Theratyping cystic fibrosis patients to guide elexacaftor/tezacaftor/ivacaftor out-of-label prescription.

BACKGROUND: Around 20% of people with cystic fibrosis (pwCF) do not have access to the triple combination elexacaftor/tezacaftor/ivacaftor (ETI) in Europe because they do not carry the F508del allele on the CF transmembrane conductance regulator (CFTR) gene. Considering that pwCF carrying rare variants may benefit from ETI, including variants already validated by the US Food and Drug Administration (FDA), a compassionate use programme was launched in France. PwCF were invited to undergo a nasal brushing to investigate whether the pharmacological rescue of CFTR activity by ETI in human nasal epithelial cell (HNEC) cultures was predictive of the clinical response. METHODS: CFTR activity correction was studied by short-circuit current in HNEC cultures at basal state (dimethyl sulfoxide (DMSO)) and after ETI incubation and expressed as percentage of normal (wild-type (WT)) CFTR activity after sequential addition of forskolin and Inh-172 (ΔI ETI/DMSO%WT). RESULTS: 11 pwCF carried variants eligible for ETI according to the FDA label and 28 carried variants not listed by the FDA. ETI significantly increased CFTR activity of FDA-approved CFTR variants (I601F, G85E, S492F, M1101K, R347P, R74W;V201M;D1270N and H1085R). We point out ETI correction of non-FDA-approved variants, including N1303K, R334W, R1066C, Q552P and terminal splicing variants (4374+1G>A and 4096-3C>G). ΔI ETI/DMSO%WT was significantly correlated to change in percentage predicted forced expiratory volume in 1 s and sweat chloride concentration (p<0.0001 for both). G85E, R74W;V201M;D1270N, Q552P and M1101K were rescued more efficiently by other CFTR modulator combinations than ETI. CONCLUSIONS: Primary nasal epithelial cells hold promise for expanding the prescription of CFTR modulators in pwCF carrying rare mutants. Additional variants should be discussed for ETI indication.

"Il faut continuer à poser des questions" patient reported outcome measures in cystic fibrosis: An anthropological perspective.

BACKGROUND: People with cystic fibrosis (pwCF) are central in the development of patient-led assessment tools. Qualitative analysis of a frequently used CF-specific patient-reported outcome measure (PROM) sought patient recommendations for development of a new quality of life (QoL) tool. METHODS: We performed an inventory of PROMs, symptom-report and QoL tools used in clinical trials within the European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) and in routine clinical practice among Cystic Fibrosis Europe and ECFS members. A qualitative study using cognitive interviews with pwCF and their caregivers reviewed the Cystic Fibrosis Questionnaire (CFQ), the French initial form of the Cystic Fibrosis Questionnaire-Revised (CFQ-R). RESULTS: Survey results from 33 countries revealed over 70 tools used in routine clinical practice, utilized by clinical specialists (n=124), pwCF/parents/carers (n=49) and other allied health professionals (n=60). The CFQ-R was the main PROM used in clinical trials. The qualitative study enrolled 99 pwCF, 6 to 11 years (n=31); 12 to 18 years (n=38); >18 years (n=30) and 26 parents. Inductive thematic analysis based on the CFQ, revealed 19 key themes. Themes common across all cohorts included burden of treatment, impact of disease on day-to-day life, relationships/family, stress/mood, and nutrition. Themes unique to individual groups included, treatment when not symptomatic for the paediatric group; education/studies and planning for the future for adolescents, impact of anxiety and depression on day-to-day life for adults, and for parents, questions addressing anxiety and their role as carers. CONCLUSIONS: Patient-centeredness is paramount in development of an up-to-date PROM in the era of novel therapies.

Dissection of genetic and environmental factors involved in tomato organoleptic quality.

BACKGROUND: One of the main tomato breeding objectives is to improve fruit organoleptic quality. However, this task is made somewhat challenging by the complex nature of sensory traits and the lack of efficient selection criteria. Sensory quality depends on numerous factors, including fruit colour, texture, aroma, and composition in primary and secondary metabolites. It is also influenced by genotypic differences, the nutritional regime of plants, stage of ripening at harvest and environmental conditions. In this study, agronomic, biochemical and sensory characterization was performed on six Italian heirlooms grown in different environmental conditions. RESULT: We identified a number of links among traits contributing to fruit organoleptic quality and to the perception of sensory attributes. PCA analysis was used to highlight some biochemical, sensory and agronomic discriminating traits: this statistical test allowed us to identify which sensory attributes are more closely linked to environmental conditions and those, instead, linked to the genetic constitution of tomato. Sweetness, sourness, saltiness and tomato flavour are not only grouped in the same PCA factor, but also result in a clear discrimination of tomato ecotypes in the three different fields. The three different traditional varieties cluster on the basis of attributes like juiciness, granulosity, hardness and equatorial diameter, and are therefore more closely related to the genetic background of the cultivar. CONCLUSION: This finding suggests that a different method should be undertaken to improve sensory traits related to taste perception and texture. Our results might be used to ascertain in what direction to steer breeding in order to improve the flavour characteristics of tomato ecotypes.

Use of network analysis to capture key traits affecting tomato organoleptic quality.

The long-term objective of tomato breeders is to identify metabolites that contribute to defining the target flavour and to design strategies to enhance it. This paper reports the results of network analysis, based on metabolic phenotypic and sensory data, to highlight important relationships among such traits. This tool allowed a reduction in data set complexity, building a network consisting of 35 nodes and 74 links corresponding to the 74 significant (positive or negative) correlations among the variables studied. A number of links among traits contributing to fruit organoleptic quality and to the perception of sensory attributes were identified. Modular partitioning of the characteristics involved in fruit organoleptic perception captured the essential fruit parameters that regulate interactions among different class traits. The main feature of the network was the presence of three nodes interconnected among themselves (dry matter, pH, and degrees Brix) and with other traits, and nodes with widely different linkage degrees. Identification of strong associations between some metabolic and sensory traits, such as citric acid with tomato smell, glycine with tomato smell, and granulosity with dry matter, suggests a basis for more targeted investigations in the future.

Antioxidant nutritional quality of tomato.

Regular consumption of tomatoes has been associated with decreased risk of chronic degenerative diseases. Epidemiological findings confirm the observed health effects are due to the presence of different antioxidant molecules such as carotenoids, particularly lycopene, ascorbic acid, vitamin E and phenol compounds, particularly flavonoids. In this work, eight components contributing to the healthy quality of tomato (i. e. lycopene, beta-carotene, other carotenoids, flavonoids, phenolic acids, vitamins C and E, dry residue) were studied in the framework of breeding programs aiming to develop nutritional superior genotypes. Twelve tomato advanced breeding lines and six open pollinated cultivars were grown in strictly controlled conditions and analysed for their content of antioxidants. Among the 18 genotypes analysed, 10 showed a high level of total carotenoids, 6 high level of beta-carotene, 9 high lycopene levels, 15 high flavonoids and 2 relevant concentration of vitamin E. Based on such data and on a literature survey on tomato composition, an index, called index of antioxidant nutritional quality (I(QUAN)), was proposed as a tool to address the breeding programs in selecting tomato genotypes with antioxidant nutritional qualities.