Identifying Racial Disparities in Utilization and Clinical Outcomes of Ambulatory Hip Arthroscopy: Analysis of Temporal Trends and Causal Inference via Machine Learning.

Background: Arthroscopic diagnosis and treatment of femoroacetabular pathology has experienced significant growth in the last 30 years; nevertheless, reduced utilization of orthopaedic procedures has been observed among the underrepresented population. Purpose/Hypothesis: The purpose of this study was to examine racial differences in case incidence rates, outcomes, and complications in patients undergoing hip arthroscopy. It was hypothesized that racial and ethnic minority patients would undergo hip arthroscopy at a decreased rate compared with their White counterparts but that there would be no differences in clinical outcomes. Study Design: Cross-sectional study. Methods: The State Ambulatory Surgery and Services Database and the State Emergency Department Database of New York were queried for patients undergoing hip arthroscopy between 2011 and 2017. Patients were stratified into White and racial and ethnic minority races, and intergroup comparisons were performed for utilization over time, total charges billed per encounter, 90-day emergency department (ED) visits, and revision hip arthroscopy. Temporal trends in the utilization of hip arthroscopy were identified, and racial differences in secondary outcomes were analyzed with a semiparametric method known as targeted maximum likelihood estimation (TMLE) backed by a library of machine learning algorithms. Results: A total of 9745 patients underwent hip arthroscopy during the study period, with 1081 patients of minority race (11.1%). White patients underwent hip arthroscopy at 5.68 (95% CI, 4.98-6.48) times the incidence rate of racial and ethnic minority patients; these incidence rates grew annually at a ratio of 1.11 in White patients compared with 1.03 in racial and ethnic minority patients (P < .001). Based on the TMLE, racial and ethnic minority patients were significantly more likely to incur higher costs (P < .001) and visit the ED within 90 days (P = .049) but had negligible differences in reoperation rates at a 2-year follow-up (P = .53). Subgroup analysis identified that higher likelihood for 90-day ED admissions among racial and ethnic minority patients compared with White patients was associated with Medicare insurance (P = .002), median income in the lowest quartile (P = .012), and residence in low-income neighborhoods (P = .006). Conclusion: Irrespective of insurance status, racial and ethnic minority patients undergo hip arthroscopy at a lower incidence and incur higher costs per surgical encounter.

Mitochondrial DNA copy number variation in asthma risk, severity, and exacerbations.

BACKGROUND: Asthma pathophysiology is associated with mitochondrial dysfunction. Mitochondrial DNA copy number (mtDNA-CN) has been used as a proxy of mitochondrial function, with lower levels indicating mitochondrial dysfunction in population studies of cardiovascular diseases and cancers. OBJECTIVES: We investigated whether lower levels of mtDNA-CN are associated with asthma diagnosis, severity, and exacerbations. METHODS: mtDNA-CN is evaluated in blood from 2 cohorts: UK Biobank (UKB) (asthma, n = 39,147; no asthma, n = 302,302) and Severe Asthma Research Program (SARP) (asthma, n = 1283; nonsevere asthma, n = 703). RESULTS: Individuals with asthma have lower mtDNA-CN compared to individuals without asthma in UKB (beta, -0.006 [95% confidence interval, -0.008 to -0.003], P = 6.23 × 10-6). Lower mtDNA-CN is associated with asthma prevalence, but not severity in UKB or SARP. mtDNA-CN declines with age but is lower in individuals with asthma than in individuals without asthma at all ages. In a 1-year longitudinal study in SARP, mtDNA-CN was associated with risk of exacerbation; those with highest mtDNA-CN had the lowest risk of exacerbation (odds ratio 0.333 [95% confidence interval, 0.173 to 0.542], P = .001). Biomarkers of inflammation and oxidative stress are higher in individuals with asthma than without asthma, but the lower mtDNA-CN in asthma is independent of general inflammation or oxidative stress. Mendelian randomization studies suggest a potential causal relationship between asthma-associated genetic variants and mtDNA-CN. CONCLUSION: mtDNA-CN is lower in asthma than in no asthma and is associated with exacerbations. Low mtDNA-CN in asthma is not mediated through inflammation but is associated with a genetic predisposition to asthma.

Anatomic fibular-based posterolateral corner reconstruction with two femoral tunnels demonstrates lowest residual laxity with external rotation and varus stresses: a systematic review and network meta-analysis of in-vitro biomechanical studies.

PURPOSE: To perform a systematic review and network meta-analysis of in vitro cadaveric, biomechanical studies evaluating described techniques for posterolateral corner (PLC) reconstruction, including fibular-based and tibiofibular-based techniques. METHODS: PubMed/MEDLINE, Embase, and Cochrane Library were searched in 12/2023 for cadaveric studies evaluating PLC reconstruction. After descriptive summary, a series of frequentist network meta-analyses comparing 1) non-anatomic fibular-based (single femoral tunnel), 2) anatomic fibular-based (double femoral tunnel), and 3) anatomic tibiofibular based PLC reconstructions to the intact knee were performed for both external rotation (ER) and varus laxity from 0-90˚ of knee flexion. Pooled treatment estimates were calculated as mean differences (MD) with 95% confidence intervals (CI) using random effects models. RESULTS: A total of 31 studies were included. Non-anatomic fibular-based reconstructions demonstrated increased ER laxity compared to the intact state between 30-90˚ of flexion (mean differences for 0˚: 1.66 [95% CI -0.27-3.59], p=0.093, 30˚: 2.29 [95% CI 0.44-4.13], p=0.015. 60˚: 3.04 [95% CI 0.95-5.12], p=0.004, 90˚: 4.30 [95% CI 1.41-7.19], p=0.004). The anatomic fibular-based and tibiofibular-based (except at 0˚ for tibiofibular) reconstructions restored ER stability at all flexion values. All three reconstructions restored varus stability compared to the intact state in all scenarios except the anatomic fibular-based techniques at 0˚ (MD 0.85 [95% CI 0.06 to 1.63], p=0.034). Across the assessed ER and varus laxity states, the anatomic fibular-based reconstruction was ranked "best" in 5 of 8 scenarios. CONCLUSION: PLC reconstructions utilizing non-anatomic fibular-based techniques demonstrated increased residual laxity in ER from 30-90˚ of knee flexion. Conversely, anatomic fibular- and tibiofibular- based reconstructions demonstrated ER and varus laxity similar to that of the intact knee state across the majority of assessed knee flexion values. CLINICAL RELEVANCE: Various techniques have been described for PLC reconstruction, however, no study has comprehensively compared the biomechanical properties of these reconstructions to one another.

Proresolving Lipid Mediators in the Respiratory System.

Lung inflammation, infection, and injury can lead to critical illness and death. The current means to pharmacologically treat excessive uncontrolled lung inflammation needs improvement because many treatments are or will become immunosuppressive. The inflammatory response evolved to protect the host from microbes, injury, and environmental insults. This response brings phagocytes from the bloodstream to the tissue site to phagocytize and neutralize bacterial invaders and enables airway antimicrobial functions. This physiologic response is ideally self-limited with initiation and resolution phases. Polyunsaturated essential fatty acids are precursors to potent molecules that govern both phases. In the initiation phase, arachidonic acid is converted to prostaglandins and leukotrienes that activate leukocytes to transmigrate from postcapillary venules. The omega-3 fatty acids (e.g., DHA and EPA) are precursors to resolvins, protectins, and maresins, which are families of chemically distinct mediators with potent functions in resolution of acute and chronic inflammation in the respiratory system.

Long-term Outcomes of Partial Meniscectomy for Degenerative Medial Meniscus Posterior Root Tears.

Background: Previous studies have demonstrated that medial meniscus posterior root tear (MMPRT) repair is superior to debridement in terms of patient-reported outcomes, rates of conversion to total knee arthroplasty (TKA), and long-term costs. Despite the known poor midterm outcomes, there is a paucity of long-term results of partial meniscectomy for degenerative MMPRTs. Purpose: To 1) evaluate long-term patient-reported and radiographic outcomes of patients who underwent partial medial meniscectomy (PMM) for MMPRTs, and 2) determine the rate of and risk factors for conversion to total knee TKA. Study Design: Case series; Level of evidence, 4. Methods: A previously identified cohort of 26 patients treated with partial meniscectomy for isolated MMPRTs between 2005 and 2013 was prospectively followed for long-term outcomes at a minimum 10-year follow-up. Patients were evaluated for International Knee Documentation Committee (IKDC) outcome score, reoperation, and conversion to TKA. Failure was defined as conversion to arthroplasty or a severely abnormal IKDC subjective score <75.4. Results: This study included 26 patients (10 men, 16 women; mean age, 54 ± 8.7 years [range, 38-71 years] at diagnosis; body mass index, 32.9 ± 5.5) who were followed for a mean of 14.0 ± 3.6 years (range, 10.1-19.6 years). At the final follow-up, 1 patient was deceased and 18 (72%) of the remaining 25 patients had progressed to TKA, with 1 (4%) patient undergoing repeat meniscectomy. The 6 (24%) patients who had not progressed to TKA or revision surgery reported a mean IKDC score of 57 ± 23. Nineteen patients underwent subsequent surgery and 5 demonstrated severely abnormal IKDC scores resulting in a clinical failure rate of 96% (24 of the 25 living patients) at a mean 14-year follow-up. Conclusion: PMM for medial meniscus posterior horn root tears demonstrated 72% progression to TKA and 96% failure according to subjective clinical outcomes at a minimum 10-year follow-up.

Multiligament knee injury (MLKI): an expert consensus statement on nomenclature, diagnosis, treatment and rehabilitation.

Multiligament knee injuries (MLKIs) represent a broad spectrum of pathology with potentially devastating consequences. Currently, disagreement in the terminology, diagnosis and treatment of these injuries limits clinical care and research. This study aimed to develop consensus on the nomenclature, diagnosis, treatment and rehabilitation strategies for patients with MLKI, while identifying important research priorities for further study. An international consensus process was conducted using validated Delphi methodology in line with British Journal of Sports Medicine guidelines. A multidisciplinary panel of 39 members from 14 countries, completed 3 rounds of online surveys exploring aspects of nomenclature, diagnosis, treatment, rehabilitation and future research priorities. Levels of agreement (LoA) with each statement were rated anonymously on a 5-point Likert scale, with experts encouraged to suggest modifications or additional statements. LoA for consensus in the final round were defined 'a priori' if >75% of respondents agreed and fewer than 10% disagreed, and dissenting viewpoints were recorded and discussed. After three Delphi rounds, 50 items (92.6%) reached consensus. Key statements that reached consensus within nomenclature included a clear definition for MLKI (LoA 97.4%) and the need for an updated MLKI classification system that classifies injury mechanism, extent of non-ligamentous structures injured and the presence or absence of dislocation. Within diagnosis, consensus was reached that there should be a low threshold for assessment with CT angiography for MLKI within a high-energy context and for certain injury patterns including bicruciate and PLC injuries (LoA 89.7%). The value of stress radiography or intraoperative fluoroscopy also reached consensus (LoA 89.7%). Within treatment, it was generally agreed that existing literature generally favours operative management of MLKI, particularly for young patients (LoA 100%), and that single-stage surgery should be performed whenever possible (LoA 92.3%). This consensus statement will facilitate clinical communication in MLKI, the care of these patients and future research within MLKI.

A new Anticalin protein for IL-23 inhibits non-type 2 allergen-driven mouse lung inflammation and airway hyperresponsiveness.

Severe asthma is a syndromic label assigned to patients based on clinical parameters, yet there are diverse underlying molecular endotypes in severe asthma pathobiology. Immunophenotyping of asthma biospecimens commonly includes a mixture of granulocytes and lymphocytes. Recently, a subset of severe asthma patients was defined as non-type 2 with neutrophil-enriched inflammation associated with increased Th17 CD4+ T cells and IL-17 levels. Here, we used an allergen-driven mouse model of increased IL-17 and mixed granulocyte lung inflammation to determine the impact of upstream regulation by an Anticalin protein that specifically binds IL-23. Airway administration of the IL-23 binding Anticalin protein (AcIL-23) decreased lung neutrophils, eosinophils, macrophages, and lymphocytes, IL-17+ CD4 T cells, mucous cell metaplasia and methacholine-induced airway hyperresponsiveness. Selective targeting of IL-23 with a monoclonal antibody (IL-23p19) (αIL-23) also decreased macrophages, IL-17+ CD4 T cells and airway hyperresponsiveness. In contrast, a monoclonal antibody against IL-17A (αIL-17A) had no significant effect on airway hyperresponsiveness, but did decrease lung neutrophils, macrophages, and IL-17+ CD4 T cells. Targeting the IL-23 pathway did not significantly change IL-5+ or IL-13+ CD4 T cells. Together, these data indicate that airway AcIL-23 mirrored the activity of systemic anti-IL-23 antibody to decrease airway hyperresponsiveness in addition to mixed granulocytic inflammation, and that these protective actions were broader than blocking only IL-17A or IL-5, which selectively decreased airway neutrophils and eosinophils, respectively.

Comparison of Asthma Phenotypes in Severe Asthma Cohorts (SARP, U-BIOPRED, ProAR and COREA) From 4 Continents.

PURPOSE: Asthma is a clinical syndrome with various underlying pathomechanisms and clinical phenotypes. Genetic, ethnic, and geographic factors may influence the differences in clinical presentation, severity, and prognosis. We compared the characteristics of asthma based on the geographical background by analyzing representative cohorts from the United States, Europe, South America, and Asia using the Severe Asthma Research Program (SARP), Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED), Program for Control of Asthma in Bahia (ProAR), and Cohort for Reality and Evolution of Adult Asthma in Korea (COREA), respectively. METHODS: The clinical characteristics and medications for the SARP (n = 669), U-BIOPRED (n = 509), ProAR (n = 996), and COREA (n = 3,748) were analyzed. Subgroup analysis was performed for severe asthma. RESULTS: The mean age was highest and lowest in the COREA and SARP, respectively. The asthma onset age was lowest in the ProAR. The mean body mass index was highest and lowest in the SARP and COREA, respectively. Baseline pulmonary function was lowest and highest in the U-BIOPRED and COREA, respectively. The number of patients with acute exacerbation in the previous year was highest in U-BIOPRED. The mean blood eosinophil count was highest in COREA. The total immunoglobulin E was highest in the ProAR. The frequency of atopy was highest in the SARP. The principal component analysis plot revealed differences among all cohorts. CONCLUSIONS: The cohorts from 4 different continents exhibited different clinical and physiological characteristics, probably resulting from the interplay between genetic susceptibility and geographical factors.

15-epi-lipoxin A5 promotes neutrophil exit from exudates for clearance by splenic macrophages.

Specialized proresolving mediators (SPMs) promote local macrophage efferocytosis but excess leukocytes early in inflammation require additional leukocyte clearance mechanism for resolution. Here, neutrophil clearance mechanisms from localized acute inflammation were investigated in mouse dorsal air pouches. 15-HEPE (15-hydroxy-5Z,8Z,11Z,13E,17Z-eicosapentaenoic acid) levels were increased in the exudates. Activated human neutrophils converted 15-HEPE to lipoxin A5 (5S,6R,15S-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), 15-epi-lipoxin A5 (5S,6R,15R-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), and resolvin E4 (RvE4; 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid). Exogenous 15-epi-lipoxin A5, 15-epi-lipoxin A4 and a structural lipoxin mimetic significantly decreased exudate neutrophils and increased local tissue macrophage efferocytosis, with comparison to naproxen. 15-epi-lipoxin A5 also cleared exudate neutrophils faster than the apparent local capacity for stimulated macrophage efferocytosis, so the fate of exudate neutrophils was tracked with CD45.1 variant neutrophils. 15-epi-lipoxin A5 augmented the exit of adoptively transferred neutrophils from the pouch exudate to the spleen, and significantly increased splenic SIRPa+ and MARCO+ macrophage efferocytosis. Together, these findings demonstrate new systemic resolution mechanisms for 15-epi-lipoxin A5 and RvE4 in localized tissue inflammation, which distally engage the spleen to activate macrophage efferocytosis for the clearance of tissue exudate neutrophils.

Arthroscopic Fractional Lengthening After Total Hip Arthroplasty Results in Improved Patient-Reported Outcomes and Low Rates of Revision Total Hip Arthroplasty.

Purpose: To report the clinical outcomes and reoperation rates of arthroscopic and endoscopic iliopsoas release at short-term follow-up after ipsilateral total hip arthroplasty (THA) at 2 separate medical institutions and to evaluate whether demographic and radiographic parameters are associated with postoperative patient-reported outcomes (PROs). Methods: Patients with iliopsoas tendinitis in the setting of prior THA who underwent arthroscopic iliopsoas fractional lengthening from 1988 to 2023 at 2 academic institutions were reviewed. Patients were included if they had 12 months of follow-up and underwent evaluation of preoperative anterior acetabular component overhang, surgery satisfaction, postoperative subjective hip flexion strength and anterior groin pain improvement, modified Harris Hip Score, Single Assessment Numeric Evaluation score, Tegner activity scale score, visual analog scale (VAS) score, and revision hip arthroplasty. Results: Sixty hips in 58 patients (19 male and 39 female patients) were followed up for a mean of 39.3 months (range, 12.0-105.9 months) postoperatively. Of the patients, 77% reported feeling "much better" or "slightly better," 75% reported improved anterior groin pain, and 60% reported improved subjective hip flexion strength. The surgery satisfaction rating was 7.2 ± 3.3 (scale of 0 to 10). The mean postoperative modified Harris Hip Score, VAS score for pain at rest, VAS score for pain with use, and Single Assessment Numeric Evaluation score were 73.9 ± 19.4, 1.3 ± 2.4, 3.8 ± 2.9, and 71.9 ± 21.9, respectively. Preoperative anterior acetabular component overhang was 3.3 ± 6.5 mm and did not significantly correlate with postoperative PROs (P ≥ .45). The Tegner score improved from 2.5 ± 1.7 preoperatively to 2.9 ± 1.4 postoperatively (P = .0253). Three patients underwent revision arthroplasty at a mean of 25.3 months (range, 11.6-40.4 months) postoperatively, with an acetabular component revision rate of 3.3%. Conclusions: Satisfactory outcomes and low revision arthroplasty rates were observed in patients undergoing arthroscopic iliopsoas lengthening after THA. There was no statistically significant relation between anterior acetabular component overhang and final PROs. Level of Evidence: Level IV, therapeutic case series.

Editorial Commentary: Combined Anterior Cruciate Ligament/Medial Collateral Ligament Injuries: Surgeons Should Have a Low Threshold to Operate on the Medial Collateral Ligament.

Combined anterior cruciate ligament/medial collateral ligament (ACL/MCL) injuries are relatively common, and multiple factors are involved in surgical decision-making, particularly when it comes to the MCL. Historically, most surgeons treated the MCL conservatively and performed staged MCL reconstruction after MCL reconstruction only if there was persistent medial instability. This was followed by a nonoperative approach for the MCL (when reconstructing the ACL) unless there was evidence of extreme (grade III or >1 cm) valgus instability, valgus malalignment, or mid-substance or tibial-sided injury, avulsion, or Stener lesion. However, the most recent research demonstrates that combined ACL/MCL injuries present a higher risk of ACL reconstruction failure and subsequent revision compared to ACL injuries alone. With growing biomechanical and clinical evidence, more surgeons are repairing or reconstructing the MCL in these combined injuries. Although there is no clear consensus, we recommend surgeons consider surgically treating the MCL to avoid not only excessive force on the ACL graft but also persistent valgus laxity, which can lead to ACL failure. For distal MCL avulsions, repairs have shown excellent midterm outcomes, especially if the tissue quality is pristine. If the tissue quality is not repairable, then we would advocate for repairing whatever tissue is repairable and augmenting with an MCL reconstruction. For mid-substance MCL injuries, if surgical intervention is required, we advocate for MCL reconstruction. For proximal tears, the same criteria used for distal tears apply with management based on tissue quality and joint stability after repair. The ACL is a secondary stabilizer to valgus loads, and MCL deficiency results in tremendous strain on ACL graft reconstructions. If the MCL is even mildly incompetent, we strongly advocate for treating the MCL surgically in this setting.

Peroxidase-mediated mucin cross-linking drives pathologic mucus gel formation in IL-13-stimulated airway epithelial cells.

Mucus plugs occlude airways to obstruct airflow in asthma. Studies in patients and in mouse models show that mucus plugs occur in the context of type 2 inflammation, and studies in human airway epithelial cells (HAECs) show that IL-13-activated cells generate pathologic mucus independently of immune cells. To determine how HAECs autonomously generate pathologic mucus, we used a magnetic microwire rheometer to characterize the viscoelastic properties of mucus secreted under varying conditions. We found that normal HAEC mucus exhibited viscoelastic liquid behavior and that mucus secreted by IL-13-activated HAECs exhibited solid-like behavior caused by mucin cross-linking. In addition, IL-13-activated HAECs shows increased peroxidase activity in apical secretions, and an overlaid thiolated polymer (thiomer) solution shows an increase in solid behavior that was prevented by peroxidase inhibition. Furthermore, gene expression for thyroid peroxidase (TPO), but not lactoperoxidase (LPO), was increased in IL-13-activated HAECs and both TPO and LPO catalyze the formation of oxidant acids that cross-link thiomer solutions. Finally, gene expression for TPO in airway epithelial brushings was increased in patients with asthma with high airway mucus plug scores. Together, our results show that IL-13-activated HAECs autonomously generated pathologic mucus via peroxidase-mediated cross-linking of mucin polymers.

Association of Posterior Tibial Slope With Outcomes After Multiligamentous Knee Reconstruction for Knee Dislocation Grades 2 to 4.

Background: Patients with isolated anterior cruciate ligament (ACL) reconstruction have demonstrated an increased risk of ACL graft failure and lower patient-reported outcome (PRO) scores when increased posterior tibial slope (PTS) is present. However, there is a paucity of literature evaluating the effect of PTS on outcomes after combined bicruciate multiligamentous knee reconstruction. Purpose: To determine whether differences exist for graft failure rates or PRO scores based on PTS after combined bicruciate multiligamentous knee reconstruction. Study Design: Cohort study; Level of evidence, 3. Methods: All patients who underwent combined ACL and posterior cruciate ligament (PCL) reconstruction between 2000 and 2020 at our institution were identified. Exclusion criteria were age <18 years, knee dislocation grade 5 injuries, concomitant osteotomy procedures, and <2 years of clinical follow-up. Demographic and outcomes data were collected from our prospectively gathered multiligamentous knee injury database. Lysholm and International Knee Documentation Committee (IKDC) scores were analyzed in relation to PTS. Outcomes were compared for patients with a PTS above and below the mean for the total cohort, PTS >12° versus <12°, positive versus negative Lachman test at follow-up, and positive versus negative posterior drawer test at follow-up. Results: A total of 98 knees in 98 patients were included in the study, with a mean clinical follow-up of 5.1 years (median, 4.6 years; range, 2-16 years). The mean PTS was 8.7° (range, 0.4°-16.9°). Linear regression analysis showed no significant correlation between PTS and IKDC or Lysholm scores. Patients with a PTS above the mean of 8.7° trended toward lower IKDC (P = .08) and Lysholm (P = .06) scores. Four patients experienced ACL graft failure and 5 patients experienced PCL graft failure. There were no differences in graft failure rates or PRO scores for patients with a PTS >12°. Patients with a positive Lachman test trended toward higher PTS (9.6° vs 8.5°, P = .15). Conclusion: In this series of bicruciate multiligamentous knee reconstructions at midterm follow-up, no differences in graft failures, complications, reoperations, revisions, or PRO scores based on PTS were identified. Patients with a positive Lachman test were found to have a slightly higher PTS, although this did not reach statistical significance.

A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma.

By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.

Utility of eosinophil peroxidase as a biomarker of eosinophilic inflammation in asthma.

BACKGROUND: The relative utility of eosinophil peroxidase (EPX) and blood and sputum eosinophil counts as disease biomarkers in asthma is uncertain. OBJECTIVE: We sought to determine the utility of EPX as a biomarker of systemic and airway eosinophilic inflammation in asthma. METHODS: EPX protein was measured by immunoassay in serum and sputum in 110 healthy controls to establish a normal reference range and in repeated samples of serum and sputum collected during 3 years of observation in 480 participants in the Severe Asthma Research Program 3. RESULTS: Over 3 years, EPX levels in patients with asthma were higher than normal in 27% to 31% of serum samples and 36% to 53% of sputum samples. Eosinophils and EPX correlated better in blood than in sputum (rs values of 0.74 and 0.43, respectively), and high sputum EPX levels occurred in 27% of participants with blood eosinophil counts less than 150 cells/µL and 42% of participants with blood eosinophil counts between 150 and 299 cells/µL. Patients with persistently high sputum EPX values for 3 years were characterized by severe airflow obstruction, frequent exacerbations, and high mucus plug scores. In 59 patients with asthma who started mepolizumab during observation, serum EPX levels normalized in 96% but sputum EPX normalized in only 49%. Lung function remained abnormal even when sputum EPX normalized. CONCLUSIONS: Serum EPX is a valid protein biomarker of systemic eosinophilic inflammation in asthma, and sputum EPX levels are a more sensitive biomarker of airway eosinophilic inflammation than sputum eosinophil counts. Eosinophil measures in blood frequently miss airway eosinophilic inflammation, and mepolizumab frequently fails to normalize airway eosinophilic inflammation even though it invariably normalizes systemic eosinophilic inflammation.

Vitamin D constrains inflammation by modulating the expression of key genes on Chr17q12-21.1.

Vitamin D possesses immunomodulatory functions and vitamin D deficiency has been associated with the rise in chronic inflammatory diseases, including asthma (Litonjua and Weiss, 2007). Vitamin D supplementation studies do not provide insight into the molecular genetic mechanisms of vitamin D-mediated immunoregulation. Here, we provide evidence for vitamin D regulation of two human chromosomal loci, Chr17q12-21.1 and Chr17q21.2, reliably associated with autoimmune and chronic inflammatory diseases. We demonstrate increased vitamin D receptor (Vdr) expression in mouse lung CD4+ Th2 cells, differential expression of Chr17q12-21.1 and Chr17q21.2 genes in Th2 cells based on vitamin D status and identify the IL-2/Stat5 pathway as a target of vitamin D signaling. Vitamin D deficiency caused severe lung inflammation after allergen challenge in mice that was prevented by long-term prenatal vitamin D supplementation. Mechanistically, vitamin D induced the expression of the Ikzf3-encoded protein Aiolos to suppress IL-2 signaling and ameliorate cytokine production in Th2 cells. These translational findings demonstrate mechanisms for the immune protective effect of vitamin D in allergic lung inflammation with a strong molecular genetic link to the regulation of both Chr17q12-21.1 and Chr17q21.2 genes and suggest further functional studies and interventional strategies for long-term prevention of asthma and other autoimmune disorders.

Capsular Management in Hip Arthroscopy: Interportal and T-Capsulotomy, Suspension, and Closure.

Capsular management in hip arthroscopy has recently become a popular topic in the literature. Various approaches have been developed around the critical balance between safe and satisfactory exposure while maintaining hip joint stability and the restoration of capsular integrity at the conclusion of the case. Advocates for capsular closure recognize the role of the capsule in providing hip joint stability and aim to reestablish normal hip biomechanics through capsule preservation. Several recent studies have also shown capsular management strategies to influence both clinical outcomes and risk of revision surgery. We present an effective method for capsular management in hip arthroscopy that consistently allows excellent exposure and working space while allowing for facile, anatomic closure.

A novel DNase assay reveals low DNase activity in severe asthma.

Secreted deoxyribonucleases (DNases), such as DNase-I and DNase-IL3, degrade extracellular DNA, and endogenous DNases have roles in resolving airway inflammation and guarding against autoimmune responses to nucleotides. Subsets of patients with asthma have high airway DNA levels, but information about DNase activity in health and in asthma is lacking. To characterize DNase activity in health and in asthma, we developed a novel kinetic assay using a Taqman probe sequence that is quickly cleaved by DNase-I to produce a large product signal. We used this kinetic assay to measure DNase activity in sputum from participants in the Severe Asthma Research Program (SARP)-3 (n = 439) and from healthy controls (n = 89). We found that DNase activity was lower than normal in asthma [78.7 relative fluorescence units (RFU)/min vs. 120.4 RFU/min, P < 0.0001]. Compared to patients with asthma with sputum DNase activity in the upper tertile activity levels, those in the lower tertile of sputum DNase activity were characterized clinically by more severe disease and pathologically by airway eosinophilia and airway mucus plugging. Carbamylation of DNase-I, a post-translational modification that can be mediated by eosinophil peroxidase, inactivated DNase-I. In summary, a Taqman probe-based DNase activity assay uncovers low DNase activity in the asthma airway that is associated with more severe disease and airway mucus plugging and may be caused, at least in part, by eosinophil-mediated carbamylation.NEW & NOTEWORTHY We developed a new DNase assay and used it to show that DNase activity is impaired in asthma airways.

Editorial Commentary: Surgical Videos on YouTube Are Not Peer Reviewed and Have Low Educational Value.

The rise of online platforms like YouTube for health information has prompted scrutiny over the quality of medical/surgical-related video content. Recent research on YouTube videos regarding anterior cruciate ligament reconstruction (ACLR) with quadriceps tendon autograft shows low educational quality and reliability using established assessment tools. Physicians primarily published content, with longer videos, and physician-generated videos, generally correlating with higher quality. However, YouTube's inadequacy as a reliable source for ACLR information underscores the need for alternative educational resources. Orthopaedic health care professionals must play a pivotal role in guiding patients toward credible sources and take aim at improving online content quality. Understanding patient preferences for online resources is essential for enhancing patient education, the patient-provider relationship, and decision-making in orthopaedic care.

Gasdermin B, an asthma-susceptibility gene, promotes MAVS-TBK1 signalling and airway inflammation.

RATIONALE: Respiratory virus-induced inflammation is the leading cause of asthma exacerbation, frequently accompanied by induction of interferon-stimulated genes (ISGs). How asthma-susceptibility genes modulate cellular response upon viral infection by fine-tuning ISG induction and subsequent airway inflammation in genetically susceptible asthma patients remains largely unknown. OBJECTIVES: To decipher the functions of gasdermin B (encoded by GSDMB) in respiratory virus-induced lung inflammation. METHODS: In two independent cohorts, we analysed expression correlation between GSDMB and ISG s. In human bronchial epithelial cell line or primary bronchial epithelial cells, we generated GSDMB-overexpressing and GSDMB-deficient cells. A series of quantitative PCR, ELISA and co-immunoprecipitation assays were performed to determine the function and mechanism of GSDMB for ISG induction. We also generated a novel transgenic mouse line with inducible expression of human unique GSDMB gene in airway epithelial cells and infected the mice with respiratory syncytial virus to determine the role of GSDMB in respiratory syncytial virus-induced lung inflammation in vivo. RESULTS: GSDMB is one of the most significant asthma-susceptibility genes at 17q21 and acts as a novel RNA sensor, promoting mitochondrial antiviral-signalling protein (MAVS)-TANK binding kinase 1 (TBK1) signalling and subsequent inflammation. In airway epithelium, GSDMB is induced by respiratory viral infections. Expression of GSDMB and ISGs significantly correlated in respiratory epithelium from two independent asthma cohorts. Notably, inducible expression of human GSDMB in mouse airway epithelium led to enhanced ISGs induction and increased airway inflammation with mucus hypersecretion upon respiratory syncytial virus infection. CONCLUSIONS: GSDMB promotes ISGs expression and airway inflammation upon respiratory virus infection, thereby conferring asthma risk in risk allele carriers.