The safety signal detection and analysis of monoclonal antibodies against SARS-CoV-2 based on real-world evidence - the suitable selectivity for different populations.

OBJECTIVE: Bebtelovimab (BEB), Tixagevimab/Cilgavimab (TIX/CIL), and Sotrovimab (SOT) are important agents against the severe acute respiratory syndrome coronavirus 2-Omicron strain. However, due to their short duration of application, little is known about their safety profiles. This research aimed to explore the safety profile of these monoclonal antibodies (mAbs) via real-world evidence databases and data mining tools. MATERIALS AND METHODS: Safety reports were retrieved from the database of the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System from April 2022 to March 2023. To detect the safety signal, the disproportionality analysis was performed using the reporting odds ratio method. RESULTS: SOT had the greatest proportion of "skin and subcutaneous tissue disorders" and "disorders of investigations"; BEB showed significant associations with "gastrointestinal disorders" and "nervous system disorders"; TIX/CIL had the weakest correlation with "skin and subcutaneous tissue disorders" and "general disorders and administration site conditions". Furthermore, there were still other signals related to nervous system disorders, gastrointestinal disorders only caused by BEB. TIX/CIL has been reported solely to be associated with multiple types of cardiovascular disorders. As for SOT alone, signals were strongly related to infusion reactions and hypersensitivity. CONCLUSIONS: In summary, SOT may be unsuitable for allergic patients and may lead to abnormal test results. BEB showed the highest correlations with gastrointestinal and neuropsychiatric events. In addition, its infusion reactions should also be noted. TIX/CIL can lead to a variety of cardiovascular events.

[Clinical features of primary sclerosing cholangitis and inflammatory bowel disease].

Objective: To explore disease characteristics of primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) and compare the differences between PSC with and without IBD. Methods: Study design was cross sectional. Forty-two patients with PSC who were admitted from January 2000 to January 2021 were included. We analyzed their demographic characteristics, clinical manifestations, concomitant diseases, auxiliary examination, and treatment. Results: The 42 patients were 11-74(43±18) years of age at diagnosis. The concordance rate of PSC with IBD was 33.3%, and the age at PSC with IBD diagnosis was 12-63(42±17) years. PSC patients with IBD had higher incidences of diarrhea and lower incidences of jaundice and fatigue than in those without IBD (all P<0.05). Alanine aminotransferase, total bilirubin, direct bilirubin, total bile acid and carbohydrate antigen 19-9 levels were higher in PSC patients without IBD than in those with IBD (all P<0.05). The positive rates for antinuclear antibodies and fecal occult blood were higher in PSC patients with IBD than in those without IBD (all P<0.05). Patients with PSC complicated with ulcerative colitis mainly experienced extensive colonic involvement. The proportion of 5-aminosalicylic acid and glucocorticoid application in PSC patients with IBD was significantly increased compared with that of PSC patients without IBD (P=0.025). Conclusions: The concordance rate of PSC with IBD is lower at Peking Union Medical College Hospital than in Western countries. Colonoscopy screening may benefit PSC patients with diarrhea or fecal occult blood-positive for early detection and diagnosis of IBD.

[Value of the monocyte-to-lymphocyte ratio in the prognostic evaluation of hepatitis B-related acute-on-chronic liver failure].

Objective: To investigate the predictive value of the monocyte-to-lymphocyte ratio (MLR) for survival in patients with hepatitis B-related acute-on-chronic liver failure (HBV-ACLF). Methods: 92 cases with HBV-ACLF who were admitted to the General Hospital of Western Theater Command from October 2014 to October 2017 were selected. Clinical indicators were retrospectively collected, and their survival condition was followed up for 90 days, with the end point as death or liver transplantation. MLR levels predictive value among patients after 90 days of involvement was compared by analyzing the differences between the survival and death groups and its correlation with various indicators of liver function for prognosis. Results: 92 cases were included in this study, with a 90-day survival rate of 52% (48/92), and a mortality rate of 48% (44/92). MLR for survival and death groups were 0.520 (0.310, 0.828) and 0.740 (0.440, 1.120), respectively. MLR level was significantly higher in the death than survival group (P<0.05). Receiver operating characteristic curve (ROC) analysis showed that the area under the ROC curve (AUC) and 95% confidence interval for the survival group was 0.640 (0.527-0.754). The cutoff value for MLR was 0.399 at which the sensitivity and specificity were 0.864 and 0.396, respectively. Survival analysis showed that the 90-day survival rate was significantly lower in the high MLR group than corresponding low MLR group (P=0.011). Logistic multivariate regression analysis showed that after adjusting for other factors, MLR level was an independent prognostic factor in patients with HBV-ACLF. Conclusions: MLR can be used as a potential prognostic indicator for patients with HBV-ACLF, and its clinical value needs to be verified by large-scale prospective randomized trials.

[Status of HVPG clinical application in China in 2021].

Objective: The investigation and research on the application status of Hepatic Venous Pressure Gradient (HVPG) is very important to understand the real situation and future development of this technology in China. Methods: This study comprehensively investigated the basic situation of HVPG technology in China, including hospital distribution, hospital level, annual number of cases, catheters used, average cost, indications and existing problems. Results: According to the survey, there were 70 hospitals in China carrying out HVPG technology in 2021, distributed in 28 provinces (autonomous regions and municipalities directly under the central Government). A total of 4 398 cases of HVPG were performed in all the surveyed hospitals in 2021, of which 2 291 cases (52.1%) were tested by HVPG alone. The average cost of HVPG detection was (5 617.2±2 079.4) yuan. 96.3% of the teams completed HVPG detection with balloon method, and most of the teams used thrombectomy balloon catheter (80.3%). Conclusion: Through this investigation, the status of domestic clinical application of HVPG has been clarified, and it has been confirmed that many domestic medical institutions have mastered this technology, but it still needs to continue to promote and popularize HVPG technology in the future.

[The 494th case: acute pancreatitis, acute acalculous cholecystitis and anaphylaxis].

A young male patient with abdominal pain and fever was diagnosed as acute hyper-triglyceridemicpancreatitis is clear. During the recovery of pancreatitis, the patient developed acute acalculous cholecystitis, as well as carbapenem-resistant Enterobacter infection and Cytomegaloviremia, and had anaphylaxis for several times after the use of antibiotics, which cannot be completely explained by drug allergy. This paper analyzes the possible causes of multiple diseases in the same patient in detail.

[Clinicopathological characteristics of rectal neuroendocrine neoplasms].

Objective: Clinicopathological characteristics of neuroendocrine neoplasms are highly heterogeneous based on variable origins.Our study aims to explore the clinical features of rectal neuroendocrine neoplasm (RNEN). Methods: Patients with histologically diagnosed rectal neuroendocrine neoplasms were retrospectively analyzed between January 2012 and December 2020. Epidemiological characteristics, clinical manifestations, complete blood count, endoscopy findings, and pathological features were recorded and analyzed. T-test was used for measurement data analysis, Chi-square test was performed for classification data analysis, and Binary logistic regression was applied for analyzing risk factors of metastasis. Results: Among 172 patients, the male to female ratio was 107 to 65 with an average age of (52±12) years (16-77 years). Altered bowel habit was the most common initial symptom (58/172, 33.7%), followed by abdominal pain (36/172, 20.9%) and loss of body weight (27/172, 15.7%). One hundred and sixty-one cases were neuroendocrine tumors, 9 were neuroendocrine carcinomas and 2 were mixed neuroendocrine-non-neuroendocrine neoplasms. Most endoscopic presentations were polypoid lesions (147/172, 85.5%), mainly limited to mucosa (48/172, 27.9%) and submucosa (96/172, 55.8%). Twenty-nine patients developed lymph node invasion or distant metastasis at diagnosis. There were statistical difference of neutrophil-to-lymphocyte ratios (NLR) among groups with different tumor size (<10 mm vs. 10-20 mm vs.>20 mm, mean NLR 1.79±0.55 vs. 2.27±1.23 vs. 2.95±0.66, P<0.01. Compared with non-metastatic group, the metastatic group presented higher NLR(2.61±0.81 vs. 1.89±0.80, P<0.01). Tumor size (<10 mm vs. 10-20 mm vs.>20 mm, OR 1.00 vs. 2.10 vs. 5.25×109, P =0.001), invasion to bowel wall (mucosa vs. submucosa vs. muscularis vs. serosa invasion,OR 1.00 vs. 3.26 vs. 14.11 vs. 39.42, P=0.008), and NLR (NLR<2.25 vs. NLR≥2.25, OR 1.00 vs. 5.19, P =0.024) were risk factors for metastasis. Conclusion: Metastasis of RNEN is related with tumor size, degree of bowel invasion and NLR. High NLR is a poor prognostic factor of RNEN.

[The Chinese guidelines for the diagnosis and treatment of pancreatic neuroendocrine neoplasms (2020)].

Pancreatic neuroendocrine neoplasms (pNENs) are highly heterogeneous, and the management of pNENs patients can be intractable. To address this challenge, an expert committee was established on behalf of the Group of Pancreatic Surgery, Chinese Society of Surgery, Chinese Medical Association, which consisted of surgical oncologists, gastroenterologists, medical oncologists, endocrinologists, radiologists, pathologists, and nuclear medicine specialists. By reviewing the important issues regarding the diagnosis and treatment of pNENs, the committee concluded evidence-based statements and recommendations in this article, in order to further improve the management of pNENs patients in China.

[The incidence risk of elevated fasting blood glucose in people with fatty liver disease: a cohort study of 40 000 people over the past 10 years].

Objective: To analyze the time point when patients with fatty liver disease had a significantly higher risk of elevated fasting blood glucose than those without in the physical examination group in Karamay Central Hospital, factors affecting the incidence of elevated blood glucose in patients with fatty liver disease, and the influence of the number of influencing factors on it. Methods: Physical examination data from Karamay Central Hospital during September 2008 to April 2017 were retrospectively analyzed. Combined with the survival analysis, the 1-,3-, 5-, and 7-year prevalence rates of elevated fasting glucose occurs in people with and without fatty liver disease were analyzed. Z-test was used to compare the survival rate difference at each time point. Cox regression model was used for multivariate analysis. Results: 10 802 people were in the fatty liver group. The elevated fasting blood glucose incidence density was 61/1 000 person-years, and the 1-, 3-, 5-, and 7-year prevalence rates were 2%, 16%, 28%, and 38%, respectively. 29 579 people were in the non-fatty liver group. The elevated fasting blood glucose incidence density was 23/1000 person-years, and the 1-, 3-, 5-, and 7-year prevalence rates were 1%, 7%, 11%, and 16%, respectively. The short-term and long-term elevated fasting blood glucose incidence risk were significantly higher in fatty liver group than non-fatty liver group(P < 0.001). The elevated fasting blood glucose incidence risk was apparently higher in fatty liver group than that of non-fatty liver group from the first year onward (P < 0.001). Age≥50 year's old (HR = 1.954, 95% CI :1.792-2.132), elevated body mass index (HR = 1.397, 95% CI : 1.198-1.629), blood pressure (HR = 1.284, 95% CI : 1.181-1.397), triglycerides (HR = 1.171, 95% CI: 1.077-1.274) were independent risk factors, which promoted the elevated fasting blood glucose incidence risk in patients with fatty liver disease. Fatty liver combined with the above 2, 3, and 4 risk factors had apparently increased the incidence risk of elevated fasting blood glucose (P < 0.001). Conclusion: People with fatty liver disease had a higher risk of elevated fasting blood glucose from the first year than those without. Age≥50 year's old, elevated blood pressure, body mass index and triglyceride might increase risk of elevated fasting blood glucose in patients with fatty liver disease, combined with the above 2,3 or 4 risk factors can increase the risk of elevated fasting blood glucose.

[The variation of serum uric acid levels among patients with myocardial infarction treated with ticagrelor and the association between serum uric acid and platelet reactivity].

Objectives: To compare the impact of ticagrelor or clopidogrel on serum uric acid levels among patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI) and further evaluate the effects of variation of serum uric acid levels on platelet reactivity. Methods: STEMI patients who admitted to Fuwai Hospital from April 2017 to January 2020, and underwent primary PCI and discharged alive with aspirin and ticagrelor or clopidogrel were included in this study. Patients were divided into ticagrelor group and clopidogrel group. The baseline clinical data were collected. Serum uric acid and creatinine levels at baseline and 30 days post-PCI were measured. Light transmittance aggregometry was used to assess maximum aggregation rate induced by adenosine diphosphate and arachidonic acid. The changes of serum uric acid and creatinine were compared between the two groups. Multivariate logistic regression was performed to evaluate independent related factors for rise in the uric acid levels, and the effect of variation of serum uric acid level on platelet reactivity was analyzed. Results: A total of 967 patients were included, the age was (59.4±12.1) years, and 163 case were female. There were 550 cases in ticagrelor group (56.9%) and 417 cases in clopidogrel group (43.1%). Baseline serum uric acid and creatinine levels were similar between the 2 groups. At 30 days, the serum uric acid level [(347.2±96.5) mmol/L vs. (341.2±105.3) mmol/L, P=0.009] and absolute [46.4 (-2.4, 88.1) mmol/L vs. 25.0 (-21.9, 73.0) mmol/L, P=0.001] and percentage [13.2 (-0.01, 29.0) % vs. 7.9 (-5.7, 25.0) %, P=0.007] increase in the serum uric acid levels were significantly higher in ticagrelor group than in clopidogrel group. The level of serum creatinine at 30 days was significantly lower in ticagrelor group than in clopidogrel group [(89.7±21.3) µmol/L vs. (94.4±43.9) µmol/L, P<0.05], whereas there were no differences in absolute [8.0 (-1.4, 16.6) µmol/L vs. 7.8 (-2.0, 16.6) µmol/L] and percentage [10.5 (-1.7%, 22.6%) vs. 9.8 (-2.4%, 22.1%)] change in the serum creatinine between the 2 groups (all P>0.05). Logistic regression analysis showed that, after adjusting for confounding factors, ticagrelor therapy was an independent related factor of serum uric acid elevation (OR=1.582, 95% CI:1.023-2.447, P=0.039). The variation of the serum uric acid levels did not affect platelet aggregation and the percentage of high platelet reactivity in both groups. Conclusions: Ticagrelor use is related to a significant increase in the serum uric acid levels at 30 days post-PCI in this patient cohort. The variations in the uric acid levels do not increase the percentage of high platelet reactivity in STEMI patients treated with ticagrelor or clopidogrel.

Correlations of endothelin-1 gene polymorphisms and hypertensive intracerebral hemorrhage.

OBJECTIVE: The aim of this study was to investigate the correlations of endothelin-1 (ET-1) gene polymorphisms with the occurrence of hypertensive intracerebral hemorrhage (HICH). PATIENTS AND METHODS: In this case-control study, 100 HICH patients and 100 controls with matched race, age and gender were enrolled as research subjects. Single nucleotide polymorphisms (rs1920453, rs1022436 and rs1035627) in the promoter region of ET-1 gene were typed via conformational difference gel electrophoresis. Whether the distribution frequency of ET-1 genotypes conformed to Hardy-Weinberg equilibrium was evaluated by chi-square test. The correlations of different gene polymorphisms and alleles in the promoter region of ET-1 gene with the occurrence of HICH were analyzed. Furthermore, the associations of rs1920453 polymorphism in the promoter region of ET-1 gene with neurological deficit scores and laboratory parameters of HICH patients were explored. RESULTS: It was found that ET-1 gene polymorphisms (rs1920453, rs1022436 and rs1035627) conformed to Hardy-Weinberg equilibrium (p>0.05). Gene-based association analysis indicated that only rs1920453 polymorphism and alleles were correlated with the occurrence of HICH (p<0.05). However, rs1022436 and rs1035627 polymorphisms and alleles had no association with HICH (p>0.05). Additionally, NIHSS score and high-density lipoprotein cholesterol level were prominently higher in HICH patients with CG and GG genotypes of ET-1 gene polymorphism rs1920453 than those in patients with CC genotype (p<0.05). CONCLUSIONS: Rs1920453 in the promoter region of ET-1 gene is correlated with the occurrence of HICH.

[Associations between postprocedural D-dimer, hs-CRP, LDL-C levels and prognosis of acute myocardial infarction patients treated by percutaneous coronary intervention].

Objective: To investigate the association between postprocedural D-dimer, high sensitivity C-reactive protein(hs-CRP) and low-density lipoprotein-cholesterol(LDL-C) and outcomes of acute myocardial infarction (AMI) patients treated by percutaneous coronary intervention(PCI), in order to clarify the impacts of thrombotic, inflammatory and cholesterol risks on long-term prognosis. Methods: Patients with AMI who underwent emergency PCI from January 2010 to June 2017 in Fuwai Hospital with complete baseline data were enrolled. Patients were stratified into four groups according to quartiles of D-dimer, hs-CRP and LCL-C. Cox regression was used to analyze the relationship between these biomarkers and prognosis. Restricted cubic spline (RCS) was used to characterize the continuous association between risk of all-cause death and biomarkers. The primary outcome was all-cause death. Results: A total of 3 614 patients were included in the analysis. The age was (59.2±12.0) years old, and 2 845 (78.7%) were male and 3 161 (87.5%) patients were diagnosed as ST-segment elevation myocardial infarction. The follow-up time was 652 (414, 1 880) days. Survival analysis showed that postprocedural D-dimer and hs-CRP were significantly associated with all-cause mortality (all P<0.05). Cox regression with multiple adjustments showed that patients with D-dimer≥580 µg/L presented higher risk of all-cause death (HR=2.03, 95%CI 1.22-3.38, P=0.006), compared to patients with D-dimer<220 µg/L. RCS analysis showed that risk of all-cause death was stably high when D-dimer reached 500 µg/L. Multivariable Cox regression also showed that patients with hs-CRP<2.74 mg/L (HR=1.86, 95%CI 1.10-3.15, P=0.020)or hs-CRP≥11.99 mg/L (HR=2.14, 95%CI 1.35-3.40, P=0.001) presented higher mortality compared to patients whose hs-CRP was 2.74-7.18 mg/L. RCS analysis indicated a J-shaped relation between hs-CRP and mortality, as greater risk of death was observed when hs-CRP was lower than 2 mg/L or higher than 10 mg/L. LDL-C was not associated with outcomes (all P>0.05). Conclusions: Postprocedural D-dimer is significantly associated with long-term prognosis of AMI patients treated by PCI. Patients with extremely high or low levels of hs-CRP presents worse outcomes. Intensive and tailored antithrombotic or anti-inflammatory therapies should be considered for patients with increased thrombotic risk and those with extremely high or low inflammatory risk.

Quantification of late gadolinium enhancement cardiovascular MRI in patients with coronary artery chronic total occlusion.

AIM: To determine the most accurate and reproducible semi-automated greyscale thresholding technique for quantifying late gadolinium enhancement (LGE) in cardiovascular magnetic resonance imaging (CMRI), by using positron-emission tomography (PET) as the reference standard in patients with coronary artery chronic total occlusion (CTO). MATERIALS AND METHODS: LGE in CMRI, single-photon-emission computed tomography (SPECT), and PET were performed within 1 week in each of 63 patients with known CTO. The presence and quantity of LGE were determined with greyscale thresholds of 2, 4, 5, 6, and 8 standard deviations (SDs) above the mean signal intensity for normal remote myocardium and full width at half maximum (FWHM). The infarcted myocardium was delineated by PET. RESULTS: Sixty-three patients and 1,008 segments were analysed. Based on patient analysis, with PET as the reference standard, the 5 SD method yielded the strongest correlation (r=0.85, p<0.0001) compared with the 2 SDs (r=0.42), 4 SDs (r=0.73), 6 SDs (r=0.81), 8 SDs (r=0.71), and FWHM (r=0.69; p<0.001 for all comparisons). The 5 SDs threshold quantification showed high interobserver and intra-observer agreement (intraclass correlation coefficient [ICC]=0.90, p<0.0001; ICC=0.93, p<0.0001, respectively). CONCLUSIONS: Semi-automated LGE CMRI greyscale thresholding with 5 SDs above the mean signal intensity for normal remote myocardium yields the strongest correlation to the extent of LGE identified using PET and is highly reproducible in patients with CTO.

Lnc-RNA BLACAT1 regulates differentiation of bone marrow stromal stem cells by targeting miR-142-5p in osteoarthritis.

OBJECTIVE: Osteogenic differentiation of bone marrow stromal stem cells (BMSCs) is beneficial to the treatment of osteoarthritis (OA). Lnc-RNA BLACAT1 involves in occurrence and development of various diseases. However, the role of Lnc-RNA BLACAT1 in BMSCs differentiation under inflammation remains unclear. MATERIALS AND METHODS: Rat BMSCs were isolated and randomly divided into control group and inflammation group (addition of IL-6). The inflammation group was further divided into BLACAT1 siRNA group and BLACAT1 siRNA+miR-142-5p inhibitor group, followed by analysis of Lnc-RNA BLACAT1 expression by real time PCR, BMSCs proliferation, Caspase 3 activity, ALP activity, expression of Runx2, OC and PPARγ2 by real time PCR, and secretion of TNF-α and IL-1ß by enzyme-linked immunosorbent assay (ELISA). The bioinformatics software and the Luciferase reporter system analyze the targeted relationship between BLACAT1 and miR-142-5p. RESULTS: In inflammation group, Lnc-BLACAT1 expression was increased, along with inhibited BMSCs proliferation, increased Caspase 3 activity, decreased ALP activity, and expression of Runx2 and OC, increased PPARγ2 expression and secretion of TNF-α and IL-1ß. The difference was statistically significant compared with control group (p<0.05). MiR-142-5p is the target miRNA of Lnc-RNA BLACAT1. BLACAT1 siRNA down-regulated BLACAT1 expression, promoted cell proliferation, inhibited Caspase 3 activity, increased ALP activity and Runx2 and OC expression, decreased PPARγ2 expression and TNF-α and IL-1ß secretion. Compared with inflammation group, the difference was statistically significant (p<0.05). Of note, BLACAT1 siRNA+miR-142-5p inhibitor group reversed the effect of siRNA-mediated knockdown of BLACAT1. CONCLUSIONS: Lnc-RNA BLACAT1 expression was increased in inflammatory BMSCs, and knockdown of BLACAT1 promoted proliferation and osteogenic differentiation of BMSCs targeting miR-142-5p.