Ferritin, inflammation, and iron deficiency in acute heart failure: evidence from the EDIFICA cohort.

BACKGROUND: Ferritin is commonly used to evaluate iron stores and guide therapeutic decisions regarding intravenous iron supplementation. However, in the context of AHF, inflammation-driven upregulation of ferritin might disrupt its correlation with iron stores, restricting iron bioavailability and potentially amplifying the inflammatory response. AIM: This study aims to assess the clinical and prognostic associations of ferritin levels in an AHF cohort and to determine whether the prognostic value of ferritin is influenced by the presence of infection, inflammatory activation, and other markers of iron deficiency. METHODS: The association between ferritin and clinical outcomes (180 days) in AHF was evaluated in a cohort of 526 patients from the EDIFICA registry. RESULTS: The median ferritin plasma concentration at admission was 180 pg/mL. Patients with higher ferritin levels at admission were predominantly men, exhibiting a high prevalence of chronic kidney disease and alcohol consumption, and presenting with lower blood pressure and a higher incidence of clinical infection. Higher ferritin levels were associated with increased risk of the composite of heart failure hospitalization or cardiovascular death (Tertile 2: HR 1.75; 95% CI 1.10-2.79; p = 0.017; Tertile 3: HR 1.79; 95% CI 1.08-2.97; p = 0.025), independently of classical HF prognostic factors, inflammatory and iron-related markers. No significant associations were found between admission serum iron or transferrin saturation tertiles, iron status categories, or guideline-defined iron deficiency (ID) criteria and the primary composite outcome. However, at discharge, patients who met the criteria for defective iron utilization, low iron storage, or guideline-defined ID had a lower risk of the composite endpoint compared to those with normal iron utilization or who did not meet the guideline-defined ID criteria, respectively. CONCLUSIONS: Elevated ferritin levels are independently associated with poor prognosis in AHF. Low ferritin levels are associated with a favorable outcome and do not carry significant value in identifying ID in this population.

Current management of inherited retinal degenerations in Portugal (IRD-PT survey).

Inherited retinal dystrophies/degenerations (IRDs) are the leading cause of visual impairment and incurable familial blindness in the Western world. Given the clinical and genetic heterogeneity, establishing a molecular diagnosis is especially relevant. The aim of this study was to perform the first nationwide survey to understand the prevalence and current management of IRDs in Portugal. A response was obtained from 26 healthcare providers (HCP) (76.5% response rate). Only 4 respondents reported not managing IRD patients. Most HCPs (68.1%) reported managing up to 100 patients, while three currently manage between 501 and 1000 patients. Based on the Portuguese population, an estimated IRD prevalence of 0.031%, i.e., about 1 in 3000 individuals, was calculated. In most HCPs (86.3%), most patients are adults, and non-syndromic retinitis pigmentosa is the most frequent diagnosis. Only 4 HCPs currently use the national, web-based IRD registry (IRD-PT). However, all but one respondent expressed interest in participating in such a registry. Genetic testing is available in 54.5%, with 58.3% HCPs reporting solved rates between 61-80%, but 4 to 9 months to get a genetic test result in 83.4% of cases. Based on this survey, the prevalence of biallelic RPE65-associated disease in Portugal is 0.00031%, i.e., approximately 1:300,000 individuals. Data from this study provide vital background information on national differences in the diagnosis and management of IRD patients. Nationwide implementation of the IRD-PT registry should be encouraged and supported to provide population-based reference data and to identify patients eligible for current and future therapies.

Micro-arc driven porous ZrO2 coating for tailoring surface properties of titanium for dental implants application.

Titanium (Ti) is an ideal material for dental implants due to its excellent properties. However, corrosion and mechanical wear lead to Ti ions and particles release, triggering inflammatory responses and bone resorption. To overcome these challenges, surface modification techniques are used, including micro-arc oxidation (MAO). MAO creates adherent, porous coatings on Ti implants with diverse chemical compositions. In this context, zirconia element stands out in its wear and corrosion properties associated with low friction and chemical stability. Therefore, we investigated the impact of adding zirconium oxide (ZrO2) to Ti surfaces through MAO, aiming for improved electrochemical and mechanical properties. Additionally, the antimicrobial and modulatory potentials, cytocompatibility, and proteomic profile of surfaces were investigated. Ti discs were divided into four groups: machined - control (cpTi), treated by MAO with 0.04 M KOH - control (KOH), and two experimental groups incorporating ZrO2 at concentrations of 0.04 M and 0.08 M, composing the KOH@Zr4 and KOH@Zr8 groups. KOH@Zr8 showed higher surface porosity and roughness, even distribution of zirconia, formation of crystalline phases like ZrTiO4, and hydrophilicity. ZrO2 groups showed better mechanical performance including higher hardness values, lower wear area and mass loss, and higher friction coefficient under tribological conditions. The formation of a more compact oxide layer was observed, which favors the electrochemical stability of ZrO2 surfaces. Besides not inducing greater biofilm formation, ZrO2 surfaces reduced the load of pathogenic bacteria evidenced by the DNA-DNA checkerboard analysis. ZrO2 surfaces were cytocompatible with pre-osteoblastic cells. The saliva proteomic profile, evaluated by liquid chromatography coupled with tandem mass spectrometry, was slightly changed by zirconia, with more proteins adsorbed. KOH@Zr8 group notably absorbed proteins crucial for implant biological responses, like albumin and fibronectin. Incorporating ZrO2 improved the mechanical and electrochemical behavior of Ti surfaces, as well as modulated biofilm composition and provided suitable biological responses.

Use of autologous micrografts associated with xenogeneic anorganic bone in vertical bone augmentation procedures with Barbell Technique®.

INTRODUCTION: Bidirectional vertical ridge augmentation in the posterior maxilla is very challenging. PURPOSE: To evaluate the regenerative potential of micrografts, derived from periosteum or bone tissue, added to an anorganic xenograft in vertical reconstruction of the posterior maxilla, by a prospective, controlled study. MATERIALS AND METHODS: After clinical selection and the analysis of CBCT scans, 24 posterior maxillary sites, in 19 patients, were treated by using Barbell Technique®. Sites requiring both inlay and onlay reconstruction were enrolled in the study. In the Control Group (CG, n = 8), a xenograft was used in the inlay site and for the onlay site, a 1:1 mix of xenograft and an autograft was used. In Test Group 1 (TG1, n = 8), both inlay and onlay sites were grafted with the xenograft associated with the micrografts derived from periosteum. In Test Group 2 (TG2, n = 8), both inlay and onlay sites were grafted with the xenograft associated with the micrografts derived from bone. Six months after the procedures, CBCT scans were obtained, and bone biopsy samples were harvested during implant placement surgery. The bone specimens were analyzed histomorphometrically, by measuring the percentages of vital mineralized tissue (VMT), non vital mineralized tissue (NVMT) and non mineralized tissue (NMT). Immunohistochemically, the levels of VEGF were categorized by a score approach. RESULTS: Histomorphometric analysis revealed, for the inlay grafts, no significant difference among the groups for VMT, NVMT and NMT. However, for onlay grafts, CG achieved a higher amount of VMT in comparison with TG2, and the opposite occurred for NMT values. In this regard, no statistical difference was observed between CG and TG1. Concerning immunohistochemistry, the VEGF values for CG and TG1 were slightly higher than those obtained by TG2 for both inlay and onlay grafts, but without statistical significance. CBCT analysis showed a similar level of gain for all groups, for both inlay and onlay bone augmentation sites. Clinically, one implant (in CG) within a total of 50 implants installed, had early failure and was replaced after 3 months. All patients received implant supported prosthesis. CONCLUSION: This study indicated that the clinical use of micrograft derived from periosteum may have some potential to increase bone formation in onlay reconstructions, unlike the micrograft derived from bone tissue.

SGLT2 inhibitors and kidney outcomes across the spectrum of kidney disease: a systematic review and meta-analysis.

BACKGROUND: SGLT2 inhibitors have shown to reduce clinically meaningful kidney outcomes in individuals with chronic kidney disease at high risk for adverse outcomes. The effect of these agents in preventing clinically meaningful kidney outcomes in populations at lower risk remain uncertain. We aim to evaluate the effect of SGLT2 inhibitors on kidney outcomes across the Kidney Disease: Improving Global Outcomes (KDIGO) classification and urinary albumin-to-creatinine ratio (UACR) levels. METHODS: We have searched MEDLINE (PubMed), EMBASE and the Cochrane Central Register of Controlled Trials from inception up to August 8th, 2023. In pairs, researchers selected large (≥500 subjects per arm) randomized placebo-controlled trials of SGLT2 inhibitors, with a minimum duration of one year. Researchers independently extracted study-level data and assessed within-study risk of bias with the RoB 2.0 tool and quality of evidence with GRADE. RESULTS: We included 10 trials, encompassing 78,184 participants and a median follow-up of 2.7 years. Risk of bias was overall low. We performed meta-analyses summarizing individual study hazard ratios (HR) and 95% confidence intervals (CI) using a random-effects model. SGLT2 inhibitors reduced the composite kidney outcome across all KDIGO (HR [95% CI]: low 0.48 [0.32-0.71], moderate 0.60 [0.39-0.93], high 0.59 [0.47-0.74], very high 0.59 [0.49-0.72]) and UACR (HR [95% CI]: <30 mg/g 0.62 [0.50-0.78], ≥30 ≤300 mg/g 0.80 [0.67-0.96], >300 mg/g 0.61 [0.52-0.73]) groups, without evidence of heterogeneity between groups. LIMITATIONS: Small proportion of subjects without diabetes in low-risk groups and lack of standardization of composite outcomes. CONCLUSIONS: SGLT2 inhibitors consistently reduce kidney outcomes across the spectrum of KDIGO classes and UACR levels.

Hypothyroidism alters the rhythmicity of the central clock, body temperature and metabolism: evidence of Bmal1 transcriptional regulation by T3.

In mammals, the central circadian oscillator is located in the suprachiasmatic nucleus (SCN). Hypothalamus-pituitary-thyroid axis components exhibit circadian oscillation, regulated by both central clock innervation and intrinsic circadian clocks in the anterior pituitary and thyroid glands. Thyroid disorders alter the rhythmicity of peripheral clocks in a tissue-dependent response; however, whether these effects are influenced by alterations in the master clock remains unknown. This study aimed to characterize the effects of hypothyroidism on the rhythmicity of SCN, body temperature (BT) and metabolism, and the possible mechanisms involved in this signalling. C57BL/6J adult male mice were divided into Control and Hypothyroid groups. Profiles of spontaneous locomotor activity (SLA), BT, oxygen consumption ( V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ) and respiratory quotient (RQ) were determined under free-running conditions. Clock gene expression, and neuronal activity of the SCN and medial preoptic nucleus (MPOM) area were investigated in light-dark (LD) conditions. Triiodothyronine (T3) transcriptional regulation of Bmal1 promoter activity was evaluated in GH3-transfected cells. Hypothyroidism delayed the rhythmicity of SLA and BT, and altered the expression of core clock components in the SCN. The activity of SCN neurons and their outputs were also affected, as evidenced by the loss of circadian rhythmicity in V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ and RQ and alterations in the neuronal activity pattern of MPOM. In GH3 cells, T3 increased Bmal1 promoter activity in a time-dependent manner. Thyroid hormone may act as a temporal cue for the central circadian clock, and the uncoupling of central and peripheral clocks might contribute to a wide range of metabolic and thermoregulatory impairments observed in hypothyroidism. KEY POINTS: Hypothyroidism alters clock gene expression in the suprachiasmatic nucleus (SCN). Thyroid hypofunction alters the phase of spontaneous locomotor activity and body temperature rhythms. Thyroid hormone deficiency alters the daily pattern of SCN and medial preoptic nucleus neuronal activities. Hypothyroidism alterations are extended to daily oscillations of oxygen consumption and metabolism, which might contribute to the development of metabolic syndrome. Triiodothyronine increases Bmal1 promoter activity acting as temporal cue for the central circadian clock.

Cardiovascular phenotypes in type 2 diabetes: Latent class analysis of the CANVAS Program and CREDENCE trial.

AIM: To identify unique clinical phenotypes in type 2 diabetes (T2D) and investigate their treatment response to canagliflozin using latent class analysis. METHODS: This was a pooled latent class analysis of the individuals in the CANVAS Program and CREDENCE trial. The co-primary endpoints were hospitalization for heart failure (HHF) and the composite of cardiovascular death (CVD) or HHF. Secondary endpoints included three-point major adverse CV events, its individual components, and all-cause mortality. We completed Cox proportional hazards models to evaluate the effect of canagliflozin across phenotypes. RESULTS: Four distinct phenotypes were identified: Phenotype 1 (n = 966, 6.6%), with the lowest prevalence of heart failure, kidney dysfunction and hypertension; Phenotype 2 (n = 4169, 28.7%), primarily comprising females with a high prevalence of atherosclerotic vascular disease (ASCVD); Phenotype 3 (n = 7108, 48.9%), predominately males with a high prevalence of ASCVD; and Phenotype 4 (n = 2300, 15.8%), possessing the highest prevalences of HF and renal dysfunction. A hierarchical increase in the risk of the primary endpoint was observed across the phenotypes, with the highest CV risk observed for Phenotype 4 (hazard ratio for HHF: 7.57 [95% CI: 4.19-13.69]). Canagliflozin significantly reduced HHF and the composite CVD or HHF across phenotypes (all P values for interaction > .05). CONCLUSION: We identified four clinically distinct T2D phenotypes with differential CV risks. Canagliflozin reduced the risk of CV events, irrespective of the phenotype, emphasizing its broad therapeutic acceptability.

Predictive value of follow-up infarct volume on functional outcomes in middle cerebral artery M2 segment vessel occlusion stroke treated with mechanical thrombectomy.

BACKGROUND: Medium vessel occlusion (MeVO) strokes, particularly affecting the M2 segment of the middle cerebral artery, represent a critical proportion of acute ischemic strokes, posing significant challenges in management and outcome prediction. The efficacy of mechanical thrombectomy (MT) in MeVO stroke may warrant reliable predictors of functional outcomes. This study aimed to investigate the prognostic value of follow-up infarct volume (FIV) for predicting 90-day functional outcomes in MeVO stroke patients undergoing MT. METHODS: This multicenter, retrospective cohort study analyzed data from the Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy (MAD-MT) registry, covering patients with acute ischemic stroke due to M2 segment occlusion treated with MT. We examined the relationship between 90-day functional outcomes, measured by the modified Rankin Scale (mRS), and follow-up infarct volume (FIV), assessed through CT or MRI within 12-36 h post-MT. RESULTS: Among 130 participants, specific FIV thresholds were identified with high specificity and sensitivity for predicting outcomes. A FIV ⩽5 ml was highly specific for predicting favorable and excellent outcomes. The optimal cut-off for both prognostications was identified at ⩽15 ml by the Youden Index, with significant reductions in the likelihood of favorable outcomes observed above a 40 ml threshold. Receiver Operator Curve (ROC) analyses confirmed FIV as a superior predictor of functional outcomes compared to traditional recanalization scores, such as final modified thrombolysis in cerebral infarction score (mTICI). Multivariable analysis further highlighted the inverse relationship between FIV and positive functional outcomes. CONCLUSIONS: FIV within 36 h post-MT serves as a potent predictor of 90-day functional outcomes in patients with M2 segment MeVO strokes. Establishing FIV thresholds may aid in the prognostication of stroke outcomes, suggesting a role for FIV in guiding post intervention treatment decisions and informing clinical practice. Future research should focus on validating these findings across diverse patient populations and exploring the integration of FIV measurements with other clinical and imaging markers to enhance outcome prediction accuracy.

Reaffirmation of Mechanistic Proteomic Signatures Accompanying SGLT2 Inhibition in Patients With Heart Failure: A Validation Cohort of the EMPEROR Program.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert a distinctive pattern of direct biological effects on the heart and kidney under experimental conditions, but the meaningfulness of these signatures for patients with heart failure has not been fully defined. OBJECTIVES: We performed the first mechanistic validation study of large-scale proteomics in a double-blind randomized trial of any treatment in patients with heart failure. METHODS: In a discovery cohort from the EMPEROR (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and Reduced Ejection Fraction) program, we studied the effect of randomized treatment with placebo or empagliflozin on 1,283 circulating proteins in 1,134 patients with heart failure with a reduced or preserved ejection fraction. In a validation cohort, we expanded the number to 2,155 assessed proteins, which were measured in 1,120 EMPEROR participants who had not been studied previously. RESULTS: In the validation cohort, 25 proteins were the most differentially enriched by empagliflozin (ie, ≥15% between-group difference and false discovery rate <1% at 12 weeks with known effects on the heart or kidney): 1) 13 proteins promote autophagy and other cellular quality-control functions (IGFBP1, OTUB1, DNAJB1, DNAJC9, RBP2, IST1, HSPA8, H-FABP, FABP6, ATPIFI, TfR1, EPO, IGBP1); 2) 12 proteins enhance mitochondrial health and ATP production (UMtCK, TBCA, L-FABP, H-FABP, FABP5, FABP6, RBP2, IST1, HSPA8, ATPIFI, TfR1, EPO); 3) 7 proteins augment cellular iron mobilization or erythropoiesis (TfR1, EPO, IGBP1, ERMAP, UROD, ATPIF1, SNCA); 4) 3 proteins influence renal tubular sodium handling; and 5) 9 proteins have restorative effects in the heart or kidneys, with many proteins exerting effects in >1 domain. These biological signatures replicated those observed in our discovery cohort. When the threshold for a meaningful between-group difference was lowered to ≥10%, there were 58 additional differentially enriched proteins with actions on the heart and kidney, but the biological signatures remained the same. CONCLUSIONS: The replication of mechanistic signatures across discovery and validation cohorts closely aligns with the experimental effects of SGLT2 inhibitors. Thus, the actions of SGLT2 inhibitors-to promote autophagy, restore mitochondrial health and production of ATP, promote iron mobilization and erythropoiesis, influence renal tubular ion reabsorption, and normalize cardiac and renal structure and function-are likely to be relevant to patients with heart failure. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction [EMPEROR-Preserved], NCT03057951; EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced], NCT03057977).

Efficacy, safety, and impact of fluorescein in frameless stereotactic needle biopsies - a case series.

Stereotactic needle biopsy stands as a crucial method for diagnosing intracranial lesions unsuitable for surgical intervention. Nonetheless, the potential for sampling errors lead to innovative approaches to enhance diagnostic precision. This study contrasts the outcomes of patients undergoing fluorescein-assisted frameless stereotactic needle biopsy with those receiving traditional biopsies to evaluate the impact on diagnostic accuracy and safety. This study included patients with contrast-enhancing intracranial lesions, comprising a prospective group undergoing fluorescein-assisted biopsies and a retrospective group undergoing conventional biopsies at the same institution. We've collected data on demographics, procedural specifics, diagnostic outcomes, and postoperative events. A comparative analysis involved 43 patients who received fluorescein-assisted biopsies against 77 patients who underwent conventional biopsies. The average age was 60.5 years. The fluorescein group exhibited a 93% success rate in diagnosis, markedly higher than the 70.1% in the non-fluorescein group (OR = 5.67; 95%IC: 1.59-20.24; p < 0.01). The rate of complications was statistically similar across both cohorts. Despite its established value, stereotactic needle biopsy is susceptible to inaccuracies and complications. The application of fluorescence-based adjuncts like 5-ALA and fluorescein has been investigated to improve diagnostic fidelity and reduce risks. These technologies potentially minimize the necessity for multiple biopsies, decrease surgical duration, and provide immediate verification of tumor presence. Fluorescein-assisted stereotactic biopsy emerges as an effective, secure alternative to conventional methods.

First report of the association between Wolbachia and Cotesia flavipes (Hymenoptera: Braconidae): effect on life history parameters of the parasitoid.

The symbiosis between microorganisms and host arthropods can cause biological, physiological, and reproductive changes in the host population. The present study aimed to survey facultative symbionts of the genera Wolbachia, Arsenophonus, Cardinium, Rickettsia, and Nosema in Cotesia flavipes (Cameron) (Hymenoptera: Braconidae) and Diatraea saccharalis (Fabricius) (Lepidoptera: Crambidae) in the laboratory and evaluate the influence of infection on the fitness of these hosts. For this purpose, 16S rDNA primers were used to detect these facultative symbionts in the host species, and the hosts' biological and morphological features were evaluated for changes resulting from the infection caused by these microorganisms. The bacterial symbionts studied herein were not detected in the D. saccharalis samples analysed, but the endosymbiont Wolbachia was detected in C. flavipes and altered the biological and morphological aspects of this parasitoid insect. The results of this study may help to elucidate the role of Wolbachia in maintaining the quality of populations/lineages of C. flavipes.

Polymyxin B adjuvants against polymyxin B- and carbapenem-resistant Gram-negative bacteria.

Aim: Polymyxin B (PMB) is one of the few therapeutic options for treating infections caused by carbapenem-resistant Gram-negative bacteria (CR-GNB). However, the emergence of PMB-resistant CR-GNB strains has prompted the exploration of antibiotic adjuvants as potential therapeutic avenues. Thus, this study evaluates the potential of 3,5-dinitrobenzoic acid derivatives (DNH01, DNH11, DNH13 and DNH20) and isoniazid-N-acylhydrazones (INZ1-7, INZ9 and INZ11) as adjuvants to enhance PMB efficacy against CR-GNB.Materials & methods: MIC, MBC and drug combination assays were conducted using multidrug-resistant clinical isolates of Enterobacterales and Acinetobacter baumannii. In addition, the effects of PMB and PMB + DNH derivatives were assessed through flow cytometry and scanning electron microscopy (SEM).Results: DNH01, DNH11 and DNH20, unlike the INH-acylhydrazones, significantly restored PMB activity (MIC ≤ 2 µg/ml) in 80% of the tested isolates. Flow cytometry and SEM assays confirmed that DNH derivatives rescued the activity of PMB, yielding results comparable to those expected for PMB alone but at 256-fold lower concentrations.Conclusion: These findings suggest DNH derivatives hold substantial promise as PMB adjuvants to combat PMB-resistant CR-GNB infections.

[Box: see text].

From the mechanism of action to clinical management: A review of cardiovascular toxicity in adult treated with CAR-T therapy.

Chimeric antigen receptor T-cell therapy represents an innovative approach to immunotherapy and currently stands out, particularly for oncohematological patients refractory to traditional treatments. Ongoing trials are further expanding its clinical use for new oncological and non-oncological indications, potentially leading to newer treatment options soon. This new approach, however, also presents challenges, including cardiovascular toxicity. Little is reported in pivotal studies, and some recent retrospective observations suggest a non-negligible incidence of side effects with presentation ranging from mild adverse cardiovascular events to fatal complications in which, in most cases, there is a direct or indirect association with cytokine release syndrome. In this literature review, the hypotheses of an important interface between cytokine release syndrome and cardiotoxicity by chimeric antigen receptor T-cell therapy will be addressed, as will current knowledge about risk factors for cardiotoxicity and recommendations for pre-therapy evaluation, post-infusion monitoring and clinical management of these complications.

Convergence of mcr-1 and broad-spectrum ß-lactamase genes in Escherichia coli strains from the environmental sector.

The mcr-type gene encodes the main plasmid-mediated mechanism of colistin resistance and has been reported in several bacterial species obtained from different sources. Anthropogenic activities in the environment favor the evolution of antimicrobial resistance. Indeed, mcr-1-positive Escherichia coli strains were susceptible to non-polymyxins antimicrobials, but now emerging as multidrug-resistant (MDR) lineages. In this regard, hundreds of surface water and agricultural soil samples were screened for the presence of E. coli carrying the mcr-type genes and mcr-1-positive strains were subjected to in-depth genomic analysis. Almost all colistin-resistant strains were classified as MDR, highlighting those obtained from soils that showed resistance to extended-spectrum cephalosporins and carbapenems. International and high-risk clones of E. coli were identified, with ST10 and ST1720 shared between water and soil samples. Resistome analysis showed a broad resistome (AMR, metal tolerance, and biocide resistance). The mcr-1.1 and mcr-1.26 allelic variants were detected on IncX4 and IncI2 plasmids. Curiously, mcr-1-positive E. coli strains from agricultural soils harbored plasmid-mediated blaCTX-M-1, blaCTX-M-8, or blaKPC-2 genes. Virulome analysis demonstrated traits of a high putative virulence potential, with the presence of extraintestinal pathogenic E. coli. Comparative analysis revealed the persistence and dissemination of plasmid-mediated antimicrobial resistance genes in genetically diversity E. coli strains at the human-animal-environmental interface. These findings demonstrate a possible emerging AMR trend with the convergence of resistance to colistin and broad-spectrum ß-lactams in environmental-derived E. coli strains.

The curious case of the rare Citrobacter pasteurii isolated from an endangered primate in Brazil.

The genus Citrobacter comprises clinically important human pathogens but has been less frequently associated with wildlife infections. Citrobacter pasteurii was first identified as causing human diarrhea and remains rarely documented. In this study, a Gram-negative bacterial strain, named A318, was identified as causing diarrhea in a black lion tamarin. This strain was biochemically identified as Trabulsiella guamensis, a species of unusual nature, and was submitted to whole-genome characterization. Curiously, phylogenomic analysis showed that A318 strain belonged to the genus Citrobacter, with confirmation of the species C. pasteurii by average nucleotide identity (99.02 %) and digital DNA-DNA hybridization (93.80 %) analyzes. Cases of misidentification of C. pasteurii as Citrobacter youngae were detected and corrected in this study. In addition to the genome sequence of the type strain of C. pasteurii, only two others from the Australian cockle and Portuguese silver gull are publicly available. Single nucleotide polymorphism differences among all C. pasteurii indicated a highly diverse population. No acquired antimicrobial resistance genes and plasmid replicons were found. Therefore, our findings emphasize the importance of gold-standard methods for accurate identification and underscores the importance of continued surveillance and research to mitigate the risks posed by zoonotic and zooanthroponotic pathogens.

Mechanical Thrombectomy Versus Intravenous Thrombolysis in Distal Medium Vessel Acute Ischemic Stroke: A Multinational Multicenter Propensity Score-Matched Study.

Background and Purpose: The management of acute ischemic stroke (AIS) due to distal medium vessel occlusion (DMVO) remains uncertain, particularly in comparing the effectiveness of intravenous thrombolysis (IVT) plus mechanical thrombectomy (MT) versus IVT alone. This study aimed to evaluate the safety and efficacy in DMVO patients treated with either MT-IVT or IVT alone. Methods: This multinational study analyzed data from 37 centers across North America, Asia, and Europe. Patients with AIS due to DMVO were included, with data collected from September 2017 to July 2023. The primary outcome was functional independence, with secondary outcomes including mortality and safety measures such as types of intracerebral hemorrhage. Results: The study involved 1,057 patients before matching, and 640 patients post-matching. Functional outcomes at 90 days showed no significant difference between groups in achieving good functional recovery (modified Rankin Scale 0-1 and 0-2), with adjusted odds ratios (OR) of 1.21 (95% confidence interval [CI] 0.81 to 1.79; P=0.35) and 1.00 (95% CI 0.66 to 1.51; P>0.99), respectively. Mortality rates at 90 days were similar between the two groups (OR 0.75, 95% CI 0.44 to 1.29; P=0.30). The incidence of symptomatic intracerebral hemorrhage was comparable, but any type of intracranial hemorrhage was significantly higher in the MT-IVT group (OR 0.43, 95% CI 0.29 to 0.63; P<0.001). Conclusion: The results of this study indicate that while MT-IVT and IVT alone show similar functional and mortality outcomes in DMVO patients, MT-IVT presents a higher risk of hemorrhagic complications, thus MT-IVT may not routinely offer additional benefits over IVT alone for all DMVO stroke patients. Further prospective randomized trials are needed to identify patient subgroups most likely to benefit from MT-IVT treatment in DMVO.

R-954, a bradykinin B1 receptor antagonist, as a potential therapy in a preclinical endometriosis model.

Endometriosis is a gynecological condition characterized by the growth of endometrium-like tissues outside of the uterine cavity. Currently available drugs are efficacious in treating endometriosis-related pain, however it's not a targeted treatment. The aim of this work is to evaluate the effects of R-954, a bradykinin B1 receptor antagonist, in a murine model of endometriosis. The model was induced in animals through autologous transplantation of part of the uterine horn. After 51 days, it was observed that implants developed into endometriotic lesions. The administration of R-954 or progesterone, for 15 consecutive days, prevented the progression of cyst development, reduced the size and weight of the cysts. Both treatments also reduced cellular infiltrate and production of inflammatory mediators (interleukin-1ß, interleukin-6, tumor necrosis factor). However, only R-954 decreased angiogenic factors (VEGF and VEGF receptor). In addition, treatment with the antagonist did not interfere in the females' estrous cycle, as well as prevented gestational losses (reduction in the number of intermediate resorptions in pregnant females with endometriosis). Data suggested that R-954 has anti-inflammatory and anti-angiogenic effects; does not influence the estrous cycle; and prevents the number of gestational losses suggesting it as a good candidate for endometriosis treatment.