Basket trial, as an innovative clinical trial design concept, marks the transformation of medical research from the traditional large-scale and single-disease treatment to the precise and individualized treatment. By gradually incorporating the Bayesian method during development, the trial design becomes more scientific and reasonable and increases its efficiency. The fundamental principle of the Bayesian method is the utilization of prior knowledge in conjunction with new observational data to dynamically update the posterior probability. This flexibility enhances the basket trial's capacity to effectively adapt to variations during the research process. Consequently, it enables researchers to dynamically adjust research strategies based on accumulated data and improve the predictive accuracy regarding treatment responses. In addition, the design concept of the basket trial aligns with the traditional Chinese medicine(TCM) principle of "homotherapy for heteropathy". The principle of "homotherapy for heteropathy" emphasizes that under certain conditions, different diseases may have the same treatment. Similarly, basket trials allow using a uniform trial design across multiple diseases, offering enhanced operational and significant practical value in the realm of TCM, particularly within the context of syndrome-based disease research. By introducing basket trials, the design of TCM clinical studies will be more scientific and yield higher-quality evidence. This study systematically categorized various Bayesian methods and models utilized in basket trials, evaluated their strengths and weaknesses, and identified their appropriate application contexts, so as to offer a practical guide for designing basket trials in the realm of TCM.
Bayes Theorem ; Humans ; Medicine, Chinese Traditional/methods* ; Research Design ; Clinical Trials as Topic/methods* ; Drugs, Chinese Herbal/therapeutic use*

Emerging evidences have indicated the role of ferroptosis in the progression of metabolic-associated fatty liver disease (MAFLD); thus, inhibiting ferroptosis is a promising strategy for the development of MAFLD therapeutics. Recent studies have demonstrated the antioxidative effect of the gut commensal bacterium Akkermansia muciniphila (A. muc); however, whether it can alleviate ferroptosis remains unclear. The current study indicates A. muc intervention efficiently reversed high-fat high-fructose diet (HFHFD)-induced lipid peroxidation and ferroptosis in the liver. These beneficial effects were mediated by activation of the hepatic AMPK/SIRT1/PGC-1α axis, as evidenced by the finding that AMPK deficiency abrogated the amelioration of lipid peroxidation in vitro and in vivo. Furthermore, the short-chain fatty acids (SCFAs) were enriched upon A. muc treatment, and acetate was identified as a key activator of hepatic AMPK signalling. Mechanistically, microbiota-derived acetate was transported to the liver and metabolized to adenosine monophosphate (AMP), which triggered AMPK activation. Furthermore, a colonization assay in germ-free mice confirmed that A. muc mediated antiferroptotic effects in the absence of other microbes. These data indicated that A. muc exerts antiferroptotic effects against MAFLD, at least partially by producing acetate, which activates the hepatic AMPK/SIRT1/PGC-1α axis to alleviate ferroptosis via the inhibition of polyunsaturated fatty acid (PUFA) synthesis.

OBJECTIVES: To analyze the differentially expressed exosomal miRNAs in patients with chronic heart failure (CHF) complicated by hyperuricemia (HUA) and explore their potential as novel diagnostic molecular markers and their target genes. METHODS: This study was conducted among 30 CHF patients with HUA (observation group) and 30 healthy volunteers (control group) enrolled between September, 2020 and September, 2023. Peripheral blood samples were collected from 6 CHF patients with HUA for analyzing exosomal miRNAs by high-throughput sequencing, and the results were validated in the remaining 24 patients using qRT-PCR. GO and KEGG enrichment analyses were performed to predict the the target genes of the identified differential miRNAs. We also validated the differentially expressed miRNAs by animal experiment. RESULTS: A total of 42 differentially expressed exosomal miRNAs were detected in observation group by high-throughput sequencing; among them, miR-27a-5p was significantly upregulated (P=0.000179), and miR-139-3p was significantly downregulated (P=0.000058). In the 24 patients with both CHF and PUA, qRT-PCR validated significant upregulation of miR-27a-5p (P=0.004) and downregulation of miR-139-3p (P=0.005) in serum exosomes. When combined, miR-27a-5p and miR-139-3p had a maximum area under the curve (AUC) of 0.899 (95% CI: 0812-0.987) for predicting CHF complicated by HUA. GO and KEGG enrichment analyses suggested that the differential expressions of miR-27a-5p and miR-139-3p was associated with the activation of the AMPK-mTOR signaling pathway to activate the autophagic response. We obtained the same conclusion from animal experiment. CONCLUSIONS Upregulated exosomal miR-27a-5p combined with downregulated exosomal miR-139-3p expression can serve as a novel molecular marker for diagnosis of CHF complicated by HUA, and their differential expression may promote autophagy in cardiomyocytes by activating the AMPK-mTOR signaling pathway.
Humans ; Hyperuricemia/diagnosis* ; Heart Failure/genetics* ; MicroRNAs/metabolism* ; Exosomes/metabolism* ; Chronic Disease ; Male ; Female ; Middle Aged ; Animals

OBJECTIVES: To investigate the effects of periodontitis induced by Prevotella nigrescens (Pn) combined with ligation on cognitive functions in mice. METHODS: Twenty-four C57BL/6J mice were randomly divided into control group, ligation group, and ligation + Pn treatment (P+Pn) group. Experimental periodontitis was induced by silk ligation of the first molars followed by topical application of Pn for 6 weeks. After modeling, alveolar bone resorption was assessed using micro-CT and histological analysis. Learning and memory abilities of the mice were evaluated using open field test (OFT), novel object recognition test (NORT), and Morris water maze test (MWM). Seven weeks after the start of modeling, the mice were sacrificed for examining histopathological changes in the hippocampus using HE and Nissl staining. RESULTS: After 6 weeks of molar ligation, micro-CT revealed horizontal alveolar bone resorption and furcation exposure in the mice, and histological analysis showed apical migration of the junctional epithelium, epithelial ridge hyperplasia, and lymphocyte infiltration, and these changes were obviously worsened in P+Pn group. Alveolar bone height decreased significantly in both ligation groups compared to the control group. Cognitive tests showed that the mice in both of the ligation groups traveled shorter distances in OFT, showed reduced novel object preference in NORT, and exhibited longer escape latencies in MWM, and the mice in P+Pn group had significantly poorer performances in the tests. Histologically, obvious neuronal cytoplasmic degeneration, necrosis, nuclear pyknosis, vacuolation, and reduced Nissl bodies and viable neurons were observed in the hippocampal regions of the mice in the two ligation groups. CONCLUSIONS Pn infection aggravates alveolar bone destruction, accelerates necrosis and causes morphological abnormalities of neuronal cells in the hippocampus to reduce cognitive functions of mice with periodontitis.
Animals ; Periodontitis/microbiology* ; Mice ; Mice, Inbred C57BL ; Cognition ; Alveolar Bone Loss ; Hippocampus/pathology* ; Male ; Inflammation ; Maze Learning

With the continuous advancement and innovation in medical equipment technology, the transition between high-flow oxygen therapy, non-invasive ventilation, and invasive ventilation can be easily achieved by adjusting the ventilation mode of ventilators. During the weaning phase for tracheotomized patients, it is necessary to disconnect the ventilator circuit, change the ventilator mode, and gradually extend the weaning time to achieve complete ventilator liberation. During the weaning process, due to patients' excessive dependence on the ventilator, there may be situations where respiratory endpoints and Y-connectors of the ventilator are reconnected for invasive ventilation. However, during the weaning process, the Y-connector and expiratory end connectors are exposed to the air, which cannot ensure the tightness of the ventilator circuit, easily increasing the probability of ventilator circuit contamination and subsequently the risk of ventilator-associated pneumonia (VAP). To overcome these issues, the research team of department of critical care medicine of Zhongda Hospital Southeast University has designed a ventilator circuit interface protective device for weaning and has obtained a National Utility Model Patent of China (ZL 2023 2 1453385.8). The main body of the protective device is a Y-connector plug, consisting of multiple components, including a sealing piece, a protective cover, a sealing plug, an interface 1 (connects with the patient's tracheal tube), an interface 2 (connects with the respiratory branch of the ventilator), and an interface 3 (connects with the expiratory branch of the ventilator), featuring a unique design and easy operation. During the patient's weaning training process, the interface 1 and interface 2 is disconnected from the patient's tracheal tube and respiratory branch, respectively. The interface 1 is plugged with a stopper, and the interface 2 is covered with a protective cover to ensure the tightness of the expiratory branch and Y-connector of the ventilator. During the period when the patient is using the ventilator, the protective cover and plug are removed, and connecting them together ensures the tightness of the device itself, reducing the incidence of VAP caused by ventilator circuit contamination, avoiding nosocomial infections, and shortening the prolonged use of invasive ventilation, increased complication rate, extended hospital stay, and increased medical cost associated with weaning.
Humans ; Ventilator Weaning/methods* ; Equipment Design ; Ventilators, Mechanical ; Respiration, Artificial/instrumentation* ; Pneumonia, Ventilator-Associated/prevention & control*

ObjectiveTo investigate the therapeutic effect of Dayuanyin on acute lung injury induced by H1N1 infection and decipher the potential mechanism. MethodThe constituents in Dayuanyin were analyzed by ultra-high performance liquid chromatography-quadrupole-exactive orbitrap mass spectrometry （UHPLC-Q-Exactive Orbitrap MS）. Forty-eight female BALB/c mice were randomized into normal， model， oseltamivir （19.5 mg·kg^-1）， and low-， medium-， and high-dose （2.73， 5.46， 10.92 g·kg^-1） Dayuanyin groups. The normal and model groups were administrated with deionized water by gavage， and the other groups were administrated with the corresponding drugs by gavage. On day 3 of drug administration， the normal group received nasal inhalation of normal saline， and the other groups were inoculated intranasally with A/RP/8/34 （H1N1） for the modeling of influenza virus infection. Mice were administrated with drugs continuously for 7 days and weighed daily. Sampling was performed 12 h after the last administration， and the lung tissue was weighed to calculate the lung index. Hematoxylin-eosin staining was performed to observe the pathological and morphological changes of the lung tissue and bronchi. The cytometric bead array （CBA） was used to measure the serum levels of interferon-gamma （IFN-γ）， C-X-C motif ligand 1 （CXCL1）， tumor necrosis factor-alpha （TNF-α）， chemokine ligand 2 （CCL2）， interleukin-12p70 （IL-12p70）， chemokine ligand 5 （CCL5）， interleukin-1β （IL-1β）， chemokine （C-X-C motif） ligand 10 （CXCL10）， granulocyte-macrophage colony-stimulating factor （GM-CSF）， interleukin-10 （IL-10）， interferon-beta （IFN-β）， interferon-alpha （IFN-α）， and interleukin-6 （IL-6）. According to the results of mass spectrometry and network pharmacology， we analyzed the mechanism of Dayuanyin in treating acute lung injury caused by H1N1. The protein levels of extracellular signal-regulated kinase 1/2 （ERK1/2）， p38 mitogen-activated protein kinase （p38 MAPK）， nuclear factor-kappa B （NF-κB）， and their phosphorylated forms were determined by Western blot. The mRNA levels of myeloid differentiation factor 88 （MyD88）， Toll-like receptor 3 （TLR3）， Toll-like receptor 7 （TLR7）， and Toll-like receptor 8 （TLR8） in the lung tissue were measured by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. ResultA total of 57 compounds， including paeoniflorin and baicalein， were detected in Dayuanyin. Compared with the normal group， the model group showed decreased body weight （P<0.01）， lung edema and hemorrhage， increased lung index （P<0.01）， and elevated levels of IFN-γ， IL-12p70， CCL5， IL-1β， CXCL10， GM-CSF， IFN-β， and IL-6 （P<0.01）. Compared with the model group， Dayuanyin attenuated alveolar wall thickening， capillary congestion， and immune cell infiltration， reduced the alterations in body weight and lung index （P<0.01）， and down-regulated the protein levels of IFN-γ， IL-12p70， CCL5， IL-1β， CXCL10， GM-CSF， IFN-β， and IL-6 （P<0.01）. A total of 57 key genes were predicted by network pharmacological analysis， of which the MAPK signaling pathway was the main target signaling pathway. Compared with the normal group， the model group showed up-regulation in the protein levels of phosphorylation （p）-ERK1/2， p-p38 MAPK， and p-NF-κB （P<0.01） and the mRNA levels of TLR7， TLR8， MyD88， and TLR3 （P<0.05， P<0.01）. Compared with the model group， Dayuanyin lowered the phosphorylation levels of ERK1/2， p38 MAPK， and NF-κB p65 in a dose-dependent manner （P<0.01） and down-regulated the mRNA levels of TLR3， TLR7， TLR8， and MyD88 （P<0.01）. ConclusionDayuanyin can prevent and control H1N1 infection-induced acute lung injury by inhibiting the TLR/MAPK/NF-κB signaling pathway.

The tumor microenvironment (TME) is comprised of tumor cells, immune cells and stromal cells, moreover the intricate interactions among these cellular components play a vital role in tumor initiation and progression. Within the TME, immune cells and stromal cells engage in cytotoxic or inflammatory responses to counteract tumor cells, but they employ a range of immune regulatory mechanisms to facilitate tumor evasion. Previous treatments for lymphoma mainly targeted malignant cells themselves. However, with the clinical application of immune checkpoint inhibitors, bispecific antibodies and chimeric antigen receptor T-cell therapy, the elimination of TME-mediated tumor protection has gained increasing attention. By harnessing the high-throughput and multi-dimensional analytical capabilities of mass cytometry (CyTOF) and imaging mass cytometry (IMC), it has become feasible to systematically analyze the composition of the lymphoma TME using large-scale samples.

Objective:To study the current status of longitudinal extrauterine growth restriction (EUGR) in extremely preterm infants (EPIs) and to develop a prediction model based on clinical data from multiple NICUs.Methods:From January 2017 to December 2018, EPIs admitted to 32 NICUs in North China were retrospectively studied. Their general conditions, nutritional support, complications during hospitalization and weight changes were reviewed. Weight loss between birth and discharge > 1SD was defined as longitudinal EUGR. The EPIs were assigned into longitudinal EUGR group and non-EUGR group and their nutritional support and weight changes were compared. The EPIs were randomly assigned into the training dataset and the validation dataset with a ratio of 7∶3. Univariate Cox regression analysis and multiple regression analysis were used in the training dataset to select the independent predictive factors. The best-fitting Nomogram model predicting longitudinal EUGR was established based on Akaike Information Criterion. The model was evaluated for discrimination efficacy, calibration and clinical decision curve analysis.Results:A total of 436 EPIs were included in this study, with a mean gestational age of (26.9±0.9) weeks and a birth weight of (989±171) g. The incidence of longitudinal EUGR was 82.3%(359/436). Seven variables (birth weight Z-score, weight loss, weight growth velocity, the proportion of breast milk ≥75% within 3 d before discharge, invasive mechanical ventilation ≥7 d, maternal antenatal corticosteroids use and bronchopulmonary dysplasia) were selected to establish the prediction model. The area under the receiver operating characteristic curve of the training dataset and the validation dataset were 0.870 (95% CI 0.820-0.920) and 0.879 (95% CI 0.815-0.942), suggesting good discrimination efficacy. The calibration curve indicated a good fit of the model ( P>0.05). The decision curve analysis showed positive net benefits at all thresholds. Conclusions:Currently, EPIs have a high incidence of longitudinal EUGR. The prediction model is helpful for early identification and intervention for EPIs with higher risks of longitudinal EUGR. It is necessary to expand the sample size and conduct prospective studies to optimize and validate the prediction model in the future.

ObjectiveTo analyze the clinical and epidemiological characteristics of confirmed cases of human monkeypox infection in Changning District， Shanghai， and to explore their clinical and epidemiological characteristics. MethodsClinical data from 10 reported cases of monkeypox in individuals residing in Changning District or identified by local medical institutions between July 20 and September 30， 2023， were collected. Epidemiological case investigations were conducted， and throat swabs， anal swabs， and rash swabs were collected by the treating medical institutions. Real-time fluorescence quantitative PCR was used for monkeypox virus nucleic acid testing， and descriptive epidemiological analysis was applied to analyze the epidemiological characteristics of the cases. ResultsAll 10 confirmed cases of human monkeypox infection were all young males with an average age of 35.4 years， all of whom belonged to the men who have sex with men （MSM） population， with no occupational clustering. The primary clinical symptoms included fever， rash， enlarged inguinal lymph nodes， and muscle soreness. Nine cases presented with a rash， and seven cases experienced fever symptoms. Among the 10 cases， one experienced fever， rash， enlarged lymph nodes， and muscle soreness； two had fever， rash， and enlarged lymph nodes； two had fever， rash， and systemic soreness； two had only a rash； one had fever or rash； and one was asymptomatic. Among the nine cases with a rash， the rash was mainly localized to the genital or anal area， with fewer cases presenting rashes on the limbs or trunk simultaneously. All cases reported a history of non-exclusive MSM behavior within 21 days before the onset of the disease. The interval between the last suspected high-risk exposure and the onset of symptoms was 4 to 10 days， with an average interval of 6.9 days. The time from the onset of fever to the appearance of a rash was 0 to 5 days， with an average of 1.87 days. ConclusionThe main clinical manifestations of human infection with monkeypox are fever， rash， and enlarged inguinal lymph nodes. The MSM population is a high-risk group for monkeypox infection， and its source of infection may be associated with MSM exposure. Early-stage symptoms are mild， leading to potential underdiagnosis. Additionally， patients may conceal information during the investigation process， which increases the difficulty of epidemic prevention and control.