AUC Levels Research Articles

P-1163. The Efficacy and Safety of Tosufloxacin in the Treatment of Bacterial Infections in Children: Systematic Review

Abstract Background In recent years, the use of antibiotics in pediatric patients has garnered significant attention due to the rise in drug-resistant bacteria. Tosufloxacin(TFLX) was used in pediatric pneumonia, otitis media, cholera, and anthrax. However, the limited use of TFLX in children is attributed to its adverse effects on bones and muscles. This article retrospectively analyzed the effectiveness and safety of TFLX in treating bacterial infections in children. Methods A comprehensive search was conducted on PubMed, Web of Science, and Embase, up to March 2024. Data regarding the pharmacokinetics, efficacy, and safety of TFLX use in children were included. Results A total of 26 articles were involved, indicating that the pharmacokinetic outcomes of 222 children with infectious diseases were significantly correlated with their body weight following administration of 4 or 6mg/kg of TFLX. The incidence of adverse reactions was associated with AUC and Cmax levels, where higher values of these parameters corresponded to increased adverse reactions. Notably, TFLX exhibited promising efficacy against MRMP, potentially surpassing macrolides, with minocycline showing superior efficacy compared to TFLX. Real-world data revealed a 100% clinical efficacy of TFLX in treating bacterial pneumonia in children. Moreover, a study involving 172 children with otitis media reported 97.7% and 94.1% clinical effectiveness rates for 4mg/kg and 6mg/kg doses of TFLX, respectively. Similar conclusions were drawn across various studies. Children under 2 years old, due to their functional and immune immaturity, benefitted from TFLX treatment for otitis media. The drug also demonstrated efficacy as a secondary option for children with refractory otitis media. Safety assessments highlighted diarrhea as the primary adverse reaction associated with TFLX, with minimal joint-related adverse effects. Some studies indicated a higher incidence of adverse reactions with 6mg/kg compared to 4mg/kg doses, suggesting a dose-dependent relationship. Overall, TFLX exhibited a good safety profile in pediatric infection management. Conclusion The application of TFLX in children with pneumonia and otitis media may be safe and effective, but its efficacy in MRMP is weaker than that of minocycline. Disclosures All Authors: No reported disclosures

Triglycerides to apolipoprotein A1 ratio: an effective insulin resistance-associated index in identifying metabolic dysfunction-associated fatty liver disease in type 2 diabetes mellitus

BackgroundThe triglycerides to Apolipoprotein A1 ratio (TG/APOA1) holds promise to be a more valuable index of insulin resistance for the diagnosis of metabolic dysfunction-associated fatty liver disease (MAFLD) in type 2 diabetes mellitus (T2DM). This study aims to evaluate the correlation between TG/APOA1 and MAFLD, as well as compare the efficacy of TG/APOA1 with triglycerides to high-density lipoprotein cholesterol ratio (TG/HDL-c) and triglyceride-glucose (TyG) index in identifying MAFLD among individuals with T2DM.MethodThis study consecutively recruited 779 individuals with T2DM for the investigation. The unenhanced abdominal CT scans were conducted to measure CT liver-spleen attenuation measurement (CTL-S). The CTL-S less than 1.0 and without other liver comorbidities were considered to be MAFLD. The binomial logistic regression analysis and restricted cubic spines (RCS) were employed to evaluate the association between TG/APOA1 and MAFLD. The receiver operating characteristic (ROC) curve analysis was performed to compare the efficacy of TG/APOA1 with TG/HDL-c and TyG index identifying MAFLD.ResultsThe TG/APOA1 exhibited a substantial increase in the MAFLD group (P<0.05). Even after adjustments for potential confounding factors, TG/APOA1 exhibited significant associations with nonalcoholic fatty liver disease fibrosis score (β=0.266, P<0.001), fibrosis-4 index (β=0.123, P=0.029), aspartate aminotransferase-to-platelet ratio index (β=0.113, P=0.037), and CTL-S (β=-0.225, P<0.001). Meanwhile, TG/APOA1 contributed to an independent variable for MAFLD, the odds ratio with a 95% CI was 2.092 (1.840-2.380) in the total population, 2.123 (1.810-2.511) in men, and 2.162 (1.824-2.587) in women. Additionally, the results also revealed a nonlinear association between elevated TG/APOA1 and higher MAFLD risk according to the RCS analysis whether in the total population, men, or women (P for nonlinearity and overall <0.001). Furthermore, TG/APOA1 had higher AUC level compared to TG/HDL-c and TyG index in the total population (0.769 vs 0.742, P=0.025; 0.769 vs 0.694, P < 0.001), men (0.776 vs 0.744, P=0.044; 0.776 vs 0.709, P < 0.001), and women (0.762 vs 0.728, P=0.041; 0.762 vs 0.674, P < 0.001).ConclusionTG/APOA1 serves as an effective index of insulin resistance in identifying MAFLD, offering advantages in the screening of MAFLD in T2DM.

Preclinical evaluation of an anchored immunotherapy strategy with aluminum hydroxide-tethered interleukin-12 in dogs with advanced malignant melanoma.

Melanoma is an aggressive cancer in dogs involving skin and mucosa similar to people. Anchored immunotherapeutics offer a novel approach to increase intratumoral retention of therapeutic payloads while decreasing systemic exposure, and this strategy can be critically evaluated through a comparative oncology approach. JEN-101 is an anchored canine interleukin-12 (IL-12) tethered to aluminum hydroxide administered by local injection. A Phase I study was conducted to determine the tolerability, activity, and immune responses of JEN-101 in dogs with advanced melanoma. A 3+3 dose escalation design was used to evaluate intratumoral injection of JEN-101 at 1, 3, 10, or 20 μg/kg every three weeks for four cycles. A second course was allowable in the absence of disease progression or toxicity. Peripheral blood, serum, and tumor biopsies were collected at baseline and at pre-specified timepoints for pharmacokinetic and immune analyses, which included serum cytokines, immunohistochemistry, and gene expression assessment. JEN-101 was well tolerated with adverse events being fever, lethargy, and isolated elevated liver enzymes. Five dogs experienced grade 3 events and no grade 4 events were observed. Pharmacokinetic analysis showed a trend towards dose-related Cmax within 8 hours of injection. Responding dogs demonstrated increased systemic interferon-γ and IL-10 AUC levels and local recruitment of CD3+ T cells. Increased pro-inflammatory and antigen processing gene expressions were identified in responding lesions. JEN-101 was well tolerated with evidence of biologic and therapeutic activities. Anchored IL-12 immunotherapy merits further investigation in dogs with melanoma and our approach represents an immune competent model to inform human clinical trials.

Effect of Camellia flava (Pitard) Sealy flower extract on the degeneration of Islets of Langerhans and insulin resistance in alloxan-induced hyperglycemia model on Swiss albino mice

Diabetes has always been a matter of concern to health experts as well as the community due to the increasing number of patients with diabetes and the severe consequences it may cause. Many attempts have been made to discover new treatment options for diabetes, and herbal medicines are currently considered to have great potential. This study was conducted to evaluate the effect of Camellia flava flower extract on the degeneration of the islets of Langerhans and insulin resistance in an alloxan-induced hyperglycemia model in Swiss albino mice. Hyperglycemic conditions were induced by alloxan (55 mg/kg, i.v.). The animals were then treated with glibenclamide (10 mg/kg, p.o.) and flower extract at doses of 1.09 and 2.19 g/kg, p.o. The results showed that the blood glucose, AUC, HbA1c, and HOMA-IR levels of two groups of mice receiving flower extract were considerably lower than those of the hyperglycemic untreated group (p < 0.05). The body weights of these two groups were also lower than the untreated group on the last day of the experiment, though the differences were not significant (p > 0.05). However, this was not observed when assessing insulin levels as well as relative organ weights. In biochemical tests, creatinine and AST and ALT concentrations were evaluated. There was no significant variation in creatinine and AST concentrations between the five experimental groups, whereas mice treated with glibenclamide and flower extract at both doses showed a remarkable decline in ALT concentration (p < 0.05). The hepatic histomicrographs were consistent with ALT results, while the H&E staining of kidneys showed no difference between groups. Histomicrographs of the pancreas revealed that the treatment groups using glibenclamide and flower extract had larger islets of Langerhans than those of the alloxan-treated group. Based on these results, this study demonstrated that Camellia flava flower extract exerted several beneficial effects, including blood sugar level reduction, weight loss promotion, and organ protection, hence making it a new potential herbal medication for the management of diabetes.

Anti-Obesity and Antidiabetic Effects of Fig (Ficus carica L.) Fermented Extract Using Lactobacillus plantarum BT-LP-01

This study aimed to assess the effect of fermented fig (Ficus carica L., FF) on obesity and diabetes in a mouse model. FF was cultured with the lactic acid bacterium Lactobacillus plantarum BT-LP-01 and isolated from fig peels. The antioxidant results demonstrated that FF exhibited DPPH and ABTS radical scavenging activities. In addition, FF showed high levels of total polyphenol and total flavonoids. Body and organ weight and dietary intake were significantly decreased in the FF groups compared to the HFD group. The FF group showed improved recovery in lipid metabolism and liver function compared to the HFD group. In addition, the FF group showed a significant decrease in serum C-P and insulin concentrations compared to the HFD group. FF-administered mice showed a dose-dependent recovery of fasting blood glucose and IPGTT and AUC levels compared to the HFD group. Furthermore, FF groups showed a decreased expression in FAS, C/EBPα, and FABP4, as well as significantly increased expression in ACC in the liver. This study demonstrates that FF is effective in reducing and inhibiting adipogenesis as well as lowering body weight, the blood glucose level, and lipid-related factors. These research findings demonstrate that FF is effective in treating obesity and diabetes.

Circulating miRNA-4701-3p as a predictive biomarker of cardiovascular disease which induces angiogenesis by inhibition of TOB2

Angiogenesis is mainly regulated by the delivery of VEGF-dependent signaling to cells. However, the angiogenesis mechanism regulated by VEGF-induced miRNA is still not understood. After VEGF treatment in HUVECs, we screened the changed miRNAs through small-RNA sequencing and found VEGF-induced miR-4701-3p. Furthermore, the GFP reporter gene was used to reveal that TOB2 expression was regulated by miR-4701-3p, and it was found that TOB2 and miR-4701-3p modulation could cause angiogenesis in an in-vitro angiogenic assay. Through the luciferase assay, it was confirmed that the activation of the angiogenic transcription factor MEF2 was regulated by the suppression and overexpression of TOB2 and miR-4701-3p. As a result, MEF2 downstream gene mRNAs that induce angiogenic function were regulated. We used the NCBI GEO datasets to reveal that the expression of TOB2 and MEF2 was significantly changed in cardiovascular disease. Finally, it was confirmed that the expression of circulating miR-4701-3p in the blood of myocardial infarction patients was remarkably increased. In patients with myocardial infarction, circulating miR-4701-3p was increased regardless of age, BMI, and sex, and showed high AUC levels in specificity and sensitivity analysis (AUROC) (AUC = 0.8451, 95 % CI 0.78–0.90). Our data showed TOB2-mediated modulation of MEF2 and its angiogenesis by VEGF-induced miR-4701-3p in vascular endothelial cells. In addition, through bioinformatics analysis using GEO data, changes in TOB2 and MEF2 were revealed in cardiovascular disease. We suggest that circulating miR-4701-3p has high potential as a biomarker for myocardial infarction.

Abstract PO3-29-04: Patient selection for high RSK2 expression is key for achieving improved PFS in metastatic breast cancer in the PMD-026 Phase 1/1b study

Abstract Background: PMD-026 is a first in class, reversible, oral small molecule inhibitor of p90 ribosomal S6 kinase (RSK), a kinase family activated by the MAPK and PDK-1 pathways, which regulate substrates involved in cancer cell proliferation and drug resistance. Both pathways are implicated in HR+ and triple negative breast cancer (TNBC). RSK2 can modulate the growth of breast cancer (BC) by promoting cell cycle progression through G2/M, specifically through pYB-1S102 which nucleates spindle pole formation in M-phase of cancer cells. This mechanism of action (MOA) for PMD-026 can be monitored by measuring the loss of pYB-1S102 and pCDK2Y15, a marker for G2/M arrest. Therefore, PMD-026 presents a novel mechanism to inhibit resistance at G1/S which is common for CDK4/6 inhibitors as well as ADCs such as those that contain Topoisomerase 1 conjugates. Here in, we show for the first time that PMD-026 inhibits P-YB-1S102 and pCDK2y15 in a dose-dependent manner in TNBC cells and address whether this could be translated as a pharmacodynamic marker of PMD-026 activity in patients. To guide patient selection, we are co-developing a unique and simple IHC based companion diagnostic (CDx) with Roche based on the principle that activated RSK2 translocates from the cytoplasm into the nucleus. In mBC, RSK2 was found to be highly expressed in ~70% of patients using a staining algorithm. An H-score was developed and ultimately H-score >180 (75% nuclear staining with staining intensity of 2+ or 3+ by IHC) was used as the cut-off in our Phase 1/1b trial retrospective study. This IHC assay will be used to select patients in the upcoming Phase II, as PFS in the PMD-026 Phase I/1b study showed remarkable differences when comparing patients with high and low RSK2. Results: In this Phase 1/1b study, PMD-026 was evaluated in an ethnically diverse population of women across all breast cancer subtypes. Patients had a median of 5 prior lines of therapy and PMD-026 achieved stable disease in 44% (11/25) of the subjects. Consistent with the MOA, PMD-026 inhibited pCDK2Y15 in PBMCs from patients at C1D15. Corresponding plasma concentrations were ~ 1µM, which correlates with the IC90 of PMD-026 in preclinical models. To guide patient selection in the future, the RSK2 IHC with an H:Score >180 was used to evaluate patient outcomes. Using this criterion, PFS was significantly longer in RSK2 high vs low patients (3.6 months vs 1.3 month, HR = 0.27, p = 0.031, N=20 patients representing de novo TNBC and HR+/CDK4/6 refractory subtypes). Upon further analysis, patients who had 5 lines of therapy or less benefited the most. PFS in these less heavily pretreated RSK2 high patients was 4.8 months vs 1.3 months for RSK2 low patients (HR = 0.07, p = 0.001 N=14 representing the same subtypes above). It was clear that the time on study was longer for patients with high RSK2 vs low, and this was specifically noted in de novo TNBC and HR+ patients that previously failed CDK4/6 inhibitors as well as endocrine therapies. A key observation in this study was that the PFS benefit was based on the RSK2 levels and not on any pharmacokinetic differences between patients, as the AUC (p=0.53), Cmax (p=0.73) and plasma levels (p=0.76) did not differ between RSK2 high and RSK2 low groups. These data strongly support the activity of this first in class RSK inhibitor, PMD-026, in RSK2 high breast cancers. Our integrated IHC based CDx strategy plans to prospectively enroll RSK2 high patients for our Phase 2 trials will be described. Conclusions/Translational Significance: CDx guided breast cancer therapeutics are often lacking for the treatment of TNBC, as well as HR+ breast cancers that have failed CDK4/6 inhibitors. The ability to identify patients who could potentially benefit most from RSK-targeted agents such as PMD-026 is an important step forward in delivering practice changing therapies for patients. Citation Format: Sandra Dunn, Judy Wang, Hyo Han, Robert Wesolowski, Amita Patnaik, Shakeela Bahadur, Nicolaos Palaskas, My-my Huynh, Aarthi Jayanthan, Gerrit Los, Andrew Dorr. Patient selection for high RSK2 expression is key for achieving improved PFS in metastatic breast cancer in the PMD-026 Phase 1/1b study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-29-04.

Prediction analysis of TBI 24-h survival outcome based on machine learning

BackgroundTraumatic brain injury (TBI) is the major reason for the death of young people and is well known for its high mortality and morbidity. This paper aim to predict the 24h survival of patients with TBI. MethodsA total of 1224 samples were involved in this analysis, and the clinical indicators involved included age, gender, blood pressure, MGAP and other fields, among which the target variable was “outcome”, which was a binary variable. The methods mainly involved in this paper include data visualization analysis, single factor analysis, feature engineering analysis, random forest model (RF), K-Nearst Neighbors (KNN) model, and so on. Logistic regression model (LR) and deep neural network model (DNN). We will oversample the training set using the SMOTE method because of the very unbalanced labeling of the sample itself. ResultsAlthough the accuracy of all models is very high, the recall rate is relatively low. The DNN model with the best performance only reaches 0.17, and the corresponding AUC is 0.80. After resampling, we find that the recall rate of positive samples of all models has increased a lot, but the AUC of some models has decreased. Finally, the optimal model is LR, whose positive sample recall rate is 0.67 and AUC is 0.82. ConclusionThrough resampling, we obtained that the best model is the RF model, whose recall rate and AUC are the best, and the AUC level is about 0.87, indicating that the accuracy performance of the model is still good.

An explainable machine learning model for prediction of high-risk nonalcoholic steatohepatitis

Early identification of high-risk metabolic dysfunction-associated steatohepatitis (MASH) can offer patients access to novel therapeutic options and potentially decrease the risk of progression to cirrhosis. This study aimed to develop an explainable machine learning model for high-risk MASH prediction and compare its performance with well-established biomarkers. Data were derived from the National Health and Nutrition Examination Surveys (NHANES) 2017-March 2020, which included a total of 5281 adults with valid elastography measurements. We used a FAST score ≥ 0.35, calculated using liver stiffness measurement and controlled attenuation parameter values and aspartate aminotransferase levels, to identify individuals with high-risk MASH. We developed an ensemble-based machine learning XGBoost model to detect high-risk MASH and explored the model’s interpretability using an explainable artificial intelligence SHAP method. The prevalence of high-risk MASH was 6.9%. Our XGBoost model achieved a high level of sensitivity (0.82), specificity (0.91), accuracy (0.90), and AUC (0.95) for identifying high-risk MASH. Our model demonstrated a superior ability to predict high-risk MASH vs. FIB-4, APRI, BARD, and MASLD fibrosis scores (AUC of 0.95 vs. 0.50, 0.50, 0.49 and 0.50, respectively). To explain the high performance of our model, we found that the top 5 predictors of high-risk MASH were ALT, GGT, platelet count, waist circumference, and age. We used an explainable ML approach to develop a clinically applicable model that outperforms commonly used clinical risk indices and could increase the identification of high-risk MASH patients in resource-limited settings.

Abstract CT103: Next generation capecitabine (NGC-Cap) in phase 1b trial significantly increases 5-FU exposure while improving safety profile compared to capecitabine

Abstract Background: Capecitabine (Cape) at the recommended dose of 1,000 - 1,250 mg/m2 bid has been shown to frequently cause clinically meaningful side effects such as myelosuppression and hand-foot syndrome (HFS), both of which may require dose modification, interruption, or discontinuation. HFS is caused by 5-FU catabolites while myelosuppression is caused by 5-FU anabolites. NGC-Cap combines ethynyl-uracil (PCS6422), an irreversible inhibitor of the DPD catabolism enzyme, and Cape. Methods: The Phase 1b trial is a 3+3 design with up to 5 ascending Cape doses from 75 mg qd to 300 mg bid. Cape is given 7 days on/7 days off every 14 days with a single dose of PCS6422 given 16-24 hours before the start of every cycle. The 5-FU AUC(0-9 hrs), Cmax, and T1/2 were calculated on Day 1 when DPD inhibition is at its maximum. New cohorts are opened following a review of the safety data by a cohort review committee after the second cycle. Blood samples are obtained for PK analysis of PCS6422, Cape, and Cape metabolites (e.g., 5-FU, FBAL). All patients have cancer refractory or intolerant to existing available therapies. Radiological tumor response evaluation (RECIST 1.1) is performed every 8 weeks. Results: 18 patients were enrolled in the first 4 dose levels of Cape in NGC-Cap. The 5-FU AUC (geometric mean, CV%) for the 150 and 225 mg bid NGC-Cap cohorts were 3,802 (23%) and 6,311 (37%) ng-hr/ml, respectively. These AUCs were approximately 5-10 times the AUC(0-inf) of 698 (33%) previously reported for a larger dose of approximately 2,250 mg of monotherapy Cape (Mono-Cape) (Reigner 1998). Similarly, the 5-FU Cmaxs (geometric mean, CV%) for these 2 cohorts were greater at 694 (22%) and 1,056 (28%) ng/ml than the Cmax of Mono-Cape at 310 (50%). The 5-FU T1/2 (arithmetic mean, CV%) of 3.54 (18%) and 5.72 (51%) hrs for these two NGC-Cap cohorts were also much longer than the 0.84 (25%) hrs for Mono-Cape. Although 150 and 225 bid NGC-Cap cohorts produced greater Cmax and AUC levels than Mono-Cape, the side effect profile from anabolites for the 150 cohort was better than Mono-Cape while the profile for the 225 cohort was similar to Mono-Cape. The extremely low FBAL catabolite formation and exposure (AUC of < 250 vs 31,400 for Mono-Cape) across all NGC-Cap doses also resulted in only 1 patient having Grade 1 HFS. Conclusion: The Phase 1b trial has already revealed some of the potential benefits of NGC-Cap over Mono-Cap. 1.NGC-Cap can provide a greater 5-FU exposure based on AUC and Cmax with a better or similar side effect profile.2.Side effects from the 5-FU catabolites are minimal and less severe for NGC-Cap.3.Side effects from 5-FU anabolites are dependent on 5-FU exposure with less exposure leading to fewer side effects that may also be less severe.4.NGC-Cap is to be further evaluated in a Phase 2 trial with the expectation that NGC-Cap will provide a better efficacy and safety profile than Cape. Citation Format: David Young, Sian Bigora, Mary Nyberg, Kayla Parks, Amit Mahipar, Patrick Boland, Eric Feldman, Howard Hochster. Next generation capecitabine (NGC-Cap) in phase 1b trial significantly increases 5-FU exposure while improving safety profile compared to capecitabine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT103.

Using Genetic Algorithm Feature Selection to Optimize XGBoost Performance in Australian Credit

To reduce credit risk in credit institutions, credit risk management practices need to be implemented so that lending institutions can survive in the long term. Data mining is one of the techniques used for credit risk management. Where data mining can find information patterns from big data using classification techniques with the resulting level of accuracy. This research aims to increase the accuracy of classification algorithms in predicting credit risk by applying genetic algorithms as the best feature selection method. Thus, the most important feature will be used to search for credit risk information. This research applies a classification method using the XGBoost classifier on the Australian credit dataset, then carries out an evaluation by measuring the level of accuracy and AUC. The results show an increase in accuracy of 2.24%, with an accuracy value of 89.93% after optimization using a genetic algorithm. So, through research on genetic algorithm feature selection, we can improve the accuracy performance of the XGBoost algorithm on the Australian credit dataset.

Antioxidant and Antidiabetic Properties of a Thinned-Nectarine-Based Nanoformulation in a Pancreatic β-Cell Line.

Pancreatic β-cells play a crucial role in maintaining glucose homeostasis, although they are susceptible to oxidative damage, which can ultimately impair their functionality. Thinned nectarines (TNs) have gained increasing interest due to their high polyphenol and abscisic acid (ABA) content, both of which possess antidiabetic properties. Nevertheless, the efficacy of these bioactive compounds may be compromised by limited stability and bioavailability in vivo. This study aimed to develop nanoformulations (NFs) containing pure ABA or a TN extract (TNE) at an equivalent ABA concentration. Subsequently, the insulinotropic and antioxidant potential of the NFs and their unformulated (free) forms were compared in MIN-6 pancreatic cells exposed to varying glucose (5.5 mM and 20 mM) and iron (100 µM) concentrations. NF-TNE treatment exhibited enhanced antioxidant activity compared to free TNE, while ABA-based groups showed no significant antioxidant activity. Moreover, MIN6 cells incubated with both high glucose and iron levels demonstrated significantly higher insulin AUC levels after treatment with all samples, with NF-TNE displaying the most pronounced effect. In conclusion, these results highlight the additional beneficial potential of TNE due to the synergistic combination of bioactive compounds and demonstrate the significant advantage of using a nanoformulation approach to further increase the benefits of this and similar phytobioactive molecules.

A Preliminary Feasibility Study on Screening Cognitive Impairment based on Multi‐Modal Biomarkers and Stacking Ensemble AI Approach

AbstractBackgroundEarly screening of cognitive impairment is crucial for patients demanding timely treatment. The need for cost‐effective, easily accessible, and accurate tools to detect cognitive decline rapidly progressed with the breakout of the COVID‐19 pandemic. In this work, we proposed a mobile‐app based cognitive assessment tool, “Alzguard‐D”, equipped with two digital biomarkers along with a cognitive task. Next, we investigated the efficacy of “Alzguard‐D” in early screening of cognitive impairment using a machine learning approach.MethodNine “Alzguard‐D” tasks were designed based on three biomarkers: Keystroke, speech and eye movement (Table 1; Figure 1). Total of 289 participants were recruited from the national institute of dementia, welfare center, and nursing homes. The participants first completed the Korean Mini‐Mental State Examination (K‐MMSE; 2nd Edition), then performed all tasks in “Alzguard‐D”. “Alzguard‐D” took approximately 20 to 30 minutes. The participants were then categorized to healthy control (HC; n = 241) and cognitively impaired (CI; n = 48), defined as when the scores of K‐MMSE were one standard deviation below the age, education and gender‐matched norm. Given the data, we investigated the extent in which the combination of digital biomarkers and cognitive tasks improves the screening accuracy. We used a stacking ensemble model where the first stack analyzed speech and eye movement, and the second performed the classification.ResultThe screening result confirmed that the addition of digital biomarkers collected by “Alzguard‐D” significantly improved the classification performance (p < 0.0001; sample paired t‐test). CatBoost algorithm statistically outperformed all other candidate algorithms (Bagging, Logistic Regression, LGBM, Naïve Bayes, XGBoost, Random Forest, SVM, Gradient Boosting). We then conducted an ablation study with three classifiers trained with (i) Cog+Bio, (ii) Bio and (iii) Cog. Cog+Bio achieved the highest AUC score, 0.876 (max: 0.942), followed by Bio with 0.783 (max: 0.845), then Cog with 0.677 (max: 0.726) (Figure 2).ConclusionA combination of cognitive and digital biomarkers significantly increased the screening performance of cognitive impairment, and employing an intermediate feature‐level ensemble approach to effectively analyze the collected multi‐modal data increased the AUC levels.

Prospective Pharmacokinetic Evaluation of Venetoclax (VEN) in AML Demonstrates Significant and Variable Drug Interactions with Azole Antifungals That Increase Ven Exposure, Reduce Clearance, and Necessitate Re-Evaluation of Dose Adjustments

Background: Venetoclax (VEN) in combination with hypomethylating agents (HMA) or low dose cytarabine (LDAC) is the standard of care for the treatment of newly diagnosed AML in pts aged ≥ 75 yrs. or unfit for intensive chemotherapy. While considered low-intensity, myelosuppression is universal, leading to increased rates of infection in the setting of neutropenia. Antifungal prophylaxis during induction has significantly lowered treatment-related mortality (TRM) attributed to invasive fungal infections (Cornely et al, 2007). Azole antifungals, the treatment of choice, pose significant drug-drug interactions through inhibition of CYP3A4 and p-glycoprotein (P-gp), both responsible for VEN metabolism and clearance. This interaction alters VEN pharmacokinetics (PK), increases its exposure, and therefore requires substantial dose adjustments (Agarwal et al, 2017). We previously showed that dose adjusted VEN plus HMA when used concomitantly with azoles retains efficacy, but still resulted in prolonged myelosuppression (Rausch et al, 2022). Little real-world PK data exists to confirm whether the recommended dose adjustments are appropriate or require further refinement. Methods: Pharmacokinetic analysis was conducted during the induction cycle of the phase II study of cladribine plus LDAC and VEN as previously described (Kadia et al, 2022). VEN was administered on days 1-21 during induction and was dose-adjusted to either 100 mg (later amended to 50 mg), 100 mg, or 400 mg daily when used with posaconazole (posa), voriconazole (vori), or caspofungin (caspo), respectively. Dose adjustments were based on package insert recommendations. Prior to amendment, VEN 100 mg was administered with posa based on previously published PK analysis suggesting a 75% dose reduction of VEN with concomitant posa (Agarwal et al, 2017). Steady state VEN PK analysis was conducted on day 8 and trough levels were collected on days 12 and 16 of cycle 1. Levels obtained with concomitant caspo served as a reference level, assuming no significant interaction between VEN and caspo. VEN levels were analyzed via an institutionally developed liquid chromatography coupled mass spectrometry (LCMS) assay and PK analysis was conducted via non-compartmental method using WinOnlin. Results: Forty patients, median age 68 (range, 61-78), were included for pharmacokinetic analysis. Average VEN AUC (area under the exposure) and Cmax (maximum observed plasma concentration) was higher with concomitant vori or posa than with caspo regardless of dose adjustments. Posa in combination with VEN 100 mg increased average AUC by 103% and Cmax by 63%. Vori with VEN 100 mg increased AUC and Cmax by 77% and 43%, respectively. Among the 3 groups, posa with VEN 50 mg resulted in a VEN AUC and Cmax most similar to that observed with caspo and VEN 400 mg. Concomitant posa delayed VEN clearance by 74% with VEN 50 mg and 79% with VEN 100 mg. As a result, the accumulation index observed with posa was 12.5 + 19.98 with VEN 100 mg, 9.2 + 17.5 with VEN 50 mg, and 3.7 + 1.92 with vori, compared to 1.7 + 0.5 with caspo. Although there was interpatient variability in VEN trough levels, we observed consistent intra-patient trough levels. In addition, significant correlation between VEN AUC and VEN trough levels (p = 1 x 10 -4, r 2 = 0.89) was observed. Conclusions: Despite dose adjustments, VEN AUC is significantly higher among pts receiving azole antifungals compared to those receiving caspo. Posa resulted in more potent inhibition of VEN clearance and greater accumulation compared to vori, despite both agents considered strong CYP3A4 inhibitors. This may be a result of the dual inhibitory effect of posa on both CYP3A4 and P-gp activity or more potent inhibition of CYP3A4. Based on PK evaluation, our data suggest VEN 50 mg with concomitant posa provides more similar drug exposure to VEN 400 mg and may be more appropriate than 70 mg or 100 mg in this setting. Given the high accumulation index observed with posa, PK analyses during cycle 2 are ongoing. While there is inter-patient variability in VEN PK, intra-patient trough levels are consistent, correlate well with VEN AUC, and could be used for therapeutic drug monitoring.

Real-Life Vancomycin Therapeutic Drug Monitoring in Coagulase-Negative Staphylococcal Bacteremia in Neonatal and Pediatric Intensive Care Unit: Are We Underestimating Augmented Renal Clearance?

Bloodstream infections (BSI) from coagulase-negative-staphylococci (CoNS) are among the most frequent healthcare-related infections. Their treatment involves the use of vancomycin, a molecule whose optimal pharmacokinetic/pharmacodynamic (PK/PD) target for efficacy and safety is an area-under-curve/minimum inhibitory concentration (AUC/MIC) ratio ≥ 400 with AUC < 600. BSIs from CoNS in pediatric and neonatal intensive care unit that occurred at the Gaslini Institute over five years were evaluated to investigate the efficacy of vancomycin therapy in terms of achieving the desired PK/PD target and determining whether any variables interfere with the achievement of this target. AUC/MIC ≥ 400 with AUC < 600 at 48 and 72 h after therapy initiation was achieved in only 21% of the neonatal population and 25% of the pediatric population. In the pediatric population, an inverse correlation emerged between estimated glomerular filtration rate (eGFR) and achieved AUC levels. Median eGFR at 72 h was significantly higher (expression of hyperfiltration) in events with AUC < 400, compared with those with AUC ≥ 400 (p < 0.001). A cut-off value of eGFR in the first 72 h has been identified (145 mL/min/1.73 m2), beyond which it is extremely unlikely to achieve an AUC ≥ 400, and therefore a higher dose or a different antibiotic should be chosen.

THU115 Sex-Specific And Shared Associations Between Vasopressin Levels And Body Composition In Adults With Obesity

Abstract Disclosure: F. Galbiati: None. M. Wronski: None. A. Aulinas Maso: None. M. Muhammed: None. R. Boutin: None. K. Liya: None. S. Carter: None. H. Nazarloo: None. J.M. Davis: None. K. Holman: None. J. Gydus: None. S. Smith: None. E. Asanza: None. M. Bredella: None. M. Torriani: None. F. Plessow: None. E.A. Lawson: Advisory Board Member; Self; OXT Therapeutics. Grant Recipient; Self; Tonix Pharmaceuticals. Background: Arginine-vasopressin (AVP) is a sexually dimorphic neurohormone shown in preclinical studies to have relevant metabolic effects, including reducing food intake, inducing lipolysis, and promoting muscle regeneration in male mice. However, findings are inconsistent, possibly due to the opposing effects of AVP at different receptor subtypes, and little is known about the effects of AVP on metabolism in humans. We hypothesized that AVP may act as signal of energy availability, such that in adults with obesity, integrated AVP levels around a standardized meal would be positively associated with BMI, adiposity, and lean mass. We also predicted that relationships between AVP and body composition measures would differ by sex. Methods: We performed a cross-sectional study of 53 adults with obesity (56% females; age [mean±SD] 33.7±6.2 years; BMI 36.9±4.9 kg/m2). We obtained plasma AVP levels fasting and 30, 60, and 120 minutes after a standardized meal. We computed area under the curve with respect to ground (AUC) for an integrated measure of AVP levels around the meal. Participants underwent body composition assessment by dual-energy X-ray absorptiometry (total fat, truncal fat, and lean mass) and magnetic resonance imaging (abdominal visceral and subcutaneous fat). We performed Pearson’s correlation (normally distributed variables) and Spearman’s correlation (non-normally distributed variables) to investigate the relationship between AVP levels and body composition parameters. Fisher’s Z test was performed to analyze the difference between correlation coefficients across sexes. Results: Age and AVP AUC did not differ based on sex (p=0.300). Total fat mass (p=0.013) was higher while total lean mass (p&amp;lt;0.0001) and abdominal visceral fat (p=0.001) were lower in females than males; BMI, truncal fat, and abdominal subcutaneous fat did not differ by sex (p’s≥0.09). Across all participants, AVP AUC levels were positively correlated with BMI (rs=0.36, p=0.008), total fat mass (r=0.33, p=0.013), truncal fat (r=0.35; p=0.010), abdominal subcutaneous fat (r=0.30, p=0.028), and total lean mass (r=0.38, p=0.005), but not with abdominal visceral fat (p=0.331). Within sex-based group, a robust positive correlation between AVP AUC and abdominal subcutaneous fat mass was present in males (r=0.56, p=0.004), but not females (r=0.04, p=0.592) [(by Fisher’s Z test, p=0.024). There were no other sex differences in correlations (by Fisher’s Z test, p≥0.108). Conclusions: Our data in humans showing a link between integrated AVP and body composition support preclinical data indicating that AVP is a metabolically active hormone. Additionally, we identified sex differences in the relationship between AVP and subcutaneous fat mass. Further investigation of sex-specific and shared metabolic effects of AVP in humans will be important. Presentation: Thursday, June 15, 2023

The impact of smoking status on clopidogrel responsiveness in patients with coronary artery disease who undergo percutaneous coronary intervention

Background: Previous studies have pointed out the disproportionate action of clopidogrel in inhibiting platelet aggregation due to smoking more than ten cigarettes per a day. This study was designed to examine whether smoking enhances clopidogrel responsiveness in patients who are clinically diagnosed with coronary artery disease (CAD), following percutaneous coronary intervention (PCI). Methods: A total of 324 IHD participants were enrolled in a case-control study. Platelet function test was performed to all participants two hours before PCI procedure to measure clopidogrel response. Participants were then categorized into a non-responder group (case group n = 111) and responder group (control group n = 213). Each group was subdivided into a smoker group and a non-smoker group. All participants received clopidogrel loading dose equivalent to 600 mg and scheduled for elective PCI. Participants’ age, gender, family history of chronic illnesses was recorded in this study. Results: Smoking participants displayed a significant higher level of hemoglobin as compared to the non-smoking participants among the responder and the non-responder study groups (14.6±0.55 vs. 13.12±0.38, P &lt; 0.029; 14.3±0.31 versus 12.96±0.39, P &lt; 0.033) but lower AUC level (17±9 vs. 45±6, P &lt; 0.005; 62±3 vs. 95±7, P &lt; 0.008). Additionally, smoking intensity enhanced clopidogrel responsiveness by odd’s ratio 0.4213 at 95% C.I. (0.259 - 0.684), P &lt; 0.0002. Conclusions: Current smokers had a good response to clopidogrel therapy which exerted a beneficial effect when undergoing PCI as compared to non-smokers. The marked difference in AUC between smokers and non-smokers could be related to the variance in hemoglobin level. The smokers’ paradox needs further justification to confirm this concept.

Effects of Catha edulis (Khat) on the Pharmacokinetics of Metformin in Diabetic Rats Using UPLC/MS/MS Analysis and Its Impact on Hepatic CYP450 Enzymes

Catha edulis Forsk., commonly known as Khat, is a stimulant plant that is chewed in the Horn of Africa and the southern regions of the Arabian Peninsula. It is often used alongside conventional drugs, but there is a lack of research on its interactions with other drugs. In this study, our aim was to investigate the possibility of an herb–drug interaction between KT extract and metformin (MT) by exploring the effect of KT on the in vivo pharmacokinetics of MT in diabetic Wistar albino rats and monitoring blood glucose levels through time intervals, comparing when MT was given alone and co-administered with KT. Rats were given 500 mg/kg of KT extract and 300 mg/kg of MT daily for 7 days. The pharmacokinetic parameters of MT were analyzed using UPLC-MS/MS. The quantification was conducted using multiple reaction monitoring (MRM) in positive ion mode. The transitions used were (m/z) 130.006→59.939 for MT and 260.125→116.018 for propranolol as an internal standard (IS). An Acquity UPLC BEH HSS T3 C18 column was used with isocratic elution, and the mobile phase was formic acid (0.1%): acetonitrile (70:30 v/v) at a flow rate of 0.25 mL/min. In addition, the study delved into the in vitro impact of KT on the CYP3A4 enzyme, seeking to identify any potential disruptions in MT’s metabolism that could alter its pharmacokinetics. The effect of KT extract on CYP3A4 enzyme activity was investigated using fluorescence-based enzyme assays and a CYP3A4 Inhibitor Screening Kit. The results indicated that the combined treatment showed increased systemic exposure to MT, with Cmax and AUC levels increasing by 33.42% and 45.23%, respectively. Additionally, the combination treatment led to significantly lower fasting blood glucose (FBG) levels compared to the groups treated with MT alone. It was found that at a concentration of 500 µg/mL, the CYP3A4 enzyme activity was maximally suppressed by approximately 57%, while at 250 µg/mL, it was inhibited by almost 50%. In comparison, the standard Ketoconazole only inhibited CYP3A4 activity by approximately 58%. Therefore, the in vitro results suggest that KT extract has the potential to affect CYP3A4 activity at high doses. In conclusion, the combination treatment resulted in a significant increase in MT’s blood sugar-lowering effects. Therefore, it is important to be aware of this potential interaction and to monitor blood sugar levels closely when using KT alongside MT.

Tip loaded cyclodextrin-carvedilol complexes microarray patches

Carvedilol, a β-blocker prescribed for chronic heart failure, suffers from poor bioavailability and rapid first pass metabolism when administered orally. Herein, we present the development of tip microarray patches (MAPs) composed of ternary cyclodextrin (CD) complexes of carvedilol for transdermal delivery. The ternary complex with hydroxypropyl γ-cyclodextrin (HPγCD) and poly(vinyl pyrrolidone) (PVP) reduced the crystallinity of carvedilol, as evidenced by DSC, XRD, NMR, and SEM analysis. MAPs were fabricated using a two-step process with the ternary complex as the needle layer. The resulting MAPs were capable of breaching ex vivo neonatal porcine skin to a depth ≈600 μm with minimal impact to needle height. Upon insertion, the needle dissolved within 2 h, leading to the transdermal delivery of carvedilol. The MAPs displayed minimal toxicity and acceptable biocompatibility in cell assays. In rats, MAPs achieved significantly higher AUC levels of carvedilol than oral administration, with a delayed Tmax and sustained plasma levels over several days. These findings suggest that the carvedilol-loaded dissolving MAPs have the potential to revolutionise the treatment of chronic heart failure.

P-788 Embryo vitrification affects the epigenome of preimplantation embryos and the effects are inherited by the female offsprings.

Abstract Study question How does embryo vitrification regulates the transcriptome of preimplantation embryos through epigenetic regulation and how are the effects transmitted to the female offsprings? Summary answer Embryo vitrification changed the DNA methylation level of preimplantation embryo and disturbed glycolipid metabolism of female offsprings in mice. What is known already Vitrification is a type of embryo cryopreservation increasingly frequently used clinically. The effect of embryo freezing on the health of offspring has been widely concerned. Some clinical studies have shown that offspring obtained from frozen embryo transplantation has higher birth weight and may be at higher risk of certain birth defects, increased risk of type 1 diabetes and cancer. But not all studies agree. The offspring safety of vitrification needs further follow-up research. Mouse model is a helpful tool for us to carry up follow-up study and explore mechanism. Study design, size, duration After superovulation and mating of ICR mice, we obtained 8-Cell embryos. In Vitrify Group, the 8-Cell embryos underwent vitrification and thawing and culture in vitro till blastocysts. In InVitro Group, the 8-Cell embryos were directly cultured in vitro till blastocysts. We transplanted these blastocysts into surrogate mice to get offspring of InVitro and Vitrify. Along with offspring of natural conception (NC), we observed their growth and development and glycolipid metabolism until 18 weeks old. Participants/materials, setting, methods Single embryo RNA-seq and Whole Genome Bisulfite Sequencing (WGBS) were performed to get transcriptome and DNA methylation atlas. Immunofluorescence of blastocysts was performed to test level of 5mC/5hmC and Tet2. Glucose and insulin tolerance test (GTT/ITT), serum lipid level test were performed on offspring to examine the glycolipid metabolism status. Liver transmission electron microscope photographs were take to observe ultramicrostructure. Liver RNA-seq and WGBS were performed to verify the variation on pathways concerning glycolipid metabolism. Main results and the role of chance Pseudo-time analysis from RNA-seq of 16-Cell, morula and blastocyst showed a relative developmental time lag in Vitrify. Differentially expressed genes (DEGs) of vitrify group at the blastocyst stage are mainly enriched in lipid metabolism, insulin signal, TOR signal regulation, gamete production related DNA methylation pathways. GSEA analysis revealed down-regulation of insulin response pathway genes. WGBS showed a trend of genome-wide methylation increase in vitrify group. Immunofluorescence confirmed this observation as the fluorescence intensity ratio of 5mC/5hmC was increased. RNA-seq, qPCR and western-blot showed a lower expression level of Tet2. These results suggested that the demethylation was insufficient in vitrify group. Blastocyst differentially methylated genes (DMRs) from WGBS were enriched in insulin response pathways. In offspring, birth weight of Vitrify offspring is higher than InVitro. GTT and ITT showed an elevated level of AUC in Vitrify 10-week-female, indicating an impaired glucose tolerance. And the fasting serum cholesterol level was elevated in Vitrify 10-week-female, indicating an impaired lipid metabolism. Under transmission electron microscope, we saw swollen mitochondria in liver of Vitrify 10-week-female. We extracted RNA from 10-week-female for RNA-seq, DEGs were enriched in cholesterol biosynthesis pathway. We extracted DNA from 10-week-female for WGBS, DEGs were enriched in cAMP and AMPK signaling pathway. Limitations, reasons for caution We have not confirm the precise molecular site affected by vitrification, clarify the mechanism and conduct the rescue test yet, which we are currently working on. This study is just the first step in this direction, and more efforts are needed. Wider implications of the findings Although more clinical trials and basic science studies are required, our findings provide valuable information for preventive and clinical decisions, as ‘freeze-all’ strategy springs up in many centers. Embryo vitrification needs more cautious consideration. Optimizing embryo vitrification protocols are needed according to the mechanism to minimize unwanted effects. Trial registration number 2021YFC2700601