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Discoveries & Impact (March 2022)

March 17, 2022
by Elisabeth Reitman, Jane E. Dee and Julie Parry

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

Viewpoint: Moving Beyond Averages

Conventional reporting of randomized clinical trial (RCT) data focuses on averages, which could obscure the expected benefit of a treatment for individual patients. In a recent viewpoint published in JAMA Surgery led by Makoto Mori, MD, a cardiothoracic surgery resident, and Harlan Krumholz, MD, at the Center for Outcomes Research and Evaluation (CORE), the authors discuss how existing RCT data could be leveraged to predict individualized outcomes of a treatment by developing a prediction model ‘in parallel.’ Such models, in the emergence of clinical decision support tools, present new opportunities in medicine. The authors note that transparency is key to improve clinical decision-making support tools.

Best practices in implementing such models include:

  • External validation before clinical implementation.
  • Considerations for adequate sample size.
  • User training and monitoring.

Mori M, Spertus JA, Krumholz HM. Data-Driven Individualized Surgical Decision-making: Beyond "Better on Average" Clinical Trial Results. JAMA Surgery 2022, 157(2): 93-94. doi: 10.1001/jamasurg.2021.5614. PMID: 34817547.

HCC in Noncirrhotic Livers

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Globally, HCC is projected to cause over 1 million deaths annually by 2025. While HCC typically arises in a damaged liver with advanced fibrosis or cirrhosis, the incidence of HCC in non-cirrhotic livers is increasing.

In this new research from the Yale School of Medicine and the Yale Center for Analytical Sciences, scientists wanted to determine the histological and clinical differences between HCCs arising in patients with- and without cirrhosis. The team identified 378 cases of HCC from pathology archives; 95 of the 378 cases occurred in patients without cirrhosis. They found that in the patients without cirrhosis, HCC was more common in those with viral hepatitis B infection (a known risk factor); and tumors were larger, more aggressive, and more advanced. The authors urge future studies on the development of HCC in patients without cirrhosis.

Learn more about the research published in the American Journal of Clinical Pathology.

Jain A, Mazer B, Deng Y, Ciarleglio M, Jain D, Taddei T, Zhang X. Hepatocellular Carcinoma. American Journal Of Clinical Pathology 2022, 157(2): 305-313. doi: 10.1093/ajcp/aqab125. PMID: 34542582.

XLH Leads to Multiple Musculoskeletal Issues Earlier

X-linked hypophosphatemia (XLH) is a rare, genetic skeletal disease caused by over production of FGF23, a hormone made by bone cells. Overproduction of FGF23 causes life-long low blood phosphorus. Patients typically present in childhood with rickets causing bowing of the legs. A misshapen skull and dental abscesses can also be seen in early childhood. Adults with XLH suffer from frequent fractures, bone pain, calcifications around joints, and spinal stenosis and rapidly advancing osteoarthritis.

Scientists across five institutions sought to further understand the evolution of musculoskeletal features in adults with XLH to drive improved care for those with this ailment. They analyzed data from a clinical trial of adults with XLH and information collected from a cross-sectional, multinational survey to learn their history of fractures, osteoarthritis, osteophytes, and other musculoskeletal challenges.

They concluded that patients with XLH “bear a substantial burden of multiple musculoskeletal features, emerging decades earlier than in the general population, as early as in their 20s, and progressively accumulating with age.” Learn more in The Journal of Clinical Endocrinology & Metabolism.

Javaid MK, Ward L, Pinedo-Villanueva R, Rylands AJ, Williams A, Insogna K, Imel EA. Musculoskeletal Features in Adults With X-linked Hypophosphatemia: An Analysis of Clinical Trial and Survey Data. The Journal Of Clinical Endocrinology And Metabolism 2022, 107(3): e1249-e1262. doi: 10.1210/clinem/dgab739. PMID: 34636401. PMCID: PMC8852215.

Personalize Cautious Opioid Prescribing in Patients Treated w/ Dialysis

In patients with kidney failure, dialysis is a life-saving treatment. Unfortunately, many patients on hemodialysis suffer from moderate-to-severe pain that is often under-treated. Managing pain in this patient population can be challenging for a host of reasons.

In a Review article published in Nature Reviews Nephrology, the authors explore the use of opioid therapy for patients with chronic severe pain on hemodialysis. They stress that the use of opioids must be personalized for each patient, carefully monitored for harm, and implemented cautiously. They also stress the use of universal precautions for all patients on long-term opioid therapy and explore the potential role of buprenorphine to treat severe pain in this patient population. Areas for further investigation are considered as well. Read more in “Opioids for chronic pain management in patients with dialysis-dependent kidney failure.”

Tobin DG, Lockwood MB, Kimmel PL, Dember LM, Eneanya ND, Jhamb M, Nolin TD, Becker WC, Fischer MJ. Opioids for chronic pain management in patients with dialysis-dependent kidney failure. Nature Reviews. Nephrology 2022, 18(2): 113-128. doi: 10.1038/s41581-021-00484-6. PMID: 34621058. PMCID: PMC8792317.

Anesthesia Alone Not Associated W/ Cognitive Recovery In Healthy Adults

For older surgical patients, postoperative delirium and decreased cognitive function can complicate recovery. The cause of this dysfunction is unknown.

Researchers sought to understand the role of anesthesia on cognitive recovery in older adults in the absence of surgery. They designed a study for healthy adults from ages 40 to 80, and evaluated their cognitive function before and after anesthesia using the Postoperative Quality of Recovery Scale (PQRS) cognitive subtest and MRI screening.

They found that cognitive function recovery was swift and didn’t differ by age. Learn more in Anesthesia & Analgesia.

Baxter MG, Mincer JS, Brallier JW, Schwartz A, Ahn H, Nir T, McCormick PJ, Ismail M, Sewell M, Allore HG, Ramsey CM, Sano M, Deiner SG. Cognitive Recovery by Decade in Healthy 40- to 80-Year-Old Volunteers After Anesthesia Without Surgery. Anesthesia And Analgesia 2022, 134(2): 389-399. doi: 10.1213/ANE.0000000000005824. PMID: 34889804. PMCID: PMC8760160.

Need For Care Improvements For APL Patients

Acute promyelocytic leukemia (APL) is a rare form of acute myeloid leukemia (AML) and accounts for almost 10% of newly diagnosed cases in the U.S. Treatments for patients with APL varies from those with AML, but can lead to hemorrhagic complications and death.

Authors of a new paper in Blood Advances used data from the Vizient Clinical Data Base to look at 1464 APL patients for associations with adverse outcomes. They found that 79.3% of the patients were treated with therapy in accordance with the National Comprehensive Cancer Network guidelines. Of those patients, 14% died in the hospital or were released to hospice.

They stress the need to improved care for patients with APL. Learn more.

Bewersdorf JP, Prozora S, Podoltsev NA, Shallis RM, Huntington SF, Neparidze N, Wang R, Zeidan AM, Davidoff AJ. Practice patterns and real-life outcomes for patients with acute promyelocytic leukemia in the United States. Blood Advances 2022, 6(2): 376-385. doi: 10.1182/bloodadvances.2021005642. PMID: 34724703. PMCID: PMC8791583.

Convalescent Plasma Therapy Shows No Significant Benefit to Hospitalized COVID-19 Patients

In an effort to determine the safety and efficacy of using convalescent plasma (CCP) compared with a placebo in hospitalized patients with COVID-19, researchers designed a randomized, double-blind placebo-controlled trial from April 17, 2020 to March 15, 2021. The trial enrolled 941 participants at 21 U.S. hospitals. The patients had been hospitalized for three days or less, or had gone to the hospital within seven days of when their symptoms began. All of them needed supplemental oxygen to help them breathe.

The researchers concluded that CCP did not benefit patients, although it might have early in the pandemic when Remdesivir and corticosteroids were not in use.

Ortigoza MB, Yoon H, Goldfeld KS, Troxel AB, Daily JP, Wu Y, Li Y, Wu D, Cobb GF, Baptiste G, O'Keeffe M, Corpuz MO, Ostrosky-Zeichner L, Amin A, Zacharioudakis IM, Jayaweera DT, Wu Y, Philley JV, Devine MS, Desruisseaux MS, Santin AD, Anjan S, Mathew R, Patel B, Nigo M, Upadhyay R, Kupferman T, Dentino AN, Nanchal R, Merlo CA, Hager DN, Chandran K, Lai JR, Rivera J, Bikash CR, Lasso G, Hilbert TP, Paroder M, Asencio AA, Liu M, Petkova E, Bragat A, Shaker R, McPherson DD, Sacco RL, Keller MJ, Grudzen CR, Hochman JS, Pirofski LA, Parameswaran L, Corcoran AT, Rohatgi A, Wronska MW, Wu X, Srinivasan R, Deng FM, Filardo TD, Pendse J, Blaser SB, Whyte O, Gallagher JM, Thomas OE, Ramos D, Sturm-Reganato CL, Fong CC, Daus IM, Payoen AG, Chiofolo JT, Friedman MT, Wu DW, Jacobson JL, Schneider JG, Sarwar UN, Wang HE, Huebinger RM, Dronavalli G, Bai Y, Grimes CZ, Eldin KW, Umana VE, Martin JG, Heath TR, Bello FO, Ransford DL, Laurent-Rolle M, Shenoi SV, Akide-Ndunge OB, Thapa B, Peterson JL, Knauf K, Patel SU, Cheney LL, Tormey CA, Hendrickson JE. Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients: A Randomized Clinical Trial. JAMA Internal Medicine 2022, 182(2): 115-126. doi: 10.1001/jamainternmed.2021.6850. PMID: 34901997. PMCID: PMC8669605.

When the Doctor Becomes the Patient

Elizabeth Prsic, MD, explains how she learned more about the patient experience in a month when she underwent genetic testing than she did during her years of medical training.

“The rational, evidence-based physician I had been cultivating over the past decade turned off her pager and went home for the day. I was left a … patient,” she wrote in Cancer Care Chronicles in JAMA Oncology.

“When you become the N = 1, the world becomes infinitely smaller and less certain. The unlikely or impossible can happen to you, and you care considerably less about the larger clinical picture, the public health perspective, the meta-analysis, the statistics, the cost. To be honest, I cared solely about myself, my breasts, my ovaries, my family. While this may seem a normal reaction to the layperson, as a physician, it was a unique and disorienting experience.”

Prsic E. Pink Ribbons. JAMA Oncology 2022, 8(2): 207. doi: 10.1001/jamaoncol.2021.6413. PMID: 34854869.

Reducing Kidney Graft Loss After Transplant

The failure of allografts during kidney transplantation is often due to interstitial fibrosis, tubular atrophy, and inflammation. Researchers used a deep-learning technique to help them recognize healthy versus diseased kidney tissue. Their model accurately recognized kidney tissue compartments and mononuclear leukocytes. The deep-learning approach accurately detected and quantified pathological lesions from baseline or post-transplant biopsies, and demonstrated a superior ability to predict post-transplant graft loss. The method has the potential to be used as a prevention, risk stratification or monitoring tool, explained the authors in Kidney International.

Yi Z, Salem F, Menon MC, Keung K, Xi C, Hultin S, Haroon Al Rasheed MR, Li L, Su F, Sun Z, Wei C, Huang W, Fredericks S, Lin Q, Banu K, Wong G, Rogers NM, Farouk S, Cravedi P, Shingde M, Smith RN, Rosales IA, O'Connell PJ, Colvin RB, Murphy B, Zhang W. Deep learning identified pathological abnormalities predictive of graft loss in kidney transplant biopsies. Kidney International 2022, 101(2): 288-298. doi: 10.1016/j.kint.2021.09.028. PMID: 34757124.

A Better Understanding of Williams Syndrome Emerges in Recent Study

Yale-PCCSM Clinical Fellow John C. Huston, MD, is the first author of an original paper that was published in Journal of Autism and Developmental Disorders that characterizes repetitive behaviors in children and adults with Williams syndrome, a rare genetic neurological disorder. The study used three standardized and validated rating scales to evaluate one type of repetitive thoughts (obsessions) and three types of repetitive behaviors -- compulsions, tics, and stereotypies such as repetitive movement or sound.

Nineteen males and 41 females participated in the study. Fifty subjects (83.3%) had at least a repetitive movement or sound (stereotypy). None of the subjects had tics. Increased anxiety was associated with increased severity of obsessions, but not severity of compulsions or stereotypies. Read more:

Huston JC, Thom RP, Ravichandran CT, Mullett JE, Moran C, Waxler JL, Pober BR, McDougle CJ. Repetitive Thoughts and Repetitive Behaviors in Williams Syndrome. Journal Of Autism And Developmental Disorders 2022, 52(2): 852-862. doi: 10.1007/s10803-021-04979-w. PMID: 33837487.

Low Antibody Levels Associated w/ Hospitalization of Patients w/ Primary Antibody Deficiency & COVID-19

High-dose Immunoglobulin G (IgG) antibody therapy helps to regulate inflammatory responses in people with COVID-19. However, there are few studies on the effect of IgG replacement therapy (IgGRT) on people with COVID-19 who also have primary antibody deficiency (PAD). Yale researchers and colleagues performed a retrospective chart review of patients with COVID-19 from March 2020 to August 2021 to identify those who also have PAD and treated with IgGRT. After analyzing the data, they concluded that it’s “tempting to speculate that maintaining higher IgG levels may positively modulate the cellular immune response and inflammation, leading to favorable outcome of COVID-19.” Read about the study’s methods and outcomes in The Journal of Allergy and Clinical Immunology: In Practice.

Kuster JK, Unlu S, Makin TA, Par-Young J, Simonov M, Shafi S, Balanda M, Randolph C, Steele R, Hsu FI, Price C, Kohli-Pamnani A, Borish L, Lawrence MG, Kang I, Shin JJ. Low IgG trough and lymphocyte subset counts are associated with hospitalization for COVID-19 in patients with primary antibody deficiency. The Journal Of Allergy And Clinical Immunology. In Practice 2022, 10(2): 633-636.e3. doi: 10.1016/j.jaip.2021.11.030. PMID: 34929372. PMCID: PMC8683251.

Submitted by Julie Parry on March 17, 2022