Defining the appropriate waiting time between multiple-breath nitrogen washout measurements

Research lette

Early respiratory viral infections in infants with cystic fibrosis

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.Background Viral infections contribute to morbidity in cystic fibrosis (CF), but the impact of respiratory viruses on the development of airway disease is poorly understood. Methods Infants with CF identified by newborn screening were enrolled prior to 4 months of age to participate in a prospective observational study at 4 centers. Clinical data were collected at clinic visits and weekly phone calls. Multiplex PCR assays were performed on nasopharyngeal swabs to detect respiratory viruses during routine visits and when symptomatic. Participants underwent bronchoscopy with bronchoalveolar lavage (BAL) and a subset underwent pulmonary function testing. We present findings through 8.5 months of life. Results Seventy infants were enrolled, mean age 3.1 ± 0.8 months. Rhinovirus was the most prevalent virus (66%), followed by parainfluenza (19%), and coronavirus (16%). Participants had a median of 1.5 viral positive swabs (range 0–10). Past viral infection was associated with elevated neutrophil concentrations and bacterial isolates in BAL fluid, including recovery of classic CF bacterial pathogens. When antibiotics were prescribed for respiratory-related indications, viruses were identified in 52% of those instances. Conclusions Early viral infections were associated with greater neutrophilic inflammation and bacterial pathogens. Early viral infections appear to contribute to initiation of lower airway inflammation in infants with CF. Antibiotics were commonly prescribed in the setting of a viral infection. Future investigations examining longitudinal relationships between viral infections, airway microbiome, and antibiotic use will allow us to elucidate the interplay between these factors in young children with CF

Early changes in rpS6 phosphorylation and BH3 profiling predict response to chemotherapy in AML cells

Blasts from different patients with acute myeloid leukemia (AML) vary in the agent(s) to which they are most responsive. With a myriad of novel agents to evaluate, there is a lack of predictive biomarkers to precisely assign targeted therapies to individual patients. Primary AML cells often survive poorly in vitro, thus confounding conventional cytotoxicity assays. The purpose of this work was to assess the potential of two same-day functional predictive assays in AML cell lines to predict long-term response to chemotherapy. (i) Ribosomal protein S6 (rpS6) is a downstream substrate of PI3K/akt/mTOR/ kinase and MAPK kinase pathways and its dephosphorylation is also triggered by DNA double strand breaks. Phospho-rpS6 is reliably measurable by flow cytometry and thus has the potential to function as a biomarker of responsiveness to several therapeutic agents. (ii) A cell’s propensity for apoptosis can be interrogated via a functional assay termed “Dynamic BH3 Profiling” in which mitochondrial outer membrane permeabilization in drug-treated cells can be driven by pro-apoptotic BH3 domain peptides such as PUMA-BH3. The extent to which a particular cell is primed for apoptosis by the drug can be determined by measuring the amount of cytochrome C released on addition of BH3 peptide. We demonstrate that phospho-rpS6 expression and PUMA-BH3 peptide-induced cytochrome C release after 4 hours both predict long term chemoresponsiveness to tyrosine kinase inhibitors and DNA double strand break inducers in AML cell lines. We also describe changes in expression levels of the prosurvival BCL-2 family member Mcl-1 and the pro-apoptotic protein BIM after short term drug culture

Seasonal changes in basking shark vertical space-use in the north-east Atlantic

This is the final version. Available on open access from Springer via the DOI in this recordMobile marine species can exhibit vast movements both horizontally and vertically. Spatial analysis of vertical movements may help improve an understanding of the processes that influence space-use. Previously, vertical space-use of basking sharks (Cetorhinus maximus) in the north-east Atlantic described movements largely within waters of the continental shelf during summer and autumn months, with few records of detailed vertical behaviour during winter. We use archival satellite telemetry data from 32 basking sharks (twelve females, six males, and fourteen of unknown sex measuring 4-5 m (n = 6), 5-6 m (n = 10), 6-7 m (n = 7), 7-8 m (n = 8), and 8-9 m (n = 1) estimated total length) tracked over four years (2012-2015). The satellite tags provided depth and temperature data for a cumulative 4,489 days (mean 140 ± 97 days per shark, range: 10-292 days) in order to describe vertical space-use and thermal range of basking sharks in the north-east Atlantic. Basking sharks exhibit seasonality in vertical space-use, revealing repeated ‘yo-yo’ movement behaviour with periods of occupancy at depths greater than 1,000 metres in late winter/early spring. Describing seasonal vertical space-use in marine megavertebrates can increase knowledge of movements throughout their environment including physiological and morphological constraints to movement, nutrient transfer, and overlap with anthropogenic threats in order to inform future conservation strategies.Scottish Natural HeritageUniversity of ExeterNER

The influence of sighing respirations on infant lung function measured using multiple breath washout gas mixing techniques

There is substantial interest in studying lung function in infants, to better understand the early life origins of chronic lung diseases such as asthma. Multiple breath washout (MBW) is a technique for measuring lung function that has been adapted for use in infants. Respiratory sighs occur frequently in young infants during natural sleep, and in accordance with current MBW guidelines, result in exclusion of data from a substantial proportion of testing cycles. We assessed how sighs during MBW influenced the measurements obtained using data from 767 tests conducted on 246 infants (50% male; mean age 43 days) as part of a large cohort study. Sighs occurred in 119 (15%) tests. Sighs during the main part of the wash‐in phase (before the last 5 breaths) were not associated with differences in standard MBW measurements compared with tests without sighs. In contrast, sighs that occurred during the washout were associated with a small but discernible increase in magnitude and variability. For example, the mean lung clearance index increased by 0.36 (95% CI: 0.11–0.62) and variance increased by a multiplicative factor of 2 (95% CI: 1.6–2.5). The results suggest it is reasonable to include MBW data from testing cycles where a sigh occurs during the wash‐in phase, but not during washout, of MBW. By recovering data that would otherwise have been excluded, we estimate a boost of about 10% to the final number of acceptable tests and 6% to the number of individuals successfully tested

Approximate Deadline-Scheduling with Precedence Constraints

We consider the classic problem of scheduling a set of n jobs non-preemptively on a single machine. Each job j has non-negative processing time, weight, and deadline, and a feasible schedule needs to be consistent with chain-like precedence constraints. The goal is to compute a feasible schedule that minimizes the sum of penalties of late jobs. Lenstra and Rinnoy Kan [Annals of Disc. Math., 1977] in their seminal work introduced this problem and showed that it is strongly NP-hard, even when all processing times and weights are 1. We study the approximability of the problem and our main result is an O(log k)-approximation algorithm for instances with k distinct job deadlines

Red Companions to a z=2.15 Radio Loud Quasar

We have conducted observations of the environment around the z=2.15 radio loud quasar 1550-269 in search of distant galaxies associated either with it or the z=2.09 CIV absorber along its line of sight. Such objects will be distinguished by their red colours, R-K>4.5. We find five such objects in a 1.5 arcmin^2 field around the quasar, with typical K magnitudes of ~20.4 and no detected R band emission. We also find a sixth object with K=19.6+/-0.3, and undetected at R, just two arcseconds from the quasar. The nature of all these objects is currently unclear, and will remain so until we have determined their redshifts. We suggest that it is likely that they are associated with either the quasar or the CIV absorber, in which case their properties might be similar to those of the z=2.38 red Ly-alpha emitting galaxies discovered by Francis et al. (1997). The small separation between the quasar and the brightest of our objects suggests that it may be the galaxy responsible for the CIV metal line absorption system. The closeness to the quasar and the red colour might have precluded similar objects from being uncovered in previous searches for emission from CIV and eg. damped absorbers.Comment: To appear in "Photometric Redshifts and High Redshift Galaxies", eds. R. Weymann, L. Storrie-Lombardi, M. Sawicki & R. Brunne

Respiratory impedance in healthy unsedated South African infants: Effects of maternal smoking

Background and objective: Non-invasive techniques for measuring lung mechanics in infants are needed for a better understanding of lung growth and function, and to study the effects of prenatal factors on subsequent lung growth in healthy infants. The forced oscillation technique requires minimal cooperation from the individual but has rarely been used in infants. The study aims to assess the use of the forced oscillation technique to measure the influence of antenatal exposures on respiratory mechanics in unsedated infants enrolled in a birth cohort study in Cape Town, South Africa. Methods: Healthy term infants were studied at 6–10 weeks of age using the forced oscillation technique. Respiratory impedance was measured in the frequency range 8–48 Hz via a face mask during natural sleep. Respiratory system resistance, compliance and inertance were calculated from the impedance spectra. Results: Of 177 infants tested, successful measurements were obtained in 164 (93%). Median (25–75%) values for resistance, compliance and inertance were 50.2 (39.5–60.6) cmH2O.s.L−1, 0.78 (0.61–0.99) mL.cmH2O−1 and 0.062 (0.050–0.086) cmH2O.s2.L−1, respectively. As a group, male infants had 16% higher resistance (P = 0.006) and 18% lower compliance (P  = 0.02) than females. Infants whose mothers smoked during pregnancy had a 19% lower compliance than infants not exposed to tobacco smoke during pregnancy (P = 0.005). Neither maternal HIV infection nor ethnicity had a significant effect on respiratory mechanics. Conclusions: The forced oscillation technique is sensitive enough to demonstrate the effects of tobacco smoke exposure and sex in respiratory mechanics in healthy infants. This technique will facilitate assessing perinatal influences of lung function in infancy

The political economy of the Jospin government

This article explores the political economy of the French Socialist Party (PS), beginning with the neo-liberal U-turn of 1983. It then charts the re-evaluation of the PS's political economic foundations after the 1993 defeat, the rejection of the neo-liberal 'pensée unique', and the rehabilitation of a broadly Keynesian frame of reference. The article goes on to explore how this shift has fed through into the Jospin government's policy and positions at both the national and international level. It explores aspirations to reinvent the EU as a Keynesian social democratic 'policy space', and at the national level, employment, macroeconomic, and structural policies