Immunomodulatory hydrogel orchestrates pro-regenerative response of macrophages and angiogenesis for chronic wound healing.

Chronic wound healing often encounters challenges characterized by prolonged inflammation and impaired angiogenesis. While the immune response plays a pivotal role in orchestrating the intricate process of wound healing, excessive inflammation can hinder tissue repair. In this study, a bilayer alginate hydrogel system encapsulating polyelectrolyte complex nanoparticles (PCNs) loaded with anti-inflammatory cytokines and angiogenic growth factors is developed to address the challenges of chronic wound healing. The alginate hydrogel is designed using two distinct crosslinking methods to achieve differential degradation, thereby enabling precise spatial and temporal controlled release of PCNs. Initially, interleukin-10 (IL-10) is released to mitigate inflammation, while unsaturated PCNs bind and remove accumulated pro-inflammatory cytokines at the wound site. Subsequently, angiogenic growth factors, including vascular endothelial growth factor and platelet-derived growth factor, are released to promote vascularization and vessel maturation. Our results demonstrate that the bilayer hydrogel exhibits distinct degradation kinetics between the two layers, facilitating the staged release of multiple signaling molecules. In vitro experiments reveal that IL-10 can activate the Jak1/STAT3 pathway, thereby suppressing pro-inflammatory cytokines and chemokines while down-regulating inflammation-related genes. In vivo studies demonstrate that application of the hydrogel in chronic wounds using diabetic murine model promotes healing by positively modulating multiple integral reparative mechanisms. These include reducing inflammation, promoting macrophage polarization towards a pro-regenerative phenotype, enhancing keratinocyte migration, stimulating angiogenesis, and expediting wound closure. In conclusion, our hydrogel system effectively mitigates inflammatory responses and provides essential physiological cues by inducing a synergistic angiogenic effect, thus offering a promising approach for the treatment of chronic wounds.

Association between TIMP1 polymorphism and female neuromyelitis optica spectrum disorder in Chinese population.

Aims: Earlier studies have indicated an association between the TIMP1 polymorphism and the risk of certain autoimmune diseases, as well as a link between higher TIMP1 levels and blood-brain barrier (BBB) disruption in neuromyelitis optica spectrum disorders (NMOSD). This study aimed to explore the correlation between TIMP1 polymorphism and NMOSD phenotypes. Methods: Genotyping of three loci (rs4898, rs2070584, rs6609533) in the TIMP1 gene was performed in 126 NMOSD patients and 213 healthy controls (HCs) from North China using the SNaPshot sequencing technique, and a correlation analysis was done between phenotypes and TIMP1 genotype. Results: The frequency of the rs4898-T, rs2070584-T, and rs6609533-G alleles was significantly higher in NMOSD patients than those in HCs (p < 0.05). Accordingly, the rs4898-TT, rs2070584-TT, and rs6609533-GG genotypes were found at a higher frequency in patients than in controls (p < 0.05). Haplotype analysis showed TIMP1 T-T-G (rs4898-rs2070584-rs6609533) frequency was higher in female NMOSD patients (p = 0.019), and the frequency of T-T-G haplotypes in the BBB disrupted group was higher compared with that in the BBB normal group (p = 0.04). Conclusions: TIMP1 rs4898-T, rs2070584-T, and rs6609533 polymorphism may contribute to the susceptibility of Female NMOSD patients in the Chinese Population. TIMP1 T-T-G (rs4898-rs2070584-rs6609533) haplotype is more common among female NMOSD patients and is linked to heightened disruption of the BBB.

Electroencephalographic Microstates During Sleep and Wake in Schizophrenia.

Background: Aberrant functional connectivity is a hallmark of schizophrenia. The precise nature and mechanism of dysconnectivity in schizophrenia remains unclear, but evidence suggests that dysconnectivity is different in wake versus sleep. Microstate analysis uses electroencephalography (EEG) to investigate large-scale patterns of coordinated brain activity by clustering EEG data into a small set of recurring spatial patterns, or microstates. We hypothesized that this technique would allow us to probe connectivity between brain networks at a fine temporal resolution and uncover previously unknown sleep-specific dysconnectivity. Methods: We studied microstates during sleep in patients with schizophrenia by analyzing high-density EEG sleep data from 114 patients with schizophrenia and 79 control participants. We used a polarity-insensitive k-means analysis to extract a set of 6 microstate topographies. Results: These 6 states included 4 widely reported canonical microstates. In patients and control participants, falling asleep was characterized by a shift from microstates A, B, and C to microstates D, E, and F. Microstate F was decreased in patients during wake, and microstate E was decreased in patients during sleep. The complexity of microstate transitions was greater in patients than control participants during wake, but this reversed during sleep. Conclusions: Our findings reveal behavioral state-dependent patterns of cortical dysconnectivity in schizophrenia. Furthermore, these findings are largely unrelated to previous sleep-related EEG markers of schizophrenia such as decreased sleep spindles. Therefore, these findings are driven by previously undescribed sleep-related pathology in schizophrenia.

EEG microstates are stereotyped patterns of scalp voltage topography that provide information about brain activity at millisecond-level temporal resolution. We used this method to study brain activity in schizophrenia during sleep and wake. We found state-dependent case-control differences in EEG microstates that were unrelated to the results of classic EEG analyses. These differences reflect aberrant neural functioning during sleep in patients with schizophrenia.

Active Left Atrial Ejection Fraction as a Non-Invasive Marker in Pulmonary Hypertension Secondary to Heart Failure.

BACKGROUND: Patients with pulmonary hypertension (PH) secondary to left heart failure (HF) exhibit a complex pathophysiological profile and poor prognosis. Left atrial function is pivotal in the progression of this disease, yet its predictive significance remains exclusive. This study aimed to explore the predictive capability of LA metrics in this population and compare them with other common predictors. METHODS: In this retrospective study, consecutive patients with PH secondary to HF who underwent cardiac magnetic resonance (CMR) imaging between December 2010 and December 2021 were enrolled. The composite endpoint was defined as all-cause death, heart-lung transplantation, or left ventricular assist device implantation. Survival analyses were performed using Kaplan-Meier curves and Cox regression analyses. RESULTS: A total of 174 patients with PH secondary to HF, with a mean age of 53.2 ± 14.9 years, including 90 men, were included in the final analysis. During a median follow-up of 31.9 months, 58 patients (33.3%) with PH reached the endpoints. There was a fair correlation between active left atrial ejection fraction (LAEF) and pulmonary artery wedge pressure (r = -0.397, p = 0.044). Active LAEF had a strong correlation with oxygen consumption at anaerobic threshold (r = 0.769, p < 0.001) and peak oxygen consumption (r = 0.754, p < 0.001). Active LAEF demonstrated comparable prognostic performance to other variables measured by echocardiography or CMR. After adjusting for clinical variables and left ventricular ejection fraction, active LAEF was still an independent predictor for adverse events (C-statistic: 0.784). Subgroup analysis among HF patients with preserved ejection fraction demonstrated that those with active LAEF ≤ 8.6% had a 7.05-fold higher risk of experiencing the composite endpoint compared to those with active LAEF > 8.6%. CONCLUSION: Although active LAEF does not demonstrate statistical improvement in outcome discrimination compared to established metrics, it may still merit consideration for assessing disease severity and prognosis in patients with PH secondary to HF. The integration of active LAEF and HF subtypes may stratify individuals at different levels of risk.

Meticulous nursing care for coronary CT angiography: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: This study aimed to investigate the effects of meticulous nursing care (MNC) for patients with coronary heart disease undergoing coronary CT angiography (CCTA). METHODS: We conducted a comprehensive search of the Cochrane Library, PubMed, EMBASE, China National Knowledge Infrastructure, and Wangfang databases from inception to January 1, 2024. Randomized clinical trials (RCTs) evaluating the effects of MNC for CCTA were included. Outcomes assessed included self-rating anxiety scale (SAS), self-rating depression scale (SDS), overall satisfaction of nursing care (OSNC), examination time (ET, min), radiation dose received (RDR, mSv), breathing control time (BCT), and heart rate control time (HRCT).The methodological quality of all included RCTs was evaluated using the Cochrane risk-of-bias tool, while statistical analysis was conducted using RevMan 5.4 software. RESULTS: Six eligible trials involving 1064 patients were included. The results of the meta-analysis showed significant differences in SAS (MD = -2.84, 95% CI [-3.31, -2.37], I2 = 0%, P < .001), SDS (MD = -2.55, 95% CI [-3.51, -1.58], I2 = 0%, P < .001), OSNC (OR = 3.13, 95% CI [1.59, 6.17], I2 = 23%, P = .001), BCT (MD = -23.43, 95% CI [-25.07, -21.80], I2 = 45%, P < .001), HRCT (MD = -20.08, 95% CI [-21.70, -18.46], I2 = 29%, P < .001), ET (MD = -2.31, 95% CI [-2.56, -2.06], I2 = 5%, P < .001), and RDR (MD = -2.11, 95% CI [-2.45, -1.77], I2 = 0%, P < .001). CONCLUSION: MNC may benefit for patients with coronary heart disease undergoing CCTA. Future studies are still needed to warrant the current findings.

Transcriptomic analysis of the response mechanisms of black rockfish (Sebastes schlegelii) under noise stress from offshore wind farms.

During the operational phase of offshore wind farms, the generation of low-frequency underwater noise has received widespread attention due to its potential adverse impact on fish health. This study conducted a field survey of underwater noise at offshore wind farms located in Shandong province, China. Subsequently, a small-scale experiment was conducted to study the stress on black rockfish (Sebastes schlegelii). The fish were exposed to noise with dominant frequency of 80 Hz, 125 Hz and 250 Hz. These frequencies are same with the frequencies from wind power noise (wpn) at the actual site. After a 40-day experimental period, transcriptome sequencing was conducted on brain, liver, and kidney tissues of black rockfish to elucidate the underlying molecular mechanisms involved in the response to noise stress originating from offshore wind farms. The results revealed that the 125 Hz group exhibited the highest number of differentially expressed genes (DEGs) between the noise-exposed and control check group (CK group), with a total of 797 in the brain, 1076 in the liver, and 2468 in the kidney. Gene Ontology (GO) analysis showed that DEGs were significantly enriched in entries related to cellular processes, membrane components, binding, and metabolism. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that DEGs were enriched mainly in metabolism, immunity, apoptosis, signal transduction, and diseases. The findings indicate that prolonged exposure to underwater noise from offshore wind farms may induce metabolic imbalance, immune dysfunction, and an increased risk of myocardial diseases in black rockfish.

The IGF2BP3/Notch/Jag1 pathway: A key regulator of hepatic stellate cell ferroptosis in liver fibrosis.

INTRODUCTION: Liver fibrosis is primarily driven by the activation of hepatic stellate cells (HSCs), which involves various epigenetic modifications. OBJECTIVES: N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotic cells, influences numerous physiological and pathological processes. Nevertheless, the role of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a reader gene mediating m6A modifications, in liver fibrosis remains unclear. METHODS AND RESULTS: This study demonstrated that IGF2BP3 knockout reduces liver fibrosis by promoting HSC ferroptosis (FPT) and inactivating HSCs. Multi-omics analysis revealed that HSC-specific IGF2BP3 knockout decreased m6A content in Jagged1 (Jag1), a key component of the Notch signalling pathway. Furthermore, IGF2BP3 deficiency significantly reduced the expression of hairy and enhancer of split-1 (Hes1), a transcription factor in the Notch/Jag1 signalling pathway, with mRNA levels declining to 35%-62% and protein levels to 28%-35%. Additionally, it suppressed glutathione peroxidase 4 (GPX4) (decreased to approximately 31%-38%), a negative regulator of FPT, thereby facilitating HSC FPT progression and reducing profibrotic gene expression. CONCLUSION: These findings uncover a novel IGF2BP3/Notch/Jag1 signalling pathway involving HSC FPT, suggesting promising targets for ameliorating liver fibrosis. KEY POINTS/HIGHLIGHTS: IGF2BP3 deficiency inactivates Jag1 signalling. IGF2BP3 deficiency-mediated m6A modifications promote HSC ferroptosis. IGF2BP3 inhibition facilitates ferroptosis in HSCs via the Hes1/GPX4 axis. IGF2BP3 deficiency inactivates Jag1/Notch1/3/Hes1 signalling pathway inactivation, leading to the decrease in GPX4, which contributes to HSC ferroptosis.

Advancements in the interventional therapy and nursing care on deep vein thrombosis in the lower extremities.

This review examines recent advancements in interventional treatments and nursing care for lower extremity deep vein thrombosis (DVT), highlighting significant innovations and their clinical applications. It discusses the transition to novel anticoagulants such as Direct Oral Anticoagulants, which offer a safer profile and simplified management compared to traditional therapies. Mechanical interventions, including balloon angioplasty and venous stenting, are detailed for their roles in improving immediate and long-term vascular function in acute DVT cases. Furthermore, the use of image-guided techniques is presented as essential for enhancing the accuracy and safety of DVT interventions. Additionally, this study outlines advances in nursing care strategies, emphasizing comprehensive preoperative and postoperative evaluations to optimize patient outcomes. These evaluations facilitate tailored treatment plans, crucial for managing the complex needs of DVT patients. Long-term care strategies are also discussed, with a focus on patient education to ensure adherence to treatment protocols and to prevent recurrence. The synthesis aims to inform healthcare professionals about cutting-edge practices in DVT management, promoting a deeper understanding of how these advancements can be integrated into clinical practice. It also underscores the necessity for ongoing research to address challenges such as cost-effectiveness and patient compliance, ensuring that future treatments are both accessible and effective.

The Effect of Short-Term Kinesiology Taping on Neuromuscular Controls in Hallux Valgus During Gait: A Study of Muscle and Kinematic Synergy.

To investigate the biomechanical mechanisms underlying the pathogenesis and explore the effects of kinesiology taping (KT) on neuromuscular control in HV patients. The study population consisted of 16 young controls (YC group) and 15 patients with hallux valgus (HV group). All subjects underwent a natural velocity gait assessment. Additionally, 11 patients from the HV group received KT intervention over a period of one month, consisting of 15 sessions administered every other day. After the one-month intervention, these patients underwent a gait assessment and were included in the HV-KT group. The electromyography (EMG) and joint motion were evaluated using non-negative matrix factorization (NNMF) to compare the difference in muscle and kinematic synergy among the three groups. The center of plantar pressure (COP) and ground reaction force (GRF) were measured by the force platform. The number of synergies did not differ within the three groups, but the structure of muscle synergies and kinematic synergies differed in the HV group. The KT intervention (HV-KT group) altered the structure of synergies. The correlation between kinematic synergies and muscular synergies was lower in the HV group than in the YC group, whereas the correlation between the two increased after the KT intervention in the HV group. During gait, the HV group tended to activate more muscles around foot joints to maintain body stability. The visual analogue scale (VAS) scores, hallux valgus angle (HVA), and COP were significantly decreased after the intervention ( [Formula: see text]). HV patients exhibited altered kinematic and muscular synergies structures as well as muscle activation. Also, it weakened the balance and athletic ability of HV patients. KT intervention improved neuromuscular control to provide a better gait performance.

Left-behind cumulative risk and academic adjustment in Chinese middle school students: The moderating effect of growth mindset.

Left-behind children, as a large-scale disadvantaged group, encounter an array of risk factors that impede their academic development because of parental migration. The current study aimed at investigating the roles of left-behind cumulative risk and growth mindset on academic adjustment and exploring whether growth mindset moderated the association between left-behind cumulative risk and academic adjustment in left-behind middle school students. A total of 1184 left-behind middle school students (615 males; 12-16 years) participated in the study. Results indicated that left-behind cumulative risk is negatively associated with academic adjustment in middle school students (ß = -.199, t(1183) = -7.229, p < .001). Besides, growth mindset has a protective effect on left-behind middle school students' academic adjustment (ß = .386, t(1183) = 14.070, p < .001) and a moderating effect on the relationship between left-behind cumulative risk and academic adjustment (ß = .394, t(1182) = 4.057, p < .001, ΔR2 = .012). These findings suggest that family risk factors related to left-behind status affect the academic adjustment of left-behind middle school students in a superposition way, while the positive individual factor of growth mindset could protect the negative impact caused by parental migration.

STQD-Det: Spatio-Temporal Quantum Diffusion Model for Real-time Coronary Stenosis Detection in X-ray Angiography.

Detecting coronary stenosis accurately in X-ray angiography (XRA) is important for diagnosing and treating coronary artery disease (CAD). However, challenges arise from factors like breathing and heart motion, poor imaging quality, and the complex vascular structures, making it difficult to identify stenosis fast and precisely. In this study, we proposed a Quantum Diffusion Model with Spatio-Temporal Feature Sharing to Real-time detect Stenosis (STQD-Det). Our framework consists of two modules: Sequential Quantum Noise Boxes module and spatio-temporal feature module. To evaluate the effectiveness of the method, we conducted a 4-fold cross-validation using a dataset consisting of 233 XRA sequences. Our approach achieved the F1 score of 92.39% with a real-time processing speed of 25.08 frames per second. These results outperform 17 state-of-the-art methods. The experimental results show that the proposed method can accomplish the stenosis detection quickly and accurately.

Synergistically Utilizing a Liquid Bridge and Interconnected Porous Superhydrophilic Structures to Achieve a One-Step Fog Collection Mode.

Conventional fog collection efficiency is subject to the inherent inefficiencies of its three constituent steps: fog capture, coalescence, and transportation. This study presents a liquid bridge synergistic fog collection system (LSFCS) by synergistically utilizing a liquid bridge and interconnected porous superhydrophilic structures (IPHS). The results indicate that the introduction of liquid bridge not only greatly accelerates water droplet transportation, but also facilitates the IPHS in maintaining rough structures that realize stable and efficient fog capture. During fog collection, the lower section of the IPHS is covered by a water layer, however due to the effect of the liquid bridge, the upper section protrudes out, while covered by a connective thin water film that does not obscure the microstructures of the upper section. Under these conditions, a one-step fog collection mode is realized. Once captured by the IPHS, fog droplets immediately coalesce with the water film, and are simultaneously transported into a container under the effect of the liquid bridge. The LSFCS achieves a collection efficiency of 6.5 kg m-2 h-1, 2.3 times that of a system without a liquid bridge. This study offers insight on improving fog collection efficiency, and holds promise for condensation water collection or droplet manipulation.

Quantitative Assessment of Acute Intracranial Clot and Collaterals on High-Resolution Magnetic Resonance Imaging.

INTRODUCTION: There has been an increasing demand for imaging methods that provide a comprehensive evaluation of intracranial clot and collateral circulation, which are helpful for clinical decision-making and predicting functional outcomes. We aimed to quantitatively evaluate acute intracranial clot burden and collaterals on high-resolution magnetic resonance imaging (HR-MRI). METHODS: We analyzed acute ischemic stroke patients with internal carotid artery or middle cerebral artery occlusion in a prospective multicenter study. The clot burden was scored on a scale of 0-10 based on the clot location on HR-MRI. The collateral score was assigned on a scale of 0-3 using the minimum intensity projection from HR-MRI. Uni- and multivariable logistic regression analyses were performed to assess their correlation with clinical outcome (modified Rankin Scale >2 at 90 days). Thresholds were defined to dichotomize into low- and high-score groups, and predictive performances were assessed for clinical and radiologic outcomes. RESULTS: Ninety-nine patients (mean age of 60.77 ± 11.54 years) were included in the analysis. The interobserver correlation was 0.89 (95% CI: 0.77-0.95) for the clot burden score and 0.78 (95% CI: 0.53-0.90) for the collateral score. Multivariable logistic regression analysis demonstrated that the collateral score (odds ratio: 0.41, 95% CI: 0.19-0.90) was significantly associated with clinical outcomes. A better functional outcome was observed in the group with clot burden scores greater than 7 (p = 0.011). A smaller final infarct size and a higher diffusion-weighted imaging-based Alberta Stroke Program Early Computed Tomography Score were observed in the group with collateral scores greater than 1 (all p < 0.05). CONCLUSIONS: HR-MRI offers a new tool for quantitative assessment of clot burden and collaterals simultaneously in future clinical practices and research endeavors.

Muscle synergy and kinematic synergy analyses during sit-to-stand motions in hallux valgus patients before and after treatment with Kinesio taping.

OBJECTIVES: To explore the impact of hallux valgus (HV) on lower limb neuromuscular control strategies during the sit-to-stand (STS) movement, and to evaluate the effects of Kinesio taping (KT) intervention on these control strategies in HV patients. METHODS: We included 14 young healthy controls (HY), 13 patients in the HV group (HV), and 11 patients in the HV group (HVI) who underwent a Kinesio taping (KT) intervention during sit-to-stand (STS) motions. We extracted muscle and kinematic synergies from EMG and motion capture data using non-negative matrix factorization (NNMF). In addition, we calculated the center of pressure (COP) and ground reaction forces (GRF) to assess balance performance. RESULTS: There were no significant differences in the numbers of muscle and kinematic synergies between groups. In the HV group, knee flexors and ankle plantar flexors were abnormally activated, and muscle synergy D was differentiated. Muscle synergy D was not differentiated in the HVI group. CONCLUSION: Abnormal activation of knee flexors and plantar flexors led to the differentiation of module D in HV patients, which can be used as an indicator of the progress of HV rehabilitation. KT intervention improved motor control mechanisms in HV patients.

Irisflorentin improves functional recovery after spinal cord injury by protecting the blood-spinal cord barrier and promoting axonal growth.

Spinal cord injury (SCI) induces the disruption of the blood-spinal cord barrier (BSCB) and the failure of axonal growth. SCI activates a complex series of responses, including cell apoptosis and endoplasmic reticulum (ER) stress. Pericytes play a critical role in maintaining BSCB integrity and facilitating tissue growth and repair. However, the roles of pericytes in SCI and the potential mechanisms underlying the improvements in functional recovery in SCI remain unclear. Recent evidence indicates that irisflorentin exerts neuroprotective effects against Parkinson's disease; however, whether it has potential protective roles in SCI or not is still unknown. In this study, we found that the administration of irisflorentin significantly inhibited pericyte apoptosis, protected BSCB integrity, promoted axonal growth, and ultimately improved locomotion recovery in a rat model of SCI. In vitro, we found that the positive effects of irisflorentin on axonal growth were likely to be mediated by regulating the crosstalk between pericytes and neurons. Furthermore, irisflorentin effectively ameliorated ER stress caused by incubation with thapsigargin (TG) in pericytes. Meanwhile, the protective effect of irisflorentin on BSCB disruption is strongly related to the reduction of pericyte apoptosis via inhibition of ER stress. Collectively, our findings demonstrate that irisflorentin is beneficial for functional recovery after SCI and that pericytes are a valid target of interest for future SCI therapies.

Cross-Anatomy Transfer Learning via Shape-Aware Adaptive Fine-Tuning for 3D Vessel Segmentation.

Deep learning methods have recently achieved remarkable performance in vessel segmentation applications, yet require numerous labor-intensive labeled data. To alleviate the requirement of manual annotation, transfer learning methods can potentially be used to acquire the related knowledge of tubular structures from public large-scale labeled vessel datasets for target vessel segmentation in other anatomic sites of the human body. However, the cross-anatomy domain shift is a challenging task due to the formidable discrepancy among various vessel structures in different anatomies, resulting in the limited performance of transfer learning. Therefore, we propose a cross-anatomy transfer learning framework for 3D vessel segmentation, which first generates a pre-trained model on a public hepatic vessel dataset and then adaptively fine-tunes our target segmentation network initialized from the model for segmentation of other anatomic vessels. In the framework, the adaptive fine-tuning strategy is presented to dynamically decide on the frozen or fine-tuned filters of the target network for each input sample with a proxy network. Moreover, we develop a Gaussian-based signed distance map that explicitly encodes vessel-specific shape context. The prediction of the map is added as an auxiliary task in the segmentation network to capture geometry-aware knowledge in the fine-tuning. We demonstrate the effectiveness of our method through extensive experiments on two small-scale datasets of coronary artery and brain vessel. The results indicate the proposed method effectively overcomes the discrepancy of cross-anatomy domain shift to achieve accurate vessel segmentation for these two datasets.

Association of physical activity trajectories over 8 years and risk of knee replacement: data from the osteoarthritis initiative.

BACKGROUND: To identify physical activity (PA) trajectories in adults with or at risk of knee osteoarthritis and to evaluate the association of PA trajectories with incident knee replacement (KR). METHODS: This study used data from the Osteoarthritis Initiative. The Physical Activity Scale for the Elderly and the KR were assessed annually from baseline to 9 years. Individuals were included if they did not undergo KR surgery at baseline and had data on PA at ≥ 1 visit before KR. Latent class growth mixture Modeling was used to identify the optimal trajectories of PA before KR. Log-binomial regression models were used to assess the association between PA trajectories and the risk of KR. Data analyses were conducted in all individuals and those with radiographic osteoarthritis (ROA) and significant knee pain (Western Ontario and McMaster Osteoarthritis Index pain score of ≥ 5 on a 0-20 scale) at baseline, respectively. RESULTS: Of 4731 participants (mean age 61.1 years, 58.5% female), four distinct and slightly declined PA trajectories were identified. Compared to individuals with a "Low" PA trajectory, those with "Medium-low", "Medium-high", or "High" PA trajectories were not significantly associated with the risk of KR (risk ratios: 0.97-1.19, all p > 0.05). Similar PA trajectories and associations with the risk of KR were observed in the subgroups of individuals with radiographic osteoarthritis and those with significant knee pain at baseline, respectively. CONCLUSION: In participants with or at risk of knee osteoarthritis, PA slightly declines over time and may play no role in the risk of KR.

Stereodivergent Synthesis of Pyridyl Cyclopropanes via Enzymatic Activation of Pyridotriazoles.

Hemoproteins have recently emerged as powerful biocatalysts for new-to-nature carbene transfer reactions. Despite this progress, these strategies have remained largely limited to diazo-based carbene precursor reagents. Here, we report the development of a biocatalytic strategy for the stereoselective construction of pyridine-functionalized cyclopropanes via the hemoprotein-mediated activation of pyridotriazoles (PyTz) as stable and readily accessible carbene sources. This method enables the asymmetric cyclopropanation of a variety of olefins, including electron-rich and electrodeficient ones, with high activity, high stereoselectivity, and enantiodivergent selectivity, providing access to mono- and diarylcyclopropanes that incorporate a pyridine moiety and thus two structural motifs of high value in medicinal chemistry. Mechanistic studies reveal a multifaceted role of 7-halogen substitution in the pyridotriazole reagent toward favoring multiple catalytic steps in the transformation. This work provides the first example of asymmetric olefin cyclopropanation with pyridotriazoles, paving the way to the exploitation of these attractive and versatile reagents for enzyme-catalyzed carbene-mediated reactions.

PCSK9 Inhibitor with Statin Therapy for Intracranial Artery Stenosis ( PISTIAS): Rationale and design of a multicenter randomized controlled trial.

RATIONALE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors enable an additional 54-75% reduction in low-density lipoprotein cholesterol (LDL-C) in statin-treated patients, demonstrating plaque regression in coronary artery disease. However, the impact of achieving an extremely low level of LDL-C with PCSK9 inhibitors (e.g. Evolocumab) on symptomatic intracranial atherosclerosis remains unexplored. AIM AND HYPOTHESIS: To determine whether combining Evolocumab and statins achieves a more significant symptomatic intracranial plaque regression than statin therapy alone. SAMPLE SIZE ESTIMATES: With a sample size of 1000 subjects, a two-sided α of 0.05, and 20% lost to follow-up, the study will have 83.3% power to detect the difference in intracranial plaque burden. METHODS AND DESIGN: This is an investigator-initiated multicenter, randomized, open-label, outcome assessor-blinded trial, evaluating the impact of combining Evolocumab and statins on intracranial plaque burden assessed by high-resolution magnetic resonance imaging at baseline in patients undergoing a clinically indicated acute stroke or transient ischemic attack due to intracranial artery stenosis, and after 24 weeks of treatment. Subjects (n = 1000) were randomized 1:1 into two groups to receive either Evolocumab 140 mg every 2 weeks with statin therapy or statin therapy alone. STUDY OUTCOMES: The primary endpoint is the change in intracranial plaque burden assessed by high-resolution magnetic resonance imaging, performed at baseline and at the end of the 24-week treatment period. DISCUSSION: This trial will explore whether more significant intracranial plaque regression is achievable with the treatment of combining Evolocumab and statins, providing information about efficacy and safety data. TRIAL REGISTRATION NUMBER: ChiCTR2300068868; https://www.chictr.org.cn/.

A Poly(amino acid)-Based Nanomedicine Strategy: Telomere-Telomerase Axis Targeting and Magnetic Resonance Imaging in Hepatocellular Carcinoma Treatment.

Targeting telomere maintenance has emerged as a promising strategy for hepatocellular carcinoma (HCC) treatment. However, given the duality of the telomere-telomerase axis in telomere maintenance, a comprehensive strategy is urgently needed. Herein, we develop a poly(amino acid) (D-PAAs)-based strategy for spatiotemporal codelivery of telomerase inhibitor, BIBR1523, and AKT inhibitor, isobavachalcone. By leveraging D-PAAs' modifiability, we synthesize polymer-inhibitor conjugates (PB and PI) and a folic acid-decorated tumor-targeting vector (PF). These building blocks undergo micellization to fabricate a codelivery nanomedicine (P-BI@P-FA) by exploiting D-PAAs' noncovalent assembly. P-BI@P-FA improves the pharmacokinetics, tumor selectivity, and bioavailability of small molecule inhibitors and initiates a dual telomere-specific inhibition by combining telomerase deactivation with telomere disruption. Furthermore, a hybrid tumor-targeting magnetic nanosystem is designed using D-PAAs and manganese dioxide to showcase magnetic resonance imaging capacities. Our D-PAAs-based strategy addresses the pressing need for telomere-specific HCC treatment while allowing for diagnostic application, presenting a promising avenue for nanomedicine design.