Alzheimer's disease (AD) classification models usually segment the entire brain image into voxel blocks and assign them labels consistent with the entire image, but not every voxel block is closely related to the disease. To this end, an AD auxiliary diagnosis framework based on weakly supervised multi-instance learning (MIL) and multi-scale feature fusion is proposed, and the framework is designed from three aspects: within the voxel block, between voxel blocks, and high-confidence voxel blocks. First, a three-dimensional convolutional neural network was used to extract deep features within the voxel block; then the spatial correlation information between voxel blocks was captured through position encoding and attention mechanism; finally, high-confidence voxel blocks were selected and combined with multi-scale information fusion strategy to integrate key features for classification decision. The performance of the model was evaluated on the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Open Access Series of Imaging Studies (OASIS) datasets. Experimental results showed that the proposed framework improved ACC and AUC by 3% and 4% on average compared with other mainstream frameworks in the two tasks of AD classification and mild cognitive impairment conversion classification, and could find the key voxel blocks that trigger the disease, providing an effective basis for AD auxiliary diagnosis.
Alzheimer Disease/diagnosis* ; Humans ; Neuroimaging/methods* ; Neural Networks, Computer ; Brain/diagnostic imaging* ; Magnetic Resonance Imaging ; Deep Learning ; Machine Learning

Despite that sleep disturbance and poor neurocognitive performance are common complaints among coronavirus disease 2019 (COVID-19) survivors, few studies have focused on the effect of post-COVID-19 sleep disturbance (PCSD) on cognitive function. This study aimed to identify the impact of PCSD on neurocognitive function and explore the associated risk factors for the worsening of this condition. This cross-sectional study was conducted via the web-based assessment in Chinese mainland. Neurocognitive function was evaluated by the modified online Integrated Cognitive Assessment (ICA) and the Number Ordering Test (NOT). Propensity score matching (PSM) was utilized to match the confounding factors between individuals with and without PCSD. Univariate analyses were performed to evaluate the effect of PCSD on neurocognitive function. The risk factors associated with worsened neurocognitive performance in PCSD individuals were explored using binary logistic regression. A total of 8692 individuals with COVID-19 diagnosis were selected for this study. Nearly half (48.80%) of the COVID-19 survivors reported sleep disturbance. After matching by PSM, a total of 3977 pairs (7954 individuals in total) were obtained. Univariate analyses revealed that PCSD was related to worse ICA and NOT performance (P<0.05). Underlying disease, upper respiratory infection, loss of smell or taste, severe pneumonia, and self-reported cognitive complaints were associated with worsened neurocognitive performance among PCSD individuals (P<0.05). Furthermore, aging, ethnicity (minority), and lower education level were found to be independent risk factors for worsened neurocognitive performance in PCSD individuals (P<0.05). PCSD was related to impaired neurocognitive performance. Therefore, appropriate prevention and intervention measures should be taken to minimize or prevent PCSD and eliminate its potential adverse effect on neurocognitive function.
Humans ; COVID-19/epidemiology* ; Male ; Female ; Sleep Wake Disorders/epidemiology* ; Propensity Score ; Middle Aged ; Cross-Sectional Studies ; Adult ; SARS-CoV-2 ; Aged ; Risk Factors ; China/epidemiology* ; Cognition ; Cognitive Dysfunction/etiology* ; Neuropsychological Tests

Cuproptosis, a recently identified form of regulated cell death triggered by excess intracellular copper, has emerged as a promising cytotoxic strategy for cancer therapy. However, the therapeutic efficacy of copper ionophores such as elesclomol (ES) is often hindered by cellular copper homeostasis mechanisms that limit copper influx and cuproptosis induction. To address this challenge, we developed a nanoagent utilizing outer membrane vesicle (OMV) derived from Akkermansia muciniphila (Akk) for co-delivery of antioxidant 1 copper chaperone (Atox1)-targeting siRNA and ES (siAtox1/ES@OMV) to tumors. In vitro, we demonstrated that Atox1 knockdown via siRNA significantly disrupted copper export mechanisms, resulting in elevated intracellular copper levels. Simultaneously, ES facilitated efficient copper influx and mitochondrial transport, leading to Fe-S cluster depletion, increased proteotoxic stress, and robust cuproptosis. In vivo, siAtox1/ES@OMV achieved targeted tumor delivery and induced pronounced cuproptosis. Furthermore, leveraging the immunomodulatory properties of OMVs, siAtox1/ES@OMV promoted T-cell infiltration and the activation of tumor-reactive cytotoxic T cells, enhancing tumor immune responses. The combination of siAtox1/ES-induced cuproptosis and immunogenic cell death synergistically suppressed tumor growth in both subcutaneous breast cancer and orthotopic rectal cancer mouse models. This study highlights the potential of integrating copper homeostasis disruption with a copper ionophore using an immunomodulatory OMV-based vector, offering a promising combinatorial strategy for cancer therapy.

Objectives:To assess the prognostic impact of the neoadjuvant rectal (NAR) score following neoadjuvant short-course radiotherapy and consolidation chemotherapy in locally advanced rectal cancer (LARC), as well as its value in guiding decisions for adjuvant chemotherapy.Methods:Between August 2015 and August 2018, patients were eligible from the STELLAR phase III trial (NCT02533271) who received short-course radiotherapy plus consolidation chemotherapy and for whom the NAR score could be calculated. Based on the NAR score, patients were categorized into low (＜8), intermediate (8-16), and high (＞16) groups. The Kaplan-Meier method, log rank tests, and multivariate Cox proportional hazard regression models were used to evaluate the impact of the NAR score on disease-free survival (DFS).Results:Out of the 232 patients, 24.1%, 48.7%, and 27.2% had low (56 cases), intermediate (113 cases), and high NAR scores (63 cases), respectively. The median follow-up period was 37 months, with 3-year DFS rates of 87.3%, 68.3%, and 53.4% ( P＜0.001) for the low, intermediate, and high NAR score groups. Multivariate analysis demonstrated that the NAR score (intermediate NAR score: HR, 3.10, 95% CI, 1.30-7.37, P=0.011; high NAR scores: HR=5.44, 95% CI, 2.26-13.09, P＜0.001), resection status ( HR, 3.00, 95% CI, 1.64-5.52, P＜0.001), and adjuvant chemotherapy ( HR, 3.25, 95% CI, 2.01-5.27, P＜0.001) were independent prognostic factors for DFS. In patients with R0 resection, the 3-year DFS rates were 97.8% and 78.0% for those with low and intermediate NAR scores who received adjuvant chemotherapy, significantly higher than the 43.2% and 50.6% for those who did not ( P＜0.001, P=0.002). There was no significant difference in the 3-year DFS rate (54.2% vs 53.3%, P=0.214) among high NAR score patients, regardless of adjuvant chemotherapy. Conclusions:The NAR score is a robust prognostic indicator in LARC following neoadjuvant short-course radiotherapy and consolidation chemotherapy, with potential implications for subsequent decisions regarding adjuvant chemotherapy. These findings warrant further validation in studies with larger sample sizes.

Objectives:To assess the prognostic impact of the neoadjuvant rectal (NAR) score following neoadjuvant short-course radiotherapy and consolidation chemotherapy in locally advanced rectal cancer (LARC), as well as its value in guiding decisions for adjuvant chemotherapy.Methods:Between August 2015 and August 2018, patients were eligible from the STELLAR phase III trial (NCT02533271) who received short-course radiotherapy plus consolidation chemotherapy and for whom the NAR score could be calculated. Based on the NAR score, patients were categorized into low (＜8), intermediate (8-16), and high (＞16) groups. The Kaplan-Meier method, log rank tests, and multivariate Cox proportional hazard regression models were used to evaluate the impact of the NAR score on disease-free survival (DFS).Results:Out of the 232 patients, 24.1%, 48.7%, and 27.2% had low (56 cases), intermediate (113 cases), and high NAR scores (63 cases), respectively. The median follow-up period was 37 months, with 3-year DFS rates of 87.3%, 68.3%, and 53.4% ( P＜0.001) for the low, intermediate, and high NAR score groups. Multivariate analysis demonstrated that the NAR score (intermediate NAR score: HR, 3.10, 95% CI, 1.30-7.37, P=0.011; high NAR scores: HR=5.44, 95% CI, 2.26-13.09, P＜0.001), resection status ( HR, 3.00, 95% CI, 1.64-5.52, P＜0.001), and adjuvant chemotherapy ( HR, 3.25, 95% CI, 2.01-5.27, P＜0.001) were independent prognostic factors for DFS. In patients with R0 resection, the 3-year DFS rates were 97.8% and 78.0% for those with low and intermediate NAR scores who received adjuvant chemotherapy, significantly higher than the 43.2% and 50.6% for those who did not ( P＜0.001, P=0.002). There was no significant difference in the 3-year DFS rate (54.2% vs 53.3%, P=0.214) among high NAR score patients, regardless of adjuvant chemotherapy. Conclusions:The NAR score is a robust prognostic indicator in LARC following neoadjuvant short-course radiotherapy and consolidation chemotherapy, with potential implications for subsequent decisions regarding adjuvant chemotherapy. These findings warrant further validation in studies with larger sample sizes.

Objective To explore the differential expression of the key microfilament cytoskeleton-binding proteins in immature dendritic cells(imDCs)during antigen phagocytosis.Methods Monocytes(MOs)were isolated from peripheral blood of healthy individuals and cultured with recombinant human granulocyte-macrophage colony stimulating factor(rhGM-CSF)and recombinant human interleukin-4(rhIL-4)for 6 days to obtain imDCs.ImDCs were co-cultured with low molecular weight(40 kDa)and high molecular weight(150 kDa)dextrans for 1,3 and 6 hours,respectively.Flow cytometry was used to detect the percentage of imDCs phagocytosing dextran and the expression of immunophenotype molecules.The localization of filamentous actin(F-actin),PFN1,WASP,and α-actinin in cells were observed by immunofluorescence imaging.The differential expression of MCBPs at the mRNA and protein levels were respectively detected by q-PCR and Western blotting.Finally,the MCBPs with the highest component coefficients were identified based on the stepwise regression and principal component analysis method in systems biology algorithms.Results During the process of antigen phagocytosis,imDCs phagocytized low molecular weight antigens at a faster rate,with a phagocytic duration of approximately three hours.Their cell phenotypes and morphology gradually differentiated into mDCs,and F-actin remodeling was occurred significantly.The expression of MCBPs such as PFN1,CDM,WASP,CAPZB,Filamin A,α-actinin were downregulated,while the expression of WAVE1,Arp2/3 complex,and Fascin were upregulated.The mRNA expression of signaling protein Rac1 was upregulated,while the mRNA expressions of CDC42 and RhoA were downregulated.The immunofluorescence results showed that PFN1,WASP,and α-actinin were transposed during the antigen phagocytosis process of imDCs.The results of stepwise regression and principal component analysis showed that PFN1 had the highest component coefficient.Conclusions PFN1 may be a key MCBPs involved in the process of antigen phagocytosis of imDCs,which is of great significance for further understanding the relationship between changes in the cytoskeleton structure of imDCs and their immunological functions.

The aim of this study was to explore the impact of chronic apical periodontitis(CAP)on atherosclerosis in apoE-/-mice fed high-fat diet(HFD).This investigation focused on the gut microbiota,metabolites,and intestinal barrier function to uncover potential links between oral health and cardiovascular disease(CVD).In this study,CAP was shown to exacerbate atherosclerosis in HFD-fed apoE-/-mice,as evidenced by the increase in plaque size and volume in the aortic walls observed via Oil Red O staining.16S rRNA sequencing revealed significant alterations in the gut microbiota,with harmful bacterial species thriving while beneficial species declining.Metabolomic profiling indicated disruptions in lipid metabolism and primary bile acid synthesis,leading to elevated levels of taurochenodeoxycholic acid(TCDCA),taurocholic acid(TCA),and tauroursodeoxycholic acid(TDCA).These metabolic shifts may contribute to atherosclerosis development.Furthermore,impaired intestinal barrier function,characterized by reduced mucin expression and disrupted tight junction proteins,was observed.The increased intestinal permeability observed was positively correlated with the severity of atherosclerotic lesions,highlighting the importance of the intestinal barrier in cardiovascular health.In conclusion,this research underscores the intricate interplay among oral health,gut microbiota composition,metabolite profiles,and CVD incidence.These findings emphasize the importance of maintaining good oral hygiene as a potential preventive measure against cardiovascular issues,as well as the need for further investigations into the intricate mechanisms linking oral health,gut microbiota,and metabolic pathways in CVD development.

Acute myocardial infraction(AMI)has now become a threat to human health worldwide.Therefore,it is urgent to construct the standardized platform of integrated traditional Chinese and western medicine diagnosis and treatment for AMI.The Intensive Care Unit(ICU)team of the Second Clinical Medical School of Guangzhou University of Chinese Medicine(Guangdong Provincial Hospital of Chinese Medicine)has taken up the mission of exploring the prevention and treatment of AMI with traditional Chinese medicine and promoting and the construction of the diagnosis and treatment system of integrated traditional Chinese and western medicine for AMI.The team pioneered the trinity mode of'saving heart,treating heart and nourishing heart'for AMI,focusing on the construction of standardized platform of integrated traditional Chinese and western medicine diagnosis and treatment for AMI,creating the key technology system of Yiqi Huoxue Huatan method(the therapy mainly for replenishing qi,activating blood and dissolving phlegm)for AMI and putting it into the practice,which highlighted the achievements in the construction of the standardized platform.

Objective:To investigate effects of resistance exercise on exercise tolerance,cardiac function and somati-zation symptoms in patients with stable coronary artery disease(SCAD).Methods:SCAD patients without heart failure,who were diagnosed with coronary angiography or coronary CTA in Second Affiliated Hospital of Baotou Medical College,Inner Mongolia University of Science & Technology between June 2020 and June 2022 were select-ed.They were enrolled into groups according to voluntary principle,and 47 cases and 58 cases were finally included in control group and resistance exercise group respectively.Both groups exercised for 12 weeks according to the ex-ercise prescription.Exercise tolerance was assessed using peak oxygen uptake(VO2peak)and anaerobic threshold;left ventricular diastolic function was assessed using cardiac echocardiography mitral early-diastolic peak flow ve-locity/late-diastolic peak flow velocity(E/A);and mental health was assessed using Somatization Symptom Self-rating Scale(SSS).The occurrence of serious cardiovascular adverse events was compared between two groups after 24-week follow-up.Results:Compared with before exercise,after 12-week exercise,there were significant rise in VO2 peak[(17.53±3.92)ml·min-1·kg-1 vs.(20.35±3.70)ml·min-1·kg-1],anaerobic threshold[(11.60±3.40)ml·min-1·kg-1 vs.(12.62±3.16)ml·min-1·kg-1],E peak[(0.63±0.14)mm/s vs.(0.70±0.16)mm/s]and E/A ratio[(0.80±0.14)vs.(0.91±0.24)];and significant reductions in resting heart rate[(76.21±12.70)beats/min vs.(74.36±9.87)beats/min]and SSS score[10.00(5.00,22.25)points vs.9.50(3.00,21.00)points]in resistance exercise group(P＜0.01 all).Compared with the control group,VO2 peak[(18.59±3.93)ml·min-1·kg-1 vs.(20.35±3.70)ml·min-1·kg-1]and E/A ratio[(0.82±0.22)vs.(0.91±0.24)]were significantly higher in resistance exercise group after 12 weeks(P＜0.05 both).After 24-week follow-up,there was no significant difference in incidence rate of serious cardiovascular adverse events between two groups(P=1.000).Conclusion:Resistance exercise can significantly increase exercise tolerance,improve cardiac diastolic function and psychological health in patients with coronary artery disease.

Orodispersible films (oral dispersible films), a novel form of oral solid dosage forms, are widely used for patients with dysphagia and those with uncontrollable autonomic behavior. In this study, suvorexant orodispersible film was prepared by hot melt extrusion technology, and the disintegration time, mechanical properties, in vitro dissolution and pharmacokinetics were evaluated, compared with other orodispersible films and commercially available tablets Belsomra. All experiments were approved by the Committee on the Management and Use of Laboratory Animals of Academy of Military Medical Sciences (IACUC-DWZX-2024-504). The results showed that the dissolution rate of suvorexant orodispersible film was faster and the mechanical strength was better than that of other commercially available orodispersible film, which could meet the needs of storage and transportation. Differential scanning calorimetry and X-ray diffraction results showed that suvorexant was dispersed within the orodispersible film in an amorphous state. The in vitro dissolution of the film was observed to be four times faster than that of the commercial tablets, achieving complete dissolution within five minutes. Pharmacokinetic evaluations in Beagle dogs revealed that the self-formulated orodispersible film exhibited no significant differences in the area under the blood concentration-time curve when compared with Belsomra. However, the film showed a faster onset of action, with a peak time that was twice as rapid, and a maximum blood concentration that was twice as high as that of Belsomra. Leveraging hot melt extrusion technology, the suvorexant orodispersible film offers a straightforward, continuous production process with consistent quality. It serves as an excellent platform for the development of solvent-free film preparations tailored for patients with special needs.