Citations

Hurler–Scheie syndrome (MPS IH/S), also known as mucopolysaccharidosis type I-H/S (MPS IH/S), is a lysosomal storage disorder caused by deficiency of the enzyme alpha-L-iduronidase (IDUA) leading to the accumulation of glycosaminoglycans (GAGs) in various tissues, resulting in a wide range of symptoms affecting different organ systems. Postgenomic omics technologies offer the promise to understand the changes in proteome, phosphoproteome, and phosphorylation-based signaling in MPS IH/S. Accordingly, we report here a large dataset and the proteomic and phosphoproteomic analyses of fibroblasts derived from patients with MPS IH/S ( n = 8) and healthy individuals ( n = 8). We found that protein levels of key lysosomal enzymes such as cathepsin D, prosaposin, arylsulfatases (arylsulfatase A and arylsulfatase B), and IDUA were downregulated. We identified 16,693 unique phosphopeptides, corresponding to 4,605 proteins, in patients with MPS IH/S. We found that proteins related to the cell cycle, mitotic spindle assembly, apoptosis, and cytoskeletal organization were differentially phosphorylated in MPS IH/S. We identified 12 kinases that were differentially phosphorylated, including hyperphosphorylation of cyclin-dependent kinases 1 and 2, hypophosphorylation of myosin light chain kinase, and calcium/calmodulin-dependent protein kinases. Taken together, the findings of the present study indicate significant alterations in proteins involved in cytoskeletal changes, cellular dysfunction, and apoptosis. These new observations significantly contribute to the current understanding of the pathophysiology of MPS IH/S specifically, and the molecular mechanisms involved in the storage of GAGs in MPS more generally. Further translational clinical omics studies are called for to pave the way for diagnostics and therapeutics innovation for patients with MPS IH/S.

Background Genetics may influence symptoms experienced by breast cancer survivors (BCS) by moderating the effects of stress-reducing interventions, including the Mindfulness-Based Stress Reduction (MBSR(BC)) program, to reduce symptom severity. As part of a larger clinical trial, the aim of this study was to evaluate genetic variants as moderators of MBSR(BC) on improvements among BCS in cognitive functioning and symptoms. Methods BCS ( n = 128) were randomized to MBSR(BC) or the Breast Cancer Education Support Program. Objective neuropsychological and subjective measures of cognitive performance, and psychological and physical symptoms were collected at baseline, 6, 12, and 26 weeks. Linear mixed models were implemented to identify MBSR(BC)’s effects over time. A total of 22 single nucleotide polymorphisms (SNPs) from 20 genes known to be related to these symptoms were investigated using genomic DNA. These SNPs were tested as moderators of MBSR(BC) program effects. Results Results showed MBSR(BC) participants experienced significantly greater benefits in cognitive functioning, however, the level of benefit varied based on one’s genetic profile. Effects sizes, consistency across similar measures were investigated. Among 22 candidate SNPs, rs4680 in COMT, rs1800497 in ANKK1, and rs6277 in DRD2 demonstrated the strongest, most consistent positive effects in moderating MBSR(BC)’s impact on cognitive outcomes. Conclusions Although the effects were small, this translational research may potentially identify BCS with genotypes that would be most influenced by the MBSR(BC) program. These results may be used to develop personalized intervention programs tailored to the genetic profile of each breast cancer survivor who received chemotherapy or chemotherapy and radiation. Trial Registration ClinicalTrials.gov, https://www.ClinicalTrials.gov Registration Number: NCT02786797.

Abstract SRD5A3-CDG is a congenital disorder of glycosylation (CDG) resulting from pathogenic variants in SRD5A3 and follows an autosomal recessive inheritance pattern. The enzyme encoded by SRD5A3, polyprenal reductase, plays a crucial role in synthesizing lipid precursors essential for N-linked glycosylation. Despite insights from functional studies into its enzymatic function, there remains a gap in understanding global changes in patient cells. We sought to identify N-glycoproteomic and proteomic signatures specific to SRD5A3-CDG, potentially aiding in biomarker discovery and advancing our understanding of disease mechanisms. Using tandem mass tag (TMT)-based relative quantitation, we analyzed fibroblasts derived from five patients along with control fibroblasts. N-glycoproteomics analysis by liquid chromatography–tandem mass spectrometry (LC–MS/MS) identified 3,047 glycopeptides with 544 unique N-glycosylation sites from 276 glycoproteins. Of these, 418 glycopeptides showed statistically significant changes with 379 glycopeptides decreased (P < 0.05) in SRD5A3-CDG patient-derived samples. These included high mannose, complex and hybrid glycan-bearing glycopeptides. High mannose glycopeptides from protocadherin Fat 4 and integrin alpha-11 and complex glycopeptides from CD55 were among the most significantly decreased glycopeptides. Proteomics analysis led to the identification of 5,933 proteins, of which 873 proteins showed statistically significant changes. Decreased proteins included cell surface glycoproteins, various mitochondrial protein populations and proteins involved in the N-glycosylation pathway. Lysosomal proteins such as N-acetylglucosamine-6-sulfatase and procathepsin-L also showed reduced levels of phosphorylated mannose-containing glycopeptides. Our findings point to disruptions in glycosylation pathways as well as energy metabolism and lysosomal functions in SRD5A3-CDG, providing clues to improved understanding and management of patients with this disorder.

Abstract Objective The presence of comorbidities can substantially affect patients’ quality of life, but data regarding their impact on idiopathic inflammatory myopathies (IIMs) are limited. Methods We examined the prevalence of comorbidities in IIM patients, other autoimmune rheumatic diseases (oAIRDs) and healthy controls (HCs), using data from the self-reported COVAD-2 survey. We defined basic multimorbidity (BM) as the presence of ≥2 non-rheumatic chronic conditions and complex multimorbidity (CM) as the presence of ≥3 non-rheumatic chronic conditions affecting ≥3 organ systems. Hierarchical clustering on principal components was performed for grouping. Results Among the COVAD respondents, 1558 IIMs, 4591 oAIRDs and 3652 HCs were analysed. IIMs exhibited a high burden of comorbidities (odds ratio [OR]: 1.62 vs oAIRDs and 2.95 vs HCs, P < 0.01), BM (OR: 1.66 vs oAIRDs and 3.52 vs HCs, P < 0.01), CM (OR: 1.69 vs AIRDs and 6.23 vs HCs, P < 0.01) and mental health disorders (MHDs) (OR: 1.33 vs oAIRDs and 2.63 vs HCs, P < 0.01). Among the IIM patients, those with comorbidities or MHDs had lower PROMIS Global Physical (PGP), PROMIS Global Mental (PGM), and PROMIS Physical Function (SF10) scores, and higher fatigue (F4a) scores (all P < 0.001). PGP, PGM, SF10a and F4a were influenced by age, active disease, BM and MHDs. Four distinct clusters were identified among the IIMs according to comorbidities and PROMIS scores. Conclusion Patients with IIMs have a higher burden of comorbidities that influence physical and mental health, identifiable as clinical clusters for optimized and holistic management approaches.

Introduction: International medical graduates (IMGs) continue to play an important role in the US health care system, but little is known about their trends of matching into highly competitive residencies such as orthopedic surgery. The purpose of this study was to analyze temporal trends of IMG applicants matching into US orthopedic residency programs between 2008 and 2024 and compare them with US allopathic (MD) and osteopathic (DO) graduates. Methods: Orthopedic residency specific data for years 2008 to 2024 was obtained from the National Resident Match Program and Electronic Residency Application Service. Variables collected included total number of programs, total positions offered, number of applicants (MD, DO, and IMG), positions filled, and fill rate for each group. Trends were examined using simple linear regression modeling. Results: The number of orthopedic residency programs increased from 160 (2008) to 218 (2024), with total positions increasing from 636 (2008) to 916 (2024). The IMG fill rate decreased from 2.99% in 2008 to 0.87% in 2024 ( p < 0.01 for linear trend; β −0.069). This corresponds to an absolute number decrease of 19 IMGs in 2008 to 8 in 2024. More specifically, the proportion of US IMGs decreased from 0.94% to 0.66%, and the proportion of non-US IMGs decreased from 2.04% to 0.21%. Over the 17-year study period, a total of 105 US IMGs and 110 non-US IMGs matched into orthopedic surgery. The US MD applicant fill rate decreased significantly from 96.5% to 85.0% ( p < 0.001; β −0.944). The DO applicant fill rate increased significantly from 0.31% to 13.97% ( p < 0.0001; β 0.990). Conclusion: The declining rate of IMGs matching into orthopedic residency programs in the United States underscores the growing challenges faced by IMGs in accessing training in this competitive specialty. The notable increase in DO graduates securing orthopedic residency positions likely reflects the integration of a unified accreditation system for MD and DO residency programs established in 2020. Level of Evidence: Retrospective Cohort Study; IV

Piezo2 is a mechanically gated ion channel most commonly expressed by specialized mechanoreceptors, such as the enteroendocrine cells (EECs) of the gastrointestinal epithelium. A subpopulation of EECs expresses Piezo2 and functionally resembles the skin’s touch sensors, called Merkel cells. Low-magnitude mechanical stimuli delivered to the mucosal layer are primarily sensed by mechanosensitive EECs in a process we term “gut touch.” Piezo2 transduces cellular forces into ionic currents, a process that is sensitive to bilayer tension and cytoskeletal depolymerization. E-cadherin is a widely expressed protein that mediates cell–cell adhesion in epithelia and interacts with scaffold proteins that anchor it to actin fibers. E-cadherin was shown to interact with Piezo2 in immortalized cell models. We hypothesized that the Piezo2–E-cadherin interaction is important for EEC mechanosensitivity. To test this, we used super-resolution imaging, co-immunoprecipitation, and functional assays in primary tissues from mice and gut organoids. In tissue EECs and intestinal organoids, we observed multiple Piezo2 cellular pools, including one that overlaps with actin and E-cadherin at the cells’ lateral walls. Further, E-cadherin co-immunoprecipitated with Piezo2 in the primary colonic epithelium. We found that E-cadherin knockdown decreases mechanosensitive calcium responses in mechanically stimulated primary EECs. In all, our results demonstrate that Piezo2 localizes to the lateral wall of EECs, where it physically interacts with E-cadherin and actin. They suggest that the Piezo2–E-cadherin–actin interaction is important for mechanosensitivity in the gut epithelium and possibly in tissues where E-cadherin and Piezo2 are co-expressed in epithelial mechanoreceptors, such as skin, lung, and bladder.

Introduction: The Mindfulness-Based Stress Reduction (MBSR) Program for breast cancer survivors (BCS) is designed to enhance cognitive training through formal and informal meditational practices. This randomized clinical trial (RCT) aimed to evaluate if BCS assigned to either the MBSR(BC), Breast Cancer Education Support (BCES), or Usual Care (UC) regimens experienced greater improvements at 6, 12, and 26 weeks on objective and subjective cognitive performance. Methods: BCS ( n = 212) randomized to a three-group RCT: MBSR(BC) ( n = 91), BCES ( n = 90), or UC ( n = 31) were assessed on cognitive performance and symptoms at baseline, 6, 12, and 26 weeks. Linear mixed models were fit to evaluate the effects of the MBSR(BC) program, hypothesizing ordered effect improvements: (MBSR[BC] highest, BCES intermediate, UC lowest) along with baseline characteristics evaluated as moderators. Results: Of the BCS (mean age of 57), 73% were White, and non-Hispanic, and 77% received both chemotherapy (CT) and radiation. Cognitive performance improved in all groups. Although there were no statistically significant between-group differences in cognitive outcomes, significant symptom reductions occurred for the MBSR(BC) group ( p = 0.003). Within-group effect size analysis at 26 weeks showed substantial improvements in all three groups (effect sizes >0.50) in subjective impairments and quality of life (effect size >0.50) and objective measures of cognitive performance. MBSR(BC) showed the largest within-group effect size in the reduction of fatigue (effect size = 0.81). Effect sizes occurred in the hypothesized direction for 10 of the 18 outcomes. Discussion: Although the MBSR(BC) program did not show significant differences in cognitive performance compared with BCES and UC, all groups improved and reductions in fatigue were beneficial for MBSR(BC). Results suggest that cognitive performance may improve after CT over time considering one’s natural history. Furthermore, BCS enrolled in RCTs may be more motivated to improve their health status (NCT02786797).

Abstract Background We evaluated the association of achieving endoscopic outcomes at week 12 of induction with improvements in clinical outcomes and quality of life (QoL) at week 52 of maintenance in patients with moderately to severely active Crohn’s disease (CD) treated with upadacitinib (UPA). Methods This post hoc analysis evaluated data from 2 phase 3 induction trials (NCT03345836 and NCT03345849) and 1 maintenance (NCT03345823) trial. Clinical responders to 12-week induction therapy with UPA who also received 52-week maintenance treatment with UPA were included. Endoscopic response, remission, healing, and ulcer-free endoscopy were assessed at week 12. Meaningful improvements in clinical and QoL outcomes were evaluated at week 52. Results A significantly greater proportion of patients who achieved an endoscopic response at the end of induction, compared with patients who did not, attained Crohn’s Disease Activity Index (CDAI) remission (52.0% vs 34.6%; P ≤ .01), corticosteroid-free CDAI remission (50.0% vs 30.9%), Inflammatory Bowel Disease Questionnaire remission (52.6% vs 30.3%), and meaningful improvements in Functional Assessment of Chronic Illness Therapy—Fatigue response (46.7% vs 25.9%), overall work impairment (47.1% vs 26.5%), and daily activity impairment (53.3% vs 34.1%) (all P &lt; .05) at week 52. Similar findings were observed for patients who achieved endoscopic remission, endoscopic healing, and ulcer-free endoscopy at the end of induction vs those who did not. Conclusions Early improvement in endoscopic outcomes after UPA induction treatment was associated with long-term meaningful improvements in clinical outcomes and QoL in patients with CD. Clinical Registration number U-EXCEED induction trial (NCT03345836), U-EXCEL induction trial (NCT03345849), and U-ENDURE maintenance trial (NCT03345823).

AbstractObjectivesThe main goal of presurgical evaluation in drug‐resistant focal epilepsy is to identify a seizure onset zone (SOZ). Of the noninvasive, yet resource‐intensive tests available, ictal single‐photon emission computed tomography (SPECT) aids SOZ localization by measuring focal increases in blood flow within the SOZ via intravenous peri‐ictal radionuclide administration. Recent studies indicate that geographic and center‐specific factors impact utilization of these diagnostic procedures. Our study analyzed successful ictal SPECT acquisition (defined as peri‐ictal injection during inpatient admission) using surgery‐related data from the Pediatric Epilepsy Research Consortium (PERC) surgery database. We hypothesized that a high seizure burden, longer duration of video EEG monitoring (VEEG), and more center‐specific hours of SPECT availability would increase the likelihood of successful ictal SPECT.MethodsWe identified study participants (≤18 years of age) who underwent SPECT as part of their phase 1 VEEG from January 2018 to June 2022. We assessed association between ictal SPECT outcomes (success vs. failure) and variables including patient demographics, epilepsy history, and center‐specific SPECT practices.ResultsPhase 1 VEEG monitoring with ictal SPECT injection was planned in 297 participants and successful in 255 participants (85.86%). On multivariable analysis, the likelihood of a successful SPECT injection was higher in patients of non‐Hispanic ethnicity (p = 0.040), shorter duration VEEG (p = 0.004), and higher hours of available SPECT services (p < 0.001). Higher seizure frequency (p = 0.033) was significant only in bivariate analysis. Patients treated at centers with more operational hours were more likely to experience pre‐admission protocols prior to VEEG (p = 0.002).SignificanceThere is inter‐center variability in protocols and SPECT acquisition capabilities. Shorter duration of EEG monitoring, non‐Hispanic ethnicity (when on private insurance), extended operational hours of nuclear medicine as noted on multivariate analysis and higher seizure frequency in bivariate analysis are strongly associated with successful ictal SPECT injection.Plain Language SummaryIn pediatric patients with drug‐resistant epilepsy, single‐photon emission computed tomography (SPECT) scans can be helpful in localizing seizure onset zone. However, due to many logistical challenges described below, which include not only the half‐life of the technetium isotope used to inject intravenously during a seizure (called the ictal SPECT scan) but also available nuclear scanner time in addition to the unpredictability of seizures, obtaining an ictal SPECT during a planned elective inpatient hospital stay is not guaranteed. Thus, as healthcare costs increase, planning a prolonged hospital stay during which an ictal SPECT scan is not feasible is not optimal. We leveraged our prospective surgery database to look at center‐specific factors and patient‐specific factors associated with an ictal SPECT injection in the first, pediatric‐focussed, large‐scale, multicenter, prospective, SPECT feasibility study. We found that longer availability of the scanner is the most important center‐specific factor in assuring ictal SPECT injection. Although seizure frequency is an important patient‐specific factor on bivariate analysis, this factor lost statistical significance when other factors like patient insurance status and video EEG duration were also considered in our multivariable logistical model.