Magnetic Resonance Imaging of Fibroblast Activation Protein Using a Targeted Gadolinium-Based Contrast Agent.

The aim of this study was to synthesize a quinoline-based MRI contrast agent, Gd-DOTA-FAPI04, and assess its capacity for targeting fibroblast activation protein (FAP)-positive tumors in vivo. Gd-DOTA-FAPI04 was synthesized by attaching a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complex of gadolinium(III) to FAP inhibitor FAPI04. The longitudinal relaxation time (T1) of the contrast agent was measured using a Siemens Prisma 3.0T MR system, and the CCK-8 assay was performed to evaluate its potential cytotoxicity. Male nude mice bearing tumors grown from FAP-expressing fibrosarcoma cells were divided into experimental (n = 4) and control (n = 4) groups, and T1-weighted image enhancement was measured at different times (0, 10, 30, 60, 90, and 120 min) postinjection of Gd-DOTA-FAPI04. The control group received an additional preinjection of excess FAPI04. FAP expression in tumor tissue was investigated by using immunohistochemistry with an anti-FAP antibody. The longitudinal relaxivities of gadodiamide and Gd-DOTA-FAPI04 were measured to be 3.734 mM-1 s-1 and 5.323 mM-1 s-1, respectively. The CCK-8 assay demonstrated that Gd-DOTA-FAPI04 has minimal toxicity to cultured human fibrosarcoma cells. In vivo MRI showed that peak accumulation of Gd-DOTA-FAPI04 in FAP-expressing tumors occurred 1 h postinjection and could be blocked by preinjection of excess FAPI04. Immunohistochemical analysis of harvested tumor tissue supported the above findings. Gd-DOTA-FAPI04 is a promising contrast agent for in vivo imaging of FAP.

Water isotope ratios reflect convection intensity rather than rain type proportions in the pantropics.

Against the traditional view, a recently published theory argued that isotope ratios are higher in convective precipitation but lower in stratiform precipitation and proposed that isotope ratios reflect rain type proportions. This theory has been widely cited despite some early reservations. Whether the theory represents a faithful reflection of signals of water isotope ratios remains unclear. Here, we reassess its validity from different timescales and broader observations from the pantropics. Unexpectedly, our findings contradict the theory on daily, monthly, and even annual timescales. Pantropical precipitation isotope ratios remain strongly correlated to convection intensity but are independent of rain type proportions because stratiform precipitation isotope ratios cover a large range of values. We find that the theory has many serious weaknesses related to preferential data selection and suggest that new theories need to be validated at more locations on different timescales before gaining widespread acceptance.

A bibliometric analysis of global research on microbial immune microenvironment in melanoma from 2012 to 2022.

BACKGROUND: Melanoma is an aggressive malignancy primarily impacting the skin, mucous membranes, and pigment epithelium. The tumor microbial microenvironment encompasses both the microorganisms inhabiting the tumor vicinity and the environmental factors influencing their interactions. Emerging evidence highlights the pivotal role of the microbial immune microenvironment in melanoma. METHODS: We conducted an extensive review of scholarly works published from 2012 to 2022, utilizing The Web of Science Core Collection. Subsequently, we employed analytical tools such as VOSviewer, CiteSpace, and the R programming language to scrutinize prevailing research patterns within this domain. RESULTS: A sum of 513 articles were pinpointed, with notable input coming from the United States and China. Harvard University stood out as the top-contributing institution, while the journal Science received the most citations. Current research within this sphere chiefly focuses on two principal domains: the gut microbiota and the PD-L1 pathway concerning melanoma treatment. CONCLUSION: The study offers an extensive analysis and overview of the worldwide research landscape concerning the immune microenvironment with a focus on microbes in melanoma. It underscores the promising prospects for harnessing the microbial immune microenvironment's potential in melanoma. These findings furnish valuable insights and guidance for advancing scientific inquiry and refining clinical approaches within this dynamic field.

Osteoarthritis, osteoarthritis treatment and risk of incident dementia: a prospective cohort study based on UK Biobank.

BACKGROUND: We aimed to investigate the association between OA and treatment with dementia risk and structural brain abnormalities. METHODS: We recruited a total of 466,460 individuals from the UK Biobank to investigate the impact of OA on the incidence of dementia. Among the total population, there were 63,081 participants diagnosed with OA. We subsequently categorised the OA patients into medication and surgery groups based on treatment routes. Cox regression models explored the associations between OA/OA treatment and dementia risk, with the results represented as hazard ratios (HRs) and 95% confidence intervals (95% CI). Linear regression models assessed the associations of OA/OA therapy with alterations in cortical structure. RESULTS: During an average of 11.90 (± 1.01) years of follow-up, 5,627 individuals were diagnosed with all-cause dementia (ACD), including 2,438 AD (Alzheimer's disease), and 1,312 VaD (vascular dementia) cases. Results revealed that OA was associated with the elevated risk of ACD (HR: 1.116; 95% CI: 1.039-1.199) and AD (HR: 1.127; 95% CI: 1.013-1.254). OA therapy lowered the risk of dementia in both medication group (HR: 0.746; 95% CI: 0.652-0.854) and surgery group (HR: 0.841; 95% CI: 0.736-0.960). OA was negatively associated with cortical area, especially precentral, postcentral and temporal regions. CONCLUSIONS: Osteoarthritis increased the likelihood of developing dementia, and had an association with regional brain atrophy. OA treatment lowered the dementia risk. OA is a promising modifiable risk factor for dementia.

Effect of long snake moxibustion on gut microbiota of patients with ankylosing spondylitis.

OBJECTIVE: To study the effect of long snake moxibustion intervention on gut microbiota of patients with ankylosing spondylitis (AS) by 16S rDNA sequencing technology. METHODS: 30 AS patients and 30 healthy volunteers were recruited and treated with long snake moxibustion once a week for 12 weeks. AS patients were divided into pre-treatment and post-treatment groups. VAS, BASDAI and BASFI scores of AS patients before and after treatment were collected. 16S rDNA high-throughput sequencing technology was used to analyze the characteristics and differences of gut microbiota in AS patients before and after treatment and in healthy volunteers. RESULTS: VAS, BASDAI and BASFI scores of AS patients after long snake moxibustion treatment were lower than those of pre-treatment group (P<0.05). The results of gut microbiota Alpha diversity showed that ace and chao1 index of the post-treatment group were higher than those of the healthy group (P<0.05), but there was no statistical significance in ace and chao1 index between the pre-treatment group and the post-treatment group (P>0.05). Beta diversity analysis showed that mild classification aggregation occurred between the healthy group and the pre-treatment group , but did not reach a significant level, and there was no significant difference between the the pre-treatment group and the post-treatment group. The results of species abundance showed that, at the phylum level, compared with the healthy group, the relative abundance of Firmicutes and Proteobacteria decreased in the pre-treatment group, while the relative abundance of Bacteroidetes and Actinobacteria increased. Compared with the pre-treatment group, the relative abundance of Firmicutes increased and the relative abundance of Actinobacteria decreased in the post-treatment group, but there were no statistically significant differences in the above changes (P>0.05). At the genus level, compared with the healthy group, the relative abundances of Subdoligranulum in the pre-treatment group were increased (P<0.05), while the relative abundances of Bifidobacterium and Streptococcus were decreased (P<0.05). Compared with the pre-treatment group, the relative abundance of Romboutsia in the post-treatment group was increased (P<0.05). CONCLUSION: Long snake moxibustion can obviously improve the clinical symptoms of AS patients. The possible mechanism of action is related to regulating the abundance of gut microbiota, increasing beneficial bacteria and restoring the homeostasis of gut microorganisms.

The establishment and severity assessment of ultrasound-guided prenatal bronchopulmonary dysplasia model in rat.

To study a new method for establishing animal models of prenatal bronchopulmonary dysplasia (BPD), we used lung ultrasound score (LUS) to semi-quantitatively assess the severity of lung lesions in model rats. Lipopolysaccharide (LPS) was injected into the right lung of the fetus of the rat under ultrasound-guided, and the right lung of the neonates were scanning for LUS. Specimens were collected for pathological scoring and detection of pulmonary surfactant-associated glycoprotein (SP)-C and vascular endothelial growth factor (VEGF) expression quantity. The correlation between LUS and pathological scores was analyzed. (1) The animal models were consistent with the pathological manifestations of BPD. (2) It showed a strong positive correlation between LUS and pathological scores in animal models (r = 0.84, P < 0.005), and the expression quantity of SP-C and VEGF in lung tissue were decreased (both P < 0.05). Animal models established by ultrasound-guided puncture of the lung of rats and injection of LPS were consistent with the manifestation of BPD. This method could be used to establish animal models of BPD before birth, and the severity of BPD could be assessed by using LUS.

Multi-modal Ca2+ nanogenerator via reversing T cell exhaustion for enhanced chemo-immunotherapy.

Chemo-immunotherapy holds the advantage of specific antitumor effects by activating cytotoxic lymphocyte cells (CTLs) immune response. However, multiple barriers have limited the outcomes partly due to tumor-cell-mediated exhaustion of CTLs in the immunosuppressive tumor microenvironment (iTME). Here, we rationally designed a simple-yet-versatile Ca2+ nanogenerator to modulate iTME for enhancing 2-deoxyglucose (2-DG) mediated chemo-immunotherapy. Briefly, after 2-DG chemotherapy, CaO2 nanoparticles coated with EL4 cell membrane (denoted as CaNP@ECM) could preferentially accumulate in tumor tissue via adhesion between LFA-1 on EL4 cell membrane and ICAM-1 on inflamed endothelial cell in tumor tissues and display a series of benefits for CTLs: i) Increasing glucose availability of CTLs while reducing lactic acid secretion through Ca2+ overloading mediated inhibition of tumor cell glycolysis, as well as relieving hypoxia; ii) Reversing CTLs exhaustion via TGF-ß1 scavenging and PD-L1 blockade through PD-1 and TGF-ß1R on EL4 cell membrane; iii) Boosting tumor immunotherapy via immunologic death (ICD) of tumor cells induced by Ca2+ overloading. We demonstrate that the multi-modal Ca2+ nanogenerator rescues T cells from exhaustion and inhibits tumor growth both in vitro and in vivo. More importantly, the study also facilitate the development of glucose metabolism inhibition-based tumor immunotherapy via Ca2+ overloading.

Arginine-Rich Peptide-Rhodium Nanocluster@Reduced Graphene Oxide Composite as a Highly Selective and Active Uricase-like Nanozyme for the Degradation of Uric Acid and Inhibition of Urate Crystal.

Metal nanozymes have offered attractive opportunities for biocatalysis and biomedicine. However, fabricating nanozymes simultaneously possessing highly catalytic selectivity and activity remains a great challenge due to the lack of three-dimensional (3D) architecture of the catalytic pocket in natural enzymes. Here, we integrate rhodium nanocluster (RhNC), reduced graphene oxide (rGO), and protamine (PRTM, a typical arginine-rich peptide) into a composite facilely based on the single peptide. Remarkably, the PRTM-RhNC@rGO composite displays outstanding selectivity, activity, and stability for the catalytic degradation of uric acid. The reaction rate constant of the uric acid oxidation catalyzed by the PRTM-RhNC@rGO composite is about 1.88 × 10-3 s-1 (4 µg/mL), which is 37.6 times higher than that of reported RhNP (k = 5 × 10-5 s-1, 20 µg/mL). Enzyme kinetic studies reveal that the PRTM-RhNC@rGO composite exhibits a similar affinity for uric acid as natural uricase. Furthermore, the uricase-like activity of PRTM-RhNC@rGO nanozymes remains in the presence of sulfur substances and halide ions, displaying incredibly well antipoisoning abilities. The analysis of the structure-function relationship indicates the PRTM-RhNC@rGO composite features the substrate binding site near the catalytic site in a confined space contributed by 2D rGO and PRTM, resulting in the high-performance of the composite nanozyme. Based on the outstanding uricase-like activity and the interaction of PRTM and uric acid, the PRTM-RhNC@rGO composite can retard the urate crystallization significantly. The present work provides new insights into the design of metal nanozymes with suitable binding sites near catalytic sites by mimicking pocket-like structures in natural enzymes based on simple peptides, conducing to broadening the practical application of high-performance nanozymes in biomedical fields.

[Notch1/Akt/Foxo1 Pathway Regulated by Kisspeptin Is Involved in Endometrial Decidualization in Patients With Recurrent Spontaneous Abortion]. / kisspeptin调控Notch1/Akt/Foxo1é€šè·¯å‚ä¸Žå¤å‘æ€§æµäº§æ‚£è€ å­å®«å† è†œèœ•è†œåŒ–.

Objective: Kisspeptin, a protein encoded by the KISS1 gene, functions as an essential factor in suppressing tumor growth. The intricate orchestration of cellular processes such as proliferation and differentiation is governed by the Notch1/Akt/Foxo1 signaling pathway, which assumes a central role in maintaining cellular homeostasis. In the specific context of this investigation, the focal point lies in a meticulous exploration of the intricate mechanisms underlying the regulatory effect of kisspeptin on the process of endometrial decidualization. This investigation delves into the interplay between kisspeptin and the Notch1/Akt/Foxo1 signaling pathway, aiming to elucidate its significance in the pathophysiology of recurrent spontaneous abortion (RSA). Methods: We enrolled a cohort comprising 45 individuals diagnosed with RSA, who were admitted to the outpatient clinic of the Reproductive Center at the Second Affiliated Hospital of Soochow University between June 2020 and December 2020. On the other hand, an additional group of 50 women undergoing elective abortion at the outpatient clinic of the Family Planning Department during the same timeframe was also included. To comprehensively assess the molecular landscape, Western blot and RT-qPCR were performed to analyze the expression levels of kisspeptin (and its gene KISS1), IGFBP1 (an established marker of decidualization), Notch1, Akt, and Foxo1 within the decidua. Human endometrial stromal cells (hESC) were given targeted interventions, including treatment with siRNA to disrupt KISS1 or exposure to kisspeptin10 (the bioactive fragment of kisspeptin), and were subsequently designated as the siKP group or the KP10 group, respectively. A control group comprised hESC was transfected with blank siRNA, and cell proliferation was meticulously evaluated with CCK8 assay. Following in vitro induction for decidualization across the three experimental groups, immunofluorescence assay was performed to identify differences in Notch1 expression and decidualization morphology between the siKP and the KP10 groups. Furthermore, RT-qPCR and Western blot were performed to gauge the expression levels of IGFBP1, Notch1, Akt, and Foxo1 across the three cell groups. Subsequently, decidualization was induced in hESC by adding inhibitors targeting Notch1, Akt, and Foxo1. The expression profiles of the aforementioned proteins and genes in the four groups were then examined, with hESC induced for decidualization without adding inhibitors serving as the normal control group. To establish murine models of normal pregnancy (NP) and RSA, CBA/J×BALB/c and CBA/J×DBA/2 mice were used. The mice were respectively labeled as the NP model and RSA model. The experimental groups received intraperitoneal injections of kisspeptin10 and kisspeptin234 (acting as a blocker) and were designated as RSA-KP10 and NP-KP234 groups. On the other hand, the control groups received intraperitoneal injections of normal saline (NS) and were referred to as RSA-NS and NP-NS groups. Each group comprised 6 mice, and uterine tissues from embryos at 9.5 days of gestation were meticulously collected for observation of embryo absorption and examination of the expression of the aforementioned proteins and genes. Results: The analysis revealed that the expression levels of kisspeptin, IGFBP1, Notch1, Akt, and Foxo1 were significantly lower in patients diagnosed with RSA compared to those in women with NP (P<0.01 for kisspeptin and P<0.05 for IGFBP1, Notch1, Akt, and Foxo1). After the introduction of kisspeptin10 to hESC, there was an observed enhancement in decidualization capability. Subsequently, the expression levels of Notch1, Akt, and Foxo1 showed an increase, but they decreased after interference with KISS1. Through immunofluorescence analysis, it was observed that proliferative hESC displayed a slender morphology, but they transitioned to a rounder and larger morphology post-decidualization. Concurrently, the expression of Notch1 increased, suggesting enhanced decidualization upon the administration of kisspeptin10, but the expression decreased after interference with KISS1. Further experimentation involved treating hESC with inhibitors specific to Notch1, Akt, and Foxo1 separately, revealing a regulatory sequence of Notch1/Akt/Foxo1 (P<0.05). In comparison to the NS group, NP mice administered with kisspeptin234 exhibited increased fetal absorption rates (P<0.001) and decreased expression of IGFBP1, Notch1, Akt, and Foxo1 (P<0.05). Conversely, RSA mice administered with kisspeptin10 demonstrated decreased fetal absorption rates (P<0.001) and increased expression levels of the aforementioned molecules (P<0.05). Conclusion: It is suggested that kisspeptin might exert its regulatory influence on the process of decidualization through the modulation of the Notch1/Akt/Foxo1 signaling cascade. A down-regulation of the expression levels of kisspeptin could result in suboptimal decidualization, which in turn might contribute to the development or progression of RSA.

Expression and Clinical Relevance of Serum LncRNA NEAT1 and microRNA-31 in Patients with Advanced Lung Cancer and Pulmonary Infection.

Background: Lung cancer remains one of the leading causes of cancer-related mortality worldwide, with a substantial proportion of patients suffering from concurrent pulmonary infections. Despite advances in treatment modalities, the early diagnosis of lung cancer complicated by pulmonary infection remains challenging, often resulting in delayed intervention and poorer prognosis. Objective: This study aimed to investigate the expression and significance of serum long non-coding RNA (lncRNA) NEAT1 and microRNA-31 in patients with advanced lung cancer complicated by pulmonary infection. Methods: A total of 48 patients diagnosed with lung cancer complicated by pulmonary infection and admitted to the hospital between January 2021 and December 2021 constituted the experimental group, while 48 healthy volunteers recruited during the same period served as the healthy control group. The expression levels of NEAT1 and microRNA-31 in plasma samples obtained from peripheral blood were measured using quantitative real-time polymerase chain reaction (qRT-PCR), and their differential expression in plasma was compared between the two groups. Results: Significantly elevated levels of serum lncRNA NEAT1 and microRNA-31 were observed in the experimental group compared to the healthy control group. Furthermore, the expression levels of NEAT1 and microRNA-31 showed correlations with patient age and tumor size. Notably, the expression of NEAT1 exhibited no significant association with smoking status, whereas microRNA-31 expression displayed a significant relationship with smoking. Conclusions: Our findings demonstrate that lncRNA NEAT1 and microRNA-31 are markedly upregulated in the plasma of patients with advanced lung cancer complicated by pulmonary infection. These molecules hold promise as potential diagnostic markers for advanced lung cancer complicated by pulmonary infection and may provide early auxiliary diagnostic value for lung cancer.

Efficacy and safety of pyrotinib-based regimens in HER2 positive metastatic breast cancer: A retrospective real-world data study.

OBJECTIVE: Pyrotinib is a novel irreversible tyrosine kinase inhibitor that has shown efficacy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). This study explored the efficacy and safety of pyrotinib in the treatment of HER2-positive MBC patients in the real world. METHODS: From September 2018 to February 2022, 137 female patients with HER2-positive MBC treated in this center were enrolled in this study. The follow-up period ended on January 12, 2023. The primary endpoint of this study was progression-free survival (PFS). Overall survival (OS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), central nervous system (CNS)-PFS, CNS-ORR, CNS-CBR, CNS-DCR, and adverse event (AE) were the secondary endpoints. RESULTS: The ORR, DCR and CBR were 41.98 % (55/131), 87.79 % (115/131) and 44.27 % (58/131) in this cohort, respectively. The median PFS for this cohort was 10.37 months [95 % confidence interval (CI): 9.205-11.535] and the median OS was 37.53 months (not reached). Univariate and multivariate analyses showed that trastuzumab sensitivity was an independent predictor of improved PFS [hazard ratio (HR): 0.579 (0.371-0.904, p=0.016)] and improved OS [0.410 (0.213-0.790, p=0.008)]. Patients treated with a pyrotinib-based regimen as second-line and third-or-post-line therapy had poorer PFS [second-line: 3.315 (1.832-6.000, p<0.001); third-or-post-line: 3.304 (1.749-6.243, p<0.001)] and OS [second-line: 4.631 (1.033-20.771, p=0.045); third-or-post-line: 5.738 (1.212-27.174, p=0.028)]. There were 38 brain metastases (BM) patients in this study, the CNS-mPFS [14.37 months (7.815-20.925) vs. 7.83 months (7.047-8.613), p=0.375] and mOS [not reached vs. 36.40 months (18.551-54.249), p=0.034] were better in brain radiotherapy (BRT) group than NBRT group. 18.98 % (26/137) of patients experienced grade 3 or higher diarrhea. No AE-related death was reported. CONCLUSION: This study confirms the promising antitumor activity and acceptable safety of real-world pyrotinib-based regimens for the treatment of HER2-positive MBC patients, particularly those who are trastuzumab-sensitive and who are receiving pyrotinib-based regimens as advanced first-line therapy. It has also been demonstrated that these regimens combined with BRT, provide better intracranial responses and long-term survival benefits for these patients with BM.

Optimal Strategies for Autologous Fat Grafting in Breast Augmentation and Reconstruction: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Currently, cell-assisted lipotransfer (CAL) and platelet-rich plasma (PRP) -assisted lipotransfer have been used to overcome the low survival rate of conventional lipotransfer. However, there is still insufficient evidence to determine which technique is the best strategy for autologous fat grafting in breast cosmetic and reconstructive surgery. OBJECTIVE: The present study aimed to compare the efficacy of traditional fat transplantation, CAL, and PRP-assisted lipotransfer. METHODS: A systematic search was conducted in several databases including PUBMED, Web of Science, Cochrane, ClinicalTrials.gov, and EMBASE from January 21, 2024, to identify studies that met the inclusion criteria. Twelve studies were included after a rigorous selection process based on predefined criteria. Statistical analyses were conducted using R Ver. 4.0.5 with the netmeta and dmetar packages, employing a frequentist approach with a random-effects model. A network meta-analysis was performed to compare different fat graft procedures regarding fat survival rate and complication events. The review protocol was prospectively registered in PROSPERO (CRD42024501780). RESULTS: The results indicate that CAL and PRP-assisted lipotransfer are better than traditional fat grafts in terms of fat survival rate. And there is no significant difference in the incidence of postoperative complications between the CAL group, PRP group, and traditional group. CONCLUSION: Based on the results of network meta-analysis, it appears that both CAL and PRP-assisted lipotransfer have a higher fat survival rate for autologous fat grafting in breast augmentation and reconstruction. However, the transplantation strategy still needs to be analyzed based on actual conditions in clinical applications.

Cardiac vagal activity changes moderated the association of cognitive and cerebral hemodynamic variations in the prefrontal cortex.

Phasic cardiac vagal activity (CVA), reflecting ongoing, moment-to-moment psychophysiological adaptations to environmental changes, can serve as a predictor of individual difference in executive function, particularly executive performance. However, the relationship between phasic CVA and executive function demands requires further validation because of previous inconsistent findings. Moreover, it remains unclear what types of phasic changes of CVA may be adaptive in response to heightened executive demands. This study used the standard N-back task to induce different levels of working memory (WM) load and combined functional Near-Infrared Spectroscopy (fNIRS) with a multipurpose polygraph to investigate the variations of CVA and its interactions with cognitive and prefrontal responses as executive demands increased in fifty-two healthy young subjects. Our results showed phasic decreases in CVA as WM load increased (t (51) = -3.758, p < 0.001, Cohen's d = 0.526). Furthermore, phasic changes of CVA elicited by increased executive demands moderated the association of cognitive and cerebral hemodynamic variations in the prefrontal cortex (B = 0.038, SE = 0.014, p < 0.05). Specifically, as executive demands increased, individuals with larger phasic CVA withdrawal showed a positive relationship between cognitive and hemodynamic variations in the prefrontal cortex (ß = 0.281, p = 0.031). No such significant relationship was observed in individuals with smaller phasic CVA withdrawal. The current findings demonstrate a decrease in CVA with increasing executive demands and provide empirical support for the notion that a larger phasic CVA withdrawal can be considered adaptive in situations requiring high executive function demands.

Shared and distinctive brain networks underlying trait and state rumination.

Although trait and state rumination play a central role in the exacerbation of negative affect, evidence suggests that they are weakly correlated and exert distinct influences on emotional reactivity to stressors. Whether trait and state rumination share a common or exhibit distinct neural substrate remains unclear. In this study, we utilized functional near-infrared spectroscopy (fNIRS) combined with connectome-based predictive modeling (CPM) to identify neural fingerprints associated with trait and state rumination. CPM identified distinctive functional connectivity (FC) profiles that contribute to the prediction of trait rumination, primarily involving FC within the default mode network (DMN) and the dorsal attention network (DAN) as well as FC between the DMN, control network (CN), DAN, and salience network (SN). Conversely, state rumination was predominantly associated with FC between the DMN and CN. Furthermore, the predictive features of trait rumination can be robustly generalized to predict state rumination, and vice versa. In conclusion, this study illuminates the importance of both DMN and non-DMN systems in the emergence and persistence of rumination. While trait rumination was associated with stronger and broader FC than state rumination, the generalizability of the predictive features underscores the presence of shared neural mechanisms between the two forms of rumination. These identified connectivity fingerprints may hold promise as targets for innovative therapeutic interventions aimed at mitigating rumination-related negative affect.

Improving Antibiotic Stewardship in a Pediatric Long-term Care Facility.

OBJECTIVES: Antimicrobial stewardship is little studied in pediatric long-term care facilities. We sought to determine whether empirical ciprofloxacin for febrile respiratory illnesses could be safely reduced in our pediatric long-term care facility. METHODS: All patients living in the 45-bed facility were included. A 1-year educational intervention for antimicrobial stewardship was implemented. Days of ciprofloxacin therapy, infections, microbiology, hospitalizations, other antibiotic use, methicillin-resistant Staphylococcus aureus and Clostridioides difficile infections, and mortality were recorded at regular intervals retrospectively from 5 years before intervention and prospectively for 8 years after intervention. Data were analyzed using statistical process control charts. RESULTS: A majority of patients had tracheostomy tubes (96%) and ventilator dependence (58%). Ciprofloxacin use declined by 76% (17 to 4 days/1000 facility patient days). Antibiotic prescriptions for bacterial tracheitis decreased by 89% (38 to 4 courses per 6-month period). No increases in positive blood or urine cultures, hospitalizations, or need for hospital antibiotics were observed. CONCLUSIONS: An antimicrobial stewardship intervention in a pediatric long-term care facility led to decreases in ciprofloxacin use, bacterial tracheitis diagnoses, and overall antibiotic use without increasing negative outcomes.

Exploring the landscape of extracellular vesicle application for skin and plastic surgery: A bibliometric analysis from 2003 to 2023.

BACKGROUND: Exosomes and other secretory membrane vesicles, collectively referred to as extracellular vesicles (EVs), have garnered increasing attention in research due to their biological characteristics. Notably, studies have shown promising results regarding the role of stem cell-derived extracellular vesicles (SC-EVs) in skin and plastic surgery applications. This study aims to elucidate current trends in SC-EVs within the context of skin and plastic surgery and offer insights for future research directions in advancing this critical field. METHODS: A comprehensive search was conducted for relevant studies on SC-EVs in skin and plastic surgery spanning from 2003 to 2023, utilizing the Web of Science database. Subsequently, data analysis was performed using VOSviewer and CiteSpace. RESULTS: A total of 1089 studies were identified, with a noticeable annual increase in publications on SC-EVs' application in skin and plastic surgery. China emerged as the leading contributor to this field, with Shanghai Jiao Tong University being a notable institution. Stem Cell Research & Therapy and the International Journal of Molecular Sciences were the top journals publishing relevant articles. Author Fu Xiaobing from the Chinese People's Liberation Army General Hospital had the highest publication count in this area. Keyword co-occurrence analysis revealed six distinct clusters, with "exosomes" being the most prevalent keyword in recent years. Wound healing and skin rejuvenation emerged as primary research focuses and hotspots in this field. CONCLUSION: This comprehensive review offers insights into global trends surrounding SC-EVs in skin and plastic surgery. Analysis of journals, institutions, references, and keywords provides valuable guidance for researchers in determining future research directions.

Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

First-line hepatic arterial infusion chemotherapy plus lenvatinib and PD-(L)1 inhibitors versus systemic chemotherapy alone or with PD-(L)1 inhibitors in unresectable intrahepatic cholangiocarcinoma.

PURPOSE: Limited treatment options exist for unresectable intrahepatic cholangiocarcinoma (ICC), with systemic chemotherapy (SC) serving as the primary approach. This study aimed to assess the effectiveness of first-line hepatic arterial infusion chemotherapy (HAIC) in combination with lenvatinib and PD-(L)1 inhibitors (HLP) compared to SC combined with PD-(L)1 inhibitors (SCP) or SC alone in treating unresectable ICC. METHODS: Patient with unresectable ICC who underwent first-line treatment with HLP, SCP or SC from January 2016 to December 2022 were retrospectively analyzed. The study evaluated and compared efficacy and safety outcomes across the three treatment groups. RESULTS: The study comprised 42, 49, and 50 patients in the HLP, SCP, and SC groups, respectively. Median progression-free survival (PFS) times were 30.0, 10.2, and 6.5 months for HLP, SCP, and SC groups. While the SC group had a median overall survival (OS) time of 21.8 months, the HLP and SCP groups hadn't reached median OS. The HLP group demonstrated significantly superior PFS (p < 0.001) and OS (p = 0.014) compared to the others. Moreover, the HLP group exhibited the highest objective response rate (ORR) at 50.0% and the highest disease control rate (DCR) at 88.1%, surpassing the SC group (ORR, 6.0%; DCR, 52.0%) and SCP group (ORR, 18.4%; DCR, 73.5%) (p < 0.05). Generally, the HLP group reported fewer grades 3-4 adverse events (AEs) compared with others. CONCLUSION: In contrast to systemic chemotherapy with or without PD-(L)1 inhibitors, the triple combination therapy incorporating HAIC, lenvatinib, and PD-(L)1 inhibitors showcased favorable survival benefits and manageable adverse events for unresectable ICC.

Molecular mechanisms of gut microbiota in diabetic nephropathy.

Diabetic nephropathy is a common complication of diabetes and a considerable contributor to end-stage renal disease. Evidence indicates that glucose dysregulation and lipid metabolism comprise a pivotal pathogenic mechanism in diabetic nephropathy. However, current treatment outcomes are limited, as they only provide symptomatic relief without preventing disease progression. The gut microbiota is a group of microorganisms that inhabit the human intestinal tract and play a crucial role in maintaining host energy balance, metabolism, and immune activity. Patients with diabetic nephropathy exhibit altered gut microbiota, suggesting its potential involvement in the onset and progression of the disease. However, how a perturbed microbiota induces and promotes diabetic nephropathy remains unelucidated. This article summarizes the evidence of the impact of gut microbiota on the progression of diabetic nephropathy, with a particular focus on the molecular mechanisms involved, aiming to provide new insights into the treatment of diabetic nephropathy.

RSAD2, a pyroptosis-related gene, predicts the prognosis and immunotherapy response for colorectal cancer.

Colorectal cancer (CRC) is among the most prevalent malignant tumors, known for its high heterogeneity. Although many treatments and medications are available, the long-term survival rate of CRC patients is far from satisfactory. Pyroptosis is closely related to tumor progression. This study aimed to identify pyroptosis-related genes (PRGs) and candidate biomarkers to predict the prognosis of CRC patients. Used bioinformatics, we identified PRGs and subsequently screened 288 co-expression genes between pyroptosis-related modules and differentially expressed genes in CRC. Among these hub genes, we selected the top 24 for further analysis and found that Radical S-Adenosyl Methionine Domain Containing 2 (RSAD2) was a novel biomarker associated with the progression of CRC. We developed a risk model for RSAD2, which proved to be an independent prognostic indicator. The receiver operator characteristic analysis showed that the model had an acceptable prognostic value for patients with CRC. In addition, RSAD2 also affects the tumor immune microenvironment and prognosis of CRC. We further validated RSAD2 expression in CRC patients using RT-qPCR and the role of RSAD2 in pyroptosis. Taken together, this study comprehensively assessed the expression and prognostic value of RSAD2 in patients with CRC. These findings may offer a new direction for early CRC screening and development of future immunotherapy strategies.