Clinical-Based vs. Model-Based Adaptive Dosing Strategy: Retrospective Comparison in Real-World mRCC Patients Treated with Sunitinib

Different target exposures with sunitinib have been proposed in metastatic renal cell carcinoma (mRCC) patients, such as trough concentrations or AUCs. However, most of the time, rather than therapeutic drug monitoring (TDM), clinical evidence is preferred to tailor dosing, i.e., by reducing the dose when treatment-related toxicities show, or increasing dosing if no signs of efficacy are observed. Here, we compared such empirical dose adjustment of sunitinib in mRCC patients, with the parallel dosing proposals of a PK/PD model with TDM support. In 31 evaluable patients treated with sunitinib, 53.8% had an empirical change in dosing after treatment started (i.e., 46.2% decrease in dosing, 7.6% increase in dosing). Clinical benefit was observed in 54.1% patients, including 8.3% with complete response. Overall, 58.1% of patients experienced treatment discontinuation eventually, either because of toxicities or progressive disease. When choosing 50–100 ng/mL trough concentrations as a target exposure (i.e., sunitinib + active metabolite N-desethyl sunitinib), 45% patients were adequately exposed. When considering 1200–2150 ng/mL.h as a target AUC (i.e., sunitinib + active metabolite N-desethyl sunitinib), only 26% patients were in the desired therapeutic window. TDM with retrospective PK/PD modeling would have suggested decreasing sunitinib dosing in a much larger number of patients as compared with empirical dose adjustment. Indeed, when using target trough concentrations, the model proposed reducing dosing for 61% patients, and up to 84% patients based upon target AUC. Conversely, the model proposed increasing dosing in 9.7% of patients when using target trough concentrations and in 6.5% patients when using target AUC. Overall, TDM with adaptive dosing would have led to tailoring sunitinib dosing in a larger number of patients (i.e., 53.8% vs. 71–91%, depending on the chosen metrics for target exposure) than a clinical-based decision. Interestingly, sunitinib dosing was empirically reduced in 41% patients who displayed early-onset severe toxicities, whereas model-based recommendations would have immediately proposed to reduce dosing in more than 80% of those patients. This observation suggests that early treatment-related toxicities could have been partly avoided using prospective PK/PD modeling with adaptive dosing. Conversely, the possible impact of model-based adapted dosing on efficacy could not be fully evaluated because no clear relationship was found between baseline exposure levels and sunitinib efficacy measured at 3 months.

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Inflammation Is Associated with Voriconazole Trough Concentrations

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03820-14 ◽

2014 ◽

Vol 58 (12) ◽

pp. 7098-7101 ◽

Cited By ~ 44

Author(s):

Marjolijn J. P. van Wanrooy ◽

Lambert F. R. Span ◽

Michael G. G. Rodgers ◽

Edwin R. van den Heuvel ◽

Donald R. A. Uges ◽

...

Keyword(s):

Trough Concentration ◽

Retrospective Chart Review ◽

Therapeutic Window ◽

Therapeutic Drug ◽

C Reactive Protein ◽

Large Variability ◽

Reactive Protein ◽

Inflammatory Status ◽

Inflammatory Stimuli ◽

Trough Concentrations

ABSTRACTVoriconazole concentrations display a large variability, which cannot completely be explained by known factors. Inflammation may be a contributing factor, as inflammatory stimuli can change the activities and expression levels of cytochrome P450 isoenzymes. We explored the correlation between inflammation, reflected by C-reactive protein (CRP) concentrations, and voriconazole trough concentrations. A retrospective chart review of patients with at least one steady-state voriconazole trough concentration and a CRP concentration measured on the same day was performed. A total of 128 patients were included. A significantly (P< 0.001) higher voriconazole trough concentration was observed in patients with severe inflammation (6.2 mg/liter; interquartile range [IQR], 3.4 to 8.7 mg/liter;n= 20) than in patients with moderate inflammation (3.4 mg/liter; IQR, 1.6 to 5.4 mg/liter;n= 60) and in patients with no to mild inflammation (1.6 mg/liter; IQR, 0.8 to 3.0 mg/liter;n= 48). The patients in all three groups received similar voriconazole doses based on mg/kg body weight (P= 0.368). Linear regression analyses, both unadjusted and adjusted for covariates of gender, age, dose, route of administration, liver enzymes, and interacting coadministered medications, showed a significant association between voriconazole and CRP concentration (P< 0.001). For every 1-mg/liter increase in the CRP concentration, the voriconazole trough concentration increased by 0.015 mg/liter (unadjusted 95% confidence interval [CI], 0.011 to 0.020 mg/liter; adjusted 95% CI, 0.011 to 0.019 mg/liter). Inflammation, reflected by the C-reactive protein concentration, is associated with voriconazole trough concentrations. Further research is necessary to assess if taking the inflammatory status of a patient into account is helpful in therapeutic drug monitoring of voriconazole to maintain concentrations in the therapeutic window, thereby possibly preventing suboptimal treatment or adverse events.

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Application of the Hartford Hospital Nomogram for Plazomicin Dosing Interval Selection in Patients with Complicated Urinary Tract Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00148-19 ◽

2019 ◽

Vol 63 (10) ◽

Cited By ~ 3

Author(s):

Tomefa E. Asempa ◽

Joseph L. Kuti ◽

Julie D. Seroogy ◽

Allison S. Komirenko ◽

David P. Nicolau

Keyword(s):

Urinary Tract ◽

Area Under The Curve ◽

Complicated Urinary Tract Infection ◽

Aminoglycoside Antibiotic ◽

Similar Proportion ◽

Therapeutic Drug ◽

Dosing Interval ◽

Number Of Patients ◽

Trough Concentrations ◽

Tract Infections

ABSTRACT Plazomicin is a new FDA-approved aminoglycoside antibiotic for complicated urinary tract infections (cUTI). In the product labeling, trough-based therapeutic drug management (TDM) is recommended for cUTI patients with renal impairment to prevent elevated trough concentrations associated with serum creatinine increases of ≥0.5 mg/dl above baseline. Herein, the utility of the Hartford nomogram to prevent plazomicin trough concentrations exceeding the TDM trough of 3 μg/ml and optimize the area under the curve (AUC) was assessed. The AUC reference range was defined as the 5th to 95th percentile AUC observed in the phase 3 cUTI trial (EPIC) (121 to 368 μg · h/ml). Observed 10-h plazomicin concentrations from patients in EPIC (n = 281) were plotted on the nomogram to determine an eligible dosing interval (every 24 h [q24h], q36h, q48h). Based on creatinine clearance (CLcr), a 15- or 10-mg/kg of body weight dose was simulated with the nomogram-derived interval. The nomogram recommended an extended interval (q36h and q48h) in 31% of patients. Compared with the 15 mg/kg q24h regimen received by patients with CLcr of ≥60 ml/min in EPIC, the nomogram-derived interval reduced the proportion of patients with troughs of ≥3 μg/ml (q36h, 27% versus 0%, P = 0.021; q48h, 57% versus 0%, P = 0.002) while significantly increasing the number of patients within the AUC range. Compared with the 8 to 12 mg/kg q24h regimen (received by patients with CLcr of >30 to 59 ml/min in EPIC), the nomogram-derived interval significantly reduced the proportion of troughs of ≥3μg/ml in the q48h cohort (72% versus 0%, P < 0.001) while maintaining a similar proportion of patients in the AUC range. Simulated application of the Hartford nomogram optimized plazomicin exposures in patients with cUTI while reducing troughs to <3 μg/ml.

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Quantitative Analysis of Gentamicin Exposure in Neonates and Infants Calls into Question Its Current Dosing Recommendations

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02004-17 ◽

2018 ◽

Vol 62 (4) ◽

Cited By ~ 9

Author(s):

Tamara van Donge ◽

Marc Pfister ◽

Julia Bielicki ◽

Chantal Csajka ◽

Frederique Rodieux ◽

...

Keyword(s):

Neonatal Intensive Care ◽

Demographic Characteristics ◽

Total Daily Dose ◽

Therapeutic Drug ◽

Dosing Interval ◽

Model Based ◽

Optimal Dosing ◽

Daily Dose ◽

Dosing Regimens ◽

Trough Concentrations

ABSTRACTOptimal dosing of gentamicin in neonates is still a matter of debate despite its common use. We identified gentamicin dosing regimens from eight international guidelines and seven Swiss neonatal intensive care units. The dose per administration, the dosing interval, the total daily dose, and the demographic characteristics between guidelines were compared. There was considerable variability with respect to dose (4 to 6 mg/kg), dosing interval (24 h to 48 h), total daily dose (2.5 to 6 mg/kg/day), and patient demographic characteristics that were used to calculate individualized dosing regimens. A model-based simulation study in 1071 neonates was performed to determine the achievement of efficacious peak gentamicin concentrations according to predefined MICs (Cmax/MIC ≥ 10) and safe trough concentrations (Cmin≤ 2 mg/liter) with recommended dosing regimens. MIC targets of 0.5 and 1 mg/liter were used. Dosing optimization was performed giving priority to the first day of treatment and with the goal of simplifying dosing. Current gentamicin neonatal guidelines allow to achieve effective peak concentrations for MICs ≤ 0.5 mg/liter but not higher. Model-based simulations indicate that to attain peak gentamicin concentrations of ≥10 mg/liter, a dose of 7.5 mg/kg should be administered using an extended dosing interval regimen. Trough concentrations of ≤2 mg/liter can be maintained with a dosing interval of 36 to 48 h in neonates according to gestational and postnatal age. For treatment beyond 3 days, therapeutic drug monitoring is advised to maintain adequate serum concentrations.

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Effect of Busulphan Dose Adjustment on Regimen-Related Toxicity.

Blood ◽

10.1182/blood.v108.11.314.314 ◽

2006 ◽

Vol 108 (11) ◽

pp. 314-314

Author(s):

Zuzana Hassan ◽

Mats Remberger ◽

Olle Ringden ◽

Gunnar Oberg ◽

Albert N. Bekassy ◽

...

Keyword(s):

Total Dose ◽

Dose Adjustment ◽

Multiorgan Failure ◽

Hemorrhagic Cystitis ◽

Plasma Concentrations ◽

Conditioning Regimen ◽

Therapeutic Drug ◽

Time Interval ◽

Trough Concentrations

Abstract Stem cell transplantation (SCT) is a successful treatment for many patients with malignant and non-malignant diseases. Conditioning regimen is an important part of SCT, however, regimen-related toxicity (RRT) is a major drawback of myeloablative regimens. In order to decrease RRT, many strategies have been introduced such as therapeutic drug monitoring (TDM) and dose adjustment of busulphan and optimization of time interval between different drugs. The present study, include 470 patients collected from three transplantation centres in Sweden between 1987 and 2002. All patients underwent allogeneic or autologous SCT using busulphan-based conditioning regimen prior to SCT. We investigated the effect of TDM and dose adjustment of busulphan (Bu) on the occurrence of RRT in these patients. Bu was administered orally in total dose of 16 mg/kg with or without dose adjustment and cyclophosphamide administered iv at a total dose of 120 mg/kg. Anti-thymocyte globulin was given to all patients transplanted from unrelated or mismatched donor. Prevention of GVHD consisted of the combination cyclosporin A and four doses of methotrexate or monotherapy with either of the agents. Several strategies for TDM of Bu were based on the actual knowledge, determination of trough levels, the estimation of the area under the concentration-time curve (AUC) using full pharmacokinetics or limited sapling model with follow up of trough concentrations of Bu (Hassan, 1996). The target trough concentrations of Bu were 450–600 ng/ml, the target AUC after the first dose of Bu was 4500–5500 ng. hr/ml. For the purpose of this study, mean Bu plasma concentrations were used. Bu plasma concentrations were measured in all 470 patient, however, TDM was applied in 277 patients, while only determination of plasma concentrations of Bu without dose adjustment was used in 193 patients. Mean trough Bu plasma concentrations followed a Gaussian distribution pattern. One half of the patients had Bu trough concentrations within the range 450–650 ng/ml. The difference between adjusted and non-adjusted groups was observed (57% vs 39%, resp.). Dose adjustments decreased the variation in exposure to Bu between and within the different age groups. Veno-oclussive disease (VOD) was diagnosed in 11/277 patients (4.0%) in patients where Bu doses were adjusted according to plasma concentrations compared to 38/193 patients (19.7%) who were treated without dose adjustment (p<0.001). Busulphan plasma concentrations above 600 ng/ml predispose to VOD. Hemorrhagic cystitis (HC) was found in 8/277 patients (2.9 %) with dose adjustment compared to 26/193 patients (13.5%) without dose adjustment of Bu (p<0.001). Interstitial pneumonitis syndrome (IPS) decreased from 15 % in patients without dose adjustment to 4.3 % in patients whose doses were adjusted (p<0.001), however, almost all patients with IPS had Bu mean trough concentrations above 800 ng/ml. Multiorgan failure was diagnosed in 3/277 patients (1.1 %) with dose adjustment compared to 8/193 patients (4.1 %) without dose adjustment of Bu (p=0.03). These results show, that TDM and dose adjustment of Bu during myeloablative conditioning regimen decrease the occurrence of RRT.

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Exploring the effect of khat (Catha edulis) chewing on the pharmacokinetics of the antiplatelet drug clopidogrel in rats using the newly developed LC-MS/MS technique

Open Chemistry ◽

10.1515/chem-2020-0046 ◽

2020 ◽

Vol 18 (1) ◽

pp. 681-690

Author(s):

Hassan A. Alhazmi ◽

Adnan A. Kadi ◽

Mohamed W. Attwa ◽

Waquar Ahsan ◽

Manal Mohamed Elhassan Taha ◽

...

Keyword(s):

Cytochrome P450 ◽

Active Metabolite ◽

Dose Adjustment ◽

Internal Standard ◽

Cardiovascular Complications ◽

Antiplatelet Drug ◽

Peak Ratio ◽

Cytochrome P450 Enzymes ◽

Time Intervals ◽

Addictive Substance

AbstractClopidogrel (CLOP) is widely used worldwide for cardiovascular complications. CLOP is highly metabolized in the liver to its active metabolite by cytochrome P450 enzymes. Studies have shown that khat, an addictive substance, is a powerful inhibitor of cytochrome P450 enzymes and can influence the metabolism of drugs that are concomitantly used. Therefore, this study was designed to evaluate the effects of khat on the pharmacokinetics of CLOP in rats. In this study, rats were administered either CLOP alone or CLOP combined with khat and their plasma were obtained at different time intervals and analyzed using the newly developed and validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method using foretinib (FTB) as the internal standard. The corresponding peak area of the analyte versus FTB was used for calculating the peak ratio. The validated LC-MS/MS method resulted in the separation of the well-defined quantifiable peaks of CLOP, FTB, and CLOP metabolite within 7 min. Results showed a significant influence of khat on the peak ratio of CLOP metabolite, which was found to be significantly decreased (P < 0.05) in comparison to CLOP alone, suggesting significant decrease in the conversion of CLOP to its active metabolite due to the inhibition of CYP450 enzymes by khat. Therefore, there might be a need for dose adjustment for regular khat chewers using CLOP.

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DeepRePath: Identifying the Prognostic Features of Early-Stage Lung Adenocarcinoma Using Multi-Scale Pathology Images and Deep Convolutional Neural Networks

Cancers ◽

10.3390/cancers13133308 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3308

Author(s):

Won Sang Shim ◽

Kwangil Yim ◽

Tae-Jung Kim ◽

Yeoun Eun Sung ◽

Gyeongyun Lee ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Early Stage ◽

External Validation ◽

Area Under The Curve ◽

The Cancer Genome Atlas ◽

Deep Convolutional Neural Networks ◽

Prognostic Features ◽

Multi Scale ◽

Model Based ◽

Number Of Patients

The prognosis of patients with lung adenocarcinoma (LUAD), especially early-stage LUAD, is dependent on clinicopathological features. However, its predictive utility is limited. In this study, we developed and trained a DeepRePath model based on a deep convolutional neural network (CNN) using multi-scale pathology images to predict the prognosis of patients with early-stage LUAD. DeepRePath was pre-trained with 1067 hematoxylin and eosin-stained whole-slide images of LUAD from the Cancer Genome Atlas. DeepRePath was further trained and validated using two separate CNNs and multi-scale pathology images of 393 resected lung cancer specimens from patients with stage I and II LUAD. Of the 393 patients, 95 patients developed recurrence after surgical resection. The DeepRePath model showed average area under the curve (AUC) scores of 0.77 and 0.76 in cohort I and cohort II (external validation set), respectively. Owing to low performance, DeepRePath cannot be used as an automated tool in a clinical setting. When gradient-weighted class activation mapping was used, DeepRePath indicated the association between atypical nuclei, discohesive tumor cells, and tumor necrosis in pathology images showing recurrence. Despite the limitations associated with a relatively small number of patients, the DeepRePath model based on CNNs with transfer learning could predict recurrence after the curative resection of early-stage LUAD using multi-scale pathology images.

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Validation of an HPLC–MS/MS Method for the Determination of Plasma Ticagrelor and Its Active Metabolite Useful for Research and Clinical Practice

Molecules ◽

10.3390/molecules26020278 ◽

2021 ◽

Vol 26 (2) ◽

pp. 278

Author(s):

Jennifer Lagoutte-Renosi ◽

Bernard Royer ◽

Vahideh Rabani ◽

Siamak Davani

Keyword(s):

Active Metabolite ◽

Plasma Concentrations ◽

Antiplatelet Agent ◽

High Plasma ◽

Therapeutic Drug ◽

Routine Practice ◽

Daily Routine ◽

Limit Of Quantification ◽

Wide Range

Ticagrelor is an antiplatelet agent which is extensively metabolized in an active metabolite: AR-C124910XX. Ticagrelor antagonizes P2Y12 receptors, but recently, this effect on the central nervous system has been linked to the development of dyspnea. Ticagrelor-related dyspnea has been linked to persistently high plasma concentrations of ticagrelor. Therefore, there is a need to develop a simple, rapid, and sensitive method for simultaneous determination of ticagrelor and its active metabolite in human plasma to further investigate the link between concentrations of ticagrelor, its active metabolite, and side effects in routine practice. We present here a new method of quantifying both molecules, suitable for routine practice, validated according to the latest Food and Drug Administration (FDA) guidelines, with a good accuracy and precision (<15% respectively), except for the lower limit of quantification (<20%). We further describe its successful application to plasma samples for a population pharmacokinetics study. The simplicity and rapidity, the wide range of the calibration curve (2–5000 µg/L for ticagrelor and its metabolite), and high throughput make a broad spectrum of applications possible for our method, which can easily be implemented for research, or in daily routine practice such as therapeutic drug monitoring to prevent overdosage and occurrence of adverse events in patients.

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How shall we treat locally advanced triple negative breast cancer?

F1000Research ◽

10.12688/f1000research.20509.2 ◽

2020 ◽

Vol 8 ◽

pp. 1649

Author(s):

Paulo Luz ◽

David Dias ◽

Ana Fortuna ◽

Luis Bretes ◽

Beatriz Gosalbez

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Locally Advanced ◽

Surrogate Marker ◽

Metastatic Breast ◽

Complete Response ◽

Number Of Patients ◽

Her 2 ◽

Near Future

Triple negative breast cancer (TNBC) has been shown to respond to neoadjuvant chemotherapy (NACT). It has been established that achieving pathological complete response (pCR) for certain aggressive subtypes of breast cancer, including HER-2 (over-expressed) and TNBC, provides an important surrogate marker for predicting long-term clinical response and survival outcomes. How to increase the number of patients that achieve pCR remains challenging. Platinum-based NACT seems to be part of the solution and capecitabine, an active drug in metastatic breast cancer, but not a standard one in earlier stages may have found its place in the adjuvant setting. In the near future immunotherapy can play a role in early TNBC

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Population pharmacokinetic modeling and dosing simulations of tobramycin in pediatric patients with cystic fibrosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00737-21 ◽

2021 ◽

Author(s):

Antonin Praet ◽

Laurent Bourguignon ◽

Florence Vetele ◽

Valentine Breant ◽

Charlotte Genestet ◽

...

Keyword(s):

Cystic Fibrosis ◽

Dose Adjustment ◽

Total Body Weight ◽

Compartment Model ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Time Curve ◽

Population Pharmacokinetic Modeling ◽

Two Compartment Model ◽

Total Body

Initial dosing and dose adjustment of intravenous tobramycin in cystic fibrosis children is challenging. The objectives of this study were to develop nonparametric population pharmacokinetic (PK) models of tobramycin in children with CF to be used for dosage design and model-guided therapeutic drug monitoring. We performed a retrospective analysis of tobramycin PK data in our CF children center. The Pmetrics package was used for nonparametric population PK analysis and dosing simulations. Both the maximal concentration over the MIC (Cmax/MIC) and daily area under the concentration-time curve to the MIC (AUC 24 /MIC) ratios were considered as efficacy target. Trough concentration (Cmin) was considered as the safety target. A total of 2884 tobramycin concentrations collected in 195 patients over 9 years were analyzed. A two-compartment model including total body weight, body surface area and creatinine clearance as covariates best described the data. A simpler model was also derived for implementation into the BestDose software to perform Bayesian dose adjustment. Both models were externally validated. PK/PD simulations with the final model suggest that an initial dose of tobramycin of 15 to 17.5 mg/kg/day was necessary to achieve Cmax/MIC ≥ 10 values for MIC values up to 2 mg/L in most patients. The AUC 24 /MIC target was associated with larger dosage requirements and higher Cmin. A daily dose of 12.5 mg/kg would optimize both efficacy and safety target attainment. We recommend to perform tobramycin TDM, model-based dose adjustment, and MIC determination to individualize intravenous tobramycin therapy in children with CF.

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Introducing VancoCalc: A Free Open-Source Bayesian Vancomycin Dosing Tool for Adults (Preprint)

10.2196/preprints.30577 ◽

2021 ◽

Author(s):

Thomas Oommen ◽

Anirudh Thommandram ◽

Adam Palanica ◽

Yan Fossat

Keyword(s):

Patient Outcomes ◽

Therapeutic Monitoring ◽

Therapeutic Window ◽

Pharmacokinetic Parameters ◽

Proof Of Concept ◽

Intravenous Antibiotic ◽

Optimal Dosing ◽

Starting Dose ◽

Trough Concentrations ◽

Free Open Source

UNSTRUCTURED Vancomycin is an intravenous antibiotic with a narrow therapeutic window where concentrations must be monitored for safety and efficacy. Traditional methods of dosing vancomycin use a weight-based starting dose with interval based on renal function. Dose adjustments are often based on trough concentrations measurements and heuristics or nomograms. It has been suggested that vancomycin dose adjustments using Bayesian methods is optimal. Unfortunately, many of these Bayesian tools are costly. In the hopes of democratizing Bayesian vancomycin dosing, we created VancoCalc, a free website, as a proof of concept vancomycin dosing tool which leverages Bayesian inference. It uses individual concentrations to estimate pharmacokinetic parameters and suggest optimal dosing options based on these concentrations and estimated pharmacokinetic parameters. To gain confidence in the Bayesian process and evaluate the tool, it was used to predict vancomycin concentrations using retrospective clinical data from 52 patients. Our hope is to increase awareness of this tool and further improve on vancomycin dosing with this freely available instrument, which may have beneficial implications for therapeutic monitoring and improving patient outcomes.

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