Network analysis reveals age- and virus-specific circuits in nasal epithelial cells of extremely premature infants.

BACKGROUND AND OBJECTIVES: Viral respiratory infections significantly affect young children, particularly extremely premature infants, resulting in high hospitalization rates and increased health-care burdens. Nasal epithelial cells, the primary defense against respiratory infections, are vital for understanding nasal immune responses and serve as a promising target for uncovering underlying molecular and cellular mechanisms. METHODS: Using a trans-well pseudostratified nasal epithelial cell system, we examined age-dependent developmental differences and antiviral responses to influenza A and respiratory syncytial virus through systems biology approaches. RESULTS: Our studies revealed differences in innate-receptor repertoires, distinct developmental pathways, and differentially connected antiviral network circuits between neonatal and adult nasal epithelial cells. Consensus network analysis identified unique and shared cellular-viral networks, emphasizing highly relevant virus-specific pathways, independent of viral replication kinetics. CONCLUSION: This research highlights the importance of nasal epithelial cells in innate antiviral immune responses and offers crucial insights that allow for a deeper understanding of age-related differences in nasal epithelial cell immunity following respiratory virus infections.

Transcriptomic analysis identifies lactoferrin-induced quiescent circuits in neonatal macrophages.

Introduction: Upon birth, a hitherto naïve immune system is confronted with a plethora of microbial antigens due to intestinal bacterial colonization. To prevent excessive inflammation and disruption of the epithelial barrier, physiological mechanisms must promote immune-anergy within the neonatal gut. As high concentrations of human lactoferrin (hLF), a transferrin glycoprotein shown to modulate macrophage function, are frequently encountered in colostrum, its direct interaction with intestinal macrophages may satisfy this physiological need. Thus, the primary objective of this study was to investigate transcriptional changes induced by human lactoferrin in neonatal monocyte-derived macrophages. Methods: Cord blood-derived monocytes were differentiated with M-CSF in presence or absence of 500 µg/mL hLF for 7 days and afterwards stimulated with 1 ng/mL LPS or left untreated. RNA was then isolated and subjected to microarray analysis. Results: Differentiation of cord blood-derived monocytes in presence of hLF induced a distinct transcriptional program defined by cell cycle arrest in the G2/M phase, induction of IL-4/IL-13-like signaling, altered extracellular matrix interaction, and enhanced propensity for cell-cell interaction. Moreover, near-complete abrogation of transcriptional changes induced by TLR4 engagement with LPS was observed in hLF-treated samples. Discussion: The global transition towards an M2-like homeostatic phenotype and the acquisition of quiescence elegantly demonstrate the ontogenetical relevance of hLF in attenuating pro-inflammatory signaling within the developing neonatal intestine. The marked anergy towards proinflammatory stimuli such as LPS further underlines the glycoprotein's potential therapeutic relevance.

Cross-sectional survey and Bayesian network model analysis of traditional Chinese medicine in Austria: investigating public awareness, usage determinants and perception of scientific support.

OBJECTIVES: Despite the paucity of evidence verifying its efficacy and safety, traditional Chinese medicine (TCM) is expanding in popularity and political support. Decisions to include TCM diagnoses in the International Classification of Diseases 11th Revision and campaigns to integrate TCM into national healthcare systems have occurred while public perception and usage of TCM, especially in Europe, remains undetermined. Accordingly, this study investigates TCM's popularity, usage and perceived scientific support, as well as its relationship to homeopathy and vaccinations. DESIGN/SETTING: We performed a cross-sectional survey of the Austrian population. Participants were either recruited on the street (in-person) or online (web-link) via a popular Austrian newspaper. PARTICIPANTS: 1382 individuals completed our survey. The sample was poststratified according to data derived from Austria's Federal Statistical Office. OUTCOME MEASURES: Associations between sociodemographic factors, opinion towards TCM and usage of complementary medicine (CAM) were investigated using a Bayesian graphical model. RESULTS: Within our poststratified sample, TCM was broadly known (89.9% of women, 90.6% of men), with 58.9% of women and 39.5% of men using TCM between 2016 and 2019. Moreover, 66.4% of women and 49.7% of men agreed with TCM being supported by science. We found a positive relationship between perceived scientific support for TCM and trust in TCM-certified medical doctors (ρ=0.59, 95% CI 0.46 to 0.73). Moreover, perceived scientific support for TCM was negatively correlated with proclivity to get vaccinated (ρ=-0.26, 95% CI -0.43 to -0.08). Additionally, our network model yielded associations between TCM-related, homeopathy-related and vaccination-related variables. CONCLUSIONS: TCM is widely known within the Austrian general population and used by a substantial proportion. However, a disparity exists between the commonly held public perception that TCM is scientific and findings from evidence-based studies. Emphasis should be placed on supporting the distribution of unbiased, science-driven information.

Packed red blood cell transfusion in preterm infants.

Premature infants commonly receive adult packed red blood cells (pRBCs) during their hospital stay. As adult erythrocytes differ substantially from those of preterm infants, transfusion of adult pRBCs into preterm infants can be considered inappropriate for the physiology of a preterm infant. An absence of standardisation of transfusion protocols makes it difficult to compare and interpret pertinent clinical data, as reflected by unclear associations between pRBC transfusion and complications related to prematurity, such as bronchopulmonary dysplasia, neurodevelopmental impairment, retinopathy of prematurity, or necrotising enterocolitis. The difficulty in interpreting clinical data is further increased by differences in study designs that either overestimate pRBC-associated complications of prematurity or have not yet been designed to directly link pRBC transfusions to their respective complications. Thus, neonatal transfusion practice has become an ongoing difficulty, in which differences in transfusion guidelines hinder the ability to generate comparable clinical data, and heterogeneity in clinical data prevents the implementation of standardised transfusion protocols. To overcome these issues, novel approaches with biochemical-clinical translational designs could enable clinicians to gather causal evidence instead of circumstantial correlation.

Proteinuria in Deceased Kidney Transplant Donors for Prediction of Chronic Lesions in Pretransplant Biopsies: A Prospective Observational Study.

BACKGROUND: Pretransplant kidney graft biopsies have been suggested for organ quality assessment. Data on the association between donor proteinuria and organ quality of deceased donors are not available. METHODS: In this prospective study, we analyzed 147 pretransplant kidney biopsies from 88 deceased adult donors procured and transplanted consecutively at the Medical University Vienna between July 2017 and May 2020. Lesions in each renal compartment were scored from 0 to 5 with each ascending score representing a 20% increase in organ damage. A chronic lesions score was calculated including glomerulosclerosis, intima fibrosis, hyalinosis, interstitial fibrosis, and tubular atrophy. RESULTS: The median chronic lesion score was 2 (interquartile range [IQR] 1-4) and the median donor urinary protein to creatinine ratio (UPCR) was 382 mg/dL (IQR 222-703). There was a positive correlation between UPCR and number of chronic lesions (ß 0.15, 95% confidence interval, 0.03-0.28; P = 0.019). Biopsies with 2 or more lesions had a median UPCR of 486 mg/dL (IQR 251-717) compared with 274 mg/dL (IQR 211-556; P = 0.016) in biopsies with <2 lesions. The risk for detection of 2 or more lesions rose by 18% for every log increase in UPCR (risk ratio 1.18, 95% confidence interval, 1.03-1.25; P = 0.017). Multivariable and sensitivity analysis revealed an independent and robust association between chronic lesions and UPCR. CONCLUSIONS: Donor UPCR is associated with chronic lesions in pretransplant deceased donor kidney graft biopsies. This finding justifies further investigation of donor proteinuria for the assessment of organ quality and outcome.

Redox Properties of Human Erythrocytes Are Adapted for Vitamin C Recycling.

Ascorbic acid (AA; or vitamin C) is an important physiological antioxidant and radical scavenger. Some mammalian species, including homo sapiens, have lost the ability to synthetize AA and depend on its nutritional uptake. Erythrocytes from AA-auxotroph mammals express high amounts of the glucose transporter GLUT1. This isoform enables rapid uptake of glucose as well as dehydroascorbate (DHA), the fully oxidized form of AA. Here, we explored the effects of DHA uptake on the redox metabolism of human erythrocytes. DHA uptake enhanced plasma membrane electron transport (PMET) activity. This process is mediated by DCytb, a membrane bound cytochrome catalyzing extracellular reduction of Fe3+ and ascorbate free radical (AFR), the first oxidized form of AA. DHA uptake also decreased cellular radical oxygen species (ROS) levels. Both effects were massively enhanced in the presence of physiological glucose concentrations. Reduction of DHA to AA largely depleted intracellular glutathione (GSH) and induced the efflux of its oxidized form, GSSG. GSSG efflux could be inhibited by MK-571 (IC 50 = 5 µM), indicating involvement of multidrug resistance associated protein (MRP1/4). DHA-dependent GSH depletion and GSSG efflux were completely rescued in the presence of 5 mM glucose and, partially, by 2-deoxy-glucose (2-DG), respectively. These findings indicate that human erythrocytes are physiologically adapted to recycle AA both intracellularly via GLUT1-mediated DHA uptake and reduction and extracellularly via DCytb-mediated AFR reduction. We discuss the possibility that this improved erythrocyte-mediated AA recycling was a prerequisite for the emergence of AA auxotrophy which independently occurred at least twice during mammalian evolution.

Torque Teno Virus Load Is Associated With Subclinical Alloreactivity in Kidney Transplant Recipients: A Prospective Observational Trial.

BACKGROUND: Nonpathogenic torque teno viruses (TTVs) are highly prevalent in transplant recipients and associated with immunosuppression. Studies in kidney transplant patients have proposed assessment of TTV load for risk stratification of clinically overt graft rejection. The value of TTV quantification in the context of subclinical rejection has not been evaluated. METHODS: In this prospective trial, 307 consecutive kidney transplant recipients were subjected to per-protocol monitoring of plasma TTV. TTV was analyzed in the context of protocol biopsies (n = 82), scheduled 1 year posttransplantation. RESULTS: TTV load at the time of biopsy was lower in recipients with rejection (n = 19; according to Banff, including borderline changes suspicious for acute T cell-mediated rejection) than those without rejection (n = 63) whereby each log increase in TTV copies/mL decreased the risk for rejection by 9% (risk ratio 0.91, 95% confidence interval, 0.85-0.97; P = 0.004). Development of chronic lesions (cg, cv, ci, ct, ah, ptcml) was associated with the number of days with a TTV load <1 × 106 copies/mL between months 3 and 12 posttransplant (ß 0.07, 95% confidence interval, 0.01-0.14; P = 0.02). CONCLUSIONS: This trial demonstrates an association between TTV and subclinical graft rejection in kidney transplant recipients. A TTV load <1 × 106 copies/mL suggests suboptimal immunosuppression.

A critical examination of the main premises of Traditional Chinese Medicine.

Traditional Chinese Medicine (TCM) consists of a plethora of therapeutic approaches aiming to both characterize and treat diseases. Its utilization has gained significant popularity in the western world and is even backed by the World Health Organization's decision to include TCM diagnostic patterns into the new revision of the International Classification of Diseases code, the global standard for diagnostic health information. As these developments and potentially far-reaching decisions can affect modern healthcare systems and daily clinical work as well as wildlife conservation, its underlying factual basis must be critically examined. This article therefore provides an overview of the evidence underlying the basic TCM concepts, such as Qi, meridians, acupuncture, pulse and tongue diagnostics as well as traditional herbal treatments. Moreover, it discusses whether scientific literature on TCM reflects the current standard for evidence-based research, as described in good scientific practice and good clinical practice guidelines. Importantly, misinformation regarding the therapeutic efficacy of animal-derived substances has lead and currently leads to problems with wildlife preservation and animal ethics. Nevertheless, the (re-)discovery of artemisinin more than 50 years ago introduced a novel development in TCM: the commingling of Eastern and Western medicine, the appreciation of both systems. The need for more rigorous approaches, fulfilment of and agreement to current guidelines to achieve high-quality research are of utmost relevance. Thereby, ancient knowledge of herbal species and concoctions may serve as a possible treasure box rather than Pandora's box.