The opportunities and challenges of the disease-modifying immunotherapy for type 1 diabetes: A systematic review and meta-analysis.

There are multiple disease-modifying immunotherapies showing the potential of preventing or delaying the progression of type 1 diabetes (T1D). We designed and performed this systematic review and meta-analysis to gain an overview of what a role immunotherapy plays in the treatment of T1D. We searched PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to December 2023. We included clinical trials of immunotherapy conducted in patients with T1D that reported the incidence of hypoglycemia or changes from baseline in at least one of following outcomes: 2 h and 4 h mixed-meal-stimulated C-peptide area under the curve (AUC), fasting C-peptide, daily insulin dosage, glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG). The results were computed as the weighted mean differences (WMDs) or odds ratios (ORs) and 95% confidence intervals (CIs) in random-effect model. In all, 34 clinical trials were included. When compared with control groups, 2 h C-peptide AUC was marginally higher in patient treated with nonantigen-based immunotherapies (WMD, 0.04nmol/L, 95% CI, 0.00-0.09 nmol/L, P=0.05), which was mainly driven by the effects of T cell-targeted therapy. A greater preservation in 4 h C-peptide AUC was observed in patients with nonantigen-based immunotherapies (WMD, 0.10nmol/L, 95% CI, 0.04-0.16 nmol/L, P=0.0007), which was mainly driven by the effects of tumor necrosis factor α (TNF-α) inhibitor and T cell-targeted therapy. After excluding small-sample trials, less daily insulin dosage was observed in patient treated with nonantigen-based immunotherapies when compared with control groups (WMD, -0.07units/kg/day, 95% CI, -0.11 to -0.03units/kg/day, P=0.0004). The use of antigen-based immunotherapies was also associated with a lower daily insulin dosage versus control groups (WMD, -0.11units/kg/day, 95% CI, -0.23 to -0.00units/kg/day, P=0.05). However, changes of HbA1c or FPG were comparable between nonantigen-based immunotherapies or antigen-based immunotherapies and control groups. The risk of hypoglycemia was not increased in patients treated with nonantigen-based immunotherapies or patients treated with antigen-based immunotherapies when compared with control groups. In conclusion, nonantigen-based immunotherapies were associated with a preservation of 2 h and 4 h C-peptide AUC in patients with T1D when compared with the controls, which was mainly driven by the effects of TNF-a inhibitor and T cell-targeted therapy. Both nonantigen-based immunotherapies and antigen-based immunotherapies tended to reduce the daily insulin dosage in patients with T1D when compared with the controls. However, they did not contribute to a substantial improvement in HbA1c or FPG. Both nonantigen-based immunotherapies and antigen-based immunotherapies were well tolerated with not increased risk of hypoglycemia in patients with T1D.

Asiatic acid inhibits osteosarcoma cell migration and invasion via the AKT/Sp1/MMP1 axis.

Osteosarcoma is a malignant bone tumor affecting adolescents and children. No effective treatment is currently available. Asiatic acid (AA), a triterpenoid compound found in Centella asiatica, possesses anti-tumor, anti-inflammatory, and anti-oxidant properties in various types of tumor cells. This study aims to determine whether AA exerts antitumor effects in human osteosarcoma cells. Our results indicate that AA does not influence the viability, proliferative rate, or cell cycle phase of human osteosarcoma cells under non-toxic conditions. AA suppressed osteosarcoma cell migration and invasion by down-regulating matrix metalloproteinase 1 (MMP1) expression. Data in the TNMplot database suggested MMP1 expression was higher in osteosarcoma than in normal tissues, with associated clinical significance observed in osteosarcoma patients. Overexpression of MMP1 in osteosarcoma cells reversed the AA-induced suppression of cell migration and invasion. AA treatment decreased the expression of specificity protein 1 (Sp1), while Sp1 overexpression abolished the effect of AA on MMP1 expression and cell migration and invasion. AA inhibited AKT phosphorylation, and treatment with a PI3K inhibitor (wortmannin) increased the anti-invasive effect of AA on osteosarcoma cells via the p-AKT/Sp1/MMP1 axis. Thus, AA exhibits the potential for use as an anticancer drug against human osteosarcoma.

Licochalcone A induces endoplasmic reticulum stress-mediated apoptosis of endometrial cancer cells via upregulation of GRP78 expression.

Licochalcone A (LicA), a natural compound extracted from licorice root, has been shown to exert a variety of anticancer activities. Whether LicA has such effects on endometrial cancer (EMC) is unclear. This study aims to investigate the antitumor effects of LicA on EMC. Our results show that LicA significantly reduced the viability and induced apoptosis of EMC cells and EMC-7 cells from EMC patients. LicA was also found to induce endoplasmic reticulum (ER) stress, leading to increased expression of ER-related proteins (GRP78/PERK/IRE1α/CHOP) in EMC cell lines. Suppression of GRP78 expression in human EMC cells treated with LicA significantly attenuated the effects of LicA, resulting in reduced ER-stress mediated cell apoptosis and decreased expression of ER- and apoptosis-related proteins. Our findings demonstrate that LicA induces apoptosis in EMC cells through the GRP78-mediated ER-stress pathway, emphasizing the potential of LicA as an anticancer therapy for EMC.

A randomized trial of Bacteroides fragilis 839 on preventing chemotherapy-induced myelosuppression and gastrointestinal adverse effects in breast cancer patients.

BACKGROUND AND OBJECTIVES: To evaluate the potential benefits of Bacteroides fragilis 839 (BF839), a next-generation probiotics, in reducing myelosuppression and gastrointestinal toxicity associated with chemotherapy in breast cancer patient. METHODS AND STUDY DESIGN: 40 women with early breast cancer were randomly assigned to the BF839 (n=20) or placebo (n=20) during the administration of adjuvant chemotherapy (4 cycles of epirubicin 100mg/m2 and cyclophosphamide 600mg/m2). Myelosuppression and gastrointestinal adverse effects were monitored in both groups. RESULTS: Throughout the four treatment cycles, the percentage of patients experiencing myelosuppression was 42.5% in the BF839 group, significantly lower than the 66.3% observed in the control group (p=0.003). Two patients in the BF839 group and three patients in the placebo group received recombinant human granulocyte colony-stimulating factor (rhG-CSF) due to leuko-penia/neutropenia. When considering an ITT analysis, which included all patients regardless of rhG-CSF treatment, the BF839 group exhibited less reduction from baseline in white blood cells (-0.31±1.19 vs -1.15±0.77, p=0.012) and neutrophils (0.06±1.00 vs -0.84±0.85, p=0.004) compared to the placebo group. The difference became even more significant when excluding the patients who received rhG-CSF injections. Throughout the four treatment cycles, compared to the placebo group, the BF839 group had significantly lower rates of 3-4 grade nausea (35.0% vs 71.3%, p=0.001), vomiting (20.0% vs 45.0%, p=0.001), and diarrhea (15.0% vs 30.0%, p=0.023). CONCLUSIONS: These findings suggest that BF839 has the potential to effectively mitigate myelosuppression and gastrointestinal toxicity associated with chemotherapy in breast cancer patients.

Practical Strategy for Arsenic(III) Electroanalysis without Modifier in Natural Water: Triggered by Iron Group Ions in Solution.

Significant progress has been made in nanomaterial-modified electrodes for highly efficient electroanalysis of arsenic(III) (As(III)). However, the modifiers prepared using some physical methods may easily fall off, and active sites are not uniform, causing the potential instability of the modified electrode. This work first reports a promising practical strategy without any modifiers via utilizing only soluble Fe3+ as a trigger to detect trace-level As(III) in natural water. This method reaches an actual detection limit of 1 ppb on bare glassy carbon electrodes and a sensitivity of 0.296 µA ppb-1 with excellent stability. Kinetic simulations and experimental evidence confirm the codeposition mechanism that Fe3+ is preferentially deposited as Fe0, which are active sites to adsorb As(III) and H+ on the electrode surface. This facilitates the formation of AsH3, which could further react with Fe2+ to produce more As0 and Fe0. Meanwhile, the produced Fe0 can also accelerate the efficient enrichment of As0. Remarkably, the proposed sensing mechanism is a general rule for the electroanalysis of As(III) that is triggered by iron group ions (Fe2+, Fe3+, Co2+, and Ni2+). The interference analysis of coexisting ions (Cu2+, Zn2+, Al3+, Hg2+, Cd2+, Pb2+, SO42-, NO3-, Cl-, and F-) indicates that only Cu2+, Pb2+, and F- showed inhibitory effects on As(III) due to the competition of active sites. Surprisingly, adding iron power effectively eliminates the interference of Cu2+ in natural water, achieving a higher sensitivity for 1-15 ppb As(III) (0.487 µA ppb-1). This study provides effective solutions to overcome the potential instability of modified electrodes and offers a practical sensing platform for analyzing other heavy-metal anions.

Maize Golden2-like transcription factors boost rice chloroplast development, photosynthesis, and grain yield.

Chloroplasts are the sites for photosynthesis, and two Golden2-like factors act as transcriptional activators of chloroplast development in rice (Oryza sativa L.) and maize (Zea mays L.). Rice OsGLK1 and OsGLK2 are orthologous to maize ZmGLK1 (ZmG1) and ZmGLK2 (ZmG2), respectively. However, while rice OsGLK1 and OsGLK2 act redundantly to regulate chloroplast development in mesophyll cells, maize ZmG1 and ZmG2 are functionally specialized and expressed in different cell-specific manners. To boost rice chloroplast development and photosynthesis, we generated transgenic rice plants overexpressing ZmG1 and ZmG2, individually or simultaneously, with constitutive promoters (pZmUbi::ZmG1 and p35S::ZmG2) or maize promoters (pZmG1::ZmG1, pZmG2::ZmG2, and pZmG1::ZmG1/pZmG2::ZmG2). Both ZmG1 and ZmG2 genes were highly expressed in transgenic rice leaves. Moreover, ZmG1 and ZmG2 showed coordinated expression in pZmG1::ZmG1/pZmG2::ZmG2 plants. All Golden2-like (GLK) transgenic plants had higher chlorophyll and protein contents, Rubisco activities and photosynthetic rates per unit leaf area in flag leaves. However, the highest grain yields occurred when maize promoters were used; pZmG1::ZmG1, pZmG2::ZmG2, and pZmG1::ZmG1/pZmG2::ZmG2 transgenic plants showed increases in grain yield by 51%, 47%, and 70%, respectively. In contrast, the pZmUbi::ZmG1 plant produced smaller seeds without yield increases. Transcriptome analysis indicated that maize GLKs act as master regulators promoting the expression of both photosynthesis-related and stress-responsive regulatory genes in both rice shoot and root. Thus, by promoting these important functions under the control of their own promoters, maize GLK1 and GLK2 genes together dramatically improved rice photosynthetic performance and productivity. A similar approach can potentially improve the productivity of many other crops.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and the Risk of Fracture: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Osteoporosis and hyperlipidemia are closely correlated and statins might be associated with a decreased risk of fracture. We aimed to investigate the association between proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) therapy and the risk of fracture. The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to October 22, 2022. Randomized clinical trials (RCTs) that addressed to fracture events of participants using alirocumab, evolocumab, bococizumab or inclisiran, with a follow-up of ≥ 24 weeks were included. Meta-analyses were conducted to calculate the odds ratio (OR) with 95% confidence intervals (CIs) for major osteoporotic fracture, hip fracture, osteoporotic non-vertebral fracture, and total fracture. 30 trials assessing PCSK9i among 95, 911 adults were included. There were no significant associations between PCSK9i therapy and the risk of major osteoporotic fracture [OR 1.08 (95% Cl 0.87-1.34), p = 0.49], hip fracture [OR 1.05 (95% Cl 0.73-1.53), p = 0.79], osteoporotic non-vertebral fracture [OR 1.03 (95% Cl 0.80-1.32), p = 0.83], and total fracture [OR 1.03 (95% Cl 0.88-1.19), p = 0.74] over a period of 6-64 months. No significant associations were detected in any of the sensitivity analyses and subgroup analyses stratified by the type of PCSK9i, follow-up duration, age, sex, sample size, and patient profile. Pooled results of our meta-analysis showed that exposure to PCSK9i was not associated with reduced risks of fracture in the short term.

Differential Adaptation of Biventricular Myocardial Kinetic Energy in Patients With Repaired Tetralogy of Fallot Assessed by MR Tissue Phase Mapping.

BACKGROUND: The myocardial kinetic energy (KE) and its association with pulmonary regurgitation (PR) have yet to be investigated in repaired tetralogy of Fallot (rTOF) patients. PURPOSE: To evaluate the adaptation of myocardial KE in rTOF patients by tissue phase mapping (TPM). STUDY TYPE: Prospective. POPULATION: A total of 49 rTOF patients (23 ± 5 years old; male = 32), 47 normal controls (22 ± 1 year old; male = 29). FIELD STRENGTH/SEQUENCE: 3-T/2D dark-blood three-directional velocity-encoded gradient-echo sequence. ASSESSMENT: Left and right ventricle (LV, RV) myocardial KE in radial (KEr ), circumferential (KEø ), longitudinal (KEz ) directions. The proportions of KE in each direction to the sum of all KE (KErøz ): %KEr , %KEø , %KEz . PR fraction. STATISTICAL TEST: Student's t test, multivariable regression. Statistical significance: P < 0.05. RESULTS: In rTOF group, LV KEz remained normal in systole (P = 0.565) and diastole (P = 0.210), whereas diastolic LV %KEz (62% ± 14% vs. 72% ± 7%) and systolic LV %KEø (9% ± 6% vs. 20% ± 7%) were significantly decreased. The KEr and %KEr of both ventricles significantly increased in the rTOF group (RV in diastole: 6 ± 3 vs. 3 ± 1 µJ and 54% ± 13% vs. 27% ± 7%). The rTOF group exhibited significantly higher RV/LV ratios of %KEr (systole: 1.3 ± 0.3 vs. 1.0 ± 0.3) and %KEø (systole: 1.6 ± 0.8 vs. 1.0 ± 0.3) and significantly lower ratios of %KEz in systole (0.7 ± 0.2 vs. 1.0 ± 0.1) and diastole (0.5 ± 0.2 vs. 0.9 ± 0.1). In multivariable regression analysis, the RV peak systolic KErøz , RV systolic KEz , and LV diastolic %KEø were independently associated with PR fraction in the rTOF group (adjusted R2  = 0.479). DATA CONCLUSION: In rTOF patients, the adaptation of the KE proportion occurred earlier than that of the KE amplitude, and the biventricular balance of %KE was disrupted. PR may cause differential KE adaptation in RV and LV. TPM-derived KE may be useful in investigation of myocardial adaptation in rTOF patients. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Population attributable fractions of modifiable risk factors for microvascular complications of type 2 diabetes in China: An analysis using national cross-sectional data.

AIM: To assess the population attributable fractions (PAFs) for modifiable risk factors for microvascular complications of type 2 diabetes (T2D) in China. MATERIALS AND METHODS: Data collected from the China National HbA1c Surveillance System from 2009 to 2013 were used. The PAFs of four predefined risk factors, including an HbA1c of 7% or higher, blood pressure (BP) of 130/80 mmHg or higher, low-density lipoprotein-cholesterol (LDL-C) of 1.8 mmol/L or higher and body mass index (BMI) of 24 kg/m2 or higher, were calculated for diabetic microvascular complications, including diabetic retinopathy (DR), diabetic kidney disease (DKD) and distal symmetric polyneuropathy (DSPN). PAFs were further adjusted for age, sex and duration of diabetes. RESULTS: In total, there were 998 379 participants with T2D from nationwide mainland China included in this analysis. As for DR, an HbA1c of 7% or higher, BP of 130/80 mmHg or higher, LDL-C of 1.8 mmol/L or higher and BMI of 24 kg/m2 or higher conferred PAFs of 16.2%, 15.2%, 5.8% and 2.8%, respectively. In the case of DKD, BP of 130/80 mmHg or higher provided a PAF of 25.2%, followed by an HbA1c of 7% or higher (13.9%), BMI of 24 kg/m2 or higher (8.0%) and LDL-C of 1.8 mmol/L or higher (5.6%). As for DSPN, an HbA1c of 7% or higher, BP of 130/80 mmHg or higher, LDL-C of 1.8 mmol/L or higher and BMI of 24 kg/m2 or higher contributed to PAFs of 14.2%, 11.7%, 5.9% and 5.8%, respectively. PAFs for diabetic microvascular complications were mildly to moderately reduced after adjusting for participants' age, sex and duration of diabetes. CONCLUSIONS: Suboptimal glycaemic and BP control were the main contributors to diabetic microvascular complications, while the PAFs of unmet LDL-C and BMI control targets were quite limited for diabetic microvascular complications. In addition to glycaemic control, BP control should be especially prioritized in the management of diabetic microvascular complications to further reduce the disease burden.

Degree of exposure to psychotropic medications and mortality in people with bipolar disorder.

OBJECTIVES: To investigate the associations between psychotropic medication dosage and mortality in patients with bipolar disorder. METHODS: A nationwide cohort of individuals aged ≥15 years who had received a diagnosis of bipolar disorder in 2010 was identified from the Taiwanese national health-care database linked with the mortality registry and followed up for 5 years. The mean defined daily dose (DDD) of mood stabilizers, antipsychotics, antidepressants, and sedative-hypnotics was estimated, and survival analyses were conducted to assess the effects of degree of exposure to psychotropic medications on mortality. RESULTS: A total of 49,298 individuals (29,048 female individuals, 58.92%) with bipolar disorder were included. Compared with individuals without exposure to mood stabilizers, those prescribed mood stabilizers had a decreased overall mortality risk, regardless of exposure dosage. By contrast, compared with a reference group with no exposure to antipsychotics, individuals using antipsychotics had dose-dependent, increased mortality in both overall causes of deaths and deaths due to cardiovascular diseases, with hazard ratios of 1.13 (95% CI: 1.21-1.42) in the low-dose (<0.5 DDD) group, 1.69 (1.51-1.90) in the moderate-dose (0.5-1.5 DDD) group, and 2.08 (1.69-2.57) in the high-dose (>1.5 DDD) group for overall mortality. CONCLUSIONS: In sum, mood stabilizers were associated with decreased overall mortality in individuals with bipolar disorder, regardless of the dosage. However, the use of antipsychotics appeared to be associated with a dose-dependent increased mortality risk. Owing to study limitations, precise information on prior use of psychotropic medications, and patient's adherence to medication are not available. Potential adverse effects and benefits should be carefully considered when prescribing psychotropic medications for long-term use in patients with bipolar disorder.

Fragment Linker Prediction Using the Deep Encoder-Decoder Network for PROTACs Drug Design.

A drug discovery and development pipeline is a prolonged and complex process that remains challenging for both computational methods and medicinal chemists and has not been able to be resolved using computational methods. Deep learning has been utilized in various fields and achieved tremendous success in designing novel molecules in the pharmaceutical industry. Herein, we use state-of-the-art techniques to propose a deep neural network, AIMLinker, to rapidly design and generate meaningful drug-like proteolysis targeting chimeras (PROTACs) analogs. The model extracts the structural information from the input fragments and generates linkers to incorporate them. We integrate filters in the model to exclude nondruggable structures guided via protein-protein complexes while retaining molecules with potent chemical properties. The novel PROTACs subsequently pass through molecular docking, taking root-mean-square deviation (RMSD), relative Gibbs free energy (ΔΔGbinding), molecular dynamics (MD) simulation, and free energy perturbation (FEP) calculations as the measurement criteria for testing the robustness and feasibility of the model. The generated novel PROTACs molecules possess similar structural information with superior binding affinity to the binding pockets compared to the existing CRBN-dBET6-BRD4 ternary complexes. We demonstrate the effectiveness of the methodology of leveraging AIMLinker to design novel compounds for PROTACs molecules exhibiting better chemical properties compared to the dBET6 crystal pose.

Harnessing polyhydroxylated pyrrolidines as a stabilizer of acid alpha-glucosidase (GAA) to enhance the efficacy of enzyme replacement therapy in Pompe disease.

To discover small molecules as acid alpha-glucosidase (GAA) stabilizers for potential benefits of the exogenous enzyme treatment toward Pompe disease cells, we started from the initial screening of the unique chemical space, consisting of sixteen stereoisomers of 2-aminomethyl polyhydroxylated pyrrolidines (ADMDPs) to find out two primary stabilizers 17 and 18. Further external or internal structural modifications of 17 and 18 were performed to increase structural diversity, followed by the protein thermal shift study to evaluate the GAA stabilizing ability. Fortunately, pyrrolidine 21, possessing an l-arabino-typed configuration pattern, was identified as a specific potent rh-GAA stabilizer, enabling the suppression of rh-GAA protein denaturation. In a cell-based Pompe model, co-administration of 21 with rh-GAA protein significantly improved enzymatic activity (up to 5-fold) compared to administration of enzyme alone. Potentially, pyrrolidine 21 enables the direct increase of ERT (enzyme replacement therapy) efficacy in cellulo and in vivo.

Diagnostic value of multiple b-value diffusion-weighted imaging in discriminating the malignant from benign breast lesions.

OBJECTIVE: The conventional breast Diffusion-weighted imaging (DWI) was subtly influenced by microcirculation owing to the insufficient selection of the b values. However, the multiparameter derived from multiple b-value exhibits more reliable image quality and maximize the diagnostic accuracy. We aim to evaluate the diagnostic performance of stand-alone parameter or in combination with multiparameter derived from multiple b-value DWI in differentiating malignant from benign breast lesions. METHODS: A total of forty-one patients diagnosed with benign breast tumor and thirty-eight patients with malignant breast tumor underwent DWI using thirteen b values and other MRI functional sequence at 3.0 T magnetic resonance. Data were accepted mono-exponential, bi-exponential, stretched-exponential, aquaporins (AQP) model analysis. A receiver operating characteristic curve (ROC) was used to evaluate the diagnostic performance of quantitative parameter or multiparametric combination. The Youden index, sensitivity and specificity were used to assess the optimal diagnostic model. T-test, logistic regression analysis, and Z-test were used. P value < 0.05 was considered statistically significant. RESULT: The ADCavg, ADCmax, f, and α value of the malignant group were lower than the benign group, while the ADCfast value was higher instead. The ADCmin, ADCslow, DDC and ADCAQP showed no statistical significance. The combination (ADCavg-ADCfast) yielded the largest area under curve (AUC = 0.807) with sensitivity (68.42%), specificity (87.8%) and highest Youden index, indicating that multiparametric combination (ADCavg-ADCfast) was validated to be a useful model in differentiating the benign from breast malignant lesion. CONCLUSION: The current study based on the multiple b-value diffusion model demonstrated quantitatively multiparametric combination (ADCavg-ADCfast) exhibited the optimal diagnostic efficacy to differentiate malignant from benign breast lesions, suggesting that multiparameter would be a promising non-invasiveness to diagnose breast lesions.

Impact of the COVID-19 pandemic on population-based cancer screening, a nationwide retrospective study in Taiwan.

BACKGROUND: The Coronavirus disease 2019 (COVID-19) pandemic has placed a great burden on Taiwan's health care system. It has also had a great impact on other public health issues, including cancer screening. Delayed cancer screening was also noticed in the U.S. during the pandemic, which may have led to both delayed diagnosis and poor prognosis. In Taiwan, population-based cancer screening for breast cancer, oral cancer, colon cancer and cervical cancer has been executed and ongoing for years. METHOD: In this study we have analyzed the change in screening numbers for cancer during the period of the 2019 to 2021 COVID-19 outbreak in Taiwan. RESULTS: Through our results we found that total cancer screening numbers decreased from 307,547 to 103,289 (a 66% decrease) from the years 2020 to 2021. Specifically, a 63%, 79%, 65% and 71% decrease in screening cases was seen for colon cancer, oral cancer, cervical cancer and breast cancer, respectively, during that period. A similar condition was noticed when comparing 2019 to 2021 when the disclosed total cancer screening numbers decreased by 70% (2019-2021); 65%, 83%, 70% and 76% in colon cancer, oral cancer, cervical cancer and breast cancer, respectively. Among these various cancer screenings, oral cancer screening showed the greatest reduction rate (a drop of 83% compared to 2019 and 79% compared to 2020). We also compared the reduction rates taken from different regions in Taiwan. It was in Taipei, where most COVID-19 cases were noted, that the greatest reduction rate of cancer screening numbers occurred (a drop of76% compared to 2019 and 74% compared to 2020). A proportional decrease of screening cases was also noticed in all areas when confirmed COVID-19 cases rose. CONCLUSIONS: Screening for cancers dropped significantly due to the pandemic and its effect on long-term health needs to be evaluated. Additionally, efforts should be taken to address these cancer screening number deficits which have taken place during the COVID-19 pandemic.

Establishment and Reliability Evaluation of Prognostic Models in Diabetic Foot.

Purpose: To study the risk factors affecting amputation and survival in patients with diabetic foot (DF) and to construct a predictive model using the machine learning technique for DF foot amputation and survival and evaluate its effectiveness. Materials and Methods: A total of 200 patients with DF hospitalized in the First Affiliated Hospital of Shantou University Medical College in China were selected via cluster analysis screening, Kaplan-Meier survival calculation, amputation rate and Cox proportional hazards model investigation of risk factors associated with amputation and death. In addition, we constructed various models, including Cox proportional hazards regression analysis, the deep learning method convolution neural network (CNN) model, backpropagation (BP) neural network model, and backpropagation neural network prediction model after optimizing the genetic algorithm. The accuracy of the 4 prediction models for survival and amputation was assessed, and we evaluated the reliability of these computational models based on the size of the area under the ROC curve (AUC), sensitivity and specificity. Results: We found that the 1-year survival rate in patients with DF was 88.5%, and the 1-year amputation rate was 12.5%. Wagner's Classification of Diabetic Foot Ulcers grade, ankle-brachial index (ABI), low-density lipoprotein (LDL), and percutaneous oxygen partial pressure (TcPO2) were independent risk factors for amputation in patients with DF, while cerebrovascular disease, Sudoscan sweat gland function score, glycated hemoglobin (HbA1c) and peripheral artery disease (PAD) were independent risk factors for death in patients with DF. In addition, our results showed that in the case of amputation, the COX regression predictive model revealed an AUC of 0.788, sensitivity of 74.1% and specificity of 83.6%. The BP neural network predictive model identified an AUC of 0.874, sensitivity of 87.0% and specificity of 87.7%. An AUC of 0.909, sensitivity of 90.7% and specificity of 91.1% were found after optimizing the BP neural network prediction model via genetic algorithm. In the deep learning CNN model, the AUC, sensitivity and specificity were 0.939, 92.6%, and 95.2%, respectively. In the analysis of risk factors for death, the COX regression predictive model identified the AUC, sensitivity and specificity as 0.800, 74.1% and 85.9%, respectively. The BP neural network predictive model revealed an AUC, sensitivity and specificity of 0.937, 93.1% and 94.4%, respectively. Genetic algorithm-based optimization of the BP neural network predictive model identified an AUC, sensitivity and specificity of 0.932, 91.4% and 95.1%, respectively. The deep learning CNN model found the AUC, sensitivity and specificity to be 0.861, 82.8% and 89.4%, respectively. Conclusion: To identify risk factors for death, the BP neural network predictive model and genetic algorithm-based optimizing BP neural network predictive model have higher sensitivity and specificity than the deep learning method CNN predictive model and COX regression analysis.

Minimum taxi fleet algorithm considering human spatiotemporal behaviors.

With the development of information technology, more and more travel data have provided great convenience for scholars to study the travel behavior of users. Planning user travel has increasingly attracted researchers' attention due to its great theoretical significance and practical value. In this study, we not only consider the minimum fleet size required to meet the urban travel needs but also consider the travel time and distance of the fleet. Based on the above reasons, we propose a travel scheduling solution that comprehensively considers time and space costs, namely, the Spatial-Temporal Hopcroft-Karp (STHK) algorithm. The analysis results show that the STHK algorithm not only significantly reduces the off-load time and off-load distance of the fleet travel by as much as 81% and 58% and retains the heterogeneous characteristics of human travel behavior. Our study indicates that the new planning algorithm provides the size of the fleet to meet the needs of urban travel and reduces the extra travel time and distance, thereby reducing energy consumption and reducing carbon dioxide emissions. Concurrently, the travel planning results also conform to the basic characteristics of human travel and have important theoretical significance and practical application value.

A Transient π-π or Cation-π Interaction between Degron and Degrader Dual Residues: A Key Step for the Substrate Recognition and Discrimination in the Processive Degradation of SulA by ClpYQ (HslUV) Protease in Escherichia coli.

The Escherichia coli ATP-dependent ClpYQ protease constitutes ClpY ATPase/unfoldase and ClpQ peptidase. The Tyr91st residue within the central pore-I site of ClpY-hexamer is important for unfolding and translocating substrates into the catalytic site of ClpQ. We have identified the degron site (GFIMRP147th) of SulA, a cell-division inhibitor recognized by ClpYQ and that the Phe143rd residue in degron site is necessary for SulA native folded structure. However, the functional association of this degron site with the ClpYQ degrader is unknown. Here, we investigated the molecular insights into substrate recognition and discrimination by the ClpYQ protease. We found that the point mutants ClpYY91FQ, ClpYY91HQ, and ClpYY91WQ, carrying a ring structure at the 91st residue of ClpY, efficiently degraded their natural substrates, evidenced by the suppressed bacterial methyl-methane-sulfonate (MMS) sensitivity, the reduced ß-galactosidase activity of cpsB::lacZ, and the lowest amounts of MBP-SulA in both in vivo and in vitro degradation analyses. Alternatively, mimicking the wild-type SulA, SulAF143H, SulAF143K and SulAF143W, harboring a ring structure or a cation side-group in 143rd residue of SulA, were efficiently degraded by ClpYQ in the bacterial cells, also revealing shorter half-lives at 41 °C and higher binding affinities towards ClpY in pull-down assays. Finally, ClpYY91FQ and ClpYY91HQ, were capable of effectively degrading SulAF143H and SulAF143K, highlighting a correspondingly functional interaction between the SulA 143rd and ClpY 91st residues. According to the interchangeable substituted amino acids, our results uniquely indicate that a transient π-π or cation-π interaction between the SulA 143rd and ClpY 91st residues could be aptly gripped between the degron site of substrates and the pore site of proteases (degraders) for substrate recognition and discrimination of the processive degradation.

Utility of Epstein-Barr Virus DNA in Nasopharynx Swabs as a Reflex Test to Triage Seropositive Individuals in Nasopharyngeal Carcinoma Screening Programs.

BACKGROUND: Epstein-Barr virus (EBV) DNA detection in the nasopharynx is considered a biomarker for nasopharyngeal carcinoma (NPC). We evaluated its performance as a reflex test to triage EBV seropositives within an NPC screening program in China. METHODS: The study population was embedded within an ongoing NPC screening trial and included 1111 participants who screened positive for anti-EBV VCA (antibodies against EBV capsid antigens)/EBNA1 (EBV nuclear antigen1)-IgA antibodies (of 18 237 screened). Nasopharynx swabs were collected/tested for EBNA1 gene EBV DNA load. We evaluated performance of EBV DNA in the nasopharynx swab as a reflex test to triage EBV serological high-risk (those referred to endoscopy/MRI) and medium-risk (those referred to accelerated screening) individuals. RESULTS: By the end of 2019, we detected 20 NPC cases from 317 serological high-risk individuals and 4 NPC cases from 794 medium-risk individuals. When used to triage serological high-risk individuals, nasopharynx swab EBV DNA was detected in 19/20 cases (positivity rate among cases: 95.0%; 95% CI, 75.1%-99.9%), with a referral rate of 63.4% (201/317, 95% CI, 57.8%-68.7%) and NPC detection rate among positives of 9.5% (19/201, 95% CI, 5.8%-14.4%). The performance of an algorithm that combined serology with triage of serology high-risk individuals using EBV DNA testing yielded a sensitivity of 72.4% (95% CI, 3.0%-81.4%) and specificity of 97.6% (95% CI, 97.2%-97.9%). When used to triage EBV serological medium-risk individuals, the positivity rate among cases was 75.0% (95% CI, 19.4%-99.4%), with a referral rate of 61.8% (95% CI, 58.4%-65.2%) and NPC detection rate among positives of 0.6% (95% CI, 0.1%-1.8%). CONCLUSIONS: Nasopharynx swab EBV DNA showed promise as a reflex test to triage serology high-risk individuals, reducing referral by ca. 40% with little reduction in sensitivity compared to a serology-only screening program.

Trends of outcomes and healthcare utilization following orthopaedic procedures in adults with haemophilia: A 3-decade retrospective review.

INTRODUCTION: Haemophilic arthropathy is a serious complication of haemophilia often requiring surgical intervention. It is unclear whether advances in comprehensive care are associated with a reduction in orthopaedic interventions and peri-procedural resource utilization. AIM: To determine temporal patterns of orthopaedic interventions in persons with haemophilia (PWH), and evaluate changes in healthcare utilization and outcomes. METHODS: In this Canadian multicentre retrospective cohort study, adult PWH from Northern Alberta and British Columbia who underwent orthopaedic procedures (1990-2018) were included. Temporal changes in the type of procedures, length of stay (LOS), factor utilization and outcomes were examined. RESULTS: Sixty-five patients (78% haemophilia A) underwent 102 surgeries at a median age of 46.3. Of the 46 severe PWH, 28 (61%) were on prophylaxis at time of surgery. The proportion of total knee arthroplasties (TKA) declined over time (56% 1990-1999, 51% 2000-2009, 27% 2010-2018), with a concomitant rise in ankle arthrodesis (0% 1990-1999, 18% 2000-2009, 27% 2010-2018). Over time, PWH underwent orthopaedic procedures at an older age (P = .02). There was a significant reduction in perioperative factor VIII utilization (P = .003) and median LOS (P < .0001). Major bleeds, prosthetic joint infections and thrombosis were not observed in the last decade. CONCLUSION: In the last three decades, there was a decline in the proportion of TKA, likely reflecting the impact of widespread use of tertiary prophylaxis. However, ankle arthrodesis rates increased, suggesting that higher trough levels may be required to prevent ankle arthropathy. We observed a significant reduction in LOS and factor utilization, reflecting improvements in perioperative management.

Association between biologic therapy and fracture incidence in patients with selected rheumatic and autoimmune diseases: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: To investigate the effect of biologic therapy on risk of fracture in selected rheumatic and autoimmune diseases. METHODS: The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to June 4, 2021. Randomized clinical trials (RCTs) comparing biological disease-modifying antirheumatic drugs (bDMARDs) with non-bDMARDs or placebo in patients with five selected rheumatic and autoimmune diseases were included. Meta-analyses were conducted to calculate the odds ratio (OR) with 95 % confidence intervals (CIs) for major osteoporotic fracture, hip fracture, osteoporotic non-vertebral fracture, and total fracture. RESULTS: A total of 100 RCTs involving 51,413 participants fulfilled the inclusion criteria. In patients with psoriasis (Ps), and psoriatic arthritis (PsA), compared with placebo or non-bDMARDs therapy, the risk of major osteoporotic fracture (OR, 0.34 [95 %Cl, 0.15-0.76], p = 0.009), hip fracture (OR, 0.22 [95 %Cl, 0.05-0.89], p = 0.03), and osteoporotic non-vertebral fracture (OR, 0.26 [95 %Cl, 0.10-0.62], p = 0.003) were significantly decreased with the use of bDMARDs. In patients with rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), systemic lupus erythematosus (SLE), and inflammatory bowel diseases (IBD), the risk of fracture were not changed with biologic treatment. CONCLUSIONS: The existing evidence from RCTs indicated the use of bDMARDs was associated with a low risk of major osteoporotic fracture, hip fracture, and osteoporotic non-vertebral fracture in patients with Ps and PsA. There are still urgent needs for studies regarding the actions of biologic therapies on the risk of bone fractures in systemic inflammatory diseases.