MSTPublications: March 2025

Posted by Madeline Johnson on Friday, March 28, 2025 in New Publications .

Evaluation of Pickleball-Related Injuries at a Single Institution From 2017 to 2022.
Herzberg SD, Bowman EN, Hill KL.
Orthop J Sports Med. 2025 Feb 6;13(2):23259671251316997. doi: 10.1177/23259671251316997. eCollection 2025 Feb.
PMID: 39958695 Free PMC article.

Abstract
Background: Pickleball is currently the fastest-growing sport in the United States, and participation has increased 3-fold throughout the study period.
Purpose/hypothesis: This study aimed to evaluate the epidemiology of pickleball-related injuries, detailing the descriptive data, injury patterns, and health care utilization at a single center over 6 years. It was hypothesized that there would be a substantial increase in pickleball-related injuries during the study period, particularly with increasing age, along with increased orthopaedic visits for pickleball-related injuries.
Study design: Case series; Level of evidence, 4.
Methods: We systematically queried the Electronic Health Record System at a single institution from January 1, 2017, to December 31, 2022, to identify patients with injuries associated with pickleball participation. Data were collected on descriptive data, injury characteristics, and health care utilization.
Results: Pickleball injuries were confirmed in 487 patients, accounting for a total of 618 injuries. Patient age ranged from 12 to 82 years (mean, 62 years), and 53% of injuries occurred in male patients. The number of injuries increased 6.8-fold from 2017 to 2022. Overall, soft tissue strain or rupture (n = 296; 47.9%) was the most common injury category, followed by arthritis-related pain (n = 62; 10%) and fracture (n = 57; 9.2%). However, age-stratified analysis revealed a shift toward fractures and arthritis-related pain in patients >60 years. Women were 2 times more likely to sustain fractures. Injuries to the rotator cuff were most commonly seen (n = 67, 11%), followed by those to the back (n = 48; 7.8%) and calf (n = 35; 5.6%). Most patients (n = 426; 87%) were initially evaluated by a nonorthopaedic provider, with orthopaedic/sports medicine providers seeing 63% of patients.
Conclusion: Our institution observed a 6.8-fold increase in pickleball-related injuries from 2017 to 2022, which far outpaces the reported increase in pickleball participation nationally. Women >60 years were found to be at the highest risk of injury and were more likely to sustain fractures. Most injuries were musculoskeletal related, with soft tissue injury occurring most commonly in patients <60 years and fractures more commonly seen in patients >60 years.
Keywords: fracture; injury; muscle strain; pickleball; sports medicine.

Standardizing phenotypic algorithms for the classification of degenerative rotator cuff tear from electronic health record systems.
Herzberg SD, Garduno-Rapp NE, Ong HH, Gangireddy S, Chandrashekar AS, Wei WQ, LeClere LE, Wen W, Hartmann KE, Jain NB, Giri A.
JAMIA Open. 2025 Mar 18;8(2):ooaf014. doi: 10.1093/jamiaopen/ooaf014. eCollection 2025 Apr.
PMID: 40103752 Free PMC article.

Abstract
Objectives: Degenerative rotator cuff tears (DCTs) are the leading cause of shoulder pain, affecting 30%-50% of individuals over 50. Current phenotyping strategies for DCT use heterogeneous combinations of procedural and diagnostic codes and are concerning for misclassification. The objective of this study was to create standardized phenotypic algorithms to classify DCT status across electronic health record (EHR) systems.
Materials and methods: Using a de-identified EHR system, containing chart level data for ∼3.5 million individuals from January 1998 to December 2023, we developed and validated 2 types of algorithms-one requiring and one without imaging verification-to identify DCT cases and controls. The algorithms used combinations of International Classification of Diseases (ICD) / Current Procedural Terminology (CPT) codes and natural language processing (NLP) to increase diagnostic certainty. These hand-crafted algorithms underwent iterative refinement with manual chart review by trained personnel blinded to case-control determinations to compute positive predictive value (PPV) and negative predictive value (NPV).
Results: The algorithm development process resulted in 5 algorithms to identify patients with or without DCT with an overall predictive value of 94.5%: (1) code only cases that required imaging confirmation (PPV = 89%), (2) code only cases that did not require imaging verification (PPV = 92%), (3) NLP-based cases that did not require imaging verification (PPV = 89%), (4) code-based controls that required imaging confirmation (NPV = 90%), and (5) code and NLP-based controls that did not require imaging verification (NPV = 100%). External validation demonstrated 94% sensitivity and 75% specificity for the code-only algorithms.
Discussion: This work highlights the inaccuracy of previous approaches to phenotypic assessment of DCT reliant solely on ICD and CPT codes and demonstrate that integrating temporal and frequency requirements, as well as NLP, substantially increases predictive value. However, while the inclusion of imaging verification enhances diagnostic confidence, it also reduces sample size without necessarily improving predictive value, underscoring the need for a balance between precision and scalability in phenotypic definitions for large-scale genetic and clinical research.
Conclusions: These algorithms represent an improvement over prior DCT phenotyping strategies and can be useful in large-scale EHR studies.
Keywords: algorithms; electronic health records; rotator cuff; shoulder; sports injury.

Genome-wide meta-analysis identifies novel risk loci for uterine fibroids within and across multiple ancestry groups.
Kim J, Williams A, Noh H, Jasper EA, Jones SH, Jaworski JA, Shuey MM, Ruiz-Narváez EA, Wise LA, Palmer JR, Connolly J, Keaton JM, Denny JC, Khan A, Abbass MA, Rasmussen-Torvik LJ, Kottyan LC, Madhivanan P, Krupp K, Wei WQ, Edwards TL, Velez Edwards DR, Hellwege JN.
Nat Commun. 2025 Mar 6;16(1):2273. doi: 10.1038/s41467-025-57483-5.
PMID: 40050615 Free PMC article.

Abstract
Uterine leiomyomata or fibroids are highly heritable, common, and benign tumors of the uterus with poorly understood etiology. Previous GWAS have reported 72 associated genes but included limited numbers of non-European individuals. Here, we identify 11 novel genes associated with fibroids across multi-ancestry and ancestry-stratified GWAS analyses. We replicate a known fibroid GWAS gene in African ancestry individuals and estimate the SNP-based heritability of fibroids in African ancestry populations as 15.9%. Using genetically predicted gene expression and colocalization analyses, we identify 46 novel genes associated with fibroids. These genes are significantly enriched in cancer, cell death and survival, reproductive system disease, and cellular growth and proliferation networks. We also find that increased predicted expression of HEATR3 in uterine tissue is associated with fibroids across ancestry strata. Overall, we report genetic variants associated with fibroids coupled with functional and gene pathway enrichment analyses.

Immunoresponsive gene 1 facilitates TLR4 agonist-induced augmentation of innate antimicrobial immunity.
McBride MA, Caja KR, Patil TK, Owen AM, Luan L, Bohannon JK, Hernandez A, Stothers CL, Trenary IA, Rahim M, Young JD, Calcutt MW, Stephens VR, Davis X, Oliver MA, Hao D, Si C, McRae M, Nguyen KK, Davis NS, Wang J, Patil NK, Sherwood ER.
J Leukoc Biol. 2025 Feb 13;117(2):qiae198. doi: 10.1093/jleuko/qiae198.
PMID: 39351765 Free PMC article.

Abstract
Treatment with the toll-like receptor 4 agonist monophosphoryl lipid A conditions innate immunocytes to respond robustly to subsequent infection, a phenotype termed innate immune memory. Our published studies show that metabolic reprogramming of macrophages is a prominent feature of the memory phenotype. We undertook studies to define the functional contributions of tricarboxylic acid cycle reprogramming to innate immune memory. We observed that priming of wild-type mice with monophosphoryl lipid A potently facilitated accumulation of the tricarboxylic acid cycle metabolite itaconate at sites of infection and enhanced microbial clearance. Augmentation of itaconate accumulation and microbial clearance was ablated in Irg1-deficient mice. We further observed that monophosphoryl lipid A potently induces expression of Irg1 and accumulation of itaconate in macrophages. Compared to wild-type macrophages, the ability of Irg1-deficient macrophages to kill Pseudomonas aeruginosa was impaired. We further observed that itaconate is directly antimicrobial against P. aeruginosa at pH 5, which is characteristic of the phagolysosome, and is facilitated by reactive oxygen species. Monophosphoryl lipid A-induced augmentation of glycolysis, oxidative phosphorylation, and accumulation of the tricarboxylic acid cycle metabolites succinate and malate was decreased in Irg1 knockout macrophages compared to wild-type controls. RNA sequencing revealed suppressed transcription of genes associated with phagolysosome function and increased expression of genes associated with cytokine production and chemotaxis in Irg1-deficient macrophages. This study identifies a contribution of itaconate to monophosphoryl lipid A-induced augmentation of innate antimicrobial immunity via facilitation of microbial killing as well as impact on metabolic and transcriptional adaptations.
Keywords: immune-responsive gene 1; innate immune memory; itaconate; macrophages; monophosphoryl lipid A.

A polygenic score for height identifies an unmeasured genetic predisposition among pediatric patients with idiopathic short stature.
Shelley JP, Shi M, Peterson JF, Van Driest SL, Simmons JH, Mosley JD.
Genome Med. 2025 Mar 19;17(1):23. doi: 10.1186/s13073-025-01455-3.
PMID: 40108664 Free PMC article.

Abstract
Background: A subset of children with short stature do not have an identified clinical explanation after extensive diagnostic evaluation. We hypothesized that a polygenic score for height (PGSheight) could identify children with non-familial idiopathic short stature (ISS-NF) who carry a polygenic predisposition to shorter height that is not accounted for by existing measures.
Methods: We studied 534 pediatric participants in an electronic health record (EHR)-linked DNA biobank (BioVU) who had been evaluated for short stature by an endocrinologist. Participants were classified as having one of five short stature subtypes: primary growth disorders, secondary growth disorders, idiopathic short stature (ISS), which was sub-classified into familial (ISS-F) and non-familial (ISS-NF), and constitutional delay of puberty (ISS-DP). Differences in polygenic predisposition between subtypes were analyzed using a validated PGSheight which was standardized to a standard deviation score (SDS). Adult height predictions were generated using the PGSheight and mid-parental height (MPH). Within-child differences in height predictions were compared across subtypes. Logistic regression models and AUC analyses were used to test the ability of the PGSheight to differentiate ISS-NF from growth disorders. The incremental improvement (ΔAUC) of adding the PGSheight to prediction models with MPH was also estimated.
Results: Among the 534 participants, 29.0% had secondary growth disorders, 24.9% had ISS-F, 20.2% had ISS-NF, 17.2% had ISS-DP, and 8.6% had primary growth disorders. Participants with ISS-NF had similar PGSheight values to those with ISS-F (difference [Δ] in PGSheight SDS [95% CI] = 0.19 [- 0.31 to 0.70], p = 0.75). Predicted heights generated by the PGSheight were lower than the MPH estimate for children with ISS-NF (Δ[PGSheight – MPH] = – 0.37 SDS; p = 3.2 × 10-9) but not for children with ISS-F (Δ = – 0.07; p = 0.56). Children with ISS-NF also had lower PGSheight than children with primary growth disorders (ΔPGSheight = – 0.53 [- 1.03 to – 0.04], p = 0.03) and secondary growth disorders (Δ = – 0.45 [- 0.80 to – 0.10], p = 0.005). The PGSheight improved model discrimination between ISS-NF and children with primary (ΔAUC, + 0.07 [95% CI, 0.02 to 0.17]) and secondary growth disorders (ΔAUC, + 0.03 [95% CI, 0.01 to 0.10]).
Conclusions: Some children with ISS-NF have an unrecognized polygenic predisposition to shorter height, similar to children with ISS-F and greater than those with growth disorders. A PGSheight could aid clinicians in identifying children with a benign, polygenic predisposition to shorter height.
Keywords: Common genetic variation; Height; Idiopathic short stature; Polygenic scores; Short stature.

Genomics-Informed Drug Repurposing Strategy Identifies Novel Therapeutic Targets for Metabolic Dysfunction-Associated Steatotic Liver Disease.
Seagle HM, Akerele AT, DeCorte JA, Hellwege JN, Breeyear JH, Kim J, Levin M, Khodurksy S, Bress A, Lee K, Meiler J, Gill D, Lee JS, Heberer K, Miller DR, Reaven P, Chang KM, Lynch JA, Khankari NK, Shuey MM, Edwards TL, Vujkovic M.
medRxiv [Preprint]. 2025 Feb 21:2025.02.18.25321035. doi: 10.1101/2025.02.18.25321035.
PMID: 40034783 Free PMC article. Preprint.

Reward circuit local field potential modulations precede risk taking.
Hughes NC, Qian H, Doss DJ, Makhoul GS, Zargari M, Zhao Z, Singh B, Wang Z, Fulton JN, Johnson GW, Li R, Dawant BM, Englot DJ, Constantinidis C, Roberson SW, Bick SK.
Brain. 2025 Mar 18:awaf107. doi: 10.1093/brain/awaf107. Online ahead of print.
PMID: 40101145

Exploring beyond diagnoses in electronic health records to improve discovery: a review of the phenome-wide association study.
Wan NC, Grabowska ME, Kerchberger VE, Wei WQ.
JAMIA Open. 2025 Feb 28;8(1):ooaf006. doi: 10.1093/jamiaopen/ooaf006. eCollection 2025 Feb.
PMID: 40041255 Free PMC article. Review

Improving topic modeling performance on social media through semantic relationships within biomedical terminology.
Xin Y, Grabowska ME, Gangireddy S, Krantz MS, Kerchberger VE, Dickson AL, Feng Q, Yin Z, Wei WQ.
PLoS One. 2025 Feb 21;20(2):e0318702. doi: 10.1371/journal.pone.0318702. eCollection 2025.
PMID: 39982945 Free PMC article.

Tenascin-C Potentiates Wnt Signaling in Thyroid Cancer.
Hartmann HA, Loberg MA, Xu GJ, Schwarzkopf AC, Chen SC, Phifer CJ, Caroland K, Chen HC, Diaz D, Tigue ML, Hesterberg AB, Gallant JN, Shaddy SM, Sheng Q, Netterville JL, Rohde SL, Solórzano CC, Bischoff LA, Baregamian N, Hurley PJ, Murphy BA, Choe JH, Huang EC, Ye F, Lee E, Weiss VL.
Endocrinology. 2025 Feb 5;166(3):bqaf030. doi: 10.1210/endocr/bqaf030.
PMID: 39951495 Free PMC article.

Genetic drivers and clinical consequences of mosaic chromosomal alterations in 1 million individuals.
Zhao K, Pershad Y, Poisner HM, Ma X, Quade K, Vlasschaert C, Mack T, Khankari NK, von Beck K, Brogan J, Kishtagari A, Corty RW, Li Y, Xu Y, Reiner AP, Scheet P, Auer PL, Bick AG.
medRxiv [Preprint]. 2025 Mar 6:2025.03.05.25323443. doi: 10.1101/2025.03.05.25323443.
PMID: 40093208 Free PMC article. Preprint.

Methylation sequencing enhances interpretation of clonal hematopoiesis dynamics.
Parker AC, Van Amburg JC, Heimlich JB, Pershad Y, Mickels NA, Mack TM, Ferrell PB, Savona MR, Jones AL, Bick AG.
Blood. 2025 Feb 27;145(9):988-992. doi: 10.1182/blood.2024026555.
PMID: 39565983

Interleukin-10 production by innate lymphoid cells restricts intestinal inflammation in mice.
Li J, Jacobse J, Pilat JM, Kaur H, Gu W, Kang SW, Rusznak M, Huang HI, Barrera J, Oloo PA, Roland JT, Hawkins CV, Pahnke AP, Khalil M, Washington MK, Wilson KT, Williams CS, Peebles RS Jr, Konnikova L, Choksi YA, Hammer GE, Lau KS, Goettel JA.
Mucosal Immunol. 2025 Feb 21:S1933-0219(25)00023-6. doi: 10.1016/j.mucimm.2025.02.005. Online ahead of print.
PMID: 39988202 Free article.

Embracing Neurodiversity in Medicine-Building a More Inclusive Physician Workforce.
Hamilton RH, Williams ZJ, Brodkin ES.
JAMA. 2025 Feb 19. doi: 10.1001/jama.2025.0094. Online ahead of print.
PMID: 39969896

Characterization of neurite and soma organization in the brain and spinal cord with diffusion MRI.
Schilling KG, Palombo M, Witt AA, O’Grady KP, Pizzolato M, Landman BA, Smith SA.
bioRxiv [Preprint]. 2025 Feb 20:2025.02.19.638936. doi: 10.1101/2025.02.19.638936.
PMID: 40027805 Free PMC article. Preprint.