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Machine Learning (ML) has recently been a skyrocketing field in Computer Science. As computer hardware engineers, we are enthusiastic about hardware implementations of popular software ML architectures to optimize their performance, reliability, and resource usage. In this project, we designed a highly-configurable, real-time device for recognizing handwritten letters and digits using an Altera DE1 FPGA Kit. We followed various engineering standards, including IEEE-754 32-bit Floating-Point Standard, Video Graphics Array (VGA) display protocol, Universal Asynchronous Receiver-Transmitter (UART) protocol, and Inter-Integrated Circuit (I2C) protocols to achieve the project goals. These significantly improved our design in compatibility, reusability, and simplicity in verifications. Following these standards, we designed a 32-bit floating-point (FP) instruction set architecture (ISA). We developed a 5-stage RISC processor in System Verilog to manage image processing, matrix multiplications, ML classifications, and user interfaces. Three different ML architectures were implemented and evaluated on our design: Linear Classification (LC), a 784-64-10 fully connected neural network (NN), and a LeNet-like Convolutional Neural Network (CNN) with ReLU activation layers and 36 classes (10 for the digits and 26 for the case-insensitive letters). The training processes were done in Python scripts, and the resulting kernels and weights were stored in hex files and loaded into the FPGA's SRAM units. Convolution, pooling, data management, and various other ML features were guided by firmware in our custom assembly language. This paper documents the high-level design block diagrams, interfaces between each System Verilog module, implementation details of our software and firmware components, and further discussions on potential impacts., Comment: 27 pages, 13 figures

Chest computed tomography (CT) at inspiration is often complemented by an expiratory CT for identifying peripheral airways disease in the form of air trapping. Additionally, co-registered inspiratory-expiratory volumes are used to derive several clinically relevant measures of local lung function. Acquiring CT at different volumes, however, increases radiation dosage, acquisition time, and may not be achievable due to various complications, limiting the utility of registration-based measures, To address this, we propose Lung2Lung - a style-based generative adversarial approach for translating CT images from end-inspiratory to end-expiratory volume. Lung2Lung addresses several limitations of the traditional generative models including slicewise discontinuities, limited size of generated volumes, and their inability to model neural style at a volumetric level. We introduce multiview perceptual similarity (MEAL) to capture neural styles in 3D. To incorporate global information into the training process and refine the output of our model, we also propose self-ensembling (SE). Lung2Lung, with MEAL and SE, is able to generate large 3D volumes of size 320 x 320 x 320 that are validated using a diverse cohort of 1500 subjects with varying disease severity. The model shows superior performance against several state-of-the-art 2D and 3D generative models with a peak-signal-to-noise ratio of 24.53 dB and structural similarity of 0.904. Clinical validation shows that the synthetic volumes can be used to reliably extract several clinical endpoints of chronic obstructive pulmonary disease., 10 pages, 10 figures, 3 Tables

Real-world evaluations have demonstrated high effectiveness of vaccines against COVID-19-associated hospitalizations (1-4) measured shortly after vaccination; longer follow-up is needed to assess durability of protection. In an evaluation at 21 hospitals in 18 states, the duration of mRNA vaccine (Pfizer-BioNTech or Moderna) effectiveness (VE) against COVID-19-associated hospitalizations was assessed among adults aged ≥18 years. Among 3,089 hospitalized adults (including 1,194 COVID-19 case-patients and 1,895 non-COVID-19 control-patients), the median age was 59 years, 48.7% were female, and 21.1% had an immunocompromising condition. Overall, 141 (11.8%) case-patients and 988 (52.1%) controls were fully vaccinated (defined as receipt of the second dose of Pfizer-BioNTech or Moderna mRNA COVID-19 vaccines ≥14 days before illness onset), with a median interval of 65 days (range = 14-166 days) after receipt of second dose. VE against COVID-19-associated hospitalization during the full surveillance period was 86% (95% confidence interval [CI] = 82%-88%) overall and 90% (95% CI = 87%-92%) among adults without immunocompromising conditions. VE against COVID-19- associated hospitalization was 86% (95% CI = 82%-90%) 2-12 weeks and 84% (95% CI = 77%-90%) 13-24 weeks from receipt of the second vaccine dose, with no significant change between these periods (p = 0.854). Whole genome sequencing of 454 case-patient specimens found that 242 (53.3%) belonged to the B.1.1.7 (Alpha) lineage and 74 (16.3%) to the B.1.617.2 (Delta) lineage. Effectiveness of mRNA vaccines against COVID-19-associated hospitalization was sustained over a 24-week period, including among groups at higher risk for severe COVID-19; ongoing monitoring is needed as new SARS-CoV-2 variants emerge. To reduce their risk for hospitalization, all eligible persons should be offered COVID-19 vaccination.

BACKGROUND: Small airways are known to be affected early in the course of COPD; however, traditional spirometric indices may not accurately identify small airways disease. RESEARCH QUESTION: Can forced expiratory volume in 3 s/forced expiratory volume in 6 s (FEV(3)/FEV(6)) identify early airflow abnormalities and predict future clinically important respiratory-related outcomes, including development of COPD? STUDY DESIGN AND METHODS: The study included 832 current and former smokers with post-bronchodilator FEV(1)/FVC ≥ 0.7 from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Participants were classified as having a reduced pre-bronchodilator FEV(3)/FEV(6) based on lower limit of normal (LLN) values. Repeatability analysis was performed for FEV(3) and FEV(6). Regression modeling was used to evaluate the relationship between baseline FEV(3)/FEV(6) and outcome measures, including functional small airways disease, on thoracic imaging and respiratory exacerbations. Interval-censored analysis was used to assess progression to COPD. RESULTS: FEV(3)/FEV(6) less than the LLN at baseline, defined as reduced compared with FEV(3)/FEV(6) at or above the LLN, was associated with lower FEV(1), poorer health status (St. George’s Respiratory Questionnaire score), more emphysema, and more functional small airways disease on quantitative imaging. FEV(3) and FEV(6) showed excellent agreement between repeat measurements. A reduced FEV(3)/FEV(6) was associated with increased odds of a severe respiratory exacerbation within the first year of follow-up and decreased time to first exacerbation. A low FEV(3)/FEV(6) was also associated with development of COPD according to spirometry results (post-bronchodilator FEV(1)/FVC < 0.7) during study follow-up. INTERPRETATION: FEV(3)/FEV(6) is a routinely available and repeatable spirometric index that can be useful in the evaluation of early airflow obstruction in current and former smokers without COPD. A reduced FEV(3)/FEV(6) can identify those at risk for future development of COPD and respiratory exacerbations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov: ClinicalTrials.gov.

Christopher B Cooper,1 Robert Paine,2 Jeffrey L Curtis,3,4 Richard E Kanner,2 Carlos H Martinez,3 Catherine A Meldrum,3 Russell Bowler,5 Wanda O’Neal,6 Eric A Hoffman,7 David Couper,6 Miguel Quibrera,6 Gerald Criner,8 Mark T Dransfield,9 MeiLan K Han,3 Nadia N Hansel,10 Jerry A Krishnan,11 Stephen C Lazarus,12 Stephen P Peters,13 R Graham Barr,14 Fernando J Martinez,15 Prescott G Woodruff12 On behalf of the SPIROMICS investigators1Departments of Medicine and Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; 2Section of Pulmonary and Critical Care Medicine, Department of Veterans Affairs Medical Center, University of Utah, Salt Lake City, UT, USA; 3Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA; 4Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA; 5National Jewish Health, University of Colorado School of Medicine, Denver, CO, USA; 6University of North Carolina Marisco Lung Institute, Chapel Hill, NC, USA; 7Department of Radiology, University of Iowa, Iowa City, IA, USA; 8Department of Pulmonary and Critical Care Medicine, Temple University, Philadelphia, PA, USA; 9Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; 10Johns Hopkins University School of Medicine, Baltimore, MD, USA; 11Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA; 12Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; 13Wake Forest School of Medicine, Winston-Salem, NC, USA; 14Department of Medicine, Columbia University Medical Center, New York, NY, USA; 15Joan and Sanford I Weill Department of Medicine, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, NY, USACorrespondence: Christopher B CooperDepartments of Medicine and Physiology,David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, 37-131 CHS, Los Angeles, CA 90095, USAEmail ccooper@mednet.ucla.eduRationale: Some COPD patients develop extreme breathlessness, decreased exercise capacity and poor health status yet respiratory disability is poorly characterized as a distinct phenotype.Objective: To define respiratory disability in COPD based on available functional measures and to determine associations with risk for exacerbations and death.Methods: We analyzed baseline data from a multi-center observational study (SPIROMICS). This analysis includes 2332 participants (472 with severe COPD, 991 with mild/moderate COPD, 726 smokers without airflow obstruction and 143 non-smoking controls).Measurements: We defined respiratory disability by ≥ 4 of 7 criteria: mMRC dyspnea scale ≥ 3; Veterans Specific Activity Questionnaire < 5; 6-minute walking distance < 250 m; St George’s Respiratory Questionnaire activity domain > 60; COPD Assessment Test > 20; fatigue (FACIT-F Trial Outcome Index) < 50; SF-12 < 20.Results: Using these criteria, respiratory disability was identified in 315 (13.5%) participants (52.1% female). Frequencies were severe COPD 34.5%; mild-moderate COPD 11.2%; smokers without obstruction 5.2% and never-smokers 2.1%. Compared with others, participants with disability had more emphysema (13.2 vs. 6.6%) and air-trapping (37.0 vs. 21.6%) on HRCT (P< 0.0001). Using principal components analysis to derive a disability score, two factors explained 71% of variance, and a cut point − 1.0 reliably identified disability. This disability score independently predicted future exacerbations (ß=0.34; CI 0.12, 0.64; P=0.003) and death (HR 2.97; CI 1.54, 5.75; P=0.001). Thus, participants with disability by this criterion had almost three times greater mortality compared to those without disability.Conclusion: Our novel SPIROMICS respiratory disability score in COPD was associated with worse airflow obstruction as well as airway wall thickening, lung parenchymal destruction and certain inflammatory biomarkers. The disability score also proved to be an independent predictor of future exacerbations and death. These findings validate disability as an important phenotype in the spectrum of COPD.Keywords: disability, frailty, exacerbation rate, mortality, SPIROMICS

Rationale: Cross-sectional analysis of mucus plugs in computed tomography (CT) lung scans in the Severe Asthma Research Program (SARP)-3 showed a high mucus plug phenotype. Objectives: To determine if mucus plugs are a persistent asthma phenotype and if changes in mucus plugs over time associate with changes in lung function. Methods: In a longitudinal analysis of baseline and Year 3 CT lung scans in SARP-3 participants, radiologists generated mucus plug scores to assess mucus plug persistence over time. Changes in mucus plug score were analyzed in relation to changes in lung function and CT air trapping measures. Measurements and Main Results: In 164 participants, the mean (range) mucus plug score was similar at baseline and Year 3 (3.4 [0-20] vs. 3.8 [0-20]). Participants and bronchopulmonary segments with a baseline plug were more likely to have plugs at Year 3 than those without baseline plugs (risk ratio, 2.8; 95% confidence interval [CI], 2.0-4.1; P

Supplemental material, sj-docx-1-cic-10.1177_11795468221116838 for Influence of β1 Adrenergic Receptor Genotype on Longitudinal Measures of Left Ventricular Ejection Fraction and Responsiveness to ß-Blocker Therapy in Patients With Duchenne Muscular Dystrophy by Eli F Kelley, Troy J Cross, Craig M McDonald, CINRG Investigators, Eric P Hoffman, Christopher F Spurney and Luca Bello in Clinical Medicine Insights: Cardiology

This nonrandomized controlled trial examines efficacy of vamorolone treatment for Duchenne muscular dystrophy among boys compared with glucocorticoid treatment., Key Points Question Is long-term treatment with vamorolone associated with sustained disease modification and decrease of glucocorticoid-associated adverse outcomes among patients with Duchenne muscular dystrophy (DMD)? Findings In this nonrandomized controlled trial of 46 boys with DMD, higher-dose vamorolone treatment for up to 30 months was not associated with a change in time to stand velocity. Vamorolone was associated with continued disease-modification and similar efficacy compared with glucocorticoid treatment from 2 historical control cohorts, and long-term vamorolone treatment was associated with decreased adverse outcomes compared with traditional glucocorticoid therapy. Meaning These findings suggest that vamorolone may have potential as a standard of care disease-modifying treatment for boys with DMD., Importance Vamorolone is a synthetic steroidal drug with potent anti-inflammatory properties. Initial open-label, multiple ascending dose-finding studies of vamorolone among boys with Duchenne muscular dystrophy (DMD) found significant motor function improvement after 6 months treatment in higher-dose (ie, ≥2.0 mg/kg/d) groups. Objective To investigate outcomes after 30 months of open-label vamorolone treatment. Design, Setting, and Participants This nonrandomized controlled trial was conducted by the Cooperative International Neuromuscular Research Group at 11 US and non-US study sites. Participants were 46 boys ages 4.5 to 7.5 years with DMD who completed the 6-month dose-finding study. Data were analyzed from July 2020 through November 2021. Interventions Participants were enrolled in a 24-month, long-term extension (LTE) study with vamorolone dose escalated to 2.0 or 6.0 mg/kg/d. Main Outcomes and Measures Change in time-to-stand (TTSTAND) velocity from dose-finding baseline to end of LTE study was the primary outcome. Efficacy assessments included timed function tests, 6-minute walk test, and NorthStar Ambulatory Assessment (NSAA). Participants with DMD treated with glucocorticoids from the Duchenne Natural History Study (DNHS) and NorthStar United Kingdom (NSUK) Network were matched and compared with participants in the LTE study receiving higher doses of vamorolone. Results Among 46 boys with DMD who completed the dose-finding study, 41 boys (mean [SD] age, 5.33 [0.96] years) completed the LTE study. Among 21 participants treated with higher-dose (ie, ≥2.0 mg/kg/d) vamorolone consistently throughout the 6-month dose-finding and 24-month LTE studies with data available at 30 months, there was a decrease in mean (SD) TTSTAND velocity from baseline to 30 months (0.206 [0.070] rises/s vs 0.189 (0.124) rises/s), which was not a statistically significant change (−0.011 rises/s; CI, −0.068 to 0.046 rises/s). There were no statistically significant differences between participants receiving higher-dose vamorolone and matched participants in the historical control groups receiving glucocorticoid treatment (75 patients in DNHS and 110 patients in NSUK) over a 2-year period in NSAA total score change (0.22 units vs NSUK; 95% CI, −4.48 to 4.04]; P = .92), body mass index z score change (0.002 vs DNHS SD/mo; 95% CI, −0.006 to 0.010; P = .58), or timed function test change. Vamorolone at doses up to 6.0 mg/kg/d was well tolerated, with 5 of 46 participants discontinuing prematurely and for reasons not associated with study drug. Participants in the DNHS treated with glucocorticoids had significant growth delay in comparison with participants treated with vamorolone who had stable height percentiles (0.37 percentile/mo; 95% CI, 0.23 to 0.52 percentile/mo) over time. Conclusions and Relevance This study found that vamorolone treatment was not associated with a change in TTSTAND velocity from baseline to 30 months among boys with DMD aged 4 to 7 years at enrollment. Vamorolone was associated with maintenance of muscle strength and function up to 30 months, similar to standard of care glucocorticoid therapy, and improved height velocity compared with growth deceleration associated with glucocorticoid treatment, suggesting that vamorolone may be an attractive candidate for treatment of DMD. Trial Registration ClinicalTrials.gov Identifier: NCT03038399

Rationale: Diagnosis of chronic obstructive pulmonary disease (COPD) relies on abnormal spirometry. However, spirometry may underestimate the effects of smoking, missing smokers with respiratory disease who have minimal or no airflow obstruction. Objectives: To develop a multidimensional definition of a lung-related "resilient smoker" that is useful in research studies and then identify a resilient smoker subgroup in the SPIROMICS (SubPopulations and InteRmediate Outcome Measures In COPD Study) cohort using this definition. Methods: We performed a three-round modified Delphi survey among a panel of COPD experts to identify and reach a consensus on clinical and radiographic domains to be included in a lung-related resilient smoker definition. Consensus on domains of resilience was defined as ⩾80% of experts voting "agree" or "strongly agree" on a 5-point Likert scale. The Delphi-derived definition of resilience was applied to SPIROMICS to identify resilient smokers, whom we then characterized using known biomarkers of COPD. Results: Consensus was achieved on 6 of 12 diagnostic items, which include cough and sputum production, dyspnea, radiographic measures of emphysema and small airways disease, exacerbations, and decline in forced expiratory volume in 1 second. Although 892 SPIROMICS participants were classified as smokers with preserved lung function by spirometry, only 149 participants (16.7%) qualified as resilient smokers by our definition. Blood biomarker expression of CRP (C-reactive protein) and sTNFRSF1A (soluble tumor necrosis receptor factor1A) was lower in resilient than nonresilient smokers (P = 0.02 and P = 0.03). Conclusions: A Delphi-derived consensus definition of resilient smoker identified 83.3% of smokers with preserved spirometry as "nonresilient" based on the presence of adverse effects of smoking on the lung. Resilient smokers were biologically distinct from nonresilient smokers based on CRP measurements. Clinical trial registered with ClinicalTrials.gov (NCT01969344).

Understanding gluon density distributions and how they are modified in nuclei are among the most important goals in nuclear physics. In recent years, diffractive vector meson production measured in ultra-peripheral collisions (UPCs) at heavy-ion colliders has provided a new tool for probing the gluon density. In this Letter, we report the first measurement of $J/\psi$ photoproduction off the deuteron in UPCs at the center-of-mass energy $\sqrt{s_{_{\rm NN}}}=200~\rm GeV$ in d$+$Au collisions. The differential cross section as a function of momentum transfer $-t$ is measured. In addition, data with a neutron tagged in the deuteron-going Zero-Degree Calorimeter is investigated for the first time, which is found to be consistent with the expectation of incoherent diffractive scattering at low momentum transfer. Theoretical predictions based on the Color Glass Condensate saturation model and the gluon shadowing model are compared with the data quantitatively. A better agreement with the saturation model has been observed. With the current measurement, the results are found to be directly sensitive to the gluon density distribution of the deuteron and the deuteron breakup, which provides insights into the nuclear gluonic structure., Comment: Final published version Phys. Rev. Lett. 128, 122303

BackgroundCurrently, there is limited knowledge regarding which imaging assessments of asthma are associated with accelerated longitudinal decline in lung function.ObjectivesWe aimed to assess whether quantitative computed tomography (qCT) metrics are associated with longitudinal decline in lung function and morbidity in asthma.MethodsWe analyzed 205 qCT scans of adult patients with asthma and calculated baseline markers of airway remodeling, lung density, and pointwise regional change in lung volume (Jacobian measures) for each participant. Using multivariable regression models, we then assessed the association of qCT measurements with the outcomes of future change in lung function, future exacerbation rate, and changes in validated measurements of morbidity.ResultsGreater baseline wall area percent (β= -0.15 [95% CI= -0.26 to -0.05]; P< .01), hyperinflation percent (β= -0.25 [95% CI= -0.41 to -0.09]; P < .01), and Jacobian gradient measurements (cranial-caudal β= 10.64 [95% CI= 3.79-17.49]; P< .01; posterior-anterior β= -9.14, [95% CI= -15.49 to -2.78]; P< .01) were associated with more severe future lung function decline. Additionally, greater wall area percent (rate ratio= 1.06 [95% CI= 1.01-1.10]; P= .02) and air trapping percent (rate ratio=1.01 [95% CI= 1.00-1.02]; P= .03), as well as lower decline in the Jacobian determinant mean (rate ratio= 0.58 [95% CI= 0.41-0.82]; P< .01) and Jacobian determinant standard deviation (rate ratio= 0.52 [95% CI= 0.32-0.85]; P= .01), were associated with a greater rate of future exacerbations. However, imaging metrics were not associated with clinically meaningful changes in scores on validated asthma morbidity questionnaires.ConclusionsBaseline qCT measures of more severe airway remodeling, more small airway disease and hyperinflation, andless pointwise regional change in lung volumes were associated with future lung function decline and asthma exacerbations.

BackgroundObesity is associated with restrictive ventilatory defects and a faster rate of decline in FVC. This association is not exclusively mediated by mechanical factors and may reflect direct pulmonary injury by adipose-derived mediators.Research questionIs adipose tissue involved in the pathogenesis of interstitial lung disease (ILD)?Study design and methodsWe evaluated the association of CT measures of pericardial, abdominal visceral, and abdominal subcutaneous adipose tissue with high-attenuation areas (HAAs) and interstitial lung abnormalities (ILAs) in a large multicenter cohort study of community-dwelling adults, using multivariable-adjusted models. We secondarily evaluated the association of adipose depot size with FVC and biomarkers of obesity and inflammation.ResultsIn fully adjusted models, every doubling in pericardial adipose tissue volume was associated with a 63.4-unit increase in HAA (95%CI, 55.5-71.3), 20%increased odds of ILA (95%CI, -2%to 50%), and a 5.5%decrease in percent predicted FVC (95%CI, -6.8%to -4.3%). IL-6 levels accounted for 8%of the association between pericardial adipose tissue and HAA. Every doubling in visceral adipose tissue area was associated with a 41.5-unit increase in HAA (95%CI, 28.3-54.7), 30%increased odds of ILA (95%CI, -10%to 80%), and a 5.4%decrease in percent predicted FVC (95%CI, -6.6%to -4.3%). IL-6 and leptin accounted for 17%and 18%, respectively, of the association between visceral adipose tissue and HAA.InterpretationGreater amounts of pericardial and abdominal visceral adipose tissue were associated with CT measures of early lung injury and lower FVC in a cohort of community-dwelling adults. Adipose tissue may represent a modifiable risk factor for ILD.

BackgroundMild expiratory flow limitation may not be recognized using traditional spirometric criteria based on the ratio of FEV1/FVC.Research questionDoes slow vital capacity (SVC) instead of FVC increase the sensitivity of spirometry to identify patients with early or mild obstructive lung disease?Study design and methodsWe included 854 current and former smokers from the Subpopulations and Intermediate Outcome Measures in COPD Study cohort with a postbronchodilator FEV1/FVC≥ 0.7 and FEV1 %predicted of≥ 80%at enrollment. We compared baseline characteristics, chest CT scan features, exacerbations, and progression to COPD (postbronchodilator FEV1/FVC,< 0.7) during the follow-up period between 734 participants with postbronchodilator FEV1/SVC of≥ 0.7 and 120 with postbronchodilator FEV1/SVC < 0.7 at the enrollment. We performed multivariate linear and logistic regression models and negative binomial and interval-censored proportion hazards regression models adjusted for demographics and smoking exposure to examine the association of FEV1/SVC < 0.7 with those characteristics and outcomes.ResultsParticipants with FEV1/SVC < 0.7 were older and had lower FEV1 and more emphysema than those with FEV1/SVC≥ 0.7. In adjusted analysis, individuals with postbronchodilator FEV1/SVC < 0.7 showed a greater percentage of emphysema by 0.45%(95%CI, 0.09%-0.82%), percentage of gas trapping by 2.52%(95%CI, 0.59%-4.44%), and percentage of functional small airways disease based on parametric response mapping by 2.78%(95%CI, 0.72%-4.83%) at baseline than those with FEV1/SVC≥ 0.7. During a median follow-up time of 1,500days, an FEV1/SVC < 0.7 was not associated with total exacerbations (incident rate ratio [IRR], 1.61; 95%CI, 0.97-2.64), but was associated with severe exacerbations (IRR, 2.60; 95%CI, 1.04-4.89). An FEV1/SVC < 0.7 was associated with progression to COPD during a 3-year follow-up even after adjustment for demographics and smoking exposure (hazard ratio, 3.93; 95%CI, 2.71-5.72). We found similar results when we examined the association of prebronchodilator FEV1/SVC < 0.7 or FEV1/SVC less than the lower limit of normal with chest CT scan features and progression to COPD.InterpretationLow FEV1 to SVC in current and former smokers with normal spirometry results can identify individuals with CT scan features of COPD who are at risk for severe exacerbations and is associated with progression to COPD in the future.Trial registryClinicalTrials.gov; No.: NCT01969344T4; URL: www.clinicaltrials.gov.

Rationale: The relative roles of mucus plugs and emphysema in mechanisms of airflow limitation and hypoxemia in smokers with chronic obstructive pulmonary disease (COPD) are uncertain.Objectives: To relate image-based measures of mucus plugs and emphysema to measures of airflow obstruction and oxygenation in patients with COPD.Methods: We analyzed computed tomographic (CT) lung images and lung function in participants in the Subpopulations and Intermediate Outcome Measures in COPD Study. Radiologists scored mucus plugs on CT lung images, and imaging software automatically quantified emphysema percentage. Unadjusted and adjusted relationships between mucus plug score, emphysema percentage, and lung function were determined using regression.Measurements and Main Results: Among 400 smokers, 229 (57%) had mucus plugs and 207 (52%) had emphysema, and subgroups could be identified with mucus-dominant and emphysema-dominant disease. Only 33% of smokers with high mucus plug scores had mucus symptoms. Mucus plug score and emphysema percentage were independently associated with lower values for FEV1 and peripheral oxygen saturation (P

Authors’ original file for figure 3

Additional file 2: Table S2: Significantly enriched biological concepts for up- and down-regulated genes in male biceps 4 h post-RE. (DOCX 21 KB)

Additional file 3. Urban/rural status and food access interaction.

Additional file 3: Table S3: Enriched biological concepts for up- and down-regulated genes in male biceps 24 h post-RE. (DOCX 24 KB)

Supplemental material, sj-pdf-1-gph-10.1177_2333794X20987453 for The Influence of Metabolic Syndrome Risk Factors on Carotid Intima Media Thickness in Children by Robert Downing, Timothy Michael, Rebecca Place, Eric Hoffman and Paul Visich in Global Pediatric Health

Authors’ original file for figure 2

Additional file 1. Additional methods, figures, tables.

Additional file 9: Table S8: Genes for qRT-PCR validation and TaqMan assay used. (DOCX 12 KB)

Unsupervised learning-based medical image registration approaches have witnessed rapid development in recent years. We propose to revisit a commonly ignored while simple and well-established principle: recursive refinement of deformation vector fields across scales. We introduce a recursive refinement network (RRN) for unsupervised medical image registration, to extract multi-scale features, construct normalized local cost correlation volume and recursively refine volumetric deformation vector fields. RRN achieves state of the art performance for 3D registration of expiratory-inspiratory pairs of CT lung scans. On DirLab COPDGene dataset, RRN returns an average Target Registration Error (TRE) of 0.83 mm, which corresponds to a 13% error reduction from the best result presented in the leaderboard. In addition to comparison with conventional methods, RRN leads to 89% error reduction compared to deep-learning-based peer approaches.

Additional file 2..Participant flow chart.

Additional file 4: Supplementary Note. NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium Banner Authorship List.

Additional file 5: Table S5: Enriched biological concepts for up- and down-regulated genes in female biceps 24 h post-RE. (DOCX 17 KB)

Additional file 3: Figure S1. Associations between ACE2 gene expression and COPD, asthma, steroid use, and race. Figure S2. Associations between ACE2 gene expression and obesity. Figure S3. Associations between ACE2 gene expression and hypertension, and use of antihypertensives. Figure S4. Associations between age and ACE2 gene expression, and age and differential ACE2 exon usage. Figure S5. Associations between age and smoking status, hypertension, sex, and BMI in SPIROMICS. Figure S6. COVID-19 and other viral illness related gene set enrichment analyses in association with comorbidities in SPIROMICS, SARP, and MAST. Figure S7. Regulatory genetic effects of ACE2 and TMPRSS2, and the effect of smoking on TMPRSS2. Figure S8. Associations between COVID-19-related genes and comorbidities. Figure S9. Replication of cis-eQTLs in GTEx. Figure S10. Regulatory genetic effects of the candidate genes in the chr3 cluster associated with COVID-19. Figure S11. PheWAS associations for the 44 out of 108 lead cis-eQTLs associated with COVID-19-related genes with Phenoscanner v2.

Supplemental material, sj-pdf-1-pul-10.1177_20458940211056527 for A computational model of contributors to pulmonary hypertensive disease: impacts of whole lung and focal disease distributions by Behdad Shaarbaf Ebrahimi, Merryn H. Tawhai, Haribalan Kumar, Kelly S. Burrowes, Eric A. Hoffman, Margaret L. Wilsher, David Milne and Alys R. Clark in Pulmonary Circulation

Additional file 4: Table S4: Enriched biological concepts for up- and down-regulated genes in female biceps 4 h post-RE. (DOCX 40 KB)

Additional file 8:Discussion on common GO terms and KEGGs pathways regulated by RE in both male and female biceps. (DOCX 35 KB)

Supplemental material, sj-pdf-1-gph-10.1177_2333794X20987453 for The Influence of Metabolic Syndrome Risk Factors on Carotid Intima Media Thickness in Children by Robert Downing, Timothy Michael, Rebecca Place, Eric Hoffman and Paul Visich in Global Pediatric Health

Additional file 1: Table S1: Gene concepts enriched with sex-related differential expression genes. (DOCX 14 KB)

Additional file 6: Table S6: Differential expression of the selected genes in exercised vs. rested muscle measured by qRT-PCR. (DOCX 14 KB)

Supplemental material, sj-pdf-1-pul-10.1177_20458940211056527 for A computational model of contributors to pulmonary hypertensive disease: impacts of whole lung and focal disease distributions by Behdad Shaarbaf Ebrahimi, Merryn H. Tawhai, Haribalan Kumar, Kelly S. Burrowes, Eric A. Hoffman, Margaret L. Wilsher, David Milne and Alys R. Clark in Pulmonary Circulation

Additional file 1. Additional patient characteristics and differences tables.

Authors’ original file for figure 1

Additional file 1. Supplementary Methods.

BackgroundThe relationship between 25-hydroxyvitamin D (25-OH-vitamin D) and COPD outcomes remains unclear. Using the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), we determined associations among baseline 25-OH-vitamin D and cross-sectional and longitudinal lung function and COPD exacerbations.MethodsSerum 25-OH-vitamin D level was measured in stored samples from 1,609 SPIROMICS participants with COPD. 25-OH-vitamin D levels were modeled continuously and dichotomized as deficient (< 20ng/mL) vsnot deficient (≥ 20ng/mL). Outcomes of interest included %predicted FEV1 (current and 1-year longitudinal decline) and COPD exacerbations (separately any and severe, occurring in prior year and first year of follow-up).ResultsVitamin D deficiency was present in 21%of the cohort and was more prevalent in the younger, active smokers, and blacks. Vitamin D deficiency was independently associated with lower %predicted FEV1 (by 4.11%) at enrollment (95%CI, -6.90%to -1.34%predicted FEV1; P= .004), 1.27%predicted greater rate of FEV1 decline after 1 year (95%CI, -2.32%to -0.22%predicted/y; P= .02), and higher odds of any COPD exacerbation in the prior year (OR, 1.32; 95%CI, 1.00-1.74; P= .049). Each 10-ng/mL decrease in 25-OH-vitamin D was associated with lower baseline lung function (-1.04%predicted; 95%CI, -1.96%to -0.12%predicted; P= .03) and increased odds of any exacerbation in the year before enrollment (OR, 1.11; 95%CI, 1.01-1.22; P= .04).ConclusionsVitamin D deficiency is associated with worse cross-sectional and longitudinal lung function and increased odds of prior COPD exacerbations. These findings identify 25-OH-vitamin D levels as a potentially useful marker of adverse COPD-related outcomes.

Rationale: The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin, SERPINA1 (serpin peptidase inhibitor, clade A, member 1), in determining chronic obstructive pulmonary disease risk and severity is controversial.Objectives: To comprehensively evaluate the effects of rare SERPINA1 variants on lung function and emphysema phenotypes in subjects with significant tobacco smoke exposure using deep gene resequencing and alpha-1 antitrypsin concentrations.Methods: DNA samples from 1,693 non-Hispanic white individuals, 385 African Americans, and 90 Hispanics with ≥20 pack-years smoking were resequenced for the identification of rare variants (allele frequency

BackgroundAdipokines have inflammatory and fibrotic properties that may be critical in interstitial lung disease (ILD). We examined associations of serum adipokine levels with CT imaging-based measures of subclinical ILD and lung function among community-dwelling adults.MethodsA subset of the original Multi-Ethnic Study of Atherosclerosis cohort (n= 1,968) had adiponectin, leptin, and resistin measured during follow-up visits (2002-2005). We used regression models to examine associations of adiponectin, leptin, and resistin levels with (1) high-attenuation areas (HAAs) from CT scans (2004-2005, n= 1,144), (2) interstitial lung abnormalities (ILAs) from CT scans (2010-2012, n= 872), and (3) FVC from spirometry (2004-2006, n= 1,446). We used -(1/HAA2), which we denoted with H, to model HAA as our outcome to meet model assumptions.ResultsHigher adiponectin was associated with lower HAA on CT imaging among adults with a BMI≥ 25kg/m2 (P for BMI interaction= .07). Leptin was more strongly associated with ILA among never smokers compared with ever smokers (P for smoking interaction= .004). For every 1-SD increment of log-transformed leptin, the percent predicted FVC was 3.8%lower (95%CI,-5.0 to-2.5). Higher serum resistin levels were associated with greater HAA on CT in a fully adjusted model. For every 1-SD increment of log-transformed resistin there was an increase in H of 14.8 (95%CI, 3.4-26.3).ConclusionsHigher adiponectin levels were associated with lower HAA on CT imaging among adults with a higher BMI. Higher leptin and resistin levels were associated with lower FVC and greater HAA, respectively.

BackgroundRelative enlargement of the pulmonary artery (PA) on chest CT imaging is associated with respiratory exacerbations in patients with COPD or cystic fibrosis. We sought to determine whether similar findings were present in patients with asthma and whether these findings were explained by differences in ventricular size.MethodsWe measured the PA and aorta diameters in 233 individuals from the Severe Asthma Research Program III cohort. We also estimated right, left, and total epicardial cardiac ventricular volume indices (eERVVI, eELVVI, and eETVVI, respectively). Associations between the cardiac and PA measures (PA-to-aorta [PA/A] ratio, eERVVI-to-eELVVI [eRV/eLV] ratio, eERVVI, eELVVI, eETVVI) and clinical measures of asthma severity were assessed by Pearson correlation, and associations with asthma severity and exacerbation rate were evaluated by multivariable linear and zero-inflated negative binomial regression.ResultsAsthma severity was associated with smaller ventricular volumes. For example, those with severe asthma had 36.1mL/m2 smaller eETVVI than healthy control subjects (P= .003) and 14.1mL/m2 smaller eETVVI than those with mild/moderate disease (P= .011). Smaller ventricular volumes were also associated with a higher rate of asthma exacerbations, both retrospectively and prospectively. For example, those with an eETVVI less than the median had a 57%higher rate of exacerbations during follow-up than those with eETVVI greater than the median (P= .020). Neither PA/A nor eRV/eLV was associated with asthma severity or exacerbations.ConclusionsIn patients with asthma, smaller cardiac ventricular size may be associated with more severe disease and a higher rate of asthma exacerbations.Trial registryClinicalTrials.gov; No.: NCT01761630; URL: www.clinicaltrials.gov.

[This corrects the article DOI: 10.2147/COPD.S220164.].

RationaleSome COPD patients develop extreme breathlessness, decreased exercise capacity and poor health status yet respiratory disability is poorly characterized as a distinct phenotype.ObjectiveTo define respiratory disability in COPD based on available functional measures and to determine associations with risk for exacerbations and death.MethodsWe analyzed baseline data from a multi-center observational study (SPIROMICS). This analysis includes 2332 participants (472 with severe COPD, 991 with mild/moderate COPD, 726 smokers without airflow obstruction and 143 non-smoking controls).MeasurementsWe defined respiratory disability by ≥4 of 7 criteria: mMRC dyspnea scale ≥3; Veterans Specific Activity Questionnaire 60; COPD Assessment Test >20; fatigue (FACIT-F Trial Outcome Index)

Barjaktarevic IZ, Buhr RG, Wang X, et al. Int J ChronObstruct Pulmon Dis. 2019;14:2927– 2938. The authors have advised that there is an error in theFunding section on page 2935. The correct funding statementis as follows: FundingThis study was supported by R01HL125432-01A1 (MBD),T32HL007106-41 (RMB), and TL1TR001883-01 (RGB).SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN2682009 00014C,HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200 900019C, and HHSN268200900020C) and supplemented by contributions made through the Foundation for the NIH andthe COPD Foundation from AstraZeneca/MedImmune,Bayer, Bellerophon Therapeutics, Boehringer-IngelheimPharmaceuticals, Inc., Chiesi Farmaceutici S.p.A., ForestResearch Institute, Inc., GlaxoSmithKline, Grifols Therapeutics, Inc., Ikaria, Inc., Nycomed GmbH, TakedaPharmaceutical Company, Novartis PharmaceuticalsCorporation, ProterixBio; Regeneron Pharmaceuticals, Inc.,Sanofi, and Sunovion. The PRM analyses were supported byNHLBI HL122438 and HL138188. Mehrdad Arjomandi wassupported by a grant from the Flight Attendant MedicalResearch Institute. The authors apologize for this error. Read the original article

BackgroundChronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene®), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality.MethodsFour key disease characteristics - environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry - were evaluated in a group of 8784 current and former smokers who were participants in COPDGene® Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV1 > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined.ResultsUsing smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene® 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15-6.48) in those with all 4 disease characteristics.ConclusionsA substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop.

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide novel insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci with P-value < 5 × 10−8; 47 were previously described in association with either COPD or population-based lung function. Of the remaining 35 novel loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified enrichment for loci in lung tissue, smooth muscle and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups of quantitative imaging features and comorbidity associations. Our analyses provide further support to the genetic susceptibility and heterogeneity of COPD., Editorial summary Genome-wide analysis of chronic obstructive pulmonary disease identifies 82 loci, 35 of which are new. Integration of gene expression and genomic annotation data shows enrichment of signals in lung tissue, smooth muscle and several lung cell types.

Scleractinian corals of Tubastraea genus have a typically Indo-Pacific distribution but currently, they became globally widespread living in natural and artificial substrates of shallow tropical waters. Tubastraea corals have a confusing taxonomy and systematic history because the interspecific overlapping of some morphological characters, resulting in the proposition of many synonyms. Currently, two species of Tubastraea are recognized along the Brazilian coast: T. coccinea and T. tagusensis. Additionally, many morphotypes have been observed and, although the genus to be widely distributed in the Western Atlantic, few characterization studies were performed. Here we sought to investigate the taxonomy of Tubastraea species based on morphological characters of Arraial do Cabo species and a molecular approach using the ITS gene on samples from southeastern coast of the United States and Brazil. In this study, we observed three morphotypes in Brazil that were delimitated and identified as belonging to three distinct species: T. aurea, T. coccinea and Tubastraea sp. Morphologically, T. aurea is different from T. coccinea mainly due to larger corallites, presenting one more cycle of septa. Tubastraea sp., previously identified as Tubastraea tagusensis in Brazil (Arraial do Cabo), exhibited distinct morphological characteristics compared to the original species description. Molecular analyses showed that Brazilian Tubastraea fell into two well supported monophyletic clades and samples collected from the Florida overlapped in both clades. Our genetic data also indicated that all three morphotypes found in Brazil were genetically distinct (i.e. they did not share haplotypes). Florida samples showed greater diversity, presenting haplotypes in at least four other internal clades. Moreover, the similarity of samples found in both Brazil and southeastern US provide evidence of a possible relationship between these populations. This study highlights the need for an integrative approach to further examine species delimitation in Tubastraea, which is essential for the clarification and management of bioinvasions events by sun coral species.

Figure S2. (a) Internal properties in different clustering methods to find the best clustering approaches as well as the optimal number of clusters; (b) Bootstrapping stability analysis between K-means and hierarchical clustering with 4 or 5 numbers of clusters. (DOCX 58 kb)

Figure S3. Predicting imaged-based cluster using only 5 important variables. Variables are βtissueRV (Total), Jacobian (Total), βtissueTLC (Total), Dh* (RMB) and ADI (Total) with 81% accuracy. (DOCX 59 kb)

Table S1. The confusion matrices to assess the possible overlap between current and former smoker clusters. Values are presented as the number of subjects (%). (DOCX 15 kb)