Melatonin does not reduce delirium severity in hospitalized older adults: Results of a randomized placebo-controlled trial.

BACKGROUND: Delirium is common in older inpatients, causing distress, cognitive decline, and death. Current therapies are unsatisfactory, limited by lack of efficacy and adverse effects. There is an urgent need for effective delirium treatment. Sleep wake cycle is disturbed in delirium; endogenous Melatonin is perturbed, and exogenous Melatonin is a safe and effective medication for sleep disorders. This study aims to determine the effect of oral Melatonin 5 mg immediate release (IR) nightly for five nights on the severity of delirium in older (≥65 years) medical inpatients. METHODS: This was a double-blinded, randomized controlled trial in general internal medicine units of a tertiary teaching hospital. Older inpatients with Confusion Assessment Method positive, hyperactive or mixed delirium within 48 h of admission or onset of in-hospital delirium were included. The primary outcome was change in delirium severity measured with the Memorial Delirium Assessment Scale (MDAS). A previous pilot trial showed 120 participants randomized 1:1 to Melatonin or Placebo would provide 90% power to demonstrate a 3-point reduction in the MDAS. RESULTS: One hundred and twenty participants were randomized, 61 to Melatonin 5 mg and 59 to Placebo. The medication was well tolerated. The mean MDAS improvement was 4.9 (SD 7.6) in the Melatonin group and 5.4 (SD 7.2) in the Placebo group, p-value 0.42, a non-significant difference. A post-hoc analysis showed length of stay (LOS) was shorter in the intervention group (median 9 days [Interquartile Range (IQR) 4, 12] vs. Placebo group 10 [IQR 6, 16] p-value = 0.033, Wilcoxon Rank Sum test). CONCLUSIONS: This trial does not support the hypothesis that Melatonin reduces the severity of delirium. This may be due to no effect of Melatonin, a smaller effect than anticipated, an effect not captured on a multidimensional delirium assessment scale, or a type II statistical error. Melatonin may improve LOS; this hypothesis should be studied.

Susceptible Young Adults and Development of COPD Later in Life.

RATIONALE: Chronic obstructive pulmonary disease (COPD) has its origin in early life, and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) proposes a pre-disease state "pre-COPD". OBJECTIVE: We tested the hypothesis that susceptible young adults identified with chronic bronchitis and subtle lung function impairment will develop COPD later in life. METHODS: We followed random non-obstructive individuals aged 20-50years from two population-based cohorts from different smoking eras, the Copenhagen General Population Study from 2003(N=5497) and Copenhagen City Heart Study from 1976-78(N=2609), for 10 and 25years for development of COPD(forced expiratory volume in one second[FEV1]/forced vital capacity[FVC]<0.70) and COPD GOLD 2-4 (additionally FEV1<80% predicted). MEASUREMENTS AND MAIN RESULTS: After 10 years follow-up, 28% developed COPD and 13% COPD GOLD 2-4 in individuals susceptible to COPD compared to 8% and 1% in those without any susceptibility to COPD. Correspondingly, after 25years, 22% versus 13% developed COPD and 20% versus 8% developed COPD GOLD 2-4. More than half of incident COPD cases developed from a susceptible state. Compared to those without susceptibility to COPD, multivariable adjusted odds ratios in those susceptible to COPD were 3.42(95% confidence interval:2.78-4.21) for COPD and 10.1(6.77-15.2) for COPD GOLD 2-4 after 10years, and 1.54(1.23-1.93) and 2.12(1.64-2.73) after 25years. The ability of a COPD risk score consisting of the susceptibility state to COPD with smoking and asthma as risk factors to predict COPD later in life was high. CONCLUSIONS: Our study suggests the existence of a pre-disease state of COPD, which can be used for early identification of susceptible individuals at risk for COPD later in life.

Chronic cough associated with COPD exacerbation, pneumonia and death in the general population.

Background: Chronic cough affects up to 10% of the general population and was previously perceived as a comorbidity of underlying conditions, but is nowadays classified as a disease in its own entity that could confer increased risk of morbidity and mortality. We tested the hypothesis that chronic cough is associated with increased risk of COPD exacerbation, pneumonia and all-cause mortality in the general population. Methods: We identified 2801 individuals with chronic cough, defined as cough lasting >8 weeks, among 44 756 randomly selected individuals from the Copenhagen General Population Study, and recorded COPD exacerbations, pneumonia and all-cause mortality during follow-up. Results: During up to 5.9 years of follow-up (median 3.4 years), 173 individuals experienced COPD exacerbation, 767 experienced pneumonia and 894 individuals died. Individuals with chronic cough versus those without had cumulative incidences at age 80 years of 12% versus 3% for COPD exacerbation, 30% versus 15% for pneumonia, and 25% versus 13% for death from all causes. After adjustment for age, sex and smoking, individuals with chronic cough versus those without had adjusted hazard ratios of 4.6 (95% CI 2.9-7.2) for COPD exacerbation, 2.2 (1.7-2.7) for pneumonia and 1.7 (1.4-2.0) for all-cause mortality. Among current smokers aged >60 years with airflow limitation, those with versus without chronic cough had an absolute 5-year risk of 10% versus 4% for COPD exacerbation, 16% versus 8% for pneumonia and 19% versus 12% for all-cause mortality. Conclusion: Chronic cough is associated with higher risks of COPD exacerbation, pneumonia and death, independent of airflow limitation and smoking.

Fraction of exhaled nitric oxide is higher in liver transplant recipients than in controls from the general population: a cohort study.

Background: Fraction of exhaled nitric oxide with an expiratory flow of 50 mL/s (FENO50) is a biomarker of eosinophilic airway inflammation. Liver transplant recipients have an increased risk of pulmonary infections, but little is known about the burden of chronic pulmonary diseases in this group. We aimed to assess the prevalence of elevated FENO50 in liver transplant recipients and compare it to controls from the general population. Methods: FENO50 was measured in 271 liver transplant recipients from The Danish Comorbidity in Liver Transplant Recipients (DACOLT) study and 1,018 age- and sex-matched controls from The Copenhagen General Population Study (CGPS). Elevated FENO50 was defined as ≥25 or ≥50 parts per billion (ppb). The analyses were adjusted for known and suspected confounders. Results: The median age of the liver transplant recipients was 55 years (interquartile range (IQR) 46-64), and 58% were men. The liver transplant recipients had a higher median FENO50 than the controls [16 ppb (IQR 10-26) vs. 13 ppb (IQR 8-18.), p < 0.001]. Furthermore, the liver transplant recipients had a higher prevalence of elevated FENO50 (for FENO50 ≥25 ppb 27% vs. 11%, p < 0.001 and ≥50 ppb 4% vs. 2%, p = 0.02). The results were similar after adjusting for age, sex, smoking status, use of airway medication, and blood eosinophil counts [the adjusted odds ratio (OR) for FENO50 ≥25 ppb was 3.58 (95% CI: 2.50-5.15, p < 0.0001) and the adjusted OR for FENO50 ≥50 ppb was 3.14 (95% CI: 1.37-7.20, p = 0.007)]. Conclusion: The liver transplant recipients had elevated FENO50, implying increased eosinophilic airway inflammation. The clinical impact of this finding needs further investigation.

Predicting exacerbations in COPD in the Danish general population.

BACKGROUND: Risk of exacerbations in individuals with mild chronic obstructive pulmonary disease (COPD) in the general population is less well described than in more advanced disease. We hypothesized that in addition to history of previous exacerbation also other clinical characteristics predict future moderate exacerbations. METHODS: In 96,462 individuals in the Copenhagen General Population Study, we identified 3175 with clinical COPD defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 0.70 and FEV1 <80% predicted in symptomatic individuals without asthma. We estimated the importance of age, sex, FEV1, modified Medical Research Council (mMRC) dyspnea scale, chronic bronchitis, exacerbation history, comorbidities, cohabitation, body mass index, smoking, and blood eosinophils for the 1-year and 3-year future risk of moderate COPD exacerbations and developed a prediction tool for future exacerbations in COPD in the general population based on easily available clinical information. RESULTS: We observed 265 exacerbations in 2543 maintenance treatment naïve individuals with COPD and 197 exacerbations in 632 individuals with COPD on maintenance treatment. In the maintenance treatment naïve group, exacerbation history (hazard ratio (HR): 8.53), low FEV1 (HR: 4.82 for <30% predicted versus 50-79% predicted), and higher age (HR: 1.46 for ≥75 years versus <65 years) were significant predictors of future exacerbations. In the group on maintenance treatment, male sex and mMRC ≥2 also predicted higher risk with borderline significance. CONCLUSIONS: In addition to exacerbation history also higher age and lower FEV1 predict future exacerbation risk in COPD in the general population.

Type-2 inflammation and lung function decline in chronic airway disease in the general population.

BACKGROUND: It is unclear if type-2 inflammation is associated with accelerated lung function decline in individuals with asthma and chronic obstructive pulmonary disease (COPD). We tested the hypothesis that type-2 inflammation indicated by elevated blood eosinophils (BE) and fraction of exhaled nitric oxide (FeNO) is associated with accelerated lung function decline in the general population. METHODS: We included adults from the Copenhagen General Population Study with measurements of BE (N=15 605) and FeNO (N=2583) from a follow-up examination and assessed forced expiratory volume in 1 s (FEV1) decline in the preceding 10 years. Based on pre- and post-bronchodilator lung function, smoking history and asthma at follow-up examination, participants were assigned as not having airway disease, asthma with full reversibility (AR), asthma with persistent obstruction (APO), COPD, and not classifiable airflow limitation (NAL). RESULTS: FEV1 decline in mL/year increased with 1.0 (95% CI 0.6 to 1.4, p<0.0001) per 100 cells/µL higher BE and with 3.2 (95% CI 2.0 to 4.5, p<0.0001) per 10 ppb higher FeNO. Adjusted FEV1 decline in mL/year was 18 (95% CI 17 to 20) in those with BE<300 cells/µL and FeNO<20 ppb, 22 (19-25) in BE≥300 cells/µL or FeNO≥20 ppb, and 27 (21-33) in those with BE≥300 cells/µL and FeNO≥20 ppb (p for trend<0.0001). Corresponding FEV1 declines were 24 (19-29), 33 (25-40) and 44 (31-56) in AR (0.002), 26 (14-37), 36 (12-60) and 56 (24-89) in APO (0.07), 32 (27-36), 31 (24-38) and 44 (24-65) in COPD (0.46), and 27 (21-33), 35 (26-45), and 37 (25-49) in NAL (0.10), respectively. CONCLUSIONS: Type-2 inflammation indicated by elevated BE and FeNO is associated with accelerated FEV1 decline in individuals with chronic airway disease in the general population, and this association was most pronounced in an asthma-like phenotype.

COPD and Smoking Status - It Does Matter: Characteristics and Prognosis of COPD According to Smoking Status.

Background: Chronic obstructive pulmonary disease is a chronic, often progressive disease, which in most patients is caused by tobacco smoking. Our study focuses on differences in COPD-related outcomes between never smokers, former smokers, and current smokers. Methods: A nationwide, population-based cohort study utilizing Danish health registries. Clinical and socioeconomic variables including smoking status, comorbidities, and dyspnea were obtained. Poisson and Cox Regression were used to calculate the impact of these clinical parameters on the risk of moderate and severe exacerbations and mortality during 12 months of follow-up. Results: A total of 49,826 patients ≥40 years of age, with a hospital diagnosis of COPD in 2008-2017, were identified (mean age 69.2 years, 52% females). A total of 2127 (4%) were never smokers, 29,854 (60%) were former smokers and 17,845 (36%) current smokers. Compared to former and current smokers, never smokers reported a lower modified Medical Research Council score and had a milder COPD stage according to the Global Initiative for Chronic Obstructive Lung Disease classification. During follow-up, never smokers had a significantly lower risk of severe exacerbations (hazard ratio 0.87, 95% confidence interval [CI] 0.78-0.97) and a lower rate of death (mortality ratio 0.75, 95% CI 0.70-0.81) compared to patients with a smoking history. Discussion: Our nationwide study showed that COPD in never smokers is characterized by a lower level of dyspnea, milder lung function impairment, and a lower risk of exacerbations and death. At the same time, we found active smokers to have the highest risk. These findings highlight the need for campaigns to prevent smoking and may help general practitioners as well as other health care professionals to motivate patients with COPD to stop smoking.

Lessons learnt in the first year of an Australian pediatric cardio oncology clinic.

BACKGROUND: Modern oncological therapies together with chemotherapy and radiotherapy have broadened the agents that can cause cardiac sequelae, which can manifest for pediatric oncology patients while on active treatment. Recommendations for high-risk patients who should be monitored in a pediatric cardio-oncology clinic have previously been developed by expert Delphi consensus by our group. In 2022 we opened our first multidisciplinary pediatric cardio-oncology clinic adhering to these recommendations in surveillance and management. OBJECTIVES: Our pediatric cardio-oncology clinic aimed to: (i) Document cardiovascular toxicities observed within a pediatric cardio-oncology clinic and. (ii) Evaluate the applicability of the Australian and New Zealand Pediatric Cardio-Oncology recommendations. METHODS: Monthly multidisciplinary cardio-oncology clinics were conducted in an Australian tertiary pediatric hospital. Structured standardised approaches to assessment were built into the electronic medical record (EMR). All patients underwent baseline echocardiogram and electrocardiogram assessment together with vital signs in conjunction with standard history and examination. RESULTS: Nineteen (54%) individuals had a documented cardiovascular toxicity or pre-existing risk factor prior to referral. The two most common cardiovascular toxicities documented during clinic review included Left Ventricular Dysfunction (LVD) and hypertension. Of note 3 (8.1%) patients had CTCAE grade III LVD. An additional 10 (27%) patients reviewed in clinic had CTCAE grade I hypertension. None of these patients had hypertension noted within their referral. Cascade testing for cardiac history was warranted in 2 (5.4%) of patients. CONCLUSIONS: Pediatric cardio-oncology clinics are likely beneficial to documenting previously unrecognised cardiotoxicity and relevant cardiac family histories, whilst providing an opportunity to address lifestyle risk factors.

Impact of the metabolic syndrome on cardiopulmonary morbidity and mortality in individuals with lung function impairment: a prospective cohort study of the Danish general population.

Background: Whether the metabolic syndrome plays a role for the prognosis of individuals with lung function impairment (preserved ratio impaired spirometry (PRISm) or airflow limitation) is unclear. We hypothesised that the metabolic syndrome in individuals with lung function impairment is associated with increased cardiopulmonary morbidity and mortality. Methods: The Copenhagen General Population Study was initiated in 2003 based on a random sample of white men and women aged 20-100 years drawn from the Danish general population. The risk of ischemic heart disease/heart failure, respiratory disease, and all-cause mortality was analysed with Cox models adjusted for age, sex, current smoking, and asthma during 15 years of follow-up. Findings: Among 106,845 adults, 86,159 had normal lung function, 6126 had PRISm, and 14,560 had airflow limitation. We observed 10,448 hospital admissions for ischemic heart disease/heart failure, 21,140 for respiratory disease, and 11,125 deaths. Individuals with versus individuals without the metabolic syndrome generally had higher 5-year absolute risk of all outcomes, including within those with normal lung function, mild-moderate-severe PRISm, and very mild-mild-moderate-severe airflow limitation alike. Compared to individuals without the metabolic syndrome and with normal lung function, those with both the metabolic syndrome and severe PRISm had hazard ratios of 3.74 (95% CI: 2.53-5.55; p < 0.0001) for ischemic heart disease/heart failure, 5.02 (3.85-6.55; p < 0.0001) for respiratory disease, and 5.32 (3.76-7.54; p < 0.0001) for all-cause mortality. Corresponding hazard ratios in those with both the metabolic syndrome and severe airflow limitation were 2.89 (2.34-3.58; p < 0.0001) for ischemic heart disease/heart failure, 5.98 (5.28-6.78; p < 0.0001) for respiratory disease, and 4.16 (3.50-4.95; p < 0.0001) for all-cause mortality, respectively. The metabolic syndrome explained 13% and 27% of the influence of PRISm or airflow limitation on ischemic heart disease/heart failure and all-cause mortality. Interpretation: The metabolic syndrome conferred increased risk of cardiopulmonary morbidity and mortality at all levels of lung function impairment. Funding: Danish Lung Foundation, Danish Heart Foundation, Capital Region of Copenhagen, and Boehringer Ingelheim. JV is supported by the NIHR Manchester BRC.

Serological testing for syphilis in the differential diagnosis of cognitive decline and polyneuropathy in geriatric patients.

BACKGROUND: In the 19th century, neurosyphilis was the most frequent cause of dementia in Western Europe. Now dementia caused by syphilis has become rare in Germany. We studied whether routine testing of patients with cognitive abnormalities or neuropathy for antibodies against Treponema pallidum has therapeutic consequences in geriatric patients. METHODS: A Treponema pallidum electrochemiluminescence immunoassay (TP-ECLIA) is routinely performed in all in-patients treated at our institution with cognitve decline or neuropathy and no or insufficient previous diagnostic workup. Patients with a positive TP-ECLIA treated from October 2015 to January 2022 (76 months) were retrospectively evaluated. In cases of positive TP-ECLIA, further specific laboratory investigations were performed to assess whether antibiotic therapy was indicated. RESULTS: In 42 of 4116 patients (1.0%), TP-ECLIA detected antibodies directed against Treponema in serum. Specifity of these antibodies was ensured by immunoblot in 22 patients (11 × positiv, 11 × borderline values). Treponema-specific IgM was detectable in the serum of one patient, in 3 patients the Rapid Plasma Reagin (RPR) test, a modified Venereal Disease Research Laboratory test (VDRL), in serum was positiv. CSF analysis was performed in 10 patients. One patient had CSF pleocytosis. In 2 other patients, the Treponema-specific IgG antibody index was elevated. 5 patients received antibiotic therapy (4 × ceftriaxone 2 g/d i.v., 1 × doxycycline 300 mg/d p.o.). CONCLUSION: In approx. 1‰ of patients with previously undiagnosed or not sufficiently diagnosed cognitive decline or neuropathy, the diagnostic workup for active syphilis resulted in a course of antibiotic treatment.

Exacerbations Predict Severe Cardiovascular Events in Patients with COPD and Stable Cardiovascular Disease-A Nationwide, Population-Based Cohort Study.

Objective: Patients with chronic obstructive pulmonary disease (COPD) commonly present with cardiovascular disease (CVD). We investigated the association between COPD exacerbations and major cardiovascular (CV) events in a COPD population with a history of CVD. Methods: This population-based and register-based cohort study identified all Danish COPD patients aged ≥40 years who visited a hospital-based, pulmonary outpatient clinic for COPD between 1st January, 2010, and 31st December, 2016, from a nationwide COPD registry. Patients with a history of a major CV event 36‒6 months prior to their COPD measurement date and no CV event 6 months before this date were included. During a 6-month assessment period, the risks of a new CV event (hospitalization with fatal/non-fatal stroke, myocardial infarction, or heart failure) and moderate and severe COPD exacerbations were evaluated. Odds ratios with 95% confidence intervals for CV events and death were estimated using adjusted logistic regression models. Results: Of the 1501 COPD patients included, 55% experienced a COPD exacerbation and 13% experienced both an exacerbation and a CV event during follow-up (6 months). The odds of a CV event were 1.5 times higher in patients with a moderate exacerbation and more than 6-times higher in those with a severe exacerbation vs patients with no exacerbation(s). The majority of CV events occurred within 30 days post exacerbation in patients who experienced both an exacerbation and a CV event. In total, 113 patients died during the study period: 28% of deaths were caused by CVD and 72% by reasons other than CVD, mostly COPD. Conclusion: In patients with known CVD, severe COPD exacerbations are associated with increased odds of major CV events that occur within 30 days post exacerbation, highlighting the need to prevent exacerbations in COPD patients with concomitant CVD to potentially improve both respiratory and CV health.

Internal Transcribed Spacer and 16S Amplicon Sequencing Identifies Microbial Species Associated with Asbestos in New Zealand.

Inhalation of asbestos fibres can cause lung inflammation and the later development of asbestosis, lung cancer, and mesothelioma, and the use of asbestos is banned in many countries. In most countries, large amounts of asbestos exists within building stock, buried in landfills, and in contaminated soil. Mechanical, thermal, and chemical treatment options do exist, but these are expensive, and they are not effective for contaminated soil, where only small numbers of asbestos fibres may be present in a large volume of soil. Research has been underway for the last 20 years into the potential use of microbial action to remove iron and other metal cations from the surface of asbestos fibres to reduce their toxicity. To access sufficient iron for metabolism, many bacteria and fungi produce organic acids, or iron-chelating siderophores, and in a growing number of experiments these have been found to degrade asbestos fibres in vitro. This paper uses the internal transcribed spacer (ITS) and 16S amplicon sequencing to investigate the fungal and bacterial diversity found on naturally-occurring asbestos minerals, asbestos-containing building materials, and asbestos-contaminated soils with a view to later selectively culturing promising species, screening them for siderophore production, and testing them with asbestos fibres in vitro. After filtering, 895 ITS and 1265 16S amplicon sequencing variants (ASVs) were detected across the 38 samples, corresponding to a range of fungal, bacteria, cyanobacterial, and lichenized fungal species. Samples from Auckland (North Island, New Zealand) asbestos cement, Auckland asbestos-contaminated soils, and raw asbestos rocks from Kahurangi National Park (South Island, New Zealand) were comprised of very different microbial communities. Five of the fungal species detected in this study are known to produce siderophores.

Mortality Risk and Serious Cardiopulmonary Events in Moderate-to-Severe COPD: Post Hoc Analysis of the IMPACT Trial.

Background: In the InforMing the Pathway of COPD Treatment (IMPACT) trial, single-inhaler fluticasone furoate (FF) /umeclidinium (UMEC) /vilanterol (VI) significantly reduced severe exacerbation rates and all-cause mortality (ACM) risk versus UMEC/VI among patients with chronic obstructive pulmonary disease (COPD). This post hoc analysis aimed to define the risk of ACM during and following a moderate/severe exacerbation, and further determine the benefit-risk profile of FF/UMEC/VI versus FF/VI and UMEC/VI using a cardiopulmonary composite adverse event (AE) endpoint. Methods: The 52-week, double-blind IMPACT trial randomized patients with symptomatic COPD and ≥1 exacerbation in the prior year 2:2:1 to once-daily FF/UMEC/VI 100/62.5/25mcg, FF/VI 100/25mcg, or UMEC/VI 62.5/25mcg. Post hoc endpoints included the risk of ACM during, 1-90 and 91-365 days post moderate or severe exacerbation and time-to-first cardiopulmonary composite event. Results: Of the 10,355 patients included, 5034 (49%) experienced moderate/severe exacerbations. Risk of ACM was significantly increased during a severe exacerbation event compared with baseline (hazard ratio [HR]: 41.22 [95% confidence interval (CI) 26.49-64.15]; p<0.001) but not significantly different at 1-90 days post-severe exacerbation (HR: 2.13 [95% CI: 0.86-5.29]; p=0.102). Moderate exacerbations did not significantly increase the risk of ACM during or after an exacerbation. Cardiopulmonary composite events occurred in 647 (16%), 636 (15%), and 356 (17%) patients receiving FF/UMEC/VI, FF/VI, and UMEC/VI, respectively; FF/UMEC/VI significantly reduced cardiopulmonary composite event risk versus UMEC/VI by 16.5% (95% CI: 5.0-26.7; p=0.006). Conclusion: Results confirm a substantial mortality risk during severe exacerbations, and an underlying CV risk. FF/UMEC/VI significantly reduced the risk of a composite cardiopulmonary AE versus UMEC/VI.

Single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol versus dual therapy in current and former smokers with COPD: IMPACT trial post hoc analysis.

BACKGROUND: Smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). In IMPACT, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy significantly reduced moderate/severe exacerbation rates and improved lung function and health status versus FF/VI or UMEC/VI in COPD patients. This post hoc analysis investigated trial outcomes by smoking status. METHODS: IMPACT was a double-blind, 52-week trial. Patients aged ≥40 years with symptomatic COPD and ≥1 moderate/severe exacerbation in the prior year were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 µg, FF/VI 100/25 µg, or UMEC/VI 62.5/25 µg. Endpoints assessed by smoking status at screening included rate and risk of moderate/severe exacerbations, change from baseline in trough forced expiratory volume in 1 s, and St George's Respiratory Questionnaire total score at Week 52. Safety was also assessed. RESULTS: Of the 10,355 patients in the intent-to-treat population, 3,587 (35%) were current smokers. FF/UMEC/VI significantly reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in current (rate ratio 0.85 [95% confidence interval: 0.77-0.95]; P = 0.003 and 0.86 [0.76-0.98]; P = 0.021) and former smokers (0.85 [0.78-0.91]; P < 0.001 and 0.70 [0.64-0.77]; P < 0.001). FF/UMEC/VI significantly reduced time-to-first on-treatment moderate/severe exacerbation versus FF/VI and UMEC/VI in former smokers, and versus FF/VI in current smokers. Similar trends were seen for lung function and health status. Former smokers receiving inhaled corticosteroid-containing therapy had higher pneumonia incidence than current smokers. CONCLUSIONS: FF/UMEC/VI improved clinical outcomes versus dual therapy regardless of smoking status. Benefits of FF/UMEC/VI versus UMEC/VI were greatest in former smokers, potentially due to relative corticosteroid resistance in current smokers. CLINICAL TRIAL REGISTRATION: GSK (CTT116855/NCT02164513).

'A Missed Therapeutic Opportunity? SGLT-2 Inhibitor Use in General Medicine Patients With Heart Failure: A Retrospective Audit of Admissions to a Tertiary Health Service'.

Objective: Sodium-glucose co-transporter-2 inhibitors (SGLT2-I's) are novel oral hypoglycaemic agents, with proven decreased MACE and re-hospitalisation risk in type 2 diabetic patients with concomitant heart failure. This study aimed to assess the current practice in the use of SGLT2-I's in general medical units at a large metropolitan health service. Methods/Results: A retrospective audit was conducted of patients admitted to general medicine over a 12 month period (between April 2018 and 2019). Inclusion criteria included decompensated heart failure of any aetiology and ejection fraction, and type 2 diabetes mellitus with an HbA1c ⩾ 7 within 6 months of the admission period. A total of 150 admissions fulfilled criteria. Baseline demographics and comorbidities identified an older, more comorbid population than reference trials. These included age (75% over 75 years), smoking history (46%), hypertension (83%), chronic kidney disease grade IV or V (26%), previous myocardial infarction (57%), stroke (18%), atrial fibrillation (55%) and known left ventricular ejection fraction < 50% (38%). Co-prescribed medications included ACE-I/ARB (53%), beta-blocker (67%), loop diuretic (87%), thiazide (7%), MRA (31%), insulin (57%), metformin (47%), sulphonylurea (31%), DPP-4 Inhibitor (21%), GLP-1 analogue (6%) and 15% of patients had an HbA1c > 10. There was a significant difference between patients in our study eligible for and prescribed metformin (66/111) compared to SGLT-2 inhibitors (4/25) (P = .013). A total of 26 patients had readmissions within 28 days, of which one had been discharged on an SGLT2-I. Conclusion: The results of this study identified significant under prescribing of SGLT2-I's in eligible type 2 diabetic patients with heart failure admitted under general medicine.

Small and long RNA transcriptome of whole human cerebrospinal fluid and serum as compared to their extracellular vesicle fractions reveal profound differences in expression patterns and impacts on biological processes.

BACKGROUND: Next generation sequencing (NGS) of human specimen is expected to improve prognosis and diagnosis of human diseases, but its sensitivity urges for well-defined sampling and standardized protocols in order to avoid error-prone conclusions. METHODS: In this study, large volumes of pooled human cerebrospinal fluid (CSF) were used to prepare RNA from human CSF-derived extracellular vesicles (EV) and from whole CSF, as well as from whole human serum and serum-derived EV. In all four fractions small and long coding and non-coding RNA expression was analyzed with NGS and transcriptome analyses. RESULTS: We show, that the source of sampling has a large impact on the acquired NGS pattern, and differences between small RNA fractions are more distinct than differences between long RNA fractions. The highest percentual discrepancy between small RNA fractions and the second highest difference between long RNA fractions is seen in the comparison of CSF-derived EV and whole CSF. Differences between miR (microRNA) and mRNA fractions of EV and the respective whole body fluid have the potential to affect different cellular and biological processes. I.e. a comparison of miR in both CSF fractions reveals that miR from EV target four transcripts sets involved in neurobiological processes, whereas eight others, also involved in neurobiological processes are targeted by miR found in whole CSF only. Likewise, three mRNAs sets derived from CSF-derived EV are associated with neurobiological and six sets with mitochondrial metabolism, whereas no such mRNA transcript sets are found in the whole CSF fraction. We show that trace amounts of blood-derived contaminations of CSF can bias RNA-based CSF diagnostics. CONCLUSIONS: This study shows that the composition of small and long RNA differ significantly between whole body fluid and its respective EV fraction and thus can affect different cellular and molecular functions. Trace amounts of blood-derived contaminations of CSF can bias CSF analysis. This has to be considered for a meaningful RNA-based diagnostics. Our data imply a transport of EV from serum to CSF across the blood-brain barrier.

Time-Dependent Risk of Cardiovascular Events Following an Exacerbation in Patients With Chronic Obstructive Pulmonary Disease: Post Hoc Analysis From the IMPACT Trial.

Background The association between chronic obstructive pulmonary disease exacerbations and increased cardiovascular event risk has not been adequately studied in a heterogenous population with both low and high cardiovascular risk. Methods and Results This post hoc analysis of the IMPACT (Informing the Pathway of COPD Treatment) trial (N=10 355 symptomatic patients with chronic obstructive pulmonary disease at risk of exacerbations) evaluated time-dependent risk of cardiovascular adverse events of special interest (CVAESI) following exacerbations and impact of exacerbation history, cardiovascular risk factors, and study treatment on this association. Risk (time-to-first) of CVAESI or CVAESI resulting in hospitalization or death was assessed during and 1 to 30, 31 to 90, and 91 to 365 days after resolution of moderate or severe exacerbations. CVAESI risk was compared between the period before and during/after exacerbation. CVAESI risk increased significantly during a moderate (hazard ratio [HR], 2.63 [95% CI, 2.08-3.32]) or severe (HR, 21.84 [95% CI, 17.71-26.93]) exacerbation and remained elevated for 30 days following an exacerbation (moderate: HR, 1.63 [95% CI, 1.28-2.08]; severe: HR, 1.75 [95% CI, 0.99-3.11; nonsignificant]) and decreased over time, returning to baseline by 90 days. Risk of CVAESI resulting in hospitalization or death also increased during an exacerbation (moderate: HR, 2.46 [95% CI, 1.53-3.97]; severe: HR, 41.29 [95% CI, 30.43-56.03]) and decreased in a similar time-dependent pattern. Results were consistent regardless of exacerbation history, cardiovascular risk at screening, or study treatment. Conclusions Overall risk of cardiovascular events was higher during and in the 30 days following chronic obstructive pulmonary disease exacerbations, even among those with low cardiovascular risk, highlighting the need for exacerbation prevention and vigilance for cardiovascular events following exacerbations. Registration URL: https://clinicaltrials.gov/ct2/show/NCT02164513; Unique identifier: NCT02164513.

Spatial and temporal variation of routine parameters: pitfalls in the cerebrospinal fluid analysis in central nervous system infections.

The cerebrospinal fluid (CSF) space is convoluted. CSF flow oscillates with a net flow from the ventricles towards the cerebral and spinal subarachnoid space. This flow is influenced by heartbeats, breath, head or body movements as well as the activity of the ciliated epithelium of the plexus and ventricular ependyma. The shape of the CSF space and the CSF flow preclude rapid equilibration of cells, proteins and smaller compounds between the different parts of the compartment. In this review including reinterpretation of previously published data we illustrate, how anatomical and (patho)physiological conditions can influence routine CSF analysis. Equilibration of the components of the CSF depends on the size of the molecule or particle, e.g., lactate is distributed in the CSF more homogeneously than proteins or cells. The concentrations of blood-derived compounds usually increase from the ventricles to the lumbar CSF space, whereas the concentrations of brain-derived compounds usually decrease. Under special conditions, in particular when distribution is impaired, the rostro-caudal gradient of blood-derived compounds can be reversed. In the last century, several researchers attempted to define typical CSF findings for the diagnosis of several inflammatory diseases based on routine parameters. Because of the high spatial and temporal variations, findings considered typical of certain CNS diseases often are absent in parts of or even in the entire CSF compartment. In CNS infections, identification of the pathogen by culture, antigen detection or molecular methods is essential for diagnosis.

Plasma immunoglobulin E and risk of exacerbation and mortality in chronic obstructive pulmonary disease: A contemporary population-based cohort.

BACKGROUND: Novel biomarkers and targeted treatments are needed for patients with chronic obstructive pulmonary disease (COPD). OBJECTIVE: To test the hypothesis that high plasma immunoglobulin (Ig)E concentrations associate with increased risk of exacerbation and mortality in individuals with COPD in the general population. METHODS: Among 46,598 adults in the Copenhagen General Population Study, we included 1559 with COPD, defined as forced expiratory volume in 1 second/forced vital capacity < 0.70 and forced expiratory volume in 1 second < 80% predicted in individuals aged ≥ 40 years with chronic respiratory symptoms and smoking exposure ≥ 10 pack-years, and without asthma. We assessed risk of future severe exacerbation and all-cause mortality according to baseline plasma IgE ≥ 76 IU/mL, a clinical cutoff for omalizumab treatment in severe asthma. RESULTS: During 14 years of follow-up (median, 6.9; interquartile range, 3.4), we recorded 224 severe exacerbations and 434 deaths in 1559 individuals with COPD. Individuals with COPD with IgE ≥ 76 IU/mL vs those with < 76 IU/mL had a multivariable adjusted hazard ratio (HR) of 1.43 (95% confidence interval, 1.07-1.89) for severe exacerbation and 1.30 (1.05-1.62) for all-cause mortality. Compared with individuals with IgE < 76 IU/mL and blood eosinophils < 300 cells/µL, the multivariable adjusted HR for severe exacerbation was 1.12 (0.76-1.67) for those with IgE < 76 IU/mL and blood eosinophils ≥ 300 cells/µL, 1.62 (1.17-2.24) for IgE ≥ 76 IU/mL and blood eosinophils < 300 cells/µL, and 1.06 (0.63-1.77) for those with IgE ≥ 76 IU/mL and blood eosinophils ≥ 300 cells/µL. Corresponding HRs for all-cause mortality were 1.27 (0.99-1.63), 1.47 (1.14-1.88), and 1.17 (0.83-1.64), respectively. CONCLUSION: High plasma IgE was associated with an increased risk of severe exacerbation and all-cause mortality in individuals with COPD in the general population, independent of blood eosinophils.

Prognosis of Patients with Chronic Obstructive Pulmonary Disease Not Eligible for Major Clinical Trials.

Rationale: Randomized controlled trials only include a subset of patients with chronic obstructive pulmonary disease (COPD) fulfilling strict inclusion criteria. Thus, most patients with COPD in a real-world setting do not have the necessary evidence to support treatment effectiveness. Objectives: To test the hypotheses that most individuals with COPD in the general population are not represented in major clinical trials despite clinically significant disease with exacerbations and early death. Methods: In 105,630 adults from a Danish contemporary population-based cohort, we defined COPD as age 40 or more years, chronic respiratory symptoms, history of smoking exposure, and airflow limitation with FEV1/FVC < 0.70. Outcomes included acute exacerbations and all-cause mortality. Symptomatic smokers without COPD were used as a reference group. Measurements and Main Results: Of all, 7,516 (7%) and 16,079 (15%) were symptomatic smokers with and without COPD. Only 44% of those with COPD were eligible for major clinical trials when applying FEV1 < 80% predicted, smoking history of 10 or more pack-years, and no comorbid asthma as common inclusion criteria. During the median 8.9 years of follow-up, we observed 2,130 acute exacerbations and 3,973 deaths in symptomatic smokers. Compared with symptomatic smokers without COPD, multivariable-adjusted hazard ratios for exacerbations were 7.45 (95% confidence interval, 5.41-10.3) and 29.0 (21.1-39.8) in those with COPD, respectively, excluded and eligible for clinical trials. Corresponding hazard ratios for all-cause mortality were 1.21 (1.11-1.31) and 1.67 (1.54-1.81), respectively. Conclusions: More than half of individuals with COPD in the general population are excluded from major clinical trials; however, these individuals have a clinically significant disease with exacerbations and early death compared with symptomatic smokers without COPD.