Randomized controlled trial(RCT) represents the "gold standard" for estimating the causal effects of interventions; however, their implementation in the field of health policy evaluation is frequently hindered by logistical feasibility and ethical constraints. Target Trial Emulation (TTE), a framework originating in clinical epidemiology, facilitates rigorous causal inference from observational data by explicitly emulating the design of an idealized "target trial". Recently, the application of TTE has transitioned from individual-level clinical interventions—such as pharmacological or surgical treatments—to population-level health policy evaluations. This interdisciplinary translation is not a localized conceptual shift but necessitates a series of comprehen-sive methodological adaptations. This paper systematically delineates the core logic of extending the TTEframework into the realm of health policy, providing a profound analysis of the transformation and reconstruction of critical elements, including study units, intervention definitions, time zero, causal estimands, and analytical strategies. Furthermore, it examines the unique challenges inherent in policy contexts, such as policy heterogeneity, staggered adoption, concurrent policy interference, and data granularity limitations. The paper also evaluates the integration of analytical methods, such as instrumental variables (IV) and difference-in-differences (DID), within the TTE framework. This synthesis aims to provide methodological guidance and prospective insights for conducting high-quality policy evaluations using real-world data (RWD).

BackgroundThe middle school stage represents a crucial period for the development of borderline personality features. Negative parenting styles and emotional regulation strategies are associated with the formation of borderline personality features. However， the moderating role of emotional regulation strategies between negative parenting styles and borderline personality features among middle school students remains unclear. ObjectiveTo explore the moderating influence of emotional regulation strategies in the relationship between negative parenting styles and borderline personality features among middle school students， and to provide references for the intervention of borderline personality features. MethodsIn October 2023， a total of 5 965 middle school students from three middle schools in Nanning， Guangxi Zhuang Autonomous Region were selected by cluster sampling， and assessed by the Borderline Personality Features Scale for Children （BPFS-C）， the Egna Minnen Barndoms Uppfostran （EMBU）， and the Emotion Regulation Questionnaire-Chinese Revised Version （ERQ-CRV）. Pearson correlation analysis was used to test the correlation between the scores of each scale， and the model 1 of the Process macro program was used to conduct the moderating effect test. ResultsA total of 5 572 middle school students （93.41%） completed this study， and 1 388 of them （24.91%） were identified as having high borderline personality features. The BPFS-C score of middle school students was positively correlated with the score of the negative parenting style dimension of EMBU （r=0.367， P<0.01）， negatively correlated with the score of the cognitive reappraisal dimension of ERQ-CRV （r=-0.168， P<0.01）， and positively correlated with the score of the expression inhibition dimension of ERQ-CRV （r=0.344， P<0.01）. Cognitive reappraisal played a negative moderating effect between negative parenting styles and borderline personality features （β=-0.072， 95% CI： -0.104–-0.041， P<0.01）， while expressive suppression played a positive moderating effect （β=0.076， 95% CI： 0.055–0.097， P<0.01）. ConclusionCognitive reappraisal strategy may help mitigate the negative influence of negative parenting styles on middle school students' borderline personality features， while expressive suppression may exacerbate the harm of negative parenting styles to the borderline personality features of middle school students.

Objective To investigate the protective effect and underlying mechanism of human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Exo) on renal ischemia-reperfusion injury (IRI). Methods hucMSC-Exos were isolated and characterized. A mouse renal IRI model was established and the animals were divided into Sham, IRI, IRI+hucMSC-Exo, IRI+hucMSC-Exo+JY-2 and Sham+JY-2 groups. Serum creatinine (Scr) and blood urea nitrogen (BUN) were measured. Hematoxylin-eosin (HE) staining was used to evaluate renal histopathology. Enzyme-linked immune absorbent assay was performed to determine serum interleukin (IL)-1β and IL-18 levels. Western blotting was used to detect the expression of activating transcription factor 3 (ATF3), Toll-like receptor 4 (TLR4), nuclear factor (NF)-κB, NOD-like receptor protein 3 (NLRP3), cysteineyl aspartate specific proteinase (Caspase)-1 p20 and Gasdermin D(GSDMD). Real-time fluorescent quantitative polymerase chain reaction was employed to measure ATF3, TLR4 and NF-κB messenger RNA (mRNA). Immunohistochemistry was conducted to examine NLRP3, Caspase-1 p20 and GSDMD. An in vitro hypoxia/reoxygenation (H/R) model was established in HK-2 cells and divided into Control, H/R, H/R+hucMSC-Exo, H/R+hucMSC-Exo+JY-2 and Control+JY-2 groups. Western blotting was used to detect the expression of ATF3, TLR4 and NF-κB. Real-time fluorescent quantitative polymerase chain reaction was used to measure NLRP3, GSDMD and Caspase-1 mRNA. Results HucMSC-Exos were successfully isolated and identified. Compared with the Sham group, the IRI group exhibited elevated Scr and BUN, higher tubular injury scores, increased protein expression levels of ATF3, TLR4, NF-κB p65, NLRP3, Caspase-1 p20 and GSDMD, and raised mRNA expression levels of ATF3, TLR4, NF-κB. Compared with the IRI group, the IRI+hucMSC-Exo group showed decreased Scr and BUN, lower tubular injury scores, up-regulated ATF3 protein and mRNA, down-regulated TLR4, NF-κB p65, NLRP3, Caspase-1 p20 and GSDMD protein, and declined TLR4 and NF-κB mRNA. Compared with the IRI+hucMSC-Exo group, the IRI+hucMSC-Exo+JY-2 group exhibited increased Scr and BUN levels, elevated renal tubular injury scores, decreased ATF3 protein expression levels, elevated protein expression levels of TLR4, NF-κB p65, NLRP3, Caspase-1 p20, and GSDMD, decreased ATF3 mRNA expression levels, and elevated mRNA expression levels of TLR4 and NF-κB. (all P < 0.05). Compared with the Control group, the expression levels of ATF3, TLR4 and NF-κB p65 proteins were increased in the H/R group, and the expression levels of NLRP3, Caspase-1 and GSDMD mRNA were increased. Compared with the H/R group, the expression level of ATF3 protein was increased, the expression levels of TLR4 and NF-κB p65 proteins were decreased, and the expression levels of NLRP3, Caspase-1 and GSDMD mRNA were decreased in the H/R+hucMSC-Exo group. Compared with the H/R+hucMSC-Exo group, the expression level of ATF3 protein was decreased, the expression levels of TLR4 and NF-κB p65 proteins were increased, and the expression levels of NLRP3, Caspase-1 and GSDMD mRNA were increased in the H/R+hucMSC-Exo+JY-2 group (all P < 0.05). Conclusions HucMSC-Exos alleviate renal IRI by up-regulating ATF3, thereby negatively regulating the TLR4/NF-κB signaling pathway and subsequently inhibiting pyroptosis.

Objective: To develop and validate a clinically actionable prediction model for postoperative pulmonary complications (PPCs) in cardiac surgery patients, focusing on modifiable preoperative risk factors amenable to targeted optimization. Methods: In this prospective observational cohort study, 492 adults undergoing open-chest cardiac surgery between August 15, 2023 and December 31, 2023 were analyzed. Prespecified predictors included gas exchange variables, pulmonary function, inspiratory muscle strength, and physical performance. Univariable and multivariable logistic regression analyses were used to develop the prediction model. Discrimination was assessed by the area under the receiver operating characteristic curve (AUC). Results: A total of 90 patients (14.1%) developed PPCs after surgery. Five independent predictors were identified: elevated arterial PaCO2 (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.00–1.26), oxygen desaturation (SpO2<93%) (OR 12.47, 95% CI 3.51–48.13), reduced gait speed (OR 0.17, 95% CI 0.04–0.71), lower FEV1/FVC ratio (OR 0.96, 95% CI 0.92–1.00), and diminished inspiratory muscle strength (MIP % predicted) (OR 0.96, 95% CI 0.92–0.99). The model demonstrated good discriminative ability with an AUC of 0.86 (95% CI 0.80–0.93) in the training cohort and 0.87 (95% CI 0.74–0.93) in the validation cohort. Conclusion This parsimonious model achieved high predictive accuracy using five modifiable physiological variables. By targeting abnormalities in gas exchange, pulmonary mechanics, muscle strength, and functional reserve, the model offers a practical tool to guide individualized prehabilitation strategies for reducing PPC risk in cardiac surgery patients.

[This corrects the article DOI: 10.1016/j.apsb.2022.05.019.].

One of the basic questions in the aging field is whether there is a fundamental difference between the aging of lower invertebrates and mammals. A major difference between the lower invertebrates and mammals is the abundancy of noncoding RNAs, most of which are not conserved. We have previously identified a noncoding RNA Terc-53 that is derived from the RNA component of telomerase Terc. To study its physiological functions, we generated two transgenic mouse models overexpressing the RNA in wild-type and early-aging Terc-/- backgrounds. Terc-53 mice showed age-related cognition decline and shortened life span, even though no developmental defects or physiological abnormality at an early age was observed, indicating its involvement in normal aging of mammals. Subsequent mechanistic study identified hyaluronan-mediated motility receptor (Hmmr) as the main effector of Terc-53. Terc-53 mediates the degradation of Hmmr, leading to an increase of inflammation in the affected tissues, accelerating organismal aging. adeno-associated virus delivered supplementation of Hmmr in the hippocampus reversed the cognition decline in Terc-53 transgenic mice. Neither Terc-53 nor Hmmr has homologs in C. elegans. Neither do arthropods express hyaluronan. These findings demonstrate the complexity of aging in mammals and open new paths for exploring noncoding RNA and Hmmr as means of treating age-related physical debilities and improving healthspan.
Animals ; Mice ; RNA, Untranslated/metabolism* ; Aging/genetics* ; Mice, Transgenic ; Telomerase/metabolism* ; RNA/genetics* ; Hippocampus/metabolism* ; Humans ; Mice, Inbred C57BL

Objective To explore the effects and mechanisms of human umbilical cord mesenchymal stem cell (HUC-MSC)-derived exosomes (Exo) pretreated with Huangkui capsules on renal ischemia-reperfusion injury (IRI). Methods HUC-MSCs were cultured in media containing different concentrations of Huangkui capsules for 24 hours to determine cell viability and select an appropriate concentration for subsequent experiments. HUC-MSCs were pretreated with 50 μg/mL Huangkui capsules for 24 hours, and Exo were extracted using an exosome extraction kit. The morphology was observed under a transmission electron microscope, particle size was measured by nanoparticle tracking analysis, and the expression of exosomal membrane surface marker proteins was detected by Western blot. Human renal tubular epithelial cells (HK-2 cells) were randomly divided into hypoxia/reoxygenation group (M group), hypoxia/reoxygenation + Exo group (E group), and hypoxia/reoxygenation + Huangkui capsules pretreated Exo group (H group). Western blotting was used to measure the expression of endoplasmic reticulum stress (ERS)-related proteins, and real-time fluorescent quantitative reverse transcription polymerase chain reaction was used to measure the expression of ERS-related gene messenger RNA (mRNA). Mice were randomly divided into sham operation group (Sham group), ischemia-reperfusion group (I/R group), ischemia-reperfusion + Exo group (E group), and ischemia-reperfusion + Huangkui capsules pretreated Exo group (H group). Renal histological assessment, serum creatinine (Scr), blood urea nitrogen (BUN) measurement and inflammatory factor detection were performed 24 hours later. Results Both Exo and Huangkui capsules prereated Exo had a bilayer membrane structure and a cup-shaped morphology; their average particle sizes were 116.8 nm and 81.3 nm, respectively. Both expressed CD9, CD63, TSG101. Compared with the M group, the E group had decreased relative expression of transcription factor 6 (ATF6) and protein kinase R-like endoplasmic reticulum kinase (PERK) proteins, increased mRNA relative expression, increased relative expression of C/EBP homologous protein (CHOP) protein, and decreased mRNA relative expression. Compared with the E group, the H group had decreased relative expression of ATF6, PERK, CHOP proteins, and decreased mRNA relative expression of ATF6 and PERK (all P<0.05). Animal experimental results showed that compared with the Sham group, the I/R group had increased renal tubular injury scores, Scr, BUN, interleukin (IL)-1β, IL-10, IL-18, tumor necrosis factor (TNF)-α levels. Compared with the I/R group, the E and H groups had decreased renal tubular injury scores and Scr, BUN, IL-1β, IL-10, IL-18, TNF-α levels. Compared with the E group, the H group had decreased renal tubular injury scores and Scr, BUN, IL-1β, IL-10, IL-18, TNF-α levels (all P<0.05). Conclusions Huangkui capsules pretreatment HUC-MSC-derived Exo may alleviate renal IRI by inhibiting ERS.

Objective:To explore the correlation between serum nidogen-2 (NID-2) and thoracic aortic calcification in patients with chronic kidney disease (CKD), and construct a risk prediction model based on NID-2 to evaluate its value in predicting the risk of the severe thoracic aortic calcification and cardiovascular and cerebrovascular events in CKD patients.Methods:It was a prospective cohort study. Patients with CKD at stage 3 to 5D in the Zhongda Hospital Affiliated to Southeast University from January 2022 to January 2023 were enrolled. Syngo.via software was used to evaluate the volume of thoracic aortic calcification, and enzyme-linked immunosorbent assay was employed to determine the level of serum NID-2. According to the volume of thoracic aortic calcification, the patients were divided into three groups: no calcification group, mild calcification group and severe calcification group. The top 25% of the patients were defined as no or mild calcification group, and the latter 75% were defined as severe calcification group. The follow-up period was one year. During the follow-up period, cardiovascular and cerebrovascular events, as well as all-cause death among the enrolled patients were recorded. Logistic regression analysis was used to screen the influencing factors of thoracic aortic calcification. Based on the results of logistic regression analysis, a nomogram prediction model was constructed. The receiver operating characteristic curve (ROC curve), calibration curve, and decision curve were employed to evaluate the discrimination, calibration and clinical practicality of the nomogram model.Results:A total of 132 patients were included, with 91 males (68.94%) and age of (56.51±16.37) years. There were 60 CKD 3-5 stage patients (non-dialysis, 45.45%) and 72 CKD 5D patients (dialysis, 54.55%). Serum ND-2 levels differed significantly among healthy individuals, dialysis patients and non-dialysis patients ( H=70.651, P<0.001). There was no statistically significant difference in serum NID-2 level between the no or mild calcification group and the severe calcification group in dialysis patients ( Z=350.00, P=0.426). The serum NID-2 level in the severe calcification group was significantly higher than that in the no or mild calcification group in non-dialysis patients ( Z=242.00, P=0.019). In non-dialysis patients, there was a statistically significant correlation between serum NID-2 level and volume of thoracic aortic calcification ( r=0.40, P<0.001). In dialysis patients, there was no statistically significant correlation between serum NID-2 level and volume of each segment of thoracic aortic calcification (all P>0.05). The univariate logistic regression analysis showed that, age, hemoglobin, serum albumin, estimated glomerular filtration rate, NID-2, hypertension, type 2 diabetes mellitus and cerebral infarction were correlated factors of thoracic aortic calcification in non-dialysis patients (all P<0.05). Multivariate logistic regression analysis showed that age ( OR=1.22, 95% CI 1.08-1.50, P=0.010) was an independent correlated factor of thoracic aortic calcification in non-dialysis patients. The above related variables of univariate logistic regression analysis were incorporated into a nomogram to construct a predictive model for severe vascular calcification in non-dialysis patients, yielding an AUC of 0.94 (95% CI 0.89-0.99) in ROC curve, with a sensitivity of 83% and a specificity of 95%. A nomogram model based on above variables for predicting cardiovascular and cerebrovascular events in non-dialysis patients demonstrated an AUC of 0.95 (95% CI 0.90-1.00) in ROC curve, with a sensitivity of 95% and a specificity of 87%. Conclusions:In non-dialysis patients, serum NID-2 level in the severe calcification group is significantly higher than that in the no or mild calcification group. The serum NID-2 is a related factor of thoracic aortic calcification and cardiovascular and cerebrovascular events in non-dialysis patients. The nomogram prediction model constructed by combining NID-2 with age, hemoglobin, serum albumin, estimated glomerular filtration rate, hypertension, type 2 diabetes mellitus and cerebral infarction has a high predictive value for the risk of thoracic aortic calcification as well as cardiovascular and cerebrovascular events in non-dialysis patients.

Objective:To develop a deep learning-based segmentation model MT-UNet to automatically segment bone metastases and benign bone lesions in bone scintigraphy with SPECT/CT.Methods:A total of 93 patients (48 males and 45 females, age 28-84 years) who underwent bone SPECT/CT in the Department of Nuclear Medicine, General Hospital of Northern Theater Command from June 2023 to December 2023 were enrolled retrospectively in this study, with a total of 184 bone lesions (94 benign lesions and 90 metastatic tumors). The MT-UNet was employed to segment bone lesions in SPECT, CT and SPECT/CT images respectively. Comparative analysis with 8 segmentation models was performed. The training set and validation set were divided by using 5-fold cross-validation and transfer learning was introduced to further enhance the robustness of the model. An additional cohort of 22 patients (15 males and 7 females, age 37-87 years) who received bone SPECT/CT in the Department of Nuclear Medicine, General Hospital of Northern Theater Command from April 2023 to May 2023 were included, comprising 40 bone lesions (22 benign lesions and 18 metastatic tumors) as the test set of MT-UNet. Segmentation performance of different models was assessed using accuracy, sensitivity, specificity, AUC, intersection over union and Dice similarity coefficient (DSC). Delong test was used to compare the segmentation efficacy among different models in the test set.Results:In the validation set, MT-UNet demonstrated DSC of 0.940, 0.962, and 0.963 for SPECT, CT, and SPECT/CT bone lesion segmentation, respectively, which were outperformed other models. Following transfer learning implementation, the SPECT/CT model′s DSC was improved to 0.984. In the test set, MT-UNet maintained comparable segmentation performance to the validation set, with significant AUC differences among the three models ( Z values: from -15.42 to -9.27, all P<0.01). Compared with conventional image interpretation, MT-UNet-based segmentation reduced physician interpretation time from 164min to 102min. Conclusion:MT-UNet has shown good performance in automatic segmentation of bone metastases and benign bone lesions, and is expected to become an important part of SPECT/CT image intelligent diagnosis system for bone metastases.

BACKGROUND: Renal osteodystrophy (ROD) is a skeletal pathology associated with chronic kidney disease-mineral and bone disorder (CKD-MBD) that is characterized by aberrant bone mineralization and remodeling. ROD increases the risk of fracture and mortality in CKD patients. The underlying mechanisms of ROD remain elusive, partially due to the absence of an appropriate animal model. To address this gap, we established a stable mouse model of ROD using an optimized adenine-enriched diet and conducted exploratory analyses through ribonucleic acid sequencing (RNA-seq). METHODS: Eight-week-old male C57BL/6J mice were randomly allocated into three groups: control group ( n = 5), adenine and high-phosphate (HP) diet group ( n = 20), and the optimized adenine-containing diet group ( n = 20) for 12 weeks. We assessed the skeletal characteristics of model mice through blood biochemistry, microcomputed tomography (micro-CT), and bone histomorphometry. RNA-seq was utilized to profile gene expression changes of ROD. We elucidated the functions of differentially expressed genes (DEGs) using gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and gene set enrichment analysis (GSEA). DEGs were validated via quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: By the fifth week, adenine followed by an HP diet induced rapid weight loss and high mortality rates in the mouse group, precluding further model development. Mice with optimized adenine diet-induced ROD displayed significant abnormalities in serum creatinine and blood urea nitrogen levels, accompanied by pronounced hyperparathyroidism and hyperphosphatemia. The femur bone mineral density (BMD) of the model mice was lower than that of control mice, with substantial bone loss and cortical porosity. ROD mice exhibited substantial bone turnover with an increase in osteoblast and osteoclast markers. Transcriptomic profiling revealed 1907 genes with upregulated expression and 723 genes with downregulated expression in the femurs of ROD mice relative to those of control mice. Pathway analyses indicated significant enrichment of upregulated genes in the sphingolipid metabolism pathway. The significant upregulation of alkaline ceramidase 1 ( Acer1 ), alkaline ceramidase 2 ( Acer2 ), prosaposin-like 1 ( Psapl1 ), adenosine A1 receptor ( Adora1 ), and sphingosine-1-phosphate receptor 5 ( S1pr5 ) were successfully validated in mouse femurs by qRT-PCR. CONCLUSIONS Optimized adenine diet mouse model may be a valuable proxy for studying ROD. RNA-seq analysis revealed that the sphingolipid metabolism pathway is likely a key player in ROD pathogenesis, thereby providing new avenues for therapeutic intervention.
Animals ; Mice ; Chronic Kidney Disease-Mineral and Bone Disorder/genetics* ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; Sphingolipids/metabolism* ; Transcriptome/genetics* ; Signal Transduction/genetics* ; X-Ray Microtomography ; Adenine