Transanal intersphincteric under direct view in the jackknife position combined with laparoscopic total mesorectal excision for treating ultra-low rectal cancer.

Aim: To investigate the effect and clinical advantage of transanal intersphincteric (ISR) under direct view in the jackknife position combined with laparoscopic total mesorectal excision (TME) for treating ultra-low rectal cancer. Additionally, the feasibility of this surgical technique was evaluated. Method: This was a retrospective, single-center, single-arm pilot study. Ten patients with ultra-low rectal cancer underwent treatment by the same surgical team for direct view transanal ISR combined with laparoscopic TME in the Department of Anorectal Surgery, Huizhou Central People's Hospital between January 2021 and June 2021. The relevant clinical data were collected and analyzed. Results: All the patients underwent complete mesenteric resection without conversion to laparotomy. The circumferential and distal resection margins (CRM and DRM) were negative. The mean distance between the lower margin of the tumor and the anal margin was 2.8 ± 0.8 cm, and the mean margin of distal resection was 1.2 ± 0.2 cm. TNM pathological stages I, II, III, and IV were observed in 6, 2, 2, and 0 cases, respectively. The median follow-up period was 15 months (interquartile range, 8 months). The mean Wexner and Low Anterior Resection Syndrome scores at 12 months after ileostomy were 8.1 ± 2.1 and 22.4 ± 5.7, respectively. Conclusion: Transanal ISR under direct view in the jackknife position combined with laparoscopic TME is safe and feasible for the treatment of ultralow rectal cancer.

Rosa roxburghii fermented juice mitigates LPS-induced acute lung injury by modulation of intestinal flora and metabolites.

Acute lung injury (ALI) is a severe pulmonary condition with high mortality and morbidity, lacking effective pharmacotherapeutic options. Rosa roxburghii Tratt, a unique fruit from southwestern China, is valued for its rich nutritional content and functional properties. Fermentation is known to enhance the nutritional value, flavor, and shelf life of foods. In this study, we investigated the effects of fermented Rosa roxburghii juice (RRFJ) on gut microbiota, metabolites, and the levels of short-chain fatty acids in the intestines, as well as its impact on lung tissue and intestine tissue injury, inflammation, and oxidative stress in murine models. The results showed that RRFJ modulated gut microbiota and metabolites, increased short-chain fatty acid levels, and consequently reduced lung tissue injury, inflammation, and oxidative stress in mice with ALI. These findings suggest that RRFJ has the potential to serve as a functional dietary adjunct in the management of acute lung injury, providing a scientific basis for its therapeutic role.

Machine Learning Model to Predict Early Recurrence in Patients with Perihilar Cholangiocarcinoma Planned Treatment with Curative Resection: A Multicenter Study.

BACKGROUND & AIMS: Early recurrence is the leading cause of death for patients with perihilar cholangiocarcinoma (pCCA) after surgery. Identifying high-risk patients preoperatively is important. This study aimed to construct a preoperative prediction model for the early recurrence of pCCA patients planned treatment with curative resection. METHODS: This study ultimately enrolled 400 pCCA patients after curative resection in five hospitals between 2013 and 2019. They were randomly divided into training (n=300) and testing groups (n=100) at a ratio of 3:1. Associated variables were identified via LASSO regression. Four machine learning models were constructed: support vector machine (SVM), random forest (RF), logistic regression, and K-nearest neighbors (KNN). The predictive ability of the models was evaluated via receiver operating characteristic (ROC) curves, precision-recall curve (PRC) curves, and decision curve analysis (DCA). KaplanMeier survival curves were drawn for the high/low-risk population. RESULTS: Five factors, CA19-9, tumor size, total bilirubin, hepatic artery invasion, and portal vein invasion, were selected by LASSO regression. In both the training and testing groups, the ROC curve (AUC: 0.983 vs 0.952) and the PRC (0.981 vs 0.939) showed that RF was the best. The cutoff value for distinguishing high- and low-risk patients was 0.51. KM survival curves revealed that in both groups, there was a significant difference in RFS between high- and low-risk patients (P<0.001). CONCLUSION: This study used preoperative variables from a large, multicenter database to construct a machine learning model that could effectively predict the early recurrence of pCCA patients planned treatment with curative resection and help clinicians make better treatment decisions.

Characterization and biocompatibility of a bilayer PEEK-based scaffold for guiding bone regeneration.

BACKGROUND: Polyetheretherketone (PEEK) is well known for its excellent physical-chemical properties and biosafety. The study aimed to open up a new method for clinical application of PEEK to reconstruct large-scale bone defects. METHODS: A bilayer scaffold for bone regeneration was prepared by combining a sulfonated PEEK barrier framework (SPEEK) with a hydrogel layer loaded with aspirin (ASA) and nano-hydroxyapatite (nHAP) by the wet-bonding of Polydopamine (PDA). RESULTS: The hydrogel was successfully adhered to the surface of SPEEK, resulting in significant changes including the introduction of bioactive groups, improved hydrophilicity, and altered surface morphology. Subsequent tests confirmed that the bilayer scaffold exhibited enhanced compression resistance and mechanical compatibility with bone compared to a single hydrogel scaffold. Additionally, the bilayer scaffold showed stable and reliable bonding properties, as well as excellent biosafety verified by cell proliferation and viability experiments using mouse embryo osteoblast precursor (MC3T3-E1) cells. CONCLUSION: The bilayer bone regeneration scaffold prepared in this study showed promising potential in clinical application for bone regeneration.

Effects of aripiprazole on prolactin levels and differences in effectiveness in patients with schizophrenia: a post-hoc analysis of the real-world data of a multicenter study.

Objectives: To investigate the effect of aripiprazole on prolactin levels in patients with schizophrenia and analyze whether varying baseline prolactin levels affect the effectiveness and safety of aripiprazole, in a real-life diagnostic and therapeutic setting in a post-hoc analysis. Methods: In this post-hoc analysis, patients with schizophrenia in the acute phase were divided into an elevated-prolactin group and a normal-prolactin group. After 8 weeks of aripiprazole treatment, changes in the proportion of patients with an abnormal prolactin level were analyzed in both groups, and the efficacy and safety of aripiprazole were compared between the two groups. Results: The elevated-prolactin group had more women, a longer duration of disease, and lower Positive and Negative Syndrome Scale (PANSS) total and subscale scores at baseline compared with the normal-prolactin group (all P < 0.05), and there was no significant difference in the proportion of patients with prior use of antipsychotic medication between the two groups. Regardless of previous antipsychotic use, patients in both groups developed hyperprolactinemia (23/168 [13.7%] in those who had taken antipsychotics vs. 43/375 [11.4%] in those who had not). After 8 weeks of aripiprazole treatment, the proportion of patients with abnormal prolactin in the elevated-prolactin group significantly decreased with prolonged treatment (P < 0.001), and aripiprazole had no significant effect on the normal-prolactin group (P = 0.250). Normal-prolactin group showed better efficacy than the elevated-prolactin group, and the differences in efficacy between the two groups was observed from week 4 to the endpoint (all p<0.05). In total, 87.2% (68/78) patients experienced mild to moderate adverse events in the elevated-prolactin group, which was significantly more frequent compared with the normal-prolactin group 71.0% (365/514). Conclusions: In this real-world study, for patients with acute schizophrenia, aripiprazole was effective in lowering the proportion of patients with abnormal prolactin levels, while it had no significant effect on patients with normal baseline prolactin. After adjusting for factors such as sex, age, prior antipsychotic drugs use history and disease severity, effectiveness and safety of aripiprazole in patients with normal baseline prolactin was significantly better than that in patients with elevated baseline prolactin.

Prevalence and correlates of non-suicidal self-injury among patients with bipolar disorder: A multicenter study across China.

BACKGROUND: Non-suicidal self-injury (NSSI) is increasingly prevalent among patients with bipolar disorder (BD), raising concerns in psychology and mental health. Investigating the incidence and factors associated with NSSI is crucial for developing prevention and intervention strategies. METHODS: NSSI behaviors were identified using the Ottawa Self-injury Inventory. The Clinically Useful Depression Outcome Scale supplemented with questions for the DSM-5 specifier of mixed features (CUDOS-M) and the Mini International Neuropsychiatric Interview (Hypo-)Manic Episode with Mixed Features-DSM-5 Module (MINI-M) were used to evaluate clinical symptoms. Non-parametric tests, chi-square tests, point-biserial correlation and logistic regression analyses were employed for the purposes of data analysis. RESULTS: The enrolled sample comprised 1044 patients with BD from 20 research centers across China. Out of 1044 individuals, 446 exhibited NSSI behaviors, with 101 of them being adolescents, leading to a prevalence of 78.3 % among adolescent patients. The most common methods for females and males were "cutting" (41.2 %) and "hitting" (34.7 %), respectively. By binary logistic regression analysis, young age, female, bipolar type II disorder, with suicidal ideation and mixed states, depressive symptoms and without family history of mental disorder were correlates of NSSI in patients with BD (P < 0.05). LIMITATIONS: As a cross-sectional study, causality between NSSI behaviors and associated factors cannot be established. Reporting and recall biases may occur due to self-rating scales and retrospective reports. CONCLUSION: Our study indicates a concerning prevalence of NSSI, particularly among young patients with BD in China. Future research should focus on understanding NSSI behaviors in this population and developing effective interventions.

Design of Quasi-Metal-Organic Frameworks for Solid Polymer Electrolytes Enabling an Ultra-Stable Interface with Li Metal Anode.

Solid polymer electrolytes (SPEs) are crucial in the development of lithium metal batteries. Recently, metal-organic frameworks (MOFs) with open metal sites (OMSs) have shown promise as solid fillers to improve the performance of SPEs. However, the number of OMS-containing MOFs is quite limited, comprising less than 5% of the total MOFs. When considering yield, cost, and processability, the commonly used OMS-containing MOFs are no more than 10 types, causing great limitations. Herein, we reported a simple and universal methodology that converted OMS-free MOFs to OMS-rich quasi-MOFs for developing high-performance SPEs, and explored the underlying mechanism. The "OMS-polymer" and "OMS-ion" interactions were investigated in detail to elucidate the role of quasi-MOFs on battery performance. It was found that quasi-MOFs, functioning as ion sieves, can effectively regulate ion migration, thus promoting uniform Li deposition and enabling an ultra-stable interface. As a result, the Li symmetric cell stably ran over 3000 h at 0.3 mA cm-2, while the full cell retained 85% of its initial capacity after 1500 cycles at 1.0 C. Finally, universal testing was performed using other MOFs, confirming the generalizability and effectiveness of our design concept.

Descriptive epidemiology of gastroschisis in China from 2007 to 2020: a nationwide surveillance-based study.

BACKGROUND: Gastroschisis is a common abdominal wall defect that increases infant mortality risk and health care costs. However, recent epidemiological data on gastroschisis in China is limited. METHODS: Using 2007-2020 data from the Chinese Birth Defects Monitoring Network (CBDMN), we analyzed gastroschisis prevalence rates stratified by birth year, maternal age group, residence area, geographical region, and infant sex. We also examined the temporal variations in prevalence, pregnancy outcomes of affected infants, prenatal diagnoses, and co-occurring anomalies. RESULTS: From 2007 to 2020, a total of 6,813 cases of gastroschisis were identified among 25,909,000 births, comprising 4,675 isolated and 2,138 non-isolated cases. Prevalence rates per 10,000 live and still births were 2.63, 1.80, and 0.83 for the overall, isolated, and non-isolated gastroschisis, respectively, all showing a decreasing trend over the study period. The prevalence of overall gastroschisis varied significantly by maternal age (< 20 years, 9.88/10,000; 20-24 years, 4.17/10,000; 25-29 year, 2.08/10,000; 30-34 years, 1.88/10,000;≥35 years, 2.24/10,000), maternal residence (urban, 2.45/10,000; rural, 2.85/10,000), geographic region (central, 2.54/10,000; east, 2.57/10,000; west, 2.80/10,000), and infant sex (male, 2.13/10,000; female, 1.79/10,000). Non-isolated gastroschisis cases had a higher early neonatal mortality rate than isolated cases (41.91% vs. 28.10%) and frequently co-occurred with musculoskeletal anomalies. CONCLUSIONS: This study highlights a declining trend in gastroschisis prevalence in Chinese population, a contrast to previous studies, and underscores the need for improved perinatal management due to adverse pregnancy outcomes associated with this condition.

The relationship between serum lipid with sarcopenia: Results from the NHANES 2011-2018 and bidirectional Mendelian randomization study.

BACKGROUND: The relationship between serum lipids and sarcopenia remains unclear due to conflicting results in previous studies. OBJECTIVE: To explore the associations and potential causality between serum lipids, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and total cholesterol (TC), and sarcopenia. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) were analysed using multivariable regression and restricted cubic splines (RCSs) to assess the associations between serum lipids and sarcopenia. Bidirectional Mendelian randomization (MR) was employed to investigate the causal relationships with sarcopenia-related traits such as appendicular lean mass (ALM), hand grip strength, and usual walking pace. RESULTS: Serum HDL-C and TG levels were inversely associated with ALMBMI, with each 1-unit increase linked to a 0.13 % and 1.32 % decrease, respectively. Elevated TG, but not HDL-C, LDL-C, or TC levels, was significantly associated with an increased risk of sarcopenia (P for trend = 0.001). RCS analysis revealed a log-shaped dose-response relationship between TG and sarcopenia risk (P overall <0.001, P non-linear <0.001), with a cutoff value of 92.75 mg/dL. Genetically predicted HDL-C, LDL-C, and TG were associated with ALM. Conversely, ALM showed an inverse causal relationship with all four serum lipids. Additionally, genetically predicted usual walking pace influenced HDL-C and TG levels (P < 0.001). CONCLUSION: The study reveals a nonlinear association between TG levels and sarcopenia risk, and a bidirectional association between lipid profiles and muscle mass, underscoring the need for further research to elucidate these mechanisms.

Enhanced non-viral gene delivery via calcium phosphate/DNA co-precipitates with low-voltage pulse electroporation in NK-92 cells for immunocellular therapy.

Achieving high cell transfection efficiency is essential for various cell types in numerous disease applications. However, the efficient introduction of genes into natural killer (NK) cells remains a challenge. In this study, we proposed a design strategy for delivering exogenous genes into the NK cell line, NK-92, using a modified non-viral gene transfection method. Calcium phosphate/DNA nanoparticles (pDNA-CaP NPs) were prepared using co-precipitation methods and combined with low-voltage pulse electroporation to facilitate NK-92 transfection. The results demonstrated that the developed pDNA-CaP NPs exhibited a uniform diameter of approximately 393.9 nm, a DNA entrapment efficiency of 65.8%, and a loading capacity of 15.9%. Furthermore, at three days post-transfection, both the transfection efficiency and cell viability of NK-92 were significantly improved compared to standalone plasmid DNA (pDNA) electroporation or solely relying on the endocytosis pathway of pDNA-CaP NPs. This study provides valuable insights into a novel approach that combines calcium phosphate nanoparticles with low-voltage electroporation for gene delivery into NK-92 cells, offering potential advancements in cell therapy.

Study on the Influences of Inter-Governmental Information Flow and Interdepartmental Collaborative Supervision on Pork Quality: A Case Study in China.

To study the influences of the degree of interdepartmental collaborative supervision on the behavioral strategy selection of pig farmers, pig slaughterers, and pork processing manufacturers in the pork supply chain system, this study established a three-party evolutionary game model involving pig farmers, pig slaughterers, and pork processing manufacturers based on the social co-governance framework by focusing on the interdepartmental information sharing mechanism and cooperative governance. Here, we examined how the degree of collaborative supervision among government departments influences the behavioral strategy selection of these parties by focusing on key mechanisms such as information sharing and interdepartmental collaborative governance. Our findings revealed that within a social co-governance system, the strategic choices of the three entities in the pork supply chain closely correlate with the coordination level of collaborative supervision among government departments, particularly through information-sharing mechanisms. Additionally, the strategies are influenced by market-based contract supervision among entities, consumer reporting intensity, and the collaborative governance capabilities of the government, market actors, and consumers. Higher levels of social co-governance are associated with fewer risky links in the pork supply chain and reduced overall risk. Key factors affecting the behavioral strategy selection of the subjects in the pork supply chain include interdepartmental collaborative governance among government departments (e.g., optimizing random inspection frequencies, adjusting economic penalties, and disclosing enterprise market credit information via information sharing mechanisms), consumer complaint probabilities, and the intensity of mutual supervision among enterprises. Therefore, to enhance pork supply chain quality and mitigate risks, it is crucial to enhance the coordination of collaborative supervision among government departments, encourage consumer reporting, and improve market-based mutual supervision mechanisms among upstream and downstream subjects in the supply chain.

Ex-vivo Liver Resection and Autotransplantation for Liver Malignancy: A Large Volume Retrospective Clinical Study.

OBJECTIVE: To assess the effectiveness of optimized ex-vivo liver resection and autotransplantation (ELRA) for treating liver malignancies. SUMMARY BACKGROUND DATA: ELRA is a promising surgery for radical resection of conventionally unresectable tumors, despite the disappointing long-term prognosis during its' developmental stages. A recent multicenter study reported 5-year overall and disease-free survival rates (OS, DFS) of 28% and 20.8%, respectively. METHODS: We retrospectively analyzed data of patients who underwent ELRA for advanced liver cancers between 2009 and 2022. We applied ELRA via our novel surgical indication classification system where the surgical risk with curative intent for advanced liver malignancy was controllable using the ex-vivo approach. The ELRA was optimized for determinacy, predictability, and controllability via the precision liver surgery paradigm (PLS). RESULTS: Thirty-seven cases with liver malignancies were enrolled. The operative time and anhepatic phase duration were 649.6±200.0 and 261.2±74.5 min, respectively, while the intraoperative blood loss was 1902±1192 mL. Negative resection margins were achieved in all patients, and the 90-day morbidity at Clavien-Dindo IIIa/IIIb and mortality rates were 27.0% and 24.3%. Post-ELRA 1-, 3-, and 5-year actual OS rates were 62.2%, 37.8%, and 35.1%, respectively, and 1-, 3-, and 5-year actual DFS were 43.2%, 24.3%, and 18.9%, respectively. CONCLUSIONS: Long-term outcomes of ELRA under the PLS for advanced liver malignancy were favorable. Appropriate criteria for disease selection & surgical indications and optimized procedures together can improve surgical treatment and patient prognosis.

Cardiac magnetic resonance imaging for discrimination of hypertensive heart disease and hypertrophic cardiomyopathy: a systematic review and meta-analysis.

Introduction: Differentiating hypertensive heart disease (HHD) from hypertrophic cardiomyopathy (HCM) is crucial yet challenging due to overlapping clinical and morphological features. Recent studies have explored the use of various cardiac magnetic resonance (CMR) parameters to distinguish between these conditions, but findings have remained inconclusive. This study aims to identify which CMR parameters effectively discriminate between HHD and HCM and to investigate their underlying pathophysiological mechanisms through a meta-analysis. Methods: The researchers conducted a systematic and comprehensive search for all studies that used CMR to discriminate between HHD and HCM and calculated the Hedges'g effect size for each of the included studies, which were then pooled using a random-effects model and tested for the effects of potential influencing variables through subgroup and regression analyses. Results: In this review, 26 studies encompassing 1,349 HHD and 1,581 HCM cases were included for meta-analysis. Analysis revealed that HHD showed a significant lower in T1 mapping (g = -0.469, P < 0.001), extracellular volume (g = -0.417, P = 0.024), left ventricular mass index (g = -0.437, P < 0.001), and maximal left ventricular wall thickness (g = -2.076, P < 0.001), alongside a significant higher in end-systolic volume index (g = 0.993, P < 0.001) and end-diastolic volume index (g = 0.553, P < 0.001), compared to HCM. Conclusion: This study clearly demonstrates that CMR parameters can effectively differentiate between HHD and HCM. HHD is characterized by significantly lower diffuse interstitial fibrosis and myocardial hypertrophy, along with better-preserved diastolic function but lower systolic function, compared to HCM. The findings highlight the need for standardized CMR protocols, considering the significant influence of MRI machine vendors, post-processing software, and study regions on diagnostic parameters. These insights are crucial for improving diagnostic accuracy and optimizing treatment strategies for patients with HHD and HCM. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023470557, PROSPERO (CRD42023470557).

Screening chondrocyte necroptosis-related genes in the diagnosis and treatment of osteoarthritis.

Background: Osteoarthritis (OA) is the most common form of joint diseases, with hallmark of cartilage degeneration. Recent studies have shown that the pathogenesis of OA is associated with chondrocyte necroptosis. Methods: In this study, we used single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data to analyze necroptosis regulation in OA chondrocytes. We performed enrichment analysis, carried out experimental validation, constructed machine learning models, and docked drug molecules. Results: After least absolute shrinkage and selection operator (LASSO) algorithm screening, 4 hub genes (RIPK3, CYBB, HSP90AB1, and TRAF5) with diagnostic characteristics were obtained. Following the comparison of multiple models, the Bayesian model with an average area under curve (AUC) value of 0.944 was finally selected. We found that nimesulide exhibited strong binding affinity to CYBB and HSP90AB1, and experimentally verified that nimesulide reduced the expression of RIPK3 and CYBB, suggesting its potential as an inhibitor of chondrocyte necroptosis. Furthermore, scRNA-seq results showed that necroptosis in OA was significantly upregulated on regulatory chondrocytes (RegC) compared to other chondrocyte subtypes. Conclusions: The results indicate that nimesulide might be used to treat OA by inhibiting chondrocyte necroptosis through down-regulation of RIK3 and CYBB genes. This study reveals the role of chondrocyte necroptosis in OA, and suggests a potential therapeutic strategy by regulating necroptosis with nimesulide.

Clinical significance of modified unilateral puncture percutaneous vertebroplasty guided by 3D- printed guides in the treatment of osteoporotic vertebral compression fractures: a retrospective study.

OBJECTIVE: To investigate the clinical significance of using 3D printing guides in modified unilateral puncture percutaneous vertebroplasty (PVP) for the treatment of osteoporotic vertebral compression fractures (OVCF), and to explore a new method for preventing paravertebral vein leakage during PVP in conjunction with a previous study of the optimal puncture-side bone cement/vertebral volume ratio(PSBCV/VV%). METHODS: This retrospective study analyzed 99 patients who underwent unilateral puncture PVP between January 2023 and December 2023. Patients were divided into a guide plate group (46 patients) and a conventional group (53 patients). The guide plate group underwent modified unilateral puncture PVP with the guidance of 3D printing guides, while the conventional group underwent unilateral puncture PVP using the conventional pedicle approach. The distribution of bone cement, surgical outcomes, and the occurrence of cement leakage into paravertebral veins were observed in both groups. RESULTS: The guide plate group had significantly shorter operating time and required fewer fluoroscopies compared to the conventional group. The amount of bone cement volume (BCV) used in the guide plate group was higher, but the amount of bone cement volume on the puncture side(PSBCV), the PSBCV/VV%, and the rate of paravertebral vein leakage were lower in the guide plate group compared to the conventional group (P < 0.05). Within each group, significant improvements in anterior vertebral margin height, Cobb angle, visual analog scale (VAS) score, and Oswestry Disability Index (ODI) were observed at 1 day and 1 month postoperatively compared to preoperative values (P < 0.05). CONCLUSION: Using 3D printing guides in modified unilateral puncture PVP is a safe and effective method for treating OVCF. And it has the advantages of short operation time, less fluoroscopy, even distribution of bone cement, and a low rate of paravertebral vein leakage.

Effect of depression and the antidepressant fluoxetine on osseointegration-A pre-clinical in vivo experimental study.

OBJECTIVE: The aim of this study was to explore the effect of depression and selective serotonin reuptake inhibitors on implant osseointegration and bone healing. METHODS: Forty-eight 6- to 8-week-old SPF Sprague-Dawley male rats were randomly divided into four groups: the Control group, the Fluoxetine group, the Depression group and the De&Flu group. The rats in the Depression group and the De&Flu group were subjected to a depression modelling process, and the rats in the Control group and the Fluoxetine group were raised normally. Then, a titanium implant was placed in the right tibia of each rat. In the Fluoxetine group and De&Flu group, fluoxetine was injected subcutaneously daily, while subcutaneously injecting physiological saline in the Control group and Depression group. Collecting serum from the rats used for ELISA. The surgical area was cut for microcomputed tomography and histology observation. RESULTS: After 12 weeks, bone mineral density was lower in the De&Flu group than in the Control group, Depression group and Fluoxetine group. Bone mineral density was also lower in the Depression group and the Fluoxetine group than in the Control group. The percentage of bone-implant contact (BIC%) in De&Flu rats was lower than in the Control, Depression and Fluoxetine groups. The BIC% in the Depression group and the Fluoxetine group was lower than in the Control group. CONCLUSIONS: Depression and fluoxetine negatively affect bone density and implant osseointegration independently, and this damaging effect is exacerbated when both factors are present. The mechanism may be related to the dysregulation of the hypothalamic-pituitary-adrenal axis and inflammation in the body.

New therapeutic target NCF1-directed multi-bioactive conjugate therapies prevent preterm birth and adverse pregnancy outcomes.

Preterm birth (PTB) is a leading cause of neonatal morbidity and mortality worldwide, yet the cellular and molecular mechanisms driving this condition remain undeciphered, thus limiting discovery of new therapies. In-depth analyses of human and mouse tissues associated with PTB, in combination with cellular studies, indicated that aberrantly high-expressed neutrophil cytoplasmic factor (NCF) 1 leads to oxidative distress, recruitment, and pro-inflammatory activation of neutrophils and macrophages, while sequentially overexpressed pro-inflammatory mediators induce contractions of uterine smooth muscle cells (USMCs) as well as apoptosis of USMCs and amniotic epithelial cells, thereby causing PTB. According to these new findings, we rationally engineered an amphiphilic macromolecular conjugate LPA by covalently integrating low-molecular-weight heparin, a reactive oxygen species-responsive/scavenging component, and an anti-inflammatory peptide. This bioengineered macromolecular conjugate can self-assemble into multi-bioactive nanoparticles (LPA NP). In a mouse model of PTB, LPA NP effectively delayed PTB and inhibited adverse pregnancy outcomes, by regulating NCF1-mediated oxidative-inflammatory cascades, i.e., attenuating oxidative stress, inhibiting inflammatory cell activation, reducing local inflammation, and decreasing contraction/apoptosis of myometrial cells. Packaging LPA NP into temperature-responsive, self-healing, and bioadhesive hydrogel further potentiated its in vivo efficacies after intravaginal delivery, by prolonging retention time, sustaining nanotherapy release, and increasing bioavailability in the placenta/uterus. Importantly, both the conjugate/nanotherapy and hydrogel formulations exhibited excellent safety profiles in pregnant mice, with negligible side effects on the mother and offspring.

An Osteoimmunomodulatory Biopatch Potentiates Stem Cell Therapies for Bone Regeneration by Simultaneously Regulating IL-17/Ferroptosis Signaling Pathways.

Currently, there are still great challenges in promoting bone defect healing, a common health problem affecting millions of people. Herein an osteoimmunity-regulating biopatch capable of promoting stem cell-based therapies for bone regeneration is developed. A totally biodegradable conjugate is first synthesized, which can self-assemble into bioactive nano micelles (PPT NMs). This nanotherapy effectively improves the osteogenesis of periodontal ligament stem cells (PDLSCs) under pathological conditions, by simultaneously regulating IL-17 signaling and ferroptosis pathways. Incorporation of PPT NMs into biodegradable electrospun nanofibers affords a bioactive patch, which notably improves bone formation in two rat bone defect models. A Janus bio patch is then engineered by integrating the bioactive patch with a stem cell sheet of PDLSCs. The obtained biopatch shows additionally potentiated bone regeneration capacity, by synergistically regulating osteoimmune microenvironment and facilitating stem cell differentiation. Further surface functionalization of the biopatch with tannic acid considerably increases its adhesion to the bone defect, prolongs local retention, and sustains bioactivities, thereby offering much better repair effects in rats with mandibular or cranial bone defects. Moreover, the engineered bioactive patches display good safety. Besides bone defects, this osteoimmunity-regulating biopatch strategy can be applied to promote stem cell therapies for spinal cord injury, wound healing, and skin burns.