Nanotechnologies seek to overcome inherent deficiencies of conventional diagnosis and treatment, which attracted sustained attention and a limited number of nanomedicines approved by the FDA. However, the critical gaps in clinical translation remain, and nanomedicines that were initially heralded as magic bullets have yet to reach their realistic potential. The major obstacles of fabrication technologies may be overlooked in the nanoparticles' journey. Suboptimal manufacturing strategies partly hampered the inefficient transformation. In this review, we discuss the nanoparticle manufacturing strategies of "Top-Down" and "Bottom-Up" on precise nanoscale fabrication, including artificial intelligence introduced to guided nanomedicine fabrication for accelerating the transformation. Re-engineering existing nanomedicine fabrication, individual manufacturing, and modular technology might highlight the dilemmas of nanomedicines to meet their initial expectations.

Objective:To determine the prevalence, risk factors, and longitudinal associations of loneliness during mid- to late pregnancy with anxiety and depressive symptoms in late pregnancy.Methods:In this prospective cohort study, 1 107 pregnant women at 24-28 weeks' gestation were enrolled between June 2021 and December 2022. Psychological status was assessed during mid-pregnancy (24-28 weeks) and late pregnancy (≥32 weeks) using standardized electronic questionnaires, including the Revised University of California Los Angeles Loneliness Scale (UCLA) Loneliness Scale-Short Form (Cronbach's α=0.82), Patient Health Questionnaire-9 ( α=0.86), and Generalized Anxiety Disorder-7 ( α=0.88). Multivariate logistic regression identified independent risk factors for loneliness. Cross-lagged path models analyzed the longitudinal predictions between loneliness and anxiety/depressive symptoms. Results:The prevalence of loneliness decreased significantly from 10.8% (120/1 107) in mid-pregnancy to 4.8% (37/777) in late pregnancy ( χ2=21.81, P<0.001). Multivariate analysis identified independent risk factors for loneliness: age <30 years ( OR=1.70, 95% CI: 1.15-2.50), annual household income <50 000 CNY ( OR=2.53, 95% CI: 1.28-5.02), unemployment during pregnancy ( OR=1.57, 95% CI: 1.03-2.39), history of alcohol consumption ( OR=1.63, 95% CI: 1.03-2.56), and the presence of mid-pregnancy depressive ( OR=2.76, 95% CI: 1.51-5.04) and anxiety symptoms ( OR=1.65, 95% CI: 1.01-2.71) (all P<0.05). Cross-lagged path models indicated bidirectional associations between loneliness and both anxiety ( β=0.32, P<0.01) and depressive symptoms ( β=0.28, P<0.01). However, the predictive effect of loneliness on subsequent depressive and anxiety symptoms ( β=0.28-0.32) was substantially stronger than the reverse prediction (mid-pregnancy anxiety on late-pregnancy loneliness: β=0.12; mid-pregnancy depression on late-pregnancy loneliness: β=0.11). Loneliness demonstrated high temporal stability (autoregressive effects β=0.29-0.32). Conclusion:Loneliness in mid-pregnancy exhibits a symmetric bidirectional association with anxiety and depressive symptoms in late pregnancy, suggesting it may be a core driver in the development of these emotional symptoms. Younger maternal age (<30 years), low household income (<50 000 CNY/year), unemployment during pregnancy, and a history of alcohol consumption were associated with a higher risk of loneliness and should be prioritized for psychological screening and intervention.

Objective:To investigate the effects of exercise preconditioning on hippocampal microglia polarization and my-elin loss in vascular dementia(VD)model rats.Method:Sixty male SPF SD rats were randomly divided into sham group,model group,exercise precondition-ing sham group and exercise preconditioning model group,with 15 rats in each group.The exercise precondi-tioning rats was trained in weightless swimming exercise for 4 weeks(5sessions/week,30min/session)before mod-eling.The VD model was established by bilateral common carotid artery ligation.Behavioral tests were conduct-ed using the Morris water maze,and the demyelination in the CA1 region of the hippocampus was observed by Luxol fast blue staining.The polarization of microglia in the CA1 region of the hippocampus was observed by immunofluorescence double labeling staining,and the contents of interleukin 4(IL-4),interleukin 10(IL-10),interleukin-1 beta(IL-1β),and tumor necrosis factor-α(TNF-α)in the serum were detected by ELISA.Result:Four weeks after modeling,the average escape latency of rats in the model group was prolonged and the number of platform crossings was reduced compared with the sham group(P<0.05);the average escape laten-cy of rats in the exercise preconditioning model group was prolonged and the number of platform crossings was reduced compared with the exercise preconditioning sham group(P<0.05);the escape latency of rats in the model group was prolonged compared with the exercise preconditioning model group(P<0.05).The histological demyelination score showed that compared with the sham group,the demyelination in the model group was in-creased(P<0.05);the demyelination in the exercise preconditioning model group was increased compared with the exercise preconditioning sham group(P<0.05);the demyelination in the model group was increased compared with the exercise preconditioning model group(P<0.05).Compared with the sham group,the expression of in-ducible nitric oxide synthase(iNOS)protein in the CA1 region of the hippocampus in the model group was in-creased,while the expression of arginase1(Arg1)protein was decreased(P<0.05).Compared with the exercise preconditioning sham group,the expression of iNOS protein in the CA1 region of the hippocampus in the exer-cise preconditioning model group was significantly increased(P<0.05),while the expression of Arg-1 protein was significantly decreased(P<0.05).Compared with the exercise preconditioning model group,the expression of iN-OS protein in the CA1 region of the hippocampus in the model group was increased,while the expression of Arg1 protein was decreased(P<0.05).Compared with the sham group,the contents of IL-4 and IL-10 in the se-rum of rats in the model group decreased,while the contents of IL-1β and TNF-α increased(P<0.05).Compared with the exercise preconditioning sham group,the contents of IL-4 and IL-10 in the serum of rats in the exer-cise preconditioning model group decreased,while the contents of IL-1β and TNF-α increased(P<0.05).Com-pared with the exercise preconditioning model group,the content of IL-4 in the serum of rats in the model group decreased,while the content of IL-1β increased(P<0.05).Conclusion:Exercise preconditioning can promote microglial M2 polarization and myelin fragment phagocyto-sis,inhibit hippocampal nerve inflammation,and improve the learning and memory ability of rats with vascu-lar dementia.

Objective:To investigate the effects of exercise preconditioning on hippocampal microglia polarization and my-elin loss in vascular dementia(VD)model rats.Method:Sixty male SPF SD rats were randomly divided into sham group,model group,exercise precondition-ing sham group and exercise preconditioning model group,with 15 rats in each group.The exercise precondi-tioning rats was trained in weightless swimming exercise for 4 weeks(5sessions/week,30min/session)before mod-eling.The VD model was established by bilateral common carotid artery ligation.Behavioral tests were conduct-ed using the Morris water maze,and the demyelination in the CA1 region of the hippocampus was observed by Luxol fast blue staining.The polarization of microglia in the CA1 region of the hippocampus was observed by immunofluorescence double labeling staining,and the contents of interleukin 4(IL-4),interleukin 10(IL-10),interleukin-1 beta(IL-1β),and tumor necrosis factor-α(TNF-α)in the serum were detected by ELISA.Result:Four weeks after modeling,the average escape latency of rats in the model group was prolonged and the number of platform crossings was reduced compared with the sham group(P<0.05);the average escape laten-cy of rats in the exercise preconditioning model group was prolonged and the number of platform crossings was reduced compared with the exercise preconditioning sham group(P<0.05);the escape latency of rats in the model group was prolonged compared with the exercise preconditioning model group(P<0.05).The histological demyelination score showed that compared with the sham group,the demyelination in the model group was in-creased(P<0.05);the demyelination in the exercise preconditioning model group was increased compared with the exercise preconditioning sham group(P<0.05);the demyelination in the model group was increased compared with the exercise preconditioning model group(P<0.05).Compared with the sham group,the expression of in-ducible nitric oxide synthase(iNOS)protein in the CA1 region of the hippocampus in the model group was in-creased,while the expression of arginase1(Arg1)protein was decreased(P<0.05).Compared with the exercise preconditioning sham group,the expression of iNOS protein in the CA1 region of the hippocampus in the exer-cise preconditioning model group was significantly increased(P<0.05),while the expression of Arg-1 protein was significantly decreased(P<0.05).Compared with the exercise preconditioning model group,the expression of iN-OS protein in the CA1 region of the hippocampus in the model group was increased,while the expression of Arg1 protein was decreased(P<0.05).Compared with the sham group,the contents of IL-4 and IL-10 in the se-rum of rats in the model group decreased,while the contents of IL-1β and TNF-α increased(P<0.05).Compared with the exercise preconditioning sham group,the contents of IL-4 and IL-10 in the serum of rats in the exer-cise preconditioning model group decreased,while the contents of IL-1β and TNF-α increased(P<0.05).Com-pared with the exercise preconditioning model group,the content of IL-4 in the serum of rats in the model group decreased,while the content of IL-1β increased(P<0.05).Conclusion:Exercise preconditioning can promote microglial M2 polarization and myelin fragment phagocyto-sis,inhibit hippocampal nerve inflammation,and improve the learning and memory ability of rats with vascu-lar dementia.

Oral squamous cell carcinoma(OSCC)accounts for over 90％of oral malignancies,with more than 370 000 new cases and approximately 188 000 deaths annually worldwide.In China,there are roughly 65 000 new cases and 35 000 deaths each year,showing a significant upward trend compared with 2015 statistics.Despite continuous advancements in treatment modalities,the 5-year survival rate remains stagnant at 50％-60％,where tumor heterogeneity and therapy resistance persist as fundamental barriers to precision oncology.To address these critical challenges,this study established a standardized bioban-king protocol for OSCC patient-derived organoids(PDOs)(Patent:Method for constructing an oral squa-mous cell carcinoma organoid bank,ZL202311378598.3).Through groundbreaking optimization of cul-ture media,enzymatic digestion kinetics,and stepwise cryopreservation,we achieved a biobanking suc-cess rate exceeding 95％and pioneered synchronous cultivation of matched primary tumors,lymph node metastases,and adjacent normal mucosa from individual patients,preserving spatial heterogeneity and stromal interactions.Leveraging this platform,we developed high-throughput drug screening:Quantified heterogeneity-driven differential chemoresponse using adenosine triphosphate(ATP)-based viability as-says;We discovered resistance mechanisms:Identified sialylated cancer IgG(SIA-cIgG)-mediated cis-platin resistance(primary/secondary)through PTPN13 suppression,with anti-SIA-cIgG combination therapy demonstrating synergistic efficacy.Besides,we elucidated metastatic drivers:CRISPR-Cas9-edited organoids revealed WDR54 promoted metastasis via H3K4me3/H4K16ac epigenetic reprogramming,activating epithelial-mesenchymal plasticity(EMP)and inducing partial epithelial-mesenchymal transi-tion(pEMT).This"holographic patient-mirroring"platform provided unprecedented resolution for OSCC precision therapy and had been formally incorporated into the Chinese Stomatological Association Techni-cal Guidelines(Technical guideline for establishing patient-derived oral squamous cell carcinoma or-ganoid banks,CHSA 2024-08).Future integration of immune-competent organoids,3D-bioprinted vas-culature,and multi-omics-AI systems will accelerate personalized oncology.These innovations will accelerate clinical translation of personalized therapeutic regimens,ultimately bridging the gap between bench research and bedside application.

Objective:To determine the prevalence, risk factors, and longitudinal associations of loneliness during mid- to late pregnancy with anxiety and depressive symptoms in late pregnancy.Methods:In this prospective cohort study, 1 107 pregnant women at 24-28 weeks' gestation were enrolled between June 2021 and December 2022. Psychological status was assessed during mid-pregnancy (24-28 weeks) and late pregnancy (≥32 weeks) using standardized electronic questionnaires, including the Revised University of California Los Angeles Loneliness Scale (UCLA) Loneliness Scale-Short Form (Cronbach's α=0.82), Patient Health Questionnaire-9 ( α=0.86), and Generalized Anxiety Disorder-7 ( α=0.88). Multivariate logistic regression identified independent risk factors for loneliness. Cross-lagged path models analyzed the longitudinal predictions between loneliness and anxiety/depressive symptoms. Results:The prevalence of loneliness decreased significantly from 10.8% (120/1 107) in mid-pregnancy to 4.8% (37/777) in late pregnancy ( χ2=21.81, P<0.001). Multivariate analysis identified independent risk factors for loneliness: age <30 years ( OR=1.70, 95% CI: 1.15-2.50), annual household income <50 000 CNY ( OR=2.53, 95% CI: 1.28-5.02), unemployment during pregnancy ( OR=1.57, 95% CI: 1.03-2.39), history of alcohol consumption ( OR=1.63, 95% CI: 1.03-2.56), and the presence of mid-pregnancy depressive ( OR=2.76, 95% CI: 1.51-5.04) and anxiety symptoms ( OR=1.65, 95% CI: 1.01-2.71) (all P<0.05). Cross-lagged path models indicated bidirectional associations between loneliness and both anxiety ( β=0.32, P<0.01) and depressive symptoms ( β=0.28, P<0.01). However, the predictive effect of loneliness on subsequent depressive and anxiety symptoms ( β=0.28-0.32) was substantially stronger than the reverse prediction (mid-pregnancy anxiety on late-pregnancy loneliness: β=0.12; mid-pregnancy depression on late-pregnancy loneliness: β=0.11). Loneliness demonstrated high temporal stability (autoregressive effects β=0.29-0.32). Conclusion:Loneliness in mid-pregnancy exhibits a symmetric bidirectional association with anxiety and depressive symptoms in late pregnancy, suggesting it may be a core driver in the development of these emotional symptoms. Younger maternal age (<30 years), low household income (<50 000 CNY/year), unemployment during pregnancy, and a history of alcohol consumption were associated with a higher risk of loneliness and should be prioritized for psychological screening and intervention.

Objective:To evaluate the efficacy and safety of Qingxuan Zhike granules in improving cough symptoms and shortening the course of influenza (wind-heat invading lung) in children.Methods:In this multicenter, randomized, controlled clinical trial, a total of 240 outpatient influenza patients from 7 hospitals, including the First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, from April 2023 to December 2023 were collected.The subjects were randomly divided into the control group and the experimental group via SAS software using the block randomization method.The differences between two groups were compared with t test, corrected t test and χ2 test.Subjects in the control group were given Oseltamivir phosphate granules, orally, twice a day (weight ≤15 kg, 30 mg/time; weight >15-23 kg, 45 mg/time; weight >23-40 kg, 60 mg/time; weight >40 kg, 75 mg/time; age≥13 years, 75 mg/time).In addition to Oseltamivir phosphate granules, subjects in the experimental group were also given Qingxuan Zhike granules, orally, 3 times a day (1-3 years old, 1/2 bag each time; >3-6 years old, 3/4 bag each time; >6-14 years old, 1 bag each time).After 5 days of treatment, the medication was suspended for 2 days.The effect of cough, antipyretic effect, clinical recovery rate, clinical recovery time, Canadian Acute Respiratory Illness and Flu Scale (CARIFS) score, traditional Chinese medicine (TCM) syndrome effect, complication rate, and adverse reactions were evaluated between the two groups. Results:Finally, 232 cases were included in the study, including 115 cases in the experimental group and 117 cases in the control group.Before and after treatment, there were no significant difference in CARIFS cough score between the experimental group and the control group (all P>0.05).After treatment, the change in CARIFS cough score in the experimental group [(-1.00±0.91) scores]was significantly higher than that in the control group [(-0.75±0.98) scores] ( t=-1.995, P=0.047).After treatment, the change in TCM syndrome cough score in the experimental group [(-1.69±1.51) scores] was significantly higher than that in the control group [(-0.97±1.63) scores] ( t′=-0.035, P=0.001).The time of complete regression of fever in the experimental group [(44.82±22.72) h] was shorter than that in the control group [(51.35±27.07) h], and the difference between the two groups was statistically significant ( t=-1.966, P=0.050).The fever score showed that the area under the curve between the CARIFS symptom fever score and time in the experimental group was 4.40±2.42, while that in the control group was 5.12±2.44, and the difference between the two groups was statistically significant ( t=-2.252, P=0.025).The clinical recovery rate was 93.91%(108/115) in the experimental group and 92.31%(108/117) in the control group, and there was no significant difference between the two groups ( χ2=0.233, P>0.05).The clinical recovery time in the experimental group [(2.93±1.21) d] was shorter than that in the control group [(3.29±1.15) d], and the difference between the two groups was statistically significant ( t=-2.279, P=0.024).After treatment, there was a significant difference in TCM syndrome score variation between the experimental group [(-12.00±4.13) scores] and the control group [(-10.85±4.31) scores] ( t′=-2.067, P=0.040).No complication occurred in both groups, and there was no significant difference in the incidence of adverse events between the two groups ( χ2=1.299, P>0.05). Conclusions:Qingxuan Zhike granules combined with Oseltamivir phosphate can effectively improve the cough symptoms associated with influenza in children, shorten the time and course of fever, and improve the TCM syndrome score; thus, they are safe in clinical application.

AIM:To investigate the effects of exercise preconditioning(EP)combined with electroacupunc-ture(EA)on learning and memory ability of rats with vascular dementia(VD),and to explore role of hippocampal ferrop-tosis in this process.METHODS:Seventy-two male SD rats were randomly divided into non-EP group and EP group,with 36 rats in each group.The rats were subjected to EP,and subsequently to establish the VD model.The rats from non-EP group were randomly divided into sham group,model group(VD group)and VD-EA group,each with 12 rats,while those in EP group were randomly divided into EP-sham group,EP-VD group and EP-VD-EA group,each with 12 rats.All rats in EP group underwent 4 weeks of swimming exercise training,5 d per week,30 min per day.At the end of the 4th week,the rats in VD,EP-VD,EP-VD-EA and VD-EA groups were used to induce the VD model,and the rats in sham and EP-sham groups received a sham surgery to simulate the VD model.On the 7th day after successful modeling,the rats in EP-VD-EA and VD-EA groups were treated with EA for 4 weeks,6 d per week,30 min per day.At the end of the inter-vention,the learning and memory ability of the rats was evaluated using Morris water maze.Neuron morphology in the CA1 area of rat hippocampus was observed through Nissl staining.Ferrous ion(Fe2+),malondialdehyde(MDA)and re-duced glutathione(GSH)contents in the rat hippocampal tissues were quantified using the colorimetric assay.The expres-sion levels of ferroptosis-related proteins,nuclear factor E2-related factor 2(Nrf2)and glutathione peroxidase 4(GPX4),in the hippocampal tissues were quantified by Western blot method.RESULTS:Compared with sham group,the rats in VD group exhibited longer mean evasion latency and decreased number of traversals across the plateau(P<0.01).The neurons in the CA1 region of the hippocampus were loose and disorganized,exhibiting an irregular cellular morphology.The hippocampal Fe2+and MDA content was elevated,and the GSH content was reduced(P<0.01).The protein levels of hippocampal Nrf2 and GPX4 were decreased(P<0.01).Compared with VD group,the rats in EP-VD,EP-VD-EA and VD-EA groups showed a shorter average escape latency and an increased number of traversals across the plateau(P<0.05).Neurons in the hippocampal CA1 area were more neatly arranged,showing regular cellular morphology.The hip-pocampal Fe2+and MDA contents of the rats in EP-VD group were significantly reduced(P<0.01),while the GSH content was elevated(P<0.05).Hippocampal Fe2+and MDA contents were significantly reduced and GSH contents were signifi-cantly increased in EP-EA and EA groups(P<0.01).The protein levels of hippocampal Nrf2 and GPX4 in EP-VD,EP-VD-EA and VD-EA groups were significantly increased(P<0.01).CONCLUSION:Exercise preconditioning combined with EA improves learning and memory ability in VD rats by reducing hippocampal intra-neuronal iron overload,maintain-ing organismal redox homeostasis,and inhibiting ferroptosis.

Objective:To retrieve and evaluate the evidence on the risk grading management of high-risk diabetic foot patients, so as to provide reference for the management of diabetic foot.Methods:According to the "6S" pyramid model of evidence-based resources, evidence on risk grading management of high-risk diabetic foot patients was retrieved in Web of Science, UpToDate, Cochrane Library, PubMed, China National Knowledge Infrastructure, WanFang Data, VIP and other databases, guide websites, and professional association websites. The search period was from the establishment of the database to January 1, 2024.Results:A total of 11 articles were included, including 8 guidelines, one systematic review, one expert consensus, and one expert opinion. There were 24 pieces of best evidence about the risk grading management of high-risk diabetic foot patients, covering 8 aspects of risk assessment, risk grading, health records establishment, screening frequency, health education, foot management, exercise management and referral.Conclusions:The best evidence of risk grading management of high-risk diabetic foot patients summarized can provide reference for clinical nurses to carry out evidence-based practice.

The orbitofrontal cortex (ORB), a region crucial for stimulus-reward association, decision-making, and flexible behaviors, extensively connects with other brain areas. However, brain-wide inputs to projection-defined ORB neurons and the distribution of inhibitory neurons postsynaptic to neurons in specific ORB subregions remain poorly characterized. Here we mapped the inputs of five types of projection-specific ORB neurons and ORB outputs to two types of inhibitory neurons. We found that different projection-defined ORB neurons received inputs from similar cortical and thalamic regions, albeit with quantitative variations, particularly in somatomotor areas and medial groups of the dorsal thalamus. By counting parvalbumin (PV) or somatostatin (SST) interneurons innervated by neurons in specific ORB subregions, we found a higher fraction of PV neurons in sensory cortices and a higher fraction of SST neurons in subcortical regions targeted by medial ORB neurons. These results provide insights into understanding and investigating the function of specific ORB neurons.
Animals ; Neurons/physiology* ; Mice ; Prefrontal Cortex/cytology* ; Parvalbumins/metabolism* ; Brain Mapping/methods* ; Neural Pathways/physiology* ; Somatostatin/metabolism* ; Male ; Interneurons/physiology* ; Mice, Inbred C57BL ; Thalamus/physiology* ; Mice, Transgenic