Alzheimer's disease as a causal risk factor for diabetic retinopathy: a Mendelian randomization study.

Objectives: This study aims to investigate the causal relationship between Alzheimer's Disease (AD) and Diabetic Retinopathy (DR). Methods: Employing Mendelian Randomization (MR), Generalized Summary-data-based Mendelian Randomization (GSMR), and the MR-Steiger test, this study scrutinizes the genetic underpinnings of the hypothesized causal association between AD and DR, as well as its Proliferative DR (PDR) and Non-Proliferative DR (NPDR) subtypes. Comprehensive data from Genome-Wide Association Studies (GWAS) were analyzed, specifically AD data from the Psychiatric Genomics Consortium (71,880 cases/383,378 controls), and DR, PDR, and NPDR data from both the FinnGen consortium (FinnGen release R8, DR: 5,988 cases/314,042 controls; PDR: 8,383 cases/329,756 controls; NPDR: 3,446 cases/314,042 controls) and the IEU OpenGWAS (DR: 14,584 cases/176,010 controls; PDR: 8,681 cases/204,208 controls; NPDR: 2,026 cases/204,208 controls). The study also incorporated Functional Mapping and Annotation (FUMA) for an in-depth analysis of the GWAS results. Results: The MR analyses revealed that genetic susceptibility to AD significantly increases the risk of DR, as evidenced by GWAS data from the FinnGen consortium (OR: 2.5090; 95% confidence interval (CI):1.2102-5.2018, false discovery rate P-value (PFDR)=0.0201; GSMR: bxy=0.8936, bxy_se=0.3759, P=0.0174), NPDR (OR: 2.7455; 95% CI: 1.3178-5.7197, PFDR=0.0166; GSMR: bxy=0.9682, bxy_se=0.3802, P=0.0126), and PDR (OR: 2.3098; 95% CI: 1.2411-4.2986, PFDR=0.0164; GSMR: bxy=0.7962, bxy_se=0.3205, P=0.0129) using DR GWAS from FinnGen consortium. These results were corroborated by DR GWAS datasets from IEU OpenGWAS. The MR-Steiger test confirmed a significant association of all identified instrumental variables (IVs) with AD. While a potential causal effect of DR and its subtypes on AD was identified, the robustness of these results was constrained by a low power value. FUMA analysis identified OARD1, NFYA, TREM1 as shared risk genes between DR and AD, suggesting a potential genetic overlap between these complex diseases. Discussion: This study underscores the contribution of AD to an increased risk of DR, as well as NPDR and PDR subtypes, underscoring the necessity of a holistic approach in the management of patients affected by these conditions.

Lactobacillus plantarum-derived extracellular vesicles protect against ischemic brain injury via the microRNA-101a-3p/c-Fos/TGF-ß axis.

Currently, the reported source of extracellular vesicles (EVs) for the treatment of ischemic stroke（IS）is limited to mammals. Moreover, these EVs are restricted to clinical translation by the high cost of cell culture. In this respect, Lactobacillus plantarum culture is advantaged by low cost and high yield. However, it is poorly understood whether Lactobacillus plantarum-derived EVs (LEVs) are applicable for the treatment of IS. Here, our results demonstrated that LEVs reduced apoptosis in ischemic neuron both in vivo and in vitro. As revealed by high-throughput sequencing, miR-101a-3p expression was significantly elevated by LEV treatment in OGD/R-induced neurons, as confirmed in the tMCAO mice treated with LEVs. Mechanistically, c-Fos was directly targeted by miR-101a-3p. In addition, c-Fos determined ischemia-induced neuron apoptosis in vivo and in vitro through the TGF-ß1 pathway, miR-101a-3p inhibition aggravated ischemia-induced neuron apoptosis in vitro and in vivo, and miR-101a-3p overexpression produced the opposite results. Hsa-miR-101-3p was downregulated in the plasma of patients with IS but upregulated in the patients with neurological recovery after rt-PA intravenous thrombolysis. In conclusion, Our results demonstrated for the first time that LEVs might inhibit neuron apoptosis via the miR-101a-3p/c-Fos/TGF-ß axis, and has-miR-101-3p is a potential marker of neurological recovery in IS patients.

Mesenchymal Stem Cells Improve Cognitive Impairment and Reduce Aß Deposition via Promoting AQP4 Polarity and Relieving Neuroinflammation in Rats With Chronic Hypertension-Induced Cerebral Small-Vessel Disease.

Cerebral small-vessel disease (CSVD) is the main cause of vascular cognitive impairment (VCI), and the accumulation of amyloid ß-protein (Aß) may be significantly involved in CSVD-induced VCI. The imbalance between Aß production and clearance is believed to be an important pathological mechanism of Aß deposition in Alzheimer disease. In this study, we aimed to disclose the roles of aquaporin 4 (AQP4) and neuroinflammation in CSVD, which were the key factors for Aß clearance and production, respectively, and the effect of mesenchymal stem cells (MSCs) on Aß deposition and these two factors. The stroke-prone renovascular hypertensive (RHRSP) rats were grouped and received MSC and MSC + AS1517499 (an inhibitor of pSTAT6). The latter was used to explore the underlying mechanism. The cognitive function, white matter lesions, Aß expression, expression, and polarity of AQP4, neuroinflammation and the STAT6 pathway were investigated. Compared with sham-operated rats, RHRSP rats showed spatial cognitive impairment, white matter lesions and Aß deposition. Moreover, AQP4 polarity disorder and neuroinflammatory activation were found, which were linked to Aß deposition. Treatment with MSCs markedly improved cognitive tasks and reduced Aß deposition but failed to reduce white-matter lesions. Furthermore, MSCs not only promoted AQP4 polarity but also alleviated neuroinflammation probably through the STAT6 pathway. The present study demonstrated that Aß deposition, AQP4 polarity disorder and neuroinflammation might be involved in CSVD and the regulatory effects of MSCs on them suggested potential therapeutic value for CSVD.

Mir-184 Contributes to Brain Injury Through Targeting PPAP2B Following Ischemic Stroke in Male Rats.

Our previous study revealed that miR-184 expression is significantly altered in the brain following ischemic stroke in rats. However, it is unknown whether this alteration in miR-184 expression contributes to brain injury after ischemic stroke. Here, we aim to address the potential of miR-184 to impact nerve injury following ischemia and reperfusion. Rats received ICV injection of miR-184 adenovirus or empty vector and were subjected to right middle cerebral artery occlusion (MCAO) to establish an ischemic stroke model. We cultured SH-SY5Y cells under oxygen-glucose deprivation/reoxygenation (OGD/R) and transfected them with miR-184 lentivirus to explore the primary mechanisms. To evaluate miR-184 expression, neurological function deficits, the cerebral infarct volume, cell viability, and apoptosis, qRT-PCR analysis of miR-184 expression, the modified neurological severity score (mNSS) system, TTC staining, the CCK-8 assay, flow cytometry, and dual-luciferase reporter assays were utilized. We found that miR-184 expression was downregulated and that the cerebral infarct volume and mNSSs were increased following ischemic stroke; however, increasing the level of miR-184 alleviated brain damage. Overexpression of miR-184 resulted in increased viability and reduced apoptosis of SH-SY5Y cells following OGD/R in vitro. We identified the phosphatidic acid phosphatase type 2B (PPAP2B) gene as a direct target gene of miR-184. In summary, our results reveal that attenuation of miR-184 levels in ischemic stroke contributes to ischemic injury through targeting PPAP2B mRNA-mediated apoptosis, which may be a promising therapeutic target for ischemic stroke.

Comparison between linear and nonlinear machine-learning algorithms for the classification of thyroid nodules.

BACKGROUND: A key challenge in thyroid carcinoma is preoperatively diagnosing malignant thyroid nodules. The purpose of this study was to compare the classification performance of linear and nonlinear machine-learning algorithms for the evaluation of thyroid nodules using pathological reports as reference standard. METHODS: Ethical approval was obtained for this retrospective analysis, and the informed consent requirement was waived. A total of 1179 thyroid nodules (training cohort, n = 700; validation cohort, n = 479) were confirmed by pathological reports or fine-needle aspiration (FNA) biopsy. The following ultrasonography (US) featu res were measured for each nodule: size (maximum diameter), margins, shape, aspect ratio, capsule, hypoechoic halo, composition, echogenicity, calcification pattern, vascularity, and cervical lymph node status. We analyzed five nonlinear and three linear machine-learning algorithms. The diagnostic performance of each algorithm was compared by using the area under the curve (AUC) of the receiver operating characteristic curve. We repeated this process 1000 times to obtain the mean AUC and 95% confidence interval (CI). RESULTS: Overall, nonlinear machine-learning algorithms demonstrated similar AUCs compared with linear algorithms. The Random Forest and Kernel Support Vector Machines algorithms achieved slightly greater AUCs in the validation cohort (0.954, 95% CI: 0.939-0.969; 0.954 95%CI: 0.939-0.969, respectively) than other algorithms. CONCLUSIONS: Overall, nonlinear machine-learning algorithms share similar performance compared with linear algorithms for the evaluation the malignancy risk of thyroid nodules.

A nomogram for individual prediction of vascular invasion in primary breast cancer.

OBJECTIVES: To explore the feasibility of preoperative prediction of vascular invasion (VI) in breast cancer patients using nomogram based on multiparametric MRI and pathological reports. METHODS: We retrospectively collected 200 patients with confirmed breast cancer between January 2016 and January 2018. All patients underwent MRI examinations before the surgery. VI was identified by postoperative pathology. The 200 patients were randomly divided into training (n = 100) and validation datasets (n = 100) at a ratio of 1:1. Least absolute shrinkage and selection operator (LASSO) regression was used to select predictors most associated with VI of breast cancer. A nomogram was constructed to calculate the area under the curve (AUC) of receiver operating characteristics, sensitivity, specificity, accuracy, positive prediction value (PPV) and negative prediction value (NPV). We bootstrapped the data for 2000 times without setting the random seed to obtain corrected results. RESULTS: VI was observed in 79 patients (39.5%). LASSO selected 10 predictors associated with VI. In the training dataset, the AUC for nomogram was 0.94 (95% confidence interval [CI]: 0.89-0.99, the sensitivity was 78.9% (95%CI: 72.4%-89.1%), the specificity was 95.3% (95%CI: 89.1%-100.0%), the accuracy was 86.0% (95%CI: 82.0%-92.0%), the PPV was 95.7% (95%CI: 90.0%-100.0%), and the NPV was 77.4% (95%CI: 67.8%-87.0%). In the validation dataset, the AUC for nomogram was 0.89 (95%CI: 0.83-0.95), the sensitivity was 70.3% (95%CI: 60.7%-79.2%), the specificity was 88.9% (95%CI: 80.0%-97.1%), the accuracy was 77.0% (95%CI: 70.0%-83.0%), the PPV was 91.8% (95%CI: 85.3%-98.0%), and the NPV was 62.7% (95%CI: 51.7%-74.0%). The nomogram calibration curve shows good agreement between the predicted probability and the actual probability. CONCLUSION: The proposed nomogram could be used to predict VI in breast cancer patients, which was helpful for clinical decision-making.

Development and validation of an ultrasound-based nomogram to improve the diagnostic accuracy for malignant thyroid nodules.

OBJECTIVES: The aim of this study was to develop an ultrasound-based nomogram to improve the diagnostic accuracy of the identification of malignant thyroid nodules. METHODS: A total of 1675 histologically proven thyroid nodules (1169 benign, 506 malignant) were included in this study. The nodules were grouped into the training dataset (n = 700), internal validation dataset (n = 479), or external validation dataset (n = 496). The grayscale ultrasound features included the nodule size, shape, aspect ratio, echogenicity, margins, and calcification pattern. We applied least absolute shrinkage and selection operator (lasso) regression to select the strongest features for the nomogram. Nomogram discrimination (area under the receiver operating characteristic curve, AUC) and calibration were assessed. The nomogram was subjected to bootstrapping validation (1000 bootstrap resamples) to calculate a mean AUC and 95% confidence interval (CI). RESULTS: The nomogram showed good discrimination in the training dataset, with an AUC of 0.936 (95% CI: 0.918-0.953) and good calibration. Application of the nomogram to the internal validation dataset also resulted in good discrimination (AUC: 0.935; 95% CI, 0.915-0.954) and good calibration. The model tested in an external validation dataset demonstrated a lower AUC of 0.782 (95% CI: 0.776-0.789). CONCLUSIONS: This ultrasound-based nomogram can be used to quantify the probability of malignant thyroid nodules. KEY POINTS: • Ultrasound examination is helpful in the differential diagnosis of malignant and benign thyroid nodules. • However, ultrasound accuracy relies heavily on examiner experience. • A less subjective diagnostic model is desired, and the developed nomogram for thyroid nodules showed good discrimination and good calibration.

Risk factors of cerebral microbleeds in young and middle-aged patients with hypertension.

Objective This study aimed to investigate the incidence and related risk factors of cerebral microbleeds (CMBs) in young and middle-aged patients with hypertension. Methods The study included 232 young and middle-aged (18-59 years-old) patients with hypertension from September 2014 to December 2016 in the Department of Neurology, Affiliated Hospital of Guizhou Medical University, China. The data were recorded which included demographics, vascular risk factors, medication history, and imaging data of patients. CMBs were evaluated based on the microbleeds anatomical rating scale. Results Of the enrolled participants, 115 were CMB positive, accounting for 49.6%. CMBs were more prone to occur in deep regions than in others (39.13%). Multiple cerebral microbleeds were associated with white matter hyperintensities(WMH), dyslipidemia, hyperhomocysteine, and uric acid. Moreover, WMH, dyslipidemia, ever smoker, antiplatelets use, and hyperhomocysteine were found to be risk factors for deep or infratentorial CMBs in young and middle-aged patients with hypertension. However, the lobar CMBs only had an independent correlation with dyslipidemia in these participants. Conclusions The incidence of CMBs in patients with hypertension was relatively high. It mostly occurred in a deep or infratentorial area with more vascular-associated risk factors. However, in patients with lobar CMBs, factors associated with lipid metabolism, such as amyloid deposition and unidentified genotype variation, may be crucial. Screening and regular follow-ups of CMBs by Susceptibility Weighted Imaging and active prevention in young and middle-aged patients with hypertension have clinical significance for timely understanding and predicting the occurrence and development of related cerebrovascular disease events.

Segmental neurofibromatosis type 1 complicated with multiple intracranial arteriovenous fistulas: A case study.

Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disorder that primarily affects the skin and the nervous system. This condition is called segmental NF1 (also called neurofibromatosis type V) when clinical features are limited to one area of the body. Segmental NF1 is generally thought to result from somatic mosaicism due to a postzygotic mutation in the NF1 gene, thus a test for NF1 gene abnormalities in peripheral blood is usually negative. Here we report a 31-year-old male presenting with epileptic seizures, who had a history of neurofibromas confirmed by biopsy, but lacked a family history of neurofibromatosis. Multiple signs highly suggestive of NF1 and cerebrovascular abnormities were seen, including distended scalp vessels, gingival hyperplasia, cutaneous masses, skin nodules, and café-au-lait macules. Cerebral computed tomography angiography and venography revealed multiple intracranial arteriovenous fistula. However, NF1 genetic testing of peripheral blood failed to detect mutations, deletions or rearrangements in any of the coding exons or neighboring splice sites. A diagnosis of segmental NF1 was still warranted. To the best of our knowledge, this is the first case study of segmental NF1 complicated with multiple intracranial arteriovenous fistulas.

Exploration and validation of radiomics signature as an independent prognostic biomarker in stage III-IVb nasopharyngeal carcinoma.

There is no consensus on specific prognostic biomarkers potentially improving survival of nasopharyngeal carcinoma (NPC), especially in advanced-stage disease. The prognostic value of MRI-based radiomics signature is unclear. A total of 970 quantitative features were extracted from the tumor of 100 untreated NPC patients (stage III-IVb) (discovery set: n = 70, validation set: n = 30). We then applied least absolute shrinkage and selection operator (lasso) regression to select features that were most associated with progression-free survival (PFS). Candidate prognostic biomarkers included age, gender, overall stage, hemoglobin, platelet counts and radiomics signature. We developed model 1 (without radiomics signature) and model 2 (with radiomics signature) in the discovery set and then tested in the validation set. Multivariable Cox regression analysis was used to yield hazard ratio (HR) of each potential biomarker. We found the radiomics signature stratified patients in the discovery set into a low or high risk group for PFS (HR = 5.14, p < 0.001) and was successfully validated for patients in the validation set (HR = 7.28, p = 0.015). However, the other risk factors showed no significantly prognostic value (all p-values for HR, > 0.05). Accordingly, pretreatment MRI-based radiomics signature is a non-invasive and cost-effective prognostic biomarker in advanced NPC patients, which would improve decision-support in cancer care.

Development of a preprocedure nomogram for predicting contrast-induced acute kidney injury after coronary angiography or percutaneous coronary intervention.

Most of the risk models for predicting contrast-induced acute kidney injury (CI-AKI) are available for postcontrast exposure prediction, thus have limited values in practice. We aimed to develop a novel nomogram based on preprocedural features for early prediction of CI-AKI in patients after coronary angiography (CAG) or percutaneous coronary intervention (PCI). A total of 245 patients were retrospectively reviewed from January 2015 to January 2017. Least absolute shrinkage and selection operator (Lasso) regression model was applied to select most strong predictors for CI-AKI. The CI-AKI risk score was calculated for each patient as a linear combination of selected predictors that were weighted by their respective coefficients. The discrimination of nomogram was assessed by C-statistic. The occurrence of CI-AKI was 13.9% (34 out of 245). We identified ten predictors including sex, diabetes mellitus, lactate dehydrogenase level, C-reactive protein, years since drinking, chronic kidney disease (CKD), stage of CKD, stroke, acute myocardial infarction, and systolic blood pressure. The CI-AKI prediction nomogram obtained good discrimination (C-statistic, 0.718, 95%CI: 0.637-0.800, p = 7.23 × 10-5). The cutoff value of CI-AKI risk score was -1.953. Accordingly, the novel nomogram we developed is a simple and accurate tool for preprocedural prediction of CI-AKI in patients undergoing CAG or PCI.

Multi-center study on patient selection for and the oncologic safety of intraoperative radiotherapy (IORT) with the Xoft Axxent® eBx® System for the management of early stage breast cancer in Taiwan.

BACKGROUND: In this multi-center study, we report the patient selection criteria for and preliminary oncologic outcomes associated with intraoperative radiotherapy (IORT) delivered by the Xoft Axxent® eBx® system for early-stage breast cancer in Taiwan. METHODS: Patients with early breast cancer in Taiwan received breast conserving surgery and received IORT with Xoft Axxent® eBx® System during 2013-2015 was search from database of Taiwan IORT study cooperative group (T-IORTSCG). Patients' clinicopathologic characteristics and early post-operative results were collected and reported. RESULTS: During the study period, 26 hospitals in Taiwan performed a total of 261 Xoft IORT procedures for breast cancer. The mean age of them was 52.9 ± 9.8 years (37-72), and tumor size was 1.5 ± 0.8 cm (0.1-4.2 cm) for invasive cancer and 1.2 ± 0.8 cm (range, 0.2-3.0 cm) for ductal carcinoma in situ (DCIS) lesions. Lymph node metastasis was found in 6 (2.3%) patients. The patients received IORT in Taiwan differed markedly from those used in the ELIOT and TARGIT-A studies. Specifically, patients selected for IORT in Taiwan tended to be younger, their tumors tended to be larger and the prevalence of lymph node metastasis tended to be lower. Among these 261 patients, 8 (3.1%) patients required whole breast radiotherapy. During a mean follow up of 15.6 months, locoregional recurrence was observed in 2 (0.8%) patients. CONCLUSION: In real world experience, patients received IORT differed quite significantly with criteria formulated by trials. The preliminary results of IORT in Taiwan showed it is well acceptable by patients and clinicians.

Machine Learning Algorithms for Risk Prediction of Severe Hand-Foot-Mouth Disease in Children.

The identification of indicators for severe HFMD is critical for early prevention and control of the disease. With this goal in mind, 185 severe and 345 mild HFMD cases were assessed. Patient demographics, clinical features, MRI findings, and laboratory test results were collected. Gradient boosting tree (GBT) was then used to determine the relative importance (RI) and interaction effects of the variables. Results indicated that elevated white blood cell (WBC) count > 15 × 109/L (RI: 49.47, p < 0.001) was the top predictor of severe HFMD, followed by spinal cord involvement (RI: 26.62, p < 0.001), spinal nerve roots involvement (RI: 10.34, p < 0.001), hyperglycemia (RI: 3.40, p < 0.001), and brain or spinal meninges involvement (RI: 2.45, p = 0.003). Interactions between elevated WBC count and hyperglycemia (H statistic: 0.231, 95% CI: 0-0.262, p = 0.031), between spinal cord involvement and duration of fever ≥3 days (H statistic: 0.291, 95% CI: 0.035-0.326, p = 0.035), and between brainstem involvement and body temperature (H statistic: 0.313, 95% CI: 0-0.273, p = 0.017) were observed. Therefore, GBT is capable to identify the predictors for severe HFMD and their interaction effects, outperforming conventional regression methods.

CT and MRI findings in focal eosinophilic infiltration of the liver.

OBJECTIVES: To investigate the findings of computed tomography (CT) and magnetic resonance imaging (MRI) of focal eosinophilic infiltration (FEI) of the liver. METHODS: A retrospective study including 29 patients with confirmed FEI of the liver was performed. We evaluated the lesions' number, distribution, size, shape, margin, attenuation or signal intensity characteristics, the enhancement pattern, and some special features. Spearman correlation analysis was used to analyze the correlation between the number of lesions and the eosinophil counts in peripheral blood. RESULTS: In all, 108 lesions were detected in 29 cases, including two cases with single lesion and the remaining 27 cases with multiple lesions. The mean size of all lesions was 34 mm (range, from 3 to 61 mm). 95 (88%) lesions were located in subcapsular parenchyma or surrounding the portal vein. Most (66%) subcapsular lesions were wedge shaped and all lesions surrounding portal vein were round shaped. However, the hepatic parenchymal lesions were irregular or round shaped. All lesions showed ill-defined margins. On pre-contrast CT images, the lesions showed slightly low attenuation or iso-attenuating. On T1-weighted and T2-weighted images, the lesions were slightly iso-/hypointense and hyperintense, respectively. A total of 23 (79.3%) cases were gradually enhanced. Branches of portal vein went through the lesions in all cases; 12 had 'stripe sign' and 16 had 'halo ring sign.' Spearman analysis indicated a significant correlation between the number of lesions and the increased eosinophils in peripheral blood (r = 0.627, p = 0.0003). CONCLUSIONS: Special CT and MRI features and increased eosinophils may strongly suggest the diagnosis of FEI of the liver.

[Lignans from stems of Sambucus williamsii].

OBJECTIVE: To study the chemical constitutents of the 60% ethanol extract of the stems of Sambucus williamsii. METHOD: Compounds were isolated and purified by Diaion D101, silica gel,Sephadex LH-20, ODS column chromatography and preparative HPLC. Their structures were identified by spectroscopic methods. RESULT: Seven lignans were isolated and identified as erythro-guaiacylglycerol-beta-O-4'-sinapyl ether (1), 1-( 4'-hydroxy-3'-methoxyphenyl) -2- [4"-( 3-hydroxypropyl) -2", 6"-dimethoxyphenoxy] propane-1,3-diol (2), isolariciresinol (3), burselignan (4), lyoniresinol (5), 5-methoxy-isolariciresinol (6), cycloolivil (7). CONCLUSION: All these compounds were obtained from this genus for the first time.