Data accuracy, consistency and completeness of the national Swiss cystic fibrosis patient registry: Lessons from an ECFSPR data quality project.

BACKGROUND: Good data quality is essential when rare disease registries are used as a data source for pharmacovigilance studies. This study investigated data quality of the Swiss cystic fibrosis (CF) registry in the frame of a European Cystic Fibrosis Society Patient Registry (ECFSPR) project aiming to implement measures to increase data reliability for registry-based research. METHODS: All 20 pediatric and adult Swiss CF centers participated in a data quality audit between 2018 and 2020, and in a re-audit in 2022. Accuracy, consistency and completeness of variables and definitions were evaluated, and missing source data and informed consents (ICs) were assessed. RESULTS: The first audit included 601 out of 997 Swiss people with CF (60.3 %). Data quality, as defined by data correctness ≥95 %, was high for most of the variables. Inconsistencies of specific variables were observed because of an incorrect application of the variable definition. The proportion of missing data was low with <5 % for almost all variables. A considerable number of missing source data occurred for CFTR variants. Availability of ICs varied largely between centers (10 centers had >5 % of missing documents). After providing feedback to the centers, availability of genetic source data and ICs improved. CONCLUSIONS: Data audits demonstrated an overall good data quality in the Swiss CF registry. Specific measures such as support of the participating sites, training of data managers and centralized data collection should be implemented in rare disease registries to optimize data quality and provide robust data for registry-based scientific research.

Production of ß-carotene with Dunaliella salina CCAP19/18 at physically simulated outdoor conditions.

Batch growth and ß-carotene production of Dunaliella salina CCAP19/18 was investigated in flat-plate gas-lift photobioreactors with a light path of 2 cm, operated in physically simulated outdoor conditions. Dunaliella salina CCAP19/18 showed robust growth with respect to pH 8.0-9.0 and 15-35°C at increasing salinity, simulating the evaporation of open photobioreactors. The highest ß-carotene concentration of 25 mg L-1 (3 mg gCDW -1) was observed in batch processes at pH 8.5, 15-30°C and increasing salinity up to 110 g L-1, simulating a typical Mediterranean summer climate. Intracellular ß-carotene accumulation of D. salina CCAP19/18 was shown to be independent of light availability, although nutrient limitation (K2HPO4, MgSO4, and/or ammonium ferric citrate) seems to enable stable ß-carotene content in the algal cells despite increasing cell densities in the photobioreactor. Fully controlled, lab-scale photobioreactors simulating typical climate conditions of any region of interest are valuable tools for enabling a realistic characterization of microalgae on a laboratory scale, for production processes projected in open photobioreactor systems (e.g. thin-layer cascade photobioreactors).

Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas.

Intrinsic malignant brain tumors, such as glioblastomas are frequently resistant to immune checkpoint blockade (ICB) with few hypermutated glioblastomas showing response. Modeling patient-individual resistance is challenging due to the lack of predictive biomarkers and limited accessibility of tissue for serial biopsies. Here, we investigate resistance mechanisms to anti-PD-1 and anti-CTLA-4 therapy in syngeneic hypermutated experimental gliomas and show a clear dichotomy and acquired immune heterogeneity in ICB-responder and non-responder tumors. We made use of this dichotomy to establish a radiomic signature predicting tumor regression after pseudoprogression induced by ICB therapy based on serial magnetic resonance imaging. We provide evidence that macrophage-driven ICB resistance is established by CD4 T cell suppression and Treg expansion in the tumor microenvironment via the PD-L1/PD-1/CD80 axis. These findings uncover an unexpected heterogeneity of response to ICB in strictly syngeneic tumors and provide a rationale for targeting PD-L1-expressing tumor-associated macrophages to overcome resistance to ICB.

Dietary tryptophan links encephalogenicity of autoreactive T cells with gut microbial ecology.

The interaction between the mammalian host and its resident gut microbiota is known to license adaptive immune responses. Nutritional constituents strongly influence composition and functional properties of the intestinal microbial communities. Here, we report that omission of a single essential amino acid - tryptophan - from the diet abrogates CNS autoimmunity in a mouse model of multiple sclerosis. Dietary tryptophan restriction results in impaired encephalitogenic T cell responses and is accompanied by a mild intestinal inflammatory response and a profound phenotypic shift of gut microbiota. Protective effects of dietary tryptophan restriction are abrogated in germ-free mice, but are independent of canonical host sensors of intracellular tryptophan metabolites. We conclude that dietary tryptophan restriction alters metabolic properties of gut microbiota, which in turn have an impact on encephalitogenic T cell responses. This link between gut microbiota, dietary tryptophan and adaptive immunity may help to develop therapeutic strategies for protection from autoimmune neuroinflammation.

Studies on the scale-up of biomass production with Scenedesmus spp. in flat-plate gas-lift photobioreactors.

Microalgae are flagged as next-generation biomass feedstock for sustainable chemicals and fuels, because they actively metabolize the climate gas CO2, do not impact food production, and are not associated with land-use change. Scaling microalgae cultivation processes from lab to pilot scale is key to assessing their economic and ecologic viability. In this work, process performances of two different Scenedesmus species were studied using a 300 L flat-plate gas-lift photobioreactor system (14 m2 photosynthetically active area) equipped with a customized, broad-spectrum LED illumination system. Scaling up of batch processes from laboratory scale (1.8 L, 0.09 m2) to the geometrically equivalent pilot scale resulted in reduced volumetric biomass productivities of up to 11% and reduced areal biomass productivities of up to 7.5% at the pilot scale. Since biofilm formation was solely detected at pilot scale, biofilm most likely impaired scalability. Nevertheless, repeated addition of nutrients (BG-11) at pilot scale resulted in a 13.5 gCDW L-1 biomass concentration within a 15 day process time with S. obtusiusculus at constant incident-photon flux densities of 1400 µmol photons m-2 s-1 and more than 19.5 gCDW L1 after 30 days with Scenedesmus ovalternus SAG 52.80 at constant incident-photon flux densities of 750 µmol photons m-2 s-1. This resulted in areal biomass productivities of 14 gCDW m-2 day-1 (S. ovalternus) and 19 gCDW m-2 day-1 (S. obtusiusculus), respectively.

Reaction engineering analysis of Scenedesmus ovalternus in a flat-plate gas-lift photobioreactor.

Microalgal strains of the genus Scenedesmus are a promising resource for commercial biotechnological applications. The temperature-, pH- and light-dependent growth of Scenedesmus ovalternus has been investigated on a laboratory scale. Best batch process performance was obtained at 30°C, pH 8.0 and an incident photon flux density of 1300µmolphotonsm-2s-1 using a flat-plate gas-lift photobioreactor. Highest growth rate (0.11h-1) and space-time yield (1.7±0.1gCDWL-1d-1) were observed when applying these reaction conditions. Biomass concentrations of up to 7.5±0.1gCDWL-1 were achieved within six days (25.0±0.5gCDWm-2d-1). The light-dependent growth kinetics of S. ovalternus was identified using Schuster's light transfer model and Andrews' light inhibition model (KS=545µmolphotonsm-2s-1; KI=2744µmolphotonsm-2s-1; µmax=0.21h-1). The optimal mean integral photon flux density for growth of S. ovalternus was estimated to be 1223µmolphotonsm-2s-1.