2025
Pre‐Diagnosis Alkaline Phosphatase and Antimitochondrial Antibody Positivity Vary by Race/Ethnicity Among Patients With Primary Biliary Cholangitis
Caines A, Lu M, Wu T, Trudeau S, Melkonian C, Gonzalez H, Sahota A, Schmidt M, Daida Y, Bowlus C, Gordon S. Pre‐Diagnosis Alkaline Phosphatase and Antimitochondrial Antibody Positivity Vary by Race/Ethnicity Among Patients With Primary Biliary Cholangitis. Journal Of Gastroenterology And Hepatology 2025 PMID: 40551359, DOI: 10.1111/jgh.17035.Peer-Reviewed Original ResearchPrimary biliary cholangitisAntimitochondrial antibody positivityAntimitochondrial antibodiesYears prior to diagnosisAMA-positiveNHW patientsBiliary cholangitisDiagnosis of primary biliary cholangitisBlack patientsPrimary biliary cholangitis patientsAlkaline phosphatasePositive antimitochondrial antibodyElevated alkaline phosphataseEvaluate racial differencesPre-DiagnosisAsian American Pacific IslanderPBC patientsAAPI patientsPatient groupALP levelsPatientsDiagnosisNHWCholangitisNon-HispanicGly-βMCA modulates bile acid metabolism to reduce hepatobiliary injury in Mdr2 KO mice
Hasan M, Wang H, Luo W, Du Y, Li T. Gly-βMCA modulates bile acid metabolism to reduce hepatobiliary injury in Mdr2 KO mice. AJP Gastrointestinal And Liver Physiology 2025, 329: g45-g57. PMID: 40418643, PMCID: PMC12178242, DOI: 10.1152/ajpgi.00044.2025.Peer-Reviewed Original ResearchConceptsKO miceBile acid compositionBile acid pool sizeBile acid poolBile acid hydrophobicityHepatic bile acidsHepatobiliary toxicityBile acid metabolismMale miceTherapeutic benefitCholestasis modelMdr2-KO miceDecreased liver injuryBile acidsSerum alkaline phosphataseBile acid absorptionAlkaline phosphataseFecal bile acid excretionAcid compositionDiminished therapeutic efficacyImpaired bile flowAcid metabolismHepatobiliary injuryUnique pharmacokineticsBiliary injurySafety and efficacy of elafibranor in primary sclerosing cholangitis: The ELMWOOD phase II randomized-controlled trial
Levy C, Abouda G, Bilir B, Bonder A, Bowlus C, Campos-Varela I, Cazzagon N, Chandok N, Cheent K, Cortez-Pinto H, Demir M, Dill M, Eksteen B, Fenkel J, Gilroy R, Ko H, Jacobson I, Kallis Y, Kugelmas M, Luketic V, Mangia A, Montano-Loza A, Mukhopadhya A, Olveira A, Patel B, Pietrangelo A, Pradhan F, Salcedo M, Shiffman M, Sprinzl K, Swann R, Thorburn D, Thuluvath P, Trivedi P, Turnes J, Zein C, Gomes da Silva H, Jaitly S, Miller B, Milligan C, Tavenard A, Kowdley K. Safety and efficacy of elafibranor in primary sclerosing cholangitis: The ELMWOOD phase II randomized-controlled trial. Journal Of Hepatology 2025 PMID: 40350321, DOI: 10.1016/j.jhep.2025.04.025.Peer-Reviewed Original ResearchTreatment-emergent adverse eventsPrimary sclerosing cholangitisEnhanced liver fibrosisEnhanced Liver Fibrosis scoreSclerosing cholangitisBiochemical improvementRates of treatment-emergent adverse eventsSerious treatment-emergent adverse eventsLS mean treatment differenceAlkaline phosphataseAlkaline phosphatase normalizationDouble-blind periodDouble-blind trialMarkers of fibrosisMean treatment differenceLong-term outcomesChronic liver diseaseAlkaline phosphatase levelsPrimary endpointImprove pruritusWell-toleratedSafety profileAdverse eventsPlaceboUrsodeoxycholic acid
2024
Black Tea Kombucha Consumption: Effect on Cardiometabolic Parameters and Diet Quality of Individuals with and without Obesity
Fraiz G, Costa M, Cardoso R, Hébert J, Zhao L, Corich V, Giacomini A, Milagro F, Barros F, Bressan J. Black Tea Kombucha Consumption: Effect on Cardiometabolic Parameters and Diet Quality of Individuals with and without Obesity. Fermentation 2024, 10: 384. DOI: 10.3390/fermentation10080384.Peer-Reviewed Original ResearchDiet qualityCardiometabolic parametersDiet quality of individualsDietary total antioxidant capacityWorsening diet qualityPre-post interventionHealthy eating patternsHealth of individualsTreatment of obesityIn vitro studiesPost-interventionHOMA-IREating patternsTotal cholesterolMetabolic healthObesityTotal antioxidant capacityDiet of individualsCompare differencesQuality of individualsAlkaline phosphataseIndividualsPositive impactDietHealth
2022
30-Day Postoperative Outcomes in Adults with Obstructive Sleep Apnea Undergoing Upper Airway Surgery
Knoedler S, Knoedler L, Baecher H, Kauke-Navarro M, Obed D, Hoch C, Diehm Y, Vosler P, Harréus U, Kneser U, Panayi A. 30-Day Postoperative Outcomes in Adults with Obstructive Sleep Apnea Undergoing Upper Airway Surgery. Journal Of Clinical Medicine 2022, 11: 7371. PMID: 36555986, PMCID: PMC9783895, DOI: 10.3390/jcm11247371.Peer-Reviewed Original ResearchObstructive sleep apneaOSA surgeryPostoperative outcomesMedical complicationsSleep apneaSurgeons National Surgical Quality Improvement Program databaseNational Surgical Quality Improvement Program databaseMulti-institutional national databaseQuality Improvement Program databaseUpper airway surgeryTotal complication rateHistory of diabetesImprovement Program databasePositive safety profileAlkaline phosphatasePostoperative complicationsComplication ratePostoperative periodAirway surgeryFrequent comorbiditiesMale sexSafety profileUpper airwaySurgery outcomesChronic disordersThe Enthesopathy of XLH Is a Mechanical Adaptation to Osteomalacia: Biomechanical Evidence from Hyp Mice
Macica CM, Luo J, Tommasini SM. The Enthesopathy of XLH Is a Mechanical Adaptation to Osteomalacia: Biomechanical Evidence from Hyp Mice. Calcified Tissue International 2022, 111: 313-322. PMID: 35618776, DOI: 10.1007/s00223-022-00989-7.Peer-Reviewed Original ResearchConceptsUltimate strengthLoading conditionsMaximum strainNormal loading conditionsTensile testsMechanical propertiesTensile stiffnessWT miceHyp miceMechanical loadingMechanical stressBiomechanical testingSoft boneStiffnessBone matrixAlkaline phosphataseMajor comorbiditiesAchilles insertionClinical picturePhysical functionMechanical adaptationHyperplastic expansionMurine modelTriceps suraeStrength
2021
Adjunct Fenofibrate Up‐regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis
Gallucci GM, Trottier J, Hemme C, Assis DN, Boyer JL, Barbier O, Ghonem NS. Adjunct Fenofibrate Up‐regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis. Hepatology Communications 2021, 5: 2035-2051. PMID: 34558841, PMCID: PMC8631103, DOI: 10.1002/hep4.1787.Peer-Reviewed Original ResearchConceptsSerum bile acidsSerum alkaline phosphataseBile acidsTreatment responseIncomplete responseTotal serum bile acidsElevated serum alkaline phosphatasePeroxisome proliferator-activated receptor alphaProliferator-activated receptor alphaAlkaline phosphatasePrimary sclerosing cholangitisPrimary biliary cholangitisStandard of careSerum ALP levelsBile acid glucuronidationCytotoxic bile acidsPrimary human hepatocytesBA detoxificationFenofibrate therapySclerosing cholangitisAdult patientsBiliary cholangitisLiver failureCombination therapyImproved outcomesGenetic Variation in the Mitochondrial Glycerol‐3‐Phosphate Acyltransferase Is Associated With Liver Injury
Hakim A, Moll M, Brancale J, Liu J, Lasky‐Su J, Silverman EK, Vilarinho S, Jiang ZG, Pita‐Juárez Y, Vlachos IS, Zhang X, Åberg F, Afdhal NH, Hobbs BD, Cho MH. Genetic Variation in the Mitochondrial Glycerol‐3‐Phosphate Acyltransferase Is Associated With Liver Injury. Hepatology 2021, 74: 3394-3408. PMID: 34216018, PMCID: PMC8639615, DOI: 10.1002/hep.32038.Peer-Reviewed Original ResearchConceptsAlcohol-associated liver diseaseChronic liver diseaseLiver diseaseLiver injuryAlanine aminotransferaseAspartate aminotransferaseElevated body mass indexLevels of ALTDose-dependent riskFatty liver diseaseBody mass indexAlkaline phosphataseMass General Brigham BiobankWeekly alcohol consumptionGenetic variantsMitochondrial glycerol-3-phosphate acyltransferaseLiver biochemistryHDL cholesterolLDL cholesterolTotal cholesterolMass indexRevision codesVLDL productionGlycerol-3-phosphate acyltransferaseTotal bilirubinEffect of Eight Weeks Aerobic Exercise and Vitamin-D Supplementation on Osteocalcin and Alkaline Phosphatase Gene Expression in Male Rats Poisoned with Hydrogen Peroxide
Eimari Eskandari R, Homaee H, Moradi L. Effect of Eight Weeks Aerobic Exercise and Vitamin-D Supplementation on Osteocalcin and Alkaline Phosphatase Gene Expression in Male Rats Poisoned with Hydrogen Peroxide. Journal Of Shahid Sadoughi University Of Medical Sciences 2021 DOI: 10.18502/ssu.v29i7.7267.Peer-Reviewed Original ResearchEffects of exerciseVitamin DEight-week aerobic exerciseAlkaline phosphatase gene expressionInteraction effect of exerciseWeeks aerobic exerciseAlkaline phosphataseAdult male Wistar ratsVitamin D supplementationIndependent t-testBone tissue of ratsMale Wistar ratsAerobic exercisePost hoc testTissues of ratsExpression of alkaline phosphataseGene expressionDaily doseExerciseMale ratsWistar ratsIncreased alkaline phosphataseGroup 2Sham groupBone tissueHepatic safety of repeated treatment with pyronaridine‐artesunate versus artemether–lumefantrine in patients with uncomplicated malaria: a secondary analysis of the WANECAM 1 data from Bobo-Dioulasso, Burkina Faso
Compaoré Y, Zongo I, Somé A, Barry N, Nikiéma F, Kaboré T, Ouattara A, Kabré Z, Wermi K, Zongo M, Yerbanga R, Sagara I, Djimdé A, Ouédraogo J. Hepatic safety of repeated treatment with pyronaridine‐artesunate versus artemether–lumefantrine in patients with uncomplicated malaria: a secondary analysis of the WANECAM 1 data from Bobo-Dioulasso, Burkina Faso. Malaria Journal 2021, 20: 64. PMID: 33514368, PMCID: PMC7847156, DOI: 10.1186/s12936-021-03593-6.Peer-Reviewed Original ResearchConceptsHepatic adverse eventsArtemether-lumefantrineAL armAdverse eventsElevated ALTMalaria episodesUncomplicated malariaHepatic safetyDirect bilirubinPA armFirst-line anti-malarial drugHepatic safety profileUncomplicated malaria episodesElevated total bilirubinBobo-DioulassoLogistic regression modelsAnti-malarial drugsAlkaline phosphataseSubsequent malariaUnscheduled daysStudy armsSafety profileResultsA totalClinical trialsTotal bilirubin
2020
Abnormal Liver Function Tests in Patients With COVID‐19: Relevance and Potential Pathogenesis
Bertolini A, van de Peppel I, Bodewes FAJA, Moshage H, Fantin A, Farinati F, Fiorotto R, Jonker JW, Strazzabosco M, Verkade HJ, Peserico G. Abnormal Liver Function Tests in Patients With COVID‐19: Relevance and Potential Pathogenesis. Hepatology 2020, 72: 1864-1872. PMID: 32702162, PMCID: PMC7404414, DOI: 10.1002/hep.31480.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsAbnormal liver function testsLiver function testsCOVID-19 patientsAspartate aminotransferaseFunction testsHospitalized coronavirus disease 2019 (COVID-19) patientsSevere COVID-19 diseaseCoronavirus disease 2019 (COVID-19) patientsElevated liver function testsPre-existing liver diseaseDrug-induced liver injuryCOVID-19Hyper-inflammatory statusAlanine aminotransferase levelsLopinavir/ritonavirOvert liver failureStart of treatmentUse of acetaminophenCause of deathPlasma aspartate aminotransferaseUpper reference limitSARS-CoV-2COVID-19 diseaseAlkaline phosphataseALT elevationLong-Term Follow-up of Hypophosphatemic Bone Disease Associated With Elemental Formula Use: Sustained Correction of Bone Disease After Formula Change or Phosphate Supplementation
Eswarakumar AS, S. N, Ward LM, Backeljauw P, Wasserman H, Weber DR, DiMeglio LA, Imel EA, Gagne J, Cody D, Zimakas P, Topor LS, Agrawal S, Calabria A, Tebben P, Faircloth RS, Gordon R, Casey L, Carpenter TO. Long-Term Follow-up of Hypophosphatemic Bone Disease Associated With Elemental Formula Use: Sustained Correction of Bone Disease After Formula Change or Phosphate Supplementation. Clinical Pediatrics 2020, 59: 1080-1085. PMID: 32666808, DOI: 10.1177/0009922820941097.Peer-Reviewed Original ResearchConceptsElemental formula useBone diseaseFormula useHypophosphatemic bone diseaseTerm Follow-upLong-term outcomesSerum phosphorus concentrationSerum alkaline phosphatase activitySerum alkaline phosphataseSeverity/durationTime of correctionChart reviewSerum phosphorusDisease AssociatedFollow-upPhosphate supplementationExtent of recoveryDiseaseDiagnosisFormula changesRadiology reportsSupplementationAlkaline phosphataseAlkaline phosphatase activityReportSyncytiotrophoblast extracellular microvesicle profiles in maternal circulation for noninvasive diagnosis of preeclampsia
Levine L, Habertheuer A, Ram C, Korutla L, Schwartz N, Hu RW, Reddy S, Freas A, Zielinski PD, Harmon J, Molugu SK, Parry S, Vallabhajosyula P. Syncytiotrophoblast extracellular microvesicle profiles in maternal circulation for noninvasive diagnosis of preeclampsia. Scientific Reports 2020, 10: 6398. PMID: 32286341, PMCID: PMC7156695, DOI: 10.1038/s41598-020-62193-7.Peer-Reviewed Original ResearchConceptsSyncytin-1Preeclampsia groupMaternal circulationExtracellular vesiclesCommon placental pathologyHigh expressionDiagnosis of preeclampsiaConditions of preeclampsiaBone alkaline phosphatasePotential physiologic roleTissue-specific biomarkersExtracellular microvesiclesPlasma extracellular vesiclesAlkaline phosphatasePreeclampsia subjectsNormal pregnancyPlacental pathologyCell extracellular vesiclesImproved biomarkersMaternal bloodPreeclampsiaPlacental syncytiotrophoblastMaternal plasmaPlacental alkaline phosphatasePhysiologic role
2019
Rhythmic Fluctuations in Levels of Liver Enzymes During Menstrual Cycles of Healthy Women and Effects of Body Weight
Lai C, Jadhav S, Njei B, Ye A, Wactawski-Wende J, Mumford S, Schisterman E, Rotman Y. Rhythmic Fluctuations in Levels of Liver Enzymes During Menstrual Cycles of Healthy Women and Effects of Body Weight. Clinical Gastroenterology And Hepatology 2019, 18: 2055-2063.e2. PMID: 31811951, PMCID: PMC7269853, DOI: 10.1016/j.cgh.2019.11.047.Peer-Reviewed Original ResearchConceptsLevels of liver enzymesMenstrual cycleLevels of alanine aminotransferaseBody mass indexLiver enzymesAlanine aminotransferaseSex hormonesMenstruating womenMass indexAssociation of sex hormonesPost hoc analysis of dataPhases of menstrual cycleAlkaline phosphataseHealthy menstruating womenNormal menstrual cycleAlanine aminotransferase valuesFemale sex hormonesMid-follicular phaseAbstractText Label="RESULTS">Levels of estrogenMarkers of oxidative stressLiver enzyme measurementsLevels of progesteroneLevels of alkaline phosphataseNon-reproductive organs2797 Fenofibrate and PSC: A Case Series From a Single Center Liver Registry
Shah S, Silveira M, Assis D, Cusack L. 2797 Fenofibrate and PSC: A Case Series From a Single Center Liver Registry. The American Journal Of Gastroenterology 2019, 114: s1544-s1545. DOI: 10.14309/01.ajg.0000600720.33625.bb.Peer-Reviewed Original ResearchPrimary sclerosing cholangitisPrimary biliary cholangitisCase seriesUrsodeoxycholic acidLarge-duct primary sclerosing cholangitisTreatment of primary sclerosing cholangitisNo current effective therapyRetrospective single-center case seriesPrimary sclerosing cholangitis patientsSingle-center case seriesAlkaline phosphataseRisk scorePrimary sclerosing cholangitis treatmentPost-FFSAlkaline phosphatase reductionPatients due to lackAcute kidney injuryCholestatic liver diseaseAlkaline phosphatase levelsCurrent effective therapiesSerum alkaline phosphataseInflammatory bowel diseaseIntrahepatic diseaseAutoimmune hepatitisRecurrent cholangitisEffects of Vedolizumab in Patients With Primary Sclerosing Cholangitis and Inflammatory Bowel Diseases
Lynch KD, Chapman RW, Keshav S, Montano-Loza AJ, Mason AL, Kremer AE, Vetter M, de Krijger M, Ponsioen CY, Trivedi P, Hirschfield G, Schramm C, Liu CH, Bowlus CL, Estes DJ, Pratt D, Hedin C, Bergquist A, de Vries AC, van der Woude CJ, Yu L, Assis DN, Boyer J, Ytting H, Hallibasic E, Trauner M, Marschall HU, Daretti LM, Marzioni M, Yimam KK, Perin N, Floreani A, Beretta-Piccoli BT, Rogers JK, Group I, Levy C. Effects of Vedolizumab in Patients With Primary Sclerosing Cholangitis and Inflammatory Bowel Diseases. Clinical Gastroenterology And Hepatology 2019, 18: 179-187.e6. PMID: 31100458, PMCID: PMC6941216, DOI: 10.1016/j.cgh.2019.05.013.Peer-Reviewed Original ResearchConceptsPrimary sclerosing cholangitisInflammatory bowel diseaseEffect of vedolizumabSerum levelsLast followSclerosing cholangitisBowel diseaseStudy groupInternational PSC Study GroupAlkaline phosphataseLiver-related eventsLiver-related outcomesPresence of cirrhosisProportion of patientsSubset of patientsMedian serum levelsAnalysis of patientsInternational Study GroupLarge international cohortNorth American centersBacterial cholangitisCirrhosis decompensationEntire cohortClinical dataIntegrin α4β7Rickets severity predicts clinical outcomes in children with X-linked hypophosphatemia: Utility of the radiographic Rickets Severity Score
Thacher TD, Pettifor JM, Tebben PJ, Creo AL, Skrinar A, Mao M, Chen CY, Chang T, San Martin J, Carpenter TO. Rickets severity predicts clinical outcomes in children with X-linked hypophosphatemia: Utility of the radiographic Rickets Severity Score. Bone 2019, 122: 76-81. PMID: 30772600, DOI: 10.1016/j.bone.2019.02.010.Peer-Reviewed Original ResearchConceptsRickets Severity ScoreSerum alkaline phosphataseSeverity scoreSevere self-reported painPediatric Outcomes Data Collection InstrumentPhase 2 clinical trialAlkaline phosphataseLess physical functionSelf-reported painSevere clinical featuresHeight z-scoreRadiographic Global ImpressionPediatric Orthopaedic SocietyIntra-rater reliabilitySubstantial inter-rater reliabilityClinical featuresClinical outcomesBilateral kneesGlobal ImpressionPhysical functionSubstantial intra-rater reliabilityWeek 64Clinical trialsBurosumab treatmentFunctional impairment
2018
Real-world outcomes in patients with metastatic castration-resistant prostate cancer receiving second-line chemotherapy versus an alternative androgen receptor-targeted agent (ARTA) following early progression on a first-line ARTA in a US community oncology setting
Oh W, Cheng W, Miao R, Vekeman F, Gauthier-Loiselle M, Duh M, Drea E, Szatrowski T. Real-world outcomes in patients with metastatic castration-resistant prostate cancer receiving second-line chemotherapy versus an alternative androgen receptor-targeted agent (ARTA) following early progression on a first-line ARTA in a US community oncology setting. Urologic Oncology Seminars And Original Investigations 2018, 36: 500.e1-500.e9. PMID: 30201382, DOI: 10.1016/j.urolonc.2018.08.002.Peer-Reviewed Original ResearchMeSH KeywordsAgedAndrogen AntagonistsAndrostenesAntineoplastic Combined Chemotherapy ProtocolsBenzamidesDisease ProgressionDisease-Free SurvivalDocetaxelHumansKaplan-Meier EstimateMaleMiddle AgedNitrilesPhenylthiohydantoinProportional Hazards ModelsProstatic Neoplasms, Castration-ResistantRetrospective StudiesTaxoidsTreatment OutcomeConceptsSecond-line chemotherapyProstate-specific antigenMetastatic castration-resistant prostate cancerAndrogen receptor-targeted agentsCastration-resistant prostate cancerReceptor-targeted agentsOverall survivalEarly progressionProstate cancerOpioid usePoor prognosisEastern Cooperative Oncology Group performance scoreSecond-line therapy initiationTime to PSA progressionUS community oncology settingLactate dehydrogenaseRetrospective observational studyUS community settingsGroup performance scoreCommunity oncology settingAlkaline phosphatasePSA progressionClinical responsePrognostic featuresTherapy initiation
2017
Patient characteristics and overall survival in patients with post-docetaxel metastatic castration-resistant prostate cancer in the community setting
Oh W, Miao R, Vekeman F, Sung J, Cheng W, Gauthier-Loiselle M, Dhawan R, Duh M. Patient characteristics and overall survival in patients with post-docetaxel metastatic castration-resistant prostate cancer in the community setting. Medical Oncology 2017, 34: 160. PMID: 28795333, PMCID: PMC5550521, DOI: 10.1007/s12032-017-1014-2.Peer-Reviewed Original ResearchConceptsMetastatic castration-resistant prostate cancerProstate-specific antigenSecond-line therapy initiationCastration-resistant prostate cancerOverall survivalTherapy initiationProstate cancerPost-docetaxel metastatic castration-resistant prostate cancerMetastatic castration-resistant prostate cancer patientsPatient characteristicsAndrogen receptor-targeted therapiesFirst-line therapy initiationPost-docetaxel mCRPC patientsTreatment sequenceAssess treatment sequencingPost-docetaxel patientsReceptor-targeted therapyHigh-risk featuresNinety-five patientsHigh-risk patientsSecond-line ARTAlkaline phosphataseLower mean haemoglobinHigh-risk scoreMCRPC patientsReal-world Characteristics and Outcomes of Patients With Metastatic Castration-resistant Prostate Cancer Receiving Chemotherapy Versus Androgen Receptor-targeted Therapy After Failure of First-line Androgen Receptor-targeted Therapy in the Community Setting
Oh W, Miao R, Vekeman F, Sung J, Cheng W, Gauthier-Loiselle M, Dhawan R, Duh M. Real-world Characteristics and Outcomes of Patients With Metastatic Castration-resistant Prostate Cancer Receiving Chemotherapy Versus Androgen Receptor-targeted Therapy After Failure of First-line Androgen Receptor-targeted Therapy in the Community Setting. Clinical Genitourinary Cancer 2017, 16: 50-57. PMID: 28729067, DOI: 10.1016/j.clgc.2017.06.004.Peer-Reviewed Original ResearchAndrogen receptor-targeted therapiesMetastatic castration-resistant prostate cancerSecond-line TTReceptor-targeted therapyProstate-specific antigenOverall survivalOpioid useAlbumin levelsMedian prostate-specific antigenSecond-line therapy initiationCastration-resistant prostate cancerResponse rateSevere disease profilesSecond-line therapyPoor prognosis patientsOptimal treatment sequenceOutcomes of patientsAlkaline phosphataseImproved OSPrognosis patientsTherapy initiationProstate cancerLow hemoglobinPoor prognosisMultivariate analysis
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