Prognostic value of serial coronary computed tomography angiography-derived perivascular fat-attenuation index and plaque volume in patients with suspected coronary artery disease.

AIMS: To investigate the prognostic value of serial coronary computed tomography angiography (CCTA) derived plaque information, fractional flow reserve (CT-FFR), and perivascular fat-attenuation index (FAI) on major adverse cardiac events (MACE) in patients with suspected coronary artery disease. MATERIALS AND METHODS: A total of 252 patients who underwent serial CCTA between January 2018 and December 2021 and were followed until June 2022. MACE were recorded. The analysis indexes included percent diameter stenosis (%DS), lesion length, plaque volume, CT-FFR, and FAI, with an emphasis on their changes between the baseline and follow-up CCTAs. Multivariate regression analysis were employed to identify independent risk factors for MACE. RESULTS: After a median follow-up of 48-month, MACE occurred in 32 patients (12.7%). Patients with MACE displayed more severe stenosis, longer lesions, and larger plaque volumes in both baseline and follow-up CCTAs compared with no-MACE patients (all P<0.05). Patients with MACE displayed more severe stenosis, longer lesion, and larger plaque volume in both baseline and follow-up CCTAs compared with no-MACE patients. In addition, MACE patients also showed lower CT-FFR and higher △CT-FFR. Although FAI was significantly higher in MACE patients at baseline CCTA, FAI was notably increased in MACE patients, and decreased in the no-MACE patients (all P<0.05). Logistic regression analysis showed that ΔFAI, %DS, and plaque volume were independent predictors of MACE, with ΔFAI being the most significant (OR: 16.725, P<0.000). A multivariable model showed a significantly improved C-index of 0.903 (95% confidence interval: 0.836-0.970) for MACE prediction, when compared with single index alone. CONCLUSIONS: Serial CCTA-derived ΔFAI, %DS, and plaque volume are crucial independent predictors of MACE in patients with suspected coronary artery disease, highlighting the importance of CCTA in patient risk stratification and prognostic assessment.

The Relationship Between Systemic Lupus Erythematosus and Osteoporosis Based on Different Ethnic Groups: a Two-Sample Mendelian Randomization Analysis.

The previous observational studies could not overcome the effects of confounding variables and reverse causality. We aimed to determine whether there is a causal relationship between systemic lupus erythematosus and osteoporosis in East Asian and European populations, respectively, by two-sample Mendelian Randomization analysis. We obtained and downloaded data from publicly available genome-wide association study databases and analyses for East Asian and European populations, including systemic lupus erythematosus (SLE), osteoporosis (OP), multisite bone mineral density (BMD), and OP with fracture. After screening for instrumental single-nucleotide polymorphisms (SNPs) significantly correlated to SLE, the inverse-variance weighted (IVW) method was used for calculating the ratio and 95% confidence interval, besides utilizing MR-Egger, weighted median, and weighted mode to assess the robustness of the primary outcome. Moreover, multiple analyses, including MR-PRESSO, MR-Egger intercept, Cochran's Q test, as well as "leave-one-out" sensitivity, were used for evaluating horizontal pleiotropy, heterogeneity, and stability. Finally, we exchanged exposure and outcome and performed a reverse MR analysis. IVW (OR = 1.05, 95% CI = 1.01-1.09, P = 0.009) indicated a significant positive correlation between genetically predicted SLE and OP in East Asians. Furthermore, neither heterogeneity nor horizontal pleiotropy was observed. In Europe, there was no significant genetically predicted causal relation between SLE and OP. Bi-directional MR analysis showed no reverse causality between SLE and OP. In the East Asian population, genetically predicted SLE may have had a positive causal relationship with OP. In Europe, there is insufficient evidence for a potential causal relation between SLE and OP or BMD and fracture, and the correlations currently observed may be attributed to a variety of confounder variables.

Intestinal Translocation of Live Porphyromonas gingivalis Drives Insulin Resistance.

Periodontitis has been emphasized as a risk factor of insulin resistance-related systemic diseases. Accumulating evidence has suggested a possible "oral-gut axis" linking oral infection and extraoral diseases, but it remains unclear whether periodontal pathogens can survive the barriers of the digestive tract and how they play their pathogenic roles. The present study established a periodontitis mouse model through oral ligature plus Porphyromonas gingivalis inoculation and demonstrated that periodontitis aggravated diet-induced obesity and insulin resistance, while also causing P. gingivalis enrichment in the intestine. Metabolic labeling strategy validated that P. gingivalis could translocate to the gastrointestinal tract in a viable state. Oral administration of living P. gingivalis elicited insulin resistance, while administration of pasteurized P. gingivalis had no such effect. Combination analysis of metagenome sequencing and nontargeted metabolomics suggested that the tryptophan metabolism pathway, specifically indole and its derivatives, was involved in the pathogenesis of insulin resistance caused by oral administration of living P. gingivalis. Moreover, liquid chromatography-high-resolution mass spectrometry analysis confirmed that the aryl hydrocarbon receptor (AhR) ligands, mainly indole acetic acid, tryptamine, and indole-3-aldehyde, were reduced in diet-induced obese mice with periodontitis, leading to inactivation of AhR signaling. Supplementation with Ficz (6-formylindolo (3,2-b) carbazole), an AhR agonist, alleviated periodontitis-associated insulin resistance, in which the restoration of gut barrier function might play an important role. Collectively, these findings reveal that the oral-gut translocation of viable P. gingivalis works as a fuel linking periodontitis and insulin resistance, in which reduction of AhR ligands and inactivation of AhR signaling are involved. This study provides novel insight into the role of the oral-gut axis in the pathogenesis of periodontitis-associated comorbidities.

Prevotella intermedia Aggravates Subclinical Hypothyroidism.

Subclinical hypothyroidism (SCH) has been shown to be associated with microbiota. However, the association between SCH and oral microbiota has not yet been elucidated. The results of our previous clinical studies showed that Prevotella intermedia was abundant in the oral microbiota of SCH patients. This study aimed to investigate the relationship between SCH and oral microbiota, verify the pathogenicity of P. intermedia in SCH, and preliminarily explore the possible mechanism. The SCH mouse model with oral application of P. intermedia was established, and the variance in the mouse oral microbiota and changes in thyroid function and metabolism were detected in mice. Student's t test and analysis of variance were used for statistical analysis. Oral application of P. intermedia changed the composition of the oral microbiota of SCH mice, which enhanced the damage to the thyroid and decreased the expression of functional genes of the thyroid. Moreover, P. intermedia decreased oxygen consumption and aggravated glucose and lipid metabolism disorders in SCH mice. Glucose tolerance and insulin tolerance decreased, and the triglyceride content of the liver and inflammatory infiltration in adipose tissue increased in SCH mice after P. intermedia stimulation. Mechanistically, P. intermedia increased the proportion of CD4+ T cells in cervical lymph nodes and thyroids in SCH mice. Th1 cells were suggested to play an important role in the pathogenesis of SCH involving P. intermedia. In conclusion, P. intermedia aggravated SCH manifestations, including thyroid dysfunction and glucose and lipid metabolism disorders, by causing immune imbalance in mice. This study sheds new light on the pathogenesis of SCH from the perspective of oral microbiota.

Sinomenine ameliorates adjuvant-induced arthritis by inhibiting the autophagy/NETosis/inflammation axis.

Studies have found that neutrophil extracellular traps (NETs) which are the specific dying form of neutrophil upon activation have fundamental role in the rheumatoid arthritis onset and progression. The purpose of this study was to explore the therapeutic effect of Sinomenine on adjuvant-induced arthritis in mice, and the neutrophil activities regulated by Sinomenine. The rheumatoid arthritis model was established by local injection of adjuvant and the Sinomenine treatment was administered orally for 30 days, during which, arthritic scores were evaluated and the joint diameter was measured to determine disease progression. The joint tissues and serum were acquired for further tests after sacrifice. Cytometric beads assay was performed to measure the concentration of cytokines. For paraffin-embedded ankle tissues, hematoxylin and erosin staining and Safranin O-fast staining were adopted to monitor the tissue changes of joint. In order to analyze the inflammation, NETs and autophagy of neutrophils in vivo, immunohistochemistry assays were applied to detect the protein expression levels in the local joints. To describe the effect brought by Sinomenine on inflammation, autophagy and NETs in vitro, the western blotting and the immunofluorescence assays were performed. The joint symptoms of the adjuvant induced arthritis were alleviated by the Sinomenine treatment significantly in terms of the ankle diameter and scores. The improvement of local histopathology changes and decrease of inflammatory cytokines in the serum also confirmed the efficacy. The expression levels of interleukin-6, P65 and p-P65 in the ankle areas of mice were remarkably reduced by Sinomenine. Compared with the model group, the decreased expression levels of lymphocyte antigen 6 complex and myeloperoxidase in the Sinomenine treating group showed the inhibitory effect of Sinomenine on the neutrophil migration. The expression of protein arginine deiminase type 4 (PAD4), ctrullinated histone H3 (CitH3) and microtubule-associated protein 1 light chain 3B (LC3B) had the similar tendency. Upon activation of lipopolysaccharide (LPS) in vitro, Sinomenine suppressed the phosphorylation of P65, extracellular signal-regulated kinase (ERK) and P38 of neutrophil. Meanwhile, Sinomenine inhibited NETs formation induced by phorbol 12-myristate 13-acetate (PMA), which were demonstrated by the decreased expression of neutrophil elastase (NE), PAD4 and CitH3. Sinomenine also inhibited PMA-induced autophagy in vitro based on the changes of Beclin-1 and LC3B. Sinomenine has good efficacy in treating adjuvant induced arthritis via regulating neutrophil activities. Apart from inhibiting activation of nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, the mechanism includes suppression of NETs formation via autophagy inhibition.

[Advances in the relationship between lung cancer and microbiota].

Interaction exists in lung cancer and microbiota. Lung microecological homeostasis can improve the immune tolerance, enhance immune suppression, and inhibit inflammatory responses, to reduce the lung cancer; while lung cancer can lead to pulmonary microecological imbalance, change the lung environment, and promote tumor cell proliferation. Therefore, modulating microbial flora and microecological immunotherapy may be a potential and preventive treatment for lung cancer, to restore tumor immunosuppression and improve patient survival. However, the individual differences in the lung microecology, because of different genetics, ethnic characteristics, and dietary habits, increasing the difficulty of precise diagnosis and treatment, which is also the current bottleneck in the application of microecological immunotherapy. Otherwise, the effectiveness of regulatory measures such as probiotics, prebiotics or antimicrobials is questionable. The research on microbial flora is still in its infancy, and further exploration is needed to form a standardized, effective, and precise treatment plan. So, standardized, effective, and precise microbial flora treatment strategies need to be further explored.

[Application and challenges of neuroimaging technology in mechanisms and treatment of drug addiction].

Neuroimaging technologies can non-invasively characterize the structure and function of addiction brain, reveal the neural mechanism of addictive behavior, and provide a priori for the potential targets of brain stimulation. Neuroimaging technologies has played an important role in the study of drug addiction diseases, relapse prediction, and therapeutic evaluation of non-invasive brain stimulations, but it also faces many challenges. In this manuscript, we discuss the classification and analysis methods of neuroimaging technologies, its application in addiction and challenges, thus to promote the application of neuroimaging technology in the treatment of drug addiction.

[Analysis of clinical phenotype and genotype of Chinese children with disorders of sex development].

Objective: To explore the heterogeneity and correlation of clinical phenotypes and genotypes in children with disorders of sex development (DSD). Methods: A retrospective study of 1 235 patients with clinically proposed DSD in 36 pediatric medical institutions across the country from January 2017 to May 2021. After capturing 277 DSD-related candidate genes, second-generation sequencing was performed to analyzed the heterogeneity and correlation combined with clinical phenotypes. Results: Among 1 235 children with clinically proposed DSD, 980 were males and 255 were females of social gender at the time of initial diagnosis with the age ranged from 1 day of age to 17.92 years. A total of 443 children with pathogenic variants were detected through molecular genetic studies, with a positive detection rate of 35.9%. The most common clinical phenotypes were micropenis (455 cases), hypospadias (321 cases), and cryptorchidism (172 cases) and common mutations detected were in SRD5A2 gene (80 cases), AR gene (53 cases) and CYP21A2 gene (44 cases). Among them, the SRD5A2 mutation is the most common in children with simple micropenis and simple hypospadias, while the AMH mutation is the most common in children with simple cryptorchidism. Conclusions: The SRD5A2 mutation is the most common genetic variant in Chinese children with DSD, and micropenis, cryptorchidism, and hypospadias are the most common clinical phenotypes. Molecular diagnosis can provide clues about the biological basis of DSD, and can also guide clinicians to perform specific clinical examinations. Target sequence capture probes and next-generation sequencing technology can provide effective and economical genetic diagnosis for children with DSD.

The liquid Kangfuxin (KFX) has efficient antifungal activity and can be used in the treatment of vulvovaginal candidiasis in mice.

Vulvovaginal candidiasis (VVC) is an infectious disease caused mainly by Candida albicans. Kangfuxin (KFX) is a traditional Chinese medicine preparation made from Periplaneta americana extracts, which promotes wound healing and enhances body immunity and also acts as an antifungal agent. Here, we evaluated the effect of KFX in the treatment of VVC in vitro and in vivo. The minimum inhibitory concentration (MIC50 ) of KFX against C. albicans ranged from 7·65 to 20·57%. In addition, KFX was more efficient than fluconazole (FLC) in inhibiting the drug-resistant C. albicans, and the effect was more intense after 8 h. The KFX treatment also exhibited good activity in vivo. It restored the body weight and reduced the vulvovaginal symptoms in mice induced with VVC. It downregulated the expression of the hyphae-related gene, HWP1, thus inhibiting the growth and development of C. albicans hyphae. It also increased the number of neutrophils and promoted the secretion of interleukin-17A (IL-17A); however, the levels of interleukin-8 (IL-8) and interleukin-1ß (IL-1ß) decreased in mice with VVC. We deduce that KFX effectively treats vaginal candidiasis in two ways: by inhibiting the growth and development of mycelia to reduce colonization of C. albicans and by promoting the secretion and release of IL-17A and neutrophils in high numbers to fight C. albicans infection. This study provides a theoretical basis for the use of KFX for the clinical treatment of VVC.

[Analysis of factors related to one-year mortality in elderly patients following hip fracture surgery].

Objective: To analyze the related factors that affect the one-year mortality in elderly patients following hip fracture surgery. Methods: The clinical data of the elderly patients who needed a surgery for hip fracture in the Second Affiliated Hospital of Wenzhou Medical University from January 2017 to April 2018 were retrospectively analyzed. According to the inclusion criteria of the study, 489 cases were included. Then the information of patients including age, sex, Charlson comorbidity index, type of fracture, Braden score at admission, American Society of Anesthesiologists (ASA) score, length of hospital stay, type of anesthesia, whole blood cells analysis were collected. Univariate and multivariate Cox regression analyses were conducted to investigate the factors related to one-year mortality of patients. Results: After excluding 39 patients, 450 patients were finally included. Patients in this cohort study had a mortality rate of 3.33% (15/450) at 1 month, 7.78% (35/450) at half a year, and 10.89% (49/450) at 1 year after surgery. Univariate analysis showed that age, sex, ASA score, type of fracture, Charlson comorbidity index, Braden score at admission, type of analgesia, preoperative hemoglobin concentration, preoperative albumin concentration, postoperative delirium of high activity correlated with one-year mortality after surgery. Further, multivariate Cox regression analysis revealed that age>80 years old (HR=2.32, 95%CI: 1.11-4.85, P=0.025), Charlson comorbidity index ≥ 3 (HR=3.24, 95%CI:1.75-6.03, P<0.001), Braden score at admission ≤16 (HR=1.93, 95%CI:1.03-3.57, P=0.040) and postoperative delirium of high activity (HR=2.49, 95%CI:1.16-5.35, P=0.019) were risk factors for one-year mortality. Conclusions: The current study indicates that one-year mortality rate of elderly patients following hip fracture surgery is 10.89%. Meanwhile, age>80 years, Charlson comorbidity index ≥ 3, Braden score at admission ≤ 16, postoperative delirium of high activity are risk factors for one-year mortality.

The safety and efficacy of transarterial chemoembolisation with bleomycin for hepatocellular carcinoma unresponsive to doxorubicin: a prospective single-centre study.

AIM: To investigate the safety and efficacy of transarterial chemoembolisation (TACE) with bleomycin for hepatocellular carcinoma (HCC) unresponsive to doxorubicin. MATERIALS AND METHODS: A randomised controlled trial was undertaken of HCC patients resistant to TACE with doxorubicin to assess the survival benefits of the experimental group (TACE with bleomycin) compared with the control group (TACE with doxorubicin). One hundred and seventy patients were allocated randomly between December 2015 and December 2017, and 80 patients of each group were analysed. The modified response evaluation criteria in solid tumours (mRECIST) was used to evaluated the tumour response every 4-6 weeks. The primary endpoint was median progression-free survival (mPFS) and median overall survival (mOS). Safety was assessed by post-procedure complications. RESULTS: The study was completed in October 2018. Objective response rate (ORR) of the experimental group was 27.5% (22/80), mPFS and mOS was 5.8 and 8.1 months. ORR of the control group was 7.5% (6/80), mPFS and mOS was 2.9 and 4 months. The ORR were significantly different between two groups (χ2 = 0.348, p<0.05). The differences of mPFS and mOS between the two groups were statistically significant (χ2 = 2.865, p<0.05 and χ2 = 0.926, p<0.05, respectively). There were no significant difference in post-procedure complications (p>0.05) and no major complications occurred. CONCLUSION: It is suggested that TACE with bleomycin is a safe and effective method for HCC and bleomycin can be a second-line chemotherapeutic agent for the HCC patients unresponsive to TACE with doxorubicin.

Controlling selectivity in N-heterocycle directed borylation of indoles.

Electrophilic borylation of indoles with BX3 (X = Cl or Br) using directing groups installed at N1 can proceed at the C2 or the C7 position. The six membered heterocycle directing groups utilised herein, pyridines and pyrimidine, result in indole C2 borylation being the dominant outcome (in the absence of a C2-substituent). In contrast, C7 borylation was achieved using five membered heterocycle directing groups, such as thiazole and benzoxazole. Calculations on the borylation of indole substituted with a five (thiazole) and a six (pyrimidine) membered heterocycle directing group indicated that borylation proceeds via borenium cations with arenium cation formation having the highest barrier in both cases. The C7 borylated isomer was calculated to be the thermodynamically favoured product with both five and six membered heterocycle directing groups, but for pyrimidine directed indole borylation the C2 product was calculated to be the kinetic product. This is in contrast to thiazole directed indole borylation with BCl3 where the C7 borylated isomer is the kinetic product too. Thus, heterocycle ring size is a useful way to control C2 vs. C7 selectivity in N-heterocycle directed indole C-H borylation.

Nomogram predicting early neurological improvement in ischaemic stroke patients treated with endovascular thrombectomy.

BACKGROUND AND PURPOSE: Early neurological improvement (ENI) after endovascular thrombectomy (EVT) has been associated with favorable outcomes. This study aimed to identify the optimal definition of ENI and develop a nomogram for predicting ENI after EVT in acute ischaemic stroke. METHODS: Patients with EVT were enrolled from a multicenter registry as the training cohort. The receiver operating characteristic curve was used to estimate the optimal threshold for ENI at 24 h of EVT. Logistic regression analysis was utilized to generate the best-fit nomogram for predicting ENI. The discrimination of the nomogram was assessed using the area under the receiver operating characteristic curve (AUC). An additional 447 patients from two stroke centers were prospectively recruited as the test cohort for validating the nomogram. RESULTS: A total of 612 patients with EVT were included in the training cohort. The optimal threshold for predicting 3-month favorable outcome (modified Rankin Scale 0-2) was an improvement of the National Institutes of Health Stroke Scale (NIHSS) score by ≥6 points (AUC 0.875; sensitivity 79.5%; specificity 90.7%). Age, blood glucose, recanalization, symptomatic intracranial hemorrhage (sICH) and baseline Alberta Stroke Program Early Computed Tomography Score (ASPECTS) were independently associated with ENI, and were incorporated in the nomogram. The AUC of the nomogram was 0.795 in the training cohort and 0.752 in the test cohort. CONCLUSIONS: A reduction of NIHSS score ≥6 appeared to be the optimal definition of ENI. The nomogram composed of age, blood glucose, recanalization, sICH and baseline ASPECTS may predict the probability of ENI in ischaemic stroke patients treated with EVT.

[Influence of fasting duration on blood volume status of pediatric patients evaluated by ultrasonic technique].

Objective: To evaluate the influence of preoperative fasting duration on blood volume status of pediatric patients during induction based on ultrasonic technique. Methods: One hundred and ten pediatric patients, scheduled for elective operation in the Second Affiliated Hospital & Yuying Children's Hospital, were recruited during January and October in 2018. After sedation by inhalation of sevoflurane, the maximum (expiratory) and minimum (inspiratory) diameter of inferior vena cava (IVC(max), IVC(min)) and aorta velocity-time integral (VTI) in apical five-chamber cardiac view were measured with an ultrasound machine. Respiratory variabilities of these parameters were further calculated. Furthermore, passive leg raising (PLR) test was performed and above measurements/calculations were repeated. The correlation between the duration of fasting and IVC respiratory variations index (IVC(RVI)) or aortic VTI variability (ΔVTI) was then analyzed. Results: Before PLR, IVC(max), IVC(min) and IVC(RVI) were (0.78±0.19), (0.43±0.15) cm and 0.45±0.12, respectively. After PLR, IVC(max) and IVC(min) increased to (0.94±0.20), (0.55±0.18) cm, while IVC(RVI) decreased to 0.42±0.13, the differences were statistically significant (t=15.66, 10.85, 3.14, all P<0.05). However, IVC(max), IVC(min) and IVC(RVI) were not significantly correlated with the duration of fasting analyzed by linear regression (before PLR: r=0.052, 0.163, 0.171; after PLR, r=0.062, 0.169, 0.165, all P>0.05). Before PLR, expiratory aortic VTI (VTI(max)), inspiratory aortic VTI (VTI(min)) and ΔVTI were 21±5, 17±4 and 17±8, respectively. After PLR, the VTI(max) and VTI(min) significantly increased to 23±5 and 19±4 (t=13.60, 10.43, all P<0.05), but ΔVTI was not changed significantly, which was 17±8(t=0.34, P>0.05). Linear regression analysis showed that VTI(max), VTI(min) and ΔVTI were not significantly correlated with the duration of fasting (before PLR: r=0.111, 0.100, 0.047; after PLR: r=0.003, 0.033, 0.073, all P>0.05). Further multiple linear regression analysis indicated that, age and body weight were independent factors influencing IVC(RVI) and ΔVTI before and after PLR (IVC(RVI): ß=-0.441, 0.515, -0.451, 0.507; ΔVTI: ß=-0.442, 0.545, -2.422, 2.850; all P<0.05). However, the duration of fasting was not correlated with IVC(RVI) and ΔVTI after adjusting the age and weight (IVC(RVI): ß=0.177, 0.160; ΔVTI: ß=0.037, 0.054; all P>0.05). Conclusion: Age and weight, but not preoperative fasting duration, are correlated with respiratory variabilities of inferior vena cava diameter and aortic VTI in pediatric patients.

MiR-30 suppresses lung cancer cell 95D epithelial mesenchymal transition and invasion through targeted regulating Snail.

Since this article has been suspected of research misconduct and the corresponding authors did not respond to our request to prove originality of data and figures, "MiR-30 suppresses lung cancer cell 95D epithelial mesenchymal transition and invasion through targeted regulating Snail, by M.-J. Fan, Y.-H. Zhong, W. Shen, K.-F. Yuan, G.-H. Zhao, Y. Zhang, S.-K. Wang, published in Eur Rev Med Pharmacol Sci 2017; 21 (11): 2642-2649-PMID: 28678320" has been withdrawn. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/12883.