Long-term safety, durability of response, cessation and switching of biologics.

PURPOSE OF REVIEW: Severe asthma patients suffer from decreased quality of life, and increased asthma symptoms, exacerbations, hospitalizations, and risk of death. Biologics have revolutionized treatment for severe asthma. However, with multiple biologic agents now available, clinicians must consider initial selection the long-term effectiveness of biologics. Additionally, patients have overlapping eligibilities and clinicians may consider switching between biologics for improved response. Finally, careful assessment of biologics cessation is needed for severe asthma patients who depend on these add-on therapies for asthma control. RECENT FINDINGS: Evidence for long-term durability and safety varies by biologic agent. In general, initial benefits noted from these agents (ex. exacerbation reduction) is, at minimum, sustained with long term use. Rates of adverse events and serious adverse events, including those requiring cessation of a biologics are low with long term use. Further studies are needed to understand the development of antidrug antibodies but currently their prevalence rates are low. Adverse events and insufficient efficacy are common reasons for biologic cessation or switching. Discontinuation maybe associated with waning of benefits but can be considered in certain situations. Biologic switching can be associated with improved asthma control. SUMMARY: Biologics are safe and effective long-term therapies for the management of asthma. Discontinuation must be carefully considered and if possible avoided. Reasons for insufficient efficacy must be evaluated and if needed, biologic switching should be considered.

Questions in Mild Asthma: An Official American Thoracic Society Research Statement.

Background: Patients with mild asthma are believed to represent the majority of patients with asthma. Disease-associated risks such as exacerbations, lung function decline, and death have been understudied in this patient population. There have been no prior efforts from major societies to describe research needs in mild asthma. Methods: A multidisciplinary, diverse group of 24 international experts reviewed the literature, identified knowledge gaps, and provided research recommendations relating to mild asthma definition, pathophysiology, and management across all age groups. Research needs were also investigated from a patient perspective, generated in conjunction with patients with asthma, caregivers, and stakeholders. Of note, this project is not a systematic review of the evidence and is not a clinical practice guideline. Results: There are multiple unmet needs in research on mild asthma driven by large knowledge gaps in all areas. Specifically, there is an immediate need for a robust mild asthma definition and an improved understanding of its pathophysiology and management strategies across all age groups. Future research must factor in patient perspectives. Conclusions: Despite significant advances in severe asthma, there remain innumerable research areas requiring urgent attention in mild asthma. An important first step is to determine a better definition that will accurately reflect the heterogeneity and risks noted in this group. This research statement highlights the topics of research that are of the highest priority. Furthermore, it firmly advocates the need for engagement with patient groups and for more support for research in this field.

Benralizumab improves symptoms of patients with severe, eosinophilic asthma with a diagnosis of nasal polyposis.

BACKGROUND: Clinically meaningful improvement in the Sino-Nasal Outcome Test-22 (SNOT-22) was observed in patients with severe, eosinophilic asthma, and nasal polyposis (NP) treated with benralizumab in the ANDHI trial. A post hoc assessment of the effects of benralizumab on SNOT-22 response and asthma efficacy measures in these patients was conducted for further characterization of the efficacy and safety of benralizumab for patients with severe asthma and NP. METHODS: Adults with severe, eosinophilic asthma who had experienced ≥2 prior-year exacerbations despite high-dosage inhaled corticosteroid plus additional controller[s] were randomized to 24 weeks of benralizumab or placebo. Patients with physician-diagnosed chronic rhinosinusitis with NP of any severity ongoing at baseline who consented to participate were included in the current ANDHI NP substudy population. Effect on NP symptoms was assessed by the SNOT-22, with an improvement of at least 8.9 defined as clinically significant (responder). Effects on chronic asthma outcomes were assessed by means of annualized asthma exacerbation rate (AER), St. George's Respiratory Questionnaire (SGRQ) total score, forced expiratory volume in one second (FEV1 ), and Asthma Control Questionnaire-6 (ACQ-6). All p-values were nominal. RESULTS: Of the ANDHI population (n = 656), 23% (n = 153) participated in the NP substudy (n = 96 benralizumab; n = 57 placebo). Patients were 50% female, with mean age of 53 years, had prior-year AER = 3.3; mean pre-bronchodilator FEV1  = 55% predicted; and median blood eosinophil count â€‹= 510 cells/µl. For patients with high baseline SNOT-22 scores (>30), benralizumab treatment improved symptoms of NP as measured by SNOT-22 from baseline to Week 24 compared with placebo (Week 24: -10.44 [p = .0176]). Percentage of responders to SNOT-22 was greater for benralizumab vs. placebo (71.3% vs. 45.5%; p = .0036), and effect was enhanced for patients with high baseline SNOT-22 scores (>30). A 69% reduction vs. placebo in annualized AER (0.77 vs. 2.47; p < .0001) and greater clinically meaningful improvements from baseline in SGRQ total score (-16.7), FEV1 (+0.32 L), and ACQ-6 (-0.88) were observed (p < .0001). Benralizumab was well-tolerated. Frequency of adverse events (AEs) was similar for benralizumab (76.0%) and placebo (73.7%) groups. Most common AEs (frequency ≥5%) reported at a greater frequency in benralizumab vs. placebo included headache, sinusitis, pyrexia, and influenza. CONCLUSIONS: These substudy data from ANDHI demonstrated the efficacy profile of benralizumab for patients with severe, eosinophilic asthma and NP, with improvement in SNOT-22 and asthma outcomes.

Biologic use and outcomes among adults with severe asthma treated by US subspecialists.

BACKGROUND: Multiple biologics are now available for severe asthma (SA) treatment and can improve outcomes for patients. However, few available data describe the real-world use and effectiveness of multiple approved biologics, including biologic switching, among subspecialists in the United States. OBJECTIVE: To evaluate biologic use and associated exacerbation outcomes in a large cohort of subspecialist-treated US adults with SA. METHODS: CHRONICLE is an ongoing, noninterventional study of subspecialist-treated US adults with SA receiving biologics, maintenance systemic corticosteroids, or those persistently uncontrolled by high-dose inhaled corticosteroids with additional controllers. For enrolled patients, sites report asthma exacerbations and medication use starting 12 months before enrollment. For patients enrolled between February 2018 and February 2021, biologic use and exacerbation outcomes before and after biologic initiation are described. RESULTS: Among 2793 enrolled patients, 66% (n = 1832) were receiving biologics. The most used biologic (> 1 biologic use per patient allowed) was omalizumab (47%), followed by benralizumab (27%), mepolizumab (26%), dupilumab (18%), and reslizumab (3%). Overall, 16% of patients had biologic switches, 13% had stops, and 89% had ongoing biologic use. Patients starting and switching biologics experienced a 58% (1.80 vs 0.76 per patient-year) and 49% (1.47 vs 0.75 per patient-year) reduction in exacerbations, respectively (both P < .001), with a numerically greater reduction observed among those starting non-anti-immunoglobulin E biologics compared with anti-immunoglobulin E. CONCLUSION: Real-world starting and switching of biologic therapies for SA were associated with meaningful reductions in exacerbations. With increasing biologic options available, individualized approaches to therapy may improve patient outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03373045.

Phenotyping, Precision Medicine, and Asthma.

The traditional one-size-fits all approach based on asthma severity is archaic. Asthma is a heterogenous syndrome rather than a single disease entity. Studies evaluating observable characteristics called phenotypes have elucidated this heterogeneity. Asthma clusters demonstrate overlapping features, are generally stable over time and are reproducible. What the identification of clusters may have failed to do, is move the needle of precision medicine meaningfully in asthma. This may be related to the lack of a straightforward and clinically meaningful way to apply what we have learned about asthma clusters. Clusters are based on both clinical factors and biomarkers. The use of biomarkers is slowly gaining popularity, but phenotyping based on biomarkers is generally greatly underutilized even in subspecialty care. Biomarkers are more often used to evaluate type 2 (T2) inflammatory signatures and eosinophils (sputum and blood), fractional exhaled nitric oxide (FeNO) and serum total and specific immunoglobulin (Ig) E reliably characterize the underlying inflammatory pathways. Biomarkers perform variably and clinicians must be familiar with their advantages and disadvantages to accurately apply them in clinical care. In addition, it is increasingly clear that clinical features are critical in understanding not only phenotypic characterization but in predicting response to therapy and future risk of poor outcomes. Strategies for asthma management will need to leverage our knowledge of biomarkers and clinical features to create composite scores and risk prediction tools that are clinically applicable. Despite significant progress, many questions remain, and more work is required to accurately identify non-T2 biomarkers. Adoption of phenotyping and more consistent use of biomarkers is needed, and we should continue to encourage this incorporation into practice.

Gore Cardioform atrial septal occluder: deployment procedure and techniques for closing challenging secundum atrial septal defects.

Ostium secundum atrial septal defects are mostly closed in the cardiac catheterisation laboratories using either Amplatzer® (Abbott Laboratories, IL) atrial septal occluder, Gore® Cardioform septal occluder and more recently using the recently approved (US FDA approval June 2019) Gore® Cardioform atrial septal defect occluder (W. L. Gore & Associates, AZ). Similar to any new device in the market, there is a learning curve to the deployment of this device. We therefore aim to report the key features about this new Gore Cardioform atrial septal defect occluder device with special emphasis on technical aspects that can be employed during transcatheter closure of challenging ostium secundum atrial septal defects using this device.

The M2a Macrophage Phenotype Accompanies Pulmonary Granuloma Resolution in Mmp12 Knock-Out Mice Instilled with Multiwall Carbon Nanotubes.

Sarcoidosis is a chronic disease with unknown etiology and pathophysiology, characterized by granuloma formation. Matrix Metalloproteinase-12 (MMP12) is an elastase implicated in active granulomatous sarcoidosis. Previously, we reported that oropharyngeal instillation of multiwall carbon nanotubes (MWCNT) into C57Bl/6 mice induced sarcoid-like granulomas and upregulation of MMP12. When Mmp12 knock-out (KO) mice were instilled with MWCNT, granuloma formation occurred 10 days post-instillation but subsequently resolved at 60 days. Thus, we concluded that MMP12 was essential to granuloma persistence. The aim of the current study was to identify potential mechanisms of granuloma resolution in Mmp12KO mice. Strikingly, an M2 macrophage phenotype was present in Mmp12KO but not in C57Bl/6 mice. Between 10 and 60 days, macrophage populations in MWCNT-instilled Mmp12KO mice demonstrated an M2c to M2a phenotypic shift, with elevations in levels of IL-13, an M2 subtype-regulating factor. Furthermore, the M2 inducer, Apolipoprotein E (ApoE), and Matrix Metalloproteinase-14 (MMP14), a promoter of collagen degradation, were upregulated in 60-day MWCNT-instilled Mmp12KO mice. In conclusion, alveolar macrophages express two M2 phenotypes in Mmp12KO mice: M2c at 10 days when granulomas form, and M2a at 60 days when granulomas are resolving. Findings suggest that granuloma resolution in 60-day Mmp12KO mice requires an M2a macrophage phenotype.

Asthma deaths in North Carolina: 1999-2016.

Introduction: Despite the significant decline in overall death rates in the U.S. over the past decade, many asthma deaths could have been avoided. Eastern North Carolina (N.C.) is an economically challenged region with significant health disparities and a high prevalence of asthma. Objective: The primary purpose of this project was to examine trends of asthma deaths across N.C. and identify counties in the state with the highest mortality rates over an 18-year period. Methods: CDC WONDER was used to query and evaluate age-adjusted asthma mortality rates from 1999 to 2016 among residents in N.C., greater than 1 year of age. Asthma death data were derived from death certificates using ICD-10 underlying cause-of-death codes J45 (asthma) and J46 (status asthmaticus). The Join point regression program was used to test statistical significance in age-adjusted rates for the U.S. and N.C. over the entire study period. Results: N.C. experienced a total of 2,066 decedents assigned as the underlying cause of deaths for an overall death rate of 12.5 per 1,000,000 persons. Death rates were highest among females (14.6 deaths per 1,000,000) and black or African Americans (24.7 per 1,000,000). Discussion: Overall asthma mortality rates in N.C. decreased. However, several rural and impoverished counties in eastern N.C. with a large percent of blacks or African-Americans, had the highest asthma death rates in the state. Conclusion: Healthcare providers should remain highly cognizant to provide optimal asthma management, education, and follow-up with asthma patients to help avoid unnecessary asthma related deaths.

Peroxisome Proliferator-activated Receptor-γ Deficiency Exacerbates Fibrotic Response to Mycobacteria Peptide in Murine Sarcoidosis Model.

We established a murine model of multiwall carbon nanotube (MWCNT)-elicited chronic granulomatous disease that bears similarities to human sarcoidosis pathology, including alveolar macrophage deficiency of peroxisome proliferator-activated receptor γ (PPARγ). Because lymphocyte reactivity to mycobacterial antigens has been reported in sarcoidosis, we hypothesized that addition of mycobacterial ESAT-6 (early secreted antigenic target protein 6) to MWCNT might exacerbate pulmonary granulomatous pathology. MWCNTs with or without ESAT-6 peptide 14 were instilled by the oropharyngeal route into macrophage-specific PPARγ-knockout (KO) or wild-type mice. Control animals received PBS or ESAT-6. Lung tissues, BAL cells, and BAL fluid were evaluated 60 days after instillation. PPARγ-KO mice receiving MWCNT + ESAT-6 had increased granulomas and significantly elevated fibrosis (trichrome staining) compared with wild-type mice or PPARγ-KO mice that received only MWCNT. Immunostaining of lung tissues revealed elevated fibronectin and Siglec F expression on CD11c+ infiltrating alveolar macrophages in the presence of MWCNT + ESAT-6 compared with MWCNT alone. Analyses of BAL fluid proteins indicated increased levels of transforming growth factor (TGF)-ß and the TGF-ß pathway mediator IL-13 in PPARγ-KO mice that received MWCNT + ESAT-6 compared with wild-type or PPARγ-KO mice that received MWCNT. Similarly, mRNA levels of matrix metalloproteinase 9, another requisite factor for TGF-ß production, was elevated in PPARγ-KO mice by MWCNT + ESAT-6. Analysis of ESAT-6 in lung tissues by mass spectrometry revealed ESAT-6 retention in lung tissues of PPARγ-KO but not wild-type mice. These data indicate that PPARγ deficiency promotes pulmonary ESAT-6 retention, exacerbates macrophage responses to MWCNT + ESAT-6, and intensifies pulmonary fibrosis. The present findings suggest that the model may facilitate understanding of the effects of environmental factors on sarcoidosis-associated pulmonary fibrosis.

Obesity and adult asthma: diagnostic and management challenges.

PURPOSE OF REVIEW: Despite advances in our understanding of the obese asthma phenotype, heterogeneity and large gaps in knowledge have hindered significant advances in directed interventions. RECENT FINDINGS: Obesity is associated with poorer asthma-related outcomes and increased risk of progression to severe asthma. Obese asthma is associated with variability in the expression of inflammatory markers, lung function impairments, and response to conventional and biologic therapies. In addition, traditional asthma biomarkers are not as reliable in obese patients. Several mechanistic pathways that uniquely impact asthma in obesity have been identified. Pathways involving innate lymphoid cells (ILC) type 2 (ILC-2) cells, surfactant protein-A, cell division control protein (CDC)42, interleukin (IL)-6, IL-17, and IL-33 are likely causal inflammatory pathways. Obesity also confounds lung function parameters making accurate diagnosis more challenging. As such, personalized asthma therapies directed towards obese asthma endotypes remain elusive. SUMMARY: Obesity confounds traditional asthma biomarkers and lung function measurements, thus defining obese asthma endotypes remains challenging. Novel pathways are being identified and hold promise for future targeted therapies. However, we are in dire need of updated guidelines regarding asthma diagnosis in obese patients and the development of biomarkers that more accurately identify specific endotypes.

The Effects of Obesity in Asthma.

PURPOSE OF REVIEW: Rising costs and increasing morbidity makes the identification and treatment of high-risk asthma phenotypes important. In this review, we outline the complex relationship between obesity and asthma. RECENT FINDINGS: Studies have confirmed a bi-directional relationship between obesity and asthma. Pathophysiological factors implicated include genetic risk, the effect of diet and microbiome, and obesity-related cytokines. There have been robust, albeit derived, efforts to phenotype this group with distinct clinical presentations based on age of onset of asthma. Unfortunately, the poor performance of biomarkers and traditional lung function testing has impeded diagnosis, phenotyping, and management of the obese asthma patient. There is also a lack of targeted interventions with weight loss showing some benefits. Obesity increases the prevalence of asthma and is associated with worse outcomes. There are unique research and clinical challenges while managing this group of patients.

Association Between Health Literacy, Electronic Health Literacy, Disease-Specific Knowledge, and Health-Related Quality of Life Among Adults With Chronic Obstructive Pulmonary Disease: Cross-Sectional Study.

BACKGROUND: Despite the relatively high prevalence of low health literacy among individuals living with chronic obstructive pulmonary disease (COPD), limited empirical attention has been paid to the cognitive and health literacy-related skills that can uniquely influence patients' health-related quality of life (HRQoL) outcomes. OBJECTIVE: The aim of this study was to examine how health literacy, electronic health (eHealth) literacy, and COPD knowledge are associated with both generic and lung-specific HRQoL in people living with COPD. METHODS: Adults from the COPD Foundation's National Research Registry (n=174) completed a cross-sectional Web-based survey that assessed sociodemographic characteristics, comorbidity status, COPD knowledge, health literacy, eHealth literacy, and generic/lung-specific HRQoL. Hierarchical linear regression models were tested to examine the roles of health literacy and eHealth literacy on generic (model 1) and lung-specific (model 2) HRQoL, after accounting for socioeconomic and comorbidity covariates. Spearman rank correlations examined associations between ordinal HRQoL items and statistically significant hierarchical predictor variables. RESULTS: After adjusting for confounding factors, health literacy, eHealth literacy, and COPD knowledge accounted for an additional 9% of variance in generic HRQoL (total adjusted R2=21%; F9,164=6.09, P<.001). Health literacy (b=.08, SE 0.02, 95% CI 0.04-0.12) was the only predictor positively associated with generic HRQoL (P<.001). Adding health literacy, eHealth literacy, and COPD knowledge as predictors explained an additional 7.40% of variance in lung-specific HRQoL (total adjusted R2=26.4%; F8,161=8.59, P<.001). Following adjustment for covariates, both health literacy (b=2.63, SE 0.84, 95% CI 0.96-4.29, P<.001) and eHealth literacy (b=1.41, SE 0.67, 95% CI 0.09-2.73, P<.001) were positively associated with lung-specific HRQoL. Health literacy was positively associated with most lung-specific HRQoL indicators (ie, cough frequency, chest tightness, activity limitation at home, confidence leaving home, sleep quality, and energy level), whereas eHealth literacy was positively associated with 5 of 8 (60%) lung-specific HRQoL indicators. Upon controlling for confounders, COPD knowledge (b=-.56, SE 0.29, 95% CI -1.22 to -0.004, P<.05) was inversely associated with lung-specific HRQoL. CONCLUSIONS: Health literacy, but not eHealth literacy, was positively associated with generic HRQoL. However, both health literacy and eHealth literacy were positively associated with lung-specific HRQoL, with higher COPD knowledge indicative of lower lung-specific HRQoL. These results confirm the importance of considering health and eHealth literacy levels when designing patient education programs for people living with COPD. Future research should explore the impact of delivering interventions aimed at improving eHealth and health literacy among patients with COPD, particularly when disease self-management goals are to enhance HRQoL.

Transcriptional survey of alveolar macrophages in a murine model of chronic granulomatous inflammation reveals common themes with human sarcoidosis.

Mohan A, Malur A, McPeek M, Barna BP, Schnapp LM, Thomassen MJ, Gharib SA. Transcriptional survey of alveolar macrophages in a murine model of chronic granulomatous inflammation reveals common themes with human sarcoidosis. Am J Physiol Lung Cell Mol Physiol 314: L617-L625, 2018. First published December 6, 2017; doi: 10.1152/ajplung.00289.2017 . To advance our understanding of the pathobiology of sarcoidosis, we developed a multiwall carbon nanotube (MWCNT)-based murine model that shows marked histological and inflammatory signal similarities to this disease. In this study, we compared the alveolar macrophage transcriptional signatures of our animal model with human sarcoidosis to identify overlapping molecular programs. Whole genome microarrays were used to assess gene expression of alveolar macrophages in six MWCNT-exposed and six control animals. The results were compared with the transcriptional profiles of alveolar immune cells in 15 sarcoidosis patients and 12 healthy humans. Rigorous statistical methods were used to identify differentially expressed genes. To better elucidate activated pathways, integrated network and gene set enrichment analysis (GSEA) was performed. We identified over 1,000 differentially expressed between control and MWCNT mice. Gene ontology functional analysis showed overrepresentation of processes primarily involved in immunity and inflammation in MCWNT mice. Applying GSEA to both mouse and human samples revealed upregulation of 92 gene sets in MWCNT mice and 142 gene sets in sarcoidosis patients. Commonly activated pathways in both MWCNT mice and sarcoidosis included adaptive immunity, T-cell signaling, IL-12/IL-17 signaling, and oxidative phosphorylation. Differences in gene set enrichment between MWCNT mice and sarcoidosis patients were also observed. We applied network analysis to differentially expressed genes common between the MWCNT model and sarcoidosis to identify key drivers of disease. In conclusion, an integrated network and transcriptomics approach revealed substantial functional similarities between a murine model and human sarcoidosis particularly with respect to activation of immune-specific pathways.

Airway Obstruction Caused by Iron Pill Aspiration: An Interventional Pulmonology Approach to Prevent Surgery.

Iron Pill Aspiration (IPA) is a challenging medical condition that requires prompt management to prevent detrimental outcomes. One of the most serious complications of IPA is airway inflammation which commonly leads to severe obstruction. Airway complications may require surgical intervention including the resection of the affected lung. Prompt recognition and management of IPA can reduce the risk of airway complications and may prevent the need of a surgical intervention. Bronchoscopic management entails the use of flexible and rigid bronchoscopes along with balloon bronchoplasty, ablation of the inflammatory tissue causing obstruction and airway stenting. In this report, we describe a case of severe airway obstruction secondary to iron pill aspiration with favourable outcome following bronchoscopic multimodalities intervention including temporary airway stenting.

Asthma-Related Emergency Department Visits in North Carolina, 2010-2014.

BACKGROUND The purpose of this study was to compare asthma-related emergency department (ED) visit rates across North Carolina. Results from this study can inform health planning while helping public health and health care professionals in identifying geographical areas and targeting age groups to reduce the asthma burden in North Carolina.METHODS This was a retrospective data analysis between 2010 and 2014 among North Carolina patients presenting to an ED with a first or second listed diagnosis code related to asthma (ICD-9-CM, 493.xx). Data was obtained from the North Carolina Disease Event Tracking and Epidemiology Collection Tool. Annual, age-adjusted rates were standardized to the 2000 US standard population using the direct method. Repeated measures ANOVA was conducted to compare differences between mean values of asthma-related ED visit rates in regions, urbanicity, and age groups across years.RESULTS Asthma ED rates were consistently higher in the east (85.1 per 10,000) compared with other regions. While most age group ED rates fluctuated over the study period, univariate test results indicated statistical increases in ED asthma visits among the groups aged 5 to 9 years (P < .01), and 65 and over (P < .03).CONCLUSION Public health officials should recognize the disproportionate burden of asthma-related ED visits, particularly among rural and impoverished counties in the eastern portion of North Carolina when prioritizing health concerns across North Carolina.

Temperature controlled radiofrequency ablation at different sites for treatment of obstructive sleep apnea syndrome: a systematic review and meta-analysis.

BACKGROUND: This study seeks to determine the efficacy of temperature controlled radiofrequency tissue ablation (TCRFTA) to alleviate symptoms of obstructive sleep apnea (OSA) and reduce polysomnographic measures of OSA in the first year post-treatment. METHODS: Systematic review and meta-analysis. Two independent searches of MEDLINE, EMBASE bibliographic databases, and Evidence Based Medicine Reviews to identify publications relevant to OSA and TCRFTA. Effectiveness of TCRFTA was measured separately for application of TCRFTA at the base of tongue and soft palate, and for multilevel intervention using the respiratory disturbance index (RDI), lowest oxygen saturation (LSAT), Epworth sleepiness scale (ESS), and bed partner's rating of snoring using a visual analogue scale (VAS snoring). The most recent search was conducted in April 2013. Statistical analysis was performed using Review Manager Version 5.2 using a relative measure of effect, i.e., ratio of means (RoM). RESULTS: Our initial search resulted in 29 eligible studies, and subsequently, 20 studies were included in the meta-analysis. Substantial and consistent improvement in PSG and subjective outcomes were observed post-TCRFTA in the base of tongue (BOT) and multilevel surgery groups only. Application of TCRFTA at the BOT was associated with a significant reduction in RDI (RoM 0.60, CI 0.47-0.76), ESS (RoM 0.59, CI 0.51-0.67), and VAS snoring (RoM 0.48, CI 0.37-0.62) and increase in lowest oxygen saturation (RoM 1.05, CI 1.01-1.10). Similarly, a significant reduction in RDI (RoM 0.61, CI 0.47-0.80) and ESS (RoM 0.79, CI -0.71 to 0.88) was observed after multilevel TCRFTA, but substantial heterogeneity between these studies was observed. CONCLUSION: TCRFTA is clinically effective in reducing RDI levels and symptoms of sleepiness in patients with OSA syndrome when directed at the base of tongue or as a multilevel procedure.

The reliability and validity of patient-reported chronic obstructive pulmonary disease exacerbations.

PURPOSE OF REVIEW: Despite the increasing awareness of their pathogenesis and clinical consequences, research on and clinical management of acute exacerbations of chronic obstructive lung disease (AECOPDs) have been hindered by the lack of a consistent and reliable definition. Symptom-based definitions of exacerbations are sensitive to events and account for unreported exacerbations. Event (healthcare utilization)-based definitions are somewhat more definitive but miss unreported events. Objective quantification of symptoms in AECOPD is now possible with the development of the Exacerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT-PRO), a patient-reported outcome (PRO) measure. RECENT FINDINGS: Several studies have revealed that unreported AECOPDs are more frequent than reported events and are associated with long-term adverse consequences. New antibiotic development for AECOPD has been hampered by the lack of validated measures for resolution of exacerbations. As a result of these observations, a unique collaborative effort between academia, industry and regulatory agencies resulted in the development of the EXACT-PRO. It consists of 14 questions that generate a score between 0 and 100, and it has been shown to have excellent reliability and validity. SUMMARY: In the absence of a reliable biomarker, the definition and measurement of exacerbations has been subjective and imprecise. PRO measures such as EXACT can provide much needed objectivity in assessing symptom-defined exacerbations, which may translate into a uniform outcome measure in clinical trials. With further development and validation, it may have a role in clinical practice in the earlier detection of exacerbations, stratification of an exacerbation severity and the assessment of clinical response to treatment.

Lab on skin: real-time metabolite monitoring with polyphenol film based subdermal wearable patches.

The advent of digital technologies has spurred the development of wearable sensing devices marking a significant shift in obtaining real-time physiological information. The principal objective is to transition from blood-centric monitoring to minimally invasive modalities, which will enable movement from specialised settings to more accessible environments such as the practices of general practitioners or even home settings. While subcutaneously implanted continuous monitoring devices have demonstrated this transition, detection of analytes from sample matrices like skin interstitial fluid (ISF), is a frontier that offers attractive minimally invasive routes for detection of biomarkers. This manuscript presents a comprehensive overview of our work in subdermal wearable biosensing patches for the simultaneous monitoring of glucose and lactate from ISF in ambulatory conditions. The performance of the subdermal wearable glucose monitoring patch was evaluated over a duration of three days, which is the longest reported duration reported till date. The subdermal wearable lactate sensing patch was worn for the duration of the exercise. Our findings highlight a critical observation that biofouling effects become apparent after a 24 h period. The data presented in this manuscript extends on the knowledge in the areas of continuous metabolite monitoring by introducing multifunctional polyphenol polymer films that can be used for both glucose and lactate monitoring with appropriate modifications. This study underscores the potential of subdermal wearable patches as versatile tools for real-time metabolite monitoring, positioning them as valuable assets in the evolution of personalised healthcare in diverse settings.

Mild asthma: Lessons learned and remaining questions.

Patients living with mild disease represent the largest proportion of asthma patients. There are significant challenges in proposing a definition that would best describe these patients, while also accurately identifying at-risk individuals. Current literature suggests considerable inflammatory and clinical heterogeneity within this group. Research has shown that these patients are at risk of poor control, exacerbations, lung function decline, and death. Despite conflicting data on its prevalence, eosinophilic inflammation appears to be a predictor of poorer outcomes in mild asthma. There is an immediate need to better understand phenotypic clusters in mild asthma. It is also important to understand factors that influence disease progression and remission, as it is evident that both vary in mild asthma. Guided by robust literature that supports inhaled corticosteroid-based strategies over short-acting beta-agonist (SABA) reliant regimens, the management of these patients has evolved considerably. Unfortunately, SABA use remains high in clinical practice despite strong advocacy from the Global Initiative for Asthma. Future mild asthma research should explore the role of biomarkers, develop prediction tools based on composite risk scores, and explore targeted therapies at least for at-risk individuals.