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Discoveries & Impact (September 2022)

September 15, 2022
by Amy Anderson, Jane E. Dee, Julie Parry and Elisabeth Reitman

Discoveries & Impact highlights select scientific discoveries for each of the 11 section in the Department of Internal Medicine.

Yale Researchers Call for Strategies to Eliminate Inequities in Access to Peripheral Artery Disease Care Among Adults Who Share a Hispanic Background

Adults who share a Hispanic background and who get hospitalized for symptoms of peripheral artery disease (PAD) are more likely to only receive care at later stages of their disease, and get their treatment through the emergency department (ED) instead of early stage disease care, elective care as compared with non-Hispanic white patients, according to a Yale-led study published Aug. 26 in the Journal of Vascular Surgery.

For the new study, the Yale team, led by first author Paulina Luna-Martinez, MD (Yale SOM ‘22), under mentorship of Carlos Mena-Hurtado, MD, associate professor of medicine (cardiology) and Kim Smolderen, PhD, associate professor of medicine (cardiology and psychiatry) and co-directors of the Vascular Medicine OutcomeS (VAMOS) research program, evaluated the socioeconomic profile, risk factors, process of care, and outcomes in patients with PAD who have a Hispanic background.

PAD affects an estimated 8.5 million Americans. Prior studies have shown that undetected and undertreated PAD greatly reduces a person’s mobility and quality of life. The Yale study suggests that patients’ PAD care for those with a Hispanic background may get underdiagnosed and undertreated, and only gets noticed when they present at a late stage of their disease, which may greatly impact their amputation risk.

Using a national database, the research team identified 1,018,220 PAD hospitalizations. Between 2011-2017, they discovered that compared with non-Hispanic patients, Hispanics adults with severe PAD had longer hospitalizations. These patients were more often admitted through the emergency department and received less revascularization procedures and underwent more amputations.

The findings indicate that earlier targeted screening and management strategies for PAD care are needed among vulnerable populations, aimed at improving access to outpatient care and expanding health care coverage.

“The prevalence of peripheral artery disease is growing, especially among younger patients with a diverse risk profile and those with minority backgrounds. Demographics are also quickly changing with patients sharing a Hispanic background, representing a larger segment of the PAD population. It is therefore important to document current gaps in their care and outcomes and come with multiprong approaches to reduce access to care barriers and provide high quality care across the spectrum of PAD,” said Mena-Hurtado.

“We are learning that timely and integrated care models, with an eye for whole person care, cultural sensitive care, including behavioral health care, has the potential to improve patient outcomes and promote more inclusive care,” said Smolderen.

Yale’s Paulina Luna, Kristie Harris, and Miguel Algara contributed to this study. Yulanka Castro-Dominguez at Case Western Reserve University and Carolina Severiche-Mena at Universidad Pontificia Bolivariana are co-authors of this study.

Luna P, Harris K, Castro-Dominguez Y, Algara M, Severiche-Mena C, Smolderen KG, Mena-Hurtado C. Risk Profiles, Access to Care, and Outcomes in Hispanics Hospitalized for Lower Extremity Peripheral Artery Disease. J Vasc Surg. 2022 Aug 26:S0741-5214(22)02210-8. doi: 10.1016/j.jvs.2022.08.021. Epub ahead of print. PMID: 36037965.

Advance Care Planning for Improving Caregiver Outcomes

An opinion piece by Terri Fried, MD, in the Journal of the American Geriatrics Society, presents a new approach to advance care planning (ACP), the process by which individuals prepare for serious illness and a time when they are no longer able to make healthcare decisions. While approaches to ACP have evolved over the last 20 years, the objective of ACP has remained providing care meeting the patient’s goals. The essay argues that the provision of goal-concordant care cannot and should not be the expected outcome from ACP. Goals may change and often considerations other than goals are more important factors in determining appropriate care. Instead, ACP should be considered a process focused on improving caregiver outcomes. Fried also offers new approaches to measure ACP’s successes. “Surrogate decision-making by caregivers is associated with an elevated risk of post-traumatic stress disorder and other adverse outcomes, and these outcomes can be improved with ACP,” said Fried. Read more in the Journal of American Geriatrics Society.

T Fried. Journal of American Geriatrics Society. 2022 Aug 16. Online ahead of print. PMID: 35974460. DOI: 10.1111/jgs.18000

COVID-19 Does Not Appear to Cause Severe Disease in Previously Healthy Children

A mystery surrounding the pandemic is the immunologic responses in children hospitalized with COVID-19. Scientists may have discovered a clue, as reported in Science.

The authors — Kevan Herold, MD, C.N.H. Long Professor of Immunobiology and of Medicine, Carl Pierce, an MD/PhD candidate and Betsy C. Herold, MD, both from the Albert Einstein College of Medicine — suggest that milder symptoms in pediatric patients compared with adults is caused by the rapid engagement of the pediatric mucosal immune system.

Previous studies have maintained that the risks most children face from COVID-19 are low. Young children infected with SARS-CoV-2 have less morbidity and mortality than adults. Preliminary data has suggested that children may have less robust T cell responses versus adults. Current theories suggest that the innate response plays an important role. The authors conclude that vaccinations are critical to stop the spread of more transmissible SARS-CoV-2 variants and additional research is needed to understand the differences in COVID-19 outcomes.

C. A. Pierce, K. C. Herold, B. C. Herold, J. Chou, A. Randolph, B. Kane, et al. Science 2022 Vol. 377 Issue 6611 Pages 1144-1149 DOI: doi:10.1126/science.ade1675.

Evaluating The Accuracy of Medicare Risk Adjustment for Alzheimer’s Disease and Related Dementias

In 2020, Medicare reintroduced Alzheimer’s disease and related dementias (ADRD) Hierarchical Condition Categories (HCCs) to risk adjust Medicare Advantage and accountable care organization (ACO) payments. The potential for Medicare spending increases from this policy change are not well understood because the baseline accuracy of ADRD HCCs is uncertain. Using linked 2016–18 claims and electronic health record data from a large ACO, researchers including Yale post-doctoral fellow Natalia Festa with the National Clinician Scholars Program and Geriatric Clinical Epidemiology and Aging Related Research (T32), evaluated the accuracy of claims-based ADRD HCCs against a reference standard of clinician-adjudicated disease. Using claims from Medicare Parts A and B, and electronic health record data, the researchers observed that provider organizations may have strong financial incentives to improve the accuracy with which they document and code ADRD diagnoses. Read their findings in Health Affairs.

Festa N, Price M, Weiss M, M V R Moura L, Benson N M, Zafar S, Blacker D, Normand S-L, Newhouse JP, Hsu J. Evaluating The Accuracy of Medicare Risk Adjustment for Alzheimer’s Disease and Related Dementias. Health Affairs, DOI: 10.1377/hlthaff.2022.00185. PMID: 36067434.

Studying Infections in People Using Ventricular Assist Devices

A ventricular assist device helps pump blood from the lower chambers of the heart to the rest of the body in people with severe heart failure, patients who are waiting for a heart transplant, or people with temporary heart failure. As infection is a leading cause of illness and death in patients with a ventricular assist device, researchers studied the role that multidrug-resistant organisms play in infections in people on ventricular assist device support. They evaluated people from July 2008 to September 2018 at a single site for multidrug-resistant organism colonization after implantation. These organisms included methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus species, and extended-spectrum beta-lactamase producing gram-negative bacteria. Read their findings in ASAIO Journal.

Roberts SC, Nam HH, Kumar RN, Wu T, Harap RS, Pham DT, Rich JD, Stosor V. Colonization with Multidrug-resistant Organisms in Patients with Ventricular Assist Devices. ASAIO Journal (American Society For Artificial Internal Organs : 1992) 2022, 68(8): 1048-1053. doi: 10.1097/MAT.0000000000001634. PMID: 34967790.

Chemo Drugs Studied in Elderly and Frail People with Head and Neck Cancer

Yale researchers studied a three-drug early chemotherapy regimen for head and neck cancer and found reasonable survival rates in patients, including those who are elderly and frail. The three drugs, paclitaxel, carboplatin, and cetuximab, have had promising results when given to patients at the beginning of their treatment for metastatic/recurrent head and neck cancer. Given their tolerability, the regimen is used in frail and elderly patients who are 75 and older. Yale researchers used software to generate a cohort of adult patients with head and neck cancer from 2014-2019 to better understand outcomes such as survival without progressive disease and overall survival rates. Their findings led them to conclude that the three drugs are well-tolerated and provide patients with favorable survival rates. Read more in Head & Neck.

Forman R, Deshpande H, Burtness B, Bhatia AK. Efficacy and toxicity of weekly paclitaxel, carboplatin, and cetuximab as induction chemotherapy or in cases of metastases or relapse for head and neck cancer with a focus on elderly or frail patients. Head & Neck 2022, 44(8): 1777-1786. doi: 10.1002/hed.27077. PMID: 35488876.

COVID-19 Impairs the Adaptive Immunity of Kidney Transplant Recipients even when Immunosuppressive Medications are Reduced, Study Finds

During the COVID-19 pandemic, kidney transplant recipients with COVID experienced severe symptoms and poor outcomes. Many physicians reduced the dose of the immunosuppressive anti-rejection medication given to these patients, concerned that the immunosuppressive drugs that kidney transplant recipients take could inhibit protective anti-COVID-19 immunity. Surprisingly, reported rates of acute rejection have been low despite this reduced immunosuppression in kidney transplant recipients. A new study led by Madhav Menon, MD, in Journal of the American Society of Nephrology provides a potential explanation.

For the study, the blood of 64 kidney transplant patients with COVID-19 was analyzed, including acute and post-acute cases. In the blood of acute cases, certain genes were over-expressed and others were under-expressed with higher COVID-19 severity. Analyses revealed increased expression of genes involved in innate immune pathways, but decreased expression of genes involved in the activation of adaptive immune pathways. There was "recovery" in adaptive immune activation pathways when post-acute cases were analyzed, suggesting a transient effect during acute COVID. Read more in JASN.

Zeguo Sun, Zhongyang Zhang, Khadija Banu, Yorg Al Azzi, Anand Reghuvaran, Samuel Fredericks, Marina Planoutene, Susan Hartzell, Yesl Kim, John Pell, Gregory Tietjen, William Asch, Sanjay Kulkarni, Richard Formica, Meenakshi Rana, Jonathan S. Maltzman, Weijia Zhang, Enver Akalin, Peter S. Heeger, Paolo Cravedi, Madhav C Menon. Blood transcriptomes of SARS-CoV-2 infected kidney transplant recipients associated with immune insufficiency proportionate to severity. Journal of the American Society of Nephrology Aug 30 2022; doi: 10.1681/ASN.2022010125

Early Mechanical Ventilation for Grade IV Hepatic Encephalopathy Associated with Increased Mortality Among Patients with Cirrhosis

Unresponsive patients with toxic-metabolic encephalopathies often are placed on a ventilator to protect the airway. However, among patients with preexisting conditions, mechanical ventilation may itself be associated with risks such as hypotension, aspiration, delirium, and infection. In a study published in Acute Critical Care, Clinical Fellow Saad Saffo, MD, and Guadalupe Garcia-Tsao, MD, attempt to determine if early mechanical ventilation for airway protection was associated with increased mortality in patients with cirrhosis and grade IV hepatic encephalopathy. They analyzed data from 1,975 inpatients with cirrhosis. Patients who received mechanical ventilation within 2 days of admission were compared to those who did not. Read more about their methods and results here.

Saffo S, Garcia-Tsao G. Early mechanical ventilation for grade IV hepatic encephalopathy is associated with increased mortality among patients with cirrhosis: an exploratory study. Acute And Critical Care 2022 doi: 10.4266/acc.2022.00528. PMID: 35977889.

New Suggested Nasal Therapy Would Use Extracellular Vesicles to Treat Long COVID

A perspective piece by Philip W. Askenase, MD, professor of medicine (immunology), to be published in Frontiers in Nanotechnology, proposes new therapy of dominant central nervous system aspects of chronic, clinical long COVID-19. This proposed therapy is with extracellular vesicle exosomes (EVs) derived from healing mesenchymal stromal cells (MSC). The proposed therapy would be administered nasally using these EVs targeting central nervous system macrophage-like microglia and the neurovascular capillary endothelium that are dominantly involved in the most common neuro psychiatric aspects of long Covid syndromes.Such patients are the most common long Covid population estimated to evolve from about 10% of Covid infections -- mostly unhospitaized patients and even those with originally asymptomatic cases of the acute viral illness.

The past decade has seen a rapid growth of scientific knowledge of extracellular vesicles. These are cell-released nano sized vesicles that play important roles in cell-to-cell communication; mainly by passage to other targeted cells of gene expression altering miRNAS. The potential for harnessing EVs for diagnosis and treatment of disease is being more broadly recognized, and their use as standalone therapeutics is being explored. Prior published work by the Askenase lab has shown their crucial role in T cell mediated antigen-specific immunological tolerance and in amelioration of an animal model of spinal cord injury. In this case, MSC-derived EVs target a macrophage subpopulation at the nervous system lesion site to alter their genetic programs and induce them to release host secondary EVs that improve altered neuro vascular integrity that is proposed to be ameliorating of neuro psychiatric aspects of long Covid syndromes. Read more in Frontiers.

P W Askenase. RECOMMENDATION: Treatment of Clinical Long COVID Encephalopathies with Nasal Administered Mesenchymal Stromal Cell Extracellular Vesicles. Front. Nanotechnol.Sec. Biomedical Nanotechnology. doi: 10.3389/fnano.2022.987117

Submitted by Jane E. Dee on September 15, 2022