How consistently do physicians diagnose and manage drug-induced interstitial lung disease? Two surveys of European ILD specialist physicians

Introduction Currently there are no general guidelines for diagnosis or management of suspected drug-induced (DI) interstitial lung disease (ILD). The objective was to survey a sample of current European practice in the diagnosis and management of DI-ILD, in the context of the prescribing information approved by regulatory authorities for 28 licenced drugs with a recognised risk of DI-ILD. Methods Consultant physicians working in specialist ILD centres across Europe were emailed two surveys via a website link. Initially, opinion was sought regarding various diagnostic and management options based on seven clinical ILD case vignettes and five general questions regarding DI-ILD. The second survey involved 29 statements regarding the diagnosis and management of DI-ILD, derived from the results of the first survey. Consensus agreement was defined as 75% or greater. Results When making a diagnosis of DI-ILD, the favoured investigations used (other than computed tomography) included pulmonary function tests, bronchoscopy and blood tests. The preferred method used to decide when to stop treatment was a pulmonary function test. In the second survey, the majority of the statements were accepted by the 33 respondents, with only four of 29 statements not achieving consensus when the responses “agree” and “strongly agree” were combined as one answer. Conclusion The two surveys provide guidance for clinicians regarding an approach to the diagnosis and management of DI-ILD in which the current evidence base is severely lacking, as demonstrated by the limited information provided by the manufacturers of the drugs associated with a high risk of DI-ILD that we reviewed

Free breathing lung T1 mapping using image registration in patients with idiopathic pulmonary fibrosis

Purpose To assess the use of image registration for correcting respiratory motion in free breathing lung T1 mapping acquisition in patients with idiopathic pulmonary fibrosis (IPF). Theory and Methods The method presented used image registration to synthetic images during postprocessing to remove respiratory motion. Synthetic images were generated from a model of the inversion recovery signal of the acquired images that incorporated a periodic lung motion model. Ten healthy volunteers and 19 patients with IPF underwent 2D Look‐Locker T1 mapping acquisition at 1.5T during inspiratory breath‐hold and free breathing. Eight healthy volunteers and seven patients with IPF underwent T1 mapping acquisition during expiratory breath‐hold. Fourteen patients had follow‐up scanning at 6 months. Dice similarity coefficient (DSC) was used to evaluate registration efficacy. Results Image registration increased image DSC (P < .001) in the free breathing inversion recovery images. Lung T1 measured during a free breathing acquisition was lower in patients with IPF when compared with healthy controls (inspiration: P = .238; expiration: P = .261; free breathing: P = .021). Measured lung T1 was higher in expiration breath‐hold than inspiration breath‐hold in healthy volunteers (P < .001) but not in patients with IPF (P = .645). There were no other significant differences between lung T1 values within subject groups. Conclusions The registration technique significantly reduced motion in the Look‐Locker images acquired during free breathing and may improve the robustness of lung T1 mapping in patients who struggle to hold their breath. Lung T1 measured during a free breathing acquisition was significantly lower in patients with IPF when compared with healthy controls

Three Generations in Type I Compactifications

Generalizing the recent work on three-family Type I compactifications, we classify perturbative Type I vacua obtained via compactifying on the T^6/Z_2 X Z_2 X Z_3 orbifold with all possible Wilson lines. In particular, we concentrate on models with gauge groups containing the Standard Model gauge group SU(3)_c X SU(2)_w X U(1)_Y as a subgroup. All of the vacua we obtain contain D5-branes and are non-perturbative from the heterotic viewpoint. The models we discuss have three-chiral families. We study some of their phenomenological properties, and point out non-trivial problems arising in these models in the phenomenological context.Comment: 16 pages, revtex, minor misprints correcte

The detection of Gravitational Waves

This chapter is concerned with the question: how do gravitational waves (GWs) interact with their detectors? It is intended to be a theory review of the fundamental concepts involved in interferometric and acoustic (Weber bar) GW antennas. In particular, the type of signal the GW deposits in the detector in each case will be assessed, as well as its intensity and deconvolution. Brief reference will also be made to detector sensitivity characterisation, including very summary data on current state of the art GW detectors.Comment: 33 pages, 12 figures, LaTeX2e, Springer style files --included. For Proceedings of the ERE-2001 Conference (Madrid, September 2001

Real world experience of response to pirfenidone in patients with idiopathic pulmonary fibrosis: a two centre retrospective study

Introduction: Pirfenidone has been shown to reduce the decline in forced vital capacity (FVC) compared to placebo in patients with idiopathic pulmonary fibrosis (IPF). Previous studies have suggested that patients with a more rapid decline in FVC during the period before starting pirfenidone experience the greatest benefit from treatment. The purpose of this retrospective observational study was to investigate the response to pirfenidone in IPF patients, comparing two groups stratified by the annual rate of decline in FVC % predicted prior to treatment. Methods: Using the rate of decline in FVC % predicted in the 12 months prior to pirfenidone, patients were stratified into slow (<5%) or rapid (≥5%) decliner groups. Comparisons in the lung function response to pirfenidone in these two groups were performed. Results: Pirfenidone resulted in no statistically significant reduction in the median annual rate of decline in FVC or FVC % predicted. In the rapid decliners, pirfenidone significantly reduced the median (IQR) annual rate of decline in FVC % predicted (-8.7 (-14.2 - -7.0) %/yr vs 2.0 (-7.1 - 6.0) %/yr; n=17; p<0.01). In the slow decliners, pirfenidone did not reduce the median (IQR) annual rate of decline in FVC % predicted (-1.3 (-3.2 - 1.3) %/yr vs -5.0 (-8.3 - -0.35) %/yr; n=17; p=0.028). Conclusions: We demonstrate the greater net effect of pirfenidone in IPF patients declining rapidly. We suggest that using an annual rate of decline in FVC of <5% and ≥5% may be useful in counselling patients with regard to pirfenidone treatment

Genetic Variants of the Renin-Angiotensin-Aldosterone System and Reverse Remodeling After Cardiac Resynchronization Therapy

Background: Reverse remodeling (RR) after cardiac resynchronization therapy (CRT) is associated with favorable clinical outcomes in heart failure (HF). The renin-angiotensin-aldosterone system (RAAS) is involved in the remodeling process. Methods and Results: We assessed the association between RR and 8 common RAAS gene variants, which were determined by TaqMan assays, in 156 outpatients with chronic HF. RR was defined as a O15% decrease in left ventricular end systolic volume (LVESV) at 9 (interquartile range 7e12) months after CRT. We matched 76 patients who did not show RR (RR) to 80 RR? control subjects by age, sex, HF etiology, New York Heart Association (NYHA) functional class and left ventricular ejection fraction (LVEF). The frequency of the minor allele of the NR3C2 gene (rs5522 C/T), encoding the mineralocorticoid receptor, was higher in RR than in RR (24/126 vs 10/150; P value after false discovery rate correction: <.0193). Conversely, LVESV decreased significantly less after CRT in carriers of the NR3C2 minor C allele (P 5 .02). After adjustment for age, sex, NYHA functional class, previous myocardial infarction, atrial fibrillation, and LVEF, RR remained independently associated with NR3C2 C allele carriage (odds ratio 3.093, 95% confidence interval 1.253e7.632). Conclusions: The association of RR after CRT with a common polymorphism in the mineralocorticoid receptor gene involved in aldosterone signaling suggests a possible role for variants in RAAS genes in progressive LV function decline, despite apparently effective CRT

Experimental and quantitative imaging techniques in interstitial lung disease.

Interstitial lung diseases (ILDs) are a heterogeneous group of conditions, with a wide and complex variety of imaging features. Difficulty in monitoring, treating and exploring novel therapies for these conditions is in part due to the lack of robust, readily available biomarkers. Radiological studies are vital in the assessment and follow-up of ILD, but currently CT analysis in clinical practice is qualitative and therefore somewhat subjective. In this article, we report on the role of novel and quantitative imaging techniques across a range of imaging modalities in ILD and consider how they may be applied in the assessment and understanding of ILD. We critically appraised evidence found from searches of Ovid online, PubMed and the TRIP database for novel and quantitative imaging studies in ILD. Recent studies have explored the capability of texture-based lung parenchymal analysis in accurately quantifying several ILD features. Newer techniques are helping to overcome the challenges inherent to such approaches, in particular distinguishing peripheral reticulation of lung parenchyma from pleura and accurately identifying the complex density patterns that accompany honeycombing. Robust and validated texture-based analysis may remove the subjectivity that is inherent to qualitative reporting and allow greater objective measurements of change over time. In addition to lung parenchymal feature quantification, pulmonary vessel volume analysis on CT has demonstrated prognostic value in two retrospective analyses and may be a sign of vascular changes in ILD which, to date, have been difficult to quantify in the absence of overt pulmonary hypertension. Novel applications of existing imaging techniques, such as hyperpolarised gas MRI and positron emission tomography (PET), show promise in combining structural and functional information. Although structural imaging of lung tissue is inherently challenging in terms of conventional proton MRI techniques, inroads are being made with ultrashort echo time, and dynamic contrast-enhanced MRI may be used for lung perfusion assessment. In addition, inhaled hyperpolarised 129Xenon gas MRI may provide multifunctional imaging metrics, including assessment of ventilation, intra-acinar gas diffusion and alveolar-capillary diffusion. PET has demonstrated high standard uptake values (SUVs) of 18F-fluorodeoxyglucose in fibrosed lung tissue, challenging the assumption that these are 'burned out' and metabolically inactive regions. Regions that appear structurally normal also appear to have higher SUV, warranting further exploration with future longitudinal studies to assess if this precedes future regions of macroscopic structural change. Given the subtleties involved in diagnosing, assessing and predicting future deterioration in many forms of ILD, multimodal quantitative lung structure-function imaging may provide the means of identifying novel, sensitive and clinically applicable imaging markers of disease. Such imaging metrics may provide mechanistic and phenotypic information that can help direct appropriate personalised therapy, can be used to predict outcomes and could potentially be more sensitive and specific than global pulmonary function testing. Quantitative assessment may objectively assess subtle change in character or extent of disease that can assist in efficacy of antifibrotic therapy or detecting early changes of potentially pneumotoxic drugs involved in early intervention studies

A Three-Family SU(4)c⊗SU(2)w⊗U(1)SU(4)_c \otimes SU(2)_w \otimes U(1) Type I Vacuum

We construct a four dimensional chiral N=1 space-time supersymmetric perturbative Type I vacuum corresponding to a compactification on a toroidal Z_2 X Z_2 X Z_3 orbifold with a discrete Wilson line. This model is non-perturbative from the heterotic viewpoint. It has three chiral families in the SU(4)_c X SU(2)_w X U(1) subgroup of the total gauge group. We compute the tree-level superpotential in this model. There appears to be no obvious obstruction to Higgs the gauge group down to SU(3)_c X SU(2)_w X U(1)_Y and obtain the Standard Model gauge group with three chiral families.Comment: 8 pages, revtex, minor misprints corrected, some notations and discussions simplifie

Voxel-wise comparison of co-registered quantitative CT and hyperpolarised gas diffusion-weighted MRI measurements in IPF

The patterns of idiopathic pulmonary fibrosis (IPF) lung disease that directly correspond to elevated hyperpolarised gas diffusion-weighted (DW) MRI metrics are currently unknown. This study aims to develop a spatial co-registration framework for a voxel-wise comparison of hyperpolarised gas DW-MRI and CALIPER quantitative CT patterns. Sixteen IPF patients underwent 3He DW-MRI and CT at baseline, and eleven patients had a 1-year follow-up DW-MRI. Six healthy volunteers underwent 129Xe DW-MRI at baseline only. Moreover, 3He DW-MRI was indirectly co-registered to CT via spatially aligned 3He ventilation and structural 1H MRI. A voxel-wise comparison of the overlapping 3He apparent diffusion coefficient (ADC) and mean acinar dimension (LmD) maps with CALIPER CT patterns was performed at baseline and after 1 year. The abnormal lung percentage classified with the LmD value, based on a healthy volunteer 129Xe LmD, and CALIPER was compared with a Bland–Altman analysis. The largest DW-MRI metrics were found in the regions classified as honeycombing, and longitudinal DW-MRI changes were observed in the baseline-classified reticular changes and ground-glass opacities regions. A mean bias of −15.3% (95% interval −56.8% to 26.2%) towards CALIPER was observed for the abnormal lung percentage. This suggests DW-MRI may detect microstructural changes in areas of the lung that are determined visibly and quantitatively normal by CT