Coffee and tea are commonly consumed during pregnancy. While several of their components, like caffeine, have strong pharmacological effects, the effect on the unborn fetus remains unclear. Caffeine ...intake has been associated with abortion, preterm birth and fetal growth restriction, but a general consensus on caffeine restriction is still lacking. We aimed to investigate antenatal coffee, tea and caffeine consumption and the effect on birth weight and length, gestational age at birth and hypertensive disorders in pregnancy.
A total of 936 healthy pregnancies from the WHISTLER birth cohort with data on coffee and tea consumption were included. Maternal and child characteristics as well as antenatal coffee and tea consumption were obtained through postpartum questionnaires. Reported consumption was validated using available preconceptional data. Caffeine intake was calculated from coffee and tea consumption. Linear and logistic regression was used to assess the association with birth outcome and hypertensive disorders.
After adjustment for smoking and maternal age, a daily consumption of more than 300mg of caffeine compared to less than 100mg of caffeine was significantly associated with an increased gestational age (linear regression coefficient = 2.00 days, 95%CI = 0.12-4.21, P = 0.03). Tea consumption was significantly related to a higher risk of pregnancy induced hypertension (OR = 1.13, 95%CI = 1.04-1.23, P = 0.004). No associations concerning coffee consumption or birth weight and birth length were observed.
Daily caffeine consumption of more than 300mg is possibly associated with an increase in gestational age at birth. A possible relation between high tea consumption and increased risk for pregnancy induced hypertension warrants further research. For most outcomes, we found no significant associations with coffee or tea intake.
A new era for people with cystic fibrosis Bierlaagh, Marlou C.; Muilwijk, Danya; Beekman, Jeffrey M. ...
European journal of pediatrics,
09/2021, Volume:
180, Issue:
9
Journal Article
Peer reviewed
Open access
Cystic fibrosis is the most prevalent inherited disease caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The impaired electrolyte homeostasis caused by the ...mutated or absent protein leads to symptoms in multiple organ systems. However, the pulmonary manifestation with chronic infections and eventually respiratory failure remains the most important threat. Until one decade ago, only symptomatic treatment was available. However, since 2012, different combinations of CFTR modulators are available for people with cystic fibrosis (pwCF) that carry different mutations. The advent of these drugs has impressively changed life expectancy and quality of life in people with cystic fibrosis and raised new challenges regarding long-term complications and tapering of conventional therapies.
Conclusion
: In this review, we provide an update on the latest developments around diagnostics, treatment, and prognosis of pwCF.
What is Known:
• Cystic fibrosis is an incurable and life-shortening disease asking for life-long symptomatic treatment.
• Three combination CFTR modulating drugs has gained marked approval over the last 10 years.
What is New:
• The emerge of new (modulating) therapies contribute to the increasing life expectancy.
• A high unmet need to develop new therapies for people with CF who cannot access or benefit from these drugs remains. This review gives an update on the current status.
Adenine base editing (ABE) enables enzymatic conversion from A-T into G-C base pairs. ABE holds promise for clinical application, as it does not depend on the introduction of double-strand breaks, ...contrary to conventional CRISPR/Cas9-mediated genome engineering. Here, we describe a cystic fibrosis (CF) intestinal organoid biobank, representing 664 patients, of which ~20% can theoretically be repaired by ABE. We apply SpCas9-ABE (PAM recognition sequence: NGG) and xCas9-ABE (PAM recognition sequence: NGN) on four selected CF organoid samples. Genetic and functional repair was obtained in all four cases, while whole-genome sequencing (WGS) of corrected lines of two patients did not detect off-target mutations. These observations exemplify the value of large, patient-derived organoid biobanks representing hereditary disease and indicate that ABE may be safely applied in human cells.
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•664 patients and 154 CFTR mutations represented in an organoid biobank•Adenine base editors enable efficient repair of nonsense mutations in CFTR•xCas9 increases the target scope of CFTR repair in our biobank•Adenine base editors cause no detectable off-target effects during repair
Here, we show the generation of an extensive cystic fibrosis patient-derived intestinal organoid biobank. We use this biobank to study gene correction by adenine base editors and show genetic repair of four selected nonsense mutations in CFTR without any genome-wide off-target effects on canonical and non-canonical PAMs.
We recently established conditions allowing for long-term expansion of epithelial organoids from intestine, recapitulating essential features of the in vivo tissue architecture. Here we apply this ...technology to study primary intestinal organoids of people suffering from cystic fibrosis, a disease caused by mutations in CFTR, encoding cystic fibrosis transmembrane conductance regulator. Forskolin induces rapid swelling of organoids derived from healthy controls or wild-type mice, but this effect is strongly reduced in organoids of subjects with cystic fibrosis or in mice carrying the Cftr F508del mutation and is absent in Cftr-deficient organoids. This pattern is phenocopied by CFTR-specific inhibitors. Forskolin-induced swelling of in vitro-expanded human control and cystic fibrosis organoids corresponds quantitatively with forskolin-induced anion currents in freshly excised ex vivo rectal biopsies. Function of the CFTR F508del mutant protein is restored by incubation at low temperature, as well as by CFTR-restoring compounds. This relatively simple and robust assay will facilitate diagnosis, functional studies, drug development and personalized medicine approaches in cystic fibrosis.
In vitro drug tests using patient-derived stem cell cultures offer opportunities to individually select efficacious treatments. Here, we provide a study that demonstrates that in vitro drug responses ...in rectal organoids from individual patients with cystic fibrosis (CF) correlate with changes in two in vivo therapeutic endpoints. We measured individual in vitro efficaciousness using a functional assay in rectum-derived organoids based on forskolin-induced swelling and studied the correlation with in vivo effects. The in vitro organoid responses correlated with both change in pulmonary response and change in sweat chloride concentration. Receiver operating characteristic curves indicated good-to-excellent accuracy of the organoid-based test for defining clinical responses. This study indicates that an in vitro assay using stem cell cultures can prospectively select efficacious treatments for patients and suggests that biobanked stem cell resources can be used to tailor individual treatments in a cost-effective and patient-friendly manner.
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•Organoids of CF patients were used to quantitate individual drug response in vitro•Organoid responses correlate with two clinical response parameters ppFEV1 and SCC•In vivo (non)responders were identified with a PPV of 100% and a NPV of 80%•Organoids may be used for personalized medicine in cystic fibrosis
Berkers et al. demonstrate that stem cell cultures (organoids) can be a tool for personalized medicine. They show a high correlation between in vitro and in vivo effects of drugs and demonstrate good-to-excellent predictive values of the organoid test for preclinical identification of responders to CFTR modulators.
Approximately 10% of all pathological mutations are nonsense mutations which are responsible for the most severe cases of genetic diseases but for which no treatment regimens are available.The main ...strategy for treating nonsense mutations is by enhancing ribosomal readthrough of premature stop codons through the action of readthrough compounds, thus restoring production of full-length protein.Most preclinical studies on readthrough compounds have yielded positive results, but have been performed in reporter-based assays despite recent scientific developments that have significantly improved disease models, such as patient-derived cells in functional assays.Clinical trials have yielded disappointing results, and further interpretation of readthrough compound efficacy across clinical trials is challenging because of differences in research design, treatment length, and clinical endpoints.Characterization of factors that contribute to the translational gap between readthrough compounds in preclinical studies versus clinical trial results is necessary to make sense of nonsense mutation therapy.
Approximately 10% of all pathological mutations are nonsense mutations that are responsible for several severe genetic diseases for which no treatment regimens are currently available. The most widespread strategy for treating nonsense mutations is by enhancing ribosomal readthrough of premature termination codons (PTCs) to restore the production of the full-length protein. In the past decade several compounds with readthrough potential have been identified. However, although preclinical results on these compounds are promising, clinical studies have not yielded positive outcomes. We review preclinical and clinical research related to readthrough compounds and characterize factors that contribute to the observed translational gap.
ObjectivesTo investigate the associations of physical activity (PA) and sedentary behaviour in early childhood with asthma and reduced lung function in later childhood within a large collaborative ...study.DesignPooling of longitudinal data from collaborating birth cohorts using meta-analysis of separate cohort-specific estimates and analysis of individual participant data of all cohorts combined.SettingChildren aged 0–18 years from 26 European birth cohorts.Participants136 071 individual children from 26 cohorts, with information on PA and/or sedentary behaviour in early childhood and asthma assessment in later childhood.Main outcome measureQuestionnaire-based current asthma and lung function measured by spirometry (forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity) at age 6–18 years.ResultsQuestionnaire-based and accelerometry-based PA and sedentary behaviour at age 3–5 years was not associated with asthma at age 6–18 years (PA in hours/day adjusted OR 1.01, 95% CI 0.98 to 1.04; sedentary behaviour in hours/day adjusted OR 1.03, 95% CI 0.99 to 1.07). PA was not associated with lung function at any age. Analyses of sedentary behaviour and lung function showed inconsistent results.ConclusionsReduced PA and increased sedentary behaviour before 6 years of age were not associated with the presence of asthma later in childhood.
Introduction
The simultaneously increased prevalence of atopic diseases and decreased prevalence of infectious diseases might point to a link between the two entities. Past work mainly focused on ...either atopic diseases or recurrent infections. We aim to investigate whether risk factors for atopic diseases (ie, asthma, allergic rhinitis, atopic dermatitis, and/or food allergy) differ from risk factors for recurrent respiratory tract infections (RRTIs) in children.
Methods
Cross‐sectional data were used from 5517 children aged 1 to 18 years who participated in an Electronic Portal for children between 2011 and 2019. Univariable/multivariable logistic regression analyses were performed to determine risk factors for any atopic disease and RRTIs.
Results
Children aged ≥5 years were more likely to have any atopic disease (adjusted odds ratio OR: 1.50‐2.77) and less likely to have RRTIs (OR: 0.68‐0.84) compared to children aged less than 5 years. Female sex (OR: 0.72; 95% confidence interval CI: 0.63‐0.81), low birth weight (OR: 0.74; 95% CI: 0.57‐0.97) and dog ownership (OR: 0.79; 95% CI: 0.66‐0.95) reduced the odds of any atopic disease, but not of RRTIs. Daycare attendance (OR: 1.22; 95% CI: 1.02‐1.47) was associated with RRTIs, but not with atopic diseases. A family history of asthma, allergic rhinitis, atopic dermatitis, and RRTIs was significantly associated with the same entity in children, with OR varying from 1.58 (95% CI: 1.35‐1.85) in allergic rhinitis to 2.20 (95% CI: 1.85‐2.61) in asthma.
Conclusion
Risk factors for atopic diseases are distinct from risk factors for RRTIs, suggesting that the changing prevalence of both entities is not related to shared risk factors.
Fatigue in childhood chronic disease Nap-van der Vlist, Merel M; Dalmeijer, Geertje W; Grootenhuis, Martha A ...
Archives of disease in childhood,
11/2019, Volume:
104, Issue:
11
Journal Article
Peer reviewed
Recently, in adults, the incidence and severity of fatigue was found to exist rather independently from the somatic diagnosis. Since fatigue is distressing when growing up with a chronic disease, we ...aim to investigate: (1) the prevalence and extent of fatigue among various paediatric chronic diseases and (2) the effect of fatigue on health-related quality of life (HRQoL).
Cross-sectional study in two children's hospitals.
Children and adolescents 2-18 years of age with cystic fibrosis, an autoimmune disease or postcancer treatment visiting the outpatient clinic.
Fatigue and HRQoL were assessed using the Pediatric Quality of Life Inventory (PedsQL) multidimensional fatigue scale (with lower scores indicating more fatigue) and PedsQL generic core scales, respectively. Linear regression analysis and analysis of covariance were used to compare fatigue scores across disease groups and against two control groups. The effect of fatigue on HRQoL was calculated. Data were adjusted for age, sex and reporting method.
481 children and adolescents were assessed (60% participation rate, mean age 10.7±4.9, 42% men). Children and adolescents with chronic disease reported more fatigue than the general population (mean difference -6.6, 95% CI -8.9 to -4.3 (range 0-100)), with a prevalence of severe fatigue of 21.2%. Fatigue scores did not differ significantly between disease groups on any fatigue domain. Fatigue was associated with lower HRQoL on all domains.
Fatigue in childhood chronic disease is a common symptom that presents across disease, age and sex groups. Fatigue affects HRQoL. Our findings underscore the need to systematically assess fatigue. Future studies should determine possible biological and psychosocial treatment targets.
Ivacaftor has been shown to restore the functionality of the S1251N (also known as c.3752G>A) mutated CFTR, which may cause alterations in both airway and gut physiology and micro-environment, ...resulting in a change of microbiota in these organs. The aim of the present study was to analyze the effects of ivacaftor on the microbial community composition of both airway and gut in subjects with CF carrying one S1251N mutation, using a 16S rRNA gene-based sequencing approach. In 16 subjects with CF, repetitive samples from airways and gut were collected just before, and 2 months after, and, for 8 patients, also 9 and 12 months after, start of ivacaftor. 16S rRNA based sequencing identified 344 operational taxonomical units (OTUs) in a total of 139 samples (35 nasopharyngeal, 39 oropharyngeal, 29 sputum, and 36 fecal samples). Ivacaftor significantly enhanced bacterial diversity and overall microbiota composition in the gut (
< 0.01). There were no significant changes in the overall microbial composition and alpha diversity in upper and lower airways of these patients after ivacaftor treatment. Treatment with ivacaftor induces changes in gut microbiota whereas airway microbiota do not change significantly over time.
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