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Suneela Zaigham,1 Hanan Tanash,2 Peter M Nilsson,1,3 Iram F Muhammad1 1Department of Clinical Sciences, Lund University, Malmö, Sweden; 2Department of Respiratory Medicine, Skåne University Hospital, Lund University, Malmö, Sweden; 3Department of Internal Medicine, Skåne University Hospital, Malmö, SwedenCorrespondence: Suneela Zaigham, Department of Clinical Sciences, Lund University, Malmö, Sweden, Tel +46 708737179, Email suneela.zaigham@med.lu.sePurpose: The triglyceride-glucose index (TyG index) is a marker of insulin resistance and metabolic dysfunction and has the advantage of being universally available. Although recent evidence suggests the TyG index has relevance to respiratory health, there have been no prospective studies assessing its value as a biomarker for chronic lung diseases. We aim to assess the TyG index as a potential risk marker for future incident COPD events in the general population.Patients and Methods: Baseline TyG index was assessed in 28,282 middle-aged men and women without previous history of chronic obstructive pulmonary disease (COPD) from the Malmö Preventive Project (men between 1974 and 1982 and women between 1982 and 1992). All subjects were followed up prospectively, and Cox proportional hazards regression was used to assess incident COPD events according to quartiles of TyG index.Results: After an average of 31 years of follow-up, TyG index was a strong predictor of future COPD events even after adjusting for potential confounders (Q4 (highest TyG index) HR (95% CI): 1.21 (1.09– 1.35) vs Q1 (reference), p-trend < 0.001). After stratifying by sex, the results remained statistically significant in women only (Q4 vs Q1 HR 1.72 (1.41– 2.09)). Additionally, the risk remained significant in a cohort of life-long never smokers (Q4 vs Q1 HR 1.47 (1.08– 2.01)).Conclusion: A raised TyG index is a novel risk marker of future incident COPD events in women. Insulin resistance as reflected by the TyG index can precede the development of obstructive lung disease and as such may be an easily measurable and useful predictor of COPD in women.Keywords: chronic obstructive pulmonary disease, cohort study, epidemiology, risk prediction, triglyceride-glucose index

Abstract Introduction This study aimed to evaluate the consistency of lung cancer case assessments across multidisciplinary team (MDT) sites in Denmark. The goal was to appraise the comparability of outcomes between hospitals in a real-world context. Methods We prepared sixty comprehensive, fictitious lung cancer case stories, complete with images, and distributed them to the four primary lung cancer MDT conferences in Denmark. These cases were subsequently evaluated as had they been ordinary patients during regular MDT meetings. We compared the conclusions on assigned TNM stage and proposed treatment intent using Kappa statistics. Results The consensus on assigned stage (Stages IA-B, IIA-B, IIIA-B, IV, and undetermined) corresponded to a Fleiss’ Kappa-value of 0.62 (95% CI: 0.52–0.71). The overall assessment of curability, categorized as Curable, Incurable, and Undetermined, corresponded to a Kappa-value of 0.72 (CI: 0.61–0.84). However, for cases unanimously judged by all MDT sites to be Stage III, the concordance on treatment intent was poor, with an agreement coefficient of only 0.32 (95% CI: -0.27–0.97). Conclusion In detail, the level of agreement on assigned stages was less than desired. In consequence, comparative analyses of treatment results from different hospitals or centres may be prone to bias caused by systematic differences in stage assessment or intent of treatment. The least consensus was observed for cases in Stage III, indicating a need for quality improvement efforts to ensure a higher degree of consistency in MDT decisions.

Introduction We assessed the impact of recruitment criteria on lung cancer detection in a future Danish screening programme with low-dose CT.Methods We combined data from two Danish population-based health examination surveys with eligibility criteria from seven randomised controlled trials on lung cancer screening. Incident lung cancers were identified by linkage with the National Pathology Data Bank (Patobank). For an average of 4.4 years of follow-up, we calculated sensitivity, specificity, efficient frontier and number needed to screen (NNS) for lung cancer detection.Results When applying the different eligibility criteria to the 48 171 persons invited to the two surveys, the number of lung cancer cases identified in the target groups varied from 46 to 68. The National Lung Screening Trial (NLST) criteria had the highest sensitivity of 62.6% (95% CI 52.7 to 71.8) and the Dutch-Belgian NEderlands-Leuvens Screening ONderzoek (NELSON) criteria had the highest specificity 81.6% (95% CI 81.0 to 82.1). Sensitivity was higher for men than for women (NLST criteria 71.7% (95% CI 57.7 to 83.2) and 53.7% (95% CI 39.6 to 67.4), respectively). The NLST criteria identified the target population obtaining the lowest NNS with 46.3. The application of the NLST criteria showed that the higher the sensitivity, the lower the number of false-negative cases and, thus, the lower the NNS.Conclusions This study highlights the impact of the definition of the at-risk population on lung cancer screening efficacy. We found lower sensitivity among women regardless of screening criteria used. This should be carefully addressed in a possible screening programme.

Objective: To compare the diagnostic performance of bone scintigraphy and 18F-NaF-PET/CT in detection of bone metastasis in newly diagnosed high-grade prostate cancer patients. Study Design: Comparative cross-sectional study. Place and Duration of Study: Nuclear Medical Centre, Armed Forces Institute of Pathology and Armed Forces Institute of Radiology and Imaging, Rawalpindi Pakistan, from Jul 2020 to Dec 2022. Methodology: Newly diagnosed high-grade prostate cancer patients with Gleason score ≥8 who underwent bone scintigraphy followed by 18F-NaF-PET/CT (Sodium Fluoride-Positron Emission Tomography/Computerized Tomography) for staging during study duration were included. We compared the diagnostic accuracy of both imaging modalities in detecting bone metastasis using two-point scale scoring system i.e., metastasis present or not present on per patient basis. Results: A total of 45 patients with mean age 69.66±9.38 years and mean Prostatic Surface Antigen level 36.21±65.07 ng/ml were included. 18F-NaF-PET/CT detected bone metastasis in all 25 patients with bone metastasis (100%) compared to 20(80%) by bone scan. 4 patients had false-positive bone scan while 2 had false-positive 18F-NaF-PET/CT scan. Overall 18F-NaF-PET/CT demonstrated a higher sensitivity, specificity, positive predictive value, negative predictive value and accuracy compared to bone scan (100% vs 80%, 90% vs 80%, 92.59% vs 83.33%, 100% vs 76.19%, 95.56% vs 80% respectively). Conclusion: 18F-NaF-PET/CT has better diagnostic performance than bone scintigraphy for the detection of bone metastasis in newly diagnosed high-grade prostate cancer patients.

The effect of specimen width and incorporation of a circular hole on the tensile behaviour of commercially available aluminium alloy AA 1100 was studied using finite element analysis (FEA) for convergence with the already published experimental work of other researchers. Static structural analysis was conducted to simulate tensile loading of Japanese industrial standard (JIS) specimen JIS Z 2201 No. 13B and No. 5 until the point of the ultimate tensile strength (UTS) was reached. A strain rate of 0.25 mm/s was used for both the neat specimen and the one bearing a circular hole of 8 mm in diameter at the centre of the specimen. The numerical results exhibited a good agreement with the experimental work by comparison of the percentage elongation for numerical and experimental data. The normal stresses calculated using analytical and numerical approaches also reflected a good convergence. For neat specimens of JIS Z 2201 No. 13B and No. 5, a 100 % increase in specimen width enhanced the load required to reach UTS by 100 %, while elongation was increased by 30 %. On the other hand, for specimens of JIS Z 2201 No. 13B and No. 5, bearing an 8 mm circular hole reduced the load required to reach UTS by 300 %, while elongation was only increased by 25 %. The 200 % decrease in load required to reach UTS and 57 % reduction in elongation was observed by incorporating an 8 mm circular hole in the neat specimens.

The paper describes the corrosion based degradation of aluminium alloys using an analytical and numerical framework. The corrosion rate was calculated using analytical equations for aluminium sheets subjected to a corrodent. Parametric analysis for the pit morphology, diameter, depth and distribution on the plate was conducted using finite element analysis. A comparison between elliptical and circular pits of the same area was also made for stress magnification using numerical analysis. It was observed that the stress generated at constant load when a specimen corrodes due to pitting is directly proportional to the pit diameter and pit depth. Zigzag pit morphologies due to the combined effect of mechanical degradation and corrosion have the highest stress at the corners of the pattern, while circular pits have the highest stress at the centre of the pit. The zigzag pit morphology has more detrimental effects than circular pits. For multiple distributed pits, the pits closer to the specimen edges exhibit higher stress values than those near the centre of the specimen. The effect of multiple or quantitatively increased number of pits having smaller geometric properties has a more detrimental effect than a single pit with larger geometric attributes.

This research paper has used a three-dimensional approach that combines Finite Element Analysis, the famous three-factor Design of Experiments by Taguchi, with the third dimension. An idea to optimize a Lithium (Li) and Lead (Pb) based Toroid is presented as they are known hazardous materials. The approach emphasized generating different run orders by a parametric variation of outer diameter, thickness, and base metal on the minimum and maximum specifications. Based on the Design of Experiments, the calculated run orders were modelled and simulated under the specified loading conditions to select the best combination of parameters. The analytical stresses generated in the combinations were compared with the numerical counterparts for model validation. On-Mises stress and deformation results from the simulation were analyzed to select the optimized design of Toroid structure and the final shape was modelled accordingly. The analytical and numerical stresses also showed good agreement with each other, supporting the validity of the presented approach. The method effectively models such specimens before fabrication, so that all material and geometric aspects can be finalized before risking physical contact with the actual worker.

Iron deficiency induces chlorosis in plants but only when phosphate supply is sufficient. Here, the authors show that phosphate-dependency is governed by a ROS-mediated retrograde signaling pathway involving the PHT4;4 chloroplast ascorbate transporter and the bZIP58 nuclear transcription factor.

Abstract Airways segmentation is important for research about pulmonary disease but require a large amount of time by trained specialists. We used an openly available software to improve airways segmentations obtained from an artificial intelligence (AI) tool and retrained the tool to get a better performance. Fifteen initial airway segmentations from low-dose chest computed tomography scans were obtained with a 3D-Unet AI tool previously trained on Danish Lung Cancer Screening Trial and Erasmus-MC Sophia datasets. Segmentations were manually corrected in 3D Slicer. The corrected airway segmentations were used to retrain the 3D-Unet. Airway measurements were automatically obtained and included count, airway length and luminal diameter per generation from the segmentations. Correcting segmentations required 2–4 h per scan. Manually corrected segmentations had more branches (p

Objective: To validate ‘stress only’ protocol against ‘rest stress protocol in normal and essentially normal cases undergoing Tc99m MIBI gated myocardial perfusion Single Photon Emission Computed Tomography imaging. Study Design: A retrospective observational study. Place and Duration of Study: Department of Nuclear Cardiology, Armed Forces Institute of Cardiology/National Institute of Heart Disease, Rawalpindi, Pakistan, from Jul to Sep 2019. Methodology: 136 cases were included. Patients underwent Tc-99m gated Single Photon Emission Computed Tomography MPI using a single day, rest/stress protocol. The rest study was performed first with 8-10 mCi Tc-99m MIBI followed by stress study, 3 hours later with 3 times the rest dose. The most common stress technique was pharmacological stress and bicycle ergometer exercise with 0.14 mg/kg/min adenosine infusion. Few patients underwent physical stress using Bruce protocol, achieving a minimum of 85% of the target heart rate. Mages–stress followed by rest–were evaluated by two experienced nuclear cardiologists (blinded to the MPI reports) and interpreted as ‘normal’ or ‘essentially normal’. Results: Evaluation of stress-only and rest-stress Single Photon Emission Computed Tomography myocardial images yielded a concordance rate of 84.56% with Cohen’s kappa coefficient of 0.69. Conclusion: Substantial agreement and good concordance were found in normal and essentially normal ‘stress only’ and ‘rest stress protocols.

Objective: To evaluate the diagnostic accuracy of C-14 Urea Breath Test for detection of helicobacter pylori infection in patients with gastritis. Study Design: Cross-sectional validation study. Place and Duration of Study: Nuclear Medical Centre, Armed Forces Institute of Pathology, from Feb to Aug 2016. Methodology: After fulfilling inclusion and exclusion criteria, 110 patients of both genders, aged between 18-50 years, were enrolled. Prior written informed consent was obtained from each patient. First, they were assessed by C-14 Urea Breath Test, followed by endoscopic biopsy and histopathology. Results of C-14 Urea Breath Test were compared to histopathology diagnosis which was taken as gold standard. Results: Patients’ ages ranged from 18-50 years with a mean ± SD of 37.45 ± 10.21 years. Seventy four (67.3%) of them were males and 36 (32.7%) were females. Sixty four (58.2%) patients were suspected of helicobacter pylori on C-14 Urea breath test. However, histopathology of endoscopic biopsy confirmed helicobacter pylori in 66 (60%) patients yielding 64 true positive, 44 true negative and 2 false negative cases. Calculated sensitivity was 96.97%, specificity 100% and accuracy was 98.18% for C-14 Urea Breath Test with negative and positive predictive values of 95.65% and 100% respectively. Conclusion: C-14 Urea Breath Test is highly accurate, sensitive and specific test for detection of helicobacter pylori infection, irrespective of patient’s age and gender.

Abstract This paper presents a fully automatic and end-to-end optimised airway segmentation method for thoracic computed tomography, based on the U-Net architecture. We use a simple and low-memory 3D U-Net as backbone, which allows the method to process large 3D image patches, often comprising full lungs, in a single pass through the network. This makes the method simple, robust and efficient. We validated the proposed method on three datasets with very different characteristics and various airway abnormalities: (1) a dataset of pediatric patients including subjects with cystic fibrosis, (2) a subset of the Danish Lung Cancer Screening Trial, including subjects with chronic obstructive pulmonary disease, and (3) the EXACT’09 public dataset. We compared our method with other state-of-the-art airway segmentation methods, including relevant learning-based methods in the literature evaluated on the EXACT’09 data. We show that our method can extract highly complete airway trees with few false positive errors, on scans from both healthy and diseased subjects, and also that the method generalizes well across different datasets. On the EXACT’09 test set, our method achieved the second highest sensitivity score among all methods that reported good specificity.

Objective: To determine diagnostic accuracy of 99mTc labelled Ubiquicidin (29-41) SPECT/CT for detection of osteomyelitis in diabetic foot patients by taking bone biopsy as gold standard. Study Design: Cross-sectional validation study. Place and Duration of Study: Nuclear Medical Centre, Armed Forces Institute of Pathology, from Apr 2017 to Mar 2018. Methodology: Study assessed 122 patients of both genders, aged between 30-80 years (mean age=55.3 years), presenting with diabetic foot ulcers having suspicion of osteomyelitis, by 99mTc-Ubiquicidin (29-41) SPECT/CT followed by bone biopsy (histopathology and culture) taken as gold standard. Results: Among 122 patients [94 male (77%) and 28 female (23%)], osteomyelitis was histopathologically confirmed in 113 patients. 107 out of these patients were positive for osteomyelitis on 99mTc-UBI (29-41) SPECT/CT (true positives) while 6 were false negative. Out of 9 patients declared negative for osteomyelitis on histopathology and culture, 8 were negative on 99mTc-UBI (29-41) SPECT/CT as well (true negative) while only 1 case came out to be positive (false positive). Thus, the 99mTc-UBI (29-41) scan showed 94.6% sensitivity, 88.89% specificity, 99% positive predictive value, 57% negative predictive value with overall 94.2% diagnostic accuracy. Conclusion: 99mTc labelled Ubiquicidin (29-41) SPECT/CT scan can precisely localize infective focus, in diabetic foot osteomyelitis, with simultaneous discrimination between bone and soft tissues.

Abstract Background Interstitial lung abnormalities (ILA) are common in participants of lung cancer screening trials and broad population-based cohorts. They are associated with increased mortality, but less is known about disease specific morbidity and healthcare utilisation in individuals with ILA. Methods We included all participants from the screening arm of the Danish Lung Cancer Screening Trial with available baseline CT scan data (n = 1990) in this cohort study. The baseline scan was scored for the presence of ILA and patients were followed for up to 12 years. Data about all hospital admissions, primary healthcare visits and medicine prescriptions were collected from the Danish National Health Registries and used to determine the participants’ disease specific morbidity and healthcare utilisation using Cox proportional hazards models. Results The 332 (16.7%) participants with ILA were more likely to be diagnosed with one of several respiratory diseases, including interstitial lung disease (HR: 4.9, 95% CI: 1.8–13.3, p = 0.008), COPD (HR: 1.7, 95% CI: 1.2–2.3, p = 0.01), pneumonia (HR: 2.0, 95% CI: 1.4–2.7, p

Introduction Pleural empyema is a frequent disease with a high morbidity and mortality. Current standard treatment includes antibiotics and thoracic ultrasound (TUS)-guided pigtail drainage. Simultaneously with drainage, an intrapleural fibrinolyticum can be given. A potential better alternative is surgery in terms of video-assisted thoracoscopic surgery (VATS) as first-line treatment. The aim of this study is to determine the difference in outcome in patients diagnosed with complex parapneumonic effusion (stage II) and pleural empyema (stage III) who are treated with either VATS surgery or TUS-guided drainage and intrapleural therapy (fibrinolytic (Alteplase) with DNase (Pulmozyme)) as first-line treatment.Methods and analysis A national, multicentre randomised, controlled study. Totally, 184 patients with a newly diagnosed community acquired complicated parapneumonic effusion or pleural empyema are randomised to either (1) VATS procedure with drainage or (2) TUS-guided pigtail catheter placement and intrapleural therapy with Actilyse and DNase. The total follow-up period is 12 months. The primary endpoint is length of hospital stay and secondary endpoints include for example, mortality, need for additional interventions, consumption of analgesia and quality of life.Ethics and dissemination All patients provide informed consent before randomisation. The research project is carried out in accordance with the Helsinki II Declaration, European regulations and Good Clinical Practice Guidelines. The Scientific Ethics Committees for Denmark and the Danish Data Protection Agency have provided permission. Information about the subjects is protected under the Personal Data Processing Act and the Health Act. The trial is registered at www.clinicaltrials.gov, and monitored by the regional Good clinical practice monitoring unit. The results of this study will be published in peer-reviewed journals and presented at various national and international conferences.Trial registration number NCT04095676.

Developmental plasticity of plant root systems has been intensively studied, but the mechanisms underpinning robustness remain unclear. Here, the authors show that DNA-methylation-mediated transcriptional repression serves as a backup system to control lateral root development when auxin signalling is perturbed.

Chronic inflammation such as asthma may lead to higher risks of malignancy, which may be inhibited by anti-inflammatory medicine such as inhaled corticosteroids (ICS). The aim of this study was to evaluate if patients with asthma-Chronic Obstructive Pulmonary Disease (COPD) overlap have a higher risk of malignancy than patients with COPD without asthma, and, secondarily, if inhaled corticosteroids modify such a risk in a nationwide multi-center retrospective cohort study of Danish COPD-outpatients with or without asthma. Patients with asthma-COPD overlap were propensity score matched (PSM) 1:2 to patients with COPD without asthma. The endpoint was cancer diagnosis within 2 years. Patients were stratified depending on prior malignancy within 5 years. ICS was explored as a possible risk modifier. We included 50,897 outpatients with COPD; 88% without prior malignancy and 20% with asthma. In the PSM cohorts, 26,003 patients without prior malignancy and 3331 patients with prior malignancy were analyzed. There was no association between asthma-COPD overlap and cancer with hazard ratio (HR) = 0.92, CI = 0.78–1.08, p = 0.31 (no prior malignancy) and HR = 1.04, CI = 0.85–1.26, and p = 0.74 (prior malignancy) as compared to patients with COPD without asthma. ICS did not seem to modify the risk of cancer. In conclusion, in our study, asthma-COPD overlap was not associated with an increased risk of cancer events.

Objective: To determine the accuracy of intraoperative radionuclide scintigraphy for detection of sentinel lymph node (SLN), using 99mTc-Nanocolloids, in patients with early breast carcinoma. Study Design: Cross sectional analytical study. Place and Duration of Study: Nuclear Medical Centre, Armed Forces Institute of Pathology, Rawalpindi and department of Surgery, Pak Emirates Military Hospital, Rawalpindi, from Jul 2012 to Jun 2013. Patients and Methods: After fulfilling the inclusion and exclusion criteria and taking written informed consent, 67 patients of carcinoma breast were enrolled in the study. Each patient was injected with 37 MBq of 99mTc- Nanocolloids, via sub areolar, peri-tumoural route, pre-operatively. SLNs were identified using handheld gamma probe followed by excision biopsy. Patients, then, underwent modified radical mastectomy with dissection of axillary lymph nodes (ALN) and the samples were sent for histopathology. Results: Out of 67 patients, 28 to 77 years of age (mean ± SD of 49.61 ± 11.572 years), 17.9% (12) patients had T1tumour while 82.1% (55) had T2 tumour (mean ± SD of 3.48 cm ± 1.050 cm). Histopathology revealed no metastasis in SLNs as well as ALN of 55.2% (37) patients while 40.3% (27) patients were positive for both. However, in 4.5% (3) patients SLNs were negative for metastasis with positive ALN. Diagnostic accuracy was calculated to be 95.5%, sensitivity 90%, false negative rate 4.5% and negative predictive value 92.5%. Conclusion: Intraoperative radionuclide scintigraphy, using 99mTc-Nanocolloids and handheld gamma probe is a reasonably accurate technique for localization of SLNs in early breast carcinoma.

Soil water uptake is a major determinant of plant performance and stress tolerance. Here the authors show that, by affecting xylem formation in the root, natural variation at the Arabidopsis XND1 locus has contrasting effects on root hydraulics and drought tolerance versus pathogen resistance.

Hypothesis We hypothesise that the validated HUNT Lung Cancer Risk Model would perform better than the NLST (USA) and the NELSON (Dutch‐Belgian) criteria in the Danish Lung Cancer Screening Trial (DLCST).Methods The DLCST measured only five out of the seven variables included in validated HUNT Lung Cancer Model. Therefore a ‘Reduced’ model was retrained in the Norwegian HUNT2-cohort using the same statistical methodology as in the original HUNT model but based only on age, pack years, smoking intensity, quit time and body mass index (BMI), adjusted for sex. The model was applied on the DLCST-cohort and contrasted against the NLST and NELSON criteria.Results Among the 4051 smokers in the DLCST with 10 years follow-up, median age was 57.6, BMI 24.75, pack years 33.8, cigarettes per day 20 and most were current smokers. For the same number of individuals selected for screening, the performance of the ‘Reduced’ HUNT was increased in all metrics compared with both the NLST and the NELSON criteria. In addition, to achieve the same sensitivity, one would need to screen fewer people by the ‘Reduced’ HUNT model versus using either the NLST or the NELSON criteria (709 vs 918, p=1.02e-11 and 1317 vs 1668, p=2.2e-16, respectively).Conclusions The ‘Reduced’ HUNT model is superior in predicting lung cancer to both the NLST and NELSON criteria in a cost-effective way. This study supports the use of the HUNT Lung Cancer Model for selection based on risk ranking rather than age, pack year and quit time cut-off values. When we know how to rank personal risk, it will be up to the medical community and lawmakers to decide which risk threshold will be set for screening.

Patients with severe chronic obstructive pulmonary disease (COPD) experience frequent acute exacerbations and require repeated courses of corticosteroid therapy, which may lead to adverse effects. Methotrexate (MTX) has anti-inflammatory properties. The objective of this study was to describe the risk of COPD exacerbation in patients exposed to MTX. In this nationwide cohort study of 58,580 COPD outpatients, we compared the risk of hospitalization-requiring COPD exacerbation or death within 180 days in MTX vs. non-MTX users in a propensity-score matched study population as well as an unmatched cohort, in which we adjusted for confounders. The use of MTX was associated with a reduction in risk of COPD exacerbation in the propensity-score matched population at 180 days follow-up (HR 0.66, CI 0.66–0.66, p < 0.001). Similar results were shown in our sensitivity analyses at 180-day follow-up on unmatched population and 365-day follow-up on matched and unmatched population (HR 0.76 CI 0.59–0.99, HR 0.81 CI 0.81–0.82 and HR 0.92 CI 0.76–1.11, respectively). MTX was associated with a lower risk of COPD exacerbation within the first six months after study entry. The finding seems biologically plausible and could potentially be a part of the management of COPD patients with many exacerbations.

Background: Haemoptysis is a common symptom and can be an early sign of lung cancer. Careful investigation of patients with haemoptysis may lead to early diagnosis. The strategy for investigation of these patients, however, is still being debated. Objectives: We studied whether the combination of computed tomography (CT) and bronchoscopy had a higher sensitivity for malignant and non-malignant causes of haemoptysis than CT alone. Methods: The study was a retrospective, non-randomised, two-centre study and included patients who were referred from primary care for the investigation of haemoptysis. Results: A total of 326 patients were included in the study (mean age 60.5 [SD 15.3] years, 63.3% male). The most common aetiologies of haemoptysis were cryptogenic (52.5%), pneumonia (16.3%), emphysema (8.0%), bronchiectasis (5.8%) and lung cancer (4.0%). In patients diagnosed with lung cancer, bronchoscopy, CT and the combination of bronchoscopy and CT had a sensitivity of 0.61, 0.92 (p

Heterologous expression of genes in budding yeast Saccharomyces cerevisiae (S. cerevisiae) is especially suitable to functionally study the corresponding encoded protein at the cellular level (Bonneaud et al., 1991). This is mainly because many strains defective in specific activities are available and could be complemented by homologous genes existing across the eukaryotic kingdom (http://www.yeastgenome.org/). However, the protocol we describe here is not a complementation but a “gain-of-function” assay. It is based on a drop-test assay that we have set up to assess the cellular zinc tolerance conferred by the expression of heterologous genes in the wild-type S. cerevisiae. Different dilutions of a yeast culture expressing the heterologous gene of interest are grown on a range of zinc-enriched plates, and are then compared to the control yeast expressing the empty vector. Working with different concentrations of both yeast and zinc are essential to succeed in describing zinc tolerance phenotype upon yeast transformation (Mirouze et al., 2006). This test has also proven to be valuable to differentiate among related members of gene families as exemplified for Arabidopsis Plant Defensin type1 (Shahzad et al., 2013).

Gene duplication is a major mechanism facilitating adaptation to changing environments. From recent genomic analyses, the acquisition of zinc hypertolerance and hyperaccumulation characters discriminating Arabidopsis halleri from its zinc sensitive/non-accumulator closest relatives Arabidopsis lyrata and Arabidopsis thaliana was proposed to rely on duplication of genes controlling zinc transport or zinc tolerance. Metal Tolerance Protein 1 (MTP1) is one of these genes. It encodes a Zn(2+)/H(+) antiporter involved in cytoplasmic zinc detoxification and thus in zinc tolerance. MTP1 was proposed to be triplicated in A. halleri, while it is present in single copy in A. thaliana and A. lyrata. Two of the three AhMTP1 paralogues were shown to co-segregate with zinc tolerance in a BC1 progeny from a cross between A. halleri and A. lyrata. In this work, the MTP1 family was characterized at both the genomic and functional levels in A. halleri. Five MTP1 paralogues were found to be present in A. halleri, AhMTP1-A1, -A2, -B, -C, and -D. Interestingly, one of the two newly identified AhMTP1 paralogues was not fixed at least in one A. halleri population. All MTP1s were expressed, but transcript accumulation of the paralogues co-segregating with zinc tolerance in the A. halleri X A. lyrata BC1 progeny was markedly higher than that of the other paralogues. All MTP1s displayed the ability to functionally complement a Saccharomyces cerevisiae zinc hypersensitive mutant. However, the paralogue showing the least complementation of the yeast mutant phenotype was one of the paralogues co-segregating with zinc tolerance. From our results, the hypothesis that pentaplication of MTP1 could be a major basis of the zinc tolerance character in A. halleri is strongly counter-balanced by the fact that members of the MTP1 family are likely to experience different evolutionary fates, some of which not concurring to increase zinc tolerance.

Background: The risk of coronavirus (COVID-19) can be affected by the presence of certain chronic conditions. It is unknown if individuals with severe hereditary alpha-1-antitrypsin deficiency (AATD) faced an increased risk of severe COVID-19 infection during the pandemic and if COPD in this population affected the risk of severe COVID-19 outcomes., Aim: Our aim was to investigate COVID-19 outcomes in individuals with severe AATD and to identify if COPD was a risk factor for severe disease., Methods: Between 2021-2023 we interviewed 863 individuals with severe AATD (phenotype PiZZ) included in the Swedish National AATD Registry. Details on COVID-19 outcomes were collected. Cox regression models were used to assess risk of mild and severe COVID-19 by presence of COPD., Results: Of 863 subjects with severe AATD, 231 reported COVID-19 infection (208 mild and 23 severe COVID-19). Subjects with severe COVID-19 were older, had lower FEV 1 values, were more likely ever-smokers and had more comorbidities compared to those with mild COVID-19. Subjects with COPD had over a 5-fold increased risk of severe COVID-19 compared to those without COPD (HR 5.43 (95% CI 1.61-18.27, p=0.006). After adjusting for potential confounders including smoking habits the risk remained significant (HR 3.72 (95% CI 1.04-13.23, p=0.043))., Conclusion: Most patients with severe AATD exhibit mild symptoms of COVID-19 infection, managing them in the community. Patients who also have COPD are at increased risk of severe COVID-19 infection., Competing Interests: The authors report no conflicts of interest., (© 2024 Tanash et al.)

Background: Breathlessness is common in the population and can be related to a range of medical conditions. We aimed to evaluate the burden of breathlessness related to different medical conditions in a middle-aged population., Methods: Cross-sectional analysis of the population-based Swedish CArdioPulmonary bioImage Study of adults aged 50-64 years. Breathlessness (modified Medical Research Council [mMRC] ≥ 2) was evaluated in relation to self-reported symptoms, stress, depression; physician-diagnosed conditions; measured body mass index (BMI), spirometry, venous haemoglobin concentration, coronary artery calcification and stenosis [computer tomography (CT) angiography], and pulmonary emphysema (high-resolution CT). For each condition, the prevalence and breathlessness population attributable fraction (PAF) were calculated, overall and by sex, smoking history, and presence/absence of self-reported cardiorespiratory disease., Results: We included 25,948 people aged 57.5 ± [SD] 4.4; 51% women; 37% former and 12% current smokers; 43% overweight (BMI 25.0-29.9), 21% obese (BMI ≥ 30); 25% with respiratory disease, 14% depression, 9% cardiac disease, and 3% anemia. Breathlessness was present in 3.7%. Medical conditions most strongly related to the breathlessness prevalence were (PAF 95%CI): overweight and obesity (59.6-66.0%), stress (31.6-76.8%), respiratory disease (20.1-37.1%), depression (17.1-26.6%), cardiac disease (6.3-12.7%), anemia (0.8-3.3%), and peripheral arterial disease (0.3-0.8%). Stress was the main factor in women and current smokers., Conclusion: Breathlessness mainly relates to overweight/obesity and stress and to a lesser extent to comorbidities like respiratory, depressive, and cardiac disorders among middle-aged people in a high-income setting-supporting the importance of lifestyle interventions to reduce the burden of breathlessness in the population., (© 2024. The Author(s).)

Background: Previous studies have shown that the ratio between alveolar volume (V A ) and total lung capacity (TLC) reflects ventilation heterogeneity in subjects with chronic obstructive pulmonary disease (COPD). However, the ratio and its correlation to respiratory symptoms had to our knowledge not previously been investigated in subjects with mild chronic airflow obstruction or without airflow obstruction (normal ratio FEV 1 /VC). The purpose of this study was to investigate potential connection between V A /TLC and respiratory symptoms, smoking habits and lung function parameters in subjects with normal spirometry and with mild chronic airflow obstruction., Methods: We examined 450 subjects (82 non-smokers with normal spirometry, 298 subjects who smoked or had smoked earlier but had a normal spirometry and 70 subjects with chronical airflow obstruction) with routine lung function tests and a questionnaire regarding respiratory symptoms., Results: This study showed 31 out of 54 subjects with a low V A /TLC had a normal ratio FEV 1 /VC. Of these subjects, 58.1 % had respiratory symptoms, compared to the group with normal ratio for both V A /TLC and FEV 1/ VC where 35.8 % had respiratory symptoms (p-value 0.02)., Conclusion: This study has shown that within the group of subjects with a normal ratio FEV 1 /VC, those with a decreased ratio V A /TLC had a higher prevalence of respiratory symptoms compared to subjects with a normal V A /TLC ratio. These findings indicate that including the ratio V A /TLC in the evaluation of a pulmonary function test assessment might increase the possibility to identify subjects with early or at risk of lung disease., Competing Interests: Declaration of competing interest The authors declare the following financial interests/ personal relationships which may be considered as potential competing interests: P Wollmer reports a relationship with Chiesi Pharma that includes consulting or advisory. P Wollmer has patent issued to Method and device for pulmonary function measurement., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Reduced lung function is associated with cardiovascular mortality, but the relationships with atherosclerosis are unclear. The population-based Swedish CArdioPulmonary BioImage study measured lung function, emphysema, coronary CT angiography, coronary calcium, carotid plaques and ankle-brachial index in 29,593 men and women aged 50-64 years. The results were confirmed using 2-sample Mendelian randomization. Lower lung function and emphysema were associated with more atherosclerosis, but these relationships were attenuated after adjustment for cardiovascular risk factors. Lung function was not associated with coronary atherosclerosis in 14,524 never-smokers. No potentially causal effect of lung function on atherosclerosis, or vice versa, was found in the 2-sample Mendelian randomization analysis. Here we show that reduced lung function and atherosclerosis are correlated in the population, but probably not causally related. Assessing lung function in addition to conventional cardiovascular risk factors to gauge risk of subclinical atherosclerosis is probably not meaningful, but low lung function found by chance should alert for atherosclerosis., (© 2023. The Author(s).)

Background: Interstitial lung abnormalities (ILA) are incidental findings on chest computed tomography (CT). These patterns can present at an early stage of fibrotic lung disease. Our aim was to estimate the prevalence of ILA in the Swedish population, in particular in never-smokers, and find out its association with demographics, comorbidities and symptoms., Methods: Participants were recruited to the Swedish CArdioPulmonary BioImage Study (SCAPIS), a population-based survey including men and women aged 50-64 years performed at six university hospitals in Sweden. CT scan, spirometry and questionnaires were performed. ILA were defined as cysts, ground-glass opacities, reticular abnormality, bronchiectasis and honeycombing., Findings: Out of 29 521 participants, 14 487 were never-smokers and 14 380 were men. In the whole population, 2870 (9.7%) had ILA of which 134 (0.5%) were fibrotic. In never-smokers, the prevalence was 7.9% of which 0.3% were fibrotic. In the whole population, age, smoking history, chronic bronchitis, cancer, coronary artery calcium score and high-sensitive C-reactive protein were associated with ILA. Both ILA and fibrotic ILA were associated with restrictive spirometric pattern and impaired diffusing capacity of the lung for carbon monoxide. However, individuals with ILA did not report more symptoms compared with individuals without ILA., Interpretation: ILA are common in a middle-aged Swedish population including never-smokers. ILA may be at risk of being underdiagnosed among never-smokers since they are not a target for screening., Competing Interests: Conflict of interest: I. Pesonen reports fees from Boehringer Ingelheim for lectures and participation on advisory boards. Conflict of interest: A. Egeston reports consulting fees from BioCryst, payment/honoraria from AstraZeneca and an unrestricted research grant from CSL-Behring. Conflict of interest: Ö.I. Emilsson reports payment from study work from Boehringer Ingelheim, unrelated to this publication. Conflict of interest: E. Hagström reports payments to institution from Pfizer and Amgen, small personal fees from Amgen, NovoNordisk, Bayer and AstraZeneca, and a small personal fee from Amarin AB for participation on an advisory board. He is the co-chair of the Swedish secondary prevention registry and the national coordinator for the trials DalCore DAL301 DalGne, Regeneron R1500-CL-1643 and Aegis II/Perfuse. Conflict of interest: L.E.G.W. Vanfleteren reports grants paid to his institution from the Swedish Heart and Lung Foundation and the family Kamprad foundation, and payments/honoraria from AstraZeneca, GSK, Boehringer, Novartis, Chiesi, Pulmonx for lectures and presentations. He also reports personal payments for participation on a data safety monitoring board or advisory board for AstraZeneca. He was member of the board for the Swedish National Airway registry. He is as associate editor of this journal. Conflict of interest: P. Wollmer received fees for lectures from Chiesi Pharma outside the scope of the study. He also has a patent issued for a device and method for pulmonary function measurement outside the scope of the study. Conflict of interest: S. Zaigham reports a research project grant from Magnus Bergvalls Stiftelse, and support for meeting attendance from the Swedish Heart and Lung Foundation and Bror Hjerpstedts Stiftelse. Conflict of interest: C.M. Sköld reports research grants from Boehringer Ingelheim for pulmonary fibrosis research, payments for lectures and educational activities related to pulmonary fibrosis, and participation on advisory boards related to pulmonary fibrosis. Conflict of interest: All other authors declare no conflicts of interest., (Copyright ©The authors 2023.)

Background: Impulse oscillometry (IOS) is sensitive in detecting lung function impairment. In small studies, impaired IOS relates better to respiratory symptoms than spirometry. We studied how IOS related to spirometry and respiratory symptoms in a large population of individuals (n=10 360) in a cross-sectional analysis., Methods: Normal values for IOS and spirometry were defined in healthy, never-smoking individuals, aged 50-64 years, from the Swedish CArdioPulmonary bioImage Study (n=3664 for IOS and 3608 for spirometry). For IOS, abnormal values for resistance at 5 Hz ( R ) and at 20 Hz and area of reactance were defined using the 95th percentile. Abnormal reactance at 5 Hz for IOS and abnormal conventional spirometry indices (forced expiratory volume in 1 s (FEV 5 ) and at 20 Hz and area of reactance were defined using the 95th percentile. Abnormal reactance at 5 Hz for IOS and abnormal conventional spirometry indices (forced expiratory volume in 1 s (FEV 1 ), forced and slow vital capacity and their ratios) were defined using the 5th percentile., Results: Abnormal IOS parameters were found in 16% of individuals and were associated with increased odds ratios for nearly all respiratory symptoms when adjusted for age, gender and smoking. In individuals with normal spirometry, abnormal IOS resistance was related to cough and dyspnoea, while abnormal reactance was related to wheeze. In these individuals, the combination of abnormal R 5 with abnormal reactance resulted in approximately two-fold higher likelihood for having cough, chronic bronchitis and dyspnoea, even when further adjusting for FEV 1 , expressed as % predicted., Conclusions: Abnormal IOS is related to increased respiratory burden in middle-aged individuals with normal spirometry, especially when resistance and reactance parameters are combined. The different relationships between respiratory symptoms and reactance and resistance warrant further research., Competing Interests: Conflict of interest: J. Sundström reports stock or stock options in Anagram Kommunikation AB and Symptoms Europe AB, not related to the present work. Conflict of interest: P. Wollmer reports personal fees from Chiesi Pharmaceuticals outside the submitted work, has a patent for a device and method for pulmonary capacity measurements issued, not related to the present work. Conflict of interest: All other authors declare no conflicts of interest with regard to the present study., (Copyright ©The authors 2023.)

Rationale: Postbronchodilator spirometry is used for the diagnosis of chronic obstructive pulmonary disease. However, prebronchodilator reference values are used for spirometry interpretation. Objectives: To compare the resulting prevalence rates of abnormal spirometry and study the consequences of using pre- or postbronchodilator reference values generated within SCAPIS (Swedish CArdioPulmonary bioImage Study) when interpreting postbronchodilator spirometry in a general population. Methods: SCAPIS reference values for postbronchodilator and prebronchodilator spirometry were based on 10,156 and 1,498 never-smoking, healthy participants, respectively. We studied the associations of abnormal spirometry, defined by using pre- or postbronchodilator reference values, with respiratory burden in the SCAPIS general population (28,851 individuals). Measurements and Main Results: Bronchodilation resulted in higher predicted medians and lower limits of normal (LLNs) for FEV 1 /FVC ratios. The prevalence of postbronchodilator FEV 1 /FVC ratio lower than the prebronchodilator LLN was 4.8%, and that of postbronchodilator FEV 1 /FVC lower than the postbronchodilator LLN was 9.9%, for the general population. An additional 5.1% were identified as having an abnormal postbronchodilator FEV 1 /FVC ratio, and this group had more respiratory symptoms, emphysema (13.5% vs. 4.1%; P  < 0.001), and self-reported physician-diagnosed chronic obstructive pulmonary disease (2.8% vs. 0.5%, P  < 0.001) than subjects with a postbronchodilator FEV 1 /FVC ratio greater than the LLN for both pre- and postbronchodilation. Conclusions: Pre- and postbronchodilator spirometry reference values differ with regard to FEV 1 /FVC ratio. Use of postbronchodilator reference values doubled the population prevalence of airflow obstruction; this was related to a higher respiratory burden. Using postbronchodilator reference values when interpreting postbronchodilator spirometry might enable the identification of individuals with mild disease and be clinically relevant.

Background: Epidemiological studies have shown that impaired lung function is common and associated with increased risk of cardiovascular disease. Increased levels of several inflammatory and cardiovascular disease-related plasma proteins have been associated with impaired lung function. The aim was to study the association between plasma proteomics and forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC) and FEV 1 /FVC ratio., Methods: We used a discovery and replication approach in two community-based cohorts, EpiHealth and the Malmö Offspring Study (total n=2874), to cross-sectionally study 242 cardiovascular disease- and metabolism-linked proteins in relation to FEV 1 , FVC (both % predicted) and FEV 1 /FVC ratio. A false discovery rate of 5% was used as the significance threshold in the discovery cohort., Results: Plasma fatty acid-binding protein 4, interleukin-1 receptor antagonist, interleukin-6 and leptin were negatively associated with FEV 1 and paraoxonase 3 was positively associated therewith. Fatty acid-binding protein 4, fibroblast growth factor 21, interleukin-1 receptor antagonist, interleukin-6 and leptin were negatively associated with FVC and agouti-related protein, insulin-like growth factor-binding protein 2, paraoxonase 3 and receptor for advanced glycation end products were positively associated therewith. No proteins were associated with FEV 1 /FVC ratio. A sensitivity analysis in EpiHealth revealed only minor changes after excluding individuals with known cardiovascular disease, diabetes or obesity., Conclusions: Five proteins were associated with both FEV 1 and FVC. Four proteins associated with only FVC and none with FEV 1 /FVC ratio, suggesting associations mainly through lung volume, not airway obstruction. However, additional studies are needed to investigate underlying mechanisms for these findings., Competing Interests: Conflict of interest: A. Rydell has received lecturing fees from AstraZeneca. K. Lisspers has received lecturing fees from AstraZeneca, Novartis and Boehringer Ingelheim; and payments for advisory board membership from AstraZeneca, Boehringer Ingelheim and GlaxoSmithKline. S. Zaigham has received a research grant from Magnus Bergvalls Stiftelse. P.M. Nilsson has received lecturing fees from Novartis, Novo Nordisk, Amgen and Boehringer Ingelheim. J. Ärnlöv has received lecturing fees from AstraZeneca and Novartis, and served on advisory boards for AstraZeneca and Boehringer Ingelheim on subjects unrelated to this study. The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

Background: Triglyceride-glucose (TyG) index is a useful low-cost marker of insulin resistance. We aimed to evaluate the association between TyG index and arterial stiffness, incidence of diabetes, adverse cardiovascular outcomes, and all-cause and cardiovascular mortality in two large prospective Swedish cohorts, the Malmö Diet and Cancer Study-Cardiovascular Cohort (MDCS-CV) and the Malmö Preventive Project (MPP)., Methods: Association between baseline TyG index and arterial stiffness, measured by carotid femoral pulse wave velocity (c-f PWV), was assessed using linear regression and general linear models, adjusting for covariates. Cox proportional hazard regression was used to assess the association between TyG index and incidence of diabetes, coronary events (CE), stroke, atrial fibrillation (AF), heart failure, and all-cause and cardiovascular mortality., Results: After multivariable adjustment, baseline TyG index was significantly associated with increased arterial stiffness (β for c-f PWV = 0.61, p = 0.018). Participants in the highest quartile of TyG index vs. lowest quartile had an increased incidence of diabetes (HR: 3.30, 95% CI: 2.47-4.41), CE (HR: 1.53, 95% CI: 1.41-1.68), stroke (HR: 1.30, 95% CI: 1.18-1.44), all-cause mortality (HR: 1.22, 95% CI: 1.16-1.28), and cardiovascular mortality (HR: 1.37, 95% CI: 1.26-1.49) after adjustment for covariates. Per unit increase in TyG index was associated with increased heart failure risk. No significant association was observed for incident AF., Conclusion: Elevated TyG index is positively associated with increased arterial stiffness and increased incidence of diabetes, CE, stroke, and all-cause and cardiovascular mortality. The results suggest that TyG index can potentially be useful in the identification of those at increased long-term risk of adverse health outcomes., 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 © 2023 Muhammad, Bao, Nilsson and Zaigham.)

Aims: Reduced lung function and adverse health outcomes are often observed. This study characterizes genetic susceptibility for reduced lung function and risk of developing a range of adverse health outcomes., Methods: We studied 27,438 middle-aged adults from the Malmö Diet and Cancer study (MDCS), followed up to 28.8 years. Trait-specific Polygenic scores (PGS) for forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) were constructed for each participant using MDCS genetic data and summary statistics from the latest GWAS of lung function. Linear regression models and cox proportional hazards regression models were used to assess associations between adverse health outcomes and lung function-PGS., Results: FEV 1 -PGS and FVC-PGS were significantly associated with mean sBP at baseline after adjustments (FEV 1 -PGS Q1 (highest PGS = highest lung function): 140.7mmHg vs. Q4: 141.5mmHg, p-value 0.008). A low FVC-PGS was significantly associated with the risk of future diabetic events after adjustments (Q4 vs. Q1 HR: 1.22 (CI 1.12-1.32), p-trend < 0.001) and had added value to risk prediction models for diabetes. Low FEV 1 -PGS was significantly associated with future coronary events (Q4 vs. Q1 HR: 1.13 (CI: 1.04-1.22), p-trend 0.008). No significant association was found between PGS and sudden cardiac death, chronic kidney disease or all-cause mortality. Results remained largely unchanged in a subgroup of subjects when further adjusted for apolipoproteins., Conclusion: Genetic susceptibility for reduced lung function is associated with higher sBP, increased risk of diabetes and to a lesser extent, future coronary events, suggesting etiological roles of lung function on these outcomes. Using PGS, high-risk groups could be early detected to implement early lifestyle changes to mitigate the risk., (© 2022. The Author(s).)

Hepatocyte growth factor (HGF) is released by stressed human vascular cells and promotes vascular cell repair responses in both autocrine and paracrine ways. Subjects with a low capacity to express HGF in response to systemic stress have an increased cardiovascular risk. Human atherosclerotic plaques with a low content of HGF have a more unstable phenotype. The present study shows that subjects with a low ability to express HGF in response to metabolic stress have an increased risk to suffer myocardial infarction and stroke., Competing Interests: The work was supported by the Swedish Society for Medical Research, Emil and Wera Cornell Foundation, Hjelt Foundation, the Swedish Research Council, the Swedish Foundation for International Cooperation in Research and Higher Education, Crafoord Foundation, the Swedish Medical Society, Diabetes Foundation, Swedish Heart and Lung Foundation, Diabetes Research and Wellness Foundation, Albert Påhlssons Foundation, Skåne University Hospital (SUS) Foundations and funds, Lund University Infrastructure grant “Malmö Population-based Cohorts” (STYR 2019/2046), and Lund University Diabetes Center (Swedish Research Council–Strategic Research Area Excellence of Diabetes Research in Sweden (Exodiab) grant number 2009-1039 and the Swedish Foundation for Strategic Research grant number IRC15-006), National Natural Science Foundation of China grant 82120108004 (Dr Liang) and 82100479 (Dr Chen). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Background: Premature ventricular complexes (PVCs) are known to predict heart failure (HF) and premature atrial contractions (PACs) are known to predict atrial fibrillation (AF) and stroke. PVCs and PACs share pathophysiological mechanisms; however, the combined effects of PVCs and PACs on HF, AF, and stroke risk have not been studied., Objectives: To study elevated PVC counts on 24-hour electrocardiogram monitoring (24hECG) in relation to incidence of AF, HF, and stroke, and whether this effect is altered by PAC frequency., Methods: The prospective population-based Malmö Diet and Cancer study includes 24hECG registrations in 375 AF- and HF-free subjects (mean age 65 years, 55% women). During 17 years of follow-up there were 28 HF, 89 AF, and 28 stroke events. The hazard ratios (HR) of elevated PVC counts (defined as the top quartile, ≥77/24 hours) vs lower quartiles were assessed using multivariable adjusted Cox regression models., Results: Elevated PVC counts predicted incident AF (HR 1.9, 95% confidence interval [CI] 1.2-3.0) and HF (HR 3.1, 95% CI 1.4-7.0). Results were similar after adjustment for NT-proBNP and PACs. Multiform PVCs were associated with even higher risks (HR 2.8, 95% CI: 1.7-4.6 for AF; HR 5.0, 95% CI 2.2-11.7 for HF), as was the presence of both elevated PACs and PVCs (9% of the population, HR 4.1, 95% CI 2.4-6.8 for AF and HR 4.3, 95% CI 1.7-11.4 for HF). No significant association was found between elevated PVC counts and incident stroke., Conclusion: Elevated PVC counts predict incident AF and HF, particularly if PVCs are multiform or occur in combination with elevated PAC counts., (© 2022 Heart Rhythm Society. Published by Elsevier Inc.)

Background: Although coronary events (CE) and ischemic stroke share many risk factors, there are also some important differences. The aim of this paper was to assess the association of risk factors in relation to incident CE and ischemic stroke and to evaluate the heterogeneity in patterns of risk factors between the two outcomes., Method: Traditional risk factors and inflammatory markers associated with coronary events and ischemic stroke were measured in the Malmö Diet and Cancer Cohort (MDCS, n = 26 519), where a total of 2270 incident ischemic stroke and 3087 incident CE occurred during a mean follow up time 19 ± 6 years, and in relation to inflammatory markers in the cardiovascular sub-cohort (MDC-CV, n = 4795). Cox regression analysis was used to obtain hazard ratios. A modified Lunn-McNeil competing risk analysis was conducted to assess the significance of any differences in risk profiles of these outcomes., Results: Most cardiovascular risk factors were associated both with incident CE and ischemic stroke. However, current smoking, ApoB, low ApoA1, male sex and education level of ≤ 9 years of schooling were preferentially associated with CE compared to ischemic stroke. Conversely, age showed a stronger association with ischemic stroke than with CE., Conclusion: CE and ischemic stroke have broadly similar risk factors profiles. However, there are some important differential associations, as well as substantial differences in the magnitude of the association. These could reflect the distinct biology of atherogenesis in different vascular beds. The difference in the determinants highlights the importance of looking at CE and ischemic stroke, two manifestations of cardiovascular disease, separately., (© 2021. The Author(s).)

Background: Fractional exhaled nitric oxide (FE NO ) is a marker of type 2 airway inflammation used in clinical practice in asthma. However, reference values are needed to broaden the clinical use of FE NO and this is within the scope of a newly started Global Lung Function Initiative task force. We aim to study FE NO levels with special emphasis on the upper limit of normal (ULN) in relation to the type and degree of IgE sensitisation., Methods: FE NO was measured in 1855 non-smoking, respiratory healthy subjects from the Swedish CArdioPulmonary bioImage Study (SCAPIS). Atopic subjects (n = 424), defined as being IgE-sensitised to aeroallergens (ImmunoCAP Phadiatop™, ≥0.35 PAU/l) were compared to non-atopic subjects (<0.35 PAU/l, n = 1431). Atopic subjects were further characterised according to their grade of IgE sensitisation (IgE antibody tertiles: (T1<1.16, T2 1.16-3.72 and T3 >3.72 PAU/l) and sensitisation to perennial (cat or mite) or seasonal (birch) allergens., Results: Subjects IgE-sensitised to cat or mite had higher FE NO compared to non-atopic subjects (FE NO (ppb): median 20.0 vs. 15.0, and ULN 50.4 vs. 33.0, p < 0.001). This was seen to a lesser extent for subjects IgE-sensitised to birch only (median 18.0 vs. 15.0, and ULN 38.0 vs. 33.0, p = 0.048). Atopic subjects with a high degree of IgE sensitisation (Phadiatop: >3.72 PAU/l) had the highest FE NO compared to non-atopic subjects (median 20.0 vs. 15.0, and ULN 56.0 vs. 33.0, p < 0.001)., Conclusions: The type and degree of IgE sensitisation should be considered in generating FE NO reference values., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To assess the association of cardiometabolic risk factors with hospitalisation or death due to COVID-19 in the general population., Design, Setting and Participants: Swedish population-based cohort including 29 955 participants., Exposures: Cardiometabolic risk factors assessed between 2014 and 2018., Main Outcome Measures: Hospitalisation or death due to COVID-19, as registered in nationwide registers from 31 January 2020 through 12 September 2020. Associations of cardiometabolic risk factors with the outcome were assessed using logistic regression adjusted for age, sex, birthplace and education., Results: Mean (SD) age was 61.2 (4.5) and 51.5% were women. 69 participants experienced hospitalisation or death due to COVID-19. Examples of statistically significant associations between baseline factors and subsequent hospitalisation or death due to COVID-19 included overweight (adjusted OR (aOR) vs normal weight 2.73 (95% CI 1.25 to 5.94)), obesity (aOR vs normal weight 4.09 (95% CI 1.82 to 9.18)), pre-diabetes (aOR vs normoglycaemia 2.56 (95% CI 1.44 to 4.55)), diabetes (aOR vs normoglycaemia 3.96 (95% CI 2.13 to 7.36)), sedentary time (aOR per hour/day increase 1.10 (95% CI 1.02 to 1.17)), grade 2 hypertension (aOR vs normotension 2.44 (95% CI 1.10 to 5.44)) and high density lipoprotein cholesterol (aOR per mmol/L increase 0.33 (95% CI 0.17 to 0.65)). Statistically significant associations were not observed for grade 1 hypertension (aOR vs normotension 1.03 (95% CI 0.55 to 1.96)), current smoking (aOR 0.56 (95% CI 0.24 to 1.30)), total cholesterol (aOR per mmol/L increase 0.90 (95% CI 0.71 to 1.13)), low density lipoprotein cholesterol (aOR per mmol/L increase 0.90 (95% CI 0.69 to 1.15)) and coronary artery calcium score (aOR per 10 units increase 1.00 (95% CI 0.99 to 1.01))., Conclusions: In a large population-based sample from the general population, several cardiometabolic risk factors were associated with hospitalisation or death due to COVID-19., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Many of those who suffer from a first acute coronary event (CE) die suddenly during the day of the event, most of them die outside hospital. Poor lung function is a strong predictor of future cardiac events; however, it is unknown whether the pattern of lung function impairment differs for the prediction of sudden cardiac death (SCD) versus non-fatal CEs. We examined measures of lung function in relation to future SCD and non-fatal CE in a population-based study., Methods: Baseline spirometry was assessed in 28 584 middle-aged subjects, without previous history of CE, from the Malmö Preventive Project. The cohort was followed prospectively for incidence of SCD (death on the day of a first CE, inside or outside hospital) or non-fatal CE (survived the first day). A modified version of the Lunn McNeil's competing risk method for Cox regression was used to run models for both SCD and non-fatal CE simultaneously., Results: A 1-SD reduction in forced expiratory volume in 1 s (FEV 1 ) was more strongly associated with SCD than non-fatal CE even after full adjustment (FEV 1 : HR for SCD: 1.23 (1.15 to 1.31), HR for non-fatal CE 1.08 (1.04 to 1.13), p value for equal associations=0.002). Similar associations were found for forced vital capacity (FVC) but not FEV 1 /FVC. The results remained significant even in life-long never smokers (FEV 1 : HR for SCD: 1.34 (1.15 to 1.55), HR for non-fatal CE: 1.11 (1.02 to 1.21), p value for equal associations=0.038). Similar associations were seen when % predicted values of lung function measures were used., Conclusions: Low FEV 1 is associated with both SCD and non-fatal CE, but consistently more strongly associated with future SCD. Measurement with spirometry in early life could aid in the risk stratification of future SCD. The results support the use of spirometry for a global assessment of cardiovascular risk., Competing Interests: Competing interests: PW reports grants from Swedish Heart and Lung Foundation during the conduct of the study, and personal fees from Chiesi Pharma, personal fees from GlaxoSmithKline, outside the submitted work. PW has a patent device and method for pulmonary function measurement issued., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The forced oscillation technique (FOT) provides detailed information about the mechanics of the respiratory system, while requiring minimal co-operation by the patient. FOT may be abnormal in subjects with normal spirometry and appears to be more closely related to airway symptoms. It is, therefore, attractive in epidemiological studies, where a large number of different examinations are made in each subjects in a short period of time. Current technical standards recommend the mean of three consecutive measurements to be used, but there is limited information regarding within-session variability of FOT measurements., Objective: The purpose of this study was to examine the within-session variability in FOT measurements in a large, population-based sample., Methods: We performed three consecutive FOT measurements in 700 subjects using the impulse oscillometry system. The first measurement was compared to the mean of three measurements for resistance at 5 and 20 Hz (R5 and R20, respectively), R5-R20, reactance at 5 Hz (X5) and resonant frequency (f res )., Results: The differences between the first and the mean of three measurements (median, interquartile range) were minimal, for example 0.002, -0.008 to 0.014 kPa L -1  s for R5 and -0.001, -0.008 to 0.005 kPa L -1  s for X5. Findings were numerically similar for men and women as well as for subjects with and without airflow obstruction at spirometry., Conclusions: We conclude that, whereas in clinical situations, three FOT measurements are to be preferred, a single measurement may suffice in epidemiological studies., (© 2021 The Authors. Clinical Physiology and Functional Imaging published by John Wiley & Sons Ltd on behalf of Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Background: Arterial ageing is characterised by degradation of elastic fibres and increased stiffness of elastic arteries. Although low lung function and arterial stiffness are strongly related to age, the association between lung function and arterial ageing has not been widely explored. We used a large population-based study of 50-64 year olds to assess the association between lung function (measured by spirometry and CO diffusing capacity (D LCO )) and arterial stiffness (measured by carotid-femoral pulse-wave velocity (c-f PWV))., Methods: Participants from the Swedish CArdioPulmonary bioImage Study (SCAPIS) cohort with information on spirometry (n = 8941) and D LCO (n = 8616) were included. General linear models (lung function quartiles) and linear regression was used to determine the association between lung function and c-f PWV., Results: FEV 1 (L), FVC (L), D LCO (mmol/(min kPa)) and D LCO /V A (mmol/(min kPa L)) were significantly and inversely associated with c-f PWV after adjustments; mean PWV (m/s) in Q1 (highest lung function) vs Q4: FEV 1 ; 8.45 vs 8.60, p-value 0.001; FVC; 8.45 vs 8.57, p-value 0.018; D LCO ; 8.46 vs 8.60, p-value 0.002; and D LCO /V A ; 8.47 vs 8.58, p-value 0.001. In sex-stratified analyses, significant findings were reflected for FEV 1 and D LCO in men only. The results remained significant for D LCO in all never smokers and in all participants without COPD or airflow limitation on spirometry., Conclusions: A reduction in spirometry and D LCO is associated with elevated arterial stiffness in middle-aged men. A reduction in D LCO is associated with higher c-f PWV even in never smokers and in those without COPD or airflow limitation on spirometry., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Red cell distribution width (RDW) reflects heterogeneity of the erythrocyte volumes. High RDW is a novel risk marker, which has been associated with mortality and morbidity both from cardiovascular and respiratory diseases, but the association between RDW and measures of lung function in the general population remains unclear., Methods: The associations of RDW with spirometry, diffusing capacity (D LCO ) and impulse oscillometry (IOS) were investigated among 5767, 5496 and 5598 subjects (aged 50-64 years), respectively, from the Swedish CArdioPulmonary bioImage Study (SCAPIS). Multiple linear regression and general linear models were performed to examine the relationships of lung function measures and RDW, with adjustment for potential confounding factors., Results: Forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC) and FEV 1 /FVC were significantly and inversely associated with RDW after multivariate adjustments. For 1- standard deviation (SD) increase in RDW, FEV 1 decreased with 0.034 L (95%CI: -0.046 to -0.022 L), p < 0.001; FVC with 0.031 L (95%CI: -0.045 to -0.017 L), p < 0.001; and FEV 1 /FVC with 0.003 (95%CI: -0.004 to -0.001), p = 0.002. Significant associations of RDW and D LCO were only found among smokers. For IOS, pulmonary reactance rather than resistance was significantly associated with RDW: X 5 decreased 0.002 kPa/(L/s) (95%CI: -0.003 to -0.0002 kPa/(L/s)), p = 0.025, per 1-SD higher RDW., Conclusions: We found significant negative associations between RDW and measures of lung function. However, the effect sizes are small and RDW is not likely to be a sensitive marker of impaired lung function in middle-aged individuals from the general population., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. A complex relationship exists between TRAIL and the lung where both elevated TRAIL and TRAIL deficiency are associated with lung impairment. In neonatal mice, TRAIL is thought to translate respiratory infections into chronic lung disease but the association between TRAIL and lung function in childhood has not been assessed., Aim: To assess the cross-sectional relationship between TRAIL levels and lung function in school-aged children., Methods: The study cohort consisted of 170 school-aged children attending four schools in Malmö, Sweden. Lung volumes, impulse oscillometry (IOS) and serum TRAIL were measured for all children. Linear regression was used to assess changes in lung function per 1-SD increase in TRAIL. General linear models were used to assess mean lung function by tertiles (T) of TRAIL., Results: Mean age was 9.9 years (±0.6). A 1-SD increase in TRAIL was associated with lower values of FEV 1 and FEV 1 /VC (change in FEV 1 (L) and FEV 1 /VC ratio: -0.047, p-value 0.002, and -0.011, p-value 0.020, respectively) and higher values of lung resistance (change in R 5 and R 20 (kPa/(L/s)): 0.035, p-value <0.001 and 0.027, p-value 0.004, respectively). These associations remained significant after excluding children with pre-existing lung disease. Higher TRAIL levels were associated with more negative values for X 5 in general linear models (Mean X 5 (kPa/(L/s)) in T1 (low TRAIL): -0.193 vs T3 (high TRAIL): -0.216, p-value 0.026)., Conclusions: High TRAIL levels are significantly associated with markers of pulmonary airflow obstruction in school-aged children., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Advanced glycation end-products (AGEs) have been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, the association between AGE accumulation in the skin measured by skin autofluorescence (SAF) and lung function in healthy subjects has not been explored in detail. We use a population-based study of 50-64-year-olds to assess spirometry, diffusing capacity of the lung for carbon monoxide ( D LCO ) and impulse oscillometry (IOS) in relation to SAF., Methods: Participants with information on SAF, lung function and potential confounding variables were included from the Swedish Cardiopulmonary Bioimage Study (SCAPIS) cohort (spirometry, n=4111; D , n=3889; IOS, n=3970). Linear regression was used to assess changes in lung function (as measured by spirometry (forced expiratory volume in 1 s (FEV LCO , n=3889; IOS, n=3970). Linear regression was used to assess changes in lung function (as measured by spirometry (forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC) and FEV 1 /FVC), D LCO and IOS (resistance measured at 5 ( R 5 ) and 20 Hz ( R 20 ), R 5 - R 20 , area of reactance, reactance measured at 5 Hz ( X- 5 ), and resonant frequency)) by a 1-sd increase in SAF., Results: FEV 1 , FVC and D LCO were significantly and inversely associated with SAF after adjustment for potential confounding factors (per 1-sd increase in SAF: FEV 1 -0.03 L (95% CI -0.04- -0.02 L), p<0.001; FVC -0.03 L (95% CI -0.05- -0.02 L), p<0.001; D LCO -0.07 mmol·min -1 ·kPa -1 (95% CI -0.11- -0.03 mmol·min -1 ·kPa -1 ), p<0.001). This association was also found in nonsmokers and in non-COPD subjects. Pulmonary reactance ( X 5 ) but not pulmonary resistance ( R 5 , R ·s (95% CI -0.003-0.00 kPa·L 20 ·s), p=0.042), which was mirrored in non-COPD patients but not in current nonsmokers.R 5 - R 20 ) was significantly associated with SAF (per 1-sd increase in SAF: X 5 -0.001 kPa·L -1 ·s (95% CI -0.003-0.00 kPa·L -1 ·s), p=0.042), which was mirrored in non-COPD patients but not in current nonsmokers., Conclusions: AGE accumulation, as measured by SAF, is significantly associated with lung function decrements indicative of changes in the lung parenchyma., Competing Interests: Conflict of interest: S. Zaigham has nothing to disclose. Conflict of interest: M. Persson has nothing to disclose. Conflict of interest: A. Jujic has nothing to disclose. Conflict of interest: S. Frantz has nothing to disclose. Conflict of interest: Y. Borné has nothing to disclose. Conflict of interest: A. Malinovschi has nothing to disclose. Conflict of interest: P. Wollmer reports grants from the Swedish Heart and Lung Foundation, Skåne Region and Lund University, during the conduct of the study; and personal fees from AstraZeneca and Chiesi Pharmaceuticals, outside the submitted work. Conflict of interest: G. Engström has nothing to disclose., (Copyright ©ERS 2020.)