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The ATLASGAL survey has characterised the properties of approximately 1000 embedded HII regions and found an empirical relationship between the clump mass and bolometric luminosity that covers 3-4 orders of magnitude. Comparing this relation with simulated clusters drawn from an initial mass function and using different star formation efficiencies we find that a single value is unable to fit the observed luminosity to mass ($L/M$) relation. We have used a Monte Carlo simulation to generate 200,000 clusters using the $L/M$-ratio as a constraint to investigate how the star formation efficiency changes as a function of clump mass. This has revealed that the star formation efficiency decreases with increasing clump mass with a value of 0.2 for clumps with masses of a few hundred solar masses and dropping to 0.08 for clumps with masses of a few thousand solar masses. We find good agreement between our results and star formation efficiencies determined from counts of embedded objects in nearby molecular clouds. Using the star formation efficiency relationship and the infrared excess time for embedded star formation of $2\pm1$, Myr we estimate the Galactic star formation rate to be approximately $0.9\pm0.45$ Msun yr$^{-1}$, which is in good agreement with previously reported values. This model has the advantage of providing a direct means of determining the star formation rate and avoids the difficulties encountered in converting infrared luminosities to stellar mass that affect previous galactic and extragalactic studies., Comment: 13 pages, 10 figures, accepted for publication in MNRAS

Transposable elements in eukaryotic organisms have historically been considered “selfish,” at best conferring indirect benefits to their host organisms. The Starships are a recently discovered feature in fungal genomes that are, in some cases, predicted to confer beneficial traits to their hosts and also have hallmarks of being transposable elements. Here, we provide experimental evidence that Starships are indeed autonomous transposons, using the model Paecilomyces variotii , and identify the HhpA “Captain” tyrosine recombinase as essential for their mobilization into genomic sites with a specific target site consensus sequence. Furthermore, we identify multiple recent horizontal gene transfers of Starships , implying that they jump between species. Fungal genomes have mechanisms to defend against mobile elements, which are frequently detrimental to the host. We discover that Starships are also vulnerable to repeat-induced point mutation defense, thereby having implications on the evolutionary stability of such elements.

Sleep-related breathing disorders are a common problem in infancy and childhood. The most common type of sleep-related breathing disorder in this age group is obstructive sleep apnea syndrome (OSAS), generally caused by factors affecting airway patency, such as tonsillar hypertrophy or obesity. However, in adults OSAS can also be caused by processes affecting the brainstem, such as central nervous system tumors. This report describes a 2-year-old girl who presented with symptoms of snoring, restless sleep, repeated night-time waking, and apneic events while asleep. She had no comorbidities, and examination revealed normal-sized tonsils. A sleep study demonstrated severe OSAS with an obstructive apnea/hypopnea index of 34. Her OSAS completely resolved on excision of the tumor. The case highlights the importance of neurological examination as part of evaluation of OSAS, especially in cases where tonsils are not enlarged and there are no other risk factors for OSAS. CITATION: Buller F, Kamal MA, Brown SK, et al. Obstructive sleep apnea syndrome as a rare presentation in a young girl with a central nervous system tumor. J Clin Sleep Med. 2022;18(4):1211–1214.

The COVID-19 pandemic has resulted in unprecedent changes to clinical practice, and as the impact upon delivery of exercise services for people with cystic fibrosis (CF) in the United Kingdom was unknown, this was characterised via a national survey.An electronic survey was distributed to healthcare professionals involved in the exercise management of CF via established professional networks.In total, 31 CF centres participated. Findings included significant reductions in exercise testing and widespread adaptation to deliver exercise training using telehealth methods. Promisingly, 71% stated that they would continue using virtual methods of engaging patients in future practice.These findings highlight adaptation to the COVID-19 pandemic and the need to develop sustainable and standardised telehealth services to manage patients moving forwards.

Fungal spore killers are a class of selfish genetic elements that positively bias their own inheritance by killing non-inheriting gametes following meiosis. As killing takes place specifically within the developing fungal ascus, a tissue which is experimentally difficult to isolate, our understanding of the mechanisms underlying spore killers are limited. In particular, how these loci kill other spores within the fungal ascus is largely unknown. Here, we overcome these experimental barriers by developing model systems in 2 evolutionary distant organisms, Escherichia coli (bacterium) and Saccharomyces cerevisiae (yeast), similar to previous approaches taken to examine the

Transposable elements in eukaryotic organisms have historically been considered ‘selfish’, at best conferring indirect benefits to their host organisms. The Starships are a recently discovered feature in fungal genomes that are predicted to confer beneficial traits to their hosts and also have hallmarks of being transposable elements. Here, we provide experimental evidence that Starships are indeed autonomous transposons, using the model Paecilomyces variotii, and identify the HhpA ‘Captain’ tyrosine recombinase as essential for their mobilization into genomic sites with a specific target site consensus sequence. Furthermore, we identify multiple recent horizontal gene transfer of Starships, implying that they frequency jump between species. Fungal genomes have mechanisms to defend against mobile elements, which are frequently detrimental to the host. We discover that Starships are also vulnerable to repeat-induced point mutation defence, thereby having implications on the evolutionary stability of such elements.

Background The impact of lumacaftor/ivacaftor on exercise tolerance in people with cystic fibrosis (CF) has not been thoroughly studied. Methods We conducted a multisite Phase 4 trial comparing the impact of lumacaftor/ivacaftor on exercise tolerance with that of placebo in participants ≥ 12 years of age with CF homozygous for F508del-CFTR. The primary endpoint was relative change from baseline in maximum oxygen consumption (VO2max) during cardiopulmonary exercise testing (CPET) at Week 24. The key secondary endpoint was relative change from baseline in exercise duration during CPET at Week 24. Other secondary endpoints included changes in other indices of exercise tolerance and changes in CF assessments; safety and tolerability were assessed as an endpoint. Results Seventy participants were randomized to receive lumacaftor/ivacaftor (n = 34) or placebo (n = 36). The least-squares mean difference for lumacaftor/ivacaftor versus placebo in relative change in VO2max from baseline at Week 24 was −3.2% (95% CI: −9.2, 2.9; P=0.3021); the least-squares mean difference in relative change from baseline in exercise duration at Week 24 was −3.2% (95% CI: −8.0, 1.6). Safety results were consistent with the known lumacaftor/ivacaftor safety profile. Conclusions Definitive conclusions regarding the impact of lumacaftor/ivacaftor on exercise tolerance cannot be drawn from these results; however, multicenter studies using CPETs can be reliably performed with multiple time points and conventional methods, provided that calibration can be achieved. Future studies of exercise tolerance may benefit from lessons learned from this study. NCT02875366.

ObjectiveThe impact on executive function performance of sleep-related disorders in asthmatic children has been scarcely studied in community settings. The aims of the present study were to assess the prevalence of sleep-related breathing disorders (SRBD) in children with intermittent or mild persistent asthma in primary care settings, and to examine the possible correlations with measures of executive function.MethodsWe performed a case–control study including 76 children with asthma (intermittent or mild persistent) and 85 healthy controls. The parents of both patients and controls completed the Paediatric Seep Questionnaire (PSQ) and the Behaviour Rating Inventory of Executive Function (BRIEF) questionnaire.ResultsWe did not find any statistically significant differences regarding the scales of PSQ. Additionally, there were no statistical differences between asthmatic children and controls regarding the scales of the BRIEF questionnaire. In both asthmatic children and controls the score of the scale of obstructive sleep-related breathing disorder was significantly correlated with the T scores of the two composite scales (BRI and MI) and the Global Executive Composite.ConclusionIn children with intermittent or mild persistent asthma under the care of private general paediatricians there were no statistically significant differences regarding subjective SBD compared to the healthy controls. Also there were no statistical differences between asthmatic children and controls regarding behavioural correlates of executive function during everyday life.

ObjectivesRegular exercise testing is recommended for people with cystic fibrosis (pwCF), as is the provision and regular review of exercise training programmes. A previous survey on exercise testing and training for pwCF in the UK was conducted over a decade ago. With the landscape of CF changing considerably during this time, this survey aimed to evaluate UK-based exercise testing and training practices for pwCF a decade on.DesignCross-sectional, online survey.ParticipantsA survey was distributed electronically to UK CF clinics and completed by the individual primarily responsible for exercise services. Descriptive statistics and qualitative analyses were undertaken.ResultsIn total, 31 CF centres participated, representing ~50% of UK specialist clinics. Of these, 94% reported using exercise testing, 48% of which primarily use cardiopulmonary exercise testing. Exercise testing mostly occurs at annual review (93%) and is most often conducted by physiotherapists (62%). A wide variation in protocols, exercise modalities, normative reference values and cut-offs for exercise-induced desaturation are currently used. All centres reportedly discuss exercise training with pwCF; 94% at every clinic appointment. However, only 52% of centres reportedly use exercise testing to inform individualised exercise training. Physiotherapists typically lead discussions around exercise training (74%).ConclusionsThese data demonstrate that the majority of respondent centres in the UK now offer some exercise testing and training advice for pwCF, representing a marked improvement over the past decade. However, continued efforts are now needed to standardise exercise practices, particularly regarding field testing practices and the translation of test results into personalised training programmes for pwCF.

Context. While over 1000 supernova remnants (SNRs) are estimated to exist in the Milky Way, only less than 400 have been found to date. In the context of this apparent deficiency, more than 150 SNR candidates were recently identified in the D-configuration Very Large Array (VLA-D) continuum images of the 4--8 GHz global view on star formation (GLOSTAR) survey, in the Galactic longitude range $-2^\circ, Comment: To be published in A&A. 21 pages, 15 figures

A new species is described in the Mucorales family Syncephalastraceae: Syncephalastrum contaminatum, isolated as an in vitro culture from a laboratory contaminant. The species has variable copies of the internal transcribed spacer (ITS) regions, requiring cloning of these regions prior to Sanger sequencing before subsequent use in phylogenetic comparisons with other fungi. The genome of the strain was sequenced using short paired-reads to yield a draft genome of 28.6 Mb. Syncephalastrum contaminatum is distinguished by diverse DNA sequences at several loci from the other species of Syncephalastrum, including only 81% sequence identity with its ITS regions to that of S. racemosum. Its merosporangium produces four or more asexual spores and the genome sequencing information suggests that the species is heterothallic. The identification of this species highlights the limited knowledge about the early lineages of fungi both in Australia and globally.

Fungal spore-killers are a class of selfish genetic elements that positively bias their own inheritance by killing non-inheriting gametes following meiosis. As killing takes place specifically within the developing fungal ascus, a tissue which is experimentally difficult to isolate, our understanding of the mechanisms underlying spore killers are limited. In particular, how these loci kill other spores within the fungal ascus is largely unknown. Here we overcome these experimental barriers by developing model systems in two evolutionary distant organisms, Escherichia coli (bacterium) and Saccharomyces cerevisiae (yeast). Using these systems, we show that the Podospora anserina spore killer protein Spok1 enacts killing through targeting DNA.Significance StatementNatural gene drives have shaped the genomes of many eukaryotes and recently have been considered for applications to control undesirable species. In fungi these loci are called spore-killers. Despite their importance in evolutionary processes and possible applications our understanding of how they enact killing is limited. We show that the spore killer protein Spok1, which has homologues throughout the fungal tree of life, acts via DNA disruption. Spok1 is only the second spore killer locus in which the cellular target of killing has been identified and is the first known to target DNA. We also show that the DNA disrupting activity of Spok1 is functional in both bacteria and yeast suggesting a highly conserved mode of action.

Class II methanol (CH$_{3}$OH) masers are amongst the clearest signposts of recent high-mass star formation (HMSF). A complete catalogue outlines the distribution of star formation in the Galaxy, the number of young star-forming cores, and the physical conditions of their environment. The Global View on Star Formation (GLOSTAR) survey, which is a blind survey in the radio regime of 4$-$8 GHz, maps the Galactic mid-plane in the radio continuum, 6.7 GHz methanol line, the 4.8 GHz formaldehyde line, and several radio recombination lines. We present the analysis of the observations of the 6.7 GHz CH$_{3}$OH maser transition using data from the D-configuration of the Very Large Array (VLA). We analyse the data covering Galactic longitudes from $-2^{\circ}< l, Accepted in A&A July 18, 2022

As part of the Global View on Star Formation (GLOSTAR) survey we have used the Karl G. Jansky Very Large Array (VLA) in its B-configuration to observe the part of the Galactic plane between longitudes of 28° and 36° and latitudes from −1° to +1° at the C-band (4–8 GHz). To reduce the contamination of extended sources that are not well recovered by our coverage of the (u, υ)-plane, we discarded short baselines that are sensitive to emission on angular scales >4″. The resulting radio continuum images have an angular resolution of 1.″0 and a sensitivity of ~60 µJy beam−1, making it the most sensitive radio survey covering a large area of the Galactic plane with this angular resolution. An automatic source extraction algorithm was used in combination with visual inspection to identify a total of 3325 radio sources. A total of 1457 radio sources are ≥7σ and comprise our highly reliable catalog; 72 of these are grouped as 22 fragmented sources, for example, multiple components of an extended and resolved source To explore the nature of the cataloged radio sources, we searched for counterparts at millimeter and infrared wavelengths. Our classification attempts resulted in 93 H II region candidates, 104 radio stars, and 64 planetary nebulae, while it is suggested that most of the remaining radio sources are extragalactic sources. We investigated the spectral indices (α, Sv ∝ vα) of radio sources classified as H II region candidates and found that many have negative values. This may imply that these radio sources represent young stellar objects that are members of the star clusters around the high-mass stars that excite the H II regions, but not these H II regions themselves. By comparing the peak flux densities from the GLOSTAR and CORNISH surveys, we have identified 49 variable radio sources, most of them with an unknown nature. Additionally, we provide a list of 1866 radio sources detected within 5 to 7σ levels.

Laboratory experiments play a key role in deciphering the chemistry of the interstellar medium (ISM) and the role that product complex organic molecules (COMs) may play in the origins of life. However, to date, most studies in experimental astrochemistry have made use of reductionist approaches to experimental design in which chemical responses to variations in a single parameter are investigated while all other parameters are held constant. Although such work does afford insight into the chemistry of the ISM, it is likely that several important points, such as the relative importance of an experimental parameter in determining the chemical outcome of a reaction and the interaction between parameters, remain ambiguous. In light of this, we propose adopting a new systems astrochemistry framework for experimental studies which draws on current work performed in the field of prebiotic chemistry, and present the basic tenants of such an approach in this article. This systems approach would focus on the emergent properties of the chemical system by performing the simultaneous variation of multiple experimental parameters and would allow for the effect of each parameter, as well as their interactions, to be quantified. We anticipate that the application of systems science to laboratory astrochemistry, coupled with developments in hyphenated analytical techniques and data analytics, will uncover significant new data hitherto unknown, and will aid in better linking laboratory experiments to observations and modelling work., Comment: 32 pages including 11 figures and 2 tables. To be submitted in Frontiers in Astronomy and Space Science

Rationale: The long-term effects of vigorous physical activity (PA) on lung function in cystic fibrosis are unclear. Objectives: To evaluate effects of a 12-month partially supervised PA intervention using motivational feedback. Methods: In a parallel arm multicenter randomized controlled trial (ACTIVATE-CF), relatively inactive patients aged ≥12 years were randomly assigned (1:1 ratio) to an intervention group or control group. The intervention group consented to add 3 hours of vigorous PA per week, while the control group was asked not to change their PA behavior. Primary endpoint was change in percent predicted forced expiratory volume in 1s (ΔFEV1) at 6 months. Secondary endpoints included PA, exercise capacity, exercise motives, time to first exacerbation and exacerbation rates, quality of life, anxiety, depression, and stress, and blood glucose control. Data were analyzed using mixed linear models. Measurements and Main Results: 117 patients (40% of target sample size) were randomized to an intervention (n=60) or control group (n=57). After 6 months, ΔFEV1 was significantly higher in the control group compared to the intervention group (2.70% predicted, 95% CI 0.13 to 5.26; p=0.04). The intervention group reported increased vigorous PA compared with the control group at each study visit, had higher exercise capacity at 6 and 12 months, and higher PA at 12 months. No effects were seen in other secondary outcomes. Conclusions: ACTIVATE-CF increased vigorous PA and exercise capacity, with effects carried over for the subsequent 6 months, but resulted in better FEV1 in the control group. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT01744561.

Robust antifungal screening is technically challenging particularly for filamentous fungi. We present a method for undertaking antifungal screening assays that builds upon existing broth dilution protocols and incorporates time resolved image-based assessment of fungal growth. We show that the method performs with different fungi, particularly those for which spores can be used as inoculum, and with different compound classes, can accurately assess susceptibility or otherwise in only few hours, performs well even without replication and can even account for differences in inherent growth properties of strains.

Robust antifungal screening is technically challenging particularly for filamentous fungi. We present a method for undertaking antifungal screening assays that builds upon existing broth dilution protocols and incorporates time resolved image-based assessment of fungal growth. We show that the method performs with different fungi, particularly those for which spores can be used as inoculum, and with different compound classes, can accurately assess susceptibility or otherwise in only few hours and can even account for differences in inherent growth properties of strains.

The Structure, Excitation, and Dynamics of the Inner Galactic InterStellar Medium (SEDIGISM) survey has produced high (spatial and spectral) resolution $^{13}$CO (2-1) maps of the Milky Way. It has allowed us to investigate the molecular interstellar medium in the inner Galaxy at an unprecedented level of detail and characterise it into molecular clouds. In a previous paper, we have classified the SEDIGISM clouds into four morphologies. However, how the properties of the clouds vary for these four morphologies is not well understood. Here, we use the morphological classification of SEDIGISM clouds to find connections between the cloud morphologies, their integrated properties, and their location on scaling relation diagrams. We observe that ring-like clouds show the most peculiar properties, having, on average, higher masses, sizes, aspect ratios and velocity dispersions compared to other morphologies. We speculate that this is related to the physical mechanisms that regulate their formation and evolution, for example, turbulence from stellar feedback can often results in the creation of bubble-like structures. We also see a trend of morphology with virial parameter whereby ring-like, elongated, clumpy and concentrated clouds have virial parameters in a decreasing order. Our findings provide a foundation for a better understanding of the molecular cloud behaviour based on their measurable properties., Accepted for publication in A&A. 28 pages (17 of Appendices), 32 figures, 6 tables

Rationale: The prognostic value of cardiopulmonary exercise testing (CPET) for survival in cystic fibrosis (CF) in the context of current clinical management, when controlling for other known prognostic factors, is unclear. Objectives: To determine the prognostic value of CPET-derived measures beyond peak oxygen uptake (VO 2 peak) following rigorous adjustment for other predictors. Methods: Data from 10 CF centers in Australia, Europe, and North America were collected retrospectively. A total of 510 patients completed a cycle CPET between January 2000 and December 2007, of which 433 fulfilled the criteria for a maximal effort. Time to death/lung transplantation was analyzed using Cox proportional hazards regression. In addition, phenotyping using hierarchical Ward clustering was performed to characterize high-risk subgroups. Measurements and Main Results: Cox regression showed, even after adjustment for sex, FEV1% predicted, body mass index (z-score), age at CPET, Pseudomonas aeruginosa status, and CF-related diabetes as covariates in the model, that VO 2 peak in % predicted (hazard ratio [HR], 0.964; 95% confidence interval [CI], 0.944-0.986), peak work rate (% predicted; HR, 0.969; 95% CI, 0.951-0.988), ventilatory equivalent for oxygen (HR, 1.085; 95% CI, 1.041-1.132), and carbon dioxide (HR, 1.060; 95% CI, 1.007-1.115) (all P < 0.05) were significant predictors of death or lung transplantation at 10-year follow-up. Phenotyping revealed that CPET-derived measures were important for clustering. We identified a high-risk cluster characterized by poor lung function, nutritional status, and exercise capacity. Conclusions: CPET provides additional prognostic information to established predictors of death/lung transplantation in CF. High-risk patients may especially benefit from regular monitoring of exercise capacity and exercise counseling.

The COVID-19 pandemic has resulted in unprecedent change to clinical practice. As the impact upon delivery of exercise services for people with cystic fibrosis (CF) in the UK was unknown, this was characterised via a national survey. In total, 31 CF centres participated. Principal findings included a significant reduction in exercise testing, and widespread adaptation to deliver exercise training using telehealth methods. Promisingly, 71% stated that they would continue to use virtual methods of engaging patients in future practice. This does, however, highlight a need to develop sustainable and more standardised telehealth services further to manage patients moving forwards.

BACKGROUND A 25-hydroxyvitamin D (25OHD) may exert immunomodulatory effects on respiratory health, which may translate to improvements in exercise physiology. Thus, we aimed to investigate whether plasma 25OHD is associated with lung function and aerobic fitness in people with cystic fibrosis (pwCF). METHODS A multicentre retrospective review of pwCF (> 9 years old) attending the Royal Hospital for Sick Children (Edinburgh) or Wessex CF-Unit (Southampton) was performed between July 2017 and October 2019. Demographic and clinical data were collected. Plasma 25OHD measured closest in time to clinical cardiopulmonary exercise testing and/or spirometry [forced expiratory volume (FEV1 )% predicted] was recorded. Pancreatic insufficiency was diagnosed based on faecal elastase of

Recently, we reported the discovery of a kpc-scale CO structure in the inner Galaxy which we named the Gangotri wave. The structure is at least 2 kpc in extent and its vertical distribution is wave-like in morphology. The analysis of the velocity data suggests Gangotri wave being a spur of the Milky Way or a sub-branch of the Norma arm. Following the discovery, there is a rebuttal published, expressing concerns on identifying the inner Galaxy CO emission features as a single coherent structure. In this article, we aim to address the concerns of the rebuttal article, hoping to clarify some of the criticisms.

BackgroundSevere disease directly associated with SARS-CoV-2 infection in children is rare. However, the indirect consequences of the COVID-19 pandemic on paediatric health have not been fully quantified. We examined paediatric health-care utilisation, incidence of severe disease, and mortality during the lockdown period in Scotland.MethodsThis national retrospective cohort study examined national data for emergency childhood primary and secondary care utilisation following national lockdown on March 23, 2020. To determine whether social distancing measures and caregiver behavioural changes were associated with delayed care-seeking and increased disease severity on presentation, unplanned, emergency admissions requiring invasive mechanical ventilation for the two national Paediatric Intensive Care Units (PICUs) were analysed. PICU admissions were grouped by diagnostic category, and disease severity on presentation calculated. National statutory death records were consulted to establish childhood mortality rates and causes of death. For all observations, the lockdown period was compared to equivalent dates in 2016-2019.FindingsWe identified 273,455 unscheduled primary care attendances; 462,437 emergency department attendances; 54,076 emergency hospital admissions; 413 PICU emergency admissions; and 415 deaths during the lockdown study period and equivalent dates in previous years. The rates of emergency presentations to primary and secondary care fell during lockdown in comparison to previous years. Emergency PICU admissions for children requiring invasive mechanical ventilation also fell, with an odds ratio of 0·52 for chance of admission during lockdown (95% CI 0·37-0·73, p < 0·001). Clinical severity scores did not suggest children were presenting with more advanced disease. The greatest reduction in PICU admissions was for diseases of the respiratory system; those for injury, poisoning or other external causes were equivalent to previous years. Mortality during lockdown did not change significantly compared to 2016-2019.InterpretationNational lockdown led a reduction in paediatric emergency care utilisation, without associated evidence of severe harm.FundingNoneResearch in contextEvidence before this studyData on the indirect effects of the COVID-19 pandemic on children at a population level are limited. We searched PubMed and medRxiv on October 13, 2020, for studies published from Jan 1, 2020 examining the indirect effects of non-pharmaceutical interventions (NPIs), and associated changes in caregiver health-care seeking behaviour, on the risk of severe paediatric disease and death. We used the search terms COVID-19, SARS-CoV-2, non-pharmaceutical interventions, indirect, and children, as well as manually searching references in other relevant papers. Terms were searched individually and in combination as necessary, with no language restrictions. We identified one study that modelled the indirect effects of the COVID-19 pandemic on child deaths in low- and middle-income countries. Other studies analysed in isolation the effects of NPIs and other behavioural changes on emergency department attendances, hospital admission rates, paediatric intensive care unit (PICU) admission rates, or the incidence of specific presentations, such as asthma exacerbations. Some case series described delayed care-seeking for children with non-SARS-CoV-2 disease. We did not identify any national studies examining the indirect effects of the COVID-19 pandemic on the incidence of severe paediatric disease and mortality.Added value of this studyThis national study quantified the changes following national lockdown in Scotland on March 23, 2020. We examined data for unscheduled primary care and emergency department attendances, emergency hospital admissions, emergency paediatric intensive care unit (PICU) admissions requiring invasive mechanical ventilation, and paediatric mortality. Rates were compared with previous years. We found a reduction in paediatric emergency care utilisation rates associated with national lockdown. This reduction is likely to be due to a combination of changes in health care seeking behavior, and a fall in overall burden of paediatric infectious disease. These measures did not appear to have been associated with evidence of severe harm to children in Scotland, as evidenced by severity scores on presentation to PICU or mortality.Implications of all the available evidenceThis is the first comprehensive population-based assessment at a national level of the indirect effects of the COVID-19 pandemic on severe paediatric morbidity and mortality. Despite a significant reduction in health-care utilisation rates, we did not find associated evidence of severe harm. This study will assist policy makers, health-care providers and the public in evaluating the effects of lockdown on the risk of severe paediatric disease at a population level.

Background: Robin sequence (RS) is a congenital disorder resulting in upper airway obstruction (UAO) of variable severity, with no current consensus about best-practice management. We aimed to identify differences in outcomes of infants with RS according to how UAO was treated. Methods: 13-month surveillance study; a monthly reporting card was distributed to 3500 paediatricians and all cleft teams, with data collection at initial report and at median age 2 years. Results: Of 173 infants with RS, 74% required an airway adjunct (AA); nasopharyngeal airway (NPA) 57%, CPAP 25%, ETT 15%, tracheostomy 12%, multiple AA types 30%. 29% were discharged with NPA for median 5 months. 9 infants had NPA inserted aged >4 weeks (late NPA), including 6 after discharge. Non-isolated RS was more common in infants with tracheostomy (68%) than those discharged with NPA (42%) or no AA (36%). 7 infants died at median 43 days old; 86% required AA, 43% had a tracheostomy, all had non-isolated RS. Infants discharged with NPA had a longer duration of NG feeds than those with no AA (5 months vs 2 months) and were less likely to be orally fed at f/u (84% vs 98%). Less than half with tracheostomy were orally fed at f/u. Developmental delay (DD) was more common with tracheostomy (47%) than discharge with NPA (20%), late NPA (22%) or no AA (27%). DD was least common in isolated RS (15%). Conclusion: UAO requiring AA in RS is common and may be late in onset, with close f/u required post-hospital discharge. RS infants who required tracheostomy had higher mortality, delayed oral feeding and higher DD incidence. This likely reflects a more severe RS phenotype with increased rate of non-isolated RS.

Introduction: Birth prevalence of Robin sequence (RS) has been reported as 1 case per 8000–14000 live births by epidemiological studies from other European countries. As no mandatory craniofacial anomaly registry exists in the United Kingdom and Ireland (UK/I), birth prevalence of RS is not known. We report findings from the first national study of RS epidemiology and management in the UK/I. Methods: A surveillance study was conducted throughout UK/I (Jan 2016-Jan 2017) utilising a monthly reporting card distributed to 3500 paediatricians/neonatologists and all regional cleft teams. For each reported live-born infant with RS, clinical data were prospectively collected from clinicians at the time of reporting with follow-up at median 2 years of age. Completion rate of the follow-up survey was 95%. Results: 163 infants with RS (52% female, 83% Caucasian, 87% term births) were born in UK/I in 2016, giving a birth prevalence of 1:5100 live births. Prevalence varied from 1:2500 to 1:6000 across the 5 countries of UK/I. 52% had isolated RS. 29% had a confirmed syndrome, the most common of which was Stickler syndrome (SS; n=17, 10% of all RS cases), and 12% had a chromosomal abnormality with known RS association. 9% (n=15) had a family history of orofacial cleft, of which 53% had SS and 33% had isolated RS. Conclusion: This prospective study utilising a dual reporting source identified a higher birth prevalence of RS in UK/I than reported by studies from other countries with comparable diagnostic criteria. Further studies are required to investigate whether this finding is attributable to different profiles of genetic or environmental risk factors within these populations.

The impact of lumacaftor/ivacaftor on exercise tolerance in people with cystic fibrosis (CF) has not been thoroughly studied.We conducted a multisite Phase 4 trial comparing the impact of lumacaftor/ivacaftor on exercise tolerance with that of placebo in participants ≥ 12 years of age with CF homozygous for F508del-CFTR. The primary endpoint was relative change from baseline in maximum oxygen consumption (VOSeventy participants were randomized to receive lumacaftor/ivacaftor (n = 34) or placebo (n = 36). The least-squares mean difference for lumacaftor/ivacaftor versus placebo in relative change in VODefinitive conclusions regarding the impact of lumacaftor/ivacaftor on exercise tolerance cannot be drawn from these results; however, multicenter studies using CPETs can be reliably performed with multiple time points and conventional methods, provided that calibration can be achieved. Future studies of exercise tolerance may benefit from lessons learned from this study. NCT02875366.

Here we explore the diversity of one morphologically distinguishable genus in the

The horizontal transfer of large gene clusters by mobile elements is a key driver of prokaryotic adaptation in response to environmental stresses. Eukaryotic microbes face similar stresses; however, a parallel role for mobile elements has not been established. A stress faced by many microorganisms is toxic metal ions in their environment. In fungi, identified mechanisms for protection against metals generally rely on genes that are dispersed within an organism's genome. Here, we discover a large (∼85 kb) region that confers tolerance to five metal/metalloid ions (arsenate, cadmium, copper, lead, and zinc) in the genomes of some, but not all, strains of a fungus, Paecilomyces variotii. We name this region HEPHAESTUS (Hφ) and present evidence that it is mobile within the P. variotii genome with features characteristic of a transposable element. HEPHAESTUS contains the greatest complement of host-beneficial genes carried by a transposable element in eukaryotes, suggesting that eukaryotic transposable elements might play a role analogous to bacteria in the horizontal transfer of large regions of host-beneficial DNA. Genes within HEPHAESTUS responsible for individual metal tolerances include those encoding a P-type ATPase transporter-PcaA-required for cadmium and lead tolerance, a transporter-ZrcA-providing tolerance to zinc, and a multicopper oxidase-McoA-conferring tolerance to copper. In addition, a subregion of Hφ confers tolerance to arsenate. The genome sequences of other fungi in the Eurotiales contain further examples of HEPHAESTUS, suggesting that it is responsible for independently assembling tolerance to a diverse array of ions, including chromium, mercury, and sodium.

The horizontal transfer of large gene clusters by mobile elements is a key driver of prokaryotic adaptation in response to environmental stresses. Eukaryotic microbes face similar environmental stresses yet a parallel role for mobile elements has not yet been established. A stress faced by all microorganisms is the prevalence of toxic metals in their environment. In fungi, identified mechanisms for protection against metals generally rely on genes that are dispersed within an organism’s genome. Here we have discovered a large (∼85 kb) region that confers resistance to several metals in the genomes of some, but not all, strains of a fungus,Paecilomyces variotii. We name this regionHEPHAESTUS(Hϕ) and present evidence that this region is mobile within theP. variotiigenome with features highly characteristic of a transposable element. While large gene clusters including those for the synthesis of secondary metabolites have been widely reported in fungi, these are not mobile within fungal genomes.HEPHAESTUScontains the greatest complement of host-beneficial genes carried by a transposable element in eukaryotes. This suggests that eukaryotic transposable elements might play a role analogous to their bacterial counterparts in the horizontal transfer of large regions of host-beneficial DNA. Genes withinHEPHAESTUSresponsible for individual metal resistances include those encoding a P-type ATPase transporter, PcaA, required for cadmium and lead resistance, a transporter, ZrcA, providing resistance to zinc, and a multicopper oxidase, McoA, conferring resistance to copper. Additionally, a subregion ofHϕconferring resistance to arsenate was identified. The presence of a strikingly similar cluster in the genome of another fungus,Penicillium fuscoglaucum, suggests thatHEPHAESTUSarrived inP. variotiivia horizontal gene transfer.

Introduction Epilepsy and OSA are common conditions, affecting 0.5%1 and 6%2 of children respectively. Pilot data utilising the PSQ-SRBD reported a high risk of OSA in 55% of CWE versus 7% of controls.3 This study assessed symptoms of OSA in CWE and typically-developing children using subjective questionnaires, and compared these with objective level I polysomnography. Methods Ethical approval was granted. Written informed consent/assent was obtained from participants/caregivers. CWE aged 5–18 years were recruited from an NHS epilepsy clinic during 2017–2019, along with age- and sex-matched typically-developing controls. Children with significant co-morbidities were excluded. Anthropometric data were collected. OSA symptoms were rated by child/caregiver using the children’s Epworth Sleepiness Scale (cESS) and PSQ-SRBD, with PSQ-SRBD ≥0.33 indicative of OSA (reported sensitivity 81%, specificity 87%).4 Polysomnography (SOMNOScreen plus™, SOMNOmedics, Randersacker, Germany) was conducted in accordance with AASM Version 2.3 (2016) guidelines.5 Standard statistical analyses were undertaken using SPSS 25 (IBM Corp., Armonk, NY, USA). Significance was taken as p Results Fifty-two children completed the protocol (35 CWE, 17 controls), with polysomnography data available for 44 children. Table 1 summarises anthropometric, questionnaire and polysomnography data; CWE were significantly sleepier on cESS and more likely to score ≥0.33 on PSQ-SRBD. Children with PSQ-SRBD ≥0.33 had higher BMI (22.3±6.0 v. 19.1±3.7 kg/m2, p=0.03), higher cESS (8(4–12) v. 3(1–5), 1/hour); see table 2. Discussion Study limitations include small study numbers and low (o)AHI. Notwithstanding these limitations, CWE had significantly higher cESS and PSQ-SRBD scores than controls, reflecting previously published data. The utility of PSQ-SRBD in predicting OSA in CWE is low, in contrast to studies performed in healthy children. The study is ongoing. References Joint Epilepsy Council of the UK and Ireland. Epilepsy prevalence, incidence and other statistics 2011. Marcus CL, et al. Diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics 2012; 130: e714-e755. Urquhart DS, et al. Observational pilot study of reported symptoms of Obstructive Sleep Apnoea (OSA) in children with epilepsy and healthy controls. Dev Med Child Neurol 2016; 58: 1063–1068. Chervin RD, et al. Pediatric sleep questionnaire (PSQ): Validity and reliability of scales for sleep-disordered breathing, snoring, sleepiness, and behavioral problems. Sleep Med 2000; 1: 21–32. Berry RB, et al. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications, Version 2.3. 2016; Westchester, IL: American Academy of Sleep Medicine.

Annual review exercise testing is recommended by the Cystic Fibrosis (CF) Trust. Testing to date has focused on evaluating aerobic fitness, a key prognostic indicator. Tests available range from simple field tests, to comprehensive evaluations of aerobic exercise (dys)function – cardiopulmonary exercise testing (CPET).‘Field tests’, although easy to perform are limited in the information they provide. Whereas CPET, the ‘gold standard’ measure of aerobic fitness, is recommended as the first choice exercise test by the European CF Society Exercise Working Group. CPET offers a precise cardiovascular, respiratory and metabolic evaluation of exercise capacity, including assessment of mechanism(s) of exercise limitation.

BACKGROUND: Robin sequence (RS) is a congenital disorder characterized by cleft palate, micrognathia, and glossoptosis which can result in clinically significant upper airway obstruction (UAO). Historically, incidence of RS in the UK has been estimated as 1 in 8500 live births. Our study describes birth prevalence, clinical characteristics, and management of RS in the East of Scotland (EoS) region.METHODS: Retrospective case note review of infants born in EoS from 2004 to 2013 with a clinical diagnosis of RS. Cases were identified by searching the regional cleft service patient database and review of Hospital Activity Statistics data. Regional live birth rate provided the denominator for incidence calculations.RESULTS: A total of 105 cases of RS were identified, giving a birth prevalence of 1:2685 live births. No trends in annual incidence were observed over the 10-year period. Intrauterine exposure to potentially teratogenic agents was identified in 17% cases, including Methadone in 8% cases. Signs of UAO were present in 93% of infants, 63% of whom required active airway management. Nasopharyngeal airway (NPA) was the most commonly used intervention (53% cases), whilst only 7% required surgical management. Infants with an underlying syndrome or additional anomalies (RS+) were significantly more likely to be admitted to a tertiary center and require surgical airway or feeding support compared to those with isolated RS.CONCLUSIONS: RS incidence in EoS is substantially higher than that reported within other populations, and than previously reported in the UK. A possible association with intrauterine Methadone exposure warrants further investigation.

The measurement of exercise capacity in persons with cystic fibrosis by Cardiopulmonary Exercise Testing (CPET) offers a functional assessment of lung performance and efficiency in a dynamic setting. Exercise performance can measured against predicted values and the mechanism by which exercise limitation occurs can be identified. In healthy subjects, exercise is limited by cardiac output, such that a significant breathing reserve exists at the end of exercise. However, other mechanisms of exercise limitation which may be identified in CF subjects include ventilatory limitation, and/or limitation due to physical deconditioning. A detailed understanding of exercise capacity and the mechanism for exercise limitation may enable health professionals to tailor an individualised exercise programme for each CF patient.

An insertional mutant with reduced pathogenicity on Brassica napus was identified in the plant pathogenic fungus Leptosphaeria maculans. The transfer-DNA molecule from Agrobacterium tumefaciens inserted into a gene encoding a protein with similarity to Sit4-associated proteins (SAPs). In contrast to Saccharomyces cerevisiae which has four members of the SAP family, there is a single copy of the gene in L. maculans. The mutant had normal spore production and spore germination, but altered hyphal branching, suggesting that nutrient signaling is impaired in the strain. This is the first time that a SAP gene has been mutated in a filamentous fungus and links the function of SAP proteins to plant pathogenesis and hyphal branching.

Sleep-disordered breathing in children includes disorders of breathing that affect airway patency e.g. obstructive sleep apnoea (OSA), and also conditions that affect respiratory drive (central sleep disorders) or cause hypoventilation, either as a direct central effect or due to peripheral muscle weakness. OSA is an increasingly-recognised clinical entity affecting up to 5.7% young children. OSA, if left untreated, may be associated with adverse effects on growth and development including adverse cognitive and behavioural outcomes. Evidence also exists to suggest that untreated OSA may impact on later cardiovascular risk. Close attention should be paid to assessing and investigating this relatively common condition. This review deals with the presentation, investigation, management, and sequelae of OSA, as well as providing an overview of the presentation, investigation, management of central apnoea in children.

A high proportion of children and adolescents who have "difficult" or therapy-resistant asthma, are found to have poor adherence to maintenance therapies. Such individuals are thus difficult asthmatics (for reasons of poor adherence) rather than being young people with true difficult asthma. In our centers, once daily ICS/ULABA (Relvar™) is considered if there is an increase in reported interval symptoms, asthma attacks requiring hospital attendance or rescue oral prednisolone, or persistently low lung function despite reported regular use of a twice daily ICS/LABA preparation. In the majority of these young people, a clinical history of overt non-adherence or a clinical suspicion of covert non-adherence will be noted.The aim of our retrospective cohort study was to assess the clinical effectiveness of Relvar™ in a selected adolescent asthma population.In a pre-selected group of adolescents with likely poor prior adherence to inhaled therapies, a change to Relvar™ (once daily combined ICS/ULABA) led to improvements in asthma control, as assessed by ED attendances and oral steroid burden.A prospective study to verify these findings and also explore the effects on quality of life, asthma control, and adherence is warranted.

BACKGROUND: Severe scoliosis can affect respiratory function in growing patients and produce cardiopulmonary complications, leading to significant morbidity. The development of spinal deformity may impact on young patients’ level of function and reported quality of life (QOL). The aim of this study was to investigate the relationship between lung function, exercise capacity and quality of life in young patients with spinal deformity. METHODS: This is a retrospective analysis of 104 patients (31% male, 69% female with mean age 14.9yrs). 77% of patients had an adolescent idiopathic scoliosis, with the remainder having other scoliosis diagnoses or Scheuermann’s kyphosis. Principal outcomes included Spirometry [FEV(1), FVC], Whole Body Plethysmography, Cardiopulmonary Exercise Testing [CPET] and patient outcome questionnaires (with SRS-22). CPET measures included maximal exercise capacity [VO(2peak)] as well as VO(2) at ventilatory threshold [VT] expressed as %predicted VO(2max)-a measure of physical conditioning, and minute ventilation [V(E)] from which breathing reserve [BR] could be calculated. RESULTS: Mean (±SD) main thoracic scoliosis was 59.9⁰ (±15.2⁰), and mean kyphosis in those with Scheuermann’s condition was 95.3⁰ (±11.5⁰). No correlation was elicited between FEV(1) or FVC (%predicted) and VO(2peak) (%predicted) in this patient cohort. Greater thoracic curves were associated with lower FEV(1) (%predicted), r = −0.343, p = 0.001, FVC (%predicted), r = −0.307, p = 0.003 and BR (%) at the end of exercise (r = −0.-0.459, p

Background Viriditoxin is one of the ‘classical’ secondary metabolites produced by fungi and that has antibacterial and other activities; however, the mechanism of its biosynthesis has remained unknown. Results Here, a gene cluster (vdt) responsible for viriditoxin synthesis was identified, via a bioinformatics analysis of the genomes of Paecilomyces variotii and Aspergillus viridinutans that both are viriditoxin producers. The function of the eight-membered gene cluster of P. variotii was characterized by targeted gene disruptions, revealing the roles of each gene in the synthesis of this molecule and establishing its biosynthetic pathway, which includes a Baeyer–Villiger monooxygenase catalyzed reaction. Additionally, a predicted catalytically-inactive hydrolase was identified as being required for the stereoselective biosynthesis of (M)-viriditoxin. The subcellular localizations of two proteins (VdtA and VdtG) were determined by fusing these proteins to green fluorescent protein, to establish that at least two intracellular structures are involved in the compartmentalization of the synthesis steps of this metabolite. Conclusions The predicted pathway for the synthesis of viriditoxin was established by a combination of genomics, bioinformatics, gene disruption and chemical analysis processes. Hence, this work reveals the basis for the synthesis of an understudied class of fungal secondary metabolites and provides a new model species for understanding the synthesis of biaryl compounds with a chiral axis. Electronic supplementary material The online version of this article (10.1186/s40694-019-0072-y) contains supplementary material, which is available to authorized users.

We present the SCUBA-2 850 ${\mu}m$ component of JINGLE, the new JCMT large survey for dust and gas in nearby galaxies, which with 193 galaxies is the largest targeted survey of nearby galaxies at 850 ${\mu}m$. We provide details of our SCUBA-2 data reduction pipeline, optimised for slightly extended sources, and including a calibration model adjusted to match conventions used in other far-infrared data. We measure total integrated fluxes for the entire JINGLE sample in 10 infrared/submillimetre bands, including all WISE, Herschel-PACS, Herschel-SPIRE and SCUBA-2 850 ${\mu}m$ maps, statistically accounting for the contamination by CO(J=3-2) in the 850 ${\mu}m$ band. Of our initial sample of 193 galaxies, 191 are detected at 250 ${\mu}m$ with a $\geq$ 5${\sigma}$ significance. In the SCUBA-2 850 ${\mu}m$ band we detect 126 galaxies with $\geq$ 3${\sigma}$ significance. The distribution of the JINGLE galaxies in far-infrared/sub-millimetre colour-colour plots reveals that the sample is not well fit by single modified-blackbody models that assume a single dust-emissivity index $(\beta)$. Instead, our new 850 ${\mu}m$ data suggest either that a large fraction of our objects require $\beta < 1.5$, or that a model allowing for an excess of sub-mm emission (e.g., a broken dust emissivity law, or a very cold dust component 10 K) is required. We provide relations to convert far-infrared colours to dust temperature and $\beta$ for JINGLE-like galaxies. For JINGLE the FIR colours correlate more strongly with star-formation rate surface-density rather than the stellar surface-density, suggesting heating of dust is greater due to younger rather than older stellar-populations, consistent with the low proportion of early-type galaxies in the sample., Comment: Accepted by MNRAS; data available at http://www.star.ucl.ac.uk/JINGLE/

The objective of this document was to standardise published cardiopulmonary exercise testing (CPET) protocols for improved interpretation in clinical settings and multicentre research projects. This document: 1) summarises the protocols and procedures used in published studies focusing on incremental CPET in chronic lung conditions; 2) presents standard incremental protocols for CPET on a stationary cycle ergometer and a treadmill; and 3) provides patients' perspectives on CPET obtained through an online survey supported by the European Lung Foundation. We systematically reviewed published studies obtained from EMBASE, Medline, Scopus, Web of Science and the Cochrane Library from inception to January 2017. Of 7914 identified studies, 595 studies with 26 523 subjects were included. The literature supports a test protocol with a resting phase lasting at least 3 min, a 3-min unloaded phase, and an 8- to 12-min incremental phase with work rate increased linearly at least every minute, followed by a recovery phase of at least 2-3 min. Patients responding to the survey (n=295) perceived CPET as highly beneficial for their diagnostic assessment and informed the Task Force consensus. Future research should focus on the individualised estimation of optimal work rate increments across different lung diseases, and the collection of robust normative data. Funding was received from the European Respiratory Society, grant number TF-2016-12. The research of Jana De Brandt is financially supported by FWO (grant #11B4718N) and the research of Chris Burtin is partially sponsored by Limburg Kankerfonds. Funding information for this article has been deposited with the Crossref Funder Registry. Hebestreit, H (reprint author), Univ Kinderklin, ERN LUNG, Josef Schneider Str 2, D-97080 Wurzburg, Germany. hebestreit@uni-wuerzburg.de

JINGLE is a new JCMT legacy survey designed to systematically study the cold interstellar medium of galaxies in the local Universe. As part of the survey we perform 850um continuum measurements with SCUBA-2 for a representative sample of 193 Herschel-selected galaxies with M*>10^9Msun, as well as integrated CO(2-1) line fluxes with RxA3m for a subset of 90 of these galaxies. The sample is selected from fields covered by the Herschel-ATLAS survey that are also targeted by the MaNGA optical integral-field spectroscopic survey. The new JCMT observations combined with the multi-wavelength ancillary data will allow for the robust characterization of the properties of dust in the nearby Universe, and the benchmarking of scaling relations between dust, gas, and global galaxy properties. In this paper we give an overview of the survey objectives and details about the sample selection and JCMT observations, present a consistent 30 band UV-to-FIR photometric catalog with derived properties, and introduce the JINGLE Main Data Release (MDR). Science highlights include the non-linearity of the relation between 850um luminosity and CO line luminosity, and the serendipitous discovery of candidate z>6 galaxies., MNRAS in press, 25 pages

Introduction Children perceived to have difficult asthma often have poor treatment adherence.1 In asthma, long-term inhaled corticosteroids (ICS) are often abandoned by patients who feel little short-term benefit.2 Medication adherence often differentiates ‘difficult asthma’ from ‘difficult asthmatics’. Relvar (fluticasone furoate/vilanterol) is a once daily combined ICS/LABA preparation licensed for children aged >12 years. Relvar is considered in our centre for asthmatic patients reporting increased symptoms, demonstrating regular exacerbations or reduced lung function and those with reported/suspected poor adherence to twice daily combined ICS/LABA preparations. Methods Retrospective cohort study of patients prescribed Relvar. Data collected included FEV1 (percent predicted/absolute volumes), fraction of expired nitric oxide (FeNO), emergency department (ED)attendances and hospital/primary care prescriptions for rescue oral steroids (2 years before and after commencing Relvar). Data were analysed using paired t-test (Graphpad prism software). Results Thirty-nine patients (15 female) were studied with mean age of commencing Relvar 13 years. Mean (sd) baseline FEV1 of 84 (9.48)%predicted and FeNO 58.5 (43) ppb were noted prior to commencing Relvar. No statistical difference was in%FEV1 pre and post-Relvar (p=0.3652) was seen. FeNO was lower post-Relvar but did not reach statistical significance (p=0.21). Given the large confidence intervals (−5 to +25 ppb) statistical significance may have been achieved with a larger sample size. ED attendances were significantly reduced after commencing Relvar (p=0.004). 19/39 primary care teams responded, with no significant difference in prednisolone courses prescribed in primary care (p=0.1545 [95% CI −0.63 to 3.68]). However, hospital (p=0.0043 [95% CI 0.26 to 1.28]) and total (p=0.0087 [95% CI 0.27 to 1.77]) prednisolone courses were significantly reduced post Relvar. Conclusions In patients with poor adherence to ICS we found that once daily treatment with Relvar significantly reduced ED attendances and oral prednisolone use. Once daily medication may be more acceptable to patients, and in some instances it could be delivered within a school setting to ensure adherence. A prospective study including quality of life/asthma control test measures is planned. References Bracken M, et al. Arch Dis Child 2009;94:780–4. Klok T, et al. Ped All Imm 2015;26:197–205.