Citations

Neuropathic pain is a debilitating chronic condition that lacks effective treatment. The role of cytokine- and chemokine-mediated neuroinflammation in its pathogenesis has been well documented. Follistatin (FST) is a secreted protein known to antagonize the biological activity of cytokines in the transforming growth factor–β (TGF-β) superfamily. The involvement of FST in neuropathic pain and the underlying mechanism remain largely unknown. Here, we report that FST was up-regulated in A-fiber sensory neurons after spinal nerve ligation (SNL) in mice. Inhibition or deletion of FST alleviated neuropathic pain and reduced the nociceptive neuron hyperexcitability induced by SNL. Conversely, intrathecal or intraplantar injection of recombinant FST, or overexpression of FST in the dorsal root ganglion (DRG) neurons, induced pain hypersensitivity. Furthermore, exogenous FST increased neuronal excitability in nociceptive neurons. The biolayer interferometry (BLI) assay and coimmunoprecipitation (co-IP) demonstrated direct binding of FST to the insulin-like growth factor–1 receptor (IGF1R), and IGF1R inhibition reduced FST-induced activation of extracellular signal–regulated kinase (ERK) and protein kinase B (AKT), as well as neuronal hyperexcitability. Further co-IP analysis revealed that the N-terminal domain of FST exhibits the highest affinity for IGF1R, and blocking this interaction with a peptide derived from FST attenuated Nav1.7-mediated neuronal hyperexcitability and neuropathic pain after SNL. In addition, FST enhanced neuronal excitability in human DRG neurons through IGF1R. Collectively, our findings suggest that FST, released from A-fiber neurons, enhances Nav1.7-mediated hyperexcitability of nociceptive neurons by binding to IGF1R, making it a potential target for neuropathic pain treatment.

Abstract Background Children with inflammatory bowel disease (IBD) may have diminished serologic response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and increased risk for subsequent severe coronavirus disease 2019 (COVID-19) infection. We sought to describe outcomes among those who developed SARS-CoV-2 infection following vaccination, characterize SARS-CoV-2 antibodies 1 year post-vaccination, and identify factors associated with durable serologic response. Methods We recruited children with IBD who received ≥2 doses of SARS-CoV-2 vaccine and prospectively collected data on (1) demographics, IBD characteristics, and therapy and (2) SARS-CoV-2 vaccination, testing, and infection symptoms. Serum was obtained for measurement of anti-receptor-binding domain IgG antibodies following a 2-part immunization at 12 and 52 weeks. Results We enrolled 298 participants (mean age 11.9 ± 3.82, 50% female, 67% Crohn’s disease). Symptomatic COVID-19 infection after vaccination occurred in half of the participants, although only 2 (1%) required hospitalization. Anti-tumor necrosis factor alpha (TNF-α) was associated with higher likelihood of symptomatic COVID-19 infection, with an adjusted hazard ratio of 2.7 (95% CI, 1.5-5.0; P = .001). Nearly all participants (99%) had detectable antibody at Week 52. Children aged 1-5 years had lower 52-week antibody level compared to older children (P = .04), as did those on anti-TNF-α therapy (P = .007) and those who received only 2 vaccine doses prior to Week 52 (P < .001). Conclusions SARS-CoV-2 vaccination provides lasting serologic response and protection against severe COVID-19 for most children with IBD, despite the use of lower vaccine doses in younger children and wide-ranging classes of immunosuppressive therapies.

AbstractThe characterization of single extracellular vesicle (EV) has been an emerging tool for the early detection of various diseases despite there being challenges regarding how to interpret data with different protocols or instruments. In this work, standard EV particles were characterized for single CD9+, single CD81+ or double CD9+/CD81+ tetraspanin molecule positivity with two single EV analytic technologies in order to optimize their EV sample preparation after antibody labelling and analysis methods: NanoImager for direct stochastic optical reconstruction microscopy (dSTORM)‐based EV imaging and characterization, and Flow NanoAnalyzer for flow‐based EV quantification and characterization. False positives from antibody aggregates were found during dSTORM‐based NanoImager imaging. Analysis of particle radius with lognormal fittings of probability density histogram enabled the removal of antibody aggregates and corrected EV quantification. Furthermore, different machine learning models were trained to differentiate antibody aggregates from EV particles and correct EV quantification with increased double CD9+/CD81+ population. With Flow NanoAnalyzer, EV samples were prepared with different dilution or fractionation methods, which increased the detection rate of CD9+/CD81+ EV population. Comparing the EV phenotype percentages measured by two instruments, differences in double positive and single positive particles existed after percentage correction, which might be due to the different detection limit of each instrument. Our study reveals that the characterization of individual EVs for tetraspanin positivity varies between two platforms—the NanoImager and the Flow NanoAnalyzer—depending on the EV sample preparation methods used after antibody labelling. Additionally, we applied machine learning models to correct for false positive particles identified in imaging‐based results by fitting size distribution data.

Abstract Objective SNOMED CT provides a standardized terminology for clinical concepts, allowing cohort queries over heterogeneous clinical data including Electronic Health Records (EHRs). While it is intuitive that missing and inaccurate subtype (or is-a) relations in SNOMED CT reduce the recall and precision of cohort queries, the extent of these impacts has not been formally assessed. This study fills this gap by developing quantitative metrics to measure these impacts and performing statistical analysis on their significance. Material and Methods We used the Optum de-identified COVID-19 Electronic Health Record dataset. We defined micro-averaged and macro-averaged recall and precision metrics to assess the impact of missing and inaccurate is-a relations on cohort queries. Both practical and simulated analyses were performed. Practical analyses involved 407 missing and 48 inaccurate is-a relations confirmed by domain experts, with statistical testing using Wilcoxon signed-rank tests. Simulated analyses used two random sets of 400 is-a relations to simulate missing and inaccurate is-a relations. Results Wilcoxon signed-rank tests from both practical and simulated analyses (P-values < .001) showed that missing is-a relations significantly reduced the micro- and macro-averaged recall, and inaccurate is-a relations significantly reduced the micro- and macro-averaged precision. Discussion The introduced impact metrics can assist SNOMED CT maintainers in prioritizing critical hierarchical defects for quality enhancement. These metrics are generally applicable for assessing the quality impact of a terminology’s subtype hierarchy on its cohort query applications. Conclusion Our results indicate a significant impact of missing and inaccurate is-a relations in SNOMED CT on the recall and precision of cohort queries. Our work highlights the importance of high-quality terminology hierarchy for cohort queries over EHR data and provides valuable insights for prioritizing quality improvements of SNOMED CT's hierarchy.

AbstractBackground and PurposeSpinal cord stimulation (SCS) is approved by the Food and Drug Administration for treating chronic intractable pain in the back, trunk, or limbs through stimulation of the dorsal column. Numerous studies have used swine as an analog of the human spinal cord to better understand SCS and further improve its efficacy. We performed high‐resolution imaging of the porcine spinal cord with intact dura mater using micro‐computed tomography (μCT) to construct detailed 3‐dimensional (3D) visualizations of the spinal cord and characterize the morphology of the dorsal and ventral rootlets.MethodsWe obtained spinal cords from Yorkshire/Landrace crossbred swine (N = 7), stained samples with osmium tetroxide, and performed μCT imaging of the T12‐T15 levels at isotropic voxel resolutions ranging from 3.3 to 50 μm. We measured the anatomical morphology using the 3D volumes and compared our results to measurements previously collected from swine and human spinal cords via microdissection techniques in prior literature.ResultsWhile the porcine thoracic‐lumbar spinal cord is a popular model for SCS, we highlight multiple notable differences compared to previously published T8‐T12 human measurements including rootlet counts (porcine dorsal/ventral: 12.2 ± 2.6, 26.6 ± 3.4; human dorsal/ventral: 5.3 ± 1.3, 4.4 ± 2.4), rootlet angles (porcine ventral‐rostral: 161 ± 1°, ventral‐caudal: 155 ± 6°, dorsal‐rostral: 148 ± 9°, dorsal‐caudal: 142 ± 6°; human ventral‐rostral: 170 ± 3°, ventral‐caudal: 22 ± 10°, dorsal‐rostral: 171 ± 3°, dorsal‐caudal: 15 ± 7°), and the presence and count of dorsal rootlet bundles.ConclusionsDetailed measurements and highlighted differences between human and porcine spinal cords can inform variations in modeling and electrophysiological experiments between the two species. In contrast to other approaches for measuring the spinal cord and rootlet morphology, our method keeps the dura intact, reducing potential artifacts from dissection.

Abstract: In knee arthroscopy procedures, maintaining the opening of the medial compartment requires an assistant. Creating the posterior portal in knee arthroscopy is also a challenge because of the shape changes of the thick muscle. The leg is usually placed on the surgical bed, is angled off the lateral aspect of the bed, or drapes over the surgical bed in which the leg plates are removed. However, the aforementioned positions have some limits because of surgical convenience and procedural stability. In this Technical Note, we propose an approach to improve the existing knee positions using a metal round stool as a foot support. The method aims to reduce reliance on human assistants during knee arthroscopy procedures and restore the natural positioning of leg muscles, potentially improving procedural outcomes. Technique Video video See video under supplementary data.

Abstract Disclosure: R. Sandooja: None. J. Saini: None. R. Gregg garcia: None. C. Zhang: None. S. Achenbach: None. E. Atkinson: None. J. Van Gompel: None. W.F. Young: None. I. Bancos: None. Hydrocortisone vs Prednisone During Recovery Following Surgical Cure for Endogenous Hypercortisolism: A Longitudinal Observational Study Introduction: Glucocorticoid withdrawal syndrome (GWS) is a constellation of symptoms that occurs after successful surgery for endogenous hypercortisolism. The objective of this study is to compare hydrocortisone versus prednisone on GWS symptoms. Methods: Study design: Single-center prospective longitudinal cohort study, 2019-2023. Participants: Adults with Cushing syndrome (CS) and mild autonomous cortisol secretion (MACS) with post-operative adrenal insufficiency treated with either hydrocortisone or prednisone for glucocorticoid replacement. Measurements: Clinical and biochemical severity scores for hypercortisolism were calculated. Quality of life (QOL) was assessed using Short Form-36 (SF-36) and Cushing QOL surveys. GWS was assessed using weekly AddiQoL surveys for the first 12 weeks after surgery. Results: Of 131 patients, 91 (69%) patients were treated with hydrocortisone and 40 (31%) with prednisone. No differences in age (median age 51 vs 53 years, P=0.62), sex (84 vs 85% women, P=0.83), etiology of hypercortisolism (ACTH-dependent: 44% vs 48%, P=0.26), clinical severity of hypercortisolism (median score 13 vs 12, P=0.97), or biochemical severity of hypercortisolism (median score of 6 in both, P=0.31) were noted between groups. When assessed at 4-, 8-, and 12-weeks post-surgery, the prevalence and trajectory of symptoms (fatigue, myalgias/arthralgias, sleep, headaches, nausea, weakness) were similar in patients treated with hydrocortisone and prednisone (P>0.05 for all). However, patients treated with prednisone were less likely to report mood changes (8.5% vs 20.9%, P= 0.004) compared to those treated with hydrocortisone. When compared to the presurgical baseline, the overall Cushing QOL score 12 weeks post-surgery improved in both groups (mean delta 8.9 vs 13.0, P=0.21). No differences in the hydrocortisone vs prednisone treatment were found in the SF-36 physical component score (mean delta of -1.7 vs 0.3, P=0.23) and SF-36 mental component score (mean delta 2.3 vs 5.0, P=0.22). Using multivariable analysis, age (estimate 0.22, P= 0.005), clinical severity score (estimate -0.73, P<0.001), female sex (estimate -5.45, P= 0.046) but not glucocorticoid type (estimate -0.06, P=0.98) were associated with the overall GWS symptom burden at 12 weeks. Conclusion: Use of prednisone after curative surgery for hypercortisolism was associated with lower mood symptoms, but did not impact the overall severity or trajectory of other symptoms associated with GWS. Baseline clinical severity of hypercortisolism, age, and female sex were associated with GWS burden. Presentation: 6/1/2024

Abstract Disclosure: J. Saini: None. C.D. Zhang: None. V. Fell: None. E. Atkinson: None. S. Achenbach: None. I. Bancos: None. Background: Several studies employing computed tomography (CT) scans for body composition measurements have reported lower muscle mass and a higher proportion of visceral fat in patients with mild autonomous cortisol secretion (MACS) compared to referent subjects. While a CT scan assesses visceral adipose tissue (VAT) at a single slice level (L3), no studies have evaluated the overall VAT in patients with MACS using Dual-Energy X-ray absorptiometry (DXA). Objective: To determine the impact of MACS on VAT using DXA scan as compared to referent subjects. Methods: We conducted a single-center cross-sectional study of adults with 75 MACS and 75 referent subjects. MACS was defined as serum cortisol>1.8 mcg/dL after 1 mg dexamethasone suppression test in patients with adrenal adenomas and no features of overt hypercortisolism. Referent subjects were included if they had abdominal imaging and had no adrenal disorders. All the participants underwent a full body DXA scan between 04/2019 and 07/2022. We applied the CoreScan software to estimate the (1) total lean and fat mass (2) visceral fat mass and volume (3) lean android, fat android, and android mass, and compared measurements of patients and referent subjects using linear regression models adjusted for sex and BMI. Results: A total of 75 patients with MACS (median age 57.0 years, IQR 47.8-65.6, 67% women) and 75 referent subjects (median age 57.6 years, IQR 49.1-65.8, 67% women) were included. Patients had a higher BMI compared to referent subjects (median 31.7 kg/m2, IQR 27.4-37.9 vs 28.7, IQR, 25.4-33.8, P=0.004). The median post-DST cortisol in patients was 3.1 mcg/dL (IQR, 2.2-5.2). When compared to referent subjects, and after adjustment for sex and BMI, patients had a similar total body fat (estimate=846, p-value=0.28) and lean mass (estimate=-201, p-value=0.83), similar android fat mass (estimate=59, p-value=0.64) but lower gynoid fat mass (estimate=400, 0.007). Notably, sex and BMI-adjusted analysis also showed that patients had a higher VAT fat mass (estimate= -225, p-value=0.084) and a higher VAT fat mass/total mass ratio (estimate= -0.007, p-value=0.026). Conclusions: When adjusted for BMI and sex, patients with MACS do not demonstrate differences in overall fat and lean mass. However, we showed that MACS is associated with increased visceral adiposity, a known cardiovascular risk factor. Body composition assessment by DXA could be a safer and less expensive alternative in the evaluation and follow-up of patients with MACS. Presentation: 6/2/2024