Thromboembolic events in Janus kinase inhibitors: A pharmacovigilance study from 2012 to 2021 based on the Food and Drug Administration's Adverse Event Reporting System.

AIMS: As a new type of drug developed rapidly in recent years, Janus kinase inhibitors (JAKinibs) have caused controversy due to possible adverse reactions of thromboembolism. The aim of this study was to analyse and evaluate the association between thromboembolic events and the use of JAKinibs, on the base of the latest data in the Food and Drug Administration's Adverse Event Reporting System. METHODS: A disproportionality analysis was conducted, utilizing data from 1 January 2012 to 30 September 2021 in the FAERS. For each drug-adverse event pair, reporting odds ratio (ROR) and information components (IC) were calculated. RESULTS: A total of 15 positive safety signals were detected within the FAERS: ruxolitinib was significantly associated with portal vein thrombosis (ROR025 = 3.49, IC025 = 1.50); tofacitinib immediate release with pulmonary embolism (ROR025 = 2.09, IC025 = 1.02) and thrombosis (ROR025 = 1.15, IC025 = 0.18); tofacitinib extended release with pulmonary embolism (ROR025 = 1.27, IC025 = 0.26) and thrombosis (ROR025 = 1.29, IC025 = 0.33); baricitinib with deep vein thrombosis (ROR025 = 8.27, IC025 = 3.00), portal vein thrombosis (ROR025 = 1.97, IC025 = 0.63), pulmonary embolism (ROR025 = 7.90, IC025 = 2.94), thrombosis (ROR025 = 2.04, IC025 = 0.93) and venous thrombosis (ROR025 = 2.15, IC025 = 0.81); upadacitinib with pulmonary embolism (ROR025 = 1.25, IC025 = 0.25), pulmonary thrombosis (ROR025 = 5.32, IC025 = 2.33) and thrombosis (ROR025 = 2.72, IC025 = 1.39); and filgotinib with pulmonary embolism (ROR025 = 4.83, IC025 = 2.10). In the analysis of the time to onset of thromboembolic events, no obviously recognizable pattern was found. Several safety signals with embolic and thrombotic events (Standardised MedDRA Query) were found in the study. CONCLUSION: This pharmacovigilance study covered 8 types of JAKinib that are already on the market, and provided new safety signals based on past safety information. Some of these signals still need more medical evidence.

Advancing necrotizing enterocolitis prediction through iterative monitoring.

Background: Necrotizing enterocolitis (NEC) is a severe inflammatory intestinal disease in preterm infants, marked by heightened morbidity and mortality. Timely prediction of NEC is significant in the management of critical neonates. However, it is difficult to predict NEC accurately because of the multi-factorial pathogenesis. This study aimed to develop a prediction model through repeated measurement data to further improve the accuracy of prediction in NEC. Methods: We retrospectively collected clinical data of premature infants admitted to the Neonatology Department of the First Affiliated Hospital of Anhui Medical University from January 2016 to December 2023. The infants were categorized into the NEC group (Bell's stage ≥ II) (n=150) and the non-NEC group (n=150). The clinical baseline data of the NEC and non-NEC groups were matched. Laboratory examination indicators were collected on the 1st day, the 7th day after birth, and the day of NEC onset. Univariate and multivariate logistic regression analyses were conducted to identify independent factors influencing NEC. A nomogram was constructed based on these factors to predict NEC. The concordance index and calibration plot were used to assess the efficiency of the nomogram in the training and validation cohorts. Results: This study demonstrated that antenatal steroids, antenatal antibiotics, probiotics treatment before NEC, anion gap (AG, day 7), and mean corpuscular volume (MCV, day 7) were independent risk factors which combined to accurately predict NEC. A nomogram of NEC was created utilizing these five predictors. With an area under the receiver operator characteristic (ROC) curve of 0.835 [95% confidence interval (CI): 0.785-0.884]. Concordance index for the training and validation groups were 0.835 and 0.848, respectively. As the calibration plots indicate, the predicted probability of NEC is highly consistent with the actual observation. Conclusions: The risk estimation nomogram for NEC offers clinical value by guiding early prediction, targeted prevention, and early intervention strategies for NEC.

Dietary Carbohydrates, Genetic Susceptibility, and Gout Risk: A Prospective Cohort Study in the UK.

This study aimed to investigate the associations between carbohydrate intake and gout risk, along with interactions between genetic susceptibility and carbohydrates, and the mediating roles of biomarkers. We included 187,387 participants who were free of gout at baseline and completed at least one dietary assessment in the UK Biobank. Cox proportional hazard models were used to estimate the associations between carbohydrate intake and gout risk. Over a median follow-up of 11.69 years, 2548 incident cases of gout were recorded. Total carbohydrate intake was associated with a reduced gout risk (Q4 vs. Q1: HR 0.67, 95% CI 0.60-0.74), as were total sugars (0.89, 0.80-0.99), non-free sugars (0.70, 0.63-0.78), total starch (0.70, 0.63-0.78), refined grain starch (0.85, 0.76-0.95), wholegrain starch (0.73, 0.65-0.82), and fiber (0.72, 0.64-0.80), whereas free sugars (1.15, 1.04-1.28) were associated with an increased risk. Significant additive interactions were found between total carbohydrates and genetic risk, as well as between total starch and genetic risk. Serum urate was identified as a significant mediator in all associations between carbohydrate intake (total, different types, and sources) and gout risk. In conclusion, total carbohydrate and different types and sources of carbohydrate (excluding free sugars) intake were associated with a reduced risk of gout.

Association between combined exposure to ambient air pollutants, genetic risk, and incident gout risk: A prospective cohort study in the UK Biobank.

BACKGROUND: Limited research has been conducted on the association between long-term exposure to air pollutants and the incidence of gout. OBJECTIVES: This study aims to assess the individual and combined effects of prolonged exposure to five air pollutants (NO2, NOx, PM10, PMcoarse and PM2.52) on the incidence of gout among 458,884 initially gout-free participants enrolled in the UK Biobank. METHODS: Employing a land use regression model, we utilized an estimation method to ascertain the annual concentrations of the five air pollutants. Subsequently, we devised a weighted air pollution score to facilitate a comprehensive evaluation of exposure. The Cox proportional hazards model was utilized to investigate the association between ambient air pollution and gout risk. Interaction and stratification analyses were conducted to evaluate age, sex, BMI, and genetic predisposition as potential effect modifiers in the air pollution-gout relationship. Furthermore, mediation analyses were conducted to explore the potential involvement of biomarkers in mediating the association between air pollution and gout. RESULTS: Over a median follow-up time of 12.0 years, 7,927 cases of gout were diagnosed. Significant associations were observed between the risk of gout and a per IQR increase in NO2 (HR3: 1.05, 95 % CI4: 1.02-1.08, p = 0.003), NOx (HR: 1.04, 95 % CI: 1.01-1.06, p = 0.003), and PM2.5 (HR: 1.03, 95 % CI: 1.00-1.06, p = 0.030). Per IQR increase in the air pollution score was associated with an elevated risk of gout (p = 0.005). Stratified analysis revealed a significant correlation between the air pollution score and gout risk in participants ≥60 years (HR: 1.05, 95 % CI: 1.02-1.09, p = 0.005), but not in those <60 years (p = 0.793), indicating a significant interaction effect with age (p-interaction=0.009). Mediation analyses identified five serum biomarkers (SUA:15.87 %, VITD: 5.04 %, LDLD: 3.34 %, GGT: 1.90 %, AST: 1.56 %5) with potential mediation effects on this association. CONCLUSIONS: Long-term exposure to air pollutants, particularly among the elderly population, is associated with an increased risk of gout. The underlying mechanisms of these associations may involve the participation of five serum biomarkers.

Neonatal sequential organ failure assessment score within 72†h after delivery reliably predicts bronchopulmonary dysplasia in very preterm infants.

Background: The neonatal sequential organ failure assessment (nSOFA) score is an operational definition of organ dysfunction employed to predict sepsis-associated mortality. However, the relationship between the nSOFA score and bronchopulmonary dysplasia (BPD) has not been investigated clearly. This study evaluates whether the nSOFA score within 72 h after delivery could be used to predict the occurrence of BPD in very preterm infants. Methods: In this retrospective, single-center cohort study, preterm infants born between 2019 and 2021 were investigated, the nSOFA score was calculated from medical records after admission to the neonatal intensive care unit (NICU) within 72 h after delivery, and the peak value was used for calculation. A logistic regression model was used to evaluate the relationship between the nSOFA score and BPD. Propensity score matching and subgroup analysis were performed to verify the reliability of the results. Results: Of 238 infants meeting the inclusion criteria, 93 infants (39.1%) were diagnosed with BPD. The receiver operating characteristic curve of the nSOFA score in predicting BPD was 0.790 [95% confidence interval (CI): 0.731-0.849]. The logistic regression model showed that an increment of one in the nSOFA score was related to a 2.09-fold increase in the odds of BPD (95% CI: 1.57-2.76) and 6.36-fold increase when the nSOFA score was higher than 1.5 (95% CI: 2.73-14.79). Conclusions: The nSOFA score within 72 h after delivery is independently related to BPD and can be used to identify high-risk infants and implement early interventions.

Morbid obesity impacts mortality among inpatients with type a aortic dissection: an analysis of the national inpatient sample.

BACKGROUND: Stanford type A aortic dissection (T(A)AD) is one of the most dangerous cardiovascular diseases and morbid obesity is associated with the prognosis of many cardiovascular diseases. The aim of this study is to investigate the impact of morbid obesity on in-hospital mortality, total hospital costs and discover the prevalence of morbid obesity among inpatients with T(A)AD. METHODS: Patients with a primary diagnosis of T(A)AD were identified from the National Inpatient Sample database (NIS) from 2008 to 2017. These patients were categorized into non-obesity, obesity and morbid obesity. Multivariable regression models were utilized to assess the association between obesity/morbid obesity and in-hospital mortality, total cost and other clinical factors. The temporal trend in prevalence of obesity/morbid obesity in T(A)ADs and the trend of in-hospital mortality among different weight categories were also explored. RESULTS: From the NIS database 8489 T(A)AD inpatients were identified, of which 7230 (85.2%) patients were non-obese, 822 (9.7%) were obese and 437 (5.1%) were morbid obese. Morbid obesity was associated with increased risk of in-hospital mortality (odds ratio [OR] 1.39; 95% confidence interval [CI] 1.03-1.86), 8% higher total cost compared with the non-obese patients. From 2008 to 2017, the rate of obesity and morbid obesity in patients with T(A)AD have significantly increased from 7.36 to 11.33% (P < 0.001) and from 1.95 to 7.37% (P < 0.001). Factors associated with morbid obesity in T(A)ADs included age, female, elective admission, hospital region, dyslipidemia, smoking, rheumatoid arthritis/collagen vascular diseases, chronic pulmonary disease, diabetes and hypertension. CONCLUSIONS: Morbid obesity are connected with worse clinical outcomes and more health resource utilization in T(A)AD patients. Appropriate medical resource orientation and weight management education for T(A)AD patients may be necessary.

A Prediction Model of Extubation Failure Risk in Preterm Infants.

Objectives: This study aimed to identify variables and develop a prediction model that could estimate extubation failure (EF) in preterm infants. Study Design: We enrolled 128 neonates as a training cohort and 58 neonates as a validation cohort. They were born between 2015 and 2020, had a gestational age between 250/7 and 296/7 weeks, and had been treated with mechanical ventilation through endotracheal intubation (MVEI) because of acute respiratory distress syndrome. In the training cohort, we performed univariate logistic regression analysis along with stepwise discriminant analysis to identify EF predictors. A monogram based on five predictors was built. The concordance index and calibration plot were used to assess the efficiency of the nomogram in the training and validation cohorts. Results: The results of this study identified a 5-min Apgar score, early-onset sepsis, hemoglobin before extubation, pH before extubation, and caffeine administration as independent risk factors that could be combined for accurate prediction of EF. The EF nomogram was created using these five predictors. The area under the receiver operator characteristic curve was 0.824 (95% confidence interval 0.748-0.900). The concordance index in the training and validation cohorts was 0.824 and 0.797, respectively. The calibration plots showed high coherence between the predicted probability of EF and actual observation. Conclusions: This EF nomogram was a useful model for the precise prediction of EF risk in preterm infants who were between 250/7 and 296/7 weeks' gestational age and treated with MVEI because of acute respiratory distress syndrome.

Safety of SGLT2 Inhibitors: A Pharmacovigilance Study from 2013 to 2021 Based on FAERS.

Background: Sodium-glucose co-transporter-2 inhibitors (SGLT2is) are widely used in clinical practice for their demonstrated cardiorenal benefits, but multiple adverse events (AEs) have been reported. We aimed to describe the distribution of SGLT2i-related AEs in different systems and identify important medical event (IME) signals for SGLT2i. Methods: Data from the first quarter (Q1) of 2013-2021 Q2 in FAERS were selected to conduct disproportionality analysis. The definition of AEs and IMEs relied on the system organ classes (SOCs) and preferred terms (PTs) by the Medical Dictionary for Regulatory Activities (MedDRA-version 24.0). Two signal indicators, the reported odds ratio (ROR) and information component (IC), were used to estimate the association between SGLT2is and IMEs. Results: A total of 57,818 records related to SGLT2i, with 22,537 SGLT2i-IME pairs. Most SGLT2i-related IMEs occurred in monotherapy (N = 21,408, 94.99%). Significant signals emerged at the following SOCs: "metabolism and nutrition disorders" (N = 9,103; IC025 = 4.26), "renal and urinary disorders" (3886; 1.20), "infections and infestations" (3457; 0.85). The common strong signals were observed in diabetic ketoacidosis, ketoacidosis, euglycaemic diabetic ketoacidosis and Fournier's gangrene. Unexpected safety signals such as cellulitis, osteomyelitis, cerebral infarction and nephrolithiasis were detected. Conclusion: Our pharmacovigilance analysis showed that a high frequency was reported for IMEs triggered by SGLT2i monotherapy. Different SGLT2is caused different types and the association strengths of IMEs, while they also shared some specific PTs. Most of the results are generally consistent with previous studies, and more pharmacoepidemiological studies are needed to validate for unexpected AEs. Based on risk-benefit considerations, clinicians should be well informed about important medical events that may be aggravated by SGLT2is.

Activation of SREBP-1c alters lipogenesis and promotes tumor growth and metastasis in gastric cancer.

PURPOSE: Aggressively growing tumors are characterized by significant variations in metabolites, including lipids, and can involve the elevated synthesis ofde novo fatty acids. METHODS: Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)-based metabolomics and lipidomics were performed to compare human gastric cancer tissues and adjacent normal tissues from clinical patients. A series of cellular and molecular biological methods were applied to validate the lipidomics results. RESULTS: Palmitic acid (PA) was found to be significantly downregulated in gastric cancer tissues, and it was found that a high concentration of PA specifically inhibited cell proliferation and impaired cell invasiveness and migrationin vitro in AGS, SGC-7901, and MGC-803 gastric cancer cell lines. Moreover, sterol regulatory element-binding protein 1 (SREBP-1c) was activated in human gastric cancer tissues, and it promoted the expression of a series of genes associated with the synthesis of fatty acids, such as SCD1 and FASN. SREBP-1c knockdown rescued the migration and invasion defects in AGS and SGC-7901 gastric cancer cells. CONCLUSION: Taken together, our findings confirmed the variation in fatty acid synthesis in gastric cancer and identified SREBP-1c as a promising target for gastric cancer treatment.

Amphiprotic Side-Chain Functionalization Constructing Highly Proton/Vanadium-Selective Transport Channels for High-Performance Membranes in Vanadium Redox Flow Batteries.

A novel amphiprotic side-chain-functionalized membrane was for the first time designed for vanadium redox flow battery (VFB). Different from frequently used blending amphiprotic membranes, the one proposed here is allowed to possess high anion-exchange capacity (IECa) without sacrificing the cation-exchange capacity (IECc) because both IECa and IECc increased with the grafting degree of side chains. Having a high IECa, the membrane prepared here exhibits an ultralow vanadium permeability (<10-8 cm2 s-1), which leads to very high Coulombic efficiencies (97-98% at 40-200 mA cm-2) of VFB and good cell self-discharge durability. Moreover, the high IECc contributes to a decent ionic conductivity (area resistance: 0.5 Ω cm-2), which ensures a high-voltage efficiency of the cell. On the basis of these good properties, the VFB single cell with this membrane achieves a high energy efficiency (e.g., 77.4% at 200 mA cm-2) that is higher than those of Nafion 212 and other reported amphiprotic membranes. These results indicate that the approach proposed here is an ideal option to prepare amphiprotic membranes for VFBs with high efficiency and good durability.