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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pulmonary function and nutritional status are important determinants of exercise capacity in patients with cystic fibrosis (CF). Studies investigating the effects of determinants, such as genotype or ...infection and inflammation, are scarce and have never been analysed in a multivariate longitudinal model. A prospective longitudinal cohort study was performed to evaluate whether genotype, chronic inflammation and infection were associated with changes in exercise capacity. Furthermore, we investigated whether exercise capacity can predict clinical outcome. 504 exercise tests of 149 adolescents with CF were evaluated. Maximal oxygen uptake corrected for body mass % predicted declined 20% during adolescence, and was associated with immunoglobulin (Ig)G levels and chronic Pseudomonas aeruginosa infection. A lower exercise capacity was associated with a higher mortality, steeper decline in pulmonary function and greater increase in IgG levels. Since a decline in exercise capacity during adolescence was negatively associated with IgG levels and chronic P. aeruginosa infection, these data emphasise the importance of prevention and treatment of chronic inflammation and infections in patients with CF. Furthermore, a lower exercise capacity was associated with a higher mortality rate, steeper decline in pulmonary function and higher increase in IgG levels with increasing age in adolescents with CF. This stresses the value of regular exercise testing for assessing prognosis in adolescents with CF.
To estimate the association between obesity and poor asthma control or risk of exacerbations in asthmatic children and adolescents, and to assess whether these associations are different by sex.A ...meta-analysis was performed on unpublished data from three North-European paediatric asthma cohorts (BREATHE, PACMAN (Pharmacogenetics of Asthma medication in Children: Medication with Anti-inflammatory effects) and PAGES (Pediatric Asthma Gene Environment Study)) and 11 previously published studies (cross-sectional and longitudinal studies). Outcomes were poor asthma control (based on asthma symptoms) and exacerbations rates (asthma-related visits to the emergency department, asthma-related hospitalisations or use of oral corticosteroids). Overall pooled estimates of the odds ratios were obtained using fixed- or random-effects models.In a meta-analysis of 46 070 asthmatic children and adolescents, obese children (body mass index ≥95th percentile) compared with non-obese peers had a small but significant increased risk of asthma exacerbations (OR 1.17, 95% CI 1.03-1.34; I
: 54.7%). However, there was no statistically significant association between obesity and poor asthma control (n=4973, OR 1.23, 95% CI 0.99-1.53; I
: 0.0%). After stratification for sex, the differences in odds ratios for girls and boys were similar, yet no longer statistically significant.In asthmatic children, obesity is associated with a minor increased risk of asthma exacerbations but not with poor asthma control. Sex does not appear to modify this risk.
This study systematically reviewed and quantified the relationship between exposure to antibiotics during the first 2 years of life and the risk of allergies/atopies including hay fever, eczema, food ...allergy, positive skin prick testing (SPT), or elevated allergen‐specific serum/plasma immunoglobulin (Ig) E levels later in life. PubMed and Web of Science databases were searched for observational studies published from January 1966 through November 11, 2015. Overall pooled estimates of the odds ratios (ORs) were obtained using fixed or random‐effects models. Early‐life exposure to antibiotics appears to be related to an increased risk of allergic symptoms of hay fever, eczema, and food allergy later in life. The summary OR for the risk of hay fever (22 studies) was 1.23, 95% confidence interval (CI):1.13‐1.34; I2: 77.0%. The summary OR for the risk of eczema (22 studies) was 1.26, 95% CI: 1.15‐1.37; I2: 74.2%, and the summary OR for food allergy (3 studies) was 1.42, 95% CI: 1.08‐1.87; I2: 80.8%. However, no association was found for antibiotics exposure early in life and objective atopy measurements including positive SPT or elevated allergen‐specific serum/plasma IgE levels.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Atmospheric carbon dioxide records indicate that the land surface has acted as a strong global carbon sink over recent decades, with a substantial fraction of this sink probably located in the ...tropics, particularly in the Amazon. Nevertheless, it is unclear how the terrestrial carbon sink will evolve as climate and atmospheric composition continue to change. Here we analyse the historical evolution of the biomass dynamics of the Amazon rainforest over three decades using a distributed network of 321 plots. While this analysis confirms that Amazon forests have acted as a long-term net biomass sink, we find a long-term decreasing trend of carbon accumulation. Rates of net increase in above-ground biomass declined by one-third during the past decade compared to the 1990s. This is a consequence of growth rate increases levelling off recently, while biomass mortality persistently increased throughout, leading to a shortening of carbon residence times. Potential drivers for the mortality increase include greater climate variability, and feedbacks of faster growth on mortality, resulting in shortened tree longevity. The observed decline of the Amazon sink diverges markedly from the recent increase in terrestrial carbon uptake at the global scale, and is contrary to expectations based on models.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
AIM: Tropical forests store 25% of global carbon and harbour 96% of the world's tree species, but it is not clear whether this high biodiversity matters for carbon storage. Few studies have teased ...apart the relative importance of forest attributes and environmental drivers for ecosystem functioning, and no such study exists for the tropics. LOCATION: Neotropics. METHODS: We relate aboveground biomass (AGB) to forest attributes (diversity and structure) and environmental drivers (annual rainfall and soil fertility) using data from 144,000 trees, 2050 forest plots and 59 forest sites. The sites span the complete latitudinal and climatic gradients in the lowland Neotropics, with rainfall ranging from 750 to 4350 mm year⁻¹. Relationships were analysed within forest sites at scales of 0.1 and 1 ha and across forest sites along large‐scale environmental gradients. We used a structural equation model to test the hypothesis that species richness, forest structural attributes and environmental drivers have independent, positive effects on AGB. RESULTS: Across sites, AGB was most strongly driven by rainfall, followed by average tree stem diameter and rarefied species richness, which all had positive effects on AGB. Our indicator of soil fertility (cation exchange capacity) had a negligible effect on AGB, perhaps because we used a global soil database. Taxonomic forest attributes (i.e. species richness, rarefied richness and Shannon diversity) had the strongest relationships with AGB at small spatial scales, where an additional species can still make a difference in terms of niche complementarity, while structural forest attributes (i.e. tree density and tree size) had strong relationships with AGB at all spatial scales. MAIN CONCLUSIONS: Biodiversity has an independent, positive effect on AGB and ecosystem functioning, not only in relatively simple temperate systems but also in structurally complex hyperdiverse tropical forests. Biodiversity conservation should therefore be a key component of the UN Reducing Emissions from Deforestation and Degradation strategy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Aim: To test the extent to which the vertical structure of tropical forests is determined by environment, forest structure or biogeographical history. Location: Pan-tropical. Methods: Using height ...and diameter data from 20,497 trees in 112 non-contiguous plots, asymptotic maximum height (H AM ) and height—diameter relationships were computed with nonlinear mixed effects (NLME) models to: (1) test for environmental and structural causes of differences among plots, and (2) test if there were continental differences once environment and structure were accounted for; persistence of differences may imply the importance of biogeography for vertical forest structure. NLME analyses for floristic subsets of data (only/excluding Fabaceae and only/excluding Dipterocarpaceae individuals) were used to examine whether family-level patterns revealed biogeographical explanations of cross-continental differences. Results: H AM and allometry were significantly different amongst continents. H AM was greatest in Asian forests (58.3 ± 7.5 m, 95% CI), followed by forests in Africa (45.1 ± 2.6 m), America (35.8 ± 6.0 m) and Australia (35.0 ± 7.4 m), and height—diameter relationships varied similarly; for a given diameter, stems were tallest in Asia, followed by Africa, America and Australia. Precipitation seasonality, basal area, stem density, solar radiation and wood density each explained some variation in allometry and H AM yet continental differences persisted even after these were accounted for. Analyses using floristic subsets showed that significant continental differences in H AM and allometry persisted in all cases. Main conclusions: Tree allometry and maximum height are altered by environmental conditions, forest structure and wood density. Yet, even after accounting for these, tropical forest architecture varies significantly from continent to continent. The greater stature of tropical forests in Asia is not directly determined by the dominance of the family Dipterocarpaceae, as on average non-dipterocarps are equally tall. We hypothesise that dominant large-statured families create conditions in which only tall species can compete, thus perpetuating a forest dominated by tall individuals from diverse families.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Objectives To predict peak oxygen uptake (VO2peak) from the peak work rate (Wpeak) obtained during a cycle ergometry test using the Godfrey protocol in adolescents with cystic fibrosis (CF), and ...assess the accuracy of the model for prognostication clustering. Methods Out of our database of anthropometric, spirometric and maximal exercise data from adolescents with CF (N=363; 140 girls and 223 boys; age 14.77±1.73 years; mean expiratory volume in 1 s (FEV1%pred) 86.82±17.77%), a regression equation was developed to predict VO2peak (mL/min). Afterwards, this prediction model was validated with cardiopulmonary exercise data from another 60 adolescents with CF (28 girls, 32 boys; mean age 14.6±1.67 years; mean FEV1%pred 85.43±20.01%). Results We developed a regression model VO2peak (mL/min)=216.3–138.7×sex (0=male; 1=female)+11.5×Wpeak; R2=0.91; SE of the estimate (SEE) 172.57. A statistically significant difference (107 mL/min; p<0.001) was found between predicted VO2peak and measured VO2peak in the validation group. However, this difference was not clinically relevant because the difference was within the SEE of the model. Furthermore, we found high positive predictive and negative predictive values for the model for prognostication clustering (PPV 50–87% vs NPV 82–94%). Conclusions In the absence of direct VO2peak assessment it is possible to estimate VO2peak in adolescents with CF using only a cycle ergometer. Furthermore, the regression model showed to be able to discriminate patients in different prognosis clusters based on exercise capacity.
Abstract Background Children born with esophageal atresia require an anastomosis between the proximal and distal esophagus. When this distance is too wide (long gap esophageal atresia, LGEA) ...esophageal replacement strategies have to be deployed. The aim of this study was to assess long-term respiratory morbidity and lung function after esophageal replacement with either stomach (gastric pull-up, GPU) or jejunum (jejunal interposition, JI) for LGEA. Methods Retrospective cohort study. Patients operated with GPU and JI for LGEA (1985–2007) underwent a semi-structured interview and lung function testing (LFT). Results Seven GPU-patients and eight JI-patients were included. Median age was 12 years. One patient per group could not perform LFT. Respiratory symptoms were reported by 13/15 patients (7/7 GPU-patients vs 6/8 JI-patients). All LFT items were lower than reference values; 6/13 patients showed restriction and 6/13 obstruction. All six GPU-patients had abnormal TLC and/or FEV1/FVC vs 3/7 after JI. Restriction was noted in 4/6 GPU-patients vs 2/7 JI-patients. Conclusion After esophageal replacement for LGEA many children have impaired lung function and respiratory symptoms are common. Lung volumes seem decreased after GPU compared to JI. This may be caused by the intrathoracic stomach which may limit normal lung growth. Respiratory follow-up in adult life is important after esophageal replacement. Level of evidence III
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Measuring interrupter resistance (R(int)) is an increasingly popular lung function technique and especially suitable for preschool children because it is simple, quick and requires only passive ...cooperation. A European Respiratory Society (ERS)/American Thoracic Society (ATS) Task Force recently published empirical recommendations related to procedures, limitations and interpretation of the technique. However, for valid interpretation, high-quality reference equations are required and these have been lacking. The aim of the present study was to collate R(int) data from healthy children in order to produce more robust reference equations. A further aim was to examine the influence of methodological differences on predicted R(int) values. R(int) data from healthy children were collected from published and unpublished sources. Reference equations for expiratory and inspiratory R(int) were developed using the LMS (lambda, mu, sigma) method. Data from 1,090 children (51% males) aged 3-13 yrs were collated to construct sex-specific reference equations for expiratory R(int) and data from 629 children (51% males) were collated for inspiratory R(int). Height was the best independent predictor of both expiratory and inspiratory R(int). Differences between centres were clinically irrelevant, and differences between ethnic groups could not be examined. The availability of a large and generalisable sample and the use of modern statistical techniques enabled the development of more appropriate reference equations for R(int) in young children.
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