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The COVID-19 pandemic has now affected around 190 million people worldwide, accounting for more than 4 million confirmed deaths. Besides ongoing global vaccination, finding protective and therapeutic strategies is an urgent clinical need. SARS-CoV-2 mostly infects the host organism via the respiratory system, requiring angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) to enter target cells. Therefore, these surface proteins are considered potential druggable targets. Hydrogen sulfide (H2S) is a gasotransmitter produced by several cell types and is also part of natural compounds, such as sulfurous waters that are often inhaled as low-intensity therapy and prevention in different respiratory conditions. H2S is a potent biological mediator, with anti-oxidant, anti-inflammatory, and, as more recently shown, also anti-viral activities. Considering that respiratory epithelial cells can be directly exposed to H2S by inhalation, here we tested the in vitro effects of H2S-donors on TMPRSS2 and ACE2 expression in human upper and lower airway epithelial cells. We showed that H2S significantly reduces the expression of TMPRSS2 without modifying ACE2 expression both in respiratory cell lines and primary human upper and lower airway epithelial cells. Results suggest that inhalational exposure of respiratory epithelial cells to natural H2S sources may hinder SARS-CoV-2 entry into airway epithelial cells and, consequently, potentially prevent the virus from spreading into the lower respiratory tract and the lung.

Health systems worldwide are implementing lung cancer screening programmes to identify early-stage lung cancer and maximise patient survival. Volumetry is recommended for follow-up of pulmonary nodules and outperforms other measurement methods. However, volumetry is known to be influenced by multiple factors. The objectives of this systematic review (PROSPERO CRD42022370233) are to summarise the current knowledge regarding factors that influence volumetry tools used in the analysis of pulmonary nodules, assess for significant clinical impact, identify gaps in current knowledge and suggest future research. Five databases (Medline, Scopus, Journals@Ovid, Embase and Emcare) were searched on the 21st of September, 2022, and 137 original research studies were included, explicitly testing the potential impact of influencing factors on the outcome of volumetry tools. The summary of these studies is tabulated, and a narrative review is provided. A subset of studies (n = 16) reporting clinical significance were selected, and their results were combined, if appropriate, using meta-analysis. Factors with clinical significance include the segmentation algorithm, quality of the segmentation, slice thickness, the level of inspiration for solid nodules, and the reconstruction algorithm and kernel in subsolid nodules. Although there is a large body of evidence in this field, it is unclear how to apply the results from these studies in clinical practice as most studies do not test for clinical relevance. The meta-analysis did not improve our understanding due to the small number and heterogeneity of studies testing for clinical significance.Critical relevance statementMany studies have investigated the influencing factors of pulmonary nodule volumetry, but only 11% of these questioned their clinical relevance in their management. The heterogeneity among these studies presents a challenge in consolidating results and clinical application of the evidence.Key points• Factors influencing the volumetry of pulmonary nodules have been extensively investigated.• Just 11% of studies test clinical significance (wrongly diagnosing growth).• Nodule size interacts with most other influencing factors (especially for smaller nodules).• Heterogeneity among studies makes comparison and consolidation of results challenging.• Future research should focus on clinical applicability, screening, and updated technology.

IntroductionChildhood infections, particularly those caused by helminths are considered to be important environmental exposures influencing the development of allergic diseases. However, epidemiological studies focusing on the relationship between helminth infections and risk of allergic diseases, performed worldwide, show inconsistent findings. Previous systematic reviews of observational studies published 10 or more years ago showed conflicting findings for effects of helminths on allergic diseases. Over the past 10 years there has been growing literature addressing this research area and these need to be considered in order to appreciate the most contemporary evidence. The objective of the current systematic review will be to provide an up-to-date synthesis of findings of observational studies investigating the influence of helminth infections on atopy, and allergic diseases.Methods and analysisThis systematic review protocol was registered at PROSPERO. We will search Cochrane Library, MEDLINE, EMBASE, CINAHL, AMED, ISI Web of Science, WHO Global Health Library, Scielo, IndMed, PakMediNet, KoreaMed, Ichushi for published studies from 1970 to January 2020. Bibliographies of all eligible studies will be reviewed to identify additional studies. Unpublished and ongoing research will also be searched in key databases. There will be no language or geographical restrictions regarding publications. Critical Appraisal Skills Programme quality assessment tool will be used to appraise methodological quality of included studies. A descriptive summary with data tables will be constructed, and if adequate, meta-analysis using random-effects will be performed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist will be followed for reporting of the systematic review.Ethics and disseminationSince this systematic review will be only based on published and retrievable literature, no ethics approval will be sought. The multidisciplinary team performing this systematic review will participate in relevant dissemination activities. Findings will be presented at scientific meetings and publish the systematic review in international, peer-reviewed, open-access journals.PROSPERO registration numberCRD42020167249.

BackgroundRecent recommendations for lung nodule management include volumetric analysis using tools that present intrinsic measurement variability, with possible impacts on clinical decisions and patient safety. This study was conducted to evaluate whether changes in the attenuation of the lung parenchyma adjacent to a nodule affect the performance of nodule segmentation using computed tomography (CT) studies and volumetric tools.MethodsTwo radiologists retrospectively applied two commercially available volumetric tools for the assessment of lung nodules with diameters of 5–8 mm detected by low-dose chest CT during a lung cancer screening program. The radiologists recorded the success and adequacy of nodule segmentation, nodule volume, manually and automatically (or semi-automatically) obtained long- and short-axis measurements, mean attenuation of adjacent lung parenchyma, and presence of interstitial lung abnormalities or disease, emphysema, pleural plaques, and linear atelectasis. Regression analysis was performed to identify predictors of good nodule segmentation using the volumetric tools. Interobserver and intersoftware agreement on good nodule segmentation was assessed using the intraclass correlation coefficient.ResultsIn total, data on 1265 nodules (mean patient age, 68.3 ± 5.1 years; 70.2% male) were included in the study. In the regression model, attenuation of the adjacent lung parenchyma was highly significant (odds ratio 0.987, p < 0.001), with a large effect size. Interobserver and intersoftware agreement on good segmentation was good, although one software package performed better and measurements differed consistently between software packages.ConclusionFor lung nodules with diameters of 5–8 mm, the likelihood of good segmentation declines with increasing attenuation of the adjacent parenchyma.

IntroductionIdentification and characterisation of single allergens at molecular level is important. Component-resolved diagnosis offers the possibility of higher diagnostic precision, thereby allowing better patient management. House dust mites (HDM) have a worldwide distribution. Studies from different countries have shown that IgE-mediated allergy to storage mites (SM) is important in rural and urban populations. With the availability of HDM and SM molecular allergen components, studies have investigated whether different molecular sensitisation profiles are associated with clinical disease outcomes. However, no previous systematic review has synthesised the underlying evidence.Methods and analysisWe will search Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Methodology Register), MEDLINE, EMBASE, CINAHL, AMED, ISI Web of Science (Science and Social Science Index) from inception to March 2020. Unpublished and ongoing work, as well as research in progress will be searched in www.ClinicalTrials.gov; www.controlledtrials.com and wwwanzctrorgau. We will contact an international panel of experts in this field. No language restrictions will apply; translations will be undertaken where necessary. The Critical Appraisal Skills Programme quality assessment tool will be used to appraise the methodological quality of included studies. A descriptive summary with data tables will be constructed, and if adequate, meta-analysis using random effects will be performed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist will be followed for reporting.Ethics and disseminationSince this systematic review will be only based on published and retrievable literature, no ethics approval is required. We will publish the systematic review in an international peer-reviewed journal.Trial registration numberreviewregistry959.

IntroductionStudies suggest that the prevalence of food allergy may be increasing worldwide. Results regarding the prevalence and features of adverse food reactions older people have, however, scarcely been analysed in the literature. Thus, the objective of the present systematic review will be to describe the prevalence of food allergy in older individuals, its risk factors, clinical features, as well as the most frequently and commonly involved foods.Methods and analysisWe will conduct a systematic review and meta-analysis of the incidence, prevalence and risk factors for food allergy in older individuals. We will search international electronic databases including MEDLINE, EMBASE, Cochrane Library, CINAHL, AMED and ISI Web of Science for published, unpublished and ongoing studies from 1980 toJanuary 2019. There will be no restriction on the language or geography of publication. We will use the critical appraisal skills programme quality assessment tool to appraise the methodological quality of included studies. A descriptive summary with data tables will be elaborated, and if deemed clinically relevant and statistically adequate, meta-analysis using random-effects modelling will be carried out, given the expected clinical, methodological and statistical heterogeneity of studies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist will guide reporting of the systematic review.Ethics and disseminationSince this systematic review will be solely based on published and retrievable literature, no ethics approval will be obtained. This study will allow us to draw up-to-date estimates of the prevalence of adverse food reactions in older individuals, worldwide, besides allowing the identification of its major risk factors, clinical manifestations and predominant foods responsible for such reactions. A multidisciplinary team has been assembled for this systematic review and will participate in relevant dissemination activities, namely reports, publications and presentations.PROSPERO registration numberCRD42018102140

Background The acceptance of coronary CT angiogram (CCTA) scans in the management of stable angina has led to an exponential increase in studies performed and reported incidental findings, including pulmonary nodules (PN). Using low-dose CT scans, volumetry tools are used in growth assessment and risk stratification of PN between 5 and 8 mm in diameter. Volumetry of PN could also benefit from the increased temporal resolution of CCTA scans, potentially expediting clinical decisions when an incidental PN is first detected on a CCTA scan, and allow for better resource management and planning in a Radiology department. This study aims to investigate how cardiopulmonary hemodynamic factors impact the volumetry of PN using CCTA scans. These factors include the cardiac phase, vascular distance from the main pulmonary artery (MPA) to the nodule, difference of the MPA diameter between systole and diastole, nodule location, and cardiomegaly presence. Materials and methods Two readers reviewed all CCTA scans performed from 2016 to 2019 in a tertiary hospital and detected PN measuring between 5 and 8 mm in diameter. Each observer measured each nodule using two different software packages and in systole and diastole. A multiple linear regression model was applied, and inter-observer and inter-software agreement were assessed using intraclass correlation. Results A total of 195 nodules from 107 patients were included in this retrospective, cross-sectional and observational study. The regression model identified the vascular distance (p < 0.001), the difference of the MPA diameter between systole and diastole (p < 0.001), and the location within the lower or posterior thirds of the field of view (p < 0.001 each) as affecting the volume measurement. The cardiac phase was not significant in the model. There was a very high inter-observer agreement but no reasonable inter-software agreement between measurements. Conclusions PN volumetry using CCTA scans seems to be sensitive to cardiopulmonary hemodynamic changes independently of the cardiac phase. These might also be relevant to non-gated scans, such as during PN follow-up. The cardiopulmonary hemodynamic changes are a new limiting factor to PN volumetry. In addition, when a patient experiences an acute or deteriorating cardiopulmonary disease during PN follow-up, these hemodynamic changes could affect the PN growth estimation.

Inhaled medication used for treatment of chronic obstructive lung diseases (asthma, chronic obstructive pulmonary disease-COPD, and Asthma-COPD overlap) may be associated with adverse drug reactions (ADRs). The aim of this study was to characterise spontaneous reports (SRs) of suspected ADRs received by the Portuguese Pharmacovigilance System (PPS), from 2007 to 2017. Methods: Retrospective observational study of SRs associated with single substance and combination inhalers, analysed in terms of pharmacological class of the involved drugs, sex and age range of the involved patients, and seriousness and type of ADRs. Results: 230 SRs were analysed, accounting for a total of 599 suspected ADRs. Inhaled corticosteroid/long-acting beta-2 agonist combination had the highest frequency in SRs (32.2%) and in ADRs (32.7%). There was a slight predominance in men (51.3%) and non-elderly adults were the most affected age group (39.1%). Most SRs were serious (70.4%). In total, “respiratory, thoracic and mediastinal diseases” ADRs were the most reported (19.5%), with “dyspnea” being the most frequent (4.8%). Conclusions: Most SRs were associated with controller medications and were expected. Most ADRs involved non-elderly adults, were serious and of respiratory nature and many were due to overuse of reliever medication.

Bronchial asthma is a chronic disease that affects individuals of all ages. It has a high prevalence and is associated with high morbidity and considerable levels of mortality. However, asthma is not a single disease, and multiple subtypes or phenotypes (clinical, inflammatory or combinations thereof) can be detected, namely in aggregated clusters. Most studies have characterised asthma phenotypes and clusters of phenotypes using mainly clinical and inflammatory parameters. These studies are important because they may have clinical and prognostic implications and may also help to tailor personalised treatment approaches. In addition, various metabolomics studies have helped to further define the metabolic features of asthma, using electronic noses or targeted and untargeted approaches. Besides discriminating between asthma and a healthy state, metabolomics can detect the metabolic signatures associated with some asthma subtypes, namely eosinophilic and non-eosinophilic phenotypes or the obese asthma phenotype, and this may prove very useful in point-of-care application. Furthermore, metabolomics also discriminates between asthma and other “phenotypes” of chronic obstructive airway diseases, such as chronic obstructive pulmonary disease (COPD) or Asthma–COPD Overlap (ACO). However, there are still various aspects that need to be more thoroughly investigated in the context of asthma phenotypes in adequately designed, homogeneous, multicentre studies, using adequate tools and integrating metabolomics into a multiple-level approach.

To the editor, Real-world data obtained by the MASK-air® (Mobile Airways Sentinel networK for airway diseases) app have had an impact on the knowledge about the phenotypes and management of respiratory allergic diseases. 1 Studies assessing MASK-air® data have traditionally included users ranging in age from 16 to over 90 years, and a recent paper has shown that elderly users (≥65 years) can use the MASK-air® app after a short training period. 2 However, it is not known whether the characteristics of elderly users differ from those of younger users. 2 For comparison of different age groups, effect size measures for differences in proportions and medians were estimated. TABLE 2 Characteristics and outcomes of the days from assessed MASK-air® users with self-reported rhinitis according to the age group A. Comparison of days from patients under versus above 65 years Days from patients aged <65 years (N = 333,395) Days from patients aged ≥65 years (N = 15,650) Effect size a N users (average days per user) 19,369 (17.2) 519 (30.2) - MASK-air® adherence (%)—median (IQR) 0.3 (1.3) 0.4 (1.6) - Females—N (%) 192,513 (57.7) 5154 (32.9) 0.50 Age—mean (SD) 36.5 (12.6) 68.4 (3.0) - VAS global allergy symptoms—median (IQR) 12 (27) 13 (20) 0.06 VAS nose—median (IQR) 12 (28) 13 (21) 0.06 VAS eyes—median (IQR) 4 (17) 7 (22) 0.36 VAS asthma—median (IQR) All users 0 (10) b 1 (11) b 0.95 Users with reported asthma 7 (22) 14 (37) 0.48 Allergic rhinitis CSMS b—median (IQR) 10 (18) 11 (16) 0.06 Total days reporting rhinitis medication—N (%) 156,311 (46.9) 7193 (46.0) 0.02 Oral antihistamines monotherapy 57,097 (17.1) 2031 (13.0) 0.12 Intranasal steroids monotherapy 31,901 (9.6) 1539 (9.8) 0.01 Azelastine-fluticasone monotherapy 12,100 (3.6) 1042 (6.7) 0.14 Oral antihistamines + intranasal steroids 31,092 (9.3) 1346 (8.6) 0.03 Azelastine-fluticasone + other rhinitis medication 11,415 (3.4) 478 (3.1) 0.02 Allergen immunotherapy c—N (%) 103,792 (31.1) 4593 (29.3) 0.04 Self-reported asthma—N (%) 126,201 (37.9) 5490 (35.1) 0.06 Total days reporting asthma medication—N (%) 68,313 (20.5) 3938 (25.2) 0.11 SABA 8647 (2.6) 408 (2.6) 0 ICS 25,738 (7.7) 1484 (9.5) 0.06 ICS + LABA 37,457 (11.2) 2806 (17.9) 0.19 LAMA or biologics 2387 (0.7) 40 (0.3) 0.06 Other medications 14,979 (4.5) 829 (5.3) 0.04 Conjunctivitis—N (%) 240,481 (72.1) 10,347 (66.1) 0.13 Baseline symptoms d—median (IQR) 5 (3) 4 (4) 0.34 Baseline impact e—median (IQR) 1 (3) 1 (3) 0 B. Comparison of days from patients aged 65–74 years versus over 75 years Days from patients aged 65–74 years (N = 15,038) Days from patients aged ≥75 years (N = 612) Effect size a N users (average days per user) 455 (33.1) 70 (8.7) - MASK-air® adherence (%)—median (IQR) 0.4 (1.6) 0.2 (0.9) - Females—N (%) 4991 (33.2) 163 (26.6) 0.14 Age—mean (SD) 68.0 (2.4) 76.8 (2.2) - VAS global allergy symptoms—median (IQR) 13 (20) 16 (25) 0.23 VAS nose—median (IQR) 13 (21) 15 (23) 0.15 VAS eyes—median (IQR) 7 (22) 13 (20) 0.47 VAS asthma—median (IQR) All users 1 (10) c 9 (22) c 0.84 Users with reported asthma 14 (37) 11 (39) 0.18 Allergic rhinitis CSMS b—median (IQR) 10 (16) 15 (21) 0.42 Total days reporting rhinitis medication—N (%) 6752 (44.9) 441 (72.1) 0.56 Oral antihistamines monotherapy 1867 (12.4) 164 (26.8) 0.37 Intranasal steroids monotherapy 1519 (10.1) 20 (3.3) 0.28 Azelastine-fluticasone monotherapy 943 (6.3) 99 (16.2) 0.32 Oral antihistamines + intranasal steroids 1308 (8.7) 38 (6.2) 0.10 Azelastine-fluticasone + other rhinitis medication 395 (2.6) 83 (13.6) 0.43 Allergen immunotherapy c—N (%) 4593 (30.5) 0 (0) 1.17 Self-reported asthma—N (%) 5120 (34.0) 370 (60.5) 0.54 Total days reporting asthma medication—N (%) 3775 (25.1) 163 (26.6) 0.03 SABA 345 (2.3) 63 (10.3) 0.35 ICS 1429 (9.5) 55 (9.0) 0.02 ICS + LABA 2709 (18.0) 97 (15.9) 0.06 LAMA or biologics 37 (0.2) 3 (0.5) 0.05 Other medications 766 (5.1) 63 (10.3) 0.20 Conjunctivitis—N (%) 9894 (65.8) 453 (74.0) 0.18 Baseline symptoms d—median (IQR) 4 (4) 4 (4) 0 Baseline impact e—median (IQR) 1 (3) 1 (2) 0 Abbreviations: CSMS, Combined symptom-medication score; ICS, Inhaled corticosteroids; IQR, Interquartile range; LABA, Long-acting beta-agonists; LAMA, Long-acting muscarinic antagonists; SABA, Short-acting beta-agonists; SD, Standard-deviation; VAS, Visual analogue scale. aEffect size measures <0.2 indicate non-meaningful differences, between 0.2 and 0.5 indicate small differences, between 0.5 and 0.8 indicate moderate differences, and higher than 0.8 indicate large differences. bThe CSMS ranges from 0 to 100. Comparing days from users 65–74 years of age with those ≥75 (Table 2B), we observed small and moderate effect size measures in some clinical, medication and symptom-related variables.