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1.
European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation.
Budu-Aggrey, A, Kilanowski, A, Sobczyk, MK, , , Shringarpure, SS, Mitchell, R, Reis, K, Reigo, A, , , Mägi, R, et al
Nature communications. 2023;(1):6172
Abstract
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.
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2.
Narcolepsy-Like Sleepiness: A Symptom of Immediate-Type Reactions in Food-Allergic Children.
Kalb, B, Jentsch, J, Yürek, S, Neumann, K, Meixner, L, Lau, S, Niggemann, B, Beyer, K
The journal of allergy and clinical immunology. In practice. 2023;(4):1147-1153
Abstract
BACKGROUND It has been reported that sometimes children fall asleep and can barely be woken up during allergic reactions on food ingestion. Nevertheless, to date, there is scarce data on narcolepsy-like sleepiness as a symptom of allergic reactions. OBJECTIVE To investigate the frequency of narcolepsy-like sleepiness during oral food challenges and characterize this symptom regarding comorbidities, eliciting allergens, and severity of reactions. METHODS Children with immediate-type allergic reactions during oral food challenges (89% were double-blind, placebo-controlled) have been analyzed in this study. Narcolepsy-like sleepiness was defined as a somnolent condition during which patients could barely be woken up again, occurring within 2 hours of food intake and which was not due to drug side effects. Logistic generalized estimating equations were used to explore the effect of age, severity of reactions, and eliciting allergens on the occurrence of narcolepsy-like sleepiness. RESULTS In 106 (12.5%) of all 848 food-allergic children, narcolepsy-like sleepiness was observed during oral food challenges. Children with eczema had a higher risk of developing narcolepsy-like sleepiness (P = .006). Narcolepsy-like sleepiness occurred most often due to an allergic reaction to hazelnut (P = .009) or other tree nuts (P = .003). Moderate to severe reactions occurred more often than mild reactions (P = .026; odds ratio, 1.521; 95% CI, 1.051-2.202) in children with narcolepsy-like sleepiness. CONCLUSIONS We were able to show for the first time that narcolepsy-like sleepiness is a frequently occurring clinical manifestation of immediate-type allergic reactions on food ingestion in childhood. Further research is needed to unravel the underlying mechanisms to gain a deeper insight into this underestimated symptom.
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3.
EUFOREA pocket guide on the diagnosis and management of asthma: An educational and practical tool for general practitioners, non-respiratory physicians, paramedics and patients.
Diamant, Z, Jesenak, M, Hanania, NA, Heaney, LG, Djukanovic, R, Ryan, D, Quirce, S, Backer, V, Gaga, M, Pavord, I, et al
Respiratory medicine. 2023;:107361
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4.
EUFOREA summit in Brussels 2023: inspiring the future of allergy & respiratory care.
Hellings, PW, Lau, S, Scadding, GK, Bjermer, L, Backer, V, Chaker, AM, Conti, DM, De Corso, E, Diamant, Z, Djukanovic, R, et al
Frontiers in allergy. 2023;:1236977
Abstract
In March 2023, the European Forum for Research and Education in Allergy and Airways diseases (EUFOREA) organized its bi-annual Summit in Brussels with expert panel members of EUFOREA, representatives of the EUFOREA patient advisory board, and the EUFOREA board and management teams. Its aim was to define the research, educational and advocacy initiatives to be developed by EUFOREA over the next 2 years until the 10th anniversary in 2025. EUFOREA is an international non-for-profit organization forming an alliance of all stakeholders dedicated to reducing the prevalence and burden of chronic allergic and respiratory diseases via research, education, and advocacy. Based on its medical scientific core competency, EUFOREA offers an evidence-supported platform to introduce innovation and education in healthcare leading to optimal patient care, bridging the gap between latest scientific evidence and daily practice. Aligned with the mission of improving health care, the expert panels of asthma, allergic rhinitis (AR), chronic rhinosinusitis (CRS) & European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS), allergen immunotherapy (AIT) and paediatrics have proposed and elaborated a variety of activities that correspond to major unmet needs in the allergy and respiratory field. The current report provides a concise overview of the achievements, ambitions, and action plan of EUFOREA for the future, allowing all stakeholders in the allergy and respiratory field to be up-dated and inspired to join forces in Europe and beyond.
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5.
Taming PH3: State of the Art and Future Directions in Synthesis.
Hood, TM, Lau, S, Webster, RL
Journal of the American Chemical Society. 2022;(37):16684-16697
Abstract
Appetite for reactions involving PH3 has grown in the past few years. This in part is due to the ability to generate PH3 cleanly and safely via digestion of cheap metal phosphides with acids, thus avoiding pressurized cylinders and specialized equipment. In this perspective we highlight current trends in forming new P-C/P-OC bonds with PH3 and discuss the challenges involved with selectivity and product separation encumbering these reactions. We highlight the reactivity of PH3 with main group reagents, building on the early pioneering work with transition metal complexes and PH3. Additionally, we highlight the recent renewal of interest in alkali metal sources of H2P- which are proving to be useful synthons for chemistry across the periodic table. Such MPH2 sources are being used to generate the desired products in a more controlled fashion and are allowing access to unexplored phosphorus-containing species.
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6.
Managing food allergy: GA2LEN guideline 2022.
Muraro, A, de Silva, D, Halken, S, Worm, M, Khaleva, E, Arasi, S, Dunn-Galvin, A, Nwaru, BI, De Jong, NW, Rodríguez Del Río, P, et al
The World Allergy Organization journal. 2022;(9):100687
Abstract
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.
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7.
Tolerance induction through non-avoidance to prevent persistent food allergy (TINA) in children and adults with peanut or tree nut allergy: rationale, study design and methods of a randomized controlled trial and observational cohort study.
Trendelenburg, V, Dölle-Bierke, S, Unterleider, N, Alexiou, A, Kalb, B, Meixner, L, Heller, S, Lau, S, Lee, YA, Fauchère, F, et al
Trials. 2022;(1):236
Abstract
BACKGROUND Peanuts (PN) and tree nuts (TN) are among the most frequent elicitors of food allergy and can lead to life-threatening reactions. The current advice for allergic patients is to strictly avoid the offending food independently of their individual threshold level, whereas sensitized patients without allergic symptoms should frequently consume the food to avoid (re-)development of food allergy. The aim of this trial is to investigate (I) whether the consumption of low allergen amounts below the individual threshold may support natural tolerance development and (II) to what extent regular allergen consumption in sensitized but tolerant subjects prevents the (re-)development of PN or TN allergy. METHODS The TINA trial consisting of (part I) a randomized, controlled, open, parallel group, single-center, superiority trial (RCT), and (part II) a prospective observational exploratory cohort study. Children and adults (age 1-67 years) with suspected or known primary PN and/or TN allergy will undergo an oral food challenge (OFC) to determine their clinical reactivity and individual threshold. In the RCT, 120 PN or TN allergic patients who tolerate ≥100 mg of food protein will be randomized (1:1 ratio) to consumption of products with low amounts of PN or TN on a regular basis or strict avoidance for 1 year. The consumption group will start with 1/100 of their individual threshold, increasing the protein amount to 1/50 and 1/10 after 4 and 8 months, respectively. The primary endpoint is the clinical tolerance to PN or TN after 1 year assessed by OFC. In the cohort study, 120 subjects sensitized to PN and/or TN but tolerant are advised to regularly consume the food and observed for 1 year. The primary endpoint is the maintenance of clinical tolerance to PN and/or TN after 1 year assessed by challenging with the former tolerated cumulative dose. DISCUSSION This clinical trial will help to determine the impact of allergen consumption versus avoidance on natural tolerance development and whether the current dietary advice for PN or TN allergic patients with higher threshold levels is still valid. TRIAL REGISTRATION German Clinical Trials Register; ID: DRKS00016764 (RCT), DRKS00020467 (cohort study). Registered on 15 January 2020, http://www.drks.de .
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8.
Early-life respiratory tract infections and the risk of school-age lower lung function and asthma: a meta-analysis of 150 000 European children.
van Meel, ER, Mensink-Bout, SM, den Dekker, HT, Ahluwalia, TS, Annesi-Maesano, I, Arshad, SH, Baïz, N, Barros, H, von Berg, A, Bisgaard, H, et al
The European respiratory journal. 2022;(4)
Abstract
BACKGROUND Early-life respiratory tract infections might affect chronic obstructive respiratory diseases, but conclusive studies from general populations are lacking. Our objective was to examine if children with early-life respiratory tract infections had increased risks of lower lung function and asthma at school age. METHODS We used individual participant data of 150 090 children primarily from the EU Child Cohort Network to examine the associations of upper and lower respiratory tract infections from age 6 months to 5 years with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, forced expiratory flow at 75% of FVC (FEF75%) and asthma at a median (range) age of 7 (4-15) years. RESULTS Children with early-life lower, not upper, respiratory tract infections had a lower school-age FEV1, FEV1/FVC and FEF75% (z-score range: -0.09 (95% CI -0.14- -0.04) to -0.30 (95% CI -0.36- -0.24)). Children with early-life lower respiratory tract infections had a higher increased risk of school-age asthma than those with upper respiratory tract infections (OR range: 2.10 (95% CI 1.98-2.22) to 6.30 (95% CI 5.64-7.04) and 1.25 (95% CI 1.18-1.32) to 1.55 (95% CI 1.47-1.65), respectively). Adjustment for preceding respiratory tract infections slightly decreased the strength of the effects. Observed associations were similar for those with and without early-life wheezing as a proxy for early-life asthma. CONCLUSIONS Our findings suggest that early-life respiratory tract infections affect development of chronic obstructive respiratory diseases in later life, with the strongest effects for lower respiratory tract infections.
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9.
Effectiveness of Probiotic, Prebiotic, and Synbiotic Supplementation to Improve Perinatal Mental Health in Mothers: A Systematic Review and Meta-Analysis.
Desai, V, Kozyrskyj, AL, Lau, S, Sanni, O, Dennett, L, Walter, J, Ospina, MB
Frontiers in psychiatry. 2021;12:622181
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Plain language summary
Maternal mental health problems in the perinatal period are a global public health challenge. As many as one in five women develop depression and/or anxiety in the postpartum period, making them the most common complications of pregnancy and delivery. The aim of this study was to evaluate the evidence on the administration of prebiotic, probiotic, and/or synbiotic supplements during pregnancy to reduce the risk of mental health problems in the perinatal period. This study is a systemic review and meta-analysis of four studies of which three where included in the qualitative and quantitative synthesis. Results indicate limited evidence about the effectiveness of probiotics administered during pregnancy to reduce the risk of maternal mental health disorders and highlighted the lack of evidence on prebiotics and synbiotics supplementation to inform their use for similar purposes. Authors conclude that there is the need for future trials targeting microbiota interventions that test probiotic/prebiotic/synbiotic interventions that redress specific dysbioses in pregnancy gut microbiota that arise from poor mental health.
Abstract
Introduction: There is an emerging interest in modulating the gut microbiota to target the gut-brain axis and improve maternal mental health in the perinatal period. This systematic review evaluated the effectiveness of prebiotics, probiotics, and synbiotics supplementation during pregnancy to reduce the risk of maternal mental health problems in the perinatal period. Methods: Electronic biomedical databases and clinical trial registries were searched from database inception through August 2020 to identify randomized controlled clinical trials (RCTs) evaluating the effect of probiotic, prebiotic, or synbiotic supplements administered to women during pregnancy on measures of perinatal depression, anxiety, and other mental health outcomes. Study selection, risk of bias appraisal, and data extraction were independently performed by two reviewers. Pooled mean differences (MD) and odds ratios (pOR) with 95% confidence intervals (CI) were calculated in random-effects meta-analyses for the outcomes of interest in the review. Results: From 3,868 studies identified through the search strategy, three RCTs of low risk of bias involving 713 participants were included, all three testing probiotics. There were no differences between probiotics and control groups in the mean depression scores (MD -0.46; 95% CI -2.16, 1.25) at end of follow-up. Although statistical significance was not achieved, probiotics showed an advantage in the proportion of participants scoring below an established cut-off for depression (pOR 0.68; 95% CI 0.43, 1.07). Compared to placebo, probiotics in pregnancy reduced anxiety symptoms (MD -0.99; 95% CI -1.80, -0.18); however, this advantage was not translated in a reduction in the proportion of participants scoring above an established cut-off for anxiety (pOR 0.65; 95% CI 0.23, 1.85). There were no differences between probiotics and control groups in global mental health scores at end of follow-up (MD 1.09; 95% CI -2.04, 4.22). Conclusion: There is limited but promising evidence about the effectiveness of probiotics during pregnancy to reduce anxiety symptoms and reduce the proportion of women scoring ABOVE a cut-off depression score. There is a lack of RCT evidence supporting prebiotics and synbiotics supplementation for similar purposes in the perinatal period. More research is needed before prebiotics, probiotics, and synbiotics are recommended to support maternal mental health and well-being in the perinatal period. Systematic Review Registration: PROSPERO, CRD42019137158.
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10.
Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4.
Grosche, S, Marenholz, I, Esparza-Gordillo, J, Arnau-Soler, A, Pairo-Castineira, E, Rüschendorf, F, Ahluwalia, TS, Almqvist, C, Arnold, A, , , et al
Nature communications. 2021;(1):6618
Abstract
Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.