Discoveries & Impact (April 2023)

Discoveries & Impact highlights select scientific discoveries across the Department of Internal Medicine. Review the complete publications report under Related Documents.

Researchers Demonstrate a New Approach to Learning Integral Equations from Data

A new paper spearheaded by Emanuele Zappala, PhD, and David van Dijk, PhD, describes a novel technique to learn integral equations. The method, named Neural Integral Equations, uses neural networks to accurately model systems with non-local spatiotemporal dynamics from observational data alone.

Integral equations are essential for modeling many systems in physics, chemistry, biology, and engineering— in particular, systems with non-local spatiotemporal interactions, such as the brain. Efficient algorithms exist for solving integral equations; however, no method exists for learning these equations from data alone. Zappala et al. describe a framework in which continuous dynamics are learned from discretely sampled data via an iterative process that simultaneously learns and solves an integral equation, in arbitrary space-time dimensions.

Since the model makes use of “self-attention” mechanisms - a technique borrowed from natural language processing - the approach is fast and highly scalable to large and high-dimensional systems such as fluid flow and brain dynamics. To learn more about this method, read “Neural Integral Equations” here.

Zappala, E., Fonseca, A.H.D.O., Caro, J.O., van Dijk, D., 2022. Neural Integral Equations. arXiv preprint arXiv:2209.15190.

New Data on Inflammatory Bowel Disease Training in GI Fellowship

The management of inflammatory bowel disease (IBD) requires comprehensive understanding and training regarding the disease. A previous survey of gastroenterology (GI) fellows found that a substantial portion of trainees did not feel adequately trained to manage IBD. Given the ever-growing complexities of IBD management, a team of researchers led by Yale physicians conducted a multicenter study to assess the current status of IBD training among U.S. GI fellows.

The study included responses from 113 fellows regarding 20 different IBD core domains. Results showed that most fellows reported low confidence in several domains of IBD management. A dedicated IBD rotation during training was associated with higher confidence in managing pregnant patients with IBD, pouch disorders, extraintestinal manifestations, and postoperative Crohn’s disease. Importantly, fellows indicated their preference for substantially more training in IBD management during fellowship.

Read more in “Assessment of Inflammatory Bowel Disease Training Among Gastroenterology Fellows.”

Al Bawardy B, Malter L, Ehrlich AC, Rieder F, Gaidos JKJ, Proctor D, Windish DM. Assessment of Inflammatory Bowel Disease Training Among Gastroenterology Fellows. Inflamm Bowel Dis. 2023 Feb 22:izad030. doi: 10.1093/ibd/izad030. Epub ahead of print. PMID: 36810663.

Enlarged Pituitary Gland from Primary Hypothyroidism: A Case Study

Primary hypothyroidism is a condition where the thyroid gland fails to produce enough thyroid hormone. Although it is rare, primary hypothyroidism may cause the pituitary gland to enlarge. In a new paper, Yale researchers reported the case of a young female with neuropsychiatric symptoms and pituitary enlargement due to primary hypothyroidism.

The patient was admitted to the emergency department with auditory hallucinations and paranoia. Magnetic resonance imaging (MRI) of the head showed diffuse pituitary enlargement without asymmetry. This finding led to a diagnosis of physiological pituitary hyperplasia. She started intravenous levothyroxine, a thyroid hormone. Then, she was transitioned to oral levothyroxine and was discharged from the psychiatry department. Four months later, a repeat MRI showed a complete resolution of the pituitary enlargement.

Physiological causes of pituitary enlargement—like primary hypothyroidism—may be under-acknowledged. If primary hypothyroidism can be successfully identified, then hormone replacement may serve as an effective treatment over unnecessary neurosurgical intervention. Learn more in “Primary hypothyroidism presenting as neuropsychiatric symptoms and pituitary enlargement in a young woman: illustrative case.”

Haider S, Templeton K, Omay SB, Inzucchi SE. Primary hypothyroidism presenting as neuropsychiatric symptoms and pituitary enlargement in a young woman: illustrative case. J Neurosurg Case Lessons. 2023 Feb 13;5(7):CASE22496. doi: 10.3171/CASE22496. PMID: 36794728.

Addressing Errors in the Interpretation of an Elevated Lactate

The tendency for human thinking to deviate from logic is known as “cognitive bias.” Healthcare professionals may possess cognitive biases that contribute to errors in diagnoses and treatment decisions. In a recent article published in the Journal of General Internal Medicine, Yale clinicians address cognitive biases in interpreting an elevated lactate in the case of a patient with type 1 diabetes and a thiamine deficiency.

The patient was admitted to Yale-New Haven Hospital for diabetic ketoacidosis (DKA) and received standard treatments, including intravenous fluids, insulin, and dextrose. Her glucose levels normalized as expected, however, the elevation of lactic acid persisted. Cognitive biases led to an extensive workup, at significant cost and increase in hospital length of stay, before clinicians considered thiamine deficiency as a potential etiology. Empiric thiamine (vitamin B1) supplementation quickly reversed the patient’s elevated lactate levels and she was discharged from the hospital.

The authors describe multiple cognitive biases found in the case. For example, clinicians focused on a “type A” lactic acidosis (LA), typically caused by tissue hypoperfusion, and overlooked the possibility of a “type B” LA because they anchored their decision on her volume depletion on presentation. Also, the prevalence of sepsis and type A LA during the COVID-19 pandemic primed clinicians to focus on elevated lactate levels as a marker of sepsis. Learn more about de-biasing strategies in “Addressing Cognitive Biases in Interpreting an Elevated Lactate in a Patient with Type 1 Diabetes and Thiamine Deficiency.”

Chehayeb RJ, Ilagan-Ying YC, Sankey C. Addressing Cognitive Biases in Interpreting an Elevated Lactate in a Patient with Type 1 Diabetes and Thiamine Deficiency. J Gen Intern Med. 2023 Feb 22:1–5. doi: 10.1007/s11606-023-08091-w. PMID: 36814053; PMCID: PMC9946700.

New Insights on Using Procalcitonin as a Diagnostic Tool in Patients with COVID-19

A new paper by a team of researchers at Yale led by Samir Gautam MD, PhD, assesses the utility of procalcitonin, an inflammatory biomarker that has been used in the testing for bacterial pneumonia, to assess for superimposed bacterial infection in patients with severe COVID-19.

This retrospective study, consisting of 185 patients with severe COVID-19, among whom 85 had evidence of bacterial superinfection, analyzed whether procalcitonin was correlated with the presence of bacterial pneumonia. Overall, the authors demonstrated that static measurement of procalcitonin represents a poor biomarker for bacterial superinfection among those with severe COVID-19. The authors suggest that direct microbiologic sampling may be a more specific and superior method for detecting this complication among hospitalized patients with COVID-19.

Read more about “Nonutility of procalcitonin for diagnosing bacterial pneumonia in patients with severe COVID-19” here.

Cohen AJ, Glick LR, Lee S, Kunitomo Y, Tsang DA, Pitafi S, Valda Toro P, Ristic NR, Zhang E, Carey GB, Datta R, Dela Cruz CS, Gautam S. Nonutility of procalcitonin for diagnosing bacterial pneumonia in patients with severe COVID-19. Eur Clin Respir J. 2023 Feb 8;10(1):2174640. doi: 10.1080/20018525.2023.2174640. PMID: 36815942; PMCID: PMC9930745.

Assessing the Utility of Programmed Cell Death Ligand-1 (PD-L1) Immunohistochemistry Assays

Spearheaded by David Rimm, MD, a multi-institutional team of researchers have uncovered real-world data as to why immunohistological utilization of programmed cell death ligand-1 (PD-L1) may have poor specificity and low predictive value.

Historically, PD-L1 has been a contentious biomarker, partly due to the large assortment of assays and assessment methods. While the combined positive score (CPS) method is most commonly used, its reproducibility has not been rigorously tested. In this study, researchers used a series of 108 gastric or gastroesophageal junction cancer cases which were prepared under standard immunohistological practices and distributed to 14 pathologists at 13 institutions. Overall, there was very low overall percent agreement among raters when using a binary cut point, as well as no relationship between the score and actual messenger RNA content. Future studies need to assess more reliable methods when implementing techniques utilizing PD-L1 readings in the real world.

To learn more, read “Multi-Institutional Study of Pathologist Reading of the Programmed Cell Death Ligand-1 Combined Positive Score Immunohistochemistry Assay for Gastric or Gastroesophageal Junction Cancer.”

Fernandez AI, Robbins CJ, Gaule P, Agostini-Vulaj D, Anders RA, Bellizi A, Chen W, Chen ZE, Gopal P, Zhao L, Lisovsky M, Liu X, Shia J, Wang H, Yang Z, McCann L, Chan YG, Weidler J, Bates M, Zhang X, Rimm DL. Multi-Institutional Study of Pathologist Reading of the Programmed Cell Death Ligand-1 Combined Positive Score Immunohistochemistry Assay for Gastric or Gastroesophageal Junction Cancer. Mod Pathol. 2023 Feb 13;36(5):100128. doi: 10.1016/j.modpat.2023.100128. Epub ahead of print. PMID: 36889057.

Imaging Shows Cholinergic System Changes Associated w/ Cognitive Function Among People Who Stopped Smoking

A new study from Yale School of Medicine assesses the cholinergic system and cognition among people who recently stopped smoking using positron emission tomography (PET) brain imaging. The authors assessed fifteen recently abstinent smokers and twenty one never smokers.

Using the radiotracer (-)-[18F]flubatine and PET, researchers demonstrated that administration of physostigmine, an acetylcholinesterase inhibitor, increased acetylcholine levels in the cortex, and that a larger increase in acetylcholine was associated with worse cognitive function, based on executive function, verbal learning, and working memory tests, among people who recently stopped smoking.

Read more in Neuropsychopharmacology.

Calakos KC, Hillmer AT, Anderson JM, LeVasseur B, Baldassarri SR, Angarita GA, Matuskey D, Kapinos M, Zheng MQ, Huang Y, Cosgrove KP. Cholinergic system adaptations are associated with cognitive function in people recently abstinent from smoking: a (-)-[18F]flubatine PET study. Neuropsychopharmacology. 2023 Mar;48(4):683-689. doi: 10.1038/s41386-023-01535-1. Epub 2023 Jan 21. PMID: 36681758; PMCID: PMC9938267.

Proteomics Analysis Finds Similarities in Host Responses to West Nile Virus Infection and Lyme Disease

The study of changes in serum proteins in human disease states has aided our understanding of disease mechanisms and may facilitate the identification of protein biomarkers as diagnostic tools. A longitudinal serum proteomics analysis, led by a multi-institutional team including several Yale researchers, has found marked similarities in initial host response pathways in patients infected with West Nile virus or with the bacterium that causes Lyme disease.

Researchers looked at blood samples of 23 participants with one of the two diseases, analyzing host proteome responses during acute and recovery phases using two methods: a depletion-based high-throughput shotgun proteomics pipeline and a non-depleting blotting-based low-throughput platform. Both detection methods proved effective, leading to the identification of host proteome responses that were shared in both diseases as well as a small number of proteins that distinguished each from the other. The study also revealed that proteome changes continued for months into the recovery phases of both infections.

The study is the first to compare the serum proteomes of two arthropod-borne infections, identifying key host response similarities despite distinct diseases and vectors. Read more in “Longitudinal Serum Proteomics Analyses Identify Unique and Overlapping Host Response Pathways in Lyme Disease and West Nile Virus Infection.”

Boada P, Fatou B, Belperron AA, Sigdel TK, Smolen KK, Wurie Z, Levy O, Ronca SE, Murray KO, Liberto JM, Rashmi P, Kerwin M, Montgomery RR, Bockenstedt LK, Steen H, Sarwal MM. Longitudinal serum proteomics analyses identify unique and overlapping host response pathways in Lyme disease and West Nile virus infection. Front Immunol. 2022 Dec 9;13:1012824. doi: 10.3389/fimmu.2022.1012824. PMID: 36569838; PMCID: PMC9784464.