Discoveries & Impact (May 2022)

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

Endoscopic Removal of Wire Bristle From Pancreas

The accidental ingestion of a wire bristle from a grill cleaning brush leads to hundreds of emergency department (ED) visits annually. In the Electronic Image of the Month, Yale’s Advanced Endoscopy team shared images from the case of a 78-year-old woman who presented in the ED with upper abdominal pain and nausea. A CT scan showed a hyperdensity extending from the duodenal wall into the pancreas. The object was removed via endoscopy. Learn more in Clinical Gastroenterology And Hepatology.

Lerner BA, Aslanian HR, Muniraj T. Endoscopic Removal of Ingested Wire Bristle from the Pancreas. Clinical Gastroenterology And Hepatology : The Official Clinical Practice Journal Of The American Gastroenterological Association 2022, 20(4): e649-e650. doi: 10.1016/j.cgh.2021.02.022. PMID: 33609785. PMCID: PMC8368074.

Switching Generic Levothyroxine Sodium Meds = No Difference in TSH Levels

Levothyroxine sodium is a commonly prescribed medication for people with hypothyroidism, or low thyroid hormone. While it is available as a generic or brand-name product, levothyroxine sodium in its generic form is less widely prescribed due to a concern about switching levothyroxine products and regulating of thyroid hormone levels.

In this study, conducted as part of the FDA-funded Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI), researchers evaluated data from 15,829 patients in a large database that includes commercially insured and Medicare Advantage enrollees to see if serum thyrotropin (TSH) levels changed upon the switch to generic levothyroxine sodium. The team discovered that normal TSH levels did not differ between patients who used the same generic levothyroxine sodium medications as compared to those who switched between different generic versions. These findings contradict current expert guideline recommendations. Read more in JAMA Internal Medicine or in FDA’s Spotlight on CDER Science.

Brito JP, Deng Y, Ross JS, Choi NH, Graham DJ, Qiang Y, Rantou E, Wang Z, Zhao L, Shah ND, Lipska KJ. Association Between Generic-to-Generic Levothyroxine Switching and Thyrotropin Levels Among US Adults. JAMA Internal Medicine 2022, 182(4): 418-425. doi: 10.1001/jamainternmed.2022.0045. PMID: 35226058. PMCID: PMC8886450.

Is Delayed HIV Presentation In Older Adults a Troubling Cycle?

The use of antiretroviral therapy (ART) has extended the lives of many people living with HIV. As people are living longer with the disease, the prevalence of HIV among people over 50 years of age has increased and their rate of new infection has risen dramatically. Equally concerning, delayed HIV presentation is much more common in this age group than among younger individuals.

The research team conducted a structured review of literature and found that “older age was consistently associated with delayed presentation.” They also evaluated data from the International epidemiology Databases to Evaluate AIDS (IeDEA) global consortium. In North America alone, 21% of patients were between 50 and 64 years old upon presentation, and in that age group, 42% presented late.

The authors urge the implementation of interventions tailored to older individuals and outline six possible strategies. Learn more in The Lancet HIV.

Justice AC, Goetz MB, Stewart CN, Hogan BC, Humes E, Luz PM, Castilho JL, Nash D, Brazier E, Musick B, Yiannoutsos C, Malateste K, Jaquet A, Cornell M, Shamu T, Rajasuriar R, Jiamsakul A, Althoff KN. Delayed presentation of HIV among older individuals: a growing problem. The Lancet. HIV 2022, 9(4): e269-e280. doi: 10.1016/S2352-3018(22)00003-0. PMID: 35218732.

Use GZLM-gamma Model for Circadian Phase Markers

In many of the sleep and circadian studies that use cosinor analysis, a general linear model (GLM) is used to model circadian phase markers. To determine if a generalized linear model with gamma distribution (GZLM-gamma) might improve analysis and detection of daily variations of circadian phase markers, researchers evaluated heart rate, actigraphic activity, and urinary 6-sulfatoxymelatonin (aMT6s) of patients in the medical intensive care unit.

They determined that using GZLM-gamma resulted in an improved fit for these markers and increased the detection of circadian rhythm. Read more in “Enhancing cosinor analysis of circadian phase markers using the gamma distribution.”

Doyle MM, Murphy TE, Miner B, Pisani MA, Lusczek ER, Knauert MP. Enhancing cosinor analysis of circadian phase markers using the gamma distribution. Sleep Medicine 2022, 92: 1-3. doi: 10.1016/j.sleep.2022.01.015. PMID: 35306404.

Abnormal ZAP70 Supports Progression of CLL, Other Malignancies

Previously, the role of ZAP70 in lymphoid malignancies and autoimmune diseases was unknown. In this new Yale review, researchers describe how abnormal SYK and ZAP70 co-expression supports the progression of chronic lymphocytic leukemia, acute lymphoblastic leukemia, mantle cell lymphoma, and other B-cell malignancies. ZAP70 redirects SYK and downstream B-cell receptor signaling to allow malignant B-cells to escape from NFAT-mediated negative selection and instead activate the phosphoinositide 3-kinase (PI3K) pathway.

This review highlights the “central role of autoimmunity checkpoints as a barrier against the malignant transformation of B-cells.” The authors suggest that a better understanding of the workings of lymphocyte selection and their pathological dysfunction is warranted. Read more in Cellular Signaling.

Leveille E, Chan LN, Mirza AS, Kume K, Müschen M. SYK and ZAP70 kinases in autoimmunity and lymphoid malignancies. Cellular Signalling 2022, 94: 110331. doi: 10.1016/j.cellsig.2022.110331. PMID: 35398488.

Lifeline to People in Ukraine with HIV and Opioid Use Disorder

In addition to the harm the war in Ukraine is causing to people and communities, it also is creating a crisis among those with HIV and opioid use disorder. With a disrupted supply of methadone and buprenorphine, which are prescribed as medications for opioid use disorder, some doctors are reducing dosages. But the consequences of a disrupted supply chain to patients are substantial, explain Frederick L. Altice, MD, and co-authors of a Viewpoint published in Lancet Public Health, “Extending a lifeline to people with HIV and opioid use disorder during the war in Ukraine.” They write that “withdrawal symptoms from opioids will not only accentuate the stresses and anxieties of war, but many patients could then relapse to injectable opioids, elevating their risk for overdose, skin and soft tissue infections, and transmission of blood-borne viruses such as HIV or hepatitis C virus.” The authors also provide strategies for an immediate response to the problem.

Frederick L Altice, Daniel J Bromberg, Sergii Dvoriak, Anna Meteliuk, Iryna Pykalo, Zahedul Islam, Lyu Azbel, Lynn M. Madden. Extending a lifeline to people with HIV and opioid use disorder during the war in Ukraine. Lancet Public Health 2022. PMID: 35358424 DOI: 10.1016/S2468-2667(22)00083-4

Standard Testing for ID'ing Low ERBB2 Breast Cancer Has Limitations

The inaccuracy of standard immunohistochemistry (IHC) testing to identify ERBB2-low breast cancer could result in misidentification of patients who may benefit instead from treatment with the FDA-approved drug fam-trastuzumab deruxtecan-nxki, according to research in JAMA Oncology. Investigators assessed two-years’ worth of College of American Pathologists (CAP) ERBB2 surveys from 2019 to 2020 and a second independent dataset from Yale School of Medicine’s archive of breast biopsies and showed low reader agreement for HER2 0 (not eligible for therapy) and 1+ (eligible for therapy) cases. Read the full report, “Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue,” in JAMA Oncology.

Fernandez AI, Liu M, Bellizzi A, Brock J, Fadare O, Hanley K, Harigopal M, Jorns JM, Kuba MG, Ly A, Podoll M, Rabe K, Sanders MA, Singh K, Snir OL, Soong TR, Wei S, Wen H, Wong S, Yoon E, Pusztai L, Reisenbichler E, Rimm DL. Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue. JAMA Oncology 2022, 8(4): 1-4. doi: 10.1001/jamaoncol.2021.7239. PMID: 35113160. PMCID: PMC8814969.

Strongyloides Stercoralis Infection ID'd on Urine Microscopy

A urine microscopy performed as part of a diagnostic workup for kidney injury revealed a motile larva of Strongloides stercoralis. Based on the incidental urine microscopy and other findings, the patient was thought to have a chronic Strongyloides infection. The detection of parasites on urine microscopy is relatively rare, but can be an important first point of discovery of disease. Furthermore, Strongyloides stercoralis infection presents a significant diagnostic challenge, with poor sensitivity of the most widely available testing, say the authors of a BMJ case report. Read the study here.

Baker ML, Brewster UC. Strongyloides stercoralis infection identified on urine microscopy. BMJ Case Reports 2022, 15(4) doi: 10.1136/bcr-2022-250078. PMID: 35379686. PMCID: PMC8981339.

Effectiveness of Inhaled Glucocorticoid Strategy in Black and Latinx Asthma Patients

Black and Latinx patients bear a disproportionate burden of asthma. Attempts to reduce this disparity have been mostly unsuccessful, and guideline recommendations have not been based on studies of Black and Latinx patients. However, an easy-to-use, patient-centered approach to managing moderate to severe asthma resulted in improved outcomes for Black and Latinx adults, according to findings of the PREPARE study published in The New England Journal of Medicine. Among those adults with moderate to severe asthma, the use of an inhaled glucocorticoid, short-acting bronchodilator, and one-time instruction on its use for symptom relief when added to usual care, led to a lower rate of severe asthma exacerbations. Read the full trial results in NEJM. Also read the editorial comment, “Breaking the Skin Color Barriers for Asthma Medications – It’s Not Black, Brown, or White.”

Israel E, Cardet JC, Carroll JK, Fuhlbrigge AL, She L, Rockhold FW, Maher NE, Fagan M, Forth VE, Yawn BP, Arias Hernandez P, Kruse JM, Manning BK, Rodriguez-Louis J, Shields JB, Ericson B, Colon-Moya AD, Madison S, Coyne-Beasley T, Hammer GM, Kaplan BM, Rand CS, Robles J, Thompson O, Wechsler ME, Wisnivesky JP, McKee MD, Jariwala SP, Jerschow E, Busse PJ, Kaelber DC, Nazario S, Hernandez ML, Apter AJ, Chang KL, Pinto-Plata V, Stranges PM, Hurley LP, Trevor J, Casale TB, Chupp G, Riley IL, Shenoy K, Pasarica M, Calderon-Candelario RA, Tapp H, Baydur A, Pace WD. Reliever-Triggered Inhaled Glucocorticoid in Black and Latinx Adults with Asthma. The New England Journal Of Medicine 2022, 386(16): 1505-1518. doi: 10.1056/NEJMoa2118813. PMID: 35213105.

Update on Axial Spondyloarthritis Treatment

Diagnosis and management of axial spondyloarthritis (axSpA) has vastly improved over the past two decades, says Abhijeet Danve, MD, and colleague in a review of the management of the disease, “Treatment of axial spondyloarthritis: an update,” in Nature Reviews Rheumatology. New therapies have become available, which are associated with substantial improvement in symptoms, signs and quality of life. The four broad categories of approved treatment options are NSAIDs (since the 1950s), TNF inhibitors (first FDA approval in 2003), IL-17 inhibitors (first FDA approval in 2016) and JAK inhibitors (first FDA approved in 2022). In addition, there have been a host of new developments in the axSpA field, including new treatment guidelines, studies on radiographic progression and treatment strategies. This Review explores the recent developments in the management of axSpA.

Danve A, Deodhar A. Treatment of axial spondyloarthritis: an update. Nature Reviews. Rheumatology 2022, 18(4): 205-216. doi: 10.1038/s41584-022-00761-z. PMID: 35273385.