The handling of missing data in trial-based economic evaluations: should data be multiply imputed prior to longitudinal linear mixed-model analyses?

Introduction

For the analysis of clinical effects, multiple imputation (MI) of missing data were shown to be unnecessary when using longitudinal linear mixed-models (LLM). It remains unclear whether this also applies to trial-based economic evaluations. Therefore, this study aimed to assess whether MI is required prior to LLM when analyzing longitudinal cost and effect data.

Methods

Two-thousand complete datasets were simulated containing five time points. Incomplete datasets were generated with 10, 25, and 50% missing data in follow-up costs and effects, assuming a Missing At Random (MAR) mechanism. Six different strategies were compared using empirical bias (EB), root-mean-squared error (RMSE), and coverage rate (CR). These strategies were: LLM alone (LLM) and MI with LLM (MI-LLM), and, as reference strategies, mean imputation with LLM (M-LLM), seemingly unrelated regression alone (SUR-CCA), MI with SUR (MI-SUR), and mean imputation with SUR (M-SUR).

Results

For costs and effects, LLM, MI-LLM, and MI-SUR performed better than M-LLM, SUR-CCA, and M-SUR, with smaller EBs and RMSEs as well as CRs closers to nominal levels. However, even though LLM, MI-LLM and MI-SUR performed equally well for effects, MI-LLM and MI-SUR were found to perform better than LLM for costs at 10 and 25% missing data. At 50% missing data, all strategies resulted in relatively high EBs and RMSEs for costs.

Conclusion

LLM should be combined with MI when analyzing trial-based economic evaluation data. MI-SUR is more efficient and can also be used, but then an average intervention effect over time cannot be estimated.

     

Memory CD8+ T cells upregulate glycolysis and effector functions under limiting oxygen conditions

Memory CD8⁺ T cells are indispensable for maintaining long-term immunity against intracellular pathogens and tumors. Despite their presence at oxygen-deprived infected tissue sites or in tumors, the impact of local oxygen pressure on memory CD8⁺ T cells remains largely unclear. We sought to elucidate how oxygen pressure impacts memory CD8⁺ T cells arising after infection with Listeria monocytogenes-OVA. Our data revealed that reduced oxygen pressure during in vitro culture switched CD8⁺ T cell metabolism from oxidative phosphorylation to a glycolytic phenotype. Quantitative proteomic analysis showed that limiting oxygen conditions increased the expression of glucose transporters and components of the glycolytic pathway, while decreasing TCA cycle and mitochondrial respiratory chain proteins. The altered CD8⁺ T cell metabolism did not affect the expansion potential, but enhanced the granzyme B and IFN-γ production capacity. In vivo, memory CD8⁺ T cells cultured under low oxygen pressure provided protection against bacterial rechallenge. Taken together, our study indicates that strategies of cellular immune therapy may benefit from reducing oxygen during culture to develop memory CD8⁺ T cells with superior effector functions.     

Mass spectrometry-based analysis on the impact of whole blood donation on the global plasma proteome

Background

Biomonitoring may provide important insights into the impact of a whole blood donation for individual blood donors.

Study Design and Methods

Here, we used unbiased mass spectrometry (MS)-based proteomics to assess longitudinal changes in the global plasma proteome, after a single blood donation for new and regular donors. Subsequently, we compared plasma proteomes of 76 male and female whole blood donors, that were grouped based on their ferritin and hemoglobin (Hb) levels.

Results

The longitudinal analysis showed limited changes in the plasma proteomes of new and regular donors after a whole blood donation during a 180-day follow-up period, apart from a significant short-term decrease in fibronectin. No differences were observed in the plasma proteomes of donors with high versus low Hb and/or ferritin levels. Plasma proteins with the highest variation between and within donors included pregnancy zone protein, which was associated with sex, Alfa 1-antitrypsin which was associated with the allelic variation, and Immunoglobulin D. Coexpression analysis revealed clustering of proteins that are associated with platelet, red cell, and neutrophil signatures as well as with the complement system and immune responses, including a prominent correlating cluster of immunoglobulin M (IgM), immunoglobulin J chain (JCHAIN), and CD5 antigen-like (CD5L).

Discussion

Overall, our proteomic approach shows that whole blood donation has a limited impact on the plasma proteins measured. Our findings suggest that plasma profiling can be successfully employed to consistently detect proteins and protein complexes that reflect the functionality and integrity of platelets, red blood cells, and immune cells in blood donors and thus highlights its potential use for donor health monitoring.     

Tacit knowledge in dyads of persons with profound intellectual and multiple disabilities and their caregivers: An interpretative literature study

Background

Caring for persons with profound intellectual and multiple disabilities (PIMD) demands specific expertise. Tacit knowledge seems to play an important role, but little is known about its nature, including what is necessary for its development and transfer.

Aim

To gain understanding of the nature and development of tacit knowledge between persons with PIMD and their caregivers.

Method

We conducted an interpretative synthesis of literature on tacit knowledge in caregiving dyads with persons with PIMD, persons with dementia or infants. Twelve studies were included.

Results

Tacit knowledge is about caregivers and care-recipients becoming sensitive and responsive to each other's cues and together crafting care routines. Learning takes place in a constant process of action and response that transforms those involved.

Conclusion

Building tacit knowledge together is necessary for persons with PIMD to learn to recognise and express their needs. Suggestions are made for ways to facilitate its development and transfer.