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Excessive inflammation causes chronic diseases and tissue damage. Although there has been drug treatment, its side effects are relatively large. Searching for effective anti-inflammatory drugs from natural products has become the focus of attention. First isolated from Trichoderma longibraciatum, trichodimerol is a natural product with TNF inhibition. In this study, lipopolysaccharide (LPS)-induced RAW264.7 macrophages were used as a model to investigate the anti-inflammatory activity of trichodimerol. The results of nitric oxide (NO) detection, enzyme-linked immunosorbent assay (ELISA), and reactive oxygen species (ROS) showed that trichodimerol could reduce the production of NO, ROS, and the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α. Western blotting results showed that trichodimerol could inhibit the production of inflammatory mediators such as cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) and the protein expression of nuclear transcription factor-kappaB (NF-κB), p-IKK, p-IκB, Toll-like receptor 4 (TLR4), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), cysteinyl aspartate specific proteinase (Caspase)-1, and ASC, which indicated that trichodimerol may inhibit inflammation through the NF-κB and NLRP3 pathways. At the same time, molecular docking showed that trichodimerol can directly combine with the TLR4-MD2 complex. Hence, trichodimerol inhibits inflammation by obstructing the interaction between LPS and the TLR4-MD2 heterodimer and suppressing the downstream NF-κB and NLRP3 pathways.

Background: Excessive inflammation results in severe tissue damage as well as serious acute or chronic disorders, and extensive research has focused on finding new anti-inflammatory hit compounds with safety and efficacy profiles from natural products. As promising therapeutic entities for the treatment of inflammation-related diseases, fusaproliferin and its analogs have attracted great interest. However, the underlying anti-inflammatory mechanism is still poorly understood and deserves to be further investigated.Methods: For the estimation of the anti-inflammatory activity of fusaproliferin (1) and its analogs (2-4)in vitro and in vivo, lipopolysaccharide (LPS)-induced RAW264.7 macrophages and zebrafish embryos were employed. Then, transcriptome analysis was applied to guide subsequent western blot analysis of critical proteins in related signaling pathways. Surface plasmon resonance assays (SPR) combined with molecular docking analyses were finally applied to evaluate the affinity interactions between 1-4 and TLR4 and provide a possible interpretation of the downregulation of related signaling pathways.Results: 1-4 significantly attenuated the production of inflammatory messengers, including nitric oxide (NO), reactive oxygen species (ROS), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), as well as nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in LPS-induced RAW264.7 macrophages. Transcriptome analyses based on RNA-seq indicated the ability of compound 1 to reverse LPS stimulation and the nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPKs) signaling pathways contribute to the anti-inflammatory process. Experimental verification at the protein level revealed that 1 can inhibit the activation of inhibitor of NF-κB kinase (IKK), degradation of inhibitor of NF-κB (IκB), and phosphorylation of NF-κB and reduce nuclear translocation of NF-κB. 1 also decreased the phosphorylation of MAPKs, including p38, extracellular regulated protein kinases (ERK), and c-Jun N-terminal kinase (JNK). SPR assays and molecular docking results indicated that 1-4 exhibited affinity for the TLR4 protein with KD values of 23.5–29.3 μM.Conclusion: Fusaproliferin and its analogs can be hit compounds for the treatment of inflammation-associated diseases.

Background: Kawasaki disease (KD) is a self-limiting illness with acute systematic vascular inflammation. It causes pathological changes in mostly medium and small-sized arteries, especially the arteria coronaria, which adds the risk of developing coronary heart disease in adults.Materials and methods: We detected the miR-223-3p expression in 30 KD patients combined with 12 normal controls using miRNA microarrays and RT-PCR. A KD mouse model was constructed using Candida albicans water insoluble substance (CAWS). We also checked the miR-223-3p's expression using qRT-PCR. The Luciferase reporting system was implemented to validate the correlation between miR-223-3p and Interleukin-6 receptor subunit beta (IL-6ST). TNF-α was used to stimulate human coronary artery endothelial cells (HCAECs), and miR-223-3p activator or inhibitor and KD serum were used to treat HCAECs. A Western blotting automatic quantitative analysis protein imprinting system was used to test the expression of signal transducer and the activator of transcription 3 (STAT3), phosphorylated-signal transducer and the activator of transcription 3 (pSTAT3) and NF-κB p65.Results: Clinical trials found that miR-223-3p expressions were markedly different (more than 2-fold) between the acute KD group and the control group. E-selectin and intercellular cell adhesion molecule-1 (ICAM-1) levels were also significantly higher (about 2-fold) in KD especially with coronary artery lesions. MiR-223-3p could alleviate vascular endothelial damage in KD mice, and IL-6 (Interleukin-6), E-selectin and ICAM-1 were simultaneously negative. The values of IL-6, E-selectin, and ICAM-1 mRNA expressions decreased, while the value of IL-6ST was increased between the agonist treated mice and KD mice. The RT-qPCR consequences displayed that miR-223-3p explored the highest expression on the third day in both the KD mice as well as the agonist group. MiR-223-3p can directly combine with IL-6ST 3' untranslatable regions (UTR) and held back the IL-6's expression. Overexpression of miR-223 down regulated IL6ST expression and decreased the expression of p-STAT3 and NF-κB p65, while the miR-223 inhibitor could reverse the above process.Conclusion: MiR-223-3p is an important regulatory factor of vascular endothelial damage in KD and could possibly become a potential target of KD treatment in the future.

Interferon gamma (IFNγ) is a Th1 cytokine that is critical for innate and adaptive immunity. Toll-like receptors (TLRs) signaling pathways are critical in early host defense against invading pathogens. miR-146a has been reported to participate in the regulation of host immunity. The known mechanisms of integrations between the IFNγ and TLR signaling pathways are incompletely understood, especially in teleosts. In this study, orange-spotted grouper (Epinephelus coioides) IFNγ1 and IFNγ2, their biological activities, especially their involvements in TLR pathway, were explored. We identified and cloned two IFNγ genes of E. coioides, namely EcIFNγ1 and EcIFNγ2. The produced recombinant E. coioides IFNγ1 (rEcIFNγ1) and IFNγ2 (rEcIFNγ2) proteins showed functions, which are similar to those of other bony fishes, such as enhancing nitric oxide responses and respiratory burst response. rEcIFNγ2 could regulate TLR pathway by enhancing the promoter activity of miR-146a upstream sequence and thus increasing the expression level of miR-146a, which possibly targets TNF receptor-associated factor 6 (TRAF6), a key adapter molecule in TLR signaling pathway. Taken together, these findings unravel a novel regulatory mechanism of anti-inflammatory response by IFNγ2, which could mediate TLR pathway through IFNγ2–miR-146a–TRAF6 negative regulation loop. It is suggested that IFNγ2 may provide a promising therapeutic, which may help to fine tune the immune response.

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive inherited syndrome characterized by hyperkinetic movements, seizures, cognitive impairment, neuropsychiatric symptoms, elevated serum biochemical indicators and acanthocytes detection in peripheral blood smear. Vacuolar protein sorting 13A (VPS13A) gene mutations have been proven to be genetically responsible for the pathogenesis of ChAc. Herein, based on the typical clinical symptoms and neuroimaging features, we present two suspected ChAc cases which are further genetically confirmed by four novel VPS13A gene mutations. Nevertheless, the sharp contrast between the population base and published ChAc reports implies that ChAc is considerably underdiagnosed in China. Therefore, we conclude several suggestive features and propose a diagnostic path of ChAc from a clinical, genetic and neuroimaging perspective, aiming to facilitate the diagnosis and management of ChAc in China.

One evolutionary adaptation in motor activity control of animals is the anticipation of food that drives foraging under natural conditions and is mimicked in laboratory with daily scheduled food availability. Food anticipation is characterized by increased activity a few hours before the feeding period. Here we report that 2-h food availability during the normal inactive phase of rats not only increases activity levels before the feeding period but also alters the temporal organization of motor activity fluctuations over a wide range of time scales from minutes up to 24 h. We demonstrate this multiscale alteration by assessing fractal patterns in motor activity fluctuations—similar fluctuation structure at different time scales—that are robust in intact animals with ad libitum food access but are disrupted under food restriction. In addition, we show that fractal activity patterns in rats with ad libitum food access are also perturbed by lesion of the dorsomedial hypothalamic (DMH)—a neural node that is involved in food anticipatory behavior. Instead of further disrupting fractal regulation, food restriction restores the disrupted fractal patterns in these animals after the DMH lesion despite the persistence of the 24-h rhythms. This compensatory effect of food restriction is more clearly pronounced in the same animals after the additional lesion of the suprachiasmatic nucleus (SCN)—the central master clock in the circadian system that generates and orchestrates circadian rhythms in behavior and physiological functions in synchrony with day-night cycles. Moreover, all observed influences of food restriction persist even when data during the food anticipatory and feeding period are excluded. These results indicate that food restriction impacts dynamics of motor activity at different time scales across the entire circadian/daily cycle, which is likely caused by the competition between the food-induced time cue and the light-entrained circadian rhythm of the SCN. The differential impacts of food restriction on fractal activity control in intact and DMH-lesioned animals suggest that the DMH plays a crucial role in integrating these different time cues to the circadian network for multiscale regulation of motor activity.

For thousands of years, human beings have engaged in rhythmic activities such as drumming, dancing, and singing. Rhythm can be a powerful medium to stimulate communication and social interactions, due to the strong sensorimotor coupling. For example, the mere presence of an underlying beat or pulse can result in spontaneous motor responses such as hand clapping, foot stepping, and rhythmic vocalizations. Examining the relationship between rhythm and speech is fundamental not only to our understanding of the origins of human communication but also in the treatment of neurological disorders. In this paper, we explore whether rhythm has therapeutic potential for promoting recovery from speech and language dysfunctions. Although clinical studies are limited to date, existing experimental evidence demonstrates rich rhythmic organization in both music and language, as well as overlapping brain networks that are crucial in the design of rehabilitation approaches. Here, we propose the “SEP” hypothesis, which postulates that (1) “sound envelope processing” and (2) “synchronization and entrainment to pulse” may help stimulate brain networks that underlie human communication. Ultimately, we hope that the SEP hypothesis will provide a useful framework for facilitating rhythm-based research in various patient populations.

There is a need to identify biomarkers that predict degree of chronic speech fluency/language impairment and potential for improvement after stroke. We previously showed that the Arcuate Fasciculus lesion load (AF-LL), a combined variable of lesion site and size, predicted speech fluency in patients with chronic aphasia. In the current study, we compared lesion loads of such a structural map (i.e., AF-LL) with those of a functional map [i.e., the functional gray matter lesion load (fGM-LL)] in their ability to predict speech fluency and naming performance in a large group of patients. The fGM map was constructed from functional brain images acquired during an overt speaking task in a group of healthy elderly controls. The AF map was reconstructed from high-resolution diffusion tensor images also from a group of healthy elderly controls. In addition to these two canonical maps, a combined AF-fGM map was derived from summing fGM and AF maps. Each canonical map was overlaid with individual lesion masks of 50 chronic aphasic patients with varying degrees of impairment in speech production and fluency to calculate a functional and structural lesion load value for each patient, and to regress these values with measures of speech fluency and naming. We found that both AF-LL and fGM-LL independently predicted speech fluency and naming ability; however, AF lesion load explained most of the variance for both measures. The combined AF-fGM lesion load did not have a higher predictability than either AF-LL or fGM-LL alone. Clustering and classification methods confirmed that AF lesion load was best at stratifying patients into severe and non-severe outcome groups with 96% accuracy for speech fluency and 90% accuracy for naming. An AF-LL of greater than 4 cc was the critical threshold that determined poor fluency and naming outcomes, and constitutes the severe outcome group. Thus, surrogate markers of impairments have the potential to predict outcomes and can be used as a stratifier in experimental studies.

The growing interest in complementary interventions for stroke recovery necessitates the need for neural insights to aid in making evidence-based clinical decisions. This systematic review examined the brain activation effects of complementary therapies, including acupuncture (n = 5), motor imagery therapy (MIT) (n = 5), music (n = 3), and virtual reality (VR) interventions (n = 3), on clinical outcomes and neural activity in stroke patients. All therapies engaged motor and sensory networks, frontal regions, parietal regions, and temporal regions, suggesting their potential to improve motor control, attention, memory, and cognitive function. Acupuncture activated motor areas in both hemispheres, while MIT stimulated frontoparietal regions in both sides of the brain, supporting whole-body integration in recovery. In contrast, VR therapy exhibited ipsilesional lateralization, while music therapy showed left-lateralization. The review also found that increased interhemispheric connectivity between motor regions, along with intrahemispheric ipsilesional connectivity between motor, cognitive, and sensory areas, is key to achieving better clinical outcomes.Systematic Review Registrationhttp://www.crd.york.ac.uk/PROSPERO, identifier (ID: CRD42023455192).

Background and purposeThe immune response following aneurysmal subarachnoid hemorrhage (aSAH) can exacerbate secondary brain injury and impact clinical outcomes. As the immune response after aSAH is a dynamic process, we aim to track and characterize immune cell trajectories over time to identify patterns associated with various clinical outcomes.MethodsIn this retrospective single-center study of patients with aSAH, we analyzed immune cell count trajectories, including neutrophil, monocyte, and lymphocyte counts, collected from day 1 to day 14. These trajectories were classified into four distinct clusters utilizing the k-means longitudinal clustering method. A comprehensive multivariable analysis was performed to explore the associations of these immune cell clusters with various clinical outcomes. These outcomes included a Modified Rankin Scale score (mRS) of 3 to 6, indicative of poor functional outcomes, along with complications including shunt dependency, vasospasm, and secondary cerebral infarction.ResultsIn this study, 304 patients with aSAH were analyzed. The trajectories of immune cell counts, including neutrophils, monocytes, and lymphocytes, were successfully categorized into four distinct clusters for each immune cell type. Within neutrophil clusters, both persistent neutrophilia and progressive neutrophilia were associated with poor functional outcomes, shunt dependency, and vasospasm, with resolving neutrophilia showing a lesser degree of these associations. Within monocyte clusters, early monocytosis was associated with vasospasm, whereas delayed monocytosis was associated with shunt dependency. Within lymphocyte clusters, both early transient lymphopenia and early prolonged lymphopenia were associated with poor functional outcomes.ConclusionOur study demonstrates that distinct immune cell trajectories post-aSAH, identified through unsupervised clustering, are significantly associated with specific clinical outcomes. Understanding these dynamic immune responses may provide key insights with potential for future therapeutic strategies.

IntroductionPsoriasis, a persistent skin condition caused by the disorder of the immune system, impacts approximately 1.25 million individuals globally. Nevertheless, the presence of adverse effects in conventional clinical drugs necessitates further exploration of novel medications or combination therapies to mitigate these reactions and enhance their effectiveness.MethodsHence, our intention here in this paper is to utilize the lipid nanoparticle delivery system for overcoming the volatility and hydrophobic properties of α-pinene, a naturally occurring compound renowned for its anti-inflammatory and antiviral effects, and further explore its potential pharmacological applications both in vitro and in vivo.ResultsThe production of α-pinene lipid nanoparticles (APLNs) was achieved through the utilization of high pressure homogenization methods. APLNs was successfully fabricated with enhanced stability and water solubility. Meanwhile, the application of APLNs could drastically reduce the expression of lipopolysaccharide (LPS)-induced inflammation-related factors in THP-1 cells. Administration of APLNs to a mouse model of auricular swelling could effectively reduce redness and swelling in the auricles of mice as well. Furthermore, APLNs were also found to alleviate skin damage in mice with Imiquimod (IMQ)-induced psoriasis model, as well as decrease the levels of psoriasis-related protein nuclear factor kappa-B (NF-κB) and interleukin-17 (IL-17), interleukin-23 (IL-23), and other inflammation-related cytokines. More importantly, utilization of APLNs successfully mitigated the systemic inflammatory reactions in mice, resulting in the reduction of spleen-to-body ratio (wt%) and of inflammatory cytokines’ expression in the serum.DiscussionOverall, our results suggest that with the help of lipid nanoparticle encapsulation, APLNs possess a better pharmacological effect in anti-inflammation and could potentially serve as an anti-psoriasis drug.

Chimeric antigen receptor T (CAR-T) cell therapy is a new treatment for cancers, but reports on curing immune-related skin diseases are limited. We report a case of successful CAR-T-cell therapy in a patient with refractory/relapsed diffuse large B-cell lymphoma (R/R DLBCL) who was incidentally cured of chronic generalized plaque psoriasis. The patient, a 65-year-old male who had a known history of psoriasis for 45 years, did not receive immunotherapy for psoriasis during this period. Imaging, molecular biology and immunology diagnostics confirmed DLBCL. After several weeks of standard-dose R-CHOP chemotherapy, the patient achieved partial remission, but according to CT, the patient relapsed, and there was no significant improvement in her psoriasis symptoms. Subsequently, the patient was enrolled in the CD19 CAR-T-cell therapy group. Four weeks after CAR-T-cell infusion, the patient’s abdominal pain disappeared, and there was a significant improvement in overall skin lesions. One year later, follow-up results indicated complete remission of R/R DLBCL (confirmed by PET-CT), with only minimal residual psoriatic skin lesions limited to the patient’s neck. The results of using CAR-T-cell therapy to achieve an incidental cure for psoriasis highlight the potential for exploring cell-based therapies for complex autoinflammatory skin diseases.

BackgroundRegulated cell death (RCD) is a genetically controlled form of cell death that plays an important role in organogenesis, tissue remodeling, and pathogenesis of cancers. Transforming growth factor-beta-activation kinase 1 (TAK1) is a member of the serine/threonine protein kinase family, which can respond to internal and external stimuli and participate in inflammatory responses through multiple signaling pathways and cellular processes. In the last two decades, the regulatory roles of TAK1 at the crossroads of multiple RCD pathways, including apoptosis, necroptosis, pyroptosis, and PANoptosis were revealed by 801 articles retrieved from the Web of Science Core Collection database. To analyze global research trends and hotspots concerning the role of TAK1 in RCD, the bibliometric and visualized analysis were applied in the current study.MethodsThe data for this bibliometrics study were retrieved from the Web of Science Core Collection database. The search formula was (TS=(Apoptosis) OR TS=(pyroptosis) OR TS=(Necroptosis) OR TS=(PANoptosis) OR TS=(Autophagy) OR TS=(Ferroptosis) OR TS=(cuproptosis)) AND ((TS=(TAK1)) OR TS=(MAP3K7)). The co-occurrence and co-cited analysis on basic bibliometric parameters were conducted by VOSviewer. The dual-map overlay of journals, citation bursts, keyword timelines, and keyword bursts were analyzed by CiteSpace.ResultsA total of 801 articles from 46 countries have been included in the analysis. The number of publications demonstrates a consistent increase from 1999 to 2024. The primary research institutions driving this field are Osaka University Notably, the Journal of Biological Chemistry stands out as the most popular journal in this domain. These publications collectively involve contributions from 4663 authors, with Jun Tsuji emerging as a prolific author. Jun Tsuji also gains the highest co-citation frequency. Emerging research hotspots are encapsulated by keywords, including apoptosis, NF-κB, inflammation, autophagy, and TNFα.ConclusionThis is the first bibliometric and visualized study to analyze the global trends and hotspots of TAK1 in RCD. Based on the analysis of 801 articles, the results provide a retrospective and comprehensive visualized view of the research hotspots and frontiers of TAK1 at the crossroads of multiple RCD signaling pathways and propose ideas for guiding their future investigations in molecular mechanisms and therapeutic strategies in this field.

In Taiwan, lung cancer remains the leading cause of cancer-related fatalities, resulting in substantial healthcare expenses. This research aims to evaluate both the frequency and the costs of low-dose computed tomography (LDCT) in individuals suspected of having lung cancer until their diagnosis of cancer. LDCT screening was not conducted on a population-wide scale, and asymptomatic participants had to cover the expenses for the screening personally or reimburse from other sources. If the screening results were positive or suspicious, National Health Insurance (NHI) could be utilized for subsequent follow-up examinations. This cohort study utilized the NHI Database and focused on individuals with suspected cases of lung cancer identified between 2010 and 2014. A total of 17,572 suspected new lung cancer cases were initially identified and assigned to the relevant International Classification of Diseases codes. Individuals with suspected lung cancer received a diagnosis following an average follow-up period of 2.24 (95%CI, 2.11-2.37) years, and required the use of 2.36 (95%CI, 2.20-2.51) repeated CT scans. The NHI expenditures incurred by the use of CT scans for monitoring suspected lung cancer cases were relatively modest.

The sustainable performance of higher education institutes (HEIs) is key to efficiently manage educational institutes in the long run, to get financial aid from the government, and to keep the interest of stakeholders in the institutions. Researchers have focused on examining the impact of a sustainable curriculum, sustainable teaching methodologies, sustainable campuses, and tools for assessing sustainability in HEIs in past literature. The present bibliometric analysis, combined with network analysis, aims to explore the literature to identify research gaps in the field of sustainable performance or sustainability performance of HEIs. We have employed a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram to analyze the results obtained from Scopus, Web of Science (WoS), and EBSCOhost databases. A bibliometric analysis using Biblioshiny web application and VOSviewer software was performed on the 263 articles included in the study after screening. The results revealed that the annual growth rate of publications is increasing, indicating that the sustainability performance of HEIs is gaining momentum after the introduction of the Sustainable Development Goals (SDGs) in 2017. The production of articles in the field is highest from advanced European countries and the United States, but only a few articles are published from Asian countries. The authors with the highest number of publications and the most cited research article in the field are Leal Filho and Wals, respectively. Authors keywords in HEIs (or institutions) not only have a strong link with sustainability, sustainable education, green campus, and sustainability assessment but also have a small network with sustainable performance, green knowledge sharing, green knowledge management, green human resource management practices, green teams, change management, and organizational commitment. These findings can be used by future researchers to identify unexplored research areas in different contexts.

The objective of this review is to examine the potential benefits and challenges of CT-based lung function imaging in radiotherapy over recent decades. This includes reviewing background information, defining related concepts, classifying and reviewing existing studies, and proposing directions for further investigation. The lung function imaging techniques reviewed herein encompass CT-based methods, specifically utilizing phase-resolved four-dimensional CT (4D-CT) or end-inspiratory and end-expiratory CT scans, to delineate distinct functional regions within the lungs. These methods extract crucial functional parameters, including lung volume and ventilation distribution, pivotal for assessing and characterizing the functional capacity of the lungs. CT-based lung ventilation imaging offers numerous advantages, notably in the realm of thoracic radiotherapy. By utilizing routine CT scans, additional radiation exposure and financial burdens on patients can be avoided. This imaging technique also enables the identification of different functional areas of the lung, which is crucial for minimizing radiation exposure to healthy lung tissue and predicting and detecting lung injury during treatment. In conclusion, CT-based lung function imaging holds significant promise for improving the effectiveness and safety of thoracic radiotherapy. Nevertheless, challenges persist, necessitating further research to address limitations and optimize clinical utilization. Overall, this review highlights the importance of CT-based lung function imaging as a valuable tool in radiotherapy planning and lung injury monitoring.

BackgroundBell palsy (BP) is the most common cause of acute peripheral facial palsy which leads to functional and esthetic disturbances in patients and has a negative influence on daily living. Electroacupuncture (EA) has been considered an alternative treatment for improving facial function in patients with BP. However, there is no agreement on the preferred waveform type of the EA for treating BP.MethodsThis is a study protocol for a pilot randomized, two-arm, three-center, clinical trial at the Third Affiliated hospital of Zhejiang Chinese Medical University, the First Affiliated hospital of Zhejiang Chinese Medical University, and the Hangzhou First People’s Hospital. The trial began in November 2023 and is expected to end in December 2025. Sixty patients with BP whose electroneurography (ENoG) value is at least 20% and 60 patients with BP whose ENoG value is less than 20% will be randomly assigned to the low frequency continuous waveform group or the intermittent waveform group in a 1:1 ratio. Participants will receive 4 weeks of EA treatment and clinical assessments. The primary outcome is the change from baseline score of the Facial Nerve Grading System 2.0. The secondary outcomes include the change from baseline score of the Sunnybrook grading scale and the change from baseline amplitude of the compound muscle action potential of the affected side in the ENoG tests.DiscussionThis is the first study protocol to compare the treatment effect and safety of EA with low frequency continuous waveform and intermittent waveform for different severity groups of BP. This study will contribute to subsequent studies for exploring optimal EA parameters for BP treatment.Clinical trial registrationClinicalTrials.gov, NCT06063954.

ObjectiveWe previously developed the use of side to side (s-s) bypass for the treatment of adult moyamoya disease (MMD) and discovered several kinds of distinct blood flow models intraoperatively, which we observed through indocyanine green-video angiography (ICG-VA). The purpose of this paper was to investigate the correlation between blood flow model (BFM) identified in s-s bypass and the incidence of postoperative cerebral hyperperfusion syndrome (CHS) among patients with MMD.MethodsWe analyzed 166 hemispheres from 153 patients diagnosed with MMD, including 118 hemispheres with s-s bypass and 48 with end to side (e-s) bypass. We categorized the enrolled patients into three pairs of comparison groups based on postoperative CHS (CHS or non-CHS) in s-s bypass, blood flow models (BFM I or BFM II) and surgical approach (s-s bypass or e-s bypass). Patients’ demographics and characteristics were compared between groups.ResultsAmong patients who developed CHS, the occurrence of BFM I was more frequent than that of BFM II (0.154 vs. 0.019, p = 0.029 0.05), BFM I group showed no discrepancy (10/65, 0.154, p = 0.906 > 0.05) while BFM II group was different (1/53, 0.019, p = 0.047

BackgroundImmunity reconstitution (IR) is crucial for pediatric patients undergoing hematopoietic stem cell transplantation (HSCT), but the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on lymphocyte subsets post-transplant remains unclear. Therefore, we assessed immune cell dynamics in children after SARS-CoV-2 infection.MethodsWe enrolled 42 children, including 21 post-HSCT SARS-CoV-2 infected and 21 matched, non-infected historical controls (1:1 matching based on propensity scores). The time from HSCT to SARS-CoV-2 infection in the infected group was determined by the beginning of follow-up for the non-infected group. The primary endpoint was 270-day IR kinetics post-infection.ResultsOur findings showed similar recovery trends between the infected group and non-infected group both in UCB and HID recipients. In the UCB cohort, the NK cell reconstitution in the infected group was poorer compared to the non-infected group, but this difference did not reach statistical significance (P = 0.178). Furthermore, HID transplantation might be a trend towards poor CD19+ T-cell reconstitution [hazard ratio (HR): 0.43, 95% CI: 0.18–1.04, p = 0.06]. No statistically significant difference was observed in terms of secondary infections across the UCB (P = 0.150) and HID (P = 0.980) cohorts as well as there was no discernible difference in overall survival between the two groups (P = 1).ConclusionsOur analysis reveals that SARS-CoV-2 might temporarily impaired the IR process in the short term, with recovery to a comparable trend as observed in non-infected patients approximately 9 months post-infection.

Epilepsy is an irregular and recurrent cerebral dysfunction that significantly impacts the affected individual's social functionality and quality of life. This study aims to integrate cognitive dynamic attributes of the brain into seizure prediction, evaluating the effectiveness of various characterization perspectives for seizure prediction, while delving into the impact of varying fragment lengths on the performance of each characterization. We adopted microstate analysis to extract the dynamic properties of cognitive states, calculated the EEG-based and microstate-based features to characterize nonlinear attributes, and assessed the power values across different frequency bands to represent the spectral information of the EEG. Based on the aforementioned characteristics, the predictor achieved a sensitivity of 93.82% on the private FH-ZJU seizure dataset and 93.22% on the Siena Scalp EEG dataset. The study outperforms state-of-the-art works in terms of sensitivity metrics in seizure prediction, indicating that it is crucial to incorporate cognitive dynamic attributes of the brain in seizure prediction.

BackgroundPrimary healthcare policies are widely implemented globally. However, many people with chronic diseases find that community-based chronic disease services do not meet their needs. There is a critical need for more evidence on the sustainability and optimization of chronic disease management in Chinese communities, especially from the demand side. Policymakers require detailed data on the needs of chronic disease patients regarding community health services.MethodsA discrete choice experiment was conducted to measure the preferences of people with chronic diseases. Researchers recruited participants in Sichuan Province, China, and conducted face-to-face surveys. The mixed logit model evaluated participants’ preferences for six attributes, estimating willingness to pay and relative importance, and performing subgroup analysis based on the initial model results.ResultsA total of 395 respondents participated in this study. Six attributes included all influenced the preference of people with chronic diseases for community health services. The most valued attribute for people with chronic diseases was drug accessibility (coefficient = 2.761, p

IntroductionAerobic composting is an effective method for utilizing chicken manure. However, its low carbon to nitrogen (C/N) ratio leads to slow heating and short high-temperature phases, which reduce composting efficiency and product quality.MethodsTo address this issue, splinted mushroom cultivation residues were added to adjust the C/N ratio, and exogenous thermophilic composting strains were introduced to increase composting temperature. This study analyzed the relationship between physicochemical metabolites and microbial community structure during high-temperature chicken manure composting.Results and discussionBased on metagenomic and physicochemical analyses, results showed that the exogenous microbial agents extended the thermophilic phase by three-times, reduced the heating phase duration by 75%, and increased nitrogen, phosphorus, potassium, and soluble organic carbon contents by 3.61, 21.63, 7.21, and 39.03%, respectively. Genes associated with amino acid metabolism were significantly enriched during the heating phase, while genes involved in the tricarboxylic acid cycle were more active in the thermophilic phase. During the thermophilic phase, bacterial diversity and richness decreased compared to the heating and cooling phases. Functional microbes such as Bacillus, Caldicoprobacter, and Virgibacillus showed a positive correlation with the key differential metabolites. While Actinomadura, Saccharomonospora, Paenibacillus, and Aneurinibacillus displayed an opposite correlation. Further experiments demonstrated that the increased temperature during the thermophilic phase triggered the upregulation of oleic acid metabolism and piperidine metabolism pathways in functional microorganisms, leading to the production of heat stabilizers and protective agents like oleic acid, gallic acid, and 2-piperidone. This phenomenon helped maintain microbial viability during the thermophilic phase and improved composting efficiency.

IntroductionUreaplasma urealyticum (UU) is a common pathogen associated with genital tract infections in infertile males. However, its impact on semen quality, embryo development, and in vitro fertilization (IVF) outcomes remains underexplored. This study aims to evaluate the effect of male UU infection on semen parameters, embryo development, pregnancy outcomes, and neonatal health in infertile couples.MethodsA retrospective analysis was conducted on 1,215 infertile couples at the First Hospital of USTC. Participants were divided into two groups based on the male partner’s UU infection status: UU-positive (n=249) and UU-negative (n=966). Semen parameters (sperm concentration, motility, morphology, anti-sperm antibodies, DNA stainability) were assessed. Embryo development was evaluated through fertilization rates and blastocyst formation rates. Pregnancy outcomes (clinical pregnancy, live birth rates, miscarriage rate) and neonatal health (gestational age, birth weight, Apgar scores, preterm delivery) were also compared.ResultsSemen parameters, including sperm concentration, motility, and morphology, were similar between the UU-positive and UU-negative groups. However, the UU-positive group had significantly higher levels of anti-sperm antibodies (ASA) (p=0.020) and higher DNA stainability (HDS) (p=0.014). Despite these differences, embryo quality, as measured by fertilization rates and blastocyst formation rates, was not significantly different between the two groups. Pregnancy outcomes, including clinical pregnancy and live birth rates, were also comparable. While the UU-positive group had a slightly higher miscarriage rate, this difference was not statistically significant. Neonatal outcomes, including gestational age, birth weight, Apgar scores, and preterm delivery rate, did not differ significantly between the two groups.DiscussionThe study suggests that while male UU infection may adversely affect certain semen parameters, its impact on IVF outcomes—such as embryo quality, pregnancy rates, and neonatal health—appears to be minimal. These findings support the continued use of IVF as a viable and safe option for infertile couples with male UU infection, as it does not significantly influence reproductive or neonatal outcomes.

Predicting the ocean state in a reliable and interoperable way, while ensuring high-quality products, requires forecasting systems that synergistically combine science-based methodologies with advanced technologies for timely, user-oriented solutions. Achieving this objective necessitates the adoption of best practices when implementing ocean forecasting services, resulting in the proper design of system components and the capacity to evolve through different levels of complexity. The vision of OceanPrediction Decade Collaborative Center, endorsed by the UN Decade of Ocean Science for Sustainable Development 2021-2030, is to support this challenge by developing a “predicted ocean based on a shared and coordinated global effort” and by working within a collaborative framework that encompasses worldwide expertise in ocean science and technology. To measure the capacity of ocean forecasting systems, the OceanPrediction Decade Collaborative Center proposes a novel approach based on the definition of an Operational Readiness Level (ORL). This approach is designed to guide and promote the adoption of best practices by qualifying and quantifying the overall operational status. Considering three identified operational categories - production, validation, and data dissemination - the proposed ORL is computed through a cumulative scoring system. This method is determined by fulfilling specific criteria, starting from a given base level and progressively advancing to higher levels. The goal of ORL and the computed scores per operational category is to support ocean forecasters in using and producing ocean data, information, and knowledge. This is achieved through systems that attain progressively higher levels of readiness, accessibility, and interoperability by adopting best practices that will be linked to the future design of standards and tools. This paper discusses examples of the application of this methodology, concluding on the advantages of its adoption as a reference tool to encourage and endorse services in joining common frameworks.

BackgroundCognitive impairment and frailty are common issues in older adults. Understanding the co-development trajectories of these conditions can provide valuable sights for early detection and intervention in high-risk individuals.ObjectivesThis study aims to identify the co-development of cognitive function and frailty and explore the associated characteristics.MethodsWe analyzed data from 8,418 individuals aged 55 years and above who participated in the China Health and Retirement Longitudinal Survey between 2011 and 2018. Group-based dual trajectory modeling and logistic regression were used to identify trajectory groups and assess associations with risk factors.ResultsTwo distinct dual trajectories were identified: “Consistently Robust” group (76.12%) and “Consistently Severe” group (23.88%). Factors such as being female, older age, lower levels of education, residing in rural areas, being unmarried, and having comorbidities such as hypertension, diabetes, complete tooth loss, vision impairment, or hearing impairment were associated with a higher likelihood of being assigned to the “Consistently Severe” group.ConclusionOur findings suggest a co-development pattern between cognitive function and frailty in Chinese older adults aged 55 years and above. While cognitive impairment may be irreversible, frailty is a condition that can be potentially reversed. Early detecting is crucial in preventing cognitive decline, considering the shared trajectory of these conditions.

ObjectiveThis study aimed to investigate the causal relationship between insomnia and the risk of myocardial infarction (MI) and explore potential mediators such as smoking initiation, alcohol consumption and body mass index (BMI) using mendelian randomization (MR) analysis.MethodsData from 1,207,228 individuals of European ancestry were obtained from the UK Biobank and 23andMe for insomnia-related genetic associations. Genetic instruments for MI, smoking initiation, alcohol consumption, and BMI were derived from large-scale genome-wide association studies. Univariate MR analysis mainly utilized the inverse variance weighting method, and multivariable MR analysis assessed the mediation effects of smoking initiation and BMI.ResultsThe univariate MR analysis revealed a 96% increased risk of MI in individuals with insomnia [odds ratio (OR) = 1.96; 95% CI: 1.67, 2.31]. Smoking initiation and BMI were identified as potential mediators. The multivariable MR analysis indicated smoking initiation accounted for 29% of the total effect (95% CI: 13%, 61%), while BMI accounted for 15% (95% CI: 7%, 27%), with a combined mediation proportion of 54% (95% CI: 31%, 91%).ConclusionsThe results of this MR analysis demonstrate that insomnia increases the risk of MI. Quitting smoking and losing weight may reduce this risk; however, there is still a portion of the impact of insomnia on MI that cannot be explained. Therefore, further investigation into other potentially modifiable intermediate factors is necessary.

BackgroundRecently, serum metabolites have shown potential in predicting survival outcomes and may be related to the pathogenesis of prostate cancer. Nevertheless, the precise impact concerning the genetic effect of metabolites on prostate cancer risk remains obscure. In this context, we conducted a Mendelian randomization (MR) study aiming to explore the causality between genetically determined metabolites and the risk of prostate cancer.MethodsWe conducted a two-sample MR analysis aiming to identify the underlying metabolites associated with prostate cancer. Exposure information was obtained from the largest metabolome-based genome-wide association (GWAS) data containing 7,824 Europeans. Genome-wide association analysis was utilized to detect instrumental variables (IVs) for metabolites. We applied the inverse-variance weighted (IVW) approach as the primary method, and to augment the reliability and robustness of our findings, additional analysis methods encompassing weighted median, MR-Egger, and leave-one-out analysis were utilized. MR-Egger intercept test was implemented to explore the pleiotropy. Cochran’s Q test was utilized to quantify the degree of heterogeneity. Additionally, we performed metabolic pathway analysis and single-cell RNA sequencing analysis.ResultsWe found that three serum metabolites were causally associated with prostate cancer after utilizing rigorous screening standards. Utilizing single nucleotide polymorphisms as IVs, a 1-SD increase in fructose was associated with 77% higher risk of prostate cancer (OR:1.77, 95%CI: 1.05-2.97, PIVW=0.031), a 1-SD increase in N1-methyl-3-pyridone-4-carboxamide was associated with 29% higher risk of prostate cancer (OR:1.29, 95%CI: 1.05-1.58, PIVW=0.017), and a 1-SD increase in 12-hydroxyeicosatetraenoate (12-HETE) was associated with 18% higher risk of prostate cancer (OR:1.18, 95%CI: 1.07-1.31, PIVW=0.0008). Metabolites that were causally linked to the risk of prostate cancer were mainly enriched in the valine, leucine and isoleucine biosynthesis pathway (P=0.026) and the nicotinate and nicotinamide metabolism pathway (P=0.048).ConclusionsOur MR analysis provided suggestive evidence supporting the causal relationships between three identified serum metabolites and prostate cancer, necessitating further investigation to elucidate the underlying mechanisms through which these blood metabolites and metabolic pathways may impact the initiation and progression of prostate cancer.

Diabetes mellitus (DM), a major global health concern, is a chronic metabolic disorder. Bioactive compounds sourced from numerous marine natural products recently have drawn attention as novel therapeutic approaches. Considering these chemicals and their role in cellular redox modulation by involving the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway, the current study attempts to highlight their anti-diabetic effects and the molecular mechanisms involved. Reactive oxygen species (ROS)-mediated oxidative stress, inflammation, and cellular damage are linked to most human pathologies specifically DM. The Nrf2/HO-1 pathway is a key defense mechanism developed by the cells to combat ROS burst. Marine natural compounds have strong pharmacological potential in triggering cellular antioxidant defense mechanisms by declining oxidative damage and inflammation linked to DM. How marine natural products potentially alleviate DM specifically type 2 diabetes (T2D) and its related issues is especially focused on. The literature was thoroughly analyzed to open a discussion about specific marine compounds and their well-established anti-diabetic effects to elucidate possible therapeutic applications. Furthermore, opportunities and the pros and cons of using these marine bioactive compounds as complementary treatment for DM are also discussed. The diverse characteristics of marine natural products, specifically with regard to redox control, offer promising opportunities for drug discovery and therapeutic interventions in clinical trials.

Duck adeno-associated Virus (DAAV) is a novel pathogen that was recently discovered in ducks. To establish a molecular detection assay for DAAV for further epidemiological investigation and pathogenic mechanism. Here, we designed specific primers and probes according to the sequence characteristics of the newly discovered DAAV and then established a TaqMan real-time PCR method (TaqMan-qPCR) for the detection of DAAV. Our data showed that the established TaqMan-qPCR for detecting DAAV had high sensitivity, with the lowest detection limit of 29.1 copies/μL. No cross reaction was found with duck circovirus (DuCV), H9N2 subtype avian influenza virus (AIV), avian Tembusu virus (ATmV). duck hepatitis A virus 1 and 3 (DHAV-1 and DHAV-3), duck adenovirus A (DAdV-A), duck adenovirus 3 (DAdV-3), or duck enteritis virus (DEV). The repeatability was excellent, with the coefficients of variation of repeated intragroup and intergroup tests ranging from 0.12–0.21% and 0.62–1.42%, respectively. Seventy-eight clinical samples collected from diseased or deceased ducklings were tested. The results showed that the DAAV positive rate was 21.79%, and a triple infection (DAAV+MDPV+GPV) was found. These data provide technical support for further molecular epidemiological surveillance and pathogenic mechanism studies of DAAV infection.

ObjectivesOver the years when disease-modifying antirheumatic drugs (DMARDs) have been used in rheumatoid arthritis patients, reports of malignancies have emerged. This study aims to investigate the association between malignancies and DMARDs by using data extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS).MethodsFAERS data (January 2019 to December 2023) were reviewed. For each drug-event pair, the disproportionality analysis was conducted to evaluate the risk of malignancy. Multivariate logistic regression was implemented to mitigate potential biases. Moreover, the time to onset of malignancy was also evaluated.ResultsWe conducted a detailed search for rheumatoid arthritis indications and identified a total of 17,412 adverse event reports associated with malignancies, with selective DMARDs designated as the role code “primary suspect”. At the preferred term level, there were 198 positive signals, among which the lower limit of the 95% confidence interval for the information component is 3.55 for squamous cell carcinoma of the skin, 2.39 for breast cancer, and 2.27 for lymphoproliferative disorder. In comparison to other DMARDs, targeted synthetic DMARDs were associated with a broader range of malignancies at both preferred term and Standardized MedDRA Queries levels. The number of adverse events reported in female patients is approximately 2–3 times higher than men, and the median age across the population was approximately 62 years. In terms of onset time, the conventional synthetic DMRADs exhibited a relatively longer median time, ranging from 3.58 to 7.08 years, while the targeted synthetic DMARDs demonstrated a shorter median time of 0.83–1.67 years.ConclusionOur study uncovers varying degrees of malignancy risks related to DMARDs, with a significantly higher risk observed in targeted synthetic DMARDs. Additionally, novel malignancy signals, not documented in product labels, have been detected. In the future, further research will be necessary to validate our findings.

Inflammatory bowel disease (IBD) is a chronic, systemic gastrointestinal disorder characterized by episodic inflammation that requires life-long management. Although the etiology of IBD is not fully understood, it is hypothesized to involve a multifaceted interplay among genetic susceptibility, the host immune response, and environmental factors. Previous studies have largely concluded that IBD is associated with this complex interplay; however, more recent evidence underscores the significant role of dietary habits as risk factors for the development of IBD. In this review, we review the molecular mechanisms of high-sugar and high-fat diets in the progression of IBD and specifically address the impacts of these diets on the gut microbiome, immune system regulation, and integrity of the intestinal barrier, thereby highlighting their roles in the pathogenesis and exacerbation of IBD.

Biological dinitrogen (N2) fixation, the energetically expensive conversion of N2 gas to ammonia, plays an essential role in balancing the nitrogen budget in the ocean. Accumulating studies show detectable N2 fixation rates below the euphotic zone in various marine systems, revealing new insights of marine N2 fixation. However, the reported rates are highly variable and frequently fall close to detection limits, raising the question of the ubiquity and significance of N2 fixation in the global dark ocean. Using highly sensitive isotopic labeling incubation including a set of control incubations, we confirm the occurrence of mesopelagic N2 fixation in the South China Sea. Interestingly, we consistently observed that ca. 30% of samples show a significant elevation of 15N in the particulate nitrogen after incubation at most depths (200 - 1000 m). Although this approach does not allow accurate quantification of N2 fixation rates, our data suggest the occurrence of dark N2 fixation yet with highly heterogeneous signals in the mesopelagic zone of the South China Sea. A data compilation of reported N2 fixation in the global dark ocean further reveals that such heterogeneity has also been observed elsewhere, unveiling the ubiquitous heterogeneity in mesopelagic N2 fixation. Thus, we call for more observations to constrain mesopelagic N2 fixation budgets and to understand the underlying mechanism for such heterogeneity.

Fish segmentation in underwater videos can be used to accurately determine the silhouette size of fish objects, which provides key information for fish population monitoring and fishery resources survey. Some researchers have utilized underwater optical flow to improve the fish segmentation accuracy of underwater videos. However, the underwater optical flow is not evaluated and screen in existing works, and its predictions are easily disturbed by motion of non-fish. Therefore, in this paper, by analyzing underwater optical flow data, we propose a robust underwater segmentation network, RUSNet, with adaptive screening and fusion of input information. First, to enhance the robustness of the segmentation model to low-quality optical flow inputs, a global optical flow quality evaluation module is proposed for evaluating and aligning the underwater optical flow. Second, a decoder is designed by roughly localizing the fish object and then applying the proposed multidimension attention (MDA) module to iteratively recover the rough localization map from the spatial and edge dimensions of the fish. Finally, a multioutput selective fusion method is proposed in the testing stage, in which the mean absolute error (MAE) of the prediction using a single input is compared with that obtained using multisource input. Then, the information with the highest confidence is selected for predictive fusion, which facilitates the acquisition of the ultimate underwater fish segmentation results. To verify the effectiveness of the proposed model, we trained and evaluated it using a publicly available joint underwater video dataset and a separate DeepFish public dataset. Compared with the advanced underwater fish segmentation model, the proposed model has greater robustness to low-quality background optical flow in the DeepFish dataset, with the mean pixel accuracy (mPA) and mean intersection over union (mIoU) values reaching 98.77% and 97.65%, respectively. On the joint dataset, the mPA and mIoU of the proposed model are 92.61% and 90.12%, respectively, which are 0.72% and 1.21% higher than those of the advanced underwater video object segmentation model MSGNet. The results indicate that the proposed model can adaptively select the input and accurately segment fish in complex underwater scenes, which provides an effective solution for investigating fishery resources.

BackgroundMost epithelial ovarian cancer (EOC) eventually develops recurrence. Identification of high-risk patients can prompt earlier intervention and improve long-term outcomes. We used laboratory and clinical data to create models based on machine learning for EOC platinum resistance recurrence identification.MethodsThis study was designed as a retrospective cohort analysis. Initially, we identified 1,392 patients diagnosed with epithelial ovarian cancer who underwent platinum-based chemotherapy at Yunnan Cancer Hospital between January 1, 2012, and June 30, 2022. We collected data on the patients’ clinicopathologic characteristics, routine laboratory results, surgical information, details of chemotherapy regimens, and survival outcomes. Subsequently, to identify relevant variables influencing the recurrence of platinum resistance, we screened thirty potential factors using two distinct variable selection methods: Lasso regression and multiple logistic regression analysis. Following this screening process, five machine learning algorithms were employed to develop predictive models based on the selected variables. These included decision tree analysis (DTA), K-Nearest neighbor (KNN), support vector machine (SVM), random forest (RF), and eXtreme gradient boosting (XGBoost). The performance of these models was compared against that of traditional logistic regression. To ensure robust internal validation and facilitate comparison among model performance metrics, a five-fold cross-validation method was implemented. Key performance indicators for the models included the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and average accuracy. Finally, we will visualize these models through nomograms, decision tree diagrams, variable importance plots, etc., to assist clinicians in their practice.ResultsMultiple logistic regression analysis identified eight variables associated with platinum resistance recurrence. In the lasso regression, seven variables were selected. Based on the findings from both Lasso regression and multiple logistic regression analysis, models were developed using these 7 and 8 factors. Among these, the XGBoost model derived from multiple logistic regression exhibited superior performance and demonstrated good discrimination during internal validation, achieving an AUC of 0.784, a sensitivity of 0.735, a specificity of 0.713, an average accuracy of 80.4%, with a cut-off value set at 0.240. Conversely, the LR model based on lasso regression yielded commendable results as well; it achieved an AUC of 0.738, a sensitivity of 0.541, a specificity of 0.836, with a cut-off value established at 0.154 and an accuracy rate of 79.6%. Finally, we visualized both models through nomograms to illustrate the significance of each variable involved in their development.ConclusionsWe have successfully developed predictive models for platinum-resistant recurrence of epithelial ovarian cancer, utilizing routine clinical and laboratory data. Among these models, the XGBoost model—derived from variables selected through multiple logistic regression—demonstrated the best performance. It exhibited high AUC values and average accuracy during internal validation, making it a recommended tool for clinical use. However, due to variations in time and context, influencing factors may change over time; thus, continuous evolution of the model is necessary. We propose a framework for this ongoing model adaptation.

The application of micro/nanomotors (MNMs) in the gastrointestinal tract has become a Frontier in the treatment of gastrointestinal diseases. These miniature robots can enter the gastrointestinal tract through oral administration, achieving precise drug delivery and therapy. They can traverse mucosal layers and tissue barriers, directly targeting tumors or other lesion sites, thereby enhancing the bioavailability and therapeutic effects of drugs. Through the application of nanotechnology, these MNMs are able to accomplish targeted medication release, regulating drug release in response to either external stimuli or the local biological milieu. This results in reduced side effects and increased therapeutic efficacy. This review summarizes the primary classifications and power sources of current MNMs, as well as their applications in the gastrointestinal tract, providing inspiration and direction for the treatment of gastrointestinal diseases with MNMs.

In the development of quantum technologies, a reliable means for characterizing quantum devices, be it a measurement device, a state-preparation device, or a transformation device, is crucial. However, the conventional approach based on, for example, quantum state tomography or process tomography relies on assumptions that are often not necessarily justifiable in a realistic experimental setting. Although the device-independent (DI) approach to this problem bypasses the shortcomings above by making only minimal, justifiable assumptions, most of the theoretical proposals to date only work in the idealized setting where independent and identically distributed (i.i.d.) trials are assumed. Here, we provide a versatile solution for rigorous device-independent certification that does not rely on the i.i.d. assumption. Specifically, we describe how the prediction-based ratio (PBR) protocol and martingale-based protocol developed for hypothesis testing can be applied in the present context to achieve a device-independent certification of desirable properties with confidence interval (CI). To illustrate the versatility of these methods, we demonstrate how we can use them to certify—with finite data—the underlying negativity, Hilbert space dimension, entanglement depth, and fidelity to some target pure state. In particular, we provide examples showing how the amount of certifiable negativity and fidelity scales with the number of trials and how many experimental trials one needs to certify a qutrit state space or the presence of genuine tripartite entanglement. Overall, we have found that the PBR protocol and the martingale-based protocol often offer similar performance, even though the latter does have to presuppose any witness (Bell-like inequality). In contrast, our findings also show that the performance of the martingale-based protocol may be severely affected by one’s choice of Bell-like inequality. Intriguingly, a Bell function useful for self-testing does not necessarily give the optimal confidence-gain rate for certifying the fidelity to the corresponding target state.

Classic Formulas (Jing fang) are considered the essence and authority of Traditional Chinese Medicine (TCM) due to their long history and proven efficacy. These formulas play a pivotal role in all kinds of different disease prevention and therapeutic strategies. Yiyi Fuzi Baijiang San (YYFZBJS), one of the Classic Formulas, was originally developed for the treatment of chronic intestinal abscess. With the accumulation of clinical experience and the exploration of modern pharmacological research in recent years, YYFZBJS has been extensively employed to address a broad spectrum of conditions such as colorectal cancer. Although numerous studies have explored the clinical efficacy and underlying mechanisms of YYFZBJS, no comprehensive review summarizing these findings exists to date. This study aims to systematically review and critically assess the current clinical and mechanistic research on YYFZBJS, with the objective of providing valuable insights and guidance for TCM research in the future.

Diabetes is one of the most common metabolic diseases worldwide, leading to complications, mortality, and significant healthcare expenditures, which impose a substantial social and financial burden globally. A diabetic environment can induce metabolic changes, negatively affecting tendon homeostasis, leading to alterations in biomechanical properties and histopathology. Numerous studies have investigated the mechanisms through which diabetes exerts pathological effects on tendons, including increased free radical production, oxidative stress, inflammatory responses, deposition of advanced glycation end products (AGEs), and microvascular changes. These metabolic changes damages tendon structure, biomechanics, and tendon repair processes. The proliferation of tendon stem cells decreases, apoptosis increases, and abnormal differentiation, along with abnormal expression of myofibroblasts, ultimately lead to insufficient tendon repair, fibrosis, and remodeling. Although researches unveiling the effects of diabetes on tendinopathy, fibrosis or contracture, and tendon injury healing are growing, systematic understanding is still lacking. Therefore, this review summarizes the current research status and provides a comprehensive overview, offering theoretical guidance for future in-depth exploration of the impact of diabetes on tendons and the development of treatments for diabetes-related tendon diseases.

AimsPrevious studies on the association between vitamin E and blood pressure (BP) levels are controversial. Our study aimed to evaluate the association between blood vitamin E (alpha-tocopherol and gamma-tocopherol) levels and systolic and diastolic BP in an adult population with diabetes and without diabetes.MethodsOur study data were obtained from a biomarker project of the Midlife in the United States (MIDUS) study. A total of 1068 subjects were included, and the associations between alpha-tocopherol and gamma-tocopherol levels and systolic and diastolic BP were further analyzed by smooth curve and multivariate linear regression analyses.ResultsOur smooth curve analysis showed an almost linear correlation between blood vitamin E (alpha-tocopherol and gamma-tocopherol) levels and systolic and diastolic BP. Furthermore, we found that blood gamma-tocopherol levels were positively and independently associated with systolic BP (B=0.427, 95% CI 0.067-0.787, P=0.020) and diastolic BP (B=0.289, 95% CI 0.072-0.507, P=0.009) when the data were adjusted for age, gender, body mass index (BMI), ever smoked cigarettes regularly, number of years of consuming alcohol and regular exercise or activity for 20 minutes or more at least 3 times/week. Consistently, blood alpha-tocopherol levels were also positively associated with systolic BP (B=0.150, 95% CI 0.064-0.235, P=0.001) and diastolic BP (B=0.056, 95% CI 0.004-0.107, P=0.035) after these variables were adjusted. However, these significant relationships exist only in subjects without diabetes, but not in subjects with diabetes.ConclusionsWe observed for the first time that blood vitamin E (alpha-tocopherol and gamma-tocopherol) levels were positively associated with systolic and diastolic BP in subjects without diabetes.

AimsAssessing the cost-effectiveness of Nivolumab with Gemcitabine–Cisplatin for Advanced Urothelial Carcinoma (aUC) treatment from the perspective of Chinese payers.MethodsA Markov model assessed economic outcomes, estimating health outcomes in quality-adjusted life years (QALYs). One-way and probabilistic sensitivity analyses were conducted to assess the impact of uncertainties on the results.ResultsThe base-case analysis showed Nivolumab plus Gemcitabine–Cisplatin yielded 0.59 QALYs at an extra cost of $78,780.61, leading to an incremental cost-effectiveness ratios (ICER) of $133,526.46/QALY. One-way sensitivity analysis highlighted Nivolumab’s cost as the key factor, while probabilistic sensitivity analysis showed a 0% chance of cost-effectiveness for Nivolumab plus Gemcitabine–Cisplatin in aUC treatment.ConclusionNivolumab plus Gemcitabine–Cisplatin is not cost-effective in the treatment of aUC.

IntroductionLow back pain (LBP) was commonly induced by intervertebral disc degeneration (IVDD), which is accompanied by the loss of disc height and osteophyte generation. Cell-based therapy is a promising treatment for preventing the degeneration of interverbral disc. In our study, allogeneic fibroblasts are shown to ameliorate intervertebral disc degeneration by reducing osteophytes in rabbits.MethodsWe established a rabbits-derived fibroblast (Rab-Fib) which could be expanded in vitro and constructed puncture-induced intervertebral disc degeneration rabbit model. Histologic and imaging examinations and analyses were performed after 2 weeks, 3 months, and 12 months.ResultsOur data indicate that stable and reliably-extracted allogeneic fibroblasts can effectively ameliorate intervertebral disc degeneration by reducing osteophytes.ConclusionOur study provides a basis for advancing the further translation of fibroblasts in intervertebral disc therapy.

Immune checkpoint inhibitor-related diabetes mellitus (ICI-DM) is a rare complication that medical oncologists seldom encounter in routine practice. The sporadic nature and intrinsic complexity of ICI-DM make it challenging to analyze comprehensively in experimental settings. In this review, we examine phase 3 clinical trials on ICIs and published case reports of ICI-DM, aiming to summarize its incidence, clinical features, management, and prognosis. Phase 3 clinical trials reveal that the incidence of ICI-DM is higher with combination therapies, such as anti-PD-1 and anti-CTLA-4 or anti-PD-L1, compared to anti-PD-1 monotherapy. ICI-DM typically presents as severe hyperglycemia with a fulminant onset and is often associated with diabetic ketoacidosis, accompanied by unexpectedly low HbA1c and C-peptide levels. ICI-DM shares similarities with classic type 1 diabetes, particularly in terms of autoimmunity and genetic predisposition. This includes a high prevalence of islet autoantibodies and susceptibility to certain HLA haplotypes, often with concurrent endocrine gland dysfunction. This suggests that genetic susceptibility and exposure to ICIs may both be necessary for triggering islet autoimmunity and inducing ICI-DM. Notably, patients with positive islet autoantibodies, such as glutamic acid decarboxylase antibody and islet-associated antigen 2 antibody, tend to experience rapid onset of ICI-DM after ICI exposure. Although patients with ICI-DM generally show a high objective response rate to immunotherapy, a significant proportion also face the need to permanently discontinued treatment. Further research is urgently needed to determine whether permanent discontinuation of immunotherapy is necessary and whether this discontinuation negatively impacts overall survival.

BackgroundAdolescence is a pivotal developmental phase, marked by a high prevalence of mental health issues. The Singapore Youth Epidemiology and Resilience (YEAR) study aims to assess the prevalence of mental health symptoms, sociodemographic risk factors, and the protective role of resilience in a multi-ethnic, Asian school-going adolescent population.MethodsSchool-based adolescents aged 11-18 and their parents were invited from a stratified sample of national schools, designed to be demographically representative of the mainstream school-going population. In the screening phase, adolescents completed a battery of questionnaires including the Youth Self-Report (YSR), Child Behaviour Checklist (CBCL), and the Singapore Youth Resilience Scale (SYRESS). Thereafter, diagnostic interviews were conducted on high-risk and control participants. Data analysis was conducted to establish prevalence rates of mental health symptoms, and to examine the associations between mental health symptoms, sociodemographic factors, and resilience.ResultsThe final study sample consisted of 3336 adolescents and 2475 parents. Based on adolescents’ response on the YSR, 37.3%, 13.1% and 27.7% of the YEAR Study population scored in the clinical range for internalizing, externalizing and total problems respectively. Based on parents’ reporting on their children on the CBCL, 15.9%, 4.0% and 11.2% scored in the clinical range for internalizing, externalizing and total problems respectively. Sociodemographic risk factors for specific mental health symptoms were identified, including belonging to the age category of 15-16 (OR, 1.8-2.2) and those living in either a 4-, 5-room or executive flat (OR, 0.6-0.7), or in condominiums and other apartments (OR, 0.4-0.6). Total resilience scores were moderately correlated with total [rs(3334) = -.49, p