SubGE-DDI: A new prediction model for drug-drug interaction established through biomedical texts and drug-pairs knowledge subgraph enhancement.

Biomedical texts provide important data for investigating drug-drug interactions (DDIs) in the field of pharmacovigilance. Although researchers have attempted to investigate DDIs from biomedical texts and predict unknown DDIs, the lack of accurate manual annotations significantly hinders the performance of machine learning algorithms. In this study, a new DDI prediction framework, Subgraph Enhance model, was developed for DDI (SubGE-DDI) to improve the performance of machine learning algorithms. This model uses drug pairs knowledge subgraph information to achieve large-scale plain text prediction without many annotations. This model treats DDI prediction as a multi-class classification problem and predicts the specific DDI type for each drug pair (e.g. Mechanism, Effect, Advise, Interact and Negative). The drug pairs knowledge subgraph was derived from a huge drug knowledge graph containing various public datasets, such as DrugBank, TwoSIDES, OffSIDES, DrugCentral, EntrezeGene, SMPDB (The Small Molecule Pathway Database), CTD (The Comparative Toxicogenomics Database) and SIDER. The SubGE-DDI was evaluated from the public dataset (SemEval-2013 Task 9 dataset) and then compared with other state-of-the-art baselines. SubGE-DDI achieves 83.91% micro F1 score and 84.75% macro F1 score in the test dataset, outperforming the other state-of-the-art baselines. These findings show that the proposed drug pairs knowledge subgraph-assisted model can effectively improve the prediction performance of DDIs from biomedical texts.

Association Between the Red Blood Cell Distribution Width and 30-Day Mortality in Intensive Care Patients Undergoing Cardiac Surgery: A Retrospective Observational Study Based on the Medical Information Mart for Intensive Care-IV Database.

Background: Millions of patients undergo cardiac surgery each year. The red blood cell distribution width (RDW) could help predict the prognosis of patients who undergo percutaneous coronary intervention or coronary artery bypass surgery. We investigated whether the RDW has robust predictive value for the 30-day mortality among patients in an intensive care unit (ICU) after undergoing cardiac surgery. Methods: Using the Medical Information Mart for Intensive Care-IV Database, we retrieved data for 11,634 patients who underwent cardiac surgery in an ICU. We performed multivariate Cox regression analysis to model the association between the RDW and 30-day mortality and plotted Kaplan-Meier curves. Subgroup analyses were stratified using relevant covariates. Receiver operating characteristic (ROC) curves were used to determine the predictive value of the RDWs. Results: The total 30-day mortality rate was 4.2% (485/11,502). The elevated-RDW group had a higher 30-day mortality rate than the normal-RDW group (P&0.001). The robustness of our data analysis was confirmed by performing subgroup analyses. Each unit increase in the RDW was associated with a 17% increase in 30-day mortality when the RDW was used as a continuous variable (adjusted hazard ratio=1.17, 95% confidence interval, 1.10-1.25). Our ROC results showed the predictive value of the RDW. Conclusions: An elevated RDW was associated with a higher 30-day mortality in patients after undergoing cardiac surgery in an ICU setting. The RDW can serve as an efficient and accessible method for predicting the mortality of patients in ICUs following cardiac surgery.

Assessment of relationships between frailty and chronic pain: a bidirectional two-sample Mendelian randomisation study.

BACKGROUND: Previous observational studies have indicated a complex association between chronic pain and frailty. This study aimed to examine the bidirectional causal relationship between frailty and chronic pain and to quantify mediating effects of known modifiable risk factors. METHODS: A bidirectional two-sample Mendelian randomisation (MR) analysis was applied in this study. Summary genome-wide association statistics for frailty, as defined by both frailty index (FI) and Fried Frailty Score (FFS), pain at seven site-specific chronic pain (SSCP) (headache, facial, neck/shoulder, stomach/abdominal, back, hip and knee) and multisite chronic pain (MCP) were extracted from populations of European ancestry. Genetic instrumental variables strongly correlated with each exposure were selected. The inverse-variance-weighted method was the primary method used in the MR, supplemented by a range of sensitivity and validation analyses. Two-step MR analysis was undertaken to evaluate the mediating effects of several proposed confounders. RESULTS: Genetically predicted higher FI and FFS were associated with an increased risk of MCP and specific types of SSCP, including neck/shoulder pain, stomach/abdominal pain, back pain, hip pain and knee pain. In the reverse direction analysis, genetic liability to MCP was found to be associated with increased FI and FFS. These results remained consistent across sensitivity and validation assessments. Two-step MR suggested a mediating role for body mass index, smoking initiation, physical inactivity, educational attainment and depression. CONCLUSIONS: Our research provided genetic evidence that the association between frailty and chronic pain was bidirectional where the coexistence of both conditions will exacerbate each other.

A real-world disproportionality analysis of anti-VEGF drugs from the FDA Adverse Event Reporting System.

BACKGROUND: The association between anti-vascular endothelial growth factor (VEGF) drugs and ocular adverse events (AEs) has been reported, but large real-world studies of their association with systemic AEs are still lacking. METHODS: A disproportionality analysis of reports from the FDA Adverse Event Reporting System from January 2004 to September 2021 was conducted to detect the significant ADR signals with anti-VEGF drugs (including aflibercept, bevacizumab, brolucizumab, pegaptanib, and ranibizumab). RESULTS: A total of 2980 reported cases with 7125 drug-AEs were included. Five drugs were all associated with eye disorders, and pegaptanib and ranibizumab were also associated with cardiac disorders. For ranibizumab, pegaptanib, bevacizumab and aflibercept, the proportions of cardiac AEs were 8.57%, 5.62%, 3.43% and 3.20%, respectively, and the proportions of central nervous AEs were 8.81%, 7.41, 5.86% and 5.68%, respectively. In multiple comparisons, ranibizumab was significantly higher than bevacizumab and aflibercept in the proportion of cardiac AEs (P < 0.001), and ranibizumab was significantly higher than aflibercept in central nervous AEs (P < 0.001). CONCLUSIONS: Our findings support the associations between anti-VEGF drugs and ocular AEs, cardiac AEs, and central nervous AEs. After intravitreal injection, attention should not only be paid to ocular symptoms, but also to systemic symptoms.

WITHDRAWN: The Analgesic Effect of Regional Blocks for Modified Radical Mastectomy: A Network Meta-analysis.

Ahead of Print article withdrawn by publisher.

Association between glucose-to-lymphocyte ratio and in-hospital mortality in intensive care patients with sepsis: A retrospective observational study based on Medical Information Mart for Intensive Care IV.

Background: This study aimed to evaluate the association between the glucose-to-lymphocyte ratio (GLR) and in-hospital mortality in intensive care unit (ICUs) patients with sepsis. Methods: This is a retrospective cohort study. Patients with sepsis from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database had their baseline data and in-hospital prognosis retrieved. Multivariable Cox regression analyses were applied to calculate adjusted hazard ratios (HR) with 95% confidence intervals (CI). Survival curves were plotted, and subgroup analyses were stratified by relevant covariates. To address the non-linearity relationship, curve fitting and a threshold effect analysis were performed. Results: Of the 23,901 patients, 10,118 patients with sepsis were included. The overall in-hospital mortality rate was 17.1% (1,726/10,118). Adjusted for confounding factors in the multivariable Cox regression analysis models, when GLR was used as a categorical variable, patients in the highest GLR quartile had increased in-hospital mortality compared to patients in the lowest GLR quartile (HR = 1.26, 95% CI: 1.15-1.38). When GLR was used as a continuous variable, each unit increase in GLR was associated with a 2% increase in the prevalence of in-hospital mortality (adjusted HR = 1.02, 95% CI: 1.01-1.03, p = 0.001). Stratified analyses indicated that the correlation between the GLR and in-hospital mortality was stable. The non-linear relationship between GLR and in-hospital mortality was explored in a dose-dependent manner. In-hospital mortality increased by 67% (aHR = 1.67, 95% CI: 1.45-1.92) for every unit GLR increase. When GLR was beyond 1.68, in-hospital mortality did not significantly change (aHR: 1.04, 95% CI: 0.92-1.18). Conclusion: There is a non-linear relationship between GLR and in-hospital mortality in intensive care patients with sepsis. A higher GLR in ICU patients is associated with in-hospital mortality in the United States. However, further research is needed to confirm the findings.

Which is the best analgesia treatment for total knee arthroplasty: Adductor canal block, periarticular infiltration, or liposomal bupivacaine? A network meta-analysis.

STUDY OBJECTIVE: To review all randomized controlled trials (RCTs) comparing the analgesic efficacy of adductor canal block (ACB), periarticular infiltration (PAI), and any other mode of these treatments in analgesia, such as PAI with liposomal bupivacaine (LB), continuous adductor canal block (cACB) or ACB + PAI, after total knee arthroplasty (TKA). DESIGN: Systematic review and network meta-analysis of RCTs. PATIENTS: We searched PubMed, Embase, and the Cochrane database to detect all relevant RCTs on investigating the analgesic effects of ACB, PAI and LB for TKA published until April 2020. INTERVENTIONS: Use of different analgesic methods of ACB, PAI, cACB, ACB + PAI and LB. MEASUREMENTS: The primary endpoint was visual analog scale (VAS) score at rest and movement. The secondary endpoints were opioids consumption, length of hospitalization and knee range of motion (ROM). We used Cochrane risk of bias to assess the quality of evidence for outcomes. RESULTS: Forty-two studies involving 3785 patients with 5 different methods containing ACB, PAI, ACB + PAI, continuous ACB (cACB), LB, were evaluated. According to surface under the cumulative ranking curve value, 24 h resting VAS score was the lowest the ACB + PAI (88.4%), followed by cACB (73.4%); Resting VAS score at 48 h and movement VAS score at 24 h and 48 h was the lowest in the cACB (99.9%, 92% and 100%). Total opioids consumption was the least in LB (81.4%) before cACB (60.8%). ROM was the largest in the ACB + PAI (84.1%) before cACB (78.8%). CONCLUSION: Although all analgesic methods available were not evaluated, and further studies are needed to establish our results, the 24 h resting VAS score was lowest in ACB + PAI and 48 h resting and movement VAS score was lowest in cACB. CLINICAL TRIAL REGISTRATION: PROSPERO (CRD 42020168102).

Dermal bioaccessibility of plasticizers in indoor dust and clothing.

Several studies indicate that human exposure to plasticizers via dermal pathway is not negligible, but the dermal bioaccessibility of phthalates and alternative plasticizers from the important environmental matrix including indoor dust and clothing and the importance weight of dermal exposure to those pollutants have been poorly studied. An in vitro physiologically based extraction test was employed to investigate the dermal bioaccessibility of target phthalates and alternative plasticizers from indoor dust and clothing. Temperature, incubation time, sweat/sebum ratio and solid/liquid ratio were selected to study their effects on the bioaccessibility. The bioaccessibility of Diethyl phthalates (DEP), dibutyl phthalate (DBP), bis-2-ethylhexyl phthalate (DEHP), Acetyl tributyl citrate (ATBC), bis-2-ethylhexyladipate (DEHA) and bis-2-ethylhexyl terephthalate (DEHT) in indoor dust were 66.20 ±â€¯1.93%, 94.27 ±â€¯1.31%, 80.37 ±â€¯8.09%, 75.02 ±â€¯2.12%, 94.50 ±â€¯3.42% and 74.09 ±â€¯3.79%, respectively, under the condition of 1:1 sweat/sebum ratio, 1/100 solid/liquid ratio (indoor dust), 1:1 area/area ratio (1:1, clothing) and 90 min incubation time at 36.3 °C which are chosen based on the experimental results and human physical conditions. DBP showed the highest bioaccessibility in all samples. The time course of the plasticizer release was fitted to a first-order one-compartment model. DBP showed the highest release rate (k1) calculated from the model, which was consistent with the bioaccessibility result. Risk assessment indicated that dermal exposure of DBP was an important exposure route, accounting for about 21.58% of total intake, and indoor dust was an important exposure media when considering the dermal bioaccessibility.

N-terminal residues of an HIV-1 gp41 membrane-proximal external region antigen influence broadly neutralizing 2F5-like antibodies.

The Human immunodeficiency virus type 1 (HIV-1) gp41 membrane proximal external region (MPER) is targeted by broadly neutralizing antibodies (e.g. 2F5, 4E10, Z13e and m66.6), which makes this region a promising target for vaccine design. One strategy to elicit neutralizing antibodies against the MPER epitope is to design peptide immunogens mimicking neutralization structures. To probe 2F5-like neutralizing antibodies, two yeast-displayed antibody libraries from peripheral blood mononuclear cells from a HIV-1 patient were screened against the 2F5 epitope peptide SP62. Two 2F5-like antibodies were identified that specifically recognized SP62. However, these antibodies only weakly neutralized HIV-1 primary isolates. The epitopes recognized by these two 2F5-like antibodies include not only the 2F5 epitope (amino acids (aa) 662-667 in the MPER) but also several other residues (aa 652-655) locating at the N-terminus in SP62. Experimental results suggest that residues of SP62 adjacent to the 2F5 epitope influence the response of broadly neutralizing 2F5-like antibodies in vaccination. Our findings may aid the design of vaccine immunogens and development of therapeutics against HIV-1 infection.