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Neuroimmune interactions have emerged as critical modulators of allergic inflammation, and type 2 innate lymphoid cells (ILC2s) are an important cell type for mediating these interactions. Here, we show that ILC2s expressed both the neuropeptide calcitonin gene-related peptide (CGRP) and its receptor. CGRP potently inhibited alarmin-driven type 2 cytokine production and proliferation by lung ILC2s both in vitro and in vivo. CGRP induced marked changes in ILC2 expression programs in vivo and in vitro, attenuating alarmin-driven proliferative and effector responses. A distinct subset of ILCs scored highly for a CGRP-specific gene signature after in vivo alarmin stimulation, suggesting CGRP regulated this response. Finally, we observed increased ILC2 proliferation and type 2 cytokine production as well as exaggerated responses to alarmins in mice lacking the CGRP receptor. Together, these data indicate that endogenous CGRP is a critical negative regulator of ILC2 responses in vivo.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Linfócitos/fisiologia , Neuropeptídeos/metabolismo , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Alarminas/metabolismo , Animais , Peptídeo Relacionado com Gene de Calcitonina/genética , Proliferação de Células , Células Cultivadas , Retroalimentação Fisiológica , Imunidade Inata , Interleucina-33/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuroimunomodulação , Neuropeptídeos/genética , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/genética , Transdução de Sinais , Células Th2/imunologiaRESUMO
The resolution of infection is an active process with specific molecular and cellular mechanisms that temper inflammation and enhance pathogen clearance. Here, the specialized pro-resolving mediator (SPM) Maresin 1 (MaR1) inhibited respiratory syncytial virus (RSV)-induced inflammation. inlerleukin-13 production from type 2 innate lymphoid cells (ILC) and CD4 T helper type 2 cells was decreased by exogenous MaR1. In addition, MaR1 increased amphiregulin production and decreased RSV viral transcripts to promote resolution. MaR1 also promoted interferon-ß production in mouse lung tissues and also in pediatric lung slices. MaR1 significantly inhibited the RSV-triggered aberrant inflammatory phenotype in FoxP3-expressing Tregs. The receptor for MaR1, leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6), was constitutively expressed on Tregs. Following RSV infection, mice lacking Lgr6 had exacerbated type 2 immune responses with an increased viral burden and blunted responses to MaR1. Together, these findings have uncovered a multi-pronged protective signaling axis for MaR1-Lgr6, improving Tregs's suppressive function and upregulating host antiviral genes resulting in decreased viral burden and pathogen-mediated inflammation, ultimately promoting restoration of airway mucosal homeostasis.
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Pneumonia Viral , Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Camundongos , Animais , Imunidade Inata , Linfócitos , Inflamação , Ácidos Docosa-Hexaenoicos/farmacologia , Receptores Acoplados a Proteínas GRESUMO
Airborne pathogens and environmental stimuli evoke immune responses in the lung. It is critical to health that these responses be controlled to prevent tissue damage and the compromise of organ function. Resolution of inflammation is a dynamic process that is coordinated by biochemical and cellular mechanisms. Recently, specialized proresolving mediators (SPMs) have been identified in resolution exudates. These molecules orchestrate anti-inflammatory and proresolving actions that are cell type specific. In this review, we highlight SPM biosynthesis, the influence of SPMs on the innate and adaptive immune responses in the lung, as well as recent insights from SPMs on inflammatory disease pathophysiology. Uncovering these mediators and cellular mechanisms for resolution is providing new windows into physiology and disease pathogenesis.
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Ácidos Graxos Ômega-3/metabolismo , Lipoxinas/metabolismo , Pneumopatias/imunologia , Imunidade Adaptativa , Animais , Humanos , Imunidade Inata , Pneumopatias/metabolismoRESUMO
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.
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Lipoxinas , Macrófagos , Neutrófilos , Baço , Animais , Neutrófilos/metabolismo , Neutrófilos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Humanos , Lipoxinas/metabolismo , Lipoxinas/farmacologia , Baço/metabolismo , Baço/citologia , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/farmacologia , Ácido Eicosapentaenoico/metabolismo , Camundongos Endogâmicos C57BL , Fagocitose , Masculino , Inflamação/metabolismo , Ácidos HeptanoicosRESUMO
Rationale: Density thresholds in computed tomography (CT) lung scans quantify air trapping (AT) at the whole-lung level but are not informative for AT in specific bronchopulmonary segments. Objectives: To apply a segment-based measure of AT in asthma to investigate the clinical determinants of AT in asthma. Methods: In each of 19 bronchopulmonary segments in CT lung scans from 199 patients with asthma, AT was categorized as present if lung attenuation was less than -856 Hounsfield units at expiration in ⩾15% of the lung area. The resulting AT segment score (0-19) was related to patient outcomes. Measurements and Main Results: AT varied at the lung segment level and tended to persist at the patient and lung segment levels over 3 years. Patients with widespread AT (⩾10 segments) had more severe asthma (P < 0.05). The mean (±SD) AT segment score in patients with a body mass index ⩾30 kg/m2 was lower than in patients with a body mass index <30 kg/m2 (3.5 ± 4.6 vs. 5.5 ± 6.3; P = 0.008), and the frequency of AT in lower lobe segments in obese patients was less than in upper and middle lobe segments (35% vs. 46%; P = 0.001). The AT segment score in patients with sputum eosinophils ⩾2% was higher than in patients without sputum eosinophilia (7.0 ± 6.1 vs. 3.3 ± 4.9; P < 0.0001). Lung segments with AT more frequently had airway mucus plugging than lung segments without AT (48% vs. 18%; P ⩽ 0.0001). Conclusions: In patients with asthma, air trapping is more severe in those with airway eosinophilia and mucus plugging, whereas those who are obese have less severe trapping because their lower lobe segments are spared.
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Asma , Eosinofilia , Obesidade , Tomografia Computadorizada por Raios X , Humanos , Asma/diagnóstico por imagem , Asma/fisiopatologia , Masculino , Feminino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/fisiopatologia , Adulto , Eosinofilia/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Idoso , Índice de Massa CorporalRESUMO
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.
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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.
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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.
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Asma , Desoxirribonuclease I , Escarro , Humanos , Asma/metabolismo , Asma/enzimologia , Feminino , Masculino , Escarro/metabolismo , Escarro/enzimologia , Adulto , Pessoa de Meia-Idade , Desoxirribonuclease I/metabolismo , Desoxirribonucleases/metabolismoRESUMO
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.
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Proteínas Adaptadoras de Transdução de Sinal , Asma , Gasderminas , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Animais , Humanos , Asma/metabolismo , Asma/genética , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Predisposição Genética para Doença , Infecções por Vírus Respiratório Sincicial/metabolismo , Infecções por Vírus Respiratório Sincicial/genética , Células Epiteliais/metabolismo , Linhagem Celular , Brônquios/metabolismo , Brônquios/patologia , Pneumonia/metabolismo , Pneumonia/genética , Pneumonia/virologia , Feminino , Pulmão/metabolismo , Pulmão/patologiaRESUMO
INTRODUCTION: Previous bronchoalveolar lavage fluid (BALF) proteomic analysis has evaluated limited numbers of subjects for only a few proteins of interest, which may differ between asthma and normal controls. Our objective was to examine a more comprehensive inflammatory biomarker panel in quantitative proteomic analysis for a large asthma cohort to identify molecular phenotypes distinguishing severe from nonsevere asthma. METHODS: Bronchoalveolar lavage fluid from 48 severe and 77 nonsevere adult asthma subjects were assessed for 75 inflammatory proteins, normalized to BALF total protein concentration. Validation of BALF differences was sought through equivalent protein analysis of autologous sputum. Subjects' data, stratified by asthma severity, were analysed by standard statistical tests, principal component analysis and 5 machine learning algorithms. RESULTS: The severe group had lower lung function and greater health care utilization. Significantly increased BALF proteins for severe asthma compared to nonsevere asthma were fibroblast growth factor 2 (FGF2), TGFα, IL1Ra, IL2, IL4, CCL8, CCL13 and CXCL7 and significantly decreased were platelet-derived growth factor a-a dimer (PDGFaa), vascular endothelial growth factor (VEGF), interleukin 5 (IL5), CCL17, CCL22, CXCL9 and CXCL10. Four protein differences were replicated in sputum. FGF2, PDGFaa and CXCL7 were independently identified by 5 machine learning algorithms as the most important variables for discriminating severe and nonsevere asthma. Increased and decreased proteins identified for the severe cluster showed significant protein-protein interactions for chemokine and cytokine signalling, growth factor activity, and eosinophil and neutrophil chemotaxis differing between subjects with severe and nonsevere asthma. CONCLUSION: These inflammatory protein results confirm altered airway remodelling and cytokine/chemokine activity recruiting leukocytes into the airways of severe compared to nonsevere asthma as important processes even in stable status.
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Asma , Fator A de Crescimento do Endotélio Vascular , Adulto , Humanos , Proteômica , Fator 2 de Crescimento de Fibroblastos , Citocinas/metabolismo , Lavagem Broncoalveolar , Quimiocinas , Líquido da Lavagem BroncoalveolarRESUMO
OBJECTIVE: Randomized controlled trials (RCTs) are a gold standard for estimating the benefits of clinical interventions, but their decision-making utility can be limited by relatively short follow-up time. Longer-term follow-up of RCT participants is essential to support treatment decisions. However, as time from randomization accrues, loss to follow-up and competing events can introduce biases and require covariate adjustment even for intention-to-treat effects. We describe a process for synthesizing expert knowledge and apply this to long-term follow-up of an RCT of treatments for meniscal tears in patients with knee osteoarthritis (OA). METHODS: We identified 2 post-randomization events likely to impact accurate assessment of pain outcomes beyond 5 years in trial participants: loss to follow-up and total knee replacement (TKR). We conducted literature searches for covariates related to pain and TKR in individuals with knee OA and combined these with expert input. We synthesized the evidence into graphical models. RESULTS: We identified 94 potential covariates potentially related to pain and/or TKR among individuals with knee OA. Of these, 46 were identified in the literature review and 48 by expert panelists. We determined that adjustment for 50 covariates may be required to estimate the long-term effects of knee OA treatments on pain. CONCLUSION: We present a process for combining literature reviews with expert input to synthesize existing knowledge and improve covariate selection. We apply this process to the long-term follow-up of a randomized trial and show that expert input provides additional information not obtainable from literature reviews alone.
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Traumatismos do Joelho , Osteoartrite do Joelho , Humanos , Osteoartrite do Joelho/complicações , Osteoartrite do Joelho/terapia , Dor/etiologia , Modalidades de FisioterapiaRESUMO
Chronic obstructive pulmonary disease (COPD) is associated with age and smoking, but other determinants of the disease are incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related state in which somatic mutations in clonal blood populations induce aberrant inflammatory responses. Patients with CHIP have an elevated risk for cardiovascular disease, but the association of CHIP with COPD remains unclear. We analyzed whole-genome sequencing and whole-exome sequencing data to detect CHIP in 48 835 patients, of whom 8444 had moderate to very severe COPD, from four separate cohorts with COPD phenotyping and smoking history. We measured emphysema in murine models in which Tet2 was deleted in hematopoietic cells. In the COPDGene cohort, individuals with CHIP had risks of moderate-to-severe, severe, or very severe COPD that were 1.6 (adjusted 95% confidence interval [CI], 1.1-2.2) and 2.2 (adjusted 95% CI, 1.5-3.2) times greater than those for noncarriers. These findings were consistently observed in three additional cohorts and meta-analyses of all patients. CHIP was also associated with decreased FEV1% predicted in the COPDGene cohort (mean between-group differences, -5.7%; adjusted 95% CI, -8.8% to -2.6%), a finding replicated in additional cohorts. Smoke exposure was associated with a small but significant increased risk of having CHIP (odds ratio, 1.03 per 10 pack-years; 95% CI, 1.01-1.05 per 10 pack-years) in the meta-analysis of all patients. Inactivation of Tet2 in mouse hematopoietic cells exacerbated the development of emphysema and inflammation in models of cigarette smoke exposure. Somatic mutations in blood cells are associated with the development and severity of COPD, independent of age and cumulative smoke exposure.
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Hematopoiese Clonal , Doença Pulmonar Obstrutiva Crônica/genética , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Razão de Chances , Doença Pulmonar Obstrutiva Crônica/etiologia , Fatores de Risco , Fumar/efeitos adversos , Sequenciamento do ExomaRESUMO
Rationale: CC16 is a protein mainly produced by nonciliated bronchial epithelial cells (BECs) that participates in host defense. Reduced CC16 protein concentrations in BAL and serum are associated with asthma susceptibility. Objectives: Few studies have investigated the relationship between CC16 and asthma progression, and none has focused on BECs. In this study, we sought to determine if CC16 mRNA expression levels in BECs are associated with asthma severity. Methods: Association analyses between CC16 mRNA expression levels in BECs (242 asthmatics and 69 control subjects) and asthma-related phenotypes in Severe Asthma Research Program were performed using a generalized linear model. Measurements and Main Results: Low CC16 mRNA expression levels in BECs were significantly associated with asthma susceptibility and asthma severity, high systemic corticosteroids use, high retrospective and prospective asthma exacerbations, and low pulmonary function. Low CC16 mRNA expression levels were significantly associated with high T2 inflammation biomarkers (fractional exhaled nitric oxide and sputum eosinophils). CC16 mRNA expression levels were negatively correlated with expression levels of Th2 genes (IL1RL1, POSTN, SERPINB2, CLCA1, NOS2, and MUC5AC) and positively correlated with expression levels of Th1 and inflammation genes (IL12A and MUC5B). A combination of two nontraditional T2 biomarkers (CC16 and IL-6) revealed four asthma endotypes with different characteristics of T2 inflammation, obesity, and asthma severity. Conclusions: Our findings indicate that low CC16 mRNA expression levels in BECs are associated with asthma susceptibility, severity, and exacerbations, partially through immunomodulation of T2 inflammation. CC16 is a potential nontraditional T2 biomarker for asthma development and progression.
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Asma , Uteroglobina , Humanos , Asma/genética , Asma/metabolismo , Biomarcadores , Células Epiteliais/metabolismo , Inflamação/metabolismo , Estudos Prospectivos , Estudos Retrospectivos , RNA Mensageiro/metabolismo , Uteroglobina/genética , Uteroglobina/metabolismoRESUMO
Rationale: Extrapulmonary manifestations of asthma, including fatty infiltration in tissues, may reflect systemic inflammation and influence lung function and disease severity. Objectives: To determine if skeletal muscle adiposity predicts lung function trajectory in asthma. Methods: Adult SARP III (Severe Asthma Research Program III) participants with baseline computed tomography imaging and longitudinal postbronchodilator FEV1% predicted (median follow-up 5 years [1,132 person-years]) were evaluated. The mean of left and right paraspinous muscle density (PSMD) at the 12th thoracic vertebral body was calculated (Hounsfield units [HU]). Lower PSMD reflects higher muscle adiposity. We derived PSMD reference ranges from healthy control subjects without asthma. A linear multivariable mixed-effects model was constructed to evaluate associations of baseline PSMD and lung function trajectory stratified by sex. Measurements and Main Results: Participants included 219 with asthma (67% women; mean [SD] body mass index, 32.3 [8.8] kg/m2) and 37 control subjects (51% women; mean [SD] body mass index, 26.3 [4.7] kg/m2). Participants with asthma had lower adjusted PSMD than control subjects (42.2 vs. 55.8 HU; P < 0.001). In adjusted models, PSMD predicted lung function trajectory in women with asthma (ß = -0.47 Δ slope per 10-HU decrease; P = 0.03) but not men (ß = 0.11 Δ slope per 10-HU decrease; P = 0.77). The highest PSMD tertile predicted a 2.9% improvement whereas the lowest tertile predicted a 1.8% decline in FEV1% predicted among women with asthma over 5 years. Conclusions: Participants with asthma have lower PSMD, reflecting greater muscle fat infiltration. Baseline PSMD predicted lung function decline among women with asthma but not men. These data support an important role of metabolic dysfunction in lung function decline.
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Asma , Pulmão , Adulto , Humanos , Feminino , Masculino , Adiposidade , Volume Expiratório Forçado , Obesidade , Músculo Esquelético/diagnóstico por imagemRESUMO
Although patellar tendon grafts are most commonly used for anterior cruciate ligament reconstruction in the United States, hamstring autograft is most commonly used worldwide. Hamstring advantages include easy, quick harvest; low morbidity; ease of rehabilitation (compared with patellar tendon grafts); and relatively less pain. Historically, both the semitendinosus (ST) and gracilis are harvested, but by doubling, tripling, or quadrupling the ST to achieve an 8-mm graft, the gracilis can be spared, resulting in less knee flexion weakness. However, recent research has shown no clinically important difference between ST and ST-gracilis patient outcomes.
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Reconstrução do Ligamento Cruzado Anterior , Músculo Grácil , Tendões dos Músculos Isquiotibiais , Humanos , Reconstrução do Ligamento Cruzado Anterior/métodos , Tendões dos Músculos Isquiotibiais/transplante , Músculo Grácil/transplante , Lesões do Ligamento Cruzado Anterior/cirurgia , Coleta de Tecidos e Órgãos/métodos , Resultado do Tratamento , Ligamento Cruzado Anterior/cirurgiaRESUMO
Although isolated posterior cruciate ligament (PCL) injuries often can be treated successfully without surgical intervention, in the setting of persistent instability or multiligamentous knee injury, PCL reconstruction is indicated. PCL reconstructions often have resulted in persistent postoperative laxity. Recent research suggests there may be a role for suture tape-augmented grafts, which have demonstrated decreased clinical and radiographic laxity as well as improved rates of return to previous level of activity, as compared with PCL reconstruction alone. Several biomechanical studies also have supported the use of suture tape augmentation in PCL reconstruction, and the use of suture tape augmentation or internal bracing and ligament surgery is gaining widespread popularity. These ultrahigh molecular weight polyethylene/polyester suture tapes have been shown to be safe and effective. We may be at the point at which the evidence supports the use of suture tape augmentation of PCL reconstruction.
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Reconstrução do Ligamento Cruzado Posterior , Ligamento Cruzado Posterior , Humanos , Ligamento Cruzado Posterior/cirurgia , Ligamento Cruzado Posterior/lesões , Instabilidade Articular/cirurgia , Suturas , Traumatismos do Joelho/cirurgia , Técnicas de Sutura , Fita CirúrgicaRESUMO
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.
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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.
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Reconstrução do Ligamento Cruzado Anterior , Mídias Sociais , Gravação em Vídeo , Humanos , Educação de Pacientes como Assunto , Revisão por ParesRESUMO
PURPOSE: To evaluate long-term patient-reported outcomes and achievement rates of patient acceptable symptomatic state (PASS) in young athletes undergoing hip arthroscopy, and to report long-term sports continuance and reoperation. METHODS: Inclusion criteria consisted of age <24 years at surgery, femoroacetabular impingement undergoing primary hip arthroscopy with labral repair, and participation in sport with intent to return to sport after surgery. The enrollment period was from April 2009 to June 2014. Modified Harris Hip Scores (mHHS), Hip Outcome Score (HOS), HOS Activities of Daily Living (HOS-ADL), and HOS Sport (HOS-Sport) were collected preoperatively, 2 years' postoperatively, and final follow-up. Patients were evaluated for PASS achievement, reoperation, and sports participation. RESULTS: Forty-two hips in 37 patients (11 male, 26 female, age: 17.7 ± 2.1 years, range 13.6-23.0, body mass index 22.8 ± 2.9, range 17.6-33.7) met inclusion criteria and were followed for 10.0 ± 1.3 years (range 8.5-13.0) postoperatively. Mean mHHS, HOS-ADL and HOS-Sports outcome scores at minimum 8.5 years were 82.2 ± 12.9, 89.6 ± 10.9, and 81.8 ± 16.4, respectively, with significant (P < .001) postoperative improvements. Thirty survey respondents (83%) met PASS for mHHS, 27 (75%) for HOS-ADL, and 24 (67%) for HOS-Sports. At minimum 8.5-year follow-up, only 9 of 37 (24%) cited their hip as the reason for stopping sport. Of the remaining patients, 17 of 28 (61%), continued playing their initial sport. There was no difference in patient-reported outcomes between patients who endorsed sports continuance and patients who did not report sports continuance and did not cite their hip as a reason (P ≥ .229). At final follow-up, 4 hips (10%) had undergone subsequent surgical intervention at a mean of 4.8 ± 3.3 years (range 1.0-8.4) postoperatively. CONCLUSIONS: Durable mid-term outcomes and satisfactory PASS achievement rates are observed in young amateur athletes undergoing primary hip arthroscopy. At minimum 8.5-year follow up, approximately 1 in 4 patients discontinue their sports due to hip related reasons. LEVEL OF EVIDENCE: Level IV, case-series.
Assuntos
Impacto Femoroacetabular , Articulação do Quadril , Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Adulto , Articulação do Quadril/cirurgia , Seguimentos , Atividades Cotidianas , Resultado do Tratamento , Impacto Femoroacetabular/cirurgia , Atletas , Artroscopia , Estudos RetrospectivosRESUMO
BACKGROUND: Inhaled corticosteroids (CSs) are the backbone of asthma treatment, improving quality of life, exacerbation rates, and mortality. Although effective for most, a subset of patients with asthma experience CS-resistant disease despite receiving high-dose medication. OBJECTIVE: We sought to investigate the transcriptomic response of bronchial epithelial cells (BECs) to inhaled CSs. METHODS: Independent component analysis was performed on datasets, detailing the transcriptional response of BECs to CS treatment. The expression of these CS-response components was examined in 2 patient cohorts and investigated in relation to clinical parameters. Supervised learning was used to predict BEC CS responses using peripheral blood gene expression. RESULTS: We identified a signature of CS response that was closely correlated with CS use in patients with asthma. Participants could be separated on the basis of CS-response genes into groups with high and low signature expression. Patients with low expression of CS-response genes, particularly those with a severe asthma diagnosis, showed worse lung function and quality of life. These individuals demonstrated enrichment for T-lymphocyte infiltration in endobronchial brushings. Supervised machine learning identified a 7-gene signature from peripheral blood that reliably identified patients with poor CS-response expression in BECs. CONCLUSIONS: Loss of CS transcriptional responses within bronchial epithelium was related to impaired lung function and poor quality of life, particularly in patients with severe asthma. These individuals were identified using minimally invasive blood sampling, suggesting these findings may enable earlier triage to alternative treatments.