Cardiac macrophages are heterogenous in phenotype and functions, which has been associated with differences in their ontogeny. Despite extensive research, our understanding of the precise role of different subsets of macrophages in ischemia/reperfusion (I/R) injury remains incomplete. We here investigated macrophage lineages and ablated tissue macrophages in homeostasis and after I/R injury in a CSF1R-dependent manner. Genomic deletion of a fms-intronic regulatory element (FIRE) in the Csf1r locus resulted in specific absence of resident homeostatic and antigen-presenting macrophages, without affecting the recruitment of monocyte-derived macrophages to the infarcted heart. Specific absence of homeostatic, monocyte-independent macrophages altered the immune cell crosstalk in response to injury and induced proinflammatory neutrophil polarization, resulting in impaired cardiac remodeling without influencing infarct size. In contrast, continuous CSF1R inhibition led to depletion of both resident and recruited macrophage populations. This augmented adverse remodeling after I/R and led to an increased infarct size and deterioration of cardiac function. In summary, resident macrophages orchestrate inflammatory responses improving cardiac remodeling, while recruited macrophages determine infarct size after I/R injury. These findings attribute distinct beneficial effects to different macrophage populations in the context of myocardial infarction.

The global increase in neurodegenerative disorders is one of the most crucial public health issues. Oral polyamine intake was shown to improve memory performance which is thought to be mediated at least in part via increased autophagy induced in brain cells. In Alzheimer’s Disease, T-cells were identified as important mediators of disease pathology. Since autophagy is a central regulator of cell activation and cytokine production, we investigated the influence of polyamines on T-cell activation, autophagy, and the release of Th1/Th2 cytokines from blood samples of patients (n=22) with cognitive impairment or dementia in comparison to healthy controls (n=12) ex vivo. We found that spermine downregulated all investigated cytokines in a dose-dependent manner. Spermidine led to an upregulation of some cytokines for lower dosages, while high dosages downregulated all cytokines apart from upregulated IL-17A. Autophagy and T-cell activation increased in a dose-dependent manner by incubation with either polyamine. Although effects in patients were seen in lower concentrations, alterations were similar to controls.

Chest radiographs (CXRs) are still of crucial importance in primary diagnostics, but their interpretation poses difficulties at times. Can a convolutional neural network-based artificial intelligence (AI) system that interprets CXRs add value in an emergency unit setting? A total of 563 CXRs acquired in the emergency unit of a major university hospital were retrospectively assessed twice by three board-certified radiologists, three radiology residents, and three emergency unit-experienced nonradiology residents (NRRs). They used a two-step reading process: (1) without AI support; and (2) with AI support providing additional images with AI overlays. Suspicion of four suspected pathologies (pleural effusion, pneumothorax, consolidations suspicious for pneumonia, and nodules) was reported on a five-point confidence scale. Confidence scores of the board-certified radiologists were converted into four binary reference standards of different sensitivities. Performance by radiology residents and NRRs without AI support/with AI support were statistically compared by using receiver-operating characteristics (ROCs), Youden statistics, and operating point metrics derived from fitted ROC curves. NRRs could significantly improve performance, sensitivity, and accuracy with AI support in all four pathologies tested. In the most sensitive reference standard (reference standard IV), NRR consensus improved the area under the ROC curve (mean, 95% CI) in the detection of the time-critical pathology pneumothorax from 0.846 (0.785-0.907) without AI support to 0.974 (0.947-1.000) with AI support (P < .001), which represented a gain of 30% in sensitivity and 2% in accuracy (while maintaining an optimized specificity). The most pronounced effect was observed in nodule detection, with NRR with AI support improving sensitivity by 53% and accuracy by 7% (area under the ROC curve without AI support, 0.723 [0.661-0.785]; with AI support, 0.890 [0.848-0.931]; P < .001). Radiology residents had smaller, mostly nonsignificant gains in performance, sensitivity, and accuracy with AI support. We found that in an emergency unit setting without 24/7 radiology coverage, the presented AI solution features an excellent clinical support tool to nonradiologists, similar to a second reader, and allows for a more accurate primary diagnosis and thus earlier therapy initiation.

RNA-binding proteins regulate RNA fate and govern post-transcriptional gene regulation. A new family of RNA-binding proteins is represented by regulatory RNases (Regnase, also known as Zc3h12 or MCPIP), which have emerged as important players in immune homoeostasis. Four members, Regnase1-4, have been identified to date. Here we summarize recent findings on the role of Regnase in the regulation of RNA biology and its consequences for cell functions and inflammatory processes.

Background: Tissue-resident macrophages have mixed developmental origins. They derive in variable extent from yolk sac (YS) hematopoiesis during embryonic development. Bone marrow (BM) hematopoietic progenitors give rise to tissue macrophages in postnatal life, and their contribution increases upon organ injury. Since the phenotype and functions of macrophages are modulated by the tissue of residence, the impact of their origin and developmental paths has remained incompletely understood. Methods: In order to decipher cell-intrinsic macrophage programs, we immortalized hematopoietic progenitors from YS and BM using conditional HoxB8, and carried out an in-depth functional and molecular analysis of differentiated macrophages. Results: While YS and BM macrophages demonstrate close similarities in terms of cellular growth, differentiation, cell death susceptibility and phagocytic properties, they display differences in cell metabolism, expression of inflammatory markers and inflammasome activation. Reduced abundance of PYCARD (ASC) and CASPASE-1 proteins in YS macrophages abrogated interleukin-1β production in response to canonical and non-canonical inflammasome activation. Conclusions: Macrophage ontogeny is associated with distinct cellular programs and immune response. Our findings contribute to the understanding of the regulation and programming of macrophage functions.

(1) Background: Chest radiography (CXR) is still a key diagnostic component in the emergency department (ED). Correct interpretation is essential since some pathologies require urgent treatment. This study quantifies potential discrepancies in CXR analysis between radiologists and non-radiology physicians in training with ED experience. (2) Methods: Nine differently qualified physicians (three board-certified radiologists [BCR], three radiology residents [RR], and three non-radiology residents involved in ED [NRR]) evaluated a series of 563 posterior-anterior CXR images by quantifying suspicion for four relevant pathologies: pleural effusion, pneumothorax, pneumonia, and pulmonary nodules. Reading results were noted separately for each hemithorax on a Likert scale (0–4; 0: no suspicion of pathology, 4: safe existence of pathology) adding up to a total of 40,536 reported pathology suspicions. Interrater reliability/correlation and Kruskal–Wallis tests were performed for statistical analysis. (3) Results: While interrater reliability was good among radiologists, major discrepancies between radiologists’ and non-radiologists’ reading results could be observed in all pathologies. Highest overall interrater agreement was found for pneumothorax detection and lowest agreement in raising suspicion for malignancy suspicious nodules. Pleural effusion and pneumonia were often suspected with indifferent choices (1–3). In terms of pneumothorax detection, all readers mainly decided for a clear option (0 or 4). Interrater reliability was usually higher when evaluating the right hemithorax (all pathologies except pneumothorax). (4) Conclusions: Quantified CXR interrater reliability analysis displays a general uncertainty and strongly depends on medical training. NRR can benefit from radiology reporting in terms of time efficiency and diagnostic accuracy. CXR evaluation of long-time trained ED specialists has not been tested.