Mitochondrial dysfunction in chondrocytes is a key pathogenic factor in osteoarthritis (OA), but directly modulating mitochondria in vivo remains a significant challenge. This study is the first to verify a correlation between mitochondrial dysfunction and the downregulation of the FOXO3 gene in the cartilage of OA patients, highlighting the potential for regulating mitophagy via FOXO3 gene modulation to alleviate OA. Consequently, we developed a chondrocyte-targeting CRISPR/Cas9-based FOXO3 gene-editing tool (FoxO3) and integrated it within a nanoengineered 'truck' (NETT, FoxO3-NETT). This was further encapsulated in injectable hydrogel microspheres (FoxO3-NETT@SMs) to harness the antioxidant properties of sodium alginate and the enhanced lubrication of hybrid exosomes. Collectively, these FoxO3-NETT@SMs successfully activate mitophagy and rebalance mitochondrial function in OA chondrocytes through the Foxo3 gene-modulated PINK1/Parkin pathway. As a result, FoxO3-NETT@SMs stimulate chondrocytes proliferation, migration, and ECM production in vitro, and effectively alleviate OA progression in vivo, demonstrating significant potential for clinical applications.

Over the past few decades, tumor immunotherapy has revolutionized the landscape of cancer clinical treatment. There is a flourishing development of combination strategies to improve the anti-tumor efficacy of mono-immunotherapy. However, instead of a straightforward combination of multiple therapeutics, it is more preferable to pursue a synergistic effect by designing rational combinations as well as administration strategies, which are based on a comprehensive understanding of the physiological and pathological features. In this case, the timing and spatial distribution of the combination drugs become essential factors in achieving improved therapeutic outcomes. Therefore, the concept of Sequential Drug Delivery System (SDDS) is proposed to define the spatiotemporally programmed drug delivery/release through triggers of internal conditions and/or external interventions, thus complying with the dynamic disease evolution and the human immunity. This review summarizes the recent advancements in biomaterial-based SDDSs used for spatiotemporally-tuned combination tumor immunotherapy. Furthermore, the rationales behind various engineering strategies are discussed. Finally, an overview of potential synergistic mechanisms as well as their prospects for combination immunotherapy is presented.

A 61-year-old patient was admitted in November 2024 with the chief complaint of “marked enlargement of uterine myoma for 2 months after menopause”. This patient was diagnosed with uterine myoma 8 years ago and underwent modified radical mastectomy for right breast cancer in April 2023. Postoperative pathology revealed invasive carcinoma (SBR grade Ⅲ). Upon admission, examination results showed a cystic-solid mass in the posterior wall of the uterus and an elevated CA153 level of 273 U/mL. Transabdominal total hysterectomy and bilateral adnexectomy were performed. HE staining postoperatively indicated uterine myoma with involvement of invasive lobular carcinoma. Immunohistochemistry showed positivity for pan-cytokeratin (CKpan, ＋), GATA3 (＋), desmin (muscle＋), and estrogen receptor (ER, 90%＋ ＋ ＋), confirming the diagnosis of breast cancer metastasis to the uterine myometrium. CDK4/6 inhibitor, anastrozole, and zoledronic acid were used after surgery. Metastasis of invasive lobular carcinoma to the uterine myometrium is rare. Rapid enlargement of uterine myoma in breast cancer patients should alert clinicians to consider the possibility of metastasis, which must be confirmed by pathological examination.

Objective:To assess the safety of sitagliptin added to metformin on cardiovascular adverse events in real world patients with type 2 diabetes mellitus(T2DM).Methods:Real world data from Yinzhou Regional Health Care Database were used to select T2DM patients with diagnosis and treatment records in the platform from January 1,2017 to December 31,2022.According to drug prescription records,the patients were divided into metformin plus sitagliptin group(combination group)and metformin monotherapy group(monotherapy group).A series of retrospective cohorts were constructed according to the index date.Finally,full retrospective cohorts were constructed according to propensity score model,including baseline covariates that might be related to outcomes,to match the subjects in the combination group and monotherapy group for the purpose of increasing the comparability of baseline characteristics.The participants were followed up from the index date until the first occurrence of the following events:Diagnosis of outcomes,death,or the end of the study period(December 31,2022).Cox proportional risk model was used to estimate the hazard ratio(HR)and 95％confidence interval(CI)of sitagliptin added to metformin on 3-point major adverse cardiovascular events(3P-MACE)combination outcome and secondary cardiovascular outcomes.Results:Before propensity score matching,the proportion of the pa-tients in combination group using insulin,α glucosidase inhibitors,sodium-glucose transporter 2 inhibi-tors(SGLT-2I)and glienides at baseline was higher than that in monotherapy group,and the baseline fasting blood glucose(FBG)and hemoglobin A1c(HbA1c)levels in combination group were higher than those in monotherapy group.After propensity score matching,5 416 subjects were included in the combination group and the monotherapy group,and baseline characteristics were effectively balanced be-tween the groups.The incidence densities of 3P-MACE were 6.41/100 person years and 6.35/100 per-son years,respectively.Sitagliptin added to metformin did not increase or decrease the risk of 3P-MACE compared with the metformin monotherapy(HR=1.00,95％CI:0.91-1.10).In secondary outcomes analysis,the incidence of cardiovascular death was lower in the combination group than in the monothera-py group(HR=0.59,95％CI:0.41-0.85),and no association was found between sitagliptin and the risk of myocardial infarction and stroke(HR=1.12,95％CI:0.89-1.41;HR=0.99,95％CI:0.91-1.12).Conclusion:In T2DM patients in Yinzhou district of Ningbo,compared with metformin alone,sitagliptin added to metformin may reduce the risk of cardiovascular death,and do not increase the inci-dence of overall cardiovascular events.The results of this study can provide real-world evidence for post-marketing cardiovascular safety evaluation of sitagliptin.

Objective To investigate the effect of day chemotherapy on medical expenses of breast cancer patients.Methods The medical expenses of breast cancer patients in the First Affiliated Hospital of Guangxi Medical Universtiy from January 2019 to September 2023 were retrospectively investigated.Interrupted time series analysis was used to analyze the changes and trend of medical expenses and expenses structure of breast cancer before and after the implementation of day chemotherapy.Results The number of 8066 cases with breast cancer were included in this study.After day chemotherapy,the total expenses and each expense detail decreased significantly(P＜0.001).The total expenses,medicine expense,examination expenses and other expenses showed an upward trend before implementation of day chemotherapy(P＜0.05),the laboratory expenses showed a downward trend before implementation of day chemotherapy(P＜0.001).The total medical expenses decreased by 7306.34 yuan immediately after the implementation of day chemotherapy.The expenses of laboratory test,treatment,examination,nursing,medicine,health materials and other expenses were decreased by 599.59 yuan,1674.34 yuan,1470.66 yuan,91.37 yuan,3473.91 yuan,231.51 yuan and 436.73 yuan,respectively.Conclusion The implementation of day chemotherapy for breast cancer has significantly reduced all kinds of costs,which is conductive to reducing disease burden of patients.

Objective:To construct a diabetes foot prediction model for adult patients with type 2 diabetes based on retrospective cohort study using data from a regional health data platform.Methods:Using Yinzhou Health Information Platform of Ningbo, adult patients with newly diagnosed type 2 diabetes from January 1, 2015 to December 31, 2022 were included in this study and divided randomly the train and test sets according to the ratio of 7∶3. LASSO regression model and bidirectional stepwise regression model were used to identify risk factors, and model comparisons were conducted with net reclassification index, integrated discrimination improvement and concordance index. Univariate and multivariate Cox proportional hazard regression models were constructed, and a nomogram plot was drawn. Area under the curve (AUC) was calculated as a discriminant evaluation indicator for model validation test its calibration ability, and calibration curves were drawn to test its calibration ability.Results:No significant difference existed between LASSO regression model and bidirectional stepwise regression model, but the better bidirectional stepwise regression model was selected as the final model. The risk factors included age of onset, gender, hemoglobin A1c, estimated glomerular filtration rate, taking angiotensin receptor blocker and smoking history. AUC values (95% CI) of risk outcome prediction at year 5 and 7 were 0.700 (0.650-0.749) and 0.715(0.668-0.762) for the train set and 0.738 (0.667-0.801) and 0.723 (0.663-0.783) for the test set, respectively. The calibration curves were close to the ideal curve, and the model discrimination and calibration powers were both good. Conclusions:This study established a convenient prediction model for diabetic foot and classified the risk levels. The model has strong interpretability, good discrimination power, and satisfactory calibration and can be used to predict the incidence of diabetes foot in adult patients with type 2 diabetes to provide a basis for self-assessment and clinical prediction of diabetic foot disease risk.

Objective:To develop a prediction model for the risk of diabetic retinopathy (DR) in patients with newly diagnosed type 2 diabetes mellitus (T2DM).Methods:Patients with new diagnosis of T2DM recorded in Yinzhou Regional Health Information Platform between January 1, 2015 and December 31, 2022 were included in the study. The predictor variables were selected by using Lasso-Cox proportional hazards regression model. Cox proportional hazards regression models were used to establish the prediction model for the risk of DR. Bootstrap method (500 resamples) was used for internal validation, and the performance of the model was assessed by C-index, the receiver operating characteristic curve and area under the curve (AUC), and calibration curve.Results:The predictor variables included in the final model were age of T2DM onset, education level, fasting plasma glucose, glycated hemoglobin A1c, urinary albumin, estimated glomerular filtration rate, and history of lipid-lowering agent and angiotensin converting enzyme inhibitor uses. The C-index of the final model was 0.622, and the mean corrected C-index was 0.623 (95% CI: 0.607-0.634). The AUC values for predicting the risk of DR after 3, 5, and 7 years were 0.631, 0.620, and 0.624, respectively, with a high degree of overlap of the calibration curves with the ideal curves. Conclusion:In this study, a simple and practical risk prediction model for DR risk prediction was developed, which could be used as a reference for individualized DR screening and intervention in newly diagnosed T2DM patients.

Objective:To construct a risk prediction model for diabetes kidney disease (DKD).Methods:Patients newly diagnosed with type 2 diabetes mellitus (T2DM) between January 1, 2015, and December 31, 2022, were selected as study subjects from the Yinzhou Regional Health Information Platform in Ningbo City. The Lasso method was used to screen the risk factors, and the DKD risk prediction model was established using Cox proportional hazard regression models. Bootstrap 500 resampling was applied for internal validation.Results:The study included 49 706 subjects, with an median ( Q1, Q3) age of 60.00 (50.00, 68.00) years old, and 55% were male. A total of 4 405 subjects eventually developed DKD. Age at first diagnosis of T2DM, BMI, education level, fasting plasma glucose, glycated hemoglobin A1c, urinary albumin, past medical history (hyperuricemia, rheumatic diseases), triglycerides, and estimated glomerular filtration rate were included in the final model. The final model's C-index was 0.653, with an average of 0.654 after Bootstrap correction. The final model's area under the receiver operating characteristic curve for predicting 4-year, 5-year, and 6-year was 0.657, 0.659, and 0.664, respectively. The calibration curve was closely aligned with the ideal curve. Conclusions:This study constructed a DKD risk prediction model for newly diagnosed T2DM patients based on real-world data that is simple, easy to use, and highly practical. It provides a reliable basis for screening high-risk groups for DKD.

Objective:To investigate the clinical features of 17q12 microdeletion cases before and after delivery, and provide a reference for prenatal diagnosis and genetic counseling.Methods:A retrospective analysis was conducted on five fetuses diagnosed with 17q12 microdeletion by single nucleotide polymorphism array in Quanzhou Women's and Children's Hospital between April 2020 and June 2023. Clinical data including prenatal ultrasonography findings, genetic causes, parental clinical features, and postnatal outcomes were summarized and analyzed using descriptive statistical analysis.Results:The five fetuses had normal results of karyotype analysis of amniotic fluid, but carried a microdeletion of 1.4 to 1.8 Mb in the 17q12 region of the chromosome, involving 20 genes listed in the Online Mendelian Inheritance in Man database. Pedigree verification was performed on all five cases and the results indicated one maternally inherited case with the mother having polycystic kidneys complicated by left hydronephrosis, one de novo case, and three paternally inherited cases with one father having multiple cysts in both kidneys and two fathers showing no abnormalities. Multiple abnormalities were found in the five fetuses by prenatal ultrasonography, including enhanced renal parenchymal echogenicity in four cases and pyelectasis in one case. Two cases chose to terminate the pregnancies, while the other three continued the pregnancies to full term. Postnatal follow-ups showed that one case was normal in growth and development with no abnormalities by renal ultrasound; one case developed polycystic kidney; one case with normal renal ultrasound findings had a speech disorder and symptoms of suspected autism at the age of three. Conclusions:The main manifestation of 17q12 microdeletion is enhanced renal parenchymal echogenicity in the fetal stage and postnatal polycystic kidney. In prenatally diagnosed cases, pedigree verification is necessary as an objective and scientific genetic counseling is helpful in pregnancy decision-making.

Objective:To explore the relationship among sleep phenotypes, attention deficit and hyperactivity impulsivity (ADHD) symptoms and cognitive information processing in children with ADHD.Methods:A total of 244 children with ADHD aged 6-12 were selected from December 2021 to December 2022.Swanson, Nolan and Pelham rating scale Ⅳ(SNAP-Ⅳ) was used to evaluate the core symptoms of ADHD.Sleep disturbance scale for children (SDSC) was used to evaluate six sleep phenotypes((disorders in initiating and maintaining sleep (DIMS), sleep breathing disorders(SDB), sleep-wake transition disorders(SWTD), disorders of arousal(DA), disorders of excessive somnolence (DOES), and Nocturnal hyperhidrosis(SHY)). Das-Naglieri cognitive function assessment system (DN-CAS) was used to evaluate the cognitive information processing (planning, simultaneous processing, attention and successive processing). Descriptive statistical analysis, Spearman correlation analysis, and mediation analysis were conducted by SPSSAU 23.0 and Zstats software, respectively.Results:Correlation analysis showed that DIMS, SDB, SWTD, DA and DOES were significantly and positively correlated with attention deficit ( r=0.190-0.349, all P<0.01).DIMS(2.14(1.71, 2.57)), SWTD(1.67(1.33, 2.00)) and SHY(2.00(1.50, 3.00)) were significantly positively correlated with hyperactive impulsivity (1.44(1.00, 2.00))( r=0.193, 0.242, 0.133, P<0.05). Attention deficit(1.78(1.44, 2.33)) was significantly and negatively correlated with successive processing(105.00(96.00, 112.00)) ( r=-0.127, P<0.05). The results of multiple linear regression analysis showed that after controlling for sex, age, verbal IQ and operational IQ, DIMS ( β=0.152, P<0.05) and SWTD ( β=0.178, P<0.05) had significant positive predictive effects on hyperactive impulsivity symptoms. DOES ( β=0.259, P<0.01) had significant positive predictive effects on attention deficit symptoms. Attention deficit ( β=-0.183, P<0.05) had a significant negative predictive effect on successive processing. Mediation effect analysis showed that attention deficit played a complete mediating role between DOES and successive processing(effect=-0.179, Bootstrap 95% CI=-0.196--0.110). Conclusion:Different sleep phenotypes are associated with ADHD core symptoms and different dimensions of cognitive information processing processes. DOES indirectly affects successive processing capability by attention deficit symptoms.