The efficacy of the Dyson air purifier on asthma control: A single-center, investigator-led, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Air pollution is associated with poor asthma outcomes. High-efficiency particulate air air purifiers may reduce air pollution and thus improve asthma outcomes. However, the efficacy of such devices for this purpose remains inconclusive. OBJECTIVE: To investigate the effects of reducing the levels of pollutants on asthma outcomes in adults, using a novel Dyson high-efficiency particulate air air purifier. METHODS: In a single-center, double-blinded, randomized controlled trial, participants (N = 50) were randomized at a 1:1 ratio to active filters (intervention) or to dummy filters (placebo) for a total of 78 weeks. The primary outcomes were the changes in Asthma Control Questionnaire 6 (ACQ6) and Asthma-specific Quality of Life Questionnaire (AQLQ) scores from baseline. The secondary outcomes were changes in indoor air pollution and lung function measurements. The coronavirus disease 2019 pandemic limited spirometry measurements to 2 time points and assessment of fractional exhaled nitric oxide and bronchial hyperresponsiveness to baseline only. RESULTS: Air pollutant levels were significantly lower in the intervention group compared with the placebo group (P = .0003). Both groups had a significant improvement in their ACQ6 and AQLQ. However, there were no significant between-group differences in ACQ6, AQLQ, or spirometry, compared with baseline in multivariable repeated measures models. CONCLUSION: The Dyson air purifier significantly improved air quality. However, there were no significant improvements in asthma control, quality of life, or measures of lung function in the intervention group compared with the control group despite improvements in indoor air quality. Larger, extended studies are required to confirm or refute these findings, especially given that the coronavirus disease 2019 pandemic prevented the procurement of detailed objective data. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04729530; ttps://clinicaltrials.gov/ct2/show/NCT04729530.

Preconceptional smoking alters spermatozoal miRNAs of murine fathers and affects offspring's body weight.

BACKGROUND: Active smoking has been reported among 7% of teenagers worldwide, with ages ranging from 13 to 15 years. An epidemiological study suggested that preconceptional paternal smoking is associated with adolescent obesity in boys. We developed a murine adolescent smoking model before conception to investigate the paternal molecular causes of changes in offspring's phenotype. METHOD: Male and female C57BL/6J mice were exposed to increasing doses of mainstream cigarette smoke (CS) from onset of puberty for 6 weeks and mated with room air (RA) controls. RESULTS: Thirteen miRNAs were upregulated and 32 downregulated in the spermatozoa of CS-exposed fathers, while there were no significant differences in the count and morphological integrity of spermatozoa, as well as the proliferation of spermatogonia between CS- and RA-exposed fathers. Offspring from preconceptional CS-exposed mothers had lower body weights (p = 0.007). Moreover, data from offspring from CS-exposed fathers suggested a potential increase in body weight (p = 0.062). CONCLUSION: We showed that preconceptional paternal CS exposure regulates spermatozoal miRNAs, and possibly influences the body weight of F1 progeny in early life. The regulated miRNAs may modulate transmittable epigenetic changes to offspring, thus influence the development of respiratory- and metabolic-related diseases such as obesity, a mechanism that warrants further studies for elaborate explanations.

Sex-specific associations of asthma acquisition with changes in DNA methylation during adolescence.

BACKGROUND: Underlying biological mechanisms involved in sex differences in asthma status changes from pre- to post-adolescence are unclear. DNA methylation (DNAm) has been shown to be associated with the risk of asthma. OBJECTIVE: We hypothesized that asthma acquisition from pre- to post-adolescence was associated with changes in DNAm during this period at asthma-associated cytosine-phosphate-guanine (CpG) sites and such an association was sex-specific. METHODS: Subjects from the Isle of Wight birth cohort (IOWBC) with DNAm in blood at ages 10 and 18 years (n = 124 females, 151 males) were studied. Using a training-testing approach, epigenome-wide CpGs associated with asthma were identified. Logistic regression was used to examine sex-specific associations of DNAm changes with asthma acquisition between ages 10 and 18 at asthma-associated CpGs. The ALSPAC birth cohort was used for independent replication. To assess functional relevance of identified CpGs, association of DNAm with gene expression in blood was assessed. RESULTS: We identified 535 CpGs potentially associated with asthma. Significant interaction effects of DNAm changes and sex on asthma acquisition in adolescence were found at 13 of the 535 CpGs in IOWBC (P-values <1.0 × 10-3 ). In the replication cohort, consistent interaction effects were observed at 10 of the 13 CpGs. At 7 of these 10 CpGs, opposite DNAm changes across adolescence were observed between sexes in both cohorts. In both cohorts, cg20891917, located on IFRD1 linked to asthma, shows strong sex-specific effects on asthma transition (P-values <.01 in both cohorts). CONCLUSION AND CLINICAL RELEVANCE: Gender reversal in asthma acquisition is associated with opposite changes in DNAm (males vs females) from pre- to post-adolescence at asthma-associated CpGs. These CpGs are potential biomarkers of sex-specific asthma acquisition in adolescence.

Prediction models for childhood asthma: A systematic review.

BACKGROUND: The inability to objectively diagnose childhood asthma before age five often results in both under-treatment and over-treatment of asthma in preschool children. Prediction tools for estimating a child's risk of developing asthma by school-age could assist physicians in early asthma care for preschool children. This review aimed to systematically identify and critically appraise studies which either developed novel or updated existing prediction models for predicting school-age asthma. METHODS: Three databases (MEDLINE, Embase and Web of Science Core Collection) were searched up to July 2019 to identify studies utilizing information from children ≤5 years of age to predict asthma in school-age children (6-13 years). Validation studies were evaluated as a secondary objective. RESULTS: Twenty-four studies describing the development of 26 predictive models published between 2000 and 2019 were identified. Models were either regression-based (n = 21) or utilized machine learning approaches (n = 5). Nine studies conducted validations of six regression-based models. Fifteen (out of 21) models required additional clinical tests. Overall model performance, assessed by area under the receiver operating curve (AUC), ranged between 0.66 and 0.87. Models demonstrated moderate ability to either rule in or rule out asthma development, but not both. Where external validation was performed, models demonstrated modest generalizability (AUC range: 0.62-0.83). CONCLUSION: Existing prediction models demonstrated moderate predictive performance, often with modest generalizability when independently validated. Limitations of traditional methods have shown to impair predictive accuracy and resolution. Exploration of novel methods such as machine learning approaches may address these limitations for future school-age asthma prediction.

Best time to assess complete clinical response after chemoradiotherapy in squamous cell carcinoma of the anus (ACT II): a post-hoc analysis of randomised controlled phase 3 trial.

BACKGROUND: Guidelines for anal cancer recommend assessment of response at 6-12 weeks after starting treatment. Using data from the ACT II trial, we determined the optimum timepoint to assess clinical tumour response after chemoradiotherapy. METHODS: The previously reported ACT II trial was a phase 3 randomised trial of patients of any age with newly diagnosed, histologically confirmed, squamous cell carcinoma of the anus without metastatic disease from 59 centres in the UK. We randomly assigned patients (by minimisation) to receive either intravenous mitomycin (one dose of 12 mg/m2 on day 1) or intravenous cisplatin (one dose of 60 mg/m2 on days 1 and 29), with intravenous fluorouracil (one dose of 1000 mg/m2 per day on days 1-4 and 29-32) and radiotherapy (50·4 Gy in 28 daily fractions); and also did a second randomisation after initial therapy to maintenance chemotherapy (fluorouracil and cisplatin) or no maintenance chemotherapy. The primary outcome was complete clinical response (the absence of primary and nodal tumour by clinical examination), in addition to overall survival and progression-free survival from time of randomisation. In this post-hoc analysis, we analysed complete clinical response at three timepoints: 11 weeks from the start of chemoradiotherapy (assessment 1), 18 weeks from the start of chemoradiotherapy (assessment 2), and 26 weeks from the start of chemoradiotherapy (assessment 3) as well as the overall and progression-free survival estimates of patients with complete clinical response or without complete clinical response at each assessment. We analysed both the overall trial population and a subgroup of patients who had attended each of the three assessments by modified intention-to-treat. This study is registered at controlled-trials.com, ISRCTN 26715889. FINDINGS: We enrolled 940 patients from June 4, 2001, until Dec 16, 2008. Complete clinical response was achieved in 492 (52%) of 940 patients at assessment 1 (11 weeks), 665 (71%) of patients at assessment 2 (18 weeks), and 730 (78%) of patients at assessment 3 (26 weeks). 691 patients attended all three assessments and in this subgroup, complete clinical response was reported in 441 (64%) patients at assessment 1, 556 (80%) at assessment 2, and 590 (85%) at assessments 3. 151 (72%) of the 209 patients who had not had a complete clinical response at assessment 1 had a complete clinical response by assessment 3. In the overall trial population of 940 patients, 5 year overall survival in patients who had a clinical response at assessments 1, 2, 3 was 83% (95% CI 79-86), 84% (81-87), and 87% (84-89), respectively and was 72% (66-78), 59% (49-67), and 46% (37-55) for patients who did not have a complete clinical response at assessments 1, 2, 3, respectively. In the subgroup of 691 patients, 5 year overall survival in patients who had a clinical response at assessment 1, 2, 3 was 85% (81-88), 86% (82-88), and 87% (84-90), respectively, and was 75% (68-80), 61% (50-70), and 48% (36-58) for patients who did not have a complete clinical response at assessment 1, 2, 3, respectively. Similarly, progression-free survival in both the overall trial population and the subgroup was longer in patients who had a complete clinical response, compared with patients who did not have a complete clinical response, at all three assessments. INTERPRETATION: Many patients who do not have a complete clinical response when assessed at 11 weeks after commencing chemoradiotherapy do in fact respond by 26 weeks, and the earlier assessment could lead to some patients having unnecessary surgery. Our data suggests that the optimum time for assessment of complete clinical response after chemoradiotherapy for patients with squamous cell carcinoma of the anus is 26 weeks from starting chemoradiotherapy. We suggest that guidelines should be revised to indicate that later assessment is acceptable. FUNDING: Cancer Research UK.

Exome sequence read depth methods for identifying copy number changes.

Copy number variants (CNVs) play important roles in a number of human diseases and in pharmacogenetics. Powerful methods exist for CNV detection in whole genome sequencing (WGS) data, but such data are costly to obtain. Many disease causal CNVs span or are found in genome coding regions (exons), which makes CNV detection using whole exome sequencing (WES) data attractive. If reliably validated against WGS-based CNVs, exome-derived CNVs have potential applications in a clinical setting. Several algorithms have been developed to exploit exome data for CNV detection and comparisons made to find the most suitable methods for particular data samples. The results are not consistent across studies. Here, we review some of the exome CNV detection methods based on depth of coverage profiles and examine their performance to identify problems contributing to discrepancies in published results. We also present a streamlined strategy that uses a single metric, the likelihood ratio, to compare exome methods, and we demonstrated its utility using the VarScan 2 and eXome Hidden Markov Model (XHMM) programs using paired normal and tumour exome data from chronic lymphocytic leukaemia patients. We use array-based somatic CNV (SCNV) calls as a reference standard to compute prevalence-independent statistics, such as sensitivity, specificity and likelihood ratio, for validation of the exome-derived SCNVs. We also account for factors known to influence the performance of exome read depth methods, such as CNV size and frequency, while comparing our findings with published results.

Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer.

BACKGROUND: It is not known whether low-dose radioiodine (1.1 GBq [30 mCi]) is as effective as high-dose radioiodine (3.7 GBq [100 mCi]) for treating patients with differentiated thyroid cancer or whether the effects of radioiodine (especially at a low dose) are influenced by using either recombinant human thyrotropin (thyrotropin alfa) or thyroid hormone withdrawal. METHODS: At 29 centers in the United Kingdom, we conducted a randomized noninferiority trial comparing low-dose and high-dose radioiodine, each in combination with either thyrotropin alfa or thyroid hormone withdrawal before ablation. Patients (age range, 16 to 80 years) had tumor stage T1 to T3, with possible spread to nearby lymph nodes but without metastasis. End points were the rate of success of ablation at 6 to 9 months, adverse events, quality of life, and length of hospital stay. RESULTS: A total of 438 patients underwent randomization; data could be analyzed for 421. Ablation success rates were 85.0% in the group receiving low-dose radioiodine versus 88.9% in the group receiving the high dose and 87.1% in the thyrotropin alfa group versus 86.7% in the group undergoing thyroid hormone withdrawal. All 95% confidence intervals for the differences were within ±10 percentage points, indicating noninferiority. Similar results were found for low-dose radioiodine plus thyrotropin alfa (84.3%) versus high-dose radioiodine plus thyroid hormone withdrawal (87.6%) or high-dose radioiodine plus thyrotropin alfa (90.2%). More patients in the high-dose group than in the low-dose group were hospitalized for at least 3 days (36.3% vs. 13.0%, P<0.001). The proportions of patients with adverse events were 21% in the low-dose group versus 33% in the high-dose group (P=0.007) and 23% in the thyrotropin alfa group versus 30% in the group undergoing thyroid hormone withdrawal (P=0.11). CONCLUSIONS: Low-dose radioiodine plus thyrotropin alfa was as effective as high-dose radioiodine, with a lower rate of adverse events. (Funded by Cancer Research UK; ClinicalTrials.gov number, NCT00415233.).

Do Cell-Cycle Phase-Specific Markers Predict Disease Grade, Stage, and Outcome in Cervical Carcinoma?

AIMS: Multiparameter analysis of cell cycle markers has shown a strong relationship between cell cycle progression and tumor grade, stage, and clinical outcome in penile, renal, ovarian, and breast cancers. We sought to link expression of cell cycle phase-specific markers in cervical cancer to tumor grade, stage, and clinical outcome to investigate their potential use as prognostic and predictive markers. METHODS: Pretreatment biopsy material was obtained from 35 patients with cervical cancer (stage IB2-IVA) and 12 normal cervix control cases. Each patient was treated with neoadjuvant chemotherapy followed by chemoradiation. Immunohistochemical staining was performed using a panel of cell cycle phase markers: replication licensing factors: Mcm2 (minichromosome maintenance 2) and geminin, and the standard proliferation marker Ki67 (clone MIB-1). RESULTS: The expression levels of each cell cycle biomarker were very high in all cases of squamous cell carcinoma of the cervix regardless of grade or stage of disease. In our cohort, all cases displayed an aggressive, so-called actively cycling phenotype. Univariate analysis showed that none of the cell cycle biomarkers predicted grade, stage, or clinical outcome. CONCLUSIONS: Cell cycle phase-specific markers do not appear to predict disease grade, stage, or outcome in our sample of patients with cervical cancer. This is not surprising, given that the expression of each cell cycle biomarker was very high in all cases.Indeed, all the cases of squamous cell carcinoma of the cervix (n = 28) and all but 1 of the adenocarcinomas (n = 7) in this study displayed an aggressive "actively cycling" phenotype. This predominance of actively cycling tumors is unusual and may reflect the viral etiology underlying the disease. These preliminary findings raise many interesting questions including the prognostic value of disease grade and markers of proliferation in cervical tumors as reliable prognostic indicators. Further work on a larger cohort of patients is warranted.

Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial.

BACKGROUND: Chemoradiation became the standard of care for anal cancer after the ACT I trial. However, only two-thirds of patients achieved local control, with 5-year survival of 50%; therefore, better treatments are needed. We investigated whether replacing mitomycin with cisplatin in chemoradiation improves response, and whether maintenance chemotherapy after chemoradiation improves survival. METHODS: In this 2 × 2 factorial trial, we enrolled patients with histologically confirmed squamous-cell carcinoma of the anus without metastatic disease from 59 centres in the UK. Patients were randomly assigned to one of four groups, to receive either mitomycin (12 mg/m(2) on day 1) or cisplatin (60 mg/m(2) on days 1 and 29), with fluorouracil (1000 mg/m(2) per day on days 1-4 and 29-32) and radiotherapy (50.4 Gy in 28 daily fractions); with or without two courses of maintenance chemotherapy (fluorouracil and cisplatin at weeks 11 and 14). The random allocation was generated by computer and patients assigned by telephone. Randomisation was done by minimisation and stratified by tumour site, T and N stage, sex, age, and renal function. Neither patients nor investigators were masked to assignment. Primary endpoints were complete response at 26 weeks and acute toxic effects (for chemoradiation), and progression-free survival (for maintenance). The primary analyses were done by intention to treat. This study is registered at controlled-trials.com, number 26715889. FINDINGS: We enrolled 940 patients: 472 were assigned to mitomycin, of whom 246 were assigned to no maintenance, 226 to maintenance; 468 were assigned to cisplatin, of whom 246 were assigned to no maintenance, 222 to maintenance. Median follow-up was 5.1 years (IQR 3.9-6.9). 391 of 432 (90.5%) patients in the mitomycin group versus 386 of 431 (89.6%) in the cisplatin group had a complete response at 26 weeks (difference -0.9%, 95% CI -4.9 to 3.1; p=0.64). Overall, toxic effects were similar in each group (334/472 [71%] for mitomycin vs 337/468 [72%] for cisplatin). The most common grade 3-4 toxic effects were skin (228/472 [48%] vs 222/468 [47%]), pain (122/472 [26%] vs 135/468 [29%]), haematological (124/472 [26%] vs 73/468 [16%]), and gastrointestinal (75/472 [16%] vs 85/468 [18%]). 3-year progression-free survival was 74% (95% CI 69-77; maintenance) versus 73% (95% CI 68-77; no maintenance; hazard ratio 0.95, 95% CI 0.75-1.21; p=0.70). INTERPRETATION: The results of our trial--the largest in anal cancer to date--show that fluorouracil and mitomycin with 50.4 Gy radiotherapy in 28 daily fractions should remain standard practice in the UK. FUNDING: Cancer Research UK.

Associations of Breathing Pattern Disorder and Nijmegen Score With Clinical Outcomes in Difficult-to-Treat Asthma.

BACKGROUND: Breathing pattern disorder (BPD) reflects altered biomechanical patterns of breathing that drive breathing difficulty and commonly accompanies difficult-to-treat asthma. Diagnosis of BPD has no gold standard, but Nijmegen Questionnaire (NQ) >23 is commonly used. OBJECTIVES: We sought to advance clinical characterization of BPD and better understand the clinical utility of NQ in difficult asthma in patients from the Wessex AsThma CoHort of difficult asthma (WATCH) study. METHODS: Associations between demographic and clinical factors in difficult asthma and BPD, ascertained by clinical diagnosis (yes/no, n = 476), by NQ scores (≤23: normal [no suggestion of BPD] and >23: abnormal [suggested BPD], n = 372), as well as the continuous raw NQ scores were assessed in univariate models to identify significant risk factors associated with the 3 BPD outcomes. For the clinician-diagnosed and NQ-based BPD, associations of continuous factors were assessed using the independent samples t test or the Mann-Whitney U test as appropriate for the data distribution or by the Spearman correlation test. Dichotomous associations were evaluated using χ2 tests. Multivariable logistic (dichotomous outcomes) and linear regression models (continuous outcomes) were developed to identify predictive factors associated with clinician-diagnosed and NQ-based BPD, dichotomous and continuous. Patients with data on NQ scores were grouped into NQ quartiles (low, moderate, high, and very high). The patterns of association of the quartiles with 4 health-related questionnaire outcomes were assessed using linear regression analyses. RESULTS: Multivariable regression identified that clinically diagnosed BPD was associated with female sex (odds ratio [OR]: 1.85; 95% confidence interval [CI]: 1.07, 3.20), comorbidities (rhinitis [OR: 2.46; 95% CI: 1.45, 4.17], gastroesophageal reflux disease [GORD] [OR: 2.77; 95% CI: 1.58, 4.84], inducible laryngeal obstruction [OR: 4.37; 95% CI: 2.01, 9.50], and any psychological comorbidity [OR: 1.86; 95% CI: 1.13, 3.07]), and health care usage (exacerbations [OR: 1.07; 95% CI: 1.003, 1.14] and previous intensive care unit (ICU) admissions [OR: 2.03; 95% CI: 1.18, 3.47]). Abnormal NQ-based BPD diagnosis was associated with history of eczema (OR: 1.83; 95% CI: 1.07, 3.14), GORD (OR: 1.94; 95% CI: 1.15, 3.27), or any psychological comorbidity (OR: 4.29; 95% CI: 2.64, 6.95) at multivariable regression. Differences between clinical and NQ-based BPD traits were also found with 42% discordance in BPD state between these definitions. Multivariable linear regression analysis with NQ as a continuous outcome showed positive association with worse asthma outcomes (admission to ICU, P = .037), different phenotypic traits (female sex, P = .001; ever smoker, P = .025), and greater multimorbidity (GORD, P = .002; sleep apnea, P = .04; and any psychological comorbidity, P < .0001). CONCLUSION: BPD is associated with worse health outcomes and negative health impacts in difficult asthma within a multimorbidity disease model. It therefore merits better recognition and prompt treatment. Clinical diagnosis and NQ offer different perspectives on BPD, so this goal may be best addressed by considering clinical features alongside the magnitude of NQ.

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude.

BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N). CONCLUSIONS: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.

Multimorbidity in Difficult Asthma: The Need for Personalised and Non-Pharmacological Approaches to Address a Difficult Breathing Syndrome.

Three to ten percent of people living with asthma have difficult-to-treat asthma that remains poorly controlled despite maximum levels of guideline-based pharmacotherapy. This may result from a combination of multiple adverse health issues including aggravating comorbidities, inadequate treatment, suboptimal inhaler technique and/or poor adherence that may individually or collectively contribute to poor asthma control. Many of these are potentially "treatable traits" that can be pulmonary, extrapulmonary, behavioural or environmental factors. Whilst evidence-based guidelines lead clinicians in pharmacological treatment of pulmonary and many extrapulmonary traits, multiple comorbidities increase the burden of polypharmacy for the patient with asthma. Many of the treatable traits can be addressed with non-pharmacological approaches. In the current healthcare model, these are delivered by separate and often disjointed specialist services. This leaves the patients feeling lost in a fragmented healthcare system where clinical outcomes remain suboptimal even with the best current practice applied in each discipline. Our review aims to address this challenge calling for a paradigm change to conceptualise difficult-to-treat asthma as a multimorbid condition of a "Difficult Breathing Syndrome" that consequently needs a holistic personalised care attitude by combining pharmacotherapy with the non-pharmacological approaches. Therefore, we propose a roadmap for an evidence-based multi-disciplinary stepped care model to deliver this.

Integration of Genomic Risk Scores to Improve the Prediction of Childhood Asthma Diagnosis.

Genome-wide and epigenome-wide association studies have identified genetic variants and differentially methylated nucleotides associated with childhood asthma. Incorporation of such genomic data may improve performance of childhood asthma prediction models which use phenotypic and environmental data. Using genome-wide genotype and methylation data at birth from the Isle of Wight Birth Cohort (n = 1456), a polygenic risk score (PRS), and newborn (nMRS) and childhood (cMRS) methylation risk scores, were developed to predict childhood asthma diagnosis. Each risk score was integrated with two previously published childhood asthma prediction models (CAPE and CAPP) and were validated in the Manchester Asthma and Allergy Study. Individually, the genomic risk scores demonstrated modest-to-moderate discriminative performance (area under the receiver operating characteristic curve, AUC: PRS = 0.64, nMRS = 0.55, cMRS = 0.54), and their integration only marginally improved the performance of the CAPE (AUC: 0.75 vs. 0.71) and CAPP models (AUC: 0.84 vs. 0.82). The limited predictive performance of each genomic risk score individually and their inability to substantially improve upon the performance of the CAPE and CAPP models suggests that genetic and epigenetic predictors of the broad phenotype of asthma are unlikely to have clinical utility. Hence, further studies predicting specific asthma endotypes are warranted.