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BACKGROUND: The SQ tree sublingual immunotherapy (SLIT)-tablet is authorised for treatment of allergic rhinoconjunctivitis with or without asthma in trees of the birch homologous group in 21 European countries. The primary objective of this study was to explore the safety in real-life. METHODS: In a prospective, non-interventional post-authorisation safety study (EUPAS31470), adverse events (AEs) and adverse drug reactions (ADRs) at first administration and follow-up visits, symptoms, medication use, and pollen food syndrome were recorded by physicians in 6 European countries during the first 4-6 months of treatment. RESULTS: ADRs with the SQ tree SLIT-tablet were reported in 57.7% of 1069 total patients (median age 36.0 years, 53.7% female) during the entire observation period (severity, mild-to-moderate: 70.1%, severe: 4.7%, serious: 0.7%) and in 45.9% after first administration. ADRs were not increased with pollen exposure at first administration. With coadministration of the SQ tree and grass SLIT-tablet AEs were reported in 73.8% of patients and in 52.8% with the SQ tree SLIT-tablet alone. Nasal and eye symptoms improved in 86.9% and 80.9% of patients and use of symptomatic medication in 76.0%. PFS with symptoms was reported in 43.0% of patients at baseline and in 4.3% at the individual last visit. CONCLUSIONS: The results of this non-interventional safety study with the SQ tree SLIT-tablet confirm the safety profile from placebo-controlled clinical trials and support effectiveness in real-life according to the published efficacy data. Safety was not impaired by pollen exposure at first administration or co-administration with other SLIT-tablets.
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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 ß2-agonist bronchodilator (suggesting reversibility). "Probable" asthma would include symptom chronicity, self-reported symptom relief with ß2-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.
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Heart failure is a serious medical condition with a poor prognosis. Current treatments can only help manage the symptoms and slow the progression of heart failure. However, there is currently no cure to prevent and reverse cardiac remodeling. Transcription factors are in a central role in various cellular processes, and in the heart, GATA4 and NKX2-5 transcription factors mediate hypertrophic responses and remodeling. We have identified compounds that modulate the synergistic interaction of GATA4 and NKX2-5 and shown that the most promising compound (1, 3i-1000) is cardioprotective in vitro and in vivo. However, direct evidence of its binding site and mechanism of action has not been available. Due to the disordered nature of transcription factors, classical target engagement approaches cannot be utilized. Here, we synthesized a small-molecule ligand-binding pulldown probe of compound 1 to utilize affinity chromatography alongside CETSA, AlphaScreen, and molecular modeling to study ligand binding. These results provide the first evidence of direct physical binding of compound 1 selectively to GATA4. While developing drugs that target transcription factors presents challenges, advances in technologies and knowledge of intrinsically disordered proteins enable the identification of small molecules that can selectively target transcription factors.
Sujet(s)
Défaillance cardiaque , Facteurs de transcription , Humains , Protéine homéotique Nkx-2.5/métabolisme , Ligands , Facteurs de transcription/métabolisme , Chromatographie d'affinité , Facteur de transcription GATA-4/métabolisme , Protéines à homéodomaine/métabolismeRÉSUMÉ
Monitoring is a major component of asthma management in children. Regular monitoring allows for diagnosis confirmation, treatment optimization, and natural history review. Numerous factors that may affect disease activity and patient well-being need to be monitored: response and adherence to treatment, disease control, disease progression, comorbidities, quality of life, medication side-effects, allergen and irritant exposures, diet and more. However, the prioritization of such factors and the selection of relevant assessment tools is an unmet need. Furthermore, rapidly developing technologies promise new opportunities for closer, or even "real-time," monitoring between visits. Following an approach that included needs assessment, evidence appraisal, and Delphi consensus, the PeARL Think Tank, in collaboration with major international professional and patient organizations, has developed a set of 24 recommendations on pediatric asthma monitoring, to support healthcare professionals in decision-making and care pathway design.
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Asthme , Humains , Asthme/diagnostic , Asthme/thérapie , Enfant , Qualité de vie , Antiasthmatiques/usage thérapeutique , Méthode Delphi , Monitorage physiologique/méthodesRÉSUMÉ
OBJECTIVES: Down syndrome (DS) is associated with airway abnormalities including a narrowed trachea. It is uncertain whether this narrowed trachea in DS is a consequence of deviant fetal development or an acquired disorder following endotracheal intubation after birth. This study aimed to compare the tracheal morphology in DS and non-DS fetuses using microfocus computed tomography (micro-CT). METHODS: Twenty fetal samples were obtained from the Dutch Fetal Biobank and divided into groups based on gestational age. Micro-CT images were processed to analyze tracheal length, volume, and cross-sectional area (CSA). RESULTS: Mean tracheal length and tracheal volume were similar in DS and non-DS fetuses for all gestational age groups. Mean, minimum, and maximal tracheal CSA were statistically significantly increased in the single DS fetus in the group of 21-24 weeks of gestation, but not in other gestational age groups. In 90% of all studied fetuses, the minimum tracheal CSA was located in the middle third of the trachea. CONCLUSION: Tracheal development in DS fetuses was similar to non-DS fetuses between 13 and 21 weeks of gestation. This suggests that the narrowed tracheal diameter in DS children may occur later in fetal development or results from postnatal intubation trauma. The narrowest part of the trachea is in majority of DS and non-DS fetuses the middle third. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 2024.
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BACKGROUND: The prevalence of heart failure is constantly increasing, and the prognosis of patients remains poor. New treatment strategies to preserve cardiac function and limit cardiac hypertrophy are therefore urgently needed. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used as an experimental platform for cardiac in vitro studies. However, in contrast to adult cardiomyocytes, hiPSC-CMs display immature morphology, contractility, gene expression and metabolism and hence express a naive phenotype that resembles more of a foetal cardiomyocyte. METHODS: A library of 14 novel compounds was synthesized in-house and screened for GATA4-NKX2-5 reporter activity and cellular toxicity. The most potent compound, 3i-1262, along with previously reported GATA4-acting compounds, were selected to investigate their effects on hypertrophy induced by endothelin-1 or mechanical stretch. Morphological changes and protein expression were characterized using immunofluorescence staining and high-content analysis. Changes in gene expression were studied using qPCR and RNA sequencing. RESULTS: The prototype compound 3i-1262 inhibited GATA4-NKX2-5 synergy in a luciferase reporter assay. Additionally, the isoxazole compound 3i-1262 inhibited the hypertrophy biomarker B-type natriuretic peptide (BNP) by reducing BNP promoter activity and proBNP expression in neonatal rat ventricular myocytes and hiPSC-CMs, respectively. Treatment with 3i-1262 increased metabolic activity and cardiac troponin T expression in hiPSC-CMs without affecting GATA4 protein levels. RNA sequencing analysis revealed that 3i-1262 induces gene expression related to metabolic activity and cell cycle exit, indicating a change in the identity and maturity status of hiPSC-CMs. The biological processes that were enriched in upregulated genes in response to 3i-1262 were downregulated in response to mechanical stretch, and conversely, the downregulated processes in response to 3i-1262 were upregulated in response to mechanical stretch. CONCLUSIONS: There is currently a lack of systematic understanding of the molecular modulation and control of hiPSC-CM maturation. In this study, we demonstrated that the GATA4-interfering compound 3i-1262 reorganizes the cardiac transcription factor network and converts hypertrophic signalling towards enhanced cardiomyocyte identity and maturity. This conceptually unique approach provides a novel structural scaffold for further development as a modality to promote cardiomyocyte specification and maturity.
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Cellules souches pluripotentes induites , Myocytes cardiaques , Humains , Rats , Animaux , Myocytes cardiaques/métabolisme , Cellules souches pluripotentes induites/métabolisme , Hypertrophie/métabolisme , Facteurs de transcription/métabolisme , Transduction du signal , Facteur de transcription GATA-4/génétique , Facteur de transcription GATA-4/métabolismeRÉSUMÉ
BACKGROUND: The role of early airway hyperresponsiveness (AHR) in the lung function of school-age children is currently unclear. OBJECTIVE: To conduct a prospective follow-up study of lung function in schoolchildren with a history of lower airway symptoms and AHR to methacholine in early childhood and to compare the findings to schoolchildren with no previous or current lung diseases. We also explored symptoms and markers of type 2 inflammation. METHODS: In 2004 to 2011, data on atopic markers, lung function, and AHR to methacholine were obtained from 193 symptomatic children under 3 years old. In 2016 to 2018, a follow-up sample of 84 children (median age, 11 years; IQR, 11-12) underwent measurements of atopic parameters, lung function, and AHR to methacholine. Moreover, in 2017 to 2018, 40 controls (median age, 11 years; IQR, 9-12) participated in the study. RESULTS: Schoolchildren with early childhood lower airway symptoms and increased AHR had more frequent blood eosinophilia than their peers without increased AHR and lower prebronchodilator forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity Z-scores than those without increased AHR and controls. Post-bronchodilator values were not significantly different between the two AHR groups. Atopy in early childhood (defined as atopic eczema and at least 1 positive skin prick test result) was associated with subsequent lung function and atopic markers, but not AHR. CONCLUSION: In symptomatic young children, increased AHR was associated with subsequent obstructive lung function, which appeared reversible by bronchodilation, and blood eosinophilia, indicative of type 2 inflammation.
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Hyperréactivité bronchique , Éosinophilie , Hypersensibilité immédiate , Hypersensibilité respiratoire , Enfant , Humains , Enfant d'âge préscolaire , Chlorure de méthacholine , Études de suivi , Études prospectives , Volume expiratoire maximal par seconde , Tests de provocation bronchique , Hypersensibilité respiratoire/diagnostic , Poumon , Inflammation , Hyperréactivité bronchique/diagnosticRÉSUMÉ
Therapeutic mRNAs are generated using modified nucleotides, namely N1-methylpseudouridine (m1Ψ) triphosphate, so that the mRNA evades detection by the immune system. RNA modifications, even at a single-nucleotide position, perturb RNA structure, although it is not well understood how structure and function is impacted by globally modified RNAs. Therefore, we examined the metastasis-associated lung adenocarcinoma transcript 1 triple helix, a highly structured stability element that includes single-, double-, and triple-stranded RNA, globally modified with N6-methyladenosine (m6A), pseudouridine (Ψ), or m1Ψ. UV thermal denaturation assays showed that m6A destabilizes both the Hoogsteen and Watson-Crick faces of the RNA by â¼20 °C, Ψ stabilizes the Hoogsteen and Watson-Crick faces of the RNA by â¼12 °C, and m1Ψ has minimal effect on the stability of the Hoogsteen face of the RNA but increases the stability of the Watson-Crick face by â¼9 °C. Native gel-shift assays revealed that binding of the methyltransferase-like protein 16 to the metastasis-associated lung adenocarcinoma transcript 1 triple helix was weakened by at least 8-, 99-, and 23-fold, respectively, when RNA is globally modified with m6A, Ψ, or m1Ψ. These results demonstrate that a more thermostable RNA structure does not lead to tighter RNA-protein interactions, thereby highlighting the regulatory power of RNA modifications by multiple means.
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ARN long non codant , ARN , Methyltransferases/génétique , Methyltransferases/métabolisme , Conformation d'acide nucléique , Nucléotides , Pseudouridine , ARN/métabolisme , ARN long non codant/génétique , ARN long non codant/métabolismeRÉSUMÉ
AIM: Examining health-related quality of life (HRQoL) is important to improve patient care. In this study, we translate and evaluate the Finnish versions of the Food Allergy Specific Quality of Life Questionnaires (FAQLQs) from a Finnish perspective and undertake a detailed evaluation of the 10-question Parent Form Questionnaire (FAQLQ-PF10). METHODS: This validation study was performed to evaluate the Finnish versions of the FAQLQs. Validation was performed by analysing clinical characteristics, factor loadings and Cronbach's α reliability estimates. The inclusion criteria for participants in this study were having a doctor-diagnosed food allergy or being a parent of a child with a doctor-diagnosed food allergy and being able to answer the questionnaire in Finnish. RESULTS: Altogether, 247 questionnaires were completed in this study. Most of the respondents had multiple food allergies (77%, 189/247). Spearman's correlations related to the 10-question parent form (FAQLQ-PF10), the 30-question parent form (FAQLQ-PF) and the Food Allergy Severity Measurement-Parent Form (FAIM-PF) were statistically significant (p value = 0.000-0.007). The reliability of the Finnish versions of the FAQLQs measured by Cronbach's α was overall good (0.75-0.981). CONCLUSION: The Finnish versions of the FAQLQs are reliable and suitable to use, and the FAQLQ-PF10 has good usability.
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Hypersensibilité alimentaire , Qualité de vie , Enfant , Humains , Reproductibilité des résultats , Finlande , Hypersensibilité alimentaire/diagnostic , Enquêtes et questionnaires , ParentsRÉSUMÉ
BACKGROUND: Difficulties in recovery persisting for months have been reported in patients with severe COVID-19. Our aim was to investigate respiratory and overall recovery one year after hospital discharge. METHODS: Finnish patients hospitalised due to COVID-19 during the first wave of the pandemic were recruited to a survey of symptoms, quality of life (RAND-36), work status, and health care use one year after hospital discharge. Patients with lung function test and chest x-ray results available from 3-6 months after hospital discharge underwent spirometry and a chest x-ray at one year. RESULTS: Ninety-six patients responded to the one-year survey, 32 underwent spirometry and 32 a chest x-ray. Of those working full-time before COVID-19, median duration of sick leave was 40 days and 10% had not returned to work at one year. Health-care service use related to COVID-19 after discharge was reported by 79%, 50% using primary care, 34% occupational health care and 32% specialist care, respectively. Tiredness, fatigue, and physical difficulties increased in follow-up (p = 0.022-0.033). Quality of life did not change. Chest x-ray abnormalities decreased in follow-up, with an abnormal chest x-ray in 58% at 3-6 months and 25% at one year. A restrictive spirometry pattern was more common at one year (16 vs. 34%, p = 0.014). CONCLUSIONS: Prolonged symptoms are common, some patients have decreased lung function, and a small minority of patients still have not returned to work one year after severe COVID-19. This calls for further research into the underlying causes and risk factors for prolonged recovery.
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Early-onset, persistent atopic dermatitis (AD) is proposed as a distinct subgroup that may have specific genotypic features. FLG gene loss-of-function variants are the best known genetic factors contributing to epidermal barrier impairment and eczema severity. In a cohort of 140 Finnish children with early-onset moderate-to-severe AD, we investigated the effect of coding variation in FLG and 13 other genes with epidermal barrier or immune function through the use of targeted amplicon sequencing and genotyping. A FLG loss-of-function variant (Arg501Ter, Ser761fs, Arg2447Ter, or Ser3247Ter) was identified in 20 of 140 patients showing higher transepidermal water loss values than patients without these variants. Total FLG loss-of-function variant frequency (7.14%) was significantly higher than in the general Finnish population (2.34%). When tested separately, only Arg2447Ter showed a significant association with AD (P = 0.003104). In addition, a modest association with moderate-to-severe pediatric AD was seen for rs12730241 and rs6587667 (FLG2:Gly137Glu). Loss-of-function variants, previously reported pathogenic variants, or statistically significant enrichment of nonsynonymous coding region variants were not found in the 13 candidate genes studied by amplicon sequencing. However, higher IgE and eosinophil counts were found in carriers of potentially pathogenic DOCK8 missense variants, suggesting that the role of DOCK8 variation in AD should be further investigated in larger cohorts.
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BACKGROUND: Digital health technology (DHT) is a growing area in the treatment of chronic diseases. Study results on DHT's effect on asthma control have been mixed, but benefits have been seen for adherence, self-management, symptoms, and quality of life. The aim was to evaluate the impact of an interactive web-based asthma treatment platform on asthma exacerbations and health care visits. METHODS: In this real-life study, we retrospectively collected data on adult patients registered on a web-based interactive asthma treatment platform between December 2018 and May 2021. Patients who activated their accounts were active users, and patients who did not were inactive users and considered as controls. We compared the number of exacerbations, total number of exacerbation events defined as the sum of oral corticosteroid (OCS) and antimicrobial courses, emergency room visits, hospitalizations, and asthma-related health care visits before and one year after the registration on the platform. Statistical tests used included the t-test, Pearson's chi-square test and Poisson regression models. RESULTS: Of 147 patients registered on the platform, 106 activated their accounts and 41 did not. The active users had significantly fewer total number of exacerbation events (2.56 per person years, relative decline 0.78, 95% CI 0.6 to 1.0) and asthma-related health care visits (2.38 per person years, relative decline 0.84, 95% CI 0.74 to 0.96) than before registration to the platform, whereas the reductions in health care visits and the total number of exacerbation events were not significant in the inactive users. CONCLUSIONS: An interactive web-based asthma platform can reduce asthma-related health care visits and exacerbations when used actively.
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Antiasthmatiques , Asthme , Adulte , Humains , Qualité de vie , Études rétrospectives , Asthme/traitement médicamenteux , Hormones corticosurrénaliennes/usage thérapeutique , Internet , Antiasthmatiques/usage thérapeutiqueRÉSUMÉ
BACKGROUND: The underlying mechanisms of an immediate food-induced allergic reaction involve mast cell degranulation and recruitment of other effector cells, such as lymphocytes, eosinophils, and basophils. How the interaction of various mediators and cells results in anaphylaxis is not fully understood. OBJECTIVE: To evaluate changes in platelet-activating factor (PAF), platelet-activating factor acetylhydrolase (PAF-AH), tryptase, eosinophils, basophils, and eosinophil cationic protein (ECP) in cashew nut-induced anaphylaxis. METHODS: Open cashew nut challenges were performed on 106 children (aged 1-16 years), sensitized to cashew nut, with earlier allergic reaction to cashew nut or no known exposure. PAF, PAF-AH, tryptase, ECP, eosinophils, and basophils were measured at 4 time points. RESULTS: Of 72 challenges with positive results, 34 were defined as anaphylactic. Eosinophil count decreased progressively during an anaphylactic reaction at all 4 time points (P < .005*) compared with baseline. Although significant PAF elevation was observed 1 hour from moderate-to-severe reaction (P = .04*), PAF seemed to peak especially in anaphylaxis but did not achieve statistical significance. PAF peak ratio (peak PAF/baseline PAF) was significantly greater in anaphylactic reactions compared with the no-anaphylaxis group (P = .008*). Maximal percentage change in eosinophils revealed negative correlation to severity score and PAF peak ratio (Spearman's rho -0.424 and -0.516, respectively). Basophils decreased significantly in moderate-to-severe reactions and in anaphylaxis (P < .05*) compared with baseline. Delta-tryptase (peak tryptase minus baseline) did not differ significantly between anaphylaxis and the no-anaphylaxis subgroups (P = .05). CONCLUSION: PAF is a specific anaphylaxis biomarker. Marked decline of eosinophils during anaphylaxis may be related to robust secretion of PAF reflecting migration of eosinophils to target tissues.
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Anacardium , Anaphylaxie , Enfant , Humains , Tryptases/métabolisme , Noix , Facteur d'activation plaquettaire/métabolisme , Facteur d'activation plaquettaire/pharmacologie , Granulocytes éosinophiles , LymphocytesRÉSUMÉ
BACKGROUND: Childhood atopic dermatitis (AD) is often followed by other atopic comorbidities such as asthma. AIM: To compare the effectiveness of topical tacrolimus (TAC) and topical corticosteroids (TCSs) and their impact on airway inflammation and bronchial hyperresponsiveness in patients with paediatric AD. METHODS: This was a 3-year randomized open-label comparative follow-up study of 152 1-3-year-old children with moderate-to-severe AD (trial registration: EudraCT2012-002412-95). Frequent study visits including clinical examinations, laboratory investigations (total IgE, specific IgEs, blood eosinophils), skin prick and respiratory function tests to assess airway inflammation and bronchial hyperresponsiveness (exhaled nitric oxide, airway responsiveness to exercise and methacholine) were performed. RESULTS: Changes in eczema parameters at 36â months were similar in the TCS and TAC groups for mean body surface area (BSA) difference 1.4 [95% confidence interval (CI) -1.48 to 4.19); P = 0.12], mean Eczema Area and Severity Index (EASI) difference 0.2 (95% CI -1.38 to 1.82; P = 0.2), mean Investigator's Global Assessment (IGA) difference, 0.3 (95% CI -0.12 to 0.67; P = 0.12) and mean transepidermal water loss (TEWL) difference at the eczema site, -0.3 (95% CI -4.93 to 4.30; P = 0.96) and at the control site, 1.4 (95% CI -0.96 to 3.60, P = 0.19). The control-site TEWL increased more towards the end of follow-up in the TCS vs. TAC group (mean change difference -4.2, 95% CI -8.14 to -0.29; P = 0.04). No significant impact on development of airway inflammation or bronchial hyperresponsiveness occurred in early effective eczema-treatment responders vs. others ('early' vs. 'other' response was defined as the difference in treatment response to airway outcomes in BSA, EASI or IGA at 3â months). CONCLUSION: Children with moderate-to-severe AD benefit from long-term treatment with TCS or TAC. There were no significant differences in treatment efficacy. No differences in the impact on airways occurred between early effective treatment responders vs. others.
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Eczéma atopique , Eczéma , Humains , Enfant , Enfant d'âge préscolaire , Tacrolimus/effets indésirables , Eczéma atopique/traitement médicamenteux , Études de suivi , Eczéma/traitement médicamenteux , Hormones corticosurrénaliennes/effets indésirables , Inflammation/traitement médicamenteux , Résultat thérapeutique , Immunoglobuline A , Indice de gravité de la maladie , Méthode en double aveugleRÉSUMÉ
Heart formation requires transcriptional regulators that underlie congenital anomalies and the fetal gene program activated during heart failure. Attributing the effects of congenital heart disease (CHD) missense variants to disruption of specific protein domains allows for a mechanistic understanding of CHDs and improved diagnostics. A combined chemical and genetic approach was employed to identify novel CHD drivers, consisting of chemical screening during pluripotent stem cell (PSC) differentiation, gene expression analyses of native tissues and primary cell culture models, and the in vitro study of damaging missense variants from CHD patients. An epigenetic inhibitor of the TATA-Box Binding Protein Associated Factor 1 (TAF1) bromodomain was uncovered in an unbiased chemical screen for activators of atrial and ventricular fetal myosins in differentiating PSCs, leading to the development of a high affinity inhibitor (5.1 nM) of the TAF1 bromodomain, a component of the TFIID complex. TAF1 bromodomain inhibitors were tested for their effects on stem cell viability and cardiomyocyte differentiation, implicating a role for TAF1 in cardiogenesis. Damaging TAF1 missense variants from CHD patients were studied by mutational analysis of the TAF1 bromodomain, demonstrating a repressive role of TAF1 that can be abrogated by the introduction of damaging bromodomain variants or chemical TAF1 bromodomain inhibition. These results indicate that targeting the TAF1/TFIID complex with chemical compounds modulates cardiac transcription and identify an epigenetically-driven CHD mechanism due to damaging variants within the TAF1 bromodomain.
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Cardiopathies congénitales , Facteurs de transcription , Humains , Facteurs de transcription/génétique , Facteurs de transcription/métabolisme , Domaines protéiques , Protéines nucléaires/métabolisme , Facteur de transcription TFIID/génétique , Facteur de transcription TFIID/métabolisme , Cardiopathies congénitales/génétique , Épigenèse génétiqueRÉSUMÉ
Contact with natural environments enriches the human microbiome, promotes immune balance and protects against allergies and inflammatory disorders. In Finland, the allergy & asthma epidemic became slowly visible in mid 1960s. After the World War II, Karelia was split into Finnish and Soviet Union (now Russia) territories. This led to more marked environmental and lifestyle changes in the Finnish compared with Russian Karelia. The Karelia Allergy Study 2002-2022 showed that allergic conditions were much more common on the Finnish side. The Russians had richer gene-microbe network and interaction than the Finns, which associated with better balanced immune regulatory circuits and lower allergy prevalence. In the Finnish adolescents, a biodiverse natural environment around the homes associated with lower occurrence of allergies. Overall, the plausible explanation of the allergy disparity was the prominent change in environment and lifestyle in the Finnish Karelia from 1940s to 1980s. The nationwide Finnish Allergy Programme 2008-2018 implemented the biodiversity hypothesis into practice by endorsing immune tolerance, nature contacts, and allergy health with favorable results. A regional health and environment programme, Nature Step to Health 2022-2032, has been initiated in the City of Lahti, EU Green Capital 2021. The programme integrates prevention of chronic diseases (asthma, diabetes, obesity, depression), nature loss, and climate crisis in the spirit of Planetary Health. Allergic diseases exemplify inappropriate immunological responses to natural environment. Successful management of the epidemics of allergy and other non-communicable diseases may pave the way to improve human and environmental health.
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BACKGROUND: Milk oral immunotherapy (OIT) may increase the amount of milk protein that can be ingested without triggering an allergic reaction. It is important to understand why some patients benefit from the treatment while others do not. OBJECTIVE: The aim was to define the differences in the milk allergen component-specific (casein, α-lactalbumin, ß-lactoglobulin) immunoglobulin (sIg [sIgE, sIgG4, and sIgA]) levels relative to the long-term outcomes of milk OIT. METHODS: In this long-term, open-label follow-up study, 286 children started milk OIT between 2005 and 2015. Follow-up data were collected at two points: the post-buildup phase and long term (range 1-11 years, median 6 years). Comparisons of sIg levels were made among three outcome groups of self-reported long-term milk consumption (high-milk dose, low-milk dose, and avoidance). RESULTS: A total of 168 (59%) of the 286 patients on OIT participated. Most patients (57%) were in the high-dose group; here, 80% of these patients had a baseline casein sIgE value less than 28 kUA/L, they had the lowest casein sIgE levels at all time (p < .001), their casein sIgG4/IgE levels increased, and long-term casein sIgA was highest compared with the low-dose and avoidance groups (p = .02). Low-milk dose group had the highest casein sIgG4/IgE levels in long term (p = .002). CONCLUSION: The baseline Ig profiles and responses to milk OIT differed depending on long-term milk consumption. Lower casein sIgE levels were associated with better outcome. Milk casein sIgA differed in the long term among high-milk consumers.
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Caséines , Hypersensibilité au lait , Humains , Enfant , Études de suivi , Finlande , Immunoglobuline E , Allergènes , Immunothérapie , Hypersensibilité au lait/thérapie , Hypersensibilité au lait/étiologie , Administration par voie orale , Immunoglobuline A sécrétoire , Désensibilisation immunologique/effets indésirablesRÉSUMÉ
The populational heterogeneity of a disease, in part due to comorbidity, poses several complexities. Individual comorbidity profiles, on the other hand, contain useful information to refine phenotyping, prognostication, and risk assessment, and they provide clues to underlying biology. Nevertheless, the spectrum and the implications of the diagnosis profiles remain largely uncharted. Here we mapped comorbidity patterns in 100 common diseases using 4-year retrospective data from 526,779 patients and developed an online tool to visualize the results. Our analysis exposed disease-specific patient subgroups with distinctive diagnosis patterns, survival functions, and laboratory correlates. Computational modeling and real-world data shed light on the structure, variation, and relevance of populational comorbidity patterns, paving the way for improved diagnostics, risk assessment, and individualization of care. Variation in outcomes and biological correlates of a disease emphasizes the importance of evaluating the generalizability of current treatment strategies, as well as considering the limitations that selective inclusion criteria pose on clinical trials.