Comparative Effectiveness of Step-up Therapies in Children with Asthma Prescribed Inhaled Corticosteroids : A Historical Cohort Study

This work was supported by the Respiratory Effectiveness Group. Acknowledgments We thank the Respiratory Effectiveness Group for funding this work, Annie Burden for assistance with statistics, and Simon Van Rysewyk and Lisa Law for assistance with medical writing.Peer reviewedPostprin

Culture of airway epithelial cells from neonates sampled within 48-hours of birth

Peer reviewedPublisher PD

Inconsistent Divergence of Mitochondrial-DNA in the Spontaneously Hypertensive Rat

We have recently shown that the spontaneously hypertensive rat (SHR) and the Wistar-Kyoto (WKY) rat differ at a frequency of 1 per 62 bases in their nuclear DNA (Hypertension 1992;19:425-427). Given the origin of these strains this level of divergence was unexpected. To investigate the origin of this nuclear divergence we have examined mitochondrial DNA. Mitochondrial DNA was isolated from SHR and WKY rats, digested with several restriction enzymes, electrophoresed in 1.0% agarose gels, and the fragments visualized with ethidium bromide staining. This approach allowed us to analyze 220 base pairs of mitochondrial DNA. No differences were detected between SHR and WKY rats. Comparison with the King-Holtzman rat strain produced differences at an average of 1 per 52 base pairs. We also examined several SHR and WKY rats from within our colonies and found no differences suggesting intrastrain homogeneity for mitochondrial DNA phenotypes. These data indicate that the SHR and WKY rat share a recent, common maternal ancestor. This result is consistent with the published origins of the SHR and WKY rat strains. Together with the nuclear divergence results, the data suggest that the original Wistar colony from which SHR and WKY rats were derived was probably highly polymorphic for nuclear genes

Applying UK real world primary care data to predict asthma attacks in 3776 well-characterised children : a retrospective cohort study

FUNDING This analysis was funded by Respiratory Effectiveness Group DATA AVAILABILITY STATEMENT Data are available from Clinical Practice Research Datalink (https://www.cprd.com/home/) and Optimum Patient Care (http://optimumpatientcare.org/about-us/).Peer reviewedPublisher PD

Glutathione S-Transferase Genotype Protects against In Utero Tobacco–linked Lung Function Deficits

We would like to thank all the previous contributors to the Perth Infant Asthma Follow up study including David Mullane, Desmond Cox, Kimberley Franks, Lou Landau, Jack Goldblatt, Sally Young, Siew-Kim Khoo, Neil Gibson, Veena Judge, Lyle Palmer, Paul O’Keefe, Jackie Arnott, Steve Stick, Peter Rye, Catherine Hayden and Sunalene Devadason.Peer reviewedPostprin

A systematic review of maternal smoking during pregnancy and fetal measurements with meta-analysis

Funding: The study was supported by the European Cooperation in Science and Technology, who provided funds for publication. KMG is supported by the National Institute for Health Research through the NIHR Southampton Biomedical Research Centre and by the European Union's Seventh Framework Programme (FP7/2007-2013), projects Early Nutrition and ODIN under grant agreement numbers 289346 and 613977.Peer reviewedPublisher PD

Abrogation of Stem Loop Binding Protein (Slbp) function leads to a failure of cells to transition from proliferation to differentiation, retinal coloboma and midline axon guidance deficits

Through forward genetic screening for mutations affecting visual system development, we identified prominent coloboma and cell-autonomous retinal neuron differentiation, lamination and retinal axon projection defects in eisspalte (ele) mutant zebrafish. Additional axonal deficits were present, most notably at midline axon commissures. Genetic mapping and cloning of the ele mutation showed that the affected gene is slbp, which encodes a conserved RNA stem-loop binding protein involved in replication dependent histone mRNA metabolism. Cells throughout the central nervous system remained in the cell cycle in ele mutant embryos at stages when, and locations where, post-mitotic cells have differentiated in wild-type siblings. Indeed, RNAseq analysis showed down-regulation of many genes associated with neuronal differentiation. This was coincident with changes in the levels and spatial localisation of expression of various genes implicated, for instance, in axon guidance, that likely underlie specific ele phenotypes. These results suggest that many of the cell and tissue specific phenotypes in ele mutant embryos are secondary to altered expression of modules of developmental regulatory genes that characterise, or promote transitions in, cell state and require the correct function of Slbp-dependent histone and chromatin regulatory genes

Indirect effects of the COVID-19 pandemic on paediatric healthcare use and severe disease: a retrospective national cohort study

OBJECTIVES: To determine the indirect consequences of the COVID-19 pandemic on paediatric healthcare utilisation and severe disease at a national level following lockdown on 23 March 2020. DESIGN: National retrospective cohort study. SETTING: Emergency childhood primary and secondary care providers across Scotland; two national paediatric intensive care units (PICUs); statutory death records. PARTICIPANTS: 273 455 unscheduled primary care attendances; 462 437 emergency department attendances; 54 076 emergency hospital admissions; 413 PICU unplanned emergency admissions requiring invasive mechanical ventilation; and 415 deaths during the lockdown study period and equivalent dates in previous years. MAIN OUTCOME MEASURES: Rates of emergency care consultations, attendances and admissions; clinical severity scores on presentation to PICU; rates and causes of childhood death. For all data sets, rates during the lockdown period were compared with mean or aggregated rates for the equivalent dates in 2016–2019. RESULTS: 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 as a proportion of cases for the entire population, with an OR of 0.52 for likelihood of admission during lockdown (95% CI 0.37 to 0.73), compared with the equivalent period in previous years. 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 with 2016–2019. CONCLUSIONS: National lockdown led to a reduction in paediatric emergency care utilisation, without associated evidence of severe harm

Fitter women did not have attenuated hemodynamic responses to psychological stress compared with age-matched women with lower levels of fitness

According to the \u27cross stressor adaptation hypothesis\u27, regular exercise acts as a buffer against the detrimental effects of stress. Nevertheless, evidence that higher levels of cardiorespiratory fitness moderate hemodynamic responses to acute psychological stress is inconclusive, especially in women. Women aged 30-50 years (in the mid-follicular phase of the menstrual cycle) with higher (n = 17) and lower (n = 17) levels of fitness were subjected to a Trier Social Stress Test (TSST). Continuous, non-invasive measurements were made of beat-to-beat, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), stroke volume (SV), cardiac output (CO), left ventricular ejection time (LVET), maximum slope, pulse interval (PI) and total peripheral resistance (TPR). Maximal oxygen consumption was significantly (p<0.001) higher in the \u27higher fit\u27 women. Lower fit women had higher fasting glucose, resting heart rate, waist to hip ratios and elevated serum triglyceride and cholesterol/ HDL ratios compared with higher fit women (p<0.05 for all). While all measured parameters (for both groups)displayed significant (p<0.001) responses to the TSST, only HR, PI and LVET differed significantly between higher and lower fit women (p<0.001 for all) with the higher fit women having the larger response in each case. It was also found that higher fit women had significantly shorter time to recovery for maximum slope compared with the lower fit women. These findings provide little support for the notion that higher levels of cardiorespiratory fitness result in lower cardiovascular responsivity to psychological stress in women but may indicate that lower fit women have blunted responses to stress

Genome-wide changes in genetic diversity in a population of Myotis lucifugus affected by white-nose syndrome

Novel pathogens can cause massive declines in populations, and even extirpation of hosts. But disease can also act as a selective pressure on survivors, driving the evolution of resistance or tolerance. Bat white-nose syndrome (WNS) is a rapidly spreading wildlife disease in North America. The fungus causing the disease invades skin tissues of hibernating bats, resulting in disruption of hibernation behavior, premature energy depletion, and subsequent death. We used whole-genome sequencing to investigate changes in allele frequencies within a population of Myotis lucifugus in eastern North America to search for genetic resistance to WNS. Our results show low F-ST values within the population across time, i.e., prior to WNS (Pre-WNS) compared to the population that has survived WNS (Post-WNS). However, when dividing the population with a geographical cut-off between the states of Pennsylvania and New York, a sharp increase in values on scaffold GL429776 is evident in the Post-WNS samples. Genes present in the diverged area are associated with thermoregulation and promotion of brown fat production. Thus, although WNS may not have subjected the entire M. lucifugus population to selective pressure, it may have selected for specific alleles in Pennsylvania through decreased gene flow within the population. However, the persistence of remnant sub-populations in the aftermath of WNS is likely due to multiple factors in bat life history.Peer reviewe