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This brief presents an innovative technique for precise reference generation based on “digital-alike” operation. The bias of pn-junctions is defined trough pulse timings, while respective PTAT and CTAT signals are sampled from the voltage-decay of a capacitor. The greatly simple structures offer intrinsic supply robustness and use charge sharing or addition, to achieve large reverse-bandgap levels. Here, we employ the bulk-to-substrate diode of any baseline process combined with charge-pump function, instead of BJT devices. Two different circuit ideas were designed in 16-nm FinFET, with ultra-low power requirements. The first version achieves an untrimmed $3\sigma $ -accuracy of ±0.82%, realizing 235-mV reference output down to 0.85-V supply. A second IP carries lowest complexity using a single diode only: it consumes 21 nA at $1680~\mu \text{m}^{2}$ active area, and provides larger levels of Vref ~370 mV at merely ±2.7 mV total spread from silicon data. Unlike prior art, the compact reverse bandgaps do not require typical analog structures, like resistors, matched biasing, or differential amplifiers. [ABSTRACT FROM AUTHOR]

Epilepsy affects about 50 million people worldwide of which one third is refractory to medication. An automated and reliable system that warns of impending seizures would greatly improve patient’s quality of life by overcoming the uncertainty and helplessness due to the unpredicted events. Here we present new seizure prediction results including a performance comparison of different methods. The analysis is based on a new set of intracranial EEG data that has been recorded in our working group during presurgical evaluation. We applied two different methods for seizure prediction and evaluated their performance pseudoprospectively. The comparison of this evaluation with common statistical evaluation reveals possible reasons for overly optimistic estimations of the performance of seizure forecasting systems.

To cite this article: Chen LY, Eberlein M, Alsaaty S, Martinez-Anton A, Barb J, Munson PJ, Danner RL, Liu Y, Logun C, Shelhamer JH, Woszczek G. Cooperative and redundant signaling of leukotriene B4 and leukotriene D4 in human monocytes. Allergy 2011; 66: 1304-1311. Abstract Background: Leukotriene B4 (LTB4) and cysteinyl leukotrienes (cysLTs) are important immune mediators, often found concomitantly at sites of inflammation. Although some of the leukotriene-mediated actions are distinctive (e.g., bronchial constriction for cysLTs), many activities such as leukocyte recruitment to tissues and amplification of inflammatory responses are shared by both classes of leukotrienes. Objective: We used human monocytes to characterize leukotriene-specific signaling, gene expression signatures, and functions and to identify interactions between LTB4- and cysLTs-induced pathways. Methods: Responsiveness to leukotrienes was assessed using oligonucleotide microarrays, real-time PCR, calcium mobilization, kinase activation, and chemotaxis assays. Results: Human monocytes were found to express mRNA for high- and low-affinity LTB4 receptors, BLT1 and BLT2, but signal predominantly through BLT1 in response to LTB4 stimulation as shown using selective agonists, inhibitors, and gene knock down experiments. LTB4 acting through BLT1 coupled to G-protein α inhibitory subunit activated calcium signaling, p44/42 mitogen-activated protein kinase, gene expression, and chemotaxis. Twenty-seven genes, including immediate early genes (IEG), transcription factors, cytokines, and membrane receptors were significantly up-regulated by LTB4. LTB4 and LTD4 had similar effects on signaling, gene expression, and chemotaxis indicating redundant cell activation pathways but costimulation with both lipid mediators was additive for many monocyte functions. Conclusion: Leukotriene B4 and LTD4 display both redundant and cooperative effects on intracellular signaling, gene expression, and chemotaxis in human monocytes. These findings suggest that therapies targeting either leukotriene alone may be less effective than approaches directed at both. [ABSTRACT FROM AUTHOR]

As part of a research project, a new hybrid forming process for ultrathin three-dimensional glass elements was developed. In a continuous process chain, the three-part procedure enables large-area gravity-assisted bending of thin glass, partial deep-drawing of individual small structures using CO2 laser radiation and cutting of flexible inner and outer contours. Using an experimental setup with a laser scanning system, novel component designs can be generated in a highly flexible and reproducible manner. This can open up new application fields or expand existing ones, for example in the area of cover glasses for display technology.

Abstract Background The balance between reactive oxygen species (ROS) and endogenous anti-oxidants is important in maintaining healthy tissues. Excessive ROS states occur in diseases such as ARDS and Idiopathic Pulmonary Fibrosis. Redox imbalance breaks down the extracellular matrix component hyaluronan (HA) into fragments that activate innate immune responses and perpetuate tissue injury. HA fragments, via a TLR and NF-κB pathway, induce inflammatory gene expression in macrophages and epithelial cells. NAC and DMSO are potent anti-oxidants which may help balance excess ROS states. Methods We evaluated the effect of H2O2, NAC and DMSO on HA fragment induced inflammatory gene expression in alveolar macrophages and epithelial cells. Results NAC and DMSO inhibit HA fragment-induced expression of TNF-α and KC protein in alveolar and peritoneal macrophages. NAC and DMSO also show a dose dependent inhibition of IP-10 protein expression, but not IL-8 protein, in alveolar epithelial cells. In addition, H2O2 synergizes with HA fragments to induce inflammatory genes, which are inhibited by NAC. Mechanistically, NAC and DMSO inhibit HA induced gene expression by inhibiting NF-κB activation, but NAC had no influence on HA-fragment-AP-1 mediated gene expression. Conclusion ROS play a central role in a pathophysiologic "vicious cycle" of inflammation: tissue injury generates ROS, which fragment the extracellular matrix HA, which in turn synergize with ROS to activate the innate immune system and further promote ROS, HA fragment generation, inflammation, tissue injury and ultimately fibrosis. The anti-oxidants NAC and DMSO, by inhibiting the HA induced inflammatory gene expression, may help re-balance excessive ROS induced inflammation.

Objective: Up to a third of patients with epilepsy fail to achieve satisfactory seizure control. A reliable method of predicting seizures would alleviate psychological and physical impact. Dysregulation in heart rate variability (HRV) has been found to precede epileptic seizures and may serve as an extracerebral predictive biomarker. This study aims to identify the preictal HRV dynamics and unveil the factors impeding the clinical application of ECG-based seizure prediction., Methods: Thirty-nine adult patients (eight women; median age: 38, [IQR = 31, 56.5]) with 252 seizures were included. Each patient had more than three recorded epileptic seizures, each at least 2 hours apart. For each seizure, one hour of ECG prior to seizure onset was analyzed and 97 HRV features were extracted from overlapping three-minute windows with 10s stride. Two separate patient-specific experiments were performed using a support vector machine (SVM). Firstly, the separability of training data was examined in a non-causal trial. Secondly, the prediction was attempted in pseudo-prospective conditions. Finally, visualized HRV data, clinical metadata, and results were correlated., Results: The mean receiver operating characteristic (ROC) area under the curve (AUC) for the non-causal experiment was 0.823 (±0.12), with 208 (82.5%) seizures achieving an improvement over chance (IoC) classification score (p < 0.05, Hanley & McNeil test). In pseudo-prospective classification, the ROC-AUC was 0.569 (±0.17), and 86 (49.4%) seizures were classified with IoC. Off-sample optimized SVMs failed to improve performance. Major limiting factors identified include non-stationarity, variable preictal duration and dynamics. The latter is expressed as both inter-seizure onset zone (SOZ) and intra-SOZ variability., Significance: The pseudo-prospective preictal classification achieving IoC in approximately half of tested seizures suggests the presence of genuine preictal HRV dynamics, but the overall performance does not warrant clinical application at present. The limiting factors identified are often overlooked in non-causal study designs. While current deterministic prediction methods prove inadequate, probabilistic approaches may offer a promising alternative., Plain Language Summary: Many patients with epilepsy suffer from uncontrollable seizures and would greatly benefit from a reliable seizure prediction method. Currently, no such system is available to meet this need. Previous studies suggest that changes in the electrocardiogram (ECG) precede seizures by several minutes. In our work, we evaluated whether variations in heart rate could be used to predict epileptic seizures. Our findings indicate that we are still far from achieving results suitable for clinical application and highlight several limiting factors of present seizure prediction approaches., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: The apparent randomness of seizure occurrence affects greatly the quality of life of persons with epilepsy. Since seizures are often phase-locked to multidien cycles of interictal epileptiform activity, a recent forecasting scheme, exploiting RNS data, is capable of forecasting seizures days in advance., Methods: We tested the use of a bandpass filter to capture the universal mid-term dynamics enabling both patient-specific and cross-patient forecasting. In a retrospective study, we explored the feasibility of the scheme on three long-term recordings obtained by the NeuroPace RNS System, the NeuroVista intracranial, and the UNEEG subcutaneous devices, respectively., Results: Better-than-chance forecasting was observed in 15 (83 %) of 18 patients, and in 16 (89 %) patients for daily and hourly forecast, respectively. Meaningful forecast up to 30 days could be achieved in 4 (22 %) patients for hourly forecast frequency. The cross-patient performance decreased only marginally and was patient-wise strongly correlated with the patient-specific one. Comparable performance was obtained for NeuroVista and UNEEG data sets., Significance: The feasibility of cross-patient forecasting supports the universal importance of mid-term dynamics for seizure forecasting, demonstrates promising inter-subject-applicability of the scheme on ultra long-term EEG recordings, and highlights its huge potential for clinical use., Competing Interests: Declaration of Competing Interest J.D.-H. is a full-time employee at UNEEG medical, a company developing and producing a subscalp EEG device. T.K. has performed consultancy for UNEEG medical. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Competing Interests: The authors declare no funding or conflicts of interest.

Background: Pre-existing chronic kidney disease (CKD) may have an impact on post-lung transplant survival and the development of end stage kidney disease (ESKD)., Methods: We analyzed the US transplant database from 2006 to 2020. Adult patients who received their first lung transplant and were not on dialysis were included. Multivariable Cox regression was used to assess the effect of pretransplant eGFR on mortality and cumulative incidence competing risk was used to explore the effect on ESKD., Results: The adjusted hazard ratio (aHR) for mortality showed a "U" shaped association with eGFR with a rising mortality at <60 and >100 ml/min/1.73m 2 . The increase in mortality with higher eGFR was only seen in those <30 year and were primarily in whites with a lower body mass index and in patients with cystic fibrosis (CF). The aHR for ESKD increased below an eGFR of 100 rising to 1.74 at an eGFR of 60. Any decrease in eGFR between listing and transplant >10% was associated with higher risk of ESKD., Conclusions: The U-shaped association of pretransplant eGFR with post-transplant mortality correlated with younger age, lower BMI and a diagnosis of CF. The aHR for ESKD following lung transplantation increased exponentially with worsening eGFR pretransplant., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: Although autism spectrum disorder (ASD) is a relatively common, well-known but heterogeneous neuropsychiatric disorder, specific knowledge about characteristics of this heterogeneity is scarce. There is consensus that IQ contributes to this heterogeneity as well as complicates diagnostics and treatment planning. In this study, we assessed the accuracy of the Autism Diagnostic Observation Schedule (ADOS/2) in the whole and IQ-defined subsamples, and analyzed if the ADOS/2 accuracy may be increased by the application of machine learning (ML) algorithms that processed additional information including the IQ level., Methods: The study included 1,084 individuals: 440 individuals with ASD (with a mean IQ level of 3.3 ± 1.5) and 644 individuals without ASD (with a mean IQ level of 3.2 ± 1.2). We applied and analyzed Random Forest (RF) and Decision Tree (DT) to the ADOS/2 data, compared their accuracy to ADOS/2 cutoff algorithms, and examined most relevant items to distinguish between ASD and Non-ASD. In sum, we included 49 individual features, independently of the applied ADOS module., Results: In DT analyses, we observed that for the decision ASD/Non-ASD, solely one to four items are sufficient to differentiate between groups with high accuracy. In addition, in sub-cohorts of individuals with (a) below (IQ level ≥4)/ID and (b) above average intelligence (IQ level ≤ 2), the ADOS/2 cutoff showed reduced accuracy. This reduced accuracy results in (a) a three times higher risk of false-positive diagnoses or (b) a 1.7 higher risk for false-negative diagnoses; both errors could be significantly decreased by the application of the alternative ML algorithms., Conclusions: Using ML algorithms showed that a small set of ADOS/2 items could help clinicians to more accurately detect ASD in clinical practice across all IQ levels and to increase diagnostic accuracy especially in individuals with below and above average IQ level., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wolff, Eberlein, Stroth, Poustka, Roepke, Kamp-Becker and Roessner.)

Objective: Seizure forecasting using machine learning is possible, but the performance is far from ideal, as indicated by many false predictions and low specificity. Here, we examine false and missing alarms of two algorithms on long-term datasets to show that the limitations are less related to classifiers or features, but rather to intrinsic changes in the data., Methods: We evaluated two algorithms on three datasets by computing the correlation of false predictions and estimating the information transfer between both classification methods., Results: For 9 out of 12 individuals both methods showed a performance better than chance. For all individuals we observed a positive correlation in predictions. For individuals with strong correlation in false predictions we were able to boost the performance of one method by excluding test samples based on the results of the second method., Conclusions: Substantially different algorithms exhibit a highly consistent performance and a strong coherency in false and missing alarms. Hence, changing the underlying hypothesis of a preictal state of fixed time length prior to each seizure to a proictal state is more helpful than further optimizing classifiers., Significance: The outcome is significant for the evaluation of seizure prediction algorithms on continuous data., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Diagnosing the cause of hypoxemia and dyspnea can be complicated in complex patients with multiple comorbidities. This "Case Study in Physiology" describes an man with obesity admitted to the hospital for relapse of acute lymphoblastic leukemia, who experienced progressive hypoxemia, shortness of breath, and dyspnea on exertion during his hospitalization. After initial empirical treatment with diuresis and antibiotics failed to improve his symptoms and because an arterial blood gas measurement was not readily available, we applied a novel, recently described physiological method to estimate the arterial partial pressure of oxygen from the peripheral saturation measurement and calculate the alveolar-arterial oxygen difference to discern the source of his hypoxemia and dyspnea. Using basic physiological principles, we describe how hypoventilation, anemia, and the use of a β blocker and furosemide, collaborated to create a "perfect storm" in this patient that impaired oxygen delivery and limited utilization. This case illustrates the application of innovative physiology methodology in medicine and provides a strong rationale for continuing to integrate physiology education in medical education. NEW & NOTEWORTHY Discerning the cause of dyspnea and hypoxemia in complex patients can be difficult. We describe the "real world" application of an innovative methodology to untangle the underlying physiology in a patient with multiple comorbidities. This case further demonstrates the importance of applying physiology to interrogate the underlying cause of a patient's symptoms when treatment based on probability fails.

Pulmonary metastasectomy has become an important part of the multimodality treatment. Surgical practice is based on observational studies published during the last decades, since no randomized clinical trials exist on the topic. However, the overall survival can be improved after pulmonary metastasectomy in carefully selected patients. The objective of resection of pulmonary metastases is to remove all tumor while preserving as much normal pulmonary parenchyma as possible and reduce invasiveness. Contrary, nonsurgical local treatment options for pulmonary metastases include thermal ablation techniques and stereotactic ablative body radiation. Thermal ablation techniques include microwave, cryotherapy and radiofrequency ablation. The present review article gives an overview on the topic and should help thoracic surgeons to make the right decisions in their daily practice., Competing Interests: Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-2019-pm-09). The series “Pulmonary Metastases” was commissioned by the editorial office without any funding or sponsorship. SB serves as an unpaid editorial board member of Journal of Thoracic Disease. The authors have no other conflicts of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)

Background: Spirometry results can yield a diagnosis of normal air flow, air flow obstruction, or preserved ratio impaired spirometry (PRISm), defined as a reduced FEV 1 or FVC in the setting of preserved FEV 1 /FVC. Previous studies have estimated the prevalence of PRISm to be 7-12%. Our objective was to examine the prevalence of PRISm in a spirometry database and to identify factors associated with PRISm., Methods: We performed a retrospective analysis of 21,870 spirometries; 1,616 were excluded because of missing data or extremes of age, height, or weight. We calculated the prevalence of PRISm in prebronchodilator and postbronchodilator pulmonary function tests. Subsequently, we calculated the prevalence of PRISm by various age, race, body mass index, and diagnosis categories, as well as by gender and smokers versus nonsmokers. Finally, in the subset of the cohort with FEV 1 < lower limit of normal, we performed a multivariable logistic regression analysis to identify factors associated with PRISm., Results: We identified 18,059 prebronchodilator spirometries, and 22.3% of these yielded a PRISm diagnosis. This prevalence remained stable in postbronchodilator spirometries (17.7%), after excluding earlier pulmonary function tests for subjects with multiple pulmonary function tests (20.7% in prebronchodilator and 24.3% in postbronchodilator), and when we limited the analysis to prebronchodilator spirometries that met American Thoracic Society criteria (20.6%). The PRISm prevalence was higher in subjects 45-60 y old (24.4%) and in males (23.7%) versus females (17.9%). The prevalence rose with body mass index and was higher for those with a referral diagnosis of restrictive lung disease (50%). PRISm prevalence was similar between races and smokers versus nonsmokers. In a multivariable analysis, higher % of predicted FEV 1 (odds ratio 1.51, 95% CI 1.42-1.60), body mass index (odds ratio 1.52, 95% CI 1.39-1.68), and restrictive lung disease (odds ratio 4.32, 95% CI 2.54-7.57) were associated with a diagnosis of PRISm. Smoking was inversely associated (odds ratio 0.55, 95% CI 0.46-0.65) with PRISm., Conclusions: In a spirometry database at an academic medical center, the PRISm prevalence was 17-24%, which is higher than previously reported., (Copyright © 2021 by Daedalus Enterprises.)

Anatomic resections with bronchial and/or vascular resections and reconstruction, so called sleeve resections were originally performed in patients with impaired cardio-pulmonary reserves. Nowadays, sleeve resections are established surgical procedures of first choice for tracheobronchial pathologies, whenever anatomically and oncologically feasible. Experienced thoracic surgeons have a broad surgical armentarium to avoid a pneumonectomy and the morbidity and mortality associated with it. Sleeve resections are associated with better outcomes in all aspects. Thus, sleeve resection is not an alternative for pneumonectomy and vice versa. In this review article we set out to provide a contemporary overview on this topic., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd.2020.02.65). The series “Airway Surgery” was commissioned by the editorial office without any funding or sponsorship. SB served as the unpaid Guest Editor for the series and serves as the unpaid editorial board of Journal of Thoracic Disease from Nov 2018 to Oct 2020. The other authors have no other conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation. Spirometry loops are not smooth curves and have undulations and peaks that likely reflect heterogeneity of airflow. Objectives: To assess whether the Peak Index, the number of peaks adjusted for lung size, is associated with clinical outcomes. Methods: We analyzed spirometry data of 9,584 participants enrolled in the COPDGene study and counted the number of peaks in the descending part of the expiratory flow-volume curve from the peak expiratory flow to end-expiration. We adjusted the peaks count for the volume of the lungs from peak expiratory flow to end-expiration to derive the Peak Index. Multivariable regression analyses were performed to test associations between the Peak Index and lung function, respiratory morbidity, structural lung disease on computed tomography (CT), forced expiratory volume in 1 second (FEV 1 ) decline, and mortality. Results: The Peak Index progressively increased from Global Initiative for Chronic Obstructive Lung Disease stage 0 through 4 ( P  < 0.001). On multivariable analysis, the Peak Index was significantly associated with CT emphysema (adjusted β = 0.906; 95% confidence interval [CI], 0.789 to 1.023; P  < 0.001) and small airways disease (adjusted β = 1.367; 95% CI, 1.188 to 1.545; P  < 0.001), St. George's Respiratory Questionnaire score (adjusted β = 1.075; 95% CI, 0.807 to 1.342; P  < 0.001), 6-minute-walk distance (adjusted β = -1.993; 95% CI, -3.481 to -0.506; P  < 0.001), and FEV 1 change over time (adjusted β = -1.604; 95% CI, -2.691 to -0.516; P  = 0.004), after adjustment for age, sex, race, body mass index, current smoking status, pack-years of smoking, and FEV 1. The Peak Index was also associated with the BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index and mortality ( P  < 0.001). Conclusions: The Peak Index is a spirometry metric that is associated with CT measures of lung disease, respiratory morbidity, lung function decline, and mortality.Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

Rabbit antithymocyte globulin (rATG) is known to yield false-positive Histoplasma antigenemia. The fourth generation MiraVista Histoplasma antigen assay was modified to block this effect (MiraVista Diagnostics, Indianapolis, Indiana). We report a case of rATG-induced false-positive Blastomyces and Histoplasma antigenemia in a lung transplant recipient despite modifications of these antigen assays.

Objectives: Resection of tumour spread on a very thin visceral pleura might be challenging, and collateral damage to the lung parenchyma might occur. We aimed to develop an operative technique, which might facilitate the parenchyma-sparing destruction of the visceral pleura. This experimental work investigated the effects of a neodymium:yttrium aluminum garnet (Nd:YAG) laser on the visceral pleura in an ex vivo porcine lung model., Methods: We used a diode-pumped Nd:YAG laser (Limax® 120, KLS Martin, Tuttlingen, Germany) to investigate the effects on the visceral pleural in 20 porcine lungs. The laser was applied on a standardized length in 4 different settings: Group I (80 W, 6 s), Group II (80 W, 12 s), Group III (120 W, 6 s) and Group IV (120 W, 12 s). All specimens were analysed histologically., Results: The mean thickness of the visceral pleura was 81 ± 10 μm. Increasing power levels and longer application duration resulted in significantly enhanced laser destruction effects. The mean depths of the carbonization zone were 142 ± 42 µm, 378 ± 137 µm, 607 ± 155 µm and 1371 ± 271 μm for Groups I-IV, respectively (P < 0.001). The ratio of carbonization zone to pleural thickness was measured for each section (C/P ratio) to quantify the thermal effects. The corresponding C/P ratio for Groups I-IV were 1.72 ± 0.55, 4.98 ± 1.96, 7.11 ± 1.61 and 17.35 ± 4.35, respectively (P < 0.001)., Conclusions: Our study showed that increasing power levels and application duration of the laser lead to a significantly increased carbonization and destruction zones. Further in vivo human studies should evaluate the feasibility of laser application for a potential translational relevance for human use., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Tools to measure lung and airways volume are critical for pulmonary researchers interested in evaluating the impact of disease or novel therapies on the lung. Barometric plethysmography is a classic technique to evaluate the lung volume with a long history of clinical use. Volumetric capnography utilizes the profile of exhaled carbon dioxide to determine the volume of the conducting airways, or dead space, and provides an index of airways homogeneity. These techniques may be used independently, or in combination to evaluate the dependence of airways volume and homogeneity on lung volume. This paper provides detailed technical instructions to replicate these techniques and our representative data demonstrates that the airways volume and homogeneity are highly correlated to lung volume. We also provide a macro for the analysis of capnographic data, which can be modified or adapted to fit different experimental designs. The advantage of these measures is that their advantages and limitations are supported by decades of experimental data, and they can be made repeatedly in the same subject without expensive imaging equipment or technically advanced analysis algorithms. These methods may be particularly useful for investigators interested in perturbations that change both the functional residual capacity of the lung and airways volume.

The diagnosis of chronic obstructive pulmonary disease (COPD) relies on demonstration of airflow obstruction. Traditional spirometric indices miss a number of subjects with respiratory symptoms or structural lung disease on imaging. We hypothesized that utilizing all data points on the expiratory spirometry curves to assess their shape will improve detection of mild airflow obstruction and structural lung disease. We analyzed spirometry data of 8307 participants enrolled in the COPDGene study, and derived metrics of airflow obstruction based on the shape on the volume-time (Parameter D), and flow-volume curves (Transition Point and Transition Distance). We tested associations of these parameters with CT measures of lung disease, respiratory morbidity, and mortality using regression analyses. There were significant correlations between FEV 1 /FVC with Parameter D (r = -0.83; p < 0.001), Transition Point (r = 0.69; p < 0.001), and Transition Distance (r = 0.50; p < 0.001). All metrics had significant associations with emphysema, small airway disease, dyspnea, and respiratory-quality of life (p < 0.001). The highest quartile for Parameter D was independently associated with all-cause mortality (adjusted HR 3.22,95% CI 2.42-4.27; p < 0.001) but a substantial number of participants in the highest quartile were categorized as GOLD 0 and 1 by traditional criteria (1.8% and 33.7%). Parameter D identified an additional 9.5% of participants with mild or non-recognized disease as abnormal with greater burden of structural lung disease compared with controls. The data points on the flow-volume and volume-time curves can be used to derive indices of airflow obstruction that identify additional subjects with disease who are deemed to be normal by traditional criteria.