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Abstract Background Bacterial antimicrobial resistance (AMR) is a global threat to both humans and livestock. Despite this, there is limited global consensus on data-informed, priority areas for intervention in both sectors. We compare current livestock AMR data collection efforts with other variables pertinent to human and livestock AMR to identify critical data gaps and mutual priorities. Methods We globally synthesized livestock AMR data from open-source surveillance reports and point prevalence surveys stratified for six pathogens (Escherichia coli, Staphylococcus aureus, non-typhoidal Salmonella, Campylobacter spp., Enterococcus faecalis, Enterococcus faecium) and eleven antimicrobial classes important in human and veterinary use, published between 2000 and 2020. We also included all livestock species represented in the data: cattle, chickens, pigs, sheep, turkeys, ducks, horses, buffaloes, and goats. We compared this data with intended priorities calculated from: disability-adjusted life years (DALYs), livestock antimicrobial usage (AMU), livestock biomass, and a global correlation exercise between livestock and human proportion of resistant isolates. Results Resistance to fluoroquinolones and macrolides in Staphylococcus aureus were identified as priorities in many countries but, less than 10% of these reported livestock AMR data. Resistance data for Escherichia coli specific to cattle, chickens, and pigs, which we prioritized, were also well collected. AMR data collection on non-typhoidal Salmonella and other livestock species were often not prioritized. Of 232 categories prioritized by at least one country, data were only collected for 48% (n = 112). Conclusions The lack of livestock AMR data globally for broad resistance in Staphylococcus aureus could underplay their zoonotic threat. Countries can bolster livestock AMR data collection, reporting, and intervention setting for Staphylococcus aureus as done for Escherichia coli. This framework can provide guidance on areas to strengthen AMR surveillance and decision-making for humans and livestock, and if done routinely, can adapt to resistance trends and priorities.

Abstract Aging is often associated with decline in brain processing power and neural predictive capabilities. To challenge this notion, we used magnetoencephalography (MEG) and magnetic resonance imaging (MRI) to record the whole-brain activity of 39 older adults (over 60 years old) and 37 young adults (aged 18–25 years) during recognition of previously memorised and varied musical sequences. Results reveal that when recognising memorised sequences, the brain of older compared to young adults reshapes its functional organisation. In fact, it shows increased early activity in sensory regions such as the left auditory cortex (100 ms and 250 ms after each note), and only moderate decreased activity (350 ms) in medial temporal lobe and prefrontal regions. When processing the varied sequences, older adults show a marked reduction of the fast-scale functionality (250 ms after each note) of higher-order brain regions including hippocampus, ventromedial prefrontal and inferior temporal cortices, while no differences are observed in the auditory cortex. Accordingly, young outperform older adults in the recognition of novel sequences, while no behavioural differences are observed with regards to memorised ones. Our findings show age-related neural changes in predictive and memory processes, integrating existing theories on compensatory neural mechanisms in non-pathological aging.

Abstract Generative deep learning is reshaping drug design. Chemical language models (CLMs) – which generate molecules in the form of molecular strings – bear particular promise for this endeavor. Here, we introduce a recent deep learning architecture, termed Structured State Space Sequence (S4) model, into de novo drug design. In addition to its unprecedented performance in various fields, S4 has shown remarkable capabilities to learn the global properties of sequences. This aspect is intriguing in chemical language modeling, where complex molecular properties like bioactivity can ‘emerge’ from separated portions in the molecular string. This observation gives rise to the following question: Can S4 advance chemical language modeling for de novo design? To provide an answer, we systematically benchmark S4 with state-of-the-art CLMs on an array of drug discovery tasks, such as the identification of bioactive compounds, and the design of drug-like molecules and natural products. S4 shows a superior capacity to learn complex molecular properties, while at the same time exploring diverse scaffolds. Finally, when applied prospectively to kinase inhibition, S4 designs eight of out ten molecules that are predicted as highly active by molecular dynamics simulations. Taken together, these findings advocate for the introduction of S4 into chemical language modeling – uncovering its untapped potential in the molecular sciences.

IntroductionThe ongoing emergence of SARS-CoV-2 variants poses significant challenges to existing therapeutics. The spike (S) glycoprotein is central to both viral entry and cell-to-cell transmission via syncytia formation, a process that confers resistance to neutralizing antibodies. The mechanisms underlying this resistance, particularly in relation to spike-mediated fusion, remain poorly understood.MethodsWe analyzed two clinical SARS-CoV-2 isolates differing by a single amino acid substitution in the S protein. Using biochemical and cell-based assays, we evaluated entry kinetics, syncytia formation, and the neutralizing efficacy of convalescent sera. These parameters were further correlated with S-mediated cell-cell fusion activity.ResultsThe single amino acid substitution significantly altered entry kinetics and enhanced syncytia formation. This modification did not diminished the neutralizing capacity of convalescent sera, but it increased the efficiency of S-induced cell-cell fusion. These findings highlight the mutation’s impact on viral transmissibility and immune evasion.DiscussionOur study demonstrates that even minor changes in the S protein can profoundly influence SARS-CoV-2 transmissibility and resistance to antibody-mediated neutralization. Understanding the molecular basis of S-mediated cell-cell fusion is crucial for anticipating the impact of emerging variants and developing next-generation therapeutic strategies. These insights provide a framework for predicting variant fitness and optimizing treatment approaches against future SARS-CoV-2 variants.

Neurogenesis occurs in the adult brain in the hippocampal dentate gyrus, an area that contains neurons which are vulnerable to insults and injury, such as severe seizures. Previous studies showed that increasing adult neurogenesis reduced neuronal damage after these seizures. Because the damage typically is followed by chronic life-long seizures (epilepsy), we asked if increasing adult-born neurons would prevent epilepsy. Adult-born neurons were selectively increased by deleting the pro-apoptotic gene Bax from Nestin-expressing progenitors. Tamoxifen was administered at 6 weeks of age to conditionally delete Bax in Nestin-CreERT2Baxfl/fl mice. Six weeks after tamoxifen administration, severe seizures (status epilepticus; SE) were induced by injection of the convulsant pilocarpine. After mice developed epilepsy, seizure frequency was quantified for 3 weeks. Mice with increased adult-born neurons exhibited fewer chronic seizures. Postictal depression was reduced also. These results were primarily in female mice, possibly because they were more affected by Bax deletion than males, consistent with sex differences in Bax. The female mice with enhanced adult-born neurons also showed less neuronal loss of hilar mossy cells and hilar somatostatin-expressing neurons than wild-type females or males, which is notable because loss of these two hilar cell types is implicated in epileptogenesis. The results suggest that selective Bax deletion to increase adult-born neurons can reduce experimental epilepsy, and the effect shows a striking sex difference. The results are surprising in light of past studies showing that suppressing adult-born neurons can also reduce chronic seizures.

Despite the spread of novel-generation cochlear-implant (CI) magnetic systems, access to magnetic resonance imaging (MRI) for CI recipients is still limited due to safety concerns. The aim of this study is to assess and record the experiences of Hires Ultra 3D (Advanced Bionics) recipients who underwent an MRI examination. A multicentric European survey about this topic was conducted focusing on safety issues, and the results were compared with the current literature. We collected a total of 65 MRI scans performed in 9 otologic referral centers for a total of 47 Hires Ultra 3D recipients, including, for the first time, 2 children and 3 teenagers. Preventive measures were represented by scanning time and sedation for children. Head wrapping was used in eight cases, and six of the eight cases received local anesthesia, even if both measures were not needed. Only three patients complained of pain (3/65 examinations, 4.6%) due to the tight head bandage, and one of the three cases required MRI scan interruption. No other adverse events were reported. We believe that these results should encourage MRI execution in accordance with manufacturer recommendations for Ultra 3D recipients.

Objective of the study: to investigate the drivers of the bidirectional relationships (that is, “scientific research with considerations of immediate use of results” and “scientific research without considerations of immediate use of results”) established between research groups and the small and medium-sized Brazilian enterprises (SMEs). Methodology/approach: estimation of four logistic regression models to investigate the drivers of the bidirectional relationships between research groups from the Directory of Research Groups in Brazil of the National Council for Scientific and Technological Development and 1819 enterprises with up to 499 employees. Main results: the economic sector and the access to public funding are able to influence the establishment of the bidirectional relationships between research groups and SMEs. Some specificities of the drivers of the bidirectional relationships are identified in different size ranges of SMEs. Theoretical/methodological contributions: adoption of a comprehensive database on collaboration between research groups and SMEs, based on informations from the Directory of Research Groups and the Annual Report of Social Information, and an approach to a theme that is insufficiently adressed in the literature. Relevance/originality: the assessment of how different categories of drivers influence the establishment of the bidirectional relationships between research groups and SMEs and the characterization of the drivers of these relationships in different size ranges of interactive enterprises. Social/Management Contributions: Innovation policy should address the factors that drive knowledge-related cooperation between public research organizations and SMEs.

Objetivo do estudo: investigar os fatores direcionadores (drivers) dos relacionamentos de tipo bidirecional (isto é, “pesquisa científica com considerações de uso imediato dos resultados” e “pesquisa cientifica sem considerações de uso imediato dos resultados”) estabelecidos entre grupos de pesquisa (GPs) e pequenas e médias empresas (PMEs) brasileiras. Metodologia/abordagem: estimação de quatro modelos de regressão logística para investigar os fatores direcionadores dos relacionamentos de tipo bidirecional estabelecidos entre GPs do Diretório dos Grupos de Pesquisa no Brasil (DGP) do Conselho Nacional de Desenvolvimento Científico e Tecnológico e 1819 empresas com até 499 empregados. Principais resultados: o setor de atividade e o acesso ao financiamento público são capazes de influenciar o estabelecimento de relacionamentos bidirecionais entre GPs e PMEs. Ademais, são identificadas especificidades dos drivers dos relacionamentos bidirecionais nas diferentes faixas de porte de PMEs. Contribuições teóricas/ metodológicas: exploração de uma base de dados abrangente sobre a colaboração entre GPs e PMEs, a partir da junção de informações do DGP e da Relação Anual de Informações Sociais (RAIS), e abordagem de uma temática ainda pouco explorada na literatura. Relevância/originalidade: avaliação de como diferentes categorias de fatores direcionadores conformam o estabelecimento de relacionamentos bidirecionais entre GPs e PMEs e caracterização dos drivers desses relacionamentos nas diferentes faixas de porte das empresas Contribuições sociais/para a gestão: a política de inovação deve contemplar os fatores direcionadores da cooperação entre as organizações públicas de pesquisa e PMEs relacionada ao conhecimento.

IntroductionThe Janus kinase (JAK) family includes four cytoplasmic tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) constitutively bound to several cytokine receptors. JAKs phosphorylate downstream signal transducers and activators of transcription (STAT). JAK-STAT5 pathways play a critical role in basophil and mast cell activation. Previous studies have demonstrated that inhibitors of JAK-STAT pathway blocked the activation of mast cells and basophils.MethodsIn this study, we investigated the in vitro effects of ruxolitinib, a JAK1/2 inhibitor, on IgE- and IL-3-mediated release of mediators from human basophils, as well as substance P-induced mediator release from skin mast cells (HSMCs).ResultsRuxolitinib concentration-dependently inhibited IgE-mediated release of preformed (histamine) and de novo synthesized mediators (leukotriene C4) from human basophils. Ruxolitinib also inhibited anti-IgE- and IL-3-mediated cytokine (IL-4 and IL-13) release from basophils, as well as the secretion of preformed mediators (histamine, tryptase, and chymase) from substance P-activated HSMCs.DiscussionThese results indicate that ruxolitinib, inhibiting the release of several mediators from human basophils and mast cells, is a potential candidate for the treatment of inflammatory disorders.

C. difficile infection (CDI) has an important impact on both human and animal health. The rapid detection and monitoring of C. difficile PCR-ribotypes (RTs) cause of CDI is critical to control and prevent this infection. This study reports the first application of the Molecular Beacon (MB)-based real-time PCR method in genotyping important C. difficile RTs of the main evolutionary clades. The cdtR gene was used as target and the cdtR sequences were analyzed after extraction from deposited genomes or were obtained after sequencing from strains of different origin. cdtR alleles were identified after sequence comparisons and MB-based real-time PCR assays were developed to discriminate them. In total, 550 cdtR sequences were compared, 38 SNPs were found, and five different cdtR alleles were identified. In total, one or two alleles were associated to the RTs grouped in the same evolutionary clade. A MB-based real-time assay was designed for each allele and for optimized testing of the C. difficile strains. The results obtained demonstrated that the MB-based real-time PCR assays developed in this study represent a powerful, original, and versatile tool to identify C. difficile types/clades and to monitor changes in the population structure of this important pathogen.

This study investigates the effectiveness of amplitude transformation in enhancing the performance and robustness of Multiscale Fuzzy Entropy for Alzheimer’s disease detection using electroencephalography signals. Multiscale Fuzzy Entropy is a complexity measure particularly sensitive to intra- and inter-subject variations in signal amplitude, as well as the selection of key parameters such as embedding dimension (m) and similarity criterion (r), which often result in inconsistent outcomes when applied to multivariate data, such as electroencephalography signals. To address these challenges and to generalize the possibility of adopting Multiscale Fuzzy Entropy as a diagnostic tool for Alzheimer’s disease, this research explores amplitude transformation preprocessing on electroencephalography signals in Multiscale Fuzzy Entropy calculation across varying parameters. The statistical analysis of the obtained results demonstrates that amplitude transformation preprocessing significantly enhances Multiscale Fuzzy Entropy’s ability to detect Alzheimer’s disease, achieving higher and more consistent significant comparison percentages, with an average of 73.2% across all parameter combinations, compared with only one raw data combination exceeding 65%. Clustering analysis corroborates these findings, showing that amplitude transformation improves the differentiation between Alzheimer’s disease patients and healthy subjects. These results highlight the potential of amplitude transformation to stabilize Multiscale Fuzzy Entropy performance, making it a more reliable tool for early Alzheimer’s disease detection.

IntroductionThe field of Medicines Development faces a continuous need for educational evolution to match the interdisciplinary and global nature of the pharmaceutical industry. This paper discusses the outcomes of a 7-year collaboration between King’s College London and the Global Medicines Development Professionals (GMDP) Academy, which aimed to address this need through a blended e-learning program.MethodsThe collaboration developed a comprehensive curriculum based on the PharmaTrain syllabus, delivered through a combination of asynchronous and synchronous e-learning methods. The program targeted a diverse range of professionals serving in areas related to Medical Affairs.ResultsOver seven annual cohorts, 682 participants from eighty-six countries were enrolled in the program. The program’s effectiveness was assessed using Kirkpatrick’s model, showing elevated levels of satisfaction (over 4.0 on a five-point scale), suggesting significant gains in competence at the cognitive level and leveraged performance. Notably, 70% of responding alumni reported significant improvement in their functions, corroborated by 30% of their supervisors. The further long-term impact of the program on their respective organization has not been established.DiscussionThe GMDP Academy’s program has significantly contributed to life-long learning in Medicines Development, addressing educational gaps and fostering interdisciplinary collaboration. Its success highlights the importance of continuous education in keeping pace with the industry’s evolving demands and underscores the potential of blended learning in achieving educational objectives in pharmaceutical medicine.

Summary: Background: The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced. Methods: The EPICOVIDEHA registry (National Clinical Trials Identifier, NCT04733729) gathers COVID-19 data from hematological malignancy patients since the pandemic's start worldwide. It spans various global locations, allowing comprehensive analysis over the first three years (2020–2022). Findings: The EPICOVIDEHA registry collected data from January 2020 to December 2022, involving 8767 COVID-19 cases in hematological malignancy patients from 152 centers across 41 countries, with 42% being female. Over this period, there was a significant reduction in critical infections and an overall decrease in mortality from 29% to 4%. However, hospitalization, particularly in the ICU, remained associated with higher mortality rates. Factors contributing to increased mortality included age, multiple comorbidities, active malignancy at COVID-19 onset, pulmonary symptoms, and hospitalization. On the positive side, vaccination with one to two doses or three or more doses, as well as encountering COVID-19 in 2022, were associated with improved survival. Interpretation: Patients with hematological malignancies still face elevated risks, despite reductions in critical infections and overall mortality rates over time. Hospitalization, especially in ICUs, remains a significant concern. The study underscores the importance of vaccination and the timing of COVID-19 exposure in 2022 for enhanced survival in this patient group. Ongoing monitoring and targeted interventions are essential to support this vulnerable population, emphasizing the critical role of timely diagnosis and prompt treatment in preventing severe COVID-19 cases. Funding: Not applicable.

Background: Juvenile urinary bladder rhabdomyosarcoma is a known entity, however literature regarding its clinical behavior and endoscopic features is scarce. The aim of this study was to describe clinical, endoscopic features and outcome of urinary bladder rhabdomyosarcoma in dogs. Case Description: Dogs undergoing transurethral endoscopy and with a histological diagnosis of urinary bladder rhabdomyosarcoma were retrospectively collected. Seven dogs with a median age of 18 months (range 6-32 months) were included in this retrospective, multicenter, descriptive study. Median tumor size was 58 mm (range 30-65 mm), and tumor location was bladder neck in three cases, trigone in two cases and bladder body in two cases. Two dogs had monolateral ureteral obstruction. Two dogs presented with regional lymphadenopathy and one dog had lung lesions suggestive of metastatic disease. A grape-like mass was reported in four cases and solid in two, with variable consistency (two friables, two firms, two not reported). Tumor treatments included surgery in three cases, surgery and adjuvant doxorubicin in one case, and palliative therapy in three cases. Overall median survival time was 45 days. Survival times were shorter (range 20-45 days) for dogs treated with palliative care than for dogs treated with curative-intent treatment (range 70-120 days). Conclusion: Urinary bladder rhabdomyosarcoma should be considered as a differential diagnosis in young dogs presenting with bladder masses. In this study, urinary bladder rhabdomyosarcoma confirmed its aggressive clinical behavior. Surgery and chemotherapy seem to increase survival times but prognosis remains poor. [Open Vet J 2023; 13(11.000): 1498-1503]