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The spread of multidrug-resistant strains of Neisseria gonorrhoeae, the etiologic agent of gonorrhea, represents a global health emergency. Therefore, the development of a safe and effective vaccine against gonorrhea is urgently needed. In previous studies, murine monoclonal antibody (mAb) 2C7 was raised against gonococcal lipooligosaccharide (LOS). mAb 2C7 elicits complement-dependent bactericidal activity against gonococci, and its glycan epitope is expressed by almost every clinical isolate. Furthermore, we identified a peptide, cyclic peptide 2 (CP2) that mimicked the 2C7 LOS epitope, elicited bactericidal antibodies in mice, and actively protected in a mouse vaginal colonization model. In this study, we performed structural analyses of mAb 2C7 and its complex with the CP2 peptide by X-ray crystallography, NMR spectroscopy, and molecular dynamics (MD) simulations. The crystal structure of Fab 2C7 bound to CP2 showed that the peptide adopted a beta-hairpin conformation and bound the Fab primarily through hydrophobic interactions. We employed NMR spectroscopy and MD simulations to map the 2C7 epitope and identify the bioactive conformation of CP2. We also used small-angle X-ray scattering (SAXS) and native mass spectrometry to obtain further information about the shape and assembly state of the complex. Collectively, our new structural information suggests strategies for humanizing mAb 2C7 as a therapeutic against gonococcal infection and for optimizing peptide CP2 as a vaccine antigen.

Streptococcus gordonii is a Gram-positive bacterial species that typically colonizes the human oral cavity, but can also cause local or systemic diseases. Serine-rich repeat (SRR) glycoproteins exposed on the S. gordonii bacterial surface bind to sialylated glycans on human salivary, plasma, and platelet glycoproteins, which may contribute to oral colonization as well as endocardial infections. Despite a conserved overall domain organization of SRR adhesins, the Siglec-like binding regions (SLBRs) are highly variable, affecting the recognition of a wide range of sialoglycans. SLBR-N from the SRR glycoprotein of S. gordonii UB10712 possesses the remarkable ability to recognize complex core 2 O-glycans. We here employed a multidisciplinary approach, including flow cytometry, native mass spectrometry, isothermal titration calorimetry, NMR spectroscopy from both protein and ligand perspectives, and computational methods, to investigate the ligand specificity and binding preferences of SLBR-N when interacting with mono- and disialylated core 2 O-glycans. We determined the means by which SLBR-N preferentially binds branched α2,3-disialylated core 2 O-glycans: a selected conformation of the 3'SLn branch is accommodated into the main binding site, driving the sTa branch to further interact with the protein. At the same time, SLBR-N assumes an open conformation of the CD loop of the glycan-binding pocket, allowing one to accommodate the entire complex core 2 O-glycan. These findings establish the basis for the generation of novel tools for the detection of specific complex O-glycan structures and pave the way for the design and development of potential therapeutics against streptococcal infections.

BACKGROUND: In suspected myocardial infarction (MI), guidelines recommend using high-sensitivity cardiac troponin (hs-cTn)-based approaches. These require fixed assay-specific thresholds and timepoints, without directly integrating clinical information. Using machine-learning techniques including hs-cTn and clinical routine variables, we aimed to build a digital tool to directly estimate the individual probability of MI, allowing for numerous hs-cTn assays. METHODS: In 2,575 patients presenting to the emergency department with suspected MI, two ensembles of machine-learning models using single or serial concentrations of six different hs-cTn assays were derived to estimate the individual MI probability (ARTEMIS model). Discriminative performance of the models was assessed using area under the receiver operating characteristic curve (AUC) and logLoss. Model performance was validated in an external cohort with 1688 patients and tested for global generalizability in 13 international cohorts with 23,411 patients. RESULTS: Eleven routinely available variables including age, sex, cardiovascular risk factors, electrocardiography, and hs-cTn were included in the ARTEMIS models. In the validation and generalization cohorts, excellent discriminative performance was confirmed, superior to hs-cTn only. For the serial hs-cTn measurement model, AUC ranged from 0.92 to 0.98. Good calibration was observed. Using a single hs-cTn measurement, the ARTEMIS model allowed direct rule-out of MI with very high and similar safety but up to tripled efficiency compared to the guideline-recommended strategy. CONCLUSION: We developed and validated diagnostic models to accurately estimate the individual probability of MI, which allow for variable hs-cTn use and flexible timing of resampling. Their digital application may provide rapid, safe and efficient personalized patient care. TRIAL REGISTRATION NUMBERS: Data of following cohorts were used for this project: BACC ( www. CLINICALTRIALS: gov ; NCT02355457), stenoCardia ( www. CLINICALTRIALS: gov ; NCT03227159), ADAPT-BSN ( www.australianclinicaltrials.gov.au ; ACTRN12611001069943), IMPACT ( www.australianclinicaltrials.gov.au , ACTRN12611000206921), ADAPT-RCT ( www.anzctr.org.au ; ANZCTR12610000766011), EDACS-RCT ( www.anzctr.org.au ; ANZCTR12613000745741); DROP-ACS ( https://www.umin.ac.jp , UMIN000030668); High-STEACS ( www. CLINICALTRIALS: gov ; NCT01852123), LUND ( www. CLINICALTRIALS: gov ; NCT05484544), RAPID-CPU ( www. CLINICALTRIALS: gov ; NCT03111862), ROMI ( www. CLINICALTRIALS: gov ; NCT01994577), SAMIE ( https://anzctr.org.au ; ACTRN12621000053820), SEIGE and SAFETY ( www. CLINICALTRIALS: gov ; NCT04772157), STOP-CP ( www. CLINICALTRIALS: gov ; NCT02984436), UTROPIA ( www. CLINICALTRIALS: gov ; NCT02060760).

Giant cell arteritis is a large-vessel vasculitis usually seen in older adults. The inflammatory process results in systemic, ophthalmic, and neurological lesions. It is difficult to diagnose in older adults and may present as a medical emergency. Here, we report the case of an 83-year-old woman who presented with bitemporal headache, jaw claudication, glossodynia, failure to thrive, and amaurosis fugax. The findings supported the hypothesis of giant cell arteritis. Despite receiving treatment, the patient died of an acute myocardial infarction. Headache in older adults raises the possibility of giant cell arteritis, especially when combined with an ophthalmic emergency. Many symptoms indicate the condition, but the diagnosis may be challenging, especially for the generalist physician.

Protein–glycan interactions play pivotal roles in numerous biological processes, ranging from cellular recognition to immune response modulation. Understanding the intricate details of these interactions is crucial for deciphering the molecular mechanisms underlying various physiological and pathological conditions. Computational techniques have emerged as powerful tools that can help in drawing, building and visualising complex biomolecules and provide insights into their dynamic behaviour at atomic and molecular levels. This review provides an overview of the main computational tools useful for studying biomolecular systems, particularly glycans, both in free state and in complex with proteins, also with reference to the principles, methodologies, and applications of all-atom molecular dynamics simulations. Herein, we focused on the programs that are generally employed for preparing protein and glycan input files to execute molecular dynamics simulations and analyse the corresponding results. The presented computational toolbox represents a valuable resource for researchers studying protein–glycan interactions and incorporates advanced computational methods for building, visualising and predicting protein/glycan structures, modelling protein–ligand complexes, and analyse MD outcomes. Moreover, selected case studies have been reported to highlight the importance of computational tools in studying protein–glycan systems, revealing the capability of these tools to provide valuable insights into the binding kinetics, energetics, and structural determinants that govern specific molecular interactions.

Hydrogen, as a versatile and sustainable energy carrier, plays a pivotal role in the global transition towards a low-carbon economy. However, the safe and efficient operation of hydrogen production plants is paramount to exploiting the full potential of this clean energy source. This scientific article investigates typical HILP (High Intensity Low Probability) scenarios that can occur in hydrogen production plants and storage. The assessment is based on a HazOp (Hazard and Operability) study on a representative electrolysis unit. The study has been conducted through a multidisciplinary approach, integrating knowledge from chemical engineering, process safety and risk analysis, focusing on consequence modelling, to understand root causes, potential impacts and mitigation strategies. Through the analysis of plant design and operation parameters, the article identifies common vulnerabilities in hydrogen production processes. The main accident scenarios explored include equipment failures and leaks, each with the potential to compromise plant safety and disrupt production. Furthermore, the article analyses the dynamic interaction between technological progress and safety protocols in shaping the risk landscape of hydrogen production and storage facilities. The insights from this analysis help to propose possible risk management strategies, emphasising the importance of proactive safety measures, early detection systems and effective emergency response plans. By elucidating the typical incident scenarios in hydrogen production plants, this article seeks to enhance industry awareness, facilitate knowledge sharing, and drive continuous improvement in the design, operation, and maintenance of hydrogen facilities. The findings presented herein offer valuable insights for engineers, researchers, and policymakers working towards the widespread adoption of hydrogen as a clean and sustainable energy solution.

The management of dust hazards within industrial environments remains a critical concern, as sadly testified by the catastrophic events occurred in recent history. Dust Hazard Analysis (DHA) is a risk assessment technique used for identifying, managing, and mitigating the risks related to the handling, production, and storage of combustible dusts. This study explores the efficacy of employing a semi-quantitative approach within the framework of DHA, leveraging a Risk Matrix to assess and define the severity and likelihood of potential hazardous events associated with combustible dust. The semi-quantitative method presented herein integrates qualitative expert judgments with quantitative data, fostering a comprehensive evaluation of various scenarios involving dust-related hazards: central to this approach is the utilization of a Risk Matrix, where severity and likelihood classes are intersected to generate risk levels associated with identified dust-related scenarios. This allows the prioritization of mitigation strategies, focusing resources on high-risk scenarios while acknowledging lower-risk occurrences. Furthermore, the use of a common Risk Matrix facilitates the decision-making process, allowing the same benchmark to be applied to the recommendations and actions emerging from different risk assessment techniques (e.g., HazOp). The study underscores the value of a semi-quantitative approach in DHA, highlighting the potential and the limitations of the current model, offering a structured methodology that aids stakeholders in decision-making processes concerning risk mitigation and control measures, ensuring the safety and integrity of industrial operations.

The main goal of process safety is to analyse and reduce risks related to industrial processes in order to ensure that the final risk on people and environment is as low as possible. To establish whether the risk related to the process is tolerable or not it is therefore necessary to calculate the risk associated with the events under consideration and to compare the result with the selected tolerability criteria: this is the common approach used in Quantitative Risk Assessment (QRA) analysis. The risk associated with an event, whatever is its nature (on people, on the environment or financial) is a function of the likelihood of the event (generally expressed in events/year) and the consequences (expressed in terms of damage) of the event itself. The aim of this article is to focus on the first parameter (frequency evaluation): the main goal is not to write a math paper on frequency calculation (there are a lot of articles and specialised sources in the scientific literature that deal with the theory of probability calculation and, therefore, it would not make sense to focus on math) but to report the main conceptual errors in frequency calculation found in existing risk analysis reports. Frequency calculation depends especially on the quality of the performed hazard identification study (e.g HAZOP) and on the proper identification of the common cause failures present within a complex system which, if not properly identified, can lead to an incorrect assessment of the likelihood of a dangerous event. The final scope is to show how it is possible to fall into pitfalls during frequencies calculation if the hazards identification is not properly performed and if dependencies between safeguards are not properly assessed: usually these errors lead to obtain frequency values that have no physical meaning.

Abstract Inducible gene expression systems can be used to control the expression of a gene of interest by means of a small-molecule. One of the most common designs involves engineering a small-molecule responsive transcription factor (TF) and its cognate promoter, which often results in a compromise between minimal uninduced background expression (leakiness) and maximal induced expression. Here, we focus on an alternative strategy using quantitative synthetic biology to mitigate leakiness while maintaining high expression, without modifying neither the TF nor the promoter. Through mathematical modelling and experimental validations, we design the CASwitch, a mammalian synthetic gene circuit based on combining two well-known network motifs: the Coherent Feed-Forward Loop (CFFL) and the Mutual Inhibition (MI). The CASwitch combines the CRISPR-Cas endoribonuclease CasRx with the state-of-the-art Tet-On3G inducible gene system to achieve high performances. To demonstrate the potentialities of the CASwitch, we apply it to three different scenarios: enhancing a whole-cell biosensor, controlling expression of a toxic gene and inducible production of Adeno-Associated Virus (AAV) vectors.

Besides increasing plant growth, several Plant Growth Promoting Rhizobacteria (PGPR), can enhance tolerance to biotic and/or abiotic stresses of numerous plant species. While cultivated plants are frequently subject to combined stresses in the field, there is limited knowledge of the effect of PGPR on plants undergoing simultaneous stress conditions. Therefore, we tested the beneficial properties of the halotolerant PGPR Serratia sp. strain C2, previously shown to enhance salt stress tolerance in barley, on tomato plants exposed to salinity, to Potato Virus Y (PVY) infection, and both stresses simultaneously. In our experimental conditions, C2 inoculation improved tomato tolerance to salt stress and positively correlated with a 46–68 % decrease in the level of PVY RNA compared to non-inoculated tomato plants. Morphometric, physiological and biochemical analyses (e.g., chlorophyll, sugar and proline accumulation, oxidative stress status and NDVI) indicated that C2 treatments had beneficial effects on tomato growth under simple and combined stress conditions. This is the first report of a PGPR enhancing tolerance not only to individually induced salinity and PVY infection, but also to both stresses in combination. Moreover, the expression analysis of selected genes involved in stress responses and RNA silencing-mediated antiviral immunity suggests that C2 can interfere with distinct defence response pathways to enhance stress tolerance in tomato. These pioneering results support the perspective of using PGPR as multi-spectrum and multi-host biostimulants for improving plant growth and protection from biotic, abiotic, and combined stresses to promote sustainable crop production in the face of environmental changes.

Objective: Non-neurosurgeons in regional and rural hospitals may be required to operate on patients presenting with a traumatic brain injury where timely transfer to a tertiary hospital is not possible. Confidence and experience can vary significantly due to limited access to hands-on training. Increasing availability to advanced 3D printed models opens new opportunities to provide accurate head models suitable for this purpose. This study evaluated the experience of regional clinicians and nurses following a neurotrauma workshop where 3D printed head models were used to provide training in burr hole and craniotomy procedures. Methods: A neurotrauma seminar and workshop was hosted at the Sunshine Coast Health Institute, in the state of Queensland, Australia. The workshop component allowed 26 local clinicians and nurses to gain hands-on experience with a 3D printed head model, guided by neurosurgeons from the closest tertiary hospital. Following training, participants completed a short survey. Results: Prior to this workshop, most participants had never performed a burr hole (58 %, n=15) or interacted with a 3D printed model (69 %, n=18). Overall, most participants indicated that the 3D printed model performed better (58 %, n=15) and much better (15 %, n=4) than their expectations. 81 % (n=21) left the workshop with improved confidence in performing burr hole and craniotomy procedures. Despite some melting of the plastic, 96 % (n=25) of participants would recommend this model to their colleagues.

Abstract The European Commission requested the EFSA Panel on Plant Health to prepare and deliver risk assessments for commodities listed in Commission Implementing Regulation (EU) 2018/2019 as ‘High risk plants, plant products and other objects'. This Scientific Opinion covers plant health risks posed by plants of Prunus avium possibly grafted on rootstocks of either P. avium, P. canescens, P. cerasus, P. pseudocerasus or their hybrids imported from the UK, taking into account the available scientific information, including the technical information provided by the UK. All pests associated with the commodities were evaluated against specific criteria for their relevance for this opinion. Three quarantine pests Scirtothrips dorsalis, tobacco ringspot virus and tomato ringspot virus), one protected zone EU quarantine pest (Bemisia tabaci (European population), and three non‐ regulated pests (Colletotrichum aenigma, Eulecanium excrescens and Takahashia japonica) that fulfilled all relevant criteria were selected for further evaluation. The risk mitigation measures proposed in the technical Dossier from the UK were evaluated, taking into account the possible limiting factors. For these pests, expert judgement is given on the likelihood of pest freedom, taking into consideration the risk mitigation measures acting on the pest, including uncertainties associated with the assessment. The degree of pest freedom varies among the pests evaluated, with Colletotrichum aenigma being the pest most frequently expected on the imported potted plants. The Expert Knowledge Elicitation indicated with 95% certainty that between 9971 and 10,000 plants per 10,000 would be free from the above‐mentioned fungus.

Abstract The European Commission requested the EFSA Panel on Plant Health to prepare and deliver risk assessments for commodities listed in Commission Implementing Regulation (EU) 2018/2019 as ‘High risk plants, plant products and other objects’. This Scientific Opinion covers plant health risks posed by potted plants and bundles of bare‐root plants or cell grown young plants or graftwood/budwood of Prunus spinosa imported from the United Kingdom, taking into account the available scientific information, including the technical information provided by the UK. All pests associated with the commodities were evaluated against specific criteria for their relevance for this opinion. One quarantine pest, Scirtothrips dorsalis, one protected zone quarantine pest Bemisia tabaci (European population) and one non‐regulated pest, the scale Eulecanium excrescens, that fulfilled all relevant criteria were selected for further evaluation. The risk mitigation measures proposed in the technical Dossier from the UK were evaluated, taking into account the possible limiting factors. For these pests, expert judgement is given on the likelihood of pest freedom, taking into consideration the risk mitigation measures acting on the pest, including uncertainties associated with the assessment. The degree of pest freedom varies among the pests evaluated, with E. excrescens being the pest most frequently expected on the imported potted plants. The Expert Knowledge Elicitation indicated with 95% certainty that between 9981 and 10,000 plants per 10,000 would be free from the above‐mentioned scale.

Abstract Aims The current European Society of Cardiology (ESC) guidelines provide clear indications for the treatment of acute and chronic heart failure (HF). Nevertheless, there is a constant need for real‐world evidence regarding the effectiveness, adherence, and persistence of drug therapy. We investigated the use of sacubitril/valsartan for the treatment of HF with reduced ejection fraction in real‐world clinical practice in Italy. Methods and results An observational, retrospective, non‐interventional cohort study based on electronic medical records from nine specialized hospital HF centres in Italy was carried out on patients with prescription of sacubitril/valsartan. Overall, 948 patients had a prescription of sacubitril/valsartan, with 924 characterized over 6 months and followed up for 12 months. Pharmacoutilization data at 1 year of follow‐up were available for 225 patients {mean age 69.7 years [standard deviation (SD) = 10.8], 81.8% male}. Of those, 398 (45.2%) reached the target dose of sacubitril/valsartan of 97/103 mg in a mean time of 6.9 (SD = 6.2) weeks. Blood pressure and hypotension in 61 patients (65%) and worsening of chronic kidney disease in 10 patients (10.6%) were the main reasons for not reaching the target dose. Approximatively 50% of patients had a change in sacubitril/valsartan dose during follow‐up, and 158 (70.2%) were persistent with the treatment during the last 3 months of follow‐up. A sensitivity analysis (persistence during the last 4 months of follow‐up) showed persistence for 162 patients (72.0%). Adherence data, available for 387 patients, showed full adherence for 205 (53%). Discontinuation (102/717 patients, 14.2%) was mainly due to hypotension and occurred after a mean time of 34.3 (SD = 28.7) weeks. During follow‐up, out of 606 patients with available data, 434 patients (71.6%) had an HF add‐on drug or drugs concomitant with sacubitril/valsartan. HF‐related hospitalization during follow‐up was numerically higher in non‐persistent (16/67 patients, 23.9%) vs. patients persistent to sacubitril/valsartan (30/158, 19%) (P = 0.405). Conclusions Real‐world data on the use of sacubitril/valsartan in clinical practice in Italy show a rapid titration to the target dose, high therapeutic adherence enabling a good level of therapeutic management in line with ESC guidelines for patients with reduced ejection fraction.

In order to collect information on ichthyofauna of a deep-sea vulnerable marine ecosystem (VME) network along the Apulian margin (central Mediterranean Sea), two low-impact sampling tools were used in three VMEs characterized by cold-water corals (CWC), namely Bari Canyon (BC), off Monopoli (Mn), and off Santa Maria di Leuca (SML). Using an experimental longline, 53 deployments were carried out between a 314 and 650 m depth for a total of 217 fishing hours, whereas when using the baited lander MEMO (Marine Environment MOnitoring system), 31 deployments were carried out between 427 and 792 m, for a total of 223 h of video recordings. A total of 37 taxa were recorded, comprising 13 Chondrichthyes and 24 Osteichthyes. The similarities in species observed among the VMEs confirm the presence of a network of CWC-VMEs along the Apulian margin, whereas some differences detected are due to the different abundance of some species, such as Galeus melastomus, Helicolenus dactylopterus, and Phycis blennoides. The presence of commercial species, vulnerable/endangered cartilaginous fishes, and large and sexually mature individuals of G. melastomus, H. dactylopterus, and Pagellus bogaraveo in all the VMEs confirms that the network of CWC-VMEs along the Apulian margin can act as a network of refuge areas and an essential fish habitat (EFH) for species threatened by fishing activities.

In this study, we aimed to assess the capacity of a physics-based earthquake simulator to improve our understanding of the seismogenic process. In this respect, we applied a previously tested earthquake simulator to two well-known and completely different seismogenic fault systems, namely the Italian Apennines and the Nankai subduction in Japan, for which long historical records of strong earthquakes are available. They are characterized by different fault mechanisms, fault sizes, and slip rates. Because of the difference in slip rates, the time scale of the seismicity patterns is different for the two systems (several hundreds of years for the Apennines and a few tens of years for the Nankai Fault). The results of simulations that produced synthetic catalogues of 100,000 years show these significant long-term seismicity patterns characterizing the seismic cycles for both seismogenic areas as follows: The average stress and the occurrence rate of earthquakes increase in the long term as the next major earthquake approaches; while the average stress increases uniformly, the occurrence rate stops increasing well in advance of the mainshocks; the b-value exhibits a long-term increase before major earthquakes and a fast decrease shortly before the mainshocks. Even if no specific statistical tool was applied for the quantification of the similarities between the seismicity patterns of the two seismic areas, such similarities are clearly justified by the large number of seismic cycles included in the 100,000-year synthetic catalogues. The paper includes a discussion on the capability of the simulation algorithm to reliably represent the real long-term seismogenic process. This question is difficult to answer because the available historical observations are of too short a duration to provide significant statistical results. In spite of the limitations characterizing the use of earthquake simulators for time-dependent earthquake hazard assessment, and the lack of convincing mechanistic explanations of the specific seismic patterns reproduced by our simulator algorithm, our results encourage further investigations into the application of simulators for the development of seismogenic models, including short-term features.

ObjectivesThe aim of the current study was 3-fold: 1) to examine the factorial structure of the Comprehensive Assessment of At-Risk Mental States (CAARMS) in help-seeking individuals undergoing an assessment on suspicion of psychosis risk; 2) to investigate the association of CAARMS factors with functioning; 3) and to test the association of any derived factors with the longitudinal outcome of transition to psychosis.MethodsThe study included 101 patients. First, a principal component analysis (PCA) was conducted using the Varimax rotation method. A minimum initial eigenvalues of greater than or equal to 1.0, analysis of Scree plots, percentage of variance explained by each component, reliability (Cronbach’s alpha) of factors above 0.7 and Parallel Analysis were the criteria used to determine the appropriate number of factors Second, Spearman correlations were run to analyze the relationship between CAARMS factors and sociodemographic and functional variables (i.e. age, schooling, Social and Occupational Functioning Assessment Scale-SOFAS- and Health of the Nation Outcome Scales-HoNOS- scores). Third, we performed a Logistic regression analysis to evaluate the association between baseline CAARMS factors and the risk of transition to psychosis at the 6-month follow-up.ResultsA total of 101 consecutive patiens were recruited. We found that: 1) a 6 factor model solution as the most appropriate, jointly accounting for 65% of the variance; 2) factors 1 (“negative-interpersonal”), 2 (“cognitive-disorganization”), 3 (“positive”), and 4 (“motor-physical changes”) were negatively correlated with SOFAS total score; factors 1, 2, and 3 showed positive correlations with HoNOS total score; factors 2 and 3 present similar patterns of correlations, factor 3 manifesting the strongest association with HoNOS symptoms, HONOS and SOFAS total score. Both factors 5 and 6 show significant associations with HoNOS behavioral impairment; 3) after 6 months 28 participants (30.1%) converted to psychosis. Factors 2 and 3 were positively associated with the risk of transition to psychosis; whereas, the factor 5 (“affective factor”) was negatively associated with the outcome variable.ConclusionsIt is thus crucial to recognize the type and severity of psychopathology in help-seeking individuals in order to intensive clinical monitoring of subclinical psychopathology risk profiles, and design specific care pathways.

BackgroundHeart failure (HF) significantly affects the morbidity, mortality, and quality of life of patients. New therapeutic strategies aim to improve the functional capacity and quality of life of patients while controlling HF-related risks. Real-world data on both the functional and cardiopulmonary exercise capacities of patients with HF with reduced ejection fraction upon sacubitril/valsartan use are lacking.MethodsA multicenter, retrospective, cohort study, called REAL.IT, was performed based on the data collected from the electronic medical records of nine specialized HF centers in Italy. Cardiopulmonary exercise testing was performed at baseline and after 12 months of sacubitril/valsartan therapy, monitoring carbon dioxide production (VCO2) and oxygen consumption (VO2).ResultsThe functional capacities of 170 patients were evaluated. The most common comorbidities were hypertension and diabetes (i.e., 53.5 and 32.4%, respectively). At follow-up, both the VO2 peak (from 15.1 ± 3.7 ml/kg/min at baseline to 17.6 ± 4.7 ml/kg/min at follow-up, p

Abstract The European Commission requested the EFSA Panel on Plant Health to prepare and deliver risk assessments for commodities listed in Commission Implementing Regulation (EU) 2018/2019 as ‘High‐risk plants, plant products and other objects’. This Scientific Opinion covers plant health risks posed by defoliated 1‐ or 2‐year old bare root plants for planting (grafted or not) of 12 Prunus species (Prunus armeniaca, P. avium, P. canescens, P. cerasifera, P. cerasus, P. davidiana, P. domestica, P. dulcis, P. fontanesiana, P. persica, P. salicina, P. tomentosa) imported from Moldova, taking into account the available scientific information, including the technical information provided by the applicant country. The evaluation identified three EU‐quarantine pests, Erwinia amylovora (protected zone quarantine pest), Xiphinema rivesi non‐EU populations and Xanthomonas arboricola pv. pruni (protected zone quarantine pest), which were selected for further evaluation, based on defined criteria, including their presence in the applicant country. It should be noted that there is uncertainty regarding whether all relevant pests have been identified due to a limited number of scientific publications and pest surveys in Moldova. For the three selected pests, the risk mitigation measures proposed in the technical dossier from Moldova were evaluated taking into account the possible limiting factors. For these pests, an expert judgement is given on the likelihood of pest freedom taking into consideration the risk mitigation measures acting on it, including uncertainties associated with the assessment. The degree of pest freedom varies among the pests evaluated, with Erwinia amylovora being the pest most frequently expected on the imported plants. The Expert Knowledge Elicitation indicated, with 95% certainty, that between 9823 and 10,000 bundles (comprising 10–20 plants per bundle) out of 10,000 bundles would be free from E. amylovora.

Background: Prevention of latent tuberculosis infection (LTBI) in healthcare workers (HCWs) to ensure the “Right to Occupational Safety” is a special challenge globally, as HCWs have a higher risk of acquiring the infection in hospital settings because of frequent close exposure to patients suffering from tuberculosis (TB). Methods: Aretrospective study was performed with the aim of assessing the prevalence of LTBI related to demographical and occupational risk factors among HCWs employed in a large hospital in Italy. The study involved 1461 HCWs screened for LTBI by Mantoux tuberculin skin test (TST) and then confirmed with Interferon Gamma Release Assay (IGRA) test in case of positivity. Immunosuppressed and BGC-vaccinated workers were tested directly with IGRA. Results: LTBI was diagnosed in 4.1% of the HCWs and the prevalence resulted lower than other studies conducted in low TB incidence countries. The variables significantly linked with higher frequency of the infection were: age ≥40 years (OR = 3.14; 95% CI: 1.13–8.74; p < 0.05), length of service ≥15 years (OR = 4.11; 95% CI: 1.48–11.43; p < 0.05) and not being trained on TB prevention (OR = 3.46; 95% CI: 1.85–6.46; p < 0.05). Not trained HCWs presented a higher risk of LTBI also after adjustment for age and length of service, compared to trained HCWs. Conclusions: screening of HCWs for LTBI should be always considered in routinely occupational surveillance in order to early diagnose the infection and prevent its progression. Safety policies in hospital settings centered on workers’ training on TB prevention is crucial to minimize LTBI occurrence in HCWs.

Abstract Background Randomized controlled trials (RCTs) reported contrasting results about reverse left ventricular remodeling (LVR) after sodium-glucose co-transporter-2 inhibitors (SGLT2i) therapy in patients with heart failure (HF). Methods and results We performed a metanalysis of RCTs of SGLT2i administration in HF outpatients published until June 2022 searching four electronic databases. The protocol has been published in PROSPERO. Primary LVR outcome was change in absolute LV end-diastolic (LVEDV) and end-systolic volume (LVESV) from baseline to study endpoint. Secondary outcomes included changes in LVEDV and LVESV indexed to body surface area, LV Mass index (LVMi), LV ejection fraction (LVEF), and N-terminal pro-B-type natriuretic peptide (NTproBNP). Mean differences (MDs) with 95% CIs were pooled. A total of 9 RCTs (1385 patients) were analyzed. All of them reported data on LVEF. Six trials reported data on LVESV and LVEDV (n = 951); LVMi was available in 640. SGLT2i treatment significantly reduced LVEDV [MD= -10.59 ml (-17.27; -3.91), P = 0.0019], LVESV [MD= -8.80 ml (-16.91; -0.694), P = 0.0334], and LVMI [MD= -5.34 gr/m2 (-9.76; -0.922), P = 0.0178], while LVEF significantly increased [MD = + 1.98% (0.67; 0.306), P = 0.0031]. By subgroup analysis, the beneficial effects of SGLT2i on LVEF did not differ by imaging method used, time to follow-up re-evaluation, or HF phenotype. Reduction in LV volumes tended to be greater in HF with reduced EF (HFrEF) than in those with preserved EF (HFpEF), while the opposite was observed for LVMi. Conclusions Treatment with SGLT2i significantly reversed cardiac volumes, improving LV systolic function and LV mass, particularly in HFrEF patients.

Streptococcus gordonii and Streptococcus sanguinis, commensal bacteria present in the oral cavity of healthy individuals, upon entry into the bloodstream can become pathogenic, causing infective endocarditis (IE). Sialic acid-binding serine-rich repeat adhesins on the microbial surface represent an important factor of successful infection to cause IE. They contain Siglec-like binding regions (SLBRs) that variously recognize different repertoires of O-glycans, with some strains displaying high selectivity and others broader specificity. We here dissect at an atomic level the mechanism of interaction of SLBR-B and SLBR-H from S. gordonii with a multivarious approach that combines NMR spectroscopy and computational and biophysical studies. The binding pockets of both SLBRs are broad enough to accommodate extensive interactions with sialoglycans although with key differences related to strain specificity. Furthermore, and significantly, the pattern of interactions established by the SLBRs are mechanistically very different from those reported for mammalian Siglecs despite them having a similar fold. Thus, our detailed description of the binding modes of streptococcal Siglec-like adhesins sparks the development of tailored synthetic inhibitors and therapeutics specific for Streptococcal adhesins to counteract IE, without impairing the interplay between Siglecs and glycans.

In Equids, undetected twin pregnancy represents the most important cause of abortion and is also associated with high neonatal mortality rates. Therefore, the detection and management of twin pregnancies is pivotal to allow the continuation of single pregnancies. Although pre-fixation manual crushing of one embryo is the most common management of twin pregnancies, and the impact of natural reduction has been reported in mares, very little is known about donkeys. The present study aimed to report results on the natural reduction occurrence and post-fixation manual crushing management of twin pregnancies in the Martina Franca donkey breed. Methods: Twenty-five twin pregnancies were detected at 11–13 days after ovulation. At 16 days after ovulation, twin pregnancies were classified as unilateral or bilateral and left untreated. The occurrence of natural reduction of one embryo was assessed at 20–21 days after ovulation, and post-fixation manual crushing of one embryo was performed in those cases in which natural reduction did not occur. The pregnancy rate at 28 days after ovulation and live foal rate were recorded. Result: Sixteen out of 25 twin pregnancies were unilateral and nine bilateral. At 20–21 days after ovulation, the natural reduction of one embryo occurred in 87.5% of the unilateral and in none of the bilateral twin pregnancies. The remaining twin pregnancies were treated by post-fixation manual crushing of one embryo. The 28-days-after-ovulation single embryo pregnancy rate was 93.8% for unilateral twin pregnancies and 88.9% for bilateral twin pregnancies, with an overall pregnancy rate of 92%. The live foal rate was 87%. Conclusions: The success rate of natural reduction within 20–21 days after ovulation, the 28-days-after-ovulation pregnancy rate, and the live foal rate suggest that waiting for the natural reduction of one embryo and choosing the post-fixation manual crushing of one embryo could be considered as an alternative to traditional early pre-fixation manual crushing in the Martina Franca donkey breed.

The Martina Franca (MF) donkey breed (Equus asinus) primarily inhabits the rural areas surrounding the homonymous municipality, as well as neighboring municipalities in the provinces of Bari and Brindisi, all located in the Apulia region of Italy. The objective of this study was to assess the current phenotype through the evaluation of 27 morphologic measurements. The study was conducted on 73 female and 18 male breeding animals from eight different herds located in central and southern Italy. Statistical analysis was performed in order to demonstrate statistical differences between males and females, as well as sexual dimorphism and uniformity of all measurements in both genders. The results demonstrated that the mean of three parameters used for the evaluation of an MF donkey (height at withers, circumference of thorax, and shin circumference) are highly representative of the population, with minimal dispersion Cv^ = 0.05–0.06 up to a maximum of 10%, as evidenced by relatively low standard deviations across observed measurements in both genders. Regarding sexual dimorphism, a statistically significant difference was found between males and females. This dimorphism is linked to reproductive activity and is useful during gestation. Overall, our findings suggest that the MF donkey phenotype has been largely preserved over time with high uniformity in males, slight inhomogeneity in the female population, and less variability in both genders.

In veterinary medicine, the use of loco-regional anesthesia techniques is increasing. The Quadratus Lumborum block (QL) is an interfascial loco-regional technique that involves the release of local anesthetic (LA) between the Quadratus Lumborum and the Small Psoas (Pm) muscle. The study aims to evaluate the effect of the QL block on reducing the total amount of opioids in dogs undergoing pre-scrotal orchiectomy. A group of 36 dogs was enrolled in a randomized blinded study. The animals were divided into two groups: 18 in the experimental group (QL) and 18 in the control group (C). The QL group received 0.4 mL kg−1 of ropivacaine 0.5% for each hemiabdomen (total amount of 3 mg kg−1 of ropivacaine, 1.5 mg kg−1 per side). The C group was brought into the operating room (OR) after receiving the same clipping as the QL group. In the intraoperative period, opioid consumption in the QL group was significantly lower than in the C group. No differences were found in the post-operative phase. No side effects were reported when performing the QL technique. The QL block performed at the level of L6 appears to be a valid approach to reducing opioid use in dogs undergoing orchidectomy with a pre-scrotal surgical approach.

Chondrosarcoma (ChS), a malignant cartilage-producing tumor, is the second most frequently diagnosed osseous sarcoma after osteosarcoma. It represents a very heterogeneous group of malignant chemo- and radiation-resistant neoplasms, accounting for approximately 20% of all bone sarcomas. The majority of ChS patients have a good prognosis after a complete surgical resection, as these tumors grow slowly and rarely metastasize. Conversely, patients with inoperable disease, due to the tumor location, size, or metastases, represent a great clinical challenge. Despite several genetic and epigenetic alterations that have been described in distinct ChS subtypes, very few therapeutic options are currently available for ChS patients. Therefore, new prognostic factors for tumor progression as well as new treatment options have to be explored, especially for patients with unresectable or metastatic disease. Recent studies have shown that a correlation between immune infiltrate composition, tumor aggressiveness, and survival does exist in ChS patients. In addition, the intra-tumor microvessel density has been proven to be associated with aggressive clinical behavior and a high metastatic potential in ChS. This review will provide an insight into the ChS microenvironment, since immunotherapy and antiangiogenic agents are emerging as interesting therapeutic options for ChS patients.

Background: Psychological distress is recognised as the most common mental health difficulty in emerging adult (18-to-24-year-old) female academic students. This study aimed to test a novel model positing physical activity habits as a protective factor for psychological distress through the mediating role of physical and psychological parameters. Adherence to the Mediterranean diet and self-reported physical health status were included as physical parameters. Self-reported psychological health status and time spent on leisure activities were the psychological parameters considered. Method: Data were collected between April and May 2021. Correlation analyses and a multiple mediation model were computed on 411 online questionnaires filled out by 18-to-24-year-old female students from the University of blind (Italy). Results: The multiple indirect effects were significant (β = −0.088; p

Le présent article pose la question de la conjonction du cultisme et du transhumanisme : comment se fait-il que bien des films abordant le thème du transhumanisme sont devenus des objets culte ? Pour y répondre, il faut d’abord circonscrire le phénomène du cultisme tel qu’il est apparu au xxe siècle dans les salles de cinéma, depuis ses origines avant-gardistes et contre-culturelles jusqu’à la vogue du cinéma d’animation japonais. Il faut aussi considérer les caractéristiques formelles de l’objet culte, notamment son aspect fragmentaire, en rediscutant la théorie d’Umberto Eco. Le propos peut ensuite se focaliser sur le film culte Ghost in the Shell, dont l’adaptation en prises de vue réelles date de 2017. L’accueil mitigé fait à cette adaptation, plus encore que le film lui-même, offre un terrain d’investigation idéal car il fait saillir certains traits du public cultiste, comme l’intellectualisme et l’exotisme. Enfin, une scène du film est retenue et commentée au moyen de la notion de moment de vérité développée par Roland Barthes, afin de penser la dimension adolescente et mélancolique de l’imaginaire culto-transhumaniste.

ABSTRACT: Background: The presence of myocardial scar is associated with poor prognosis in several underlying diseases. Late-gadolinium-enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging reveals clinically silent “unrecognized myocardial scar” (UMS), but the etiology of UMS often remains unclear. This population-based CMR study evaluated prevalence, localization, patterns, and risk factors of UMS. Methods: The study population consisted of 1064 consecutive Hamburg City Health Study participants without a history of coronary heart disease or myocarditis. UMS was assessed by standard-phase-sensitive-inversion-recovery LGE CMR. Results: Median age was 66 [quartiles 59, 71] years and 37% (388/1064) were females. UMS was detected in 244 (23%) participants. Twenty-five participants (10%) had ischemic, and 217 participants (89%) had non-ischemic scar patterns, predominantly involving the basal inferolateral left-ventricular (LV) myocardium (75%). Two participants (1%) had coincident ischemic and non-ischemic scar. The presence of any UMS was independently associated with LV ejection fraction (odds ratios (OR) per standard deviation (SD) 0.77 (confidence interval (CI) 0.65–0.90), p = 0.002) and LV mass (OR per SD 1.54 (CI 1.31–1.82), p

Abstract Aims Sacubitril/valsartan has changed the treatment of heart failure with reduced ejection fraction (HFrEF), due to the positive effects on morbidity and mortality, partly mediated by left ventricular (LV) reverse remodelling (LVRR). The aim of this multicenter study was to identify echocardiographic predictors of LVRR after sacubitril/valsartan administration. Methods and results Patients with HFrEF requiring therapy with sacubitril/valsartan from 13 Italian centres were included. Echocardiographic parameters including LV global longitudinal strain (GLS) and global peak atrial longitudinal strain by speckle tracking echocardiography were measured to find the predictors of LVRR [= LV end‐systolic volume reduction ≥10% and ejection fraction (LVEF) improvement ≥10% at follow‐up] at 6 month follow‐up as the primary endpoint. Changes in symptoms [New York Heart Association (NYHA) class] and neurohormonal activations [N‐terminal pro‐brain natriuretic peptide (NT‐proBNP)] were also evaluated as secondary endpoints; 341 patients (excluding patients with poor acoustic windows and missing data) were analysed (mean age: 65 ± 10 years; 18% female, median LVEF 30% [inter‐quartile range: 25−34]). At 6 month follow‐up, 82 (24%) patients showed early complete response (LVRR and LVEF ≥ 35%), 55 (16%) early incomplete response (LVRR and LVEF