Exogenous pulmonary surfactant in COVID-19 ARDS. The similarities to neonatal RDS suggest a new scenario for an 'old' strategy

Acute respiratory distress syndrome (ARDS) related to SARS-CoV-2 infection has some unusual characteristics that differentiate it from the pathophysiology described in the more 'typical' ARDS. Among multiple hypotheses, a close similarity has been suggested between COVID-19 ARDS and neonatal respiratory distress syndrome (RDS). With this opinion paper, we investigated the pathophysiological similarities between infant respiratory diseases (RDS and direct neonatal ARDS (NARDS)) and COVID-19 in adults. We also analysed, for the first time, similarities in the response to exogenous surfactant administration in terms of improved static compliance in RDS and direct NARDS, and adult COVID-19 ARDS. In conclusion, we believe that if the pathological processes are similar both from the pathophysiological point of view and from the response in respiratory mechanics to a recruitment treatment such as surfactant, perhaps the latter could be considered a plausible option and lead to recruitment in clinical trials currently ongoing on patients with COVID-19

Postnatal adaptations of phosphatidylcholine metabolism in extremely preterm infants: implications for choline and PUFA metabolism

BACKGROUND: Lipid metabolism in pregnancy delivers PUFAs from maternal liver to the developing fetus. The transition at birth to diets less enriched in PUFA is especially challenging for immature, extremely preterm infants who are typically supported by total parenteral nutrition. OBJECTIVE: The aim was to characterize phosphatidylcholine (PC) and choline metabolism in preterm infants and demonstrate the molecular specificity of PC synthesis by the immature preterm liver in vivo. METHODS: This MS-based lipidomic study quantified the postnatal adaptations to plasma PC molecular composition in 31 preterm infants <28 weeks' gestational age. Activities of the cytidine diphosphocholine (CDP-choline) and phosphatidylethanolamine-N-methyltransferase (PEMT) pathways for PC synthesis were assessed from incorporations of deuterated methyl-D9-choline chloride. RESULTS: The concentration of plasma PC in these infants increased postnatally from median values of 481 (IQR: 387-798) µM at enrollment to 1046 (IQR: 616-1220) µM 5 d later (P < 0.001). Direct incorporation of methyl-D9-choline demonstrated that this transition was driven by an active CDP-choline pathway that synthesized PC enriched in species containing oleic and linoleic acids. A second infusion of methyl-D9-choline chloride at day 5 clearly indicated continued activity of this pathway. Oxidation of D9-choline through D9-betaine resulted in the transfer of 1 deuterated methyl group to S-adenosylmethionine. A very low subsequent transfer of this labeled methyl group to D3-PC indicated that liver PEMT activity was essentially inactive in these infants. CONCLUSIONS: This study demonstrated that the preterm infant liver soon after birth, and by extension the fetal liver, was metabolically active in lipoprotein metabolism. The low PEMT activity, which is the only pathway for endogenous choline synthesis and is responsible for hormonally regulated export of PUFAs from adult liver, strongly supports increased supplementation of preterm parenteral nutrition with both choline and PUFAs

ATR based infrared spectroscopy for the diagnosis of neonatal respiratory distress syndrome

Optical spectroscopy offers a potential non-invasive, label free and rapid method to assist clinicians to diagnose diseases for which biomarkers are known. Neonatal respiratory distress syndrome (nRDS) diagnosis in preterm infants is known to be correlated with the lecithin/sphingomyelin ratio (LS ratio) in gastric aspirates, with a ratio less than 2.2 indicating that surfactant replacement therapy is needed. Currently no widespread method exists that can give clinically relevant answers in less than 2 hours from the point of sample collection as it is difficult to identify those who could benefit from prompt surfactant treatment. Various LS ratios were generated using pure dipalmitoylphosphatidylcholine (DPPC) and sphingomyelin (SM) dissolved in dichloromethane and infrared spectra generated using Attenuated Total Reflection (ATR) assisted Fourier Transform InfraRed spectrometry (FTIR). Subsequent analysis obtained the LS ratio using the spectra alone. Further, we demonstrate the application of principal component regression (PCR) and partial least squares (PLS) fits to measured spectra to assist in the determination of the LS ratio using a model trained with multiple runs of the different batches of the same concentration

Virtual reality pre-prosthetic hand training with physics simulation and robotic force interaction

Virtual reality (VR) rehabilitation systems have been proposed to enable prosthetic hand users to perform training before receiving their prosthesis. Improving pre-prosthetic training to be more representative and better prepare the patient for prosthesis use is a crucial step forwards in rehabilitation. However, existing VR platforms lack realism and accuracy in terms of the virtual hand and the forces produced when interacting with the environment. To address these shortcomings, this work presents a VR training platform based on accurate simulation of an anthropomorphic prosthetic hand, utilising an external robot arm to render realistic forces that the user would feel at the attachment point of their prosthesis. Experimental results with non-disabled participants show that training with this platform leads to a significant improvement in Box and Block scores compared to training in VR alone and a control group with no prior training. Results performing pick-and-place tasks with a wider range of objects demonstrates that training in VR alone negatively impacts performance, whereas the proposed platform has no significant impact on performance. User perception results highlight that the platform is much closer to using a physical prosthesis in terms of physical demand and effort, however frustration is significantly higher during training

Prediction of Neonatal Respiratory Distress Biomarker Concentration by Application of Machine Learning to Mid-Infrared Spectra

The authors of this study developed the use of attenuated total reflectance Fourier transform infrared spectroscopy (ATR–FTIR) combined with machine learning as a point-of-care (POC) diagnostic platform, considering neonatal respiratory distress syndrome (nRDS), for which no POC currently exists, as an example. nRDS can be diagnosed by a ratio of less than 2.2 of two nRDS biomarkers, lecithin and sphingomyelin (L/S ratio), and in this study, ATR–FTIR spectra were recorded from L/S ratios of between 1.0 and 3.4, which were generated using purified reagents. The calibration of principal component (PCR) and partial least squares (PLSR) regression models was performed using 155 raw baselined and second derivative spectra prior to predicting the concentration of a further 104 spectra. A three-factor PLSR model of second derivative spectra best predicted L/S ratios across the full range (R2: 0.967; MSE: 0.014). The L/S ratios from 1.0 to 3.4 were predicted with a prediction interval of +0.29, −0.37 when using a second derivative spectra PLSR model and had a mean prediction interval of +0.26, −0.34 around the L/S 2.2 region. These results support the validity of combining ATR–FTIR with machine learning to develop a point-of-care device for detecting and quantifying any biomarker with an interpretable mid-infrared spectrum

Tracking Target Signal Strengths on a Grid using Sparsity

Multi-target tracking is mainly challenged by the nonlinearity present in the measurement equation, and the difficulty in fast and accurate data association. To overcome these challenges, the present paper introduces a grid-based model in which the state captures target signal strengths on a known spatial grid (TSSG). This model leads to \emph{linear} state and measurement equations, which bypass data association and can afford state estimation via sparsity-aware Kalman filtering (KF). Leveraging the grid-induced sparsity of the novel model, two types of sparsity-cognizant TSSG-KF trackers are developed: one effects sparsity through $\ell_1$-norm regularization, and the other invokes sparsity as an extra measurement. Iterative extended KF and Gauss-Newton algorithms are developed for reduced-complexity tracking, along with accurate error covariance updates for assessing performance of the resultant sparsity-aware state estimators. Based on TSSG state estimates, more informative target position and track estimates can be obtained in a follow-up step, ensuring that track association and position estimation errors do not propagate back into TSSG state estimates. The novel TSSG trackers do not require knowing the number of targets or their signal strengths, and exhibit considerably lower complexity than the benchmark hidden Markov model filter, especially for a large number of targets. Numerical simulations demonstrate that sparsity-cognizant trackers enjoy improved root mean-square error performance at reduced complexity when compared to their sparsity-agnostic counterparts.Comment: Submitted to IEEE Trans. on Signal Processin

Metabolism of a synthetic compared with a natural therapeutic pulmonary surfactant in adult mice

Secreted pulmonary surfactant phosphatidylcholine (PC) has a complex intra-alveolar metabolism that involves uptake and recycling by alveolar type II epithelial cells, catabolism by alveolar macrophages, and loss up the bronchial tree. We compared the in vivo metabolism of animal-derived poractant alfa (Curosurf) and a synthetic surfactant (CHF5633) in adult male C57BL/6 mice. The mice were dosed intranasally with either surfactant (80 mg/kg body weight) containing universally 13C-labeled dipalmitoyl PC (DPPC) as a tracer. The loss of [U13C]DPPC from bronchoalveolar lavage and lung parenchyma, together with the incorporation of 13C-hydrolysis fragments into new PC molecular species, was monitored by electrospray ionization tandem mass spectrometry. The catabolism of CHF5633 was considerably delayed compared with poractant alfa, the hydrolysis products of which were cleared more rapidly. There was no selective resynthesis of DPPC and, strikingly, acyl remodeling resulted in preferential synthesis of polyunsaturated PC species. In conclusion, both surfactants were metabolized by similar pathways, but the slower catabolism of CHF5633 resulted in longer residence time in the airways and enhanced recycling of its hydrolysis products into new PC species

Association of Long-Term Exposure to Transportation Noise and Traffic-Related Air Pollution with the Incidence of Diabetes: A Prospective Cohort Study.

BACKGROUND: Evidence for an association between transportation noise and cardiovascular disease has increased; however, few studies have examined metabolic outcomes such as diabetes or accounted for environmental coexposures such as air pollution, greenness, or walkability. OBJECTIVES: Because diabetes prevalence is increasing and may be on the causal pathway between noise and cardiovascular disease, we examined the influence of long-term residential transportation noise exposure and traffic-related air pollution on the incidence of diabetes using a population-based cohort in British Columbia, Canada. METHODS: We examined the influence of transportation noise exposure over a 5-y period (1994-1998) on incident diabetes cases in a population-based prospective cohort study (n=380,738) of metropolitan Vancouver (BC) residents who were 45-85 y old, with 4-y of follow-up (1999-2002). Annual average transportation noise (Lden), air pollution [black carbon, particulate matter with aerodynamic diameter <2.5μm (PM2.5), nitrogen oxides], greenness [Normalized Difference Vegetation Index (NDVI)], and neighborhood walkability at each participant's residence were modeled. Incident diabetes cases were identified using administrative health records. RESULTS: Transportation noise was associated with the incidence of diabetes [interquartile range (IQR) increase, 6.8 A-weighted decibels (dBA); OR=1.08 (95% CI: 1.05, 1.10)]. This association remained after adjustment for environmental coexposures including traffic-related air pollutants, greenness, and neighborhood walkability. After adjustment for coexposure to noise, traffic-related air pollutants were not associated with the incidence of diabetes, whereas greenness was protective. CONCLUSION: We found a positive association between residential transportation noise and diabetes, adding to the growing body of evidence that noise pollution exposure may be independently linked to metabolic health and should be considered when developing public health interventions. https://doi.org/10.1289/EHP1279

A randomized controlled trial of nebulized surfactant for the treatment of severe COVID-19 in adults (COVSurf trial)

SARS-CoV-2 directly targets alveolar epithelial cells and can lead to surfactant deficiency. Early reports suggested surfactant replacement may be effective in improving outcomes. The aim of the study to assess the feasibility and efficacy of nebulized surfactant in mechanically ventilated COVID-19 patients. Patients were randomly assigned to receive open-labelled bovine nebulized surfactant or control (ratio 3-surfactant: 2-control). This was an exploratory dose–response study starting with 1080 mg of surfactant delivered at 3 time points (0, 8 and 24 h). After completion of 10 patients, the dose was reduced to 540 mg, and the frequency of nebulization was increased to 5/6 time points (0, 12, 24, 36, 48, and an optional 72 h) on the advice of the Trial Steering Committee. The co-primary outcomes were improvement in oxygenation (change in PaO2/FiO2 ratio) and ventilation index at 48 h. 20 patients were recruited (12 surfactant and 8 controls). Demographic and clinical characteristics were similar between groups at presentation. Nebulized surfactant administration was feasible. There was no significant improvement in oxygenation at 48 h overall. There were also no differences in secondary outcomes or adverse events. Nebulized surfactant administration is feasible in mechanically ventilated patients with COVID-19 but did not improve measures of oxygenation or ventilation