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Background Post-COVID-19 condition encompasses symptoms following COVID-19 infection that linger at least 4 weeks after the end of active infection. Symptoms are wide ranging, but breathlessness is common. Purpose To determine if the previously described lung abnormalities seen on hyperpolarized (HP) pulmonary xenon 129 (129Xe) MRI scans in participants with post-COVID-19 condition who were hospitalized are also present in participants with post-COVID-19 condition who were not hospitalized. Materials and Methods In this prospective study, nonhospitalized participants with post-COVID-19 condition (NHLC) and posthospitalized participants with post-COVID-19 condition (PHC) were enrolled from June 2020 to August 2021. Participants underwent chest CT, HP 129Xe MRI, pulmonary function testing, and the 1-minute sit-to-stand test and completed breathlessness questionnaires. Control subjects underwent HP 129Xe MRI only. CT scans were analyzed for post-COVID-19 interstitial lung disease severity using a previously published scoring system and full-scale airway network (FAN) modeling. Analysis used group and pairwise comparisons between participants and control subjects and correlations between participant clinical and imaging data. Results A total of 11 NHLC participants (four men, seven women; mean age, 44 years ± 11 [SD]; 95% CI: 37, 50) and 12 PHC participants (10 men, two women; mean age, 58 years ±10; 95% CI: 52, 64) were included, with a significant difference in age between groups (P = .05). Mean time from infection was 287 days ± 79 (95% CI: 240, 334) and 143 days ± 72 (95% CI: 105, 190) in NHLC and PHC participants, respectively. NHLC and PHC participants had normal or near normal CT scans (mean, 0.3/25 ± 0.6 [95% CI: 0, 0.63] and 7/25 ± 5 [95% CI: 4, 10], respectively). Gas transfer (DLCO) was different between NHLC and PHC participants (mean DLCO, 76% ± 8 [95% CI: 73, 83] vs 86% ± 8 [95% CI: 80, 91], respectively; P = .04), but there was no evidence of other differences in lung function. Mean red blood cell–to-tissue plasma ratio was different between volunteers (mean, 0.45 ± 0.07; 95% CI: 0.43, 0.47]) and PHC participants (mean, 0.31 ± 0.10; 95% CI: 0.24, 0.37; P = .02) and between volunteers and NHLC participants (mean, 0.37 ± 0.10; 95% CI: 0.31, 0.44; P = .03) but not between NHLC and PHC participants (P = .26). FAN results did not correlate with DLCO) or HP 129Xe MRI results. Conclusion Nonhospitalized participants with post-COVID-19 condition (NHLC) and posthospitalized participants with post-COVID-19 condition (PHC) showed hyperpolarized pulmonary xenon 129 MRI and red blood cell–to-tissue plasma abnormalities, with NHLC participants demonstrating lower gas transfer than PHC participants despite having normal CT findings.

BackgroundLong-COVID is an umbrella term used to describe ongoing symptoms following COVID-19 infection after four weeks. Symptoms are wide-ranging but breathlessness is one of the most common and can persist for months after the initial infection. Investigations including Computed Tomography (CT), and physiological measurements (lung function tests) are usually unremarkable. The mechanisms driving breathlessness remain unclear, and this may be hindering the development of effective treatments.MethodsEleven non-hospitalised Long-COVID (NHLC, 4 male), 12 post-hospitalised COVID-19 (PHC, 10 male) patients were recruited from a Post-COVID Assessment clinic, and thirteen healthy controls (6 female) were recruited to undergo Hyperpolarized Xenon Magnetic Resonance Imaging (Hp-XeMRI). NHLC and PHC participants underwent contemporaneous CT, Hp-XeMRI, lung function tests, 1-minute sit-to-stand test and breathlessness questionnaires. Statistical analysis included group and pair-wise comparisons between patients and controls, and correlations between patient clinical and imaging data.ResultsNHLC and PHC patients were 287 ± 79 [range 190-437] and 149 ± 68 [range 68-269] days from infection, respectively. All NHLC patients had normal CT scans, and the PHC had normal or near normal CT scans (0.3/25 ± 0.6 [range 0-2] and 7/25 ± 5 [range 4-8], respectively). There was a significant difference in TLco (%) between NHLC and PHC patients (76 ± 8 % vs 86 ± 8%, respectively, p = 0.04) but no differences in other measurements of lung function. There were significant differences in RBC:TP mean between volunteers (0.45 ± 0.07, range [0.33-0.55]) and PHC (0.31 ± 0.11, [range 0.16-0.37]) and NHLC (0.35 ± 0.09, [range 0.26-0.58]) patients, but not between NHLC and PHC (p = 0.26).ConclusionThere are RBC:TP abnormalities in NHLC and PHC patients, with NHLC patients also demonstrating lower TLco than PHC patients despite their having normal CT scans. These abnormalities are present many months after the initial infection.Summary statementHyperpolarized Xenon MRI and TLco demonstrate significantly impaired gas transfer in non-hospitalised long-COVID patients when all other investigations are normal.Key resultsThere are significant differences in RBC:TP mean between healthy controls and PHC/NHLC patients (0.45 ± 0.07, range [0.33-0.55], 0.31 ± 0.11, [range 0.16-0.37], 0.35 ± 0.09, [range 0.26-0.58], respectively, p < 0.05 after correction for multiple comparisons) indicating a change in lung compartment volumes between groups.There was a significant difference in TLco (%) between NHLC and PHC patients (76 ± 8 % vs 86 ± 8%, respectively, p = 0.04), despite normal or near normal FEV (%) (100 ± 13% [range 72-123%] and 88 ± 21% [range 62-113%], p>0.05.There were significant differences in CT abnormalities between NHLC and PHC patients (0.3/25 ± 0.6 [range 0-2] and 7/25 ± 5 [range 4-8], respectively) despite similarly impaired RBC:TP.

Background:SARS-CoV-2 targets angiotensin-converting enzyme 2 (ACE2) expressing cells in the respiratory tract. There are reports of breathlessness in patients many months post-infection. Purpose:This study aimedd to determine if hyperpolarized129Xe MRI (XeMRI) imaging could identify the possible cause of breathlessness in patients three months after hospital discharge following COVID-19 infection. Materials and Methods:This prospective study was undertaken between August and December 2020, with patients and healthy control volunteers enrolled. All patients underwent: lung function tests; ventilation and dissolved phase XeMRI, with the mean Red Blood Cell (RBC):Tissue Plasma (TP) ratio to be calculated; and a low dose chest CT scored for the degree of post-COVID-19 abnormalities. Healthy controls underwent XeMRI. The intraclass correlation coefficient was calculated for volunteer and patient scans, to assess repeatability. A Wilcoxon rank-sum test and Cohen's effect size calculated to assess for differences between RBC:TP in patient and controls. Results:9 patients (mean age 57±7 years, Male = 6) and 5 volunteers (29 ± 3 years, Female = 5) were enrolled. Patient mean time from hospital discharge was 169, range 116-254 days. There was a difference in RBC:TP between patients and controls (0.3 ± 0.1 versus 0.5 ± 0.1, respectively, p = 0.001, effect size = 1.36). There was significant difference between the RBC and gas phase spectral full width at half maximum (FWHM) between volunteers and patients (median ± 95 % confidence interval, 567 ± 1 vs 507 ± 81, p = 0.002 and 104 ± 2 vs 122 ± 17, p = 0.004, respectively). Results were reproducible with Intraclass Correlation Coefficients of 0.82 and 0.88 for patients and volunteers respectively. Participants had normal or near normal CT scans, mean 7/25, range 0-10/25. Conclusion:Xe MRI showed alveolar-capillary diffusion limitation in all 9 post COVID-19 pneumonia patients despite normal or nearly normal CT scans. See also the editorial byDietrich.

This study describes the use of cynomolgus macaques of Chinese origin (CCM) to evaluate the efficacy and immunogenicity of the BCG vaccine against high dose aerosol Mycobacterium tuberculosis challenge. Progressive disease developed in three of the unvaccinated animals within 10 weeks of challenge, whereas all six vaccinated animals controlled disease for 26 weeks. Three unvaccinated animals limited disease progression, highlighting the intrinsic ability of this macaque species to control disease in comparison to macaques of other species and genotypes. Low levels of IFNγ were induced by BCG vaccination in CCM suggesting that IFNγ alone does not provide a sufficiently sensitive biomarker of vaccination in this model. An early response after challenge, together with the natural bias towards terminal effector memory T-cell populations and the contribution of monocytes appears to enhance the ability of CCM to naturally control infection. The high dose aerosol challenge model of CCM has value for examination of the host immune system to characterise control of infection which would influence future vaccine design. Although it may not be the preferred platform for the assessment of prophylactic vaccine candidates, the model could be well suited for testing post-exposure vaccination strategies and drug evaluation studies.

This study describes the use of cynomolgus macaques of Chinese origin (CCM) to evaluate the efficacy and immunogenicity of the BCG vaccine against high dose aerosol Mycobacterium tuberculosis challenge. Progressive disease developed in three of the unvaccinated animals within ten weeks of challenge, whereas all six vaccinated animals controlled disease for 26 weeks. Three unvaccinated animals limited disease progression, highlighting the intrinsic ability of this macaque species to control disease in comparison to macaques of other species and genotypes. Low levels of IFNγ were induced by BCG vaccination in CCM suggesting that IFNγ alone does not provide a sufficiently sensitive biomarker of vaccination in this model. An early response after challenge, together with the natural bias towards terminal effector memory T-cell populations and the contribution of monocytes appears to enhance the ability of CCM to naturally control infection. The high dose aerosol challenge model of CCM has value for examination of the host immune system to characterise control of infection which would influence future vaccine design. Although it may not be the preferred platform for the assessment of prophylactic vaccine candidates, the model could be well suited for testing post-exposure vaccination strategies and drug evaluation studies.

A single intradermal vaccination with MTBVAC given to adult rhesus macaques was well tolerated and conferred a significant improvement in outcome following aerosol exposure to M. tuberculosis compared to that provided by a single BCG vaccination. Vaccination with MTBVAC resulted in a significant reduction in M. tuberculosis infection-induced disease pathology measured using in vivo medical imaging, in gross pathology lesion counts and pathology scores recorded at necropsy, the frequency and severity of pulmonary granulomas and the frequency of recovery of viable M. tuberculosis from extrapulmonary tissues following challenge. The immune profiles induced following immunisation with MTBVAC reflect those identified in human clinical trials of MTBVAC. Evaluation of MTBVAC- and TB peptide-pool-specific T-cell cytokine production revealed a predominantly Th1 response from poly- (IFN-γ+TNF-α+IL2+) and multi-(IFN-γ+TNF-α+) functional CD4 T cells, while only low levels of Th22, Th17 and cytokine-producing CD8 T-cell populations were detected together with low-level, but significant, increases in CFP10-specific IFN-γ secreting cells. In this report, we describe concordance between immune profiles measured in clinical trials and a macaque pre-clinical study demonstrating significantly improved outcome after M. tuberculosis challenge as evidence to support the continued development of MTBVAC as an effective prophylactic vaccine for TB vaccination campaigns.

Imaging is used in human medicine to diagnose disease and monitor treatment efficacy. Computed tomography (CT) positron emission tomography (PET) and magnetic resonance (MR) are applied to animal models of infectious diseases to increase data quality, enhance their relevance to the clinical situation, and to address ethical issues through reduction of numbers and refinement of study designs. The time required for collection of MR and PET-CT scans means that normal breathing produces motion artefacts that can render images unacceptable. We report, for the first time, the use of high frequency jet ventilation (HFJV) for respiratory management during imaging of macaques. HFJV enables continuous gaseous exchange, resulting in cessation of spontaneous breathing motion thus providing a motionless field without the potential stresses induced by repeated breath-hold strategies.

Until validated correlates of protection are identified, animal models remain the only way to test the efficacy of the new vaccines and drugs urgently needed to fight the global epidemic caused by infection with Mycobacterium tuberculosis. Non-human primates (NHP) offer the most relevant models of human tuberculosis (TB) and are central to the development process for new interventions. Efficacy evaluations are dependent on the capability of the test model to discriminate improved outcomes between treated groups after experimental exposure to M. tuberculosis and therefore the ability to measure TB-induced disease burden is central to the process. We have developed a score system that allows us to quantify the disease burden induced in macaques by infection with M. tuberculosis, based on the extent and features of disease visible on computed tomography (CT) images. The CT determined disease burden was then verified against that obtained using an established pathology-based approach. Trials of the system as a tool to measure disease burden have shown the approach capable of revealing differences between treatment groups in order to: (a) characterise outcome of infection and enable model refinement; (b) demonstrate the efficacy of drug treatment regimens by showing differences in outcome between test groups. Initial trials suggest that the imaging-based score system provides a valuable additional tool for the measurement of TB-induced disease burden that offers the opportunity to apply both refinement and reduction within studies.

PURPOSE: To examine the feasibility of imaging-based spirometry using high-temporal-resolution projection MRI and hyperpolarized xenon 129 ((129)Xe) gas. MATERIALS AND METHODS: In this prospective exploratory study, five healthy participants (age range, 25–45 years; three men) underwent an MRI spirometry technique using inhaled hyperpolarized (129)Xe and rapid two-dimensional projection MRI. Participants inhaled (129)Xe, then performed a forced expiratory maneuver while in an MR imager. Images of the lungs during expiration were captured in time intervals as short as 250 msec. Volume-corrected images of the lungs at expiration commencement (0 second), 1 second after expiration, and 6 seconds after expiration were extracted to generate forced expiratory volume in 1 second (FEV(1)), forced vital capacity (FVC), and FEV(1)/FVC ratio pulmonary maps. For comparison, participants performed conventional spirometry in the sitting position using room air, in the supine position using room air, and in the supine position using a room air and (129)Xe mixture. Paired t tests with Bonferroni corrections for multiple comparisons were used for statistical analyses. RESULTS: The mean MRI-derived FEV(1)/FVC value was lower in comparison with conventional spirometry (0.52 ± 0.03 vs 0.70 ± 0.05, P < .01), which may reflect selective (129)Xe retention. A secondary finding of this study was that 1 L of inhaled (129)Xe negatively impacted pulmonary function as measured by conventional spirometry (in supine position), which reduced measured FEV(1) (2.70 ± 0.90 vs 3.04 ± 0.85, P < .01) and FEV(1)/FVC (0.70 ± 0.05 vs 0.79 ± 0.04, P < .01). CONCLUSION: A forced expiratory maneuver was successfully imaged with hyperpolarized (129)Xe and high-temporal-resolution MRI. Derivation of regional lung spirometric maps was feasible. Keywords: MR-Imaging, MR-Dynamic Contrast Enhanced, MR-Functional Imaging, Pulmonary, Thorax, Diaphragm, Lung, Pleura, Physics Supplemental material is available for this article. © RSNA, 2021

The recent centenary commemorations of the 1916 Easter Rising were notable for the considerable effort the Irish government put into making them inclusive. However, inclusiveness in this context masks the fact that the commemorations were exclusive of a particular brand of memory that traces in very uncomplicated fashion its own lineage back not just to 1916, but also specifically to the political violence utilized by the Easter Rising rebels. Not included within the state category of the inclusive, for example, was the second largest Easter Rising commemoration in the North, fronted by masked and uniformed figures. This article seeks to shed light on the tenebrous netherworld where the tradition of armed republicanism - through a combination of its own "purist" volition and state strategies of de-legitimization and marginalization - has been confined. It is written from the perspective that the dialectic between revolutionary memory and constitutional memory is an example of how the past is assessed through the prism of the present, and not with an eye for accuracy.

Objectives To investigate the use of a fast dynamic hyperpolarised 129Xe ventilation magnetic resonance imaging (DXeV-MRI) method for detecting and quantifying delayed ventilation in patients with chronic obstructive pulmonary disease (COPD). Methods Three male participants (age range 31–43) with healthy lungs and 15 patients (M/F = 12:3, age range = 48–73) with COPD (stages II–IV) underwent spirometry tests, quantitative chest computed tomography (QCT), and DXeV-MRI at 1.5-Tesla. Regional delayed ventilation was captured by measuring the temporal signal change in each lung region of interest (ROI) in comparison to that in the trachea. In addition to its qualitative assessment through visual inspection by a clinical radiologist, delayed ventilation was quantitatively captured by calculating a covariance measurement of the lung ROI and trachea signals, and quantified using both the time delay, and the difference between the integrated areas covered by the signal-time curves of the two signals. Results Regional temporal ventilation, consistent with the expected physiological changes across a free breathing cycle, was demonstrated with DXeV-MRI in all patients. Delayed ventilation was observed in 13 of the 15 COPD patients and involved variable lung ROIs. This was in contrast to the control group, where no delayed ventilation was demonstrated (p = 0.0173). Conclusions DXeV-MRI offers a non-invasive way of detecting and quantifying delayed ventilation in patients with COPD, and provides physiological information on regional pulmonary function during a full breathing cycle. Key Points • Dynamic xenon MRI allows for the non-invasive detection and measurement of delayed ventilation in COPD patients. • Dynamic xenon MRI during a free breathing cycle can provide unique information about pulmonary physiology and pulmonary disease pathophysiology. • With further validation, dynamic xenon MRI could offer a non-invasive way of measuring collateral ventilation which can then be used to guide lung volume reduction therapy (LVRT) for certain COPD patients. Electronic supplementary material The online version of this article (10.1007/s00330-019-06415-1) contains supplementary material, which is available to authorized users.

Purpose To derive lobar ventilation in patients with chronic obstructive pulmonary disease (COPD) using a rapid time-series hyperpolarized xenon-129 (HPX) magnetic resonance imaging (MRI) technique and compare this to ventilation/perfusion single-photon emission computed tomography (V/Q-SPECT), correlating the results with high-resolution computed tomography (CT) and pulmonary function tests (PFTs). Materials and methods Twelve COPD subjects (GOLD stages I–IV) participated in this study and underwent HPX-MRI, V/Q-SPECT/CT, high-resolution CT, and PFTs. HPX-MRI was performed using a novel time-series spiral k-space sampling approach. Relative percentage ventilations were calculated for individual lobe for comparison to the relative SPECT lobar ventilation and perfusion. The absolute HPX-MRI percentage ventilation in each lobe was compared to the absolute CT percentage emphysema score calculated using a signal threshold method. Pearson’s correlation and linear regression tests were performed to compare each imaging modality. Results Strong correlations were found between the relative lobar percentage ventilation with HPX-MRI and percentage ventilation SPECT (r = 0.644; p

Purpose To perform magnetic resonance imaging (MRI), human lung imaging, and quantification of the gas-transfer dynamics of hyperpolarized xenon-129 (HPX) from the alveoli into the blood plasma. Materials and methods HPX MRI with iterative decomposition of water and fat with echo asymmetry and least-square estimation (IDEAL) approach were used with multi-interleaved spiral k-space sampling to obtain HPX gas and dissolved phase images. IDEAL time-series images were then obtained from ten subjects including six normal subjects and four patients with pulmonary emphysema to test the feasibility of the proposed technique for capturing xenon-129 gas-transfer dynamics (XGTD). The dynamics of xenon gas diffusion over the entire lung was also investigated by measuring the signal intensity variations between three regions of interest, including the left and right lungs and the heart using Welch’s t test. Results The technique enabled the acquisition of HPX gas and dissolved phase compartment images in a single breath-hold interval of 8 s. The y-intersect of the XGTD curves were also found to be statistically lower in the patients with lung emphysema than in the healthy group (p

Summary Well characterised animal models that can accurately predict efficacy are critical to the development of an improved TB vaccine. The use of high dose challenge for measurement of efficacy in Non-human primate models brings the risk that vaccines with the potential to be efficacious against natural challenge could appear ineffective and thus disregarded. Therefore, there is a need to develop a challenge regimen that is more relevant to natural human infection. This study has established that ultra-low dose infection of macaques via the aerosol route can be reproducibly achieved and provides the first description of the development of TB disease in both rhesus and cynomolgus macaques following exposure to estimated retained doses in the lung of less than 10 CFU of Mycobacterium tuberculosis. CT scanning in vivo and histopathology revealed differences in the progression and burden of disease between the two species. Rhesus macaques exhibited a more progressive disease and cynomolgus macaques showed a reduced disease burden. The ability to deliver reproducible ultra-low dose aerosols to macaques will enable the development of refined models of M. tuberculosis infection for evaluation of the efficacy of novel tuberculosis vaccines that offers increased clinical relevance and improved animal welfare.

Dynamic contrast-enhanced magnetic resonance lymphangiography is a radiation-free, high spatial resolution technique which is increasingly used to evaluate thoracic lymphatic disorders and for pre-procedural planning. DCE has the added advantage of allowing dynamic real-time evaluation of lymphatic flow. It can be employed to investigate commonly encountered clinical situations such as recurrent pleural effusions following trauma, thoracic duct injury after thoracic surgery, and exclude diseases and congenital malformations of the thoracic lymphatic system. The imaging procedure and protocol are detailed in this case series to highlight the application of dynamic contrast-enhanced magnetic resonance lymphangiography in everyday practice and its importance to guide surgical planning.

McIntyre looks at the widespread fragmentation within republicanism and examines the more salient causes. He contends that within the nationalist constituency, constitutional nationalism has a hegemonic position that is virtually unassailable from within. The chapter questions what—if any—potential there exists for republicanism to overcome its disparate composition to the point where it can challenge the current nationalist hegemon.

Purpose To develop and optimize a rapid dynamic hyperpolarized 129Xe ventilation (DXeV) MRI protocol and investigate the feasibility of capturing pulmonary signal‐time curves in human lungs. Theory and Methods Spiral k‐space trajectories were designed with the number of interleaves N int = 1, 2, 4, and 8 corresponding to voxel sizes of 8 mm, 5 mm, 4 mm, and 2.5 mm, respectively, for field of view = 15 cm. DXeV images were acquired from a gas‐flow phantom to investigate the ability of N int = 1, 2, 4, and 8 to capture signal‐time curves. A finite element model was constructed to investigate gas‐flow dynamics corroborating the experimental signal‐time curves. DXeV images were also carried out in six subjects (three healthy and three chronic obstructive pulmonary disease subjects). Results DXeV images and numerical modelling of signal‐time curves permitted the quantification of temporal and spatial resolutions for different numbers of spiral interleaves. The two‐interleaved spiral (N int = 2) was found to be the most time‐efficient to obtain DXeV images and signal‐time curves of whole lungs with a temporal resolution of 624 ms for 13 slices. Signal‐time curves were well matched in three healthy volunteers. The Spearman's correlations of chronic obstructive pulmonary disease subjects were statistically different from three healthy subjects (P

BACKGROUND:New interventions for tuberculosis are urgently needed. Non-human primate (NHP) models provide the most relevant pre-clinical models of human disease and play a critical role in vaccine development. Models utilising Asian cynomolgus macaque populations are well established but the restricted genetic diversity of the Mauritian cynomolgus macaques may be of added value. METHODS:Mauritian cynomolgus macaques were exposed to a range of doses of M. tuberculosis delivered by aerosol, and the outcome was assessed using clinical, imaging and pathology-based measures. RESULTS:All macaques developed characteristic clinical signs and disease features of tuberculosis (TB). Disease burden and the ability to control disease were dependent on exposure dose. Mauritian cynomolgus macaques showed less variation in pulmonary disease burden and total gross pathology scores within exposure dose groups than either Indian rhesus macaques or Chinese cynomolgus macaques. CONCLUSIONS:The genetic homogeneity of Mauritian cynomolgus macaques makes them a potentially useful model of human tuberculosis.

Intradermal (ID) BCG injection provides incomplete protection against TB in humans and experimental models. Alternative BCG vaccination strategies may improve protection in model species, including rhesus macaques. This study compares the immunogenicity and efficacy of BCG administered by ID and intravenous (IV) injection, or as an intratracheal mucosal boost (ID + IT), against aerosol challenge with Mycobacterium tuberculosis Erdman strain. Disease pathology was significantly reduced, and survival improved, by each BCG vaccination strategy, relative to unvaccinated animals. However, IV induced protection surpassed that achieved by all other routes, providing an opportunity to explore protective immunological mechanisms using antigen-specific IFN-γ ELISpot and polychromatic flow cytometry assays. IFN-γ spot forming units and multifunctional CD4 T-cell frequencies increased significantly following each vaccination regimen and were greatest following IV immunisation. Vaccine-induced multifunctional CD4 T-cells producing IFN-γ and TNF-α were associated with reduced disease pathology following subsequent M.tb challenge; however, high frequencies of this population following M.tb infection correlated with increased pathology. Cytokine producing T-cells primarily occupied the CD4 transitional effector memory phenotype, implicating this population as central to the mycobacterial response, potentially contributing to the stringent control observed in IV vaccinated animals. This study demonstrates the protective efficacy of IV BCG vaccination in rhesus macaques, offering a valuable tool for the interrogation of immunological mechanisms and potential correlates of protection.

The status of most violent liberal democracy in the world is not one that any country or region, unless perversely enamoured of dysfunction, would seek to covet. Yet, some place has to get it, and ...

SummaryNon-human primates (NHP) provide a key component in the preclinical assessment pathway for new TB vaccines. In the established models, Mycobacterium tuberculosis challenge is typically delivered to airways of macaques either by aerosol or bronchoscopic instillation and therefore, an understanding of these delivery routes would facilitate the comparison of data generated from models using different challenge methods. This study compared the clinical effects, antigen-specific IFNγ response profiles and disease burden following delivery of comparable doses of M. tuberculosis to the lungs of rhesus macaques by either aerosol or bronchoscopic instillation. The outcome of infection in terms of clinical effects and overall disease burden was comparable between both routes of challenge. However, the pathology in the lungs differed as disease was localised to the site of inoculation following bronchoscopic instillation while aerosol exposure resulted in lesions being evenly distributed through the lung. Whilst the IFNγ response to PPD was similar, responses to CFP10 and ESAT6 peptide pools measured with an ex vivo ELISPOT differed with regards to responses to the N-terminal regions depending on the route of infection. Both challenge routes therefore provide valid and comparable models for evaluation of new TB vaccines, although subtle differences in host responses may occur.

Summary Three rhesus macaques (Macaca mulatta) were challenged with Mycobacterium tuberculosis (Mtb), Erdman strain, as part of studies to investigate lesion development at early time points in tuberculosis (TB) and to assess computed tomography (CT) as a method of monitoring disease progression in vivo. Animals were challenged with either a high, mid or low dose of aerosolized Mtb. The low-dose animal was killed humanely at 24 days post challenge (dpc) and the remaining animals at 25 dpc. Abnormalities in clinical parameters were observed in all animals, but clinical signs relating to respiratory disease were not seen. Pulmonary changes consistent with TB infection were detected by CT at 21 dpc and magnetic resonance imaging (MRI) post mortem. Pulmonary nodule counts obtained from both imaging techniques were directly proportional to the challenge dose and correlated with gross and microscopical lesion counts. On gross and microscopical examination, lesions of similar size and morphology were observed in the lungs of all three animals, with the majority containing necrotic foci. Concomitant gross and microscopical, granulomatous lesions were observed in the tracheobronchial lymph nodes of all animals together with evidence of systemic spread. These findings further contribute to our understanding and knowledge of early lesion formation in the lungs of non-human primates.

In the preface to this book, the author Dipak K. Gupta reveals that he hails from “a long line of terrorists and their adversaries.” 1 More importantly when he arrived at college in Calcutta he ali...

As someone who served many years in prison for being a “terrorist,” I incline to bristle when meeting the term in the work of academics. The intense and prolonged Irish prison protests of three dec...

The dynamic behind modern Irish republicanism is not an aspiration to complete the ‘unfinished business’. It is the structural exclusion, perceived and real, experienced by nationalists within the North of Ireland. Republicanism crystallises opposition to this exclusion. The British state has only ever had one consistent strategic objective ‐ to render ineffectual the military capacity of the IRA. This strategic thread has weaved its way through all major British state initiatives from Sunningdale to the Downing Street Declaration. Tracing the evolution of republican thinking and responses to Sunningdale, the Anglo Irish Agreement and the Downing Street Declaration, illustrates to what extent the British state has been successful in securing its strategic objectives.

Objective To assess the use of fetal magnetic resonance imaging (MRI) in obtaining a definitive prenatal diagnosis of cleft palate. Design All expectant mothers with a sonographically diagnosed fetal cleft lip or a previously affected child with cleft palate were offered antenatal MRI at around 34 weeks' gestation. Images were interpreted by a consultant radiologist who was blinded to the ultrasound diagnosis. Two MRI readings were performed: one at the time of examination and one at the end of the study to elicit the radiologist's learning curve. MRI findings were correlated with the birth diagnosis. Setting Tertiary referral center for facial clefts—the Spires Cleft Centre, Oxford Children's Hospital, Oxford, United Kingdom. Participants Study participants included 49 pregnant women between 24 and 37 weeks' gestation, four with a family history of cleft posterior palate and 45 with a facial cleft on a 20-week ultrasound. Results The positive predictive value of fetal MRI for involvement of the palate was 96%, and the negative predictive value was 80%. The accuracy in predicting palatal clefting of four different MRI signs is discussed. The radiologist's interpretation skills significantly improved between the two MRI readings. Conclusions Fetal MRI enables us to predict accurately the extent of a cleft palate after an ultrasound diagnosis of cleft lip. With more accurate diagnosis of the severity of the cleft, we can counsel patients more precisely and plan postnatal management correctly.