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Frailty in cirrhosis or advanced chronic liver disease (ACLD) is a relevant prognostic factor. In the present study, we aimed to analyze potential biomarkers associated with frailty and its improvement in patients with ACLD. We analyzed the serum of outpatients with ACLD who participated in a previous study (Román, Hepatol Commun 2024) in which frailty was assessed using the liver frailty index (LFI), and patients who were frail or prefrail were randomized to a multifactorial intervention (home exercise, branched-chain amino acids, and probiotics) or control for 12 months. We determined a biomarker battery of inflammation, bacterial translocation, and liver damage in blood and urine and blood metabolomics by 1 H-NMR. Thirty-seven patients were included. According to the LFI, 32 patients were frail or prefrail, and 5 were robust. At baseline, LFI correlated with LBP, sCD163, mtDNA, FGF-21, urinary NGAL, urinary claudin-3, and the metabolites mannose, ethanol, and isoleucine. During the study, patients in the intervention group showed an improvement in LFI and a decrease in CRP, LBP, sCD163, and ccK18 compared to the control group. Metabolomics showed a decrease in dimethyl sulfone and creatinine and an increase in malonate, ornithine, isoleucine, and valine in the intervention group. We conclude that frailty in patients with ACLD is associated with biomarkers of systemic inflammation, bacterial translocation, and liver damage, and alterations of amino acid and short-chain fatty acid metabolism.

Pseudomonas species constitute a significant group of pathogens in aquarium fish and frequently cause haemorrhagic septicaemia. This study conducted a taxonomic characterization of Pseudomonas isolates from aquarium fish exhibiting deep ulceration and general disease signs. A polyphasic approach was employed to ascertain the taxonomic affiliation of the strains. The overall genome relatedness indices of digital DNA-DNA hybridization (dDDH) and average nucleotide identity (ANI) between the strains and the other members of the genus Pseudomonas were found to be below the established thresholds of 70 and 95-96%, respectively. Whole-genome based phylogenetic analysis revealed that strains 119P T and 120P were closely related to P. arcuscaelestis. Strain 137P T was related to P. peradeniyensis, while strains 147P T and 148P were closely related to P. japonica. The morphological, physiological, and biochemical characteristics of the strains and the genome relatedness indices of dDDH and ANI below the established thresholds confirmed the classification of the strains as three novel species. Genome analyses of the strains were also conducted to determine their biosynthesis-related gene clusters, virulence features and ecological distribution patterns. Based on polyphasic characterization, the strains 119P T , 120P, 137P T , 147P T , and 148P are novel species within the genus Pseudomonas, for which the following names are proposed: Pseudomonas auratipiscis sp. nov., with the strain 119P T as the type strain (=DSM 117162  T , =LMG 33381 T ); Pseudomonas carassii sp. nov., with the strain 137P T as the type strain (=DSM 117060 T , =LMG 33378 T ); and Pseudomonas ulcerans sp. nov. 147P T , as the type strain (=DSM 117163 T , =LMG 33377 T )., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Eltrombopag (ELT) is a thrombopoietin-receptor agonist that stimulates platelet (PLT) production in patients with primary immune thrombocytopenia (ITP). One potential mechanism of ELT is modulating the inflammatory response by increasing PLTs binding to leucocytes. This study examined the effect of ELT on leucocyte-PLTs complexes in 38 ITP patients. Patients, predominantly females with a mean age of 59 years, underwent treatments like corticosteroids, intravenous immunoglobulin and splenectomy. Compared to healthy donors, ITP patients exhibited lower percentages of lymphocyte with bound PLTs, but similar monocyte- or neutrophil with bound PLTs. ELT treatment increased PLTs counts and all types of leucocyte with bound PLTs. Network analysis showed dynamic changes in leucocyte with bound PLTs relationships due to ELT. Machine learning indicated that higher percentages of monocytes with bound PLTs were linked to a better clinical response to ELT. A possible mechanism was an increased IL-10 production in monocytes with bound PLTs from responder patients. This study provides insights into the immunological changes in ITP patients undergoing ELT and suggests potential predictive biomarkers for treatment response and disease monitoring., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Lentiviral vector (LVV)-mediated cell and gene therapies have the potential to cure diseases that currently require lifelong intervention. However, the requirement for plasmid transfection hinders large-scale LVV manufacture. Moreover, large-scale plasmid production, testing, and transfection contribute to operational risk and the high cost associated with this therapeutic modality. Thus, we developed LVV packaging and producer cell lines, which reduce or eliminate the need for plasmid transfection during LVV manufacture. To develop a packaging cell line, lentiviral packaging genes were stably integrated by random integration of linearized plasmid DNA. Then, to develop EGFP - and anti-CD19 chimeric antigen receptor-encoding producer cell lines, transfer plasmids were integrated by transposase-mediated integration. Single-cell isolation and testing were performed to isolate the top-performing clonal packaging and producer cell lines. Production of LVVs that encode various cargo genes revealed consistency in the production performance of the packaging and producer cell lines compared to the industry-standard four-plasmid transfection method. By reducing or eliminating the requirement for plasmid transfection, while achieving production performance consistent with the current industry standard, the packaging and producer cell lines developed here can reduce costs and operational risks of LVV manufacture, thus increasing patient access to LVV-mediated cell and gene therapies., Competing Interests: All listed authors are present or past employees of OXGENE, A WuXi Advanced Therapies Company. W.V. and D.C. are employees and hold stock or stock options within the company. R.P.-M., L.D., T.P., and R.C. are named co-inventors on a patent describing the molecular configuration of the packaging elements (US20200277629A1)., (© 2024 The Author(s).)

Increased oxidative stress (OS) and the disruption of the equilibrium between the production of reactive oxygen species and antioxidants are key molecular features of unhealthy aging. OS results in the formation of oxidative posttranslational modifications (PTMs), some of which involve cysteine (Cys) residues in aging proteomes, and specifically, the formation of trioxidized Cys (t-Cys), which leads to permanent protein damage. Recent findings in rodents have uncovered that irregular regulation of t-Cys residues in the aging proteome disrupts homeostatic phosphorylation signaling, resulting in alterations to proteins that are analogous to those caused by phosphorylated serine (p-Ser) residues. This work contextualizes these significant findings and discusses the implications and molecular role(s) of t-Cys in the aging proteome. Furthermore, we present novel data, validating the increase of specific t-Cys sites associated with aging in a blood-related circulating human proteome. The scope and findings included here support the hypothesis that t-Cys residues may serve as important mechanistic and biological markers, warranting further exploration in the context of unhealthy aging and age-related major diseases.

Immune checkpoint inhibitors (ICI) have the potential to trigger unpredictable immune-related adverse events (irAEs), which can be severe. The underlying mechanisms of these events are not fully understood. As PD-L1 is upregulated by IFN, the heightened immune activation resulting from PD-1/PD-L1 inhibition may enhance the IFN response, triggering the expression of IFN-inducible genes and contributing to irAE development and its severity. In this study, we investigated the interplay between irAEs and the expression of IFN-inducible chemokines and cytokines in 134 consecutive patients with solid tumours treated with PD-(L)1 inhibitors as monotherapy or in combination with chemotherapy or other immunotherapy agents. We compared the plasma levels of IFN-associated cytokines (CXCL9/10/11, IL-18, IL-10, IL-6 and TGFβ) at various time points (at baseline, at the onset of irAE and previous to irAE onset) in three patient groups categorized by irAE development and severity: patients with serious irAEs, mild irAEs and without irAEs after PD-(L)1 inhibitors. No differences were observed between groups at baseline. However, patients with serious irAEs exhibited significant increases in CXCL9/10/11, IL-18 and IL-10 levels at the onset of the irAE compared to baseline. A network analysis and correlation patterns highlighted a robust relationship among these chemokines and cytokines at serious-irAE onset. Combining all of the analysed proteins in a cluster analysis, we identified a subgroup of patients with a higher incidence of serious irAEs affecting different organs or systems. Finally, an ROC analysis and a decision tree model proposed IL-18 levels ≥ 807 pg/mL and TGFβ levels ≤ 114 pg/mL as predictors for serious irAEs in 90% of cases. In conclusion, our study elucidates the dynamic changes in cytokine profiles associated with serious irAE development during treatment with PD-(L)1 inhibitors. The study's findings offer valuable insights into the intricate IFN-induced immune responses associated with irAEs and propose potential predictive markers for their severity.

PD-(L)1 inhibitors are part of the treatment strategy for non-small cell lung cancer (NSCLC) although its efficacy is limited to certain patients. Our study aimed to identify patients who might benefit from anti-PD-(L)1 inhibitors by analyzing the PD-L1 expression on circulating leukocytes and its evolution during treatment. One hundred thirteen NSCLC patients, according to their radiological response after 10-12 weeks of treatment, were classified into responders, stable, and progressive disease. Percentages of circulating PD-L1 + leukocytes, PD-L1 + platelets (PLTs), and leukocyte-PLT complexes were assessed using flow cytometry, and plasma concentrations of soluble immunomodulatory factors were quantified by ELISA. Responders exhibited significantly higher pre-treatment percentages of PD-L1 + neutrophils, PD-L1 + CD14 + cells, and PD-L1 + PLTs than progressors. The percentages of these populations decreased in responders post-treatment, contrasting with stables and progressors. PLTs notably contributed to PD-L1 expression in CD14 + cells and neutrophils. Plasma cytokine analysis revealed baseline differences only in IL-17 concentration among groups, whereas network analyses highlighted distinct association patterns between plasma molecules and PD-L1 + leukocytes after 10-12 weeks of treatment. Our findings suggest that pre-treatment assessment of circulating PD-L1 + neutrophils, PD-L1 + CD14 + cells, and PD-L1 + PLTs may be helpful in identifying NSCLC patients who are potential candidates for anti-PD-(L)1 therapy.

Interstitial lung diseases (ILDs) are characterized by inflammation or fibrosis of the pulmonary parenchyma. Despite the involvement of immune cells and soluble mediators in pulmonary fibrosis, the influence of antimicrobial peptides (AMPs) remains underexplored. These effector molecules display a range of activities, which include immunomodulation and wound repair. Here, we investigate the role of AMPs in the development of fibrosis in ILD. We compare the concentration of different AMPs and different cytokines in 46 fibrotic (F-ILD) and 17 non-fibrotic (NF-ILD) patients by ELISA and using peripheral blood mononuclear cells from in vitro stimulation in the presence of lysozyme or secretory leukocyte protease inhibitor (SLPI) from 10 healthy donors. We observed that bronchoalveolar lavage (BAL) levels of AMPs were decreased in F-ILD patients (lysozyme: p < 0.001; SLPI: p < 0.001; LL-37: p < 0.001; lactoferrin: p = 0.47) and were negatively correlated with levels of TGF-β (lysozyme: p = 0.02; SLPI: p < 0.001) and IL-17 (lysozyme: p < 0.001; SLPI: p < 0.001). We observed that lysozyme increased the percentage of CD86 + macrophages ( p < 0.001) and the production of TNF-α ( p < 0.001). We showed that lysozyme and SLPI were associated with clinical parameters (lysozyme: p < 0.001; SLPI: p < 0.001) and disease progression (lysozyme: p < 0.001; SLPI: p = 0.01). These results suggest that AMPs may play an important role in the anti-fibrotic response, regulating the effect of pro-fibrotic cytokines. In addition, levels of lysozyme in BAL may be a potential biomarker to predict the progression in F-ILD patients., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Aging is the primary risk factor for the development of numerous human chronic diseases. On a molecular level, it significantly impacts the regulation of protein modifications, leading to the accumulation of degenerative protein modifications (DPMs) such as aberrant serine phosphorylation (p-Ser) and trioxidized cysteine (t-Cys) within the proteome. The altered p-Ser is linked to abnormal cell signaling, while the accumulation of t-Cys is associated with chronic diseases induced by oxidative stress. Despite this, the potential cross-effects and functional interplay between these two critical molecular factors of aging remain undisclosed. This study analyzes the aging proteome of wild-type C57BL/6NTac mice over 2 years using advanced proteomics and bioinformatics. Our objective is to provide a comprehensive analysis of how t-Cys affects cell signaling and protein structure in the aging process. The results obtained indicate that t-Cys residues accumulate in the aging proteome, interact with p-Ser interacting enzymes, as validated in vitro, and alter their structures similarly to p-Ser. These findings have significant implications for understanding the interplay of oxidative stress and phosphorylation in the aging process. Additionally, they open new venues for further research on the role(s) of these protein modifications in various human chronic diseases and aging, wherein exacerbated oxidation and aberrant phosphorylation are implicated., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Species in the phylogenetic group Pseudomonas syringae are considered the most relevant plant pathogenic bacteria, but their taxonomy is still controversial. Twenty named species are validated in the current taxonomy of this group and in recent years many strains have been genome-sequenced, putative new species have been proposed and an update in the taxonomy is needed. A taxonomic study based on the core-genome phylogeny, genomic indices (ANI and GGDC) and gene content (phyletic pattern and Jaccard index) have been applied to clarify the taxonomy of the group. A phylogenomic analysis demonstrates that at least 50 phylogenomic species can be delineated within the group and that many strains whose genomes have been deposited in the databases are not correctly classified at the species level. Other species names, like " Pseudomonas coronafaciens ", have been proposed but are not validated yet. One of the putative new species is taxonomically described, and the name Pseudomonas maioricensis sp. nov. is proposed. The taxonomies of Pseudomonas avellanae and Pseudomonas viridiflava are discussed in detail as case studies. Correct strain identification is a prerequisite for many studies, and therefore, criteria are given to facilitate identification.

Extracellular vesicles (EVs) are tiny membranous structures that mediate intercellular communication. The role(s) of these vesicles have been widely investigated in the context of neurological diseases; however, their potential implications in the neuropathology subjacent to human psychiatric disorders remain mostly unknown. Here, by using next-generation discovery-driven proteomics, we investigate the potential role(s) of brain EVs (bEVs) in schizophrenia (SZ) by analyzing these vesicles from the three post-mortem anatomical brain regions: the prefrontal cortex (PFC), hippocampus (HC), and caudate (CAU). The results obtained indicate that bEVs from SZ-affected brains contain region-specific proteins that are associated with abnormal GABAergic and glutamatergic transmission. Similarly, these vesicles from the analyzed regions were implicated in synaptic decay, abnormal brain immunity, neuron structural imbalances, and impaired cell homeostasis. Our findings also provide evidence, for the first time, that networks of molecular exchange (involving the PFC, HC, and CAU) are potentially active and mediated by EVs in non-diseased brains. Additionally, these bEV-mediated networks seem to have become partially reversed and largely disrupted in the brains of subjects affected by SZ. Taken as a whole, these results open the door to the uncovering of new biological markers and therapeutic targets, based on the compositions of bEVs, for the benefit of patients affected by SZ and related psychotic disorders.

The migration and antimicrobial functions of neutrophils seem to be impaired during sepsis and contribute to the dysregulation of immune responses and disease pathogenesis. However, the role of neutrophil extracellular traps (NETs) remains to be clarified. The study aimed to analyse sequential phenotypic and functional changes of neutrophils during the time following the diagnosis of sepsis. We prospectively enrolled 49 septic and 18 non-septic patients from the intensive care unit (ICU) and emergency room (ER) and 20 healthy volunteers (HV). Baseline blood samples from septic and non-septic patients were collected within 12 h of admission to the hospital. Additional septic samples were drawn at 24, 48 and 72 h after baseline. Neutrophil phenotype and degranulation capacity were assessed by flow cytometry and NET formation was quantified by fluorescence. Neutrophils from septic patients exhibited increased CD66b, CD11b and CD177 expression but displayed reduced NET formation at baseline compared with non-septic patients and HV controls. Neutrophils expressing CD177 interacted less with platelets, were related to reduced NETosis and tended to indicate a worse sepsis outcome. In vitro experiments revealed that neutrophil function is compromised by the origin of sepsis, including the pathogen type and the affected organ. Assessing a decision tree model, our study showed that CD11b expression and NETosis values are useful variables to discriminate septic from non-septic patients. We conclude that sepsis induces changes in neutrophil phenotype and function that may compromise the effective capacity of the host to eliminate pathogens., (© 2023 John Wiley & Sons Ltd.)

Vascular dysfunction underlies the onset and progression of many life-threatening diseases, highlighting the need for improved understanding of its molecular basis. Here, we present differential systemic decellularization in vivo (DISDIVO), a protocol that enables systemic and independent study of the molecular changes in each vasculature layer in murine models of disease. We describe steps for anesthesia, perfusion surgery, and exsanguination. We then detail detachment and collection of glycocalyx and decellularization and collection of both endothelial and smooth muscle cells. For complete details on the use and execution of this protocol, please refer to Serra et al., Gallart-Palau et al., and Vinaiphat et al. 1 , 2 , 3 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

This study investigated the role of IL-35 in systemic sclerosis (SSc) patients, focusing on CD4+ T cell response and immunomodulatory cytokine production. By comparing the cytokine levels in healthy donors (HD) and SSc patients using ELISAs, we found a significantly lower plasma IL-35 concentration in the SSc patients (52.1 ± 5.6 vs. 143 ± 11.1, p < 0.001). Notably, the IL-35 levels showed a negative correlation with TGF-β ( p < 0.001) and IL-17 ( p = 0.04). Assessing the IL-35R expression across cell types in the SSc patients and HDs via flow cytometry, we found higher levels on monocytes (40.7 + 5.7 vs. 20.3 ± 1.9, p < 0.001) and lower levels on CD8+ T cells (61.8 ± 9.2 vs. 83.4 ± 0.8, p < 0.05) in the SSc patients. The addition of recombinant IL-35 to stimulated peripheral blood mononuclear cells reduced the IL-17+CD4+ T cell percentage (9.0 ± 1.5 vs. 4.8 ± 0.7, p < 0.05) and increased the IL-35+CD4+ T percentage (4.1 ± 2.3 vs. 10.2 ± 0.8, p < 0.001). In a Treg:Tresponder cell Sco-culture assay with HD and SSc samples, rIL35 decreased the cell proliferation and levels of IL-17A (178.2 ± 30.5 pg/mL vs. 37.4 ± 6.4 pg/mL, p < 0.001) and TGF-β (4194 ± 777 pg/mL vs. 2413 ± 608 pg/mL, p < 0.01). Furthermore, we observed a positive correlation between the modified Rodnan skin score (mRSS) and TGF-β ( p < 0.001), while there was a negative correlation between mRSS and IL-35 ( p = 0.004). Interestingly, higher levels of plasmatic IL-35 were detected in individuals with limited disease compared to those with diffuse disease (60.1 ± 8.0 vs. 832.3 ± 4.1, p < 0.05). These findings suggest that IL-35 exhibits anti-inflammatory properties in SSc and it may serve as a marker for disease severity and a therapeutic target.

Strains 19SMN4 T and ST27MN3 were isolated from marine sediments after enrichment with 2-methylnaphthalene and were classified as Pseudomonas stutzeri genomovar 4. Four other strains, BG 2, HT20, HT24, and A7, were isolated from sulphide-oxidizing bioreactors or activated sludge affiliated with the same clade in the 16S rRNA phylogenetic tree. P. stutzeri has been recently reclassified as a new genus, Stutzerimonas, and a preliminary analysis indicated that the strains in this study were distinct from any classified Stutzerimonas and are considered representatives of phylogenomic species 4 (pgs4). Strains 19SMN4 T and ST27MN3 were extensively characterized with phenotypic, chemotaxonomic, genomic and phylogenomic data. Strain 19SMN4 T had a well-characterized naphthalene degradative plasmid that has been compared with other plasmids, while in strain ST27MN3, the naphthalene degradative genes were detected in the chromosome sequence. Phylogenomic analysis of the core gene sequences showed that strains 19SMN4 T and ST27MN3 shared 3,995 genes and were closely related to members of the species "Stutzerimonas songnenensis" and Stutzerimonas perfectomarina, as well as to the Stutzerimonas phylogenomic species, pgs9, pgs16 and pgs24. The aggregate average nucleotide identity (ANI) indicated that strains 19SMN4 T and ST27MN3 belonged to the same genomic species, whereas the genomic indices with their closest-related type strains were below the accepted species threshold (95 %). We therefore conclude that strains 19SMN4 T and ST27MN3 represent a novel species of Stutzerimonas, for which the name Stutzerimonas decontaminans is proposed; the type strain is 19SMN4 T (=CCUG44593 T  = DSM6084 T  = LMG18521 T )., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Pulmonary fibrosis involves various types of immune cells and soluble mediators, including TGF-β and IL-35, a recently identified heterodimeric cytokine that belongs to the IL-12 cytokine family. However, the effect of regulatory IL-35 may play an important role in fibrotic diseases. The aim of this paper is to explore the immunoregulatory role of IL-35 in the development of fibrosis in interstitial lung disease (ILD). To gain a better understanding of this issue, the concentrations of IL-35 and different profibrotic cytokines in fibrotic (F-ILD) and non-fibrotic (NF-ILD) patients by ELISA were compared to that of intracellular IL-35 and IL-17 on CD4+ T cells stimulated in the presence of BAL or with different ratios of recombinant IL-35 (rIL-35) and TGF-β (rTGF-β), which were evaluated by flow cytometry. We observed that BAL concentration of IL-35 was lower in F patients (p < 0.001) and was negatively correlated with concentrations of TGF-β (p < 0.001) and IL-17 (p < 0.001). In supplemented cell cultures, BAL from NF but not F patients enhanced the percentage of IL-35 + CD4+ T (p < 0.001) cells and decreased the percentage of IL-17 + CD4+ T cells (p < 0.001). The percentage of IL-35 + CD4+ T cells correlated positively with BAL concentration of IL-35 (p = 0.02), but correlated negatively with BAL concentrations of IL-17 (p = 0.007) and TGF-β (p = 0.01). After adjusting the concentrations of recombinant cytokines to establish a TGF-β: IL-35 ratio of 1:4, an enhanced percentage of IL-35 + CD4+ T cells (p < 0.001) but a decreased percentage of IL-17 + CD4+ T cells (p < 0.001) was observed. After adding recombinant IL-35 to the BAL from F patients until a 1:4 ratio of TGF-β: IL-35 was reached, a significantly increased percentage of IL-35 + CD4+ T cells (p < 0.001) and a decreased percentage of IL-17 + CD4+ T cells (p = 0.003) was found. These results suggest that IL-35 may induce an anti-fibrotic response, regulating the effect of TGF-β and the inflammatory response on CD4+ T cells. In addition, the TGF-β: IL-35 ratio in BAL has been shown to be a potential biomarker to predict the outcome of F patients with ILD., (© 2022 John Wiley & Sons Ltd.)

Introduction: Extracellular vesicles (EVs) have been recognized as key players in numerous physiological functions. These vesicles alter their compositions attuned to the health and disease states of the organism. In men, significant changes in the proteomic composition(s) of seminal plasma EVs (sEVs) have already been found to be related to infertility., Methods: Methods: In this study, we analyze the posttranslational configuration of sEV proteomes from normozoospermic (NZ) men and non-normozoospermic (non-NZ) men diagnosed with teratozoospermia and/or asthenozoospermia by unbiased, discovery-driven proteomics and advanced bioinformatics, specifically focusing on citrulline (Cit) and homocitrulline (hCit) posttranscriptional residues, both considered product of ureido protein modifications., Results and Discussion: Significant increase in the proteome-wide cumulative presence of hCit together with downregulation of Cit in specific proteins related to decisive molecular functions have been encountered in sEVs of non-NZ subjects. These findings identify novel culprits with a higher chance of affecting fundamental aspects of sperm functional quality and define potential specific diagnostic and prognostic non-invasive markers for male infertility., Competing Interests: The 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 © 2023 Roy, Lorca, Mulet, Sánchez Milán, Baratas, de la Casa, Espinet, Serra and Gallart-Palau.)

Substances with modulatory capabilities on certain aspects of human cognition have been revered as nootropics from the dawn of time. The plant kingdom provides most of the currently available nootropics of natural origin. Here, in this systematic review, we aim to provide state-of-the-art information regarding proven and unproven effects of plant-derived nootropics (PDNs) on human cognition in conditions of health and disease. Six independent searches, one for each neurocognitive domain (NCD), were performed in parallel using three independent scientific library databases: PubMed, Cochrane and Scopus. Only scientific studies and systematic reviews with humans published between January 2000 and November 2021 were reviewed, and 256 papers were included. Ginkgo biloba was the most relevant nootropic regarding perceptual and motor functions. Bacopa monnieri improves language, learning and memory. Withania somnifera (Ashwagandha) modulates anxiety and social-related cognitions. Caffeine enhances attention and executive functions. Together, the results from the compiled studies highlight the nootropic effects and the inconsistencies regarding PDNs that require further research.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2021.2021137.

Text: Recent years have seen great advances in the use of clinical ultrasound imaging in both hospital emergency departments and out-of-hospital settings. However, all new techniques require up-to-date definitions of competencies relevant to the clinical realities of different specialties and the geographic settings in which specialists work. To that end, a group of experts in clinical ultrasound reviewed the evidence available in the literature and strictly applied the Delphi method to define the competencies relevant to emergency physicians. The group worked with the starting premise that clinical ultrasound imaging should be a common competency across the specialty.

Introduction: One of the main avoidable causes of combat-related injury death is extremity hemorrhage. Even with regular training, failure to properly apply a tourniquet is common. In this study, we sought to assess if rescuer's stress and personality traits, along with victim's state of consciousness, had a role to explain tourniquet application failure., Materials and Methods: Eighty-seven soldiers completed a sociodemographic and personality questionnaire (perceived stress, active altruism, mindfulness, and empathy) during a forward combat casualty care course. Then, they underwent a leg hemorrhage simulation on a randomly conscious or unconscious victim. Tourniquet application time and effectiveness (using popliteal artery Doppler) were recorded., Results: Tourniquet application effective rate was 37% and soldiers with higher levels of perceived stress were at greater risk of failure, especially on a conscious victim. Participants who deployed overseas and those who have undergone combat rescue training were significantly quicker to apply a tourniquet. Altruist and empathetic caregivers were slower to apply the tourniquet while mindful ones were faster., Conclusions: Combat-related injuries, even simulated, not only involve the rescuer's technical skills but also their ability to deal with stressful external stimuli. Tourniquet application speed seems to be influenced by perceived stress and personality traits of the rescuers. Frequent failures justify repeated training, and one way to pursue improvement could be to develop a personalized pedagogy adapting to the needs of the students according to their current skillset but also their perceived stress and personality determinants. In the pedagogical process (planning, goal setting, teaching, and evaluating), the state of consciousness of the victim seems to be a parameter that needs to be accounted for, but further studies are required to accurately describe its influence., (© The Association of Military Surgeons of the United States 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Tumor PD-L1 expression is a predictive biomarker for patients with NSCLC receiving PD-(L)1 blockade agents. However, although increased tumor PD-L1 expression predicts responsiveness, clinical benefit has been observed regardless of tumor PD-L1 expression, suggesting the existence of other PD-L1 sources. The aim of our study was to analyze whether integrating systemic and tumor PD-L1 is more predictive of efficacy in patients with advanced NSCLC receiving PD-(L)1 blockade agents., Material and Methods: Twenty-nine healthy donors and 119 consecutive patients with advanced NSCLC treated with PD-(L)1 drug were prospectively included. Pretreatment blood samples were collected to evaluate PD-L1 levels on circulating immune cells, platelets (PLTs), platelet microparticles (PMPs), and the plasma soluble PD-L1 concentration (sPD-L1). Tumor PD-L1 status was assessed by immunohistochemistry. The percentages of circulating PD-L1 + leukocytes, sPD-L1 levels, and tumor PD-L1 were correlated with efficacy., Results: No differences in the percentages of circulating PD-L1 + leukocytes were observed according to tumor PD-L1 expression. Significantly longer progression-free survival was observed in patients with higher percentages of PD-L1 + CD14 + , PD-L1 + neutrophils, PD-L1 + PLTs, and PD-L1 + PMPs and significantly longer overall survival was observed in patients with higher percentages of PD-L1 + CD14 + and high tumor PD-L1 expression. Integrating the PD-L1 data of circulating and tumor PD-L1 results significantly stratified patients according to the efficacy of PD-(L1) blockade agents., Conclusions: Our results suggest that integrating circulating PD-L1 + leukocytes, PLT, PMPs, and sPD-L1 and tumor PD-L1 expression may be helpful to decide on the best treatment strategy in patients with advanced NSCLC who are candidates for PD-(L)1 blockade agents., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Stutzerimonas is a recently proposed genus within the Pseudomonadaceae comprising strains in the formerly phylogenetic group of Pseudomonas stutzeri . At least sixteen named species have to be included in the genus, together with 22 genomovars of Stutzerimonas stutzeri . To clarify the taxonomy of Stutzerimonas , a core-genome phylogeny of 200 strains in the genus was inferred and monophyletic strains with average nucleotide identities (ANIb) with values equal to or higher than 95 were grouped in the same phylogenomic species. A total of 45 phylogenomic species within the genus Stutzerimonas were detected in the present study. Sixteen phylogenomic species correspond to already named species, although three of them are not yet validated and two are proposed in the present study. A synonymy was detected between P. kunmingensis and S. chloritidismutans , both members of phylogenomic species 3, with a prevalence of the S. chloritidismutans name. The correspondence of the phylogenomic species to the genome taxonomy database classification (GTDB taxonomy) is discussed. Combining phylogenomic and phenotypic data, two novel species are described ( Stutzerimonas frequens and Stutzerimonas degradans ) and two species descriptions are emended ( Stutzerimonas perfectomarina and Stutzerimonas chloritidismutans ).

Malignant pleural effusion (MPE) is a common severe complication of advanced lung adenocarcinoma (LAC). Neutrophils, an essential component of tumor infiltrates, contribute to tumor progression and their counts in MPE have been associated with worse outcome in LAC. This study aimed to evaluate phenotypical and functional changes of neutrophils induced by MPE to determine the influence of MPE immunomodulatory factors in neutrophil response and to find a possible association between neutrophil functions and clinical outcomes. Pleural fluid samples were collected from 47 LAC and 25 heart failure (HF) patients. We measured neutrophil degranulation products by ELISA, oxidative burst capacity and apoptosis by flow cytometry, and NETosis by fluorescence. The concentration of degranulation products was higher in MPE-LAC than in PE-HF. Functionally, neutrophils cultured with MPE-LAC had enhanced survival and neutrophil extracellular trap (NET) formation but had reduced oxidative burst capacity. In MPE, NETosis was positively associated with MMP-9, P-selectin, and sPD-L1 and clinically related to a worse outcome. This is the first study associating NETs with a worse outcome in MPE. Neutrophils likely contribute to tumor progression through the release of NETs, suggesting that they are a potential therapeutic target in LAC.

Pseudomonas is one the best studied bacterial genera, and it is the genus with the highest number of species among the gram-negative bacteria. Pseudomonas spp. are widely distributed and play relevant ecological roles; several species are commensal or pathogenic to humans, animals and plants. The main aim of the present minireview is the discussion of how the Pseudomonas taxonomy has evolved with the development of bacterial taxonomy since the first description of the genus in 1894. We discuss how the successive implementation of novel methodologies has influenced the taxonomy of the genus and, vice versa, how the taxonomic studies developed in Pseudomonas have introduced novel tools and concepts to bacterial taxonomy. Current phylogenomic analyses of the family Pseudomonadaceae demonstrate that a considerable number of named Pseudomonas spp. are not monophyletic with P. aeruginosa, the type species of the genus, and that a reorganization of several genera can be foreseen. Phylogenomics of Pseudomonas, Azomonas and Azotobacter within the Pseudomonadaceae is presented as a case study. Five new genus names are delineated to accommodate five well-defined phylogenetic branches that are supported by the shared genes in each group, and two of them can be differentiated by physiological and ecological properties: the recently described genus Halopseudomonas and the genus Stutzerimonas proposed in the present study. Five former Pseudomonas species are transferred to Halopseudomonas and 10 species to Stutzerimonas., (Copyright © 2021 Elsevier GmbH. All rights reserved.)