Systematic review and meta-analysis of the growth and rupture rates of small abdominal aortic aneurysms: implications for surveillance intervals and their cost-effectiveness.

BACKGROUND: Small abdominal aortic aneurysms (AAAs; 3.0-5.4 cm in diameter) are usually asymptomatic and managed by regular ultrasound surveillance until they grow to a diameter threshold (commonly 5.5 cm) at which surgical intervention is considered. The choice of appropriate surveillance intervals is governed by the growth and rupture rates of small AAAs, as well as their relative cost-effectiveness. OBJECTIVES: The aim of this series of studies was to inform the evidence base for small AAA surveillance strategies. This was achieved by literature review, collation and analysis of individual patient data, a focus group and health economic modelling. DATA SOURCES: We undertook systematic literature reviews of growth rates and rupture rates of small AAAs. The databases MEDLINE, EMBASE on OvidSP, Cochrane Central Register of Controlled Trials 2009 Issue 4, ClinicalTrials.gov, and controlled-trials.com were searched from inception up until the end of 2009. We also obtained individual data on 15,475 patients from 18 surveillance studies. REVIEW METHODS: Systematic reviews of publications identified 15 studies providing small AAA growth rates, and 14 studies with small AAA rupture rates, up to December 2009 (later updated to September 2012). We developed statistical methods to analyse individual surveillance data, including the effects of patient characteristics, to inform the choice of surveillance intervals and provide inputs for health economic modelling. We updated an existing health economic model of AAA screening to address the cost-effectiveness of different surveillance intervals. RESULTS: In the literature reviews, the mean growth rate was 2.3 mm/year and the reported rupture rates varied between 0 and 1.6 ruptures per 100 person-years. Growth rates increased markedly with aneurysm diameter, but insufficient detail was available to guide surveillance intervals. Based on individual surveillance data, for each 0.5-cm increase in AAA diameter, growth rates increased by about 0.5 mm/year and rupture rates doubled. To control the risk of exceeding 5.5 cm to below 10% in men, on average a 7-year surveillance interval is sufficient for a 3.0-cm aneurysm, whereas an 8-month interval is necessary for a 5.0-cm aneurysm. To control the risk of rupture to below 1%, the corresponding estimated surveillance intervals are 9 years and 17 months. Average growth rates were higher in smokers (by 0.35 mm/year) and lower in patients with diabetes (by 0.51 mm/year). Rupture rates were almost fourfold higher in women than men, doubled in current smokers and increased with higher blood pressure. Increasing the surveillance interval from 1 to 2 years for the smallest aneurysms (3.0-4.4 cm) decreased costs and led to a positive net benefit. For the larger aneurysms (4.5-5.4 cm), increasing surveillance intervals from 3 to 6 months led to equivalent cost-effectiveness. LIMITATIONS: There were no clear reasons why the growth rates varied substantially between studies. Uniform diagnostic criteria for rupture were not available. The long-term cost-effectiveness results may be susceptible to the modelling assumptions made. CONCLUSIONS: Surveillance intervals of several years are clinically acceptable for men with AAAs in the range 3.0-4.0 cm. Intervals of around 1 year are suitable for 4.0-4.9-cm AAAs, whereas intervals of 6 months would be acceptable for 5.0-5.4-cm AAAs. These intervals are longer than those currently employed in the UK AAA screening programmes. Lengthening surveillance intervals for the smallest aneurysms was also shown to be cost-effective. Future work should focus on optimising surveillance intervals for women, studying whether or not the threshold for surgery should depend on patient characteristics, evaluating the usefulness of surveillance for those with aortic diameters of 2.5-2.9 cm, and developing interventions that may reduce the growth or rupture rates of small AAAs. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Clinical effectiveness and cost-effectiveness of endobronchial and endoscopic ultrasound relative to surgical staging in potentially resectable lung cancer: results from the ASTER randomised controlled trial

Copyright @ Queen’s Printer and Controller of HMSO 2012. This work was produced by Sharples et al. under the terms of a commissioning contract issued by the Secretary of State for Health.Objective: To assess the clinical effectiveness and cost-effectiveness of endosonography (followed by surgical staging if endosonography was negative), compared with standard surgical staging alone, in patients with non-small cell lung cancer (NSCLC) who are otherwise candidates for surgery with curative intent. Design: A prospective, international, open-label, randomised controlled study, with a trialbased economic analysis. Setting: Four centres: Ghent University Hospital, Belgium; Leuven University Hospitals,Belgium; Leiden University Medical Centre, the Netherlands; and Papworth Hospital, UK. Participants: Inclusion criteria: known/suspected NSCLC, with suspected mediastinal lymph node involvement; otherwise eligible for surgery with curative intent; clinically fit for endosonography and surgery; and no evidence of metastatic disease. Exclusion criteria: previous lung cancer treatment; concurrent malignancy; uncorrected coagulopathy; and not suitable for surgical staging. Interventions: Study patients were randomised to either surgical staging alone (n = 118) or endosonography followed by surgical staging if endosonography was negative (n = 123). Endosonography diagnostic strategy used endoscopic ultrasound-guided fine-needle aspiration combined with endobronchial ultrasound-guided transbronchial needle aspiration, followed by surgical staging if these tests were negative. Patients with no evidence of mediastinal metastases or tumour invasion were referred for surgery with curative intent. If evidence of malignancy was found, patients were referred for chemoradiotherapy. Main outcome measures: The main clinical outcomes were sensitivity (positive diagnostic test/nodal involvement during any diagnostic test or thoracotomy) and negative predictive value (NPV) of each diagnostic strategy for the detection of N2/N3 metastases, unnecessary thoracotomy and complication rates. The primary economic outcome was cost–utility of the endosonography strategy compared with surgical staging alone, up to 6 months after randomisation, from a UK NHS perspective. Results: Clinical and resource-use data were available for all 241 patients, and complete utilities were available for 144. Sensitivity for detecting N2/N3 metastases was 79% [41/52; 95% confidence interval (CI) 66% to 88%] for the surgical arm compared with 94% (62/66; 95% CI 85% to 98%) for the endosonography strategy (p = 0.02). Corresponding NPVs were 86% (66/77; 95% CI 76% to 92%) and 93% (57/61; 95% CI 84% to 97%; p = 0.26). There were 21/118 (18%) unnecessary thoracotomies in the surgical arm compared with 9/123 (7%) in the endosonography arm (p = 0.02). Complications occurred in 7/118 (6%) in the surgical arm and 6/123 (5%) in the endosonography arm (p = 0.78): one pneumothorax related to endosonography and 12 complications related to surgical staging. Patients in the endosonography arm had greater EQ-5D (European Quality of Life-5 Dimensions) utility at the end of staging (0.117; 95% CI 0.042 to 0.192; p = 0.003). There were no other significant differences in utility. The main difference in resource use was the number of thoracotomies: 66% patients in the surgical arm compared with 53% in the endosonography arm. Resource use was similar between the groups in all other items. The 6-month cost of the endosonography strategy was £9713 (95% CI £7209 to £13,307) per patient versus £10,459 (£7732 to £13,890) for the surgical arm, mean difference £746 (95% CI –£756 to £2494). The mean difference in quality-adjusted life-year was 0.015 (95% CI –0.023 to 0.052) in favour of endosonography, so this strategy was cheaper and more effective. Conclusions: Endosonography (followed by surgical staging if negative) had higher sensitivity and NPVs, resulted in fewer unnecessary thoracotomies and better quality of life during staging, and was slightly more effective and less expensive than surgical staging alone. Future work could investigate the need for confirmatory mediastinoscopy following negative endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), the diagnostic accuracy of EUS-FNA or EBUS-TBNA separately and the delivery of both EUSFNA or EBUS-TBNA by suitably trained chest physicians.This project was funded by the NIHR Health Technology Assessment programm

Comparison of flow characteristics and vascular reactivity of radial artery and long saphenous vein grafts [NCT00139399]

BACKGROUND: The morphological and functional differences between arteries and veins may have implications on coronary artery bypass graft (CABG) survival. Although subjective differences have been observed between radial artery (RA) and long saphenous venous (LSV) grafts, these have not been quantified. This study assessed and compared the flow characteristics and in-vivo graft flow responses of RA and LSV aorto-coronary grafts. METHODS: Angiograms from 52 males taken 3.7 ± 1.0 months after CABG surgery were analyzed using adjusted Thrombolysis in Myocardial Infarction (TIMI) frame count. Graft and target coronary artery dimensions were measured using quantitative coronary angiography. Estimated TIMI velocity (V(E)) and volume flow (F(E)) were then calculated. A further 7 patients underwent in-vivo graft flow responses assessments to adenosine, acetylcholine and isosorbide dinitrate (ISDN) using intravascular Doppler. RESULTS: The V(E )for RA grafts was significantly greater than LSV grafts (P = 0.002), however there was no difference in volume F(E )(P = 0.20). RA grafts showed positive endothelium-dependent and -independent vasodilatation, and LSV grafts showed no statistically significant response to adenosine and acetylcholine. There was no difference in flow velocity or volume responses. Seven RA grafts (11%) had compromised patency (4 (6%) ≥ 50% stenosis in the proximal/distal anastomoses, and 3 (5%) diffuse narrowing). Thirty-seven (95%) LSV grafts achieved perfect patency and 2 (5%) were occluded. CONCLUSION: The flow characteristics and flow responses of the RA graft suggest that it is a more physiological conduit than the LSV graft. The clinical relevance of the balance between imperfect patency versus the more physiological vascular function in the RA graft may be revealed by the 5-year angiographic follow-up of this trial

Meta-analysis of individual-patient data from EVAR-1, DREAM, OVER and ACE trials comparing outcomes of endovascular or open repair for abdominal aortic aneurysm over 5 years

Background: The erosion of the early mortality advantage of elective endovascular aneurysm repair (EVAR) compared with open repair of abdominal aortic aneurysm remains without a satisfactory explanation. Methods: An individual-patient data meta-analysis of four multicentre randomized trials of EVAR versus open repair was conducted to a prespecified analysis plan, reporting on mortality, aneurysm-related mortality and reintervention. Results: The analysis included 2783 patients, with 14 245 person-years of follow-up (median 5·5 years). Early (0–6 months after randomization) mortality was lower in the EVAR groups (46 of 1393 versus 73 of 1390 deaths; pooled hazard ratio 0·61, 95 per cent c.i. 0·42 to 0·89; P = 0·010), primarily because 30-day operative mortality was lower in the EVAR groups (16 deaths versus 40 for open repair; pooled odds ratio 0·40, 95 per cent c.i. 0·22 to 0·74). Later (within 3 years) the survival curves converged, remaining converged to 8 years. Beyond 3 years, aneurysm-related mortality was significantly higher in the EVAR groups (19 deaths versus 3 for open repair; pooled hazard ratio 5·16, 1·49 to 17·89; P = 0·010). Patients with moderate renal dysfunction or previous coronary artery disease had no early survival advantage under EVAR. Those with peripheral artery disease had lower mortality under open repair (39 deaths versus 62 for EVAR; P = 0·022) in the period from 6 months to 4 years after randomization. Conclusion: The early survival advantage in the EVAR group, and its subsequent erosion, were confirmed. Over 5 years, patients of marginal fitness had no early survival advantage from EVAR compared with open repair. Aneurysm-related mortality and patients with low ankle : brachial pressure index contributed to the erosion of the early survival advantage for the EVAR group. Trial registration numbers: EVAR-1, ISRCTN55703451; DREAM (Dutch Randomized Endovascular Aneurysm Management), NCT00421330; ACE (Anévrysme de l'aorte abdominale, Chirurgie versus Endoprothèse), NCT00224718; OVER (Open Versus Endovascular Repair Trial for Abdominal Aortic Aneurysms), NCT00094575

BOLD Temporal Dynamics of Rat Superior Colliculus and Lateral Geniculate Nucleus following Short Duration Visual Stimulation

Background: The superior colliculus (SC) and lateral geniculate nucleus (LGN) are important subcortical structures for vision. Much of our understanding of vision was obtained using invasive and small field of view (FOV) techniques. In this study, we use non-invasive, large FOV blood oxygenation level-dependent (BOLD) fMRI to measure the SC and LGN's response temporal dynamics following short duration (1 s) visual stimulation. Methodology/Principal Findings: Experiments are performed at 7 tesla on Sprague Dawley rats stimulated in one eye with flashing light. Gradient-echo and spin-echo sequences are used to provide complementary information. An anatomical image is acquired from one rat after injection of monocrystalline iron oxide nanoparticles (MION), a blood vessel contrast agent. BOLD responses are concentrated in the contralateral SC and LGN. The SC BOLD signal measured with gradient-echo rises to 50% of maximum amplitude (PEAK) 0.2±0.2 s before the LGN signal (p<0.05). The LGN signal returns to 50% of PEAK 1.4±1.2 s before the SC signal (p<0.05). These results indicate the SC signal rises faster than the LGN signal but settles slower. Spin-echo results support these findings. The post-MION image shows the SC and LGN lie beneath large blood vessels. This subcortical vasculature is similar to that in the cortex, which also lies beneath large vessels. The LGN lies closer to the large vessels than much of the SC. Conclusions/Significance: The differences in response timing between SC and LGN are very similar to those between deep and shallow cortical layers following electrical stimulation, which are related to depth-dependent blood vessel dilation rates. This combined with the similarities in vasculature between subcortex and cortex suggest the SC and LGN timing differences are also related to depth-dependent dilation rates. This study shows for the first time that BOLD responses in the rat SC and LGN following short duration visual stimulation are temporally different. © 2011 Lau et al

Comparative genomics of the major parasitic worms

Parasitic nematodes (roundworms) and platyhelminths (flatworms) cause debilitating chronic infections of humans and animals, decimate crop production and are a major impediment to socioeconomic development. Here we report a broad comparative study of 81 genomes of parasitic and non-parasitic worms. We have identified gene family births and hundreds of expanded gene families at key nodes in the phylogeny that are relevant to parasitism. Examples include gene families that modulate host immune responses, enable parasite migration though host tissues or allow the parasite to feed. We reveal extensive lineage-specific differences in core metabolism and protein families historically targeted for drug development. From an in silico screen, we have identified and prioritized new potential drug targets and compounds for testing. This comparative genomics resource provides a much-needed boost for the research community to understand and combat parasitic worms

Particle identification in ALICE: a Bayesian approach

We present a Bayesian approach to particle identification (PID) within the ALICE experiment. The aim is to more effectively combine the particle identification capabilities of its various detectors. After a brief explanation of the adopted methodology and formalism, the performance of the Bayesian PID approach for charged pions, kaons and protons in the central barrel of ALICE is studied. PID is performed via measurements of specific energy loss ($\mathrm{d}E/\mathrm{d}x$) and time-of-flight. PID efficiencies and misidentification probabilities are extracted and compared with Monte Carlo simulations using high-purity samples of identified particles in the decay channels ${\rm K}^0_S \rightarrow \pi^-\pi^+$, $\phi \rightarrow {\rm K}^-{\rm K}^+$, and $\Lambda \rightarrow {\rm p}\pi^-$ in p-Pb collisions at $\sqrt{s_{\rm NN}}=5.02$ TeV. In order to thoroughly assess the validity of the Bayesian approach, this methodology was used to obtain corrected $p_{\rm T}$ spectra of pions, kaons, protons, and D$^0$ mesons in pp collisions at $\sqrt{s}=7$ TeV. In all cases, the results using Bayesian PID were found to be consistent with previous measurements performed by ALICE using a standard PID approach. For the measurement of D$^0 \rightarrow {\rm K}^-\pi^+$, it was found that a Bayesian PID approach gave a higher signal-to-background ratio and a similar or larger statistical significance when compared with standard PID selections, despite a reduced identification efficiency. Finally, we present an exploratory study of the measurement of $\Lambda_{\rm c}^{+}\rightarrow {\rm p} {\rm K}^-\pi^+$ in pp collisions at $\sqrt{s}=7$ TeV, using the Bayesian approach for the identification of its decay products