Recombinant Human Hepatocyte Growth Factor Plasmids for Treating Patients with Chronic Limb Threatening Ischaemia: A Systematic Review and Meta-analysis.

OBJECTIVE: Recombinant human hepatocyte growth factor (HGF) plasmids are novel alternatives to salvage limbs in patients with chronic limb threatening ischaemia (CLTI). A systematic review and meta-analysis of data were conducted to assess the therapeutic efficacy of HGF plasmids in patients with CLTI. DATA SOURCES: Randomised controlled studies evaluating HGF plasmid efficacy in patients with CLTI were identified using Medline, Embase, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov databases. REVIEW METHODS: Meta-analyses of the reported relative risks (RR) or mean differences (MD) were conducted. Subgroup analyses determined the efficacy of HGF plasmids in cohorts excluding Buerger's disease. Certainty of evidence for each outcome was assessed. RESULTS: Seven studies (n = 655) were included. Based on low certainty evidence, patients treated with HGF had a significantly higher complete ulcer healing rate (RR 1.99, 95% CI 1.30 - 3.04; p = .015) than patients treated with placebo. The HGF treatment was associated with reduced visual analogue scale (VAS) scores of pain severity (MD -1.56, 95% CI -2.12 - -1.00; p < .001) vs. placebo in patients with CLTI assessed at the 3 month follow up (low certainty evidence); no significant differences were observed in major amputation (RR 0.91, 95% CI 0.48 - 1.73; p = .77) (low certainty evidence), or all-cause mortality (RR 0.93, 95% CI 0.38 - 2.27; p = .87) (low certainty evidence) between patients treated with HGF and placebo. Low certainty evidence suggested no significant differences in change in ankle-brachial index at 6 months (MD 0.00, 95% CI -0.09 - 0.09; p = 1.0) between patients treated with HGF and placebo. The complete ulcer healing rate and improved 3 month VAS scores of pain severity benefits persisted in subgroup analyses (low certainty evidence). CONCLUSION: Hepatocyte growth factor treatment is associated with an increased complete ulcer healing rate and reduced ischaemic pain in patients with CLTI.

Prediction Value of Initial Serum Levels of SERPINA3 in Intracranial Pressure and Long-Term Neurological Outcomes in Traumatic Brain Injury.

Traumatic brain injury (TBI) is a severe neurological condition characterized by inflammation in the central nervous system. SERPINA3 has garnered attention as a potential biomarker for assessing this inflammation. Our study aimed to explore the predictive value of postoperative serum SERPINA3 levels in identifying the risk of cerebral edema and its prognostic implications in TBI. This study is a prospective observational study, including 37 patients with TBI who finally met our criteria. The Glasgow Outcome Scale (GOS), Levels of Cognitive Functioning (LCF), Disability Rating Scale (DRS), and Early Rehabilitation Barthel Index (ERBI) scores at six months after trauma were defined as the main study endpoint. We further calculated the ventricle-to-intracranial-volume ratio (VBR) at 6 months from CT scans. The study included patients with Glasgow Coma Scale (GCS) scores ranging from 3 to 8, who were subsequently categorized into two groups: the critical TBI group (GCS 3-5 points) and the severe TBI group (GCS 6-8 points). Within the critical TBI group, SERPINA3 levels were notably lower. However, among patients with elevated SERPINA3 levels, both the peak intracranial pressure (ICP) and average mannitol consumption were significantly reduced compared with those of patients with lower SERPINA3 levels. In terms of the 6-month outcomes measured via the GOS, LCF, DRS, and ERBI, lower levels of SERPINA3 were indicative of poorer prognosis. Furthermore, we found a negative correlation between serum SERPINA3 levels and the VBR. The receiver operating characteristic (ROC) curve and decision curve analysis (DCA) demonstrated the predictive performance of SERPINA3. In conclusion, incorporating the novel biomarker SERPINA3 alongside traditional assessment tools offers neurosurgeons an effective and easily accessible means, which is readily accessible early on, to predict the risk of intracranial pressure elevation and long-term prognosis in TBI patients.

Detection of Rickettsia raoultii in Vermipsylla alakurt-Like Fleas of Sheep in Northwestern China.

INTRODUCTION: To date, a total of 2574 validated flea species have been discovered. Vermipsyllidae is a family of fleas that comprises at least eight species. Vermipsylla is a genus of the family Vermipsyllidae within the order Siphonaptera of fleas. Here a novel Vermipsylla species was described, and rickettsial agent was also detected in it. METHODS: A total of 128 fleas were collected directly from 260 pastured sheep in China. Of these, eight representative fleas (four males and four females) were identified by key morphological features. Meanwhile, 120 flea DNAs, including six flea samples for molecular taxonomy, were subjected to Rickettsia spp. DNA detection. The molecular identity of fleas was determined by amplification and sequenmce analysis of four genetic markers (the 28S rDNA genes, the 18S rDNA genes, the mitochondrial cytochrome c oxidase subunit I and subunit II). In addition, five Rickettsia-specific gene fragments were used to identify the species of the rickettsial agents. The amplified products were sequenced and phylogenetically analyzed. RESULTS: The morphological characteristics of the flea species identified in this study were similar to Vermipsylla alakurt, but presented difference in hair number of the metepimeron, the third tergum, the genitals and the tibiae of hind leg. The 18S rDNA, 28S rDNA and COII genetic markers from fleas showed the highest identity to those of V. alakurt, shared 98.45% (954/969), 95.81% (892/931) and 85.86% (571/665) similarities, respectively. However, the COI sequence showed the highest identity to that of Dorcadia ioffi with 88.48% (576/651) similarity. Rickettsia raoutii tested positive in 14.17% (17/120) flea DNA samples. CONCLUSION: Our study reports the detection of R. raoultii in V. alakurt-like fleas infesting sheep in China.

Targeted mRNA Nanoparticles Ameliorate Blood-Brain Barrier Disruption Postischemic Stroke by Modulating Microglia Polarization.

The ischemic stroke is a major global health concern, with high mortality and disability rates. Unfortunately, there is a dearth of effective clinical interventions for managing poststroke neuroinflammation and blood-brain barrier (BBB) disruption that are crucial for the brain injury evolving and neurological deficits. By leveraging the pathological progression of an ischemic stroke, we developed an M2 microglia-targeting lipid nanoparticle (termed MLNP) approach that can selectively deliver mRNA encoding phenotype-switching interleukin-10 (mIL-10) to the ischemic brain, creating a beneficial feedback loop that drives microglial polarization toward the protective M2 phenotypes and augments the homing of mIL-10-loaded MLNPs (mIL-10@MLNPs) to ischemic regions. In a transient middle cerebral artery occlusion (MCAO) mouse model of an ischemic stroke, our findings demonstrate that intravenously injected mIL-10@MLNPs induce IL-10 production and enhance the M2 polarization of microglia. The resulting positive loop reinforces the resolution of neuroinflammation, restores the impaired BBB, and prevents neuronal apoptosis after stroke. Using a permanent distal MCAO mouse model of an ischemic stroke, the neuroprotective effects of mIL-10@MLNPs have been further validated by the attenuation of the sensorimotor and cognitive neurological deficits. Furthermore, the developed mRNA-based targeted therapy has great potential to extend the therapeutic time window at least up to 72 h poststroke. This study depicts a simple and versatile LNP platform for selective delivery of mRNA therapeutics to cerebral lesions, showcasing a promising approach for addressing an ischemic stroke and associated brain conditions.

How Amorphous Nanomaterials Enhanced Electrocatalytic, SERS, and Mechanical Properties.

There is ever-growing research interest in nanomaterials because of the unique properties that emerge on the nanometer scale. While crystalline nanomaterials have received a surge of attention for exhibiting state-of-the-art properties in various fields, their amorphous counterparts have also attracted attention in recent years owing to their unique structural features that crystalline materials lack. In short, amorphous nanomaterials only have short-range order at the atomic scale, and their atomic packing lacks long-range periodic arrangement, in which the coordinatively unsaturated environment, isotropic atomic structure, and modulated electron state all contribute to their outstanding performance in various applications. Given their intriguing characteristics, we herein present a series of representative works to elaborate on the structural advantages of amorphous nanomaterials as well as their enhanced electrocatalytic, surface-enhanced Raman scattering (SERS), and mechanical properties, thereby elucidating the underlying structure-function relationship. We hope that this proposed relationship will be universally applicable, thus encouraging future work in the design of amorphous materials that show promising performance in a wide range of fields.

Glycosylation-Engineered Platelet Membrane-Coated Interleukin 10 Nanoparticles for Targeted Inhibition of Vascular Restenosis.

Purpose: The purpose of this study was to improve the immune compatibility and targeting abilities of IL10 nanoparticles coated with platelet membrane (IL10-PNPs) by glycosylation engineering in order to effectively reduce restenosis after vascular injury. Materials and Methods: In this study, we removed sialic acids and added α (1,2)-fucose and α (1,3)-fucose to platelet membrane glycoprotein, thus engineering the glycosylation of IL10-PNPs (IL10-GE-PNPs). In vitro and in vivo experiments were conducted to evaluate the targeting and regulatory effects of IL10-GE-PNPs on macrophage polarization, as well as the influence of IL10-GE-PNPs on the phenotypic transformation, proliferation, and migration of smooth muscle cells, and its potential in promoting the repair function of endothelial cells within an inflammatory environment. In order to assess the distribution of IL10-GE-PNP in different organs, in vivo imaging experiments were conducted. Results: IL10-GE-PNPs were successfully constructed and demonstrated to effectively target and regulate macrophage polarization in both in vitro and in vivo settings. This regulation resulted in reduced proliferation and migration of smooth muscle cells and promoted the repair of endothelial cells in an inflammatory environment. Consequently, restenosis after vascular injury was reduced. Furthermore, the deposition of IL10-GE-PNPs in the liver and spleen was significantly reduced compared to IL10-PNPs. Conclusion: IL10-GE-PNPs emerged as a promising candidate for targeting vascular injury and exhibited potential as an innovative drug delivery system for suppressing vascular restenosis. The engineered glycosylation of IL10-PNPs improved their immune compatibility and targeting abilities, making them an excellent therapeutic option.

Spotted fever group rickettsiae in hard ticks in eastern and southern Kazakhstan.

Infections with spotted fever group rickettsiae represent a worldwide health problem, characterized by persistent high fever, headache, and rash in humans, domestic animals, and wildlife. To date, the occurrence of Rickettsia species in hard ticks has not been thoroughly studied, especially in eastern and southern Kazakhstan. A total of 1,245 adult ticks, comprising 734 Dermacentor marginatus, 219 Hyalomma scupense, 144 Hyalomma asiaticum, 84 Hyalomma marginatum, 48 Rhipicephalus turanicus, and 16 Haemaphysalis erinacei, collected from East Kazakhstan, Abay, Jetsu, Almaty, Jambyl, South Kazakhstan and Qyzylorda oblasts of Kazakhstan, were used to screen rickettsial agents using molecular methods. Rickettsia raoultii, Rickettsia slovaca, Rickettsia aeschlimannii and Rickettsia heilongjiangensis were identified using sequencing, and 31.5% (392/1245) of ticks carried rickettsial agents. The difference in the natural landscapes explains the variety of the collected ticks and expands our knowledge of Rickettsia species and their geographical distribution in Kazakhstan. To the best of our knowledge, this study reports the first finding of R. heilongjiangensis in Kazakhstan.

Diabetes mellitus and adverse outcomes after carotid endarterectomy: A systematic review and meta-analysis.

BACKGROUND: There is still uncertainty regarding whether diabetes mellitus (DM) can adversely affect patients undergoing carotid endarterectomy (CEA) for carotid stenosis. The aim of the study was to assess the adverse impact of DM on patients with carotid stenosis treated by CEA. METHODS: Eligible studies published between 1 January 2000 and 30 March 2023 were selected from the PubMed, EMBASE, Web of Science, CENTRAL, and ClinicalTrials databases. The short-term and long-term outcomes of major adverse events (MAEs), death, stroke, the composite outcomes of death/stroke, and myocardial infarction (MI) were collected to calculate the pooled effect sizes (ESs), 95% confidence intervals (CIs), and prevalence of adverse outcomes. Subgroup analysis by asymptomatic/symptomatic carotid stenosis and insulin/noninsulin-dependent DM was performed. RESULTS: A total of 19 studies (n = 122,003) were included. Regarding the short-term outcomes, DM was associated with increased risks of MAEs (ES = 1.52, 95% CI: [1.15-2.01], prevalence = 5.1%), death/stroke (ES = 1.61, 95% CI: [1.13-2.28], prevalence = 2.3%), stroke (ES = 1.55, 95% CI: [1.16-1.55], prevalence = 3.5%), death (ES = 1.70, 95% CI: [1.25-2.31], prevalence =1.2%), and MI (ES = 1.52, 95% CI: [1.15-2.01], prevalence = 1.4%). DM was associated with increased risks of long-term MAEs (ES = 1.24, 95% CI: [1.04-1.49], prevalence = 12.2%). In the subgroup analysis, DM was associated with an increased risk of short-term MAEs, death/stroke, stroke, and MI in asymptomatic patients undergoing CEA and with only short-term MAEs in the symptomatic patients. Both insulin- and noninsulin-dependent DM patients had an increased risk of short-term and long-term MAEs, and insulin-dependent DM was also associated with the short-term risk of death/stroke, death, and MI. CONCLUSIONS: In patients with carotid stenosis treated by CEA, DM is associated with short-term and long-term MAEs. DM may have a greater impact on adverse outcomes in asymptomatic patients after CEA. Insulin-dependent DM may have a more significant impact on post-CEA adverse outcomes than noninsulin-dependent DM. Whether DM management could reduce the risk of adverse outcomes after CEA requires further investigation.

The multifaceted roles of activating transcription factor 3 (ATF3) in inflammatory responses - Potential target to regulate neuroinflammation in acute brain injury.

Activating transcription factor 3 (ATF3) is one of the most important transcription factors that respond to and exert dual effects on inflammatory responses. Recently, the involvement of ATF3 in the neuroinflammatory response to acute brain injury (ABI) has been highlighted. It functions by regulating neuroimmune activation and the production of neuroinflammatory mediators. Notably, recent clinical evidence suggests that ATF3 may serve as a potential ideal biomarker of the long-term prognosis of ABI patients. This mini-review describes the essential inflammation modulatory roles of ATF3 in different disease contexts and summarizes the regulatory mechanisms of ATF3 in the ABI-induced neuroinflammation.

Ant-Neointimal Formation Effects of SLC6A6 in Preventing Vascular Smooth Muscle Cell Proliferation and Migration via Wnt/ß-Catenin Signaling.

Vascular smooth muscle cells (VSMCs) play an important role in the pathogenesis of vascular remolding, such as atherosclerosis and restenosis. Solute carrier family 6 member 6 (SLC6A6) is a transmembrane transporter that maintains a variety of physiological functions and is highly expressed in VSMCs. However, its role on VSMCs during neointimal formation remains unknown. In this study, mRNA and protein levels of SLC6A6 were examined using models of VSMC phenotype switching in vivo and in vitro and human artery samples with or without atherosclerosis. SLC6A6 gain- and loss-of-function approaches were performed by adenovirus infection or small interfering RNA (siRNA) transfection, respectively. Reactive oxygen species (ROS), proliferation, migration, and phenotype-related proteins of VSMCs were measured. Vascular stenosis rate and related genes were assessed in a rat vascular balloon injury model overexpressing SLC6A6. SLC6A6 was downregulated in dedifferentiated VSMCs, atherosclerotic vascular tissues, and injured vascular tissues. SLC6A6 suppressed VSMC proliferation and migration, while increasing contractile VSMC proteins. Mechanistically, SLC6A6 overexpression reduced ROS production and inhibited the Wnt/ß-catenin pathway. Furthermore, SLC6A6 overexpression suppressed neointimal formation in vivo. Collectively, overexpression of SLC6A6 suppresses neointimal formation by inhibiting VSMC proliferation and migration via Wnt/ß-catenin signaling and maintaining the VSMC contractile phenotype.

Inhibition of tiRNA-Gly-GCC ameliorates neointimal formation via CBX3-mediated VSMCs phenotypic switching.

Background and aim: tRNA-derived fragments (tRFs) are a new class of non-coding RNAs involved in a variety of pathological processes, but their biological functions and mechanisms in human aortic smooth muscle cells (HASMCs) phenotype transition and vascular intimal hyperplasia are unclear. Methods/results: tiRNA-Gly-GCC is upregulated in synthetic HASMCs, atherosclerotic arteries, plasma, and the balloon injured carotid artery of rats. Functionally, the inhibition of tiRNA-Gly-GCC represses HASMCs proliferation, migration, and reversed dedifferentiation, whereas the overexpression of tiRNA- Gly-GCC have contrary effects. Mechanistically, tiRNA-Gly-GCC performs these functions on HASMCs via downregulating chromobox protein homolog 3 (CBX3). Finally, the inhibition of tiRNA-Gly-GCC could ameliorate neointimal formation after vascular injury in vivo. Conclusions: tiRNA-Gly-GCC is a mediator of HASMCs phenotypic switching by targeting CBX3 and inhibition of tiRNA-Gly-GCC suppresses neointimal formation.

Tacheng Tick Virus 1 and Songling Virus Infection in Great Gerbils (Rhombomys opimus) in Northwestern China.

Tacheng tick virus 1 (TcTV-1) and Songling virus (SGLV) were originally found in human patients in China who had had tick bites. Tamdy virus (TAMV) was detected for the first time in a tick-infested person from Kyrgyzstan in 1973. In this study, 276 great gerbils (Rhombomys opimus) were collected in Xinjiang Uygur Autonomous Region in northwestern China. The total RNA of individual spleen samples was extracted, and the viral L segments of TcTV-1, SGLV, and TAMV were detected by nested reverse transcription PCR. Overall, 2.9% (8/276) and 2.2% (6/276) of spleen samples tested positive to the viral L segments for TcTV-1 and SGLV, respectively; TAMV was not detected in any samples. The SGLV from the great gerbils shared 93.7% (236/252 nucleotide [nt]) and 94.0% (78/83 amino acid [aa]) identities to SGLV detected in patients infected with SGLV in northeastern China. The TcTV-1 in great gerbils was closest to TcTV-1 from a patient in China, with 98.5% (797/809 nt) and 98.9% (265/268 aa) sequence identities. This is the first molecular evidence for the presence of TcTV-1 and SGLV in great gerbils. High genetic diversity in SGLV was observed among geographical locations. Multiregion surveillance of Tamdy orthonairoviruses in more wildlife species is necessary.

Myeloid-derived MIF drives RIPK1-mediated cerebromicrovascular endothelial cell death to exacerbate ischemic brain injury.

Macrophage migration inhibitory factor (MIF) is a multifaced protein that plays important roles in multiple inflammatory conditions. However, the role of MIF in endothelial cell (EC) death under inflammatory condition remains largely unknown. Here we show that MIF actively promotes receptor-interacting protein kinase 1 (RIPK1)-mediated cell death under oxygen-glucose deprivation condition. MIF expression is induced by surgical trauma in peripheral myeloid cells both in perioperative humans and mice. We demonstrate that MIF-loaded myeloid cells induced by peripheral surgery adhere to the brain ECs after distal middle cerebral artery occlusion (dMCAO) and exacerbate the blood-brain barrier (BBB) disruption. Genetic depletion of myeloid-derived MIF in perioperative ischemic stroke (PIS) mice with MCAO following a surgical insult leads to significant reduction in ECs apoptosis and necroptosis and the associated BBB disruption. The adoptive transfer of peripheral blood mononuclear cells (PBMC) from surgical MIFΔLyz2 mice to wild-type (WT) MCAO mice also shows reduced ECs apoptosis and necroptosis compared to the transfer of PBMC from surgical MIFf  l/f  l mice to MCAO recipients. The genetic inhibition of RIPK1 also attenuates BBB disruption and ECs death compared to that of WT mice in PIS. The administration of MIF inhibitor (ISO-1) and RIPK1 inhibitor (Nec-1s) can both reduce the brain EC death and neurological deficits following PIS. We conclude that myeloid-derived MIF promotes ECs apoptosis and necroptosis through RIPK1 kinase-dependent pathway. The above findings may provide insights into the mechanism as how peripheral inflammation promotes the pathology in central nervous system.

Dualistic roles and mechanistic insights of macrophage migration inhibitory factor in brain injury and neurodegenerative diseases.

Macrophage migration inhibitory factor (MIF) is involved in various immune-mediated pathologies and regulates both innate and adaptive immune reactions, thus being related to several acute and chronic inflammatory diseases such as rheumatoid arthritis, septic shock, and atherosclerosis. Its role in acute and chronic brain pathologies, such as stroke and neurodegenerative diseases, has attracted increasing attention in recent years. In response to stimuli like hypoxia, inflammation or infection, different cell types can rapidly release MIF, including immune cells, endothelial cells, and neuron cells. Notably, clinical data from past decades also suggested a possible link between serum MIF levels and the severity of stroke and the evolving of neurodegenerative diseases. In this review, we summarize the major and recent findings focusing on the mechanisms of MIF modulating functions in brain injury and neurodegenerative diseases, which may provide important therapeutic targets meriting further investigation.

Neuronal Serpina3n is an endogenous protector against blood brain barrier damage following cerebral ischemic stroke.

Ischemic stroke results in blood-brain barrier (BBB) disruption, during which the reciprocal interaction between ischemic neurons and components of the BBB appears to play a critical role. However, the underlying mechanisms for BBB protection remain largely unknown. In this study, we found that Serpina3n, a serine protease inhibitor, was significantly upregulated in the ischemic brain, predominantly in ischemic neurons from 6 hours to 3 days after stroke. Using neuron-specific adeno-associated virus (AAV), intranasal delivery of recombinant protein, and immune-deficient Rag1-/- mice, we demonstrated that Serpina3n attenuated BBB disruption and immune cell infiltration following stroke by inhibiting the activity of granzyme B (GZMB) and neutrophil elastase (NE) secreted by T cells and neutrophils. Furthermore, we found that intranasal delivery of rSerpina3n significantly attenuated the neurologic deficits after stroke. In conclusion, Serpina3n is a novel ischemic neuron-derived proteinase inhibitor that counterbalances BBB disruption induced by peripheral T cell and neutrophil infiltration after ischemic stroke. These findings reveal a novel endogenous protective mechanism against BBB damage with Serpina3n being a potential therapeutic target in ischemic stroke.

Biodiversity in Urban Green Space: A Bibliometric Review on the Current Research Field and Its Prospects.

Understanding the development process of urban green space and biodiversity conservation strategies in urban green space is vital for sustainable urban development. However, a systematic review of the urban green space biodiversity research is still lacking. We have retrieved 3806 articles in WOS core journals and carried out the bibliometrics analysis through the three related search terms: urban, green space, and biodiversity. We found that: (1) the year 2009 was a changing point, and the number of articles have increased exponentially since 2009. The United States, China, Europe, and Australia are closely linked, and four research centers have formed; (2) all studies can be classified into three research themes: "Pattern of Urban Green Biodiversity", "Ecological Function of Urban Green Biodiversity", and "Sustainability of Urban Green Biodiversity"; (3) based on the evolution of keywords, this field is divided into the budding stage (1998-2012) and the development stage (2012-2021). The keywords in the budding stage focus on the diversity of different species, and the keywords in the development stage focus on the ecosystem services, biodiversity protection, and residents' satisfaction; (4) the future research focus may be in three aspects: studies on green space in the less urbanized area and urban-rural ecotone, the regulation mechanism and cultural services of urban green space, and the rational layout and management of urban green space. This study hopes to provide a reference for future research on urban green space biodiversity and promote the sustainable development of urban green space.

Vascular restenosis reduction with platelet membrane coated nanoparticle directed M2 macrophage polarization.

Vascular restenosis is the main factor affecting the prognosis of angioplasty in cardiovascular diseases, and inflammation is a central link in the progression of restenosis. Previous research that applies interleukin 10 (IL10) nanoparticles can effectively regulate local inflammation, but their targeted delivery efficacy remains to be improved. In this study, IL10 nanoparticles were successfully prepared and then coated by a preactive platelet membrane. The ability to target and regulate macrophage polarization has been demonstrated, thereby regulating smooth muscle cell and endothelial cell functions. In vivo experiments were carried out in a carotid artery injury model and verified the above functions and the effect on inhibiting vascular restenosis. Immune regulation-based platelet membrane coated nanoparticle loaded with IL10 proved to be an excellent candidate for targeting vascular injury and holds promise as an innovative drug delivery system for suppressing vascular restenosis.

Rationale and design for the study of recombinant human hepatocyte growth factor plasmid in the treatment of patients with chronic limb-threatening ischemia (HOPE CLTI): Randomized, placebo-controlled, double-blind, phase III clinical trials.

BACKGROUND: Although patients with CLTI have benefited from the rapid development of endovascular techniques, many patients are considered unsuitable for revascularization procedures. A previous phase II clinical trial has suggested that recombinant human hepatocyte growth factor plasmid (NL003) can salvage limbs during the treatment of patients with CLTI. However, the safety and efficacy of this drug need to be evaluated in a larger cohort. STUDY DESIGN: HOPE CLTI is a multicenter, randomized, double-blind, placebo-controlled phase III clinical study to evaluate the efficacy and safety of intramuscular injection of NL003 in CLTI patients. This study consisted of 22 trials: HOPE CLTI-1, which includes patients with rest pain (Rutherford stage 4), and HOPE CLTI-2, which includes patients with limb ulcers (Rutherford stage 5). In both trials, patients are randomized with a 2:1 ratio of intramuscular injection of NL003 to placebo. The primary endpoint of HOPE CLTI-1 is the complete pain relief rate. The primary endpoint of HOPE CLTI-2 is the complete ulcer healing rate. The safety endpoint was assessed based on adverse events after injection of NL003. Enrollment began in July 2019. The HOPE CLTI-1 trial aims to complete the randomization of at least 300 patients, while the HOPE CLTI-2 trial aims to enroll at least 240 patients. Both trials are organized such that patients will be followed for 6 months after the first intramuscular injection. CONCLUSIONS: HITOP CLTI, which is comprised of 2 multicenter, double-blind, placebo-controlled phase III clinical trials, aims to evaluate the efficacy and safety of the intramuscular administration of NL003 in patients with CLTI.

Clinical Validation of the Impact of Branch Stent Extension on Hemodynamics in ISF-TEVAR Involving LSA Reconstruction.

Background: The study of hemodynamics regarding thoracic endovascular aortic repair (TEVAR) is helpful to improve the surgical efficacy. Objective: Correlations between hemodynamic changes and branch stent extension length and interference factors for branch stent extension length of in situ fenestration TEVAR (ISF-TEVAR) involving the left subclavian artery (LSA) were evaluated. Materials and Methods: This study retrospectively analyzed 196 patients with Stanford type B aortic dissection who received in situ laser fenestrated thoracic endovascular aortic repair with LSA fenestration from April 2014 to March 2021. Branch stent extension to the main stent graft was evaluated by the computed tomographic angiography (CTA). Hemodynamic change of LSA was defined as a 20 mmHg interbrachial systolic pressure difference. The factors affecting the extension of the branch stent were also evaluated. Results: All patients underwent ISF-TEVAR with LSA fenestration, and there was no recurrence during the follow-up. The mean length of the branch stent extension was 10.37 ± 0.34 mm, which was used to divide the patients into long and short groups. Asymptomatic hemodynamic changes (defined as a 20 mmHg interbrachial systolic pressure difference) in LSA were observed in 61 patients undergoing ISF-TEVAR involving LSA fenestration. The Spearman correlation analysis showed extension length of a branch stent >1.5 cm elevated the risk of hemodynamic changes. Conclusion: Overall, we conclude that branch stent extension length >1.5 cm induced LSA hemodynamic changes. Appropriate shortening of the stent extension length can improve the curative effect of ISF-TEVAR, especially when faced with a type II/III aortic arch and stent angles of <30 degrees.

A Potential Target for Diabetic Vascular Damage: High Glucose-Induced Monocyte Extracellular Vesicles Impair Endothelial Cells by Delivering miR-142-5p.

Endothelial dysfunction is a key accessory to diabetic cardiovascular complications, and the regulatory role of the extracellular vesicles (EVs) from the innate immune system is growing. We tested whether EVs derived from high glucose-induced monocytes could shuttle microRNAs and impair endothelial cells. EVs from high glucose- and basal glucose-treated THP-1 cells (HG-THP-1 EVs and BG-THP-1 EVs) were isolated and identified. After coculture with THP-1 EVs, human umbilical vein endothelial cells (HUVECs) were tested by proliferation, migration, reactive oxygen species (ROS) detection assays, and western blot for Nrf2/NLRP3 signaling. MiR-142-5p was predicted by miRNAs databases and further verified by RT-qPCR and dual-luciferase reporter gene assays that inhibit Nrf2 expression. The regulation of miR-142-5p in HUVECs was further evaluated. A type 1 diabetes mellitus (T1DM) mouse model was developed for miR-142-5p inhibition. Aorta tissue was harvested for hematoxylin-eosin staining and immunohistochemistry of interleukin-1ß (IL-1ß). Compared to BG-THP-1 EVs, HG-THP-1 EVs significantly reduced migration and increased ROS production in HUVECs but did not affect proliferation. HG-THP-1 EVs induced suppression of Nrf2 signaling and NLRP3 signaling activation. RT-qPCR results showed that HG-THP-1 EVs overexpressed miR-142-5p in HUVECs. The transfection of miR-142-5p mimics into HUVECs exhibited consistent regulatory effects on HG-THP-1 EVs, whereas miR-142-5p inhibitors demonstrated protective effects. The miR-142-5p antagomir significantly reduced the IL-1ß level in T1DM aortas despite morphological changes. To conclude, miR-142-5p transferred by high glucose-induced monocyte EVs participates in diabetic endothelial damage. The inhibition of miR-142-5p could be a potential adjuvant to diabetic cardiovascular protection.