Cardiovascular risk scoring and magnetic resonance imaging detected subclinical cerebrovascular disease

AIMS: Cardiovascular risk factors are used for risk stratification in primary prevention. We sought to determine if simple cardiac risk scores are associated with magnetic resonance imaging (MRI)-detected subclinical cerebrovascular disease including carotid wall volume (CWV), carotid intraplaque haemorrhage (IPH), and silent brain infarction (SBI). METHODS AND RESULTS: A total of 7594 adults with no history of cardiovascular disease (CVD) underwent risk factor assessment and a non-contrast enhanced MRI of the carotid arteries and brain using a standardized protocol in a population-based cohort recruited between 2014 and 2018. The non-lab-based INTERHEART risk score (IHRS) was calculated in all participants; the Framingham Risk Score was calculated in a subset who provided blood samples (n = 3889). The association between these risk scores and MRI measures of CWV, carotid IPH, and SBI was determined. The mean age of the cohort was 58 (8.9) years, 55% were women. Each 5-point increase (∼1 SD) in the IHRS was associated with a 9 mm3 increase in CWV, adjusted for sex (P \u3c 0.0001), a 23% increase in IPH [95% confidence interval (CI) 9-38%], and a 32% (95% CI 20-45%) increase in SBI. These associations were consistent for lacunar and non-lacunar brain infarction. The Framingham Risk Score was also significantly associated with CWV, IPH, and SBI. CWV was additive and independent to the risk scores in its association with IPH and SBI. CONCLUSION: Simple cardiovascular risk scores are significantly associated with the presence of MRI-detected subclinical cerebrovascular disease, including CWV, IPH, and SBI in an adult population without known clinical CVD

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Analysis of Volatile Biomarkers of Airway Inflammation in Breath

Breath analysis is non-invasive and acceptable to patients, and is an attractive method for the diagnosis and monitoring of airway inflammation in asthma and COPD. The measurement of the fraction of nitric oxide in exhaled breath (FENO) already has clinical applications because of its association with eosinophilic airway inflammation and the clinical response to corticosteroid, but its role has not been defined in COPD. There may also be other volatile biomarkers of airway inflammation in breath, such as hydrogen sulphide (H2S) and hydrogen cyanide (HCN). These compounds can be analysed in breath using selected ion flow tube–mass spectrometry (SIFT-MS). A study was performed to establish whether FENO levels could predict the clinical response to oral corticosteroid in COPD. A double-blind, crossover ―trial of steroid‖ was undertaken in 65 randomised patients with COPD. The predictive values of FENO for clinically significant changes in six-minute walking distance (6MWD), spirometry (FEV1), and St. George's Respiratory Questionnaire (SGRQ) were calculated. Receiver operator characteristic analysis showed the area under the curve for an increase of 0.2 litres in FEV1 was 0.69 (p=0.04) with an optimum FENO cut point of 50ppb. FENO was not a significant predictor for changes in 6MWD or SGRQ. Experiments were performed to characterise the accuracy, repeatability and dynamic response of the SIFT-MS instrument using acetone as a model volatile compound. Similar experiments were then performed using H2S and HCN. Using a SIFT-MS instrument synchronised with a pneumotachometer, the effects of expiratory flow and volume, and oral vs. nasal passage, on the concentration of a volatile compound in breath were investigated. Using known in vitro acetone concentrations of 600-3000 ppb, there was an instrument measurement bias of 8%, inter-day and intra-day CVs were 5.6% and 0.0% respectively, and the 10-90% response time was 500±50 ms (mean±SE). In 12 healthy volunteers, acetone concentrations at expiratory flows of 193±18 (mean±SD) and 313±32 ml/s were 619±1.83 (geometric mean ± logSD) and 618±1.82 ppb in the fraction 70-85% by volume of exhaled vital capacity (V70-85%), and 636±1.82 and 631±1.83 ppb in V85-100%. For H2S, the mean percentage deviation of SIFT-MS measurements from known concentrations was -12 to -13%. Inter-day and intra-day CVs were 13-22% and 15-25% respectively, and the 10-90% response time was 500±60 ms (mean±SE). For HCN, the mean percentage deviations of SIFT-MS measurements from the known concentrations were -3% to +11%. Inter-day and intra-day CVs were 9-12% and 4-6% respectively, and the dynamic response time was 620±50 ms (mean±SE). Higher concentrations of H2S and HCN were observed in oral vs. nasal exhalations, and the exhaled H2S concentration fell from rapidly after hydrogen peroxide mouthwash. The final experiment compared the concentrations of exhaled H2S and HCN in asthma and COPD patients with control subjects, and determined any relationship between these volatile compounds and biomarkers of airway inflammation. There was no difference in post-mouthwash, nasally-exhaled H2S concentration in six COPD patients vs. six control subjects (2.2±0.4 vs. 2.3±0.3 ppb (mean ± SE)) or in six asthma patients vs. six control subjects (2.1±0.2 vs. 2.2±0.2 ppb). There was no difference in nasally-exhaled HCN concentration in the COPD vs. control groups (3.4±0.3 vs. 3.1±0.4 ppb) or the asthma vs. control groups (4.8±0.4 vs. 4.4±0.8 ppb). In the COPD group, there was a negative correlation between the exhaled H2S concentration and the percentage of neutrophils in sputum (rs=-0.89, p=0.02), while in the control group, a positive correlation between the exhaled H2S concentration and the percentage of neutrophils in sputum approached significance (rs=0.77, p=0.07). The exhaled HCN concentration was negatively correlated with sputum neutrophils in COPD patients (rs=-0.49 to -0.66, p=0.16 to 0.33). Positive correlations were observed between markers of eosinophilic airway inflammation in asthma patients and the concentrations of both H2S (rs=0.6-1.0, p=<0.05 to 0.21) and HCN (rs=0.6-0.8, p=0.16-0.20) in exhaled breath. In conclusion, FENO was a weak predictor of short-term response to oral corticosteroid in COPD, its utility being limited to predicting increase in FEV1. The characteristics of the SIFT-MS analytical technique were appropriate for the on-line analysis of acetone, H2S and HCN, in exhaled breath. On-line SIFT-MS measurement of exhaled acetone concentration required control of expiratory volume but not flow. On-line SIFT-MS measurement of exhaled H2S and HCN concentration required nasal exhalation. While the concentrations of H2S and HCN in exhaled breath did not differ between patient groups and their controls, there were associations between markers of airway inflammation and the concentrations of H2S and HCN in exhaled breath that are worthy of further exploration

Analysis of Volatile Biomarkers of Airway Inflammation in Breath

Breath analysis is non-invasive and acceptable to patients, and is an attractive method for the diagnosis and monitoring of airway inflammation in asthma and COPD. The measurement of the fraction of nitric oxide in exhaled breath (FENO) already has clinical applications because of its association with eosinophilic airway inflammation and the clinical response to corticosteroid, but its role has not been defined in COPD. There may also be other volatile biomarkers of airway inflammation in breath, such as hydrogen sulphide (H2S) and hydrogen cyanide (HCN). These compounds can be analysed in breath using selected ion flow tube–mass spectrometry (SIFT-MS). A study was performed to establish whether FENO levels could predict the clinical response to oral corticosteroid in COPD. A double-blind, crossover ―trial of steroid‖ was undertaken in 65 randomised patients with COPD. The predictive values of FENO for clinically significant changes in six-minute walking distance (6MWD), spirometry (FEV1), and St. George's Respiratory Questionnaire (SGRQ) were calculated. Receiver operator characteristic analysis showed the area under the curve for an increase of 0.2 litres in FEV1 was 0.69 (p=0.04) with an optimum FENO cut point of 50ppb. FENO was not a significant predictor for changes in 6MWD or SGRQ. Experiments were performed to characterise the accuracy, repeatability and dynamic response of the SIFT-MS instrument using acetone as a model volatile compound. Similar experiments were then performed using H2S and HCN. Using a SIFT-MS instrument synchronised with a pneumotachometer, the effects of expiratory flow and volume, and oral vs. nasal passage, on the concentration of a volatile compound in breath were investigated. Using known in vitro acetone concentrations of 600-3000 ppb, there was an instrument measurement bias of 8%, inter-day and intra-day CVs were 5.6% and 0.0% respectively, and the 10-90% response time was 500±50 ms (mean±SE). In 12 healthy volunteers, acetone concentrations at expiratory flows of 193±18 (mean±SD) and 313±32 ml/s were 619±1.83 (geometric mean ± logSD) and 618±1.82 ppb in the fraction 70-85% by volume of exhaled vital capacity (V70-85%), and 636±1.82 and 631±1.83 ppb in V85-100%. For H2S, the mean percentage deviation of SIFT-MS measurements from known concentrations was -12 to -13%. Inter-day and intra-day CVs were 13-22% and 15-25% respectively, and the 10-90% response time was 500±60 ms (mean±SE). For HCN, the mean percentage deviations of SIFT-MS measurements from the known concentrations were -3% to +11%. Inter-day and intra-day CVs were 9-12% and 4-6% respectively, and the dynamic response time was 620±50 ms (mean±SE). Higher concentrations of H2S and HCN were observed in oral vs. nasal exhalations, and the exhaled H2S concentration fell from rapidly after hydrogen peroxide mouthwash. The final experiment compared the concentrations of exhaled H2S and HCN in asthma and COPD patients with control subjects, and determined any relationship between these volatile compounds and biomarkers of airway inflammation. There was no difference in post-mouthwash, nasally-exhaled H2S concentration in six COPD patients vs. six control subjects (2.2±0.4 vs. 2.3±0.3 ppb (mean ± SE)) or in six asthma patients vs. six control subjects (2.1±0.2 vs. 2.2±0.2 ppb). There was no difference in nasally-exhaled HCN concentration in the COPD vs. control groups (3.4±0.3 vs. 3.1±0.4 ppb) or the asthma vs. control groups (4.8±0.4 vs. 4.4±0.8 ppb). In the COPD group, there was a negative correlation between the exhaled H2S concentration and the percentage of neutrophils in sputum (rs=-0.89, p=0.02), while in the control group, a positive correlation between the exhaled H2S concentration and the percentage of neutrophils in sputum approached significance (rs=0.77, p=0.07). The exhaled HCN concentration was negatively correlated with sputum neutrophils in COPD patients (rs=-0.49 to -0.66, p=0.16 to 0.33). Positive correlations were observed between markers of eosinophilic airway inflammation in asthma patients and the concentrations of both H2S (rs=0.6-1.0, p=<0.05 to 0.21) and HCN (rs=0.6-0.8, p=0.16-0.20) in exhaled breath. In conclusion, FENO was a weak predictor of short-term response to oral corticosteroid in COPD, its utility being limited to predicting increase in FEV1. The characteristics of the SIFT-MS analytical technique were appropriate for the on-line analysis of acetone, H2S and HCN, in exhaled breath. On-line SIFT-MS measurement of exhaled acetone concentration required control of expiratory volume but not flow. On-line SIFT-MS measurement of exhaled H2S and HCN concentration required nasal exhalation. While the concentrations of H2S and HCN in exhaled breath did not differ between patient groups and their controls, there were associations between markers of airway inflammation and the concentrations of H2S and HCN in exhaled breath that are worthy of further exploration

Effect of Inhaled β₂-Agonist on Exhaled Nitric Oxide in Chronic Obstructive Pulmonary Disease

<div><p>The fractional exhaled nitric oxide measured at an expiratory flow of 50mL/s (FE_NO50) is a marker of airway inflammation, and high levels are associated with greater response to steroid treatment. In asthma, FE_NO50 increases with bronchodilation and decreases with bronchoconstriction, the latter potentially causing an underestimate of the degree of airway inflammation when asthma worsens. It is unknown whether the same effect occurs in chronic obstructive lung disease (COPD). Likewise, it is not known whether changes in airway calibre in COPD patients alter flow-independent parameters describing pulmonary nitric oxide exchange, such as the maximal flux of nitric oxide (NO) from the proximal airway compartment (J’aw_NO) and the distal airway/alveolar concentration of NO (CA_NO). We recruited 24 patients with COPD and performed FE_NO analysis at multiple expiratory flows before and after treatment with inhaled β₂-agonist bronchodilator therapy. For the 21 patients analysed, FE_NO50 rose from 17.1 (1.4) ppb (geometric mean (geometric SD)) at baseline, to 19.3 (1.3) ppb after bronchodilator therapy, an increase of 2.2 ppb (95% CI, 0.7–3.6; <i>P</i> = 0.005). There were non-significant changes in flow-independent NO parameters. The change in FE_NO50 correlated positively with the change in J’aw_NO (<i>r</i>_<i>s</i> = 0.67, <i>P</i> < 0.001; <i>r</i>_<i>s</i> = 0.62, <i>P</i> = 0.002 before and after correction for axial back-diffusion respectively) following bronchodilation. Inhaled bronchodilator therapy can increase exhaled nitric oxide measurements in COPD. The standardisation of inhaled bronchodilator therapy before FE_NO analysis in COPD patients should therefore be considered in both research and clinical settings.</p></div

Fabrication and Thermo-Optical Properties of the MLS Composite Primary Reflector

The Microwave Limb Sounder (MLS) is a limb-sounding radiometer sensing emissions in the millimeter and sub-millimeter range. MLS will contribute to an understanding of atmospheric chemistry by assessing stratospheric and tropospheric ozone depletion, climate forcings and volcanic effects. The heart of the antenna is the primary reflector, constructed from graphite/cyanate composites in a facesheet/core construction. The reflector has an aperture of one square meter, a mass of 8.7 kilos and final figure accuracy of 4.37 microns rms. The surface is also modified to ensure RF reflectivity, prevent solar concentration and provide thermal balance to the spacecraft The surface is prepared by precision beadblasting, then coated with vapor deposited aluminum (VDA) and finally a layer of silicon suboxide (SiO(x)) to control the infrared emissivity. The resulting surface has a solar absorptance of 0.43 and an absorptance/emittance ratio of 1.3. BRDF analysis shows that 93% of the incident thermal energy is reflected outside a 10 degree angle of cone. For its mass and aperture, we believe this reflector to have the highest figure accuracy yet achieved in a composite antenna construction

Lifetime cannabis exposure and small airway function in a population-based cohort study

Background and objective The long-term effects of cannabis on small airway function remain unclear. We investigated associations between cannabis use and small airway function in a general population sample. Methods Cannabis use was ascertained at multiple ages from age 18 to 45 years and quantified as joint-years among 895 participants in the Dunedin Multidisciplinary Health and Development Study. Small airway function at ages 38 and 45 years was measured using impulse oscillometry (IOS) before and after inhalation of salbutamol. Analyses used multiple linear regression adjusting for tobacco use, body mass index and height. Longitudinal analyses of cannabis use between 38 and 45 years also adjusted for IOS at age 38 years. Results Associations between lifetime cannabis joint-years and IOS differed between men and women: in women, cannabis use was associated with pre-bronchodilator resistance at 5 Hz (R5) and 20 Hz (R20), reactance at 5 Hz, area of reactance and resonant frequency, and marginally associated with the difference between R5 and R20. Cannabis use was only statistically significantly associated with pre-bronchodilator resonant frequency in men. Cannabis use between the ages of 38 and 45 years was associated with a similar pattern of changes in IOS measures. After salbutamol, cannabis use was only statistically significantly associated with R5 and R20 among women and none of the IOS measures among men. Conclusions Cannabis use is associated with small airway dysfunction at age 45 years, indicating an increase in peripheral airway resistance and reactance. These associations were greater and mostly only statistically significant among women. Associations were weaker and mostly nonsignificant after bronchodilator use, suggesting that cannabis-induced changes in small airways may be at least partially reversible