Clinical outcomes of colistin methanesulfonate sodium in correlation with pharmacokinetic parameters in critically ill patients with multi-drug resistant bacteria-mediated infection: A systematic review and meta-analysis.

BACKGROUND: Colistin is a viable option for multidrug resistant gram-negative bacteria emerged from inappropriate antibiotic use. Nonetheless, suboptimal colistin concentrations and nephrotoxicity risks hinder its clinical use. Thus, the aim of this study is to investigate clinical outcomes in correlation with pharmacokinetic differences and infection types in critically ill patients on intravenous colistin methanesulfornate sodium (CMS). METHODS: A systematic literature search of Embase, Google Scholars, and PubMed was performed to identify clinical trials evaluating pharmacokinetic parameters along with clinical outcomes of CMS treatment from inception to July 2023. The pooled analyses of clinical impact of CMS on nephrotoxicity, mortality, clinical cure, and colistin concentration at steady state (Css,avg) were performed. This study was registered in the PROSPERO (CRD 42023456120). RESULTS: Total of 695 critically ill patients from 17 studies were included. The mortality was substantially lower in clinically cured patients (OR 0.05; 95% CI 0.02 - 0.14), whereas the mortality rate was statistically insignificant between nephrotoxic and non-nephrotoxic patients. Inter-patient variability of pharmacokinetic parameters of CMS and colistin was observed in critically ill patients. The standard mean differences of Css,avg were statistically insignificant between clinically cure and clinically failure groups (standard mean difference (SMD) -0.25; 95% CI -0.69 - 0.19) and between nephrotoxic and non-nephrotoxic groups (SMD 0.67; 95% CI -0.27-1.61). The clinical cure rate is substantially lower in pneumonia patients (OR 0.09; 95% CI 0.01 - 0.56), and pharmacokinetic parameters pertaining to microbiological cure were different among strains. CONCLUSION: The mortality rate was substantially lower in clinically cured patients with CMS. However, no significant differences in Css,avg of colistin were examined to determine the impact of pharmacokinetic differences on clinical outcomes including mortality rate and nephrotoxicity risk. Nevertheless, the clinical cure rate is substantially lower in patients with respiratory infection than patients with urinary tract infection.

A Real-World Data Driven Pharmacovigilance Investigation on Drug-Induced Arrhythmia Using KAERS DB, a Korean Nationwide Adverse Drug Reporting System.

This study aims to investigate the prevalence and seriousness of drug-induced arrhythmia and to identify predictors associated with the seriousness of arrhythmia. Drug-induced arrhythmia cases reported to the Korean Adverse Event Reporting System Database (KAERS DB) from January 2012 to December 2021 were investigated. A disproportionality test was performed to detect the association of the etiologic medication classes and types, along with patient demographic information, with the seriousness of drug-induced arrhythmia. Logistic regression was performed to investigate the predictors that increase the risk of serious arrhythmia. The most common etiologic agent for drug-induced arrhythmia was sevoflurane, whereas serious arrhythmia was most prevalent with narcotics. Antibiotics (reporting odds ratio (ROR) 4.125; 95% CI 1.438-11.835), chemotherapy (ROR 6.994; 95% CI 2.239-21.542), and iodinated contrast media (ROR 8.273; 95% CI 3.062-22.352) had a strong association with the seriousness of drug-induced arrhythmia. Among numerous etiologic agents, ioversol (ROR 16.490; 95% CI 3.589-75.772) and lidocaine (ROR 12.347; 95% CI 2.996-50.884) were more likely to be reported with serious arrhythmia. Aging and comorbidity, primarily cancer, are the most contributing predictors associated with serious arrhythmia. Further studies on the clinical significance of patient-specific predictors for the increased risk of serious drug-induced arrhythmia are warranted to promote drug safety.

Incident infection risks depending on oral antidiabetic exposure in insulin-treated type 2 diabetes patients.

Dipeptidyl peptidase-4 inhibitors (DPP4is) and sodium glucose cotransporter-2 inhibitors (SGLT2is) have been speculated to have a potential to increase infection risks in type 2 diabetes mellitus (T2DM) patients. We performed a cohort study using the Korean health insurance data to investigate infection risks with each drug class relative to metformin in insulin-treated T2DM patients. After propensity score matching, we included 1,498 and 749 patients in DPP4i + insulin vs metformin + insulin and 300 and 549 patients in SGLT2i + insulin vs metformin + insulin, respectively. In stratified analyses per patient factor, none of the odds ratios (ORs) were associated with a statistical significance across respiratory, genital, and urinary tract infections (UTIs), except that of the male stratum for respiratory infections (OR 0.77, p = 0.04). With regard to SGLT2is, a higher risk of genital infections was analyzed with their use than with metformin therapy (OR 1.76, p = 0.03). In stratified analyses, the OR for genital infections remained significant in the baseline cardiovascular disease stratum (OR 2.29, p = 0.01). No increased UTI risk was detected with SGLT2is compared against metformin. In this study on insulin-receiving T2DM patients, DPP4is were not associated with increased infection risks, whereas SGLT2is led to a higher risk for genital infections, but not for UTIs, relative to metformin.

A nationwide pharmacovigilance investigation on trends and seriousness of adverse events induced by anti-obesity medication.

Introduction: Despite rising concerns regarding the safety of anti-obesity medications, there is a lack of comprehensive pharmacovigilance investigations utilising real-world data. We aimed to characterise the prevalence and seriousness of adverse drug events (ADEs) related to anti-obesity medications and to identify predictors associated with increased risk of serious adverse events (SAE), thereby conveying evidence on drug safety. Methods: We conducted a cross-sectional analysis on ADE cases spontaneously reported to the Korea Adverse Event Reporting System Database (KIDS-KD). ADE reports pertaining to anti-obesity medications prescribed for overweight, obesity (International Classification of Disease, 10th revision (ICD-10) code E66) and abnormal weight gain (ICD-10 code E63.5) were included in the analysis. We performed a disproportionality to detect the association of the system organ class-based ADEs with their seriousness an individual's sex by estimating reporting odds ratios (RORs) and their 95% confidence intervals (CIs). We performed logistic regression to investigate factors that are substantially associated with increased SAE risks by estimating odds ratio (OR) and their 95% CIs. Results: The most common causative anti-obesity medication was phentermine, followed by liraglutide. ADEs associated with psychiatric disorders (ROR = 1.734; 95% CI = 1.111-2.707), liver and biliary system disorders (ROR = 22.948; 95% CI = 6.613-70.635), cardiovascular disorders (ROR = 5.707; 95% CI = 1.965-16.574), and respiratory disorders (ROR = 4.567; 95% CI = 1.774-11.762) were more likely to be serious events. Additionally, men are more likely to experience ADEs related gastrointestinal disorders (ROR = 1.411) and less likely to have heart and rhythm disorders (ROR = 0.507). The risk of SAE incidences was positively correlated with being male (OR = 2.196; 95% CI = 1.296-3.721), dual or triple combination of anti-obesity medications (OR = 3.258; 95% CI = 1.633-6.501 and OR = 8.226; 95% CI = 3.046-22.218, respectively), and concomitant administration of fluoxetine (OR = 5.236; 95% CI = 2.218-12.365). Conclusions: Seriousness of anti-obesity medication-related ADEs differs among system-organ class, while sex-related differences in ADE profiles are also present. The predictors substantially increasing risk of SAE incidences include being male, having a higher number of concomitant medications (including multiple combination of anti-obesity medications), and concurrent use of fluoxetine. Nonetheless, further pharmacovigilance investigation and monitoring are needed to enhance awareness on ADEs induced by anti-obesity medications.

Impact of metformin on statin-associated myopathy risks in dyslipidemia patients.

A growing number of patients with metabolic disorders are receiving statin and antidiabetic therapies as comedications. A signal of increased risk of myotoxicity due to potential interactions between antidiabetics and statins has been detected in previous studies. To investigate the effects of metformin on myopathy risks when added to preexisting statin therapy in dyslipidemia patients, we performed a retrospective cohort study using the Korean national health insurance data in statin-treated dyslipidemia patients with or without concomitant metformin use. We compared the risk of myopathy in statin + metformin users against statin-only users. Hazard ratios (HRs) and 95% confidence intervals (CIs) have been calculated following propensity score (PS) matching between study groups and subsequent stratification per patient factors. We included 4092 and 8161 patients in PS-matched statin + metformin and statin-only groups, respectively. The risk of myopathy decreased when metformin was used together with statins (adjusted HR 0.84; 95% CI 0.71-0.99). In subgroup analyses per individual statin agent and in stratified risk analyses, no specific statin agents or patient factors were associated with statistically significant myopathy risk. This study found that a comedication with metformin was associated with decreased myopathy risk in statin-treated dyslipidemia patients compared to statin-only users. Our findings suggest that metformin may provide protective effects on potential muscle toxicities induced by statin therapy.

Clinical outcomes of renin angiotensin system inhibitor-based dual antihypertensive regimens in chronic kidney disease: a network meta-analysis.

This study comprehensively investigated clinical outcomes associated with renin angiotensin system inhibitor-based dual antihypertensive regimens in non-dialysis chronic kidney disease (CKD) patients. Keyword searches of databases were performed per PRISMA-NMA guidelines. Frequentist network meta-analysis were conducted with 16 head-to-head randomized controlled trials. The effect sizes of dichotomous and continuous variables were estimated with odds ratio (OR) and standard mean differences (SMD), respectively. The protocol is registered in PROSPERO (CRD42022365927). Dual antihypertensive regimens with combination of angiotensin receptor blockers (ARB) and calcium channel blockers (CCB) demonstrated substantially reduced odd of major cardiovascular disease (CVD) events over other regimens including angiotensin converting enzyme inhibitor (ACEI) monotherapy (OR 3.19) and ARB monotherapy (OR 2.64). Most significant reductions in systolic (SBP) and diastolic blood pressure (DBP) were observed with ARB-based CCB dual regimen over ACEI monotherapy (SMD 17.60 SBP and 9.40 for DBP), ACEI-based CCB regimen (SMD 12.90 for SBP and 9.90 for DBP), and ARB monotherapy (SMD 13.20 for SBP and 5.00 for DBP). However, insignificant differences were noticed for the odds of hyperkalemia, end stage renal disease progression, and all-cause mortality. ARB-based CCB regimen has the greatest benefits on BP reduction as well as major CVD risks in non-dialysis CKD patients.

Development of a Rapid LC-MS/MS Method for Simultaneous Quantification of Donepezil and Tadalafil in Rat Plasma: Its Application in a Pharmacokinetic Interaction Study after Oral Administration in Rats.

This study aimed to establish a simple and sensitive analytical method to simultaneously quantify donepezil (DPZ) and tadalafil (TAD) in rat plasma using lansoprazole (LPZ) as an internal standard (IS) by using liquid chromatography tandem mass spectrometry. The fragmentation pattern of DPZ, TAD, and IS was elucidated using multiple reaction monitoring in electrospray ionization positive ion mode for the quantification of precursor to production at m/z 380.1 → 91.2 for DPZ, m/z 390.2 → 268.1 for TAD, and m/z 370.3 → 252.0 for LPZ. The extracted DPZ and TAD from plasma using acetonitrile-induced protein precipitation was separated using Kinetex C18 (100 × 2.1 mm, 2.6 µm) column with a gradient mobile phase system consisting of 2 mM ammonium acetate and 0.1% formic acid in acetonitrile at a flow rate of 0.25 mL/min for 4 min. The selectivity, lower limit of quantification, linearity, precision, accuracy, stability, recovery, and matrix effect of this developed method was validated according to the guidelines of the U.S. Food and Drug Administration and the Ministry of Food and Drug Safety of Korea. The established method achieved acceptance criteria in all validation parameters, ensuring reliability, reproducibility, and accuracy, and was successfully implemented in a pharmacokinetic study on the co-administration of DPZ and TAD orally in rats.

A Real-World Data Derived Pharmacovigilance Assessment on Drug-Induced Nephropathy: Implication on Gaps in Patient Care.

This retrospective cross-sectional study aims to investigate the prevalence and seriousness of drug-induced nephrotoxicity and to identify clinical predictors intensifying the seriousness of nephrotoxicity. Adverse drug events (ADEs) reported to the Korean Adverse Event Reporting System Database (KAERS DB) from January 2012 to December 2021 were investigated. The association between the seriousness and the etiologic drug was estimated in reporting odds ratio (ROR) based on disproportionality analysis. Logistic regression was utilized to recognize predictors associated with serious nephrotoxicity. The majority of ADEs were reported in ages 30 to 59, and immunosuppressants were the most etiologic medications. ADEs involving antibiotics, including vancomycin (ROR 0.268; 95% CI 0.129-0.557), were less likely to be serious. More than 93% of cyclosporine-related ADEs were serious nephrotoxicity, whereas tacrolimus was less likely to report serious nephrotoxicity (ROR 0.356; 95% CI 0.187-0.680). The risk of serious nephrotoxicity was decreased with aging (ROR 0.955; 95% CI 0.940-0.972) while increased in women (OR 2.700; 95% CI 1.450-5.008). Polypharmacy was associated with increased risk of interstitial nephritis (OR 1.019; 95% CI 1.001-1.038). However, further studies investigating the impact of clinical practice on ADE incidences as well as clinical prognosis related to nephrotoxicity are obligated.

Viscosity-Controllable Graphene Oxide Colloids Using Electrophoretically Deposited Graphene Oxide Sheets.

Graphene oxide (GO) is one of the interesting ink materials owing to its fascinating properties, such as high dissolubility in water and high controllable electric properties. For versatile printing application, the viscosity of GO colloids should be controlled in order to meet the specific process requirements. Here, we report on the relatively rapid fabrication of viscosity-increased GO (VIGO) colloids mixed with electrophoretically deposited GO sheets (EPD-GO). As the GO colloid concentration, applied voltage, and deposition time increase, the viscosity of the GO colloids becomes high. The reason for the improved viscosity of GO colloids is because EPD-GO has parallel stacked GO sheets. The GO and VIGO colloids are compared and characterized using various chemical and structural analyzers. Consequently, our simple and fast method for the fabrication of GO colloids with enhanced viscosity can be used for producing inks for flexible and printed electronics.

Potentially Inappropriate Medication Use in Patients with Dementia.

The objective of this study was to characterize the epidemiology of using potentially inappropriate medications associated with dementia exacerbation (DPIMs) in elderly outpatients with dementia. Electronic medical records were retrospectively reviewed for geriatric patients with dementia who were prescribed at least one medication in 2016 at a tertiary, university-affiliated hospital. The 2015 Beers criteria were used to define DPIMs. Logistic regression was performed to identify factors associated with prescribing DPIMs in patients with dementia. Among 2100 patients included in our study, 987 (47.0%) patients were prescribed at least one DPIM. Benzodiazepines were the most frequently prescribed DPIM followed by anticholinergics, histamine H2-receptor blockers, and zolpidem. The risk of prescribing DPIMs was significantly increased in female patients (odds ratio (OR) 1.355) with polypharmacy (OR 5.146) and multiple comorbidities (OR 1.129) (p < 0.05 for all). Coexistence of Parkinson's disease (OR 1.799), mood disorder (OR 1.373), or schizophrenia (OR 4.116) in patients with dementia further increased the likelihood of receiving DPIMs. In conclusion, DPIMs were commonly used in elderly patients with dementia in Korea with benzodiazepines most frequently prescribed followed by anticholinergics. Female patients using polypharmacy with multiple comorbidities should be closely monitored to minimize unnecessary DPIM use and, ultimately, DPIM-related harms.

Safety Assessment on Serious Adverse Events of Targeted Therapeutic Agents Prescribed for RAS Wild-Type Metastatic Colorectal Cancer: Systematic Review and Network Meta-Analysis.

Despite substantially elevated risk of serious adverse events (SAEs) from targeted therapy in combination with chemotherapy, comprehensive pharmacovigilance research is limited. This study aims to systematically assess SAE risks of commonly prescribed targeted agents (bevacizumab, cetuximab, and panitumumab) in patients with rat sarcoma viral oncogene homolog (RAS) wild-type metastatic colon cancer. Keyword searches of Cochrane Library, Clinical Key and MEDLINE were conducted per PRISMA-NMA guidelines. Frequentist network meta-analysis was performed with eight randomized controlled trials to compare relative risk (RR) of 21 SAE profiles. The risks of hematological, gastrointestinal, neurological SAE were insignificant among targeted agents (p > 0.05). The risk of serious hypertension was substantially elevated in bevacizumab-based chemotherapy (p < 0.05), whereas panitumumab-based chemotherapy had markedly elevated risk of serious thromboembolism (RR 3.65; 95% CI 1.30−10.26). Although both cetuximab and panitumumab demonstrated increased risk of serious dermatological and renal toxicities, panitumumab-based chemotherapy has relatively higher risk of skin toxicity (RR 15.22; 95% CI 7.17−32.35), mucositis (RR 3.18; 95% CI 1.52−6.65), hypomagnesemia (RR 20.10; 95% CI 5.92−68.21), and dehydration (RR 2.81; 95% CI 1.03−7.67) than cetuximab-based chemotherapy. Thus, further studies on risk stratification and SAE management are warranted for safe administration of targeted agents.

Effects of Early Initiation of High-Dose Dexamethasone Therapy on Pro-Inflammatory Cytokines and Mortality in LPS-Challenged Mice.

This study aims to explore the effects of early dexamethasone therapy at low to high doses on the survival and inflammatory responses in lipopolysaccharide (LPS)-challenged mice. We performed two-series experiments to explore the impact of early dexamethasone therapy at different doses (0.5 mg/kg, 1.5 mg/kg, and 5 mg/kg; PO) on pro-inflammatory cytokine levels, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), as well as survival in LPS-treated mice (10 mg/kg, IP). Dexamethasone was administered daily from 24 h before and 5 days after LPS challenge. Dose-dependent improved survival was demonstrated with dexamethasone (p < 0.05). Body weight was significantly decreased within 24 h of LPS injection, with significantly greater weight loss in the dexamethasone groups (p < 0.05). Weight changes were significantly associated with the days after LPS administration (p < 0.01), but not with the dexamethasone dose (p > 0.05). Mice treated with high-dose dexamethasone (5 mg/kg) had a significantly lowered serum TNF-α (134.41 ± 15.83 vs. 408.83 ± 18.32) and IL-6 (22.08 ± 4.34 vs. 91.27 ± 8.56) compared with those without dexamethasone. This study provides essential insights that the suppression of early-phase hyperactivation of pro-inflammatory activities through the early initiation of high-dose dexamethasone therapy increases sepsis-related prognosis.

Tolerability on Serious Adverse Events of First-Line Bevacizumab and Cetuximab for RAS Wild-Type Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis.

Proper medication management is crucial in metastatic colorectal cancer because of its substantially low survival rate. There has been advancing evidence on the efficacy of the two most prescribed targeted agents (bevacizumab and cetuximab); however, comprehensive analyses on their safety are limited. This study aims to comprehensively assess the clinical safety of first-line bevacizumab and cetuximab-based chemotherapy in unresectable RAS wild-type metastatic colorectal cancer patients and to provide guidance on the selection of appropriate targeted therapeutic agents. Keyword searches of MEDLINE, Cochrane Library, and ClinicalKey were conducted per PRISMA guidelines. We performed pooled analysis on safety outcomes from six studies which administered FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (5-fluorouracil, leucovorin, irinotecan) as backbone chemotherapy. Thirty different adverse events from six categories were compared. First-line bevacizumab-based chemotherapy substantially lowered the risks of adverse events related to the dermatological (RR 0.24, 95% CI: 0.11-0.53, p < 0.00001) and renal systems (RR 0.57, 95% CI: 0.37-0.86, p = 0.007), while significantly increasing the incidence of cardiovascular adverse events (RR 4.65, 95% CI: 1.83-11.78, p = 0.001). Thus, first-line cetuximab-based chemotherapy increases patient susceptibility to dermatological and renal adverse events, especially with rash and electrolyte disorders, whereas bevacizumab-based chemotherapy increases cardiovascular risks such as hypertension and arrhythmia.

Incident Type 2 Diabetes Risk of Selective Estrogen Receptor Modulators in Female Patients with Breast Cancer.

Accumulating evidence indicates a link between diabetes and cancer. Selective estrogen receptor modulators (SERMs) may increase diabetes risk via antiestrogen effects. This study investigated incident diabetes risk of SERM treatment and its effects on metastatic cancer and death prevention in breast cancer survivors. This retrospective cohort study included female patients with early-stage breast cancer, treated with or without SERMs, between 2008 and 2020 in a tertiary care hospital in Korea. Four propensity score-matched comparison pairs were designed: SERM use versus non-use, long-term use (≥1500 days) versus non-use, tamoxifen use versus non-use, and toremifene use versus non-use; then, logistic regression analysis was performed for risk analysis. SERMs in general were not associated with an elevated risk of diabetes; however, when used for ≥1500 days, SERMs-especially toremifene-substantially increased diabetes risk in breast cancer patients (OR 1.63, p = 0.048). Meanwhile, long-term SERM treatment was effective at preventing metastatic cancer (OR 0.20, p < 0.001) and death (OR 0.13, p < 0.001). SERM treatment, albeit generally safe and effective, may increase diabetes risk with its long-term use in women with breast cancer. Further studies are required to verify the association between toremifene treatment and incident diabetes.

Comparative Safety Profiles of Sedatives Commonly Used in Clinical Practice: A 10-Year Nationwide Pharmacovigilance Study in Korea.

This study aims to compare the prevalence and seriousness of adverse events (AEs) among sedatives used in critically ill patients or patients undergoing invasive procedures and to identify factors associated with serious AEs. Retrospective cross-sectional analysis of sedative-related AEs voluntarily reported to the Korea Adverse Event Reporting System from 2008 to 2017 was performed. All AEs were grouped using preferred terms and System Organ Classes per the World Health Organization-Adverse Reaction Terminology. Logistic regression was performed to identify factors associated with serious events. Among 95,188 AEs, including 3132 (3.3%) serious events, the most common etiologic sedative was fentanyl (58.8%), followed by pethidine (25.9%). Gastrointestinal disorders (54.2%) were the most frequent AEs. The most common serious AE was heart rate/rhythm disorders (33.1%). Serious AEs were significantly associated with male sex; pediatrics; etiologic sedative with etomidate at the highest risk, followed by dexmedetomidine, ketamine, and propofol; polypharmacy; combined sedative use; and concurrent use of corticosteroids, aspirin, neuromuscular blockers, and antihistamines (reporting odds ratio > 1, p < 0.001 for all). Sedative-induced AEs are most frequently reported with fentanyl, primarily manifesting as gastrointestinal disorders. Etomidate is associated with the highest risk of serious AEs, with the most common serious events being heart rate/rhythm disorders.

New Evidence of Potential Benefits of Dexamethasone and Added on Therapy of Fludrocortisone on Clinical Outcomes of Corticosteroid in Sepsis Patients: A Systematic Review and Meta-Analysis.

The aim of this study is to investigate clinical outcomes of corticosteroid treatment in patients with sepsis or septic shock. An electronic keyword searches of PubMed, EMBASE, and Google Scholar were conducted per PRISMA guidelines. The pooled analyses on the corticosteroid impact on mortality, adverse events, and clinical outcomes were performed. Subgroup analyses on the clinical outcomes in relation to corticosteroid dose, duration, and agents were performed. Pooled analyses of 21 randomized control trials revealed substantially reduced mortality (RR 0.93, 95% CI 0.88-0.99, p = 0.02) and length of stay in intensive care unit (SMD -1.66, 95% CI -1.91--1.40, p < 0.00001) without increased risks of adverse events (RR 1.04, 95% CI 0.96-1.12, p = 0.38). No significant improvements of other clinical outcomes were observed. Subgroup analyses demonstrated substantially reduced mortality with short-term (≤7 days) low-dose (<400 mg/day) corticosteroid treatment (RR 0.91, 95% CI 0.87-0.95, p < 0.0001). Moreover, dexamethasone (RR 0.40, 95% CI 0.20-0.81, p = 0.01) and combined hydrocortisone and fludrocortisone treatment (RR 0.89, 95% CI 0.84-0.94, p < 0.00001) provided substantial reduction of mortality whereas hydrocortisone alone did not reduce the mortality risk in sepsis patients. Thus, further controlled studies on the clinical outcomes of potential corticosteroid options on sepsis-related clinical outcomes are warranted.

Clinical Benefits of Oral Anticoagulant Use in Cancer Patients at Increased Risk for Venous Thromboembolism per Khorana Index.

BACKGROUND: Cancer patients are at increased risk for venous thromboembolism (VTE) due to cancer-induced hypercoagulability. However, current guidelines do not routinely recommend prophylactic use of oral anticoagulants to prevent VTE in cancer patients. OBJECTIVE: To evaluate the efficacy and safety of novel oral anticoagulants (NOACs) versus no anticoagulant use (no-use) and, additionally, differential effects between NOACs and warfarin, in VTE and adverse bleeding prevention among cancer patients, in consideration of risk stratification by gender, high-risk chemotherapy exposure, and Khorana index. METHODS: This national health insurance data-based study with a 180-day follow-up enrolled cancer patients with or without oral anticoagulant use in 2017. The primary outcome was VTE risk in oral anticoagulant users vs non-users. Four propensity score-matched comparison pairs were designed: use vs no-use, NOAC vs no-use, warfarin vs no-use, and NOAC vs warfarin. A logistic regression model was used to investigate between-group differences in VTE and bleeding risk. RESULTS: When compared to no-use, NOACs showed substantial effects in preventing VTE complications (OR=0.40, p<0.001), primarily deep vein thrombosis (DVT) events (OR=0.38, p<0.001), in both male and female cancer patients as well as those with a Khorana score ≥1. Adverse bleeding risk was comparable or lower in NOAC-receiving female patients (p=0.13) and male patients (p=0.04), respectively. In contrast, no protective effects were found with warfarin compared to no-use in controlling thrombosis and adverse bleeding risk. In a head-to-head comparison of NOACs versus warfarin, DVT risk in those patients exposed to high-risk chemotherapy was significantly decreased with NOAC use (OR=0.19, p=0.03). CONCLUSION: NOACs can be a promising thromboprophylactic option in both male and female cancer patients with VTE risk.

P2Y12 Antiplatelet Choice for Patients with Chronic Kidney Disease and Acute Coronary Syndrome: A Systematic Review and Meta-Analysis.

This study aims to evaluate potentially appropriate antiplatelet therapy in patients with chronic kidney disease. A systematic analysis was conducted to identify the clinical outcomes of available antiplatelet therapy regimens with enhanced platelet inhibition activity (intervention of 5 regimens) over the standard dose of clopidogrel-based dual antiplatelet therapy in patients with renal insufficiency. An electronic keyword search was performed on Pubmed, Embase, and Cochrane Library per PRISMA guidelines. We performed a prespecified net clinical benefit analysis (a composite of the rates of all-cause or cardiac-related death, myocardial infarction, major adverse cardiac outcomes, and minor and major bleeding), and included 12 studies. The intervention substantially lowered the incidence of all-cause mortality (RR 0.67; p = 0.003), major adverse cardiac outcomes (RR 0.79; p < 0.00001), and myocardial infarction (RR 0.28; p = 0.00007) without major bleeding (RR 1.14; p = 0.33) in patients with renal insufficiency, but no significant differences were noticed with cardiac-related mortality and stent thrombosis. The subgroup analysis revealed substantially elevated bleeding risk in patients with severe renal insufficiency or on hemodialysis (RR 1.68; p = 0.002). Our study confirmed that the intervention considerably enhances clinical outcomes in patients with renal insufficiency, however, a standard dose of clopidogrel-based antiplatelet therapy is favorable in patients with severe renal insufficiency.

Aspirin Prophylaxis During Pregnancy: A Systematic Review and Meta-Analysis.

CONTEXT: Low-dose aspirin is used for pre-eclampsia prophylaxis during pregnancy, but a study that comprehensively investigates both maternal and perinatal outcomes from aspirin administration utilizing stratification methods is lacking. The aim of this study is to comprehensively investigate the maternal and neonatal outcomes related to aspirin prophylaxis during pregnancy in relation to dose and therapy initiation by utilizing a stratification method. EVIDENCE ACQUISITION: Placebo-controlled randomized trials investigating the effect of low-dose aspirin on maternal or perinatal outcomes with sufficient raw data and published in English from inception to August 2020 were searched for from PubMed, Embase, Cochrane Library, and Google Scholar in accordance with PRISMA guidelines. Review articles, editorials, case reports, conference abstracts, and nonplacebo-controlled studies were excluded. EVIDENCE SYNTHESIS: A total of 35 placebo-controlled randomized trials with 46,568 pregnant women were included in this meta-analysis. Aspirin prophylaxis substantially lowered the risk of pre-eclampsia, preterm birth, perinatal mortality, and intrauterine growth retardation without elevated bleeding risks. Low-dose aspirin considerably enhanced neonatal birth weight but did not decrease the risk of gestational hypertension. The subgroup analysis revealed substantially reduced pre-eclampsia risk and enhanced birth weight and gestational age at delivery in women who initiated aspirin before 20 weeks of gestation (RR=0.76, 95% CI=0.64, 0.90, p=0.001). However, the effect of aspirin dose on pregnancy outcomes was insignificant and requires further evaluation. CONCLUSIONS: Initiation of low-dose aspirin administration before 20 weeks of gestation considerably decreases the incidence of pre-eclampsia and related neonatal outcomes without increasing bleeding risk.

Repeated Irradiation with γ-Ray Induces Cancer Stemness through TGF-ß-DLX2 Signaling in the A549 Human Lung Cancer Cell Line.

Cancer stem cells (CSCs) play an important role in cancer recurrence and metastasis. It is suggested that the CSC properties in heterogeneous cancer cells can be induced by ionizing radiation (IR). This study investigated the role of DLX2 in the radioresistance and CSC properties induced by IR in NSCLC cancer cells. Here, A549 cells were exposed to fractionated irradiation at a cumulative dose of 52 Gy (4 Gy × 13 times) for a generation of radioresistant cells. After fractionated irradiation, surviving A549 cells exhibited resistance to IR and enhanced expression of various cancer stem cell markers. They also showed upregulation of mesenchymal molecular markers and downregulation of epithelial molecular markers, correlating with an increase in the migration and invasion. Fractionated irradiation triggered the secretion of TGF-ß1 and DLX2 expression. Interestingly, the increased DLX2 following fractionated irradiation seemed to induce the expression of the gene for the EGFR-ligand betacellulin via Smad2/3 signaling. To contrast, DLX2 knockdown dramatically decreased the expression of CSC markers, migration, and proliferation. Moreover, A549 cells expressing DLX2 shRNA formed tumors with a significantly smaller volume compared to those expressing control shDNA in a mouse xenograft assay. These results suggest that DLX2 overexpression in surviving NSCLC cancer cells after fractionated IR exposure is involved in the cancer stemness, radioresistance, EMT, tumor survival, and tumorigenic capability.