Knowledge-reinforced explainable next basket recommendation.

The next basket recommendation task aims to predict the items in the user's next basket by modeling the user's basket sequence. Existing next basket recommendations focus on improving recommendation performance, and most of these methods are black-box models, ignoring the importance of providing explanations to improve user satisfaction. Furthermore, most next basket recommendation methods are designed for consumer users, and few methods are proposed for business user characteristics. To address the above problems, we propose a Knowledge Reinforced Explainable Next Basket Recommendation (KRE-NBR). Specifically, we construct a basket-based knowledge graph and obtain pretrained embeddings of entities that contain rich information of the knowledge graph. To obtain high-quality user predictive vectors, we fuse user pretrained embeddings, user basket sequence level embeddings, and user repurchase embeddings. One highlight of the user repurchase embeddings is that they are able to model business user repurchase behavior. To make the results of next basket recommendations explainable, we use reinforcement learning for path reasoning to find the items recommended in the next basket and generate recommendation explanations at the same time. To the best of our knowledge, this is the first work to provide recommendation explanations for next basket recommendations. Extensive experiments on real datasets show that the recommendation performance of our proposed approach outperforms several state-of-the-art baselines.

The typical developmental trajectory and energy requirements of Shitou goose during the embryonic stage.

Low hatchability has been a persistent challenge in the goose industry. Establishing standard atlases and comprehending embryonic development patterns are essential to improving the hatching rates of goose eggs. However, comprehensive descriptions of normal atlases, embryonic development, and energy requirements in geese are lacking. In this study, a total of 120 fertile eggs from well-known large Shitou goose were incubated using 12 nesting purebred female geese. During hatching, both the temperature of the eggshells and the weight of eggs were recorded, and daily photographs of the embryos were captured to monitor their development closely. After hatching, counted the number of pores per unit area of eggshells by choosing eggs from without sperm, dead embryos, and normally hatched. Furthermore, 150 Shitou goose eggs were hatched by automatic incubator, with adjustments made based on observed normal developmental stages that incubated by female geese. The eggs were carefully opened to meticulously document embryonic morphology and create a detailed development map. Measurements were taken of the eye diameter, length of the lower beak, tarsometatarsus bone, and embryo length. Subsequently, an analysis was conducted to assess the calcium, phosphorus, crude protein, and crude fat content to study the energy requirements for embryo development. characteristics on the 7th, 15th, 23rd and 28th days of Shitou goose hatching corresponded to the 5th, 10th, 17th and 19th days of chicken egg incubation, respectively. These days were distinguished individually by "visible embryo's eye", "closure", "sealing the door", and "flashing hair". Besides, the hatch rate of the incubator reached 86.67%, and the cumulative water loss rate increased with embryo age. Notably, normally developing embryos displayed a significantly higher number of pores on the eggshell surface compared to dead embryos (P < 0.05). Additionally, embryonic body length, eyeball diameter, and lower beak length exhibited continuous growth until day 19 of incubation, while tarsometatarsus length increased steadily from days 12 to 31. Liver size measurement began on the 10th day of incubation, while both leg and chest muscles showed continuous growth from the 12th day. For energy demand, the embryo primarily relied on protein sourced from the egg yolk within the first 10 days of development. Afterward, the egg yolk provided both protein and fat for embryonic growth. In summary, this study has generated a comprehensive developmental map for Shitou goose embryos, offering valuable insights into their growth and morphological changes throughout the incubation period. This map can serve as a reference for optimizing machine incubation techniques to enhance goose egg hatching rates and provide fresh perspectives on the development of geese.

Evidence of being cured for nasopharyngeal carcinoma: results of a multicenter patient-based study in China.

Background: The survival rates of patients with nasopharyngeal carcinoma (NPC) have improved significantly, but there is no consensus on whether they can be considered cured. We aimed to determine whether a statistical cure could be achieved for patients with NPC in the contemporary therapeutic landscape. Methods: This retrospective multicenter study enrolled 6315 patients with nonmetastatic NPC from nonendemic and endemic regions of China from 2007 to 2020. We applied mixture and nonmixture cure models to estimate the cure probabilities and cure times by incorporating background mortality for the general population, matching by gender, age, and diagnosed year. Findings: With death as the uncured event, the probability of patients with NPC achieving a life expectancy at par with the general population was 78.1%. Considering progression as the uncured event, the likelihood of patients attaining a life expectancy without progression equivalent to that of the general population was 72.4%. For individuals, the probabilities of achieving cure were conditional and time-dependent, requiring approximately 7.1 and 4.7 years with 95% certainty, respectively. The corresponding cure times for uncured patients were 8.9 and 6.8 years, respectively. The cure probability was correlated with age, Eastern Cooperative Oncology Group score, TNM staging, Epstein-Barr virus DNA copies, and lactate dehydrogenase. The correlation was excellent between 5-year overall survival/progression-free survival and cure fractions. Interpretation: Statistical cure is potentially achievable among patients with NPC undergoing contemporary treatment modalities. The results hold significant potential implications for both clinical practice and patient perspectives. Funding: National High Level Hospital Clinical Research Funding; Beijing Xisike Clinical Oncology Research Foundation; Beijing hope run fund.

Single-cell sequencing combined with spatial transcriptomics reveals that the IRF7 gene in M1 macrophages inhibits the occurrence of pancreatic cancer by regulating lipid metabolism-related mechanisms.

AIM: The main focus of this study is to explore the molecular mechanism of IRF7 regulation on RPS18 transcription in M1-type macrophages in pancreatic adenocarcinoma (PAAD) tissue, as well as the transfer of RPS18 by IRF7 via exosomes to PAAD cells and the regulation of ILF3 expression. METHODS: By utilising single-cell RNA sequencing (scRNA-seq) data and spatial transcriptomics (ST) data from the Gene Expression Omnibus database, we identified distinct cell types with significant expression differences in PAAD tissue. Among these cell types, we identified those closely associated with lipid metabolism. The differentially expressed genes within these cell types were analysed, and target genes relevant to prognosis were identified. Flow cytometry was employed to assess the expression levels of target genes in M1 and M2 macrophages. Cell lines with target gene knockout were constructed using CRISPR/Cas9 editing technology, and cell lines with target gene knockdown and overexpression were established using lentiviral vectors. Additionally, a co-culture model of exosomes derived from M1 macrophages with PAAD cells was developed. The impact of M1 macrophage-derived exosomes on the lipid metabolism of PAAD cells in the model was evaluated through metabolomics analysis. The effects of M1 macrophage-derived exosomes on the viability, proliferation, division, migration and apoptosis of PAAD cells were assessed using MTT assay, flow cytometry, EdU assay, wound healing assay, Transwell assay and TUNEL staining. Furthermore, a mouse PAAD orthotopic implantation model was established, and bioluminescence imaging was utilised to assess the influence of M1 macrophage-derived exosomes on the intratumoural formation capacity of PAAD cells, as well as measuring tumour weight and volume. The expression of proliferation-associated proteins in tumour tissues was examined using immunohistochemistry. RESULTS: Through combined analysis of scRNA-seq and ST technologies, we discovered a close association between M1 macrophages in PAAD samples and lipid metabolism signals, as well as a negative correlation between M1 macrophages and cancer cells. The construction of a prognostic risk score model identified RPS18 and IRF7 as two prognostically relevant genes in M1 macrophages, exhibiting negative and positive correlations, respectively. Mechanistically, it was found that IRF7 in M1 macrophages can inhibit the transcription of RPS18, reducing the transfer of RPS18 to PAAD cells via exosomes, consequently affecting the expression of ILF3 in PAAD cells. IRF7/RPS18 in M1 macrophages can also suppress lipid metabolism, cell viability, proliferation, migration, invasion and intratumoural formation capacity of PAAD cells, while promoting cell apoptosis. CONCLUSION: Overexpression of IRF7 in M1 macrophages may inhibit RPS18 transcription, reduce the transfer of RPS18 from M1 macrophage-derived exosomes to PAAD cells, thereby suppressing ILF3 expression in PAAD cells, inhibiting the lipid metabolism pathway, and curtailing the viability, proliferation, migration, invasion of PAAD cells, as well as enhancing cell apoptosis, ultimately inhibiting tumour formation in PAAD cells in vivo. Targeting IRF7/RPS18 in M1 macrophages could represent a promising immunotherapeutic approach for PAAD in the future.

The Impact of Fentanyl on the Effective Dose of Remimazolam-Induced Sedation in Elderly Female Patients: An Up-and-Down Sequential Allocation Trial.

Purpose: This study aimed to investigate the influence of fentanyl on the effective dose of remimazolam-induced sedation in elderly female patients undergoing general anesthesia. Patients and Methods: Sixty female patients aged 65-80 years undergoing selective general anesthesia were randomized into two groups: Group R+F received an initial dose of remimazolam (7.5 mg) with fentanyl (1 µg/kg), while Group R received remimazolam alone. Dosing adjustments (±2.5 mg) were made based on the response of the preceding patient using the up-and-down allocation technique. The ED50 and ED95 were calculated using a sequential formula and probit regression. Probit regression was also used to assess the relative potency of remimazolam between groups. Sedation levels were evaluated using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale. Results: The ED50 for remimazolam was significantly lower in Group R+F compared to Group R (p= 0.007). Probit regression estimated the ED50 and ED95 values for Group R+F at 4.878 mg (95% CI, 3.845-5.859) and 8.184 mg (95% CI, 6.636-13.546), respectively. In contrast, Group R demonstrated ED50 and ED95 values of 6.733 mg (95% CI, 5.533-8.068) and 11.298 mg (95% CI, 9.101-19.617), respectively. Conclusion: This study provides compelling evidence that the administration of 1 µg/kg of fentanyl significantly reduces the required sedative dose of remimazolam by approximately 30% during induction in elderly patients. Importantly, the concomitant use of 1 µg/kg of fentanyl does not increase the risk of adverse effects such as hypotension, respiratory depression.

Unraveling the signaling network between dysregulated microRNA and mRNA expression in sevoflurane-induced developmental neurotoxicity in rat.

Research has indicated that general anesthesia may cause neuroapoptosis and long-term cognitive dysfunction in developing animals, however, the precise mechanisms orchestrating these outcomes remain inadequately elucidated within scholarly discourse. The purpose of this study was to investigate the impact of sevoflurane on the hippocampus of developing rats by analyzing the changes in microRNA and mRNA and their interactions. Rats were exposed to sevoflurane for 4 h on their seventh day after birth, and the hippocampus was collected for analysis of neuroapoptosis by Western blot and immunohistochemistry. High-throughput sequencing was conducted to analyze the variances in miRNA and mRNA expression levels, and the Morris water maze was employed to assess long-term memory in rats exposed to sevoflurane after 8 weeks. The results showed that sevoflurane exposure led to dysregulation of 5 miRNAs and 306 mRNAs in the hippocampus. Bioinformatic analysis revealed that these dysregulated miRNA-mRNA target pairs were associated with pathological neurodevelopment and developmental disorders, such as regulation of axonogenesis, regulation of neuron projection development, regulation of neuron differentiation, transmission of nerve impulse, and neuronal cell body. Further analysis showed that these miRNAs formed potential network interactions with 44 mRNAs, and two important nodes were identified, miR-130b-5p and miR-449c-5p. Overall, this study suggests that the dysregulation of the miRNA-mRNA signaling network induced by sevoflurane may contribute to neurodevelopmental toxicity in the hippocampus of rats and be associated with long-term cognitive dysfunction.

Effect of early endothelial function improvement on subclinical target organ damage in hypertensives.

Endothelial dysfunction is acknowledged as a marker for subclinical target organ damage (STOD) in hypertension, though its therapeutic potential has not yet been clarified. This study assessed whether early endothelial function improvement (EEFI) reduced STOD in patients with essential hypertension (EH). We conducted a retrospective cohort analysis of 456 EH patients initially free from STOD. Endothelial function was assessed using brachial artery flow-mediated dilation (FMD), with values ≤ 7.1% indicating dysfunction. Patients were initially categorized by endothelial status (dysfunction: n = 180, normal: n = 276), and further divided into improved or unimproved groups based on changes within three months post-enrollment. During a median follow-up of 25 months, 177 patients developed STOD. The incidence of STOD was significantly higher in patients with initial dysfunction compared to those with normal function. Kaplan-Meier analysis indicated that the improved group had a lower cumulative incidence of STOD compared to the unimproved group (p < 0.05). Multivariable Cox regression confirmed EEFI as an independent protective factor against STOD in EH patients (p < 0.05), regardless of their baseline endothelial status, especially in those under 65 years old, non-smokers, and with low-density lipoprotein cholesterol levels ≤ 3.4 mmol/L. In conclusion, EEFI significantly reduces STOD incidence in EH patients, particularly in specific subgroups, emphasizing the need for early intervention in endothelial function to prevent STOD.

The synaptic correlates of serial position effects in sequential working memory.

Sequential working memory (SWM), referring to the temporary storage and manipulation of information in order, plays a fundamental role in brain cognitive functions. The serial position effect refers to the phenomena that recall accuracy of an item is associated to the order of the item being presented. The neural mechanism underpinning the serial position effect remains unclear. The synaptic mechanism of working memory proposes that information is stored as hidden states in the form of facilitated neuronal synapse connections. Here, we build a continuous attractor neural network with synaptic short-term plasticity (STP) to explore the neural mechanism of the serial position effect. Using a delay recall task, our model reproduces the the experimental finding that as the maintenance period extends, the serial position effect transitions from the primacy to the recency effect. Using both numerical simulation and theoretical analysis, we show that the transition moment is determined by the parameters of STP and the interval between presented stimulus items. Our results highlight the pivotal role of STP in processing the order information in SWM.

Epidermal growth factor receptor­targeted antibody nimotuzumab combined with chemoradiotherapy improves survival in patients with locally advanced head and neck squamous cell carcinoma: a propensity score matching real-world study.

Patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) have poor survival outcomes. The real-world efficacy of nimotuzumab plus intensity modulated radiotherapy (IMRT)-based chemoradiotherapy in patients with LA-HNSCC remains unclear. A total of 25,442 HNSCC patients were screened, and 612 patients were matched by propensity score matching (PSM) (1:1). PSM was utilized to balance known confounding factors. Patients who completed at least five doses of nimotuzumab were identified as study group. The primary end point was 3-year overall survival (OS) rate. Log-rank test examined the difference between two survival curves and Cloglog transformation test was performed to compare survival at a fixed time point. The median follow-up time was 54.2 (95% confidence interval [CI]: 52.7-55.9) months. The study group was associated with improved OS (hazard ratio [HR] = 0.75, 95% CI: 0.57-0.99, p = 0.038) and progression-free survival (PFS) (HR = 0.74, 95% CI: 0.58-0.96, p = 0.021). Subgroup analysis revealed that aged 50-60 year, IV, N2, radiotherapy dose ≥ 60 Gy, without previous surgery, and neoadjuvant therapy have a trend of survival benefit with nimotuzumab. Nimotuzumab showed favorable safety, only 0.2% had nimotuzumab-related severe adverse events. Our study indicated the nimotuzumab plus chemoradiotherapy provides survival benefits and safety for LA-HNSCC patients in an IMRT era.

Short-term skin reactions and changes in stratum corneum following different ways of facial sheet mask usage.

BACKGROUND: The global facial mask market grows steadily at 8.5 % annually. However, prolonged use may lead to skin inflammation. OBJECTIVE: To investigate how various mask types and wearing durations impact skin physiology and aquaporins3 (AQP3) expression in healthy subjects. METHODS: We used a randomized controlled design to investigate the effects of three types of facial masks (pure water, hyaluronan, and bifida ferment lysate) and four different duration(5, 15, 25, and 40 min) on various skin parameters in volunteers, assessing moisture content, transepidermal water loss (TEWL), sebum, corneocyte size, and AQP3 expression before and after mask application, while also evaluating adverse reactions, discomfort, and noncompliance. RESULT: Hydration and TEWL increased at first, then decreased. Sebum increased with all types of masks, particularly after 40 min. Vasodilation and AQP3 expression were linked to mask duration. Corneocyte sizes remained constant. The main adverse reactions were redness (10.71 %, n = 28) and dryness (57.14 %, n = 28), especially with pure water masks lasting over 25 min. CONCLUSION: Short-term use of facial sheet masks (<25 min) benefits skin with improved hydration, reduced redness, and AQP3 activation, while prolonged use can lead to increased dryness and redness.

Long-term outcomes and prognosis of neuroendocrine neoplasms of the head and neck: a cohort from a single institution.

BACKGROUND: Neuroendocrine neoplasm is a rare cancer of head and neck. This study aimed to evaluate clinical features, treatment outcomes, and prognostic factors of neuroendocrine neoplasm of head and neck treated at a single institution. METHODS: Between Nov 2000 and Nov 2021, ninety-three patients diagnosed with neuroendocrine neoplasms of head and neck treated at our institution were reviewed retrospectively. The initial treatments included chemotherapy (induction, adjuvant, or concurrent) combined with radiotherapy in 40 patients (C + RT group), surgery followed by post-operative RT in 34 (S + RT group), and surgery plus salvage therapy in 19 patients (S + Sa group). RESULTS: The median follow-up time was 64.5 months. 5-year overall survival rate (OS), progression-free survival rate (PFS), loco-regional relapse-free survival free rate (LRRFS) and distant metastasis-free survival rate (DMFS) were 64.5%, 51.6%, 66.6%, and 62.1%, respectively. For stage I-II, the 5-year LRRFS for patients' treatment regimen with or without radiotherapy (C + RT and S + RT groups versus S + Sa group) was 75.0% versus 12.7% (p = 0.015) while for stage III-IV, the 5-year LRRFS was 77.8% versus 50.0% (p = 0.006). The 5-year DMFS values for patients with or without systemic therapy (C + RT group versus S + RT or S + Sa) were 71.2% and 51.5% (p = 0.075). 44 patients (47.3%) experienced treatment failure and distant metastasis was the main failure pattern. CONCLUSIONS: Radiotherapy improved local-regional control and played an important role in the management of HNNENs. The optimal treatment regimen for HNNENs remains the combination of local and systemic treatments.

Ocean internal tides suppress tropical cyclones in the South China Sea.

Tropical Cyclones (TCs) are devastating natural disasters. Analyzing four decades of global TC data, here we find that among all global TC-active basins, the South China Sea (SCS) stands out as particularly difficult ocean for TCs to intensify, despite favorable atmosphere and ocean conditions. Over the SCS, TC intensification rate and its probability for a rapid intensification (intensification by ≥ 15.4 m s-1 day-1) are only 1/2 and 1/3, respectively, of those for the rest of the world ocean. Originating from complex interplays between astronomic tides and the SCS topography, gigantic ocean internal tides interact with TC-generated oceanic near-inertial waves and induce a strong ocean cooling effect, suppressing the TC intensification. Inclusion of this interaction between internal tides and TC in operational weather prediction systems is expected to improve forecast of TC intensity in the SCS and in other regions where strong internal tides are present.

Safety and efficacy of intravenous thrombolysis before mechanical thrombectomy in patients with atrial fibrillation.

BACKGROUND: Intravenous thrombolysis (IVT) before endovascular thrombectomy (EVT) is the standard treatment for patients with acute ischemic stroke caused by large vessel occlusion (AIS-LVO). However, the efficacy and safety of IVT before EVT in AIS-LVO patients with atrial fibrillation (AF) remains controversial. Thus, this study aims to assess the benefit of IVT plus EVT and direct EVT alone in AIS-LVO patients with AF. METHOD: Relevant studies that evaluated the outcomes of IVT plus EVT versus direct EVT alone in AIS-LVO patients with AF were systematically searched in PubMed, Embase, and Cochrane Library from inception to August 10, 2023. The outcomes included successful reperfusion (score of 2b to 3 for thrombolysis in cerebral infarction), symptomatic intracerebral hemorrhage (sICH), good clinical outcome (modified Rankin scale score ≤ 2) at 3 months, and 3-month mortality. RESULT: Eight eligible observational studies involving 6998 (3827 in the IVT plus EVT group and 3171 in the direct EVT group) patients with AIS-LVO complicated by AF were included. Compared with direct EVT, IVT plus EVT resulted in better 3-month clinical outcomes (odds ratio [OR] 1.27, 95% confidence interval [CI] 1.05-1.54) and lower 3-month mortality (OR 0.78, 95% CI 0.68-0.88). However, the incidence of sICH (OR 1.26, 95% CI 0.91-1.75) and the rate of successful reperfusion (OR 0.98, 95% CI 0.83-1.17) were not significantly different between treatment modalities. CONCLUSION: IVT plus EVT leads to better functional outcomes and lower mortality in AIS-LVO patients with AF. Withholding IVT plus EVT from patients with AF alone may not be justified.

OTUB1/NDUFS2 axis promotes pancreatic tumorigenesis through protecting against mitochondrial cell death.

Pancreatic cancer is one of the most fatal cancers in the world. A growing number of studies have begun to demonstrate that mitochondria play a key role in tumorigenesis. Our previous study reveals that NDUFS2 (NADH: ubiquinone oxidoreductase core subunit S2), a core subunit of the mitochondrial respiratory chain complex I, is upregulated in Pancreatic adenocarcinoma (PAAD). However, its role in the development of PAAD remains unknown. Here, we showed that NDUFS2 played a critical role in the survival, proliferation and migration of pancreatic cancer cells by inhibiting mitochondrial cell death. Additionally, protein mass spectrometry indicated that the NDUFS2 was interacted with a deubiquitinase, OTUB1. Overexpression of OTUB1 increased NDUFS2 expression at the protein level, while knockdown of OTUB1 restored the effects in vitro. Accordingly, overexpression and knockdown of OTUB1 phenocopied those of NDUFS2 in pancreatic cancer cells, respectively. Mechanically, NDUFS2 was deubiquitinated by OTUB1 via K48-linked polyubiquitin chains, resulted in an elevated protein stability of NDUFS2. Moreover, the growth of OTUB1-overexpressed pancreatic cancer xenograft tumor was promoted in vivo, while the OTUB1-silenced pancreatic cancer xenograft tumor was inhibited in vivo. In conclusion, we revealed that OTUB1 increased the stability of NDUFS2 in PAAD by deubiquitylation and this axis plays a pivotal role in pancreatic cancer tumorigenesis and development.

Type III interferon inhibits bladder cancer progression by reprogramming macrophage-mediated phagocytosis and orchestrating effective immune responses.

BACKGROUND: Interferons (IFNs) are essential for activating an effective immune response and play a central role in immunotherapy-mediated immune cell reactivation for tumor regression. Type III IFN (λ), related to type I IFN (α), plays a crucial role in infections, autoimmunity, and cancer. However, the direct effects of IFN-λ on the tumor immune microenvironment have not been thoroughly investigated. METHODS: We used mouse MB49 bladder tumor models, constructed a retroviral vector expressing mouse IFN-λ3, and transduced tumor cells to evaluate the antitumor action of IFN-λ3 in immune-proficient tumors and T cell-deficient tumors. Furthermore, human bladder cancer samples (cohort 1, n=15) were used for immunohistochemistry and multiplex immunoflurescence analysis to assess the expression pattern of IFN-λ3 in human bladder cancer and correlate it with immune cells' infiltration. Immunohistochemistry analysis was performed in neoadjuvant immunotherapy cohort (cohort 2, n=20) to assess the correlation between IFN-λ3 expression and the pathological complete response rate. RESULTS: In immune-proficient tumors, ectopic Ifnl3 expression in tumor cells significantly increased the infiltration of cytotoxic CD8+ T cells, Th1 cells, natural killer cells, proinflammatory macrophages, and dendritic cells, but reduced neutrophil infiltration. Transcriptomic analyses revealed significant upregulation of many genes associated with effective immune response, including lymphocyte recruitment, activation, and phagocytosis, consistent with increased antitumor immune infiltrates and tumor inhibition. Furthermore, IFN-λ3 activity sensitized immune-proficient tumors to anti-PD-1/PD-L1 blockade. In T cell-deficient tumors, increased Ly6G-Ly6C+I-A/I-E+ macrophages still enhanced tumor cell phagocytosis in Ifnl3 overexpressing tumors. IFN-λ3 is expressed by tumor and stromal cells in human bladder cancer, and high IFN-λ3 expression was positively associated with effector immune infiltrates and the efficacy of immune checkpoint blockade therapy. CONCLUSIONS: Our study indicated that IFN-λ3 enables macrophage-mediated phagocytosis and antitumor immune responses and suggests a rationale for using Type III IFN as a predictive biomarker and potential immunotherapeutic candidate for bladder cancer.

A prospective randomized double-blind study comparing the dose-response curves of epidural ropivacaine for labor analgesia initiation between parturients with and without obesity.

Background: Previous studies have explored the median effective concentration (EC50) of ropivacaine for labor epidural analgesia in parturients with obesity. However, the clinical relevance of the 90% effective concentration (EC90) remains unclear. This study aimed to determine and compare the dose-response curve of epidural ropivacaine for labor analgesia between parturients with and without obesity. Methods: Parturients were divided into two groups based on body mass index (BMI): group N, consisting of parturients with BMI <30 kg/m2, and group O, consisting of parturients with BMI >30 kg/m2. Within each group, the patients were randomized to receive one of five concentrations (0.0375%, 0.075%, 0.1125%, 0.15%, or 0.1875%) of epidural ropivacaine for labor analgesia. Analgesia was induced with a loading dose of 15 mL of the assigned concentration. Visual analogue scale (VAS) scores were recorded at baseline and 30 min post-dose to calculate the response (%) using the formula [(baseline VAS pain score-VAS pain score at 30 min)/baseline VAS pain score] ×100%. The EC50 and EC90 values were determined via nonlinear regression analysis. Results: The EC50 and EC90 values of ropivacaine were 0.061% (95% confidence interval [CI], 0.056%-0.066%) and 0.177% (95% CI, 0.152%-0.206%) in group N and 0.056% (95% CI, 0.051%-0.061%) and 0.161% (95% CI, 0.138%-0.187%) in group O, respectively. No significant differences were observed in the EC50 and EC90 values between the two groups (p-values = 0.121 and 0.351, respectively. Conclusion: In conclusion, within the parameters of this study, our findings suggest that obesity, characterized by a mean BMI value of 30.9, does not significantly influence the EC50 and EC90 values of epidural ropivacaine for labor analgesia. Further investigations are warranted to elucidate the dose-response relationship between ropivacaine and obesity with higher BMI values. Clinical trial registration: https://www.chictr.org.cn/showproj.html?proj=190747, Identifier ChiCTR2300073273.

Preclinical evaluation of the SARS-CoV-2 Mpro inhibitor RAY1216 shows improved pharmacokinetics compared with nirmatrelvir.

Although vaccines are available for SARS-CoV-2, antiviral drugs such as nirmatrelvir are still needed, particularly for individuals in whom vaccines are less effective, such as the immunocompromised, to prevent severe COVID-19. Here we report an α-ketoamide-based peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), designated RAY1216. Enzyme inhibition kinetic analysis shows that RAY1216 has an inhibition constant of 8.4 nM and suggests that it dissociates about 12 times slower from Mpro compared with nirmatrelvir. The crystal structure of the SARS-CoV-2 Mpro:RAY1216 complex shows that RAY1216 covalently binds to the catalytic Cys145 through the α-ketoamide group. In vitro and using human ACE2 transgenic mouse models, RAY1216 shows antiviral activities against SARS-CoV-2 variants comparable to those of nirmatrelvir. It also shows improved pharmacokinetics in mice and rats, suggesting that RAY1216 could be used without ritonavir, which is co-administered with nirmatrelvir. RAY1216 has been approved as a single-component drug named 'leritrelvir' for COVID-19 treatment in China.

Inhibition of HMGB1 improves experimental mice colitis by mediating NETs and macrophage polarization.

OBJECTIVE: Inflammatory bowel disease (IBD) is listed by the World Health Organization as one of the modern intractable diseases. High mobility histone box 1 (HMGB1), originally described as a non-histone nucleoprotein involved in transcriptional regulation, was later identified as a pro-inflammatory cytokine that may contribute to the pathogenesis of inflammatory diseases such as IBD. Neutrophil extracellular traps (NETs) play an important role in the pathophysiology of IBD The aim of this study was to investigate the role of HMGB1 in experimental colitis mice and its potential mechanisms of action. METHODS: We first constructed the experimental colitis mouse model. Intervention of mice by rhHMGB1 supplementation or HMGB1 inhibition. The pathological morphology of the colon was observed using HE staining. Apoptosis of colonic tissue intestinal epithelial cells was evaluated using Tunel assay. The expression of HMGB1, ZO-1 and occludin in colon tissue was detected by immunohistochemistry, ELISA and western-blot. We also assessed the effects of HMGB1 on colonic injury, NETs content, macrophage polarization and inflammatory cells in mice. The regulatory effect of HMGB1 inhibition on NETs was assessed by combining DNase I. RESULTS: Inhibition of HMGB1 significantly reduced the inflammatory model in experimental colitis mice, as evidenced by reduced body weight, increased colonic length, reduced DAI scores and apoptosis, reduced inflammatory response, and improved colonic histopathological morphology and intestinal mucosal barrier function. Meanwhile, inhibition of HMGB1 was able to reduce the expression of CD86, citH3 and MPO and increase the expression of CD206 in the colonic tissue of mice. In addition, DNase I intervention was also able to improve colonic inflammation in mice. And the best effect was observed when DNase I and inhibition of HMGB1 were intervened together. CONCLUSION: Inhibition of HMGB1 ameliorates IBD by mediating NETs and macrophage polarization.

Optimizing Cervical Target Volume in Patients with Nasopharyngeal Cancer Based On Nodal Drainage Distance.

PURPOSE: To determine the potential nodal drainage distances of nasopharyngeal carcinoma (NPC) by investigating spatial distribution of metastatic lymph nodes (LN). EXPERIMENTAL DESIGN: Patients with NPC harboring at least two ipsilateral metastatic LNs were enrolled. LN spreading distances were analyzed in nonrestricted direction, cranial-to-caudal direction, and between the two most caudal LNs. Euclidean distance (ED) and vertical distance (VD) between any two LNs were computed. The nearest-neighbor ED and VD covering 95% of LNs or patients (p95-ED and p95-VD) were considered drainage distances, and were further validated by independent internal and external cohorts with recurrent LNs. RESULTS: In all, 5,836 metastatic LNs in 948 patients were contoured. Corresponding to the three scenarios, per-LN level, the p95-EDs were 2.83, 3.28, and 3.55 cm, and p95-VDs were 2.17, 2.32, and 2.63 cm, respectively. Per-patient level, the p95-EDs were 3.25, 3.95, and 3.81 cm, and p95-VDs were 2.67, 2.81, and 2.73 cm, respectively. In internal validation, over 95% of recurred LNs occurred within ED of 2.91 cm and VD of 0.82 cm to the neighbor LN, and the corresponding distances in external validation were 2.77 and 0.67 cm, respectively. CONCLUSIONS: In NPC, the maximum LN drainage distance was 3.95 cm without considering the direction. Specifically, in cranial-to-caudal direction, the sufficient vertical drainage distance was 2.81 cm, indicating that a 3-cm extension from the most inferior node may be rational as caudal border of the prophylactic clinical target volume (CTV). These findings promote in-depth understanding of nodal spreading patterns, uncovering paramount evidence for individualized CTV.

Dissecting the roles of calcium cycling and its coupling with voltage in the genesis of early afterdepolarizations in cardiac myocyte models.

Early afterdepolarizations (EADs) are abnormal depolarizations during the plateau phase of the action potential, which are known to be associated with lethal arrhythmias in the heart. There are two major hypotheses for EAD genesis based on experimental observations, i.e., the voltage (Vm)-driven and intracellular calcium (Ca)-driven mechanisms. In ventricular myocytes, Ca and Vm are bidirectionally coupled, which can affect each other's dynamics and result in new dynamics, however, the roles of Ca cycling and its coupling with Vm in the genesis of EADs have not been well understood. In this study, we use an action potential model that is capable of independent Vm and Ca oscillations to investigate the roles of Vm and Ca coupling in EAD genesis. Four different mechanisms of EADs are identified, which are either driven by Vm oscillations or Ca oscillations alone, or oscillations caused by their interactions. We also use 5 other ventricular action potential models to assess these EAD mechanisms and show that EADs in these models are mainly Vm-driven. These mechanistic insights from our simulations provide a theoretical base for understanding experimentally observed EADs and EAD-related arrhythmogenesis.