Hydrogel-exosome system in tissue engineering: A promising therapeutic strategy.

Characterized by their pivotal roles in cell-to-cell communication, cell proliferation, and immune regulation during tissue repair, exosomes have emerged as a promising avenue for "cell-free therapy" in clinical applications. Hydrogels, possessing commendable biocompatibility, degradability, adjustability, and physical properties akin to biological tissues, have also found extensive utility in tissue engineering and regenerative repair. The synergistic combination of exosomes and hydrogels holds the potential not only to enhance the efficiency of exosomes but also to collaboratively advance the tissue repair process. This review has summarized the advancements made over the past decade in the research of hydrogel-exosome systems for regenerating various tissues including skin, bone, cartilage, nerves and tendons, with a focus on the methods for encapsulating and releasing exosomes within the hydrogels. It has also critically examined the gaps and limitations in current research, whilst proposed future directions and potential applications of this innovative approach.

UPK3A+ umbrella cell damage mediated by TLR3-NR2F6 triggers programmed destruction of urothelium in Hunner-type interstitial cystitis/painful bladder syndrome.

Urothelial damage and barrier dysfunction emerge as the foremost mechanisms in Hunner-type interstitial cystitis/bladder pain syndrome (HIC). Although treatments aimed at urothelial regeneration and repair have been employed, their therapeutic effectiveness remains limited due to the inadequate understanding of specific cell types involved in damage and the lack of specific molecular targets within these mechanisms. Therefore, we harnessed single-cell RNA sequencing to elucidate the heterogeneity and developmental trajectory of urothelial cells within HIC bladders. Through reclustering, we identified eight distinct clusters of urothelial cells. There was a significant reduction in UPK3A+ umbrella cells and a simultaneous increase in progenitor-like pluripotent cells (PPCs) within the HIC bladder. Pseudotime analysis of the urothelial cells in the HIC bladder revealed that cells faced challenges in differentiating into UPK3A+ umbrella cells, while PPCs exhibited substantial proliferation to compensate for the loss of UPK3A+ umbrella cells. The urothelium in HIC remains unrepaired, despite the substantial proliferation of PPCs. Thus, we propose that inhibiting the pivotal signaling pathways responsible for the injury to UPK3A+ umbrella cells is paramount for restoring the urothelial barrier and alleviating lower urinary tract symptoms in HIC patients. Subsequently, we identified key molecular pathways (TLR3 and NR2F6) associated with the injury of UPK3A+ umbrella cells in HIC urothelium. Finally, we conducted in vitro and in vivo experiments to confirm the potential of the TLR3-NR2F6 axis as a promising therapeutic target for HIC. These findings hold the potential to inhibit urothelial injury, providing promising clues for early diagnosis and functional bladder self-repair strategies for HIC patients. © 2024 The Pathological Society of Great Britain and Ireland.

Characteristics of bone metabolism in the male patients with diabetic neuropathy.

BACKGROUND: This study aimed to evaluate the characteristics of bone metabolism and fracture risk in the type 2 diabetes mellitus (T2DM) patients with distal symmetric polyneuropathy (DSPN). METHODS: A total of 198 T2DM individuals were recruited from January 2017 to December 2020. Patients with DSPN were evaluated by strict clinical and sensory thresholds. Biochemical parameters and bone mineral density (BMD) were measured. The BMD, bone turnover markers, and probability of fracture were compared between two groups, and the factors related to BMD and probability of hip fracture in 10 years were further explored. RESULTS: Compared with type 2 diabetes mellitus without distal symmetric polyneuropathy (T2DN-) patients, type 2 diabetes mellitus with distal symmetric polyneuropathy (T2DN+) patients had lower level of cross-linked C-telopeptide (CTX) (0.32 ± 0.19 vs 0.38 ± 0.21 ng/mL, p = 0.038) and higher level of bone-specific alkaline phosphatase (BALP) (15.28 ± 5.56 vs 12.58 ± 4.41 µg/mL, p = 0.003). T2DN+ patients had higher BMD of lumbar L1-L4 (1.05 ± 0.19 vs 0.95 ± 0.37, p = 0.027) and higher probability of hip fracture (0.98 ± 0.88 vs 0.68 ± 0.63, p = 0.009) as compared to T2DN- individuals. Univariate correlation analysis showed that BALP level (coefficient (coef) = -0.054, p = 0.038), CTX level (coef = -2.28, p = 0.001), and hip fracture risk (coef = -1.02, p < 0.001) were negatively related to the BMD of L1-L4. As for the risk of hip fracture evaluated by WHO Fracture Risk Assessment Tool (FRAX), age (coef = 0.035, p < 0.001), use of insulin (coef = 0.31, p =0.015), and levels of BALP (coef = 0.031, p = 0.017) and CTX (coef = 0.7, p = 0.047) were positively related to the risk of hip fracture. Multivariate regression analysis showed that CTX level (coef = -1.41, p = 0.043) was still negatively related to BMD at the lumbar spine. CONCLUSION: This study indicates that T2DM patients with DSPN have special bone metabolism represented by higher BALP level and lower CTX level which may increase BMD at the lumbar spine.

MTFR2-dependent mitochondrial fission promotes HCC progression.

BACKGROUND: The role of mitochondrial dynamics, encompassing fission, fusion, and mitophagy, in cancer progression has been extensively studied. However, the specific impact of mitochondrial dynamics on hepatocellular carcinoma (HCC) is still under investigation. METHODS: In this study, mitochondrial dynamic genes were obtained from the MitoCarta 3.0 database, and gene expression data were collected from The Cancer Genome Atlas (TCGA) database. Based on the expression of these dynamic genes and differentially expressed genes (DEGs), patients were stratified into two clusters. Subsequently, a prognostic model was constructed using univariate COX regression and the least absolute shrinkage and selection operator (LASSO) regression, and the prognostic signature was evaluated. We analyzed the interaction between these model genes and dynamic genes to identify hub genes and reveal mitochondrial status. Furthermore, we assessed immune infiltration, tumor mutational burden (TMB), tumor stemness indices (TSI), and the response to immune checkpoint block (ICB) therapy using the TIDE algorithm and risk scores. Additionally, transmission electron microscopy (TEM), hematoxylin-eosin (H&E) staining, immunohistochemistry (IHC), western blotting (WB), and immunofluorescence (IF) were conducted to afford detailed visualization of the morphology of the mitochondria and the expression patterns of fission-associated proteins. RESULTS: Patients in Cluster 2 exhibited heightened mitochondrial fission and had a worse prognosis. The up-regulated dynamic genes in Cluster 2 were identified as fission genes. GO/KEGG analyses reconfirmed the connection of Cluster 2 to augmented mitochondrial fission activities. Subsequently, a ten-gene prognostic signature based on the differentially expressed genes between the two clusters was generated, with all ten genes being up-regulated in the high-risk group. Moreover, the potential links between these ten signature genes and mitochondrial dynamics were explored, suggesting their involvement in mediating mitochondrial fission through interaction with MTFR2. Further investigation revealed that the high-risk group had an unfavorable prognosis, with a higher mutation frequency of TP53, increased immune checkpoint expression, a higher TIS score, and a lower TIDE score. The mitochondrial imbalance characterized by increased fission and upregulated MTFR2 and DNM1L expression was substantiated in both HCC specimens and cell lines. CONCLUSIONS: In conclusion, we developed a novel MTFR2-related prognostic signature comprising ten mitochondrial dynamics genes. These genes play crucial roles in mitochondrial fission and have the potential to serve as important predictors and therapeutic targets for HCC.

Interpreting epigenetic causes of recurrent hypokalemia and seizures: Gitelman syndrome co-exist with pseudohypoparathyroidism type 1B.

We describe a unique case of 27-year-old male with Gitelman syndrome (GS) co-exist with pseudohypoparathyroidism type 1B (PHP1B). The patient presented with a 5-year history of seizures, tetany, and numbness of the extremities. Further examinations showed recurrent hypokalemia, inappropriate kaliuresis, hypocalcemia, hyperphosphatemia, and elevated PTH levels. A novel variant of autosomal recessive GS (p.Val287Met SLC12A3) and a novel 492.3Kb deletion containing the whole of STX16, were discovered by a whole-exome sequencing. Following the diagnosis, calcitriol, calcium, and potassium supplements were started. Hematuria calcium and phosphorus levels, as well as blood potassium levels, have recovered and remained within normal ranges after 3 years of follow-up. Our findings have important consequences for supporting the idea that heterozygosity for variants have effects on the patients' clinical performance with autosomal recessive inheritance disorders. Further study is need for the putative effects of the variant. Likewise, further investigation with regards to the gene-gene interaction relations between GS and other electrolyte imbalance disorders is warranted.

A Self-Assembly Pro-Coagulant Powder Capable of Rapid Gelling Transformation and Wet Adhesion for the Efficient Control of Non-Compressible Hemorrhage.

Rapid and effective control of non-compressible massive hemorrhage poses a great challenge in first-aid and clinical settings. Herein, a biopolymer-based powder is developed for the control of non-compressible hemorrhage. The powder is designed to facilitate rapid hemostasis by its excellent hydrophilicity, great specific surface area, and adaptability to the shape of wound, enabling it to rapidly absorb fluid from the wound. Specifically, the powder can undergo sequential cross-linking based on "click" chemistry and Schiff base reaction upon contact with the blood, leading to rapid self-gelling. It also exhibits robust tissue adhesion through covalent/non-covalent interactions with the tissues (adhesive strength: 89.57 ± 6.62 KPa, which is 3.75 times that of fibrin glue). Collectively, this material leverages the fortes of powder and hydrogel. Experiments with animal models for severe bleeding have shown that it can reduce the blood loss by 48.9%. Studies on the hemostatic mechanism also revealed that, apart from its physical sealing effect, the powder can enhance blood cell adhesion, capture fibrinogen, and synergistically induce the formation of fibrin networks. Taken together, this hemostatic powder has the advantages for convenient preparation, sprayable use, and reliable hemostatic effect, conferring it with a great potential for the control of non-compressible hemorrhage.

Promotion of uterine reconstruction by a tissue-engineered uterus with biomimetic structure and extracellular matrix microenvironment.

The recurrence rate for severe intrauterine adhesions is as high as 60%, and there is still lack of effective prevention and treatment. Inspired by the nature of uterus, we have developed a bilayer scaffold (ECM-SPS) with biomimetic heterogeneous features and extracellular matrix (ECM) microenvironment of the uterus. As proved by subtotal uterine reconstruction experiments, the mechanical and antiadhesion properties of the bilayer scaffold could meet the requirement for uterine repair. With the modification with tissue-specific cell-derived ECM, the ECM-SPS had the ECM microenvironment signatures of both the endometrium and myometrium and exhibited the property of inducing stem cell-directed differentiation. Furthermore, the ECM-SPS has recruited more endogenous stem cells to promote endometrial regeneration at the initial stage of repair, which was accompanied by more smooth muscle regeneration and a higher pregnancy rate. The reconstructed uterus could also sustain normal pregnancy and live birth. The ECM-SPS may thereby provide a potential treatment for women with severe intrauterine adhesions.

The influence of parental rearing style on the incidence of panic disorder, major depressive disorder and the comorbidity among Chinese college students.

BACKGROUND: Panic disorder (PD), major depressive disorder (MDD), and the comorbidity (PD&MDD) in college students have caused a heavy disease burden for individuals and families. However, little was known for the comorbidity, especially the impact of parental rearing style on the incidence of the PD&MDD comorbidity. METHODS: A cohort study was conducted among 6652 Chinese college students. Composite International Diagnostic Interview (CIDI-3.0) was used for disease diagnosis. The parental rearing styles were measured by the Egna Minnen Beträffande Uppfostran (EMBU) scale and factor analysis was used to reduce the dimension of the EMBU scale. Multinomial logistic regression models were used to determine the relationships between parenting styles and disease incidence. SPSS version 26.0 was used for all statistical analyses. RESULTS: The 1-year incidence of PD, MDD, and PD&MDD comorbidity was 0.27 %, 2.04 %, and 0.21 %, respectively. Emotional warmth mode (OR = 0.753, 95%CI: 0.631-0.899, P < 0.01) were only negatively correlated with major depressive disorder. However, punishment denial mode (OR = 1.857, 95%CI: 1.316-2.620, P < 0.01) and over-participation mode (OR = 1.862, 95%CI: 1.176-2.949, P < 0.01) were positively correlated with the comorbidity of panic disorder and major depressive disorder. LIMITATIONS: The limited follow-up period was only 1 year in this study which had impacted the collection of new onset cases. CONCLUSIONS: Parental rearing style has a long-term influence on the psychiatric status of college students. Parenting style interventions working as the second level of mental disorder prevention will play an important role in MDD, PD and comorbidity prevention.

Multifunctional two-component in-situ hydrogel for esophageal submucosal dissection for mucosa uplift, postoperative wound closure and rapid healing.

Endoscopic submucosal dissection (ESD) for gastrointestinal tumors and premalignant lesions needs submucosal fluid cushion (SFC) for mucosal uplift before dissection, and wound care including wound closure and rapid healing postoperatively. Current SFC materials as well as materials and/or methods for post-ESD wound care have single treatment effect and hold corresponding drawbacks, such as easy dispersion, short duration, weak hemostasis and insufficient repair function. Thus, designing materials that can serve as both SFC materials and wound care is highly desired, and remains a challenge. Herein, we report a two-component in-situ hydrogel prepared from maleimide-based oxidized sodium alginate and sulfhydryl carboxymethyl-chitosan, which gelated mainly based on "click" chemistry and Schiff base reaction. The hydrogels showed short gelation time, outstanding tissue adhesion, favorable hemostatic properties, and good biocompatibility. A rat subcutaneous ultrasound model confirmed the ability of suitable mucosal uplift height and durable maintenance time of AM solution. The in vivo/in vitro rabbit liver hemorrhage model demonstrated the effects of hydrogel in rapid hemostasis and prevention of delayed bleeding. The canine esophageal ESD model corroborated that the in-situ hydrogel provided good mucosal uplift and wound closure effects, and significantly accelerated wound healing with accelerating re-epithelization and ECM remodeling post-ESD. The two-component in-situ hydrogels exhibited great potential in gastrointestinal tract ESD.

Combined treatment with sacubitril/valsartan plus dapagliflozin in patients affected by heart failure with reduced ejection fraction.

Background: Data about real-world effects of combined therapy with sacubitril/valsartan plus dapagliflozin in patients affected by heart failure (HF) with reduced ejection fraction (HFrEF) has not been widely reported. In this article, the benefits of dapagliflozin and sacubitril/valsartan respect to improvements of cardiac function in patients with HFrEF would be investigated. Methods: HF patients prescribed sacubitril/valsartan between January 2020 and January 2022 in a tertiary teaching hospital were selected using the Computerized Patient Record System. Patients were divided into two groups according to whether they were taking dapagliflozin. Clinical parameters at baseline and during follow-up were retrospectively collected and analyzed. Results: Total of 136 consecutive patients were recruited for this study. 72 patients treated with sacubitril/valsartan and dapagliflozin were assigned to Group A, and another 64 patients receiving sacubitril/valsartan monotherapy were assigned to Group B. After treatment with sacubitril/valsartan plus dapagliflozin for a median follow-up period of 189 days (IQR, 180-276), significant improvements of cardiac function were achieved in Group A. Median N-terminal pro-B-type natriuretic peptide (NT-proBNP) level was significantly decreased from 2585 pg/ml (1014-3702.5) to 1260.5 pg/ml (439.8-2214.3) (P < 0.001). Mean left ventricular ejection fraction (LVEF) improved from 34.7 ± 4.6% to 39.2 ± 7.5% (P < 0.001). Mean daily dose of loop diuretics decreased from 37.1 ± 17.3 mg/day to 25.9 ± 18.5 mg/day (P < 0.001). Regarding safety, both systolic blood pressure (P = 0.002) and diastolic blood pressure (P = 0.002) significantly decreased. For patients in Group B, significant improvements in mean LVEF (P < 0.001), decreases in mean daily dose of loop diuretics (P = 0.001) and reductions in diastolic blood pressure (P = 0.023) were observed. Strikingly, both median Δ NT-proBNP (P = 0.04) and median Δ LAD (P = 0.006) in Group A were more pronounced in comparison with those seen in Group B. Conclusions: The combined use of sacubitril/valsartan and dapagliflozin was associated with improved cardiac function in patents with HFrEF, and led to greater reductions in LAD and NT-proBNP levels compared to sacubitril/valsartan monotherapy. These findings suggest that the combination therapy may offer more potent cardiovascular benefits.

Intelligent recognition of CTCs from gallbladder cancer by ultrasensitive electrochemical cytosensor and diagnosis of chemotherapeutic resistance.

Gallbladder carcinoma (GBC) is one of most aggressive and lethal malignancies. Early diagnosis of GBC is crucial for determining appropriate treatment and improving chances of cure. Chemotherapy represents the main therapeutic regimen for unresectable GBC patients to inhibit tumor growth & metastasis. But, chemoresistance is the major cause of GBC recurrence. Thus, there is an urgent need to explore potentially non-invasive and point-of-care approaches to screen GBC and monitor their chemoresistance. Herein, we established an electrochemical cytosensor to specifically detect circulating tumor cells (CTCs) and their chemoresistance. Trilayer of CdSe/ZnS quantum dots (QDs) were cladded upon SiO2 nanoparticles (NPs), forming Tri-QDs/PEI@SiO2 electrochemical probes. Upon conjugation of anti-ENPP1, the electrochemical probes were able to specifically label captured CTCs from GBC. The detection of CTCs and chemoresistance were realized by square wave anodic stripping voltammetric (SWASV) responses to anodic stripping current of Cd 2+ ion when cadmium in electrochemical probes was dissolved and eventually electrodeposited on bismuth film-modified glassy carbon electrode (BFE). Taking use of this cytosensor, one ensured the screening of GBC and limit of detection for CTCs approaches to ～10 cells/mL. Furthermore, by monitoring phenotypic changes of CTCs after drug treatment, the diagnosis of chemoresistance was achieved by our cytosensor.

The Beneficial Effects of a Multispecies Probiotic Supplement on Glycaemic Control and Metabolic Profile in Adults with Type 1 Diabetes: A Randomised, Double-Blinded, Placebo-Controlled Pilot-Study.

Objective: In this pilot-study, the effects of a multispecies probiotic supplement on glycaemic control and metabolic parameters in adults with type 1 diabetes (T1DM) were explored. Material and Methods: A total of 50 T1DM patients were enrolled and randomly placed into a group receiving capsules containing multi-probiotic strains (Bifidobacterium longum, Lactobacterium bulagricumi, Streptococcus thermophilus) and insulin (probiotics group, n = 27) or a group receiving a placebo and insulin (placebo group, n = 23). All patients underwent continuous glucose monitoring at baseline and 12 weeks after intervention. The primary outcomes were determined by comparing factors such as changes in fasting blood glucose (FBG) and haemoglobin A1c (HbA1c) between the groups. Results: Probiotic supplementation significantly reduced FBG (-1.0 ± 4.7 vs 1.8 ± 4.7 mmol/L, p = 0.048), 30 min postprandial glucose (-0.5 ± 4.6 vs 1.9 ± 3.3 mmol/L, p = 0.0495), and low-density lipoprotein cholesterol (-0.07 ± 0.45 vs 0.32 ± 0.78 mmol/L, p = 0.0413), compared with the placebo. Although not statistically significant, probiotic supplementation also lowered HbA1c levels by 0.49% (-5.33 mmol/mol, p = 0.310). Besides, no significant difference was observed in the continuous glucose monitoring (CGM) parameters between the two groups. Further subgroup analysis revealed a significant reduction in mean sensor glucose (MSG; -0.75 (-2.11, 0.48) mmol/L vs 1.51 (-0.37, 2.74) mmol/L, p = 0.010) and time above range (TAR; -5.47 (-20.1, 3.04)% vs 18.9 (-1.11, 35.6)%, p = 0.006), as well as an greater improvement in the time in range (TIR; 9.32 (-4.84, 16.6)% vs -19.9 (-31.4, 0.69)%, p = 0.005) in male patients than female patients in the probiotics group. Conclusion: Multispecies probiotics exerted beneficial effects on fasting and postprandial glucose and lipid profiles in adult T1DM patients, especially for male patients and those with higher baseline FBG levels.

Efficacy and safety of low-dose sacubitril/valsartan in heart failure patients: A systematic review and meta-analysis.

BACKGROUND: Controversy has persisted over the clinical benefits of low-dose sacubitril/valsartan in patients with heart failure (HF). HYPOTHESIS: Low-dose sacubitril/valsartan might also be effective and safe in HF patients. METHODS: Electronic databases including PubMed, Ovid, and Cochrane Library were systematically retrieved from inception to August 5, 2021. Review manager 5.4 and Stata 15.1 were employed in this systematic review and meta-analysis. Key efficacy outcomes of interest included HF hospitalization, all-cause mortality, left ventricular ejection fraction (LVEF), N-terminal pro-B-type natriuretic peptide (NT-proBNP), together with New York Heart Association (NYHA) functional class. The safety outcome was systolic blood pressure (SBP). The grading of recommendations assessment, development, and evaluation approach was conducted to evaluate the quality of evidence for each outcome. RESULTS: A total of 1269 studies were screened and 9 real-world studies met the inclusion criteria were included in the meta-analysis, with 1697 participants. Compared with low-dose sacubitril/valsartan, high-dose sacubitril/valsartan significantly reduced the risk of HF hospitalization (odds ratio [OR]: 0.4, 95% confidence interval [CI]: 0.27-0.61, p < .0001) and the risk of all-cause mortality (OR: 0.23, 95% CI: 0.11-0.47, p < .0001). However, there were no appreciable differences in improvements of NYHA (OR: 0.59, 95% CI: 0.15-2.35, p = .45), changes of LVEF (mean difference [MD]: 2.73%, 95% CI: -2.24% to 7.7%, p = .28), changes of NT-proBNP (MD: 43.09, 95% CI: -28.41 to 114.59, p = .24) and changes of SBP (MD: 3.01, 95% CI: -4.62 to 10.64, p = .44) between groups with low-dose and high-dose sacubitril/valsartan. CONCLUSIONS: Compared with high-dose sacubitril/valsartan, low-dose sacubitril/valsartan was associated with increased risks of HF hospitalization and all-cause mortality. However, no distinct between-group differences in improvements of NYHA, changes of LVEF, changes of NT-proBNP and changes of SBP were observed.

Application of metabolomics in urolithiasis: the discovery and usage of succinate.

Urinary stone is conceptualized as a chronic metabolic disorder punctuated by symptomatic stone events. It has been shown that the occurrence of calcium oxalate monohydrate (COM) during stone formation is regulated by crystal growth modifiers. Although crystallization inhibitors have been recognized as a therapeutic modality for decades, limited progress has been made in the discovery of effective modifiers to intervene with stone disease. In this study, we have used metabolomics technologies, a powerful approach to identify biomarkers by screening the urine components of the dynamic progression in a bladder stone model. By in-depth mining and analysis of metabolomics data, we have screened five differential metabolites. Through density functional theory studies and bulk crystallization, we found that three of them (salicyluric, gentisic acid and succinate) could effectively inhibit nucleation in vitro. We thereby assessed the impact of the inhibitors with an EG-induced rat model for kidney stones. Notably, succinate, a key player in the tricarboxylic acid cycle, could decrease kidney calcium deposition and injury in the model. Transcriptomic analysis further showed that the protective effect of succinate was mainly through anti-inflammation, inhibition of cell adhesion and osteogenic differentiation. These findings indicated that succinate may provide a new therapeutic option for urinary stones.

Development and validation of retrospective electronic frailty index using operational data of aged care homes.

BACKGROUND: Although elderly population is generally frail, it is important to closely monitor their health deterioration to improve the care and support in residential aged care homes (RACs). Currently, the best identification approach is through time-consuming regular geriatric assessments. This study aimed to develop and validate a retrospective electronic frailty index (reFI) to track the health status of people staying at RACs using the daily routine operational data records. METHODS: We have access to patient records from the Royal Freemasons Benevolent Institution RACs (Australia) over the age of 65, spanning 2010 to 2021. The reFI was developed using the cumulative deficit frailty model whose value was calculated as the ratio of number of present frailty deficits to the total possible frailty indicators (32). Frailty categories were defined using population quartiles. 1, 3 and 5-year mortality were used for validation. Survival analysis was performed using Kaplan-Meier estimate. Hazard ratios (HRs) were estimated using Cox regression analyses and the association was assessed using receiver operating characteristic (ROC) curves. RESULTS: Two thousand five hundred eighty-eight residents were assessed, with an average length of stay of 1.2 ± 2.2 years. The RAC cohort was generally frail with an average reFI of 0.21 ± 0.11. According to the Kaplan-Meier estimate, survival varied significantly across different frailty categories (p < 0.01). The estimated hazard ratios (HRs) were 1.12 (95% CI 1.09-1.15), 1.11 (95% CI 1.07-1.14), and 1.1 (95% CI 1.04-1.17) at 1, 3 and 5 years. The ROC analysis of the reFI for mortality outcome showed an area under the curve (AUC) of ≥0.60 for 1, 3 and 5-year mortality. CONCLUSION: A novel reFI was developed using the routine data recorded at RACs. reFI can identify changes in the frailty index over time for elderly people, that could potentially help in creating personalised care plans for addressing their health deterioration.

POI recommendation with queuing time and user interest awareness.

Point-of-interest (POI) recommendation is a challenging problem due to different contextual information and a wide variety of human mobility patterns. Prior studies focus on recommendation that considers user travel spatiotemporal and sequential patterns behaviours. These studies do not pay attention to user personal interests, which is a significant factor for POI recommendation. Besides user interests, queuing time also plays a significant role in affecting user mobility behaviour, e.g., having to queue a long time to enter a POI might reduce visitor's enjoyment. Recently, attention-based recurrent neural networks-based approaches show promising performance in the next POI recommendation task. However, they are limited to single head attention, which can have difficulty in finding the appropriate user mobility behaviours considering complex relationships among POI spatial distances, POI check-in time, user interests and POI queuing times. In this research work, we are the first to consider queuing time and user interest awareness factors for next POI recommendation. We demonstrate how it is non-trivial to recommend a next POI and simultaneously predict its queuing time. To solve this problem, we propose a multi-task, multi-head attention transformer model called TLR-M_UI. The model recommends the next POIs to the target users and predicts queuing time to access the POIs simultaneously by considering user mobility behaviours. The proposed model utilises POIs description-based user personal interest that can also solve the new categorical POI cold start problem. Extensive experiments on six real-world datasets show that the proposed models outperform the state-of-the-art baseline approaches in terms of precision, recall, and F1-score evaluation metrics. The model also predicts and minimizes the queuing time. For the reproducibility of the proposed model, we have publicly shared our implementation code at GitHub (https://github.com/sajalhalder/TLR-M_UI).

ACE2 Affects the Expression and Function of IFITM3 During SARS-CoV-2 Pseudovirus Infection in Vero E6 Cells.

COVID-19 is a globally infectious viral epidemic of great public health concern caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) plays its role as the receptor for SARS-CoV-2 through binding with S protein and the binding results in ACE2 expression decrease. The change of ACE2 is supposed to elicit a series of cellular and molecular events. Other than as the receptor, ACE2's roles on infection by regulating other molecules need to be further studied during SARS-CoV-2 infection. In the present study, we established the ACE2 knockdown model using Vero E6 cells to study how ACE2 influenced the downstream signaling molecules. Analysis of transcriptome sequencing discovered that ACE2 alteration per se caused the alteration of immune factors, including some related to the viral infection-related signaling pathways. We found that ACE2 silencing induced the reduced interferon-induced transmembrane protein 3 (IFITM3) expression. Overexpression of IFITM3 promoted the SARS-CoV-2 pseudovirus infection of Vero E6 cells lacking the ACE2. It indicates that ACE2 can affect IFITM3 expression and function to affect the SARS-CoV-2 infection. Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and contribute to explaining the rapid spread and pathogenesis especially in the case of ACE2 low expression.

Comparative efficacy and safety of two insulin aspart formulations (Rapilin and NovoRapid) when combined with metformin, for patients with diabetes mellitus: a multicenter, randomized, open-label, controlled clinical trial.

OBJECTIVE: This phase 3 confirmatory diabetes mellitus treatment study compared the safety and efficacy of Rapilin and NovoRapid insulin asparts in combination with metformin. METHODS: This 24-week, open-label, randomized, active-controlled, noninferiority phase 3 confirmatory study conducted across centers in China aimed to enroll patients with type 2 diabetes mellitus and blood sugar glucose inadequately controlled by oral antidiabetic drugs. Randomized patients received subcutaneous mealtime Rapilin or NovoRapid (3:1) injections, with metformin. The primary objectives were to demonstrate noninferiority (margin of 0.4%) in HbA1c change from baseline and compare safety profiles of Rapilin versus NovoRapid after 24 weeks. Secondary outcomes included 2-h postprandial plasma glucose (PPG), fasting plasma glucose (FPG), and patients achieving HbA1c <7.0% and ≤6.5%. RESULTS: 590 patients with type 2 diabetes mellitus were randomized to Rapilin (n = 441) and NovoRapid (n = 149) groups. After 24 weeks, the mean HbA1c change from baseline was -2.20% (Rapilin) and -2.32% (NovoRapid); the estimated treatment difference based on least-square means was 0.04% (95% CI: -0.17, 0.26), meeting the noninferiority criteria for Rapilin versus NovoRapid. Comparable improvements were reported for mean 2-hour PPG (6.14 and 6.29 mmol/L), FPG (2.02 and 1.70 mmol/L), and patients with HbA1c <7.0% (52.6% and 51.0%) and ≤6.5% (34.2% and 30.9%), in the Rapilin and NovoRapid groups, respectively, with no significant safety or immunogenicity outcome differences. CONCLUSIONS: Rapilin demonstrated non-inferior glycemic control, and matching safety and immunogenicity to NovoRapid in patients with type 2 diabetes mellitus also receiving metformin over 24 weeks. TRIAL REGISTRATION: ChiCTR20003129041.

Betaine Regulates the Production of Reactive Oxygen Species Through Wnt10b Signaling in the Liver of Zebrafish.

When fish are under oxidative stress, levels of reactive oxygen species (ROS) are chronically elevated, which play a crucial role in fish innate immunity. In the present study, the mechanism by which betaine regulates ROS production via Wnt10b/ß-catenin signaling was investigated in zebrafish liver. Our results showed that betaine enrichment of diet at 0.1, 0.2 and 0.4 g/kg induced Wnt10b and ß-catenin gene expression, but suppressed GSK-3ß expression in zebrafish liver. In addition, the content of superoxide anion (O2 ·-), hydrogen peroxide (H2O2) and hydroxyl radical (·OH) was decreased by all of the experimental betaine treatments. However, betaine enrichment of diet at 0.1, 0.2 and 0.4 g/kg enhanced gene expression and activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) and catalase (CAT) in zebrafish liver. In addition, Wnt10b RNA was further interfered in zebrafish, and the results of Wnt10b RNAi indicated that Wnt10b plays a key role in regulating ROS production and antioxidant enzyme activity. In conclusion, betaine can inhibit ROS production in zebrafish liver through the Wnt10b/ß-catenin signaling pathway.

Roles of ubiquitination in the crosstalk between tumors and the tumor microenvironment (Review).

The interaction between a tumor and the tumor microenvironment (TME) plays a key role in tumorigenesis and tumor progression. Ubiquitination, a crucial post­translational modification for regulating protein degradation and turnover, plays a role in regulating the crosstalk between a tumor and the TME. Thus, identifying the roles of ubiquitination in the process may assist researchers to investigate the mechanisms underlying tumorigenesis and tumor progression. In the present review article, new insights into the substrates for ubiquitination that are involved in the regulation of hypoxic environments, angiogenesis, chronic inflammation­mediated tumor formation, and the function of cancer­associated fibroblasts and infiltrating immune cells (tumor­associated macrophages, T­cells, myeloid­derived suppressor cells, dendritic cells, and natural killer cells) are summarized. In addition, the potential targets of the ubiquitination proteasome system within the TME for cancer therapy and their therapeutic effects are reviewed and discussed.