S100-alarmin-induced innate immune programming protects newborn infants from sepsis.

The high risk of neonatal death from sepsis is thought to result from impaired responses by innate immune cells; however, the clinical observation of hyperinflammatory courses of neonatal sepsis contradicts this concept. Using transcriptomic, epigenetic and immunological approaches, we demonstrated that high amounts of the perinatal alarmins S100A8 and S100A9 specifically altered MyD88-dependent proinflammatory gene programs. S100 programming prevented hyperinflammatory responses without impairing pathogen defense. TRIF-adaptor-dependent regulatory genes remained unaffected by perinatal S100 programming and responded strongly to lipopolysaccharide, but were barely expressed. Steady-state expression of TRIF-dependent genes increased only gradually during the first year of life in human neonates, shifting immune regulation toward the adult phenotype. Disruption of this critical sequence of transient alarmin programming and subsequent reprogramming of regulatory pathways increased the risk of hyperinflammation and sepsis. Collectively these data suggest that neonates are characterized by a selective, transient microbial unresponsiveness that prevents harmful hyperinflammation in the delicate neonate while allowing for sufficient immunological protection.

Quantification of cation-cation, anion-anion and cation-anion correlations in Li salt/glyme mixtures by combining very-low-frequency impedance spectroscopy with diffusion and electrophoretic NMR.

Directional correlations between the movements of cations and anions exert a strong influence on the charge and mass transport properties of concentrated battery electrolytes. Here, we combine, for the first time, very-low-frequency impedance spectroscopy on symmetrical Li|electrolyte|Li cells with diffusion and electrophoretic NMR in order to quantify cation-cation, anion-anion and cation-anion correlations in Li salt/tetraglyme (G4) mixtures with Li salt to G4 ratios between 1 : 1 and 1 : 2. We find that all correlations are negative, with like-ion anticorrelations (cation-cation and anion-anion) being generally stronger than cation-anion anticorrelations. In addition, we observe that like-ion anticorrelations are stronger for the heavier type of ion and that all anticorrelations become weaker with decreasing Li salt to G4 ratio. These findings are in contrast to theories considering exclusively anion-cation correlations in form of ion pairs, as the latter imply positive cation-anion correlations. We analyze in detail the influence of anticorrelations on Li+ transference numbers and on the Haven ratio. In order to rationalize our results, we derive linear response theory expressions for all ion correlations. These expressions show that the Li+ ion transport under anion-blocking conditions in a battery is governed by equilibrium center-of-mass fluctuations in the electrolytes. This suggests that in future electrolyte theories and computer simulations, more attention should be paid to equilibrium center-of-mass fluctuations.

Constitutive TNF-α signaling in neonates is essential for the development of tissue-resident leukocyte profiles at barrier sites.

Newborn infants have a high disposition to develop systemic inflammatory response syndromes (SIRSs) upon inflammatory or infectious challenges. Moreover, there is a considerable trafficking of hematopoietic cells to tissues already under noninflammatory conditions. These age-specific characteristics suggest a hitherto unappreciated crucial role of the vascular endothelium during the neonatal period. Here, we demonstrate that healthy neonates showed already strong endothelial baseline activation, which was mediated by a constitutively increased production of TNF-α. In mice, pharmacological inhibition of TNF-α directly after birth prevented subsequent fatal SIRS but completely abrogated the recruitment of leukocytes to sites of infection. Importantly, in healthy neonates, blocking TNF-α at birth disrupted the physiologic leukocyte trafficking, which resulted in persistently altered leukocyte profiles at barrier sites. Collectively, these data suggest that constitutive TNF-α-mediated sterile endothelial activation in newborn infants contributes to the increased risk of developing SIRS but is needed to ensure the postnatal recruitment of leukocytes to organs and interfaces.-Bickes, M. S., Pirr, S., Heinemann, A. S., Fehlhaber, B., Halle, S., Völlger, L., Willers, M., Richter, M., Böhne, C., Albrecht, M., Langer, M., Pfeifer, S., Jonigk, D., Vieten, G., Ure, B., von Kaisenberg, C., Förster, R., von Köckritz-Blickwede, M., Hansen, G., Viemann, D. Constitutive TNF-α signaling in neonates is essential for the development of tissue-resident leukocyte profiles at barrier sites.

Duration of SARS-CoV-2 RNA detection in COVID-19 patients in home isolation, Rhineland-Palatinate, Germany, 2020 - an interval-censored survival analysis.

We analysed consecutive RT-qPCR results of 537 symptomatic coronavirus disease (COVID-19) patients in home quarantine. Respectively 2, 3, and 4 weeks after symptom onset, 50%, 25% and 10% of patients had detectable RNA from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In patients with mild COVID-19, RNA detection is likely to outlast currently known periods of infectiousness by far and fixed time periods seem more appropriate in determining the length of home isolation than laboratory-based approaches.

Evolution of a community-centred experiential learning module: A mixed-methods approach to promote social accountability and community partnership in undergraduate medical education.

This article was migrated. The article was marked as recommended. Background: Education in social determinants of health (SDH) has become an important part of medical curricula, facilitated increasingly through students' experiential learning with communities. The Community and Workplace Centred Learning Experience (CWCLE) module of the University of Saskatchewan, Canada, intends to integrate and extend second-year medical students' attitudes, skills, and knowledge about SDH and community resources. We aimed to: 1) Solicit students' self-evaluation of their ability to perform module learning objectives, 2) Assess module impact on student attitudes toward SDH, 3) Obtain feedback from community partners and students about their community experiences, and 4) Use feedback to collaboratively develop recommendations to enhance the CWCLE module. Methods: We used a mixed-method approach to combine quantitative data with stories and personal experiences. We developed an online survey for two cohorts of students who had completed the module, soliciting students to self-evaluate their perceived abilities to perform the module's learning objectives and evaluating students' attitudes towards SDH. We invited representatives from community agencies involved in the CWCLE module to participate in focus groups. We also held separate focus groups with students who participated in the online survey to elaborate on their survey comments. Results: In total, 145 students participated in the online survey (response rate=72.5%). Eleven community agency representatives and seven students participated in five focus groups. Our results demonstrate that medical students benefit from community-based experiential learning of SDH and community resources. We trace evaluations and discussions in the ongoing development of this community-based experiential learning module from its initial, primarily medical-school driven designs, towards a substantial involvement of community-based organizations in its operation and continuing redevelopment. Conclusions: Our mixed method offered us a better understanding of module impact and opportunities for improvement. This module evaluation and reform generated opportunities for community partners to influence decisions in medical education and led to a collaborative evolution of a community-centred learning experience. Medical schools should actively engage community partners in teaching behavioural and social components of the curriculum and acknowledge their partners' expertise to promote community engagement and social accountability in medical education.

A sensitive scoring system for the longitudinal clinical evaluation and prediction of lethal disease outcomes in newborn mice.

Neonatal animal models are increasingly employed in order to unravel age-specific disease mechanisms. Appropriate tools objectifying the clinical condition of murine neonates are lacking. In this study, we tested a scoring system specifically designed for newborn mice that relies on clinical observation and examination. Both, in a neonatal sepsis model and an endotoxic shock model, the scoring results strongly correlated with disease-induced death rates. Full as well as observation-restricted scoring, reliably predicted fatality and the remaining time until death. Clinical scores even proved as more sensitive biomarker than 6 traditionally used plasma cytokine levels in detecting sepsis at an early disease stage. In conclusion, we propose a simple scoring system that detects health impairments of newborn mice in a non-invasive longitudinal and highly sensitive manner. Its usage will help to meet animal welfare requirements and might improve the understanding of neonatal disease mechanisms.