Medicine and Health Sciences Commons^™

Patients' Perceptions And Patient-Reported Outcomes In Progressive-Fibrosing Interstitial Lung Diseases, Jeffrey J. Swigris, Kevin K. Brown, Rayid Abdulqawi, Ketan Buch, Daniel F. Dilling, Dirk Koschel, Krishna Thavarajah, Rade Tomic, Yoshikazu Inoue

Internal Medicine Faculty Publications

The effects of interstitial lung disease (ILD) create a significant burden on patients, unsettling almost every domain of their lives, disrupting their physical and emotional well-being and impairing their quality of life (QoL). Because many ILDs are incurable, and there are limited reliably-effective, life-prolonging treatment options available, the focus of many therapeutic interventions has been on improving or maintaining how patients with ILD feel and function, and by extension, their QoL. Such patient-centred outcomes are best assessed by patients themselves through tools that capture their perceptions, which inherently incorporate their values and judgements. These patient-reported outcome measures (PROs) can be …

Clinical Pharmacology Of Tisagenlecleucel In B-Cell Acute Lymphoblastic Leukemia., Karen Thudium Mueller, Edward Waldron, Stephan A. Grupp, John E. Levine, Theodore W. Laetsch, Michael A. Pulsipher, Michael W. Boyer, Keith August, Jason Hamilton, Rakesh Awasthi, Andrew M. Stein, Denise Sickert, Abhijit Chakraborty, Bruce L. Levine, Carl H. June, Lori Tomassian, Sweta S. Shah, Mimi Leung, Tetiana Taran, Patricia A. Wood, Shannon L. Maude

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL).

PATIENTS AND METHODS: We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN).

RESULTS: Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders (N = 62) had ≈2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders ( …

Financial Incentives For Smoking Treatment: Protocol Of The Fiesta Trial And Fiesta Oral Microbiome Substudy, Katherine M French, Sasha Z Gonzalez, Scott E Sherman, Alissa R Link, Sadozai Zoe Malik, Chi-Hong Tseng, Saahil A Jumkhawala, Briesny Tejada, Andrew White, Joseph A Ladapo

NYMC Student Publications

BACKGROUND: Smoking is the leading preventable cause of death in the United States, but evidence-based smoking cessation therapy is underutilized. Financial incentive strategies represent an innovative approach for increasing the use of counseling and pharmacotherapy. If effective, they could supplement or supplant resource-intensive policy options, particularly in populations for whom smoking has substantial societal costs. FIESTA (Financial IncEntives for Smoking TreAtment) will randomize hospitalized smokers to receive usual smoking cessation care alone or usual smoking care augmented with financial incentives. We aim to compare the impact of these two strategies on 1) smoking abstinence, 2) use of counseling and nicotine …

Safety, Tolerability, And Pharmacokinetics Of Long-Acting Injectable Cabotegravir In Low-Risk Hiv-Uninfected Individuals: Hptn 077, A Phase 2a Randomized Controlled Trial., Raphael J Landovitz, Sue Li, Beatriz Grinsztejn, Halima Dawood, Albert Y Liu, Manya Magnus, Mina C Hosseinipour, Ravindre Panchia, Leslie Cottle, Gordon Chau, Paul Richardson, Mark A Marzinke, Craig W Hendrix, Susan H Eshleman, Yinfeng Zhang, Elizabeth Tolley, Jeremy Sugarman, Ryan Kofron, Adeola Adeyeye, David Burns, Alex R Rinehart, David Margolis, William R Spreen, Myron S Cohen, Marybeth Mccauley, Joseph J Eron

Epidemiology Faculty Publications

BACKGROUND: Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States.

METHODS AND FINDINGS: HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy …

Azithromycin For Early Pseudomonas Infection In Cystic Fibrosis. The Optimize Randomized Trial., Nicole Mayer-Hamblett, George Retsch-Bogart, Margaret Kloster, Frank Accurso, Margaret Rosenfeld, Gary Albers, Philip Black, Perry Brown, Annemarie Cairns, Stephanie D. Davis, Gavin R. Graff, Gwendolyn S. Kerby, David Orenstein, Rachael Buckingham, Bonnie W. Ramsey, Optimize Study Group

Manuscripts, Articles, Book Chapters and Other Papers

RATIONALE: New isolation of Pseudomonas aeruginosa (Pa) is generally treated with inhaled antipseudomonal antibiotics such as tobramycin inhalation solution (TIS). A therapeutic approach that complements traditional antimicrobial therapy by reducing the risk of pulmonary exacerbation and inflammation may ultimately prolong the time to Pa recurrence.

OBJECTIVES: To test the hypothesis that the addition of azithromycin to TIS in children with cystic fibrosis and early Pa decreases the risk of pulmonary exacerbation and prolongs the time to Pa recurrence.

METHODS: The OPTIMIZE (Optimizing Treatment for Early Pseudomonas aeruginosa Infection in Cystic Fibrosis) trial was a multicenter, double-blind, randomized, placebo-controlled, 18-month trial …

Wearable Cardioverter-Defibrillator After Myocardial Infarction, Jeffrey E. Olgin, Mark J. Pletcher, Eric Vittinghoff, Jerzy Wranicz, Rajesh Malik, Daniel P. Morin, Steven Zweibel, Alfred E. Buxton, Claude S. Elayi, Eugene H. Chung, Eric Rashba, Martin Borggrefe, Trisha F Hue, Carol Maguire, Feng Lin, Joel A. Simon, Stephen Hulley, Byron K. Lee, Vest Investigators

Gill Heart & Vascular Institute Faculty Publications

BACKGROUND

Despite the high rate of sudden death after myocardial infarction among patients with a low ejection fraction, implantable cardioverter–defibrillators are contraindicated until 40 to 90 days after myocardial infarction. Whether a wearable cardioverter–defibrillator would reduce the incidence of sudden death during this high-risk period is unclear.

METHODS

We randomly assigned (in a 2:1 ratio) patients with acute myocardial infarction and an ejection fraction of 35% or less to receive a wearable cardioverter–defibrillator plus guideline-directed therapy (the device group) or to receive only guideline-directed therapy (the control group). The primary outcome was the composite of sudden death or death from …

A Systematic Review Of The Efficacy And Safety Of Fecal Microbiota Transplant For Clostridium Difficile Infection In Immunocompromised Patients, Oluwaseun Shogbesan, Dilli Ram Poudel, Samjeris Victor, Asad Jehangir, Opeyemi Fadahunsi, Gbenga Shogbesan, Anthony A. Donato

Reading Hospital Internal Medicine Residency

Background: Fecal microbiota transplantation (FMT) has been shown to be effective in recurrent

Methods: We searched MEDLINE and EMBASE for English language articles published on FMT for treatment of CD infection in immunocompromised patients (including patients on immunosuppressant medications, patients with human immunodeficiency virus (HIV), inherited or primary immunodeficiency syndromes, cancer undergoing chemotherapy, or organ transplant, including-bone marrow transplant) of all ages. We excluded inflammatory bowel disease patients that were not on immunosuppressant medications. Resolution and adverse event rates (including secondary infection, rehospitalization, and death) were calculated.

Results: Forty-four studies were included, none of which were randomized designs. A total …

The High-Level Mobility Assessment Tool (Himat) In Myotonic Dystrophy Type 2: A Case Report, Kim B. Smith, Evan M. Pucillo

Physical Therapy Collection

Myotonic dystrophy type 2 (DM2) is a progressive muscular dystrophy with multi-system manifestations and can affect functional mobility, gait, and balance. Currently, there are few reports of functional outcome measures in this population. This case describes the change in function detected by the High-level Mobility Assessment Tool (HiMAT) and 30-second Chair Stand Test (CST) in a high-functioning adult female with DM2 after physical therapy treatment. The patient’s chief complaint was muscular pain and fatigue that affected activities of daily living (ADLs). Multimodal physical therapy focused on neuromuscular re-education, balance and strength training, patient education, and moderate cardiorespiratory training. Improvements were …

Trevo Stent-Retriever Mechanical Thrombectomy For Acute Ischemic Stroke Secondary To Large Vessel Occlusion Registry., Osama O Zaidat, Alicia C Castonguay, Raul G Nogueira, Diogo C Haussen, Joey D English, Sudhakar R Satti, Jennifer Chen, Hamed Farid, Candace Borders, Erol Veznedaroglu, Mandy J Binning, Ajit Puri, Nirav A Vora, Ron F Budzik, Guilherme Dabus, Italo Linfante, Vallabh Janardhan, Amer Alshekhlee, Michael G Abraham, Randall Edgell, Muhammad Asif Taqi, Ramy El Khoury, Maxim Mokin, Aniel Q Majjhoo, Mouhammed R Kabbani, Michael T Froehler, Ira Finch, Sameer A Ansari, Roberta Novakovic, Thanh N Nguyen

Articles, Abstracts, and Reports

BACKGROUND: Recent randomized clinical trials (RCTs) demonstrated the efficacy of mechanical thrombectomy using stent-retrievers in patients with acute ischemic stroke (AIS) with large vessel occlusions; however, it remains unclear if these results translate to a real-world setting. The TREVO Stent-Retriever Acute Stroke (TRACK) multicenter Registry aimed to evaluate the use of the Trevo device in everyday clinical practice.

METHODS: Twenty-three centers enrolled consecutive AIS patients treated from March 2013 through August 2015 with the Trevo device. The primary outcome was defined as achieving a Thrombolysis in Cerebral Infarction (TICI) score of ≥2b. Secondary outcomes included 90-day modified Rankin Scale (mRS), …

Iron Isomaltoside Is Superior To Iron Sucrose In Increasing Hemoglobin In Gynecological Patients With Iron Deficiency Anemia., Richard Derman, Eloy Roman, Gioi N. Smith-Nguyen, Maureen M. Achebe, Lars L. Thomsen, Michael Auerbach

Global Health Articles

No abstract provided.

Exacerbation Recovery Patterns In Newly Diagnosed Or Maintenance Treatment-Naïve Patients With Copd: Secondary Analyses Of Ticari 1 Trial Data, David M. Mannino, Emmanuelle M. Clerisme-Beaty, Joanne Franceschina, Naitee Ting, Nancy K. Leidy

Preventive Medicine and Environmental Health Faculty Publications

Background: Little is known about the recovery patterns from acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in newly diagnosed or maintenance treatment-naïve patients with COPD. This study describes the course of AECOPD in these patients at the time of treatment for the symptoms of acute respiratory tract infection (RTI).

Methods: This study was a secondary analysis of data from a 12-week, randomized clinical trial (TICARI 1) testing the efficacy and safety of once-daily tiotropium 18 µg maintenance therapy versus placebo in newly diagnosed or maintenance treatment-naïve COPD patients with acute RTI symptoms for ≤7 days. Patients received standard care …

Does Specialist Physician Supply Affect Pediatric Asthma Health Outcomes?, Guido Filler, Tom Kovesi, Erik Bourdon, Sarah Ann Jones, Laurentiu Givelichian, Cheryl Rockman-Greenberg, Jason Gilliland, Marion Williams, Elaine Orrbine, Bruno Piedboeuf

Paediatrics Publications

Background

Pediatrician and pediatric subspecialist density varies substantially among the various Canadian provinces, as well as among various states in the US. It is unknown whether this variability impacts health outcomes. To study this knowledge gap, we evaluated pediatric asthma admission rates within the 2 Canadian provinces of Manitoba and Saskatchewan, which have similarly sized pediatric populations and substantially different physician densities.

Methods

This was a retrospective cross-sectional cohort study. Health regions defined by the provincial governments, have, in turn, been classified into "peer groups" by Statistics Canada, on the basis of common socio-economic characteristics and socio-demographic determinants of health. …

Demographic, Presentation, And Treatment Factors And Racial Disparities In Ovarian Cancer Hospitalization Outcomes, Tomi F. Akinyemiju, Gurudatta Naik, Kemi Ogunsina, Daniel T. Dibaba, Neomi Vin-Raviv

Epidemiology and Environmental Health Faculty Publications

BACKGROUND: This study examines whether racial disparities in hospitalization outcomes persist between African-American and White women with ovarian cancer after matching on demographic, presentation, and treatment factors.

METHODS: Using data from the Nationwide Inpatient Sample database, 5,164 African-American ovarian cancer patients were sequentially matched with White patients on demographic (e.g., age, income), presentation (e.g., stage, comorbidities), and treatment (e.g., surgery, radiation) factors. Racial differences in-hospital length of stay, post-operative complications, and in-hospital mortality were evaluated using conditional logistic regression models.

RESULTS: White ovarian cancer patients had relatively higher odds of post-operative complications when matched on demographics (OR 1.35, 95% CI …

Delayed Sternal Closure Does Not Reduce Complications Associated With Coagulopathy And Right Ventricular Failure After Left Ventricular Assist Device Implantation, Roh Yanagida, Navin Rajagopalan, Daniel L. Davenport, Thomas A. Tribble, Mark A. Bradley, Charles W. Hoopes

Internal Medicine Faculty Publications

Delayed sternal closure (DSC) is occasionally adopted after implantation of left ventricular assist device (LVAD). Recent studies suggest that DSC be used for high risk group of patients with coagulopathy, hemodynamic instability or right ventricular failure. However, whether DSC is efficacious for bleeding complication or right ventricular failure is not known. This study is single center analysis of 52 patients, who underwent LVAD implantation. Of those 52 patients, 40 consecutive patients underwent DSC routinely. The sternum was left open with vacuum assist device after implantation of LVAD. Perioperative outcome of the patients who underwent routine DSC were compared with 12 …

Immediate Versus Delayed Insertion Of The Levonorgestrel Intrauterine Device In Postpartum Adolescents: A Randomized Pilot Study., Reni Soon, Katie Mcguire, Jennifer Salcedo, Bliss Kaneshiro

Articles, Abstracts, and Reports

This pilot study assessed the feasibility of conducting a larger randomized controlled trial comparing the proportion of adolescents using a levonorgestrel intrauterine device (LNG IUD) at six months postpartum when it is inserted immediately after vaginal delivery (within 10 minutes after placental expulsion) compared to insertion four to six weeks postpartum. Pregnant adolescents (14 to 19 years) who desired a LNG IUD for postpartum contraception were randomized to insertion of the LNG IUD either within 10 minutes of delivery of the placenta or at 4-6 weeks postpartum. Study follow-up visits were conducted at 4-6 weeks postpartum, 10 weeks postpartum, and …

Effects Of Adjunctive Eslicarbazepine Acetate On Serum Lipids In Patients With Partial-Onset Seizures: Impact Of Concomitant Statins And Enzyme-Inducing Antiepileptic Drugs., Scott Mintzer, Robert T. Wechsler, Joanne B. Rogin, Barry E. Gidal, Matthias Schwab, Elinor Ben-Menachem, Mar Carreño, Patrício Soares Da Silva, Joana Moreira, Yan Li, David Blum, Todd Grinnell

Department of Neurology Faculty Papers

PURPOSE: To evaluate the effects of eslicarbazepine acetate (ESL) on lipid metabolism and to determine whether reduced statin exposure during ESL therapy has clinical consequences.

SUBJECTS AND METHODS: We conducted a post-hoc analysis of pooled data for serum lipids (laboratory values) from three phase III, multicenter, randomized, double-blind, placebo-controlled trials of adjunctive ESL therapy (400, 800, or 1200 mg once daily) in patients with treatment-refractory partial-onset seizures. Changes from baseline in serum lipid levels were analyzed according to use of statins and/or enzyme-inducing antiepileptic drugs (EIAEDs) during the baseline period.

KEY FINDINGS: In total, 426 and 1021 placebo- and ESL-treated …

Extracorporeal Cellular Therapy (Elad) In Severe Alcoholic Hepatitis: A Multinational, Prospective, Controlled, Randomized Trial., Julie Thompson, Natasha Jones, Ali Al-Khafaji, Shahid Malik, David Reich, Santiago Munoz, Ross Macnicholas, Tarek Hassanein, Lewis Teperman, Lance Stein, Andrés Duarte-Rojo, Raza Malik, Talal Adhami, Sumeet Asrani, Nikunj Shah, Paul Gaglio, Anupama Duddempudi, Brian Borg, Rajiv Jalan, Robert Brown, Heather Patton, Rohit Satoskar, Simona Rossi, Amay Parikh, Ahmed Elsharkawy, Parvez Mantry, Linda Sher, David Wolf, Marquis Hart, Charles Landis, Alan Wigg, Shahid Habib, Geoffrey Mccaughan, Steven Colquhoun, Alyssa Henry, Patricia Bedard, Lee Landeen, Michael Millis, Robert Ashley, William Frank, Andrew Henry, Jan Stange, Ram Subramanian

Articles, Abstracts, and Reports

Severe alcoholic hepatitis (sAH) is associated with a poor prognosis. There is no proven effective treatment for sAH, which is why early transplantation has been increasingly discussed. Hepatoblastoma-derived C3A cells express anti-inflammatory proteins and growth factors and were tested in an extracorporeal cellular therapy (ELAD) study to establish their effect on survival for subjects with sAH. Adults with sAH, bilirubin ≥8 mg/dL, Maddrey's discriminant function ≥ 32, and Model for End-Stage Liver Disease (MELD) score ≤ 35 were randomized to receive standard of care (SOC) only or 3-5 days of continuous ELAD treatment plus SOC. After a minimum follow-up of …

A Standardized Comparison Of Peri-Operative Complications After Minimally Invasive Esophagectomy: Ivor Lewis Versus Mckeown., Andrew M. Brown, Michael J. Pucci, Adam C. Berger, Talar Tatarian, Nathaniel R. Evans Iii, Ernest L. Rosato, Francesco Palazzo

Department of Surgery Faculty Papers

BACKGROUND: While our institutional approach to esophageal resection for cancer has traditionally favored a minimally invasive (MI) 3-hole, McKeown esophagectomy (MIE 3-hole) during the last five years several factors has determined a shift in our practice with an increasing number of minimally invasive Ivor Lewis (MIE IL) resections being performed. We compared peri-operative outcomes of the two procedures, hypothesizing that MIE IL would be less morbid in the peri-operative setting compared to MIE 3-hole.

METHODS: Our institution's IRB-approved esophageal database was queried to identify all patients who underwent totally MI esophagectomy (MIE IL vs. MIE 3-hole) from June 2011 to …

The Efficacy Of Hippotherapy For Physical Rehabilitation: A Systematic Review, Megan Hilgers, Haley Nielsen

Occupational Therapy Capstones

Purpose: The purpose of this scholarly project is to examine existing literature pertaining to hippotherapy and conditions impacting physical health through completion of a systematic review. According to the American Hippotherapy Association (AHA, 2017), hippotherapy is defined as “how occupational therapy, physical therapy, and speech-language pathology professionals use evidence-based practice and clinical reasoning in the purposeful manipulation of equine movement to engage sensory, neuromotor, and cognitive systems to achieve functional outcomes” (What is Hippotherapy, para. 1). Hippotherapy was initially cited in occupational therapy practice in the 1980’s, but minimal attention and research have been applied to the topic as …

Cetuximab Plus Carboplatin And Paclitaxel With Or Without Bevacizumab Versus Carboplatin And Paclitaxel With Or Without Bevacizumab In Advanced Nsclc (Swog S0819): A Randomised, Phase 3 Study, Roy S. Herbst, Mary W. Redman, Edward S. Kim, Thomas J. Semrad, Lyudmila Bazhenova, Gregory Masters, Kurt Oettel, Perry Guaglianone, Christopher Reynolds, Anand Karnad, Susanne M. Arnold, Marileila Varella-Garcia, James Moon, Philip C. Mack, Charles D. Blanke, Fred R. Hirsch, Karen Kelly, David R. Gandara

Markey Cancer Center Faculty Publications

Background

EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. We hypothesised that EGFR copy number by fluorescence in-situ hybridisation (FISH) can identify patients most likely to benefit from these drugs combined with chemotherapy and we aimed to explore the activity of cetuximab with chemotherapy in patients with advanced NSCLC who are EGFR FISH-positive.

Methods

We did this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico. We randomly assigned (1:1) eligible patients with treatment-naive stage IV NSCLC to receive paclitaxel (200 mg/m ²; every …

Intra-Arterial Nitroglycerin As Directed Acute Treatment In Experimental Ischemic Stroke, Michael E. Maniskas, Jill M. Roberts, Rebecca Trueman, Annastazia E. Learoyd, Amanda A. Gorman, Justin F. Fraser, Gregory J. Bix

Neuroscience Faculty Publications

BACKGROUND: Nitroglycerin (also known as glyceryl trinitrate (GTN)), a vasodilator best known for treatment of ischemic heart disease, has also been investigated for its potential therapeutic benefit in ischemic stroke. The completed Efficacy of Nitric Oxide in Stroke trial suggested that GTN has therapeutic benefit with acute (within 6 hours) transdermal systemic sustained release therapy.

OBJECTIVE: To examine an alternative use of GTN as an acute therapy for ischemic stroke following successful recanalization.

METHODS: We administered GTN IA following transient middle cerebral artery occlusion in mice. Because no standard dose of GTN is available following emergent large vessel occlusion, we …

Lower Serum Iga Is Associated With Copd Exacerbation Risk In Spiromics., Nirupama Putcha, Gabriel G Paul, Antoine Azar, Robert A Wise, Wanda K O'Neal, Mark T Dransfield, Prescott G Woodruff, Jeffrey L Curtis, Alejandro P Comellas, M Bradley Drummond, Allison A. Lambert, Laura M Paulin, Ashraf Fawzy, Richard E Kanner, Robert Paine, Meilan K Han, Fernando J Martinez, Russell P Bowler, R Graham Barr, Nadia N Hansel

Articles, Abstracts, and Reports

BACKGROUND: Decreased but measurable serum IgA levels (≤70 mg/dL) have been associated with risk for infections in some populations, but are unstudied in COPD. This study tested the hypothesis that subnormal serum IgA levels would be associated with exacerbation risk in COPD.

METHODS: Data were analyzed from 1,049 COPD participants from the observational cohort study SPIROMICS (535 (51%) women; mean age 66.1 (SD 7.8), 338 (32%) current smokers) who had baseline serum IgA measured using the Myriad RBM biomarker discovery platform. Exacerbation data was collected prospectively (mean 944.3 (SD 281.3) days), and adjusted linear, logistic and zero-inflated negative binomial regressions …

Standard Ablation Versus Magnetic Resonance Imaging-Guided Ablation In The Treatment Of Ventricular Tachycardia., Tarek Zghaib, Esra G Ipek, Rozann Hansford, Hiroshi Ashikaga, Ronald D Berger, Joseph E Marine, David D Spragg, Harikrishna Tandri, Stefan L Zimmerman, Henry Halperin, Scott Brancato, Hugh Calkins, Charles Henrikson, Saman Nazarian

Articles, Abstracts, and Reports

No abstract provided.

Buprenorphine In Neonatal Abstinence Syndrome., Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Infants exposed in utero to opioids will demonstrate a withdrawal syndrome known as neonatal abstinence syndrome (NAS). Buprenorphine is a long-acting opioid with therapeutic use in medication-assisted treatment of opioid dependency in adults and adolescents. Emerging data from clinical trials and treatment cohorts demonstrate the efficacy and safety of sublingual buprenorphine for those infants with NAS who require pharmacologic treatment. Pharmacometric modeling will assist in defining the exposure-response relationships and facilitate dose optimization.