Imaging the Intracranial Atherosclerotic Vessel Wall Using 7T MRI: Initial Comparison with Histopathology

BACKGROUND AND PURPOSE:Several studies have attempted to characterize intracranial atherosclerotic plaques by using MR imaging sequences. However, dedicated validation of these sequences with histology has not yet been performed. The current study assessed the ability of ultra-high-resolution 7T MR imaging sequences with different image contrast weightings to image plaque components, by using histology as criterion standard.MATERIALS AND METHODS:Five specimens of the circle of Wills were imaged at 7T with 0.11 × 0.11 mm in-plane-resolution proton attenuation–, T1-, T2-, and T2*-weighted sequences (through-plane resolution, 0.11–1 mm). Tissue samples from 13 fiducial-marked locations (per specimen) on MR imaging underwent histologic processing and atherosclerotic plaque classification. Reconstructed MR images were matched with histologic sections at corresponding locations.RESULTS:Forty-four samples were available for subsequent evaluation of agreement or disagreement between plaque components and image contrast differences. Of samples, 52.3% (n = 23) showed no image contrast heterogeneity; this group comprised solely no lesions or early lesions. Of samples, 25.0% (n = 11, mostly advanced lesions) showed good correlation between the spatial organization of MR imaging heterogeneities and plaque components. Areas of foamy macrophages were generally seen as proton attenuation–, T2-, and T2*- hypointense areas, while areas of increased collagen content showed more ambiguous signal intensities. Five samples showed image-contrast heterogeneity without corresponding plaque components on histology; 5 other samples showed contrast heterogeneity based on intima-media artifacts.CONCLUSIONS:MR imaging at 7T has the image contrast capable of identifying both focal intracranial vessel wall thickening and distinguishing areas of different signal intensities spatially corresponding to plaque components within more advanced atherosclerotic plaques.

Intracranial atherosclerosis is emerging as one of the main causes of cerebral ischemic stroke and transient ischemic attack, with a high risk of recurrent ischemic events.¹ In recent years, several MR imaging sequences have been developed on 3T and 7T field strengths that specifically visualize the intracranial arterial vessel wall, enabling direct assessment of intracranial atherosclerotic plaques.^2–8 Similar to studies of carotid artery atherosclerosis almost a decade ago, several studies have recently attempted to characterize intracranial plaque components, such as intraplaque hemorrhage,^9,10 fibrous cap,¹¹ and lipid components, by using MR imaging.^12,13For the carotid arteries, much research has already been done validating image signal heterogeneity within the vessel wall with histology, the criterion standard.^14–20 Imaging carotid artery atherosclerosis has the advantage of easy access to ex vivo atherosclerotic plaque material for validation, using carotid endarterectomy specimens. It is now possible to image calcification, fibrous cap, intraplaque hemorrhage, and lipid-rich necrotic core in the carotid artery with moderate-to-good sensitivity and specificity by using multicontrast MR imaging.²⁰ Although 1 recent study showed promising preliminary results of plaque characterization by using a combined T1- and T2-weighted sequence²¹ compared with histology, dedicated validation with histology of intracranial vessel wall sequences with multiple image contrast weightings has not yet been performed. Therefore, whether MR imaging with multiple image contrast weightings has enough image contrast to also visualize various intracranial atherosclerotic plaque components remains a question.Validation of MR images with histology for intracranial atherosclerosis in vivo is much more cumbersome compared with carotid plaques, because no therapies (comparable with carotid endarterectomy) exist in which intracranial atherosclerotic plaques are removed. Furthermore, intracranial arteries are smaller than carotid (or other major peripheral) arteries,²² necessitating a high spatial resolution, and therefore high SNR, for plaque visualization. Because the SNR increases approximately linearly with field strength, 7T MR imaging might provide the spatial resolution necessary to image small atherosclerotic plaques.²² Furthermore, several dedicated intracranial vessel wall sequences at 7T have already shown promising results in the visualization of vessel wall lesions in vivo.In this feasibility study, ultra-high-resolution 7T MR imaging sequences with different image contrast weightings were developed and used in an ex vivo setting, to assess the ability (image contrast) of 7T MR imaging to image different intracranial atherosclerotic plaque components. For validation of our findings, results were compared with histology.     

Using the Consolidated Framework for Implementation Research to Identify Barriers and Facilitators for the Implementation of an Internet-Based Patient-Provider Communication Service in Five Settings: A Qualitative Study

Background

Although there is growing evidence of the positive effects of Internet-based patient-provider communication (IPPC) services for both patients and health care providers, their implementation into clinical practice continues to be a challenge.

Objective

The 3 aims of this study were to (1) identify and compare barriers and facilitators influencing the implementation of an IPPC service in 5 hospital units using the Consolidated Framework for Implementation Research (CFIR), (2) assess the ability of the different constructs of CFIR to distinguish between high and low implementation success, and (3) compare our findings with those from other studies that used the CFIR to discriminate between high and low implementation success.

Methods

This study was based on individual interviews with 10 nurses, 6 physicians, and 1 nutritionist who had used the IPPC to answer messages from patients.

Results

Of the 36 CFIR constructs, 28 were addressed in the interviews, of which 12 distinguished between high and low implementation units. Most of the distinguishing constructs were related to the inner setting domain of CFIR, indicating that institutional factors were particularly important for successful implementation. Health care providers’ beliefs in the intervention as useful for themselves and their patients as well as the implementation process itself were also important. A comparison of constructs across ours and 2 other studies that also used the CFIR to discriminate between high and low implementation success showed that 24 CFIR constructs distinguished between high and low implementation units in at least 1 study; 11 constructs distinguished in 2 studies. However, only 2 constructs (patient need and resources and available resources) distinguished consistently between high and low implementation units in all 3 studies.

Conclusions

The CFIR is a helpful framework for illuminating barriers and facilitators influencing IPPC implementation. However, CFIR’s strength of being broad and comprehensive also limits its usefulness as an implementation framework because it does not discriminate between the relative importance of its many constructs for implementation success. This is the first study to identify which CFIR constructs are the most promising to distinguish between high and low implementation success across settings and interventions. Findings from this study can contribute to the refinement of CFIR toward a more succinct and parsimonious framework for planning and evaluation of the implementation of clinical interventions.

ClinicalTrial

Clinicaltrials.gov NCT00971139; http://clinicaltrial.gov/ct2/show/NCT00971139 (Archived by WebCite at http://www.webcitation.org/6cWeqN1uY)     

CD81-Receptor Associations — Impact for Hepatitis C Virus Entry and Antiviral Therapies

Tetraspanins are integral transmembrane proteins organized in microdomains displaying specific and direct interactions with other tetraspanins and molecular partners. Among them, CD81 has been implicated in a variety of physiological and pathological processes. CD81 also plays a crucial role in pathogen entry into host cells, including hepatitis C virus (HCV) entry into hepatocytes. HCV is a major cause of liver cirrhosis and hepatocellular carcinoma. HCV entry into hepatocytes is a complex process that requires the coordinated interaction of viral and host factors for the initiation of infection, including CD81, scavenger receptor BI, claudin-1, occludin, membrane-bound host cell kinases, Niemann-Pick C1 Like 1, Harvey rat sarcoma viral oncogene homolog (HRas), CD63 and transferrin receptor 1. Furthermore, recent data in HCV model systems have demonstrated that targeting critical components of tetraspanins and associated cell membrane proteins open new avenues to prevent and treat viral infection.     

Effect of hyperglycaemia on inflammatory and stress responses and clinical outcome of pneumonia in non-critical-care inpatients: results from an observational cohort study

Aims/hypothesis

Despite the condition’s high prevalence, the influence of hyperglycaemia on clinical outcomes in non-critical-care inpatients with infections remains ill defined. In this study, we analysed associations of glucose levels at admission and during initial inpatient treatment with the inflammatory response and clinical outcome in community-acquired pneumonia (CAP) patients.

Methods

This secondary observational analysis included 880 confirmed CAP patients. We used severity-adjusted multivariate regression models to investigate associations of initial and 96 h mean glucose levels with serially measured biomarker levels over 7 days (C-reactive protein [CRP], procalcitonin, white blood cell count [WBC], pro-adrenomedullin [ProADM]) and adverse clinical course (death and intensive-care unit admission).

Results

In the 724 non-diabetic patients (82.3% of the study population), moderate or severe hyperglycaemia (glucose 6–11 mmol/l and >11 mmol/l, respectively) was associated with increased risk for adverse clinical course (adjusted OR [95% CI] 1.4 [0.8, 2.4] and 3.0 [1.1, 8.0], respectively) and with higher CRP, WBC and ProADM levels over 7 days (p?<?0.05, ANOVA, all days). In diabetic patients (n?=?156), no similar associations were found for initial hyperglycaemia, although mean 96 h glucose levels ?≥?9 mmol/l were associated with adverse clinical course (adjusted OR 5.4 [1.1, 25.8]; p?=?0.03). No effect modification by insulin treatment was detected (interaction terms p?>?0.2 for all analyses).

Conclusions/interpretation

Initial hyperglycaemia in non-diabetic CAP patients, and prolonged hyperglycaemia in diabetic or non-diabetic CAP patients, are associated with a more pronounced inflammatory response and CAP-related adverse clinical outcome. Optimal glucose targets for insulin treatment of hyperglycaemia in non-critical-care settings should be defined.     

An evidence synthesis approach to estimating the incidence of seasonal influenza in the Netherlands

Objectives

To estimate, using Bayesian evidence synthesis, the age-group-specific annual incidence of symptomatic infection with seasonal influenza in the Netherlands over the period 2005–2007.

Methods

The Netherlands population and age group distribution for 2006 defined the base population. The number of influenza-like illness (ILI) cases was estimated from sentinel surveillance data and adjusted for underascertainment using the estimated proportion of ILI cases that do not consult a general practitioner. The estimated number of symptomatic influenza (SI) cases was based on indirect evidence from the surveillance of ILI cases and the proportions of laboratory-confirmed influenza cases in the 2004/5, 2005/6 and 2006/7 respiratory years. In scenario analysis, the number of SI cases prevented by increasing vaccination uptake within the 65 + age group was estimated.

Results

The overall symptomatic infection attack rate (SIAR) over the period 2005–2007 was estimated at 2·5% (95% credible interval [CI]: 2·1–3·2%); 410 200 SI cases (95% CI: 338 500–518 600) were estimated to occur annually. Age-group-specific SIARs were estimated for <5 years at 4·9% (2·1–13·7%), for 5–14 years at 3·0% (2·0–4·7%), for 15–44 years at 2·6% (2·1–3·2%), for 45–64 years at 1·9% (1·4–2·5%) and for 65 + years at 1·7% (1·0–3·0%). Under assumed vaccination uptake increases of 5% and 15%, 1970 and 5310 SI cases would be averted.

Conclusions

By synthesising the available information on seasonal influenza and ILI from diverse sources, the annual extent of symptomatic infection can be derived. These estimates are useful for assessing the burden of seasonal influenza and for guiding vaccination policy.     

Time-course of the electrophysiological maturation and integration of transplanted cardiomyocytes

Electrophysiological maturation and integration of transplanted cardiomyocytes are essential to enhance safety and efficiency of cell replacement therapy. Yet, little is known about these important processes. The aim of our study was to perform a detailed analysis of electrophysiological maturation and integration of transplanted cardiomyocytes. Fetal cardiomyocytes expressing enhanced green fluorescent protein were transplanted into cryoinjured mouse hearts. At 6, 9 and 12days after transplantation, viable slices of recipient hearts were prepared and action potentials of transplanted and host cardiomyocytes within the slices were recorded by microelectrodes. In transplanted cells embedded in healthy host myocardium, action potential duration at 50% repolarization (APD50) decreased from 32.2±3.3ms at day 6 to 27.9±2.6ms at day 9 and 19.6±1.6ms at day 12. The latter value matched the APD50 of host cells (20.5±3.2ms, P=0.78). Integration improved in the course of time: 26% of cells at day 6 and 53% at day 12 revealed no conduction blocks up to a stimulation frequency of 10Hz. APD50 was inversely correlated to the quality of electrical integration. In transplanted cells embedded into the cryoinjury, which showed no electrical integration, APD50 was 49.2±4.3ms at day 12. Fetal cardiomyocytes transplanted into healthy myocardium integrate electrically and mature after transplantation, their action potential properties after 12days are comparable to those of host cardiomyocytes. Quality of electrical integration improves over time, but conduction blocks still occur at day 12 after transplantation. The pace of maturation correlates with the quality of electrical integration. Transplanted cells embedded in cryoinjured tissue still possess immature electrophysiological properties after 12days.