Study on the optimal elastic modulus of flexible blades for right heart assist device supporting patients with single-ventricle physiologies.

Background: Patients with single-ventricle physiologies continue to experience insufficient circulatory power after undergoing palliative surgeries. This paper proposed a right heart assist device equipped with flexible blades to provide circulatory assistance for these patients. The optimal elastic modulus of the flexible blades was investigated through numerical simulation. Methods: A one-way fluid-structure interaction (FSI) simulation was employed to study the deformation of flexible blades during rotation and its impact on device performance. The process began with a computational fluid dynamics (CFD) simulation to calculate the blood pressure rise and the pressure on the blades' surface. Subsequently, these pressure data were exported for finite element analysis (FEA) to compute the deformation of the blades. The fluid domain was then recreated based on the deformed blades' shape. Iterative CFD and FEA simulations were performed until both the blood pressure rise and the blades' shape stabilized. The blood pressure rise, hemolysis risk, and thrombosis risk corresponding to blades with different elastic moduli were exhaustively evaluated to determine the optimal elastic modulus. Results: Except for the case at 8,000 rpm with a blade elastic modulus of 40 MPa, the pressure rise associated with flexible blades within the studied range (rotational speeds of 4,000 rpm and 8,000 rpm, elastic modulus between 10 MPa and 200 MPa) was lower than that of rigid blades. It was observed that the pressure rise corresponding to flexible blades increased as the elastic modulus increased. Additionally, no significant difference was found in the hemolysis risk and thrombus risk between flexible blades of various elastic moduli and rigid blades. Conclusion: Except for one specific case, deformation of the flexible blades within the studied range led to a decrease in the impeller's functionality. Notably, rotational speed had a more significant impact on hemolysis risk and thrombus risk compared to blade deformation. After a comprehensive analysis of blade compressibility, blood pressure rise, hemolysis risk, and thrombus risk, the optimal elastic modulus for the flexible blades was determined to be between 40 MPa and 50 MPa.

Disturbance observer based fixed-time control of stochastic systems.

In this paper, the novel fixed-time anti-disturbance control scheme is proposed for a class of stochastic systems subjected to multiple disturbances and faults, and the disturbances consist of derivative-bounded disturbances and multiply noise. Based on the pole placement method, the fixed-time disturbance observer (Fixed-time DO) is devised to estimate derivative-bounded disturbances and an adaptive law is employed to approach the time-varying fault. Then a composite fixed-time controller is constructed to make the system converge to equilibrium position within a pre-specified time. At the same time, simulation examples illustrate that the proposed controller is effective and the convergence time is not related to the initial states of the system.

Biomarker-driven targeted therapy in patients with recurrent platinum-resistant epithelial ovarian cancer (BRIGHT): protocol for an open-label, multicenter, umbrella study.

BACKGROUND: Platinum-resistant, recurrent ovarian cancer has an abysmal prognosis with limited treatment options. Poly-(ADP-ribose)-polymerase (PARP), angiogenesis, and immune checkpoint inhibitors might improve the outcomes of platinum-resistant, recurrent ovarian cancer, but accurate patient selections for those therapies remain a significant clinical challenge. PRIMARY OBJECTIVE: To evaluate the efficacy and safety of biomarker-driven combinatorial therapies of pamiparib, tislelizumab, bevacizumab, and nab-paclitaxel in platinum-resistant, recurrent ovarian cancer. STUDY HYPOTHESIS: A precision medicine combination of PARP inhibitors, anti-angiogenic therapy, immunotherapy, and chemotherapy will improve disease outcomes of platinum-resistant, recurrent ovarian cancer by accounting for genomic and immunologic features. TRIAL DESIGN: The BRIGHT Trial is a prospective, open-label, multicenter, phase II, umbrella study planning to enroll 160 patients with serous, endometrioid, or clear cell platinum-resistant, recurrent ovarian cancer from 11 clinical centers in China. Patients are assigned to one of three experimental arms based on biomarkers. Patients with BRCA1/2 mutations will receive pamiparib plus bevacizumab (arm 1, n=40) regardless of CD8+ tumor-infiltrating lymphocytes count. Patients with wild-type BRCA1/2 (BRCAwt) and ≥3 CD8+ tumor-infiltrating lymphocytes count will receive the combination of tislelizumab, bevacizumab, and nab-paclitaxel (arm 2, n=50), while BRCAwt patients with <3 CD8+ tumor-infiltrating lymphocytes count will receive bevacizumab plus dose-dense nab-paclitaxel (arm 3, n=50). After completing patient enrollment in arm 2, another 20 BRCAwt patients with ≥3 CD8+ tumor-infiltrating lymphocytes count will be included as an arm 2 expansion. Treatment will continue until disease progression or intolerable toxicity, and all adverse events will be recorded. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients include those aged ≥18 with serous, endometrioid, or clear cell ovarian cancer, platinum-resistant recurrence, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. PRIMARY ENDPOINT: Objective response rate (ORR) assessed by the investigators by the RECIST 1.1 criteria. SAMPLE SIZE: 160 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Recruitment is estimated to be completed by 2024 and results may be published by 2027. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05044871.

The association of the platelet/high-density lipoprotein cholesterol ratio with self-reported stroke and cardiovascular mortality: a population-based observational study.

BACKGROUND: Previous studies have shown that the relationship between high-density lipoprotein cholesterol (HDL-C) and stroke is controversial, and the association between the platelet/high-density lipoprotein cholesterol ratio (PHR), a novel marker for inflammation and hypercoagulability states, and stroke has not been established. METHODS: This study presents an analysis of cross-sectional data from the 2005-2018 National Health and Nutrition Examination Survey (NHANES). Stroke history, HDL-C levels, and platelet counts were obtained during cross-sectional surveys. The PHR was calculated as the ratio of the number of platelets to HDL-C concentration. Weighted logistic regression was used to assess the associations of HDL-C and the PHR with stroke. Nonlinearity of this relationship was determined through restricted cubic splines (RCSs) and two-piecewise linear regression for identifying inflection points. Furthermore, Cox regression was utilized to prospectively analyze the associations of the PHR and HDL-C concentration with cardiovascular disease (CVD) mortality in stroke survivors. RESULTS: A total of 27,301 eligible participants were included in the study; mean age, 47.28 years and 50.57% were female, among whom 1,040 had a history of stroke. After full adjustment, the odds ratio (OR) of stroke associated with a per standard deviation (SD) increase in the PHR was estimated at 1.13 (95% confidence interval (CI): 1.03 - 1.24, P = 0.01), and the OR of stroke associated with a per SD increase in HDL-C was 0.95 (95% CI: 0.86-1.05, P = 0.30). The RCS indicated a nonlinear relationship for both variables (PPHR = 0.018 and PHDL-C = 0.003), and further piecewise linear regression identified inflection points at PHR = 223.684 and HDL-C = 1.4 mmol/L. Segmental regression indicated that in the PHR ≥ 223.684 segment, the estimated OR of stroke associated with a per-SD increase in the PHR was 1.20 (95% CI: 1.09 - 1.31, P < 0.001), while the association of stroke with HDL-C was not significant before or after the inflection point (P > 0.05). Furthermore, Cox regression and RCS showed that a per-SD increase in the PHR was linearly associated with a greater risk of CVD mortality among stroke survivors (HR: 1.14, 95% CI: 1.06 - 1.22, P < 0.001; nonlinear, P = 0.956), while HDL-C was not significantly associated with CVD mortality. CONCLUSION: The association between the PHR and stroke incidence exhibited a significant threshold effect, with an inflection point at 223.684. A PHR exceeding 223.684 was positively associated with stroke, while the association between HDL-C and stroke was not significant. Additionally, the PHR was positively and linearly associated with CVD mortality among stroke survivors.

Association of the Controlling Nutritional Status (CONUT) score with all-cause and cause-specific mortality in patients with diabetic kidney disease: evidence from the NHANES 2009-2018.

OBJECTIVE: To investigate the association between the Controlling Nutritional Status (CONUT) score and all-cause and cause-specific mortality in patients with diabetic kidney disease (DKD). DESIGN: A retrospective cohort study. SETTING AND PARTICIPANTS: Data on patients with DKD from the National Health and Nutrition Examination Survey 2009-2018. PRIMARY AND SECONDARY OUTCOME MEASURES: All-cause mortality, cardiovascular disease (CVD)-related mortality, diabetes-related mortality and nephropathy-related mortality. RESULTS: A total of 1714 patients were included, with 1119 (65.29%) in normal nutrition group (a score of 0-1), 553 (32.26%) in mild malnutrition group (a score of 2-4) and 42 (2.45%) in moderate and severe malnutrition group (a score of 5-12), according to the CONUT score. After controlling for age, race, marital status, smoking, hypertension, CVD, diabetic retinopathy, poverty income ratio, antidiabetics, diuretics, urinary albumin to creatinine ratio, uric acid, energy, protein, total fat, sodium and estimated glomerular filtration rate, a higher CONUT score was associated with a significantly greater risk of all-cause death (HR 1.30, 95% CI 1.15 to 1.46, p<0.001). In contrast to patients with a CONUT score of 0-1, those who scored 5-12 had significantly increased risks of all-cause death (HR 2.80, 95% CI 1.42 to 5.51, p=0.003), diabetes-related death (HR 1.78, 95% CI 1.02 to 3.11, p=0.041) and nephropathy-related death (HR 1.84, 95% CI 1.04 to 3.24, p=0.036). CONCLUSION: Moderate and severe malnutrition was associated with greater risks of all-cause death, diabetes-related death and nephropathy-related death than normal nutritional status in DKD. Close monitoring of immuno-nutritional status in patients with DKD may help prognosis management and improvement.

Nutrient intake and risk of multimorbidity: a prospective cohort study of 25,389 women.

BACKGROUND: Multimorbidity is becoming an increasingly serious public health challenge in the aging population. The impact of nutrients on multimorbidity remains to be determined and was explored using data from a UK cohort study. METHOD: Our research analysis is mainly based on the data collected by the United Kingdom Women's Cohort Study (UKWCS), which recruited 35,372 women aged 35-69 years at baseline (1995 to 1998), aiming to explore potential associations between diet and chronic diseases. Daily intakes of energy and nutrients were estimated using a validated 217-item food frequency questionnaire at recruitment. Multimorbidity was assessed using the Charlson comorbidity index (CCI) through electronic linkages to Hospital Episode Statistics up to March 2019. Cox's proportional hazards models were used to estimate associations between daily intakes of nutrients and risk of multimorbidity. Those associations were also analyzed in multinomial logistic regression as a sensitivity analysis. In addition, a stratified analysis was conducted with age 60 as the cutoff point. RESULTS: Among the 25,389 participants, 7,799 subjects (30.7%) were confirmed with multimorbidity over a median follow-up of 22 years. Compared with the lowest quintile, the highest quintile of daily intakes of energy and protein were associated with 8% and 12% increased risk of multimorbidity respectively (HR 1.08 (95% CI 1.01, 1.16), p-linearity = 0.022 for energy; 1.12 (1.04, 1.21), p-linearity = 0.003 for protein). Higher quintiles of daily intakes of vitamin C and iron had a slightly lowered risk of multimorbidity, compared to the lowest quintile. A significantly higher risk of multimorbidity was found to be linearly associated with higher intake quintiles of vitamin B12 and vitamin D (p-linearity = 0.001 and 0.002, respectively) in Cox models, which became insignificant in multinomial logistic regression. There was some evidence of effect modification by age in intakes of iron and vitamin B1 associated with the risk of multimorbidity (p-interaction = 0.006 and 0.025, respectively). CONCLUSIONS: Our findings highlight a link between nutrient intake and multimorbidity risk. However, there is uncertainty in our results, and more research is needed before definite conclusions can be reached.

Multibarrier-penetrating drug delivery systems for deep tumor therapy based on synergistic penetration strategy.

Nanotherapies, valued for their high efficacy and low toxicity, frequently serve as antitumor treatments, but do not readily penetrate deep into tumor tissues and cells. Here we developed an improved tumor-penetrating peptide (TPP)-based drug delivery system. Briefly, the established TPP iNGR was modified to generate a linear NGR peptide capable of transporting nanotherapeutic drugs into tumors through a CendR pathway-dependent, neuropilin-1 receptor-mediated process. Although TPPs have been reported to reach intended tumor targets, they often fail to penetrate cell membranes to deliver tumoricidal drugs to intracellular targets. We addressed this issue by harnessing cell penetrating peptide technology to develop a liposome-based multibarrier-penetrating delivery system (mbPDS) with improved synergistic drug penetration into deep tumor tissues and cells. The system incorporated doxorubicin-loaded liposomes coated with nona-arginine (R9) CPP and cyclic iNGR (CRNGRGPDC) molecules, yielding Lip-mbPDS. Lip-mbPDS tumor-targeting, tumor cell/tissue-penetrating and antitumor capabilities were assessed using CD13-positive human fibrosarcoma-derived cell (HT1080)-based in vitro and in vivo tumor models. Lip-mbPDS evaluation included three-dimensional layer-by-layer confocal laser scanning microscopy, cell internalization/toxicity assays, three-dimensional tumor spheroid-based penetration assays and antitumor efficacy assays conducted in an animal model. Lip-mbPDS provided enhanced synergistic drug penetration of multiple biointerfaces for potentially deep tumor therapeutic outcomes.

RNA sequencing reveals differential long noncoding RNA expression profiles in bacterial and viral meningitis in children.

BACKGROUND: We aimed to investigate the involvement of long non-coding RNA (lncRNA) in bacterial and viral meningitis in children. METHODS: The peripheral blood of five bacterial meningitis patients, five viral meningitis samples, and five healthy individuals were collected for RNA sequencing. Then, the differentially expressed lncRNA and mRNA were detected in bacterial meningitis vs. controls, viral meningitis vs. healthy samples, and bacterial vs. viral meningitis patients. Besides, co-expression and the competing endogenous RNA (ceRNA) networks were constructed. Receiver operating characteristic curve (ROC) analysis was performed. RESULTS: Compared with the control group, 2 lncRNAs and 32 mRNAs were identified in bacterial meningitis patients, and 115 lncRNAs and 54 mRNAs were detected in viral meningitis. Compared with bacterial meningitis, 165 lncRNAs and 765 mRNAs were identified in viral meningitis. 2 lncRNAs and 31 mRNAs were specific to bacterial meningitis, and 115 lncRNAs and 53 mRNAs were specific to viral meningitis. The function enrichment results indicated that these mRNAs were involved in innate immune response, inflammatory response, and immune system process. A total of 8 and 1401 co-expression relationships were respectively found in bacterial and viral meningitis groups. The ceRNA networks contained 1 lncRNA-mRNA pair and 4 miRNA-mRNA pairs in viral meningitis group. GPR68 and KIF5C, identified in bacterial meningitis co-expression analysis, had an area under the curve (AUC) of 1.00, while the AUC of OR52K2 and CCR5 is 0.883 and 0.698, respectively. CONCLUSIONS: Our research is the first to profile the lncRNAs in bacterial and viral meningitis in children and may provide new insight into understanding meningitis regulatory mechanisms.

Randomizing Human Brain Function Representation for Brain Disease Diagnosis.

Resting-state fMRI (rs-fMRI) is an effective tool for quantifying functional connectivity (FC), which plays a crucial role in exploring various brain diseases. Due to the high dimensionality of fMRI data, FC is typically computed based on the region of interest (ROI), whose parcellation relies on a pre-defined atlas. However, utilizing the brain atlas poses several challenges including (1) subjective selection bias in choosing from various brain atlases, (2) parcellation of each subject's brain with the same atlas yet disregarding individual specificity; (3) lack of interaction between brain region parcellation and downstream ROI-based FC analysis. To address these limitations, we propose a novel randomizing strategy for generating brain function representation to facilitate neural disease diagnosis. Specifically, we randomly sample brain patches, thus avoiding ROI parcellations of the brain atlas. Then, we introduce a new brain function representation framework for the sampled patches. Each patch has its function description by referring to anchor patches, as well as the position description. Furthermore, we design an adaptive-selection-assisted Transformer network to optimize and integrate the function representations of all sampled patches within each brain for neural disease diagnosis. To validate our framework, we conduct extensive evaluations on three datasets, and the experimental results establish the effectiveness and generality of our proposed method, offering a promising avenue for advancing neural disease diagnosis beyond the confines of traditional atlas-based methods. Our code is available at https://github.com/mjliu2020/RandomFR.

Longitudinal skeletal growth and growth plate morphological characteristics of chondro-tissue specific CUL7 knockout mice.

BACKGROUND: 3 M syndrome is first reported in 1975，which characterized by severe pre- and postnatal growth retardation, skeletal malformation and facial dysmorphism. These three genes (CUL7, OBSL1 and CCDC8) have been identified to be respond for 3 M syndrome, of which CUL7 is accounting for approximately 70%. To date, the molecular mechanism underlying the pathogenesis of 3 M syndrome remains poorly understood. Previous studies showed that no Cul7-/- mice could survive after birth, because of growth retardation at late gestational stage and respiratory distress after birth. The establishment of the animal model of cartilage specific Cul7 knockout mice (Cul7fl/fl;Col2a1-CreERT2 mice) has confirmed that Cul7fl/fl;Col2a1-CreERT2 mice can be selective in a time- and tissue-dependent manner, which can provide an experimental basis for further research on severe genetic diseases related to growth plates. OBJECTIVE: To establish a model of Cul7fl/fl;Col2a1-CreERT2 mice based on Cre/LoxP system, and to further observe its phenotype and morphological changes in growth plate. METHODS: The Cul7fl/fl;Col2a1-CreERT2 mice were taken as the experimental group, while the genotype of Cul7fl/+;Col2a1-CreERT2 mice were used as the control group. The gross morphological features and X-ray films of limbs in the two groups were observed every week for 3-6 consecutive weeks, and the length of the mice from nose to the tail, the length of femur and tibia were recorded. In the meantime, The histological morphology of tibial growth plates was compared between the two groups. RESULTS: A preliminary model of Cul7fl/fl;Col2a1-CreERT2 mice was established. The Cul7fl/fl;Col2a1-CreERT2 mice had abnormally short and deformed limbs (P<0.05), increased thickness of growth plate, the disorderly arranged chondrocyte columns, decreased number of cells in the proliferation zone, changes in the shape from flat to round, obviously expanded extracellular matrix, and disordered arrangement, thickening and loosening of bone trabecula at the proximal metaphysis of the femur. CONCLUSIONS: The knockout of Cul7 gene may affect both the proliferation of chondrocytes and the endochondral osteogenesis, confirming that Cul7 is essential for the normal development of bone in the body.

Mediterranean diet associated with lower frailty risk: A large cohort study of 21,643 women admitted to hospitals.

BACKGROUND: Mediterranean diet is traditionally considered as a healthy dietary pattern, while its association with frailty has not been confirmed. This study investigated associations between Mediterranean diet and risk of frailty among women admitted to hospitals in England from an older-aged women's cohort study. METHODS: A modified Mediterranean diet was evaluated from a validated 217-item food frequency questionnaire. Incident frailty was determined using a hospital frailty risk score based on linkage to Hospital Episode Statistics up to March 2019. Cox proportional hazard models were conducted to estimate hazard ratios (HR) and 95% confidence intervals (CI). Further subgroup analyses stratified by age and body mass index (BMI), and sensitivity analyses were additionally explored. RESULTS: Over a mean follow-up of 13 years, there were 14,838 (68.6%) cases of frailty out of 21,643 individuals included in this study. Compared with low adherence to Mediterranean diet, moderate adherence was associated with 5% (HR = 0.95, 95%CI: 0.91, 0.99) lower risk of frailty, with high adherence associated with even lower risk (HR = 0.89, 95%CI: 0.85, 0.94). The magnitude of above associations remained consistent in subgroups stratified by age and BMI, except the association between moderate adherence and risk of frailty was attenuated in the ≥60-year (HR = 0.99, 95%CI: 0.93, 1.06) and the BMI > 24.9 kg/m2 (HR = 0.97, 95%CI: 0.91, 1.03) subgroups. CONCLUSIONS: Adherence to Mediterranean diet was associated with lower risk of frailty. The better the adherence, the greater the magnitude of the protective association. Older and overweight women may potentially benefit from greater adherence to the Mediterranean diet regarding frailty prevention.

Macrophages regulate healing-associated fibroblasts in diabetic wound.

BACKGROUND: Recovery from a foot ulcer is compromised in a diabetic status, due to the impaired tissue microenvironment that consists of altered inflammation, angiogenesis and fibrosis. Phenotypic alterations in both macrophages and fibroblasts have been detected in the diabetic wound. Recently, a fibroblast subpopulation that expresses high matrix metalloproteinase 1 (MMP1), MMP3, MMP11 and Chitinase-3-Like Protein 1 (CHI3L1) was associated with a successful diabetic wound healing. However, it is not known whether these healing-associated fibroblasts are regulated by macrophages. METHODS AND RESULTS: We used bioinformatic tools to analyze selected public databases on normal and diabetic skin from patients, and identified genes significantly altered in diabetes. In a mouse model for diabetic wound healing, we detected not only a loss of the spatiotemporal changes in interleukin 1ß (IL1ß), IL6, IL10 and vascular endothelial growth factor A (VEGF-A) in wound macrophages, but also a compromised expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in healing-associated wound fibroblasts in a diabetic status. Co-culture with diabetic macrophages significantly reduced the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from non-diabetic wound. Co-culture with non-diabetic macrophages or diabetic macrophages supplied with IL6 significantly increased the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from diabetic wound. Moreover, macrophage-specific expression of IL6 significantly improved wound healing and angiogenesis in diabetic mice. CONCLUSIONS: Macrophages may induce the activation of wound-healing-associated fibroblasts, while the defective macrophages in diabetes may be corrected with IL6 treatment as a promising therapy for diabetic foot disease.

Fluorometric and colorimetric dual-mode sensing of α-glucosidase based on aggregation-induced emission enhancement of AuNCs.

Herein, a fluorometric and colorimetric dual-mode assay platform used for α-glucosidase (α-Glu) activity sensing based on aggregation-induced emission enhancement (AIEE) of AuNCs was developed for the first time. The quantum yield (QY) and fluorescence lifetime of AuNCs were successfully ameliorated by Ce3+-triggered AIEE (Ce@AuNCs). Subsequently, on the basis of the inner filter effect (IFE) and dynamic quenching effect (DQE) between 2,6-dichlorophenolindophenol (DCIP) and Ce@AuNCs as well as the reduction of DCIP by ascorbic acid (AA) generated from α-Glu-catalyzed hydrolysis of L-ascorbic acid-2-O-α-D-glucopyranosyl (AA2G), the marriage of fluorometric and colorimetric modes applied for α-Glu activity monitoring was achieved. Besides, the feasibility of this dual-mode sensing system was confirmed by the assays versus potential interfering substances and in real samples. In particular, this system was further applied to evaluate natural α-Glu inhibitors (AGIs) including luteolin, apigenin, and hesperidin. Overall, the multi-mode optical sensor newly designed here has the potential for the accurate discovery of natural anti-diabetes drugs and the therapy of diabetes.

Fully Aromatic Self-Assembled Hole-Selective Layer toward Efficient Inverted Wide-Bandgap Perovskite Solar Cells with Ultraviolet Resistance.

Ultraviolet-induced degradation has emerged as a critical stability concern impeding the widespread adoption of perovskite solar cells (PSCs), particularly in the context of phase-unstable wide-band gap perovskite films. This study introduces a novel approach by employing a fully aromatic carbazole-based self-assembled monolayer, denoted as (4-(3,6-dimethoxy-9H-carbazol-9-yl)phenyl)phosphonic acid (MeO-PhPACz), as a hole-selective layer (HSL) in inverted wide-band gap PSCs. Incorporating a conjugated linker plays a pivotal role in promoting the formation of a dense and highly ordered HSL on substrates, facilitating subsequent perovskite interfacial interactions, and fostering the growth of uniform perovskite films. The high-quality film could effectively suppress interfacial non-radiative recombination, improving hole extraction/transport efficiency. Through these advancements, the optimized wide-band gap PSCs, featuring a band gap of 1.68 eV, attain an impressive power conversion efficiency (PCE) of 21.10 %. Remarkably, MeO-PhPACz demonstrates inherent UV resistance and heightened UV absorption capabilities, substantially improving UV resistance for the targeted PSCs. This characteristic holds significance for the feasibility of large-scale outdoor applications.

Multimodal Imaging-Guided Photoimmunotherapy of Pancreatic Cancer by Organosilica Nanomedicine.

Immune checkpoint blockade (ICB) treatments have contributed to substantial clinical progress. However, challenges persist, including inefficient drug delivery and penetration into deep tumor areas, inadequate response to ICB treatments, and potential risk of inflammation due to over-activation of immune cells and uncontrolled release of cytokines following immunotherapy. In response, this study, for the first time, presents a multimodal imaging-guided organosilica nanomedicine (DCCGP) for photoimmunotherapy of pancreatic cancer. The novel DCCGP nanoplatform integrates fluorescence, magnetic resonance, and real-time infrared photothermal imaging, thereby enhancing diagnostic precision and treatment efficacy for pancreatic cancer. In addition, the incorporated copper sulfide nanoparticles (CuS NPs) lead to improved tumor penetration and provide external regulation of immunotherapy via photothermal stimulation. The synergistic immunotherapy effect is realized through the photothermal behavior of CuS NPs, inducing immunogenic cell death and relieving the immunosuppressive tumor microenvironment. Coupling photothermal stimulation with αPD-L1-induced ICB, the platform amplifies the clearance efficiency of tumor cells, achieving an optimized synergistic photoimmunotherapy effect. This study offers a promising strategy for the clinical application of ICB-based combined immunotherapy and presents valuable insights for applications of organosilica in precise tumor immunotherapy and theranostics.

HybridGCN for protein solubility prediction with adaptive weighting of multiple features.

The solubility of proteins stands as a pivotal factor in the realm of pharmaceutical research and production. Addressing the imperative to enhance production efficiency and curtail experimental costs, the demand arises for computational models adept at accurately predicting solubility based on provided datasets. Prior investigations have leveraged deep learning models and feature engineering techniques to distill features from raw protein sequences for solubility prediction. However, these methodologies have not thoroughly delved into the interdependencies among features or their respective magnitudes of significance. This study introduces HybridGCN, a pioneering Hybrid Graph Convolutional Network that elevates solubility prediction accuracy through the combination of diverse features, encompassing sophisticated deep-learning features and classical biophysical features. An exploration into the intricate interplay between deep-learning features and biophysical features revealed that specific biophysical attributes, notably evolutionary features, complement features extracted by advanced deep-learning models. Augmenting the model's capability for feature representation, we employed ESM, a substantial protein language model, to derive a zero-shot learning feature capturing comprehensive and pertinent information concerning protein functions and structures. Furthermore, we proposed a novel feature fusion module termed Adaptive Feature Re-weighting (AFR) to integrate multiple features, thereby enabling the fine-tuning of feature importance. Ablation experiments and comparative analyses attest to the efficacy of the HybridGCN approach, culminating in state-of-the-art performances on the public eSOL and S. cerevisiae datasets.

A midterm follow-up study of the application of a confluent aortic valve neocuspidization technique with pericardium in children.

Background: The treatment of aortic valve diseases in children remains a great challenge. We aim to report outcomes and midterm follow-up data of our confluent neocuspidization technique with pericardium for aortic valve replacement (AVR) in children. Methods: A retrospective analysis was performed on all 20 children who underwent the confluent neocuspidization technique with pericardium at Children's Hospital of Fudan University from March 2017 to May 2022. Outcome measures included echocardiographic measurements, surgical intervention, and mortality. Results: A total of 20 patients (17 males vs. 3 females), with a median age of 7.5 years [min-max, 0.3-12 years; interquartile range (IQR), 4.4-9.7 years], a median body weight of 24.0 kg (min-max, 6.0-52.3 kg; IQR, 15.6-31.0 kg), and median aortic valve annulus size before surgery of 19.0 mm (min-max, 11.0-25.0 mm; IQR, 17.1-21.5 mm), underwent the neocuspidization technique with pericardium (17 autologous pericardia and 3 bovine patch). With 50% of bicuspid aortic valve and 50% of tricuspid, they were respectively diagnosed as aortic stenosis (AS) (7/20, 35%), aortic regurgitation (AR) (8/20, 40%) and mixed AS and AR (AS & AR) (5/20, 25%). The median postoperative follow-up time was 19 months (min-max, 5-61 months; IQR, 16.3-35 months). The peak pressure gradient across the aortic valve decreased from 81.0±37.0 mmHg in AS group and AS & AR group before surgery to 25.9±15.8 mmHg within 24 hours after surgery (P<0.001) and was mostly around 25 mmHg during follow-up. All patients presented mild or less than mild regurgitation within 24 hours after surgery. There were no hospital mortalities. Three patients needed reintervention during follow-up. There was one late death related to mitral valve stenosis. Conclusions: Though the confluent neocuspidization technique with pericardium provided immediate relief of significant AS or regurgitation, the midterm outcome was suboptimal. More research is needed to find the optimal material for AVR.

Serum 25(OH)D levels are associated with disease activity and renal involvement in initial-onset childhood systemic lupus erythematosus.

Background: Vitamin D deficiency is common in patients with systemic lupus erythematosus (SLE) and may affect their disease activity and severity. Objective: This study aims to assess the vitamin D status in patients with initial-onset SLE during childhood and its association with the clinical and laboratory markers of disease activity. Method: This is a retrospective study that includes 168 patients with initial-onset SLE during childhood and 109 healthy children as controls. Clinical and laboratory data were recorded. The area under the curve (AUC) method was used to evaluate the efficacy of double-stranded deoxyribonucleic acid (dsDNA), lower 25(OH)D and complement 3 (C3) alone and in combination to diagnose the presence of renal damage in children with SLE. Result: Compared with the controls (25.53 ± 7.02 ng/ml), patients with initial-onset SLE during childhood have lower serum 25(OH)D levels (18.63 ± 5.32 ng/ml) (P < 0.05). Among patients with initial-onset SLE during childhood, SLEDAI-2K scores are significantly higher in the vitamin D insufficiency (median = 14.5) and vitamin D deficiency (median = 14.0) groups than in the vitamin D sufficiency group (median = 9.0) (P < 0.05). Patients with initial-onset SLE during childhood with lower 25(OH)D levels are more likely to have lupus nephritis (LN) and a higher SDI score (P < 0.05). Compared with patients with other types of LN (16.69 ± 3.90 ng/ml), patients with type V LN have lower levels of 25(OH)D (12.27 ± 3.53 ng/ml) (P < 0.05). The AUC was 0.803 when dsDNA antibody, 25(OH)D level and C3 were used in combination to diagnose LN in patients with SLE. Conclusion: Vitamin D deficiency and insufficiency are closely related to an increase in SLEDAI and SDI scores. Significant decrease in vitamin D level is a risk factor for LN.

Foods, Nutrients, and Risk of In-Hospital Frailty in Women: Findings from a Large Prospective Cohort Study.

Frailty is increasingly prevalent worldwide because of aging populations. Diet may play a role as a modifiable risk factor. This study aimed to investigate associations between dietary factors and risk of frailty in the UK Women's Cohort admitted to hospitals in England. Consumption of foods and nutrients was estimated using a validated 217-item food frequency questionnaire at baseline. Incident frailty was assessed via a hospital frailty risk score based on linkage with hospital episode statistics. Out of 25,186 participants admitted to hospitals, 6919 (27%) were identified with frailty and 10,562 (42%) with pre-frailty over a mean follow-up of 12.7 years. After adjustment for confounding, we observed a 12% increase in risk of frailty with each additional 10 g/MJ intake of total meat (HR = 1.12, 95%CI: 1.07, 1.17), with the highest risk observed for processed meats (HR = 1.45, 95%CI: 1.21, 1.73). Similar associations were observed with pre-frailty. Vegetable intake was associated with slightly lower risk of frailty (HR = 0.98, 95%CI: 0.97, 1.00). There was no evidence of association between most nutrient intakes and in-hospital frailty risk. Overall, our findings suggest that reducing consumption of meat, especially processed meat, in adults may be beneficial regarding the development of frailty.