Unlocking the anticancer activity of gambogic acid: a shift towards ferroptosis via a GSH/Trx dual antioxidant system.

Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in ferroptosis by regulating the cellular antioxidant response and maintaining redox balance. However, compounds that induce ferroptosis through dual antioxidant pathways based on Nrf2 have not been fully explored. In our study, we investigated the impact of Gambogic acid (GA) on MCF-7 cells and HepG2 cells in vitro. The cytotoxicity, colony formation assay and cell cycle assay demonstrated potent tumor-killing ability of GA, while its effect was rescued by ferroptosis inhibitors. Furthermore, RNA sequencing revealed the enrichment of ferroptosis pathway mediated by GA. In terms of ferroptosis indicators detection, evidences for GA were provided including reactive oxygen species (ROS) accumulation, alteration in mitochondrial membrane potential (MMP), disappearance of mitochondrial cristae, lipid peroxidation induction, malondialdehyde (MDA) accumulation promotion, iron ion accumulation as well as glutathione (GSH)/thioredoxin (Trx) depletion. Notably, Ferrostatin-1 (Fer-1) and Liproxstatin-1 (Lip-1) successfully rescued GA-induced MDA accumulation. In terms of mechanism, Nrf2 was found to play a pivotal role in GA-induced ferroptosis by inducing protein alterations through the iron metabolism pathway and GSH/Trx dual antioxidant pathway. Furthermore, GA exerted good antitumor activity in vivo through GSH/Trx dual antioxidant pathway, and Fer-1 significantly attenuated its efficacy. In conclusion, our findings first provided new evidence for GA as an inducer of ferroptosis, and Nrf2-mediated GSH/Trx dual antioxidant system played an important role in GA-induced ferroptosis.

Vascular Endothelial Growth Factor and Ischemic Stroke Risk: A Mendelian Randomization Study.

INTRODUCTION: Previous studies have reported controversial relationships between circulating vascular endothelial growth factors (VEGF) and ischemic stroke (IS). This study aims to demonstrate the causal effect between VEGF and IS using Mendelian randomization (MR). METHODS: Summary statistics data from two large-scale genome-wide association studies (GWAS) for 16,112 patients with measured VEGF levels and 40,585 patients with IS were downloaded from public databases and included in this study. A published calculator was adopted for MR power calculation. The primary outcome was any ischemic stroke, and the secondary outcomes were large-artery stroke, cardioembolic stroke, and small-vessel stroke. We used the inverse variance-weighted (IVW) method for primary analysis, supplemented by MR-Egger regression and the weighted median method. RESULTS: Nine SNPs were included to represent serum VEGF levels. The IVW method revealed no strong causal association between VEGF and any ischemic stroke (odds ratio [OR] 1.01, 95% CI 0.99-1.04, p = 0.39), cardioembolic stroke (OR 1.04, 95% CI 0.97-1.12, p = 0.28), large-artery stroke (OR 1.02, 95% CI 0.95-1.09, p = 0.62), and small-vessel stroke (OR 0.98, 95% CI 0.91-1.04, p = 0.46). These findings remained robust in sensitivity analyses. MR-Egger regression suggested no horizontal pleiotropy. CONCLUSIONS: This Mendelian randomization study found no relationship between genetically predisposed serum VEGF levels and risks of IS or its subtypes.

Effective adsorption of As(V) from aqueous solution by quaternary ammonium and Zn2+ decorated lignin-based sorbent.

Arsenic poses a serious harm to the natural environment and human health. Lignin decorated with quaternary ammonium and metal ion can effectively adsorb arsenic from aqueous solution. Zn2+/quaternary ammonium lignin was synthesized by quaternization and metallization from lignin with 3-Chloro-2-hydroxypropyl trimethylammonium chloride and ZnCl2. The morphology, functional groups and chemical compositions of adsorbent were identified by SEM-EDS, FTIR and XRD. The effects such as pH, initial As(V) concentration, contact time and adsorbent dosage on the adsorption capacity were investigated in batch system. The adsorption mechanism was explored by SEM-EDS, FTIR and XPS. It was shown that the adsorbent was rough and contained a large amount of quaternary ammonium and Zn2+. Zn2+/quaternary ammonium lignin exhibited much strong affinity towards As(V) with the maximum adsorption capacity of 70.38 mg·g-1 at 25 °C, oscillation rate of 180 r·min-1, pH of 5, initial As(V) concentration of 100 mg·L-1, contact time of 30 min and 1 g·L-1 Zn2+/quaternary ammonium lignin. The adsorption could be well described by Langmuir model and quasi-second-order kinetic model, indicating the monolayer homogeneous chemisorption nature. As(V) was adsorbed through electrostatic attraction of Zn2+ and ion exchange between H2AsO4- and Cl-.

Corrigendum: SbWRKY75- and SbWRKY41- mediated jasmonic acid signaling regulates baicalin biosynthesis.

[This corrects the article DOI: 10.3389/fpls.2023.1213662.].

Potential of unilateral combined bypass surgery to accelerate contralateral radiological progression in pediatric moyamoya disease.

Background: Surgical cerebral revascularization is recommended for treating pediatric moyamoya disease (MMD). However, whether unilateral combined bypass surgery can cause disease progression on the contralateral side is uncertain. The study aimed to investigate the vascular architecture and regional cerebral blood flow (rCBF) status of patients with pediatric MMD after successful unilateral combined bypass surgery and to identify the possible risk factors. Methods: Pediatric patients diagnosed with MMD and admitted to Xuanwu Hospital who underwent combined bypass surgery between 2019 and 2021 were enrolled. Digital subtraction angiography (DSA) and magnetic resonance imaging (MRI) with arterial spin labeling (ASL) were performed to investigate the vascular architecture and rCBF during surgery and at short-term follow-up. Suzuki's angiographic staging and moyamoya vessel grading system were both used. Progression was defined as an increase in either Suzuki stage or moyamoya vessel grade detected after unilateral surgery. All analyses were performed with conventional statistic methods. Results: A total of 27 successive patients with a median age of 8 [interquartile range (IQR), 5-14] years old were identified. On the non-operated (non-OP) side, 11 (40.7%) patients demonstrated progression, all of whom showed an increase in the moyamoya vessel grade, and 5 also displayed Suzuki stage progression during the median 4.7 (IQR, 3.7-5.7) months follow-up. However, rCBF barely changed on the non-OP side compared to preoperation [preoperation: median, 49.6, (IQR, 42.9-61.1) mL/100 g/min; postoperation: median, 50.2, (IQR, 43.5-59.3) mL/100 g/min; P=0.445]. Conclusions: Combined bypass surgery might accelerate the radiological progression on the contralateral side, which occurs before the decline of rCBF. Those with earlier Suzuki stage MMD of the non-OP side are prone to rapid progression after unilateral combined revascularization.

Clinical Efficacy of Posteromedial Approaches for Haraguchi Type II Fracture.

Objective: This study was to analyze and compare the clinical efficacy of open reduction and internal fixation through posterolateral and the posterior medial approach to treat Haraguchi Type II posterior malleolar fracture. Methods: The clinical data of 91 patients with trimalleolar fractures sent to our hospital from January 2018 to January 2020 were analyzed.All of the patients were the result of traumatic injuries, such as sprains or car accidents. All patients were treated with open reduction and internal fixation and divided into control group and observation group according to different surgical approaches. Forty-five cases were treated with the posterolateral approach(control group) and forty-six cases treated with the posteriormedial approach(observation group) . The operation status of the two groups (operating time, intraoperative blood loss, postoperative drainage, and hospital stay), postoperative status (visual analogue scale (VAS) before the operation, 1d, 3d and 7d after operation), the score of patient's American orthopedic foot and ankle society (AOFAS) at the time of discharge, fracture healing time and full weight-bearing time), efficacy and safety were recorded. Results: All cases underwent surgery, with no significant difference in the time from fracture to surgery between the control and observation groups (P > .05). Compared to the control group, the operating time, intraoperative blood loss, postoperative drainage, and hospital stay in the observation group were significantly reduced (P < .05). One day after the operation, no significant difference was shown in VAS between 2 groups (P > .05), while AOFAS score in the observation group was significantly increased (P < .05). Three and 7 days after the operation, VAS, fracture healing time, and full weight-bearing time were significantly decreased in both groups (P < .05). In the control group, the cases with excellent, good, fair, and poor efficacy were 26, 8, 5, 6, with an acceptable rate of 86.67% (39/45). In the observation group, the cases with excellent, good, fair, and poor efficacy were 29, 10, 5, and 2, with an acceptable rate of 95.65% (44/46). There was no significant difference in efficacy between the 2 groups (P > .05). During the follow-up time of 12~27 months (the median time of 18.5 months), all patients showed first-stage grade A healing, and osseous union with good fixation position and no fracture, deformation, loosening or prolapse, and no sural nerve injury or incision infection occurred. Conclusion: Both the posterolateral approach and posterior medial approach open reduction and internal fixation can be used to treat Haraguchi type II posterior malleolus fractures, with good efficacy and safety. The posterior medial approach showed faster recovery and less damage than the posterolateral approach.Overall, the posterolateral approach is more dominant in the treatment of Haraguchi Type II posterior malleolar fracture.

Inflammation-Responsive Hydrogel Spray for Synergistic Prevention of Traumatic Heterotopic Ossification via Dual-Homeostatic Modulation Strategy.

Traumatic heterotopic ossification (THO) represents one of the most prominent contributors to post-traumatic joint dysfunction, which currently lacks an effective and definitive preventative approach. Inflammatory activation due to immune dyshomeostasis during the early stages of trauma is believed to be critical in initiating the THO disease process. This study proposes a dual-homeostatic modulation (DHM) strategy to synergistically prevent THO without compromising normal trauma repair by maintaining immune homeostasis and inducing stem cell homeostasis. A methacrylate-hyaluronic acid-based hydrogel spray device encapsulating a curcumin-loaded zeolitic imidazolate framework-8@ceric oxide (ZIF-8@CeO2, CZC) nanoparticles (CZCH) is designed. Photo-crosslinked CZCH is used to form hydrogel films fleetly in periosteal soft tissues to achieve sustained curcumin and CeO2 nanoparticles release in response to acidity and reactive oxygen species (ROS) in the inflammatory microenvironment. In vitro experiments and RNA-seq results demonstrated that CZCH achieved dual-homeostatic regulation of inflammatory macrophages and stem cells through immune repolarization and enhanced efferocytosis, maintaining immune cell homeostasis and normal differentiation. These findings of the DHM strategy are also validated by establishing THO mice and rat models. In conclusion, the CZCH hydrogel spray developed based on the DHM strategy enables synergistic THO prevention, providing a reference for a standard procedure of clinical operations.

Correlation analysis of quantitative MRI measurements of thigh muscles with histopathology in patients with idiopathic inflammatory myopathy.

OBJECTIVES: To validate the correlation between histopathological findings and quantitative magnetic resonance imaging (qMRI) fat fraction (FF) and water T2 mapping in patients with idiopathic inflammatory myopathy (IIM). METHODS: The study included 13 patients with histopathologically confirmed IIM who underwent dedicated thigh qMRI scanning within 1 month before open muscle biopsy. For the biopsied muscles, FF derived from the iterative decomposition of water and fat with echo asymmetry and least-squares estimation quantitation (IDEAL-IQ) and T2 time from T2 mapping with chemical shift selective fat saturation were measured using a machine learning software. Individual histochemical and immunohistochemical slides were evaluated using a 5-point Likert score. Inter-reader agreement and the correlation between qMRI markers and histopathological scores were analyzed. RESULTS: Readers showed good to perfect agreement in qMRI measurements and most histopathological scores. FF of the biopsied muscles was positively correlated with the amount of fat in histopathological slides (p = 0.031). Prolonged T2 time was associated with the degree of variation in myofiber size, inflammatory cell infiltration, and amount of connective tissues (p ≤ 0.008 for all). CONCLUSIONS: Using the machine learning-based muscle segmentation method, a positive correlation was confirmed between qMRI biomarkers and histopathological findings of patients with IIM. This finding provides a basis for using qMRI as a non-invasive tool in the diagnostic workflow of IIM. RELEVANCE STATEMENT: By using ML-based muscle segmentation, a correlation between qMRI biomarkers and histopathology was found in patients with IIM: qMRI is a potential non-invasive tool in this clinical setting. KEY POINTS: • Quantitative magnetic resonance imaging measurements using machine learning-based muscle segmentation have good consistency and reproductivity. • Fat fraction of idiopathic inflammatory myopathy (IIM) correlated with the amount of fat at histopathology. • Prolonged T2 time was associated with muscle inflammation in IIM.

High efficient adsorption of W(VI) with a novel lignin-based biosorbent functionalized with Zn2+ and polyamine.

Functionalized lignin-based biosorbent has become popular in wastewater treatment and extraction of valuable metals. Amination and metallization modification can effectively improve the adsorption performance of adsorbent. Zn2+/polyamine lignin for adsorption of W(VI) was synthesized by quaternization, amination and metallization from lignin with 3-chloro-2-hydroxypropyl trimethylammonium chloride, tetraethylenepentamine and ZnCl2. The adsorbent was characterized by SEM-EDS, FTIR and XRD. The adsorption performance of Zn2+/polyamine lignin for W(VI) was investigated in batch system. The adsorption mechanism was revealed by zeta potential, SEM-EDS and FTIR and XPS. It was shown that Zn2+/polyamine lignin exhibited great adsorption capacity at pH of 2, 25 °C, oscillation rate of 400 r/min, initial tungsten concentration of 700 mg·L-1 and adsorption time of 720 min. The maximum adsorption capacity of 0.5 g·L-1 Zn2+/polyamine lignin for W(VI) reached 488.28 mg·g-1. The adsorption followed Langmuir model and quasi-second-order kinetic model, indicating that the adsorption was monolayer homogeneous chemisorption. W(VI) was adsorbed through electrostatic attraction of hydrogen bond and Zn2+, ion exchange with Cl- and coordination with -NH2. The adsorption capacity reduced by only 6.47 % after seven cycles of adsorption-desorption, which indicated that Zn2+/polyamine lignin had a great application prospect.

Functional divergence of CYP76AKs shapes the chemodiversity of abietane-type diterpenoids in genus Salvia.

The genus Salvia L. (Lamiaceae) comprises myriad distinct medicinal herbs, with terpenoids as one of their major active chemical groups. Abietane-type diterpenoids (ATDs), such as tanshinones and carnosic acids, are specific to Salvia and exhibit taxonomic chemical diversity among lineages. To elucidate how ATD chemical diversity evolved, we carried out large-scale metabolic and phylogenetic analyses of 71 Salvia species, combined with enzyme function, ancestral sequence and chemical trait reconstruction, and comparative genomics experiments. This integrated approach showed that the lineage-wide ATD diversities in Salvia were induced by differences in the oxidation of the terpenoid skeleton at C-20, which was caused by the functional divergence of the cytochrome P450 subfamily CYP76AK. These findings present a unique pattern of chemical diversity in plants that was shaped by the loss of enzyme activity and associated catalytic pathways.

SbWRKY75- and SbWRKY41-mediated jasmonic acid signaling regulates baicalin biosynthesis.

Introduction: Scutellaria baicalensis Georgi is a traditional Chinese medicinal plant with broad pharmacological activities whose main active ingredient is the flavonoid baicalin. Given its medicinal value and increasing market demand, it is essential to improve the plant's baicalin content. Flavonoid biosynthesis is regulated by several phytohormones, primarily jasmonic acid (JA). Methods: In this study, we conducted transcriptome deep sequencing analysis of S. baicalensis roots treated with methyl jasmonate for different durations (1, 3, or 7 hours). Leveraging weighted gene co-expression network analysis and transcriptome data, we identified candidate transcription factor genes involved in the regulation of baicalin biosynthesis. To validate the regulatory interactions, we performed functional assays such as yeast one-hybrid, electrophoretic mobility shift, and dual-luciferase assays. Results: Our findings demonstrated that SbWRKY75 directly regulates the expression of the flavonoid biosynthetic gene SbCLL-7, whereas SbWRKY41 directly regulates the expression of two other flavonoid biosynthetic genes, SbF6H and SbUGT, thus regulating baicalin biosynthesis. We also obtained transgenic S.baicalensis plants by somatic embryo induction and determined that overexpressing SbWRKY75 increased baicalin content by 14%, while RNAi reduced it by 22%. Notably, SbWRKY41 indirectly regulated baicalin biosynthesis by modulating the expression of SbMYC2.1, SbJAZ3 and SbWRKY75. Discussion: This study provides valuable insights into the molecular mechanisms underlying JA-mediated baicalin biosynthesis in S. baicalensis. Our results highlight the specific roles of transcription factors, namely SbWRKY75 and SbWRKY41, in the regulation of key biosynthetic genes. Understanding these regulatory mechanisms holds significant potential for developing targeted strategies to enhance baicalin content in S. baicalensis through genetic interventions.

AaWRKY6 contributes to artemisinin accumulation during growth in Artemisia annua.

Artemisinin, which is extracted from the plant Artemisia annua L., is a crucial drug for curing malaria and has potential applications for treating cancer, diabetes, pulmonary tuberculosis, and other conditions. Demand for artemisinin is therefore high, and enhancing its yield is important. Artemisinin dynamics change during the growth cycle of A. annua; however, the regulatory networks underlying these changes are poorly understood. Here, we collected A. annua leaves at different growth stages and identified target genes from transcriptome data. We determined that WRKY6 binds to the promoters of the artemisinin biosynthesis gene artemisinic aldehyde Δ11(13) reductase (DBR2). In agreement, overexpression of WRKY6 in A. annua resulted in higher expression levels of genes in the artemisinin biosynthesis pathway and greater artemisinin contents than in the wild type. When expression of WRKY6 was down-regulated, artemisinin biosynthesis pathway genes were also down-regulated and the content of artemisinin was lower. WRKY6 mediates the transcriptional activation of artemisinin biosynthesis by binding to the promoter of DBR2, making it a key regulator for modulating the dynamics of artemisinin changes during the A. annua growth cycle.

Design, synthesis and anti-tumor evaluation of plinabulin derivatives as potential agents targeting ß-tubulin.

Plinabulin is a promising microtubule destabilizing agent in phase 3 clinical stage for treating non-small cell lung cancer. However, the high toxicity and the poor water solubility of plinabulin limited its use and more plinabulin derivatives need to be explored. Here, two series of 29 plinabulin derivatives were designed, synthesized and evaluated for their anti-tumor effect against three types of cancer cell lines. Most of derivatives exerted obvious inhibition to the proliferation of the cell lines tested. Among them, compound 11c exerted stronger efficiency than plinabulin, and the reason might be the additional hydrogen bond between the nitrogen atom of the indole ring in compound 11c and Gln134 of ß-tubulin. Immunofluorescence assay showed that compound 11c at 10 nM significantly disrupted tubulin structure. Compound 11c also significantly induced G2/M cell cycle arrest and apoptosis in dose dependent manner. These results suggest that compound 11c might be a potential candidate for cancer treatment as antimicrotubule agent.

The transcription factors SbMYB45 and SbMYB86.1 regulate flavone biosynthesis in Scutellaria baicalensis.

Scutellaria baicalensis Georgi is an important Chinese medicinal plant that is rich in the flavones baicalin, wogonoside, and wogonin, providing it with anti-cancer, anti-inflammatory, and antibacterial properties. However, although the biosynthetic pathways of baicalin and its derivates have been elucidated, the regulation of flavone biosynthesis in S. baicalensis is poorly understood. Here, we found that the contents of baicalin and its derivates increased and that baicalin biosynthetic pathway genes were induced in response to light, and baicalin and baicalein are not exclusively produced in the roots of S. baicalensis. Based on the fact that MYB transcription factors are known to play important roles in flavone biosynthesis, we identified SbMYB45 and SbMYB86.1 in S. baicalensis and determined that they bind to the promoter of the flavone biosynthesis gene SbCHI to enhance its transcription. Moreover, overexpressing SbMYB45 and SbMYB86.1 enhanced the accumulation of baicalin in S. baicalensis leaves. We demonstrate that SbMYB45 and SbMYB86.1 bind to the cis-acting element MBSII in the promoter of CHI to redundantly induce its expression upon light exposure. These findings indicate that SbMYB45 and SbMYB86.1 transcriptionally activate SbCHI in response to light and enhance flavone contents in S. baicalensis.

Inpatient rehabilitation therapy in stroke patients with reperfusion therapy: a national prospective registry study.

BACKGROUND: Little is known about the rate of real-world inpatient rehabilitation therapy (IRT) after stroke. We aimed to determine the rate of inpatient rehabilitation therapy and its associated factors in patients who undergo reperfusion therapy in China. METHODS: This national prospective registry study included hospitalized ischemic stroke patients aged 14-99 years with reperfusion therapy between January 1, 2019, and June 30, 2020, collecting hospital-level and patient-level demographic and clinical data. IRT included acupuncture or massage, physical therapy, occupational therapy, speech therapy, and others. The primary outcome was the rate of patients receiving IRT. RESULTS: We included 209,189 eligible patients from 2191 hospitals. The median age was 66 years, and 64.2% were men. Four in five patients received only thrombolysis, and the rest 19.2% underwent endovascular therapy. The overall rate of IRT was 58.2% (95% CI, 58.0-58.5%). Differences in demographic and clinical variables existed between patients with and without IRT. The rates of acupuncture or massage, physical therapy, occupational therapy, speech therapy, and other rehabilitation interventions were 38.0%, 28.8%, 11.8%, 14.4%, and 22.9%, respectively. The rates of single and multimodal interventions were 28.3% and 30.0%, respectively. A lower likelihood of receiving IRT was associated with being 14-50 or 76-99 years old, female, from Northeast China, from Class-C hospitals, receiving only thrombolysis, having severe stroke or severe deterioration, a short length of stay, Covid-19 pandemic and having intracranial or gastrointestinal hemorrhage. CONCLUSION: Among our patient population, the IRT rate was low with limited use of physical therapy, multimodal interventions, and rehabilitation centers and varied by demographic and clinical features. The implementation of IRT remains a challenge for stroke care, warranting urgent and effective national programs to enhance post-stroke rehabilitation and the adherence to guidelines.

Starr frame-assisted minimally invasive internal fixation for pelvic fractures: Simultaneous anterior and posterior ring stability.

OBJECTIVE: We aimed to investigate the surgical techniques, efficacy, and safety of Starr frame-assisted minimally invasive internal fixation for simultaneous anterior and posterior ring stability in pelvic fractures. METHODS: The clinical data of 22 patients with anterior and posterior pelvic ring injuries who underwent Starr frame-assisted minimally invasive internal fixation were retrospectively collected. The anterior pelvic ring was fixed with an anterior subcutaneous internal fixator (INFIX), and the posterior pelvic ring was fixed with sacroiliac screws. The operative time, intraoperative blood loss, fluoroscopy times, number of assistants, complications, and weight-bearing time were analyzed. The Matta score was used to evaluate the fracture reduction. The Majeed score was used to evaluate clinical efficacy, and Gibbon's classification was used to estimate the occurrence of sacral nerve injury. RESULTS: All 22 patients were treated with sacroiliac screws for posterior ring injuries, including 12 cases with single sacroiliac screws, nine with two sacroiliac screws, and one with three sacroiliac screws. INFIX was used for all anterior ring fixation, including two screws in seven cases, three screws in 13 cases, and four screws in two cases. The fracture reduction quality was excellent in 15 cases, good in four cases, and moderate in three cases by Matta scores. All patients were followed up for 6-20 (12.5 ± 5.7) months. Callus-formation time based on postoperative X-ray was 3-8 (4.3 ± 1.2) weeks. Weight-bearing time was 3-12 (6.3 ± 2.8) weeks after surgery. At the last follow-up, 15 patients were evaluated as excellent, five as good, and two as fair according to the Majeed score. Gibbons' classification showed that one of the three patients with sacral nerve injury recovered completely and two did not recover. Complications occurred in six patients, including one with internal fixation loosening, two with anterolateral thigh paresthesia, one with malunion, one with nonunion, and one with heterotopic ossification. CONCLUSIONS: Starr frame-assisted minimally invasive internal fixation could stabilize the anterior and posterior pelvic rings simultaneously, overcoming the difficulty of fracture reduction. This technique can help patients with early postoperative weight-bearing and improved functional outcomes, providing a novel modality for the minimally invasive treatment of pelvic ring injuries.

In-stent restenosis after vertebral artery origin stenosis stenting: a nomogram for risk assessment.

OBJECTIVE: To propose a nomogram for individual risk assessment of in-stent restenosis (ISR) after vertebral artery origin stenosis (VAOS) stenting. METHODS: We included 793 patients with VAOS treated with stenting from October 2006 to May 2013, with a median follow-up of 27.8 months. Cox regression and the least absolute shrinkage and selection operator (LASSO) regression were adopted for variable selection. The nomogram was formulated and validated by concordance indexes (C-indexes) and calibration curves. An in-stent restenosis risk table (ISR-RT) was subsequently generated for risk stratification. Differences between low-, intermediate-, and high-risk levels were shown by Kaplan-Meier curves and compared by log-rank test. RESULTS: The training and validation set included 594 and 199 patients, with a mean ISR rate of 37.2% and 35.2%, respectively. Stent type (HR=1.64, 95% CI 1.26 to 2.14), stent diameter (HR=2.48, 95% CI 1.77 to 3.48), history of peripheral vascular disease (HR=2.17, 95% CI 1.17 to 4.00), history of transit ischemic attack (HR=1.45, 95% CI 1.05 to 2.14), and left-side involvement (HR=1.33, 95% CI 1.04 to 1.69) were included in the nomogram. The C-indexes at 6 and 12 months were 0.650 and 0.611 in the training set, and 0.713 and 0.603 in the validation set, respectively. Compared with low-risk patients, the intermediate- and high-level group had 1.46 (95% CI 1.05 to 2.04; p=0.0235) and 2.28 (95% CI 1.64 to 3.17; p<0.0001) higher chances of developing ISR in 2 years, respectively. CONCLUSIONS: A nomogram and a risk evaluation table were developed with good predictive ability for in-stent restenosis among patients with VAOS, which could serve as a practical approach for individualized risk evaluation.

Antibiotic use at planned central line removal in reducing neonatal post-catheter removal sepsis: a systematic review and meta-analysis.

Background: Post-catheter removal sepsis (PCRS) is a notable complication of indwelling central venous catheters (CVCs) in neonates, which is postulated to be secondary to the disruption of biofilms formed along catheter tips up on CVCs removal. It remains controversial whether this could be prevented by antibiotic use upon CVCs removal. We aimed to evaluate the protective effect of antibiotic administration at the time of CVCs removal. Methods: We searched through PubMed, EMBASE, Cochrane databases and reference lists of review articles for studies comparing the use of antibiotics versus no use within 12 h of CVCs removal. Risk of bias was assessed using the modified Newcastle-Ottawa Scale and Cochrane risk-of-bias tool accordingly. Results of quantitative analyses were presented as mean differences (MD) or odds ratio (OR). Subgroup and univariate meta-regression analyses were performed to identify heterogeneity. Results: The review included 470 CVCs in the antibiotic group and 658 in the control group. Antibiotic use within 12 h of CVCs removal did not significantly reduce the incidence of PCRS (OR = 0.35, 95% CI: 0.08-1.53), but was associated with a lower incidence of post-catheter removal blood stream infection (OR = 0.31, 95% CI: 0.11-0.86). Dosage of vancomycin and world region were major sources of heterogeneity. Conclusion: Antibiotic administration upon CVCs removal does not significantly reduce the incidence of PCRS but offers less post-catheter removal blood stream infection. Whether this will be converted to better clinical outcomes lacks evidential support. Further randomized controlled studies with longer follow-up are needed. Summary: Results of our meta-analysis suggest that antibiotic use at planned central line removal removal does not significantly reduce the incidence of PCRS but offers less blood stream infection, which might contribute to future management of central lines in neonates. Systematic Review Registration: https://www.crd.york.ac.uk/, PROSPERO (CRD42022359677).

Fetuin-A is an immunomodulator and a potential therapeutic option in BMP4-dependent heterotopic ossification and associated bone mass loss.

Heterotopic ossification (HO) is the abnormal formation of bone in extraskeletal sites. However, the mechanisms linking HO pathogenesis with bone mass dysfunction remain unclear. Here, we showed that mice harboring injury-induced and BMP4-dependent HO exhibit bone mass loss similar to that presented by patients with HO. Moreover, we found that injury-induced hyperinflammatory responses at the injury site triggered HO initiation but did not result in bone mass loss at 1 day post-injury (dpi). In contrast, a suppressive immune response promoted HO propagation and bone mass loss by 7 dpi. Correcting immune dysregulation by PD1/PDL1 blockade dramatically alleviated HO propagation and bone mass loss. We further demonstrated that fetuin-A (FetA), which has been frequently detected in HO lesions but rarely observed in HO-adjacent normal bone, acts as an immunomodulator to promote PD1 expression and M2 macrophage polarization, leading to immunosuppression. Intervention with recombinant FetA inhibited hyperinflammation and prevented HO and associated bone mass loss. Collectively, our findings provide new insights into the osteoimmunological interactions that occur during HO formation and suggest that FetA is an immunosuppressor and a potential therapeutic option for the treatment of HO.