risks associated with the excessive presence of TBHQ in food products have raised significant concerns. To address this pressing issuea novel binder-free composite composed of a manganese metal-organic framework and functionalized carbon nanofibers (Mn-MOF/f-CNF) has been developed as an electrode modifier for the ultrasensitive detection of TBHQ in food samples. The Mn-MOF/f-CNF composite was achieved using the ultrasonication method, revealing a lamellar sheet-like structure of the Mn-MOF and the curly thread-like fibrous structure of f-CNF. The developed Mn-MOF/f-CNF/SPE sensor system resulted in well-defined redox signals for TBHQ detection in a neutral pH solution. Compared to the unmodified SPE system, the modified system showed approximately a 300 mV reduction in overpotential and a twofold increase in peak current signal for TBHQ detection. The Mn-MOF/f-CNF/SPE sensor system showed a linear concentration window of 0.01 to 800 µM with a sensitivity of 6.28 µA µM-1 cm-2 and the obtained detection limit was 1.36 nM. Additionally, the proposed sensor displayed excellent reproducibility and repeatable results with an RSD of less than 5%. The real-time applicability of the Mn-MOF/f-CNF/SPE sensor system was demonstrated using real samples such as potato chips and instant noodles, showing excellent results with a recovery range of 95.1-98.5%.

Subcellular activation of ß-adrenergic receptors using a spatially restricted antagonist.

Gprotein-coupled receptors (GPCRs) regulate several physiological and pathological processes and represent the target of approximately 30% of Food and Drug Administration-approved drugs. GPCR-mediated signaling was thought to occur exclusively at the plasma membrane. However, recent studies have unveiled their presence and function at subcellular membrane compartments. There is a growing interest in studying compartmentalized signaling of GPCRs. This requires development of tools to separate GPCR signaling at the plasma membrane from the ones initiated at intracellular compartments. We leveraged the structural and pharmacological information available for ß-adrenergic receptors (ßARs) and focused on ß1AR as exemplary GPCR that functions at subcellular compartments, and rationally designed spatially restricted antagonists. We generated a cell-impermeable ßAR antagonist by conjugating a suitable pharmacophore to a sulfonate-containing fluorophore. This cell-impermeable antagonist only inhibited ß1AR on the plasma membrane. In contrast, a cell-permeable ßAR antagonist containing a nonsulfonated fluorophore efficiently inhibited both the plasma membrane and Golgi pools of ß1ARs. Furthermore, the cell-impermeable antagonist selectively inhibited the phosphorylation of PKA downstream effectors near the plasma membrane, which regulate sarcoplasmic reticulum (SR) Ca2+ release in adult cardiomyocytes, while the ß1AR Golgi pool remained active. Our tools offer promising avenues for investigating compartmentalized ßAR signaling in various contexts, potentially advancing our understanding of ßAR-mediated cellular responses in health and disease. They also offer a general strategy to study compartmentalized signaling for other GPCRs in various biological systems.

Visible-light-prompted photoelectrochemical sensors fabricated using Er3NbO7/P@g-C3N4/SnS2 nanocomposite for detecting mercury ion in environmental water samples.

Photoelectrochemical (PEC) detection technology is key for fighting pollution, leveraging the photoelectric conversion of the photoelectrode material. A specialized photoelectrode was developed to detect Hg2+ ions with exceptional sensitivity, utilizing an anodic PEC sensor composed of Er3NbO7/P@g-C3N4/SnS2 ternary nanocomposite. Rare earth metal niobates (RENs) were chosen due to their underexplored potential, whose performance was enhanced through bandgap engineering and surface modification, facilitated by P@g-C3N4 as an immobilization matrix and SnS2, belonging to the I-IV semiconductors category fostering hybrid heterojunction formation for boasting optical properties and suitable redox potentials. Introducing Hg2+ into the system, a specific amalgamation reaction occurs between reduced Hg and Sn. This reaction obstructs electron transfer to the FTO electrode surface, leading to the recombination of charges. The proposed PEC sensor exhibited remarkable analytical performance for Hg2+ detection, high sensitivity, a detection limit of 0.019 pM, excellent selectivity, and a detectable concentration range of 0.002-0.15 nM. Additionally, it demonstrated good recovery and low relative standard deviation when analyzing Hg2+ in water samples, highlighting the potential application of the heterostructure in detecting heavy metal ions via PEC technology.

Ketogenic diet effectiveness is superior for drug resistant epilepsy with causative genetic mutation than those without genetic etiology.

AIM: Epilepsy with genetic etiology is high prevalence of DRE, which is reported responsive to ketogenic diet therapy (KDT). Our retrospective cohort study attempted to investigate the KD responsiveness between DRE with genetic and non-genetic etiology. METHOD: Non-fasting gradual KD initiation protocol (GRAD-KD) and five-day diet program was implemented. Participants were categorized into genetic epilepsy or non-genetic epilepsy groups based on genetic tests. Monthly seizure frequencies and seizure reduction rate after KDT 3 months and 6 months were compared between two groups. RESULTS: Forty-six patients with genetic epilepsy and ninety-four patients with non-genetic epilepsy were recruited. Among 46 patients with genetic epilepsy, 12 patients withdrew from diet before 3 months of KDT, and 7 patients withdrew from diet before 6 months of KDT, thus, 27 patients retained the diet. Among 94 patients with non-genetic epilepsy, 20 patients withdrew from diet before 3 months of KDT, and 21 patients withdrew from diet before 6 months of KDT, 53 patients retained the diet. For the 46 patients with genetic epilepsy, 12 patients had pathogenic variants related to developmental and epileptic encephalopathy (DEE), whereas other 34 patients had disease-causing variants other than DEE. The mean monthly seizure frequencies showed significantly decreased both in patient with genetic-and non-genetic epilepsy after 6 months of KDT, however, the seizure reduction rate was significantly higher in patients with genetic epilepsy than patients with non-genetic epilepsy after 6 months of KDT. In addition, our data demonstrated that KDT could significantly reduce seizure burden in patients with non-DEE than patients with DEE. In addition, the patients with non-DEE significantly achieved greater seizure reduction rate than patients with DEE after 6 months of KDT. INTERPRETATION: Our data highlighted that KD effectiveness is more outstanding in decreasing seizure burdens for epileptic patients with genetic etiology than those without causative gene mutation. Additionally, KDT is also significantly effective for decreasing more seizure burdens for non-DEE patients than for DEE patients. We suggested epileptic patients caused by genetic mutation should implement KDT as early as possible.

Recent Advances and Mechanisms of Phage-Based Therapies in Cancer Treatment.

The increasing interest in bacteriophage technology has prompted its novel applications to treat different medical conditions, most interestingly cancer. Due to their high specificity, manipulability, nontoxicity, and nanosize nature, phages are promising carriers in targeted therapy and cancer immunotherapy. This approach is particularly timely, as current challenges in cancer research include damage to healthy cells, inefficiency in targeting, obstruction by biological barriers, and drug resistance. Some cancers are being kept at the forefront of phage research, such as colorectal cancer and HCC, while others like lymphoma, cervical cancer, and myeloma have not been retouched in a decade. Common mechanisms are immunogenic antigen display on phage coats and the use of phage as transporters to carry drugs, genes, and other molecules. To date, popular phage treatments being tested are gene therapy and phage-based vaccines using M13 and λ phage, with some vaccines having advanced to human clinical trials. The results from most of these studies have been promising, but limitations in phage-based therapies such as reticuloendothelial system clearance or diffusion inefficiency must be addressed. Before phage-based therapies for cancer can be successfully used in oncology practice, more in-depth research and support from local governments are required.

Management of Extra-Articular and Intra-Articular Distal Radius Malunion.

This article presents a comprehensive overview of managing extra-articular and intra-articular distal radius malunions (DRM), discussing the pathoanatomy, clinical, and radiologic evaluation, conservative treatment, and surgical strategies. Corrective osteotomy remains the primary surgical intervention for symptomatic DRM. Surgical planning should consider factors such as timing, approach, correction technique, implant, graft, and associated injuries. The correction of extra-articular malunion necessitates brachioradialis tenotomy, circumferential periosteum release, and intrafocal elevation with grafting to facilitate distal radius realignment following osteotomy. Computer-assisted planning with 3D-printed patient-specific instrumentation (PSI) could help execute extra-articular osteotomy with high precision. As for the management of intra-articular malunion, it may require wrist arthrotomy, arthroscopy, or PSI assistance for precise articular osteotomy and reduction of the joint surface. This review highlights the importance of early intervention, thorough preoperative planning, and appropriate surgical techniques to optimize outcomes and minimize complications. Future research should focus on large-scale randomized controlled trials to compare different surgical methods, particularly for intra-articular DRM.

Targeting the Adenosine A2A Receptor as a Novel Therapeutic Approach for Renal Cell Carcinoma: Mechanisms and Clinical Trial Review.

Renal cell carcinoma (RCC) accounts for nearly 2% of cancers diagnosed worldwide. For metastatic RCC, targeted therapy is one of the most common treatment methods. It can include approaches that target vascular endothelial growth factor (VEGFR) or rely on immune checkpoint inhibitors or mTOR inhibitors. Adenosine A2A receptor (A2AR) is a type of widely distributed G-protein-coupled receptor (GPCR). Recently, an increasing number of studies suggest that the activation of A2AR can downregulate anti-tumor immune responses and prevent tumor growth. Currently, the data on A2AR antagonists in RCC treatment are still limited. Therefore, in this article, we further investigate the clinical trials investigating A2AR drugs in RCC. We also describe the epidemiology and current treatment of RCC, along with the physiological role of A2AR, and the types of A2AR drugs that are associated with tumor treatment.

Lapidilactobacillus salsurivasis sp. nov., Secundilactobacillus muriivasis sp. nov., and Streptococcus parasalivarius sp. nov., isolated from Traditional Chinese Pickle.

Four Gram-stain-positive bacterial strains (designated 475-2T, 46-6BT, 778-2T and A810-3), isolated from traditional Chinese pickle, were characterized using a polyphasic taxonomic approach. Strain 475-2T was most closely related to the type strain of Lapidilactobacillus achengensis, having 99.9% 16S rRNA gene sequence similarity, 94.1-95.1% average nucleotide identity (ANI) and 57.6% digital DNA-DNA hybridization (dDDH) values. Strain 46-6BT was most closely related to the type strain of Secundilactobacillus similis, having 99.8% 16S rRNA gene sequence similarity, 94.3-94.9% ANI and 58.9-59.2% dDDH values. Strains 778-2T and A810-3 were phylogenetically related to the type strains of Streptococcus salivarius, Streptococcus thermophilus and Streptococcus vestibularis, having 99.7-99.9% 16S rRNA gene sequence similarities, 89.1-94.4% ANI and 39.0-55.5% dDDH values. Based upon the data obtained in the present study, three novel species, Lapidilactobacillus salsurivasis sp. nov., Secundilactobacillus muriivasis sp. nov. and Streptococcus parasalivarius sp. nov., are proposed and the type strains are 475-2T (= JCM 36613T = CCTCC AB 2023258T = LMG 33412T), 46-6BT (= JCM 36612T = CCTCC AB 2023259T = LMG 33411T) and 778-2T (= JCM 36614T = CCTCC AB 2023257T = LMG 33413T), respectively.

Effect of remimazolam on intra-operative hypotension: Systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Hypotension is common during anaesthesia. Increasing number of studies have reported that remimazolam may be associated with lower incidence of intra-operative hypotension compared with other anaesthetics. However, the results remain controversial. OBJECTIVE: This study aimed to evaluate the influence of remimazolam on intra-operative hypotension and its related outcomes (hypoxaemia, bradycardia and time to awake). DESIGN: A systematic review of randomised controlled trials (RCTs) with meta-analyses. DATA SOURCES: PubMed, Cocharane and Embase databases were searched to identify eligible RCTs published up to June 2024. ELIGIBILITY CRITERIA: RCTs published in English were eligible for inclusion. The study patients were 18 years or older who were administered with remimazolam and other positive control agents in either the pre-operative or intra-operative period. The incidence of intra-operative hypotension was identified in these studies. RESULTS: This study evaluated 34 trials including 4847 individuals. Basing on moderate-certainty evidence, we found that remimazolam administration reduced the incidence of intra-operative hypotension [risk ratio (RR) = 0.48, 95% confidence interval (95% CI): 0.41 to 0.57] and bradycardia (16 studies, n = 2869, RR = 0.40, 95% CI: 0.29 to 0.54). No difference was observed in the incidence of hypoxaemia (RR = 0.70, 95% CI: 0.48 to 1.01) and time to awake (MD = -0.91, 95% CI: -2.42 to 0.60). The remarkable association between remimazolam and hypotension remained robust and significant, regardless of general anaesthesia or procedural sedation (P < 0.01, I2 = 82%). No significant difference was found between different control drugs (P = 0.97, I2 = 82%). CONCLUSION: Moderate-quality evidence shows that remimazolam administration to patients undergoing general anaesthesia or procedural sedation decreases the incidence of intra-operative hypotension and bradycardia.

Role of HIF-1α-Activated IL-22/IL-22R1/Bmi1 Signaling Modulates the Self-Renewal of Cardiac Stem Cells in Acute Myocardial Ischemia.

Impaired tissue regeneration negatively impacts on left ventricular (LV) function and remodeling after acute myocardial infarction (AMI). Little is known about the intrinsic regulatory machinery of ischemia-induced endogenous cardiac stem cells (eCSCs) self-renewing divisions after AMI. The interleukin 22 (IL-22)/IL-22 receptor 1 (IL-22R1) pathway has emerged as an important regulator of several cellular processes, including the self-renewal and proliferation of stem cells. However, whether the hypoxic environment could trigger the self-renewal of eCSCs via IL-22/IL-22R1 activation remains unknown. In this study, the upregulation of IL-22R1 occurred due to activation of hypoxia-inducible factor-1α (HIF-1α) under hypoxic and ischemic conditions. Systemic IL-22 administration not only attenuated cardiac remodeling, inflammatory responses, but also promoted eCSC-mediated cardiac repair after AMI. Unbiased RNA microarray analysis showed that the downstream mediator Bmi1 regulated the activation of CSCs. Therefore, the HIF-1α-induced IL-22/IL-22R1/Bmi1 cascade can modulate the proliferation and activation of eCSCs in vitro and in vivo. Collectively, investigating the HIF-1α-activated IL-22/IL-22R1/Bmi1 signaling pathway might offer a new therapeutic strategy for AMI via eCSC-induced cardiac repair.

IL-6 and TIMP-1 Correlated to Airway Pathogen Colonization and Predict Disease Severity in Patients with Non-Cystic Fibrosis Bronchiectasis.

Background: Non-cystic fibrosis bronchiectasis is associated with airway pathogen colonization. We planned to investigate the inflammatory markers in patients with different airway pathogens and their correlation with disease severity. Methods: We enrolled patients aged between 20 and 75 from October 2021 to August 2022. All patients had sputum evaluation for bacterial and fungal cultures before enrollment, and were classified into four groups according to the culture results. Results: Forty-four patients with non-CF bronchiectasis and six controls were enrolled and categorized as follows: Group 1, no pathogens identified in sputum cultures (n = 14); Group 2, positive fungal culture results (n = 18); Group 3, positive P. aeruginosa culture results (n = 7); and Group 4, positive culture results for both fungi and P. aeruginosa (n = 5). Group 4 had significantly higher serum defensin α1, IL-6 and tissue inhibitors of MMP (TIMP)-1 levels than group 1 patients. The serum levels of IL-6 and TIMP-1 were positively correlated with the FACED score and negatively correlated with distance-saturation product. Conclusion: Significantly higher levels of serum IL-6 and TIMP-1 were found in the patients who had concomitant fungal and P. aeruginosa colonization, and were closely related to clinical severity and may have important roles in disease monitoring.