Emerging cell and molecular targets for treating mucus hypersecretion in asthma.

Mucus provides a protective barrier that is crucial for host defense in the lungs. However, excessive or abnormal mucus can have pathophysiological consequences in many pulmonary diseases, including asthma. Patients with asthma are treated with agents that relax airway smooth muscle and reduce airway inflammation, but responses are often inadequate. In part, this is due to the inability of existing therapeutic agents to directly target mucus. Accordingly, there is a critical need to better understand how mucus hypersecretion and airway plugging are affected by the epithelial cells that synthesize, secrete, and transport mucus components. This review highlights recent advances in the biology of mucin glycoproteins with a specific focus on MUC5AC and MUC5B, the chief macromolecular components of airway mucus. An improved mechanistic understanding of key steps in mucin production and secretion will help reveal novel potential therapeutic strategies.

Mitochondrial Dysfunction and Metabolic Reprogramming in Obesity and Asthma.

Mitochondrial dysfunction and metabolic reprogramming have been extensively studied in many disorders ranging from cardiovascular to neurodegenerative disease. Obesity has previously been associated with mitochondrial fragmentation, dysregulated glycolysis, and oxidative phosphorylation, as well as increased reactive oxygen species production. Current treatments focus on reducing cellular stress to restore homeostasis through the use of antioxidants or alterations of mitochondrial dynamics. This review focuses on the role of mitochondrial dysfunction in obesity particularly for those suffering from asthma and examines mitochondrial transfer from mesenchymal stem cells to restore function as a potential therapy. Mitochondrial targeted therapy to restore healthy metabolism may provide a unique approach to alleviate dysregulation in individuals with this unique endotype.

Is REBOA the Last Card to Control a Massive Gastrointestinal Bleeding?

INTRODUCTION: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a potential tool for the management of massive gastrointestinal bleeding (MGB). This study aims to describe the experience of the use of REBOA as adjunctive therapy in patients with MGB and to evaluate its effectiveness. METHODS: Serial cases of patients with hemorrhagic shock secondary to MGB in whom REBOA was placed were collected. Patient demographics, bleeding severity, etiology, management, and clinical outcomes were recorded. RESULTS: Between 2017 and 2020, five cases were analyzed. All patients had a severe gastrointestinal bleeding (Glasgow Blatchford Bleeding Score range 12-17; Clinical Rockal Score range 5-9). The etiologies of MGB were perforated gastric or duodenal ulcers, esophageal varices, and vascular lesions. Systolic blood pressure increased after REBOA placement and total occlusion time was 25-60 min. REBOA provided temporary hemorrhage control in all cases and allowed additional hemostatic maneuvers to be performed. Three patients survived more than 24 h. All patients died in index hospitalization. The main cause of death was related to hemorrhagic shock. CONCLUSIONS: Endovascular aortic occlusion can work as a bridge to further resuscitation and attempts at hemostasis in patients with MGB. REBOA provides hemodynamic support and may be used simultaneously with other hemostatic maneuvers, facilitating definitive hemorrhage control.

Uso de la tomografía corporal total en pacientes con heridas de arma de fuego y hemodinámicamente inestables: ¿Rompiendo paradigmas de atención inicial? / Whole-body computed tomography in hemodynamically unstable patients with gunshot wounds: A paradigm shift in trauma management?

Introducción. El objetivo del estudio fue analizar el impacto del uso de la tomografía corporal total en la evaluación de los pacientes con trauma penetrante por proyectil de arma de fuego y hemodinámicamente inestables atendidos en un centro de referencia de trauma. Métodos. Se realizó un estudio analítico, retrospectivo, con base en un subanálisis del registro de la Sociedad Panamericana de Trauma ­ Fundación Valle del Lili. Se incluyeron los pacientes con trauma penetrante por proyectil de arma de fuego atendidos entre 2018 y 2021. Se excluyeron los pacientes con trauma craneoencefálico severo, trauma leve y en condición in extremis. Resultados. Doscientos pacientes cumplieron los criterios de elegibilidad, 115 fueron estudiados con tomografía corporal total y se compararon con 85 controles. La mortalidad intrahospitalaria en el grupo de tomografía fue de 4/115 (3,5 %) vs 10/85 (12 %) en el grupo control. En el análisis multivariado se identificó que la tomografía no tenía asociación significativa con la mortalidad (aOR=0,46; IC95% 0,10-1,94). El grupo de tomografía tuvo una reducción relativa del 39 % en la frecuencia de cirugías mayores, con un efecto asociado en la disminución de la necesidad de cirugía (aOR=0,47; IC95% 0,22-0,98). Conclusiones. La tomografía corporal total fue empleada en el abordaje inicial de los pacientes con trauma penetrante por proyectil de arma de fuego y hemodinámicamente inestables. Su uso no se asoció con una mayor mortalidad, pero sí con una menor frecuencia de cirugías mayores.

Introduction. This study aims to assess the impact of whole-body computed tomography (WBCT) in the evaluation of patients with penetrating gunshot wounds (GSW) who are hemodynamically unstable and treated at a trauma referral center. Methods. An analytical, retrospective study was conducted based on a subanalysis of the Panamerican Trauma Society-FVL registry. Patients with GSW treated between 2018 and 2021 were included. Patients with severe cranioencephalic trauma, minor trauma, and those in extremis were excluded. Patients with and without WBCT were compared. The primary outcome was in-hospital mortality, and the secondary outcome was the frequency of major surgeries (thoracotomy, sternotomy, cervicotomy, and/or laparotomy) during initial care. Results. Two hundred eligible patients were included, with 115 undergoing WBCT and compared to 85 controls. In-hospital mortality in the WBCT group was 4/115 (3.5%) compared to 10/85 (12%) in the control group. Multivariate analysis showed that WBCT was not significantly associated to mortality (aOR: 0.46; 95% CI 0.10-1.94). The WBCT group had a relative reduction of 39% in the frequency of major surgeries, with an associated effect on reducing the need for surgery (aOR: 0.47; 95% CI 0.22-0.98). Conclusions. Whole-body computed tomography was employed in the initial management of patients with penetrating firearm projectile injuries and hemodynamic instability. The use of WBCT was not associated with mortality but rather with a reduction in the frequency of major surgery.

Umbral crítico de administración en pacientes con trauma severo y reanimación endovascular: ¿Un concepto útil? / Critical Administration Threshold in severe trauma patients and endovascular resuscitation: A useful concept?

Introducción. Se describe la utilidad del umbral crítico de administración (CAT por su denominación en inglés) como herramienta para la reanimación hemostática en pacientes con trauma severo y oclusión endovascular aórtica. Métodos. Revisión retrospectiva de pacientes adultos con hemorragia por trauma, con o sin oclusión endovascular aórtica (REBOA), atendidos entre enero de 2015 y junio de 2020, en un centro de trauma nivel I en Cali, Colombia. Se registraron variables demográficas, severidad del trauma, estado clínico, requerimiento transfusional, tiempo hasta CAT+ y CAT alcanzado (1, 2 ó 3). Resultados. Se incluyeron 93 pacientes, se utilizó REBOA en 36 y manejo tradicional en 57. El grupo REBOA presentó mayor volumen de sangrado (mediana de 3000 ml, RIC: 1950-3625 ml) frente al grupo control (mediana de1500 ml, RIC: 700-2975ml) (p<0,001) y mayor cantidad de glóbulos rojos transfundidos en las primeras 6 horas (mediana de 5, RIC:4-9); p=0,015 y en las primeras 24 horas (mediana de 6, RIC: 4-11); p=0,005. No hubo diferencias estadísticamente significativas en número de pacientes CAT+ entre grupos o tiempo hasta alcanzarlo. Sin embargo, el estado CAT+ durante los primeros 30 minutos de la cirugía fue mayor en grupo REBOA (24/36, 66,7 %) frente al grupo control (17/57, 29,8 %; p=0,001), teniendo este mayor tasa de mortalidad intrahospitalaria frente a los pacientes CAT-. Conclusión. El umbral crítico de administración es una herramienta útil en la reanimación hemostática de pacientes con trauma y REBOA, que podría predecir mortalidad precoz.

Introduction. The objective is to describe the utility of the Critical Administration Threshold (CAT) as a tool in hemostatic resuscitation in patients with severe trauma and REBOA. Methods. Retrospective review between January 2015 and June 2020 of adult patients with hemorrhage secondary to trauma with or without REBOA in a level I trauma center in Cali, Colombia. Demographic variables, trauma severity, clinical status, transfusion needs, time to CAT+ and number of CAT achieved (1, 2 or 3) were recorded. Results. Ninety-three patients were included, in which REBOA was used in 36 and traditional management in 57. The REBOA group had a higher bleeding volume (3000 ml), IQR: 1950-3625 ml vs the control group (1500 ml, IQR: 700-2975 ml) (p<0.001) and a higher rate of PRBC units transfused in the first 6 hours (median 5, IQR: 4-9); p=0.015 and in the first 24 hours (median 6, IQR: 4-11); p=0.005. There were no statistically significant differences in the number of CAT+ patients between groups or time to CAT+. However, CAT+ status during the first 30 minutes of surgery was higher in the REBOA Group (24/36, 66.7%) vs. the control group (17/57, 29.8%; p=0.001), having this group a higher in-hospital mortality rate vs. CAT- patients. Conclusion. CAT is a useful tool in the hemostatic resuscitation of patients with trauma and REBOA that could predict early mortality.

The relationships between Physical activity and asthma control and Body Mass Index (BMI) in patients with asthma.

OBJECTIVE: Asthma is one of the most common chronic conditions in developed countries. We examined whether physical activity (PA) is related to asthma control and body mass index (BMI) in asthma patients. METHODS: Cross-sectional data collected on PA (ActiGraph GT3X-BT), asthma control (the Asthma Control Questionnaire; ACQ), and BMI were examined in 206 adults (mean[sd] age 47.2[13.8] years; 49.5% had an obese BMI) with clinically diagnosed asthma. Relationships between PA and continuous BMI and asthma control were assessed using linear regression. Differences in PA across obesity (non-obese: <30 Kg/m2/obese: ≥30 Kg/m2) and asthma control categories (controlled: ≤0.75/uncontrolled: >0.75 ACQ score) were also examined. RESULTS: Median (p25, p75) steps counts and peak cadence were 6035 (4248, 8461) steps/day and 123 (115, 133) steps in a minute, respectively. There were nearly 2000 fewer steps/day among those with uncontrolled asthma versus controlled and among those with obese BMI versus nonobese, respectively (both p < 0.05). In regression models adjusted for relevant covariates each 1-unit increase in ACQ score was associated with -686 [95%CI -997, -13] (p ≤ 0.05) average steps/day. The statistical significance of these findings was attenuated (p ≥ 0.05) when BMI was added to the model. However, the point estimate was not reduced (-766 [95%CI -1060, 34]. CONCLUSIONS: Overall step counts were low in this population despite peak cadence values suggesting that most participants could perform moderate intensity activity. Increasing step counts should be considered an important lifestyle intervention goal in obese and non-obese asthma patients with low PA levels.

Assessing the interrelationship between asthma and obesity self-management behaviors.

Asthma and obesity are common coexisting conditions with increasing prevalence and substantial morbidity. This study examines the inter-relationship between illness and treatment beliefs in asthma and obesity and how they influence self-management behaviors. Overweight and obese adults ≥ 18 years with asthma were recruited from primary care and pulmonary practices in New York, NY and Denver, CO (n = 219). Path analysis was used to examine the relationship between asthma, weight and exercise-related illness and medication beliefs and SMB. Necessity beliefs about asthma medications and diet were associated with better medication adherence and healthier dietary behaviors (ß = 0.276, p = < 0.001, ß = 0.148, p = 0.018 respectively) whereas concerns about these self-care activities were associated with poorer adherence and worse dietary behaviors (ß = - 0.282, p < 0.001, ß = - 0.188, p = 0.003 respectively). We found no statistically significant association of exercise behaviors with any other weight or asthma illness or treatment beliefs. Our study demonstrates that necessity and concerns about treatment are associated with adherence in asthma and obesity. The lack of association of exercise behaviors with any asthma or weight related beliefs may reflect limited awareness of the impact of weight on asthma and warrants additional research.

Historic Use of Race-Based Spirometry Values Lowered Transplant Priority for Black Patients.

BACKGROUND: The lung allocation score (LAS) is a tool used to prioritize patients for lung transplantation. For patients with interstitial lung diseases (ILDs), spirometry data are used for the LAS calculation. Spirometry values such as a FVC are subjected to race-specific equations that determine expected values. The effect of race-specific equations in LAS score remains unknown. RESEARCH QUESTION: Did the use of a race-based spirometry equation lead to longer waitlist times for Black patients? STUDY DESIGN AND METHODS: We performed a retrospective analysis of patients listed for lung transplantation from 2005 through 2020 using publicly available data from the United Network for Organ Sharing. We recalculated LAS scores for Black patients using White-specific equations with the available variables. The primary objective was to evaluate the effect of race-specific equations on LAS scores and time on the transplant waitlist. RESULTS: A total of 33,845 patients listed for lung transplantation were included in the analysis. White patients were listed at lower LAS scores, a higher proportion of White patients underwent transplantation, and White patients died on the waitlist at lower rates. When recalculating LAS scores using White-specific equations, Black patients with ILD had up to a 1.9-point higher score, which resulted in additional waitlist time. INTERPRETATION: Race-specific equations led to longer wait times in Black patients listed for lung transplantation. The use of race-based equations widened already known disparities in pulmonary transplantation.

Critical systolic blood pressure threshold for endovascular aortic occlusion-A multinational analysis to determine when to place a REBOA.

BACKGROUND: Systolic blood pressure (SBP) is a potential indicator that could guide when to use a resuscitative endovascular balloon occlusion of the aorta (REBOA) in trauma patients with life-threatening injuries. This study aims to determine the optimal SBP threshold for REBOA placement by analyzing the association between SBP pre-REBOA and 24-hour mortality in severely injured hemodynamically unstable trauma patients. METHODS: We performed a pooled analysis of the aortic balloon occlusion (ABO) trauma and AORTA registries. These databases record the details related to the use of REBOA and include data from 14 countries worldwide. We included patients who had suffered penetrating and/or blunt trauma. Patients who arrived at the hospital with a SBP pre-REBOA of 0 mm Hg and remained at 0 mm Hg after balloon inflation were excluded. We evaluated the impact that SBP pre-REBOA had on the probability of death in the first 24 hours. RESULTS: A total of 1,107 patients underwent endovascular aortic occlusion, of these, 848 met inclusion criteria. The median age was 44 years (interquartile range [IQR], 27-59 years) and 643 (76%) were male. The median injury severity score was 34 (IQR, 25-45). The median SBP pre-REBOA was 65 mm Hg (IQR, 49-88 mm Hg). Mortality at 24 hours was reported in 279 (32%) patients. Math modeling shows that predicted probabilities of the primary outcome increased steadily in SBP pre-REBOA below 100 mm Hg. Multivariable mixed-effects analysis shows that when SBP pre-REBOA was lower than 60 mm Hg, the risk of death was more than 50% (relative risk, 1.5; 95% confidence interval, 1.17-1.92; p = 0.001). DISCUSSION: In patients who do not respond to initial resuscitation, the use of REBOA in SBPs between 60 mm Hg and 80 mm Hg may be a useful tool in resuscitation efforts before further decompensation or complete cardiovascular collapse. The findings from our study are clinically important as a first step in identifying candidates for REBOA. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

Weight Loss Interventions for Adults With Obesity-Related Asthma.

Obesity is a common asthma comorbidity in adults, contributing to higher patient morbidity and mortality. Conversely, weight loss can reduce the impact of obesity on asthma and improve patient outcomes by diverse mechanisms including modulating airway inflammation, reducing oxidative stress, and improving lung function. Multiple lifestyle, nonpharmacological, pharmacological, and surgical interventions are effective at reducing weight in the general population. Fewer have been studied specifically in the context of patients with asthma. However, increasingly effective pharmacologic options for weight loss highlight the need for allergists and pulmonologists to understand the range of approaches that may directly or indirectly yield clinical benefits in asthma management. Weight loss interventions often require multidisciplinary support to create strategies that can realistically achieve a patient's personalized asthma and weight goals. This includes minimizing the adverse weight effects of glucocorticoids, which remain a mainstay of asthma management. Disparities in access, cost, and insurance coverage of weight loss interventions remain acute challenges for providers and patients. Future studies are needed to elucidate mechanisms of action of specific weight loss interventions on short-term and long-term asthma outcomes.

Epigenomic response to albuterol treatment in asthma-relevant airway epithelial cells.

BACKGROUND: Albuterol is the first-line asthma medication used in diverse populations. Although DNA methylation (DNAm) is an epigenetic mechanism involved in asthma and bronchodilator drug response (BDR), no study has assessed whether albuterol could induce changes in the airway epithelial methylome. We aimed to characterize albuterol-induced DNAm changes in airway epithelial cells, and assess potential functional consequences and the influence of genetic variation and asthma-related clinical variables. RESULTS: We followed a discovery and validation study design to characterize albuterol-induced DNAm changes in paired airway epithelial cultures stimulated in vitro with albuterol. In the discovery phase, an epigenome-wide association study using paired nasal epithelial cultures from Puerto Rican children (n = 97) identified 22 CpGs genome-wide associated with repeated-use albuterol treatment (p < 9 × 10-8). Albuterol predominantly induced a hypomethylation effect on CpGs captured by the EPIC array across the genome (probability of hypomethylation: 76%, p value = 3.3 × 10-5). DNAm changes on the CpGs cg23032799 (CREB3L1), cg00483640 (MYLK4-LINC01600), and cg05673431 (KSR1) were validated in nasal epithelia from 10 independent donors (false discovery rate [FDR] < 0.05). The effect on the CpG cg23032799 (CREB3L1) was cross-tissue validated in bronchial epithelial cells at nominal level (p = 0.030). DNAm changes in these three CpGs were shown to be influenced by three independent genetic variants (FDR < 0.05). In silico analyses showed these polymorphisms regulated gene expression of nearby genes in lungs and/or fibroblasts including KSR1 and LINC01600 (6.30 × 10-14 ≤ p ≤ 6.60 × 10-5). Additionally, hypomethylation at the CpGs cg10290200 (FLNC) and cg05673431 (KSR1) was associated with increased gene expression of the genes where they are located (FDR < 0.05). Furthermore, while the epigenetic effect of albuterol was independent of the asthma status, severity, and use of medication, BDR was nominally associated with the effect on the CpG cg23032799 (CREB3L1) (p = 0.004). Gene-set enrichment analyses revealed that epigenomic modifications of albuterol could participate in asthma-relevant processes (e.g., IL-2, TNF-α, and NF-κB signaling pathways). Finally, nine differentially methylated regions were associated with albuterol treatment, including CREB3L1, MYLK4, and KSR1 (adjusted p value < 0.05). CONCLUSIONS: This study revealed evidence of epigenetic modifications induced by albuterol in the mucociliary airway epithelium. The epigenomic response induced by albuterol might have potential clinical implications by affecting biological pathways relevant to asthma.

Handgrip strength as a diagnostic tool for frailty risk in elderly patients with moderate to severe asthma.

OBJECTIVE: To evaluate handgrip strength (HGS) as a diagnostic tool for frailty risk in elderly patients with asthma, as well as to investigate the prevalence of frailty in this population. METHODS: This was a cross-sectional study including 96 patients ≥ 60 years of age diagnosed with moderate to severe asthma and treated at a tertiary referral center in Brazil. We measured HGS using a calibrated hydraulic hand dynamometer. We used a frailty scale and the AUC to assess the diagnostic accuracy of the HGS test. RESULTS: The median age of participants was 67 years. Most (78%) were women and non-White (91%) of low socioeconomic status. HGS identified those at risk for frailty, with an AUC of 71.6% (61.5-80.4%; p < 0.002), as well as a sensitivity of 73.58% and a specificity of 67.53%, on the basis of a cutoff of ≤ 19 kgf. CONCLUSIONS: HGS appears to be a simple, reliable tool for clinicians to determine frailty risk in older asthma patients in a point-of-care setting.

Meta-omics profiling of the gut-lung axis illuminates metabolic networks and host-microbial interactions associated with elevated lung elastance in a murine model of obese allergic asthma.

Obesity and associated changes to the gut microbiome worsen airway inflammation and hyperresponsiveness in asthma. Obesogenic host-microbial metabolomes have altered production of metabolites that may influence lung function and inflammatory responses in asthma. To understand the interplay of the gut microbiome, metabolism, and host inflammation in obesity-associated asthma, we used a multi-omics approach to profile the gut-lung axis in the setting of allergic airway disease and diet-induced obesity. We evaluated an immunomodulator, nitro-oleic acid (NO2-OA), as a host- and microbial-targeted treatment intervention for obesity-associated allergic asthma. Allergic airway disease was induced using house dust mite and cholera toxin adjuvant in C57BL6/J mice with diet-induced obesity to model obesity-associated asthma. Lung function was measured by flexiVent following a week of NO2-OA treatment and allergen challenge. 16S rRNA gene (from DNA, taxa presence) and 16S rRNA (from RNA, taxa activity) sequencing, metabolomics, and host gene expression were paired with a Treatment-Measured-Response model as a data integration framework for identifying latent/hidden relationships with linear regression among variables identified from high-dimensional meta-omics datasets. Targeting both the host and gut microbiota, NO2-OA attenuated airway inflammation, improved lung elastance, and modified the gut microbiome. Meta-omics data integration and modeling determined that gut-associated inflammation, metabolites, and functionally active gut microbiota were linked to lung function outcomes. Using Treatment-Measured-Response modeling and meta-omics profiling of the gut-lung axis, we uncovered a previously hidden network of interactions between gut levels of amino acid metabolites involved in elastin and collagen synthesis, gut microbiota, NO2-OA, and lung elastance. Further targeted metabolomics analyses revealed that obese mice with allergic airway disease had higher levels of proline and hydroxyproline in the lungs. NO2-OA treatment reduced proline biosynthesis by downregulation of pyrroline-5-carboxylate reductase 1 (PYCR1) expression. These findings are relevant to human disease: adults with mild-moderate asthma and BMI ≥ 25 had higher plasma hydroxyproline levels. Our results suggest that changes to structural proteins in the lung airways and parenchyma may contribute to heightened lung elastance and serve as a potential therapeutic target for obese allergic asthma.

High-fat diet and palmitic acid amplify airway type 2 inflammation.

Introduction: Metabolic dysfunction such as elevated levels of saturated fatty acids (SFA) may play a role in obese asthma, but its contribution to airway inflammation remains unclear. We sought to determine the role of high-fat diet (HFD) and palmitic acid (PA), a major form of SFA, in regulating type 2 inflammation. Methods: Airway samples from asthma patients with or without obesity, mouse models and human airway epithelial cell culture were utilized to test if SFA amplify type 2 inflammation. Results: Asthma patients with obesity had higher levels of airway PA than asthma patients without obesity. HFD increased the levels of PA in mice, and subsequently enhanced IL-13-induced airway eosinophilic inflammation. PA treatment amplified airway eosinophilic inflammation in mice that were previously exposed to IL-13 or house dust mite. IL-13 alone or in combination with PA increased dipeptidyl peptidase 4 (DPP4) release (soluble DPP4) and/or activity in mouse airways and human airway epithelial cells. Inhibition of DPP4 activity by linagliptin in mice pre-exposed to IL-13 or both IL-13 and PA increased airway eosinophilic and neutrophilic inflammation. Discussion: Our results demonstrated the exaggerating effect of obesity or PA on airway type 2 inflammation. Up-regulation of soluble DPP4 by IL-13 and/or PA may serve as a mechanism to prevent excessive type 2 inflammation. Soluble DPP4 may have the therapeutic potential in asthma patients with obesity who have an endotype with mixed airway eosinophilic and neutrophilic inflammation.

Phenotypic characteristics of asthma and morbidity are associated with distinct longitudinal changes in L-arginine metabolism.

BACKGROUND: The L-arginine metabolome is dysregulated in asthma, though it is not understood how longitudinal changes in L-arginine metabolism differ among asthma phenotypes and relate to disease outcomes. OBJECTIVES: To determine the longitudinal associations between phenotypic characteristics with L-arginine metabolites and their relationships with asthma morbidity. METHODS: This is a prospective cohort study of 321 patients with asthma followed semiannually for over 18 months with assessments of plasma L-arginine metabolites, asthma control, spirometry, quality of life and exacerbations. Metabolite concentrations and ratios were transformed using the natural logarithm. RESULTS: There were many differences in L-arginine metabolism among asthma phenotypes in the adjusted models. Increasing body mass index was associated with increased asymmetric dimethylarginine (ADMA) and depleted L-citrulline. Latinx was associated with increased metabolism via arginase, with higher L-ornithine, proline and L-ornithine/L-citrulline levels, and was found to have higher L-arginine availability compared with white race. With respect to asthma outcomes, increasing L-citrulline was associated with improved asthma control and increasing L-arginine and L-arginine/ADMA were associated with improved quality of life. Increased variability in L-arginine, L-arginine/ADMA, L-arginine/L-ornithine and L-arginine availability index over 12 months were associated with increased exacerbations, OR 4.70 (95% CI 1.35 to 16.37), OR 8.69 (95% CI 1.98 to 38.08), OR 4.17 (95% CI 1.40 to 12.41) and OR 4.95 (95% CI 1.42 to 17.16), respectively. CONCLUSIONS: Our findings suggest that L-arginine metabolism is associated with multiple measures of asthma control and may explain, in part, the relationship between age, race/ethnicity and obesity with asthma outcomes.

Gaps and Future Directions in Clinical Research on Obesity-Related Asthma.

Obesity is a major comorbidity for the development and worsening of asthma. It is associated with increased disease incidence, reduced response to inhaled and systemic steroids, increased asthma exacerbations, and poor disease control. Over the past two decades, we have learned that there are clinical asthma phenotypes associated with obesity, which have unique immune, inflammatory, and metabolic disease mechanisms. The objectives of this review are to provide a brief overview of the associations and gaps between these chronic inflammatory diseases and the role that traditional therapies have on treating patients with obesity-related asthma, and to describe new clinical research of therapeutic developments targeting mechanisms that are more specific to this patient population.

Research Priorities for Interventions to Address Health Disparities in Lung Nodule Management: An Official American Thoracic Society Research Statement.

Background: Lung nodules are common incidental findings, and timely evaluation is critical to ensure diagnosis of localized-stage and potentially curable lung cancers. Rates of guideline-concordant lung nodule evaluation are low, and the risk of delayed evaluation is higher for minoritized groups. Objectives: To summarize the existing evidence, identify knowledge gaps, and prioritize research questions related to interventions to reduce disparities in lung nodule evaluation. Methods: A multidisciplinary committee was convened to review the evidence and identify key knowledge gaps in four domains: 1) research methodology, 2) patient-level interventions, 3) clinician-level interventions, and 4) health system-level interventions. A modified Delphi approach was used to identify research priorities. Results: Key knowledge gaps included 1) a lack of standardized approaches to identify factors associated with lung nodule management disparities, 2) limited data evaluating the role of social determinants of health on disparities in lung nodule management, 3) a lack of certainty regarding the optimal strategy to improve patient-clinician communication and information transmission and/or retention, and 4) a paucity of information on the impact of patient navigators and culturally trained multidisciplinary teams. Conclusions: This statement outlines a research agenda intended to stimulate high-impact studies of interventions to mitigate disparities in lung nodule evaluation. Research questions were prioritized around the following domains: 1) need for methodologic guidelines for conducting research related to disparities in nodule management, 2) evaluating how social determinants of health influence lung nodule evaluation, 3) studying approaches to improve patient-clinician communication, and 4) evaluating the utility of patient navigators and culturally enriched multidisciplinary teams to reduce disparities.

Handgrip strength as a diagnostic tool for frailty risk in elderly patients with moderate to severe asthma / Força de preensão manual como ferramenta diagnóstica de risco de fragilidade em pacientes idosos com asma moderada a grave

ABSTRACT Objective: To evaluate handgrip strength (HGS) as a diagnostic tool for frailty risk in elderly patients with asthma, as well as to investigate the prevalence of frailty in this population. Methods: This was a cross-sectional study including 96 patients ≥ 60 years of age diagnosed with moderate to severe asthma and treated at a tertiary referral center in Brazil. We measured HGS using a calibrated hydraulic hand dynamometer. We used a frailty scale and the AUC to assess the diagnostic accuracy of the HGS test. Results: The median age of participants was 67 years. Most (78%) were women and non-White (91%) of low socioeconomic status. HGS identified those at risk for frailty, with an AUC of 71.6% (61.5-80.4%; p < 0.002), as well as a sensitivity of 73.58% and a specificity of 67.53%, on the basis of a cutoff of ≤ 19 kgf. Conclusions: HGS appears to be a simple, reliable tool for clinicians to determine frailty risk in older asthma patients in a point-of-care setting.

RESUMO Objetivo: Avaliar a força de preensão manual (FPM) como ferramenta diagnóstica de risco de fragilidade em pacientes idosos com asma e investigar a prevalência de fragilidade nessa população. Métodos: Estudo transversal com 96 pacientes com idade ≥ 60 anos e diagnóstico de asma moderada a grave, atendidos em um centro terciário de referência no Brasil. Medimos a FPM com um dinamômetro hidráulico manual calibrado. Usamos uma escala de fragilidade e a ASC para avaliar a precisão diagnóstica do teste de FPM. Resultados: A mediana da idade dos participantes foi de 67 anos. A maioria eram mulheres (78%) não brancas (91%) cujo nível socioeconômico era baixo. O ponto de corte de FPM ≤ 19 kgf identificou os participantes que apresentavam risco de fragilidade, com ASC = 71,6% (61,5-80,4%; p < 0,002), sensibilidade = 73,58% e especificidade = 67,53%. Conclusões: A FPM parece ser uma ferramenta simples e confiável para determinar, no próprio local de atendimento médico, o risco de fragilidade em pacientes idosos com asma.