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Introduction A minority of school-aged children with asthma have persistent poor control and experience frequent asthma attacks despite maximal prescribed maintenance therapy. These children have higher morbidity and risk of death. The first add-on biologic therapy, omalizumab, a monoclonal antibody that blocks immunoglobulin (Ig)E, was licensed for children with severe asthma in 2005. While omalizumab is an effective treatment, non-response is common. A second biologic, mepolizumab which blocks interleukin 5 and targets eosinophilic inflammation, was licensed in 2018, but the licence was granted by extrapolation of adult clinical trial data to children. This non-inferiority (NI) trial will determine whether mepolizumab is as efficacious as omalizumab in reducing asthma attacks in children with severe therapy resistant asthma (STRA) and refractory difficult asthma (DA).Methods and analysis This is an ongoing multicentre 1:1 randomised NI open-label trial of mepolizumab and omalizumab. Up to 150 children and young people (CYP) aged 6–17 years with severe asthma will be recruited from specialist paediatric severe asthma centres in the UK. Prior to randomisation, children will be monitored for medication adherence for up to 16 weeks to determine STRA and refractory DA diagnoses. Current prescribing recommendations of serum IgE and blood eosinophils will not influence eligibility or enrolment. The primary outcome is the 52-week asthma attack rate. Bayesian analysis using clinician-elicited prior distributions will be used to calculate the posterior probability that mepolizumab is not inferior to omalizumab. Secondary outcomes include Composite Asthma Severity Index, Paediatric Asthma Quality of Life Questionnaire, lung function measures (forced expiratory volume in one second (FEV1), bronchodilator reversibility), fractional exhaled nitric oxide, Asthma Control Test (ACT), health outcomes EuroQol 5 Dimension (EQ-5D) and optimal serum IgE and blood eosinophil levels that may predict a response to therapy. These outcomes will be analysed in a frequentist framework using longitudinal models.Ethics and dissemination The study has been approved by the South Central—Berkshire Research Ethics Committee REC Number 19/SC/0634 and had Clinical Trials Authorisation from the Medicines and Healthcare Products Regulatory Agency (MHRA) (EudraCT 2019-004085-17). All parents/legal guardians will give informed consent for their child to participate in the trial, and CYP will give assent to participate. The results will be published in peer-reviewed journals, presented at international conferences and disseminated via our patient and public involvement partners.Trial registration number ISRCTN12109108; EudraCT Number: 2019-004085-17.

Asthma is a common chronic disease in children. It is a dynamic condition—symptoms change over time, and the outcome of diagnostic tests can vary. Consequently, evaluating the onset of asthma at a single point in time, perhaps when patients are asymptomatic with limited impairment of the lung function, may result in false diagnostic conclusions. The absence of consistent gold-standard diagnostic criteria in children challenges the ability of any study to ascertain an effect of treatment on asthma prevention. A comprehensive review of the diagnostic criteria used for new-onset asthma in school-age children was conducted based on existing recommendations from published clinical guidance, alongside evidence from paediatric asthma prevention trials. Findings from the review were used to propose suggestions for diagnosing new-onset asthma in future asthma prevention trials. Despite an overall lack of consensus in the published clinical guidance, there are similarities between the various recommendations for diagnosing asthma in children, which typically involve assessing the variable symptoms and supplementing the medical history with objective measures of lung function. For future paediatric asthma prevention trials, we suggest that paediatric clinical trials should use a new-onset asthma definition that incorporates the concepts of “possible”, “probable” and “confirmed” asthma. “Possible” asthma would capture self-reported features of chronic symptoms and symptom relief with β2-agonist bronchodilator (suggesting reversibility). “Probable” asthma would include symptom chronicity, self-reported symptom relief with β2-agonist bronchodilator, and objective features of asthma (reversibility or bronchial hyper-responsiveness). A “confirmed” diagnosis would be made only if there is a positive response to controller therapy. These suggestions aim to improve the diagnosis of new-onset childhood asthma in clinical trials, which will be useful in the design and conduct of future paediatric asthma prevention trials.

Anaphylaxis is an acute, potentially fatal, systemic hypersensitivity reaction that warrants prompt diagnosis and management. It continues to be challenging to anticipate who may be at risk of a severe, life-threatening allergic reaction. Anaphylaxis can be caused by a range of allergens, such as certain foods, medications, latex, insect stings, etc. Cofactors that augment the severity of clinical symptoms and increase the risk of poor outcomes include exercise, stress, infectious diseases, underlying mast cell disease, active allergic disease such as asthma, advanced age, intake of certain medications, history of previous anaphylaxis, and delayed or missed administration of adrenaline. According to the European Anaphylaxis Registry, food is the major elicitor of anaphylaxis, especially eggs, cow milk, and nuts, in children and adolescents. Reaction to insect venom has also been noted in young adulthood. Early recognition of signs and symptoms and prompt treatment are crucial in anaphylaxis management to avoid serious and even fatal outcomes. It is crucial for both individuals and clinicians to identify the cause of anaphylaxis. Biomarkers of anaphylaxis, such as histamine, tryptase, platelet activation factor (PAF), chymase, carboxypeptidase A3, dipeptidyl peptidase I (DPPI), basogranulin, CCL-2, hsa-miR-451a, may be useful in diagnosis and management. The purpose of this review article is to present a comprehensive overview of current evidence and expert opinions regarding the risk factors that predispose individuals to anaphylaxis. Additionally, it provides insights into potential biomarkers and genetic markers for accurate diagnosis and management. This review underscores the significance of expert guidance in enhancing patient outcomes and enabling self-management of anaphylactic episodes.

BackgroundAcute severe asthma (ASA) is a leading cause of hospital attendance in children. Standard first-line therapy consists of high-dose inhaled bronchodilators plus oral corticosteroids. Treatment for children who fail to respond to first-line therapy is problematic: the use of intravenous agents is inconsistent, and side effects are frequent. High-flow humidified oxygen (HiFlo) is widely used in respiratory conditions and is increasingly being used in ASA, but with little evidence for its effectiveness. A well-designed, adequately powered randomized controlled trial (RCT) of HiFlo therapy in ASA is urgently needed, and feasibility data are required to plan such an RCT. In this study, we describe the protocol for a feasibility study designed to fill this knowledge gap. ObjectiveThis study aims to establish whether a full RCT of early HiFlo therapy in children with ASA can be conducted successfully and safely, to establish whether recruitment using deferred consent is practicable, and to define appropriate outcome measures and sample sizes for a definitive RCT. The underlying hypothesis is that early HiFlo therapy in ASA will reduce the need for more invasive treatments, allow faster recovery and discharge from hospital, and in both these ways reduce distress to children and their families. MethodsWe conducted a feasibility RCT with deferred consent to assess the use of early HiFlo therapy in children aged 2 to 11 years with acute severe wheeze not responding to burst therapy (ie, high-dose inhaled salbutamol with or without ipratropium). Children with a Preschool Respiratory Assessment Measure score ≥5 after burst therapy were randomized to commence HiFlo therapy or follow standard care. The candidate primary outcomes assessed were treatment failure requiring escalation and time to meet hospital discharge criteria. Patient and parent experiences were also assessed using questionnaires and telephone interviews. ResultsThe trial was opened to recruitment in February 2020 but was paused for 15 months owing to the COVID-19 pandemic. The trial was reopened at the lead site in July 2021 and opened at the other 3 sites from August to December 2022. Recruitment was completed in June 2023. ConclusionsThis feasibility RCT of early HiFlo therapy in children with ASA recruited to the target despite major disturbances owing to the COVID-19 pandemic. The data are currently being analyzed and will be published separately. Trial RegistrationInternational Standard Randomised Controlled Trial Number Registry ISRCTN78297040; https://www.isrctn.com/ISRCTN78297040 International Registered Report Identifier (IRRID)DERR1-10.2196/54081

Abstract Background The 2014 estimates of prevalence of food allergy (FA) in Europe published by the European Academy of Allergy and Clinical Immunology included only the eight so‐called big foods (cow's milk/egg/wheat/soy/peanut/tree nuts/fish/shellfish). Those estimates have recently been updated. Complementing this, we sought to identify and estimate the prevalence of allergy to other foods that have been reported during the last decade. Methods Six databases were searched for studies published 2012–2021. Random‐effects meta‐analysis was performed to derive pooled prevalence of allergy to each food. Results Twenty‐seven studies were included, containing a total of 66 FAs. Among the most frequently reported FAs, the lifetime and point prevalence range of self‐reported kiwi allergy was 0.1%–1.0% and 0.2%–8.1%, respectively, while the food challenge (FC)‐verified kiwi allergy point prevalence range was 0.01%–0.10%. The point prevalence range for self‐reported peach allergy was 0.2%–3.2%, while the range for FC‐verified peach allergy was 0.02%–0.05%. The lifetime and point prevalence range for self‐reported tomato allergy was 0.01%–1.8% and 0.2%–2.1%, respectively. Conclusion Allergy to some foods traditionally not considered important are now emerging as relevant FAs. The focus on FA in Europe should not be limited to the so‐called eight big FA, but extended to other types of foods which need to be considered both for clinical purposes and population risk assessment.

Abstract Regulation of cutaneous immunity is severely compromised in inflammatory skin disease. To investigate the molecular crosstalk underpinning tolerance versus inflammation in atopic dermatitis, we utilise a human in vivo allergen challenge study, exposing atopic dermatitis patients to house dust mite. Here we analyse transcriptional programmes at the population and single cell levels in parallel with immunophenotyping of cutaneous immunocytes revealed a distinct dichotomy in atopic dermatitis patient responsiveness to house dust mite challenge. Our study shows that reactivity to house dust mite was associated with high basal levels of TNF-expressing cutaneous Th17 T cells, and documents the presence of hub structures where Langerhans cells and T cells co-localised. Mechanistically, we identify expression of metallothioneins and transcriptional programmes encoding antioxidant defences across all skin cell types, that appear to protect against allergen-induced inflammation. Furthermore, single nucleotide polymorphisms in the MTIX gene are associated with patients who did not react to house dust mite, opening up possibilities for therapeutic interventions modulating metallothionein expression in atopic dermatitis.

Summary: Background: Spirometric obstruction and restriction are two patterns of impaired lung function which are predictive of poor health. We investigated the development of these phenotypes and their transitions through childhood to early adulthood. Methods: In this study, we analysed pooled data from three UK population−based birth cohorts established between 1989 and 1995. We applied descriptive statistics, regression modelling and data-driven modelling to data from three population−based birth cohorts with at least three spirometry measures from childhood to adulthood (mid-school: 8–10 years, n = 8404; adolescence: 15–18, n = 5764; and early adulthood: 20–26, n = 4680). Participants were assigned to normal, restrictive, and obstructive spirometry based on adjusted regression residuals. We considered two transitions: from 8–10 to 15–18 and from 15–18 to 20–26 years. Findings: Obstructive phenotype was observed in ∼10%, and restrictive in ∼9%. A substantial proportion of children with impaired lung function in school age (between one third in obstructive and a half in restricted phenotype) improved and achieved normal and stable lung function to early adulthood. Of those with normal lung function in school-age,

Background Biologics have proven efficacy for patients with severe asthma but there is lack of consensus on defining response. We systematically reviewed and appraised methodologically developed, defined and evaluated definitions of non-response and response to biologics for severe asthma. Methods We searched four bibliographic databases from inception to 15 March 2021. Two reviewers screened references, extracted data, and assessed methodological quality of development, measurement properties of outcome measures and definitions of response based on COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). A modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach and narrative synthesis were undertaken. Results 13 studies reported three composite outcome measures, three asthma symptoms measures, one asthma control measure and one quality of life measure. Only four measures were developed with patient input; none were composite measures. Studies utilised 17 definitions of response: 10 out of 17 (58.8%) were based on minimal clinically important difference (MCID) or minimal important difference (MID) and 16 out of 17 (94.1%) had high-quality evidence. Results were limited by poor methodology for the development process and incomplete reporting of psychometric properties. Most measures rated “very low” to “low” for quality of measurement properties and none met all quality standards. Conclusions This is the first review to synthesise evidence about definitions of response to biologics for severe asthma. While high-quality definitions are available, most are MCIDs or MIDs, which may be insufficient to justify continuation of biologics in terms of cost-effectiveness. There remains an unmet need for universally accepted, patient-centred, composite definitions to aid clinical decision making and comparability of responses to biologics.

Abstract Objective To report on the outcomes of urological cancer patients undergoing radical surgery between March–September 2020 (compared with 2019) in the European Institute of Oncology (IEO) in Milan and the South East London Cancer Alliance (SELCA). Materials and Methods Since March 2020, both institutions implemented a COVID‐19 minimal ‘green’ pathway, whereby patients were required to isolate for 14 days prior to admission and report a negative COVID‐19 polymerase chain reaction (PCR) test within 3 days of surgery. COVID‐19 positive patients had surgery deferred until a negative swab. Surgical outcomes assessed were: American Society of Anaesthesiologists (ASA) grade; surgery time; theatre time; intensive care unit (ICU) stay >24 h; pneumonia; length of stay (LOS); re‐admission. Postoperative COVID‐19 infection rates and associated mortality were also recorded. Results At IEO, uro‐oncological surgery increased by 4%, as compared with the same period in 2019 (n = 515 vs. 534). The main increase was observed for renal (16%, n = 98 vs. 114), bladder (24%, n = 45 vs. 56) and testicular (27%, n = 26 vs. 33). Patient demographics were all comparable between 2019 and 2020. Only one bladder cancer patient developed COVID‐19, reporting mild/moderate disease. There was no COVID‐19 associated mortality. In the SELCA cohort, uro‐oncological surgery declined by 23% (n = 403 vs. 312) compared with the previous year. The biggest decrease was seen for prostate (−42%, n = 156 vs. 91), penile (−100%, n = 4 vs. 0) and testicular cancers (−46%, n = 35 vs. 24). Various patient demographic characteristics were notably different when comparing 2020 versus 2019. This likely reflects the clinical decision of deferring COVID‐19 vulnerable patients. One patient developed COVID‐19, with no COVID‐19 related mortality. Conclusion The COVID‐19 minimal ‘green’ pathways that were put in place have shown to be safe for uro‐oncological patients requiring radical surgery. There were limited complications, almost no peri‐operative COVID‐19 infection and no COVID‐19‐related mortality in either cohort.

Background Prescription of three or more short-acting β2-agonist (SABA) canisters per year in adult and adolescent asthma populations is associated with a risk of severe exacerbations; however, evidence in children aged 30% of patients across all age cohorts were not prescribed inhaled corticosteroids (ICS), and the median proportion of days covered was only 33%, suggesting inadequate prescribing of ICS Conclusion In children, higher SABA prescriptions at baseline were associated with increased future exacerbation rates. These findings highlight the need for monitoring prescription of three or more SABA canisters per year to identify children with asthma at risk of exacerbations.

Background: While several scoring systems for the severity of anaphylactic reactions have been developed, there is a lack of consensus on definition and categorisation of severity of food allergy disease as a whole. Aim: To develop an international consensus on the severity of food allergy (DEfinition of Food Allergy Severity, DEFASE) scoring system, to be used globally. Methods: Phase 1: We conducted a mixed-method systematic review (SR) of 11 databases for published and unpublished literature on severity of food allergy management and set up a panel of international experts. Phase 2: Based on our findings in Phase 1, we drafted statements for a two-round modified electronic Delphi (e-Delphi) survey. A purposefully selected multidisciplinary international expert panel on food allergy (n = 60) was identified and sent a structured questionnaire, including a set of statements on different domains of food allergy severity related to symptoms, health-related quality of life, and economic impact. Participants were asked to score their agreement on each statement on a 5-point Likert scale ranging from “strongly agree” to “strongly disagree”. Median scores and percentage agreements were calculated. Consensus was defined a priori as being achieved if 70% or more of panel members rated a statement as “strongly agree” to “agree” after the second round. Based on feedback, 2 additional online voting rounds were conducted. Results: We received responses from 92% of Delphi panel members in round 1 and 85% in round 2. Consensus was achieved on the overall score and in all of the 5 specific key domains as essential components of the DEFASE score. Conclusions: The DEFASE score is the first comprehensive grading of food allergy severity that considers not only the severity of a single reaction, but the whole disease spectrum. An international consensus has been achieved regarding a scoring system for food allergy disease. It offers an evaluation grid, which may help to rate the severity of food allergy. Phase 3 will involve validating the scoring system in research settings, and implementing it in clinical practice.

Abstract Background There is increasing evidence that the airway microbiome plays a key role in the establishment of respiratory health by interacting with the developing immune system early in life. While it has become clear that bacteria are involved in this process, there is a knowledge gap concerning the role of fungi. Moreover, the inter-kingdom interactions that influence immune development remain unknown. In this prospective exploratory human study, we aimed to determine early post-natal microbial and immunological features of the upper airways in 121 healthy newborns. Results We found that the oropharynx and nasal cavity represent distinct ecological niches for bacteria and fungi. Breastfeeding correlated with changes in microbiota composition of oropharyngeal samples with the greatest impact upon the relative abundance of Streptococcus species and Candida. Host transcriptome profiling revealed that genes with the highest expression variation were immunological in nature. Multi-omics factor analysis of host and microbial data revealed unique co-variation patterns. Conclusion These data provide evidence of a diverse multi-kingdom microbiota linked with local immunological characteristics in the first week of life that could represent distinct trajectories for future respiratory health. Trial registration NHS Health Research Authority, IRAS ID 199053. Registered 5 Oct 2016. https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/breathing-together/ Video abstract

IntroductionViruses are detected in over 50% of acute asthma attacks and in a notable proportion of patients with asthma during stable disease state They are associated with worse outcomes. We will conduct a series of systematic reviews and meta-analyses to quantify the prevalence and clinical burden of various respiratory viruses in stable asthma and acute asthma attacks. In addition, we will assess the viral loads of respiratory viruses during stable and acute asthma, to explore whether viral load could differentiate attacks triggered by viruses versus those where viruses are present as "innocent bystanders".Materials and methodsBased on a prospectively registered protocol (PROSPERO, ID: CRD42023375108) and following standard methodology recommended by Cochrane, we will systematically search Medline/PubMed, EMBASE, the Cochrane Library and relevant conference proceedings for studies assessing the prevalence or clinical burden of respiratory viruses in asthma. Methodological rigour of the included studies will be appraised using a tool specific for prevalence studies and the Newcastle-Ottawa Scale respectively. In anticipation of significant clinical and methodological heterogeneity, we will conduct random effect meta-analyses. For evaluating the prevalence of viruses, we will perform meta-analyses of proportions using the inverse variance method, and the Freeman-Tukey transformation. We will conduct meta-regression analyses for exploring heterogeneity.ConclusionWe envisage that these systematic reviews and meta-analyses will quantify the prevalence and burden of respiratory viruses in stable and acute asthma and will drive future research and clinical practice.

The Subglacial Antarctic Lakes Scientific Access (SALSA) Project accessed Mercer Subglacial Lake using environmentally clean hot-water drilling to examine interactions among ice, water, sediment, rock, microbes and carbon reservoirs within the lake water column and underlying sediments. A ~0.4 m diameter borehole was melted through 1087 m of ice and maintained over ~10 days, allowing observation of ice properties and collection of water and sediment with various tools. Over this period, SALSA collected: 60 L of lake water and 10 L of deep borehole water; microbes >0.2 μm in diameter from in situ filtration of ~100 L of lake water; 10 multicores 0.32–0.49 m long; 1.0 and 1.76 m long gravity cores; three conductivity–temperature–depth profiles of borehole and lake water; five discrete depth current meter measurements in the lake and images of ice, the lake water–ice interface and lake sediments. Temperature and conductivity data showed the hydrodynamic character of water mixing between the borehole and lake after entry. Models simulating melting of the ~6 m thick basal accreted ice layer imply that debris fall-out through the ~15 m water column to the lake sediments from borehole melting had little effect on the stratigraphy of surficial sediment cores.

Abstract Background Biological therapies relieve symptoms in allergic inflammatory diseases so we systematically reviewed the evidence about whether biological monotherapy could benefit people with IgE‐mediated food allergy. Methods We searched six bibliographic databases from 1946 to 30 September 2021 for randomised and non‐randomised controlled trials about biological monotherapy in people with IgE‐mediated food allergy confirmed by oral food challenge. We used the Grading of Recommendations, Assessment, Development and Evaluation approach to narratively summarise findings from three trials with 118 participants. The studies were too heterogeneous and sparse to conduct meta‐analysis. Results We included one randomised trial about etokimab, one about omalizumab and one about the discontinued TNX‐901. All were in people with peanut allergy in the USA, mostly aged 13+ years. There was a trend towards improved tolerance of peanut during treatment, with few side effects. However, we have very low certainty about the evidence due to the small number of trials and participants. No included trial reported on quality of life or cost‐effectiveness. Conclusions There is not yet enough certainty to support offering etokimab or omalizumab widely for food allergy. Clinicians may consider the merits for individuals, but large randomised trials with standardised measures are needed to confirm the safety, efficacy and most suitable candidates, doses and durations of treatment before more universal use.

Food allergy affects approximately 2–4% of children and adults. This guideline provides recommendations for managing food allergy from the Global Allergy and Asthma European Network (GA2LEN). A multidisciplinary international Task Force developed the guideline using the Appraisal of Guidelines for Research and Evaluation (AGREE) II framework and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. We reviewed the latest available evidence as of April 2021 (161 studies) and created recommendations by balancing benefits, harms, feasibility, and patient and clinician experiences. We suggest that people diagnosed with food allergy avoid triggering allergens (low certainty evidence). We suggest that infants with cow's milk allergy who need a breastmilk alternative use either hypoallergenic extensively hydrolyzed cow's milk formula or an amino acid-based formula (moderate certainty). For selected children with peanut allergy, we recommend oral immunotherapy (high certainty), though epicutaneous immunotherapy might be considered depending on individual preferences and availability (moderate certainty). We suggest considering oral immunotherapy for children with persistent severe hen's egg or cow's milk allergy (moderate certainty). There are significant gaps in evidence about safety and effectiveness of the various strategies. Research is needed to determine the best approaches to education, how to predict the risk of severe reactions, whether immunotherapy is cost-effective and whether biological therapies are effective alone or combined with allergen immunotherapy.

Abstract Background Lebrikizumab is a monoclonal antibody that modulates activity of interleukin‐13. The Phase 3 ACOUSTICS study assessed lebrikizumab efficacy and safety in adolescents with uncontrolled asthma despite standard‐of‐care treatment. Methods Adolescents (aged 12–17 years) with uncontrolled asthma, prebronchodilator forced expiratory volume in 1 s 40%–90% predicted, and stable background therapy were randomised 1:1:1 to receive lebrikizumab 125 or 37.5 mg or placebo subcutaneously once every 4 weeks. Primary efficacy endpoint was asthma exacerbation rate over 52 weeks. Results Between August 2013 and July 2016, 579 patients were screened and 346 were randomised; 224 (65%) completed the study with 52 weeks of treatment. Lebrikizumab 125 mg (n = 116) reduced the exacerbation rate at 52 weeks versus placebo (n = 117; adjusted rate ratio [RR] 0.49 [95% CI 0.28–0.83]; 51% rate reduction). Lebrikizumab 37.5 mg (n = 113) was less effective at reducing exacerbations (RR 0.60 [95% CI 0.35–1.03]; 40% rate reduction). In patients with blood eosinophil counts ≥300 cells/μl, both lebrikizumab doses reduced exacerbations (125 mg: RR 0.44 [95% CI 0.21–0.89]; 37.5 mg: 0.42 [95% CI 0.19–0.93]). Treatment‐emergent adverse events, serious adverse events, and adverse events leading to study discontinuation occurred in 155 (68%), 7 (3%), and 5 (2%) of 229 patients who received lebrikizumab (both 125 and 37.5 mg doses) and in 72 (62%), 4 (3%), and 1 (1%) of 117 who received placebo, respectively. No deaths occurred. Conclusion Lebrikizumab 125 mg reduced asthma exacerbation rates in adolescents with uncontrolled asthma. However, the study was prematurely terminated (sponsor's decision) potentially limiting interpretation of results. Clinical trial registration NCT01875003 (www.ClinicalTrials.gov).

Abstract Background Recent reports indicate that the prevalence of food allergy is increasing, but accurate estimates remain a challenge due to cross‐reactivity and limited use of precise diagnostic methods. Molecular allergy diagnostics, in which sensitization to individual molecular allergens is measured, is emerging as a promising tool for evaluation of sensitization profiles. In this systematic review, we summarized estimates of prevalence of sensitization to molecular food allergens in the general population in Europe. Methods Following a protocol prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO; reference CRD42021266657), we searched seven databases with no restrictions on publication date or language. Two reviewers independently screened the literature, extracted data, and appraised the risk of bias in the included studies. The findings were synthesized narratively. Results From 4776 de‐duplicated records, five studies, with low to moderate overall risk of bias, were included. Forty‐six molecular allergens from 18 foods were investigated. Overall, the prevalence of sensitization was low, particularly for major allergens, and non‐existent for 10 molecular allergens (0% [95% CI 0–0.8]). The highest prevalence was seen for PR‐10 proteins, such as Cor a 1.04 (13.6% [95% CI 10.9–16.9]). Conclusions Available data, primarily from North‐western Europe, indicate that sensitization to molecular food allergens is overall low. The highest estimates were found for cross‐reactive PR‐10 proteins. There were not enough studies to discern regional differences or perform meta‐analysis, highlighting the need for more population‐representative studies in order to elucidate patterns of sensitization to molecular food allergens in Europe.

Abstract Background Transition from parent-delivered to self-management is a vulnerable time for adolescents and young adults (AYA) with allergy and asthma. There is currently no European guideline available for healthcare professionals (HCPs) on transition of these patients and local/national protocols are also mostly lacking. Methods European HCPs working with AYA with allergy and asthma were invited to complete an online survey assessing challenges of working with these patients, current transition practices and access to specific healthcare resources. Results A total of 1179 responses from 41 European countries were collected. Most HCPs (86%) reported a lack of a transition guideline and a lack of a transition process (20% paediatric HCPs, 50% of adult HCPs, 56% HCP seeing all ages). Nearly half (48%) acknowledged a lack of an established feedback system between paediatric and adult medical services. Many respondents never routinely asked about mental health issues such as self-harm or depression and are not confident in asking about self-harm (66.6%), sexuality (64%) and depression (43.6%). The majority of HCPs (76%) had not received specific training in the care of AYA although 87% agreed that transition was important for AYA with allergy and asthma. Conclusion Although there was agreement that transition is important for AYA with allergy and asthma, there are crucial limitations and variations in the current provision of transition services across Europe. Standardisation of AYA management and specific training are required. This should improve management and continuity of care during adolescence and into adulthood to achieve the best healthcare outcomes.

Один из парадоксов мейнстримного советского кино заключался в том, что оно имело склонность «создавать зрелище «маскулинной телесности, не привлекая (по большей части) внимания к ней в откровенном смысле. Тело героя было мифологизировано в патриархальных структурах, что воспринималось, как естественное положение вещей. В данной работе рассматриваются различные пути, с помощью которых режиссер Кира Муратова бросает вызов этой культурной парадигме, выдвигая на первый план более откровенное мужское тело, тем самым разрушая мужской взгляд на вещи. В этом отношении фильмы Киры Муратовой бросают вызов архетипичным образам маскулинности (и фемининности), распространенным не только в Советском Союзе или в мейнстримном кино, но и во многих других странах.

Background The prevalences of obstructive and restrictive spirometric phenotypes, and their relation to early-life risk factors from childhood to young adulthood remain poorly understood. The aim was to explore these phenotypes and associations with well-known respiratory risk factors across ages and populations in European cohorts. Methods We studied 49 334 participants from 14 population-based cohorts in different age groups (≤10, >10–15, >15–20, >20–25 years, and overall, 5–25 years). The obstructive phenotype was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) z-score less than the lower limit of normal (LLN), whereas the restrictive phenotype was defined as FEV1/FVC z-score ≥LLN, and FVC z-score

Allergic rhinitis in childhood has been often missed, mistreated and misunderstood. It has significant comorbidities, adverse effects upon quality of life and educational performance and can progress to asthma or worsen control of existing asthma. Accurate diagnosis and effective treatment are important. The new EUFOREA algorithm provides a succinct but wide- ranging guide to management at all levels, based on previous guidelines with updated evidence and has been adjusted and approved by experts worldwide.

Background: Dental age estimation using the simple average method utilizing the Demirjian 8 stage tooth developments system has not previously been compared to the 14 stage system of Moorrees. Neither method has been previously used nor compared with the Atlas method in a Kuwaiti population. The recent development of a Kuwait reference data set provides the means to determine which of these methods is the most accurate for age estimation in Kuwaiti subjects. Patients, materials and methods: The sample was dental panoramic tomographs (DPTs) from the archives of Kuwait Ministry of Health Dental Hospitals comprising 375 healthy children aged between 5 and 15 years.Each of the anonymized DPT was assessed in random order and personal details masked from the observer. Results: Intra and inter examiner agreement were calculated using Cohen's Kappa with scores of 0.76 or above which is ‘good to excellent’ agreement.The chronological age (CA) minus dental age (DA) difference using the simple average method (SAM) is an overestimate of 0.39 years for females and an underestimate of 0.14 years for males. The London Atlas overestimated the chronological age by 0.60 years for females and 0.19 years for males. Moorrees technique gave an underestimate of 1.01 years for females and 0.89 years for males.Bland-Altman plots showed an even distribution of difference around the chronological age. The Bland Altman plots showed the spread of the differences between chronological age and dental age for each of the three methods. Conclusions: The simple average method was the most accurate within, 2–3 months of chronological age. The London Atlas and Moorrees methods were less accurate.This makes the simple average method the favoured technique for dental age estimation in a forensic science setting where ethnic specific reference data are important.

Introduction Clinical recommendations for childhood asthma are often based on data extrapolated from studies conducted in adults, despite significant differences in mechanisms and response to treatments. The Paediatric Asthma in Real Life (PeARL) Think Tank aspires to develop recommendations based on the best available evidence from studies in children. An overview of systematic reviews (SRs) on paediatric asthma maintenance management and an SR of treatments for acute asthma attacks in children, requiring an emergency presentation with/without hospital admission will be conducted.Methods and analysis Standard methodology recommended by Cochrane will be followed. Maintenance pharmacotherapy of childhood asthma will be evaluated in an overview of SRs published after 2005 and including clinical trials or real-life studies. For evaluating pharmacotherapy of acute asthma attacks leading to an emergency presentation with/without hospital admission, we opted to conduct de novo synthesis in the absence of adequate up-to-date published SRs. For the SR of acute asthma pharmacotherapy, we will consider eligible SRs, clinical trials or real-life studies without time restrictions. Our evidence updates will be based on broad searches of Pubmed/Medline and the Cochrane Library. We will use A MeaSurement Tool to Assess systematic Reviews, V.2, Cochrane risk of bias 2 and REal Life EVidence AssessmeNt Tool to evaluate the methodological quality of SRs, controlled clinical trials and real-life studies, respectively.Next, we will further assess interventions for acute severe asthma attacks with positive clinical results in meta-analyses. We will include both controlled clinical trials and observational studies and will assess their quality using the previously mentioned tools. We will employ random effect models for conducting meta-analyses, and Grading of Recommendations Assessment, Development and Evaluation methodology to assess certainty in the body of evidence.Ethics and dissemination Ethics approval is not required for SRs. Our findings will be published in peer reviewed journals and will inform clinical recommendations being developed by the PeARL Think Tank.PROSPERO registration numbers CRD42020132990, CRD42020171624.

Abstract Pre-bronchodilator lung function including forced vital capacity (FVC), forced expiratory flow in 1 second (FEV1), their ratio (FEV1/FVC), and forced expiratory flow 25–75% (FEF25–75) measured at age 10, 18, and 26 years in the Isle of Wight birth cohort was analyzed for developmental patterns (trajectories). Early life risk factors before the age of 10 years were assessed for the trajectories. Method Members of the birth cohort (1989/90) were followed at age 1, 2, 4, 10, 18, and 26 years. Allergic sensitization and questionnaire data were collected. Spirometry tests were performed and evaluated according to the American Thoracic Society (ATS) criteria at 10, 18, and 26 years. To identify developmental trajectories for FVC, FEV1, FEV1/FVC, and FEF25–75 from 10 to 26 years, a finite mixture model was applied to the longitudinal lung function data, separately for males and females. Associations of early life factors with the respective lung function trajectories were assessed using log-linear and logistic regression analyses. Results Both high and low lung function trajectories were observed in men and women. FVC continued to grow beyond 18 years in men and women, whereas FEV1 peaked at age 18 years in female trajectories and in one male trajectory. For the FEV1/FVC ratios and FEF25–75 most trajectories appeared highest at age 18 and declined thereafter. However, the low FEV1/FVC trajectory in both sexes showed an early decline at 10 years. Lower birth weight was linked with lower lung function trajectories in males and females. Eczema in the first year of life was a risk factor for later lung function deficits in females, whereas the occurrence of asthma at 4 years of age was a risk factor for later lung function deficits in males. A positive skin prick test at age four was a risk for the low FEV1 trajectory in females and for the low FEV1/FVC trajectory in males. Conclusion Men and women showed distinctive lung function trajectories and associated risk factors. Lower lung function trajectories can be explained by not achieving maximally attainable function at age 18 years and by a function decline from 18 to 26 years.

Background and aims: The term “Food Allergy” refers to a complex global health problem with a wide spectrum of severity. However, a uniform definition of severe food allergy is currently missing. This systematic review is the preliminary step towards a state-of-the-art synopsis of the current evidence relating to the severity of IgE-mediated food allergy; it will inform attempts to develop a consensus to define food allergy severity by clinicians and other stakeholders. Methods: We undertook a mixed-methods systematic review, which involved searching 11 international biomedical databases for published studies from inception to 31 December 2019. Studies were independently screened against pre-defined eligibility criteria and critically appraised by established instruments. The substantial heterogeneity of included studies precluded meta-analyses and, therefore, narrative synthesis of quantitative and qualitative data was performed. Results: We found 23 studies providing eligible primary data on symptom-specific severity of food allergic reactions, and 31 previously published symptom-severity scoring systems referred to food allergic reactions. There were seven studies which assessed quality-of-life measures in patients (and family members) with different food allergy severity and two studies that investigated the economic burden of food allergy severity. Overall, the quality and the global rating of all included studies were judged as being moderate. Conclusions: There is heterogeneity among severity scoring systems used and even outcomes considered in the context of severity of food allergy. No score has been validated. Our results will be used to inform the development of an international consensus to define the severity of food allergy. Systematic review registration: A protocol was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) database with the registration number CRD42020183103 (https://www.crd.york.ac.uk/prospero/#recordDetails).

Background and aims: The term “Food Allergy” refers to a complex global health problem with a wide spectrum of severity. However, a uniform definition of severe food allergy is currently missing. This systematic review is the preliminary step towards a state-of-the-art synopsis of the current evidence relating to the severity of IgE-mediated food allergy; it will inform attempts to develop a consensus to define food allergy severity by clinicians and other stakeholders. Methods: We will undertake a systematic review, which will involve searching international biomedical databases for published studies. Studies will be independently screened against pre-defined eligibility criteria and critically appraised by established instruments. Data will be descriptively and, if possible and applicable, quantitatively synthesised. Ethics and dissemination: This study does not require any specific ethical approval since it is a systematic review. We plan to report results from this systematic review in a peer reviewed journal. These results will be used to inform the development of an international consensus to define severe food allergy. Author's potential conflicts of interest are clearly stated. PROSPERO registration number: CRD42020183103.

The culture of differentiated human airway epithelial cells allows the study of pathogen-host interactions and innate immune responses in a physiologically relevant in vitro model. As the use of primary cell culture has gained popularity the availability of the reagents needed to generate these cultures has increased. In this study we assessed two different media, Promocell and PneumaCult, during the differentiation and maintenance of well-differentiated primary nasal epithelial cell cultures (WD-PNECs). We compared and contrasted the consequences of these media on WD-PNEC morphological and physiological characteristics and their responses to respiratory syncytial virus (RSV) infection. We found that cultures generated using PneumaCult resulted in greater total numbers of smaller, tightly packed, pseudostratified cells. However, cultures from both media resulted in similar proportions of ciliated and goblet cells. There were no differences in RSV growth kinetics, although more ciliated cells were infected in the PneumaCult cultures. There was also significantly more IL-29/IFNλ1 secreted from PneumaCult compared to Promocell cultures following infection. In conclusion, the type of medium used for the differentiation of primary human airway epithelial cells may impact experimental results.

Abstract Background The European Academy of Allergy and Clinical Immunology (EAACI) is developing Guidelines on Allergen Immunotherapy (AIT) for Allergic Rhinoconjunctivitis (ARC). To inform the development of recommendations, we sought to critically assess the systematic review evidence on the effectiveness, safety and cost-effectiveness of AIT for ARC. Methods We undertook a systematic overview, which involved searching nine international biomedical databases from inception to October 31, 2015. Studies were independently screened by two reviewers against pre-defined eligibility criteria and critically appraised using the Critical Appraisal Skills Programme (CASP) Systematic Review Checklist for systematic reviews. Data were descriptively synthesized. Results Our searches yielded a total of 5932 potentially eligible studies, from which 17 systematic reviews met our inclusion criteria. Eight of these were judged to be of high, five moderate and three low quality. These reviews suggested that, in carefully selected patients, subcutaneous (SCIT) and sublingual (SLIT) immunotherapy resulted in significant reductions in symptom scores and medication requirements. Serious adverse outcomes were rare for both SCIT and SLIT. Two systematic reviews reported some evidence of potential cost savings associated with use of SCIT and SLIT. Conclusions We found moderate-to-strong evidence that SCIT and SLIT can, in appropriately selected patients, reduce symptoms and medication requirements in patients with ARC with reassuring safety data. This evidence does however need to be interpreted with caution, particularly given the heterogeneity in the populations, allergens and protocols studied. There is a lack of data on the relative effectiveness, cost-effectiveness and safety of SCIT and SLIT. We are now systematically reviewing all the primary studies, including recent evidence that has not been incorporated into the published systematic reviews.

Abstract Background There is clinical uncertainty about the effectiveness and safety of allergen immunotherapy (AIT) for the treatment of allergic asthma. Objectives To undertake a systematic overview of the effectiveness, cost-effectiveness and safety of AIT for the treatment of allergic asthma. Methods We searched nine electronic databases from inception to October 31, 2015. Systematic reviews were independently screened by two reviewers against pre-defined eligibility criteria and critically appraised using the Critical Appraisal Skills Programme quality assessment tool for systematic reviews. Data were descriptively and thematically synthesized. Results We identified nine eligible systematic reviews; these focused on delivery of AIT through the following routes: subcutaneous (SCIT; n = 3); sublingual (SLIT; n = 4); and both SCIT and SLIT (n = 2). This evidence found that AIT delivered by SCIT and SLIT can improve medication and symptom scores and measures of bronchial hyper-reactivity. The impact on measures of lung function or asthma control was however less clear. We found no systematic review level evidence on the cost-effectiveness of SCIT or SLIT. SLIT had a favorable safety profile when compared to SCIT, particularly in relation to the risk of systemic reactions. Conclusions AIT has the potential to achieve reductions in symptom and medication scores, but there is no clear or consistent evidence that measures of lung function can be improved. Bearing in mind the limitations of synthesizing evidence from systematic reviews and the fact that these reviews include mainly dated studies, a systematic review of current primary studies is now needed to update this evidence base, estimate the effectiveness of AIT on asthma outcomes and to investigate the relative effectiveness, cost-effectiveness and safety of SCIT and SLIT.

Abstract Background Clinical practice guidelines are important tools to promote evidence-based clinical care, but not all countries have the capacity or infrastructure to develop these in-house. The European Academy of Allergy and Clinical Immunology has recently developed guidelines for the prevention, diagnosis and management of food allergy and the management of anaphylaxis. In order to inform dissemination, adaptation and implementation plans, we sought to identify countries that have/do not have national guidelines for food allergy and anaphylaxis. Methods Two reviewers independently searched PubMed to identify countries with guidelines for food allergy and/or anaphylaxis from the inception of this database to December 2016. This was supplemented with a search of the Agency for Healthcare Research and Quality’s National Guideline Clearinghouse in order to identify any additional guidelines that may not have been reported in the peer-reviewed literature. Data were descriptively and narratively synthesized. Results Overall, 5/193 (3%) of countries had at least one guideline for food allergy or anaphylaxis. We found that one (1%) country had a national guideline for the prevention of food allergy, three (2%) countries had a guideline for the diagnosis of food allergy and three (2%) countries had a guideline for the management of food allergy. Three (2%) countries had an anaphylaxis guideline. Conclusions This study concludes that the overwhelming majority of countries do not have any national clinical practice guidelines for food allergy or anaphylaxis.

Abstract Background Despite the centrality of health personnel to the health of the population, the planning, production and management of human resources for health remains underdeveloped in many low- and middle-income countries (LMICs). In addition to the general shortage of health workers, there are significant inequalities in the distribution of health workers within LMICs. This is especially true for countries like Fiji, which face major challenges in distributing its health workforce across many inhabited islands. Methods In this study, we describe and measure health worker distributional inequalities in Fiji, using data from the 2007 Population Census, and Ministry of Health records of crude death rates and health workforce personnel. We adopt methods from the economics literature including the Lorenz Curve/Gini Coefficient and Theil Index to measure the extent and drivers of inequality in the distribution of health workers at the sub-national level in Fiji for three categories of health workers: doctors, nurses, and all health workers (doctors, nurses, dentists and health support staff). Population size and crude death rates are used as proxies for health care needs. Results There are greater inequalities in the densities of health workers at the provincial level, compared to the divisional level in Fiji – six of the 15 provinces fall short of the recommended threshold of 2.3 health workers per 1,000 people. The estimated decile ratios, Gini co-efficient and Thiel index point to inequalities at the provincial level in Fiji, mainly with respect to the distribution of doctors; however these inequalities are relatively small. Conclusion While populations with lower mortality tend to have a slightly greater share of health workers, the overall distribution of health workers on the basis of need is more equitable in Fiji than for many other LMICs. The overall shortage of health workers could be addressed by creating new cadres of health workers; employing increasing numbers of foreign doctors, including specialists; and increasing funding for health worker training, as already demonstrated by the Fiji government. Close monitoring of the equitable distribution of additional health workers in the future is critical.

Abstract Background The quality of acute and long-term anaphylaxis management is variable and this contributes to the poor outcomes experienced by many patients. Clinical practice guidelines have the potential to improve outcomes, but implementing guideline recommendations in routine practice is challenging. Quality indicators have the potential to support guideline implementation efforts. Objective To identify quality indicators to support the acute and long-term management of anaphylaxis. Methods We conducted a systematic review of the literature that involved searching Medline, EMBASE and CINAHL databases for peer-reviewed published literature for the period 1 January 2005–31 December 2015. Additionally we searched Google for grey and unpublished literature. The identified indicators were descriptively summarized against the most recent international anaphylaxis guidelines (i.e. those produced by the European Academy of Allergy and Clinical Immunology) and critically evaluated using the Agency for Healthcare Research and Quality’s criteria for indicator development. Results Our searches revealed 830 publications, from which we identified five sources for 54 indicators addressing both acute (n = 27) and long-term (n = 27) management of anaphylaxis. The majority of indicators were developed through expert consensus with relatively few of these having been formally piloted or tested to demonstrate that they could discriminate between variations in practice and/or that they were sensitive to change. Conclusions There is a need for a comprehensive set of quality indicators for anaphylaxis management. We have however identified some indicators for the acute and long-term management of anaphylaxis that could with relatively little additional work support efforts to translate guideline recommendations into clinical care.