Intranasal vaccination with protein bodies elicit strong protection against Streptococcus pneumoniae colonization.

Protein bodies (PBs) are particles consisting of insoluble, aggregated proteins with potential as a vaccine formulation. PBs can contain high concentrations of antigen, are stable and relatively resistant to proteases, release antigen slowly and are cost-effective to manufacture. Yet, the capacity of PBs to provoke immune responses and protection in the upper respiratory tract, a major entry route of respiratory pathogens, is largely unknown. In this study, we vaccinated mice intranasally with PBs comprising antigens from Streptococcus pneumoniae and evaluated the level of protection against nasopharyngeal colonization. PBs composed of the α-helical domain of pneumococcal surface protein A (PspAα) provided superior protection against colonization with S. pneumoniae compared to soluble PspAα. Immunization with soluble protein or PBs induced differences in antibody binding to pneumococci as well as a highly distinct antigen-specific nasal cytokine profile upon in vivo stimulation with inactivated S. pneumoniae. Moreover, immunization with PBs composed of conserved putative pneumococcal antigens reduced colonization by S. pneumoniae in mice, both as a single- and as a multi-antigen formulation. In conclusion, PBs represent a vaccine formulation that elicits strong mucosal immune responses and protection. The versatility of this platform offers opportunities for development of next-generation vaccine formulations.

Roadmap Consensus on Carotid Artery Plaque Imaging and Impact on Therapy Strategies and Guidelines: An International, Multispecialty, Expert Review and Position Statement.

Current guidelines for primary and secondary prevention of stroke in patients with carotid atherosclerosis are based on the quantification of the degree of stenosis and symptom status. Recent publications have demonstrated that plaque morphology and composition, independent of the degree of stenosis, are important in the risk stratification of carotid atherosclerotic disease. This finding raises the question as to whether current guidelines are adequate or if they should be updated with new evidence, including imaging for plaque phenotyping, risk stratification, and clinical decision-making in addition to the degree of stenosis. To further this discussion, this roadmap consensus article defines the limits of luminal imaging and highlights the current evidence supporting the role of plaque imaging. Furthermore, we identify gaps in current knowledge and suggest steps to generate high-quality evidence, to add relevant information to guidelines currently based on the quantification of stenosis.

How do we fight COVID-19? Military medical actions in the war against the COVID-19 pandemic in France.

'We are at war', French President Emmanuel Macron said in an address to the nation on 16 March 2020. As part of this national effort, the French Military Medical Service (FMMS) is committed to the fight against COVID-19. This original report aimed to describe and detail actions that the FMMS has carried out in the nationwide fight against the COVID-19 pandemic in France, as well as overseas. Experts in the field reported major actions conducted by the FMMS during the COVID-19 pandemic in France. In just few weeks, the FMMS developed ad hoc medical capabilities to support national health authorities. It additionally developed adaptive, collective en route care via aeromedical and naval units and deployed a military intensive care field hospital. A COVID-19 crisis cell coordinated the French Armed Forces health management. The French Military Centre for Epidemiology and Public Health provided all information needed to guide the decision-making process. Medical centres of the French Armed Forces organised the primary care for military patients, with the widespread use of telemedicine. The Paris Fire Brigade and the Marseille Navy Fire Battalion emergency departments ensured prehospital management of patients with COVID-19. The eight French military training hospitals cooperated with civilian regional health agencies. The French military medical supply chain supported all military medical treatment facilities in France as well as overseas, coping with a growing shortage of medical equipment. The French Armed Forces Biomedical Research Institute performed diagnostics, engaged in multiple research projects, updated the review of the scientific literature on COVID-19 daily and provided expert recommendations on biosafety. Finally, even students of the French military medical academy volunteered to participate in the fight against the COVID-19 pandemic. In conclusion, in an unprecedented medical crisis, the FMMS engaged multiple innovative and adaptive actions, which are still ongoing, in the fight against COVID-19. The collaboration between military and civilian healthcare systems reinforced the shared objective to achieve the goal of 'saving the greatest number'.

Can MRI Visual Assessment Differentiate the Variants of Primary-Progressive Aphasia?

BACKGROUND AND PURPOSE: Primary-progressive aphasia is a clinically and pathologically heterogeneous condition. Nonfluent, semantic, and logopenic are the currently recognized clinical variants. The recommendations for the classification of primary-progressive aphasia have advocated variant-specific patterns of atrophy. The aims of the present study were to evaluate the sensitivity and specificity of the proposed imaging criteria and to assess the intra- and interrater reporting agreements. MATERIALS AND METHODS: The cohort comprised 51 patients with a root diagnosis of primary-progressive aphasia, 25 patients with typical Alzheimer disease, and 26 matched control participants. Group-level analysis (voxel-based morphometry) confirmed the proposed atrophy patterns for the 3 syndromes. The individual T1-weighted anatomic images were reported by 3 senior neuroradiologists. RESULTS: We observed a dichotomized pattern of high sensitivity (92%) and specificity (93%) for the proposed atrophy pattern of semantic-variant primary-progressive aphasia and low sensitivity (21% for nonfluent-variant primary-progressive aphasia and 43% for logopenic-variant primary-progressive aphasia) but high specificity (91% for nonfluent-variant primary-progressive aphasia and 95% for logopenic-variant primary-progressive aphasia) in other primary-progressive aphasia variants and Alzheimer disease (sensitivity 43%, specificity 92%). MR imaging was least sensitive for the diagnosis of nonfluent-variant primary-progressive aphasia. Intrarater agreement analysis showed mean κ values above the widely accepted threshold of 0.6 (mean, 0.63 ± 0.16). Pair-wise interobserver agreement outcomes, however, were well below this threshold in 5 of the 6 possible interrater contrasts (mean, 0.41 ± 0.09). CONCLUSIONS: While the group-level results were in precise agreement with the recommendations, semantic-variant primary-progressive aphasia was the only subtype for which the proposed recommendations were both sensitive and specific at an individual level.

Imaging Carotid Atherosclerosis Plaque Ulceration: Comparison of Advanced Imaging Modalities and Recent Developments.

Atherosclerosis remains the leading cause of long-term mortality and morbidity worldwide, despite remarkable advancement in its management. Vulnerable atherosclerotic plaques are principally responsible for thromboembolic events in various arterial territories such as carotid, coronary, and lower limb vessels. Carotid plaque ulceration is one of the key features associated with plaque vulnerability and is considered a notable indicator of previous plaque rupture and possible future cerebrovascular events. Multiple imaging modalities have been used to assess the degree of carotid plaque ulceration for diagnostic and research purposes. Early diagnosis and management of carotid artery disease could prevent further cerebrovascular events. In this review, we highlight the merits and limitations of various imaging techniques for identifying plaque ulceration.

New-onset vitiligo and progression of pre-existing vitiligo during treatment with biological agents in chronic inflammatory diseases.

BACKGROUND: The development of vitiligo during treatment with biological agents is an unusual event and only a few isolated cases have been reported. OBJECTIVES: To describe the clinical characteristics and evolution of patients developing new-onset vitiligo following initiation of a biological agent for chronic inflammatory disease; and also to report the clinical course of pre-existing vitiligo under biological therapy. METHODS: This nationwide multicentre, retrospective study, carried out between July 2013 and January 2015, describes the characteristics of a large series of 18 patients (psoriasis N = 8, inflammatory rheumatic diseases N = 8, ulcerative colitis N = 1, uveitis N = 1) who developed new-onset vitiligo while receiving a biological agent. RESULTS: TNFα inhibitors were the most common biological agent involved (13/18) while anti-IL-12/23 and anti-IL-17 agents or abatacept were less common (4/18 and 1/18 respectively). Mean duration of biological agent exposure before vitiligo onset was 13.9 ± 16.5 months. Outcome was favourable for most patients (15/17) while maintaining the biological agent. Data were also collected for 18 patients (psoriasis N = 5, inflammatory rheumatic diseases N = 10, inflammatory bowel diseases N = 2, SAPHO N = 1) who had pre-existing vitiligo when treatment with a biological agent started (TNFα inhibitors N = 15, ustekinumab N = 1, rituximab N = 1, tocilizumab N = 1). Vitiligo progressed in seven patients and was stable or improved in eight cases. CONCLUSION: Vitiligo may thus emerge and/or progress during treatment with various biological agents, mainly TNFα inhibitors and could be a new paradoxical skin reaction. De novo vitiligo displays a favourable outcome when maintaining the biological agent, whereas the prognosis seems worse in cases of pre-existing vitiligo.

Advances in MRI for the evaluation of carotid atherosclerosis.

Carotid artery atherosclerosis is an important source of mortality and morbidity in the Western world with significant socioeconomic implications. The quest for the early identification of the vulnerable carotid plaque is already in its third decade and traditional measures, such as the sonographic degree of stenosis, are not selective enough to distinguish those who would really benefit from a carotid endarterectomy. MRI of the carotid plaque enables the visualization of plaque composition and specific plaque components that have been linked to a higher risk of subsequent embolic events. Blood suppressed T1 and T2 weighted and proton density-weighted fast spin echo, gradient echo and time-of-flight sequences are typically used to quantify plaque components such as lipid-rich necrotic core, intraplaque haemorrhage, calcification and surface defects including erosion, disruption and ulceration. The purpose of this article is to review the most important recent advances in MRI technology to enable better diagnostic carotid imaging.

Diffusion tensor invasive phenotypes can predict progression-free survival in glioblastomas.

INTRODUCTION: Glioblastomas multiformes (GBM) remain incurable in most cases. Their invasion into normal brain makes current therapies ineffective. Post-mortem studies suggest about a 25% of GBMs invade less than 1 cm from the tumour bulk and 20% invade more than 3 cm. AIM OF STUDY: The study aims to use DTI to assess tumour extension and determine how previously reported patterns relate to the progression-free survival (PFS). MATERIALS AND METHODS: Twenty-five patients with GBM treated according to the EORTC/NCIC protocol were retrospectively analysed. Patients were imaged post-operatively at 1.5 T. The sequences were composed of standard anatomical and a standard DTI sequence. As described earlier p and q maps were constructed. For each of the p and q maps, regions of interest were drawn around the visible abnormality. Patients were assigned a diffuse, localised or minimally invasive pattern. Progression was defined according to the RANO criteria (4) and PFS determined in days. Kaplan-Meier plots of survival for the three groups were plotted as were the proportion of patients who had not progressed at 24 months. RESULTS: The median PFS for the diffuse group was 278 days, for the localised group 605 days and 820 days for the minimally invasive group. Three-fourth of the minimally invasive group were progression-free at 24 months (LOG RANK 9.25; p = 0.010). CONCLUSION: It is possible to identify three invasive phenotypes in GBMs using Diffusion tensor imaging , and these three phenotypes have different progression free survival. A minimal phenotype (20% of patients) predicts a greater delay to progression.

Signal-to-noise ratio increase in carotid atheroma MRI: a comparison of 1.5 and 3 T.

OBJECTIVES: This study reports quantitative comparisons of signal-to-noise ratio (SNR) at 1.5 and 3 T from images of carotid atheroma obtained using a multicontrast, cardiac-gated, blood-suppressed fast spin echo protocol. METHODS: 18 subjects, with carotid atherosclerosis (>30% stenosis) confirmed on ultrasound, were imaged on both 1.5 and 3 T systems using phased-array coils with matched hardware specifications. T(1) weighted (T(1)W), T(2) weighted (T(2)W) and proton density-weighted (PDW) images were acquired with identical scan times. Multiple slices were prescribed to encompass both the carotid bifurcation and the plaque. Image quality was quantified using the SNR and contrast-to-noise ratio (CNR). A phantom experiment was also performed to validate the SNR method and confirm the size of the improvement in SNR. Comparisons of the SNR values from the vessel wall with muscle and plaque/lumen CNR measurements were performed at a patient level. To account for the multiple comparisons a Bonferroni correction was applied. RESULTS: One subject was excluded from the protocol owing to image quality and protocol failure. The mean improvement in SNR in plaque was 1.9, 2.1 and 2.1 in T(1)W, T(2)W and PDW images, respectively. All plaque SNR improvements were statistically significant at the p<0.05 level. The phantom experiment reported an improvement in SNR of 2.4 for PDW images. CONCLUSIONS: Significant gains in SNR can be obtained for carotid atheroma imaging at 3 T compared with 1.5 T. There was also a trend towards increased CNR. However, this was not significant after the application of the Bonferroni correction.

MR angiography and imaging for the evaluation of middle cerebral artery atherosclerotic disease.

Intracranial atherosclerotic disease may constitute the most common cause of ischemic stroke worldwide; yet, in the developed world, imaging research has largely focused on extracranial atherosclerosis. Many studies in populations of Asian, African, and Hispanic descent demonstrate the preponderance of intracranial stenosis compared with carotid stenosis. This review examines the clinical presentations of MCA atherosclerosis and stenosis and the use of noninvasive MR imaging in the assessment of intracranial vasculature. MRA is a well-validated technique that offers great advantage over traditional angiography. Advances in high-resolution MR imaging of MCA stenosis have the potential to yield excellent visualization of plaque. Future developments in high-resolution MR imaging to depict intracranial atherosclerosis are explored in this review; these advances will guide endovascular therapy and the comparison of novel interventions.

Noninvasive carotid artery imaging with a focus on the vulnerable plaque.

Currently carotid imaging has 2 main focuses: assessment of luminal stenosis and classification of atherosclerotic plaque characteristics. Measurement of the degree of stenosis is the main assessment used for current treatment decision making, but an evolving idea that is now driving imaging is the concept of vulnerable plaque, which is where plaque components are identified and used to define which plaques are at high risk of causing symptoms compared with those at low risk. This review article covers the methods used for noninvasive assessment of carotid luminal stenosis and the options available for plaque imaging.

In vivo MRI-based 3D mechanical stress-strain profiles of carotid plaques with juxtaluminal plaque haemorrhage: an exploratory study for the mechanism of subsequent cerebrovascular events.

OBJECTIVES: Atherosclerotic plaque features, such as fibrous cap erosion, ulceration and rupture and presence of haemorrhage in carotid plaque are two important characteristics associated with subsequent cerebrovascular events and juxtaluminal haemorrhage/thrombus (JLH/T) indicates these two high-risk characteristics. This study aims to investigate the association between JLH/T and subsequent events in patients suffering from transient ischaemic attack (TIA). Three-dimensional mechanical analysis was employed to represent the critical mechanical stress (P-CStress) and stretch (P-CStretch) within the plaque. METHODS: Fifty TIA patients with mild-to-moderate carotid stenosis (30-69%) underwent high-resolution magnetic resonance imaging (MRI) within 72 h of the acute event and eight were excluded from the analysis due to various reasons. A total of 21 patients were found to have JLH/T in the carotid plaque and 21 did not (N-JLH/T). During a 2-year follow-up period, 11 (52.4%) patients in the JLH/T group experienced recurrent events and none in the N-JLH/T group. Three-dimensional plaque structure was reconstructed based on the in vivo MRI for the mechanical analysis. RESULTS: P-CStress of both groups was comparable (N-JLH/T: 174.45 ± 63.96 kPa vs. JLH/T: 212.60 ± 89.54 kPa; p = 0.120), but P-CStretch of JLH/T was significantly bigger than that of N-JLH/T (N-JLH/T: 1.21 ± 0.08 vs. JLH/T: 2.10 ± 0.53; p < 0.0001). Moreover, there were much bigger variations in stress and stretch of the JLH/T group during one cardiac cycle than in those of N-JLH/T group. CONCLUSIONS: In vivo MRI-depicted JLH/T might be a high risk factor initiating recurrent events, as big deformation appearing around the rupture site might prevent healing and tear the haemorrhage/thrombus away from the host structure and prompt further thrombo-embolic events.

High-resolution magnetic resonance imaging-based biomechanical stress analysis of carotid atheroma: a comparison of single transient ischaemic attack, recurrent transient ischaemic attacks, non-disabling stroke and asymptomatic patient groups.

BACKGROUND: Vulnerable carotid plaques are associated with cerebrovascular ischaemic events. High-resolution magnetic resonance (MR) imaging not only allows the morphological assessment of such plaques, but also provides geometrical data, which can be used for biomechanical stress analysis. We assess its utility to assess the plaque stress profiles of symptomatic (transient ischaemic attack (TIA) and non-disabling stroke) and asymptomatic patients. METHODS: A total of 70 consecutive patients with confirmed underlying carotid artery disease underwent carotid MR imaging of their carotid artery in a 1.5-T MR system using a standard carotid atheroma imaging protocol. MR images were manually segmented for different plaque components and used for biomechanical stress analysis. The maximum critical stress (M-CStress) for various clinical groups was determined and compared. RESULTS: M-CStress of symptomatic plaques (n = 45) was significantly higher than for asymptomatic plaques (n = 25) (median (interquartile range (IQR): 275 kPa (190-390) vs. 165 kPa (120-200), p = 0.0001)). Within the symptomatic group, no M-CStress differences were present between the TIA (n = 30) and stroke (n = 15) patients (260 kPa (190-370) vs. 295 kPa (200-510), p = 0.31). Within the TIA patient cohort, those who had presented with recurrent TIAs (n = 6) had significantly higher stresses than patients who had suffered a single episode (n = 24) (425 kPa (285-580) vs. 250 kPa (180-310), p = 0.001). CONCLUSIONS: Symptomatic carotid plaques, particularly those associated with recurrent TIAs, have high biomechanical stresses. As there is pre-existing evidence to suggest that high biomechanical stresses are associated with plaque vulnerability, MR-imaging-based stress analysis has the potential to identify high-risk patients with vulnerable plaques.

Ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging of abdominal aortic aneurysms--a feasibility study.

OBJECTIVES: Abdominal aortic aneurysms (AAAs), being predominantly atherosclerotic in nature, have underlying inflammatory activity. As it is well established that ultrasmall superparamagnetic iron oxide (USPIO) particles accumulate in the macrophages within atheromatous lesions, USPIO-enhanced magnetic resonance (MR) imaging can be potentially effective in the quantification of the associated inflammatory processes. METHODS: A total of 14 patients underwent USPIO-enhanced MR imaging using a 1.5T-MR system. Quantitative T(2)* and T(2) relaxation time data were acquired before and 36 h after UPSIO infusion at identical AAA locations. The pre- and post-USPIO-infusion relaxation times (T(2)(∗) and T(2)) were quantified and the correlation between pre- and post-USPIO infusion T(2)* and T(2) values was investigated. RESULTS: There was a significant difference between pre- and post-infusion T(2)* and T(2) values (both respective p-values = 0.005). A significant correlation between T(2)* and T(2) values post-USPIO infusion was observed (r = 0.90, p < 0.001), which indicates USPIO uptake by the aortic wall. CONCLUSIONS: Aortic wall inflammation using USPIO-enhanced MR imaging is feasible. Use of quantitative T(2) and T(2)* pulse sequences provides a quantitative method for assessing USPIO uptake by the aortic wall.

Methodology of diffusion-weighted, diffusion tensor and magnetisation transfer imaging.

MRI offers a number of opportunities to examine characteristics of tissue well below the spatial resolution of the imaging technique. The best known of these is diffusion imaging, which allows the production of images whose contrast reflects the ability of water molecules to move through the extravascular extracellular space. Less well-known, but increasingly important, is magnetisation transfer imaging, which produces contrast based on the ability of protons to move between the free water pool and local macromolecules. Both of these techniques offer unique information about the microscopic and molecular structure of tumour tissue. This article will briefly review the underlying theory and technical aspects associated with these imaging techniques.

Imaging biomarkers of brain tumour margin and tumour invasion.

Invasion of tumour cells into the normal brain is one of the major reasons of treatment failure for gliomas. Although there is a good understanding of the molecular and cellular processes that occur during this invasion, it is not possible to detect the extent of the tumour with conventional imaging. However, there is an understanding that the degree of invasion differs with individual tumours, and yet they are all treated the same. Newer imaging techniques that probe the pathological changes within tumours may be suitable biomarkers for invasion. Imaging methods are now available that can detect subtle changes in white matter organisation (diffusion tensor imaging), tumour metabolism and cellular proliferation (using MR spectroscopy and positron emission tomography) occurring in regions of tumour that cannot be detected by conventional imaging. The role of such biomarkers of invasion should allow better delineation of tumour margins, which should improve treatment planning (especially surgery and radiotherapy) and provide information on the invasiveness of an individual tumour to help select the most appropriate therapy and help stratify patients for clinical trials.

Correlation of MR relative cerebral blood volume measurements with cellular density and proliferation in high-grade gliomas: an image-guided biopsy study.

BACKGROUND AND PURPOSE: As newer MR imaging techniques are used to assist with tumor grading, biopsy planning, and therapeutic response assessment, there is a need to relate the imaging characteristics to underlying pathologic processes. The aim of this study was to see how rCBV, a known marker of tumor vascularity, relates to cellular packing attenuation and cellular proliferation. MATERIALS AND METHODS: Nine patients with histologically proved high-grade gliomas and 1 with a supratentorial PNET requiring an image-guided biopsy were recruited. Patients underwent a DSC study. The rCBV at the intended biopsy sites was determined by using a histogram measure to derive the mean, maximum, and 75th centile and 90th centile values. This measure was correlated with histologic markers of the MIB-1 labeling index (as a marker of glioma cell proliferation) and the total number of neoplastic cells in a high-power field (cellular packing attenuation). RESULTS: There was a good correlation between rCBV and MIB-1 by using all the measures of rCBV. The mean rCBV provided the best results (r = 0.66, P < .001). The only correlation with cellular packing attenuation was with the 90% centile (rCBV(90%), r = 0.36, P = .03). The increase in rCBV could be seen over 1 cm from the edge of enhancement in 4/10 cases, and at 2 cm in 1/10. CONCLUSIONS: rCBV correlated with cellular proliferation in high-grade gliomas but not with cellular packing attenuation. The increase in rCBV extended beyond the contrast-enhancing region in 50% of our patients.

Association between biomechanical structural stresses of atherosclerotic carotid plaques and subsequent ischaemic cerebrovascular events--a longitudinal in vivo magnetic resonance imaging-based finite element study.

BACKGROUND: High-resolution magnetic resonance (MR) imaging has been used for MR imaging-based structural stress analysis of atherosclerotic plaques. The biomechanical stress profile of stable plaques has been observed to differ from that of unstable plaques; however, the role that structural stresses play in determining plaque vulnerability remains speculative. METHODS: A total of 61 patients with previous history of symptomatic carotid artery disease underwent carotid plaque MR imaging. Plaque components of the index artery such as fibrous tissue, lipid content and plaque haemorrhage (PH) were delineated and used for finite element analysis-based maximum structural stress (M-C Stress) quantification. These patients were followed up for 2 years. The clinical end point was occurrence of an ischaemic cerebrovascular event. The association of the time to the clinical end point with plaque morphology and M-C Stress was analysed. RESULTS: During a median follow-up duration of 514 days, 20% of patients (n = 12) experienced an ischaemic event in the territory of the index carotid artery. Cox regression analysis indicated that M-C Stress (hazard ratio (HR): 12.98 (95% confidence interval (CI): 1.32-26.67, p = 0.02), fibrous cap (FC) disruption (HR: 7.39 (95% CI: 1.61-33.82), p = 0.009) and PH (HR: 5.85 (95% CI: 1.27-26.77), p = 0.02) are associated with the development of subsequent cerebrovascular events. Plaques associated with future events had higher M-C Stress than those which had remained asymptomatic (median (interquartile range, IQR): 330 kPa (229-494) vs. 254 kPa (166-290), p = 0.04). CONCLUSIONS: High biomechanical structural stresses, in addition to FC rupture and PH, are associated with subsequent cerebrovascular events.