Closed circuit rebreathing to achieve inert gas wash-in for multiple breath wash-out

Multiple breath wash-out (MBW) testing requires prior wash-in of inert tracer gas. Wash-in efficiency can be enhanced by a rebreathing tracer in a closed circuit. Previous attempts to deploy this did not account for the impact of CO2 accumulation on patients and were unsuccessful. We hypothesised that an effective rebreathe wash-in could be delivered and it would not alter wash-out parameters. Computer modelling was used to assess the impact of the rebreathe method on wash-in efficiency. Clinical testing of open and closed circuit wash-in–wash-out was performed in healthy controls and adult patients with cystic fibrosis (CF) using a circuit with an effective CO2 scrubber and a refined wash-in protocol. Wash-in efficiency was enhanced by rebreathing. There was no difference in mean lung clearance index between the two wash-in methods for controls (6.5 versus 6.4; p=0.2, n=12) or patients with CF (10.9 versus 10.8; p=0.2, n=19). Test time was reduced by rebreathe wash-in (156 versus230 s for CF patients, p<0.001) and both methods were well tolerated. End wash-in CO2 was maintained below 2% in most cases. Rebreathe–wash-in is a promising development that, when correctly deployed, reduces wash-in time and facilitates portable MBW testing. For mild CF, wash-out outcomes are equivalent to an open circuit

Radical-induced hetero-nuclear mixing and low-field 13^{13}C relaxation in solid pyruvic acid

Radicals serve as a source of polarization in dynamic nuclear polarization, but may also act as polarization sink, in particular at low field. Additionally, if the couplings between the electron spins and different nuclear reservoirs are stronger than any of the reservoirs’ couplings to the lattice, radicals can mediate hetero-nuclear polarization transfer. Here, we report radical-enhanced $^{13}$C relaxation in pyruvic acid doped with trityl. Up to 40 K, we find a linear carbon $T_{1}$ field dependence between 5 mT and 2 T. We model the dependence quantitatively, and find that the presence of trityl accelerates direct hetero-nuclear polarization transfer at low fields, while at higher fields $^{13}$C relaxation is diffusion limited. Measurements of hetero-nuclear polarization transfer up to 600 mT confirm the predicted radical-mediated proton–carbon mixing

Characterising the role of small airways in severe asthma using low frequency forced oscillations: A combined computational and clinical approach

Background: Within asthma, the small airways (≤ 2mm in diameter) play an important role in pathophysiology. Using a combined clinical-computational approach, we sought to more precisely evaluate the contribution of the small airways to deep-breath induced airway dilation (in the absence of bronchial challenge), which may be impaired in severe asthma.Methods: A patient-based computational model of the FOT was used to examine the sensitivity and specificity of FOT signals to small airways constriction at frequencies of 2 & 8 Hz. A clinical study of moderate to severe asthmatics (n=24), and healthy volunteers (n=10) was performed to evaluate correlations between baseline and post deep inspiration (following bronchodilator withhold and in the absence of prior bronchial challenge) forced oscillation technique (FOT) responses (at 2Hz and 8Hz) and asthma treatment intensity, spirometry, airway hyper-responsiveness and airway inflammation.Results: Computational modelling demonstrated that baseline resistance measures at 2Hz are both sensitive and specific to anatomical narrowing in the small airways. Furthermore, small airways resistance was significantly increased in asthmatics compared to health. Despite these differences, there were no noticeable differences between asthmatics and healthy volunteers in resistive measures following deep inspiration (DI) and DI responses of small airways were amplified in the presence of spirometry defined airflow limitation.Conclusions: These results suggest that the small airways demonstrate increased resistance in moderate-to-severe asthma but dilate normally in response to deep inspirations in the absence of bronchial challenge. This suggests that effective targeting of the small airways is required to achieve functional improvements in moderate-severe asthmatic patients

Low-field thermal mixing in [1-13C] pyruvic acid for brute-force hyperpolarization

We detail the process of low-field thermal mixing (LFTM) between 1H and 13C nuclei in neat [1-13C] pyruvic acid at cryogenic temperatures (4–15 K). Using fast-field-cycling NMR, 1H nuclei in the molecule were polarized at modest high field (2 T) and then equilibrated with 13C nuclei by fast cycling (∼300–400 ms) to a low field (0–300 G) that activates thermal mixing. The 13C NMR spectrum was recorded after fast cycling back to 2 T. The 13C signal derives from 1H polarization via LFTM, in which the polarized (‘cold’) proton bath contacts the unpolarised (‘hot’) 13C bath at a field so low that Zeeman and dipolar interactions are similar-sized and fluctuations in the latter drive 1H–13C equilibration. By varying mixing time (tmix) and field (Bmix), we determined field-dependent rates of polarization transfer (1/τ) and decay (1/T1m) during mixing. This defines conditions for effective mixing, as utilized in ‘brute-force’ hyperpolarization of low-γ nuclei like 13C using Boltzmann polarization from nearby protons. For neat pyruvic acid, near-optimum mixing occurs for tmix ∼ 100–300 ms and Bmix ∼ 30–60 G. Three forms of frozen neat pyruvic acid were tested: two glassy samples, (one well-deoxygenated, the other O2-exposed) and one sample pre-treated by annealing (also well-deoxygenated). Both annealing and the presence of O2 are known to dramatically alter high-field longitudinal relaxation (T1) of 1H and 13C (up to 102–103-fold effects). Here, we found smaller, but still critical factors of ∼(2–5)× on both τ and T1m. Annealed, well-deoxygenated samples exhibit the longest time constants, e.g., τ ∼ 30–70 ms and T1m ∼ 1–20 s, each growing vs. Bmix. Mixing ‘turns off’ for Bmix > ∼100 G. That T1m ≫ τ is consistent with earlier success with polarization transfer from 1H to 13C by LFTM

Breastfeeding, lung volumes and alveolar size at school-age

Background: Previous studies found larger lung volumes at school-age in formerly breastfed children, with some studies suggesting an effect modification by maternal asthma. We wanted to explore this further in children who had undergone extensive lung function testing. The current study aimed to assess whether breastfeeding was associated with larger lung volumes and, if so, whether all compartments were affected. We also assessed association of breastfeeding with apparent diffusion coefficient (ADC), which measures freedom of gas diffusion in alveolar-acinar compartments and is a surrogate of alveolar dimensions. Additionally, we assessed whether these effects were modified by maternal asthma.Methods: We analysed data from 111 children and young adults aged 11–21 years, who had participated in detailed lung function testing, including spirometry, plethysmography and measurement of ADC of 3Helium (3He) by MR. Information on breastfeeding came from questionnaires applied in early childhood (age 1–4 years). We determined the association between breastfeeding and these measurements using linear regression, controlling for potential confounders.Results: We did not find significant evidence for an association between duration of breastfeeding and lung volumes or alveolar dimensions in the entire sample. In breastfed children of mothers with asthma, we observed larger lung volumes and larger average alveolar size than in non-breastfed children, but the differences did not reach significance levels.Conclusions: Confirmation of effects of breastfeeding on lung volumes would have important implications for public health. Further investigations with larger sample sizes are warranted

Radical-Induced Low-Field 1H Relaxation in Solid Pyruvic Acid Doped with Trityl-OX063

In dynamic nuclear polarization (DNP), radicals such as trityl provide a source for high nuclear spin polarization. Conversely, during the low-field transfer of hyperpolarized solids, the radicals’ dipolar or Non-Zeeman reservoir may act as a powerful nuclear polarization sink. Here, we report the low-temperature proton spin relaxation in pyruvic acid doped with trityl, for fields from 5 mT to 2 T. We estimate the heat capacity of the radical Non-Zeeman reservoir experimentally and show that a recent formalism by Wenckebach yields a parameter-free, yet quantitative model for the entire field range

Second Sound Measurements in 3He–4He Mixtures

We report measurements of the damping of second sound in a 0.1% 3He–4He mixture in the temperature range 100 mK to 1K and for frequencies from the fundamental cavity resonance of -700 Hz to 12 KHz. The measurements enable us to examine the phonon contribution to the damping over a much wider frequency range than hitherto. The data are compared to a theory based on ideas which are developed in detail elsewhere

Comparison of Forced and Impulse Oscillometry Measurements: A Clinical Population and Printed Airway Model Study.

The use of commercialised forced oscillation (FOT) devices to assess impedance in obstructive diseases such as asthma has gained popularity. However, it has yet to be fully established whether resistance and reactance measurements are comparable across different FOT devices, particularly in disease. We compared two commercially available FOT devices: Impulse Oscillometry (IOS) and TremoFlo FOT (Thorasys) in a) clinical adult population of healthy controls (n = 14), asymptomatic smokers (n = 17) and individuals with asthma (n = 73) and b) a 3D printed CT-derived airway tree model resistance, as well as a 3 L standardised volume reactance. Bland-Altman Plots and linear regressions were used to evaluate bias between the devices. Resistance measurements at both 5 and 20 Hz were numerically higher with IOS compared to FOT, with evidence of small and statistically significant proportional systematic bias and a positive Bland-Altman regression slope at both 5 and 20 Hz. In contrast, the IOS device recorded reactances that were less negative at both 5 Hz and 20 Hz and significantly smaller reactance areas when compared to TremoFlo. Larger statistically significant proportional systematic biases were demonstrated with both reactance at 5 Hz and reactance area (AX) between the devices with a negative Bland-Altman regression slope. The printed airway resistance and standardised volume reactance confirmed the observations seen in patients. We have demonstrated that the impulse oscillation system and TremoFlo FOT demonstrate comparative bias, particularly when comparing airway reactance in patients. Our results highlight the need for further standardisation across FOT measurement devices, specifically using variable test loads for reactance standardisation