Discoveries & Impact (February 2023)

Discoveries & Impact highlights select scientific discoveries across the Department of Internal Medicine...

Gaps in the Quality of Vascular Care Can Worsen Long-term Health Outcomes

According to a national registry, half of Medicare patients who underwent a procedure for symptom relief as it relates to lower extremity peripheral vascular disease did not receive the recommended medical therapy for long-term cardiovascular risk management.

First author Kim G. Smolderen, PhD, MSc, and senior author Carlos Mena-Hurtado, MD, co-directors of the vascular medicine outcomes group at Yale, evaluated the use of guideline-directed medical therapy (GDMT) over 24 months at a national level to help understand the impact of lack of GDMT with adverse outcomes. The study appears in the journal JACC: Cardiovascular Interventions.

The Society of Vascular Surgery and American College of Cardiology’s Vascular Quality Initiative is an ongoing effort to document the outcomes of patients undergoing peripheral artery disease (PAD) procedures. PAD is widespread among underrepresented and marginalized populations. Comorbidities including smoking, hypertension, diabetes, and heart failure are common. 1 in 5 patients with a PAD diagnosis are at risk for death, heart attack, stroke, or amputation within a year.

Secondary prevention medications such as statins, antiplatelet therapy, or ACE/ARB in hypertensive patients are needed for long-term PAD care. The research team found that patients who are discharged following a peripheral vascular intervention without the recommended medications have an increased risk of death, and a 20% increased risk of a major amputation or limb loss within two years. The unique features of this study were the use of Medicare linked outcomes data and the documentation of lack of GDMT that was linked with subsequent adverse prognosis. Undergoing expensive procedures that are intended to improve patients’ functioning and quality of life, turned out to be really low value if patients’ overall cardiovascular risk management is not addressed.

Smolderen K, Romain G, Provance J, et al. Guideline-Directed Medical Therapy and Long-Term Mortality and Amputation Outcomes in Patients Undergoing Peripheral Vascular Interventions. J Am Coll Cardiol Intv. 2023 Feb, 16 (3) 332–343.https://doi.org/10.1016/j.jcin.2022.09.022

New Hepatocellular Carcinoma Playbook Authored by Yale Hepatologists

Hepatocellular carcinoma (HCC) represents one of the most serious diseases treated by liver specialists. A recent review article from Yale hepatologists, led by Ariel Jaffe, MD, assistant professor of medicine, and Mario Strazzabosco, MD, PhD, professor of medicine, clinical program leader of the Liver Cancer Program, and co-director of the Yale Liver Center, highlights the importance of a team-based holistic approach to treating HCC and liver disease.

The paper offers a “playbook” for liver specialists, detailing comprehensive management strategies for HCC, emphasizing the importance of treating both the cancer and controlling underlying liver disease in order to preserve liver function. Additionally, the playbook details cancer prevention, covering the management of hepatitis B and C as well as risk factors such as alcohol use, obesity, and diabetes. Beyond prevention and management of HCC, the authors cover disease surveillance, transplant candidacy, longitudinal care following cancer treatment, and managing recurrence and decompensating events.

Filling a crucial gap in the hepatology literature, this new resource empowers hepatologists to confidently take an active role in the management of all parts of a patient’s HCC care. Read more in “Holistic Management of Hepatocellular Carcinoma: The Hepatologist's Comprehensive Playbook.”

Jaffe A, Taddei TH, Giannini EG, Ilagan-Ying YC, Colombo M, Strazzabosco M. Holistic management of hepatocellular carcinoma: The hepatologist's comprehensive playbook. Liver Int. 2022 Dec;42(12):2607-2619. doi: 10.1111/liv.15432. Epub 2022 Oct 11. PMID: 36161463.

Significant Barriers in Affording and Obtaining Supplies/Medications to Manage Diabetes

A new study from the Yale Diabetes Center uncovers real-world data regarding insulin affordability. In a Connecticut-based survey of 97 persons with diabetes, more than one-third of patients reported using various methods to secure insulin outside of their pharmacy due to affordability or insulin rationing actions. Nearly half of patients surveyed further reported making personal or financial sacrifices due to their insulin needs.

Forty-one percent of patients reported being within 2-3 days of running out of insulin, and 47 percent of patients reported running out of diabetes supplies prior to getting a prescription refill. As a result of barriers to insulin access and affordability, 28 and 36 percent of patients reported rationing insulin or obtaining insulin through other means beyond the pharmacy. Respondents reported risky compensatory behaviors to conserve insulin, including using expired insulin, eating fewer carbohydrates, exercising more, and seeking donations. The majority of participants surveyed had asked for and/or received some sort of support in obtaining diabetes medications and supplies.

To learn more about financial and social barriers, read the research letter, “Navigating barriers to affording and obtaining insulin and diabetes supplies.”

Wilcox AE, Lipska KJ, Weinzimer SA, Gujral J, Arakaki A, Kerandi L, Nally LM. Navigating barriers to affording and obtaining insulin and diabetes supplies. J Diabetes. 2023 Jan;15(1):71-75. doi: 10.1111/1753-0407.13344. Epub 2022 Dec 23. PMID: 36562281; PMCID: PMC9870729.

Bias in Assessments Prevalent in Minority and Asian Internal Medicine Residents

Researchers have demonstrated minority racial and ethnic internal medicine residents, defined as underrepresented in medicine (URiM) and Asian trainees, experience lower ratings on performance assessment when compared with their White peers.

An assessment of 9026 first and second-year internal medicine residents from the graduating classes of 2016 and 2017 demonstrated differences in first-year Milestone scores between Asian and White residents. Similarly, in year two, White residents received higher scores compared with URiM and Asian residents. At the final assessment, during year three, the gap between all racial groups narrowed. These analyses adjusted for USMLE Step 2 score, a proxy for medical knowledge.

The authors suggest these differences may be representative of bias in performance assessment and have implications for future career opportunities, including chief resident selection and fellowship training. The authors are developing an intervention to mitigate disparities in residency performance assessments. Learn more in JAMA Network Open.

Boatright D, Anderson N, Kim JG, Holmboe ES, McDade WA, Fancher T, Gross CP, Chaudhry S, Nguyen M, Nguemeni Tiako MJ, Colson E, Xu Y, Li F, Dziura JD, Saha S. Racial and Ethnic Differences in Internal Medicine Residency Assessments. JAMA Netw Open. 2022 Dec 1;5(12):e2247649. doi: 10.1001/jamanetworkopen.2022.47649. PMID: 36580337; PMCID: PMC9857126.

Impairment in Older Adults Related to the Presence of Multiple Chronic Conditions & Demographic Factors

Multimorbidity is the co-occurrence of two or more chronic conditions. In a recent paper published in the Journal of Multimorbidity & Comorbidity, researchers identified four groups of older adults that shared similarities across the health domains of multimorbidity, functionality, cognitive performance, and depressive symptoms—and characterized outcomes of their health.

The team analyzed 16 years of data from the Health and Retirement Study, which included responses from 11,565 older adults. Four patterns emerged, with groups organized by their levels of functional impairment, cognition, emotional health, and multimorbidity, and researchers investigated the socio-demographic factors of each group.

Their results indicated that a combination of multimorbidity and impairment levels resulted in divergent health patterns. Black, Hispanic older adults, as well as adults with lower wealth, lower education, and a history of smoking were all significantly more likely to be in the two most impaired groups.

The study suggests that early detection, prevention, and management of chronic disease and focus on structural inequities should be the goal of future research. Read more in “Multidimensional trajectories of multimorbidity, functional status, cognitive performance, and depressive symptoms among diverse groups of older adults.”

Quiñones AR, Nagel CL, Botoseneanu A, Newsom JT, Dorr DA, Kaye J, Thielke SM, Allore HG. Multidimensional trajectories of multimorbidity, functional status, cognitive performance, and depressive symptoms among diverse groups of older adults. J Multimorb Comorb. 2022 Nov 30;12:26335565221143012. doi: 10.1177/26335565221143012. PMID: 36479143; PMCID: PMC9720836.

Number of TP53 Mutations Does Not Create Different Outcome in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a type of cancer that forms in the blood and bone marrow. Mutations to the gene TP53 lead to worse outcomes for AML patients. In a recent study published in Leukemia, researchers divided a patient cohort into two classes based on the number of mutations to TP53—single or multiple mutations—and assessed whether it had an impact on prognoses.

First, the team found that AML patients with mutations in TP53 have worse outcomes compared to patients with the non-mutated gene. Also, the number of mutations to TP53 did not create any differences between the two classes. This study is the first to report on outcomes of TP53 mutation classifications from a randomized clinical trial. Read more in “Prognostic implications of mono-hit and multi-hit TP53 alterations in patients with acute myeloid leukemia and higher risk myelodysplastic syndromes treated with azacitidine-based therapy.”

Zeidan AM, Bewersdorf JP, Hasle V, Shallis RM, Thompson E, de Menezes DL, et al. Prognostic implications of mono-hit and multi-hit TP53 alterations in patients with acute myeloid leukemia and higher risk myelodysplastic syndromes treated with azacitidine-based therapy. Leukemia. 2023 Jan;37(1):240–3.

Mpox and STI Testing in Primary Care

One of the first Connecticut cases of mpox presented with a foot rash and rectal pain. In this case study, Yale researchers emphasize the high level of clinical suspicion and low threshold for STI testing necessary to successfully identify an mpox case in a primary care setting.

The patient’s atypical rash distribution, sexual history, and other negative STI results led doctors to suspect the presence of mpox. Samples were taken from the patient, which led to a diagnosis of mpox by the CDC. Mpox treatment and management measures were taken, such as contact tracing, isolation, vaccination, and safer sex recommendations.

Primary care clinicians can mitigate the spread of STIs, especially in the LGBTQ population. The authors of the paper suggest that an open approach to sexual history and expedited testing are vital during a public health crisis. Learn more in “Mpox and Sexually Transmitted Infection Testing in the Outpatient Primary Care Setting—Why LGBTQ Health Is Global Health.”

Ilagan-Ying YC, Fisher A, Zimmerman A, Pellegrino A, Roberts SC. Mpox and Sexually Transmitted Infection Testing in the Outpatient Primary Care Setting—Why LGBTQ Health Is Global Health. J GEN INTERN MED. 2023 Jan 12.

Combination Pembrolizumab and Axitinib: Further Lines of Treatment for Metastatic Renal Cell Carcinoma

First-line treatment for metastatic renal cell carcinoma include pembrolizumab/axitinib, which is a combination immune checkpoint inhibitor and vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy. The safety and efficacy of this therapeutic combination as later lines of therapy has not been studied previously. In a recent retrospective study, Yale researchers demonstrated that the combination pembrolizumab/axitinib has activity with limited adverse effect rates.

Among the thirty-eight patients assessed, second-line pembrolizumab/axitinib was used in 21 patients, third-line in five patients, and beyond in 12 patients. The median progression free survival was 9.7 months and objective response rate was 25.0 percent, and more than two-thirds of was patients had stable disease for at least six months.

Further prospective studies are warranted to examine the activity of immune checkpoint inhibitor and vascular endothelial growth factor receptor tyrosine kinase inhibitor combinations in further line treatment of metastatic renal cell carcinoma. Read more about this potential therapy in “Outcomes With Combination Pembrolizumab and Axitinib in Second and Further Line Treatment of Metastatic Renal Cell Carcinoma.”

Dizman N, Austin M, Considine B, Jessel S, Schoenfeld D, Merl MY, Hurwitz M, Sznol M, Kluger H. Outcomes With Combination Pembrolizumab and Axitinib in Second and Further Line Treatment of Metastatic Renal Cell Carcinoma. Clin Genitourin Cancer. 2023 Jan 12:S1558-7673(23)00002-2. doi: 10.1016/j.clgc.2023.01.002. Epub ahead of print. PMID: 36681606.

A New Urine Biomarker for Tubulointerstitial Fibrosis of the Kidney

Uromodulin, a protein produced in the kidney, has previously been established as a biomarker of kidney health. A new study from Yale and Johns Hopkins nephrologists determined an important relationship between uromodulin and scarring (fibrosis) of the tubulointerstitium portion of the kidney.

Researchers found uromodulin in the urine was associated with several other lab markers of kidney function, including serum creatinine, bicarbonate, and hemoglobin. Including kidney biopsies of over 360 patients, the study showed that higher levels of uromodulin were associated with lower severity tubulointerstitial fibrosis and atrophy.

This work offers insight into an important and previously uncharacterized relationship between an established kidney biomarker and histologic changes in the tubulointerstitium, providing promise for future diagnosis, surveillance, management, and treatment of kidney disease. Read more in “Urine Uromodulin as a Biomarker of Kidney Tubulointerstitial Fibrosis.”

Melchinger H, Calderon-Gutierrez F, Obeid W, Xu L, Shaw MM, Luciano RL, Kuperman M, Moeckel GW, Kashgarian M, Wilson FP, Parikh CR, Moledina DG. Urine Uromodulin as a Biomarker of Kidney Tubulointerstitial Fibrosis. Clin J Am Soc Nephrol. 2022 Sep;17(9):1284-1292. doi: 10.2215/CJN.04360422. Epub 2022 Aug 10. PMID: 35948365; PMCID: PMC9625093.

Burnout and Moral Distress Among ICU Physicians During the COVID-19 Pandemic

Burnout among physicians is characterized by emotional exhaustion and a lack of professional fulfillment. Additionally, moral distress occurs when a physician feels constrained to act in contradiction to their ethical values. In a new study published in Critical Care Medicine, researchers assessed the moral distress and burnout of ICU physicians during the COVID-19 pandemic.

The team analyzed ICU physician responses to questionnaires from 62 sites in North America. They discovered moderate levels of moral distress. The highest-ranked reasons for moral distress were regulatory issues and institutional policies. ICU physicians working with higher COVID-19 patient volumes experienced significantly higher moral distress.

Additionally, half of physicians surveyed met the criteria for burnout with at least one in five physicians using a maladaptive coping strategy. The authors suggest individual and institutional strategies to increase physician wellness. Learn more in “Wellness and Coping of Physicians Who Worked in ICUs During the Pandemic: A Multicenter Cross-Sectional North American Survey.”

Burns KEA, Moss M, Lorens E, Jose EKA, Martin CM, Viglianti EM, Fox-Robichaud A, Mathews KS, Akgun K, Jain S, Gershengorn H, Mehta S, Han JE, Martin GS, Liebler JM, Stapleton RD, Trachuk P, Vranas KC, Chua A, Herridge MS, Tsang JLY, Biehl M, Burnham EL, Chen JT, Attia EF, Mohamed A, Harkins MS, Soriano SM, Maddux A, West JC, Badke AR, Bagshaw SM, Binnie A, Carlos WG, Çoruh B, Crothers K, D'Aragon F, Denson JL, Drover JW, Eschun G, Geagea A, Griesdale D, Hadler R, Hancock J, Hasmatali J, Kaul B, Kerlin MP, Kohn R, Kutsogiannis DJ, Matson SM, Morris PE, Paunovic B, Peltan ID, Piquette D, Pirzadeh M, Pulchan K, Schnapp LM, Sessler CN, Smith H, Sy E, Thirugnanam S, McDonald RK, McPherson KA, Kraft M, Spiegel M, Dodek PM; Diversity-Related Research Committee of the Women in Critical Care (WICC) Interest Group of the American Thoracic Society. Wellness and Coping of Physicians Who Worked in ICUs During the Pandemic: A Multicenter Cross-Sectional North American Survey. Crit Care Med. 2022 Dec 1;50(12):1689-1700. doi: 10.1097/CCM.0000000000005674. Epub 2022 Oct 27. PMID: 36300945; PMCID: PMC9668381.