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[...]we urge authors to consider using causal models when testing causal associations. [...]all other methods of controlling for confounding involve implicit assumptions about causal effects, which are not transparent to the reader. The observed associations between these covariates and the outcome have not been subject to the same approach to control of confounding as the exposure. [...]residual confounding and other biases often heavily influence these associations. [...]we recommend that P values only rarely be presented in isolation (exceptions may include \"omics\" studies and tests for interaction).

Face-to-face education as the traditional basis for medical education was disrupted by the COVID-19 pandemic as learners and educators were moved online with little time for preparation. Fortunately, as online learning has grown, together with medical education shifting to problem-based and team-centered learning over the last three decades, existing resources have been adapted and improved upon to meet the challenges. Effective blended learning has resulted in innovative synchronous and asynchronous learning platforms. Clearly, to do this well requires time, effort, and adjustment from clinicians, educators, and learners, but it should result in an engaging change in teaching practice. Its success will rely on an evaluation of learning outcomes, educator and learner satisfaction, and long-term retention of knowledge. It will be important to maintain ongoing assessment of all aspects of the medical education process, including how to best teach and assess theory, physiology, pathology, history-taking, physical examination, and clinical management.Conclusion: The COVID-19 pandemic triggered emergency transitional processes for teaching and assessment in medical education which built upon existing innovations in teaching medicine with the use of technology. These strategies will continue to evolve so as to provide the basis for an enduring hybrid teaching model involving blended and e-learning in medical education.. What is Known:• Most pediatricians provide clinical teaching to medical students and residents, but few have had formal training in online educational approaches and techniques.• Being able to adapt to new and innovative integrated teaching methods is of key importance when becoming a competent teacher.What is New:• This review presents an up-to-date summary of best practice in blended and e-learning and how it may be optimally delivered.• Knowledge of the principles of e-learning, and how people learn more generally, helps pediatricians shape their clinical teaching and facilitates better interaction with medical students and residents.

The impact of evolving treatment regimens, airway clearance strategies, and antibiotic combinations on the incidence and prevalence of respiratory infection in cystic fibrosis (CF) in children and adolescents remains unclear. The incidence, prevalence, and prescription trends from 2002 to 2019 with 18,339 airway samples were analysed. Staphylococcus aureus [− 3.86% (95% CI − 5.28–2.43)] showed the largest annual decline in incidence, followed by Haemophilus influenzae [− 3.46% (95% CI − 4.95–1.96)] and Pseudomonas aeruginosa [− 2.80%95% CI (− 4.26–1.34)]. Non-tuberculous mycobacteria and Burkholderia cepacia showed a non-significant increase in incidence. A similar pattern of change in prevalence was observed. No change in trend was observed in infants < 2 years of age. The mean age of the first isolation of S. aureus ( p  < 0.001), P. aeruginosa ( p  < 0.001), H. influenza ( p  < 0.001), Serratia marcescens ( p  = 0.006) and Aspergillus fumigatus ( p  = 0.02) have increased. Nebulised amikacin (+ 3.09 ± 2.24 prescription/year, p  = 0.003) and colistin (+ 1.95 ± 0.3 prescriptions/year, p  = 0.032) were increasingly prescribed, while tobramycin (− 8.46 ± 4.7 prescriptions/year, p  < 0.001) showed a decrease in prescription. Dornase alfa and hypertonic saline nebulisation prescription increased by 16.74 ± 4.1 prescriptions/year and 24 ± 4.6 prescriptions/year ( p  < 0.001). There is a shift in CF among respiratory pathogens and prescriptions which reflects the evolution of cystic fibrosis treatment strategies over time.

ObjectiveEmpyema is the most common complication of pneumonia. Primary interventions include chest drainage and fibrinolytic therapy (CDF) or video-assisted thoracoscopic surgery (VATS). We describe disease trends, clinical outcomes and factors associated with reintervention.Design/setting/patientsRetrospective cohort of paediatric empyema cases requiring drainage or surgical intervention, 2011–2018, admitted to a large Australian tertiary children’s hospital.ResultsDuring the study, the incidence of empyema increased from 1.7/1000 to 7.1/1000 admissions (p<0.001). We describe 192 cases (174 CDF and 18 VATS), median age 3.0 years (IQR 1–5), mean fever duration prior to intervention 6.2 days (SD ±3.3 days) and 50 (26%) cases admitted to PICU. PICU admission increased during the study from 18% to 34% (p<0.001). Bacteraemia occurred in 23/192 (12%) cases. A pathogen was detected in 131/192 (68%); Streptococcus pneumoniae 75/192 (39%), S. aureus 25/192 (13%) and group A streptococcus 13/192 (7%). Reintervention occurred in 49/174 (28%) and 1/18 (6%) following primary CDF and VATS. Comparing repeat intervention with single intervention cases, a continued fever postintervention increased the likelihood for a repeat intervention (OR 1.3 per day febrile; 95% CI 1.2 to 1.4, p<0.0001). Younger age, prolonged fever preintervention and previous antibiotic treatment were not associated with initial treatment failure (all p>0.05).ConclusionWe report increasing incidence and severity of empyema in a large tertiary hospital. One in four patients required a repeat intervention after CDF. Neither clinical variables at presentation nor early investigations were able to predict initial treatment failure.

Asthma is the most common chronic condition in children worldwide. It affects daytime activities, sleep and school attendance and causes anxiety to parents, families and other carers. The quality of asthma diagnosis and management globally still needs substantial improvement. From infancy to the teenage years, there are age-specific challenges, including both underdiagnosis and overdiagnosis with stigma-related barriers to treatment in some cultures and in adolescents. Guidelines are increasingly evidence based, but their impact on improving outcomes has been negligible in many parts of the world, often due to lack of implementation. New thinking is needed to enable substantial improvements in outcomes. The disease varies globally and plans will need to differ for individual countries or places where region-specific barriers prevent optimal care. A wide selection of educational activities is needed, including community-targeted initiatives, to engage with families. The Paediatric Asthma Project Plan has been initiated to strengthen diagnosis and management of asthma. This encompasses a vision for the next 10–15 years, building on the knowledge and experience from previous educational projects. It will take into account the educational needs of patients, carers and healthcare professionals as well as the accessibility and affordability of medication, particularly in low and middle-income countries where the prevalence of asthma is rising more rapidly. This overview presents a first step for those involved in the diagnosis and management of childhood asthma to strengthen care for children globally.

ENCODE comprises thousands of functional genomics datasets, and the encyclopedia covers hundreds of cell types, providing a universal annotation for genome interpretation. However, for particular applications, it may be advantageous to use a customized annotation. Here, we develop such a custom annotation by leveraging advanced assays, such as eCLIP, Hi-C, and whole-genome STARR-seq on a number of data-rich ENCODE cell types. A key aspect of this annotation is comprehensive and experimentally derived networks of both transcription factors and RNA-binding proteins (TFs and RBPs). Cancer, a disease of system-wide dysregulation, is an ideal application for such a network-based annotation. Specifically, for cancer-associated cell types, we put regulators into hierarchies and measure their network change (rewiring) during oncogenesis. We also extensively survey TF-RBP crosstalk, highlighting how SUB1, a previously uncharacterized RBP, drives aberrant tumor expression and amplifies the effect of MYC, a well-known oncogenic TF. Furthermore, we show how our annotation allows us to place oncogenic transformations in the context of a broad cell space; here, many normal-to-tumor transitions move towards a stem-like state, while oncogene knockdowns show an opposing trend. Finally, we organize the resource into a coherent workflow to prioritize key elements and variants, in addition to regulators. We showcase the application of this prioritization to somatic burdening, cancer differential expression and GWAS. Targeted validations of the prioritized regulators, elements and variants using siRNA knockdowns, CRISPR-based editing, and luciferase assays demonstrate the value of the ENCODE resource. ENCODE is a resource comprising thousands of functional genomic datasets. Here, the authors present custom annotation within ENCODE for cancer, highlighting a workflow that can help prioritise key elements in oncogenesis.

BackgroundCommunity-acquired pneumonia (CAP) is a leading cause of childhood hospitalisation. Limited data exist on factors predicting severe disease with no paediatric-specific predictive tools.MethodsRetrospective cohort (2011–2016) of hospitalised CAP cases. We analysed clinical variables collected at hospital presentation against outcomes. Stratified outcomes were mild (hospitalised), moderate (invasive drainage procedure, intensive care) or severe (mechanical ventilation, vasopressors, death).ResultsWe report 3330 CAP cases, median age 2.0 years (IQR 1–5 years), with 2950 (88.5%) mild, 305 (9.2%) moderate and 75 (2.3%) severe outcomes. Moderate-severe outcomes were associated with hypoxia (SaO2 <90%; OR 6.6, 95% CI 5.1 to 8.5), increased work of breathing (severe vs normal OR 5.8, 95% CI 4.2 to 8.0), comorbidities (4+ comorbidities vs nil; OR 8.8, 95% CI 5.5 to 14) and being indigenous (OR 4.7, 95% CI 2.6 to 8.4). Febrile children were less likely than afebrile children to have moderate-severe outcomes (OR 0.57 95% CI 0.44 to 0.74). The full model receiver operating characteristic (ROC) area under the curve (AUC) was 0.78. Sensitivity analyses showed similar results with clinical or radiological CAP definitions. We derived a clinical tool to stratify low, intermediate or high likelihood of severe disease (AUC 0.72). High scores (≥5) had nearly eight times higher odds of moderate-severe disease than those with a low (≤1) score (OR 7.7 95% CI 5.6 to 10.5).ConclusionsA clinical risk prediction tool is needed for child CAP. We have identified risk factors and derived a simple clinical tool using clinical variables at hospital presentation to determine a child’s risk of invasive or intensive care treatment with an ROC AUC comparable with adult pneumonia tools.

Objectives: Understanding the long-term consequences of sleep-disordered breathing (SDB) in neonates is crucial. A lack of consensus on diagnostic and treatment thresholds has resulted in limited research in this area. Our study aims to describe the trajectory of SDB in a cohort of high-risk neonates and their respiratory and neurodevelopmental outcomes at 3 years of age, and explore the relationship between SDB during early infancy and neurocognitive outcomes. Methods: A retrospectively identified cohort of neonates with moderate–severe SDB were prospectively followed at 3 years of age. Data collected included last polysomnography (PSG) parameters up to the age of 3 years and sleep physician’s recommendations, duration of CPAP use, compliance with treatment, timing of SDB resolution, and neurodevelopmental outcomes. Univariate and multivariate logistic regression analyses were performed to evaluate the association between important respiratory and sleep breathing parameters with the developmental outcomes. Results: Eighty neonates were included. Respiratory and developmental outcomes were available for 58 (72.5%) and 56 (70%) patients, respectively. In most patients (47/58, 81%), SDB had resolved by 3 years of age. Survival without major developmental delay was seen in 32/56 (57%), but a significant proportion (21/56, 37.5%) demonstrated global developmental delay. Following univariate analysis, primary diagnosis, apnoea–hypopnoea index (AHI) at the time of last PSG and SDB outcome was significantly associated with developmental delay. However, these associations were not seen in multivariate analysis. Conclusions: Despite severity at baseline, SDB resolved in the majority of patients with time and treatment. Although statistically insignificant, logistic regression analysis identified some clinically important associations between neonatal SDB and neurodevelopmental outcomes.

STARR-seq technology has employed progressively more complex genomic libraries and increased sequencing depths. An issue with the increased complexity and depth is that the coverage in STARR-seq experiments is non-uniform, overdispersed, and often confounded by sequencing biases, such as GC content. Furthermore, STARR-seq readout is confounded by RNA secondary structure and thermodynamic stability. To address these potential confounders, we developed a negative binomial regression framework for uniformly processing STARR-seq data, called STARRPeaker. Moreover, to aid our effort, we generated whole-genome STARR-seq data from the HepG2 and K562 human cell lines and applied STARRPeaker to comprehensively and unbiasedly call enhancers in them.

BackgroundOscillometry may provide the feasible and sensitive tool for objective remote monitoring of paediatric asthma.MethodsObservational study of school-aged healthy, well-controlled and poorly-controlled asthma performing daily home-based oscillometry for 3–4 months, alongside objective measures of asthma control (Asthma Control Questionnaire weekly and Asthma Control Test monthly), medication use and exacerbations. Day-to-day variability calculated as coefficient of variation (CV) for resistance at 5 Hz (R5), reactance at 5 Hz (X5) and area under reactance curve (AX). Our objective was to examine feasibility, whether day-to-day variability was increased in asthma and correlations with asthma control and exacerbation burden. Clinical exacerbation patterns were examined using principal component analysis and k-means clustering of oscillometry, symptoms, breathing parameters and adherence.ResultsFeasibility was 74.9±16.0% in health (n=13, 93.7±16.2 days) and 80.6±12.9% in asthma (n=42, 101.6±24.9 days; 17 well-controlled and 27 poorly-controlled asthma). Increased day-to-day variability in all oscillometry indices occurred in asthma versus health (all p≤0.002), with CV R5 the best discriminator (area under receiver operating characteristics curve 0.88, p<0.001). CV R5 increased during exacerbation and correlated with all asthma control measures and exacerbation burden. Correlations remained when examining non-exacerbation oscillometry data. Two exacerbation patterns were found based on oscillometry data in the pre-exacerbation period, characterised by severity of impairment of R5, X5, AX and CV R5 (n=12, more severe). Findings were similar using post-exacerbation period oscillometry data (n=8, more severe). Symptoms did not differ across exacerbation patterns.ConclusionsHome-based oscillometry monitoring was highly feasible over extended periods in school-aged asthmatics. Day-to-day oscillometry variability was increased in asthma compared with health, reflected asthma control and exacerbation burden and identified differing exacerbation patterns.