CD47 and CD36 expressions in the placenta of mothers with chorioamnionitis.

INTRODUCTION: Chorioamnionitis is the inflammation of the placenta and is histologically defined as the presence of neutrophilic infiltration into the chorio-amnion membrane with and without involvement of the umbilical cord. Currently, the inflammatory mediators involved in the eliciting of inflammatory response is still largely under investigation. CD47 and CD36 are pro-inflammatory molecules that are still under investigation. The aim of this study was to determine the expressions of CD47 and CD36 in the placenta of mothers with chorioamnionitis. MATERIALS AND METHODS: This was a cross-sectional study, involving a total of 100 cases that comprised of acute subchorionitis (stage I, n=20), acute chorioamnionitis (stage II, n=20), acute necrotising chorioamnionitis (stage III, n=20) and non-chorioamnionitis placenta as control (n=40). All tissue blocks were retrieved from the archived pathology record over a period of 4 years. CD36 and CD47 immunohistochemistry were performed on all cases and their expression in various cell types on the placenta were analysed. RESULTS: CD36 was expressed only on the foetal vascular endothelial cells. Interestingly, CD47 showed positive staining on the neutrophils and its expression was significantly different between maternal inflammatory response stage II chorioamnionitis (n=13/20, p<0.001) with stage I and stage III chorioamnionitis. DISCUSSION: Our study showed CD47 was expressed in the neutrophils and it was associated with poorer perinatal outcomes and it may have a role in the pathogenesis of chorioamnionitis.

Characterization of a HIR-Fab-IDS, Novel Iduronate 2-Sulfatase Fusion Protein for the Treatment of Neuropathic Mucopolysaccharidosis Type II (Hunter Syndrome).

BACKGROUND: Mucopolysaccharidosis type II is a severe lysosomal storage disease caused by deficient activity of the enzyme iduronate-2-sulfatase. The only medicinal product approved by the US Food and Drug Administration for enzyme replacement therapy, recombinant iduronate-2-sulfatase (idursulfase, Elaprase®), is a large molecule that is not able to cross the blood-brain barrier and neutralize progressive damage of the central nervous system caused by the accumulation of glycosaminoglycans. Novel chimeric protein HIR-Fab-IDS is an anti-human insulin receptor Fab fragment fused to recombinant modified iduronate-2-sulfatase. This modification provides a highly selective interaction with the human insulin receptor, which leads to the HIR-Fab-IDS crossing the blood-brain barrier owing to internalization of the hybrid molecule by transcytosis into endothelial cells adjacent to the nervous system by the principle of a 'molecular Trojan horse'. OBJECTIVES: In this work, the physicochemical and biological characterization of a blood-brain barrier-penetrating fusion protein, HIR-Fab-IDS, is carried out. HIR-Fab-IDS consists of an anti-human insulin receptor Fab fragment fused to recombinant iduronate-2-sulfatase. METHODS: Comprehensive analytical characterization utilizing modern techniques (including surface plasmon resonance and mass spectrometry) was performed using preclinical and clinical batches of HIR-Fab-IDS. Critical quality parameters that determine the therapeutic effect of iduronate-2-sulfatase, as well as IDS enzymatic activity and in vitro cell uptake activity were evaluated in comparison with the marketed IDS product Elaprase® (IDS RP). In vivo efficiency of HIR-Fab-IDS in reversing mucopolysaccharidosis type II pathology in IDS-deficient mice was also investigated. The affinity of the chimeric molecule for the INSR was also determined by both an enzyme-linked immunosorbent assay and surface plasmon resonance. We also compared the distribution of 125I-radiolabeled HIR-Fab-IDS and IDS RP in the tissues and brain of cynomolgus monkeys after intravenous administration. RESULTS: The HIR-Fab-IDS primary structure investigation showed no significant post-translational modifications that could affect IDS activity, except for the formylglycine content, which was significantly higher for HIR-Fab-IDS compared with that for IDS RP (~ 76.5 vs ~ 67.7%). Because of this fact, the specific enzyme activity of HIR-Fab-IDS was slightly higher than that of IDS RP (~ 2.73 × 106 U/µmol vs ~ 2.16 × 106 U/µmol). However, differences were found in the glycosylation patterns of the compared IDS products, causing a minor reduced in vitro cellular uptake of HIR-Fab-IDS by mucopolysaccharidosis type II fibroblasts compared with IDS RP (half-maximal effective concentration ~ 26.0 vs ~ 23.0 nM). The efficacy of HIR-Fab-IDS in IDS-deficient mice has demonstrated a statistically significant reduction in the level of glycosaminoglycans in the urine and tissues of the main organs to the level of healthy animals. The HIR-Fab-IDS has revealed high in vitro affinity for human and monkey insulin receptors, and the radioactively labeled product has been shown to penetrate to all parts of the brain and peripheral tissues after intravenous administration to cynomolgus monkeys. CONCLUSIONS: These findings indicate that HIR-Fab-IDS, a novel iduronate-2-sulfatase fusion protein, is a promising candidate for the treatment of central nervous system manifestations in neurological mucopolysaccharidosis type II.

Healthcare service quality measurement in Malaysia: A scoping review.

INTRODUCTION: Although healthcare service industry has been thriving in Malaysia, the types of healthcare service quality models used in past research as well as their key messages had not been explored. A scoping review was performed to determine the validated healthcare service quality models, the key messages of these past studies and potential research gaps that should be addressed in future studies. MATERIALS AND METHODS: Relevant, peer-reviewed, Englishlanguage articles on healthcare service quality in Malaysia were independently searched by the authors using the SCOPUS and EMERALD databases. Articles that do not directly address healthcare service quality within the Malaysian setting were excluded. Additional articles were identified from the reference lists of the selected articles and from Google search engine. A total of 43 out of 2,749 articles were selected. RESULTS: Most of these studies (28 out of the 43 articles, 65.1%) in this scoping review used either the original or a modified version of SERVQUAL instrument to measure healthcare service quality. Significant positive relationships between tangibles, assurance and empathy with patient satisfaction were identified. As SERVQUAL primarily measures the functional dimension of service quality, this suggests that past studies on Malaysian healthcare services emphasised heavily on the functional dimension of healthcare service quality. Functional dimension refers to the expressive performance on how the healthcare service is rendered whereas technical dimension refers to the types of services rendered as well as its safety and efficacy. CONCLUSION: A pertinent research gap identified in this review is the lack of studies that measure both technical and functional dimensions comprehensively. Future research should adopt a more holistic (incorporating both technical dimension and functional dimension) measurement of healthcare service quality.

Anomalous depinning of magnetic domain walls within the ferromagnetic phase of the Weyl semimetal Co3Sn2S2.

We report bulk magnetization measurements and spatially resolved measurements of magnetic domains inCo3Sn2S2single crystals. The results indicate that a previously reported magnetic anomaly around 130 K is due to an anomalous domain wall depinning upon cooling. Our measurements also reveal a hysteresis between field-cooled-cooling and field-cooled-warming magnetization curves acquired under a constant magnetic field below 300 Oe. This observation rules out the possibility that the anomaly stems from a second-order phase transition. Our results further suggest that changes in the shape of hysteresis loops from 5 to 170 K are caused by an unusual temperature-dependent domain nucleation field that changes sign around 130 K. The Kerr rotation images of the magnetic domains confirm that the domain walls depin between 120 and 140 K.

Investigating the impact of RF saturation-pulse parameters on compartment-selective gas-phase depolarization with xenon polarization transfer contrast MRI.

PURPOSE: To demonstrate the utility of continuous-wave (CW) saturation pulses in xenon-polarization transfer contrast (XTC) MRI and MRS, to investigate the selectivity of CW pulses applied to dissolved-phase resonances, and to develop a correction method for measurement biases from saturation of the nontargeted dissolved-phase compartment. METHODS: Studies were performed in six healthy Sprague-Dawley rats over a series of end-exhale breath holds. Discrete saturation schemes included a series of 30 Gaussian pulses (8 ms FWHM), spaced 25 ms apart; CW saturation schemes included single block pulses, with variable flip angle and duration. In XTC imaging, saturation pulses were applied on both dissolved-phase resonance frequencies and off-resonance, to correct for other sources of signal loss and compromised selectivity. In spectroscopy experiments, saturation pulses were applied at a set of 19 frequencies spread out between 185 and 200 ppm to map out modified z-spectra. RESULTS: Both modified z-spectra and imaging results showed that CW RF pulses offer sufficient depolarization and improved selectivity for generating contrast between presaturation and postsaturation acquisitions. A comparison of results obtained using a variety of saturation parameters confirms that saturation pulses applied at higher powers exhibit increased cross-contamination between dissolved-phase resonances. CONCLUSION: Using CW RF saturation pulses in XTC contrast preparation, with the proposed correction method, offers a potentially more selective alternative to traditional discrete saturation. The suppression of the red blood cell contribution to the gas-phase depolarization opens the door to a novel way of quantifying exchange time between alveolar volume and hemoglobin.

Unsupervised segmentation and quantification of COVID-19 lesions on computed Tomography scans using CycleGAN.

BACKGROUND: Lesion segmentation is a critical step in medical image analysis, and methods to identify pathology without time-intensive manual labeling of data are of utmost importance during a pandemic and in resource-constrained healthcare settings. Here, we describe a method for fully automated segmentation and quantification of pathological COVID-19 lung tissue on chest Computed Tomography (CT) scans without the need for manually segmented training data. METHODS: We trained a cycle-consistent generative adversarial network (CycleGAN) to convert images of COVID-19 scans into their generated healthy equivalents. Subtraction of the generated healthy images from their corresponding original CT scans yielded maps of pathological tissue, without background lung parenchyma, fissures, airways, or vessels. We then used these maps to construct three-dimensional lesion segmentations. Using a validation dataset, Dice scores were computed for our lesion segmentations and other published segmentation networks using ground truth segmentations reviewed by radiologists. RESULTS: The COVID-to-Healthy generator eliminated high Hounsfield unit (HU) voxels within pulmonary lesions and replaced them with lower HU voxels. The generator did not distort normal anatomy such as vessels, airways, or fissures. The generated healthy images had higher gas content (2.45 ± 0.93 vs 3.01 ± 0.84 L, P < 0.001) and lower tissue density (1.27 ± 0.40 vs 0.73 ± 0.29 Kg, P < 0.001) than their corresponding original COVID-19 images, and they were not significantly different from those of the healthy images (P < 0.001). Using the validation dataset, lesion segmentations scored an average Dice score of 55.9, comparable to other weakly supervised networks that do require manual segmentations. CONCLUSION: Our CycleGAN model successfully segmented pulmonary lesions in mild and severe COVID-19 cases. Our model's performance was comparable to other published models; however, our model is unique in its ability to segment lesions without the need for manual segmentations.

Imatinib alleviates lung injury and prolongs survival in ventilated rats.

Imatinib, a tyrosine kinase inhibitor, attenuates pulmonary edema and inflammation in lung injury. However, the physiological effects of this drug and their impact on outcomes are poorly characterized. Using serial computed tomography (CT), we tested the hypothesis that imatinib reduces injury severity and improves survival in ventilated rats. Hydrochloric acid (HCl) was instilled in the trachea (pH 1.5, 2.5 mL/kg) of anesthetized, intubated supine rats. Animals were randomized (n = 17 each group) to receive intraperitoneal imatinib or vehicle immediately prior to HCl. All rats then received mechanical ventilation. CT was performed hourly for 4 h. Images were quantitatively analyzed to assess the progression of radiological abnormalities. Injury severity was confirmed via hourly blood gases, serum biomarkers, bronchoalveolar lavage (BAL), and histopathology. Serial blood drug levels were measured in a subset of rats. Imatinib reduced mortality while delaying functional and radiological injury progression: out of 17 rats per condition, 2 control vs. 8 imatinib-treated rats survived until the end of the experiment (P = 0.02). Imatinib attenuated edema after lung injury (P < 0.05), and survival time in both groups was negatively correlated with increased lung mass (R2 = 0.70) as well as other physiological and CT parameters. Capillary leak (BAL protein concentration) was significantly lower in the treated group (P = 0.04). Peak drug concentration was reached after 70 min, and the drug half-life was 150 min. Imatinib decreased both mortality and lung injury severity in mechanically ventilated rats. Pharmacological inhibition of edema could be used during mechanical ventilation to improve the severity and outcome of lung injury.

Ventilation heterogeneity imaged by multibreath wash-ins of hyperpolarized 3 He and 129 Xe in healthy rabbits.

KEY POINTS: Multibreath imaging to estimate regional gas mixing efficiency is superior to intensity-based single-breath ventilation markers, as it is capable of revealing minute but essential measures of ventilation heterogeneity which may be sensitive to subclinical alterations in the early stages of both obstructive and restrictive respiratory disorders. Large-scale convective stratification of ventilation in central-to-peripheral directions is the dominant feature of observed ventilation heterogeneity when imaging a heavy/less diffusive xenon gas mixture; smaller-scale patchiness, probably originating from asymmetric lung function at bronchial airway branching due to the interaction of convective and diffusive flows, is the dominant feature when imaging a lighter/more diffusive helium gas mixture. Since detecting low regional ventilation is crucial for characterizing diseased lungs, our results suggest that dilution with natural abundance helium and imaging at higher lung volumes seem advisable when imaging with hyperpolarized 129 Xe; this will allow the imaging gas to reach slow-filling and/or non-dependent lung regions, which might otherwise be impossible to distinguish from total ventilation shunt regions. The ability to differentiate these regions from those of total shunt is worse with typical single-breath imaging techniques. ABSTRACT: The mixing of freshly inhaled gas with gas already present in the lung can be directly assessed with heretofore unachievable precision via magnetic resonance imaging of signal build-up resulting from multiple wash-ins of a hyperpolarized (HP) gas. Here, we used normoxic HP 3 He and 129 Xe mixtures to study regional ventilation at different spatial scales in five healthy mechanically ventilated supine rabbits at two different inspired volumes. To decouple the respective effects of density and diffusion rates on ventilation heterogeneity, two additional studies were performed: one in which 3 He was diluted with an equal fraction of natural abundance xenon, and one in which 129 Xe was diluted with an equal fraction of 4 He. We observed systematic differences in the spatial scale of specific ventilation heterogeneity between HP 3 He and 129 Xe. We found that large-scale, central-to-peripheral convective ventilation inhomogeneity is the dominant cause of observed heterogeneity when breathing a normoxic xenon gas mixture. In contrast, small-scale ventilation heterogeneity in the form of patchiness, probably originating from asymmetric lung function at bronchial airway branching due to interactions between convective and diffusive flows, is the dominant feature when breathing a normoxic helium gas mixture, for which the critical zone occurs more proximally and at an imageable spatial scale. We also showed that the existence of particular underventilated non-dependent lung regions when breathing a heavy gas mixture is the result of the density of that mixture - rather than, for example, its diffusion rate or viscosity. Finally, we showed that gravity-dependent ventilation heterogeneity becomes substantially more uniform at higher inspired volumes for xenon gas mixtures compared to helium mixtures.

Lung distribution of gas and blood volume in critically ill COVID-19 patients: a quantitative dual-energy computed tomography study.

BACKGROUND: Critically ill COVID-19 patients have pathophysiological lung features characterized by perfusion abnormalities. However, to date no study has evaluated whether the changes in the distribution of pulmonary gas and blood volume are associated with the severity of gas-exchange impairment and the type of respiratory support (non-invasive versus invasive) in patients with severe COVID-19 pneumonia. METHODS: This was a single-center, retrospective cohort study conducted in a tertiary care hospital in Northern Italy during the first pandemic wave. Pulmonary gas and blood distribution was assessed using a technique for quantitative analysis of dual-energy computed tomography. Lung aeration loss (reflected by percentage of normally aerated lung tissue) and the extent of gas:blood volume mismatch (percentage of non-aerated, perfused lung tissue-shunt; aerated, non-perfused dead space; and non-aerated/non-perfused regions) were evaluated in critically ill COVID-19 patients with different clinical severity as reflected by the need for non-invasive or invasive respiratory support. RESULTS: Thirty-five patients admitted to the intensive care unit between February 29th and May 30th, 2020 were included. Patients requiring invasive versus non-invasive mechanical ventilation had both a lower percentage of normally aerated lung tissue (median [interquartile range] 33% [24-49%] vs. 63% [44-68%], p < 0.001); and a larger extent of gas:blood volume mismatch (43% [30-49%] vs. 25% [14-28%], p = 0.001), due to higher shunt (23% [15-32%] vs. 5% [2-16%], p = 0.001) and non-aerated/non perfused regions (5% [3-10%] vs. 1% [0-2%], p = 0.001). The PaO2/FiO2 ratio correlated positively with normally aerated tissue (ρ = 0.730, p < 0.001) and negatively with the extent of gas-blood volume mismatch (ρ = - 0.633, p < 0.001). CONCLUSIONS: In critically ill patients with severe COVID-19 pneumonia, the need for invasive mechanical ventilation and oxygenation impairment were associated with loss of aeration and the extent of gas:blood volume mismatch.

Diminishing Efficacy of Prone Positioning With Late Application in Evolving Lung Injury.

OBJECTIVES: It is not known how lung injury progression during mechanical ventilation modifies pulmonary responses to prone positioning. We compared the effects of prone positioning on regional lung aeration in late versus early stages of lung injury. DESIGN: Prospective, longitudinal imaging study. SETTING: Research imaging facility at The University of Pennsylvania (Philadelphia, PA) and Medical and Surgical ICUs at Massachusetts General Hospital (Boston, MA). SUBJECTS: Anesthetized swine and patients with acute respiratory distress syndrome (acute respiratory distress syndrome). INTERVENTIONS: Lung injury was induced by bronchial hydrochloric acid (3.5 mL/kg) in 10 ventilated Yorkshire pigs and worsened by supine nonprotective ventilation for 24 hours. Whole-lung CT was performed 2 hours after hydrochloric acid (Day 1) in both prone and supine positions and repeated at 24 hours (Day 2). Prone and supine images were registered (superimposed) in pairs to measure the effects of positioning on the aeration of each tissue unit. Two patients with early acute respiratory distress syndrome were compared with two patients with late acute respiratory distress syndrome, using electrical impedance tomography to measure the effects of body position on regional lung mechanics. MEASUREMENTS AND MAIN RESULTS: Gas exchange and respiratory mechanics worsened over 24 hours, indicating lung injury progression. On Day 1, prone positioning reinflated 18.9% ± 5.2% of lung mass in the posterior lung regions. On Day 2, position-associated dorsal reinflation was reduced to 7.3% ± 1.5% (p < 0.05 vs Day 1). Prone positioning decreased aeration in the anterior lungs on both days. Although prone positioning improved posterior lung compliance in the early acute respiratory distress syndrome patients, it had no effect in late acute respiratory distress syndrome subjects. CONCLUSIONS: The effects of prone positioning on lung aeration may depend on the stage of lung injury and duration of prior ventilation; this may limit the clinical efficacy of this treatment if applied late.

Measuring pulmonary gas exchange using compartment-selective xenon-polarization transfer contrast (XTC) MRI.

PURPOSE: To demonstrate the feasibility of generating red blood cell (RBC) and tissue/plasma (TP)-specific gas-phase (GP) depolarization maps using xenon-polarization transfer contrast (XTC) MR imaging. METHODS: Imaging was performed in three healthy subjects, an asymptomatic smoker, and a chronic obstructive pulmonary disease (COPD) patient. Single-breath XTC data were acquired through a series of three GP images using a 2D multi-slice GRE during a 12 s breath-hold. A series of 8 ms Gaussian inversion pulses spaced 30 ms apart were applied in-between the images to quantify the exchange between the GP and dissolved-phase (DP) compartments. Inversion pulses were either centered on-resonance to generate contrast, or off-resonance to correct for other sources of signal loss. For an alternative scheme, inversions of both RBC and TP resonances were inserted in lieu of off-resonance pulses. Finally, this technique was extended to a multi-breath protocol consistent with tidal breathing, involving 30 consecutive acquisitions. RESULTS: Inversion pulses shifted off-resonance by 20 ppm to mimic the distance between the RBC and TP resonances demonstrated selectivity, and initial GP depolarization maps illustrated stark magnitude and distribution differences between healthy and diseased subjects that were consistent with traditional approaches. CONCLUSION: The proposed DP-compartment selective XTC MRI technique provides information on gas exchange between all three detectable states of xenon in the lungs and is sufficiently sensitive to indicate differences in lung function between the study subjects. Investigated extensions of this approach to imaging schemes that either minimize breath-hold duration or the overall number of breath-holds open avenues for future research to improve measurement accuracy and patient comfort.

Metabolic Imaging and Biological Assessment: Platforms to Evaluate Acute Lung Injury and Inflammation.

Pulmonary inflammation is a hallmark of several pulmonary disorders including acute lung injury and acute respiratory distress syndrome. Moreover, it has been shown that patients with hyperinflammatory phenotype have a significantly higher mortality rate. Despite this, current therapeutic approaches focus on managing the injury rather than subsiding the inflammatory burden of the lung. This is because of the lack of appropriate non-invasive biomarkers that can be used clinically to assess pulmonary inflammation. In this review, we discuss two metabolic imaging tools that can be used to non-invasively assess lung inflammation. The first method, Positron Emission Tomography (PET), is widely used in clinical oncology and quantifies flux in metabolic pathways by measuring uptake of a radiolabeled molecule into the cells. The second method, hyperpolarized 13C MRI, is an emerging tool that interrogates the branching points of the metabolic pathways to quantify the fate of metabolites. We discuss the differences and similarities between these techniques and discuss their clinical applications.

Positional Therapy and Regional Pulmonary Ventilation.

BACKGROUND: Prone ventilation redistributes lung inflation along the gravitational axis; however, localized, nongravitational effects of body position are less well characterized. The authors hypothesize that positional inflation improvements follow both gravitational and nongravitational distributions. This study is a nonoverlapping reanalysis of previously published large animal data. METHODS: Five intubated, mechanically ventilated pigs were imaged before and after lung injury by tracheal injection of hydrochloric acid (2 ml/kg). Computed tomography scans were performed at 5 and 10 cm H2O positive end-expiratory pressure (PEEP) in both prone and supine positions. All paired prone-supine images were digitally aligned to each other. Each unit of lung tissue was assigned to three clusters (K-means) according to positional changes of its density and dimensions. The regional cluster distribution was analyzed. Units of tissue displaying lung recruitment were mapped. RESULTS: We characterized three tissue clusters on computed tomography: deflation (increased tissue density and contraction), limited response (stable density and volume), and reinflation (decreased density and expansion). The respective clusters occupied (mean ± SD including all studied conditions) 29.3 ± 12.9%, 47.6 ± 11.4%, and 23.1 ± 8.3% of total lung mass, with similar distributions before and after lung injury. Reinflation was slightly greater at higher PEEP after injury. Larger proportions of the reinflation cluster were contained in the dorsal versus ventral (86.4 ± 8.5% vs. 13.6 ± 8.5%, P < 0.001) and in the caudal versus cranial (63.4 ± 11.2% vs. 36.6 ± 11.2%, P < 0.001) regions of the lung. After injury, prone positioning recruited 64.5 ± 36.7 g of tissue (11.4 ± 6.7% of total lung mass) at lower PEEP, and 49.9 ± 12.9 g (8.9 ± 2.8% of total mass) at higher PEEP; more than 59.0% of this recruitment was caudal. CONCLUSIONS: During mechanical ventilation, lung reinflation and recruitment by the prone positioning were primarily localized in the dorso-caudal lung. The local effects of positioning in this lung region may determine its clinical efficacy.

Pulmonary pyruvate metabolism as an index of inflammation and injury in a rat model of acute respiratory distress syndrome.

Increased pulmonary lactate production is correlated with severity of lung injury and outcome in acute respiratory distress syndrome (ARDS) patients. This study was conducted to investigate the relative contributions of inflammation and hypoxia to the lung's metabolic shift to glycolysis in an experimental animal model of ARDS using hyperpolarized (HP) 13 C MRI. Fifty-three intubated and mechanically ventilated male rats were imaged using HP 13 C MRI before, and 1, 2.5 and 4 hours after saline (sham) or hydrochloric acid (HCl; 0.5 ml/kg) instillation in the trachea, followed by protective and nonprotective mechanical ventilation (HCl-PEEP and HCl-ZEEP) or the start of moderate or severe hypoxia (Hyp90 and Hyp75 groups). Pulmonary and cardiac HP lactate-to-pyruvate ratios were compared among groups for different time points. Postmortem histology and immunofluorescence were used to assess lung injury severity and quantify the expression of innate inflammatory markers and local tissue hypoxia. HP pulmonary lactate-to-pyruvate ratio progressively increased in rats with lung injury and moderate hypoxia (HCl-ZEEP), with no significant change in pulmonary lactate-to-pyruvate ratio in noninjured but moderately hypoxic rats (Hyp90). Pulmonary lactate-to-pyruvate ratio was elevated in otherwise healthy lung tissue only in severe systemic hypoxia (Hyp75 group). ex vivo histological and immunopathological assessment further confirmed the link between elevated glycolysis and the recruitment into and presence of activated neutrophils in injured lungs. HP lactate-to-pyruvate ratio is elevated in injured lungs predominantly as a result of increased glycolysis in activated inflammatory cells, but can also increase due to severe inflammation-induced hypoxia.

Investigating biases in the measurement of apparent alveolar septal wall thickness with hyperpolarized 129Xe MRI.

PURPOSE: To investigate biases in the measurement of apparent alveolar septal wall thickness (SWT) with hyperpolarized xenon-129 (HXe) as a function of acquisition parameters. METHODS: The HXe MRI scans with simultaneous gas-phase and dissolved-phase excitation were performed using 1-dimensional projection scans in mechanically ventilated rabbits. The dissolved-phase magnetization was periodically saturated, and the dissolved-phase xenon uptake dynamics were measured at end inspiration and end expiration with temporal resolutions up to 10 ms using a Look-Locker-type acquisition. The apparent alveolar septal wall thickness was extracted by fitting the signal to a theoretical model, and the findings were compared with those from the more commonly use chemical shift saturation recovery MRI spectroscopy technique with several different delay time arrangements. RESULTS: It was found that repeated application of RF saturation pulses in chemical shift saturation recovery acquisitions caused exchange-dependent gas-phase saturation that heavily biased the derived SWT value. When this bias was reduced by our proposed method, the SWT dependence on lung inflation disappeared due to an inherent insensitivity of HXe dissolved-phase MRI to thin alveolar structures with very short T2∗ . Furthermore, perfusion-based macroscopic gas transport processes were demonstrated to cause increasing apparent SWTs with TE (2.5 µm/ms at end expiration) and a lung periphery-to-center SWT gradient. CONCLUSION: The apparent SWT measured with HXe MRI was found to be heavily dependent on the acquisition parameters. A method is proposed that can minimize this measurement bias, add limited spatial resolution, and reduce measurement time to a degree that free-breathing studies are feasible.

Frontal Ostium Grade (FOG): A New Computer Tomography Grading System for Endoscopic Frontal Sinus Surgery.

OBJECTIVE: The location and size of the frontal sinus ostium are critical in determining surgical difficulty. The more anterior the ostium, the more difficult is the surgical access. We propose a novel computed tomography (CT) grading specific to the anatomical position of the frontal ostium. STUDY DESIGN: Observational study followed by a prospective part. SETTINGS: Tertiary rhinology practice. SUBJECT AND METHODS: On a specified sagittal CT cut, a vertical line was drawn through the posterior edge of the frontal process of the maxilla (frontal buttress/beak) along its vertical axis (reference [R-] line). A second (S-) line was placed at the point of upturn of the skull base. Based on if the S-line was posterior or anterior to the R-line, the frontal ostium was graded positive and more easily accessible or negative and thereby more challenging, respectively. If both lines overlapped, then a neutral (0) grading existed. RESULTS: A total of 297 CTs (594 ostia) were analyzed. In total, 394 (65%) ostia were grade positive, 52 (8.75%) were grade negative, and 103 (17.3%) were grade neutral. Ninety frontal sinusotomies were then performed using this grading system: 48 were positive, 21 negative, and 21 neutral. The average time to complete a frontal sinusotomy was 9.96 minutes for grade positive compared to 11.4 minutes for neutral and 16.05 minutes for grade negative (P < .005). CONCLUSION: This novel anatomical CT grading system is designed to be useful in planning and predicting the level of difficulty in endoscopic frontal sinus surgery.

Lactococcus lactis harbouring Ara h 2.02 alleviates allergen-specific Th2-associated responses in sensitized mice.

AIM: To study the prophylactic effect of recombinant Lactococcus lactis (rLl) harbouring Ara h 2.02 peanut allergen, in sensitized and challenged mice. METHODS AND RESULTS: Ara h 2.02 cDNA was cloned into pNZ8048 for heterologous expression in L. lactis. The purified recombinant allergen showed IgE binding comparable with native Ara h 2. Balb/c mice were fed with either recombinant (rLl), nonrecombinant L. lactis (Ll) or NaHCO3 (Sham) prior to sensitization and challenged with rAra h 2.02, whereas the baseline group was only fed with Ll. Allergen-specific immunoglobulin and splenocyte cytokines responses were determined for each mouse. Mice fed with either Ll or rLl showed significant alleviation of IgE and IgG1 compared to the Sham group. Despite no significant decrease in Th2 (IL-4, IL-13, IL-6) or increase in Th1 (IFN-γ) cytokines, both groups showed lower IL-10 level, while the IL-4 : IFN-γ ratio was significantly lower for rLl compared to Ll group. CONCLUSIONS: Oral administration of rLl harbouring Ara h 2.02 demonstrated alleviation of Th2-associated responses in allergen-challenged mice and a possible added allergen-specific prophylactic effect. SIGNIFICANCE AND IMPACT OF THE STUDY: Ara h 2.02 coupled with the intrinsic properties of probiotic L. lactis as a delivery vehicle can be explored for the development of a commercially scalable vaccine.

A Systematic Review of the Clinical Efficacy and Safety of CFTR Modulators in Cystic Fibrosis.

Several placebo-controlled trials have been recently published evaluating novel therapies targeting the defective CFTR protein. This systematic review examines the clinical efficacy and safety of CFTR modulators in individuals with cystic fibrosis (CF) with specific genetic mutations. Online sources were searched for placebo-controlled, parallel-design clinical trials investigating CFTR modulators from January 1, 2005 to March 31, 2018. The primary outcome of interest was FEV1% predicted (ppFEV1). Fourteen RCTs met our eligibility criteria. The largest improvement in ppFEV1 favouring treatment was observed for ivacaftor (IVA) in G551D individuals (≥6 years old). Both tezacaftor-ivacaftor (TEZ-IVA) and lumacaftor-ivacaftor (LUM-IVA) also improved ppFEV1 in F508del homozygous individuals but there was increased reporting of respiratory adverse events with LUM-IVA compared to placebo. IVA also significantly improved ppFEV1 in a sub-group of individuals ≥18 years old with an R117H mutation. No significant improvements in ppFEV1 were observed for IVA, LUM, or TEZ in F508del homozygous individuals, LUM or LUM-IVA in F508del heterozygous individuals, or ataluren in individuals with a nonsense mutation. Significant improvements in ppFEV1 and other clinical outcomes were observed for IVA in G551D individuals, TEV-IVA and LUM-IVA in F508del homozygous individuals, and IVA in adults with a R117H mutation.