Comparative analysis of spike-specific IgG Fc glycoprofiles elicited by adenoviral, mRNA, and protein-based SARS-CoV-2 vaccines

IgG antibodies are important mediators of vaccine-induced immunity through complement- and Fc receptor-dependent effector functions. Both are influenced by the composition of the conserved N-linked glycan located in the IgG Fc domain. Here, we compared the anti-Spike (S) IgG1 Fc glycosylation profiles in response to mRNA, adenoviral, and protein-based COVID-19 vaccines by mass spectrometry (MS). All vaccines induced a transient increase of antigen-specific IgG1 Fc galactosylation and sialylation. An initial, transient increase of afucosylated IgG was induced by membrane-encoding S protein formulations. A fucose-sensitive ELISA for antigen-specific IgG (FEASI) exploiting FcγRIIIa affinity for afucosylated IgG was used as an orthogonal method to confirm the LC-MS-based afucosylation readout. Our data suggest that vaccine-induced anti-S IgG glycosylation is dynamic, and although variation is seen between different vaccine platforms and individuals, the evolution of glycosylation patterns display marked overlaps

Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis

Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A) and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. Twenty-five participants completed the study. Geometric mean ratios (90% CI) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were: caffeine, 105% (96-115%); tolbutamide, 80% (74-86%); omeprazole, 55% (47-65%); dextromethorphan, 77% (68-86%); midazolam, 62% (49-78%), and 117% (105-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6 and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin

11-oxygenated steroid production by TART

In our article “Production of 11-oxygenated androgens by testicular adrenal rest tumors” (https://doi.org/10.1210/clinem/dgab598) we defined the production of 11-oxygenated 19-carbon steroids by testicular adrenal rest tumors (TART) in men with 21-hydroxylase deficiency (21OHD), by the quantification of these steroid hormones in the spermatic vein blood and corresponding peripheral vein blood samples of men with 21OHD. Eleven steroid hormones were quantified in left (n=7) and right (n=4) spermatic vein- and simultaneously taken peripheral blood (n=7) samples from seven men with 21OHD and TART using liquid chromatography-tandem mass spectrometry. These samples were previously obtained by Claahsen-van der Grinten et al. (DOI:10.1210/jc.2007-0337). All patients had bilateral TART, but for three patients (2, 3, and 7) no material was longer available from the right spermatic vein. For comparison, we also measured the peripheral steroid concentrations in five adrenalectomized patients and twelve age, sex, and BMI-matched controls. Additionally, steroids were measured in previously collected media (Turcu et al. DOI:10.1210/jc.2015-1023) of in vitro cultured TART cells and adrenal cells, that were treated for 24 or 48 hours with adrenocorticotropic hormone (ACTH; 10 nmol/L) or Luteinizing Hormone (LH; 25 ng/mL). In this repository we provide the raw data files and the supplementary data files. The abbreviations of the quantified steroid hormones are listed in “Overview.pdf”. The raw data can be found in three different files: Schroder_2021_peripheral_vein.csv contains the peripheral steroid hormone concentrations (ng/dL) of seven men with 21OHD and TART (P1-P7), five adrenalectomized controls (C1-C5), and twelve BMI- and age-matched healthy men (M1-M12). Schroder_2021_spermatic_vein.csv contains the steroid hormone concentrations (ng/dL) in left (n=7) and right (n=4) spermatic vein blood samples of seven men with 21OHD and TART. The corresponding numbers of the spermatic vein samples and peripheral vein samples belong to the same patient. Schroder_2021_TART_Adrenal.csv contains the steroid hormone concentrations (pg/mL) in TART-cell- or normal adrenal cell-conditioned medium under basal conditions or 24 or 48 hours of treatment with ACTH or LH. Three supplementary Tables are provided: Schroder_2021_SupplementaryTable1.pdf contains Supplementary Table 1, presenting the concentrations (nmol/L) of eleven steroid hormones in vena spermatica (v.Sp) and peripheral plasma (P) samples with corresponding ratios (R) of seven men with 21OHD and TART with left and/or right cannulated spermatic veins. Steroid concentrations below the lower limit of quantification (LLOQ) were set at 0.5*LLOQ for calculation of the ratios. Schroder_2021_SupplementaryTable2.pdf contains Supplementary Table 2, presenting the concentrations (nmol/L) of steroid hormones in TART-cell- or normal adrenal cell-conditioned medium under basal conditions or after 24 hours of treatment with ACTH. Schroder_2021_SupplementaryTable3.pdf contains Supplementary Table 3, presenting the concentrations (nmol/L) of steroid hormones in TART-cell- or normal adrenal cell-conditioned medium under basal conditions or after 48 hours of treatment with ACTH

Supplementary Material for: Long-Term Occupational Sleep Loss and Post-Retirement Cognitive Decline or Dementia

Introduction: Recent evidence suggests that poor sleep is a risk factor that contributes to the development of Alzheimer’s disease (AD). Most studies have focused on short-term effects of sleep deprivation on cognitive function, whereas longitudinal studies are limited to self-reported sleep and the risk of later-life dementia. Because sleep loss could be an early manifestation of neurodegenerative disease, reverse causality in these studies cannot be excluded. Objective: In this explorative, observational study, we investigated the effects of extended periods of extrinsically (work-related) caused sleep loss on later-life cognitive function, early dementia symptoms, and current sleep quality. Methods: We approached a community of retired male maritime pilots (approx. n = 500) through a newsletter. We investigated 50 respondents (mean age 71.7 years ± 7.7), with a history of > 25 years of work on irregular schedules, which resulted in extended periods of sleep loss. Validated questionnaires on cognitive complaints (Cognitive Failure Questionnaire [CFQ]), early dementia symptoms (Early Dementia Questionnaire [EDQ]), current sleep quality (Pittsburgh Sleep Quality Index [PSQI] and sleep-wake diaries), quality of life (QoL, EQ-5D), and mood (Hospital Anxiety and Depression Scale [HADS]) were administered by a single investigator (J.T.), who also completed an observer rating of cognitive function. Results: Scores on the CFQ, EDQ, PSQI, EQ-5D, and HADS were within normal ranges adjusted for age, sex, and education. The observer rating was not indicative of cognitive decline. Conclusion: We found no evidence that long-term exposure to work-related sleep loss had resulted in cognitive decline or early dementia symptoms in this sample of retired maritime pilots

The diagnostic accuracy of the GeneXpert ESBL-ampC prototype assay for rapid PCR-based detection of Extended-Spectrum Beta-Lactamase genes directly from urine

Contains data beloning to our research. Routine urine samples were collected between February and July 2021 in two Dutch clinical medical microbiology laboratories according to a predefined list containing certain culture characteristics. All urine samples were screened for the presence of ESBL genes (blaCTX-M2, blaCTX-M14, blaCTX-M15) with random-access qPCR using the Cepheid GeneXpert® ESBL-ampC prototype assay. The qPCR and microbiological culture results were compared. After calculation of the sensitivity and specificity, discrepancies were investigated by whole-genome sequencin

The impact of the implementation of physician assistants in inpatient care: a multicenter matched-controlled study

Medical care for admitted patients is increasingly reallocated to physician assistants (PAs), because of an increased appreciation of continuity of care, pressure to deliver healthcare efficiently, and local shortages of medical doctors (MDs). A PA is a non-physician healthcare professional licensed to practice medicine in defined domains, with variable degrees of professional autonomy. PAs who are employed for medical care for admitted patients usually work in a team compromising both PAs and MDs (i.e. residents, staff physicians or hospitalists). Although there is a worldwide trend of an increase of PAs in the management of hospitalized patients, evidence about the consequences of reallocating inpatient care from MDs to PAs for healthcare outcomes is limited. This study aimed to determine the effects of substitution of inpatient care from MDs to PAs on patients’ lenght of stay, quality and safety of care, patient experiences and costs. Also the impact on guideline adherence on medication prescribing has been investigated. In a multicenter matched-controlled study, the traditional model in which only MDs are employed for inpatient care was compared with a mixed model in which besides MDs also PAs are employed. Thirty-four wards were recruited across the Netherlands. Patients were followed from admission till one month after discharge. In total, 2,307 patients were include

Additional file 2: of Using predicate and provenance information from a knowledge graph for drug efficacy screening

Performance for different ratios between the positive and the negative cases in the training set. This file shows the performance on a balanced test set as a function of the ratio of positive and negative cases in the training set. (XLSX 14 kb

Using predicate and provenance information from a knowledge graph for drug efficacy screening

Abstract Background Biomedical knowledge graphs have become important tools to computationally analyse the comprehensive body of biomedical knowledge. They represent knowledge as subject-predicate-object triples, in which the predicate indicates the relationship between subject and object. A triple can also contain provenance information, which consists of references to the sources of the triple (e.g. scientific publications or database entries). Knowledge graphs have been used to classify drug-disease pairs for drug efficacy screening, but existing computational methods have often ignored predicate and provenance information. Using this information, we aimed to develop a supervised machine learning classifier and determine the added value of predicate and provenance information for drug efficacy screening. To ensure the biological plausibility of our method we performed our research on the protein level, where drugs are represented by their drug target proteins, and diseases by their disease proteins. Results Using random forests with repeated 10-fold cross-validation, our method achieved an area under the ROC curve (AUC) of 78.1% and 74.3% for two reference sets. We benchmarked against a state-of-the-art knowledge-graph technique that does not use predicate and provenance information, obtaining AUCs of 65.6% and 64.6%, respectively. Classifiers that only used predicate information performed superior to classifiers that only used provenance information, but using both performed best. Conclusion We conclude that both predicate and provenance information provide added value for drug efficacy screening