CTSI Insider | 2020, Quarter 4

Introduction & Welcome

Welcome to CTSI Insider, the newsletter of the Clinical & Translational Science Institute of Southeast Wisconsin. In this issue you will find news and announcements, including upcoming opportunities and events, and research trainings, as well as an overview of services available to support you. Happy reading!

CTSI & You

CTSI is here to serve you! We offer a variety of resources and services to augment the myriad of research infrastructure options available to research teams across CTSI partner institutions. CTSI offers more than 20 different services and resources all aimed at supporting you and your clinical and translational research. These include recruitment and study support services offered through our Clinical Trials Office and Adult Translational Research Unit, Biomedical Informatics consulting services, Biostatistical consults and mini-grants, research process improvement consults, and research funding available through our Pilot Translational & Clinical Studies program. Visit the CTSI website for more information.

News & Announcements

CTSI Pilot and Translational Studies Program

Fatigue and neuromuscular function in adults with achilles tendinopathy

Co-PI: Craig Young, MD
Medical College of Wisconsin

Co-PI: Sandra Hunter, PhD
Marquette University

Co-Investigators: Lauren Sara, DPT, Marquette University; Marie Hoeger Bement, MPT, PhD, Marquette University

A pilot study of a randomized sham-control auricular tens unit stimulation to improve symptoms through vagal modulation in pediatric functional gastrointestinal disorders

PI: Gisela Chelimsky, MD
Medical College of Wisconsin

Co-Investigators: Marcellus Meritt, PhD, University of Wisconsin-Milwaukee; Thomas Chelimsky, MD, Medical College of Wisconsin; Pippa Simpson, PhD, Medical College of Wisconsin; James Verbsky, MD, Medical College of Wisconsin

A randomized, double-blinded, placebo controlled pilot trial of the feasibility of high definition transcranial direct current stimulation and cognitive training in patients with mild cognitive impairment

PI: Elias Granadillo, MD
Medical College of Wisconsin

Co-Investigators: Kristy Nielson, PhD, Marquette University; Hrissanthi (Chris) Ikonomidou, MD, PhD, University of Wisconsin-Madison; Laura Hancock, PhD, University of Wisconsin-Madison; Priyanka Shah-Basak, PhD, Medical College of Wisconsin

Assessing function at a cellular scale in patients with inherited retinal degenerations

Co-PI: Thomas Connor, MD
Medical College of Wisconsin

Co-PI: Robert Cooper, PhD
Marquette University

Co-Investigator: Joseph Carroll, PhD, Medical College of Wisconsin

Bioengineered heart tissue in congenital heart disease

Co-PI: Aoy Tomita-Mitchell, PhD
Medical College of Wisconsin

Co-PI: Brandon Tefft, PhD
Medical College of Wisconsin

Co-Investigators: John LaDisa, PhD, Marquette University; Lobat Tayebi, PhD, Marquette University; Michael Mitchell, MD, Medical College of Wisconsin

Using hospital records of patients presenting to froedtert hospital to predict risk of opioid use disorder (OUD), fatal and non-fatal opioid overdose, and ed readmission

Co-PI: Stephen Hargarten, MD, MPH
Medical College of Wisconsin

Co-PI: Praveen Madiraju, PhD
Marquette University

Co-Investigator: Nicole Fumo, MPH, Medical College of Wisconsin

Missed opportunities to protect children: quality improvement in identification of substance exposures among at-risk pediatric patients

PI: Hillary Petska, MD, MPH
Medical College of Wisconsin

Co-Investigators: Mark Kostic, MD, Zablocki VA; Amy Drendel, MD, Medical College of Wisconsin; David Gummin, MD, Medical College of Wisconsin; Brian Peterson, MD, Milwaukee County Medical Examiner’s Office

Racial differences in dna-methylation profiling of human placentas in pregnancies complicated by preeclampsia

Co-PI: Anna Palatnik, MD
Medical College of Wisconsin

Co-PI: Yi-Wen Huang, PhD

Medical College of Wisconsin

Co-Investigators: Chiang-Ching Huang, PhD, University of Wisconsin-Milwaukee; Curt Sigmund, PhD, Medical College of Wisconsin

Hearing patient’s voice: contextual phenotyping of patient narratives and clinical data using ml & nlp

Co-PI: Melek Somai, MD, MPH
Medical College of Wisconsin

Co-PI: RJ Nowling, PhD
Milwaukee School of Engineering

Co-Investigators: Bradley Crotty, MD, MPH; Medical College of Wisconsin; Aaron Winn, Medical College

Investigator’s Corner

Integrated Clinical & Research Ensembles: Year in Review

In July 2019, CTSI began a novel program to integrate clinical and research faculty, community stakeholders and health system representatives in highly innovative and efficient teams to get more treatments and interventions more quickly to more patients and our community. Since then, the teams, known as “Team Science-Guided Integrated Clinical & Research Ensembles (ICRE)” have proven themselves to be an effective research mechanism for bringing together these complementary stakeholders and generating new ideas to address unmet medical needs.  COVID-19 brought forth challenges for implementing this project as originally envisioned, however newly identified unmet patient needs presented new opportunities for Ensemble research teams to develop.

Concept

The purpose of the Ensemble is to nucleate teams around an unmet medical need and translate research ideas into clinical practice. The Ensemble brings together a broad continuum of stakeholders, and is inclusive of siloed stakeholders, and others that may rarely be brought into plans to address an unmet medical need. Members could include patients, community advocates, community representatives, hospital system representatives, clinicians, basic scientists, population scientists, community health experts.

Unlike traditional research approaches that might gather faculty with similar interests to focus on a project such as a grant proposal, the Ensemble is formed to address an unmet medical need without knowing the exact steps and trajectory of the project (s). (In fact, the impact of COVID-19 provides a striking example of how some Ensembles have already altered course in order to adapt projects to new unmet patient needs and harness new opportunities.)

The immediate goal of the pre-Ensemble is to meet regularly and discuss the collection of questions that might be important in addressing the unmet need, discuss the expertise of each member and ideas for how to complement each other’s expertise in addressing questions, and to create a list of known experts or expertise that will be needed to explore the questions.

The discussions will elicit ideas for “products” that could be a device, process, medication, assay, biomarker, clinical trial, survey tool, questionnaire, extramural grant, scholarly publication, etc. The products are informed by divergent members of the pre-Ensemble.

A unique aspect of the Ensemble platform is the inclusion of CTSI’s partner institutions and their resources.  These institutions include Children’s Wisconsin, Clement Zablocki VA Medical Center, Froedtert Hospital, Marquette University, Milwaukee School of Engineering, the University of Wisconsin – Milwaukee and Versiti Blood Center of Wisconsin.  Many faculty and staff from partner institutions are members of the Ensemble teams. However, participation in the program is not limited to the region and Ensembles also include participants from across the country.  This allows for a borderless, synergistic biomedical research enterprise that is accelerating the translation of research discoveries into new and improved medical treatments.

Ensemble Formation

Between the period of July 2019 and March 2020, 10 Ensembles were formed and met regularly under project management by Mike Anello and David Zimmerman. Each of the 10 Ensembles developed and submitted an Ensemble proposal for review to obtain a $50,000 line of credit. Eight of the Ensembles were approved for funding by the CTSI Review Committee and highlights of three Ensembles are presented later in this article.

ICRE: The Basic Operating Unit of the Translational Engine

Following the onset of the COVID-19 pandemic, CTSI engaged in a COVID-19 Research Initiative in which 32 COVID-19 Ensemble teams were formed and began meeting on April 10th. These Ensemble teams were provided project management support by 17 CTSI “deputized” project managers. The team of deputized project managers is comprised of individuals who also carry out the other functions of CTSI as Program Directors, Program Managers, Project Coordinators, Administrative Assistants, Data Operations Manager, and others. CTSI also made available several supports, including expertise in community engagement, biomedical informatics, clinical trial protocol development, clinical trial execution, and biostatistics.  After several developments that involved teams splitting, merging, or disbanding due to various challenges, 17 teams have emerged and are generating impressive results. Click for descriptions of these teams Highlights of three teams are presented later in this article.

Ensemble Groups

In this newsletter each quarter we will highlighting a couple Ensembles, as well as some of the COVID-19 pre-Ensembles.

Multiple Myeloma Ensemble

Following a period of successful cancer therapy, multiple myeloma can relapse as a drug-refractory aggressive disease that leaves few therapeutic options.  This Ensemble was formed around clinicians, basic scientists, and a patient advocate with the goal of identifying tissue samples for research, as well as a cohort of patients to study therapeutic lifestyle interventions.

Throughout the past year this Ensemble has recruited a multiple myeloma patient spouse to provide perspective for outlined goals.  The team has also screened potential patients’ samples and is in the process of obtaining the appropriate MGUS and myeloma plasma cell tissues from the tissue bank for storage in a multiple myeloma biorepository.  The group has identified 258 samples from for MCW tissue bank for Dr. Janz lab to develop mouse-model experiments.

The Ensemble has also begun to identify a number of multiple myeloma patients for a cohort study, completing 19 interviews with a goal of 30.

Fecal Incontinence Ensemble

The Fecal Incontinence Ensemble discovered through a series of meetings that fecal incontinence prevalence occurs in half of all nursing home residents and no consensus exists for standard characterization/measurement of the problem, causing an inability to accurately compare prior studies.

Since being funded, the group has initiated their project plan to create a bank for patient data. They wanted to first find out how many patients were appropriate for the Ensemble project. Using four fecal incontinence diagnostic codes the, Ensemble identified 3,600 patients at Froedtert over the past 5 years.

The Ensemble developed a REDCap registry for surveys pertaining to fecal incontinence to be implemented across 4 clinics (OBGYN, Gastroenterology, Urology, Physical Therapy) to accomplish standardization of patient reports. Their IRB protocol was approved for the registry of survey and questionnaires including intake, visit, defecography, anal manometry, anal sphincter imaging (Ultrasound or MRI), endoscopy, Fecal Incontinence Quality of Life Scale,  Pelvic Floor Distress Inventory (Short form 20), and Vaizey Score (determines fecal urgency). They are now ready for implementing this into the clinics to ensure adequate data collection.

Shield Milwaukee Against Antibiotic Resistance (SMAART) Ensemble

Pictured from left: Alex Kallen, MD, MPH (CDC); Ashlie Dowdell, (DPH); Silvia Munoz-Price, MD, PhD (MCW); Nimalie Stone, MD (CDC); Michael Lin, MD, MPH (Rush University); Robert Weinstein, MD (Rush University)

This Ensemble is focused on the threat to patients from an extremely drug resistant (XDR) strain that has been able to quickly spread due to the lack of an integrated response among facilities throughout the healthcare continuum. There has been a trend of northern migration of patients, and the XDR strains they carry, occurring in Wisconsin. Evidence and previous experiences have shown that the spread of XDR organisms within hospitals can occur in a matter of months.

The SMAART Ensemble held a Post-Acute Care Emerging Multidrug-Resistant Organisms (MDRO) Education Symposium on Jan. 21st, 2020, co-sponsored by CTSI consisting of Ensemble members presenting on the antibiotic resistant threat in Milwaukee, impact on patients, responses by Chicago to similar epidemic, and next steps for Wisconsin to take to prevent the spread.

Attendance of over 70 health care leaders from throughout Wisconsin comprising of hospitals, long-term acute care, public health departments, and nursing homes.  Assembly of traditionally siloed organizations to coordinate a centralized approach towards preventing the spread of antibiotic resistant organisms.

The symposium helped educate the region’s providers for the Ensemble’s next project; a Point Prevalence Surveillance (PPS) at Milwaukee regional acute/post-acute care facilities. The team has scheduled 31 ICUs at 20 facilities to be screened totaling 562 beds. The first PPS took place on January 13, 2020 and the last is scheduled for March 30, 2020. To date they have received the whole genome sequencing results of 59 CRAB strains collected in three facilities of Southeast Wisconsin. These included environmental and human samples.

COVID-19 pre-Ensembles

Percutaneous Right Ventricular Assist Device

This pre-Ensemble determined that in comparison with conventional approaches to the management of severe COVID-19 acute respiratory distress syndrome, early introduction of percutaneous right ventricular assist device/extracorporeal membrane oxygenation support (see graphic) resulted in elimination of secondary end organ damage and lower in the hospital mortality and 30-day mortality.

A retrospective cohort study was conducted from March through June 2020, highlighting the team’s institutional experience with the treatment of 39 patients with COVID-19-associated respiratory failure. This study documented their approach to early right ventricular assist device support with venovenous extracorporeal membrane oxygenation in patients with severe acute respiratory distress syndrome due to COVID-19. Primary endpoints were in the hospital mortality, and 30-day mortality.  Secondary endpoints were acute renal failure, duration of mechanical ventilation, and length of stay.  This study was the collaborative work of 14 team members spanning 8 departments and 2 institutions.

The study highlights new and innovative methods on an evolving treatment for the most severe forms of respiratory failure due to COVID-19, which is being encountered at an ever-growing rate and for which traditional treatment options thus far have shown to be minimally effective at improving outcomes.

The BRaVe Clinic: Building Resilience Virtually

This pre-Ensemble led by Dr. Kristen Kroll identified unmet medical needs throughout the community brought on by the COVID-19 pandemic by the shared experiences of the diverse multi-instructional and multi-disciplinary group.  The group, comprised of psychologists, pharmacists, social workers, nurses, and physicians, discovered that healthcare workers were being exposed to traumatic and non-traumatic stressors (fear for self & loved ones, learned helplessness) resulting from COVID-19.  They also found that healthcare workers in previous and current pandemics also experienced psychological effects (anxiety, depression, traumatic stress). With sustained high levels of stress, cognitive functioning is impaired (medical errors).

This pre-Ensemble decided to create a mental health clinic for healthcare workers with the goal of primary and secondary prevention (i.e. prevent psychological sequelae before trauma; intervention after trauma has occurred).  The idea for the BRaVe Clinic was designed to be entirely virtual to provide training for doctoral students in providing evidence-based care via tele-behavioral health (See brochure excerpt below).  This allows for a safe method to train graduate students and provide a rare opportunity for training in telehealth.

The Greater Milwaukee Foundation awarded this pre-Ensemble $25,000 for a six-month project with the scope of broadening to serve not only healthcare workers, but also other individuals in the community at heightened risk, history of depression, or currently experiencing interpersonal violence.  Patients must be from the following counties: Milwaukee, Ozaukee, Washington, and Waukesha.

Drug Re-Purposing: A Phase II Randomized Controlled Trial of Salmeterol vs. Placebo for Inpatients with COVID 19 (The Salmeterol Trial)

This pre-Ensemble co-led by Dr. Jonathan Marchant and Dr. Tom Aufderheide designed a Phase II, multicenter, prospective, double blind, placebo controlled interventional, safety and efficacy study.  The purpose of this study is to determine the impact of SEREVENT Inhalation Aerosol salmeterol 21 mcg) 2 inhalations (INH) BID X 30 days or until death or hospital discharge versus placebo on the cumulative incidence of recovery, defined as the number of days from randomization until hospital discharge, in adults admitted to the hospital ward or ICU for treatment of COVID 19 symptoms. Their hypothesis is that SEREVENT Inhalation Aerosol will significantly reduce the number of days from randomization until hospital discharge compared with placebo.

This pre-Ensemble is capitalizing on NCATS’ Trial Innovation Network (TIN) resources and is finalizing their study design, statistics and budget with Duke’s Data Coordinating and Clinical Coordinating Centers.  The team is utilizing expertise of the CTO regulatory specialist to secure a FDA waiver of the investigational new drug (IND) requirement. and are looking into potential sources of grant funding from GlaxoSmithKline (GSK), NHLBI and NCATS.

Progress Update Symposium for COVID-19 Research Initiative

On July 20th, the COVID-19 Research Initiative held its first gathering to present results after only three months of team collaboration.  The accomplishments were impressive. Twenty-one active teams had already logged a total of 198 meetings, with an average of 9 meetings per team, involving 172 investigators from the Medical College of Wisconsin, Froedtert Hospital, Children’s Wisconsin, Versiti, University of Wisconsin-Milwaukee, Marquette University, and Milwaukee School of Engineering—A truly multi-disciplinary and multi-institutional collaboration. At this stage, the initiative was responsible for submitting 13 foundation, federal, and industry grants proposals totaling $19,280,577, with two awards for $25,000 (Greater Milwaukee Foundation) and $199,909 (National Science Foundation). In addition, four human subject research protocols and 1 institutional biosafety protocol had been approved, and patients were already being impacted through clinical interventions resulting from the nascent initiative.

CTSI Partners Working Together for You

Sam Nemanich, PhD, MSCI

The CTSI Child Advancement Network (CAN) would like to welcome a new collaborating partner, Dr. Sam Nemanich from Marquette University, College of Health Sciences!