Immune response modifiers in the treatment of asthma: A PRACTALL document of the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy and Clinical Immunology

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PLAUR polymorphisms and lung function in UK smokers

<p>Abstract</p> <p>Background</p> <p>We have previously identified Urokinase Plasminogen Activator Receptor (<it>PLAUR</it>) as an asthma susceptibility gene. In the current study we tested the hypothesis that <it>PLAUR </it>single nucleotide polymorphisms (SNPs) determine baseline lung function and contribute to the development of Chronic Obstructive Pulmonary Disease (COPD) in smokers.</p> <p>Methods</p> <p>25 <it>PLAUR </it>SNPs were genotyped in COPD subjects and individuals with smoking history (n = 992). Linear regression was used to determine the effects of polymorphism on baseline lung function (FEV₁, FEV₁/FVC) in all smokers. Genotype frequencies were compared in spirometry defined smoking controls (n = 176) versus COPD cases (n = 599) and COPD severity (GOLD stratification) using logistic regression.</p> <p>Results</p> <p>Five SNPs showed a significant association (p < 0.01) with baseline lung function; rs2302524(Lys220Arg) and rs2283628(intron 3) were associated with lower and higher FEV₁respectively. rs740587(-22346), rs11668247(-20040) and rs344779(-3666) in the 5'region were associated with increased FEV₁/FVC ratio. rs740587 was also protective for COPD susceptibility and rs11668247 was protective for COPD severity although no allele dose relationship was apparent. Interestingly, several of these associations were driven by male smokers not females.</p> <p>Conclusion</p> <p>This study provides tentative evidence that the asthma associated gene <it>PLAUR </it>also influences baseline lung function in smokers. However the case-control analyses do not support the conclusion that <it>PLAUR </it>is a major COPD susceptibility gene in smokers. PLAUR is a key serine protease receptor involved in the generation of plasmin and has been implicated in airway remodelling.</p

Measuring axial length of the eye from magnetic resonance brain imaging

BACKGROUND: Metrics derived from the human eye are increasingly used as biomarkers and endpoints in studies of cardiovascular, cerebrovascular and neurological disease. In this context, it is important to account for potential confounding that can arise from differences in ocular dimensions between individuals, for example, differences in globe size. METHODS: We measured axial length, a geometric parameter describing eye size from T(2)-weighted brain MRI scans using three different image analysis software packages (Mango, ITK and Carestream) and compared results to biometry measurements from a specialized ophthalmic instrument (IOLMaster 500) as the reference standard. RESULTS: Ninety-three healthy research participants of mean age 51.0 ± SD 5.4 years were analyzed. The level of agreement between the MRI-derived measurements and the reference standard was described by mean differences as follows, Mango − 0.8 mm; ITK − 0.5 mm; and Carestream − 0.1 mm (upper/lower 95% limits of agreement across the three tools ranged from 0.9 mm to − 2.6 mm). Inter-rater reproducibility was between − 0.03 mm and 0.45 mm (ICC 0.65 to 0.93). Intra-rater repeatability was between 0.0 mm and − 0.2 mm (ICC 0.90 to 0.95). CONCLUSIONS: We demonstrate that axial measurements of the eye derived from brain MRI are within 3.5% of the reference standard globe length of 24.1 mm. However, the limits of agreement could be considered clinically significant. Axial length of the eye obtained from MRI is not a replacement for the precision of biometry, but in the absence of biometry it could provide sufficient accuracy to act as a proxy. We recommend measuring eye axial length from MRI in studies that do not have biometry but use retinal imaging to study neurodegenerative changes so as to control for differing eye size across individuals. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12886-022-02289-y

Quantitative analysis of high-resolution computed tomography scans in severe asthma subphenotypes

BACKGROUND: Severe asthma is a heterogeneous condition. Airway remodelling is a feature of severe asthma and can be determined by the assessment of high-resolution computed tomography (HRCT) scans. The aim of this study was to assess whether airway remodelling is restricted to specific subphenotypes of severe asthma. METHODS: A retrospective analysis was performed of HRCT scans from subjects who had attended a single-centre severe asthma clinic between 2003 and 2008. The right upper lobe apical segmental bronchus (RB1) dimensions were measured and the clinical and sputum inflammatory characteristics associated with RB1 geometry were assessed by univariate and multivariate regression analyses. Longitudinal sputum data were available and were described as area under the time curve (AUC). Comparisons were made in RB1 geometry across subjects in four subphenotypes determined by cluster analysis, smokers and non-smokers, and subjects with and without persistent airflow obstruction. RESULTS: Ninety-nine subjects with severe asthma and 16 healthy controls were recruited. In the subjects with severe asthma the RB1 percentage wall area (%WA) was increased (p=0.009) and lumen area (LA)/body surface area (BSA) was decreased (p=0.008) compared with controls but was not different across the four subphenotypes. Airway geometry was not different between smokers and non-smokers and RB1 %WA was increased in those with persistent airflow obstruction. RB1 %WA in severe asthma was best associated with airflow limitation and persistent neutrophilic airway inflammation (model R(2)=0.27, p=0.001). CONCLUSIONS: Airway remodelling of proximal airways occurs in severe asthma and is associated with impaired lung function and neutrophilic airway inflammation

A Large Web-Based Observer Reliability Study of Early Ischaemic Signs on Computed Tomography. The Acute Cerebral CT Evaluation of Stroke Study (ACCESS)

BACKGROUND: Early signs of ischaemic stroke on computerised tomography (CT) scanning are subtle but CT is the most widely available diagnostic test for stroke. Scoring methods that code for the extent of brain ischaemia may improve stroke diagnosis and quantification of the impact of ischaemia. METHODOLOGY AND PRINCIPAL FINDINGS: We showed CT scans from patients with acute ischaemic stroke (n = 32, with different patient characteristics and ischaemia signs) to doctors in stroke-related specialties world-wide over the web. CT scans were shown twice, randomly and blindly. Observers entered their scan readings, including early ischaemic signs by three scoring methods, into the web database. We compared observers' scorings to a reference standard neuroradiologist using area under receiver operator characteristic curve (AUC) analysis, Cronbach's alpha and logistic regression to determine the effect of scales, patient, scan and observer variables on detection of early ischaemic changes. Amongst 258 readers representing 33 nationalities and six specialties, the AUCs comparing readers with the reference standard detection of ischaemic signs were similar for all scales and both occasions. Being a neuroradiologist, slower scan reading, more pronounced ischaemic signs and later time to CT all improved detection of early ischaemic signs and agreement on the rating scales. Scan quality, stroke severity and number of years of training did not affect agreement. CONCLUSIONS: Large-scale observer reliability studies are possible using web-based tools and inform routine practice. Slower scan reading and use of CT infarct rating scales improve detection of acute ischaemic signs and should be encouraged to improve stroke diagnosis

Body Mass and Fat Mass in Refractory Asthma: An Observational 1 Year Follow-Up Study

Background. Asthma and obesity are common; however the impact of obesity upon asthma remains uncertain. Objectives. To assess relationships between obesity and fat mass with airway inflammation, lung function, and disease control in patients with refractory asthma. Methods. 151 refractory asthma patients were characterised for measures of airway inflammation, lung function, Juniper asthma control questionnaire (JACQ), body mass index (BMI), and fat mass index (FMI) derived from dual energy X-ray absorptiometry. Patients were reassessed over 12 months. Results. 74% of patients had an elevated BMI. BMI and FMI correlated (r = 0.9, P < .001). FMI and JACQ correlated in men (r = 0.3, P = .01). After 12 months 23% lost weight. Weight change over 12 months correlated with FEV1 change (r = −0.3, P = .03), but not with change in JACQ or exacerbations. Conclusion. Increased fat mass is common in refractory asthma and is associated with asthma symptom control in men. Loss of weight is associated with improvement in lung function in refractory asthma

Arterial Obstruction on Computed Tomographic or Magnetic Resonance Angiography and Response to Intravenous Thrombolytics in Ischemic Stroke

BACKGROUND AND PURPOSE: Computed tomographic angiography and magnetic resonance angiography are used increasingly to assess arterial patency in patients with ischemic stroke. We determined which baseline angiography features predict response to intravenous thrombolytics in ischemic stroke using randomized controlled trial data. METHODS: We analyzed angiograms from the IST-3 (Third International Stroke Trial), an international, multicenter, prospective, randomized controlled trial of intravenous alteplase. Readers, masked to clinical, treatment, and outcome data, assessed prerandomization computed tomographic angiography and magnetic resonance angiography for presence, extent, location, and completeness of obstruction and collaterals. We compared angiography findings to 6-month functional outcome (Oxford Handicap Scale) and tested for interactions with alteplase, using ordinal regression in adjusted analyses. We also meta-analyzed all available angiography data from other randomized controlled trials of intravenous thrombolytics. RESULTS: In IST-3, 300 patients had prerandomization angiography (computed tomographic angiography=271 and magnetic resonance angiography=29). On multivariable analysis, more extensive angiographic obstruction and poor collaterals independently predicted poor outcome (P1 indicates benefit) in patients with (odds ratio, 2.07; 95% confidence interval, 1.18-3.64; P=0.011) versus without (odds ratio, 0.88; 95% confidence interval, 0.58-1.35; P=0.566) arterial obstruction (P for interaction 0.017). CONCLUSIONS: Intravenous thrombolytics provide benefit to stroke patients with computed tomographic angiography or magnetic resonance angiography evidence of arterial obstruction, but the sample was underpowered to demonstrate significant treatment benefit or harm among patients with apparently patent arteries. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com. Unique identifier: ISRCTN25765518