glucocorticoid
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Indications
- treatment of acute inflammation
- prevention of adrenal insufficiency*
* see perioperative glucocorticoids
Contraindications
- gastrointestinal bleeding
- renal failure
- active infection
- evidence for use in cancer pain control is weak[35]
Benefit/risk
- acute respiratory distress syndrome (ARDS)[16]
- bronchiolitis[17]
- glucocorticoids do not prevent hospital admission or reduce the length of hospital stay[17]
- sepsis & septic shock[18]
- of no benefit; no harm noted[18]
- prevention of post-herpetic neuralgia[19]
- of no benefit; no harm noted
- pharyngitis
- prednisone 60 mg, dexamethasone <= 10 mg, or betamethasone 8 mg shortens duration of symptoms[20]
- number needed to treat (NNT) = 3
- no harms noted[20]
- prednisone 60 mg, dexamethasone <= 10 mg, or betamethasone 8 mg shortens duration of symptoms[20]
- COPD exacerbation
- number needed to treat (NNT) = 10 to prevent 1 treatment failure[21]
- number needed to harm (NNH) = 7 for drug adverse effect[21]
- croup
- number needed to treat (NNT)
- 5 for respiratory benefit[22]
- 11 to avoid return visit[22]
- no harm noted
- number needed to treat (NNT)
- bacterial meningitis
- non-significant reduction in mortality[23]
- significant reduction in mortality for S pneumoniae meningitis (RR=084)[23]
- number needed to treat (NNT)
- 21 to prevent severe hearing loss
- only significant for H influenzae meningitis (RR=0.34)[23]
- 27 to prevent short-term neurologic sequellae[23]
- 21 to prevent severe hearing loss
- no beneficial effect of glucocorticoids in low-income countries[23]
- number need to harm = 16 for recurrent fever[23]
- non-significant reduction in mortality[23]
- pneumocystis pneumonia
- number needed to treat = 9-22 to reduce mortality[24]
- number need to harm = 5 to precipitate other infection[24]
- Bell's palsy
- number needed to treat = 6-11 for complete recovery[25]
- no harm noted[25]
- migraine headache
- number needed to treat = 10 to prevent 1 recurrence[26]
- unknown harms[26]
Dosage
Equivalent anti-inflammatory doses of glucocorticoids:
| glucocorticoid | equivalent dose | |
|---|---|---|
| betamethasone | 0.6 | |
| dexamethasone | 0.75 | |
| triamcinolone | 4 | |
| methylprednisolone | 4 | |
| prednisolone | 5 | |
| prednisone | 5 | |
| hydrocortisone | 20 | |
| cortisone | 25 |
* when glucocorticoid therapy is > 3-4 weeks, a taper is necessary to minimize withdrawal & promote recovery of the hypothalamic-pituitary-adrenal axis[39]
- taper to disontinue if > 7.5 mg prednisone equivalent for > 3 weeks[3]
- a taper is unnecessary when glucocorticoid therapy is < 3-4 weeks, regardless of dose[39]
- see glucocorticoid taper
* dosage adjustment in settings of physiological stress or acute illness[3]
Pharmacokinetics
- metabolized by cyt P450 3A4
- biologic 1/2life*
- hydrocortisone: 8-12 hours
- methylprednisolone: 4 hours
- prednisolone: 18-36 hours
- prednisone: 18-36 hours
- dexamethasone: 36-54 hours
* may be substantially different from elimination 1/2life
Monitor
- blood glucose every 3 months
- blood pressure
- serum calcium
- serum potassium every 3 months
- serum triglycerides
- ophthalmologic exam for long-term glucocorticoid use
- serum creatine kinase to detect steroid myopathy with use > 4 weeks
- fracture risk should be assessed within 3-6 months of long-term use (prednisone > 2.5 mg qd for > 3 months)[3]
- bone mineral density
- use of FRAX tool for adults > 40 years of age
- reassess fracture risk every 12 months[28]
Adverse effects
- bruising
- osteoporosis, osteopenia, fractures*
- may inhibit osteoblast activity
- may promote osteoblast apoptosis
- inhibition of intestinal Ca+2 transport[8]
- optimize calcium & vitamin D intake[28]
- systemic glucocorticoids associated with increased risk of fractures in children with asthma[30]
- no increase in risk with inhaled glucocorticoids
- long-term glucocorticoids <= 5 mg/day of prednisone do not seem to adversely affect bone mineral density[36]
- aseptic necrosis (avascular osteonecrosis)
- ocular adverse effects
- hypertension
- weight gain, fluid retention, edema
- glucose intolerance/hyperglycemia/diabetes mellitus
- manage glucocorticoid-induced hyperglycemia in patients who are eating with basal, prandial & correctional insulin[3]
- depression, anxiety, insomnia
- central nervous system effects
- insomnia, anxiety, irritability (60%)[12]
- steroid psychosis
- bipolar symptoms
- begins 7-10 days after starting
- dose-dependent
- memory impairment, confusion
- elevated incidence of suicide attempts, depression, mania, & delirium[13]
- acne
- gastrointestinal
- GI intolerance
- reduced tone of gastroesophageal sphincter
- gastroesophageal reflux
- upper GI bleed[5]
- increased cardiovascular risk with chronic use
- accelerated atherogenesis, hypercholesterolemia, hypertension, insulin resistance[38]
- immunosuppression
- disorder of neutrophil phagocytosis
- lymphopenia & monocytopenia
- decreased cell-mediated immunity
- opportunistic infections
- prophylaxis for pneumocystis pneumonia may be appropriate with chronic high-dose glucocorticoids[3][31]
- Cushingoid features:
- impaired wound healing
- steroid myopathy (long-term use)
- seizures
- increased risk of atrial fibrillation
- odds ratio 3.6 (current use)
- odds ratio 1.7 (long-term use)
- no increase risk for former users[9]
- mediastinal lipomatosis
- inhaled corticosteroids
- topical glucocorticoids may cause contact dermatitis (3-5%)
- inhaled glucocorticoids have no significant effect on final height or bone density in children[7]
- long-term effects or antenatal exposure may be minimal (see betamethasone)
- short-term use of oral glucocorticoids associated with increased risks for sepsis (RR=1.8), venous thromboembolism (RR=1.9), & fracture (RR=1.5)[27], gastrointestinal bleeding, & heart failure[33]
- short courses of oral glucocorticoids in children pose risks for pneumonia, GI bleed, & sepsis[34]
- erythroderma following use of systemic glucocorticoids[3]
* Calcium 1.0-1.5 g QD & vitamin D 400-800 IU QD may be helpful. Alendronate (or other bisphosphonate) may reduce bone loss & diminish risk of fractures[4][11][29].
Drug interactions
- any drug that inhibits cyt P450 3A4 may increase levels of corticosteroids
- any drug that induces cyt P450 3A4 may diminish levels of corticosteroids
- drug interaction(s) of methotrexate with biological response modifier
- drug interaction(s) of glucocorticoids with warfarin
- drug interaction(s) of NSAIDs with glucocorticoid
Test interactions
- increased neutrophil count (in vivo effect)
- increase serum glucose (in vivo effect)
- decreased thyroid binding globulin (TBG)
Mechanism of action
- decrease vascular permeability
- inhibition of airway mucous gland secretion
- decrease in number of inflammatory cells, mast cells & T helper cells in airways
- decrease in mRNA expression of cytokines
- normalization of respiratory epithelium
- increased numbers of ciliated airway cells
- decreased number of goblet cells
- inhibition of phospholipase A2
- physiologic activator of apoptosis
- immunosuppression
More general terms
More specific terms
- alclometasone dipropionate
- amcinonide
- beclomethasone; meclometasone (Vancenase, Beconase, Vanceril, Beclovent, Qvar)
- betamethasone dipropionate; betamethasone valerate (Celestone, Soluspan, Betasone)
- budesonide (Rhinocort, Pulmicort, Turbuhaler, Flexhaler, Entocort EC, Uceris, Cortiment, Eohilia)
- clobetasol propionate
- corticosterone
- cortisol; hydrocortisone (Cortef, Solu-Cortef, Alphaderm, Cetacort, Cortenema, Nutracort)
- cortisone (Cortone)
- deflazacort (Emflaza)
- desonide; prednacinolone
- desoximetasone
- dexamethasone (Decadron, Maxidex, AK-Dex, Ozurdex)
- diflorasone diacetate
- flumethasone (Bimasone)
- flunisolide (Nasalide, Nasarel AeroBid)
- fluocinolone acetonide
- fluocinonide (Fluonex)
- fluorinated glucocorticoid
- fluoromethalone
- fluorometholone (FML)
- flurandrenolide
- fluticasone (Flonase, Veramyst, Flovent, Arnuity Ellipta)
- halcinonide
- halobetasol propionate
- halogenated steroid (glucocorticoid)
- inhaled glucocorticoid
- isoflupredone (PREDEF)
- loteprednol (Lotemax, Alrex)
- medrysone
- methylprednisolone (Medrol, Solu-Medrol, Depo-Medrol)
- mometasone furoate (Asmanex, Nasonex)
- nasal glucocorticoid (nasal steroid)
- ophthalmic glucocorticoid (ophthalmic steroid)
- perioperative glucocorticoids
- prednisolone; deltahydrocortisone; metacortandralone (Pred Forte, AK-Pred, Inflamase, Pediapred, Pred Mild, Prelone, Flo-Pred, Veripred 20)
- prednisone (Deltasone, Orasone, Liquid Pred, Meticortin, Rayos)
- rimexolone (Vexol)
- topical glucocorticoid (topical steroid)
- triamcinolone (TAC, Arsitospan, Kenalog, Trivaris)
Additional terms
- glucocorticoid myopathy (steroid myopathy)
- glucocorticoid receptor; GR; nuclear receptor subfamily 3 group C member 1 (NR3C1, GRL)
- steroid (glucocorticoid) injection
Component of
References
- ↑ Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 792, 799
- ↑ Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Medical Knowledge Self Assessment Program (MKSAP) 11, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2015, 2018, 2022.
- ↑ 4.0 4.1 Journal Watch 21(6):46, 2001 Arthritis Rheum 44:202, 2001
- ↑ 5.0 5.1 Journal Watch 21(14):118, 2001 Hernandez-Diaz & Rodriguez, Am J Epidemiol 153:1089, 2001
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ 7.0 7.1 Prescriber's Letter 9(8):48 2002
- ↑ 8.0 8.1 Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004
Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013 - ↑ 9.0 9.1 deprecated reference
- ↑ Prescriber's Letter 17(5): 2010 Using Oral Corticosteroids: a Toolbox Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=260507 &pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 11.0 11.1 Grossman JM, Gordon R, Ranganath VK et al American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken). 2010 Nov;62(11):1515-26 PMID: https://www.ncbi.nlm.nih.gov/pubmed/20662044 corresponding NGC guideline withdrawn Dec 2015
- ↑ 12.0 12.1 Prescriber's Letter 18(5): 2011 Corticosteroid-Induced Psychiatric Effects Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=270508&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 13.0 13.1 Fardet L et al. Suicidal behavior and severe neuropsychiatric disorders following glucocorticoid therapy in primary care. Am J Psychiatry 2012 May 1; 169:491 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22362393
- ↑ Barnes PJ. Mechanisms and resistance in glucocorticoid control of inflammation. J Steroid Biochem Mol Biol. 2010 May 31;120(2-3):76-85 PMID: https://www.ncbi.nlm.nih.gov/pubmed/20188830
- ↑ Williams LC, Nesbitt LT Jr. Update on systemic glucocorticosteroids in dermatology. Dermatol Clin. 2001 Jan;19(1):63-77. PMID: https://www.ncbi.nlm.nih.gov/pubmed/11155587
- ↑ 16.0 16.1 16.2 16.3 The NNT: Corticosteroids for Acute Respiratory Distress Syndrome (ARDS) http://www.thennt.com/nnt/steroids-for-acute-respiratory-distress-syndrome-ards/
Adhikari N, Burns KE, Meade MO Pharmacologic therapies for adults with acute lung injury and acute respiratory distress syndrome. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD004477. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15495113 - ↑ 17.0 17.1 17.2 The NNT: Glucocorticoids for Bronchiolitis. http://www.thennt.com/nnt/steroids-for-bronchiolitis/
Fernandes RM, Bialy LM, Vandermeer B et al Glucocorticoids for acute viral bronchiolitis in infants and young children. Cochrane Database Syst Rev. 2013 Jun 4;6:CD004878 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23733383 - ↑ 18.0 18.1 18.2 The NNT: Systemic Steroids for Sepsis Syndromes http://www.thennt.com/nnt/steroids-for-sepsis/
Sprung CL et al, Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008, 358:111 PMID: https://www.ncbi.nlm.nih.gov/pubmed/18184957
Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y Corticosteroids for treating severe sepsis and septic shock. Cochrane Database Syst Rev. 2004;(1):CD002243. PMID: https://www.ncbi.nlm.nih.gov/pubmed/14973984 - ↑ 19.0 19.1 The NNT: Corticosteroids for the Prevention of Post-Herpetic Neuralgia. http://www.thennt.com/nnt/corticosteroids-for-preventing-post-herpetic-neuralgia/
He L, Zhang D, Zhou M, Zhu C. Corticosteroids for preventing postherpetic neuralgia. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD005582 PMID: https://www.ncbi.nlm.nih.gov/pubmed/18254083 - ↑ 20.0 20.1 20.2 The NNT: Corticosteroids for Acute Pharyngitis. http://www.thennt.com/nnt/steroids-for-pharyngitis/
Hayward G et al Corticosteroids for pain relief in sore throat: Systematic review and meta-analysis. BMJ 2009 Aug 6; 339:b2976 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/19661138 <Internet> http://dx.doi.org/10.1136/bmj.b2976
Little P. Sore throat in primary care. BMJ 2009 Aug 6; 339:b2476 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/19661137 <Internet> http://dx.doi.org/10.1136/bmj.b2476
Hayward G, Thompson MJ, Perera R, Corticosteroids as standalone or add-on treatment for sore throat. Cochrane Database Syst Rev. 2012 Oct 17;10:CD008268 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23076943 - ↑ 21.0 21.1 21.2 The NNT: Systemic Steroids for Acute COPD Exacerbations http://www.thennt.com/nnt/steroids-for-copd-exacerbation/
Walters JA, Gibson PG, Wood-Baker R, Hannay M, Walters EH. Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD001288. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19160195 - ↑ 22.0 22.1 22.2 The NNT: Glucocorticoids (Steroids) for Croup http://www.thennt.com/nnt/steroids-for-croup/
Russell KF, Liang Y, O'Gorman K, Johnson DW, Klassen TP. Glucocorticoids for croup. Cochrane Database Syst Rev. 2011 Jan 19;(1):CD001955 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21249651 - ↑ 23.0 23.1 23.2 23.3 23.4 23.5 23.6 The NNT: Glucocorticoid Steroids for Bacterial Meningitis. http://www.thennt.com/nnt/steroids-for-meningitis/
Brouwer MC, McIntyre P, Prasad K, van de Beek D. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2013 Jun 4;6:CD004405 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23733364 - ↑ 24.0 24.1 24.2 The NNT: Systemic Steroids for Pneumocystis Pneumonia (PCP,PJ) http://www.thennt.com/nnt/steroids-for-pcppj-pneumonia/
Briel M, Bucher HC, Boscacci R, Furrer H. Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV-infection. Cochrane Database Syst Rev. 2006 Jul 19;(3):CD006150. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16856118 - ↑ 25.0 25.1 25.2 The NNT: Systemic Corticosteroids for Bell's Palsy http://www.thennt.com/nnt/steroids-for-bells-palsy/
Salinas RA, Alvarez G, Daly F, Ferreira J. Corticosteroids for Bell's palsy (idiopathic facial paralysis). Cochrane Database Syst Rev. 2010 Mar 17;(3):CD001942 PMID: https://www.ncbi.nlm.nih.gov/pubmed/20238317
Gronseth GS and Paduga R Evidence-based guideline update: Steroids and antivirals for Bell palsy. Report of the Guideline Development Subcommittee of the American Academy of Neurology Neurology. November 7, 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23136264 <Internet> http://www.neurology.org/content/early/2012/11/07/WNL.0b013e318275978c.abstract - ↑ 26.0 26.1 26.2 The NNT: Steroids (Dexamethasone) for Prevention of Migraine Recurrence. http://www.thennt.com/nnt/steroids-for-prevention-of-migraine-recurrence/
Colman I, Friedman BW, Brown MD et al Parenteral dexamethasone for acute severe migraine headache: meta-analysis of randomised controlled trials for preventing recurrence. BMJ. 2008 Jun 14;336(7657):1359-61 PMID: https://www.ncbi.nlm.nih.gov/pubmed/18541610
Singh A, Alter HJ, Zaia B. Does the addition of dexamethasone to standard therapy for acute migraine headache decrease the incidence of recurrent headache for patients treated in the emergency department? A meta-analysis and systematic review of the literature. Acad Emerg Med. 2008 Dec;15(12):1223-33. PMID: https://www.ncbi.nlm.nih.gov/pubmed/18976336 - ↑ 27.0 27.1 Waljee AK, Rogers MA, Lin P et al Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ 2017;357:j1415 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28404617 <Internet> http://www.bmj.com/content/357/bmj.j1415
- ↑ 28.0 28.1 28.2 Buckley L, Guyatt G, Fink HA et al 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Care Res (Hoboken). 2017 Jun 6 PMID: https://www.ncbi.nlm.nih.gov/pubmed/28585410
Buckley L, Guyatt G, Fink HA et al 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheumatol. 2017 Jun 6. PMID: https://www.ncbi.nlm.nih.gov/pubmed/28585373 https://www.rheumatology.org/Portals/0/Files/Guideline-for-the-Prevention-and-Treatment-of-GIOP.pdf - ↑ 29.0 29.1 Axelsson KF, Nilsson AG, Wedel H, Lundh D, Lorentzon M. Association Between Alendronate Use and Hip Fracture Risk in Older Patients Using Oral Prednisolone. JAMA. 2017;318(2):146-155 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28697254 <Internet> http://jamanetwork.com/journals/jama/article-abstract/2643309
- ↑ 30.0 30.1 Gray N, Howard A, Zhu J et al Association Between Inhaled Corticosteroid Use and Bone Fracture in Children With Asthma. JAMA Pediatr. Published online November 13, 2017 PMID: https://www.ncbi.nlm.nih.gov/pubmed/29131874 https://jamanetwork.com/journals/jamapediatrics/article-abstract/2661821
- ↑ 31.0 31.1 Park JW, Curtis JR, Moon J et al. Prophylactic effect of trimethoprim-sulfamethoxazole for pneumocystis pneumonia in patients with rheumatic diseases exposed to prolonged high-dose glucocorticoids. Ann Rheum Dis 2018 May; 77:644. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/29092853 Free PMC Article <Internet> http://ard.bmj.com/content/77/5/644
Winthrop KL , Baddley JW. Pneumocystis and glucocorticoid use: To prophylax or not to prophylax (and when?); that is the question. Ann Rheum Dis 2018 May; 77:631 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/29459427 <Internet> http://ard.bmj.com/content/77/5/631 - ↑ Rotaus C Glucocorticoid-Induced Osteoporosis NEJM Resident 360. Dec 26, 2018 https://resident360.nejm.org/content_items/glucocorticoid-induced-osteoporosis
- ↑ 33.0 33.1 Yao TC et al. Association between oral corticosteroid bursts and severe adverse events: A nationwide population-based cohort study. Ann Intern Med 2020 Sep 1; 173:325 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32628532 https://www.acpjournals.org/doi/10.7326/M20-0432
Wallace BI, Waljee AK. Burst case scenario: Why shorter may not be any better when it comes to corticosteroids. Ann Intern Med 2020 Sep 1; 173:390 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32628530 https://www.acpjournals.org/doi/10.7326/M20-4234 - ↑ 34.0 34.1 Yao TC et al. Association of oral corticosteroid bursts with severe adverse events in children. JAMA Pediatr 2021 Apr 19; [e-pub]. PMID: https://www.ncbi.nlm.nih.gov/pubmed/33871562 https://jamanetwork.com/journals/jamapediatrics/fullarticle/2778775
- ↑ 35.0 35.1 Haywood A, Good P, Khan S et al. Corticosteroids for the management of cancer-related pain in adults. Cochrane Database Syst Rev. 2015 Apr 24;(4):CD010756. PMID: https://www.ncbi.nlm.nih.gov/pubmed/25908299 PMCID: PMC8127040 Free PMC article https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD010756.pub2/full
- ↑ 36.0 36.1 Wiebe E, Huscher D, Schaumburg D, et al. Optimising both disease control and glucocorticoid dosing is essential for bone protection in patients with rheumatic disease. Ann Rheum Dis. Published online ahead of print June 9, 2022. PMID: https://www.ncbi.nlm.nih.gov/pubmed/35680387
- ↑ NEJM Knowledge+ Psychiatry
- ↑ 38.0 38.1 NEJM Knowledge+ Complex Medical Care
- ↑ 39.0 39.1 39.2 Beuschlein F, Else T, Bancos I et a; European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and Therapy of Glucocorticoid-induced Adrenal Insufficiency. J Clin Endocrinol Metab. 2024 Jun 17;109(7):1657-1683. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38724043 PMCID: PMC11180513 Free PMC article.