This Week in Rheumatology - 2025-06-22

# This Week in Rheumatology ## Ankylosing Spondylitis Recent research on ankylosing spondylitis (AS) highlights breakthroughs in immunopathology and treatment resistance. Wu et al. (2024) identified expanded CD8+ T cell subsets with unique TCR motifs (TRAV21/TRBV9) in HLA-B27-positive axial spondyloarthritis (axSpA) patients, supporting the arthritogenic peptide hypothesis. Monoclonal antibody targeting of these T cells shows promise in phase II trials. Neutrophils also play a dual role in inflammation and bone formation, with molecules like HIF-1α and NETs emerging as potential therapeutic targets. However, unanswered questions remain about HLA-B27-bound peptides and the efficacy of single-TCR therapies. Meanwhile, Bilici et al. (2024) link anti-TNF resistance to *Helicobacter pylori* infection, with resistant AS patients showing higher IgA seropositivity, elevated inflammatory markers (ESR, CRP), and worse functional scores (BASFI, ASDAS-CRP). Their findings suggest *H. pylori* eradication could improve anti-TNF response by mitigating gut-driven inflammation. Together, these studies underscore the complexity of AS pathogenesis—from HLA-B27-dependent T cell responses to microbiome-mediated treatment resistance—while pinpointing novel targets for precision therapy. ### References - Recent Advances in the Immunopathology of Axial Spondyloarthritis: with and without HLA-B27. by Wu B, Tang A, Nakamura A. Current rheumatology reports. [PMID: 40542889](https://pubmed.ncbi.nlm.nih.gov/40542889/) - TNF inhibitor resistance in ankylosing spondylitis: is Helicobacter pylori the overlooked culprit? by Bilici R, Alp GT, Celikdelen SO, Ozturk MA, Kekilli M. Clinical rheumatology. [PMID: 40533688](https://pubmed.ncbi.nlm.nih.gov/40533688/) ## Drugs and Pharmacology Recent research highlights gabapentin's expanding clinical utility in pain and neurological disorders, tempered by significant risks. While its modulation of voltage-gated calcium channels makes it effective for conditions like diabetic neuropathy and fibromyalgia (off-label) and postherpetic neuralgia (approved), up to 25% of patients experience weight gain due to GI alterations and edema, complicating long-term adherence—particularly in metabolic disorders. More critically, gabapentin’s synergistic effects with opioids, though enabling dose reduction, amplify respiratory depression and overdose risks, especially in elderly or opioid-tolerant patients. Current evidence underscores the need for individualized dosing, patient education, and close monitoring to balance efficacy with safety. Further research is urged to refine prescribing practices and mitigate adverse outcomes. ### References - Emerging Clinical Roles of Gabapentin and Adverse Effects, Including Weight Gain, Obesity, Depression, Suicidal Thoughts and Increased Risk of Opioid-Related Overdose and Respiratory Depression: A Narrative Review. by Kaye AD, Cassagne G, Abbott BM, Dubuisson AM, Fagan JJ, Indovina I, Gungor D, Kallurkar A, Kaye AM, Shekoohi S. Current pain and headache reports. [PMID: 40540060](https://pubmed.ncbi.nlm.nih.gov/40540060/) ## Gout Recent research highlights a rising global burden of early-onset gout (EOG) in individuals aged 15–39, driven significantly by high BMI. A 2024 study using GBD 2021 data (Chen et al., *Clinical Rheumatology*) found that EOG accounted for 1.3 million new cases and 5.1 million prevalent cases worldwide in 2021, with DALYs attributable to high BMI increasing markedly—54,909 of 170,599 total DALYs. Age-standardized incidence rates rose from 36.52 to 43.60 per 100,000 between 1990 and 2021, with the highest burden in high-income North America (115.02 per 100,000) and among males. Epidemiological shifts and population growth fueled this trend, while health inequalities persisted, disproportionately affecting higher SDI regions. The findings underscore the urgent need for targeted prevention strategies addressing obesity and gout in young populations, particularly in affluent areas where high BMI’s contribution to DALYs is concentrated. ### References - The global burden and epidemiological trends of gout, particularly cases attributable to high Body Mass Index (BMI) in adolescents and young adults (aged 15-39 years): a secondary analysis from global burden of disease study 2021. by Chen F, Su X, Yang F, Yu J, Bai C, Zhang M. Clinical rheumatology. [PMID: 40533689](https://pubmed.ncbi.nlm.nih.gov/40533689/) ## Immunology Recent research highlights the intricate interplay between immune function, sex hormones, and environmental factors in autoimmune diseases. Dai et al. (2024) underscore how sex hormones drive epigenetic modifications, shaping sex-biased immune responses in autoimmunity, with implications for biomarkers and targeted therapies. Meanwhile, Luo et al. (2024) demonstrate in a meta-analysis that vitamin D supplementation (≥3 months, daily dosing) reduces thyroid autoantibodies in AITD, particularly in vitamin D-deficient patients, suggesting a modifiable environmental influence on autoimmunity. On the infectious-immune interface, DiPalma et al. (2024) reveal bidirectional links between fungal infections and autoimmunity, where fungal pathogens exacerbate immune dysregulation, while immunosuppressive therapies heighten infection risk—calling for integrated management strategies. Separately, Deichmann et al. (2024) model post-vaccine antibody kinetics against SARS-CoV-2, identifying age, sex, and comorbidities (e.g., autoimmunity, diabetes) as predictors of waning immunity, offering a tool to personalize protection estimates. Together, these studies emphasize the multifactorial nature of immune dysregulation, bridging hormonal, environmental, and infectious drivers to refine clinical approaches. ### References - Sex hormones and epigenetic dysregulation in autoimmune disease. by Dai M, Mei B, Zheng F, Ballestar E. Current opinion in immunology. [PMID: 40543376](https://pubmed.ncbi.nlm.nih.gov/40543376/) - The impacts of vitamin D supplementation on serum levels of thyroid autoantibodies in patients with autoimmune thyroid disease: a meta-analysis. by Luo D, Li B, Shan Z, Teng W, Liu Q, Li J. PeerJ. [PMID: 40538736](https://pubmed.ncbi.nlm.nih.gov/40538736/) - Predicting antibody kinetics and duration of protection against SARS-CoV-2 following vaccination from sparse serological data. by Deichmann J, Barda N, Canetti M, Peretz Y, Weiss-Ottolenghi Y, Lustig Y, Regev-Yochay G, Lipsitch M. PLoS computational biology. [PMID: 40531962](https://pubmed.ncbi.nlm.nih.gov/40531962/) - Interplay between fungal infections and autoimmunity: mechanisms and therapeutic perspectives. by DiPalma DT, Lumbreras MK, Shinohara ML. EMBO molecular medicine. [PMID: 40528008](https://pubmed.ncbi.nlm.nih.gov/40528008/) ## Infectious Diseases Recent research highlights the superior diagnostic performance of metagenomic next-generation sequencing (mNGS) in detecting co-infections among patients with connective tissue diseases (CTDs). A retrospective study of 304 CTD patients with suspected infections (Xiao et al., *Clinical Rheumatology*) found mNGS significantly outperformed conventional microbiological testing (CMT), with higher sensitivity (89.6% vs. 57.0%) and specificity (81.5%), particularly for bacterial and viral pathogens. Viral infections were the most prevalent, with shifting pathogen distributions post-COVID-19. mNGS-guided treatment adjustments improved clinical outcomes, including higher cure rates, reduced mortality, and shorter hospital stays. While mNGS alone excels, combining it with CMT optimizes pathogen identification and clinical management. This study underscores mNGS as a transformative tool for early infection detection and tailored antimicrobial therapy in CTD patients. ### References - Clinical value of metagenomic next-generation sequencing in patients with connective tissue diseases co-infections: a single-center study from southern hospital in China. by Xiao YY, Lu AL, Mo HY, He ZD, Wen JL, Yin X. Clinical rheumatology. [PMID: 40540222](https://pubmed.ncbi.nlm.nih.gov/40540222/) ## Osteoarthritis Recent research highlights the growing global burden of osteoarthritis (OA), particularly among postmenopausal women (PMW), with projections suggesting nearly 50% of PMW could be affected by 2045 (Tan et al.). OA and low back pain are primary drivers of disability-adjusted life years (DALYs) in this population, exacerbated by aging and demographic shifts, with regional disparities linked to socioeconomic factors. Meanwhile, a randomized controlled trial protocol (Yap et al.) explores combining hydroxymethylbutyrate (HMB) and undenatured type-II collagen with exercise training to improve OA-related symptoms and biomarkers in knee OA patients, aiming to address functional decline in older adults. Surgical interventions for occupational rhizarthrosis (Mendes Ribeiro et al.) demonstrate significant pain reduction and improved work capacity, particularly in manual laborers, underscoring the value of early intervention. A network meta-analysis (Chen et al.) ranks knee braces, hydrotherapy, and exercise as top non-pharmacological therapies for knee OA, with braces showing consistent efficacy across pain, function, and stiffness metrics. Together, these studies emphasize the need for tailored, multimodal approaches—spanning prevention, nutritional and exercise interventions, and surgical options—to mitigate OA's escalating impact. ### References - Global burden and trends of musculoskeletal disorders in postmenopausal elderly women: a 1990-2021 analysis with projections to 2045. by Tan J, Zhu Z, Wang X, Yang B, Liu S, Shi M, Luo Y, Du C, Sun Y, Liao J, Lei Y, Huang W. Arthritis research & therapy. [PMID: 40537855](https://pubmed.ncbi.nlm.nih.gov/40537855/) - Efficacy of oral nutrition supplementation enriched with hydroxymethylbutyrate (HMB) and undenatured type-II collagen (UC-II) combined with exercise training on osteoarthritis-related outcomes among adults with knee osteoarthritis in Klang Valley of Malaysia: study protocol for a randomised controlled trial. by Yap AXW, You YX, Ajit Singh DK, Mat S, Chong CP, Mohamad Yahaya NH, Maktar JF, Abdul Rani R, Ooi TC, Ismail M, Shahar S, Han WC, Kwan LK, Centhyea C. BMJ open. [PMID: 40537225](https://pubmed.ncbi.nlm.nih.gov/40537225/) - Occupational Rhizarthrosis Treated Surgically: Effects on Work Performance. by Mendes Ribeiro RA, Moreira S, Teofilo V, Pinelas S, Miller M, Pinho P, Norton P, Amorim N, Serdoura F, Vidinha V. La Medicina del lavoro. [PMID: 40536302](https://pubmed.ncbi.nlm.nih.gov/40536302/) - Clinical efficacy of different therapeutic options for knee osteoarthritis: A network meta-analysis based on randomized clinical trials. by Chen X, Fan Y, Tu H, Luo Y. PloS one. [PMID: 40531843](https://pubmed.ncbi.nlm.nih.gov/40531843/) ## Other Rheumatic Diseases Recent research highlights diverse advancements in managing rheumatic diseases. A meta-analysis of low-dose naltrexone (LDN) for chronic pain found it superior to placebo in fibromyalgia (SMD -0.34, p=0.0186) but comparable to active controls, despite higher adverse events (IRR 1.4 vs. placebo). In juvenile idiopathic arthritis (JIA), a Norwegian study revealed similar bone mineral density (BMD) Z-scores between JIA patients and controls, emphasizing the role of physical activity in maintaining bone health (mean Z-score 0.2 in high-activity vs. -0.3 in low-activity groups). Meanwhile, hip denervation (HD) emerged as a promising intervention for JIA-related hip arthritis, showing sustained pain reduction (VAS 5.48→0.83, p<0.0001) and functional improvement (Harris Hip Score 59.6→83.3) over 16 weeks, outperforming intra-articular steroids. For adhesive capsulitis, posterior intra-articular hydro-dilatation provided the most durable pain relief and mobility gains, though suprascapular nerve block was preferred for severe pain. Lastly, a review on IgG4-related disease underscored diagnostic challenges and the need for steroid-sparing therapies, with emerging interest in B-cell-targeted treatments amid ongoing pathogenesis debates. ### References - Low Dose Naltrexone In The Management Of Chronic Pain Syndrome: A Meta-Analysis Of Randomized Controlled Clinical Trials. by Hegde NC, Mishra A, V D, Maiti R, Hota D, Srinivasan A. Current pain and headache reports. [PMID: 40540205](https://pubmed.ncbi.nlm.nih.gov/40540205/) - Bone health in juvenile idiopathic arthritis compared with controls based on a Norwegian observational study. by Lundestad A, Cetrelli L, Angenete OW, Augdal TA, Tylleskar K, Nordal EB, Rosendahl K, Hoftun GB, Hoff M, Romundstad PR, Rygg M. RMD open. [PMID: 40537274](https://pubmed.ncbi.nlm.nih.gov/40537274/) - Hip denervation: an approach for relieving pain, restoring function, and reducing inflammation in juvenile idiopathic arthritis patients. by A K, M EA, M H, H A, A M. Clinical rheumatology. [PMID: 40536645](https://pubmed.ncbi.nlm.nih.gov/40536645/) - Comparative efficacy of supra-scapular nerve block, posterior shoulder capsule hydro-dilatation, and shoulder interval hydro-dilatation in managing shoulder adhesive capsulitis. by Elsaman A, Abdelmageed S, Daifallah OS. Clinical rheumatology. [PMID: 40533690](https://pubmed.ncbi.nlm.nih.gov/40533690/) - IgG4-Related Disease: A Review of Persistent Challenges in the Pathogenesis, Diagnosis, and Approaches to Treatment. by Parums DV. Medical science monitor : international medical journal of experimental and clinical research. [PMID: 40528331](https://pubmed.ncbi.nlm.nih.gov/40528331/) ## Psoriatic Arthritis Recent research highlights advancements in both systemic and biologic therapies for psoriasis and psoriatic arthritis (PsA). A meta-analysis by Wang et al. (2024) demonstrated that calcipotriol-acitretin combination therapy significantly outperforms monotherapy in psoriasis, with higher efficacy (RR = 1.25–1.36), greater PASI score reductions (SMD = −2.26 to −3.79), and favorable modulation of inflammatory cytokines (e.g., reduced TNF-α, IL-17, IL-23). The combination also showed a safer profile, with lower perioral dermatitis risk than acitretin alone. Meanwhile, Godding et al. (2024) evaluated real-world cost-effectiveness of biologics, revealing adalimumab (with biosimilar discounts) as the most cost-efficient for achieving PASI75/90/100 or absolute PASI ≤3/≤1 responses. Among non-biosimilar biologics, brodalumab and guselkumab had the lowest cost per responder. The study underscores the impact of price transparency and the utility of absolute PASI thresholds in cost assessments. Together, these findings emphasize optimized therapeutic strategies: combination therapies for enhanced efficacy and safety in systemic treatment, and biosimilar-driven or IL-17/IL-23-targeted biologics for cost-effective biologic management. ### References - Investigating the efficacy of calcipotriol-acitretin combination therapy versus monotherapy protocols in psoriasis and its effect on serum inflammatory factors: a systematic review and meta-analysis. by Wang H, Deng T, Wang J, Bai X, Shen Y, Qiu Y. European journal of medical research. [PMID: 40542385](https://pubmed.ncbi.nlm.nih.gov/40542385/) - Real-world Cost per Responder Among Different Classes of Biologics for the Treatment of Psoriasis. by Godding LTH, Seyger MMB, Duvetorp A, Otero ME, Ossenkoppele PM, Oostveen AM, Visch MB, Van der Voort EAM, Korver JEM, Weppner-Parren LJMT, Berends MAM, Arnold WP, Dodemont SRP, Kuijpers ALA, Mommers JM, Homan FM, Gostynski AH, Velstra B, Kleinpenning MM, Van Doorn MBA, Keijsers RRMC, Kop EN, Haeck IM, Hendricksen-Roelofzen JHJ, Vellinga D, De Jong EMGJ, Van den Reek JMPA. Acta dermato-venereologica. [PMID: 40534202](https://pubmed.ncbi.nlm.nih.gov/40534202/) ## Rheumatoid Arthritis Recent studies highlight advances in RA treatment efficacy, safety, and cardiovascular risks. Ozoralizumab (OZR) 30 mg showed rapid and sustained efficacy in MTX-inadequate responders (MTX-IR), with 12.8% achieving low disease activity (LDA) by day 3 and 70.9% by week 52 in the OHZORA trial. Growth mixture modeling identified a subgroup (55%) maintaining LDA long-term, linked to low baseline CRP and CDAI (Miyazaki et al., RMD Open). Meanwhile, the SUNSTAR trial protocol compares tocilizumab and abatacept in TNFi-IR patients, with CDAI improvement at 24 weeks as the primary endpoint, aiming to clarify optimal second-line biologic choices (Pascart et al., BMJ Open). On safety, a nationwide study found sulfasalazine and hydroxychloroquine reduced stroke risk (aOR 0.79 and 0.83, respectively), while glucocorticoids and tocilizumab increased it (aOR 1.71 and 3.47), though tocilizumab’s association warrants cautious interpretation (Ahn et al., PLOS One). Additionally, JAK inhibitor withdrawal triggers a pro-inflammatory cascade via pJAK/pSTAT rebound, potentially explaining cardiovascular risks—a phenomenon less pronounced with Type II JAKinibs (Gurevic et al., PLOS One). Together, these findings underscore the importance of personalized treatment selection, balancing rapid efficacy, long-term control, and cardiovascular safety. ### References - Early effects of ozoralizumab 30 mg in patients with rheumatoid arthritis and inadequate response to methotrexate: a post hoc trajectory analysis of the phase II/III OHZORA trial. by Miyazaki Y, Horiuchi N, Okamoto S, Matsumoto R, Takeuchi T, Tanaka Y. RMD open. [PMID: 40537275](https://pubmed.ncbi.nlm.nih.gov/40537275/) - Abatacept versus tocilizumab for the treatment of rheumatoid arthritis in TNF inhibitor inadequate responders: study protocol of the SUNSTAR randomised controlled open-label superiority trial. by Pascart T, Fautrel B, Gottenberg JE, Ducoulombier V, Richez C, Truchetet ME, Avouac J, Morel J, Basch A, Cormier G, Houvenagel E, Mariette X, Norberciak L. BMJ open. [PMID: 40527572](https://pubmed.ncbi.nlm.nih.gov/40527572/) - Risk of ischemic stroke associated with anti-rheumatic agents in patients with rheumatoid arthritis: A nationwide population-based case-control study. by Ahn SM, Kim S, Kim YJ, Hong S, Lee CK, Yoo B, Oh JS, Kim YG. PloS one. [PMID: 40526615](https://pubmed.ncbi.nlm.nih.gov/40526615/) - JAK inhibitor withdrawal causes a transient pro-inflammatory cascade: A potential mechanism for major adverse cardiac events. by Gurevic I, Meudec L, Mariette X, Nocturne G, McCoy SS. PloS one. [PMID: 40522928](https://pubmed.ncbi.nlm.nih.gov/40522928/) ## Sjogren's Disease Recent research on Sjögren’s disease (SjD) highlights advances in outcome measures, therapeutic strategies, and long-term disease progression. The NECESSITY IHI Consortium review (Bowman et al., *Annals of the Rheumatic Diseases*) underscores unmet needs in primary SjD (pSjD), emphasizing the development of the *Sjögren’s Tool for Assessing Response (STAR)*, a novel composite endpoint now undergoing validation in clinical trials. The study also explores B-cell hyperactivity, lymphoma risk, and the economic impact of pSjD, with input from regulatory agencies and patient advocates to optimize trial design and link clinical improvement to quality-of-life metrics. Meanwhile, the 9-year *SjögrenSER Prospective* study (Fernández-Castro et al., *Rheumatology International*) reveals dynamic disease evolution, with arthralgias and hematologic involvement declining over time, while pulmonary and renal manifestations persist. Key ESSDAI domains (articular, pulmonary, hematologic) showed the most variability, correlating with higher systemic treatment use. These findings underscore the need for phenotype-stratified follow-up protocols to address heterogeneous disease trajectories. Together, these studies highlight progress in outcome measurement and the importance of personalized management in SjD. ### References - Primary Sjogren's Disease: a review of unmet need, outcome measures, therapeutic advances and health economic impacts. Lessons from the NEw Clinical Endpoints in primary Sjogren's Syndrome: an Interventional Trial based on stratifYing patients (NECESSITY) Innovative Health Initiative (IHI). by Bowman SJ, Seror R, Porcher R, Arends S, de Wolff L, Verstappen G, Devauchelle-Pensec V, Jousse-Joulin S, Baldini C, Bombardieri M, Pontarini E, Hueber W, Marvel J, Goswami P, Cornec D, Fisher BA, Nayar S, Barone F, Ng WF, Gottenberg JE, Bootsma H, Dorner T, Pincemin M, Bouillot C, Hammitt KM, Wahren-Herlenius M, van Roon J, Nocturne G, Laigle L, Moingeon P, Christodoulou A, Sreih AG, van Maurik A, Chen WH, Wisniacki N, Piatrova A, Jonsson R, Gergely P, Mariette X. Annals of the rheumatic diseases. [PMID: 40527714](https://pubmed.ncbi.nlm.nih.gov/40527714/) - Long-term changes in Sjogren's disease: a 9-year prospective follow-up study from the SJOGRENSER Registry. by Fernandez-Castro M, Plaza-Almuedo Z, Rosas J, Martinez-Taboada V, Olive A, Menor-Almagro R, Serrano-Benavente B, Font-Urgelles J, Garcia-Aparicio A, Manrique-Arija S, Garcia-Vadillo JA, Lopez-Gonzalez R, Narvaez J, Rodriguez-Lozano B, Galisteo C, Gonzalez-Martin J, Vela-Casasempere P, Bohorquez C, Erausquin C, Paredes-Romero B, Riancho-Zarrabeitia L, Melchor-Diaz S, Pego-Reigosa JM, Heredia S, Moriano C, Blazquez-Canamero MA, Estrada P, Judez E, Belzunegui JM, Ramos C, Sanchez-Alonso F, Andreu JL. Rheumatology international. [PMID: 40526294](https://pubmed.ncbi.nlm.nih.gov/40526294/) ## Systemic Lupus Erythematosus Recent research on Systemic Lupus Erythematosus (SLE) highlights novel insights into disease mechanisms, prognostic tools, and targeted therapies. The FaMaLE study investigates maternal-fetal tolerance failure in pregnant SLE patients, hypothesizing its role in complications like pre-eclampsia and preterm birth. By analyzing immune cell composition in blood and placenta longitudinally, this prospective cohort aims to link dysregulation with adverse outcomes (Dankers et al., *Lupus Sci Med*). Meanwhile, Zhang et al. (*Lupus Sci Med*) identify the Total Tubulointerstitial Score (TTS) as a robust predictor of mortality and renal dysfunction in lupus nephritis, with TTS >2 independently associated with worse outcomes, underscoring the clinical relevance of tubulointerstitial lesions beyond glomerular pathology. On the therapeutic front, Chen et al. (*Arthritis Res Ther*) demonstrate that telitacicept—a dual BLyS/APRIL inhibitor—reshapes B cell subsets in active SLE, reducing naïve/transitional B cells and boosting regulatory B cells, correlating with improved clinical responses. Complementing this, Wu et al. (*Cell Mol Biol Lett*) review precision strategies targeting immune dysregulation (e.g., CAR-T for B cells, CD40L inhibitors for T-B cell crosstalk), emphasizing the need for biomarker-guided approaches to overcome patient heterogeneity. Together, these studies advance understanding of SLE pathogenesis while paving the way for mechanistically tailored interventions. ### References - Failing maternal-fetal tolerance in SLE (FaMaLE): a prospective cohort study for finding the molecular mechanisms behind pregnancy complications. by Dankers W, van Ruitenbeek JF, Germe SA, Parra Sanchez AR, van Gaal MFHM, Hortensius M, Cramer K, Rohrich-Heldens DC, de Boer M, van Baarsen LGM, Bultink IEM. Lupus science & medicine. [PMID: 40541269](https://pubmed.ncbi.nlm.nih.gov/40541269/) - Total Tubulointerstitial Score: a simple and effective predictor of long-term mortality and adverse renal outcomes in lupus nephritis. by Zhang X, Zhang M, Shi X, Xiang W, Lu Y, Tan J, Yu J, Ye H, Zhong Z, Lanping J, Tang R, Xia X, Chen W. Lupus science & medicine. [PMID: 40541267](https://pubmed.ncbi.nlm.nih.gov/40541267/) - Prospective analysis of B cell subset dynamics following telitacicept treatment in systemic lupus erythematosus. by Chen X, Hu L, Zhu L, Tu J, Gui J, Fang M, Sun L. Arthritis research & therapy. [PMID: 40533865](https://pubmed.ncbi.nlm.nih.gov/40533865/) - Immune cell aberrations in Systemic Lupus Erythematosus: navigating the targeted therapies toward precision management. by Wu Y, Zhang W, Liao Y, Sun T, Liu Y, Liu Y. Cellular & molecular biology letters. [PMID: 40524185](https://pubmed.ncbi.nlm.nih.gov/40524185/)