Associations between abdominal obesity indices with hypertension in type 2 diabetes mellitus: Chinese visceral adiposity index.

PURPOSE: This research was performed to evaluate the relationship between hypertension (HTN) and abdominal obesity index in patients with type 2 diabetes mellitus (T2DM). METHODS: Totally 1657 participants with T2DM (mean age 54 ± 12 years; 38.02% female) were enrolled. They were divided into the groups of HTN (n = 775) and non-HTN (n = 882). Anthropometric and biochemical indicators were measured and collected. A bioelectrical impedance analyzer was used to measure visceral and subcutaneous fat areas. RESULTS: Compared with the HTN group, the non-HTN group had a lower level of Chinese visceral adiposity index (CVAI) (p < 0.001). Meanwhile, among tertiles of CVAI, as CVAI increased, the proportion of patients with HTN increased, which was 33.51%, 44.30%, and 62.50%, respectively. CVAI was shown to have a significant positive correlation with HTN. (r = 0.258, p < 0.001). CVAI was independently related to an elevated risk of HTN by binary logistic regression analyses, and the OR was (95% CI) 1.013 (1.010-1.016, p < 0.001) after adjustment. The area under the receiver operating characteristic curve (AUC) of CVAI predicted HTN in T2DM patients was greater than those of other abdominal obesity indices (p < 0.001). CONCLUSION: We found that CVAI was highly positively correlated with HTN in T2DM. Compared with other indices of abdominal obesity, such as WC, BMI, WHR, VAI, and LAP, the CVAI showed superior discriminative ability in T2DM complicated with HTN. Therefore, more attention should be paid to CVAI in T2DM.

[Study on the comparison of postoperative liver injury caused by hepatic arterial perfusion chemotherapy combined with targeted immunotherapy with hepatic arterial chemoembolization combined with targeted immunotherapy for intermediate-and advanced-stage liver cancer].

Objective: To compare the postoperative liver function injury condition in patients with intermediate-and advanced-stage hepatocellular carcinoma (HCC) treated with hepatic artery infusion chemotherapy (HAIC) and hepatic artery chemoembolization (TACE) combined with immune checkpoint inhibitors (ICIs) and multi-target tyrosine kinase inhibitors (TKIs). Methods: Patients with intermediate-and advanced-stage HCC who were admitted and treated with HAIC/TACE+ICIs+TKIs therapy at Nanfang Hospital of Southern Medical University from January 2019 to November 2021, with follow-up up to July 2023, were retrospectively enrolled. The results of liver function tests within one week before interventional surgery and on the first day after surgery were recorded. The degree of postoperative liver injury was graded according to the common terminology criteria for adverse events 5.0 (CTCAE 5.0). The treatment efficacy was evaluated according to RECIST 1.1 criteria. Measurement data were compared between groups using a t-test or a non-parametric rank sum test. Enumeration data were compared between the groups using the χ(2) test or Fisher's exact probability method. The survival condition differences were analyzed by the log-rank method. Results: This study included 82 and 77 cases in the HAIC and TACE groups. There were no statistically significant differences between the two groups of patients in terms of gender, age, physical condition score, number of tumors, presence or absence of liver cirrhosis, Child-Pugh grade, albumin-bilirubin (ALBI) grade, and combined ICIs and TKIs . The HAIC group had later tumor staging, a greater tumor burden, poorer liver reserve function, and a larger proportion of patients in stage C (81.7% vs. 63.6%), χ(2)=6.573, P = 0.01). There were 53 cases (64.6% vs. 32.5%) with a maximum tumor diameter of ≥ 10cm, χ(2)=16.441, P < 0.001), and more patients had a retention rate of ≥ 10% for indocyanine green (ICG) at 15 minutes (68.3% vs. 51.9%, P = 0.035). The postoperative incidence rate of increased levels of alanine aminotransferase, aspartate aminotransferase, and total bilirubin was significantly lower in the HAIC group than that in the TACE group (28.0% vs. 63.6%, χ(2)=20.298, P < 0.001, 54.9% vs. 85.7%, χ(2)=17.917, P < 0.001;40.2% vs. 55.8%, χ(2)=3.873, P = 0.049). The number of patients with postoperative ALBI grade 3 was significantly lower in the HAIC group than that in the TACE group (6.1% vs. 16.9%, χ(2)=4.601, P = 0.032). There was no statistically significant difference in the incidence rate of postoperative hypoalbuminemia, activated partial thromboplastin time, or increased international standardized ratio between the two groups of patients. There was no statistically significant difference in median progression-free survival (7.3 months vs. 8.2 months, P = 0.296) or median overall survival (16.5 months vs. 21.9 months, P = 0.678) between the two groups of patients. Conclusion: The incidence rate of postoperative liver injury is higher in patients with intermediate-and advanced-stage HCC treated with TACE combined with ICIs and TKIs than in patients with HAIC combined with ICIs and TKIs.

Immune checkpoint inhibitor-associated new-onset primary adrenal insufficiency: a retrospective analysis using the FAERS.

BACKGROUND: Our study aimed to investigate the prevalence and demographic characteristics of immune checkpoint inhibitor-associated primary adrenal insufficiency (ICI-PAI) and to explore the risk factors of its clinical outcome using data from the US FDA Adverse Event Reporting System (FAERS). METHODS: This was a retrospective study. All cases of new-onset or newly diagnosed primary adrenal insufficiency associated with FDA-approved ICIs from 1 January 2007 to 31 December 2020 were identified and collected using FAERS. Data on age, sex category, body weight of the participating individuals, the reporting year and the prognosis of cases, and other accompanying endocrinopathies related to ICIs, were analysed. RESULTS: The incidence of ICI-PAI was 1.03% (1180/114121). Of the 1180 cases of PAI, 46 were "confirmed PAI", and 1134 were "suspected PAI". Combination therapy with anti-CTLA-4 and anti-PD-1 was related to a higher risk of PAI compared with the anti-PD-1-only group (χ2 = 92.88, p < 0.001). Male and elderly individuals showed a higher risk of ICI-PAI (male vs. female, 1.17% vs. 0.94%, χ2 = 12.55, p < 0.001; age < 65 vs. ≥ 65, 1.20 vs. 1.41%, χ2 = 6.89, p = 0.009). The co-occurrence rate of endocrinopathies other than PAI was 24.3%, which showed a higher trend in patients on nivolumab-ipilimumab treatment than in those on PD-1 inhibitors (χ2 = 3.227, p = 0.072). Body weight was negatively associated with the risk of death in the study population [p = 0.033 for the regression model; B = - 0.017, OR 0.984, 95% CI (0.969-0.998), p = 0.029]. CONCLUSION: ICI-associated PAI is a rare but important irAE. Male and elderly patients have a higher risk of ICI-PAI. Awareness among clinicians is critical when patients with a lower body weight develop PAI, which indicates a higher risk of a poor clinical outcome.

Potential biomarkers in the fibrosis progression of nonalcoholic steatohepatitis (NASH).

PURPOSE: Fibrosis is the only histological feature reflecting the severity and prognosis of nonalcoholic steatohepatitis (NASH). We aim to explore novel genes associated with fibrosis progression in NASH. METHODS: Two human RNA-seq datasets were downloaded from the public database. Weighted gene co-expression network analysis (WGCNA) was used to identify their co-expressed modules and further bioinformatics analysis was performed to identify hub genes within the modules. Finally, based on two single-cell RNA-seq datasets from mice and one microarray dataset from human, we further observed the expression of hub genes in different cell clusters and liver tissues. RESULTS: 7 hub genes (SPP1, PROM1, SOX9, EPCAM, THY1, CD34 and MCAM) associated with fibrosis progression were identified. Single-cell RNA-seq analysis revealed that those hub genes were expressed by different cell clusters such as cholangiocytes, natural killer (NK) cells, and hepatic stellate cells (HSCs). We also found that SPP1 and CD34 serve as markers of different HSCs clusters, which are associated with inflammatory response and fibrogenesis, respectively. Further study suggested that SPP1, SOX9, MCAM and THY1 might be related to NASH-associated hepatocellular carcinoma (HCC). Receiver operating characteristic (ROC) analysis showed that the high expression of these genes could well predict the occurrence of HCC. At the same time, there were significant differences in metabolism-related pathway changes between different HCC subtypes, and SOX9 may be involved in these changes. CONCLUSIONS: The present study identified novel genes associated with NASH fibrosis and explored their effects on fibrosis from a single-cell perspective that might provide new ideas for the early diagnosis, monitoring, evaluation, and prediction of fibrosis progression in NASH.

[Clinical features, risk factors and prognosis of idiopathic dilated cardiomyopathy complicated by ischemic stroke].

Objective: To analyze the clinical features, risk factors and prognosis of idiopathic dilated cardiomyopathy (DCM) complicated with ischemic stroke (IS) (DCM-IS). Methods: The clinical data of patients with idiopathic DCM (n=613) in Beijing Anzhen Hospital, Liangxiang Hospital and Fuxing Hospital from January 2016 to December 2020 were retrospectively collected, and among them, 123 cases were DCM-IS. Clinical features of patients with DCM-IS were summarized and multivariate logistic regression model was utilized to analyze the independent risk factors of DCM-IS. Furthermore, 1-year follow-up was conducted and Kaplan-Meier curve was adopted to analyze the prognosis of DCM, using all-cause death and heart transplantation as adverse outcomes. Results: Among the 70 patients with DCM-IS, 6 patients (8.6%, 6/70) were in accordance with the subtype of large artery atherosclerosis, and 47 patients (67.1%, 47/70) were in line with the subtype of cardiogenic embolism, and small artery occlusion subtype (ie, lacunar infarction) were detected in 17 cases (24.3%, 17/70). Hypertension [odds ratio (OR)=1.617, 95% confidence interval (CI): 1.049-2.491, P=0.029], hyperlipidemia (OR=1.918, 95%CI: 1.198-3.073, P=0.007), atrial fibrillation (AF) (OR=1.617, 95%CI: 1.016-2.572, P=0.043), lower estimated glomerular filtration rate (eGFR) (OR=0.986, 95%CI: 0.977-0.996, P=0.005) and a higher incidence of intracardiac thrombus (OR=6.127, 95%CI: 3.174-11.827, P<0.001) were risk factors for DCM-IS. The overall 1-year survival rate was lower in DCM-IS patients (70.7%) than DCM patients without stroke (83.6%, P=0.004), and the main causes of death included obstinate heart failure (3 cases of DCM-IS, and 5 cases of non-DCM-IS) and malignant arrhythmia (DCM-IS) (22 cases of DCM-IS, and 18 cases of non-DCM-IS). Conclusions: Among IS patients with idiopathic DCM, cardioembolism is the most common, followed by lacunar infarction, and the large-artery atherosclerotic subtype is the least common.Hypertension, hyperlipidemia, AF, lower eGFR value and higher incidence of intracardiac thrombus are risk factors for DCM-IS. DCM patients complicated with IS have poor short-term prognosis, and obstinate heart failure and malignant arrhythmia are their main causes of death.

[Identification of serum peptide biomarker for ovarian cancer diagnosis by Clin-TOF-II-MS combined with magnetic beads technology].

Objective: To explore the serum cyclic polypeptide biomarkers for ovarian cancer diagnosis. Methods: A total of 54 patients with epithelial ovarian cancer confirmed by pathology in Cancer Hospital, Chinese Academy of Medical Sciences from March 2018 to September 2018 were selected as the study subjects, and 40 healthy women with normal examination results in the cancer screening center were selected as the control. All of the samples were randomly divided into training set and validation set at the ratio of 1∶1 with a random number. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) combined with magnetic bead technology was used for detecting peptide profiling in serum samples to screen significantly differently expressed peptides between ovarian cancer group and control group of the training set (score>5). Receiver operating characteristic (ROC) curve analysis was used to screen differential peptide peaks with area under curve (AUC) ≥0.8, sensitivity and specificity>90% in the training set and validation set. Liquid chromatography-mass spectrometry (LC-MS/MS) was further used to determine the composition of differentially expressed peptides. Results: By comparing the peptide profiles of the two groups, 102 differential peptide peaks were initially detected in the mass-to-charge ratio range of 1 000 to 10 000. ROC curve analysis showed that there were 42 differential peptide peaks with AUC ≥0.8 in both training set and validation set, 19 of which were highly expressed in ovarian cancer group, and 23 were lowly expressed. There were 15 different peptide peaks in highly expressed ovarian cancer group with sensitivity and specificity over 90%. The mass-to-charge ratios were 7 744.27, 5 913.41, 5 329.87, 4 634.21, 4 202.02, 3 879.26, 3 273.35, 3 253.79, 3 234.34, 2 950.33, 2 664.51, 2 018.38, 1 893.37, 1 498.69 and 1 287.55. There were 15 different peptide peaks in lowly expressed ovarian cancer group with sensitivity and specificity over 90%, the mass-to-charge ratios were 9 288.46, 7 759.77, 5 925.24, 4 652.77, 4 210.42, 3 887.02, 3 279.90, 3 240.82, 2 962.15, 2 932.70, 2 022.42, 1 897.16, 1 501.69, 1 337.38 and 1 290.13. No protein composition was identified in 15 different peptide peaks in lowly expressed ovarian cancer group. The two protein compositions identified in 15 different peptide peaks in highly expressed ovarian cancer group were recombinant serglycin (SRGN) and fibinogen alpha chain (FGA), the mass-to-charge ratios of which were 1 498.696 and 5 913.417, respectively. The sensitivity and specificity of the two proteins for ovarian cancer diagnosis were 100%, 100% and 90.9%, 100%, respectively. Conclusion: SRGN and FGA are highly expressed in the serum of ovarian cancer patients, which may be potential diagnostic markers for ovarian cancer.

[Analysis of PARP inhibitors induced anemia in advanced and relapsed epithelial ovarian cancer].

Objective: To explore the clinical features of poly ADP-ribose polymerase (PARP) inhibitor-related anemia in advanced and relapsed epithelial ovarian cancer (EOC). Methods: Patients diagnosed with advanced or relapsed EOC and treated with PARP inhibitor at National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 2015 to October 2020 were accrued. The data included PARP inhibitors, treatment details, and lab tests before treatment and during treatment were collected and the clinical characteristics of PARP inhibitor-related anemia were analyzed. Results: (1) A total of 98 patients with a median age of 56.5 years old (30-82 years old) were enrolled in this study. All patients were treated with PARP inhibitor (65 cases of olaparib, 17 cases of niraparib, and 16 cases of fluzoparib). The median treatment duration was 37.5 weeks (4-119 weeks). (2) The anemia rate was 40% (39/98), including 5% (5/98) of grade Ⅰ, 14% (14/98) of grade Ⅱ, 11% (11/98) of grade Ⅲ, and 9% (9/98) of grade Ⅳ. Fourteen patients with pre-treatment grade Ⅰ anemia had a higher rate of anemia events than the 80 patients without pre-treatment anemia, 7/14 vs 35% (28/80; χ2=4.281, P=0.039). (3) The median anemia occurrence time was 7.0 weeks (1-52 weeks), including 41% (16/39) of anemia cases occurred in 1-4 weeks, 26% (10/39) occurred in 5-8 weeks, 13% (5/39) occurred in 9-12 weeks, 3% (1/39) occurred in 13-16 weeks, 10% (4/39) occurred in 17-20 weeks, 8% (3/39) occurred ≥21 weeks. At the time of the lowest hemoglobulin tested, the median value of mean corpuscular volume (MCV) was 106 fl,which was higher than the up limit of normal range (100 fl), 74% (29/39) of anemia patients had an elevated MCV level; the median value of mean corpuscular hemoglobin (MCH) was 36 pg, 54% (21/39) of anemia patients had an elevated MCH level; the median value of mean corpuscular hemoglobin concentration (MCHC) was 320 g/L, 69% (27/39) of anemia patients had a higher MCHC level; 92% (36/39) of anemia patients had a normal level of serum iron; 79% (31/39) of anemia patients had a normal level of transferrin. 74% (29/39) of the anemia patients were macrocytic orthochromatic anemia. (4) Among the 39 patients with anemia, 20 patients (51%, 20/39) withhold the treatment of PARP inhibitor due to grade Ⅲ or Ⅳ anemia, including 10 patients (50%, 10/20) who resumed the PARP inhibitor treatment by suppling iron, folate, and vitamin B12. The median stopping time of PARP inhibitor was 5.5 weeks (2-10 weeks), while the other 10 patients terminated the PARP inhibitor treatment for not recovering from severe anemia. Conclusions: One of the common adverse effects of PARP inhibitors is anemia, which mostly happened in the first 3 months of treatment. In the treatment of EOC, PARP inhibitor-related anemia mainly manifest as macrocytic orthochromatic anemia, and most patients with normal serum iron and transferrin.

[Clinical efficacy and safety analysis of camrelizumab combined with apatinib as a second-line therapy for unresectable hepatocellular carcinoma: a multicenter retrospective study].

Objective: To analyze the clinical efficacy and safety of camrelizumab combined with apatinib as a second-line therapy for unresectable hepatocellular carcinoma (HCC). Methods: Ninety-four cases with mid-and advanced-stage HCC who received camrelizumab combined with apatinib as second-line treatment were enrolled. Routine blood test, blood biochemical indexes, tumor stage, tumor imaging characteristics, previous treatment strategies and other clinical data before treatment were documented. Imaging examination follow-up results and adverse reactions during treatment were followed up until the end of follow-up or loss of follow-up or death. Kaplan-Meier method was used to analyze the clinical efficacy. Results: As of the last follow-up, 94 cases with mid-and advanced-stage HCC had received camrelizumab combined with apatinib as second-line treatment. Among them, 15 cases were lost to follow-up, 31 cases died, and 48 cases survived. The overall remission rate was 31.9%. The overall disease control rate was 71.3%. The median time to disease-free progression was 6.6 months. The median time to disease progression was not yet available. The 1-year cumulative survival rate was 62.3%. Grade 3 and above adverse reactions mainly included were thrombocytopenia (7.4%), abdominal pain (4.3%), active hepatitis (4.3%), leukopenia (4.3%), diarrhea (3.2%), hand-foot syndrome (3.2%). All adverse reactions were effectively controlled. Conclusion: Camrelizumab combined with apatinib can effectively prolong the survival period of patients with mid-and advanced-stage HCC, and it is well tolerated.

Ultra-long high quality catalyst-free WO3 nanowires for fabricating high-performance visible photodetectors.

This work presents a study on the controlled growth of WO3 nanowires via chemical vapor deposition without catalyst, and their potential applications in visible photodetectors. The influence of growth conditions on the morphology of WO3 nanowires is studied in order to understand the growth mechanism of WO3 nanowires, and ultra-long (60 [Formula: see text], the longest one ever reported) WO3 nanowires with a spindle shape are achieved by optimizing the growth conditions. It was found that the length of WO3 nanowires increases from 15 [Formula: see text] to 60 [Formula: see text] with increasing the argon carrier gas flow rate from 30 sccm to 90 sccm, and then saturates with further increasing the argon carrier gas flow rate. However, the length of WO3 nanowires reduces from 60 [Formula: see text] to 19 [Formula: see text] with increasing the tube inner pressure from 2.5 Torr to 3.5 Torr. The photoconductor detectors based on WO3 single nanowires present excellent device performance with a responsivity as high as 19 A W-1 at a bias of 0.1 V, a detectivity as high as 1.06 × 1011 Jones, and a response (rising and decay) time as short as 8 ms under the illumination of a 404 nm laser. These results indicate the great potential of WO3 nanowires for applications in fabricating high performance visible photodetectors.

[Analysis of treatment and prognosis of 59 cases of vulvar melanoma].

Objective: To assess the treatment and prognosis of vulvar melanoma. Methods: A total of 59 cases of primary vulvar melanoma admitted to Cancer Hospital of Peking Union Medical College, Chinese Academy of Medical Sciences from January 1st, 1981 to November 30th, 2019 were collected. The clinical characteristics, treatment, survival and prognostic factors of vulvar melanoma were analyzed retrospectively. The end date of follow-up was January 15th, 2020.The median follow-up time was 26.0 months (range:2-198 months). Results: (1) Clinical characteristics: the median age of 59 patients with vulvar melanoma was 56 years old (range:18-83 years old). According to the American Joint Committee on Cancer stage manual, there were 18, 7, 26 and 8 cases of stage Ⅰ, Ⅱ, Ⅲ and Ⅳ respectively. The lesion of 38 cases was single and the other 21 cases were multiple. The largest diameter of the tumor ranged from 0.3 to 17.0 cm.The surface of the lesion was ulcerated in 17 cases. (2) Treatment: a total of 59 cases with vulvar melanoma, 56 patients received surgery, 36 cases of them received radical resection of vulva and 20 received local extended resection of vulvar tumor due to unilateral vulva lesion. Three patients did not receive surgery,one received chemotherapy combined with interferon, one received interferon, and one received radiotherapy. Lymph node management: among the 56 patients treated by surgery, 37 patients received inguinal lymphadenectomy, 24 (65%, 24/37) of whom were confirmed with inguinal lymph node metastasis by postoperative pathological examination. Inguinal lymph nodes enlargement were not found in 19 cases by preoperative imaging and clinical examination. In these 19 patients, three patients received inguinal lymph node biopsy, among them, one (1/3) patient was confirmed with inguinal lymph node metastasis by postoperative pathological examination, and the remaining 16 patients did not receive inguinal lymph node surgery. Postoperative adjuvant treatment: among the 56 patients who received surgery, 31 received adjuvant chemotherapy，one received adjuvant radiotherapy, four received interferon therapy, 17 received combination therapy including chemotherapy, and three did not receive postoperative adjuvant therapy. (3) Survival:during the follow-up period, the median survival time of 59 patients with vulvar melanoma was 30.0 months (range:2.0-198.0 months). The 3-year survival rate was 42.5%, and the 5-year survival rate was 23.8%. The median survival time of stage Ⅰ, Ⅱ, Ⅲ and Ⅳ were 72.0, 45.0, 24.0 and 23.0 months, respectively. The difference among stage Ⅰ, Ⅱ and stage Ⅲ, Ⅳ were statistically significant （P<0.01）. The median survival time of patients undergoing radical resection of the vulva (35.0 months) and local enlarged tumor resection (29.0 months) were significantly longer than that of patients without surgery (9.0 months, P<0.01). The median survival time of the patients who underwent inguinal lymphadenectomy, lymph node biopsy and those who did not undergo surgery were 35.0, 32.0 and 30.0 months, respectively. There were no significant differences among the 3 groups (P>0.05). The median survival time of postoperative adjuvant chemotherapy patients (49.0 months) were significantly longer than that of postoperative adjuvant radiotherapy, interferon,and combination therapy including chemotherapy (9.0, 14.0 and 26.0 months, respectively, all P<0.01). (4) Prognostic factors: the univariate analysis showed that stage, vulvar operation and postoperative adjuvant treatment were the risk factors affecting the prognosis of patients with vulvar melanoma (P<0.01). Multivariate analysis revealed that stage alone was an independent risk factor affecting the prognosis of patients with vulvar melanoma (P<0.01). Conclusions: The prognosis of patients with vulvar melanoma is poor, and stage is an independent prognostic factor.Surgery combined with postoperative adjuvant chemotherapy may achieve relatively good results.

Clock mutant promotes osteoarthritis by inhibiting the acetylation of NFκB.

OBJECTIVES: To examine the effect of the circadian gene Clock on posttranscriptional function and pro-inflammatory mechanisms in osteoarthritis (OA). METHODS: The cartilage from Clock mutant mice was assessed using histology, (OA) score, and real-time polymerase chain reaction (PCR) quantification of key pro-inflammatory genes. Nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) translocation, posttranslational state and expression levels during day and night conditions were assessed using immunoblot and IP. The regulation of transcription by Clock in cartilage tissue was assessed by using chromatin immunoprecipitation (ChIP) and luciferase assays. Total acetylation level and pattern over 24 h were quantified using immunoblot and real-time PCR. Finally, the effects of exogenous Clock nanoparticle treatment were quantified by histology and immunoblot. RESULTS: The Clock mutation significantly promoted the degradation of cartilage and the expression of the key pro-inflammatory mediators, IL-1ß, IL-6 and MCP-1. The Clock mutation significantly promoted NFκB nuclear translocation. The circadian protein CLOCK positively regulates NFκB at the transcriptional level by binding the E-box domain. The Clock mutation significantly inhibited the total lysine acetylation level in cartilage and inhibited NFκB acetylation at the Lys310 residue but promoted phosphorylation at the Ser276 residue. The forced expression of Clock in vivo inhibited NFκB activation by increasing acetylation and decreasing phosphorylation levels and by decreasing cartilage damage and inflammation. CONCLUSIONS: This study demonstrates the mutation of Clock promotes inflammatory activity by mediating the posttranscriptional regulation of NFκB in OA pathogenesis.

[Approach to creating early diabetic peripheral neuropathy rat model].

OBJECTIVE: To create the early diabetic peripheral neuropathy (DPN) rat model. METHODS: After one-week adaption, 26 male Sprague-Dawley (SD) rats were divided into two groups, the control group (n=6) and the model group (n=20). High-sucrose/high-fat diet (D12451, 35% of energy from carbohydrate, 45% of energy from fat) was given to the model group for six weeks to induce insulin resistance, meanwhile normal diet was given to the control group. Afterwards, streptozocin (STZ) buffer solution (35 mg/kg bodyweight) was injected into abdomen of the model group to induce specific pancreatic injury, meanwhile an equal amount of buffer solution was given to the control group. Then 48 h later, type 2 diabetes mellitus (T2DM) was supposed to be successfully induced according to the random blood glucose more than 16.7 mmol/L in the model group. Then the basic features of the T2DM rats were evaluated, including body weight, fasting blood glucose (FBG), glucose tolerance (oral glucose tolerance test, OGTT), and insulin tolerance (intraperitoneal insulin tolerance test, IPITT). Subsequently, withdrawal thermal latency (WTL) was measured regularly to determine when the early DPN occurred. Once confirmed, sciatic nerve conduction velocity (NCV) of all the rats was conducted. RESULTS: The T2DM rats were successfully induced in the model group through high-sucrose/high-fat diet for six weeks along with STZ intraperitoneal injection (35 mg/kg bodyweight). When compared to the control group, the T2DM rats had higher FBG (P<0.001), and the glucose tolerance and insulin tolerance were both damaged (P<0.001 in OGTT, P=0.002 in IPITT). It was on the 17th day when the T2DM rats became much more sensitive to heat stimulus compared to the control group (P=0.004). Meanwhile, the sciatic NCV was conducted. There was no significant difference between the early DPN group and the control group (P=0.196). CONCLUSION: High-sucrose/high-fat diet for six weeks along with STZ intraperitoneal injection (35 mg/kg bodyweight) could successfully induce T2DM rat model, manifested by a certain extent of insulin resistance and deficiency of insulin secretion. It was about 17 days later when the early DPN emerged. In the early DPN, small fiber neuropathy came out earlier than large fiber neuropathy.

[Clinical and imaging features of acute histoplasmosis].

Objective: To investigate the clinical and imaging characteristics of acute histoplasmosis. Methods: The clinical and imaging data of 10 patients with acute histoplasmosis were studied. Their clinical and imaging characteristics were analyzed. All the patients returned from a South American republic in April 2019 and were treated at the Chongqing public health medical treatment center. Results: All the 10 patients were male, aged 30-56 years old, with an average age of 43.8 years old. Four of them were engaged in soil clearing, 2 in gas cutting, 2 in moving tools, and 2 in inspection. The disease in all the 10 patients was caused by inhaling a large amount of bacteria-bearing dust in a short time, with an incubation period of 9-13 days, and the main clinical manifestations were fever, insomnia, dizziness, headache, cough, poor appetite, rash and diarrhea. One patient's head CT showed extensive thickening and increased density of bilateral frontotemporal, parietal and occipital meninges, while the other 9 patients showed no obvious abnormalities. Chest CT findings were as follows: (1) Multiple nodular shadow: the chest CT findings of 4 patients were miliary nodular shadow with diffuse distribution in both lungs. Most of the nodules were less than 5 mm in diameter and distributed evenly or unevenly. CT findings of 6 cases showed scattered nodular shadows in both lungs, with diameters ranging from 2 to 15 mm, and obvious distribution in subpleural and inferior lobes of both lungs. (2) Consolidation shadow: in 2 cases, the size of the shadow was uneven and the density increased, mainly distributed in the subpleura and the lower lobe of both lungs. (3) Ground glass density shadow: mainly distributed around nodules, halo signs can be seen around some nodules. (4) Mediastinum and/or hilar lymph nodes were enlarged. (5) Pleural effusion: a small amount of pleural effusion was found in 4 cases. (6) Pericardial effusion in 3 cases. Abdominal CT showed splenomegaly in 8 cases and hepatomegaly in 1 case. Conclusions: Acute histoplasmosis has no specificity in clinical manifestations. However, there are still some features in CT manifestations, including multiple nodules in both lungs accompanied by halo, enlarged liver, spleen and mediastinal lymph nodes, and multiple serous cavity effusions.

[Prevalence and attribution of high-risk HPV in different histological types of cervical cancer].

Objective: To investigate the prevalence of high-risk HPV subtypes in different pathological types of cervical cancer, and analyze the attribution of carcinogenic HPV subtypes in different pathological types. Methods: A total of 1 541 patients with cervical cancer were treated between February 2009 and October 2016 in Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. The median age at diagnosis was 49 years (ranged 20-82 years old). The numbers of patients with cervical cancer from North China, Northeast China, East China, Central China and other regions (including Northwest, Southwest and South China) were 961, 244, 175, 87 and 74 cases, respectively. Pathological types: 1 337 cases of squamous cell carcinoma (SCC), 87 usual adenocarcinoma (ADC), 23 adenosquamous carcinoma (ASC), 20 mucinous carcinoma (MC), 19 clear cell carcinoma (CCC), 12 endometrioid carcinoma (EC), 25 neuroendocrine carcinoma (NEC), 9 serous carcinoma (SC), 5 villous adenocarcinoma (VADC) and 4 minimal deviation adenocarcinoma (MDAC). The prevalence of high-risk HPV in different regions, age groups at diagnosis and pathological types in cervical cancer were analyzed. The attribution of 13 high-risk HPV subtypes in different pathological types of cervical cancer based on proportional attribution method, and the attribution of high-risk HPV subtypes prevented by 9-valent HPV vaccine in SCC and ADC were calculated. Results: (1) The prevalence of high-risk HPV in 1 541 patients with cervical cancer was 86.6% (1 335/1 541). The multiple high-risk HPV infection rate in patients with SCC ≥60 years old (23.0%, 37/161) was significantly higher than those in patients aged 45-59 years old and ≤44 years old [11.4% (85/747) vs 11.7% (50/429), P<0.01], and the high-risk HPV infection rates of patients with cervical cancer in North China, Northeast China, East China, Central China and other regions were respectively 86.8% (834/961), 87.7% (214/244), 83.4% (146/175), 83.9% (73/87) and 91.9% (68/74). SCC (86.8%, 1 337/1 541) and ADC (5.6%, 87/1 541) were the most common pathological types in cervical cancer. The high-risk HPV prevalence of SCC, ADC, ASC, MC, NEC and VADC were 90.1% (1 205/1 337), 74.7% (65/87), 87.0% (20/23), 65.0% (13/20), 72.0% (18/25) and 5/5 respectively. The high-risk HPV infection rates of SC, EC, CCC and MDAC were 4/9, 3/12, 2/19 and 0/4 respectively. (2) According to proportional attribution, HPV 16 (69.5%), HPV 18 (5.6%), HPV 58 (2.2%), HPV 31 (1.9%), HPV 52 (1.4%) and HPV 33 (1.3%) were the six common high-risk HPV subtypes in SCC. While, HPV 18 (44.1%), HPV 16 (20.5%), HPV 52 (2.3%), HPV 58 (1.2%) and HPV 51 (1.2%) were the main carcinogenic subtypes in ADC. The main carcinogenic high-risk HPV subtypes of ASC, NEC and MC were HPV 18 and HPV 16. The total attribution of HPV 16, 18, 31, 33, 45, 52 and 58 prevented by 9-valent HPV vaccine in SCC and ADC were 82.6% and 68.1% respectively; the attribution of HPV 45 in SCC and ADC were only 0.8% and 0. Conclusions: SCC and ADC are the main pathological types in cervical cancer. SCC, ADC, ASC, MC, NEC and VADC are closely related to high-risk HPV infection. HPV 16 is the main carcinogenic genotypes of SCC. HPV 18 maybe play an important role in the pathogenesis of ADC.

ERAP1/ERAP2 and RUNX3 polymorphisms are not associated with ankylosing spondylitis susceptibility in Chinese Han.

Previous studies show that endoplasmic reticulum-associated aminopeptidase (ERAP1/ERAP2) and runt-related transcription factor 3 (RUNX3) gene polymorphisms are associated with AS (ankylosing spondylitis) in European Caucasians. However, contradictory results were reported in different Asian populations. The purpose of this study was to determine whether eleven candidate single nucleotide polymorphisms (SNPs) in ERAP1/ERAP2 and six in RUNX3 genes confer susceptibility to AS with or without acute anterior uveitis (AAU) [AS+ AAU+ or AS+ AAU- ] in Chinese Han. Therefore, a case-control association study was performed in 882 AS+ AAU- , 884 AS+ AAU+ and 1727 healthy controls. Genotyping was performed using the iPLEXGold genotyping assay. A meta-analysis was performed to assess the association of polymorphisms of ERAP1 with AS susceptibility in Asian populations. No association was found between SNPs of ERAP1/ERAP2/RUNX3 and susceptibility of AS with or without AAU. A case-control study between patients with human leucocyte antigen HLA-B27-positive and healthy controls also failed to demonstrate an association of the tested SNP with AS with or without AAU. Moreover, a meta-analysis showed that there was no association of rs30187, rs27037, rs27980, rs27434 and rs27582 in ERAP1 with AS in Chinese Han. Taken together, 17 SNPs in ERAP1/ERAP2 and RUNX3 genes did not confer disease susceptibility to AS in Chinese Han.

A cardioid oscillator with asymmetric time ratio for establishing CPG models.

Nonlinear oscillators are usually utilized by bionic scientists for establishing central pattern generator models for imitating rhythmic motions by bionic scientists. In the natural word, many rhythmic motions possess asymmetric time ratios, which means that the forward and the backward motions of an oscillating process sustain different times within one period. In order to model rhythmic motions with asymmetric time ratios, nonlinear oscillators with asymmetric forward and backward trajectories within one period should be studied. In this paper, based on the property of the invariant set, a method to design the closed curve in the phase plane of a dynamic system as its limit cycle is proposed. Utilizing the proposed method and considering that a cardioid curve is a kind of asymmetrical closed curves, a cardioid oscillator with asymmetric time ratios is proposed and realized. Through making the derivation of the closed curve in the phase plane of a dynamic system equal to zero, the closed curve is designed as its limit cycle. Utilizing the proposed limit cycle design method and according to the global invariant set theory, a cardioid oscillator applying a cardioid curve as its limit cycle is achieved. On these bases, the numerical simulations are conducted for analyzing the behaviors of the cardioid oscillator. The example utilizing the established cardioid oscillator to simulate rhythmic motions of the hip joint of a human body in the sagittal plane is presented. The results of the numerical simulations indicate that, whatever the initial condition is and without any outside input, the proposed cardioid oscillator possesses the following properties: (1) The proposed cardioid oscillator is able to generate a series of periodic and anti-interference self-exciting trajectories, (2) the generated trajectories possess an asymmetric time ratio, and (3) the time ratio can be regulated by adjusting the oscillator's parameters. Furthermore, the comparison between the simulated trajectories by the established cardioid oscillator and the measured angle trajectories of the hip angle of a human body show that the proposed cardioid oscillator is fit for imitating the rhythmic motions of the hip of a human body with asymmetric time ratios.

PERSEPT 1: a phase 3 trial of activated eptacog beta for on-demand treatment of haemophilia inhibitor-related bleeding.

INTRODUCTION: Haemophilia A or B patients with inhibitors have been treated with FVIIa-containing bypassing agents for over 20 years. However, due to uncertainty regarding dose response and thrombotic risk, the use of a gradual, titrated, minimal dosing strategy remains prevalent, potentially hampering early haemostasis. AIM: Evaluate the dose-dependent efficacy, safety and immunogenicity of activated eptacog beta (rhFVIIa), a new recombinant inhibitor bypassing agent for the treatment of bleeding episodes (BEs). METHODS: A Phase 3, randomized, cross-over study of initial dose regimens (IDRs) in 27 bleeding congenital haemophilia A or B subjects with inhibitors was conducted to evaluate on-demand treatment of mild/moderate BEs. Intravenous 75 µg/kg or 225 µg/kg initial doses with 75 µg/kg subsequent doses by schedule were administered until clinical response. RESULTS: The primary endpoint was sustained clinical response within 12 hours, determined by a composite of objective and pain measures. In the 75 µg/kg IDR, 84.9% (95% CI; 74.0%, 95.7%) of mild/moderate BEs at 12 hours were successfully treated compared to 93.2% (95% CI; 88.1%, 98.3%) treated in the 225 µg/kg IDR. Efficacy between the IDRs was statistically different (P<.020) in mild/moderate bleeding episodes. Both IDRs were well tolerated with no detectable immunogenic or thrombotic responses to rhFVIIa or host cell proteins. CONCLUSION: The dose-dependent efficacy seen in this study supports individualizing the initial dose of eptacog beta to optimize clinical response. By reducing uncertainty, the PERSEPT 1 results should increase the adoption of early haemostasis as a treatment goal for clinicians who treat haemorrhage in the inhibitor population.

Sex differences in the impact of nonalcoholic fatty liver disease on cardiovascular risk factors.

BACKGROUND AND AIMS: Information on sex differences in the association of nonalcoholic fatty liver disease (NAFLD) with cardiovascular disease (CVD) risk factors is scarce. We examined whether men exhibit greater differences in established CVD risk factors between NAFLD and non-NAFLD than women. METHODS AND RESULTS: We conducted a cross-sectional analysis using a cohort of 10761 apparently healthy Chinese adults who underwent comprehensive health checkups including abdominal ultrasonography. In the setting of NAFLD and non-NAFLD, although men had significantly higher levels of atherogenic lipids as indicated by higher levels of triglyceride, triglyceride/HDL-cholesterol, and lower levels of HDL-cholesterol and worsen renal function as indicated by higher levels of creatinine and lower levels of estimated glomerular filtration rate (eGFR) than female counterparts, men with NAFLD showed greater relative differences in atherogenic lipids and deteriorated renal function than women with NAFLD when compared with their non-NAFLD counterparts. The interactions between sex and NAFLD on triglyceride, HDL-cholesterol, triglyceride/HDL-cholesterol, creatinine, and eGFR were statistically significant (P < 0.05). In the multivariate Logistic regression analyses, we observed a stronger association of TG with NAFLD and comparable associations of eGFR or HDL-C with NAFLD in men compared with women. CONCLUSION: There was greater adverse influence of NAFLD per se on triglyceride, and triglyceride/HDL-cholesterol in men compared with women. The greater adverse influence of NAFLD per se on HDL-C and eGFR in men compared with women probably related to the gender differences in TG levels.

[The clinicopathological features and risk factors of recurrence in patients with mucinous borderline ovarian tumors].

Objective: To investigate the clinicopathological features and risk factors in patients with mucinous borderline ovarian tumors (MBOT). Methods: From 1999 to 2006, 66 MBOT patients in our hospital with more than ten-year follow-up were enrolled retrospectively. They were re-classified according to the literature. The clinicopathological features of different subgroups, including age, preoperative serum tumor markers, surgical methods, pathological features, surgical pathology staging, as well as the risk factors of recurrence and survival were analyzed. Results: Median age was 39 years in 66 patients. Before the surgery, 33.3% (20/60) patients had elevated CA125 and 51.7% (30/58) had elevated CA199. The accurate rate for fast frozen pathology of resected specimen was 73.4%. 21 patients underwent conservative surgery and 45 patients underwent extensive surgery. 57 patients underwent comprehensive operation and 43 cases (75.4%) resulted in stage Ⅰ. 48 of the 66 patients (72.7%) had intestinal-type tumors (IMBT) and 18 patients (27.3%) had endocervical-like tumors (EMBT). The median follow-up was 150 months. Eight recurrences (12.1%) were identified. The mean time between surgery to the initial recurrence was 26.4 months (13 to 50 months). Recurrence rate of IMBT was higher than that of EMBT (14.6% versus 5.6%) with no significance (P>0.05). All patients with pseudomyxoma had disease recurrence. Recurrence rate of stage Ⅲ patients was significantly higher than that of stage Ⅰ patients (33.3% versus 9.3%, P<0.05). During the follow-up period, tumor-related death occurred in 2 cases with a 10-year survival rate of 95.4%. Kaplan-Meier method and Log Rank analysis showed that clinical staging and peritonealmyxoma were adverse prognostic factors (P<0.05). Although the recurrence rate of patients undergoing conservative surgery was higher than that of patients with extensive surgery (23.8% versus 6.7%, P=0.047), the overall survival was almost the same between these two groups (P>0.05). Conclusions: MBOT patients have relatively good prognosis. IMBT are more common than EMBT subtypes, but recurrence rate and patient survival were almost the same between these two groups. Patients with pseudomyxoma was more likely to have disease recurrence. Patients who underwent conservative surgery resulted in higher recurrence rate but did not affect the overall survival of patient. Pseudomyxoma and clinical staging were adverse prognostic factors in MBOT patients.