The objective of this study was to describe the population pharmacokinetics of remdesivir and GS-441524 in hospitalized coronavirus disease 2019 (COVID-19) patients. A prospective observational... Show moreThe objective of this study was to describe the population pharmacokinetics of remdesivir and GS-441524 in hospitalized coronavirus disease 2019 (COVID-19) patients. A prospective observational pharmacokinetic study was performed in non-critically ill hospitalized COVID-19 patients with hypoxemia. For evaluation of the plasma concentrations of remdesivir and its metabolite GS-441524, samples were collected on the first day of therapy. A nonlinear mixed-effects model was developed to describe the pharmacokinetics and identify potential covariates that explain variability. Alternative dosing regimens were evaluated using Monte Carlo simulations. Seventeen patients were included. Remdesivir and GS-441524 pharmacokinetics were best described by a one-compartment model. The estimated glomerular filtration rate (eGFR) on GS-441524 clearance was identified as a clinically relevant covariate. The interindividual variability in clearance and volume of distribution for both remdesivir and GS-441524 was high (remdesivir, 38.9% and 47.9%, respectively; GS-441525, 47.4% and 42.9%, respectively). The estimated elimination half-life for remdesivir was 0.48 h, and that for GS-441524 was 26.6 h. The probability of target attainment (PTA) of the in vitro 50% effective concentration (EC50) for GS-441524 in plasma can be improved by shortening the dose interval of remdesivir and thereby increasing the total daily dose (PTA, 51.4% versus 94.7%). In patients with reduced renal function, the metabolite GS-441524 accumulates. A population pharmacokinetic model for remdesivir and GS-441524 in COVID-19 patients was developed. Remdesivir showed highly variable pharmacokinetics. The elimination half-life of remdesivir in COVID-19 patients is short, and the clearance of GS-441524 is dependent on the eGFR. Alternative dosing regimens aimed at optimizing the remdesivir and GS-441524 concentrations may improve the effectiveness of remdesivir treatment in COVID-19 patients. Show less
Voorzaat, B.M.; Bogt, K.E.A. van der; Bezhaeva, T.; Schaik, J. van; Eefting, D.; Putten, K. van der; ... ; Rotmans, J.I. 2020
BackgroundFood insecurity is related to risk of adverse health outcomes such as obesity, but the explanatory factors underlying this association are still unclear. This study aimed to assess the... Show moreBackgroundFood insecurity is related to risk of adverse health outcomes such as obesity, but the explanatory factors underlying this association are still unclear. This study aimed to assess the association between food insecurity and obesity, and to explore potential mediation by sociodemographic and lifestyle factors.MethodsThis cross-sectional study was conducted among 250 participants in a deprived urban area in the Netherlands. Data on sociodemographic and lifestyle factors, food insecurity status and diet quality were collected using questionnaires. Diet quality was determined based on current national dietary guidelines. BMI was calculated from self-reported height and weight. Regression analyses were performed to explore the association between food insecurity and BMI status. Mediation analyses were performed to estimate the total-, direct-, and indirect effect and proportion of total effect mediated of the food insecurity-obesity association.ResultsThe overall prevalence of food insecurity was 26%. Food insecurity was associated with obesity (OR=2.49, 95%CI=1.16, 5.33), but not with overweight (OR=1.15, 95%CI=0.54, 2.45) in the unadjusted model. The food insecurity-obesity association was partially mediated by living situation (proportion mediated: 15.4%), diet quality (-18.6%), and smoking status (-15.8%) after adjustment for other covariates.ConclusionsThe findings of this study suggest an association between food insecurity and obesity. Living situation, diet quality and smoking status explained part, but not all, of the total association between food insecurity and obesity. Future longitudinal studies are warranted to examine the temporal order of the food insecurity-obesity association and potential mediators in this relationship. In addition, food insecurity and its potential consequences need to be taken into account in obesity prevention programs and policies. Show less
Blood for determining 25-hydroxyvitamin D-3 [25(OH)D-3] is usually obtained through venipuncture although, as an alternative for serum, dried blood spot (DBS) can be considered. The aim of this... Show moreBlood for determining 25-hydroxyvitamin D-3 [25(OH)D-3] is usually obtained through venipuncture although, as an alternative for serum, dried blood spot (DBS) can be considered. The aim of this proof-of-concept study was to investigate levels of agreement between measurements of 25(OH)D-3 obtained with DBS compared with serum. 301 Chinese participants were included who completed 25(OH)D-3 measurement from DBS and from simultaneously collected blood samples obtained by venipuncture. Measurements of both DBS and serum 25(OH)D-3 were performed using liquid chromatography followed by tandem mass spectrometry. Agreement between the two methods was assessed with Passing and Bablok regression analysis and Bland-Altman plot.Measurements showed a good correlation (Pearson's correlation coefficient r = 0.929, P < 0.001) between the two methods. After recalculating for a 13% difference, a regression equation of DBS 25(OH)D-3 = -1.91 + 1.00 serum 25(OH)D-3 was found in Passing and Bablok regression analysis. Bland-Altman analysis showed a fixed bias of 1.7 nmol/L; upper and lower limit of agreement was 24.1 nmol/L and -20.7 nmol/L, respectively.Sensitivity of recalculated DBS for 25(OH)D-3 concentrations < 30 and < 50 nmol/L was 87.8% and 91.1%, respectively, and specificity was 89.2% and 83.1%, respectively.In conclusion, a good agreement was found between the measurement of 25(OH)D-3 obtained with DBS compared with serum. DBS may possibly be used in a future screening program, but it is less suitable for individualized vitamin D status assessment. Show less
Blood for determining 25-hydroxyvitamin D3 [25(OH)D3] is usually obtained through venipuncture although, as an alternative for serum, dried blood spot (DBS) can be considered. The aim of this proof... Show moreBlood for determining 25-hydroxyvitamin D3 [25(OH)D3] is usually obtained through venipuncture although, as an alternative for serum, dried blood spot (DBS) can be considered. The aim of this proof-of-concept study was to investigate levels of agreement between measurements of 25(OH)D3 obtained with DBS compared with serum. 301 Chinese participants were included who completed 25(OH)D3 measurement from DBS and from simultaneously collected blood samples obtained by venipuncture. Measurements of both DBS and serum 25(OH)D3 were performed using liquid chromatography followed by tandem mass spectrometry. Agreement between the two methods was assessed with Passing and Bablok regression analysis and Bland-Altman plot. Measurements showed a good correlation (Pearson’s correlation coefficient r=0.929, P < 0.001) betweenthe two methods. After recalculating for a 13% difference, a regression equation of DBS 25(OH)D3 = -1.91+1.00 serum 25(OH)D3 was found in Passing and Bablok regression analysis. Bland-Altman analysis showed a fixed bias of 1.7 nmol/L; upper and lower limit of agreement was 24.1 nmol/L and -20.7 nmol/L, respectively. Sensitivity of recalculated DBS for 25(OH)D3 concentrations<30 and<50 nmol/L was 87.8% and 91.1%, respectively, and specificity was 89.2% and 83.1%, respectively. In conclusion, a good agreement was found between the measurement of 25(OH)D3 obtained with DBS compared with serum. DBS may possibly be used in a future screening program, but it is less suitable for individualized vitamin D status assessment. Show less
Voorzaat, B.M.; Schaik, J. van; Bogt, K.E.A. van der; Vogt, L.; Huisman, L.; Gabreels, B.A.T.F.; ... ; Rotmans, J.I. 2017
Introduction: Vitamin D is essential for bone health since it stimulates the intestinal absorption of calcium and phosphorus from the gut, both necessary for bone mineralization. However, vitamin D... Show moreIntroduction: Vitamin D is essential for bone health since it stimulates the intestinal absorption of calcium and phosphorus from the gut, both necessary for bone mineralization. However, vitamin D deficiency is highly prevalent among several non-Western immigrant populations in the Netherlands. To date, there are no data available of the vitamin D status in the Chinese population residing in the Netherlands. Therefore, an observational study was performed to determine 25-hydroxyvitamin D (25(OH)D) concentrations and to assess potential determinants of low vitamin D status. Methods: Subjects, aged 18 years and older, with a Chinese background and residing in the Netherlands were invited to participate in the study. A questionnaire was used to assess general characteristics and lifestyle habits. Fasting blood samples were obtained in March 2014 to measure serum 25(OH)D concentration, and analysed by liquid chromatography tandem mass spectrometry. Results: 418 subjects participated in the study, 104 men and 314 women. The mean age for both men and women was 56 years. Serum 25(OH)D concentration < 50 nmol/L was more prevalent in men than in women (67.9% and 53.1%, respectively; p = 0.008). The percentage of serum 25(OH)D concentration < 25 nmol/L in men and women was 5.8% and 10.9%, respectively. Multiple logistic regression analysis, adjusted for age and gender, revealed that non-use of vitamin D supplements and fewer days per week of physical activity were significant predictors of serum 25(OH)D levels below 50 nmol/L. Conclusions: Within the Chinese population living in the Netherlands, serum 25(OH)D concentration was below 50 nmol/L in 68% of men and 53% of women. Use of vitamin D supplements by Chinese people in the Netherlands was highly protective against low 25(OH)D levels. Show less
Low vitamin D status is associated with low bone mass which, in turn, is an important predictor of fracture. However, data on this relationship in non-Caucasian populations are scarce. This review... Show moreLow vitamin D status is associated with low bone mass which, in turn, is an important predictor of fracture. However, data on this relationship in non-Caucasian populations are scarce. This review shows such an association in the Chinese population in five of the 11 included studies.INTRODUCTION: In the elderly population, the serum 25-hydroxyvitamin D [25(OH)D] concentration is often inadequate. This may cause a lower bone mineral density (BMD), which is an important predictor of fracture. It is estimated that by 2050 more than half of all hip fractures worldwide will occur in Asia. However, data on the relationship between vitamin D status and BMD in a non-Caucasian population are scarce. Therefore, this study reviews the literature on the relationship between serum 25(OH)D and BMD in the Chinese population.METHODS: A search was made in PubMed, EMBASE, Web of Science and Cochrane Library (up to December 2014) to identify relevant studies using the terms vitamin D status, bone mineral density, and Chinese.RESULTS: Of the 293 studies identified, 11 fulfilled the inclusion and exclusion criteria and were analyzed. Mean serum 25(OH)D concentrations ranged from 29-82 nmol/L. In 5 of the 11 studies, an association was found between vitamin D status and BMD in the Chinese population.CONCLUSION: The evidence for a relationship between the serum 25(OH)D concentration and BMD in the middle-aged and elderly Chinese population living in Asia appears to be limited and inconsistent. Show less
Celiac disease is caused by an uncontrolled immune response to gluten, a heterogeneous mixture of wheat storage proteins, including the alpha-gliadins. It has been shown that alpha-gliadins harbor... Show moreCeliac disease is caused by an uncontrolled immune response to gluten, a heterogeneous mixture of wheat storage proteins, including the alpha-gliadins. It has been shown that alpha-gliadins harbor several major epitopes involved in the disease pathogenesis. A major step towards elimination of gluten toxicity for celiac disease patients would thus be the elimination of such epitopes from alpha-gliadins. We have analyzed over 3,000 expressed alpha-gliadin sequences from 11 bread wheat cultivars to determine whether they encode for peptides potentially involved in celiac disease. All identified epitope variants were synthesized as peptides and tested for binding to the disease-associated HLA-DQ2 and HLA-DQ8 molecules and for recognition by patient-derived alpha-gliadin specific T cell clones. Several specific naturally occurring amino acid substitutions were identified for each of the alpha-gliadin derived peptides involved in celiac disease that eliminate the antigenic properties of the epitope variants. Finally, we provide proof of principle at the peptide level that through the systematic introduction of such naturally occurring variations alpha-gliadins genes can be generated that no longer encode antigenic peptides. This forms a crucial step in the development of strategies to modify gluten genes in wheat so that it becomes safe for celiac disease patients. It also provides the information to design and introduce safe gluten genes in other cereals, which would exhibit improved quality while remaining safe for consumption by celiac disease patients. Show less
