Arterial Spin Labeling Magnetic Resonance Imaging for Acute Disorders of Consciousness in the Intensive Care Unit.

BACKGROUND: To investigate patients with disorders of consciousness (DoC) for residual awareness, guidelines recommend quantifying glucose brain metabolism using positron emission tomography. However, this is not feasible in the intensive care unit (ICU). Cerebral blood flow (CBF) assessed by arterial spin labeling magnetic resonance imaging (ASL-MRI) could serve as a proxy for brain metabolism and reflect consciousness levels in acute DoC. We hypothesized that ASL-MRI would show compromised CBF in coma and unresponsive wakefulness states (UWS) but relatively preserved CBF in minimally conscious states (MCS) or better. METHODS: We consecutively enrolled ICU patients with acute DoC and categorized them as being clinically unresponsive (i.e., coma or UWS [≤ UWS]) or low responsive (i.e., MCS or better [≥ MCS]). ASL-MRI was then acquired on 1.5 T or 3 T. Healthy controls were investigated with both 1.5 T and 3 T ASL-MRI. RESULTS: We obtained 84 ASL-MRI scans from 59 participants, comprising 36 scans from 35 patients (11 women [31.4%]; median age 56 years, range 18-82 years; 24 ≤ UWS patients, 12 ≥ MCS patients; 32 nontraumatic brain injuries) and 48 scans from 24 healthy controls (12 women [50%]; median age 50 years, range 21-77 years). In linear mixed-effects models of whole-brain cortical CBF, patients had 16.2 mL/100 g/min lower CBF than healthy controls (p = 0.0041). However, ASL-MRI was unable to discriminate between ≤ UWS and ≥ MCS patients (whole-brain cortical CBF: p = 0.33; best hemisphere cortical CBF: p = 0.41). Numerical differences of regional CBF in the thalamus, amygdala, and brainstem in the two patient groups were statistically nonsignificant. CONCLUSIONS: CBF measurement in ICU patients using ASL-MRI is feasible but cannot distinguish between the lower and the upper ends of the acute DoC spectrum. We suggest that pilot testing of diagnostic interventions at the extremes of this spectrum is a time-efficient approach in the continued quest to develop DoC neuroimaging markers in the ICU.

Development of the Saini-Hodgins Addiction Risk Potential of Games (SHARP-G) Scale: An International Delphi study.

Background and Objectives: As the gaming industry experiences exponential growth, concerns about gaming disorder (GD) also grow. It is crucial to understand the structural features of games that can interact with individual characteristics of gamers to promote GD. This research consolidates the views of an international body of panelists to create an assessment tool for gauging the addictive potential of distinct games. Methods: Utilizing the iterative and structured Delphi method, an international panel of researchers, clinicians, and people with lived experience were recruited to offer a multifaceted viewpoint on the addictive risk associated with specific structural elements in games. Two rounds of surveys facilitated consensus. Results: The panel initially included 40 members-ten from research, eight from clinical settings, and 22 with lived experiences. The second round included 27 panelists-seven from research, eight from clinical settings, and 11 with lived experiences. The study identified 25 structural features that contribute to potentially addictive gaming patterns. Discussion and Conclusions: Consensus was found for 25 features, which were distilled into a 23-item evaluation tool. The Saini-Hodgins Addiction Risk Potential of Games Scale (SHARP-G) consists of five overarching categories: 'Social,' 'Gambling-Like Features,' 'Personal Investment,' 'Accessibility,' and 'World Design.' SHARP-G yields a total score indicating level of addiction risk. A case study applying the scale to three games of differing perceived risk levels demonstrated that that score corresponded to game risk as expected. While the SHARP-G scale requires further validation, it provides significant promise for evaluating gaming experiences and products.

Outcome-based Definition of the Lower Limit of Normal in Spirometry: A Study of 26,000 Young Adult Men.

Rationale The definition of the lower limit of normal (LLN) of spirometric variables is not well established. Objectives To investigate the relationship between spirometric abnormalities defined with different thresholds of the LLN and clinical outcomes, and to explore the possibility of using different LLN thresholds according to the pre-test probability of disease. Methods We studied the associations between pre-bronchodilator spirometric abnormalities (FEV1 < LLN, FVC < LLN, airflow obstruction, spirometric restriction) defined with different thresholds of the LLN (10th, 5th, 2.5th, 1st percentile) and multiple outcomes (prevalence of spirometric abnormalities, respiratory symptoms, all-cause and respiratory mortality) in 26,091 30-46 years old men who participated in a general population survey in Norway in 1988-1990 and were followed for 26 years. Analyses were performed with both local and GLI-2012 reference equations, stratified by pre-test risk (presence or absence of respiratory symptoms), and adjusted for age, BMI, smoking, and education. Results In the total population, the prevalence of airflow obstruction was 11.6% with GLI-LLN10, 11.0% with Local-LLN5, 6.1% with GLI-LLN5, 7.6% with Local-LLN2.5, and 3.5% with GLI-LLN2.5. The prevalence of spirometric restriction was 5.9% with GLI-LLN10, 5.2% with Local-LLN5, and 2.8% with GLI-LLN5. Increasingly lower thresholds of the LLN were associated with increasingly higher odds of respiratory symptoms and hazard of mortality for all spirometric abnormalities with both reference equations. Spirometric abnormalities defined with Local-LLN2.5 in asymptomatic subjects were associated with lower hazard of all-cause mortality (hazard ratio 1.50 (1.15, 1.95, 95% confidence intervals) for FEV1 < LLN) than those defined with Local-LLN5 in the general population (1.67 (1.50, 1.87) for FEV1 < LLN) and symptomatic subjects (1.67 (1.46, 1.91) for FEV1 < LLN). Overall, prevalence of spirometric abnormalities and associations with outcomes obtained with Local-LLN5 were comparable to those obtained with GLI-LLN10, and those obtained with Local-LLN2.5 to GLI-LLN5. Conclusions There is a relationship between statistically-based thresholds of the LLN of spirometric variables and clinical outcomes. Different thresholds of the LLN may be used in different risk subgroups of subjects, but the choice of the threshold needs to be evaluated together with the choice of reference equations.

Lower airway microbiota in COPD and healthy controls.

BACKGROUND: The lower airway microbiota in patients with chronic obstructive pulmonary disease (COPD) are likely altered compared with the microbiota in healthy individuals. Information on how the microbiota is affected by smoking, use of inhaled corticosteroids (ICS) and COPD severity is still scarce. METHODS: In the MicroCOPD Study, participant characteristics were obtained through standardised questionnaires and clinical measurements at a single centre from 2012 to 2015. Protected bronchoalveolar lavage samples from 97 patients with COPD and 97 controls were paired-end sequenced with the Illumina MiSeq System. Data were analysed in QIIME 2 and R. RESULTS: Alpha-diversity was lower in patients with COPD than controls (Pielou evenness: COPD=0.76, control=0.80, p=0.004; Shannon entropy: COPD=3.98, control=4.34, p=0.01). Beta-diversity differed with smoking only in the COPD cohort (weighted UniFrac: permutational analysis of variance R2=0.04, p=0.03). Nine genera were differentially abundant between COPD and controls. Genera enriched in COPD belonged to the Firmicutes phylum. Pack years were linked to differential abundance of taxa in controls only (ANCOM-BC (Analysis of Compositions of Microbiomes with Bias Correction) log-fold difference/q-values: Haemophilus -0.05/0.048; Lachnoanaerobaculum -0.04/0.03). Oribacterium was absent in smoking patients with COPD compared with non-smoking patients (ANCOM-BC log-fold difference/q-values: -1.46/0.03). We found no associations between the microbiota and COPD severity or ICS. CONCLUSION: The lower airway microbiota is equal in richness in patients with COPD to controls, but less even. Genera from the Firmicutes phylum thrive particularly in COPD airways. Smoking has different effects on diversity and taxonomic abundance in patients with COPD compared with controls. COPD severity and ICS use were not linked to the lower airway microbiota.

Isolated small airways obstruction predicts future chronic airflow obstruction: a multinational longitudinal study.

BACKGROUND: Chronic airflow obstruction is a key characteristic of chronic obstructive pulmonary disease. We investigated whether isolated small airways obstruction is associated with chronic airflow obstruction later in life. METHODS: We used longitudinal data from 3957 participants of the multinational Burden of Obstructive Lung Disease study. We defined isolated small airways obstruction using the prebronchodilator mean forced expiratory flow rate between 25% and 75% of the forced vital capacity (FVC) (FEF25-75) if a result was less than the lower limit of normal (

Reduced lung function and cause-specific mortality: A population-based study of Norwegian men followed for 26 years.

BACKGROUND AND AIM: Reduced lung function is associated with increased mortality, but it is unclear how different spirometric patterns are related to specific deaths. Aim of this study was to investigate these associations in a large general population cohort. METHODS: The study population consisted of 26,091 men aged 30-46 years from the Pneumoconiosis Survey of Western Norway conducted in 1988-1990 with follow-up on date and cause of death for 26 years. Cox proportional hazard models were used to estimate the association between baseline FEV1, FVC, obstructive (OSP) and restrictive spirometric pattern (RSP) (z-scores calculated according to GLI-2012 equations) and mortality (European 2012 shortlist classification (E-2012)), after adjustment for age, body mass index, smoking habits, and education. RESULTS: In total, 2462 (9%) subjects died. A predominant reduction of FEV1 (and OSP) were associated with respiratory non-cancer (E-8) (HR for one unit FEV1 z-score decrease 2.29 (95% CI 1.90, 2.77) and lung cancer mortality (E-2.1.8) (1.27(1.12, 1.44)). A similar reduction of FEV1 and FVC (and RSP) were associated with diabetes (E-4.1) (FEV1 2.21(1.67, 2.92), FVC 2.41(1.75, 3.32)), cerebrovascular (E-7.3) (1.52(1.21, 1.91), 1.54(1.19, 1.98)), ischemic heart disease (E-7.1) (1.22(1.10, 1.35), 1.21(1.08, 1.36)), neurological (E-6.3) (1.56(1.21, 2.01), 1.61(1.22, 2.13)), suicide (E-17.2) (1.37(1.13, 1.65), 1.29(1.04, 1.59)) and hematological cancer mortality (E-2.1.19-21) (1.29(1.05, 1.58), (1.26(1.00, 1.58)). No association was found between reduced lung function and mortality due to accidents, alcohol abuse, digestive and genitourinary cancer. CONCLUSIONS: Spirometric obstruction was mainly related to pulmonary mortality. Spirometric restriction was mainly related to extra-pulmonary mortality.

Calcium Channel Blockers and the Risk of Exacerbation in Patients with Chronic Obstructive Pulmonary Disease: A Nationwide Study of 48,488 Outpatients.

Patients with chronic obstructive pulmonary disease (COPD) are prone to developing arterial hypertension, and many patients are treated with the calcium channel blocker amlodipine. However, it remains unclear whether using this drug potentially affects the risk of acute severe exacerbations (AECOPD) and all-cause mortality in these patients. The data were collected from Danish national registries, containing complete information on health, prescriptions, hospital admissions, and outpatient clinic visits. The COPD patients (n = 48,488) were matched via propensity score on known predictors of the primary outcome in an active comparator design. One group was exposed to amlodipine treatment, and the other was exposed to bendroflumethiazide, since both of these drugs are considered to be the first choice for the treatment of arterial hypertension according to Danish guidelines. The use of amlodipine was associated with a reduced risk of death from all causes at the 1-year follow-up (hazard ratio 0.69, 95% confidence interval: 0.62-0.76) compared with the use of bendroflumethiazide in the matched patients. No difference in the risk of severe AECOPD was found. In the COPD patients, amlodipine use was associated with a lower risk of death from all causes compared with the use of bendroflumethiazide. Amlodipine seems to be a safe first choice for the treatment of arterial hypertension in COPD patients.

Small airways obstruction and its risk factors in the Burden of Obstructive Lung Disease (BOLD) study: a multinational cross-sectional study.

BACKGROUND: Small airways obstruction is a common feature of obstructive lung diseases. Research is scarce on small airways obstruction, its global prevalence, and risk factors. We aimed to estimate the prevalence of small airways obstruction, examine the associated risk factors, and compare the findings for two different spirometry parameters. METHODS: The Burden of Obstructive Lung Disease study is a multinational cross-sectional study of 41 municipalities in 34 countries across all WHO regions. Adults aged 40 years or older who were not living in an institution were eligible to participate. To ensure a representative sample, participants were selected from a random sample of the population according to a predefined site-specific sampling strategy. We included participants' data in this study if they completed the core study questionnaire and had acceptable spirometry according to predefined quality criteria. We excluded participants with a contraindication for lung function testing. We defined small airways obstruction as either mean forced expiratory flow rate between 25% and 75% of the forced vital capacity (FEF25-75) less than the lower limit of normal or forced expiratory volume in 3 s to forced vital capacity ratio (FEV3/FVC ratio) less than the lower limit of normal. We estimated the prevalence of pre-bronchodilator (ie, before administration of 200 µg salbutamol) and post-bronchodilator (ie, after administration of 200 µg salbutamol) small airways obstruction for each site. To identify risk factors for small airways obstruction, we performed multivariable regression analyses within each site and pooled estimates using random-effects meta-analysis. FINDINGS: 36 618 participants were recruited between Jan 2, 2003, and Dec 26, 2016. Data were collected from participants at recruitment. Of the recruited participants, 28 604 participants had acceptable spirometry and completed the core study questionnaire. Data were available for 26 443 participants for FEV3/FVC ratio and 25 961 participants for FEF25-75. Of the 26 443 participants included, 12 490 were men and 13 953 were women. Prevalence of pre-bronchodilator small airways obstruction ranged from 5% (34 of 624 participants) in Tartu, Estonia, to 34% (189 of 555 participants) in Mysore, India, for FEF25-75, and for FEV3/FVC ratio it ranged from 5% (31 of 684) in Riyadh, Saudi Arabia, to 31% (287 of 924) in Salzburg, Austria. Prevalence of post-bronchodilator small airways obstruction was universally lower. Risk factors significantly associated with FEV3/FVC ratio less than the lower limit of normal included increasing age, low BMI, active and passive smoking, low level of education, working in a dusty job for more than 10 years, previous tuberculosis, and family history of chronic obstructive pulmonary disease. Results were similar for FEF25-75, except for increasing age, which was associated with reduced odds of small airways obstruction. INTERPRETATION: Despite the wide geographical variation, small airways obstruction is common and more prevalent than chronic airflow obstruction worldwide. Small airways obstruction shows the same risk factors as chronic airflow obstruction. However, further research is required to investigate whether small airways obstruction is also associated with respiratory symptoms and lung function decline. FUNDING: National Heart and Lung Institute and Wellcome Trust. TRANSLATIONS: For the Dutch, Estonian, French, Icelandic, Malay, Marathi, Norwegian, Portuguese, Swedish and Urdu translations of the abstract see Supplementary Materials section.

Association of respiratory symptoms and lung function with occupation in the multinational Burden of Obstructive Lung Disease (BOLD) study.

BACKGROUND: Chronic obstructive pulmonary disease has been associated with exposures in the workplace. We aimed to assess the association of respiratory symptoms and lung function with occupation in the Burden of Obstructive Lung Disease study. METHODS: We analysed cross-sectional data from 28 823 adults (≥40 years) in 34 countries. We considered 11 occupations and grouped them by likelihood of exposure to organic dusts, inorganic dusts and fumes. The association of chronic cough, chronic phlegm, wheeze, dyspnoea, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)/FVC with occupation was assessed, per study site, using multivariable regression. These estimates were then meta-analysed. Sensitivity analyses explored differences between sexes and gross national income. RESULTS: Overall, working in settings with potentially high exposure to dusts or fumes was associated with respiratory symptoms but not lung function differences. The most common occupation was farming. Compared to people not working in any of the 11 considered occupations, those who were farmers for ≥20 years were more likely to have chronic cough (OR 1.52, 95% CI 1.19-1.94), wheeze (OR 1.37, 95% CI 1.16-1.63) and dyspnoea (OR 1.83, 95% CI 1.53-2.20), but not lower FVC (ß=0.02 L, 95% CI -0.02-0.06 L) or lower FEV1/FVC (ß=0.04%, 95% CI -0.49-0.58%). Some findings differed by sex and gross national income. CONCLUSION: At a population level, the occupational exposures considered in this study do not appear to be major determinants of differences in lung function, although they are associated with more respiratory symptoms. Because not all work settings were included in this study, respiratory surveillance should still be encouraged among high-risk dusty and fume job workers, especially in low- and middle-income countries.

The lower airways microbiota and antimicrobial peptides indicate dysbiosis in sarcoidosis.

BACKGROUND: The role of the pulmonary microbiome in sarcoidosis is unknown. The objectives of this study were the following: (1) examine whether the pulmonary fungal and bacterial microbiota differed in patients with sarcoidosis compared with controls; (2) examine whether there was an association between the microbiota and levels of the antimicrobial peptides (AMPs) in protected bronchoalveolar lavage (PBAL). METHODS: Thirty-five sarcoidosis patients and 35 healthy controls underwent bronchoscopy and were sampled with oral wash (OW), protected BAL (PBAL), and left protected sterile brushes (LPSB). The fungal ITS1 region and the V3V4 region of the bacterial 16S rRNA gene were sequenced. Bioinformatic analyses were performed with QIIME 2. The AMPs secretory leucocyte protease inhibitor (SLPI) and human beta defensins 1 and 2 (hBD-1 and hBD-2), were measured in PBAL by enzyme-linked immunosorbent assay (ELISA). RESULTS: Aspergillus dominated the PBAL samples in sarcoidosis. Differences in bacterial taxonomy were minor. There was no significant difference in fungal alpha diversity between sarcoidosis and controls, but the bacterial alpha diversity in sarcoidosis was significantly lower in OW (p = 0.047) and PBAL (p = 0.03) compared with controls. The beta diversity for sarcoidosis compared with controls differed for both fungi and bacteria. AMP levels were significantly lower in sarcoidosis compared to controls (SLPI and hBD-1: p < 0.01). No significant correlations were found between alpha diversity and AMPs. CONCLUSIONS: The pulmonary fungal and bacterial microbiota in sarcoidosis differed from in controls. Lower antimicrobial peptides levels were seen in sarcoidosis, indicating an interaction between the microbiota and the innate immune system. Whether this dysbiosis represents a pathogenic mechanism in sarcoidosis needs to be confirmed in experimental studies. Video Abstract.

A longitudinal study of the pulmonary mycobiome in subjects with and without chronic obstructive pulmonary disease.

BACKGROUND: Few studies have examined the stability of the pulmonary mycobiome. We report longitudinal changes in the oral and pulmonary mycobiome of participants with and without COPD in a large-scale bronchoscopy study (MicroCOPD). METHODS: Repeated sampling was performed in 30 participants with and 21 without COPD. We collected an oral wash (OW) and a bronchoalveolar lavage (BAL) sample from each participant at two time points. The internal transcribed spacer 1 region of the ribosomal RNA gene cluster was PCR amplified and sequenced on an Illumina HiSeq sequencer. Differences in taxonomy, alpha diversity, and beta diversity between the two time points were compared, and we examined the effect of intercurrent antibiotic use. RESULTS: Sample pairs were dominated by Candida. We observed less stability in the pulmonary taxonomy compared to the oral taxonomy, additionally emphasised by a higher Yue-Clayton measure in BAL compared to OW (0.69 vs 0.22). No apparent effect was visually seen on taxonomy from intercurrent antibiotic use or participant category. We found no systematic variation in alpha diversity by time either in BAL (p-value 0.16) or in OW (p-value 0.97), and no obvious clusters on bronchoscopy number in PCoA plots. Pairwise distance analyses showed that OW samples from repeated sampling appeared more stable compared to BAL samples using the Bray-Curtis distance metric (p-value 0.0012), but not for Jaccard. CONCLUSION: Results from the current study propose that the pulmonary mycobiome is less stable than the oral mycobiome, and neither COPD diagnosis nor intercurrent antibiotic use seemed to influence the stability.

Gaming My Way to Recovery: A Systematic Scoping Review of Digital Game Interventions for Young People's Mental Health Treatment and Promotion.

Nearly all young people use the internet daily. Many youth with mental health concerns, especially since the Covid-19 pandemic, are using this route to seek help, whether through digital mental health treatment, illness prevention tools, or supports for mental wellbeing. Videogames also have wide appeal among young people, including those who receive mental health services. This review identifies the literature on videogame interventions for young people, ages 12-29, and maps the data on game use by those with mental health and substance use problems, focusing on evidence for the capacity of games to support treatment in youth mental health services; how stakeholders are involved in developing or evaluating games; and any potential harms and ethical remedies identified. A systematic scoping review methodology was used to identify and assess relevant studies. A search of multiple databases identified a total of 8,733 articles. They were screened, and 49 studies testing 32 digital games retained. An adapted stepped care model, including four levels, or steps, based on illness manifestation and severity, was used as a conceptual framework for organizing target populations, mental health conditions and corresponding digital games, and study results. The 49 selected studies included: 10 studies (20.4%) on mental health promotion/prevention or education for undiagnosed youth (Step 0: 7 games); 6 studies (12.2%) on at-risk groups or suspected mental problems (Step 1: 5 games); 24 studies (49.0%) on mild to moderate mental conditions (Steps 2-3: 16 games); and 9 studies (18.4%) focused on severe and complex mental conditions (Step 4: 7 games). Two interventions were played by youth at more than one level of illness severity: the SPARX game (Steps 1, 2-3, 4) and Dojo (Steps 2-3 and 4), bringing the total game count to 35 with these repetitions. Findings support the potential integration of digital games in youth services based on study outcomes, user satisfaction, relatively high program retention rates and the potential usefulness of most games for mental health treatment or promotion/prevention. Most studies included stakeholder feedback, and involvement ratings were very high for seven games. Potential harms were not addressed in this body of research. This review provides an important initial repository and evaluation of videogames for use in clinical settings concerned with youth mental health.

Factors associated with coronary heart disease in COPD patients and controls.

BACKGROUND: COPD and coronary heart disease (CHD) frequently co-occur, yet which COPD phenotypes are most prone to CHD is poorly understood. The aim of this study was to see whether COPD patients did have a true higher risk for CHD than subjects without COPD, and to examine a range of potential factors associated with CHD in COPD patients and controls. METHODS: 347 COPD patients and 428 non-COPD controls, were invited for coronary computed tomography angiography (CCTA) and pulmonary CT. Arterial blood gas, bioelectrical impedance and lung function was measured, and a detailed medical history taken. The CCTA was evaluated for significant coronary stenosis and calcium score (CaSc), and emphysema defined as >10% of total area <-950 Hounsfield units. RESULTS: 12.6% of the COPD patients and 5.7% of the controls had coronary stenosis (p<0.01), whereas 55.9% of the COPD patients had a CaSc>100 compared to 31.6% of the controls (p<0.01). In a multivariable model adjusting for sex, age, body composition, pack-years, CRP, cholesterol/blood pressure lowering medication use and diabetes mellitus, the OR (95% CI) for having significant stenosis was 1.80 (0.86-3.78) in COPD patients compared with controls. In a similar model, the OR (95% CI) for having CaSc>100 was 1.68 (1.12-2.53) in COPD patients compared with controls. Examining the risk of significant stenosis and CaSc>100 among COPD patients, no variable was associated with significant stenosis, whereas male sex [OR 2.85 (1.56-5.21)], age [OR 3.74 (2.42-5.77)], statin use [OR 2.23 (1.23-4.50)] were associated with CaSc>100, after adjusting for body composition, pack-years, C-reactive protein, use of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), diabetes, emphysema score, GOLD category, exacerbation frequency, eosinophilia, and hypoxemia. CONCLUSION: COPD patients were more likely to have CHD, but neither emphysema score, lung function, exacerbation frequency, nor hypoxemia predicted presence of either coronary stenosis or CaSc>100.

The lower airways microbiome and antimicrobial peptides in idiopathic pulmonary fibrosis differ from chronic obstructive pulmonary disease.

BACKGROUND: The lower airways microbiome and host immune response in chronic pulmonary diseases are incompletely understood. We aimed to investigate possible microbiome characteristics and key antimicrobial peptides and proteins in idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). METHODS: 12 IPF patients, 12 COPD patients and 12 healthy controls were sampled with oral wash (OW), protected bronchoalveolar lavage (PBAL) and right lung protected sterile brushings (rPSB). The antimicrobial peptides and proteins (AMPs), secretory leucocyte protease inhibitor (SLPI) and human beta defensins 1 and 2 (hBD-1 & hBD-2), were measured in PBAL by enzyme linked immunosorbent assay (ELISA). The V3V4 region of the bacterial 16S rDNA gene was sequenced. Bioinformatic analyses were performed with QIIME 2. RESULTS: hBD-1 levels in PBAL for IPF were lower compared with COPD. The predominant phyla in IPF were Firmicutes, Bacteroides and Actinobacteria; Proteobacteria were among top three in COPD. Differential abundance analysis at genus level showed significant differences between study groups for less abundant, mostly oropharyngeal, microbes. Alpha diversity was lower in IPF in PBAL compared to COPD (p = 0.03) and controls (p = 0.01), as well as in rPSB compared to COPD (p = 0.02) and controls (p = 0.04). Phylogenetic beta diversity showed significantly more similarity for IPF compared with COPD and controls. There were no significant correlations between alpha diversity and AMPs. CONCLUSIONS: IPF differed in microbial diversity from COPD and controls, accompanied by differences in antimicrobial peptides. Beta diversity similarity between OW and PBAL in IPF may indicate that microaspiration contributes to changes in its microbiome.

ERS statement: a core outcome set for clinical trials evaluating the management of COPD exacerbations.

Clinical trials evaluating the management of acute exacerbations of COPD assess heterogeneous outcomes, often omitting those that are clinically relevant or more important to patients. We have developed a core outcome set, a consensus-based minimum set of important outcomes that we recommend are evaluated in all future clinical trials on exacerbations management, to improve their quality and comparability. COPD exacerbations outcomes were identified through methodological systematic reviews and qualitative interviews with 86 patients from 11 countries globally. The most critical outcomes were prioritised for inclusion in the core outcome set through a two-round Delphi survey completed by 1063 participants (256 patients, 488 health professionals and 319 clinical academics) from 88 countries in five continents. Two global, multi-stakeholder, virtual consensus meetings were conducted to 1) finalise the core outcome set and 2) prioritise a single measurement instrument to be used for evaluating each of the prioritised outcomes. Consensus was informed by rigorous methodological systematic reviews. The views of patients with COPD were accounted for at all stages of the project. Survival, treatment success, breathlessness, quality of life, activities of daily living, the need for a higher level of care, arterial blood gases, disease progression, future exacerbations and hospital admissions, treatment safety and adherence were all included in the core outcome set. Focused methodological research was recommended to further validate and optimise some of the selected measurement instruments. The panel did not consider the prioritised set of outcomes and associated measurement instruments to be burdensome for patients and health professionals to use.

Period and cohort effects: consequences on spirometric lung function in Norway during the 20th century.

Background and aim: Several factors can influence measured lung function over time. The aim of this study was to investigate period and cohort effects on spirometric measures in a large general population sample in Norway during the 20th century, using Global Lung Function Initiative (GLI-2012) equations as a reference. Methods: 36 466 subjects (born 1894-1969) from four cross-sectional surveys conducted between 1965 and 1999 were included, with harmonised data on smoking habits, respiratory symptoms, lung diseases, education and spirometry. Changes in forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) z-scores in healthy subjects across surveys were explored to investigate period effects. Linear mixed-effects models of FEV1 and FVC z-scores on birth cohort, with survey as random effect, were used to investigate cohort effects, both in subjects of the total population and in healthy ones. Results: Relatively higher FEV1 and FVC z-scores in healthy subjects were found in the first survey (1965-1970) compared to the more recent ones (1988-1999), suggesting period effects. FEV1 and FVC z-scores increased significantly with birth cohort from 1894 to 1935, after adjustment for covariates. A more stable trend of FEV1 and FVC z-scores with birth cohort was evidenced for subjects born more recently (1945-1969). Conclusions: An increase of lung function with year of birth was observed in Norwegian subjects during the first half of the 20th century. The impact of period effects on lung function decreased from 1965 to 1999.

Capillary function progressively deteriorates in prodromal Alzheimer's disease: A longitudinal MRI perfusion study.

Cardiovascular risk factors are associated with the development of Alzheimer's disease (AD), and increasing evidence suggests that cerebral microvascular dysfunction plays a vital role in the disease progression. Using magnetic resonance imaging, we investigated the two-year changes of the cerebral microvascular blood flow in 11 mild cognitively impaired (MCI) patients with prodromal AD compared to 12 MCI patients without evidence of AD and 10 cognitively intact age-matched controls. The pAD-MCI patients displayed widespread deterioration in microvascular cerebral perfusion associated with capillary dysfunction. No such changes were observed in the other two groups, suggesting that the dysfunction in capillary perfusion is linked to the AD pathophysiology. The observed capillary dysfunction may limit local oxygenation in AD leading to downstream ß-amyloid aggregation, tau hyperphosphorylation, neuroinflammation and neuronal dysfunction. The findings are in agreement with the capillary dysfunction hypothesis of AD, suggesting that increasing heterogeneity of capillary blood flow is a primary pathological event in AD.

Repeated bronchoscopy in health and obstructive lung disease: is the airway microbiome stable?

OBJECTIVE: Little is known concerning the stability of the lower airway microbiome. We have compared the microbiota identified by repeated bronchoscopy in healthy subjects and patients with ostructive lung diseaseases (OLD). METHODS: 21 healthy controls and 41 patients with OLD completed two bronchoscopies. In addition to negative controls (NCS) and oral wash (OW) samples, we gathered protected bronchoalveolar lavage in two fractions (PBAL1 and PBAL2) and protected specimen brushes (PSB). After DNA extraction, we amplified the V3V4 region of the 16S rRNA gene, and performed paired-end sequencing (Illumina MiSeq). Initial bioinformatic processing was carried out in the QIIME-2 pipeline, identifying amplicon sequence variants (ASVs) with the DADA2 algorithm. Potentially contaminating ASVs were identified and removed using the decontam package in R and the sequenced NCS. RESULTS: A final table of 551 ASVs consisted of 19 × 106 sequences. Alpha diversity was lower in the second exam for OW samples, and borderline lower for PBAL1, with larger differences in subjects not having received intercurrent antibiotics. Permutational tests of beta diversity indicated that within-individual changes were significantly lower than between-individual changes. A non-parametric trend test showed that differences in composition between the two exams (beta diversity) were largest in the PSBs, and that these differences followed a pattern of PSB > PBAL2 > PBAL1 > OW. Time between procedures was not associated with increased diversity. CONCLUSION: The airways microbiota varied between examinations. However, there is compositional microbiota stability within a person, beyond that of chance, supporting the notion of a transient airways microbiota with a possibly more stable individual core microbiome.

Respiratory symptoms and respiratory deaths: A multi-cohort study with 45 years observation time.

This study determined the association between respiratory symptoms and death from respiratory causes over a period of 45 years. In four cohorts of random samples of Norwegian populations with 103,881 participants, 43,731 persons had died per 31 December 2016. In total, 5,949 (14%) had died from respiratory diseases; 2,442 (41%) from lung cancer, 1,717 (29%) chronic obstructive pulmonary disease (COPD), 1,348 (23%) pneumonia, 119 (2%) asthma, 147 (2%) interstitial lung disease and 176 (3%) other pulmonary diseases. Compared with persons without respiratory symptoms the multivariable adjusted hazard ratio (HR) for lung cancer deaths increased with score of breathlessness on effort and cough and phlegm, being 2.6 (95% CI 2.1-3.2) for breathlessness score 3 and 2.1 (95% CI 1.7-2.5) for cough and phlegm score 5. The HR of COPD death was 6.4 (95% CI 5.4-7.7) for breathlessness score 3 and 3.0 (2.4-3.6) for cough and phlegm score 5. Attacks of breathlessness and wheeze score 2 had a HR of 1.6 (1.4-1.9) for COPD death. The risk of pneumonia deaths increased also with higher breathlessness on effort score, but not with higher cough and phlegm score, except for score 2 with HR 1.5 (1.2-1.8). In this study with >2.4 million person-years at risk, a positive association was observed between scores of respiratory symptoms and deaths due to COPD and lung cancer. Respiratory symptoms are thus important risk factors, which should be followed thoroughly by health care practitioners for the benefit of public health.