Pub Date : 2024-01-31DOI: 10.1101/2024.01.31.24302056
Franz Aaron Clemeno, Matthew Richardson, Salman Siddiqui
Objectives: Longitudinal data is commonly acquired in asthma studies, to help assess asthma progression in patients, and to determine predictors of future outcomes, including asthma exacerbations and asthma control. Different methods exist for quantifying temporal behaviour in routinely collected diary variables to obtain meaningful predictive biomarkers of asthma outcomes. The aims of this systematic review were to evaluate the methods for extracting biomarkers from longitudinally collected diary data in asthma and investigate associations between the extracted measures and asthma patient reported outcomes (PROs). Setting: A systematic review of MEDLINE, EMBASE, CINAHL and the Cochrane Library was conducted, using index terms relating to diary variables and asthma outcomes. Studies that focused on preschool children were excluded, to avoid confounding asthma with multi-factorial preschool wheeze. Study quality and risk of bias were assessed using the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) and the Prediction model Risk Of Bias ASessment Tool (PROBAST), respectively. Participants: Adults and/or children of school age (≥5 years old), with clinician-diagnosed asthma Primary outcomes: Asthma PROs, namely asthma exacerbations, asthma control, asthma-related quality of life and asthma severity Results: 24 full-text articles met the inclusion criteria and were included in the review. Generally, higher levels of variability in the diary variables were associated with poorer outcomes, especially increased asthma exacerbation risk, and poor asthma control. There was increasing interest in nonparametric methods to quantify complex behaviour of diary variables (6/24). TRIPOD and PROBAST highlighted a lack of consistent reporting of model performance measures and potential for model bias. Discussion: Routinely collected diary variables aid in generating asthma assessment tools, including surrogate endpoints, for clinical trials, and predictive biomarkers of adverse outcomes, warranting monitoring through remote sensors. Studies consistently lacked robust reporting of model performance. Future research should utilise diary variable-derived biomarkers.
{"title":"A systematic review of multi-variate time series approaches to extract predictive asthma biomarkers from routinely collected diary data","authors":"Franz Aaron Clemeno, Matthew Richardson, Salman Siddiqui","doi":"10.1101/2024.01.31.24302056","DOIUrl":"https://doi.org/10.1101/2024.01.31.24302056","url":null,"abstract":"Objectives: Longitudinal data is commonly acquired in asthma studies, to help assess asthma progression in patients, and to determine predictors of future outcomes, including asthma exacerbations and asthma control. Different methods exist for quantifying temporal behaviour in routinely collected diary variables to obtain meaningful predictive biomarkers of asthma outcomes. The aims of this systematic review were to evaluate the methods for extracting biomarkers from longitudinally collected diary data in asthma and investigate associations between the extracted measures and asthma patient reported outcomes (PROs).\u0000Setting: A systematic review of MEDLINE, EMBASE, CINAHL and the Cochrane Library was conducted, using index terms relating to diary variables and asthma outcomes. Studies that focused on preschool children were excluded, to avoid confounding asthma with multi-factorial preschool wheeze. Study quality and risk of bias were assessed using the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) and the Prediction model Risk Of Bias ASessment Tool (PROBAST), respectively. Participants: Adults and/or children of school age (≥5 years old), with clinician-diagnosed asthma\u0000Primary outcomes: Asthma PROs, namely asthma exacerbations, asthma control, asthma-related quality of life and asthma severity\u0000Results: 24 full-text articles met the inclusion criteria and were included in the review. Generally, higher levels of variability in the diary variables were associated with poorer outcomes, especially increased asthma exacerbation risk, and poor asthma control. There was increasing interest in nonparametric methods to quantify complex behaviour of diary variables (6/24). TRIPOD and PROBAST highlighted a lack of consistent reporting of model performance measures and potential for model bias.\u0000Discussion: Routinely collected diary variables aid in generating asthma assessment tools, including surrogate endpoints, for clinical trials, and predictive biomarkers of adverse outcomes, warranting monitoring through remote sensors. Studies consistently lacked robust reporting of model performance. Future research should utilise diary variable-derived biomarkers.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139659043","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 : 2024-01-28DOI: 10.1101/2024.01.27.24301872
Valerie E Cyphers, Swet M Patel, Brendan D McNamara, William B Ashe, Sarah J Ratcliffe, Joseph Randall Moorman, Jessica Keim-Malpass, Shrirang Mukund Gadrey, Sherry L Kausch
Introduction: Respiratory failure is a common organ failure syndrome in hospitalized patients1. Vital sign monitoring (like respiratory rate & oximetry) is a necessary aspect of risk stratification, but it is not sufficient. In one study of hospitalized patients, 46% of the patients had no significant vital sign change in the 24 hours before an unplanned intubation2. Therefore, clinicians must also monitor for physical diagnostic signs that link the appearance of breaths to respiratory instability. Many pathognomonic patterns of high-risk labored breathing have been described. For example, when rib-dominant breaths alternate with abdomen-dominant ones, the patient is said to exhibit respiratory alternans, a sign of inspiratory muscle overload3. However, the manual assessment of such signs lacks sensitivity, inter-rater reliability, and scalability4. We sought to (a) identify technologies that can measure labored breathing and (b) assess their readiness for clinical adoption by hospitals. Methods: We selected four well-established diagnostic signs of labored breathing: (1) respiratory rate variability, (2) recruitment of accessory muscles (upper-rib elevation by the scalene and sternocleidomastoid muscles), (3) Abdominal Paradox (rib-abdomen asynchrony), and (4) respiratory alternans (rib-dominant breaths alternate with abdomen-dominant ones). We systematically searched PubMed using pre-specified keywords corresponding to these four signs. We identified 2868 abstracts. Two reviewers independently screened each abstract to ensure that it reported on technology that quantified the diagnostic sign of interest. A third reviewer resolved any disagreements. We excluded 2423 articles with an abstract review and included 445 articles for full paper review. We excluded an additional 127 articles after full paper review, and we were unable to acquire 4 articles. We included the remaining 314 articles for analysis. Results: Quantification of labored breathing has been attempted for over 50 years; the earliest study included in our analysis was published in 1975. Over 30 different hardware configurations have been tried, either alone or in combination; but none of them has been validated as a comprehensive solution to measure all the four diagnostic signs that we studied. Despite enormous improvements in sensor technologies and computing capacity, the scale of investigation has not meaningfully increased since 1975. In the first decade of kinematic measurements (1975-1984), there average annual number of studies was 2.7 and the median sample size was 19. In the decade prior to our study (2013-2022), the average annual number of studies was 11.3 and the median sample size was 20. To this day, a majority of the studies are conducted in a specialized laboratories (73% between 2013-2022) rather than clinical practice settings. Most studies aimed to measure the construct validity of a technology (19%) or to describe kinematic distributions in specific clinical
{"title":"Labored breathing pattern: an unmeasured dimension of respiratory pathophysiology","authors":"Valerie E Cyphers, Swet M Patel, Brendan D McNamara, William B Ashe, Sarah J Ratcliffe, Joseph Randall Moorman, Jessica Keim-Malpass, Shrirang Mukund Gadrey, Sherry L Kausch","doi":"10.1101/2024.01.27.24301872","DOIUrl":"https://doi.org/10.1101/2024.01.27.24301872","url":null,"abstract":"Introduction: Respiratory failure is a common organ failure syndrome in hospitalized patients1. Vital sign monitoring (like respiratory rate & oximetry) is a necessary aspect of risk stratification, but it is not sufficient. In one study of hospitalized patients, 46% of the patients had no significant vital sign change in the 24 hours before an unplanned intubation2. Therefore, clinicians must also monitor for physical diagnostic signs that link the appearance of breaths to respiratory instability. Many pathognomonic patterns of high-risk labored breathing have been described. For example, when rib-dominant breaths alternate with abdomen-dominant ones, the patient is said to exhibit respiratory alternans, a sign of inspiratory muscle overload3. However, the manual assessment of such signs lacks sensitivity, inter-rater reliability, and scalability4. We sought to (a) identify technologies that can measure labored breathing and (b) assess their readiness for clinical adoption by hospitals. Methods: We selected four well-established diagnostic signs of labored breathing: (1) respiratory rate variability, (2) recruitment of accessory muscles (upper-rib elevation by the scalene and sternocleidomastoid muscles), (3) Abdominal Paradox (rib-abdomen asynchrony), and (4) respiratory alternans (rib-dominant breaths alternate with abdomen-dominant ones). We systematically searched PubMed using pre-specified keywords corresponding to these four signs. We identified 2868 abstracts. Two reviewers independently screened each abstract to ensure that it reported on technology that quantified the diagnostic sign of interest. A third reviewer resolved any disagreements. We excluded 2423 articles with an abstract review and included 445 articles for full paper review. We excluded an additional 127 articles after full paper review, and we were unable to acquire 4 articles. We included the remaining 314 articles for analysis. Results: Quantification of labored breathing has been attempted for over 50 years; the earliest study included in our analysis was published in 1975. Over 30 different hardware configurations have been tried, either alone or in combination; but none of them has been validated as a comprehensive solution to measure all the four diagnostic signs that we studied. Despite enormous improvements in sensor technologies and computing capacity, the scale of investigation has not meaningfully increased since 1975. In the first decade of kinematic measurements (1975-1984), there average annual number of studies was 2.7 and the median sample size was 19. In the decade prior to our study (2013-2022), the average annual number of studies was 11.3 and the median sample size was 20. To this day, a majority of the studies are conducted in a specialized laboratories (73% between 2013-2022) rather than clinical practice settings. Most studies aimed to measure the construct validity of a technology (19%) or to describe kinematic distributions in specific clinical","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139579496","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 : 2024-01-25DOI: 10.1101/2024.01.25.24301780
Brianna M. Goodwin Cartwright, Samuel Gratzl, Patricia J Rodriguez, Charlotte Baker, Nick Stucky
This study describes two population under age two 1) who received an RSV immunization and 2) experienced RSV-associated hospitalizations since 2018. Results show low uptake of the RSV immunization. RSV-associated hospitalizations exhibited earlier and higher peaks in the 2021/22 and 2022/23 seasons compared to previous years.
{"title":"October 2018 – December 2023 time-series analysis of pediatric RSV immunizations and RSV-associated hospitalizations","authors":"Brianna M. Goodwin Cartwright, Samuel Gratzl, Patricia J Rodriguez, Charlotte Baker, Nick Stucky","doi":"10.1101/2024.01.25.24301780","DOIUrl":"https://doi.org/10.1101/2024.01.25.24301780","url":null,"abstract":"This study describes two population under age two 1) who received an RSV immunization and 2) experienced RSV-associated hospitalizations since 2018. Results show low uptake of the RSV immunization. RSV-associated hospitalizations exhibited earlier and higher peaks in the 2021/22 and 2022/23 seasons compared to previous years.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139579495","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 : 2024-01-25DOI: 10.1101/2024.01.24.24301742
Scott M. Matson, Linh T. Ngo, Yui Sugawara, Veani Fernando, Claudia Lugo, Imaan Azeem, Alexis Harrison, Alex Alsup, Emily Nissen, Devin Koestler, Michael P. Washburn, Michaella J. Rekowski, Paul J. Wolters, Joyce S. Lee, Joshua J. Solomon, M. Kristen Demoruelle
Rationale Neutrophil counts in bronchoalveolar lavage fluid in idiopathic pulmonary fibrosis are associated with worse outcomes; however, the underlying mechanisms are unknown. Neutrophil extracellular trap formation is associated with worse outcomes in several chronic lung diseases however, there is an unknown role in idiopathic pulmonary fibrosis.
{"title":"Neutrophil extracellular trap formation linked to idiopathic pulmonary fibrosis severity and survival","authors":"Scott M. Matson, Linh T. Ngo, Yui Sugawara, Veani Fernando, Claudia Lugo, Imaan Azeem, Alexis Harrison, Alex Alsup, Emily Nissen, Devin Koestler, Michael P. Washburn, Michaella J. Rekowski, Paul J. Wolters, Joyce S. Lee, Joshua J. Solomon, M. Kristen Demoruelle","doi":"10.1101/2024.01.24.24301742","DOIUrl":"https://doi.org/10.1101/2024.01.24.24301742","url":null,"abstract":"<strong>Rationale</strong> Neutrophil counts in bronchoalveolar lavage fluid in idiopathic pulmonary fibrosis are associated with worse outcomes; however, the underlying mechanisms are unknown. Neutrophil extracellular trap formation is associated with worse outcomes in several chronic lung diseases however, there is an unknown role in idiopathic pulmonary fibrosis.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"51 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139579044","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 : 2024-01-09DOI: 10.1101/2024.01.08.24300986
Myrofora Goutaki, Yin Ting Lam, Bruna Rubbo, James D Chalmers, Panayiotis Kouis, Gemma Marsh, Jean-Francois Papon, Johanna Raidt, Phil Robinson, Laura Behan, Jane S Lucas
Background: Despite advances in primary ciliary dyskinesia (PCD) research, many questions remain; diagnosis is complex and no disease specific therapies exist. Using a mixed-methods approach, we aimed to identify priorities for clinical and epidemiological research and explore barriers to research. Methods: To obtain rich, relevant, diverse data, we performed in-depth semi-structured interviews with PCD specialists selected using purposive sampling. We transcribed, coded, and analysed interview data using thematic analysis. Based on interview themes we identified, we developed an anonymous survey and circulated it widely through the BEAT-PCD network. Results: We interviewed 28 participants from 15 countries across different disciplines and expertise levels. The main themes identified as priorities for PCD research were improving diagnosis, understanding prevalence, and disease course; phenotypic variability; disease monitoring; treatment strategies; clinical trial endpoints; and neglected research areas. In total, 136 participants (49% paediatric pulmonologists) from 36 countries completed the survey. Most commonly reported barriers for research were low awareness about PCD and difficulties securing funding -in more than one-third of cases, participants reported undertaking predominantly unfunded research. Research questions ranked highest included priorities related to further improving diagnosis, treating PCD, managing upper and lower airway problems, and studying clinical variability and disease prognosis. Conclusion: We need to overcome barriers of limited funding and low awareness and promote collaborations between centres, disciplines, experts, and patients to address PCD priorities effectively. Our results contribute to the ongoing efforts of guiding the use of existing limited research resources and setting up a roadmap for future research activities.
{"title":"Priorities and barriers for research related to primary ciliary dyskinesia","authors":"Myrofora Goutaki, Yin Ting Lam, Bruna Rubbo, James D Chalmers, Panayiotis Kouis, Gemma Marsh, Jean-Francois Papon, Johanna Raidt, Phil Robinson, Laura Behan, Jane S Lucas","doi":"10.1101/2024.01.08.24300986","DOIUrl":"https://doi.org/10.1101/2024.01.08.24300986","url":null,"abstract":"Background: Despite advances in primary ciliary dyskinesia (PCD) research, many questions remain; diagnosis is complex and no disease specific therapies exist. Using a mixed-methods approach, we aimed to identify priorities for clinical and epidemiological research and explore barriers to research.\u0000Methods: To obtain rich, relevant, diverse data, we performed in-depth semi-structured interviews with PCD specialists selected using purposive sampling. We transcribed, coded, and analysed interview data using thematic analysis. Based on interview themes we identified, we developed an anonymous survey and circulated it widely through the BEAT-PCD network.\u0000Results: We interviewed 28 participants from 15 countries across different disciplines and expertise levels. The main themes identified as priorities for PCD research were improving diagnosis, understanding prevalence, and disease course; phenotypic variability; disease monitoring; treatment strategies; clinical trial endpoints; and neglected research areas. In total, 136 participants (49% paediatric pulmonologists) from 36 countries completed the survey. Most commonly reported barriers for research were low awareness about PCD and difficulties securing funding -in more than one-third of cases, participants reported undertaking predominantly unfunded research. Research questions ranked highest included priorities related to further improving diagnosis, treating PCD, managing upper and lower airway problems, and studying clinical variability and disease prognosis.\u0000Conclusion: We need to overcome barriers of limited funding and low awareness and promote collaborations between centres, disciplines, experts, and patients to address PCD priorities effectively. Our results contribute to the ongoing efforts of guiding the use of existing limited research resources and setting up a roadmap for future research activities.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139413129","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 : 2023-12-15DOI: 10.1101/2023.12.14.23299978
J.N. Stroh, Peter D. Sottile, Yanran Wang, Bradford J. Smith, Tellen D. Bennett, Marc Moss, David J. Albers
Mechanically ventilated patients generate waveform data that corresponds to patient interaction with unnatural forcing. This breath information includes both patient and apparatus sources, imbuing data with broad heterogeneity resulting from ventilator settings, patient efforts, patient-ventilator dyssynchronies, injuries, and other clinical therapies. Lung-protective ventilator settings outlined in respiratory care protocols lack personalization, and the connections between clinical outcomes and injuries resulting from mechanical ventilation remain poorly understood. Intra- and inter-patient heterogeneity and the volume of data comprising lung-ventilator system (LVS) observations limit broader and longer-time analysis of such systems. This work presents a computational pipeline for resolving LVS systems by tracking the evolution of data-conditioned model parameters and ventilator information. For individuals, the method presents LVS trajectory in a manageable way through low-dimensional representation of phenotypic breath waveforms. More general phenotypes across patients are also developed by aggregating patient-personalized estimates with additional normalization. The effectiveness of this process is demonstrated through application to multi-day observational series of 35 patients, which reveals the complexity of changes in the LVS over time. Considerable variations in breath behavior independent of the ventilator are revealed, suggesting the need to incorporate care factors such as patient sedation and posture in future analysis. The pipeline also identifies structural similarity in pressure-volume (pV) loop characterizations at the cohort level. The design invites active learning to incorporate clinical practitioner expertise into various methodological stages and algorithm choices.
{"title":"Identifying low-dimensional trajectories of mechanically-ventilated patient systems: Empirical phenotypes of joint patient+care processes to enhance temporal analysis in ARDS research","authors":"J.N. Stroh, Peter D. Sottile, Yanran Wang, Bradford J. Smith, Tellen D. Bennett, Marc Moss, David J. Albers","doi":"10.1101/2023.12.14.23299978","DOIUrl":"https://doi.org/10.1101/2023.12.14.23299978","url":null,"abstract":"Mechanically ventilated patients generate waveform data that corresponds to patient interaction with unnatural forcing. This breath information includes both patient and apparatus sources, imbuing data with broad heterogeneity resulting from ventilator settings, patient efforts, patient-ventilator dyssynchronies, injuries, and other clinical therapies. Lung-protective ventilator settings outlined in respiratory care protocols lack personalization, and the connections between clinical outcomes and injuries resulting from mechanical ventilation remain poorly understood. Intra- and inter-patient heterogeneity and the volume of data comprising lung-ventilator system (LVS) observations limit broader and longer-time analysis of such systems. This work presents a computational pipeline for resolving LVS systems by tracking the evolution of data-conditioned model parameters and ventilator information. For individuals, the method presents LVS trajectory in a manageable way through low-dimensional representation of phenotypic breath waveforms. More general phenotypes across patients are also developed by aggregating patient-personalized estimates with additional normalization. The effectiveness of this process is demonstrated through application to multi-day observational series of 35 patients, which reveals the complexity of changes in the LVS over time. Considerable variations in breath behavior independent of the ventilator are revealed, suggesting the need to incorporate care factors such as patient sedation and posture in future analysis. The pipeline also identifies structural similarity in pressure-volume (pV) loop characterizations at the cohort level. The design invites active learning to incorporate clinical practitioner expertise into various methodological stages and algorithm choices.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138715114","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 : 2023-12-14DOI: 10.1101/2023.12.12.23299822
Ozgecan Kayalar, Pelin Duru Cetinkaya, Vahap Eldem, Serap Argun Baris, Nurdan Koktürk, Selim Can Kuralay, Hadi Rajabi, Nur Konyalilar, Deniz Mortazavi, Seval Kubra Korkunc, Sinem Erkan, Gizem Tuşe Aksoy, Gul Eyikudamaci, Pelin Pinar Deniz, Oya Baydar Toprak, Pinar Yildiz Gulhan, Gulseren Sagcan, Neslihan Kose, Aysegul Tomruk Erdem, Fusun Fakili, Onder Ozturk, Ilknur Basyigit, Hasim Boyaci, Emel Azak, Tansu Ulukavak Ciftci, Ipek Kivilcim Oguzulgen, Hasan Selcuk Ozger, Pinar Aysert Yildiz, Ismail Hanta, Ozlem Ataoglu, Merve Ercelik, Caglar Cuhadaroglu, Hacer Kuzu Okur, Muge Meltem Tor, Esra Nurlu Temel, Seval Kul, Yıldız Tutuncu, Oya Itil, Hasan Bayram
Long-COVID-19 manifests as a multisystemic condition with varied symptoms lingering beyond three weeks of acute SARS-CoV-2 infection, though its underlying mechanisms remain elusive. Aiming to decipher the long-term molecular impacts of COVID-19, we conducted a transcriptomic analysis on PBMCs from 1-year post-covid patients, including individuals without pneumonia (NP, n=10), those with severe pneumonia (SP, n=11), and healthy controls (C, n=13). Our extensive RNA sequencing revealed 4843 differentially expressed genes (DEGs) and 1056 differentially expressed long non-coding RNAs (DElncRNAs) in “C vs NP,” 1651 DEGs and 577 DElncRNAs in “C vs SP,” 954 DEGs and 148 DElncRNAs in “NP vs SP,” with 291 DEGs and 70 DElncRNAs shared across all groups. We identified 14 hub genes from 291 DEGs, with functional enrichment analysis showing upregulated DEGs mainly linked to inflammation and osteoclast differentiation, and downregulated DEGs to viral infections and immune responses. These hub genes play central roles in inflammatory and immune processes and are significantly associated with pneumonitis and diverse lung diseases. Investigations revealed unique immune cell signatures across DEG categories, associating upregulated DEGs with neutrophils and monocytes, and downregulated DEGs with CD4 memory effector T cells. Analysis of 14 hub genes showed notable upregulation in the no pneumonia group versus healthy controls, displaying complex patterns in the severe pneumonia group. Our study uncovered potential idiopathic pulmonary fibrosis signals in Long-COVID-19 patients’ PBMC transcriptome, highlighting the urgency for thorough monitoring and extended research to understand COVID-19’s lasting effects. This study sheds light on COVID-19’s transcriptomic changes and potential lasting effects, guiding future research and therapeutic approaches for Long-COVID-19.
{"title":"Comparative transcriptomic analyses of peripheral blood mononuclear cells of patients with non-pneumonia and severe pneumonia at 1 year-Long-COVID-19","authors":"Ozgecan Kayalar, Pelin Duru Cetinkaya, Vahap Eldem, Serap Argun Baris, Nurdan Koktürk, Selim Can Kuralay, Hadi Rajabi, Nur Konyalilar, Deniz Mortazavi, Seval Kubra Korkunc, Sinem Erkan, Gizem Tuşe Aksoy, Gul Eyikudamaci, Pelin Pinar Deniz, Oya Baydar Toprak, Pinar Yildiz Gulhan, Gulseren Sagcan, Neslihan Kose, Aysegul Tomruk Erdem, Fusun Fakili, Onder Ozturk, Ilknur Basyigit, Hasim Boyaci, Emel Azak, Tansu Ulukavak Ciftci, Ipek Kivilcim Oguzulgen, Hasan Selcuk Ozger, Pinar Aysert Yildiz, Ismail Hanta, Ozlem Ataoglu, Merve Ercelik, Caglar Cuhadaroglu, Hacer Kuzu Okur, Muge Meltem Tor, Esra Nurlu Temel, Seval Kul, Yıldız Tutuncu, Oya Itil, Hasan Bayram","doi":"10.1101/2023.12.12.23299822","DOIUrl":"https://doi.org/10.1101/2023.12.12.23299822","url":null,"abstract":"Long-COVID-19 manifests as a multisystemic condition with varied symptoms lingering beyond three weeks of acute SARS-CoV-2 infection, though its underlying mechanisms remain elusive. Aiming to decipher the long-term molecular impacts of COVID-19, we conducted a transcriptomic analysis on PBMCs from 1-year post-covid patients, including individuals without pneumonia (NP, n=10), those with severe pneumonia (SP, n=11), and healthy controls (C, n=13). Our extensive RNA sequencing revealed 4843 differentially expressed genes (DEGs) and 1056 differentially expressed long non-coding RNAs (DElncRNAs) in “C vs NP,” 1651 DEGs and 577 DElncRNAs in “C vs SP,” 954 DEGs and 148 DElncRNAs in “NP vs SP,” with 291 DEGs and 70 DElncRNAs shared across all groups. We identified 14 hub genes from 291 DEGs, with functional enrichment analysis showing upregulated DEGs mainly linked to inflammation and osteoclast differentiation, and downregulated DEGs to viral infections and immune responses. These hub genes play central roles in inflammatory and immune processes and are significantly associated with pneumonitis and diverse lung diseases. Investigations revealed unique immune cell signatures across DEG categories, associating upregulated DEGs with neutrophils and monocytes, and downregulated DEGs with CD4 memory effector T cells. Analysis of 14 hub genes showed notable upregulation in the no pneumonia group versus healthy controls, displaying complex patterns in the severe pneumonia group. Our study uncovered potential idiopathic pulmonary fibrosis signals in Long-COVID-19 patients’ PBMC transcriptome, highlighting the urgency for thorough monitoring and extended research to understand COVID-19’s lasting effects. This study sheds light on COVID-19’s transcriptomic changes and potential lasting effects, guiding future research and therapeutic approaches for Long-COVID-19.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138743378","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 : 2023-12-06DOI: 10.1101/2023.12.05.23299490
Polycarp Mogeni, Sharon Amima, Jennifer Gunther, Margaret Pinder, Lucy S. Tusting, Umberto D’Alessandro, Simon Cousens, Steve W. Lindsay, John Bradley
Abstract Background: Although ranges of normal respiratory rates (RR) have been described for children under five years old living in the tropics, there are few datasets recording rates in older children. The present study was designed to capture the changes in RR with age and to examine its association with nutritional status and environmental factors. Methods: A cohort of rural Gambian children aged from six months to 14 years had their RR recorded during home visits twice weekly during two annual rainy seasons. Measurements were made by trained field assistants using an electronic timer during a one-minute period. Age, sex, nutritional status, health status, time of day of data collection were recorded. A generalized additive model for location, scale and shape was used to construct the RR reference curves and a linear mixed effect model used to examine factors associated with RR. We also assessed the agreement between repeat measurements taken from a subset of study subject. Results: A total of 830 children provided 67,512 RR measurements. The median age was 6.07 years (interquartile range (IQR), 4.21–8.55) and 400 (48.2%) were female. The centile chart showed a marked nonlinear decline in RR measurements with increasing age up to six years old, after which the decline was minimal (predicted median RR of 31 breaths/minute (IQR: 29–34) among one-year-olds, 22 breaths/minute (IQR: 21–23) among six-year-olds and 21 breaths/minute (IQR: 21-22) among 13-year-olds. Age (non-linear effect, p<0.001), stunting (0.84 breaths/minute [95%CI: 0.40-1.28, p<0.001]), ambient temperature (0.38 breaths/minute [95%CI: 0.33-0.42, p<0.001] for every 1oC increase in ambient temperature) and time of day when RR measurements were taken (non-linear effect, p<0.001) were independent predictors of respiratory rate. Strikingly, children with signs of illness were associated with higher intra-observer variability. Interpretation: We constructed a RR reference chart for children aged one to 13 years and proposed a cutoff of >26 breaths/minute for raised RR among children aged >5 years bridging an important gap in this age group. Although time of data collection, nutritional status and ambient temperature were predictors of RR, the evidence is not clinically significant to warrant a change in the current WHO guidelines owing to the prevailing uncertainty in the measurement of RR. The finding that RR between repeat measurements were more variable among children with signs of illness suggests that a single RR measurements may be inadequate to reliably assess the status of sick children - a population in which accurate diagnosis is essential to enable targeted interventions with lifesaving treatment.
{"title":"Respiratory rates among rural Gambian children: a community-based cohort study","authors":"Polycarp Mogeni, Sharon Amima, Jennifer Gunther, Margaret Pinder, Lucy S. Tusting, Umberto D’Alessandro, Simon Cousens, Steve W. Lindsay, John Bradley","doi":"10.1101/2023.12.05.23299490","DOIUrl":"https://doi.org/10.1101/2023.12.05.23299490","url":null,"abstract":"Abstract\u0000Background: Although ranges of normal respiratory rates (RR) have been described for children under five years old living in the tropics, there are few datasets recording rates in older children. The present study was designed to capture the changes in RR with age and to examine its association with nutritional status and environmental factors.\u0000Methods: A cohort of rural Gambian children aged from six months to 14 years had their RR recorded during home visits twice weekly during two annual rainy seasons. Measurements were made by trained field assistants using an electronic timer during a one-minute period. Age, sex, nutritional status, health status, time of day of data collection were recorded. A generalized additive model for location, scale and shape was used to construct the RR reference curves and a linear mixed effect model used to examine factors associated with RR. We also assessed the agreement between repeat measurements taken from a subset of study subject.\u0000Results: A total of 830 children provided 67,512 RR measurements. The median age was 6.07 years (interquartile range (IQR), 4.21–8.55) and 400 (48.2%) were female. The centile chart showed a marked nonlinear decline in RR measurements with increasing age up to six years old, after which the decline was minimal (predicted median RR of 31 breaths/minute (IQR: 29–34) among one-year-olds, 22 breaths/minute (IQR: 21–23) among six-year-olds and 21 breaths/minute (IQR: 21-22) among 13-year-olds. Age (non-linear effect, p<0.001), stunting (0.84 breaths/minute [95%CI: 0.40-1.28, p<0.001]), ambient temperature (0.38 breaths/minute [95%CI: 0.33-0.42, p<0.001] for every 1oC increase in ambient temperature) and time of day when RR measurements were taken (non-linear effect, p<0.001) were independent predictors of respiratory rate. Strikingly, children with signs of illness were associated with higher intra-observer variability.\u0000Interpretation: We constructed a RR reference chart for children aged one to 13 years and proposed a cutoff of >26 breaths/minute for raised RR among children aged >5 years bridging an important gap in this age group. Although time of data collection, nutritional status and ambient temperature were predictors of RR, the evidence is not clinically significant to warrant a change in the current WHO guidelines owing to the prevailing uncertainty in the measurement of RR. The finding that RR between repeat measurements were more variable among children with signs of illness suggests that a single RR measurements may be inadequate to reliably assess the status of sick children - a population in which accurate diagnosis is essential to enable targeted interventions with lifesaving treatment.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"8 5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138546947","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 : 2023-12-05DOI: 10.1101/2023.12.05.23299258
Kaiwen Xu, Thomas Z Li, James G Terry, Aravind R Krishnan, Stephen A Deppen, Yuankai Huo, Fabien Maldonado, John Jeffrey Carr, Bennett A Landman, Kim L Sandler
Rationale: Skeletal muscle fat infiltration progresses with aging and is worsened among individuals with a history of cigarette smoking. Many negative impacts of smoking on muscles are likely reversible with smoking cessation. Objectives: To determine if the progression of skeletal muscle fat infiltration with aging is altered by smoking cessation among lung cancer screening participants. Methods: This was a secondary analysis based on the National Lung Screening Trial. Skeletal muscle attenuation in Hounsfield unit (HU) was derived from the baseline and follow-up low-dose CT scans using a previously validated artificial intelligence algorithm. Lower attenuation indicates greater fatty infiltration. Linear mixed-effects models were constructed to evaluate the associations between smoking status and the muscle attenuation trajectory. Measurements and Main Results: Of 19,019 included participants (age: 61 years, 5 [SD]; 11,290 males), 8,971 (47.2%) were actively smoking cigarettes. Accounting for body mass index, pack-years, percent emphysema, and other confounding factors, actively smoking predicted a lower attenuation in both males (β_0=-0.88 HU, P<.001) and females (β_0=-0.69 HU, P<.001), and an accelerated muscle attenuation decline-rate in males (β_1=-0.08 HU/y, P<.05). Age-stratified analyses indicated that the accelerated muscle attenuation decline associated with smoking likely occurred at younger age, especially in females. Conclusions: Among lung cancer screening participants, active cigarette smoking was associated with greater skeletal muscle fat infiltration in both males and females, and accelerated muscle adipose accumulation rate in males. These findings support the important role of smoking cessation in preserving muscle health.
{"title":"Age-related Muscle Fat Infiltration in Lung Screening Participants: Impact of Smoking Cessation","authors":"Kaiwen Xu, Thomas Z Li, James G Terry, Aravind R Krishnan, Stephen A Deppen, Yuankai Huo, Fabien Maldonado, John Jeffrey Carr, Bennett A Landman, Kim L Sandler","doi":"10.1101/2023.12.05.23299258","DOIUrl":"https://doi.org/10.1101/2023.12.05.23299258","url":null,"abstract":"Rationale: Skeletal muscle fat infiltration progresses with aging and is worsened among individuals with a history of cigarette smoking. Many negative impacts of smoking on muscles are likely reversible with smoking cessation. Objectives: To determine if the progression of skeletal muscle fat infiltration with aging is altered by smoking cessation among lung cancer screening participants. Methods: This was a secondary analysis based on the National Lung Screening Trial. Skeletal muscle attenuation in Hounsfield unit (HU) was derived from the baseline and follow-up low-dose CT scans using a previously validated artificial intelligence algorithm. Lower attenuation indicates greater fatty infiltration. Linear mixed-effects models were constructed to evaluate the associations between smoking status and the muscle attenuation trajectory. Measurements and Main Results: Of 19,019 included participants (age: 61 years, 5 [SD]; 11,290 males), 8,971 (47.2%) were actively smoking cigarettes. Accounting for body mass index, pack-years, percent emphysema, and other confounding factors, actively smoking predicted a lower attenuation in both males (β_0=-0.88 HU, P<.001) and females (β_0=-0.69 HU, P<.001), and an accelerated muscle attenuation decline-rate in males (β_1=-0.08 HU/y, P<.05). Age-stratified analyses indicated that the accelerated muscle attenuation decline associated with smoking likely occurred at younger age, especially in females. Conclusions: Among lung cancer screening participants, active cigarette smoking was associated with greater skeletal muscle fat infiltration in both males and females, and accelerated muscle adipose accumulation rate in males. These findings support the important role of smoking cessation in preserving muscle health.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":" 31","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138494276","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 : 2023-12-05DOI: 10.1101/2023.12.05.23299392
Weiling Xu, Yun Soo Hong, Bo Hu, Suzy A. A. Comhair, Allison J. Janocha, Joe G. Zein, Ruoying Chen, Deborah A. Meyers, David T. Mauger, Victor E. Ortega, Eugene R. Bleecker, Mario Castro, Loren C. Denlinger, John V. Fahy, Elliot Israel, Bruce D. Levy, Nizar N. Jarjour, Wendy C. Moore, Sally E. Wenzel, Benjamin Gaston, Chunyu Liu, Dan E. Arking, Serpil C. Erzurum
Rationale: Although airway oxidative stress and inflammation are central to asthma pathogenesis, there is limited knowledge of the relationship of asthma risk, severity, or exacerbations to mitochondrial dysfunction, which is pivotal to oxidant generation and inflammation. Objectives: We investigated whether mitochondrial DNA copy number (mtDNA-CN) as a measure of mitochondrial function is associated with asthma diagnosis, severity, oxidative stress, and exacerbations. Methods: We measured mtDNA-CN in blood in two cohorts. In the UK Biobank (UKB), we compared mtDNA-CN in mild and moderate-severe asthmatics to non-asthmatics. In the Severe Asthma Research Program (SARP), we evaluated mtDNA-CN in relation to asthma severity, biomarkers of oxidative stress and inflammation, and exacerbations. Measures and Main Results: In UK Biobank, asthmatics (n = 29,768) have lower mtDNA-CN compared to non-asthmatics (n = 239,158) (beta, -0.026 [95% CI, -0.038 to -0.014], P = 2.46x10-5). While lower mtDNA-CN is associated with asthma, mtDNA-CN did not differ by asthma severity in either UKB or SARP. Biomarkers of inflammation show that asthmatics have higher white blood cells (WBC), neutrophils, eosinophils, fraction exhaled nitric oxide (FENO), and lower superoxide dismutase (SOD) than non-asthmatics, confirming greater oxidative stress in asthma. In one year follow-up in SARP, higher mtDNA-CN is associated with reduced risk of three or more exacerbations in the subsequent year (OR 0.352 [95% CI, 0.164 to 0.753], P = 0.007). Conclusions: Asthma is characterized by mitochondrial dysfunction. Higher mtDNA-CN identifies an exacerbation-resistant asthma phenotype, suggesting mitochondrial function is important in exacerbation risk.
{"title":"Mitochondrial DNA Copy Number Variation in Asthma Risk, Severity, and Exacerbations","authors":"Weiling Xu, Yun Soo Hong, Bo Hu, Suzy A. A. Comhair, Allison J. Janocha, Joe G. Zein, Ruoying Chen, Deborah A. Meyers, David T. Mauger, Victor E. Ortega, Eugene R. Bleecker, Mario Castro, Loren C. Denlinger, John V. Fahy, Elliot Israel, Bruce D. Levy, Nizar N. Jarjour, Wendy C. Moore, Sally E. Wenzel, Benjamin Gaston, Chunyu Liu, Dan E. Arking, Serpil C. Erzurum","doi":"10.1101/2023.12.05.23299392","DOIUrl":"https://doi.org/10.1101/2023.12.05.23299392","url":null,"abstract":"Rationale: Although airway oxidative stress and inflammation are central to asthma pathogenesis, there is limited knowledge of the relationship of asthma risk, severity, or exacerbations to mitochondrial dysfunction, which is pivotal to oxidant generation and inflammation. Objectives: We investigated whether mitochondrial DNA copy number (mtDNA-CN) as a measure of mitochondrial function is associated with asthma diagnosis, severity, oxidative stress, and exacerbations. Methods: We measured mtDNA-CN in blood in two cohorts. In the UK Biobank (UKB), we compared mtDNA-CN in mild and moderate-severe asthmatics to non-asthmatics. In the Severe Asthma Research Program (SARP), we evaluated mtDNA-CN in relation to asthma severity, biomarkers of oxidative stress and inflammation, and exacerbations. Measures and Main Results: In UK Biobank, asthmatics (n = 29,768) have lower mtDNA-CN compared to non-asthmatics (n = 239,158) (beta, -0.026 [95% CI, -0.038 to -0.014], P = 2.46x10<sup>-5</sup>). While lower mtDNA-CN is associated with asthma, mtDNA-CN did not differ by asthma severity in either UKB or SARP. Biomarkers of inflammation show that asthmatics have higher white blood cells (WBC), neutrophils, eosinophils, fraction exhaled nitric oxide (F<sub>E</sub>NO), and lower superoxide dismutase (SOD) than non-asthmatics, confirming greater oxidative stress in asthma. In one year follow-up in SARP, higher mtDNA-CN is associated with reduced risk of three or more exacerbations in the subsequent year (OR 0.352 [95% CI, 0.164 to 0.753], P = 0.007). Conclusions: Asthma is characterized by mitochondrial dysfunction. Higher mtDNA-CN identifies an exacerbation-resistant asthma phenotype, suggesting mitochondrial function is important in exacerbation risk.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":" 32","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138494250","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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