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Introduction: Esketamine intranasal spray has been approved in both the USA and EU as a novel treatment in patients with treatment-resistant major depression (TRD) and for the management of acute depressive emergencies during the course of major depressive disorder (MDD). Real-world data on the effectiveness and safety of esketamine nasal spray in clinical use are limited. Objectives: To investigate the clinical effects and safety of esketamine nasal spray on depression severity and suicidal ideation during inpatient treatment in n=76 patients in a German university hospital. Methods: In this retrospective chart review, we analyzed the change in depression severity and safety after a treatment series with esketamine nasal spray combined with treatment-as-usual in patients with treatment-resistant depression (TRD) in inpatient treatment setting of a University Hospital. Depression severity has been rated with the Montgomery–Åsberg Depression Rating Scale (MADRS) as well as with the BDI-II (Beck Depression Inventory-Second Edition) before and after the treatment series. The intensity of suicidal ideation has been evaluated using MADRS item 10 on suicidal thoughts. Results: A total of 76 patients have been included (women 55.3, n=42) in this analysis. Mean BDI-II pre-treatment was 37.6 and mean MADRS was 33.6 corresponding to severe depression. Mean score on item-10 pre-treatment was 2.4 (median 2.0). On average patients received 10.9 sessions (standard deviation 4.2, median 11.0) of esketamine nasal spray (min 1, max. 19 sessions). There was clear improvement after the treatment series in both the BDI-II (mean change -10.1, p < 0.001) as well as in MADRS score (mean reduction -10.0, p < 0.001). Suicidal ideation on item-10 also decreased significantly (-0.9, p < 0.001). The effect sizes were large for all three measures: Cohen's d 1.050 for BDI-II; 0.986 for MADRS and 0.742 for changes in suicidal ideation. Overall, esketamine treatment was well tolerated. In five cases esketamine treatment has been terminated early (after a mean of 3.4 sessions) due to dissociations (n=4; 5.3%) or due to non-response (n=1). Conclusions: Esketamine nasal spray is a novel effective and safe treatment option, which leads to significant decrease in depression severity as well as in suicidal ideation. More data from real-world patients are needed to position esketamine in the algorithm of depression treatment. Rate of treatment discontinuation due to side-effects in this study was comparable to those in other esketamine studies (4.2% in Reif et al, NEJM, 2023). Disclosure of Interest: None Declared [ABSTRACT FROM AUTHOR]

Discovering the variation among genotypes is an important criterion for selecting the suitable cultivar for a certain environment. The study aimed to explore the genetic variation among 17 genotypes of barley based on grain yield and some related traits. Plants were grown under field grown conditions in the 2019-2020 and 2020-2021 growing seasons, and plant height (PH), spike per square meter (SSM), spike length (SL), spikelets per spike (NSS), seed per spike (SPS), biological yield (BY), grain yield (GY), and thousand grain weight (TGW) were measured. Results indicated that PH ranged (51.7 to 81.33 cm) and (58.20 to 79.90 cm), SSM (374 to 582) and (418 to 701), SL (7.10 to 9.63 cm) and (6.87 to 9.13 cm), NSS (9 to 15) and (8 to 17), SPS (21 to 49) and (21 to 51), BY (3466.7 to 5905.3 kg h-1) and (3731.7 to 6080 kg h-1), GY (1442 to 2192 kg h-1) and (811.8 to 1763.7 kg h-1), TGW (34 to 55.67 g) and (33.47 to 52.63 g) for the first and second year of experiment respectively. The advanced lines measurement values were higher in the second year of the experiment. It can be concluded that the advanced lines Anka-08 and Anka-11 are promising in most of the parameters. Some of the old and new cultivars still preserve their yield potential.

The measles, mumps, and rubella (MMR) vaccine protects against all-cause mortality in children, but the immunological mechanisms mediating these effects are poorly known. We systematically investigated whether MMR can induce long-term functional changes in innate immune cells, a process termed trained immunity, that could at least partially mediate this heterologous protection. In a randomized, placebo-controlled trial, 39 healthy adults received either the MMR vaccine or a placebo. Using single-cell RNA-Seq, we found that MMR caused transcriptomic changes in CD14+ monocytes and NK cells, but most profoundly in γδ T cells. Monocyte function was not altered by MMR vaccination. In contrast, the function of γδ T cells was markedly enhanced by MMR vaccination, with higher production of TNF and IFN-γ, as well as upregulation of cellular metabolic pathways. In conclusion, we describe a trained immunity program characterized by modulation of γδ T cell function induced by MMR vaccination.

Infections and vaccines can induce enhanced long-term responses in innate immune cells, establishing an innate immunological memory termed trained immunity. Here, we show that monocytes with a trained immunity phenotype, due to exposure to the Bacillus Calmette-Guérin (BCG) vaccine, are characterized by an increased biosynthesis of different lipid mediators (LM) derived from long-chain polyunsaturated fatty acids (PUFA). Pharmacological and genetic approaches show that long-chain PUFA synthesis and lipoxygenase-derived LM are essential for the BCG-induced trained immunity responses of human monocytes. Furthermore, products of 12-lipoxygenase activity increase in monocytes of healthy individuals after BCG vaccination. Grasping the underscoring lipid metabolic pathways contributes to our understanding of trained immunity and may help to identify therapeutic tools and targets for the modulation of innate immune responses., (© 2023. The Author(s).)

Itaconate is an immunomodulatory metabolite produced by immune cells under microbial stimulation and certain pro-inflammatory conditions and triggers antioxidant and anti-inflammatory responses. We show that dimethyl itaconate, a derivative of itaconate previously linked to suppression of inflammation and widely employed as an alternative to the endogenous metabolite, can induce long-term transcriptional, epigenomic, and metabolic changes, characteristic of trained immunity. Dimethyl itaconate alters glycolytic and mitochondrial energetic metabolism, ultimately leading to increased responsiveness to microbial ligand stimulation. Subsequently, mice treated with dimethyl itaconate present increased survival to infection with Staphylococcus aureus. Additionally, itaconate levels in human plasma correlate with enhanced ex vivo pro-inflammatory cytokine production. Collectively, these findings demonstrate that dimethyl itaconate displays short-term anti-inflammatory characteristics and the capacity to induce long-term trained immunity. This pro-and anti-inflammatory dichotomy of dimethyl itaconate is likely to induce complex immune responses and should be contemplated when considering itaconate derivatives in a therapeutic context., Competing Interests: Declaration of interests W.J.H.K. is a scientific advisor of Khondrion B.V. (Nijmegen, the Netherlands). This company was not involved in the data analysis and interpretation, writing of the manuscript, and the decision to submit the manuscript for publication., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Recurrent urinary tract infections (RUTIs) and recurrent vulvovaginal candidiasis (RVVCs) represent major healthcare problems all over the world. Antibiotics and antifungals are widely used for such infectious diseases, which is linked with microbial resistances and microbiota deleterious effects. The development of novel approaches for genitourinary tract infections (GUTIs) such as trained immunity-based vaccines (TIbV) is therefore highly required. MV140 is a sublingual whole-cell heat-inactivated polybacterial preparation with demonstrated clinical efficacy for RUTIs. The sublingual heat-inactivated Candida albicans vaccine V132 has been developed for RVVCs. We previously showed that the combination of MV140 and V132 promotes potent Th1/Th17 and regulatory T-cell responses against antigens contained in the formulation and unrelated antigens. The specific contribution of each preparation to such effects and the underlying molecular mechanisms remain incompletely understood., Methods: PBMC and monocytes were isolated from healthy donors and in vitro stimulated with V132, MV140 or MV140/V132. After 6 days of resting, cells were reestimulated with LPS and MV140. Analysis of cytokine production by ELISA, Seahorse assays for functional metabolic experiments and chromatin immunoprecipitation assays were performed. BALB/c mice were intraperitoneally and sublingually immunized with V132., Results: We uncover that V132 induces trained immunity in human PBMCs and purified monocytes, significantly increasing the responses triggered by subsequent stimulation with MV140. Mechanistically, V132 drives metabolic rewiring towards increased glycolysis and oxidative phosphorylation and induces epigenetic reprogramming that enhances the transcription of the pro-inflammatory genes IL6 and TNFA . Splenocytes and peritoneal cells from V132-immunize mice show increased responses upon in vitro stimulation with MV140. Remarkably, splenocytes from sublingually V132-immunized and MV140 in vivo treatment mice show stronger Th17 responses than mice exposed to excipients upon in vitro stimulation with MV140., Conclusion: Overall, we provide novel mechanistic insights into how V132-induced trained immunity enhances both innate and adaptive immune responses triggered by MV140, which might open the door for new interventions for GUTIs with important clinical implications., Competing Interests: OP has received fee for lectures or participation in Advisory Boards from Allergy Therapeutics, Amgen, AstraZeneca, Diater, GSK, Pfizer, Inmunotek SL, Novartis, Sanofi Genzyme, Stallergenes and Regeneron. OP has received research grants from Inmunotek SL, Novartis SL, MINECO, MICINNIN and CAM. JS is the founder and CEO of Inmunotek SL. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Martín-Cruz, Angelina, Baydemir, Bulut, Subiza, Netea, Domínguez-Andrés and Palomares.)

Trained immunity refers to the long-lasting memory traits of innate immunity. Recent studies have shown that trained immunity is orchestrated by sustained changes in epigenetic marks and metabolic pathways, leading to an altered transcriptional response to a second challenge. However, the potential heterogeneity of trained-immunity induction in innate immune cells has not been explored. In this study, we demonstrate cellular transcriptional programs in response to 4 different inducers of trained immunity in monocyte populations at single-cell resolution. Specifically, we identified 3 monocyte subpopulations upon the induction of trained immunity, and replicated these findings in an in vivo study. In addition, we found gene signatures consistent with these functional programs in patients with ulcerative colitis, sepsis, and COVID-19, suggesting the impact of trained-immunity programs in immune-mediated diseases.