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Effectiveness and safety of adjunctive cenobamate in people with focal-onset epilepsy: Interim results after 24-week observational period from the BLESS study
Get PDFObjective: Cenobamate is an antiseizure medication (ASM) with a dual mechanism of action that was recently approved for the treatment of focal seizures in adults. This analysis aimed to describe the outcomes at 12 and 24 weeks after starting cenobamate therapy in a real-world setting. Methods: BLESS [NCT05859854] is an ongoing, observational, retrospective and prospective cohort study to evaluate the real-world effectiveness and safety of adjunctive cenobamate in adults with uncontrolled focal epilepsy. Subgroup analysis was performed in subjects with 2 to 3 previous ASMs (early users) and those with >3 previous ASMs (late users). Results: The second interim analysis of the BLESS study included 388 participants with a median (interquartile range) age of 43.0 (31.0–54.0) years. They had a median of 6.0 (4.0–9.0) prior ASMs and a median of 7.2 (3.0–20.6) monthly seizures at baseline. The median monthly seizure frequency was reduced by 59.9% (19.2%–87.3%) from baseline to 24 weeks; 229 (59.0%) subjects had a ≥50% seizure frequency reduction, and 44 (11.3%) showed sustained seizure freedom. The proportion of participants taking ≤2 concomitant ASMs increased from 217 (56.5%) at baseline to 239 (65.7%) at 24 weeks. Among the early users (n = 76, 19.6%), the median reduction in monthly seizure frequency at 24 weeks was 78.0% (50.0–97.1%), and 76.3% of subjects had a ≥50% response rate. The frequency of adverse drug reactions (ADRs) was 5.3% and 23.4% in early and late users. The most frequent ADRs were somnolence, dizziness, and balance disorder; after the occurrence of ADRs, 63.5% of participants maintained the prescribed dose, and 5.2% permanently discontinued treatment. Significance: Cenobamate was effective in reducing seizure frequency in a real-world setting and showed a manageable safety profile. The treatment with cenobamate also reduced the burden of concomitant ASMs in both early and late users
Post-mortem diagnosis of septic arthritis by Pasteurella multocida: a case report and literature review of fatal septic arthritis
Get PDFThe diagnosis of septic arthritis remains challenging in the clinical setting, often leading to a suspicion for medical liability. Our purpose is to describe an unusual case of a post-mortem diagnosis of P. multocida fatal septic arthritis, in a healthy 67-year-old woman presenting with pain in the right shoulder. Moreover, a literature review of cases of fatal septic arthritis is provided. The multidisciplinary approach consisted of a forensic autopsy and additional post-mortem analyses (microbiology, biochemical analyses, histopathology, and revision of radiological images) carried out during the prosecutor’s investigation for medical liability. A systematic review of the literature was performed to collect cases of fatal septic arthritis and to understand its frequency and characteristics. No clear cause of death was determined after the autopsy, that only highlighted swelling and purulent exudation in the right glenohumeral joint. The microbiological swab performed on the shoulder tested positive for P. multocida, while histopathological and biochemical data were consistent with a sepsis. These results guided the interview with the woman’s relatives, until a history of a previous contact with a stray cat emerged. The cause of death was deemed as fatal septic arthritis caused by P. multocida, occurred after cat scratches and bites and only diagnosed post-mortem. The review of the literature provided 15 articles about fatal septic arthritis, only 1 caused by P. multocida, and all with ante-mortem diagnosis. Given the nonspecific symptoms, usually including a localized pain, and the absence of a clear history, e.g. of animal contact, septic arthritis might represent an under-reported clinical and pathological diagnosis, leading to a judicial autopsy for the suspicion for medical liability. The post-mortem examination, following a multidisciplinary approach including integration of the clinical history, microbiological and histopathological analysis, could represent the only opportunity for the diagnosis of the cause of death
The pivotal role of Interleukin-23 in the skin-gut-joint axis
No full textInterleukin-23 (IL-23) plays a pivotal role in the intricate interplay between the skin, gut, and joints, contributing significantly to the pathogenesis of various inflammatory diseases including psoriasis, psoriatic arthritis (PsA), inflammatory bowel disease (IBD) and Behcet's disease. In recent years, several IL-23 inhibitors have been granted approval for the treatment of psoriasis, PsA and IBD. As up to one-third of patients diagnosed with psoriasis may go on to develop PsA and given the strong immunogenetic pathway incrimination of the IL-23 pathway in both psoriasis and PsA, dermatological lead therapy for psoriasis may therefore delay the development of PsA. Furthermore, patients with psoriasis or PsA are associated with increased risk of developing IBD. There is also evidence for psoriasis-directed therapy preventing IBD in keeping with the known pivotal role of IL-23 in both intestinal homeostasis and in the pathogenesis of IBD, including ulcerative colitis and Crohn's disease. This review discusses the multifaceted roles of IL-23 in regulating immune response and maintaining tissue homeostasis within the skin-gut-joint axis. In particular, the use of IL-23 inhibitors in trials in patients with psoriasis, IBD and PsA patients will also be discussed in relation to reverse translational immunology insights around inflammation in these domains
Antibiotic Use in Surgical Wards: A Point Prevalence Survey Based on the WHO AWaRe Methodology
No full textBackground/Objectives: In surgical antibiotic prophylaxis (SAP), most studies continue to report the number of prescriptions aggregated at the hospital level, rarely integrating the World Health Organization (WHO) Access, Watch, and Reserve (AWaRe) classes with standardized volume indicators. This study aimed to evaluate the utilization of antibiotics for SAP in a large Italian teaching hospital using both the number of prescriptions and defined daily doses (DDDs) and mapped the AWaRe models across different surgical specialties to highlight differences relevant to management. Methods: We conducted a prospective hospital-wide surveillance of all consecutive patients undergoing surgical procedures between March and May 2023 at the Azienda Ospedaliero-Universitaria delle Marche. Data included demographics, surgical specialty, and all antibiotic administrations with indication. For SAP, each prescription was classified according to the 2023 WHO AWaRe framework, and consumption was quantified using the WHO ATC/DDD methodology. Results: A total of 914 patients were monitored, with complete antibiotic data for 793 (86.8%). Among 433 SAP prescriptions, the most frequently used agent was cefazolin (82%), followed by amoxicillin/β-lactamase inhibitor (5%) and metronidazole (5%). According to AWaRe, 93% of SAP prescriptions were Access agents and 7% were Watch agents; no Reserve antibiotics were used. When expressed in DDDs (total: 443.5), 87.8% were Access and 12.2% Watch. Cefazolin accounted for over 85% of Access DDDs. Conclusions: By combining AWaRe classes with DDDs and resolving results by surgical specialty, this study extends hospital-level metrics and provides a pragmatic framework for SAP benchmarking. The predominance of Access agents is consistent with management objectives, while differences across specialties identify concrete tools for local quality improvement
A Linguistics-Based Approach to Refining Automatic Intent Detection in Conversational Agent Design
Get PDFIn this paper, we propose Automatic Intent Detector (AID), a framework for automatic intent detection to facilitate the creation of a conversational agent. AID follows an eight-step process incorporating best practices from the current literature and introducing innovative approaches in certain steps. The most notable innovation within AID is the automatic labeling of clusters, which is based on detailed and sophisticated rules derived from linguistics. These rules focus on morphosyntactic analysis, while also taking into account an aspect of semantic role theory. Furthermore, as for the overall validation of the results obtained, it provides an approach based on the concepts of semantic coherence, variability, and label appropriateness. After describing AID at the technical level, we illustrate the experiments we conducted both on a dataset widely used as benchmark in the literature and on a real corporate dataset. Finally, we present a critical discussion on the results obtaine
Development of a framework to track life safety levels of occupants in the event of a fire in buildings
No full textIn the operational phase of buildings, tracking what modifications can have an impact on the expected facility performances through manual checks can be impractical, albeit very important from a facility management perspective. The transition from the traditional prescriptive method towards the performance-based approach for building design and management may facilitate quantitative assessment of performances and may lead to conscious decisions which includes preparedness in the event of emergencies. The main goal of this paper is to develop a framework, compliant with a Building Information Modelling (BIM) environment, to track fire safety performance levels, in terms of life safety of occupants. As long as this is done through the definition of Key Performance Indicators (KPIs) that are being tracked continuously, facility managers can have a comprehensive and updated overview of current performances of a facility. More specifically, a single representative KPI was set and evaluated for several fire scenarios, using a set of simulation and data management tools. The results of the assessment were processed and transformed into a visual representation, referenced to a grid superimposed over the building layout to quantitatively represent the safety of occupants at every point of the building. The results were then sent back and displayed into the BIM model, for seamless accessibility by facility managers. The proposed methodology was tested on a pilot building, assuming two fire scenarios. This approach enabled supervision of a building’s compliance with fire safety requirements, in terms of occupants’ life safety, throughout the building lifecycle
Spatial distribution of dark heartwood and wood rot in sugar maple at the northern edge of its range
No full textThe wood of sugar maple trees (Acer saccharum Marsh.) is generally perceived as containing more defects, such as dark heart-wood and wood rot, at the northern limit of its range compared to southern locations; however, assessments of these internal defects have primarily relied on direct observation, limiting the scope of analysis. To enable large-scale assessments, models are needed to estimate the internal quality of individual trees based on external defects. Accordingly, this study aimed to investigate the relationships between external and internal defects within sugar maple stems. Then, large-scale estimates of the importance of such defects were produced to understand the effects of site conditions and climate. Increment cores were sampled from 1108 trees across 108 plots. Results revealed that the probability of wood rot and the proportion of internal defects were associated with the presence of cracks and fungal fruiting bodies. Also, colder sites increased the probability of wood rot as well as the proportion of the stem affected by internal defects. Moreover, the western Balsam fir–Yellow birch subdomain had both the highest probability of wood rot and the greatest proportion of internal defects. Future studies should examine how this spatial distribution could evolve with climate change
Development of PFAS-Free Locally Concentrated Ionic Liquid Electrolytes for High-Energy Lithium and Aluminum Metal Batteries
Get PDFLithium-ion batteries (LIBs) based on graphite anodes are a widely used state-of-the-art battery technology, but their energy density is approaching theoretical limits, prompting interest in lithium-metal batteries (LMBs) that can achieve higher energy density. In addition, the limited availability of lithium reserves raises supply concerns; therefore, research on postlithium metal batteries is underway. A major issue with these metal anodes, including lithium, is dendritic formation and insufficient reversibility, which leads to safety risks due to short circuits and the use of flammable electrolytes.Ionic liquid electrolytes (ILEs), composed of metal salts and ionic liquids, offer a safer alternative due to their nonflammable nature and high thermal stability. Moreover, they can enable high Coulombic efficiency (CE) for lithium metal anodes (LMAs) and allow reversible stripping/plating of various post-lithium metals for battery application, e.g., aluminum metal batteries (AMBs). Despite these advantages, ILEs suffer from high viscosity, which impairs ion transport and wettability. To resolve these challenges, researchers have developed locally concentrated ionic liquid electrolytes (LCILEs) by adding low-viscosity nonsolvating cosolvents, e.g., hydrofluoroether, to ILEs. These cosolvents do not coordinate with cationic charge carriers, thereby reducing viscosity and improving ion transport without compromising the compatibility of electrolytes with metal anodes. However, due to the inherent difference of molecular organic solvents and ionic liquids full of charged species, the most used nonsolvating cosolvents, i.e., hydrofluoroether, are less effective for ILEs with respect to concentrated electrolytes based on conventional organic solvents. Moreover, hydrofluoroether contains environmentally problematic -CF3 and/or -CF2- groups, i.e., per- and polyfluoroalkyl substances (PFAS), with their use subject to restrictions.In this Account, we provide an overview of the endeavors of our research group on the development of PFAS-free LCILEs for high-energy LMBs and AMBs. First, aromatic organic cations and aromatic less/nonfluorinated cosolvents are proposed to weaken the organic cation-anion interaction and strengthen the organic cation-cosolvent interaction, respectively. This is with consideration of the uncovered phase nanosegregation structure of LCILEs that effectively reduces the viscosity and promotes the Li+ transport ability with respect to the conventional nonaromatic organic cations and highly fluorinated PFAS cosolvents. Then, the effect of electrolyte components that do not coordinate to Li+, including organic cations and nonsolvating cosolvents, on the SEI composition and LMA reversibility is presented, which confirms the feasibility of reaching a high lithium stripping/plating CE up to 99.7% in the developed PFAS-free LCILEs. In the subsequent discussion on cathode compatibility, we present that in addition to LiFePO4 with high cyclability but inferior energy density, nickel-rich layered oxide and sulfurized polyacrylonitrile (SPAN) can be employed to construct high-energy LMBs for PFAS-free LCILEs with different anodic stability. Additionally, the feasible application of the LCILE strategy to promote the kinetics of AMBs relying on a different anode chemistry is demonstrated. Lastly, future research directions with an emphasis on nonsolvating component optimization, electrolyte dynamics, and electrode/electrolyte interphase formation are provided
ISOLATION AND MOLECULAR CHARACTERIZATION OF LINEZOLID-RESISTANT ENTEROCOCCI OF HUMAN, ANIMAL AND ENVIRONMENTAL ORIGIN
No full textGli oxazolidinoni, linezolid (LZD) e tedizolid, sono antibiotici di ultima risorsa approvati nel trattamento di gravi infezioni umane sostenute da batteri Gram-positivi antibiotico-resistenti, inclusi MRSA, VRE, pneumococchi e micobatteri MDR. Negli ultimi anni, si è registrata una considerevole diffusione di ceppi LZD-resistenti appartenenti a specie clinicamente rilevanti, quali Enterococcus faecalis ed Enterococcus faecium, anche in ambito animale e ambientale. Lo scopo di questo studio è stato di acquisire maggiori conoscenze sulla presenza, la localizzazione e la trasferibilità dei geni di LZD-resistenza in enterococchi di diversa origine. Complessivamente, 17 enterococchi animali, ambientali e clinici presentavano almeno un gene di LZD-resistenza. I ceppi, caratterizzati genotipicamente e fenotipicamente, sono stati sottoposti a WGS. Per verificare la trasferibilità della LZD-resistenza, tutti gli enterococchi sono stati utilizzati come donatori in esperimenti di coniugazione su filtro e in acquario (solo i ceppi ambientali) e di trasformazione. La presenza in enterococchi di diversa origine di plasmidi coniugativi o mobilizzabili identici o strettamente correlati indica che nella popolazione enterococcica circolano gli stessi elementi genetici ed evidenzia il ruolo chiave svolto dai questi elementi genetici nella diffusione della LZD-resistenza in Enterococcus spp. Questi risultati sottolineano anche la capacità degli antibiotici comunemente somministrati in medicina veterinaria di co-selezionare resistenze potenzialmente trasferibili a patogeni umani con gravi conseguenze per la salute pubblica. La resistenza agli antibiotici è un fenomeno complesso e multifattoriale il cui contenimento richiede strategie preventive e a lungo termine. Un approccio One Health può ridurre in modo efficace l’insorgenza e la diffusione di enterococchi LZD-resistenti preservando l’efficacia di questi farmaci “last resort” essenziali per il benessere delle generazioni presenti e futureOxazolidinones, linezolid (LZD) and tedizolid, are last-resort antibiotics approved for the treatment of severe human infections due to drug-resistant Gram-positive bacteria, including MRSA, VRE, and MDR pneumococci and mycobacteria. In recent years, a significant spread of clinically relevant LZD-resistant bacteria, such as Enterococcus faecalis and Enterococcus faecium, has been also detected in animal and environmental settings. The aim of this study was to gain more knowledge about the occurrence, genetic location, and transferability of LZD resistance genes in enterococci recovered from different sources. Overall, 17 enterococci from animal, environment and clinical samples carried at least one LZD resistance gene. The strains, genotypically and phenotypically characterized, were subjected to WGS. To verify the transferability of LZD resistance genes, all enterococci were used as donors in filter mating, aquaria microcosm (only environmental isolates), and transformation assays. The occurrence of identical or closely related conjugative or mobilizable plasmids in enterococci from different origin indicate that the same genetic elements circulate in the enterococcal population and emphasize the key role played by these genetic elements in the spread of LZD resistance in Enterococcus spp. These findings also underline the ability of antibiotics commonly administered in veterinary medicine to co-select resistances potentially transferable to human pathogens with serious public health consequences. The antibiotic resistance is a complex and multifactorial phenomenon that requires prospective and preventive strategies which are crucial to contain it. An One Health approach can effectively mitigate the emergence and dissemination of LZD-resistant enterococci ensuring the continued effectiveness of these last-resort drugs for the well-being of both current and future generations