Background Gestational weight gain is closely related to maternal and infant health outcomes. Pregnant women are simultaneously exposed to four metals—lithium (Li), vanadium (V), uranium (U), and bismuth (Bi)—through inhalation of fine particulate matter and consumption of contaminated food and water. Existing studies suggest that exposure to these metals may be associated with gestational weight gain. However, no study has yet explored the complex relationships between exposure to mixtures of these four metals and weight gain at different stages of pregnancy. Objective To investigate the associations between mixed exposure to Li, V, U, and Bi in early pregnancy and the average weekly gestational weight gain during both early pregnancy and mid-to-late pregnancy. Methods This prospective study recruited eligible women in early pregnancy from an obstetrics clinic of a tertiary hospital in Jinan, China, between September 2021 and July 2023. Pre-pregnancy weight, current weight (at 11⁺⁰ to 13⁺⁶ weeks of gestation), and spot urine samples (≥5.0 mL) were collected at enrollment. Urinary concentrations of Li, V, Bi, and U were determined using inductively coupled plasma mass spectrometry. Participants were followed up in late pregnancy (≥28 weeks of gestation) to collect information on physical activity via questionnaire; weight measurements at the last antenatal visit (35⁺⁰ to 37⁺⁶ weeks of gestation) were obtained from the hospital information system. After adjusting for covariates, multiple linear regression and generalized additive models were used to assess the associations of individual metals with weekly weight gain in early pregnancy and in mid-to-late pregnancy. Bayesian kernel machine regression (BKMR) and quantile-based g-computation (Qgcomp) were applied to evaluate the joint effects of the metal mixture exposure on weekly weight gain at the two gestational stages. Results A total of 313 pregnant women were included. The geometric means of urinary Li, V, U, and Bi concentrations were 37.07, 0.20, 0.06, and 0.04 μg·L⁻¹, respectively; after creatinine adjustment, the corresponding values were 46.82, 0.25, 0.07, and 0.05 μg·g⁻¹ (Cr). The mean weekly gestational weight gain was (0.19±0.25) kg in early pregnancy and (0.53 ± 0.18) kg in mid-to-late pregnancy. Both multiple linear regression and generalized additive models showed that urinary V concentration was positively associated with average weekly gestational weight gain in early pregnancy, while no significant associations were found for other metals or for gestational weight gain in mid-to-late pregnancy. In the BKMR model with early-pregnancy weight gain as the outcome, V had the strongest association [posterior inclusion probability (PIP)=0.773]. When other metals were fixed at their medians, V showed a positive non-linear association with the outcome. A significant single-metal effect of V and its interaction with Li were observed. Compared with the 50th percentile of the metal mixture, the average weekly weight gain in early pregnancy increased by 0.016 (95%CI: 0.003, 0.029) and 0.018 (95%CI: 0.001, 0.036) at the 60th and 65th percentiles, respectively; conversely, at the 25th percentile, it decreased by 0.026 (95%CI: 0.002, 0.050). Overall, the joint effect of the metal mixture on early- pregnancy weight gain showed an upward trend. In the BKMR model for mid-to-late pregnancy gestational weight gain, all PIPs were<0.5, and no significant single-metal effects, interactions, or joint effects were identified. Qgcomp results confirmed a positive association between the metal mixture and early-pregnancy weight gain (b=0.031, 95%CI: 0.010, 0.051; P<0.01), with V contributing the highest positive weight (0.71). No significant association was found for weight gain in mid-to-late pregnancy (b=0.007, P=0.339). Conclusion Higher levels of co-exposure to the Li, V, Bi, and U metal mixture during early pregnancy may be associated with increased average weekly weight gain in early pregnancy. Among these metals, V exhibits a predominant role and appears to interact with Li. No association is observed between early-pregnancy metal mixture exposure and average weekly gestational weight gain in mid-to-late pregnancy. These findings suggest that monitoring and managing metal exposure during early pregnancy may be crucial for the rational regulation of gestational weight gain.

Network pharmacology has gained widespread application in drug discovery, particularly in traditional Chinese medicine (TCM) research, which is characterized by its "multi-component, multi-target, and multi-pathway" nature. Through the integration of network biology, TCM network pharmacology enables systematic evaluation of therapeutic efficacy and detailed elucidation of action mechanisms, establishing a novel research paradigm for TCM modernization. The rapid advancement of machine learning, particularly revolutionary deep learning methods, has substantially enhanced artificial intelligence (AI) technology, offering significant potential to advance TCM network pharmacology research. This paper describes the methodology of TCM network pharmacology, encompassing ingredient identification, network construction, network analysis, and experimental validation. Furthermore, it summarizes key strategies for constructing various networks and analyzing constructed networks using AI methods. Finally, it addresses challenges and future directions regarding cell-cell communication (CCC)-based network construction, analysis, and validation, providing valuable insights for TCM network pharmacology.
Medicine, Chinese Traditional/methods* ; Artificial Intelligence ; Network Pharmacology/methods* ; Humans ; Drugs, Chinese Herbal/chemistry* ; Drug Discovery

Liver transplantation (LT) has become a standard treatment for end-stage liver diseases, and graft injury is intricately associated with poor prognosis. Granzyme B (GZMB) plays a vital role in natural killer (NK) cell biology, but whether NK-derived GZMB affects graft injury remains elusive. Through the analysis of single-cell RNA-sequencing data obtained from human LT grafts and the isolation of lymphocytes from mouse livers following ischemia-reperfusion injury (IRI), we demonstrated that 2NK cells with high expression of GZMB are enriched in patients and mice. Both systemically and liver-targeted depletion of NK cells led to a notable reduction in GZMB⁺ cell infiltration, subsequently resulting in diminished graft injury. Notably, the reconstitution of Il2rg ^-/- Rag2 ^-/- mice with purified Gzmb-KO NK cells demonstrated superior outcomes compared to those with wild-type NK cells. Crucially, global knockout of GZMB and pharmacological inhibition exhibited remarkable improvements in liver function in both mouse IRI and rat LT models. Moreover, a phosphorylated derivative of FDA-approved vidarabine was identified as an effective inhibitor of mouse GZMB activity by molecular dynamics, which could provide a potential avenue for therapeutic intervention. Therefore, targeting NK cell-derived GZMB during the LT process suggests potential therapeutic strategies to improve post-transplant outcomes.

OBJECTIVE: To compare the efficacy and safety of intravenous colistin sulfate combined with nebulized inhalation versus intravenous monotherapy for pulmonary infections caused by carbapenem-resistant organism (CRO). METHODS: A multicenter retrospective cohort study was conducted. Clinical data were collected from patients admitted to the intensive care unit (ICU) of 10 tertiary class-A hospitals in Henan Province between July 2021 and May 2023, who received colistin sulfate for CRO pulmonary infections. Data included baseline characteristics, inflammatory markers [white blood cell count (WBC), neutrophil count (NEU), procalcitonin (PCT), C-reactive protein (CRP)], renal function indicators [serum creatinine (SCr), blood urea nitrogen (BUN)], life support measures, anti-infection regimens, clinical efficacy, microbiological clearance rate, and prognostic outcomes. Patients were divided into two groups: intravenous group (colistin sulfate monotherapy via intravenous infusion) and combination group ((intravenous infusion combined with nebulized inhalation of colistin sulfate). Changes in parameters before and after treatment were analyzed. RESULTS: A total of 137 patients with CRO pulmonary infections were enrolled, including 89 in the intravenous group and 48 in the combination group. Baseline characteristics, life support measures, daily colistin dose, and combination regimens (most commonly colistin sulfate plus carbapenems in both groups) showed no significant differences between two groups. The combination group exhibited higher clinical efficacy [77.1% (37/48) vs. 59.6% (52/89)] and microbiological clearance rate [60.4% (29/48) vs. 39.3% (35/89)], both P < 0.05. Pre-treatment inflammatory and renal parameters showed no significant differences between two groups. Post-treatment, the combination group showed significantly lower WBC and CRP [WBC (×10⁹/L): 8.2±0.5 vs. 10.9±0.6, CRP (mg/L): 14.0 (5.7, 26.6) vs. 52.1 (24.4, 109.6), both P < 0.05], whereas NEU, PCT, SCr, and BUN levels showed no significant between two groups. ICU length of stay was shorter in the combination group [days: 16 (10, 25) vs. 21 (14, 29), P < 0.05], although mechanical ventilation duration and total hospitalization showed no significant differences between two groups. CONCLUSIONS Intravenous colistin sulfate combined with nebulized inhalation improved clinical efficacy and microbiological clearance in CRO pulmonary infections with an acceptable safety profile.
Humans ; Colistin/therapeutic use* ; Retrospective Studies ; Administration, Inhalation ; Anti-Bacterial Agents/therapeutic use* ; Carbapenems/pharmacology* ; Male ; Female ; Middle Aged ; Gram-Negative Bacteria/drug effects* ; Aged ; Treatment Outcome ; Respiratory Tract Infections/drug therapy*

Coptis chinensis Franch. and Panax ginseng C. A. Mey. are traditional herbal medicines with millennia of documented use and broad therapeutic applications, including anti-diabetic properties. However, the synergistic effect of total alkaloids from Coptis chinensis and total ginsenosides from Panax ginseng on type 2 diabetes mellitus (T2DM) and its underlying mechanism remain unclear. The research demonstrated that the optimal ratio of total alkaloids from Coptis chinensis and total ginsenosides from Panax ginseng was 4∶1, exhibiting maximal efficacy in improving insulin resistance and gluconeogenesis in primary mouse hepatocytes. This combination demonstrated significant synergistic effects in improving glucose tolerance, reducing fasting blood glucose (FBG), the weight ratio of epididymal white adipose tissue (eWAT), and the homeostasis model assessment of insulin resistance (HOMA-IR) in leptin receptor-deficient (db/db) mice. Subsequently, a T2DM liver-specific network was constructed based on RNA sequencing (RNA-seq) experiments and public databases by integrating transcriptional properties of disease-associated proteins and protein-protein interactions (PPIs). The network recovery index (NRI) score of the combined treatment group with a 4∶1 ratio exceeded that of groups treated with individual components. The research identified that activated adenosine 5'-monophosphate-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signaling in the liver played a crucial role in the synergistic treatment of T2DM, as verified by western blot experiment in db/db mice. These findings demonstrate that the 4∶1 combination of total alkaloids from Coptis chinensis and total ginsenosides from Panax ginseng significantly improves insulin resistance and glucose and lipid metabolism disorders in db/db mice, surpassing the efficacy of individual treatments. The synergistic mechanism correlates with enhanced AMPK/ACC signaling pathway activity.
Animals ; Panax/chemistry* ; Ginsenosides/administration & dosage* ; Diabetes Mellitus, Type 2/metabolism* ; Mice ; Male ; Alkaloids/pharmacology* ; Coptis/chemistry* ; Drug Synergism ; Insulin Resistance ; Mice, Inbred C57BL ; Humans ; Transcriptome/drug effects* ; Blood Glucose/metabolism* ; Hypoglycemic Agents/administration & dosage* ; Drugs, Chinese Herbal/administration & dosage* ; Hepatocytes/metabolism*

Objective To observe the clinical effects of the stereotaxic oblique-pulling manipulation under different mechanical parameters in the treatment of patients with lumbar disc herniation,and to explore the muscle-relaxing effects of the stereotaxic oblique-pulling manipulation and the traditional lumbar oblique-pulling manipula-tion in the treatment of lumbar disc herniation under the optimal mechanical parameters.Methods Using a three-factor,three-level orthogonal test method,27 LDH patients included in this study were randomly divided into 9 parameter groups,with 3 patients in each group,and were treated with different parameters of the stereotactic angled wrench method.3 factors were set up for the pressing force,the number of times,and the treatment interval,and each factor consisted of 3 levels,i.e.,pressing force:300～400 N,400～500 N,and 500～600 N;the number of times pressed 3 levels were set up:6 times,9 times,12 times;3 levels of treatment interval:1 day interval,2 days interval,3 days interval.After screening the optimal mechanical parameters through VAS,ODI and FDD evaluation indexes,94 patients were included and randomly divided into two groups;the treatment group was stereotaxic oblique-pulling manipulation under the configuration of optimal mechanical parameters,and the control group was the traditional lumbar oblique-pulling manipulation,and the changes of patients'VAS and ODI scores as well as the thickness of multifidus muscle and cross-sectional area before and after treatment were observed in the treatment of the two groups of patients.Through the comparison of lumbar multifidus muscle between healthy volunteers and patients with lumbar keyboard herniation,the characteristics of lumbar disc herniation multifidus muscle were clarified.The correlation between each observation index and parameter was analyzed by the statistical analysis software SPSS 26.0 to derive the optimal parameters for manipulative treatment.Results Orthogonal test analysis yielded that the order of influence on the efficacy was pressing force>treatment interval>pressing times,and the pressure interval with the best efficacy was:500～600 N,the number of times was 12 times,and the Treatment internal of 2 days.The degree of degeneration of lumbar multifidus muscle in patients with lumbar disc herniation was more obvious compared with that of healthy volunteers,and the difference was stati stically signifi-cant(P<0.05).Observed in both groups of patients with lumbar disc herniation after 6 weeks of treatment time,the VAS and ODI scores of both groups decreased significantly after treatment compared with those before treatment(P<0.05),with greater improvement in the treatment group.The results of the multifidus muscle showed that after treatment,the treatment group could significantly increase the resting thickness,contraction thickness,contraction rate and cross-sectional area of the multifidus muscle had significant changes(P<0.05),in which the contraction thickness,contraction rate before and after the treatment changes were more significant than the control group.Conclusions The stereotaxic oblique-pulling manipulation is effective in the treatment of lumbar disc herniation,in which the manipulation parameter pressure of 500～600 N,the number of presses 12 times,and the treatment interval of 2 days once for the treatment of lumbar disc herniation has better analgesia and improves the dysfunction effect.Compared with the traditional lumbar oblique-pulling manipulation,the stereotaxic oblique-pulling manipulation is better in improving the pain symptoms and dysfunction of patients with lumbar disc hernia-tion,as well as the resting thickness of the multifidus muscle,the contraction thickness,the contraction rate of change,and the cross-sectional area.

Objective:To explore the spatial clustering of the mortality rate of cervical cancer in different counties (cities, districts) in Shandong Province from 1970 to 2021 and its 50-year changing trend, so as to provide basis for the implementation and evaluation of prevention and control strategies and programs such as cervical cancer screening, early diagnosis and treatment, human papilloma virus (HPV) vaccination, etc.Methods:The mortality data of cervical cancer were obtained from the death registration system of Shandong Province and the data of three retrospective surveys of death causes. The mortality rate and age-standardized mortality rate (using the population composition of China in 1964) are used to describe the changing trend of cervical cancer in different years. The contribution values of population factors and non-population factors in cervical cancer mortality change are calculated by mortality differential decomposition method. ArcGIS 10.8 software is used for spatial distribution and spatial autocorrelation analysis.Results:From 1970 to 2021, the crude mortality rate and age standardized mortality rate of cervical cancer in Shandong Province showed a trend of first rapid decline and then slow increase. The crude mortality rate and standardized mortality rate of female cervical cancer in Shandong Province in 1970-1974 were the highest, reaching 17.22/10 5 and 13.17/10 5, respectively. In 2004-2005, it dropped to the lowest levels of 1.50/10 5 and 0.83/10 5. Subsequently, it slowly rose to 4.12/10 5 and 1.56/10 5 in 2020-2021. The differential analysis of cervical cancer mortality in different years found that the change of cervical cancer mortality was caused by the combined action of population factors and non-population factors. Among them, demographic factors (aging population) led to the increase of cervical cancer mortality, but non-demographic factors (early diagnosis and treatment, HPV infection level, medical technology level, etc) lead to the decrease of cervical cancer mortality. Compared with 1970-1974, with the passage of time, the absolute values of the contribution values of population factors and non-population factors showed an increasing trend, while the contribution of non-population factors was greater than that of population factors, which led to the decline of cervical cancer mortality. From the perspective of spatial distribution, there were great regional differences in the mortality rate of cervical cancer in different counties of Shandong Province. In 2020-2021, the mortality rate of cervical cancer in all counties decreased to a great extent compared with that in 1970-1974, and the high-high and low-low concentration areas of cervical cancer mortality in different years changed obviously. The high-aggregation areas of the cervical cancer mortality rate in Shandong Province from 2020 to 2021 were mainly distributed in some counties and districts of Linyi City, Zaozhuang City, and Heze City in the southwest. Conclusions:There are significant temporal and spatial changes in the mortality rate of cervical cancer in Shandong Province from 1970 to 2021. According to these trends and their geographical and spatial clustering, prevention and control strategies of cervical cancer in different regions should be further formulated and evaluated.

Traditional open thyroid surgery often leaves a scar on the neck,which can affect cosmetic outcomes.Therefore,various endoscopic thyroidectomy approaches via extra-cervical approaches have been developed.However,due to the unique anatomical characteristics of the neck and limitations of endoscopic instruments,conventional endoscopic techniques have certain drawbacks.Robot-assisted endoscopic thyroid surgery can help overcome these limitations.At present,robotic surgical systems remain expensive and the associated surgical costs are high,limiting their widespread adoption.Most surgeons are still relatively unfamiliar with the technique.Nevertheless,with ongoing technological advancements and cost reductions,robot-assisted surgery holds great promise for broader application.Based on years of large-scale experience in endoscopic thyroid surgery at our center,and drawing upon both domestic and international experiences with robotic thyroidectomy,this paper summarizes and proposes a seven-step protocol for robot-assisted endoscopic thyroidectomy via the bilateral axillo-breast approach,aiming to provide a practical reference for the clinical adoption of this technique.

Spine fracture and dislocation are common traumatic spinal conditions that often require surgical intervention due to compromised spinal stability. Surgical approaches include anterior, posterior, and combined anterior-posterior spinal procedures. According to the specific surgical requirements, patients may be placed in the prone position or repositioned between prone and supine positions during surgery. Intraoperative repositioning has become an essential step in patient positioning. However, during repositioning, patients with spinal fracture and dislocation are at increased risk for complications such as hemodynamic instability, nerve injury, and pressure injuries to the skin and soft tissue. Notably, due to the instability of the spinal cord, even minor manipulations can further exacerbate the damage, potentially leading to severe outcomes like paraplegia. Although the current clinical guidelines provide instructive recommendations for standard position, there remains no specific protocols for intraoperative repositioning in patients with spine fracture and dislocation. With a concern for the lack of clinical studies on positioning techniques, risk prevention, and operational norms for special patients, no applicable guidelines or standards are available. A consensus was required to provide clinical reference, meet the requirements of surgical treatment, and minimize the safety risks of patients caused by improper placement of positions. Professional Committee of Operating Room Nursing of Shaanxi Nursing Association organized experts in nursing management and operating room nursing from major hospitals across China to formulate Expert consensus on intraoperative repositioning for patients with spinal fracture and dislocation ( version 2025). The consensus provides 11 recommendations covering pre-repositioning preparation, intraoperative maneuvers, and post-repositioning observation, aiming to provide references for clinical standardization of the intraoperative repositioning process and protection of patients′ safety.