Association between coenzyme Q 10-related genetic polymorphisms and statin-associated myotoxicity in Korean stroke patients.

Introduction: The purpose of this study is to identify the relationship between coenzyme Q 10 (CoQ10)-related gene polymorphisms and statin-related myotoxicity (SRM). Methods: We retrospectively analyzed prospectively collected samples from February to May 2021. To investigate the association between CoQ10-related genetic factors and SRM, we selected 37 single nucleotide polymorphisms from five genes (COQ2, COQ3, COQ5, COQ6, and COQ7). The odds ratio (OR) and adjusted OR with 95% confidence intervals (CI) were calculated for univariate and multivariable logistic regression analyses, respectively. Results: A total of 688 stroke patients were included in the analysis, including 56 SRM cases. In the multivariable analysis, two models were constructed using demographic factors only in model I, and demographic and genetic factors in model II. Compared to other statins, atorvastatin decreased the SRM risk whereas ezetimibe use increased the SRM risk in model I and model II. Patients with COQ2 rs4693075 G allele, COQ3 rs11548336 TT genotype, and COQ5 rs10849757 A allele had a 2.9-fold (95% CI: 1.6-5.3), 1.9-fold (95% CI: 1.1-3.5), and 3.3-fold (95% CI: 1.5-8.3) higher risk of SRM, respectively. Conclusion: This study could be utilized to develop a personalized medicine strategy in patients treated with statins.

Sleep-related adverse events of smoking cessation drugs: A network meta-analysis of randomized controlled trials.

Smoking cessation medications have the potential to affect the functioning of the nervous system, leading to sleep disturbances. Our study aimed to compare the sleep-related side effects (such as insomnia, abnormal dreams, nightmares, and somnolence) induced by different smoking cessation medications in non-psychiatric smokers. We conducted a thorough search of five electronic databases (Cochrane, EMBASE, PubMed, PsycInfo, and Web of Science) for randomized controlled trials. This study was registered with the PROSPERO (registration number CRD42022347976). A total of 79 full-text articles, encompassing 36,731 participants, were included in our analysis. Individuals using bupropion, bupropion in combination with a nicotinic acetylcholine receptor agonist (NRA), and bupropion in conjunction with nicotine replacement therapy (NRT) exhibited a higher likelihood of experiencing insomnia compared to those using NRT alone. Bupropion plus NRA had the highest ranking on the surface under the cumulative ranking curve (SUCRA) for insomnia risk, while placebo had the lowest ranking. Additionally, NRA plus NRT ranked first for abnormal dream outcomes, NRA alone for nightmares, and nortriptyline for somnolence, based on the SUCRA results. Healthcare providers should exercise caution when prescribing smoking cessation drugs, particularly in consideration of their potential sleep-related side effects.

Construction of a risk scoring system using clinical factors and RYR2 polymorphisms for bleeding complications in patients on direct oral anticoagulants.

Introduction: Bleeding is one of the most undesirable complications of direct oral anticoagulants (DOACs). While the ryanodine receptor (RYR2) has been related to cardiac diseases, research on bleeding complications is lacking. This study aimed to elucidate the association between RYR2 and bleeding risk to develop the risk scoring system in patients treated with DOACs. Methods: This study was a retrospective analysis of prospectively collected samples. We selected ten SNPs within the RYR2 gene, and two models were constructed (Model I: demographic factors only, Model II: demographic and genetic factors) in multivariable analysis. Independent risk factors for bleeding were used to develop a risk scoring system. Results: A total of 447 patients were included, and 49 experienced either major bleeding or clinically relevant non-major bleeding. In Model I, patients using rivaroxaban and experiencing anemia exhibited an increased bleeding risk after adjusting for covariates. Upon incorporating genetic factors into Model I, a significant association with bleeding was also observed in cases of overdosing on DOACs and in patients with a creatinine clearance (CrCl) < 30 mL/min, in addition to rivaroxaban and anemia (Model II). Among genetic factors, RYR2 rs12594 GG, rs17682073 AA, rs3766871 GG, and rs6678625 T alleles were associated with bleeding complications. The area under the receiver operating characteristic curve (AUROC) of Model I was 0.670, whereas that of Model II increased to 0.803, demonstrating better performance with the inclusion of genetic factors. Using the significant variables in Model II, a risk scoring system was constructed. The predicted bleeding risks for scores of 0, 1-2, 3-4, 5-6, 7-8, and 9-10 points were 0%, 1.2%, 4.6%, 15.7%, 41.7%, and 73.3%, respectively. Conclusion: This study revealed an association between RYR2 and bleeding complications among patients taking DOACs and established a risk scoring system to support individualized DOAC treatment for these patients.

Machine learning-based prediction of risk factors for abnormal glycemic control in diabetic cancer patients receiving nutrition support: a case-control study.

PURPOSE: To date, risk factors affecting abnormal glycemic control have not been investigated. This study aimed to analyze risk factors for hypoglycemia or hyperglycemia in diabetic cancer patients receiving nutritional support by using machine learning methods. METHODS: This retrospective two-center study was performed using medical records. Odds ratios and adjusted odds ratios were estimated from univariate and multivariate analyses, respectively. Machine learning algorithms, including five-fold cross-validated multivariate logistic regression, elastic net, and random forest, were developed to predict risk factors for hypoglycemia and hyperglycemia. RESULTS: Data from 127 patients were analyzed. The use of sulfonylurea (SU) and blood urea nitrogen (BUN) level > 20 mg/dL increased hypoglycemia by 6.3-fold (95% CI 1.30-30.47) and 5.0-fold (95% CI 1.06-23.46), respectively. In contrast, patients who received an actual energy intake/total energy expenditure (TEE) ≥ 120% and used dipeptidyl peptidase-4 (DPP-4) inhibitors had a higher risk of hyperglycemia by 19.3- (95% CI 1.46-254.78) and 3.3-fold (95% CI 1.23-8.61), respectively. An initial blood glucose level ≥ 182.5 mg/dL also increased the risk of hyperglycemia by 15.3-fold. AUROC values for all machine learning methods indicated acceptable and excellent performance for hypoglycemia and hyperglycemia. CONCLUSION: The use of SU and BUN level > 20 mg/dL increased the risk of hypoglycemia, whereas an initial blood glucose level ≥ 182.5 mg/dL, a supplied actual energy intake/ TEE ≥ 120%, and the use of DPP-4 inhibitors increased the risk of hyperglycemia.

Association between SLCO1B1 genetic polymorphisms and bleeding risk in patients treated with edoxaban.

Since SLCO1B1 encodes the uptake transporter OATP1B1, which can influence the pharmacokinetic and pharmacodynamic profiles of edoxaban, polymorphisms in SLCO1B1 may affect the edoxaban response. This study aimed to investigate the association between SLCO1B1 gene polymorphisms and the bleeding risk in patients receiving edoxaban. We genotyped 10 single-nucleotide polymorphisms (SNPs) from the SLCO1B1 gene in patients receiving edoxaban. We also analyzed rs3842 of ABCB1 as a confounder. The odds ratio (OR) and adjusted OR (AOR) were calculated from univariate and multivariable analysis, respectively. The area under the receiver operating characteristic curve (AUROC) was constructed for the discrimination of the model. A total of 159 patients receiving edoxaban were analyzed. Overdose and rs4149056 showed significant association with bleeding complications by around 11- and 5.5-fold, respectively. Additionally, patients with the rs4149057 variant allele (C) had a 3.9-fold increased bleeding risk compared with wild-type homozygote carriers (TT), whereas rs2306283 variant homozygote (GG) carriers had a 0.27-fold reduced bleeding risk compared with wild-type allele (A) carriers. Patients with the variant-type homozygote (CC) of ABCB1 rs3842 had a higher bleeding risk than T allele carriers (AOR = 5.3 and 5.9). The final models for multivariable analyses were acceptable based on the AUROC values (> 0.70). These findings may help predict bleeding risk in patients taking edoxaban and help personalize treatment.

Effects of CYP3A4*22 polymorphism on trough concentration of tacrolimus in kidney transplantation: a systematic review and meta-analysis.

Purpose: Tacrolimus (Tac) is a widely used immunosuppressive agent in kidney transplantation. Cytochrome P450 (CYP), especially CYP3A4 enzymes are responsible for the metabolism of drugs. However, the correlation between plasma Tac concentration and CYP3A4*22 gene variants is controversial. This meta-analysis aims to evaluate the association between CYP3A4*22 polymorphism and the dose-adjusted trough concentration (C0/D) of Tac in adult kidney transplant patients. Methods: We conducted a literature review for qualifying studies using the PubMed, Web of Science, and Embase databases until July 2023. For the continuous variables (C0/D and daily dose), mean difference (MD) and corresponding 95% confidence intervals (CIs) were calculated to evaluate the association between the CYP3A4 * 22 and Tac pharmacokinetics. We performed an additional analysis on the relationship of CYP3A5*3 with Tac PKs and analyzed the effects of CYP3A4*22 in CYP3A5 non-expressers. Results: Overall, eight eligible studies with 2,683 renal transplant recipients were included in this meta-analysis. The CYP3A4*22 allele was significantly associated with a higher C0/D (MD 0.57 ng/mL/mg (95% CI: 0.28 to 0.86; p = 0.0001) and lower mean daily dose requirement (MD -2.02 mg/day, 95% CI: -2.55 to -1.50; p < 0.00001). An additional meta-analysis demonstrated that carrying the CYP3A5*3 polymorphism greatly impacted Tac blood concentration. From the result with CYP3A5 non-expressers, CYP3A4*22 showed significant effects on the Tac C0/D and dose requirement even after adjusting the effect of CYP3A5*3. Conclusion: Patients with CYP3A4*22 allele showed significantly higher plasma C0/D of Tac and required lower daily dose to achieve the therapeutic trough level after kidney transplantation. These findings of our meta-analysis may provide further evidence for the effects of genetic polymorphism in CYP3A4 on the PKs of Tac, which will improve individualized treatment in a clinical setting.

Novel Gene Polymorphisms for Stable Warfarin Dose in a Korean Population: Genome-Wide Association Study.

Warfarin has a narrow therapeutic window and high intra- and inter-individual variability. Considering that many published papers on genotype-guided dosing are derived from European populations, the aim of this study was to investigate novel genetic variants associated with the variability of stable warfarin dose in the Korean population with cardiac valve replacement, using the GWAS approach. This retrospective cohort study was performed from January 1982 to December 2020 at the Severance Cardiovascular Hospital of Yonsei University College of Medicine. GWAS was performed to identify associations between genotypes and the warfarin maintenance dose, by comparing the allele frequency of genetic variants between individuals. Then, the extent of genetic and non-genetic factors on the dose variability was determined by multivariable regression analysis. The study enrolled 214 participants, and the most robust signal cluster was detected on chromosome 16 around VKORC1. Followed by VKORC1, three novel variants (NKX2-6 rs310279, FRAS1 rs4386623, and FAM201A rs1890109) showed an association with stable warfarin dose requirement in univariate analysis. The algorithm was constructed by using multivariable analysis that includes genetic and non-genetic factors, and it could explain 58.5% of the variations in stable warfarin doses. In this variability, VKORC1 rs9934438 and FRAS1 rs4386623 accounted for 33.0% and 9.9%, respectively. This GWAS analysis identified the fact that three novel variants (NKX2-6 rs310279, FRAS1 rs4386623, and FAM201A rs1890109) were associated with stable warfarin doses. Additional research is necessary to validate the results and establish personalized treatment strategies for the Korean population.

ABCG2 Gene Polymorphisms May Affect the Bleeding Risk in Patients on Apixaban and Rivaroxaban.

Purpose: Direct oral anticoagulants (DOACs) are widely used for stroke prevention in atrial fibrillation. However, they have a bleeding complication. Breast cancer resistance protein, encoded by ABCG2, is known to be an efflux transporter of apixaban and rivaroxaban among DOACs. This study aimed to investigate the association between gene variants and bleeding complications during treatment with ABCG2 substrates (apixaban and rivaroxaban). Patients and Methods: Patients treated with apixaban and rivaroxaban were enrolled from June 2018 to December 2021. Five single nucleotide polymorphisms (SNPs) of ABCG2 were selected. Previously studied genes (ABCB1, CYP3A4, and CYP3A5) were further analyzed as possible confounders. Finally, a total of 16 SNPs were examined in this case-control study. The outcome was defined as major bleeding and clinically relevant non-major bleeding. Two models were constructed using the multivariable analysis. Results: Among 293 patients, 64 were cases. The mean age of the patients was 68.8 years, and males comprised 62.5% of the study population. Model I revealed that a history of bleeding, concurrent use of proton pump inhibitor (PPI), ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with bleeding complications; the AORs (95% CI) were 6.209 (2.210-17.442), 2.385 (1.064-5.349), 2.188 (1.156-4.142), and 3.243 (1.371-7.671), respectively. Model II showed that modified HAS-BLED score, concurrent use of PPI, ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with bleeding complications. Conclusion: The modified HAS-BLED score, a history of bleeding, concurrent use of PPI, ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with the risk of bleeding complications in patients on apixaban and rivaroxaban, after adjusting for other confounders. These findings can be used to develop individualized treatment strategies for patients taking apixaban and rivaroxaban.

Interactive Associations between PPARγ and PPARGC1A and Bisphosphonate-Related Osteonecrosis of the Jaw in Patients with Osteoporosis.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare but severe adverse effect that can occur as a result of bisphosphonate treatment. This study aimed to examine the relationship between PPARγ and PPARGC1A polymorphisms and the BRONJ development in female osteoporosis patients undergoing bisphosphonate treatment. We prospectively conducted this nested case-control study at the Ewha Womans University Mokdong Hospital between 2014 and 2018. We assessed five single-nucleotide polymorphisms (SNPs) of PPARγ and six SNPs of PPARGC1A and performed a multivariable logistic regression analysis to determine the independent risk factors for developing BRONJ. There were a total of 123 patients included in this study and 56 patients (45.5%) developed BRONJ. In the univariate analysis, PPARGC1A rs2946385 and rs10020457 polymorphisms were significantly associated with BRONJ (p = 0.034, p = 0.020, respectively), although the results were not statistically significant in the multivariable analysis. Patients with the combined genotypes of GG in both PPARγ rs1151999 and PPARGC1A rs2946385 showed a 3.03-fold higher risk of BRONJ compared to individuals with other genotype combinations after adjusting for confounders (95% confidence interval (CI): 1.01-9.11). Old age (≥70 years) and duration of bisphosphonate use (≥60 months) increased the risk of BRONJ. The area under the receiver operating characteristic curve for the predicted probability was 0.78 (95% CI: 0.69-0.87, p < 0.001), demonstrating a satisfactory level of discriminatory power. Our study elucidated that PPARγ and PPARGC1A polymorphisms were interactively associated with BRONJ development. These results have potential implications for tailoring personalized treatments for females undergoing bisphosphonate therapy for osteoporosis.

Prediction of medication-related osteonecrosis of the jaws using machine learning methods from estrogen receptor 1 polymorphisms and clinical information.

Objective: The purpose of this study was to evaluate the effect of estrogen receptor 1 (ESR1) polymorphisms on the development of medication-related osteonecrosis of the jaws (MRONJ) in women with osteoporosis. Methods: A total of 125 patients taking bisphosphonates was evaluated the relationship between MRONJ occurrence and single nucleotide polymorphisms (SNPs) of ESR1. Clinical information was collected, including current age, treatment duration, and comorbidity. Univariate and Multivariable regression analyzes were performed to evaluate the independent predictive factors for MRONJ occurrence. Predictive models were constructed using machine learning methods such as Lasso regression, Random forest (RF), and Support vector machine (SVM). The area under the receiver-operating curve (AUROC) was used to evaluate the performance of a binary classifier. Result: Two SNPs of ESR1 (rs4870056 and rs78177662) were significantly associated with MRONJ development. Patients with variant allele (A) of rs4870056 showed 2.45 times (95% CI, 1.03-5.87) the odds of MRONJ occurrence compared to those with wild-type homozygote (GG) after adjusting covariates. Additionally, carriers with variant allele (T) of rs78177662 had higher odds than those with wild-type homozygote (CC) (adjusted odds ratio (aOR), 2.64, 95% CI, 1.00-6.94). Among demographic variables, age ≥ 72 years (aOR, 3.98, 95% CI, 1.60-9.87) and bisphosphonate exposure ≥48 months (aOR, 3.16, 95% CI, 1.26-7.93) were also significant risk factors for MRONJ occurrence. AUROC values of machine learning methods ranged between 0.756-0.806 in the study. Conclusion: Our study showed that the MRONJ occurrence was associated with ESR1 polymorphisms in osteoporotic women.

Comparison of pharmacogenomic information for drug approvals provided by the national regulatory agencies in Korea, Europe, Japan, and the United States.

Pharmacogenomics, which is defined as the study of changes in the properties of DNA and RNA associated with drug response, enables the prediction of the efficacy and adverse effects of drugs based on patients' specific genetic mutations. For the safe and effective use of drugs, it is important that pharmacogenomic information is easily accessible to clinical experts and patients. Therefore, we examined the pharmacogenomic information provided on drug labels in Korea, Europe, Japan, and the United States (US). The selection of drugs that include pharmacogenomic information was based on the drug list that includes genetic information from the Korea Ministry of Food and Drug Safety (MFDS) and US Food and Drug Administration (FDA) websites. Drug labels were retrieved from the sites of MFDS, FDA, European Medicines Agency, and Japanese Pharmaceuticals and Medical Devices Agency. Drugs were classified as per the Anatomical Therapeutic Chemical code, and the biomarkers, labeling sections, and necessity of genetic tests were determined. In total, 348 drugs were selected from 380 drugs with available pharmacogenomic information in Korea and the US after applying the inclusion and exclusion criteria. Of these drugs, 137, 324, 169, and 126 were with pharmacogenomics information in Korea, the US, Europe, and Japan, respectively. The most commonly represented drug class was antineoplastic and immunomodulating agents. Regarding the classification as per the mentioned biomarkers, the cytochrome P450 enzyme was the most frequently mentioned information, and the targeted anticancer drugs most commonly required genetic biomarker testing. The reasons for differences in drug labeling information based on country include differences in mutant alleles according to ethnicity, frequencies at which drug lists are updated, and pharmacogenomics-related guidelines. Clinical experts must continuously strive to identify and report mutations that can explain drug efficacy or side effects for safe drug use.

Correlation between PPARG Pro12Ala Polymorphism and Therapeutic Responses to Thiazolidinediones in Patients with Type 2 Diabetes: A Meta-Analysis.

Background: Thiazolidinediones (TZDs) are a type of oral drug that are utilized for the treatment of type 2 diabetes mellitus (T2DM). They function by acting as agonists for a nuclear transcription factor known as peroxisome proliferator-activated receptor-gamma (PPAR-γ). TZDs, such as pioglitazone and rosiglitazone, help enhance the regulation of metabolism in individuals with T2DM by improving their sensitivity to insulin. Previous studies have suggested a relationship between the therapeutic efficacy of TZDs and the PPARG Pro12Ala polymorphism (C > G, rs1801282). However, the small sample sizes of these studies may limit their applicability in clinical settings. To address this limitation, we conducted a meta-analysis assessing the influence of the PPARG Pro12Ala polymorphism on the responsiveness of TZDs. Method: We registered our study protocol with PROSPERO, number CRD42022354577. We conducted a comprehensive search of the PubMed, Web of Science, and Embase databases, including studies published up to August 2022. We examined studies investigating the association between the PPARG Pro12Ala polymorphism and metabolic parameters such as hemoglobin A1C (HbA1C), fasting plasma glucose (FPG), triglyceride (TG), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and total cholesterol (TC). The mean difference (MD) and 95% confidence intervals (CIs) between pre- and post-drug administration were evaluated. The quality of the studies included in the meta-analysis was assessed by using the Newcastle-Ottawa Scale (NOS) tool for cohort studies. Heterogeneity across studies was assessed by using the I2 value. An I2 value greater than 50% indicated substantial heterogeneity, and a random-effects model was used for meta-analysis. If the I2 value was below 50%, a fixed-effects model was employed instead. Both Begg's rank correlation test and Egger's regression test were performed to detect publication bias, using R Studio software. Results: Our meta-analysis incorporated 6 studies with 777 patients for blood glucose levels and 5 studies with 747 patients for lipid levels. The included studies were published between 2003 and 2016, with the majority involving Asian populations. Five of the six studies utilized pioglitazone, while the remaining study employed rosiglitazone. The quality scores, as assessed with the NOS, ranged from 8 to 9. Patients carrying the G allele exhibited a significantly greater reduction in HbA1C (MD = -0.3; 95% CI = -0.55 to -0.05; p = 0.02) and FPG (MD = -10.91; 95% CI = -19.82 to -2.01; p = 0.02) levels compared to those with the CC genotype. Furthermore, individuals with the G allele experienced a significantly larger decrease in TG levels than those with the CC genotype (MD = -26.88; 95% CI = -41.30 to -12.46; p = 0.0003). No statistically significant differences were observed in LDL (MD = 6.69; 95% CI = -0.90 to 14.29; p = 0.08), HDL (MD = 0.31; 95% CI = -1.62 to 2.23; p = 0.75), and TC (MD = 6.4; 95% CI = -0.05 to 12.84; p = 0.05) levels. No evidence of publication bias was detected based on Begg's test and Egger's test results. Conclusions: This meta-analysis reveals that patients with the Ala12 variant in the PPARG Pro12Ala polymorphism are more likely to exhibit positive responses to TZD treatment in terms of HbA1C, FPG, and TG levels compared to those with the Pro12/Pro12 genotype. These findings suggest that genotyping the PPARG Pro12Ala in diabetic patients may be advantageous for devising personalized treatment strategies, particularly for identifying individuals who are likely to respond favorably to TZDs.

Risk Factors for Palbociclib-Induced Early Developing Neutropenia in Patients with Hormone Receptor-Positive Metastatic Breast Cancer.

PURPOSE: This study aimed to determine the risk factors for palbociclib-induced grade 4 or grade 3 neutropenia (NP) requiring dose reduction or delayed treatment in patients with HR+/HER2-metastatic breast cancer in the first 3 cycles (early grade 3/4 NP) and whether the early developing grade 3/4 NP affects progression-free survival. METHODS: A retrospective study using electronic medical records was conducted on patients who received palbociclib for metastatic breast cancer between January 2018 and August 2022. The early grade 3/4 NP risk factors were evaluated with univariate and multivariable logistic regression analyses. In addition, the Kaplan-Meier method was used to estimate the median progression-free survival (PFS) to analyze the effect of early grade 3/4 NP on treatment. RESULTS: Out of the 264 patients included in this study, 173 (65.6%) experienced early grade 3/4 NP. A total of four models were applied for multivariable analysis to identify early grade 3/4 NP-developing factors. Low baseline ANC, WBC, PLT, and BSA were significant risk factors for early grade 3/4 NP; baseline ANC < 3700/mm3, WBC < 6.30 × 109/mm3, PLT < 230 × 109/mm3, and BSA < 1.58 m2 increased the risk by approximately 4.0-fold, 3.7-4.0-fold, 2.1-fold, and 2.0-fold, respectively. Early grade 3/4 NP did not affect PFS (p = 0.710), although patients with early grade 3/4 NP had more frequent dose reductions or treatment delays. CONCLUSIONS: Based on the results, low baseline ANC, WBC, PLT, and BSA were associated with early grade 3/4 NP. Patients with risk factors require careful monitoring, and this study is expected to help predict NP, which may appear in early treatment.

Evaluation of Low-Molecular-Weight Heparin for Treatment of Portal Vein Thrombosis in Liver Cirrhosis Patients.

Background and Objectives: Even though low-molecular-weight heparin (LMWH), including dalteparin, has a critical role in portal vein thrombosis (PVT) treatment in liver cirrhosis (LC) patients, the predictive factors and the proper dose of dalteparin for PVT treatment and relapse have not yet been investigated. Materials and Methods: This retrospective study evaluated the records of LC patients receiving dalteparin from July 2013 to June 2019. The odds ratio (OR) and adjusted OR were calculated from univariate and multivariable analyses, respectively. Results: Among data from 121 patients, the overall recanalization rate of all patients was 66.1% (80 patients). No history of variceal bleeding (OR 4.6, 95% CI: 1.88-11.43) and the case of newly developed thrombus before dalteparin treatment (OR 3.2, 95% CI: 1.24-8.08) were predictive factors associated with increased treatment response. Relapse of PVT occurred in 32 out of 80 patients (40%) who showed a recanalization. The risk of relapse was 3.1-3.9 times higher in those who took more than three months or more than six months from the diagnosis of PVT to dalteparin treatment compared to those who took less than these durations, respectively. In the dosing regimen, patients with the kg-based dosing regimen showed 2.6 times better response than those with the fixed dosing regimen. However, no difference in bleeding complications was observed. Conclusion: In the dosing regimen, the kg-based regimen that was the same as the venous thromboembolism regimen was a better option for the efficacy and safety of dalteparin therapy. Additionally, when treating PVT in LC patients, careful monitoring is recommended for patients with predictive factors for treatment response and relapse of PVT.

Association between Genetic Polymorphisms and Bleeding in Patients on Direct Oral Anticoagulants.

Objectives: The purpose of our study is to investigate the effects of apolipoprotein B (APOB) and APOE gene polymorphisms on bleeding complications in patients receiving direct oral anticoagulants (DOACs). Methods: A total of 16 single nucleotide polymorphisms (SNPs) in 468 patients were genotyped. Six SNPs of ABCB1 (rs3842, rs1045642, rs2032582, rs1128503, rs3213619, and rs3747802), one SNP of CYP3A5 (rs776746), seven SNPs of APOB (rs1042034, rs2163204, rs693, rs679899, rs13306194, rs13306198, and rs1367117), and two SNPs of APOE (rs429358 and rs7412) were analyzed by a TaqMan genotyping assay. Multivariable logistic regression analysis with selected variables was performed for the construction of a risk scoring system. Two risk scoring systems were compared (demographic factors only vs. demographic factors and genetic factors). Results: In the multivariable analyses, two models were constructed; only demographic factors were included in Model I and both demographic factors and genetic factors in Model II. Rivaroxaban and anemia showed significant association with bleeding in both models. Additionally, ABCB1 rs3842 variant homozygote carriers (CC) and APOB rs13306198 variant allele carriers (AG, AA) had a higher risk of bleeding risk compared with that of wild-type allele carriers (TT, TC) and wild-type homozygote carriers (GG), respectively. Whereas the area under the receiver operating characteristic curve (AUROC) value using demographic factors only was 0.65 (95% confidence interval (CI): 0.56-0.74), the AUROC increased to 0.72 by adding genetic factors (95% CI: 0.65-0.80). The predicted bleeding risks of bleeding in patients with 0, 1, 2, 3, 4, 5, 6, 7 and 8 points from the logistic regression curve were 0.8%, 2.0%, 5.4%, 5.2%, 12.5%, 26.9%, 47.0%, 64.3% and 82.3%, respectively. Conclusions: The study results can be used for enhancing individualized treatment strategies in patients taking DOACs, helping clinicians predict the bleeding risk.

Associations of GNAS and RGS Gene Polymorphisms with the Risk of Ritodrine-Induced Adverse Events in Korean Women with Preterm Labor: A Cohort Study.

Ritodrine, a ß2-adrenergic receptor agonist, is among most commonly prescribed tocolytic agents. This study aimed to evaluate the associations of single nucleotide polymorphisms in GNAS, RGS2, and RGS5 with the risk of ritodrine-induced adverse events (AEs) and develop a risk scoring system to identify high-risk patients. This is the prospective cohort study conducted at the Ewha Woman's University Mokdong Hospital between January 2010 and October 2016. Pregnant women were included if they were treated with ritodrine for preterm labor with regular uterine contractions (at least 3 every 10 min) and cervical dilation. A total of 6, 3, and 5 single nucleotide polymorphisms (SNPs) of GNAS, RGS2, and RGS5 genes were genotyped and compared in patients with and without ritodrine-induced AEs. A total of 163 patients were included in this study. After adjusting confounders, GNAS rs3730168 (per-allele odds ratio (OR): 2.1; 95% confidence interval (95% CI): 1.0-4.3) and RGS2 rs1152746 (per-allele OR: 2.6, 95% CI: 1.1-6.5) were significantly associated with ritodrine-induced AEs. According to the constructed risk scoring models, patients with 0, 1, 2, 3, 4, and 5 points showed 0%, 13%, 19%, 31%, 46%, and 100% risks of AEs. This study suggested that GNAS and RGS2 polymorphisms could affect the risk of AEs in patients treated with ritodrine.

Risk factors for vancomycin-associated acute kidney injury: A systematic review and meta-analysis.

AIMS: This systematic literature review and meta-analysis aimed to evaluate the risk factors for vancomycin-associated acute kidney injury (AKI) incidence. METHODS: This study assessed risk factors for vancomycin-associated AKI in adult patients by searching studies from PubMed, the Cochrane Library and Embase. Random effect models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Fifty-three studies were included in our meta-analysis. For patient factors, black race (OR 1.47, 95% CI: 1.16-1.87), Caucasian (OR 0.72, 95% CI: 0.58-0.90) and obesity (OR 1.46, 95% CI: 1.12-1.90) were associated with an increase in vancomycin-associated AKIs. In terms of vancomycin-related factors, longer treatment duration (>14 d; OR 1.73, 95% CI: 1.06-2.83), serum vancomycin trough level >15 µg/mL (OR 2.10, 95% CI: 1.43-3.07) and vancomycin trough level >20 µg/mL (OR 2.84, 95% CI: 1.48-5.44) increased the risks of vancomycin-associated AKI. For comorbidities and clinical factors, renal disease (OR 2.19, 95% CI: 1.51-3.17) showed the highest odds of vancomycin-associated AKI, followed by hepatic disease, intensive care unit admission, heart failure, sepsis, coronary heart disease and diabetes mellitus. For concomitant nephrotoxic drugs, amphotericin B (OR 5.21, 95% CI: 3.44-7.87) showed the highest odds of vancomycin-associated AKI, followed by acyclovir (OR 3.22, 95% CI: 1.39-7.46), vasopressors, loop diuretics, piperacillin-tazobactam and aminoglycoside. The use of any concomitant nephrotoxic agent (OR 1.74, 95% CI: 1.17-2.58) increased the odds of vancomycin-associated AKI. CONCLUSION: Our results may help predict the risk of vancomycin-associated AKI in the clinical setting.

Global Research Trends of Gender-Related Artificial Intelligence in Medicine Between 2001-2020: A Bibliometric Study.

This study aimed to assess the research on medical Artificial intelligence (AI) related to sex/gender and explore global research trends over the past 20 years. We searched the Web of Science (WoS) for gender-related medical AI publications from 2001 to 2020. We extracted the bibliometric data and calculated the annual growth of publications, Specialization Index, and Category Normalized Citation Impact. We also analyzed the publication distributions by institution, author, WoS subject category, and journal. A total of 3,110 papers were included in the bibliometric analysis. The number of publications continuously increased over time, with a steep increase between 2016 and 2020. The United States of America and Harvard University were the country and institution that had the largest number of publications. Surgery and urology nephrology were the most common subject categories of WoS. The most occurred keywords were machine learning, classification, risk, outcomes, diagnosis, and surgery. Despite increased interest, gender-related research is still low in medical AI field and further research is needed.

Association of the SLC47A1 Gene Variant With Responses to Metformin Monotherapy in Drug-naive Patients With Type 2 Diabetes.

CONTEXT: Although metformin is the first-line treatment for type 2 diabetes, the blood sugar-lowering effect of metformin varies among populations. SLC47A1 plays an important role in metformin pharmacokinetics and pharmacodynamics. OBJECTIVE: We performed a systematic review and meta-analysis to investigate the association between SLC47A1 rs2289669 (G > A) and the metformin response in drug-naive patients with type 2 diabetes. METHODS: Studies published until January 27, 2022, were retrieved from Cochrane CENTRAL, Embase, PubMed, and Web of Science. Two reviewers independently screened titles, abstracts, and full-text articles. Studies conducted in newly diagnosed or drug-naive patients with type 2 diabetes who received metformin monotherapy were included. A total of 6 studies involving 953 patients were included in this meta-analysis. We extracted the study characteristics and changes in glycated hemoglobin (HbA1c) levels before and after treatment according to the SLC47A1 rs2289669 genotype. Changes in HbA1c levels were analyzed using mean differences (MDs) and 95% CIs. SLC47A1 rs2289669 was associated with changes in HbA1c levels (A carrier vs GG; MD = -0.55; 95% CI, -0.91 to - 0.20; I²â€…= 63%). The sensitivity analysis yielded similar results to the main analysis (MD range, -0.64 to -0.37). When comparing all 3 genotypes, there were significant differences in HbA1c level changes between AA vs GG and GA vs GG, but not in GA vs AA. CONCLUSION: This meta-analysis showed that SLC47A1 rs2289669 is associated with the glycemic response to metformin in drug-naive patients with type 2 diabetes.

Effects of CYP2D6 genotypes on Plasmodium vivax recurrence after primaquine treatment: A meta-analysis.

OBJECTIVES: To elucidate the relationship between CYP2D6 polymorphisms and Plasmodium vivax recurrence in patients receiving primaquine-based treatment through systematic review and meta-analysis. METHODS: We searched the PubMed, EMBASE, Cochrane Library, and Web of Science databases for eligible studies published up to August of 2021. We included studies investigating the associations between CYP2D6 polymorphisms and P. vivax recurrence. We evaluated the pooled odds ratio (OR) and 95% confidence interval (CI). RESULTS: Data from nine studies, including 970 patients, were analyzed. We found that CYP2D6 poor metabolizers (PMs), intermediate metabolizers (IMs), or normal metabolizers slow (NM-Ss) were associated with a 1.8-fold (95% CI, 1.34-2.45; P = 0.0001) higher recurrence of P. vivax than normal metabolizers fast (NM-Fs), extensive metabolizers (EMs), or ultrarapid metabolizer (UMs). Subgroup analysis showed that studies on both Brazilian and Southeast or East Asian individuals had similar results to the main results. Sensitivity analysis by sequentially excluding individual studies also showed robust results (OR range: 1.63-2.01). CONCLUSIONS: This meta-analysis confirmed that CYP2D6 PMs, IMs, or NM-Ss increased the risk of P. vivax recurrence compared to NM-Fs, EMs, or UMs. The results of this study could be used to predict P. vivax recurrence and suggest CYP2D6 genotype-based primaquine dosing.