Measuring pulmonary function in COPD using quantitative chest computed tomography analysis

COPD is diagnosed and evaluated by pulmonary function testing (PFT). Chest computed tomography (CT) primarily serves a descriptive role for diagnosis and severity evaluation. CT densitometry-based emphysema quantification and lobar fissure integrity assessment are most commonly used, mainly for lung volume reduction purposes and scientific efforts. A shift towards a more quantitative role for CT to assess pulmonary function is a logical next step, since more, currently underutilised, information is present in CT images. For instance, lung volumes such as residual volume and total lung capacity can be extracted from CT; these are strongly correlated to lung volumes measured by PFT. This review assesses the current evidence for use of quantitative CT as a proxy for PFT in COPD and discusses challenges in the movement towards CT as a more quantitative modality in COPD diagnosis and evaluation. To better understand the relevance of the traditional PFT measurements and the role CT might play in the replacement of these parameters, COPD pathology and traditional PFT measurements are discussed

Evaluation of spirometry-gated computed tomography to measure lung volumes in emphysema patients

INTRODUCTION: In emphysema patient being evaluated for bronchoscopic lung volume reduction (BLVR), accurate measurement of lung volumes is important. Total lung capacity (TLC) and residual volume (RV) are commonly measured by body plethysmography but can also be derived from chest computed tomography (CT). Spirometry-gated CT scanning potentially improves the agreement of CT and body plethysmography. The aim of this study was to compare lung volumes derived from spirometry-gated CT and “breath-hold-coached” CT to the reference standard: body plethysmography. METHODS: In this single-centre retrospective cohort study, emphysema patients being evaluated for BLVR underwent body plethysmography, inspiration (TLC) and expiration (RV) CT scan with spirometer guidance (“gated group”) or with breath-hold-coaching (“non-gated group”). Quantitative analysis was used to calculate lung volumes from the CT. RESULTS: 200 patients were included in the study (mean±sd age 62±8 years, forced expiratory flow in 1 s 29.2±8.7%, TLC 7.50±1.46 L, RV 4.54±1.07 L). The mean±sd CT-derived TLC was 280±340 mL lower compared to body plethysmography in the gated group (n=100), and 590±430 mL lower for the non-gated group (n=100) (both p<0.001). The mean±sd CT-derived RV was 300±470 mL higher in the gated group and 700±720 mL higher in the non-gated group (both p<0.001). Pearson correlation factors were 0.947 for TLC gated, 0.917 for TLC non-gated, 0.823 for RV gated, 0.693 for RV non-gated, 0.539 for %RV/TLC gated and 0.204 for %RV/TLC non-gated. The differences between the gated and non-gated CT results for TLC and RV were significant for all measurements (p<0.001). CONCLUSION: In severe COPD patients with emphysema, CT-derived lung volumes are strongly correlated to body plethysmography lung volumes, and especially for RV, more accurate when using spirometry gating

Effect of Chest Computed Tomography Kernel Use on Emphysema Score in Severe Chronic Obstructive Pulmonary Disease Patients Evaluated for Lung Volume Reduction

Background: Chest computed tomography (CT) emphysema quantification is a vital diagnostic tool in patient evaluation for bronchoscopic lung volume reduction (BLVR). Smooth kernels for CT image reconstruction are generally recommended for quantitative analyses. This recommendation is not always followed, which may affect quantification of emphysema extent and eventually, treatment decisions. Objective: The main goal is to demonstrate the influence of CT reconstruction kernels on emphysema quantification in patients with severe COPD, considered for BLVR. Methods: Chest CT scans were acquired with one multi-detector CT system and reconstructed using three different kernels: smooth, medium smooth, and sharp. Other parameters were kept constant. Emphysema scores (ESs), meaning the percentage of voxels below-950 Hounsfield units, were calculated and compared to the smooth reference kernel using paired t tests. Bland-Altman plots were made to assess the biases and limits of agreement between kernels. Results: Ninety-eight COPD patient CT scans were analyzed. The sharp kernel had a systematic bias of 6.2% and limits of agreement of 16.6% to-4.2% compared to the smooth kernel. The medium smooth kernel had a systematic bias of 5.7% and limits of agreement of 9.2% and 2.2% compared to the smooth kernel. The ES differed, for a single patient, up to 18% for different kernels. Conclusions: Chest CT kernel reconstruction can lead to a significant difference in emphysema severity quantification. This may cause invalid treatment selection in COPD patients evaluated for BLVR. Standardization of a smooth CT kernel setting and/or normalization to a standard kernel is strongly recommended

The fate of Böhler's angle in conservatively-treated displaced intra-articular calcaneal fractures

Purpose: Although the predictive value of Böhler's angle on outcome remains subject of debate, the initial angle at the time of trauma still guides treatment. Changes in Böhler's angle during follow-up are frequently reported following surgical treatment of displaced intra-articular calcaneal fractures (DIACF). The aim of the present study was to determine the changes in Böhler's angle as a measure of secondary fracture displacement following conservative management of DIACF. Methods: Thirty-eight patients with a total of 44 displaced intra-articular calcaneal fractures treated conservatively with a minimum of two lateral radiographs during follow-up were analysed. Böhler's angle at different follow-up times was measured by three observers. The change in angle was compared with the angle at trauma, and influence of trauma mechanism and common calcaneal fracture classifications were determined. Results: The results showed a significant decline over time of the Böhler's angle in conservatively-treated patients of more than 11° on average at a mean follow-up of 29.2 weeks. This decrease was not related to gender, the initial angle, or the Essex-Lopresti or Sanders classification. A statistically significantly higher decrease was detected in high energetic trauma compared with low energetic trauma. Conclusion: The conservative treatment of displaced intra-articular calcaneal fractures is still a viable option, yet a significant secondary displacement in time should be taken into account, as reflected in a decrease of Böhler's angle of 11° up to one year following trauma

Vitamin B6, Inflammation, and Cardiovascular Outcome in a Population-Based Cohort:The Prevention of Renal and Vascular End-Stage Disease (PREVEND) Study

BACKGROUND: a large number of studies have linked vitamin B6 to inflammation and cardiovascular disease in the general population. However, it remains uncertain whether vitamin B6 is associated with cardiovascular outcome independent of inflammation. METHODS: we measured plasma pyridoxal 5'-phosphate (PLP), as an indicator of vitamin B6 status, at baseline in a population-based prospective cohort of 6249 participants of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study who were free of cardiovascular disease. As indicators of low-grade systemic inflammation, we measured high-sensitivity C-reactive protein and GlycA; Results: median plasma PLP was 37.2 (interquartile range, 25.1-57.0) nmol/L. During median follow-up for 8.3 (interquartile range, 7.8-8.9) years, 409 non-fatal and fatal cardiovascular events (composite outcome) occurred. In the overall cohort, log transformed plasma PLP was associated with the composite outcome, independent of adjustment for age, sex, smoking, alcohol consumption, body mass index (BMI), estimated glomerular filtration rate (eGFR), total cholesterol:high-density lipoprotein (HDL)-cholesterol ratio, and blood pressure (adjusted hazard ratio per increment of log plasma PLP, 0.66; 95% confidence interval (CI), 0.47-0.93). However, adjustment for high-sensitivity C-reactive protein and GlycA increased the hazard ratio by 9% and 12% respectively, to non-significant hazard ratios of 0.72 (95% confidence interval, 0.51-1.01) and 0.74 (95% confidence interval, 0.53-1.05). The association of plasma PLP with cardiovascular risk was modified by gender (adjusted Pinteraction = 0.04). When stratified according to gender, in women the prospective association with cardiovascular outcome was independent of age, smoking, alcohol consumption, high-sensitivity C-reactive protein, and GlycA (adjusted hazard ratio, 0.50, 95% confidence interval, 0.27-0.94), while it was not in men (adjusted hazard, 0.99, 95% confidence interval, 0.65-1.51). CONCLUSIONS: in this population-based cohort, plasma PLP was associated with cardiovascular outcome, but this association was confounded by traditional risk factors and parameters of inflammation. Notably, the association of low plasma PLP with high risk of adverse cardiovascular outcome was modified by gender, with a stronger and independent association in women

Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.

BACKGROUND: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. METHODS: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. FINDINGS: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0-20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. INTERPRETATION: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies. FUNDING: EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research

Gene expression of NMDA receptor subunits in the cerebellum of elderly patients with schizophrenia

To determine if NMDA receptor alterations are present in the cerebellum in schizophrenia, we measured NMDA receptor binding and gene expression of the NMDA receptor subunits in a post-mortem study of elderly patients with schizophrenia and non-affected subjects. Furthermore, we assessed influence of genetic variation in the candidate gene neuregulin-1 (NRG1) on the expression of the NMDA receptor in an exploratory study. Post-mortem samples from the cerebellar cortex of ten schizophrenic patients were compared with nine normal subjects. We investigated NMDA receptor binding by receptor autoradiography and gene expression of the NMDA receptor subunits NR1, NR2A, NR2B, NR2C and NR2D by in situ hybridization. For the genetic study, we genotyped the NRG1 polymorphism rs35753505 (SNP8NRG221533). Additionally, we treated rats with the antipsychotics haloperidol or clozapine and assessed cerebellar NMDA receptor binding and gene expression of subunits to examine the effects of antipsychotic treatment. Gene expression of the NR2D subunit was increased in the right cerebellum of schizophrenic patients compared to controls. Individuals carrying at least one C allele of rs35753505 (SNP8NRG221533) showed decreased expression of the NR2C subunit in the right cerebellum, compared to individuals homozygous for the T allele. Correlation with medication parameters and the animal model revealed no treatment effects. In conclusion, increased NR2D expression results in a hyperexcitable NMDA receptor suggesting an adaptive effect due to receptor hypofunction. The decreased NR2C expression in NRG1 risk variant may cause a deficit in NMDA receptor function. This supports the hypothesis of an abnormal glutamatergic neurotransmission in the right cerebellum in the pathophysiology of schizophrenia

Health benefits, costs, and cost-effectiveness of earlier eligibility for adult antiretroviral therapy and expanded treatment coverage: a combined analysis of 12 mathematical models.

BACKGROUND: New WHO guidelines recommend ART initiation for HIV-positive persons with CD4 cell counts ≤500 cells/µL, a higher threshold than was previously recommended. Country decision makers must consider whether to further expand ART eligibility accordingly. METHODS: We used multiple independent mathematical models in four settings-South Africa, Zambia, India, and Vietnam-to evaluate the potential health impact, costs, and cost-effectiveness of different adult ART eligibility criteria under scenarios of current and expanded treatment coverage, with results projected over 20 years. Analyses considered extending eligibility to include individuals with CD4 ≤500 cells/µL or all HIV-positive adults, compared to the previous recommendation of initiation with CD4 ≤350 cells/µL. We assessed costs from a health system perspective, and calculated the incremental cost per DALY averted ($/DALY) to compare competing strategies. Strategies were considered 'very cost-effective' if the$/DALY was less than the country's per capita gross domestic product (GDP; South Africa: $8040, Zambia:$1425, India: $1489, Vietnam:$1407) and 'cost-effective' if $/DALY was less than three times per capita GDP. FINDINGS: In South Africa, the cost per DALY averted of extending ART eligibility to CD4 ≤500 cells/µL ranged from$237 to $1691/DALY compared to 2010 guidelines; in Zambia, expanded eligibility ranged from improving health outcomes while reducing costs (i.e. dominating current guidelines) to$749/DALY. Results were similar in scenarios with substantially expanded treatment access and for expanding eligibility to all HIV-positive adults. Expanding treatment coverage in the general population was therefore found to be cost-effective. In India, eligibility for all HIV-positive persons ranged from $131 to$241/DALY and in Vietnam eligibility for CD4 ≤500 cells/µL cost $290/DALY. In concentrated epidemics, expanded access among key populations was also cost-effective. INTERPRETATION: Earlier ART eligibility is estimated to be very cost-effective in low- and middle-income settings, although these questions should be revisited as further information becomes available. Scaling-up ART should be considered among other high-priority health interventions competing for health budgets. FUNDING: The Bill and Melinda Gates Foundation and World Health Organization