Pub Date : 2024-03-20DOI: 10.1101/2024.03.19.24304532
Benedikt Franke, Leonid Goubergrits
Oxygenators are a lifesaving technology used for blood oxygenation and decarboxylation in case of acute respiratory failure, chronic lung disease, and during open-heart surgery. Devices typically consist of a bundle of thousands of fiber membranes in a housing, with gas flowing inside the fibers and blood flowing in the opposite direction outside the fibers. Both ends of the fiber membranes are attached with an adhesive to prevent direct contact between gas and blood. The shape of the volume through which the blood flows is determined by the housing of the oxygenator and the internal end surfaces of the bonded parts of the fiber-membrane bundle. The traditional potting process results in a volume shape that is associated with stagnation zones, which are known to promote thrombus formation. In this study, an adapted potting process is proposed which results in a blood compartment with beveled end faces of the glued bundle parts. Using a numerical study, we have demonstrated that the novel oxygenator design results in optimized flow conditions.
{"title":"Beveled shaped axial oxygenator with improved hemodynamics","authors":"Benedikt Franke, Leonid Goubergrits","doi":"10.1101/2024.03.19.24304532","DOIUrl":"https://doi.org/10.1101/2024.03.19.24304532","url":null,"abstract":"Oxygenators are a lifesaving technology used for blood oxygenation and decarboxylation in case of acute respiratory failure, chronic lung disease, and during open-heart surgery. Devices typically consist of a bundle of thousands of fiber membranes in a housing, with gas flowing inside the fibers and blood flowing in the opposite direction outside the fibers. Both ends of the fiber membranes are attached with an adhesive to prevent direct contact between gas and blood. The shape of the volume through which the blood flows is determined by the housing of the oxygenator and the internal end surfaces of the bonded parts of the fiber-membrane bundle. The traditional potting process results in a volume shape that is associated with stagnation zones, which are known to promote thrombus formation. In this study, an adapted potting process is proposed which results in a blood compartment with beveled end faces of the glued bundle parts. Using a numerical study, we have demonstrated that the novel oxygenator design results in optimized flow conditions.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"35 1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140201433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-18DOI: 10.1101/2024.03.17.24304031
Tobit Fischer, Torsten Eggert, Alina Wildenauer, Sarah Dietz-Terjung, Rainer Voisard, Christoph Schoebel
Purpose Long-term monitoring of respiratory rate (RR) is promising for the management of chronic conditions. Research interest is particularly high in chronic respiratory diseases (CRDs), especially for predicting acute exacerbations of COPD (AECOPD). The aim of the present study was to evaluate the long-term validity of a recent non-contact biomotion sensor in the home environment of CRD patients with domiciliary ventilator support, focusing on patient acceptance and usability of this device, as well as RR fluctuations related to AECOPD. Patients and methods In this prospective proof-of-concept study, 19 patients requiring non-invasive ventilation (NIV) and seven patients requiring invasive mechanical ventilation (IMV) were provided with the non-contact device for six and one month, respectively. Main indication for NIV therapy was COPD. Real-world validation of the device was performed by comparing nocturnal RR values between the non-contact system and both types of ventilators. The acceptance and operability of the biomotion sensor were evaluated using a questionnaire. COPD exacerbations that occurred during the study period were assessed for possible RR fluctuations preceding these events. Results Mean absolute error (MAE) of median RR between the NIV device and the non-contact system, based on 2326 nights, was 0.78 (SD: 1.96) breaths per minute (brpm). MAE between the IMV device and the non-contact system was 0.12 brpm (SD: 0.52) for 215 nights. The non-contact device was accepted by the patients and proved to be easy to use. In some of the overall 13 cases of AECOPD, RR time courses showed variations of increased nocturnal respiratory activity a few days before the occurrence of such events. Conclusion The present non-contact system is suitable and well accepted for valid long-term monitoring of nocturnal RR in the patient's home environment. This finding may serve as a starting point for larger studies, e.g., to develop robust AECOPD prediction rules.
{"title":"At-home validation of remote breathing monitoring: A proof-of-concept for long-term care of respiratory patients using a non-contact, radar-based biomotion sensor","authors":"Tobit Fischer, Torsten Eggert, Alina Wildenauer, Sarah Dietz-Terjung, Rainer Voisard, Christoph Schoebel","doi":"10.1101/2024.03.17.24304031","DOIUrl":"https://doi.org/10.1101/2024.03.17.24304031","url":null,"abstract":"Purpose Long-term monitoring of respiratory rate (RR) is promising for the management of chronic conditions. Research interest is particularly high in chronic respiratory diseases (CRDs), especially for predicting acute exacerbations of COPD (AECOPD). The aim of the present study was to evaluate the long-term validity of a recent non-contact biomotion sensor in the home environment of CRD patients with domiciliary ventilator support, focusing on patient acceptance and usability of this device, as well as RR fluctuations related to AECOPD.\u0000Patients and methods In this prospective proof-of-concept study, 19 patients requiring non-invasive ventilation (NIV) and seven patients requiring invasive mechanical ventilation (IMV) were provided with the non-contact device for six and one month, respectively. Main indication for NIV therapy was COPD. Real-world validation of the device was performed by comparing nocturnal RR values between the non-contact system and both types of ventilators. The acceptance and operability of the biomotion sensor were evaluated using a questionnaire. COPD exacerbations that occurred during the study period were assessed for possible RR fluctuations preceding these events.\u0000Results Mean absolute error (MAE) of median RR between the NIV device and the non-contact system, based on 2326 nights, was 0.78 (SD: 1.96) breaths per minute (brpm). MAE between the IMV device and the non-contact system was 0.12 brpm (SD: 0.52) for 215 nights. The non-contact device was accepted by the patients and proved to be easy to use. In some of the overall 13 cases of AECOPD, RR time courses showed variations of increased nocturnal respiratory activity a few days before the occurrence of such events.\u0000Conclusion The present non-contact system is suitable and well accepted for valid long-term monitoring of nocturnal RR in the patient's home environment. This finding may serve as a starting point for larger studies, e.g., to develop robust AECOPD prediction rules.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"147 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140169163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-18DOI: 10.1101/2024.03.14.24304224
Vadim Farztdinov, Boris Zuehlke, Franziska Sotzny, Fridolin Steinbeis, Martina Seifert, Claudia Kedor, Kirsten Wittke, Pinkus Tober-Lau, Kathrin Textoris-Taube, Daniela Ludwig, Clemens Dierks, Dominik Bierbaum, Leif Erik Sander, Leif Gunnar Hanitsch, Martin Witzenrath, Florian Kurth, Michael Muelleder, Carmen Scheibenbogen, Markus Ralser
Long COVID, or Post-Acute COVID Syndrome (PACS), may develop following SARS-CoV-2 infection, posing a substantial burden to society. Recently, PACS has been linked to a persistent activation of the complement system (CS), offering hope for both a diagnostic tool and targeted therapy. However, our findings indicate that, after adjusting proteomics data for age, body mass index and sex imbalances, the evidence of complement system activation disappears. Furthermore, proteomic analysis of two orthogonal cohorts-one addressing PACS following severe acute phase and another after a mild acute phase-fails to support the notion of persistent CS activation. Instead, we identify a proteomic signature indicative of either ongoing infections or sustained immune activation similar to that observed in acute COVID-19, particularly within the mild-PACS cohort.
{"title":"Role of the complement system in Long COVID","authors":"Vadim Farztdinov, Boris Zuehlke, Franziska Sotzny, Fridolin Steinbeis, Martina Seifert, Claudia Kedor, Kirsten Wittke, Pinkus Tober-Lau, Kathrin Textoris-Taube, Daniela Ludwig, Clemens Dierks, Dominik Bierbaum, Leif Erik Sander, Leif Gunnar Hanitsch, Martin Witzenrath, Florian Kurth, Michael Muelleder, Carmen Scheibenbogen, Markus Ralser","doi":"10.1101/2024.03.14.24304224","DOIUrl":"https://doi.org/10.1101/2024.03.14.24304224","url":null,"abstract":"Long COVID, or Post-Acute COVID Syndrome (PACS), may develop following SARS-CoV-2 infection, posing a substantial burden to society. Recently, PACS has been linked to a persistent activation of the complement system (CS), offering hope for both a diagnostic tool and targeted therapy. However, our findings indicate that, after adjusting proteomics data for age, body mass index and sex imbalances, the evidence of complement system activation disappears. Furthermore, proteomic analysis of two orthogonal cohorts-one addressing PACS following severe acute phase and another after a mild acute phase-fails to support the notion of persistent CS activation. Instead, we identify a proteomic signature indicative of either ongoing infections or sustained immune activation similar to that observed in acute COVID-19, particularly within the mild-PACS cohort.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140169389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-16DOI: 10.1101/2024.03.15.24304343
Gary J Connett, Scott Maguire, Tom C Larcombe, Naomi Scanlan, Supriya S Shinde, Thilini Muthukumarana, Amanda Bevan, Ruth H Keogh, Julian P Legg
Introduction: Elexacaftor, Tezacaftor, Ivacaftor (ETI) became available in the UK in August 2020 to treat people with Cystic Fibrosis (CF) aged > 12 years. We report a real-world study of clinical outcomes in young people treated with ETI at our CF centre within the first two years of its availability. Methods: Participants aged 12 to 17 were identified within our clinic, with demographic data supplemented by the UK CF registry. Comprehensive outcome data spanning two years pre and two years post-initiation of CFTR modulators were compiled from various local sources, including patient records, medication delivery logs, and clinical notes. Results: Of the 62 patients started on ETI (32 male, mean age 13.3 years), most (76%) were homozygous for the F508del mutation. Three discontinuations occurred: one pregnancy, two related to side effects. Adherence was high (Proportion of Days covered >90% both years). Following ETI initiation there was a significant increase in mean FEV1% (+11.7 units; 95% CI 7.4 - 15.6), sustained throughout the two-year treatment period. There was no association between baseline lung function and the degree of improvement or rate of decline post-treatment. Improvements were similar for all treatable genotypes. There was a small increase in BMI z-score at four months of treatment, returning to baseline by 24 months. There was a marked reduction in the need for intravenous antibiotics. Conclusions: ETI use in adolescents in a real-world setting led to sustained improvements in health outcomes, consistent with those seen in open trial extension studies
简介：Elexacaftor、Tezacaftor和Ivacaftor（ETI）于2020年8月在英国上市，用于治疗12岁的囊性纤维化（CF）患者。我们报告了我们的CF中心在ETI上市后头两年内对接受ETI治疗的年轻人的临床结果进行的一项真实世界研究：方法：我们在诊所内确定了 12 至 17 岁的参与者，并通过英国 CF 登记册补充了人口统计学数据。从病人记录、给药记录和临床笔记等各种当地资料来源收集整理了CFTR调节剂使用前两年和使用后两年的综合结果数据：在开始使用 ETI 的 62 名患者中（32 名男性，平均年龄 13.3 岁），大多数（76%）都是 F508del 基因突变的同型患者。有三例停药：一例是怀孕，两例与副作用有关。坚持治疗的比例很高（两年的治疗天数比例均为 90%）。开始 ETI 治疗后，平均 FEV1% 显著增加（+11.7 个单位；95% CI 7.4 - 15.6），并在两年的治疗期内持续增加。基线肺功能与治疗后的改善程度或下降速度之间没有关联。所有可治疗基因型的改善程度相似。治疗四个月后，体重指数 Z 值略有上升，24 个月后恢复到基线。静脉注射抗生素的需求明显减少。结论：在真实世界环境中对青少年使用 ETI 可持续改善健康状况，这与开放试验推广研究中的结果一致
{"title":"Real-world impact of Elexacaftor-Tezacaftor-Ivacaftor treatment in young people with Cystic Fibrosis: A longitudinal study","authors":"Gary J Connett, Scott Maguire, Tom C Larcombe, Naomi Scanlan, Supriya S Shinde, Thilini Muthukumarana, Amanda Bevan, Ruth H Keogh, Julian P Legg","doi":"10.1101/2024.03.15.24304343","DOIUrl":"https://doi.org/10.1101/2024.03.15.24304343","url":null,"abstract":"Introduction: Elexacaftor, Tezacaftor, Ivacaftor (ETI) became available in the UK in August 2020 to treat people with Cystic Fibrosis (CF) aged > 12 years. We report a real-world study of clinical outcomes in young people treated with ETI at our CF centre within the first two years of its availability.\u0000Methods: Participants aged 12 to 17 were identified within our clinic, with demographic data supplemented by the UK CF registry. Comprehensive outcome data spanning two years pre and two years post-initiation of CFTR modulators were compiled from various local sources, including patient records, medication delivery logs, and clinical notes.\u0000Results: Of the 62 patients started on ETI (32 male, mean age 13.3 years), most (76%) were homozygous for the F508del mutation. Three discontinuations occurred: one pregnancy, two related to side effects. Adherence was high (Proportion of Days covered >90% both years). Following ETI initiation there was a significant increase in mean FEV1% (+11.7 units; 95% CI 7.4 - 15.6), sustained throughout the two-year treatment period. There was no association between baseline lung function and the degree of improvement or rate of decline post-treatment. Improvements were similar for all treatable genotypes. There was a small increase in BMI z-score at four months of treatment, returning to baseline by 24 months. There was a marked reduction in the need for intravenous antibiotics. Conclusions: ETI use in adolescents in a real-world setting led to sustained improvements in health outcomes, consistent with those seen in open trial extension studies","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140149478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-15DOI: 10.1101/2024.03.13.24304251
Sky Vanderburg, Tyler Law, Priya B. Shete, Elisabeth D. Riviello, Carolyn M. Hendrickson, Gregory D. Burns, Vivek Jain, Michael S. Lipnick
Background: During the COVID-19 pandemic, many facilities worldwide struggled to forecast oxygen demand, which often exceeded oxygen supply to the detriment of patient care. Accurate estimates of oxygen demand by patients with COVID-19 are scarce, and proposed estimation methods have not been fully evaluated or implemented. To address this knowledge gap, oxygen demand by COVID-19 patients was calculated at a large safety-net hospital in the United States using patient consumption (demand) data, oxygen procurement (supply) data, and modeled data with a novel calculator tool. Methods: Data were extracted from electronic medical records of patients admitted with COVID-19 to Zuckerberg San Francisco General Hospital (ZSFG) from March 2020 to March 2022, including every recorded peripheral oxygen saturation (SpO2) measurement as well as oxygen delivery device(s) and settings. Total patient oxygen consumption was calculated as the sum of oxygen delivery amounts for each recorded time interval during hospitalization. Oxygen delivery amounts were calculated using delivery device-specific formulas. Patient and treatment-specific factors which may impact oxygen demand were also reported. For comparison, oxygen procurement logs from the study period were reviewed to estimate supply consumed, and the Oxygencalculator.com tool was used to model oxygen demand using an experimental patient population of the same size. Results: In total, 282,095 time points from 1,076 patients were analyzed. Two-thirds of patients received oxygen, of which 24.3% received high-flow oxygen (HFO) therapy and 16.0% received invasive mechanical ventilation (IMV) at some point. In-hospital mortality was 7.5% overall, 10.8% for patients who received oxygen, and 28.3% for patients who received IMV. The median (IQR) duration of oxygen therapy was 3.1 (0.8-8.9) days, mean (SD) oxygen flow was 5.6 (5.0) liters per minute (LPM), and mean (SD) total volume of oxygen delivered was 180,115 (510,330) liters (L) per hospitalization. Both the supply- and model-based methods overestimated oxygen consumption compared to demand estimated from patient data. Conclusions: This study represents one of the largest cohorts of patients with COVID-19 for which oxygen demand has been calculated, including patient clinical characteristics which may help explain variations in oxygen demand. Moreover, oxygen demand was quantified using a methodology that could be applied in any setting.
{"title":"Quantifying Oxygen Demand by Patients Hospitalized with COVID-19 at a Large Safety-Net Hospital Using Multiple Methodologies","authors":"Sky Vanderburg, Tyler Law, Priya B. Shete, Elisabeth D. Riviello, Carolyn M. Hendrickson, Gregory D. Burns, Vivek Jain, Michael S. Lipnick","doi":"10.1101/2024.03.13.24304251","DOIUrl":"https://doi.org/10.1101/2024.03.13.24304251","url":null,"abstract":"Background: During the COVID-19 pandemic, many facilities worldwide struggled to forecast oxygen demand, which often exceeded oxygen supply to the detriment of patient care. Accurate estimates of oxygen demand by patients with COVID-19 are scarce, and proposed estimation methods have not been fully evaluated or implemented. To address this knowledge gap, oxygen demand by COVID-19 patients was calculated at a large safety-net hospital in the United States using patient consumption (demand) data, oxygen procurement (supply) data, and modeled data with a novel calculator tool. Methods: Data were extracted from electronic medical records of patients admitted with COVID-19 to Zuckerberg San Francisco General Hospital (ZSFG) from March 2020 to March 2022, including every recorded peripheral oxygen saturation (SpO2) measurement as well as oxygen delivery device(s) and settings. Total patient oxygen consumption was calculated as the sum of oxygen delivery amounts for each recorded time interval during hospitalization. Oxygen delivery amounts were calculated using delivery device-specific formulas. Patient and treatment-specific factors which may impact oxygen demand were also reported. For comparison, oxygen procurement logs from the study period were reviewed to estimate supply consumed, and the Oxygencalculator.com tool was used to model oxygen demand using an experimental patient population of the same size. Results: In total, 282,095 time points from 1,076 patients were analyzed. Two-thirds of patients received oxygen, of which 24.3% received high-flow oxygen (HFO) therapy and 16.0% received invasive mechanical ventilation (IMV) at some point. In-hospital mortality was 7.5% overall, 10.8% for patients who received oxygen, and 28.3% for patients who received IMV. The median (IQR) duration of oxygen therapy was 3.1 (0.8-8.9) days, mean (SD) oxygen flow was 5.6 (5.0) liters per minute (LPM), and mean (SD) total volume of oxygen delivered was 180,115 (510,330) liters (L) per hospitalization. Both the supply- and model-based methods overestimated oxygen consumption compared to demand estimated from patient data. Conclusions: This study represents one of the largest cohorts of patients with COVID-19 for which oxygen demand has been calculated, including patient clinical characteristics which may help explain variations in oxygen demand. Moreover, oxygen demand was quantified using a methodology that could be applied in any setting.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"114 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140149477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-15DOI: 10.1101/2024.03.13.24304254
Claudia Crimi, Santi Nolasco, Alberto Noto, Angelantonio Maglio, Vitaliano Nicola Quaranta, Danilo Di Bona, Giulia Scioscia, Francesco Papia, Maria Filomena Caiaffa, Cecilia Calabrese, Maria D'Amato, Corrado Pelaia, Raffaele Campisi, Carolina Vitale, Luigi Ciampo, Silvano Dragonieri, Elena Minenna, Federica Massaro, Lorena Gallotti, Luigi Macchia, Massimo Triggiani, Nicola Scichilone, Giuseppe Valenti, Girolamo Pelaia, Maria Pia Foschino Barbaro, Giovanna Elisiana Carpagnano, Alessandro Vatrella, Nunzio Crimi
Background: Biological therapies, such as mepolizumab, have transformed the treatment of severe eosinophilic asthma. While mepolizumab's short-term effectiveness is established, there is limited evidence on its ability to achieve long-term clinical remission. Objective: To evaluate the long-term effectiveness and safety of mepolizumab, explore its potential to induce clinical and sustained remission, and identify baseline factors associated with the likelihood of achieving remission over 24 months. Methods: The REMI-M is a retrospective, real-world, multicenter study that analyzed 303 severe eosinophilic asthma patients who received mepolizumab. Clinical, demographic, and safety data were collected at baseline, 3, 6, 12, and 24 months. The most commonly used definitions of clinical remission, which included no exacerbations, no oral corticosteroids (OCS) use, and good asthma control with or without assessment of lung function parameters, were adopted. Sustained remission was defined as reaching clinical remission at 12 months and maintaining it until the end of the 24-month period. Results: Clinical remission rates ranged from 28.6% to 43.2% after 12 months and from 26.8% to 52.9% after 24 months, based on the different remission definitions. The proportion of patients achieving sustained remission varied between 14.6% to 29%. Factors associated with the likelihood of achieving clinical remission included the presence of aspirin-exacerbated respiratory disease, better lung function, male sex, absence of anxiety/depression, gastro-esophageal reflux disease, bronchiectasis, and reduced OCS consumption. Adverse events were infrequent. Conclusions: This study demonstrates the real-world effectiveness of mepolizumab in achieving clinical remission and sustained remission in severe eosinophilic asthma over 24 months. The identification of distinct factors associated with the likelihood of achieving clinical remission emphasizes the importance of comprehensive management of comorbidities and timely identification of patients who may benefit from biologics.
{"title":"Long-Term Clinical and Sustained REMIssion in Severe Eosinophilic Asthma treated with Mepolizumab: The REMI-M study","authors":"Claudia Crimi, Santi Nolasco, Alberto Noto, Angelantonio Maglio, Vitaliano Nicola Quaranta, Danilo Di Bona, Giulia Scioscia, Francesco Papia, Maria Filomena Caiaffa, Cecilia Calabrese, Maria D'Amato, Corrado Pelaia, Raffaele Campisi, Carolina Vitale, Luigi Ciampo, Silvano Dragonieri, Elena Minenna, Federica Massaro, Lorena Gallotti, Luigi Macchia, Massimo Triggiani, Nicola Scichilone, Giuseppe Valenti, Girolamo Pelaia, Maria Pia Foschino Barbaro, Giovanna Elisiana Carpagnano, Alessandro Vatrella, Nunzio Crimi","doi":"10.1101/2024.03.13.24304254","DOIUrl":"https://doi.org/10.1101/2024.03.13.24304254","url":null,"abstract":"Background: Biological therapies, such as mepolizumab, have transformed the treatment of severe eosinophilic asthma. While mepolizumab's short-term effectiveness is established, there is limited evidence on its ability to achieve long-term clinical remission.\u0000Objective: To evaluate the long-term effectiveness and safety of mepolizumab, explore its potential to induce clinical and sustained remission, and identify baseline factors associated with the likelihood of achieving remission over 24 months.\u0000Methods: The REMI-M is a retrospective, real-world, multicenter study that analyzed 303 severe eosinophilic asthma patients who received mepolizumab. Clinical, demographic, and safety data were collected at baseline, 3, 6, 12, and 24 months. The most commonly used definitions of clinical remission, which included no exacerbations, no oral corticosteroids (OCS) use, and good asthma control with or without assessment of lung function parameters, were adopted. Sustained remission was defined as reaching clinical remission at 12 months and maintaining it until the end of the 24-month period.\u0000Results: Clinical remission rates ranged from 28.6% to 43.2% after 12 months and from 26.8% to 52.9% after 24 months, based on the different remission definitions. The proportion of patients achieving sustained remission varied between 14.6% to 29%. Factors associated with the likelihood of achieving clinical remission included the presence of aspirin-exacerbated respiratory disease, better lung function, male sex, absence of anxiety/depression, gastro-esophageal reflux disease, bronchiectasis, and reduced OCS consumption. Adverse events were infrequent.\u0000Conclusions: This study demonstrates the real-world effectiveness of mepolizumab in achieving clinical remission and sustained remission in severe eosinophilic asthma over 24 months. The identification of distinct factors associated with the likelihood of achieving clinical remission emphasizes the importance of comprehensive management of comorbidities and timely identification of patients who may benefit from biologics.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140149711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-13DOI: 10.1101/2024.03.11.24304122
Tae Yoon Lee, John Petkau, Kate M Johnson, Stuart Turvey, Amin Adibi, Padmaja Subbarao, Mohsen Sadatsafavi
Purpose: To develop Lifetime Exposures and Asthma outcomes Projection (LEAP), a reference policy model for evaluating health outcomes and costs of asthma interventions and policies for the Canadian population. Methods: Following the best practice guidelines for development, we first created a conceptual map with a steering committee of clinician experts and economic modelers through a modified Delphi-process. Following the committee's recommendations and given the multidimensionality of risk factors and the need for modeling realistic aspects (e.g., gradual market penetration) of adopting health technologies, we opted for an open-population microsimulation design. For the first version of the model, we concentrated on several key risk factors (age, sex, family history of asthma at birth, and exposure to antibiotics in the first year of life) from the concept map. The model consists of five intertwined modules: 1) demographic, 2) risk factors, 3) asthma occurrence, 4) asthma outcomes, and 5) payoffs. The demographic module, including birth, mortality, immigration, and emigration, was based on sex- and age-specific estimates and projections from Statistics Canada. The distributions of risk factors, including family history of asthma and exposure to antibiotics, were estimated from population-based administrative databases and a population-based longitudinal birth cohort. To estimate parameters in the asthma occurrence (prevalence, incidence, reassessment) and asthma outcomes (severity, symptom control, exacerbations) modules, we performed quantitative evidence synthesis. Costs and utility weights were obtained from the literature. We conducted multiple face and internal validation assessments. Results: LEAP is capable of modeling asthma-related health outcomes at the individual and aggregate levels from 2001 onwards. Face validity was confirmed by checking the structure, equations, codes, and results. We calibrated and internally validated the age-sex stratified demographic projections to the estimates and projections from Statistics Canada, the age-sex stratified asthma prevalence to the administrative data, and the asthma control levels and exacerbation rates to the estimates from the literature. Conclusions: LEAP is the first reference Canadian asthma policy model that emerged from identified needs for health policy planning for early interventions in asthma. As an open-source and open-access platform, LEAP can provide a unified framework under which different interventions and policies can be consistently compared to identify those with the highest value proposition.
{"title":"Development and Validation of an Asthma Policy Model for Canada:Lifetime Exposures and Asthma outcomes Projection (LEAP)","authors":"Tae Yoon Lee, John Petkau, Kate M Johnson, Stuart Turvey, Amin Adibi, Padmaja Subbarao, Mohsen Sadatsafavi","doi":"10.1101/2024.03.11.24304122","DOIUrl":"https://doi.org/10.1101/2024.03.11.24304122","url":null,"abstract":"Purpose: To develop Lifetime Exposures and Asthma outcomes Projection (LEAP), a reference policy model for evaluating health outcomes and costs of asthma interventions and policies for the Canadian population. Methods: Following the best practice guidelines for development, we first created a conceptual map with a steering committee of clinician experts and economic modelers through a modified Delphi-process. Following the committee's recommendations and given the multidimensionality of risk factors and the need for modeling realistic aspects (e.g., gradual market penetration) of adopting health technologies, we opted for an open-population microsimulation design. For the first version of the model, we concentrated on several key risk factors (age, sex, family history of asthma at birth, and exposure to antibiotics in the first year of life) from the concept map. The model consists of five intertwined modules: 1) demographic, 2) risk factors, 3) asthma occurrence, 4) asthma outcomes, and 5) payoffs. The demographic module, including birth, mortality, immigration, and emigration, was based on sex- and age-specific estimates and projections from Statistics Canada. The distributions of risk factors, including family history of asthma and exposure to antibiotics, were estimated from population-based administrative databases and a population-based longitudinal birth cohort. To estimate parameters in the asthma occurrence (prevalence, incidence, reassessment) and asthma outcomes (severity, symptom control, exacerbations) modules, we performed quantitative evidence synthesis. Costs and utility weights were obtained from the literature. We conducted multiple face and internal validation assessments. Results: LEAP is capable of modeling asthma-related health outcomes at the individual and aggregate levels from 2001 onwards. Face validity was confirmed by checking the structure, equations, codes, and results. We calibrated and internally validated the age-sex stratified demographic projections to the estimates and projections from Statistics Canada, the age-sex stratified asthma prevalence to the administrative data, and the asthma control levels and exacerbation rates to the estimates from the literature. Conclusions: LEAP is the first reference Canadian asthma policy model that emerged from identified needs for health policy planning for early interventions in asthma. As an open-source and open-access platform, LEAP can provide a unified framework under which different interventions and policies can be consistently compared to identify those with the highest value proposition.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140125810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-13DOI: 10.1101/2024.03.11.24304129
Honglei Zhang, Chao Liu, Shuting Wang, Qing Wang, Xu Feng, Huawei Jiang, Yong Zhang, Xiaosan Su, Gaofeng Li
Air pollution significantly impact lung cancer progression, but there is a lack of a comprehensive molecular characterization of clinical samples associated with air pollution. Here, we performed a proteogenomic analysis of lung adenocarcinoma (LUAD) in 169 female never-smokers from the Xuanwei area (XWLC cohort), where coal smoke is the primary contributor to the high lung cancer incidence. Genomic mutation analysis revealed XWLC as a distinct subtype of LUAD separate from cases associated with smoking or endogenous factors. Mutational signature analysis suggested that Benzo[a]pyrene (BaP) is the major risk factor in XWLC. The BaP-induced mutation hotspot, EGFR-G719X, was present in 20% of XWLC which endowed XWLC with elevated MAPK pathway activations and worse outcomes compared to common EGFR mutations. Multi-omics clustering of XWLC identified four clinically relevant subtypes. These subgroups exhibited distinct features in biological processes, genetic alterations, metabolism demands, immune landscape, tumor microbiota composition and radiomic features. Finally, MAD1 and TPRN were identified as novel potential therapeutic targets in XWLC. Our study provides a valuable resource for researchers and clinicians to explore prevention and treatment strategies for air-pollution-associated lung cancers.
{"title":"Proteogenomic analysis of air-pollution-associated lung cancer reveals prevention and therapeutic opportunities","authors":"Honglei Zhang, Chao Liu, Shuting Wang, Qing Wang, Xu Feng, Huawei Jiang, Yong Zhang, Xiaosan Su, Gaofeng Li","doi":"10.1101/2024.03.11.24304129","DOIUrl":"https://doi.org/10.1101/2024.03.11.24304129","url":null,"abstract":"Air pollution significantly impact lung cancer progression, but there is a lack of a comprehensive molecular characterization of clinical samples associated with air pollution. Here, we performed a proteogenomic analysis of lung adenocarcinoma (LUAD) in 169 female never-smokers from the Xuanwei area (XWLC cohort), where coal smoke is the primary contributor to the high lung cancer incidence. Genomic mutation analysis revealed XWLC as a distinct subtype of LUAD separate from cases associated with smoking or endogenous factors. Mutational signature analysis suggested that Benzo[a]pyrene (BaP) is the major risk factor in XWLC. The BaP-induced mutation hotspot, EGFR-G719X, was present in 20% of XWLC which endowed XWLC with elevated MAPK pathway activations and worse outcomes compared to common <em>EGFR</em> mutations. Multi-omics clustering of XWLC identified four clinically relevant subtypes. These subgroups exhibited distinct features in biological processes, genetic alterations, metabolism demands, immune landscape, tumor microbiota composition and radiomic features. Finally, <em>MAD1 and TPRN</em> were identified as novel potential therapeutic targets in XWLC. Our study provides a valuable resource for researchers and clinicians to explore prevention and treatment strategies for air-pollution-associated lung cancers.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140125987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-13DOI: 10.1101/2024.03.10.24304053
Alessia Verduri, Enrico Clini, Ben Carter, Jonathan Hewitt
Background Frailty is a clinical state that increases susceptibility to minor stressor events. The risk of frailty is higher in chronic conditions, such as Chronic Obstructive Pulmonary Disease (COPD). Recent studies on COPD have shown that patients living with frailty have an increased risk of mortality. The presence of cardiovascular diseases or conditions are common in COPD and may increase the risk of death. Methods This protocol describes a European prospective cohort study of community-based people, in a stable condition with diagnosis of COPD (as defined by GOLD guidelines) across hospitals in Italy and UK. Frailty prevalence will be assessed using the Clinical Frailty Scale. At 1- and 2-year follow up, primary outcome will be the impact of frailty on the number of cardiovascular events; secondary outcomes: the influence of frailty on cardiovascular mortality, all-cause mortality, and deaths due to COPD. For the primary outcome a zero-inflated Poisson regression will compare the number of cardiovascular events at 1 year. Secondary outcomes will be analysed using the time to mortality. Discussion This multicentre study will assess the association between frailty and cardiovascular events and mortality in population with COPD. Data collection is prospective and includes routine clinical data. This research will have important implications for the management of patients with COPD to improve their quality of care, and potentially prognosis. Trial registration number: NCT05922202 (www.clinicaltrials.gov).
{"title":"Influence of frailty on cardiovascular events and mortality in patients with Chronic Obstructive Pulmonary Disease (COPD): Study Protocol for a multicentre European observational study.","authors":"Alessia Verduri, Enrico Clini, Ben Carter, Jonathan Hewitt","doi":"10.1101/2024.03.10.24304053","DOIUrl":"https://doi.org/10.1101/2024.03.10.24304053","url":null,"abstract":"Background Frailty is a clinical state that increases susceptibility to minor stressor events. The risk of frailty is higher in chronic conditions, such as Chronic Obstructive Pulmonary Disease (COPD). Recent studies on COPD have shown that patients living with frailty have an increased risk of mortality. The presence of cardiovascular diseases or conditions are common in COPD and may increase the risk of death. Methods This protocol describes a European prospective cohort study of community-based people, in a stable condition with diagnosis of COPD (as defined by GOLD guidelines) across hospitals in Italy and UK. Frailty prevalence will be assessed using the Clinical Frailty Scale. At 1- and 2-year follow up, primary outcome will be the impact of frailty on the number of cardiovascular events; secondary outcomes: the influence of frailty on cardiovascular mortality, all-cause mortality, and deaths due to COPD. For the primary outcome a zero-inflated Poisson regression will compare the number of cardiovascular events at 1 year. Secondary outcomes will be analysed using the time to mortality.\u0000Discussion This multicentre study will assess the association between frailty and cardiovascular events and mortality in population with COPD. Data collection is prospective and includes routine clinical data. This research will have important implications for the management of patients with COPD to improve their quality of care, and potentially prognosis.\u0000Trial registration number: NCT05922202 (www.clinicaltrials.gov).","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"75 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140125985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-02DOI: 10.1101/2024.02.29.24303556
Solomiia Zaremba, Alex J Miller, Erik A Ovrom, Jonathon W Senefeld, Chad C Wiggins, Paolo B Dominelli, Ravindra Ganesh, Ryan T Hurt, Brian J Bartholmai, Brian T Welch, Juan G Ripoll, Michael J Joyner, Andrew H Ramsook
Background Coronavirus disease 2019 (COVID–19) is associated with enlarged luminal areas of large conducting airways. In 10—30% of patients with acute COVID–19 infection, symptoms persist for more than 4 weeks (referred to as post–acute sequelae of COVID–19, or PASC), and it is unknown if airway changes are associated with this persistence. Thus, we aim to investigate if luminal area of large conducting airways is different between PASC and COVID–19 patients, and healthy controls. Methods In this retrospective case–control study seventy–five patients with PASC (48 females) were age–, height–, and sex–matched to 75 individuals with COVID-19 and 75 healthy controls. Using three–dimensional digital reconstruction from computed tomography imaging, we measured luminal areas of seven conducting airways, including trachea, right and left main bronchi, bronchus intermediate, right and left upper lobe, and left lower lobe bronchi. Findings Airway luminal areas between COVID–19 and PASC groups were not different (p>0.66). There were no group differences in airway luminal area (PASC vs control) for trachea and right main bronchus. However, in the remaining five airways, airway luminal areas were 12% to 39% larger among PASC patients compared to controls (p<0.05). Interpretation Patients diagnosed with COVID–19 and PASC have greater airway luminal area in most large conducting airways compared to healthy controls. No differences in luminal area between patients with COVID–19 and PASC suggest persistence of changes or insufficient time for complete reversal of changes. Funding National Heart, Lung, and Blood Institute (F32HL154320 to JWS; 5R35HL139854 to MJJ); Postdoctoral Fellowship from the Natural Sciences and Engineering Research Council of Canada (AHR).
{"title":"Increased luminal area of large conducting airways in patients with COVID-19 and post-acute sequelae of COVID-19 A retrospective case-control study","authors":"Solomiia Zaremba, Alex J Miller, Erik A Ovrom, Jonathon W Senefeld, Chad C Wiggins, Paolo B Dominelli, Ravindra Ganesh, Ryan T Hurt, Brian J Bartholmai, Brian T Welch, Juan G Ripoll, Michael J Joyner, Andrew H Ramsook","doi":"10.1101/2024.02.29.24303556","DOIUrl":"https://doi.org/10.1101/2024.02.29.24303556","url":null,"abstract":"Background Coronavirus disease 2019 (COVID–19) is associated with enlarged luminal areas of large conducting airways. In 10—30% of patients with acute COVID–19 infection, symptoms persist for more than 4 weeks (referred to as post–acute sequelae of COVID–19, or PASC), and it is unknown if airway changes are associated with this persistence. Thus, we aim to investigate if luminal area of large conducting airways is different between PASC and COVID–19 patients, and healthy controls. Methods In this retrospective case–control study seventy–five patients with PASC (48 females) were age–, height–, and sex–matched to 75 individuals with COVID-19 and 75 healthy controls. Using three–dimensional digital reconstruction from computed tomography imaging, we measured luminal areas of seven conducting airways, including trachea, right and left main bronchi, bronchus intermediate, right and left upper lobe, and left lower lobe bronchi. Findings Airway luminal areas between COVID–19 and PASC groups were not different (p>0.66). There were no group differences in airway luminal area (PASC vs control) for trachea and right main bronchus. However, in the remaining five airways, airway luminal areas were 12% to 39% larger among PASC patients compared to controls (p<0.05). Interpretation Patients diagnosed with COVID–19 and PASC have greater airway luminal area in most large conducting airways compared to healthy controls. No differences in luminal area between patients with COVID–19 and PASC suggest persistence of changes or insufficient time for complete reversal of changes. Funding National Heart, Lung, and Blood Institute (F32HL154320 to JWS; 5R35HL139854 to MJJ); Postdoctoral Fellowship from the Natural Sciences and Engineering Research Council of Canada (AHR).","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140018873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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