Efficacy and Mechanism Evaluation Programme, funded by the Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership.

No abstract

Fibrosing alveolitis, a condition characterized by a poor prognosis and a limited response to treatment, is readily identified by thin-section computed tomography (CT). Fibrotic and inflammatory histologic results, obtained at open lung biopsy, both have characteristic CT patterns. To evaluate whether CT could predict prognosis and response to therapy, we examined the CT appearances of 76 patients with lone cryptogenic fibrosing alveolitis and 66 patients with fibrosing alveolitis associated with systemic sclerosis. CT abnormalities were categorized as predominantly a ground-glass pattern (Grade 1), mixed (Grade 2), or predominantly a reticular pattern (Grade 3). In cryptogenic fibrosing alveolitis, 4-yr survival was highest in association with CT Grade 1 and higher with CT Grade 2 than with CT Grade 3, independent of the extent of abnormal lung on CT, duration of dyspnea, or severity of depression of DLCO or FVC, p < 0.001. A response to therapy in previously untreated cryptogenic fibrosing alveolitis was seen most frequently with CT Grade 1 and more frequently with CT Grade 2 than with CT Grade 3, p < 0.025. In systemic sclerosis, CT appearances were not predictive of 4-yr survival; a response to therapy was seen more frequently with CT Grade 2 (three of seven patients) than with CT Grade 3 (zero of six patients). These data have shown that CT appearances are of prognostic value in fibrosing alveolitis and that they are likely to play an increasing role in disease-staging in this condition.

In idiopathic pulmonary fibrosis, the quantitation of disease severity using pulmonary function tests is often confounded by emphysema. We have identified the composite physiologic index (CPI) most closely reflecting the morphologic extent of pulmonary fibrosis. Consecutive patients with a clinical/computed tomography (CT) diagnosis of idiopathic pulmonary fibrosis (n = 212) were divided into group I (n = 106) and group II (n = 106). The CPI was derived in group I (by fitting pulmonary function tests against disease extent on CT) and was tested in Group II. The formula for the CPI was as follows: extent of disease on CT = 91.0 - (0.65 x percent predicted diffusing capacity for carbon monoxide [DLCO]) - (0.53 x percent predicted FVC) + (0.34 x percent predicted FEV1). In group II, the CPI correlated more strongly with disease extent on CT (r2 = 0.51) than the individual pulmonary function test (DLCO the highest value, r2 = 0.38). A subanalysis demonstrated that the better fit of the CPI was ascribable to a correction of the confounding effects of emphysema. Mortality was predicted more accurately by the CPI than by a pulmonary function test in all clinical subgroups, including a separate cohort of 36 patients with histologically proven usual interstitial pneumonia (CPI, p < 0.0005; FVC, p = 0.002; PO2, p = 0.002). In conclusion, a new CPI, derived against CT and validated using split sample testing, is a more accurate prognostic determinant in usual interstitial pneumonia than an individual pulmonary function test.

Lower serum uromodulin (umod) levels correlate with decreasing kidney function, but their relationship with coronary artery disease (CAD) is unknown. We examined the relationships between serum umod, and the development of albuminuria, chronic kidney disease (CKD) and progression of coronary artery calcium (CAC) in adults with type 1 diabetes (T1D), over 12-years. Participants with T1D (n=539, mean age of 40±9, HbA1c 7.7±1.2%, 53% women) in the Coronary Artery Calcification in Type 1 Diabetes study were assessed for CAC progression (128-slice spiral CT), urinary albumin to creatinine ratio (UACR) and estimated GFR (eGFR) calculated by CKD-EPI cre-atinine. CKD was defined as eGFR <60mL/min/1.73m 2 , albuminuria as UACR ≥30 mg/g, and CAC progression as a change in the square root transformed CAC volume ≥2.5. Serum umod was measured using immunoassay kits from Meso Scale Discovery. Logistic regression was used to examine the relationship between umod and incident albuminuria, CKD, or CAC progression, controlling for age, sex, diabetes duration, HbA1c, SBP and LDL-C. Integrated discrimination index (IDI) and net-reclassification improvement (NRI) were used to assess the added prediction performance of umod to a model with age, sex, diabetes duration and ABC risk factors. CAC progression was observed in 49%, incident albuminuria in 6% and incident CKD in 6% of the subjects. Serum umod at baseline was associated with CAC progression (OR: 0.66 95% CI [0.47-0.94] per one SD=138.7 mcg/mg), incident albumin-uria (0.27 [0.11-0.65]) and incident CKD (0.39 [0.20-0.76]) in adjusted models. Results were similar for CAC progression when adjusting for baseline eGFR and UACR, and when excluding participants with CKD or albuminuria. The addition of umod to the baseline model improved relative IDI for CAC progression by 6% (p=0.008) and correctly reclassified 22% cases of CAC progression (p=0.02). In conclusion, lower serum umod levels independently predict development of CAC in adults with T1D. Several genetic variants associated with CVD have been identified in the general population. Our goal was to investigate whether these variants predicted the incidence of major adverse cardiovascular events (MACE) among type 2 diabetes (T2D) subjects at high CVD risk from the ACCORD Study. We analyzed data from 5,360 self-reported white T2D subjects with a median follow-up of 4.7 years. A genetic risk score (GRS) was derived by adding the effect size-weighted number of risk alleles at 40 CVD loci identified in the general population. The association of the GRS with MACE was evaluated by logistic regression including age, gender, and study treatments as covariates. Clinical CVD risk classes were defined as "very high" (presence of CVD at baseline or AHA-ACC 10-year MACE risk score > 15%) or "mod-erately high" (10 y risk <= 15%). The GRS ranged from 27 to 62, with each unit increase being associated with a 3% additional risk of MACE (OR 1.03; 95% CI 1.01-1.06, p=0.002). Subjects in the highest GRS tertile had a 55% increase in MACE risk as co...

A reticular pattern, with a striking anterior distribution, is a frequent finding of follow-up CT in ARDS survivors and is most strongly related to the duration of pressure-controlled inverse-ratio ventilation.

In patients with obliterative bronchiolitis, the extent of decreased attenuation at CT was most strongly related to depression of pulmonary function tests of the small airways. Decreased attenuation is the cardinal sign for further quantitative studies of obliterative bronchiolitis.

We have demonstrated that PWV is strongly related to the degree of EBCT-derived coronary artery calcium score in chronic kidney disease patients.