Faculty Bibliography

Gaucher disease (GD) is caused by biallelic GBA1/Gba1 mutations that encode defective glucocerebrosidase (GCase). Progranulin (PGRN, encoded by GRN/Grn) is a modifier of GCase, but the interplay between PGRN and GCase, specifically GBA1/Gba1 mutations, contributing to GD severity is unclear. Mouse models were developed with various dosages of Gba1 D409V mutation against the PGRN deficiency (Grn-/-) [Grn-/-;Gba1D409V/WT (PG9Vwt), Grn-/-;Gba1D409V/D409V (PG9V), Grn-/-;Gba1D409V/Null (PG9VN)]. Disease progression in those mouse models was characterized by biochemical, pathological, transcriptomic, and neurobehavioral analyses. Compared to PG9Vwt, Grn-/-;Gba1WT/Null and Grn-/- mice that had a higher level of GCase activity and undetectable pathologies, homozygous or hemizygous D409V in PG9V or PG9VN, respectively, resulted in profound inflammation and neurodegeneration. PG9VN mice exhibited much earlier onset, shorter life span, tissue fibrosis, and more severe phenotypes than PG9V mice. Glycosphingolipid accumulation, inflammatory responses, lysosomal-autophagy dysfunction, microgliosis, retinal gliosis, as well as α-Synuclein increases were much more pronounced in PG9VN mice. Neurodegeneration in PG9VN was characterized by activated microglial phagocytosis of impaired neurons and programmed cell death due to necrosis and, possibly, pyroptosis. Brain transcriptomic analyses revealed the intrinsic relationship between D409V dosage, and the degree of altered gene expression related to lysosome dysfunction, microgliosis, and neurodegeneration in GD, suggesting the disease severity is dependent on a GCase activity threshold related to Gba1 D409V dosage and loss of PGRN. These findings contribute to a deeper understanding of GD pathogenesis by elucidating additional underlying mechanisms of interplay between PGRN and Gba1 mutation dosage in modulating GCase function and disease severity in GD and GBA1-associated neurodegenerative diseases.

Tumor-educated platelets (TEPs) are a potential method of liquid biopsy for the diagnosis and monitoring of cancer. However, the mechanism underlying tumor education of platelets is not known, and transcripts associated with TEPs are often not tumor-associated transcripts. We demonstrated that direct tumor transfer of transcripts to circulating platelets is an unlikely source of the TEP signal. We used CDSeq, a latent Dirichlet allocation algorithm, to deconvolute the TEP signal in blood samples from patients with glioblastoma. We demonstrated that a substantial proportion of transcripts in the platelet transcriptome are derived from nonplatelet cells, and the use of this algorithm allows the removal of contaminant transcripts. Furthermore, we used the results of this algorithm to demonstrate that TEPs represent a subset of more activated platelets, which also contain transcripts normally associated with nonplatelet inflammatory cells, suggesting that these inflammatory cells, possibly in the tumor microenvironment, transfer transcripts to platelets that are then found in circulation. Our analysis suggests a useful and efficient method of processing TEP transcriptomic data to enable the isolation of a unique TEP signal associated with specific tumors.

BACKGROUND:The purpose of this study was to define the optimal combination of surgical technique and postoperative rehabilitation protocol for elderly patients undergoing either hemiarthroplasty (HA) or reverse total shoulder arthroplasty (rTSA) for acute proximal humerus fracture (PHF) by performing a network meta-analysis of the comparative studies in the literature. METHODS:A systematic review of the literature using Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines of MEDLINE, EMBASE, and Cochrane Library was screened from 2007 to 2023. Inclusion criteria were level I-IV studies utilizing primary HA and/or rTSA published in a peer-reviewed journal, that specified whether humeral stems were cemented or noncemented, specified postoperative rehabilitation protocol, and reported results of HA and/or rTSA performed for PHF. Early range of motion (ROM) was defined as the initiation of active ROM at ≤3 weeks after surgery. Level of evidence was evaluated based on the criteria by the Oxford Centre for Evidence-Based Medicine. Clinical outcomes were compared using a frequentist approach to network meta-analysis with a random-effects model that was performed using the netmeta package version 0.9-6 in R. RESULTS:A total of 28 studies (1119 patients) were included with an average age of 74 ± 3.7 and mean follow-up of 32 ± 11.1 months. In the early ROM cohort (Early), the mean time to active ROM was 2.4 ± 0.76 weeks compared to 5.9 ± 1.04 weeks in the delayed ROM cohort (Delayed). Overall, rTSA-Pressfit-Early resulted in statistically superior outcomes including postoperative forward elevation (126 ± 27.5), abduction (116 ± 30.6), internal rotation (5.27 ± 0.74, corresponding to L3-L1), American Shoulder and Elbow Surgeons score (71.8 ± 17), tuberosity union (89%), and lowest tuberosity nonunion rate (9.6%) in patients ≥65 year old with acute PHF undergoing shoulder arthroplasty (all P ≤ .05). In total there were 277 (14.5%) complications across the cohorts, of which 89/277 (34%) were in the HA-Cement-Delayed cohort. HA-Cement-Delayed resulted in 2-times higher odds of experiencing a complication when compared to rTSA-Cement-Delayed (P = .005). Conversely, rTSA-Cement-Early cohort followed by rTSA-Pressfit-Early resulted in a total complication rate of 4.7% and 5.4% (odds ratios, 0.30; P = .01 & odds ratios, 0.42; P = .05), respectively. The total rate of scapular notching was higher in the cemented rTSA subgroups (16.5%) vs. (8.91%) in the press fit rTSA subgroups (P = .02). CONCLUSION/CONCLUSIONS:Our study demonstrates that patients ≥65 years of age, who sustain a 3-or 4-part PHF achieve the most benefit in terms of ROM, postoperative functional outcomes, tuberosity union, and overall complication rate when undergoing rTSA with a noncemented stem and early postoperative ROM when compared to the mainstream preference-rTSA-Cement-Delayed.

We sought to determine what effect the size of a displaced coronoid fracture fragment in Monteggia injuries has on clinical outcome. Sixty-seven patients presented to an academic medical center for operative fixation of a Monteggia fracture. Radiographs were assessed for length and height of the displaced coronoid fragment using measuring tools in our center's imaging archive system. Data were analyzed using binary logistic or linear regression, as appropriate, controlling for sex, age, and Charlson Comorbidity Index. Outcome measurements included radiographic healing, range of motion, postoperative complications, and reoperation. The cohort had a mean follow-up of 16.7 months. Mean coronoid fragment area was 362.4±155.9 mm². Elbow range of motion decreased by 3.8° of elbow flexion (P<.001), 3.3° of elbow extension (P<.001), and 3.8° of forearm supination (P=.007) for every 1-cm² increase in coronoid fragment area. Complications (P=.012) and reoperation (P=.036) were associated with increasing coronoid fragment area. Nonunion rate, nerve injury, and pronation range of motion were not correlated to increasing coronoid fracture fragment area (P=.777, P=.123, and P=.351, respectively). As displaced coronoid fragment size increases in Monteggia fracture patterns, elbow range of motion decreases linearly. Coronoid displacement was also associated with increased rates of postoperative complication and need for reoperation. [Orthopedics. 2024;47(1):15-21.].

Relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains one of the leading causes of cancer mortality in children. We performed Hi-C, ATAC-seq, and RNA-seq on 12 matched diagnosis/relapse pediatric leukemia specimens to uncover dynamic structural variants (SVs) and 3D chromatin rewiring that may contribute to relapse. While translocations are assumed to occur early in leukemogenesis and be maintained throughout progression, we discovered novel, dynamic translocations and confirmed several fusion transcripts, suggesting functional and therapeutic relevance. Genome-wide chromatin remodeling was observed at all organizational levels: A/B compartments, TAD interactivity, and chromatin loops, including some loci shared by 25% of patients. Shared changes were found to drive the expression of genes/pathways previously implicated in resistance as well as novel therapeutic candidates, two of which (ATXN1 and MN1) we functionally validated. Overall, these results demonstrate chromatin reorganization under the selective pressure of therapy and offer the potential for discovery of novel therapeutic interventions.

Alopecia is traditionally classified into scarring and nonscarring subtypes, with etiopathologies ranging from androgen-mediated to immuno-inflammatory. Over 50% of men and almost 50% of women will experience some form of hair loss in their lifetime. Given this prevalence and the psychosocial significance of hair, understanding the pathophysiology and comorbidities of different types of hair loss is imperative. Other proinflammatory dermatologic disorders, such as psoriasis, are recognised to have systemic manifestations including an increased risk of cardiovascular (CV) disease, and are now considered CV risk-enhancing conditions. With increased recognition of the importance of systemic inflammation in promoting atherosclerosis, high prevalence, and improved treatment strategies, there is increased interest in establishing whether a similar association between alopecia and cardiovascular disease (CVD) exists. In this manuscript, we aim to review the current literature regarding CV risk in androgenic alopecia (AGA) and alopecia areata (AA). Additionally, we review the literature for cicatricial alopecias and highlight the need for more research into their potential associations with CV risk. Evidence from the identified AGA publications suggests an association of AGA with CV risk factors including hypertension, dyslipidemia, and insulin resistance, as well as with coronary artery disease. For AA, most of the identified studies found an association between AA and CV risk, though the relationships were not always statistically significant. Research on cicatricial alopecias and CV risk is limited and often contradictory. There is great need for more studies regarding the association between various types of alopecia and the development of CVD, and potential mechanisms. Particularly needed are more studies of cicatricial alopecias and potential associated CV risk. While some literature suggests that patients with alopecia have an increased risk of CVD, the lack of concrete evidence represents a notable gap in our current understanding.

Advancements in precision oncology over the past decades have led to new therapeutic interventions, but the efficacy of such treatments is generally limited by an adaptive process that fosters drug resistance¹. In addition to genetic mutations², recent research has identified a role for non-genetic plasticity in transient drug tolerance³ and the acquisition of stable resistance^4,5. However, the dynamics of cell-state transitions that occur in the adaptation to cancer therapies remain unknown and require a systems-level longitudinal framework. Here we demonstrate that resistance develops through trajectories of cell-state transitions accompanied by a progressive increase in cell fitness, which we denote as the 'resistance continuum'. This cellular adaptation involves a stepwise assembly of gene expression programmes and epigenetically reinforced cell states underpinned by phenotypic plasticity, adaptation to stress and metabolic reprogramming. Our results support the notion that epithelial-to-mesenchymal transition or stemness programmes-often considered a proxy for phenotypic plasticity-enable adaptation, rather than a full resistance mechanism. Through systematic genetic perturbations, we identify the acquisition of metabolic dependencies, exposing vulnerabilities that can potentially be exploited therapeutically. The concept of the resistance continuum highlights the dynamic nature of cellular adaptation and calls for complementary therapies directed at the mechanisms underlying adaptive cell-state transitions.

BACKGROUND:Vice chairs (VCs) of research play an integral role in orthopaedic departments at academic medical centers; they strategically lead research efforts and support the research careers of faculty and trainees. To our knowledge, no analysis of orthopaedic VCs of research exists in the literature, and no similar analyses have been completed in other medical specialties. We aimed to investigate the academic and demographic characteristics of orthopaedic VCs of research. METHODS:Doximity was used to identify orthopaedic residencies in the U.S. Personal and program websites were queried to identify VCs of research and collect academic and demographic characteristics. The Scopus database, the National Institutes of Health (NIH) RePORTER, and Google Scholar were used to obtain each investigator's Hirsch index (h-index) and the number and type of NIH grants awarded, respectively. RESULTS:Of the 207 orthopaedic residency programs identified, 71 (34%) had a named VC of research in the orthopaedic department. Of the top 50 medical schools, 42 were affiliated with such programs. Most VCs were men (89%). The racial and/or ethnic background of the majority of VCs was White (85%), followed by Asian (14%), and Black (1%). Most held the rank of professor (78%), followed by associate professor (18%), and assistant professor (4%). Over half were PhDs (55%), followed by MDs (37%) and MD/PhDs (8%). On average, the VCs had an h-index of 40.5. Furthermore, 65% had been awarded at least 1 NIH grant for their research, with 43% awarded at least 1 R01 grant. CONCLUSIONS:VCs of research develop research opportunities and shape the brand recognition of academic orthopaedic programs. Most orthopaedic VCs of research are men (89%); 85% each are White and have a rank of professor. Nearly half have been awarded at least 1 R01 grant from the NIH. CLINICAL RELEVANCE/CONCLUSIONS:This study outlines important academic and demographic characteristics among orthopaedic surgery VCs of research. Considering the mentorship aspect of their role, VCs of research have an opportunity to influence the diversity of incoming trainees in the field of academic orthopaedics.

Widespread pain (WP) is associated with reduced function and disability. Importantly, three-fourths of the approximately 42% of U.S. adults with obesity have WP. Moreover, rates of adult obesity are higher, and WP outcomes are worse in racialized non-Hispanic Black and Hispanic/Latino/a/X groups, potentially exacerbating existing pain disparities. Bariatric surgery significantly reduces weight and improves pain. However, recurrent or unresolved pain after bariatric surgery can hinder weight loss or facilitate weight regain. The current study conducted a secondary analysis of a longitudinal study of predictors and mechanisms of weight loss after bariatric surgery to examine the point prevalence of WP and pain trajectories 24 months post surgery. Our secondary aim was to examine the association between weight loss and pain characteristics. Our exploratory aim was to longitudinally examine racial differences in pain trajectories after bariatric surgery. Our results showed that point prevalence decreased after bariatric surgery. Additionally, significant improvements in pain trajectories occurred within the first 3 months post surgery with a pattern of pain reemergence beginning at 12 months post surgery. Hispanic/Latino/a/X participants reported a higher number of painful anatomical sites before bariatric surgery, and the rate of change in this domain for this group was faster compared with the racialized non-Hispanic Black participants. These findings suggest that pain improvements are most evident during the early stages of surgical weight loss in racialized populations of adults with WP. Thus, clinicians should routinely monitor patients' weight changes after bariatric surgery as they are likely to correspond to changes in their pain experiences. PERSPECTIVE: This article presents the prevalence and pain trajectories of racialized adults with WP after surgical weight loss. Clinicians should evaluate changes in the magnitude and spatial distribution of pain after significant weight change in these populations so that pain interventions can be prescribed with greater precision.

BACKGROUND/UNASSIGNED:The long isoform of the Wnk1 (with-no-lysine [K] kinase 1) is a ubiquitous serine/threonine kinase, but its role in vascular smooth muscle cells (VSMCs) pathophysiology remains unknown. METHODS/UNASSIGNED: RESULTS/UNASSIGNED: CONCLUSION/UNASSIGNED:deletion promotes VSMC phenotype switch toward a pathogenic proinflammatory phenotype, orchestrating deleterious vascular remodeling and spontaneous severe aortitis in mice.