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Somatic cell nuclear transfer, an important approach for the analysis of certain functional changes in the genome during differentiation and for many practical applications, is in general a low-efficiency procedure, mainly due to a low effectivity in the re-establishment of the developmental program in the reconstructed embryo. The process of reprogramming is, however, poorly understood and some additional studies are clearly necessary. The aim of this study was the ultrastructural and immunofluorescent (B23-nucleophosmin) evaluation of somatic (cumulus) cell nuclei reprogramming after their transfer into intact immature mouse oocytes, kept at the germinal vesicle (GV) stage (dbcAMP) during the whole culture. Control somatic cells and nuclear transfer-reconstructed embryos (1 and 24 h after fusion induced by polyethyleneglycol) were fixed for transmission electron mcroscopy (TEM) in 2.5% glutaraldehyde, post-fixed in 1% OsO4, dehydrated through an ethanol series, and embedded in epoxy resin. Finally, ultrathin sections were stained with uranyl acetate followed by lead citrate. The above reagents were purchased from Electron Microscopy Sciences (Hatfield, PA, USA). In parallel, we have evaluated immunocytochemically the pattern of B23 labelling in intact and reconstructed cells. The samples were fixed in 4% paraformaldehyde, incubated with an antibody against B23 (Santa Cruz, CA, USA) and then with a biotinylated secondary antibody, and detected by fluorescein isothiocyanate (FITC)-coupled Streptavidin (Jackson ImmunoResearch, Cambridgeshire, UK). Mouse cumulus cells (12/12) contain a reticulated fibrillogranular nucleolus. The cell are also positively labeled with the anti-B23 antibody. One hour after fusion, the introduced nuclei displayed shape modifications and nuclear envelope irregularities, whereas the nucleolus still showed the typical fibrillar pattern (19/19). The volume of transferred nuclei remains unchanged. Interestingly, while the oocyte nucleolus remains negative for B23, the nucleoli in transferred somatic cells were always positively labeled (45 cells). After 24 h, the transferred nuclei increased their volume up to two-three times and displayed an irregular shape with nucleoli still possessing the unchanged reticulated pattern (17/17). As in the previous experimental interval, only the somatic cell nucleus remained labeled with the anti-B23 antibody (52 cells). The GV oocyte nucleoli remained unchanged during the whole culture period, exhibiting the typical dense-fibrillar pattern. Our results showed that the immature oocyte cytoplasm possesses a limited remodelling activity. Interestingly, the evident increase in volume of transferred somatic cells indicated some changes but TEM morphology and B23 labeling pattern remained basically unchanged. We cannot, however, exclude the beneficial effect upon reprogramming if these nuclei were subsequently used for the transfer into definitive cytoplasts.This work was supported by ESF STE/05/E004. [ABSTRACT FROM AUTHOR]

Two vaccines are available to prevent serogroup B meningococcal disease, i.e. the four-component meningococcal serogroup B vaccine (4CMenB) and the bivalent-factor-H-binding-protein meningococcal serogroup B vaccine (MenB-fHbp). Currently, 4CMenB is offered as part of routine infant immunization schedules. Available immunogenicity data showed a progressive decline in protective serum bactericidal antibodies (SBA) titers, with a re-enhancement following a booster dose during infancy. Responses did not seem to be long-lasting and vaccinated individuals might be at risk of meningococcal diseases duriṇg adolescence. Only one study evaluated the possibility to administer a single booster dose to immunocompetent adolescents who received a primary series during infancy. Despite a high proportion of enrollees achieving protective SBA levels 28 days post-booster, titers tended to decrease 1 year after. Immunocompetent adolescents who received a primary series and a booster during the first two years of life might rather benefit from re-vaccination against MenB; current evidence does not support the possibility of a booster.

Background: Sex may impact clinical outcomes in patients with stroke treated with dual antiplatelet therapy (DAPT). We aimed to investigate the sex differences in the short-term outcomes of DAPT within a real-world population of patients with noncardioembolic mild-to-moderate ischemic stroke or high-risk transient ischemic attack., Methods: We performed a propensity score-matched analysis from a prospective multicentric cohort study (READAPT [Real-Life Study on Short-Term Dual Antiplatelet Treatment in Patients With Ischemic Stroke or Transient Ischemic Attack]) by including patients with noncardioembolic mild-to-moderate stroke (National Institutes of Health Stroke Scale score of 0-10) or high-risk transient ischemic attack (age, blood pressure, clinical features, duration of transient ischemic attack, presence of diabetes [ABCD 2 ] ≥4) who initiated DAPT within 48 hours of symptom onset. The primary effectiveness outcome was the 90-day risk of new ischemic stroke or other vascular events. The secondary effectiveness outcomes were the 90-day modified Rankin Scale score ordinal shift, vascular and all-cause mortality, and 24-hour early neurological improvement or deterioration. The safety outcomes included the 90-day risk of moderate-to-severe and any bleeding, symptomatic intracranial hemorrhage, and 24-hour hemorrhagic transformation. Outcomes were compared between sexes using Cox and generalized ordinal logistic regression analyses, along with calculating risk differences and ratios., Results: From 2278 patients in the READAPT study cohort, we included 1643 mild-to-moderate strokes or high-risk transient ischemic attacks treated with DAPT (mean age, 69.8±12.0 years; 34.3% women). We matched 531 women and men. The 90-day risk of new ischemic stroke or other vascular events was significantly lower among women than men (hazard ratio, 0.53 [95% CI, 0.28-0.99]; P =0.039). There were no significant differences in secondary effectiveness outcomes. The 90-day risk of safety outcomes was extremely low and did not differ between women and men (moderate-to-severe bleedings: 0.4% versus 0.8%; P =0.413; symptomatic intracranial hemorrhage: 0.2% versus 0.4%; P =0.563). Subgroup analysis for primary effectiveness outcome showed a lower 90-day risk of new ischemic stroke or other vascular events among women aged <50 years, baseline National Institutes of Health Stroke Scale score of 0 to 5, prestroke modified Rankin Scale score <2, large artery atherosclerosis cause, and no diabetes., Conclusions: Our findings suggest that women with noncardioembolic mild-to-moderate stroke or high-risk transient ischemic attack treated with DAPT may have lower short-term risk of recurrent ischemic events than men. Further research is needed to understand the mechanisms behind potential sex-based differences in outcomes after DAPT use., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05476081.

Background: Recent studies have challenged the notion that patients with brain metastasis (BM) or leptomeningeal metastasis (LM) should be excluded from systemic therapy clinical trials. This scoping study summarizes the BM/LM clinical studies published between 2010 and 2023., Methods: MEDLINE, CINAHL, CAB Abstracts, PsycINFO, Cochrane Library, HINARI, International Pharmaceutical Abstracts, PubMed, Scopus, Web of Science, and EMBASE electronic databases were searched on June 21, 2021. An updated search was performed on February 21, 2023. Eligible studies investigated a therapeutic intervention in solid tumor patients with BM and/or LM and reported a patient outcome. Extracted study-level data, including study type, publication date, geographical location, number of BM/LM patients in the study, primary tumor type, and type of therapeutic intervention, were collected., Results: 4921 unique studies were eligible for analysis. The key finding is that BM/LM clinical research is expanding globally, both in observational studies and clinical trials. Despite the shift over time toward a higher proportion of systemic therapy trials, the majority still do not include patients with symptomatic disease and lack reporting of BM/LM-specific endpoints. Globally, there has been a trend to more international collaboration in BM/LM clinical studies., Conclusions: Our analysis of the BM/LM literature charts the evolving landscape of studies involving this previously excluded population. Given the increasing clinical research activity, particularly involving late-stage systemic therapy trials, it is imperative that due consideration is given to the intracranial activity of new investigational agents. Wider adoption of standardized reporting of intracranial-specific endpoints will facilitate the evaluation of relative intracranial efficacy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Smoker's paradox usually refers to the observation of a favorable outcome of smoking patients in acute myocardial infarction., Methods: From April 2006 to December 2018 a population of 2456 patients with ST segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI) were prospectively enrolled in the MATRIX registry. Ischemic time, clinical, demographics, angiographic data, and 1-year follow-up were collected., Results: Among 2546 patients admitted with STEMI, 1007 (41 %) were current smokers. Smokers were 10 years younger and had lower crude in-hospital and 1-year mortality (1.5 % vs 6 %, p < 0.0001 and 5 % vs 11 %, p < 0.0001), shorter ischemic time (203 [147-299] vs 220 [154-334] minutes, p = 0.002) and shorter decision time (60 [30-135] vs 70 [36-170] minutes, p = 0.0063). Smoking habit [OR:0.37(95 % CI:0.18-0.75)-p < 0.01], younger age [OR 1.06 (95%CI:1.04-1.09)-p < 0.001] and shorter ischemic time [OR:1.01(95%CI:1.01-1.02)-p < 0.05] were associated to lower in-hospital mortality. Only smoking habit [HR:0.65(95 % CI: 0.44-0.9)-p = 0.03] and younger age [HR:1.08 (95%CI:1.06-1.09)-p < 0.001] were also independently associated to lower all-cause death at 1-year follow-up. After propensity matching, age, cardiogenic shock and TIMI flow <3 were associated with in-hospital mortality, while smoking habit was still associated with reduced mortality. Smoking was also associated with reduced mortality at 1-year follow-up (HR 0.54, 95 % CI [0.37-0.78]; p < 0.001)., Conclusions: Smoking patients show better outcome after PCI for STEMI at 1-year follow-up. Although "Smoking paradox" could be explained by younger age of patients, other factors may have a role in the explanation of the phenomenon., Competing Interests: Declaration of competing interest Sergio Berti is proctor for St. Jude Medical and Edwards Lifesciences LLC. The remaining authors report no financial relationships or conflicts of interest regarding the con-tent herein., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Randomized controlled trials (RCTs) proved the efficacy of short-term dual antiplatelet therapy (DAPT) in secondary prevention of minor ischemic stroke or high-risk transient ischemic attack (TIA). We aimed at evaluating effectiveness and safety of short-term DAPT in real-world, where treatment use is broader than in RCTs., Methods: READAPT (REAl-life study on short-term Dual Antiplatelet treatment in Patients with ischemic stroke or Transient ischemic attack) (NCT05476081) was an observational multicenter real-world study with a 90-day follow-up. We included patients aged 18+ receiving short-term DAPT soon after ischemic stroke or TIA. No stringent NIHSS and ABCD 2 score cut-offs were applied but adherence to guidelines was recommended. Primary effectiveness outcome was stroke (ischemic or hemorrhagic) or death due to vascular causes, primary safety outcome was moderate-to-severe bleeding. Secondary outcomes were the type of ischemic and hemorrhagic events, disability, cause of death, and compliance to treatment., Results: We included 1920 patients; 69.9% started DAPT after an ischemic stroke; only 8.9% strictly followed entry criteria or procedures of RCTs. Primary effectiveness outcome occurred in 3.9% and primary safety outcome in 0.6% of cases. In total, 3.3% cerebrovascular ischemic recurrences occurred, 0.2% intracerebral hemorrhages, and 2.7% bleedings; 0.2% of patients died due to vascular causes. Patients with NIHSS score ⩽5 and those without acute lesions at neuroimaging had significantly higher primary effectiveness outcomes than their counterparts. Additionally, DAPT start >24 h after symptom onset was associated with a lower likelihood of bleeding., Conclusions: In real-world, most of the patients who receive DAPT after an ischemic stroke or a TIA do not follow RCTs entry criteria and procedures. Nevertheless, short-term DAPT remains effective and safe in this population. No safety concerns are raised in patients with low-risk TIA, more severe stroke, and delayed treatment start., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AZ reports compensation from Angels Initiative, Boehringer-Ingelheim, Daiichi Sankyo, CSL Behring, Bayer, and Astra Zeneca; and he is member of ESO guidelines, ISA-AII guidelines, and IRETAS steering committee. RO reports compensations from Novartis and Allergan, Teva Pharmaceutical Industries, Eli Lilly and Company, SS reports compensations from Novartis, NovoNordisk, Allergan, AstraZeneca, Pfizer Canada, Inc, Eli Lilly and Company, Teva Pharmaceutical Industries, H. Lundbeck A/S, and Abbott Canada; employment by Università degli Studi dell’Aquila. MPa reports compensation from Daiichi Sankyo Company, Bristol Myers Squibb, Bayer, and Pfizer Canada, Inc. DT reports compensation from Alexion, AstraZeneca, Medtronic, and Pfizer. The other authors report no conflicts.

Open-lung ventilation during cardiopulmonary bypass (CPB) in patients undergoing heart transplantation (HTx) is a potential strategy to mitigate postoperative acute respiratory distress syndrome (ARDS). We utilized an ovine HTx model to investigate whether open-lung ventilation during CPB reduces postoperative lung damage and complications. Eighteen sheep from an ovine HTx model were included, with ventilatory interventions randomly assigned during CPB: the OPENVENT group received low tidal volume (V T ) of 3 mL/kg and positive end-expiratory pressure (PEEP) of 8 cm H 2 0, while no ventilation was provided in the NOVENT group as per standard of care. The recipient sheep were monitored for 6 h post-surgery. The primary outcome was histological lung damage, scored at the end of the study. Secondary outcomes included pulmonary shunt, driving pressure, hemodynamics and inflammatory lung infiltration. All animals completed the study. The OPENVENT group showed significantly lower histological lung damage versus the NOVENT group (0.22 vs 0.27, p = 0.042) and lower pulmonary shunt (19.2 vs 32.1%, p = 0.001). In addition, the OPENVENT group exhibited a reduced driving pressure (9.6 cm H 2 O vs. 12.8 cm H 2 O, p = 0.039), lower neutrophil (5.25% vs 7.97%, p ≤ 0.001) and macrophage infiltrations (11.1% vs 19.6%, p < 0.001). No significant differences were observed in hemodynamic parameters. In an ovine model of HTx, open-lung ventilation during CPB significantly reduced lung histological injury and inflammatory infiltration. This highlights the value of an open-lung approach during CPB and emphasizes the need for further clinical evidence to decrease risks of lung injury in HTx patients., Competing Interests: Declarations. Ethics approval and consent to participate: The project was approved by Queensland University of Technology (QUT) Animal Ethics Committee (Approval #16-1109). Ratified by the University of Queensland AEC (QUT/393/17/QUT), experiments were performed in accordance with the National Health and Medical Research Council (NHMRC) Australian Code of Practice for the Care and Use of Animals for Scientific Purposes (8th Edition 2013), the Animal Care and Protection Act 2001 (QLD) and complied with the ARRIVE Guidelines. Consent for publication: Not applicable. Competing interests: Professor John Fraser is the CEO of the Quantum Medical Innovation Fund and De Motu Cordis Pty Limited. He is also the co-founder of BiVACOR™ Pty Ltd. In addition, Prof. Fraser and his research group collaborate with Australian Red Cross Lifeblood, Fisher and Paykel healthcare, Mallinckrodt Pharmaceuticals and CSL. Professor Fraser receives reimbursement for travel costs when presenting research created collaboration with Fisher and Paykel Healthcare. Professor David McGiffin provides consultancy services to Abbott. This has no direct impact on the contents of the manuscript. The other authors do not have any conflict of interest., (© 2024. Crown.)

Background: According to the literature, about one third of patients with brain ischemic symptoms lasting <24 hours, which are classified as TIAs according to the traditional "time-based" definition, show the presence of acute ischemic lesions at neuroimaging. Recent evidence has shown that the presence of acute ischemic lesions at neuroimaging may impact on the outcome of patients with transient ischemic symptoms treated with dual antiplatelet treatment (DAPT). This uncertainty is even more compelling in recent years as short-term DAPT has become the standard treatment for any non-cardioembolic TIA or minor ischemic stroke., Methods: This is a pre-specified subgroup analysis from a prospective multicenter real-world study (READAPT). The analysis included patients with time-based TIA - i.e. those with ischemic symptoms lasting <24 hours - who started DAPT. In the whole population, we assessed the presence of acute brain ischemic lesions at neuroimaging and their association with the ABCD2 score. To assess the impact of acute brain ischemic lesions on 90-day prognosis, we performed a propensity score matching of patients with and without those lesions. We adopted a primary effectiveness outcome which was a composite of new stroke/TIA events and death due to vascular causes at 90 days., Results: We included 517 patients - 324 (62.7%) male - with a median (interquartile range - IQR) age of 74 (IQR 65-81) years; 144 patients (27.9%) had acute brain ischemic lesions at neuroimaging. The proportion of patients with brain ischemic lesions did not vary according to the ABCD2 score. At follow-up, 4 patients with brain ischemic lesions (2.8%) and 21 patients without lesions (5.6%) reported the primary effectiveness outcome, which was similar between the groups before (p=0.178) and after matching (p=0.518)., Conclusions: In our population, patients with transient ischemic symptoms and acute ischemic lesions at brain MRI had a risk of recurrent ischemic events similar to those without lesions. The risk of recurrent ischemic events was low in both groups.

Background: Short-term dual antiplatelet treatment (DAPT) is superior to single antiplatelet treatment (SAPT) for secondary prevention in non-cardioembolic minor ischemic stroke and high-risk TIA. As the real-world use of DAPT is broader than in trials, it is important to clarify its benefit/risk profile in a diverse population., Methods: Post-hoc analysis of prospectively collected data from the READAPT cohort and 3 prospective stroke registries including patients with mild-to-moderate (National Institute of Health Stroke Scale [NIHSS] score 0-10) ischemic stroke receiving early DAPT or SAPT. The primary effectiveness outcome was 90-day return to pre-stroke neurological functioning using modified Rankin Scale (mRS) score. Secondary effectiveness outcomes were 90-day mRS shift, new ischemic stroke/TIA, vascular and all-cause death, 24-h early neurological improvement or deterioration. The safety outcome was 90-day intracranial hemorrhage., Results: We matched 1008 patients treated with DAPT and 1008 treated with SAPT. Compared to SAPT, patients treated with DAPT showed higher likelihood of 90-day primary effectiveness outcome (87.5% versus 84.4%, risk difference 3.1% [95%CI 0.1%-6.1%];p=0.047, risk ratio 1.03 [95%CI 1.01-1.07];p=0.043) and higher rate of 24-h early neurological improvement (25.3% versus 15.4%, risk difference 9.9% [95%CI 6.4%-13.4%];p<0.001, risk ratio 1.65 [95%CI 1.37-1.97];p<0.001). No differences were observed for other study outcomes. Subgroup analysis confirmed benefit of DAPT over SAPT for primary effectiveness outcome in patients with moderate stroke, those treated with intravenous thrombolysis and who received antiplatelet loading dose., Conclusions: Our findings suggest that DAPT use might be safe and more effective than SAPT even in the real-world and in patients who do not strictly fulfill criteria of landmark large clinical trials.

Background: Patients with HER2-positive breast cancer have a significant risk of developing brain metastases (BrM), which have detrimental effects on survival outcomes and quality of life. Although there are several systemic treatment options available that may delay the appearance of BrM and secondary progression of previously treated BrM, there are still substantial unmet needs for this patient population and primary prevention remains elusive., Methods: A group of experts created consensus statements, through a modified Delphi process, to bridge the gap between current unmet needs, available evidence, and international guidelines., Results: The steering committee reviewed all relevant literature and formed research questions to be answered by the subsequent consensus statements. In total, 61 contributors provided feedback on the consensus statements, with 34 statements reaching agreement out of the 55 statements that were voted on altogether. Statements with consensus aimed to define BrM primary and secondary prevention, screening procedures, assessment of symptoms, treatment efficacy, and preventing the occurrence and progression of BrM, while acknowledging the possibilities and limitations in daily clinical practice. Some statements did not reach agreement for a variety of reasons, mostly due to lack of evidence., Conclusions: The consensus statements outlined in this publication provide a point of reference for daily clinical practice and can act as recommendations for clinical trial procedures and future guidelines., 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 Ltd.. All rights reserved.)

Background: The outcomes of minor ischemic stroke resulting from small artery occlusion (SAO-MIS) have not yet been characterized after dual antiplatelet treatment (DAPT) has become the standard of care. We provided updated figures on the short-term prognosis of SAO-MIS treated with early short-term DAPT and compared the outcomes of SAO-MIS versus non-SAO-MIS patients., Methods: This is a prespecified sub-analysis from a prospective multicentric real-world study (READAPT, NCT05476081) including patients with minor (NIHSS≤5) non-cardioembolic ischemic stroke treated with DAPT. The primary outcome was a composite of 90-day symptomatic ischemic stroke or major cardiovascular events. Secondary outcomes were the 90-day ordinal distribution of modified Rankin Scale (mRS) scores, 90-day excellent functional outcome (mRS of 0 to 1), and 24-h early neurological deterioration (END). Safety outcomes were 90-day intracerebral hemorrhage, moderate-to-severe and any bleedings. All outcomes were compared between SAO-MIS and non-SAO-MIS patients., Results: We included 678 MIS, of whom 253 (37.3 %) were SAO-related. At 90 days, 3 patients with SAO-MIS had primary outcome (1.2 % [95 % CI 0.2 %-3.5 %]), which were all SAO-related ischemic strokes. For the secondary outcomes, most SAO-MIS patients (n = 191, 75.5 %) had 90-day excellent functional outcome and 12 had 24-h END (4.7 % [95 % CI 2.5 %-8.3 %]). Referring to safety outcomes, 90-day intracerebral hemorrhage occurred only in one patient with SAO-MIS (0.4 % [95 % CI 0.0 %- 2.2 %]). Compared to non-SAO-MIS, the 90-day risk of recurrent vascular events was significantly lower among SAO-MIS (aHR 0.24 [95 % CI 0.08-0.68]; p = 0.007), while there were not significant differences in other secondary outcomes, nor in the risk of safety events., Conclusions: Our findings show overall favorable short-term prognosis after SAO-MIS treated with DAPT. Future studies should investigate factors associated with residual stroke risk and long-term outcomes of SAO-MIS., Competing Interests: Declaration of competing interest Andrea Zini reports compensation from Angels Initiative, Boehringer-Ingelheim, Daiichi Sankyo for consultant services; from Angels Initiative, Boehringer-Ingelheim, CSL Behring for speaking honoraria or other education services; from Daiichi Sankyo for meeting; from Bayer, and Astra Zeneca for participation on a Data Safety, Monitoring Board or Advisory Board; and he is member of ESO guidelines, ISA-AII guidelines, and IRETAS steering committee. Raffaele Ornello reports grants from Novartis and Allergan; compensation from Teva Pharmaceutical Industries, Eli Lilly and Company, and Novartis for other services; and travel support from Teva Pharmaceutical Industries. Simona Sacco reports compensation from Novartis, NovoNordisk, Allergan, AstraZeneca, Pfizer Canada, Inc., Eli Lilly and Company, Teva Pharmaceutical Industries, H. Lundbeck A/S, and Abbott Canada for consultant services; employment by University of L'Aquila; and compensation from Novartis for other services. Maurizio Paciaroni reports compensation from Daiichi Sankyo Company, Bristol Myers Squibb, Bayer, and Pfizer Canada, Inc., for consultant services. Danilo Toni reports compensation from Alexion, Astra Zeneca, Medtronic, and Pfizer for consultant services and participation on a Data Safety, Monitoring Board or Advisory Board. The other authors report no conflicts., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Escherichia coli is the most common cause of human bloodstream infections and bacterial sepsis/septic shock. However, translation of preclinical septic shock resuscitative therapies remains limited mainly due to low-fidelity of available models in mimicking clinical illness. To overcome the translational barrier, we sought to replicate sepsis complexity by creating an acutely critically-ill preclinical bacterial septic shock model undergoing active 48-h intensive care management., Aim: To develop a clinically relevant large-animal (ovine) live-bacterial infusion model for septic shock., Methods: Septic shock was induced by intravenous infusion of the live antibiotic resistant extra-intestinal pathogenic E. coli sequence type 131 strain EC958 in eight anesthetised and mechanically ventilated sheep. A bacterial dose range of 2 × 10 5 -2 × 10 9  cfu/mL was used for the dose optimisation phase (n = 4) and upon dose confirmation the model was developed (n = 5). Post-shock the animals underwent an early-vasopressor and volume-restriction resuscitation strategy with active haemodynamic management and monitoring over 48 h. Serial blood samples were collected for testing of pro-inflammatory (IL-6, IL-8, VEGFA) and anti-inflammatory (IL-10) cytokines and hyaluronan assay to assess endothelial integrity. Tissue samples were collected for histopathology and transmission electron microscopy., Results: The 2 × 10 7  cfu/mL bacterial dose led to a reproducible distributive shock within a pre-determined 12-h period. Five sheep were used to demonstrate consistency of the model. Bacterial infusion led to development of septic shock in all animals. The baseline mean arterial blood pressure reduced from a median of 91 mmHg (71, 102) to 50 mmHg (48, 57) (p = 0.004) and lactate levels increased from a median of 0.5 mM (0.3, 0.8) to 2.1 mM (2.0, 2.3) (p = 0.02) post-shock. The baseline median hyaluronan levels increased significantly from 25 ng/mL (18, 86) to 168 ng/mL (86, 569), p = 0.05 but not the median vasopressor dependency index which increased within 1 h of resuscitation from zero to 0.39 mmHg -1 (0.06, 5.13), p = 0.065, and. Over the 48 h, there was a significant decrease in the systemic vascular resistance index (F = 7.46, p = 0.01) and increase in the pro-inflammatory cytokines [IL-6 (F = 8.90, p = 0.02), IL-8 (F = 5.28, p = 0.03), and VEGFA (F = 6.47, p = 0.02)]., Conclusions: This critically ill large-animal model was consistent in reproducing septic shock and will be applied in investigating advanced resuscitation and therapeutic interventions., (© 2024. The Author(s).)

Pets have a crucial role in cancer research. Specifically, dogs and cats share the same environment as their owners and thus may serve as sentinels of naturally occurring tumors that are linked to the exposure to environmental hazards. Quantitative comparison of tumor types may reveal unusual cancer frequencies, providing directions for research and generation of hypotheses of cancer causation in a specific area and identification of risk factors. The aim of this study was to describe the data collected by the pathology-based animal cancer registry, managed by Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise (IZSAM), during 10 years of activity (2014-2023) and to assess its potential epidemiological relevance. Frequencies of tumor topography and morphology in dogs and cats were described, analyzed and compared. Proportional morbidity ratios (PMRs) were calculated, taking into consideration some potential risk factors such as species, breed, sex, diet and living environment. The database comprises 5311 tumors (n = 4719 in dogs and n = 592 in cats), with a higher prevalence in females (67.3% in dogs and 61.2% in cats). The mean age at the first diagnosis of tumors was similar between sexes and slightly lower in dogs compared to cats. PMRs highlighted certain risk and "protective" factors for the development of tumors in specific topography. The risk of developing tumors of the blood and hematopoietic system (PMR = 0.44; 95% CI: 0.21-0.94), skin and subcutaneous tissues (PMR = 0.70; 95% CI: 0.61-0.80), oral cavity and pharynx (PMR = 0.60; 95% CI: 0.24-0.89), urinary organs (PMR = 0.33; 95% CI: 0.11-0.99) and bones, joints and cartilage (PMR = 0.72; 95% CI: 0.22-0.98) was lower in non-neutered male dogs than in neutered male dogs. Non-spayed female dogs had a greater risk of developing tumors of the mammary gland (PMR = 1.75; 95% CI: 1.57-1.96), female sexual organs (PMR = 2.12; 95% CI: 1.01-4.36) and respiratory system (PMR = 2.25; 95% CI: 1.55-6.74) but less risk for cutaneous and subcutaneous tissue tumors (PMR = 0.44; 95% CI: 0.38-0.51) and blood/hematopoietic system tumors (PMR = 0.47; 95% CI: 0.26-0.85) compared to spayed female dogs. Compared with mixed breed, purebred dogs had a significantly greater risk of developing mammary gland tumors (PMR = 1.36; 95% CI: 1.20-1.54) and lower risk for respiratory (PMR = 0.15; 95% CI: 0.07-0.32), gastrointestinal (PMR = 0.63; 95% CI: 0.34-0.94) and oral (PMR = 0.59; 95% CI: 0.36-0.96) neoplasia. Non-neutered male cats had a lower risk of developing skin and subcutaneous tumors (PMR = 0.68; 95% CI: 0.50-0.92) compared with neutered cats. The risk of developing skin and subcutaneous tissues tumors was higher for dogs and cats that lived mostly outdoor (PMR dogs = 1.21; 95% CI: 1.10-1.33; PMR cats = 1.18; 95% CI: 1.08-1.47), while dogs that live mainly indoor had a greater risk to develop mammary gland tumors (PMR = 0.78; 95% CI: 0.68-0.89). Results described herein highlight the fundamental role of animal cancer registration initiatives. These efforts would contribute to the possibility of conducting multicentric collaborative studies to deepen the knowledge of the epidemiology of tumors in dogs and cats from a comparative perspective, thus fulfilling the One Health approach.

We report the off-label application of the Castor single-branch stent graft for a complicated acute intramural haematoma involving the aortic arch. The endograft was deployed in zone 1 with the single branch in the left common carotid artery through a surgical left carotid and percutaneous right femoral artery access. The procedure was completed with the construction of a left carotid-subclavian bypass followed by plug embolization of the left subclavian artery., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: The commonest echocardiographic measurement, left ventricular ejection fraction, can not necessarily predict mortality of recipients following heart transplantation potentially due to afterload dependency. Afterload-independent left ventricular stroke work index (LVSWI) is alternatively recommended by the current guideline; however, pulmonary artery catheters are rarely inserted in organ donors in most jurisdictions. We propose a novel non-invasive echocardiographic parameter, Pressure-Strain Product (PSP), as a potential surrogate of catheter-based LVSWI. This study aimed to investigate if PSP could correlate with catheter-based LVSWI in an ovine model of brain stem death (BSD) donors. The association between PSP and myocardial mitochondrial function in the post-transplant hearts was also evaluated., Methods: Thirty-one female sheep (weight 47 ± 5 kg) were divided into two groups; BSD (n = 15), and sham neurologic injury (n = 16). Echocardiographic parameters including global circumferential strain (GCS) and global radial strain (GRS) and pulmonary artery catheter-based LVSWI were simultaneously measured at 8-timepoints during 24-h observation. PSP was calculated as a product of GCS or GRS, and mean arterial pressure for PSP circ or PSP rad , respectively. Myocardial mitochondrial function was evaluated following 6-h observation after heart transplantation., Results: In BSD donor hearts, PSP circ (n = 96, rho = .547, p < .001) showed the best correlation with LVSWI among other echocardiographic parameters. PSP circ returned AUC of .825 to distinguish higher values of cardiomyocyte mitochondrial function (cut-off point; mean value of complex 1,2 O 2 Flux) in post-transplant hearts, which was greater than other echocardiographic parameters., Conclusions: PSP circ could be used as a surrogate of catheter-based LVSWI reflecting mitochondrial function., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

In the first 2 wk after hatching, broiler chickens are vulnerable to enteric pathogens due to underdeveloped gastrointestinal and immune systems. Carvacrol has been reported to improve digestive and immune functions. This study aimed to optimize immune development of broiler chickens by delivering carvacrol in ovo. Effects of 2 in ovo treatments delivered at embryonic day (E)17.5 (saline or carvacrol) were evaluated at 3 stages (E19.5, hatch, and d 14 posthatch). Hatchability, performance parameters, lymphoid organ and yolk sac weights were determined. Histomorphology assessment was performed for jejunal samples at hatch and bursa of Fabricius samples at hatch and d 14. Gene expression of immune-relevant genes was determined for jejunal, bursal, and yolk sac samples over time. At hatch, BW was 0.85% lower (P = 0.02) after in ovo carvacrol delivery compared to the controls. Interactions between in ovo treatment and age were found for gene expression. At hatch, carvacrol treatment resulted in lower expression of proinflammatory cytokines IL-8 and IFN-γ in the yolk sac compared to the controls (P = 0.05 and < .001, respectively) suggesting a potential role for carvacrol-mediated immune modulation. At d 14, carvacrol treatment led to lower expression of proinflammatory cytokine IL-6 in the bursa compared to the controls (P = 0.002). In ovo carvacrol delivery led to bursal histomorphometric changes, including a larger cortex in the bursal follicles (P = 0.03), and a higher cortex/medulla ratio (P = 0.04) compared to the controls, indicating increased B-cell stimulation and maturation. Main effects were found for carvacrol treatment in the jejunum, with overall higher expression of proinflammatory mediators IL-1β and NF-κB, and anti-inflammatory IL-10 compared to the controls (P = 0.04, 0.02, and 0.02 respectively) from E19.5 to d 14. Age-related main effects showed various alterations in expression dynamics of immune-related genes across all tissues over time. Our findings suggest changes in immune parameters occur as the chicken develops, but these mostly do not interact with in ovo carvacrol treatment. In ovo carvacrol treatment alters immune activity of broiler chickens independent of age., Competing Interests: DISCLOSURES 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 Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Since 2019, Braile Biomédica® introduced a novel custom-made abdominal endograft tailored to the aorta's anatomy, featuring sizing every 3 mm and a diameter change from 50 mm to 8 mm. This design permits uncovered fenestrations around a single Z stent, eliminating the need for bridging stents to visceral vessels. Utilizing triple stent technology, optimal neck fixation is ensured, enabling treatment of necks shorter than 2 mm, with three 360° fenestrations optimizing graft fixation. This paper aims to analyze the initial experience with this custom-made infrarenal graft for abdominal aorta aneurysm (AAA), concerning procedural success and post-procedural short-term outcomes., Results: Among 12 patients treated from May 2022 to January 2024, technical success was achieved in 91.7 %, with only one intra-procedural complication. Follow-up CT scans at 1-3 months revealed resolution of an intraoperative endoleak and two late complications: a late type III endoleak and right renal artery occlusion., Conclusions: The recent experience with Braile Biomédica® custom-made abdominal endograft demonstrates promising outcomes, particularly in treating AAAs with challenging anatomical features., 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 Elsevier Inc. All rights reserved.)

Background: The optimal treatment for acute minor ischemic stroke is still undefined. and options include dual antiplatelet treatment (DAPT), intravenous thrombolysis (IVT), or their combination. We aimed to investigate benefits and risks of combining IVT and DAPT versus DAPT alone in patients with MIS., Methods and Results: This is a prespecified propensity score-matched analysis from a prospective multicentric real-world study (READAPT [Real-Life Study on Short-Term Dual Antiplatelet Treatment in Patients With Ischemic Stroke or Transient Ischemic Attack]). We included patients with MIS (National Institutes of Health Stroke Scale score at admission ≤5), without prestroke disability (modified Rankin scale [mRS] score ≤2). The primary outcomes were 90-day mRS score of 0 to 2 and ordinal mRS distribution. The secondary outcomes included 90-day risk of stroke and other vascular events and 24-hour early neurological improvement or deterioration (≥2-point National Institutes of Health Stroke Scale score decrease or increase from the baseline, respectively). From 1373 patients with MIS, 240 patients treated with IVT plus DAPT were matched with 427 patients treated with DAPT alone. At 90 days, IVT plus DAPT versus DAPT alone showed similar frequency of mRS 0 to 2 (risk difference, 2.3% [95% CI -2.0% to 6.7%]; P =0.295; risk ratio, 1.03 [95% CI 0.98-1.08]; P =0.312) but more favorable ordinal mRS scores distribution (odds ratio, 0.57 [95% CI 0.41-0.79]; P <0.001). Compared with patients treated with DAPT alone, those combining IVT and DAPT had higher 24-hour early neurological improvement (risk difference, 20.9% [95% CI 13.1%-28.6%]; risk ratio, 1.59 [95% CI 1.34-1.89]; both P <0.001) and lower 90-day risk of stroke and other vascular events (hazard ratio, 0.27 [95% CI 0.08-0.90]; P =0.034). There were no differences in safety outcomes., Conclusions: According to findings from this observational study, patients with MIS may benefit in terms of better functional outcome and lower risk of recurrent events from combining IVT and DAPT versus DAPT alone without safety concerns., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05476081.

Background: Post-traumatic distal limb wounds cause discomfort and heal gradually by second intention. The topical application of Tri-Solfen (lidocaine hydrochloride, bupivacaine hydrochloride, adrenaline acid tartrate and cetrimide [LBAC]) produces effective postsurgical cutaneous analgesia in lambs, calves and piglets; however, its effect on wounds in horses is unknown., Methods: The antinociceptive effect, measured by mechanical threshold (MT), and the wound healing impacts of LBAC compared with saline were investigated on surgically created 20 × 20 mm distal limb wounds in 10 horses. Treatment was applied once daily for 7 days following wounding on day 0. Mechanical thresholds were measured after treatment on days 1, 2 and 3. Healing was observed for 25 days., Results: The topical application of LBAC immediately following wounding and its reapplication 24 hours later increased the average MT on the first post-traumatic day by 3 Newtons. However, no antinociceptive benefit was observed on days 2 or 3. Treatment with LBAC did not adversely affect wound healing when compared with saline., Limitations: Methodological differences preclude absolute MT comparisons between studies. The experimental design did not include a model of contaminated or naturally occurring wounds., Conclusion: LBAC may provide an early antinociceptive benefit when applied to uncontaminated surgically created wounds without compromising healing., (© 2024 The Authors. Veterinary Record published by John Wiley & Sons Ltd on behalf of British Veterinary Association.)

Chlamydiosis is one of the main causes of the progressive decline of koala populations in eastern Australia. While histologic, immunologic, and molecular studies have provided insights into the basic function of the koala immune system, the in situ immune cell signatures during chlamydial infection of the reproductive tract in koalas have not been investigated. Thirty-two female koalas and 47 males presented to wildlife hospitals with clinical signs suggestive of Chlamydia infection were euthanized with the entire reproductive tract collected for histology; immunohistochemistry (IHC) for T-cell (CD3ε, CD4, and CD8α), B-cell (CD79b), and human leukocyte antigen (HLA)-DR markers; and quantitative real-time polymerase chain reaction (rtPCR) for Chlamydia pecorum . T-cells, B-cells, and HLA-DR-positive cells were observed in both the lower and upper reproductive tracts of male and female koalas with a statistically significant associations between the degree of the inflammatory reaction; the number of CD3, CD4, CD79b, and HLA-DR positive cells; and the PCR load. CD4-positive cells were negatively associated with the severity of the gross lesions. The distribution of immune cells was also variable according to the location within the genital tract in both male and female koalas. These preliminary results represent a step forward towards further exploring mechanisms behind chlamydial infection immunopathogenesis, thus providing valuable information about the immune response and infectious diseases in free-ranging koalas., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Anthracyclines are associated with enhanced oxidative stress responsible for adverse events in patients with breast cancer. However, no study has investigated the potential anti-inflammatory role of statins in counteracting anthracycline toxicity. In this retrospective study utilizing a federated health network (TriNetX), patients with breast cancer (ICD code C50) treated with anthracyclines were categorized into two groups: statin users (for at least 6 months); and statin non-users. The primary outcome was the 5-year risk of all-cause death. Secondary outcomes were the risk of myocardial infarction, stroke, atrial fibrillation, ventricular arrhythmias, heart failure, and pulmonary embolism. Cox-regression analyses were used to produce hazard ratios (HRs) and 95% confidence intervals (CI) following 1:1 propensity score matching (PSM). We identified 3,701 statin users (68.8 ± 10.4 years) and 37,185 statin non-users (59.6 ± 12.8 years). After PSM, the 5-year risk of all-cause death was significantly lower in statin users (HR 0.82, 95% CI 0.74-0.91) compared to statins non-users. Analyzing the risk for secondary outcomes, only the risk of stroke was significantly increased in statin users (HR 1.27, 95% CI 1.01-1.61), while no associations were found for the other cardiovascular events. The risk of all-cause death in statin users was the lowest during the first year after the anthracycline's initiation. No significant difference was found between lipophilic and hydrophilic statins. In patients with breast cancer treated with anthracyclines, statin use is associated with a reduced risk of all-cause death. Prospective studies are needed to investigate the potential beneficial effect of statin initiation in cancer patients without other indications., (© 2024. The Author(s).)

Alder yellows (ALY) phytoplasma (16SrV-C) is associated with ALY, a disease of several Alnus (alder) species in Europe and A. rubra in North America. In all affected species, the symptoms are similar. However, latent infections are common. ALY phytoplasma includes different strains which may be occasionally transmitted to grapevines leading to some grapevine yellows diseases. In the current study, visual symptom assessment and PCR-based methods using universal and group-specific phytoplasma primers were used to update and extend knowledge on the occurrence, impact, and genetic diversity of ALY phytoplasma in declining and non-symptomatic A. glutinosa and A. cordata trees in the Basilicata and Campania regions of southern Italy. ALY phytoplasma was detected in 80% of alder trees examined. In symptomatic trees, no other cause of disease was observed. More than half of alder trees that tested phytoplasma-positive proved to be latently infected. A considerable genetic variability was observed among the newly recorded ALY phytoplasma strains in southern Italy in almost of the genes examined. These included 16S rRNA, 16S/23S rDNA spacer region, ribosomal protein rpsV ( rpl22 ) and rpsC ( rps3 ), map , imp, and groEL genes. Eleven new genotypes were identified at map gene sequence level. However, the genetic differences observed were not related to plant host species, geographical origin, and symptoms shown by infected alder trees. Also, this study indicates that ALY phytoplasma is more widespread than previously thought.