High-throughput functional dissection of noncoding SNPs with biased allelic enhancer activity for insulin resistance-relevant phenotypes.

Most of the single-nucleotide polymorphisms (SNPs) associated with insulin resistance (IR)-relevant phenotypes by genome-wide association studies (GWASs) are located in noncoding regions, complicating their functional interpretation. Here, we utilized an adapted STARR-seq to evaluate the regulatory activities of 5,987 noncoding SNPs associated with IR-relevant phenotypes. We identified 876 SNPs with biased allelic enhancer activity effects (baaSNPs) across 133 loci in three IR-relevant cell lines (HepG2, preadipocyte, and A673), which showed pervasive cell specificity and significant enrichment for cell-specific open chromatin regions or enhancer-indicative markers (H3K4me1, H3K27ac). Further functional characterization suggested several transcription factors (TFs) with preferential allelic binding to baaSNPs. We also incorporated multi-omics data to prioritize 102 candidate regulatory target genes for baaSNPs and revealed prevalent long-range regulatory effects and cell-specific IR-relevant biological functional enrichment on them. Specifically, we experimentally verified the distal regulatory mechanism at IRS1 locus, in which rs952227-A reinforces IRS1 expression by long-range chromatin interaction and preferential binding to the transcription factor HOXC6 to augment the enhancer activity. Finally, based on our STARR-seq screening data, we predicted the enhancer activity of 227,343 noncoding SNPs associated with IR-relevant phenotypes (fasting insulin adjusted for BMI, HDL cholesterol, and triglycerides) from the largest available GWAS summary statistics. We further provided an open resource (http://www.bigc.online/fnSNP-IR) for better understanding genetic regulatory mechanisms of IR-relevant phenotypes.

Multi-tissue transcriptome-wide association study reveals susceptibility genes and drug targets for insulin resistance-relevant phenotypes.

AIM: Genome-wide association studies (GWAS) have identified multiple susceptibility loci associated with insulin resistance (IR)-relevant phenotypes. However, the genes responsible for these associations remain largely unknown. We aim to identify susceptibility genes for IR-relevant phenotypes via a transcriptome-wide association study. MATERIALS AND METHODS: We conducted a large-scale multi-tissue transcriptome-wide association study for IR (Insulin Sensitivity Index, homeostasis model assessment-IR, fasting insulin) and lipid-relevant traits (high-density lipoprotein cholesterol, triglycerides, low-density lipoprotein cholesterol and total cholesterol) using the largest GWAS summary statistics and precomputed gene expression weights of 49 human tissues. Conditional and joint analyses were implemented to identify significantly independent genes. Furthermore, we estimated the causal effects of independent genes by Mendelian randomization causal inference analysis. RESULTS: We identified 1190 susceptibility genes causally associated with IR-relevant phenotypes, including 58 genes that were not implicated in the original GWAS. Among them, 11 genes were further supported in differential expression analyses or a gene knockout mice database, such as KRIT1 showed both significantly differential expression and IR-related phenotypic effects in knockout mice. Meanwhile, seven proteins encoded by susceptibility genes were targeted by clinically approved drugs, and three of these genes (H6PD, CACNB2 and DRD2) have been served as drug targets for IR-related diseases/traits. Moreover, drug repurposing analysis identified four compounds with profiles opposing the expression of genes associated with IR risk. CONCLUSIONS: Our study provided new insights into IR aetiology and avenues for therapeutic development.

The Value of Percutaneous Contrast-Enhanced Ultrasound in Sentinel Lymph Node Identification, Metastatic Status and Burden Diagnosis in Early Breast Cancer.

OBJECTIVE: The aim of this study was to evaluate the value of percutaneous contrast-enhanced ultrasound (PCEUS) in the identification and characterization of sentinel lymph node (SLN). METHODS: A total of 102 breast cancer patients were collected and underwent preoperative PCEUS, which was used to identify SLN and lymphatic drainage. SLNs were classified into 4 enhancement patterns, including 6 subtypes: homogeneous (I), featured inhomogeneous (II) including inhomogeneous hypoenhancement (IIa) and annular or semi-annular enhancement (IIb), focal filling defect (III) including filling defect area < 50% (IIIa) and filling defect area ≥ 50% (IIIb), and no enhancement (IV). The enhancement patterns of SLNs were compared with the final pathological diagnosis. RESULTS: The identification rate of SLNs using PCEUS was 100% (102/102); the rate of identification of LCs was 100% (102/102), and the coincidence rate was 98.0% (100/102). Four lymphatic drainage patterns (LDPs) including 5 subtypes were found: single LC/single SLN(74.5%), multiple LCs/ single SLN (13.7%) including 2 subtypes:2 LCs/1 SLN and 3 LCs/1 SLN, single LC/multiple SLNs (7.8%), and multiple LCs/multiple SLNs (3.9%). A total of 86.3% (44/51) of patients without axillary metastasis could be safely selected for types I, IIa, and IIb, while the axillary metastasis rates of types III and IV were 74.4% and 87.5%, respectively (P < .001). Compared with grayscale US, the PCEUS significant improvement in diagnosing metastatic SLNs (.794 versus .579, P < .001). For the SLN metastatic burden, Types I, IIa, IIb, and IIIa had ≤2 SLNs metastases, with a pathological coincidence rate of (64/67, 95.5%), and types IIIb and IV had >2 SLNs metastases, with a pathological coincidence rate of (25/35, 71.4%) (P < .001). The AUC of PCEUS for the diagnosis of SLN metastatic status and burden was .794 and .879, respectively (P < .001). CONCLUSION: PCEUS has a high identification rate for SLN and has good potential for diagnosing SLN metastatic status and burden by enhancement patterns.

The value of Demetics ultrasound-assisted diagnosis system in diagnosis of breast lesions and in assessment Ki-67 status of breast cancer.

PURPOSE: This study aims to explore the diagnostic efficiency of the Demetics for breast lesions and assessment of Ki-67 status. MATERIAL: This retrospective study included 291 patients. Three combined methods (method 1: upgraded BI-RADS when Demetics classified the breast lesion as malignant; method 2: downgraded BI-RADS when Demetics classified the breast lesion as benign; method 3: BI-RADS was upgraded or downgraded according to Demetrics' diagnosis) were used to compare the diagnostic efficiency of two radiologists with different seniority before and after using Demetics. The correlation between the visual heatmap by Demetics and the Ki-67 expression level of breast cancer was explored. RESULTS: The sensitivity, specificity, and area under curve (AUC) of diagnosis by Demetics, junior radiologist and senior radiologist were 89.5%, 83.1%, 0.863; 76.9%, 82.4%, 0.797 and 81.1%, 89.9%, 0.855, respectively. Method 1 was the best for senior radiologist, which increased AUC from 0.855 to 0.884. For junior radiologist, Method 3 was the best method, improving sensitivity (88.8% vs. 76.9%) and specificity (87.2% vs. 82.4%). Demetics paid more attention to the peripheral area of breast cancer with high expression of Ki-67. CONCLUSION: Demetics has shown good diagnostic efficiency in the assisted diagnosis of breast lesions and is expected to further distinguish Ki-67 status of breast cancer.

A combined clinical and specific genes' model to predict live birth for in vitro fertilization and embryo transfer patients.

BACKGROUND: We aimed to develop an accurate model to predict live birth for patients receiving in vitro fertilization and embryo transfer (IVF-ET) treatment. METHODS: This is a prospective nested case-control study. Women aged between 18 and 38 years, whose body mass index (BMI) were between the range of 18.5-24 kg/m2, who had an endometrium of ≥ 8 mm at the thickest were enrolled from 2018/9 to 2020/8. All patients received IVF-ET treatment and were followed up until Jan. 2022 when they had reproductive outcomes. Endometrial samples during the window of implantation (LH + 6 to 9 days) were subjected to analyze specific endometrial receptivity genes' expression using real-time PCR (RT-PCR). Patients were divided into live birth group and non-live birth group based on IVF-ET outcomes. Clinical signatures relevant to live birth were collected, analyzed, and used to establish a predictive model for live birth by univariate analysis (clinical model). Specific endometrial receptivity genes' expression was analyzed, selected, and used to construct a predictive model for live birth by The Least Absolute Shrinkage and Selection Operator (LASSO) analysis (gene model). Finally, significant clinical factors and genes were used to construct a combined model for predicting live birth using multivariate logistical regression (combined model). Different models' Area Under Curve (AUC) were compared to identify the most predictive model. RESULTS: Thirty-nine patients were enrolled in the study, twenty-four patients had live births, fifteen did not. In univariate analysis, the odds of live birth for women with ovulation dysfunction was 4 times higher than that for women with other IVF-ET indications (OR = 4.0, 95% CI: 1.125 - 8.910, P = 0.018). Age, body mass index, duration of infertility, primary infertility, repeated implantation failure, antral follicle counting, ovarian sensitivity index, anti-Mullerian hormone, controlled ovarian hyperstimulation protocol and duration, total dose of FSH/hMG, number of oocytes retrieved, regiment of endometrial preparation, endometrium thickness before embryo transfer, type of embryo transferred were not associated with live birth (P > 0.05). Only ovulation dysfunction was used to construct the clinical model and its AUC was 0.688. In lasso analysis, GAST, GPX3, THBS2 were found to promote the risk of live birth. AUCs for GAST, GPX3, THBS2 reached to 0.736, 0.672, and 0.678, respectively. The gene model was established based on these three genes and its AUC was 0.772. Ovulation dysfunction, GAST, GPX3, and THBS2 were finally used to construct the combined model, reaching the highest AUC (AUC = 0.842). CONCLUSIONS: Compared to the single model, the combined model of clinical (Ovulation dysfunction) and specific genes (GAST, GPX3, THBS2) was more accurate to predict live birth for IVF-ET patients.

Clinical Value of Artificial Intelligence-Based Computer-Aided Diagnosis System Versus Contrast-Enhanced Ultrasound for Differentiation of Benign From Malignant Thyroid Nodules in Different Backgrounds.

OBJECTIVES: The aim of this study was to compare the value of the AI-SONIC ultrasound-assisted diagnosis system versus contrast-enhanced ultrasound (CEUS) for differential diagnosis of thyroid nodules in diffuse and non-diffuse backgrounds. METHODS: A total of 555 thyroid nodules with pathologically confirmed diagnosis were included in this retrospective study. The diagnostic efficacies of AI-SONIC and CEUS for differentiating benign from malignant nodules in diffuse and non-diffuse backgrounds were evaluated, with pathological diagnosis as the gold standard. RESULTS: The agreement between AI-SONIC diagnosis and pathological diagnosis was moderate in diffuse backgrounds (κ = 0.417) and almost perfect in non-diffuse backgrounds (κ = 0.81). The agreement between CEUS diagnosis and pathological diagnosis was substantial in diffuse backgrounds (κ = 0.684) and moderate in non-diffuse backgrounds (κ = 0.407). In diffuse backgrounds, AI-SONIC had slightly higher sensitivity (95.7 vs 89.4%, P = .375), but CEUS had significantly higher specificity (80.0 vs 40.0%, P = .008). In non-diffuse background, AI-SONIC had significantly higher sensitivity (96.2 vs 73.4%, P < .001), specificity (82.9 vs 71.2%, P = .007), and negative predictive value (90.3 vs 53.3%, P < .001). CONCLUSION: In non-diffuse backgrounds, AI-SONIC is superior to CEUS for differentiating malignant from benign thyroid nodules. In diffuse backgrounds, AI-SONIC could be useful for screening of cases to detect suspicious nodules requiring further examination by CEUS.

Evaluating Tumor-Infiltrating Lymphocytes in Breast Cancer: The Role of Conventional Ultrasound and Contrast-Enhanced Ultrasound.

OBJECTIVES: Tumor-infiltrating lymphocytes (TILs) have emerged as an efficient biomarker predicting treatment response and prognosis of breast cancer (BC). This study aimed to evaluate the association between conventional ultrasound and contrast-enhanced ultrasound (CEUS) imaging features with TIL levels in invasive BC patients. METHODS: We retrospectively included 267 women with invasive BC who had undergone conventional ultrasound and CEUS. Patients were divided into low (≤10%) and high (>10%) TIL groups. Conventional ultrasound and CEUS features were analyzed by two sonographers. The associations between the TIL levels and imaging features were evaluated. RESULTS: Of the 267 patients, 122 with high TILs and 145 with low TIL levels. High TIL tumors were more likely to have a circumscribed margin, oval or round shape, and enhanced posterior echoes on ultrasonography (p < 0.05). In contrast, low TIL tumors were more likely to have an irregular shape, un-circumscribed, indistinct and spiculated margin (p < 0.05). In CEUS, high TIL tumors showed a more regular shape, clearer margin, more homogeneous enhancement and higher peak intensity (PI) value (p < 0.05). Logistic analysis indicated that shape, posterior features, PI, and enhanced homogeneity were independent predictors for high TIL tumors. The model combined the four independent predictors have a moderate performance in predicting high TIL tumors with AUC 0.79, sensitivity 0.72, and specificity 0.78. CONCLUSIONS: Conventional ultrasound and CEUS features were associated with TIL levels in invasive BC. Consequently, the results suggested that preoperative conventional ultrasound and CEUS may be a useful noninvasive imaging biomarker for individualized treatment decisions.

Deep learning radiomics of dual-modality ultrasound images for hierarchical diagnosis of unexplained cervical lymphadenopathy.

BACKGROUND: Accurate diagnosis of unexplained cervical lymphadenopathy (CLA) using medical images heavily relies on the experience of radiologists, which is even worse for CLA patients in underdeveloped countries and regions, because of lack of expertise and reliable medical history. This study aimed to develop a deep learning (DL) radiomics model based on B-mode and color Doppler ultrasound images for assisting radiologists to improve their diagnoses of the etiology of unexplained CLA. METHODS: Patients with unexplained CLA who received ultrasound examinations from three hospitals located in underdeveloped areas of China were retrospectively enrolled. They were all pathologically confirmed with reactive hyperplasia, tuberculous lymphadenitis, lymphoma, or metastatic carcinoma. By mimicking the diagnosis logic of radiologists, three DL sub-models were developed to achieve the primary diagnosis of benign and malignant, the secondary diagnosis of reactive hyperplasia and tuberculous lymphadenitis in benign candidates, and of lymphoma and metastatic carcinoma in malignant candidates, respectively. Then, a CLA hierarchical diagnostic model (CLA-HDM) integrating all sub-models was proposed to classify the specific etiology of each unexplained CLA. The assistant effectiveness of CLA-HDM was assessed by comparing six radiologists between without and with using the DL-based classification and heatmap guidance. RESULTS: A total of 763 patients with unexplained CLA were enrolled and were split into the training cohort (n=395), internal testing cohort (n=171), and external testing cohorts 1 (n=105) and 2 (n=92). The CLA-HDM for diagnosing four common etiologies of unexplained CLA achieved AUCs of 0.873 (95% CI: 0.838-0.908), 0.837 (95% CI: 0.789-0.889), and 0.840 (95% CI: 0.789-0.898) in the three testing cohorts, respectively, which was systematically more accurate than all the participating radiologists. With its assistance, the accuracy, sensitivity, and specificity of six radiologists with different levels of experience were generally improved, reducing the false-negative rate of 2.2-10% and the false-positive rate of 0.7-3.1%. CONCLUSIONS: Multi-cohort testing demonstrated our DL model integrating dual-modality ultrasound images achieved accurate diagnosis of unexplained CLA. With its assistance, the gap between radiologists with different levels of experience was narrowed, which is potentially of great significance for benefiting CLA patients in underdeveloped countries and regions worldwide.

Effect of secondary attack by Aeromonas hydrophila on the expression level of hif genes in common carp (Cyprinus carpio).

Hypoxia-inducible factors (hifs) are involved in infectious diseases inflammatory reactions, and immune regulation. Common carp, a representative allotetraploid species that has undergone genome-wide replication events, has important research value. In this study, common carp were infected twice with Aeromonas hydrophila. Liver tissues of common carp were collected at 4 h, 12 h, 24 h, 48 h, 3 days, 7 days post-first infection and 4 h, 12 h, 24 h post-second infection. The mRNA levels of hif genes were determined at different time points. The hif2a-2, hif3a-2, hif3b-1 and hif3b-2 expression levels in the infected group were upregulated when compared with those in the control group, whereas the expression levels of other genes were downregulated after the second infection. This indicates that the effect of A. hydrophila infection on gene expression pattern is dependent on the host, pathogen, infected tissue and gene. Pressure analysis of the hif gene family revealed that the non-synonymous substitution to synonymous substitution ratio of 12 hif genes was <1, which indicated that they were in a state of purification and selection. Combined with the differences between copy genes, the polyclonal antibodies against Hif1b-1 and Hif1b-2 were successfully prepared in this study. Western blot analysis showed that the protein expression of Hif1b-1 and Hif1b-2 reached to the highest level 48 h after the first infection. After the second A. hydrophila infection, the protein expression levels of Hif1b-1 and Hif1b-2 reached the highest levels at 4 and 48 h, respectively. This may indicate that the Hif1b-1 and Hif1b-2 genes in common carp play an important role in the immune mechanism at the protein level. The findings of this study will lay the foundation for future studies on the immune regulatory function of common carp hif genes, which may aid in devising novel therapeutic strategies for common carp diseases, such as A. hydrophila infection.

Implementation of evidence in preventing medical device-related pressure injury in ICU patients using the i-PARIHS framework.

AIM: To examine the effectiveness of implementing the evidence in preventing medical device-related pressure injury (MDRPI) in intensive care patients. BACKGROUND: MDRPI is a common problem that significantly complicates patients' medical condition. However, evidence in preventing MDRPI is not properly implemented in clinical practice. METHODS: A pre- and post-implementation study was conducted using the Integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) framework. A baseline survey was implemented; barriers and enablers of evidence implementation were analysed to inform facilitation support strategies, such as training nursing staff and developing resources and tools. Changes in nurses, patients and the system were assessed after evidence implementation. RESULTS: Nurses' knowledge scores and evidence compliance significantly improved. The incidence of MDRPI in patients decreased from 24.39% to 4.26%. Standardized care and workflows to prevent MDRPI were established. CONCLUSION: The i-PARIHS framework supported effective implementation of the evidence in preventing MDRPI, narrowing the gap between evidence and clinical practice. IMPLICATIONS FOR NURSING MANAGEMENT: We provide an effective case of transforming evidence into practice based on the i-PARIHS framework. It can be used as a reference for colleagues in intensive care unit (ICU) or other settings to implement MDRPI prevention.

Protein C receptor stimulates multiple signaling pathways in breast cancer cells.

The protein C receptor (PROCR) has emerged as a stem cell marker in several normal tissues and has also been implicated in tumor progression. However, the functional role of PROCR and the signaling mechanisms downstream of PROCR remain poorly understood. Here, we dissected the PROCR signaling pathways in breast cancer cells. Combining protein array, knockdown, and overexpression methods, we found that PROCR concomitantly activates multiple pathways. We also noted that PROCR-dependent ERK and PI3k-Akt-mTOR signaling pathways proceed through Src kinase and transactivation of insulin-like growth factor 1 receptor (IGF-1R). These pathway activities led to the accumulation of c-Myc and cyclin D1. On the other hand, PROCR-dependent RhoA-ROCK-p38 signaling relied on coagulation factor II thrombin receptor (F2R). We confirmed these findings in primary cells isolated from triple-negative breast cancer-derived xenografts (PDX) that have high expression of PROCR. To the best our knowledge, this is the first comprehensive study of PROCR signaling in breast cancer cells, and its findings also shed light on the molecular mechanisms of PROCR in stem cells in normal tissue.

Activation/Proliferation-associated Protein 2 (Caprin-2) Positively Regulates CDK14/Cyclin Y-mediated Lipoprotein Receptor-related Protein 5 and 6 (LRP5/6) Constitutive Phosphorylation.

Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are co-receptors for Wnt ligands. Upon ligand binding, LRP5/6 undergo glycogen synthase kinase 3 (GSK3)/casein kinase I (CKI)-mediated phosphorylation at multiple PPP(S/T)P motifs in the intracellular domain, which is essential for canonical Wnt signal transduction. On the other hand, in the Wnt-off state, the mitosis-specific CDK14-Cyclin Y kinase complex phosphorylates Ser-1490 of LRP5/6 at G2/M, thereby priming the receptor for Wnt-induced phosphorylation. However, it remains unclear how CDK14/Cyclin Y is recruited to LRP5/6 and whether there are other cofactors involved in this process. Previously, we identified Caprin-2 as a positive regulator of canonical Wnt signaling by promoting GSK3-depedent LRP5/6 phosphorylation upon Wnt stimulation. Here we uncovered that Caprin-2 positively regulates constitutive LRP5/6 Ser-1490 phosphorylation by complexing with CDK14/Cyclin Y. Caprin-2-mediated LRP5/6 phosphorylation is cell cycle-dependent in a pattern similar to that of CDK14/Cyclin Y-dependent LRP5/6 phosphorylation. Moreover, knockdown of Caprin-2 disrupts not only the interaction between CDK14 and Cyclin Y but also the interaction between CDK14/Cyclin Y and LRP6. Overall, our findings revealed an unrecognized role of Caprin-2 in facilitating LRP5/6 constitutive phosphorylation at G2/M through forming a quaternary complex with CDK14, Cyclin Y, and LRP5/6.

Removal of cadmium and zinc from contaminated wastewater using Rhodobacter sphaeroides.

Rhodobacter sphaeroides was used for bioremediation of wastewater polluted with cadmium (Cd) and zinc (Zn). The tolerance of the microorganism to selected heavy metals (HMs), as well as the effects of pH, temperature and inoculum size on the removal rate, was investigated. The remediation effects of R. sphaeroides were analysed at different initial concentrations of HMs. Bioremediation mechanisms were thoroughly discussed based on the results from the cell characterisation analysis. Cd and Zn could inhibit the growth of R. sphaeroides. However, Cd was more toxic than Zn, with corresponding EC50 values of 5.34 and 69.79 mg L-1. Temperature and pH had greater influence on the removal rate of HMs than inoculum size. The optimal conditions for temperature and pH were 35 °C-40 °C and pH 7, respectively. Initial concentration of HMs and remediation time also affected the removal rate. Rhodobacter sphaeroides had a relatively higher remediation effect under the present experimental conditions. The removal rates for Cd and Zn reached 97.92% and 97.76%, respectively. Results showed that biosorption and HM precipitation were the main bioremediation mechanisms. This information is necessary to better understand the removal mechanism of R. sphaeroides, and is significant for its pilot test and future practical application.

Structural insights into the C1q domain of Caprin-2 in canonical Wnt signaling.

Previously, we have identified Caprin-2 as a new regulator in canonical Wnt signaling through a mechanism of facilitating LRP5/6 phosphorylation; moreover, we found that its C-terminal C1q-related domain (Cap2_CRD) is required for this process. Here, we determined the crystal structures of Cap2_CRD from human and zebrafish, which both associate as a homotrimer with calcium located at the symmetric center. Surprisingly, the calcium binding-deficient mutant exists as a more stable trimer than its wild-type counterpart. Further studies showed that this Caprin-2 mutant disabled in binding calcium maintains the activity of promoting LRP5/6 phosphorylation, whereas the mutations disrupting Cap2_CRD homotrimer did impair such activity. Together, our findings suggested that the C-terminal CRD domain of Caprin-2 forms a flexible homotrimer mediated by calcium and that such trimeric assembly is required for Caprin-2 to regulate canonical Wnt signaling.

Meta-analysis of Ubiquilin1 gene polymorphism and Alzheimer's disease risk.

BACKGROUND: Some studies have evaluated the association between the Ubiquilin 1 (UBQLN1) gene UBQ-8i polymorphism and Alzheimer's disease (AD). However, the results remain uncertain. We carried out a meta-analysis to derive a more comprehensive estimation of this association. MATERIAL/METHODS: Case-control studies were identified by searching databases of PubMed, EMBASE, Web of Science, CNKI, CBM, Wanfang, and VIP. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. RESULTS: The UBQ-8i polymorphism was significantly associated with an increased AD risk (OR=1.15; 95%CI 1.05-1.25; P=0.002). The combination of adjusted ORs also found UBQ-8i polymorphism was significantly associated with AD risk (OR=1.15; 95%CI 1.02-1.30; P=0.02). When stratified by APOE ε4 status, both APOE ε4 carriers and APOE non-ε4 carriers with UBQ-8i polymorphism had significantly increased AD risk (OR=1.28; 95%CI 1.05-1.56; P=0.01 and OR=1.25; 95%CI 1.04-1.50; P=0.02). In the subgroup analysis according to age, UBQ-8i polymorphism was significantly associated with LOAD risk (OR=1.17; 95%CI 1.05-1.31; P=0.005), but not with EOAD risk (OR=1.12; 95%CI 0.95-1.31; P=0.17). CONCLUSIONS: These results suggest that the UBQ-8i polymorphism is associated with AD risk.

Predictive value for axillary lymph node metastases in early breast cancer: Based on contrast-enhanced ultrasound characteristics of the primary lesion and sentinel lymph node.

OBJECTIVE: To evaluate the value of contrast-enhanced ultrasound (CEUS) characteristics based on primary lesion combined with lymphatic contrast-enhanced ultrasound (LCEUS) patterns of SLN in predicting axillary lymph node metastasis (ALNM) with T1-2N0 breast cancer. METHODS: A retrospective study was conducted in 118 patients with clinically confirmed T1-2N0 breast cancer. Conventional ultrasound (CUS) and CEUS characteristics of the primary lesion and enhancement patterns of SLN were recorded. The risk factors associated with ALNM were selected by univariate and binary logistic regression analysis, and the receiver operating characteristic (ROC) curve was drawn for the evaluation of predictive ALNM metastasis performance. RESULTS: Univariate analysis showed that age, HER-2 status, tumor size, nutrient vessels, extended range of enhancement lesion, and the enhancement patterns of SLN were significant predictive features of ALNM. Further binary logistic regression analysis indicated that the extended range of enhancement lesion (p <  0.001) and the enhancement patterns of SLN (p <  0.001) were independent risk factors for ALNM. ROC analysis showed that the AUC of the combination of these two indicators for predicting ALNM was 0.931 (95% CI: 0.887-0.976, sensitivity: 75.0%, specificity: 99.8%). CONCLUSION: The CEUS characteristics of primary lesion combined with enhancement patterns of SLN are highly valuable in predicting ALNM and can guide clinical axillary surgery decision-making in early breast cancer.

Prognostic models for patients suffering a heart failure with a preserved ejection fraction: a systematic review.

The purpose of this study was to systematically review the development, performance, and applicability of prognostic models developed for predicting poor events in patients with heart failure with preserved ejection fraction (HFpEF). Databases including Embase, PubMed, Web of Science Core Collection, the Cochrane Library, China National Knowledge Infrastructure, Wan Fang, Wei Pu, and China Biological Medicine were queried from their respective dates of inception to 1 June 2023, to examine multivariate models for prognostic prediction in HFpEF. Both forward and backward citations of all studies were included in our analysis. Two researchers individually used the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS) checklist to extract data and assess the quality of the models using the Predictive Mode Bias Risk Assessment Tool (PROBAST). Among the 6897 studies screened, 16 studies derived and/or validated a total of 39 prognostic models. The sample size ranges for model development, internal validation, and external validation are 119 to 5988, 152 to 1000, and 30 to 5957, respectively. The most frequently employed modelling technique was Cox proportional hazards regression. Six studies (37.50%) conducted internal validation of models; bootstrap and k-fold cross-validation were the commonly used methods for internal validation of models. Ten of these models (25.64%) were validated externally, with reported the c-statistic in the external validation set ranging from 0.70 to 0.96, while the remaining models await external validation. The MEDIA echo score and I-PRESERVE-sudden cardiac death prediction mode have been externally validated using multiple cohorts, and the results consistently show good predictive performance. The most frequently used predictors identified among the models were age, n-terminal pro-brain natriuretic peptide, ejection fraction, albumin, and hospital stay in the last 5 months owing to heart failure. All study predictor domains and outcome domains were at low risk of bias, high or unclear risk of bias of all prognostic models due to underreporting in the area of analysis. All studies did not evaluate the clinical utility of the prognostic models. Predictive models for predicting prognostic outcomes in patients with HFpEF showed good discriminatory ability but their utility and generalization remain uncertain due to the risk of bias, differences in predictors between models, and the lack of clinical application studies. Future studies should improve the methodological quality of model development and conduct external validation of models.

Measurement properties of assessment tools of Kinesophobia in patients with cardiovascular disease: A systematic review.

Objectives: This study aimed to evaluate the measurement properties and methodological quality of assessment tools for Kinesophobia among patients with cardiovascular disease and provide a reference for healthcare professionals in selecting high-quality assessment tools. Methods: A systematic search was performed on specific databases: Embase, the Cochrane Library, PubMed, Web of Science, China National Knowledge Infrastructure, Wanfang database, China Biological Medicine disc, CINAHL, and China Science and Technology Journal Database, from inception to April 1, 2023. The researchers retrieved studies on the measurement attributes of the exercise fear scale in patients with cardiovascular diseases. They also traced back the references of the included studies to supplement relevant literature. According to the inclusion and exclusion criteria, screening and data extraction were independently undertaken by two reviewers. Two researchers individually used the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) Risk of Bias Checklist to assess the methodological quality of the scale, applied the COSMIN criteria to evaluate the measurement properties of the scale, and used a modified Grading, Recommendations, Assessment, Development, and Evaluation system to assess the certainty of evidence. Results: Seventeen studies were identified that reported the psychometric properties of six patient reported outcome measurement tools (included different languages version) The methodological quality of content validity was adequate in only two studies, the remaining patient-reported outcome measures demonstrated doubtful content validity. Limited information on cross-cultural validity/measurement invariance, measurement error, and responsiveness was retrieved. The Swedish version and the Chinese version of the Tampa Scale for Kinesiophobia Heart were graded "A." The remaining instruments were graded "B." Conclusions: The methodological and measurement attributes of the Swedish and Chinese versions of the Tampa Scale for Kinesiophobia Heart are relatively high quality and can be tentatively recommended. The measurement properties of the remaining scales remain to be verified.

Synthesis of NiII porphyrin-NiII 5,15-diazaporphyrin hybrid tapes.

NiII porphyrin (P) and NiII 5,15-diazaporphyrin (DAP) hybrid tapes were synthesized by Suzuki-Miyaura cross-coupling reactions of meso- or ß-borylated P with ß-brominated DAP followed by intramolecular oxidative fusion reactions. Meso-ß doubly linked hybrid tapes were synthesized by oxidation of singly linked precursors with DDQ-FeCl3. Synthesis of triply linked hybrid tapes was achieved by oxidation with DDQ-FeCl3-AgOTf with suppression of peripheral ß-chlorination. In these tapes, DAP segments were present as a 20π-electronic unit, but their local antiaromatic contribution was trivial. Remarkably, these hybrid tapes were stable and exhibited extremely enhanced absorption bands in the NIR region and multiple reversible redox waves. A pentameric hybrid tape showed a remarkably sharp and red-shifted band at 1168 nm with ε = 5.75 × 105 M-1 cm-1. Singly linked P-DAP dyads were oxidized with DDQ-FeCl3 to give stable radicals, which were oxidized further to afford dimeric hybrid tapes possessing a nitrogen atom at the peripheral-side meso-position.

Integrative high-throughput enhancer surveying and functional verification divulges a YY2-condensed regulatory axis conferring risk for osteoporosis.

The precise roles of chromatin organization at osteoporosis risk loci remain largely elusive. Here, we combined chromatin interaction conformation (Hi-C) profiling and self-transcribing active regulatory region sequencing (STARR-seq) to qualify enhancer activities of prioritized osteoporosis-associated single-nucleotide polymorphisms (SNPs). We identified 319 SNPs with biased allelic enhancer activity effect (baaSNPs) that linked to hundreds of candidate target genes through chromatin interactions across 146 loci. Functional characterizations revealed active epigenetic enrichment for baaSNPs and prevailing osteoporosis-relevant regulatory roles for their chromatin interaction genes. Further motif enrichment and network mapping prioritized several putative, key transcription factors (TFs) controlling osteoporosis binding to baaSNPs. Specifically, we selected one top-ranked TF and deciphered that an intronic baaSNP (rs11202530) could allele-preferentially bind to YY2 to augment PAPSS2 expression through chromatin interactions and promote osteoblast differentiation. Our results underline the roles of TF-mediated enhancer-promoter contacts for osteoporosis, which may help to better understand the intricate molecular regulatory mechanisms underlying osteoporosis risk loci.