Digital Commons Network^™

Shared And Unique Brain Network Features Predict Cognitive, Personality, And Mental Health Scores In The Abcd Study, Jianzhong Chen, Angela Tam, Valeria Kebets, Csaba Orban, Leon Qi Rong Ooi, Christopher L Asplund, Scott Marek, Nico U F Dosenbach, Simon B Eickhoff, Danilo Bzdok, Avram J Holmes, B T Thomas Yeo

Open Access Publications

How individual differences in brain network organization track behavioral variability is a fundamental question in systems neuroscience. Recent work suggests that resting-state and task-state functional connectivity can predict specific traits at the individual level. However, most studies focus on single behavioral traits, thus not capturing broader relationships across behaviors. In a large sample of 1858 typically developing children from the Adolescent Brain Cognitive Development (ABCD) study, we show that predictive network features are distinct across the domains of cognitive performance, personality scores and mental health assessments. On the other hand, traits within each behavioral domain are predicted by similar network …

A Somatic Mutation In Moesin Drives Progression Into Acute Myeloid Leukemia, Ouyang Yuan, Jeffrey A Magee, Et Al.

Open Access Publications

Acute myeloid leukemia (AML) arises when leukemia-initiating cells, defined by a primary genetic lesion, acquire subsequent molecular changes whose cumulative effects bypass tumor suppression. The changes that underlie AML pathogenesis not only provide insights into the biology of transformation but also reveal novel therapeutic opportunities. However, backtracking these events in transformed human AML samples is challenging, if at all possible. Here, we approached this question using a murine in vivo model with an MLL-ENL fusion protein as a primary molecular event. Upon clonal transformation, we identified and extensively verified a recurrent codon-changing mutation (Arg

Dissemination And Implementation Science Resources, Training, And Scientific Activities Provided Through Ctsa Programs Nationally: Opportunities To Advance D&I Research And Training Capacity, Rachel C Shelton, Rowena J Dolor, Jonathan Tobin, Ana Baumann, Catherine Rohweder, Sapana Patel, Laura-Mae Baldwin

Open Access Publications

Introduction: Clinical and Translational Science Award (CTSA) Program hubs are well-positioned to advance dissemination and implementation (D&I) research and training capacity nationally, though little is known about what D&I research support and services CTSAs provide. To address this gap, the CTSA Dissemination, Implementation, and Knowledge Transfer Working Group conducted an environmental scan of CTSAs (2017-2018).

Methods: Of 67 CTSA institutions, we contacted 43 that previously reported delivering D&I research services. D&I experts from these institutions were emailed a survey assessing D&I resources, services, training, and scientific projects. Responses were categorized and double-coded by study authors using a content analysis approach. …

Cisplatin Resistance Can Be Curtailed By Blunting Bnip3-Mediated Mitochondrial Autophagy, Caterina Vianello, Gerald W Dorn 2nd, Et Al

Open Access Publications

Cisplatin (CDDP) is commonly used to treat a multitude of tumors including sarcomas, ovarian and cervical cancers. Despite recent investigations allowed to improve chemotherapy effectiveness, the molecular mechanisms underlying the development of CDDP resistance remain a major goal in cancer research. Here, we show that mitochondrial morphology and autophagy are altered in different CDDP resistant cancer cell lines. In CDDP resistant osteosarcoma and ovarian carcinoma, mitochondria are fragmented and closely juxtaposed to the endoplasmic reticulum; rates of mitophagy are also increased. Specifically, levels of the mitophagy receptor BNIP3 are higher both in resistant cells and in ovarian cancer patient samples …

The Geriatric Emergency Care Applied Research (Gear) Network Approach: A Protocol To Advance Stakeholder Consensus And Research Priorities In Geriatrics And Dementia Care In The Emergency Department, Ula Hwang, Christopher Carpenter, Scott Dresden, Jeffrey Dussetschleger, Angela Gifford, Ly Hoang, Jesseca Leggett, Armin Nowroozpoor, Zachary Taylor, Manish Shah, The Gear And Gear 2.0 Networks

Open Access Publications

INTRODUCTION: Increasingly, older adults are turning to emergency departments (EDs) to address healthcare needs. To achieve these research demands, infrastructure is needed to both generate evidence of intervention impact and advance the development of implementation science, pragmatic trials evaluation and dissemination of findings from studies addressing the emergency care needs of older adults. The Geriatric Emergency Care Applied Research Network (https://gearnetwork.org) has been created in response to these scientific needs-to build a transdisciplinary infrastructure to support the research that will optimise emergency care for older adults and persons living with dementia.

METHODS AND ANALYSIS: In this paper, we describe our …

Murine Respiratory Tract Infection With Classical Klebsiella Pneumoniae Induces Bronchus-Associated Lymphoid Tissue, Rachel K Wasbotten, Aubree A Dahler, Joseph J Mackel, Catherine Morffy Smith, David A Rosen

Open Access Publications

Klebsiella pneumoniae is a Gram-negative, opportunistic pathogen that commonly causes nosocomial pneumonia, urinary tract infection, and septicemia. Our recent work utilizing a murine model of respiratory tract infection with classical K. pneumoniae demonstrated leukocyte aggregates in the lungs of mice at 28 days postinfection. Here, we sought to characterize the composition and development of these structures. Histopathological analyses of murine lungs revealed immune cell clusters surrounding the pulmonary vasculature and airways by 14 days postinfection, resembling inducible bronchus-associated lymphoid tissue (iBALT). Further investigation of these structures demonstrated central B cell aggregates with concomitant dispersed T cells. At day 28 postinfection, …

Development And Validation Of The Rcos Prognostic Index: A Bedside Multivariable Logistic Regression Model To Predict Hypoxaemia Or Death In Patients With Sars-Cov-2 Infection, Gerardo Alvarez-Uria, Sumanth Gandra, Venkata R Gurram, Raghu P Reddy, Manoranjan Midde, Praveen Kumar, Ketty E Arce

Open Access Publications

Introduction: Previous COVID-19 prognostic models have been developed in hospital settings and are not applicable to COVID-19 cases in the general population. There is an urgent need for prognostic scores aimed to identify patients at high risk of complications at the time of COVID-19 diagnosis.

Methods: The RDT COVID-19 Observational Study (RCOS) collected clinical data from patients with COVID-19 admitted regardless of the severity of their symptoms in a general hospital in India. We aimed to develop and validate a simple bedside prognostic score to predict the risk of hypoxaemia or death.

Results: 4035 patients were included in the development …

Applying Systems Thinking To Identify Enablers And Challenges To Scale-Up Interventions For Hypertension And Diabetes In Low-Income And Middle-Income Countries: Protocol For A Longitudinal Mixed-Methods Study, Anusha Ramani-Chander, Mark D Huffman, Et Al

Open Access Publications

INTRODUCTION: There is an urgent need to reduce the burden of non-communicable diseases (NCDs), particularly in low-and middle-income countries, where the greatest burden lies. Yet, there is little research concerning the specific issues involved in scaling up NCD interventions targeting low-resource settings. We propose to examine this gap in up to 27 collaborative projects, which were funded by the Global Alliance for Chronic Diseases (GACD) 2019 Scale Up Call, reflecting a total funding investment of approximately US$50 million. These projects represent diverse countries, contexts and adopt varied approaches and study designs to scale-up complex, evidence-based interventions to improve hypertension and …

Hereditary Alpha-Tryptasemia Modifies Clinical Phenotypes Among Individuals With Congenital Hypermobility Disorders, Maribel Vazquez, Jack Chovanec, Jiwon Kim, Thomas Dimaggio, Joshua D Milner, Clair A Francomano, Christina A Gurnett, Marco Ritelli, Marina Colombi, Jonathan J Lyons

Open Access Publications

Hereditary alpha-tryptasemia (HαT) is an autosomal dominant (AD) genetic trait characterized by elevated basal serum tryptase ≥8 ng/mL, caused by increased α-tryptase-encoding

Convection Enhanced Delivery Of The Oncolytic Adenovirus Delta24-Rgd In Patients With Recurrent Gbm: A Phase I Clinical Trial Including Correlative Studies, Erik H P Van Putten, David T Curiel, Et Al

Open Access Publications

PURPOSE: Testing safety of Delta24-RGD (DNX-2401), an oncolytic adenovirus, locally delivered by convection enhanced delivery (CED) in tumor and surrounding brain of patients with recurrent glioblastoma.

PATIENTS AND METHODS: Dose-escalation phase I study with 3+3 cohorts, dosing 107 to 1 × 1011 viral particles (vp) in 20 patients. Besides clinical parameters, adverse events, and radiologic findings, blood, cerebrospinal fluid (CSF), brain interstitial fluid, and excreta were sampled over time and analyzed for presence of immune response, viral replication, distribution, and shedding.

RESULTS: Of 20 enrolled patients, 19 received the oncolytic adenovirus Delta24-RGD, which was found to be safe and feasible. …

An International Analysis Evaluating Frontline Bendamustine With Rituximab In Extranodal Marginal Zone Lymphoma, Juan Pablo Alderuccio, Marcus P Watkins, Raya Saba, Brad S Kahl, Et Al

Open Access Publications

Extranodal marginal zone lymphoma (EMZL) is a heterogeneous non-Hodgkin lymphoma. No consensus exists regarding the standard-of-care in patients with advanced-stage disease. Current recommendations are largely adapted from follicular lymphoma, for which bendamustine with rituximab (BR) is an established approach. We analyzed the safety and efficacy of frontline BR in EMZL using a large international consortium. We included 237 patients with a median age of 63 years (range, 21-85). Most patients presented with Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (n = 228; 96.2%), stage III/IV (n = 179; 75.5%), and intermediate (49.8%) or high (33.3%) Mucosa Associated …

Machine Learning-Based Scoring Models To Predict Hematopoietic Stem Cell Mobilization In Allogeneic Donors, Jingyu Xiang, Min Shi, Mark A Fiala, Feng Gao, Michael P Rettig, Geoffrey L Uy, Mark A Schroeder, Katherine N Weilbaecher, Keith E Stockerl-Goldstein, Shamim Mollah, John F Dipersio

Open Access Publications

Mobilized peripheral blood has become the primary source of hematopoietic stem cells for both autologous and allogeneic stem cell transplantation. Granulocyte colony-stimulating factor (G-CSF) is currently the standard agent used in the allogeneic setting. Despite the high mobilization efficacy in most donors, G-CSF requires 4-5 days of daily administration, and a small percentage of the donors fail to mobilize an optimal number of stem cells necessary for a safe allogeneic stem cell transplant. In this study, we retrospectively reviewed 1361 related allogeneic donors who underwent stem cell mobilization at Washington University. We compared the standard mobilization agent G-CSF with five …

Identification Of Small Regions Of Overlap From Copy Number Variable Regions In Patients With Hypospadias, Carter H Scott, Ina E Amarillo

Open Access Publications

Hypospadias is a common form of congenital atypical sex development that is often associated with other congenital comorbidities. Many genes have been associated with the condition, most commonly single sequence variations. Further investigations of recurrent and overlapping copy number variations (CNVs) have resulted in the identification of genes and chromosome regions associated with various conditions, including differences of sex development (DSD). In this retrospective study, we investigated the DECIPHER database, as well as an internal institutional database, to identify small recurrent CNVs among individuals with isolated and syndromic hypospadias. We further investigated these overlapping recurrent CNVs to identify 75 smallest …

From Self-Efficacy To Imposter Syndrome: The Intrapersonal Traits Of Surgeons, Alexandra Medline, Helyn Grissom, Ndéye F Guissé, Victoria Kravets, Sandra Hobson, Julie Balch Samora, Mara Schenker

Open Access Publications

BACKGROUND: Demographic differences among surgical trainees regarding intrapersonal traits, such as imposter syndrome and assertiveness, have become widely acknowledged. However, many of these characteristics have not been examined in tandem, nor among both trainees and surgeons in practice. This study aimed to address these knowledge gaps.

METHODS: This was an anonymous, voluntary survey study comprised of validated measures of (1) self-efficacy, (2) imposter syndrome, (3) assertiveness, (4) perfectionism, and (5) self-rated likeability. A multimodal recruitment strategy was used and surgeons across all subspecialties were eligible for inclusion.

RESULTS: A total of 296 participants were included, with 54% identifying as female …

Opportunities For Penicillin Allergy Evaluation In Dental Clinics, Amanda Vivo, Michael J. Durkin, Iboula Kale, Taylor Boyer, Margaret A. Fitzpatrick, Charlesnika T. Evans, Marianne M. Jurasic, Gretchen Gibson, Katie J. Suda

Open Access Publications

No abstract provided.

Establishment Of Novel Neuroendocrine Carcinoma Patient-Derived Xenograft Models For Receptor Peptide-Targeted Therapy, Catherine G Tran, Jacqueline L Mudd, Ramaswamy Govindan, Paul F Cliften, Ryan C Fields

Open Access Publications

Gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) are rare cancers consisting of neuroendocrine carcinomas (NECs) and neuroendocrine tumors (NETs), which have been increasing in incidence in recent years. Few cell lines and pre-clinical models exist for studying GEP NECs and NETs, limiting the ability to discover novel imaging and treatment modalities. To address this gap, we isolated tumor cells from cryopreserved patient GEP NECs and NETs and injected them into the flanks of immunocompromised mice to establish patient-derived xenograft (PDX) models. Two of six mice developed tumors (NEC913 and NEC1452). Over 80% of NEC913 and NEC1452 tumor cells stained positive for Ki67. …

Mendelian Randomization Supports Bidirectional Causality Between Telomere Length And Clonal Hematopoiesis Of Indeterminate Potential, Tetsushi Nakao, C Charles Gu, Lisa De Las Fuentes, Et Al

Open Access Publications

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD.

Connectomic Profiling And Vagus Nerve Stimulation Outcomes Study (Connectivos): A Prospective Observational Protocol To Identify Biomarkers Of Seizure Response In Children And Youth, Lauren Siegel, Matthew D Smyth, Et Al

Open Access Publications

INTRODUCTION: Vagus nerve stimulation (VNS) is a neuromodulation therapy that can reduce the seizure burden of children with medically intractable epilepsy. Despite the widespread use of VNS to treat epilepsy, there are currently no means to preoperatively identify patients who will benefit from treatment. The objective of the present study is to determine clinical and neural network-based correlates of treatment outcome to better identify candidates for VNS therapy.

METHODS AND ANALYSIS: In this multi-institutional North American study, children undergoing VNS and their caregivers will be prospectively recruited. All patients will have documentation of clinical history, physical and neurological examination and …

Targeting Fatty Acid Β-Oxidation Impairs Monocyte Differentiation And Prolongs Heart Allograft Survival, Yuehui Zhu, Hao Dun, Li Ye, Yuriko Terada, Leah P. Shriver, Gary J. Patti, Daniel Kreisel, Andrew E. Gelman, Brian W. Wong

Open Access Publications

Monocytes play an important role in the regulation of alloimmune responses after heart transplantation (HTx). Recent studies have highlighted the importance of immunometabolism in the differentiation and function of myeloid cells. While the importance of glucose metabolism in monocyte differentiation and function has been reported, a role for fatty acid β-oxidation (FAO) has not been explored. Heterotopic HTx was performed using hearts from BALB/c donor mice implanted into C57BL/6 recipient mice and treated with etomoxir (eto), an irreversible inhibitor of carnitine palmitoyltransferase 1 (Cpt1), a rate-limiting step of FAO, or vehicle control. FAO inhibition prolonged HTx survival, reduced early T …

Frequency Of The Dopamine Receptor D3 (Rs6280) Vs. Opioid Receptor Μ1 (Rs1799971) Polymorphic Risk Alleles In Patients With Opioid Use Disorder: A Preponderance Of Dopaminergic Mechanisms?, Marjorie C Gondré-Lewis, Igor Elman, Tanya Alim, Edwin Chapman, Beverlyn Settles-Reaves, Carine Galvao, Mark S Gold, David Baron, Shan Kazmi, Eliot Gardner, Ashim Gupta, Catherine Dennen, Kenneth Blum

Open Access Publications

While opioids are a powerful class of drugs that inhibit transmission of pain signals, their use is tarnished by the current epidemic of opioid use disorder (OUD) and overdose deaths. Notwithstanding published reports, there remain gaps in our knowledge of opioid receptor mechanisms and their role in opioid seeking behavior. Thus, novel insights into molecular, neurogenetic and neuropharmacological bases of OUD are needed. We propose that an addictive endophenotype may not be entirely specific to the drug of choice but rather may be generalizable to altered brain reward circuits impacting net mesocorticolimbic dopamine release. We suggest that genetic or epigenetic …

Brain Charts For The Human Lifespan, R A I Bethlehem, J Seidlitz, S R White, C Ortinau, C D Smyser, Et Al

Open Access Publications

No abstract provided.

Protein Kinase C (Pkc)-Δ Mediates Arginine-Induced Glucagon Secretion In Pancreatic Α-Cells, Norikiyo Honzawa, Kei Fujimoto, Masaki Kobayashi, Daisuke Kohno, Osamu Kikuchi, Hiromi Yokota-Hashimoto, Eri Wada, Yuichi Ikeuchi, Yoko Tabei, Gerald W Dorn Ii, Kazunori Utsunomiya, Rimei Nishimura, Tadahiro Kitamura

Open Access Publications

The pathophysiology of type 2 diabetes involves insulin and glucagon. Protein kinase C (Pkc)-δ, a serine-threonine kinase, is ubiquitously expressed and involved in regulating cell death and proliferation. However, the role of Pkcδ in regulating glucagon secretion in pancreatic α-cells remains unclear. Therefore, this study aimed to elucidate the physiological role of Pkcδ in glucagon secretion from pancreatic α-cells. Glucagon secretions were investigated in Pkcδ-knockdown InR1G9 cells and pancreatic α-cell-specific Pkcδ-knockout (αPkcδKO) mice. Knockdown of Pkcδ in the glucagon-secreting cell line InR1G9 cells reduced glucagon secretion. The basic amino acid arginine enhances glucagon secretion via voltage-dependent calcium channels (VDCC). Furthermore, …

The Role Of Whole Blood Transfusions In Civilian Trauma: A Review Of Literature In Military And Civilian Trauma, Shane Kronstedt, Joon Lee, David Millner, Connor Mattivi, Halli Lafrankie, Lorenzo Paladino, Jeffrey Siegler

Open Access Publications

Resuscitation techniques for the management of adult trauma patients have evolved over the 20th century. Whole blood transfusions were previously used as the standard of care, whereas blood component therapy is the current method employed across most trauma centers across the United States. Prior to the transition, no studies were conducted to show improved efficacy of hemostatic potential in trauma patients. Recent conflicts in Iraq and Afghanistan have challenged the dogma that whole blood transfusions are not the standard of care and have shown potential as the superior transfusion product for adult trauma patients. The purpose of this review is …

Delphi Consensus Recommendation For Optimization Of Pulmonary Hypertension Therapy Focusing On Switching From A Phosphodiesterase 5 Inhibitor To Riociguat, Franck Rahaghi, Vijay Balasubramanian, Robert Bourge, Charles Burger, Murali Chakinala, Michael Eggert, Jean Elwing, Jeremy Feldman, Christopher King, James Klinger, Stephen Mathai, John Mcconnell, Harold Palevsky, Ricardo Restrepo-Jaramillo, Zeenat Safdar, Jeffrey Sager, Namita Sood, Roxana Sulica, R. James White, Nicholas Hill

Open Access Publications

No abstract provided.

Failed Targeted Muscle Reinnervation: Findings At Revision Surgery And Concepts For Success, John M Felder, Stahs Pripotnev, Ivica Ducic, Rachel Skladman, Austin Y Ha, Mitchell A Pet

Open Access Publications

Although it was initially described for improved myoelectric control, targeted muscle reinnervation (TMR) has quickly gained popularity as a technique for neuroma control. With this rapid increase in utilization has come broadening indications and variability in the described technique. As a result, it becomes difficult to interpret published outcomes. Furthermore, there is no literature discussing the management of failed cases which are undoubtedly occurring.

Methods: This is a retrospective case series of two patients who underwent revision surgery for failed TMR. The authors also review the current literature on TMR and outline technical and conceptual pitfalls and pearls based on …

The Siea Shrimp Flap: An Ultrathin Axial Pattern Free Flap Useable In Obese Patients, John M Felder 3rd, Brooke E Willborg, William Y Zhu

Open Access Publications

The reconstruction of distal extremity wounds poses a unique surgical challenge. In free tissue transfer, a thin, pliable skin flap is the ideal. Obese patients have a paucity of thin skin donor sites. Herein we report the discovery of a free SHRIMP flap (Superthin Harvest of a Reliable Islanded Medial Pannus flap) based on the SIEA vessels, harvested from a thick abdominal pannus at the time of cosmetic abdominoplasty. A 61-year-old woman with a chronic wound of the right Achilles tendon was evaluated for reconstruction after failing conservative measures. At the time of consultation, the patient expressed interest in abdominoplasty. …

Uncertainty Analysis Of Chest X-Ray Lung Height Measurements And Size Matching For Lung Transplantation, Rodrigo Vazquez Guillamet, Maria C. Vazquez Guillamet, Ashraf Rjob, Andrew Bierhals, Irene Bello, Alberto Jauregui Abularach, Laneshia Tague, Michael Wallendorf, Gary F. Marklin, Chad Witt, Derek E. Byers, Daniel Kreisel, Ruben Nava, Varun Puri, Ramsey Hachem, Elbert P Trulock

Open Access Publications

Background: Errors in measuring chest X-ray (CXR) lung heights could contribute to the occurrence of size-mismatched lung transplant procedures.

Methods: We first used Bland-Altman analysis for repeated measures to evaluate contributors to measurement error of chest X-ray lung height. We then applied error propagation theory to assess the impact of measurement error on size matching for lung transplantation.

Results: A total 387 chest X-rays from twenty-five donors and twenty-five recipients were measured by two raters. Individual standard deviation for lung height differences were independent of age, sex, donor

Conclusions: Individual chest X-ray lung heights are imprecise for the purpose of …

Tumor-Associated Macrophages In Multiple Myeloma: Advances In Biology And Therapy, Jennifer Sun, Chaelee Park, Nicole Guenthner, Shannon Gurley, Luna Zhang, Berit Lubben, Ola Adebayo, Hannah Bash, Yixuan Chen, Mina Maksimos, Barbara Muz, Abdel Kareem Azab

Open Access Publications

Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow (BM) and represents the second most common hematological malignancy in the world. The MM tumor microenvironment (TME) within the BM niche consists of a wide range of elements which play important roles in supporting MM disease progression, survival, proliferation, angiogenesis, as well as drug resistance. Together, the TME fosters an immunosuppressive environment in which immune recognition and response are repressed. Macrophages are a central player in the immune system with diverse functions, and it has been long established that macrophages play a critical role in both inducing …

Socioeconomic Risk Markers Of Arthropod-Borne Virus (Arbovirus) Infections: A Systematic Literature Review And Meta-Analysis, Grace M Power, Aisling M Vaughan, Luxi Qiao, Nuria Sanchez Clemente, Julia M Pescarini, Enny S Paixão, Ludmila Lobkowicz, Amber I Raja, André Portela Souza, Mauricio Lima Barreto, Elizabeth B Brickley

Open Access Publications

INTRODUCTION: Arthropod-borne viruses (arboviruses) are of notable public health importance worldwide, owing to their potential to cause explosive outbreaks and induce debilitating and potentially life-threatening disease manifestations. This systematic review and meta-analysis aims to assess the relationship between markers of socioeconomic position (SEP) and infection due to arboviruses with mosquito vectors.

METHODS: We conducted a systematic search on PubMed, Embase, and LILACS databases to identify studies published between 1980 and 2020 that measured the association of SEP markers with arbovirus infection. We included observational studies without geographic location or age restrictions. We excluded studies from grey literature, reviews and ecological …

Current And Future Nonstimulants In The Treatment Of Pediatric Adhd: Monoamine Reuptake Inhibitors, Receptor Modulators, And Multimodal Agents, Andrew J Cutler, Gregory W Mattingly, Rakesh Jain, Welton O'Neal

Open Access Publications

Attention-deficit/hyperactivity disorder (ADHD), the single most common neuropsychiatric disorder with cognitive and behavioral manifestations, often starts in childhood and usually persists into adolescence and adulthood. Rarely seen alone, ADHD is most commonly complicated by other neuropsychiatric disorders that must be factored into any intervention plan to optimally address ADHD symptoms. With more than 30 classical Schedule II (CII) stimulant preparations available for ADHD treatment, only three nonstimulants (atomoxetine and extended-release formulations of clonidine and guanfacine) have been approved by the United States Food and Drug Administration (FDA), all of which focus on modulating the noradrenergic system. Given the heterogeneity and …