Enterobacterales, with the lack of a dedicated regional IT platform reported in most cases. The results of this study depict a highly heterogeneous scenario and suggest that more efforts aimed at strengthening national AMR surveillance systems are needed.Antimicrobial resistance (AMR) national surveillance systems in Italy lack alert systems for timely detection of emerging profiles of AMR with potential relevance to public health. Furthermore, the existence of early warning systems (EWS) at subnational level is unclear. This study aims at mapping and characterizing EWS for microbiological threats available at regional level in Italy, focusing on emerging AMR, and at outlining potential barriers and facilitators to their development/implementation. To this end, a three-section, web-based survey was developed and administered to all Italian regional AMR representatives from June to August 2022. Twenty out of twenty-one regions and autonomous provinces (95.2%) responded to the survey. Among these, nine (45%) reported the implementation of EWS for microbiological threats at regional level, three (15%) reported that EWS are in the process of being developed, and eight (40%) reported that EWS are not currently available. EWS characteristics varied widely among the identified systems concerning both AMR profiles reported and data flow: the microorganisms most frequently included were extensively drug-resistant (XDR)  Antimicrobial resistance (AMR), which occurs when microorganisms  develop the ability of being resistant to one or several antimicrobial agents, has been declared by the World Health Organization (WHO) as one of the top ten global public health threats, requiring urgent multisectoral actions ,2. ImpliEnterobacterales bloodstream infections surveillance system (CRE). Through AR-ISS, Italy provides AMR data to the Global Antimicrobial Resistance and Use Surveillance System (GLASS) launched by the WHO and participates in the European Antimicrobial Resistance Surveillance Network (EARS-Net) coordinated by the European Centre for Disease Prevention and Control (ECDC) [One of the main areas of intervention identified in the plan involves surveillance, an essential tool to address policies and infection prevention and control activities whose pivotal role has been highlighted at international level ,10. In Il (ECDC) ,12.However, these AMR surveillance systems have some limitations, including the lack of an alert and early reporting system for timely detection of emerging profiles of AMR with potential relevance to public health. Furthermore, since the Italian healthcare system is a Beveridge-like model characterized by a high degree of decentralization  with 21 ® , an online survey tool, which was sent by e-mail to institutional e-mail addresses. Participation was on a voluntary basis.From June to August 2022, all Italian regional AMR representatives were invited to complete a questionnaire developed through SurveymonkeyThe questionnaire was self-administered and took approximately fifteen minutes to complete. It consisted of closed- and open-ended questions grouped into three main sections. The first section aimed at mapping EWS for microbiological threats—focusing on emerging profiles of AMR—available at the regional level in Italy. The second section explored the characteristics of existing systems . In the third section, regional AMR representatives were asked to outline barriers and facilitators to the development/implementation of EWS.In order to achieve a multidisciplinary approach, eleven experts were identified and then invited to participate to the study, including infectious diseases experts, epidemiologists and microbiologists from the ISS (Infectious Disease Department), researchers from several regional health services , and public health experts from Sant’Anna School of Advanced Study—Pisa, from the University of Pisa, and from the University of Catania. The survey was developed following consensus among the identified experts and taking into consideration the framework defined by the WHO in the context of the Emerging Antimicrobial Resistance Reporting component of the Global Antimicrobial Resistance Surveillance System (GLASS-EAR) .Data were descriptively analyzed. Specifically, data were described using counts and percentages and through graphical representations (heatmaps and maps) and tables. All analyses were carried out using Excel software—version 2303, except for the map , which wIn total, 20 out of 21 (95.2%) regions and autonomous provinces (AA.PP.) responded to the survey (Campania Region did not participate). Among those, 45%  reported the implementation of EWS for microbiological threats; 15%  reported that EWS are under development; 40%  reported that EWS at the regional level are currently not available. Among the eight regions without a structured alert system, 50%  reported the presence of a list of AMR profiles/events requiring local monitoring and endorsed at the regional level .Among the three regions where EWS are under development and the eight regions without a regional alert system, two out three and seven out of eight reported, respectively, the availability of EWS for microbiological threats—including emerging AMR—at the local level, where health services are delivered by Local Health Authorities .Among the nine available regional EWS, eight provided information concerning AMR profiles that are expected to be reported: one system included novel genetic determinants of resistance , two systems included extensively drug-resistant (XDR) phenotypes not previously detected at regional/national level, two systems included an unusual increase in critical resistance/extensive resistant phenotypes, three systems included pan-drug resistant (PDR) phenotypes, four systems included critical resistance according to microbiology laboratory assessment, and all systems included pre-defined critical resistance phenotypes .Seven out of eight EWS that included pre-defined critical resistance phenotypes provided further details on critical resistance phenotypes that are expected to be reported .Enterobacterales (seven out of seven); XDR including Colistin-resistant Enterobacterales (five out of seven); Vancomycin-resistant Daptomycin-nonsusceptible (NS) or Linezolid-resistant or Telavancin-, Dalbavancin-, Oritavancin-NS Enterococcus spp. (five out of seven); and Vancomycin-resistant or Telavancin-NS or Dalbavancin-NS or Oritavancin-NS or Tigecycline-NS or Daptomycin-NS or Linezolid-resistant Staphylococcus aureus (five out of seven). None of the existing EWS included Metronidazole-resistant Clostridioides difficile and Metronidazole-resistant Bacteroides spp.The most frequent profiles were the following: XDR In all available regional EWS, the setting where specimens are collected was hospital-based; in five out of nine , the setting included long-term care facilities, whereas in four regions/AA.PP. , the setting included the community as well.In two out of nine available regional EWS (Molise and Trento A.P.), reporting came from reference laboratories; in four out of nine , reporting involved any microbiology laboratory, and isolates were sent to a reference laboratory when deemed appropriate; in three out of nine , reporting involved any microbiology laboratory (systematic transfer of specimens to a reference laboratory is not planned); in five out of nine , reporting came from health directorates; in two out of nine (Piedmont and Trento A.P.), reporting came from public health departments.The reporting procedure involved the use of a web form/software in six out of nine available regional EWS . The procedure was paper-based in three out of nine EWS , and other methods  were included in six out of nine EWS .Clinical microbiologists were primarily in charge of reporting in seven out of nine available regional EWS . Reporting was provided to health directorates in most cases .Reporting times varied widely: of the nine regional EWS, real-time reporting was provided in two EWS ; in two EWS (Bolzano A.P. and Emilia-Romagna), reporting was provided within 24 h and in one (Sicily) within 48 h, in one (Veneto) on a monthly basis, in one (Basilicata) within 72 h, and in two EWS (Molise and Trento A.P.) at the time of results validation.A dedicated regional IT platform for structured data sharing between local and regional levels was in place in three out of nine regional EWS  and not available in the six remaining systems.Pre-defined reporting was provided by five out of nine EWS , while pre-defined reporting was not included in four EWS .Actions taken following the reporting were outlined in six out of nine available EWS  and included, in all instances, the implementation of infection and control measures at local level.Performance measurement and evaluation of available EWS were not implemented in eight out of nine EWS; in one out of nine (Trento A.P.), EWS performance measurement and evaluation were implemented, but no further details are available.Data quality monitoring was provided in three out of nine  EWS and not included in the six remaining systems .Among the nine regions/AA.PP. that implemented EWS, seven provided information concerning the availability of a formalized network of reference laboratories (RL) for confirmation of unusual antimicrobial resistance. Among these, in four out of seven , a network of reference laboratories was available; in two out of seven , a network of RL was not available; in one out of seven (Piedmont), the network was in the process of being developed.A summary of the results outlined above is provided in Among the 20 respondents, 17 provided information concerning barriers to the development and/or the implementation of regional EWS, while 14 provided information concerning facilitators.The main barriers were identified as the lack of appropriate software, privacy issues, and poor cooperation among microbiology laboratories.The main facilitators were outlined as proper data collection and appropriate technology availability, the presence of a network of microbiology laboratories, and the clear definition of responsibilities in the context of the system.Emerging antimicrobial resistance (AMR) may represent a concerning international public health risk . In OctoAs a result, the GLASS-EAR component was developed, providing a tool embedded in the GLASS IT platform where experts can share information concerning emerging AMR events that may have an impact on surveillance and control practices ,18.However, the availability of EWS for monitoring emerging AMR at the international level has not yet been deeply investigated, and the publicly available information on existing alert systems is not broadly detailed, particularly concerning methodologic aspects. Focusing on newly launched antibiotics within the healthcare setting, the requirements needed to develop a standardized resistance monitoring system were explored in a recently published study. The authors deemed as particularly relevant the implementation of an early warning surveillance as soon as a newly introduced antimicrobial agent is used locally, taking into consideration that current AMR surveillance systems mainly focus on resistance to older antimicrobial agents, and the measurement of resistance to newly launched drugs such as those considered “last resort” options seems to not yet be broadly implemented in the context of the public sector .In Italy, data on the consumption of “last resort” antibiotics, according to the AWaRe classification developed by the WHO , are avaLess than half of Italian regions have implemented alert systems at the regional level, most of which are available in northern Italy, reflecting the imbalance between the north and south of the country . FurtherAmong existing Italian regional alert systems, our study highlighted the presence of differences involving several aspects. Most of the AMR profiles investigated were included only in two regional EWS, with novel genetic determinants of resistance reported only in one system and pre-defined critical resistance phenotypes included in all existing EWS. However, none of the systems were homogeneous with the others, especially with regard to data flow. In particular, timing for reporting was defined as real-time or on a daily basis only in a few regional EWS. These findings could be explained considering that regional organizational models can be quite different, with data collection involving from one to multiple microbiology laboratories, and are consistent with a recently performed analysis of surveillance for control of antimicrobial resistance in Europe, which found that only 3% of the surveillance systems in Europe provided real-time access to AMR data .Of interest, moreover, the lack of a dedicated regional IT platform in most cases and the availability of a network of reference laboratories in four out of nine regional EWS are findings that are consistent with some of the reported barriers to the development/implementation of alert systems.These aspects need to be addressed in the process of strengthening national AMR surveillance systems, including the need for an adequate reference laboratories network at the national level and the need to achieve technological improvements. The scenario also highlights the importance of identifying examples of good practice at the subnational level and of achieving cooperation and coordination between the regional and the central levels, considering that AMR has been outlined as a serious national and regional challenge requiring a comprehensive and coordinated response . These cThe identification of a clear strategy for delivering sustainable surveillance through existing capacity and potential for innovation was outlined as an opportunity for addressing challenges as part of effective and sustainable efforts to manage the AMR threat in a recently performed analysis of existing national action plans for AMR .Several initiatives are currently ongoing in Europe in order to strengthen national surveillance and outbreak investigation capacities and improve molecular surveillance data availability and quality as well at the European level. Enterobacterales (CCRE) and additional healthcare-associated pathogens of public health relevance [Italy is among the participating countries of the EURGen-RefLabCap project  coordinated by the Technical University of Denmark  and the Statens Serum Institut  in close cooperation with the European Centre of Disease Prevention and Control (ECDC). The project aims to support national references laboratories (NRLs) in improving their capacities in detection and phenotypic and genotypic characterization of Carbapenem- and/or Colistin-Resistant elevance .Furthermore, according to the most recent report on antibiotics use in Italy, a proposal for the reorganization and strengthening of microbiology laboratories networks will be provided by the National Agency for Regional Health Services (AGENAS), aiming at supporting the National Plan Against Antimicrobial Resistance (PNCAR) .This study has some limitations. Firstly, we provided a general picture at the regional level, but we did not conduct an in-depth analysis concerning EWS available at the local level, and we did not explore the coordination between human, veterinary, and food surveillance systems, which is essential according to the “one health” approach . SecondlIn conclusion, to the best of our knowledge, this is the first study that explored the availability and the characteristics of early warning systems for emerging profiles of AMR at the regional level in Italy, providing relevant data to regional and national authorities for the achievement of one of the goals included in the National Plan Against Antimicrobial Resistance.The results of this study suggest that more efforts aimed at strengthening AMR surveillance systems currently in place in Italy are needed, including the identification of the key elements required to develop an effective national early warning system with a bidirectional data flow. Technological issues such as the availability and standardization of dedicated laboratory information management software, which could allow real-time data collection and reporting with regional coverage, need to be addressed. Furthermore, a multidisciplinary and cross-sectoral approach should be considered, establishing common objectives and methods in order to provide the integration of animal, food, and human data and timely data sharing at the national and subnational levels, preventing the spread of microorganisms that may threaten public health also at the international level.


Recently, due to the increasing spread of antimicrobial resistance (AMR), AMR has received great attention from researchers and governments. It is expected that AMR will be the most important public health issue and challenge in this century  can quickly move between humans, agriculture, and the environment  could be easily transferred from paddy soil to field water. Similarly, Han et al. reviewed recent studies on the associations of ARGs with microbiomes and the mechanisms of ARG dissemination in soil. They found that the presence of ARGs in soil is inherent and ancient, and plants and animals can absorb ARGs from the soil and then transmit them to humans. Also, Gibson et al. were the first to analyze the impact on AMR in wastewater treatment plants of the effect of microbial immigration on the indigenous resident microbial communities.As mentioned above, ARGs circulate among the environment, agriculture, and humans, which represent the different components of the One Health framework. In ecological processes, soil bacteria play an important role and are highly influenced by various agricultural activities, which impact the chemical, macroscopic, and microbiological composition. Ewbank et al. evaluated cloacal swabs from wild Fregata magnificens in the Alcatrazes Archipelago, which is a nature reserve without any human occupation before. They found a highly virulent multidrug-resistant (MDR) ST648 (O153:H9) pandemic Escherichia coli clone, which is one of the most commonly reported international sequence types (STs) in the global human–animal–environmental interface. Alcatrazes Fregata magnificens most likely have extremely limited to no direct contact with humans, due to their site fidelity and limited roosting and nesting area on the island. The authors speculated that a route of infection of Alcatrazes Fregata magnificens by the abovementioned E. coli strain may involve their continuous close contact and body fluid exchange with other frigatebirds and birds of other genera [especially (Sula leucogaster and Coragyps atratus)] using the area.Wild birds, which are an integral part of the ecological system, have been assessed as possible reservoirs and disseminators of ARGs to insular biomes in experimental studies, but their potential role as dispersers under real-world conditions remains unknown. Island settings provide a unique opportunity for scientists to evaluate and debate the spread of ARGs by wild birds in the ecological system. Shrestha et al. evaluated the association between antimicrobial use in turkey flocks and the development of AMR in North America. Using the indicator bacterium E. coli, they reported the effect of the antimicrobial treatment for certain diseases  on the development of resistance to certain antimicrobials. they concluded that from an antimicrobial management perspective, interventions at the producer level may have the greatest impact on reducing AMR establishment in E. coli isolates.Cheng et al. compared the effects of these two treatments on the microbiota of coccidia-infected broilers' cecal contents, manure compost, and loam soil. They found that both treatments suppressed certain opportunistic pathogens, but they failed to repair the large changes in the cecal microbiota caused by coccidia infection. The in vitro effect of ethanamizuril on compost and soil microbiota seemed to be slight, while salinomycin had a large impact on these microbial communities.In recent years, there has been increasing attention on the association between gut dysbiosis and AMR. Gut dysbiosis contributes to the loss of colonization resistance, which can be followed by increased AMR. However, research has mainly focused on the effect of antibiotics on the gut microbiota, while ignoring the effect of other drugs such as antiparasitic drugs. The effects of salinomycin and ethanamizuril  on the microbiota of cecal contents, manure compost, and soil were unknown. Gu et al. reported that geraniol, the main component of various essential oils, not only effectively inhibits the formation of methicillin-resistant Staphylococcus aureus biofilms, but also relieves inflammatory symptoms and potentiates vancomycin by destroying biofilm structures. There is evidence that the activity of conventional antibiotics can be enhanced when used synergistically with natural product extracts. Breser et al. studied the effect of cloxacillin and chitosan alone or in combination on non-S. aureus isolates with various lifestyles and biofilm-forming abilities. They found that the addition of chitosan to the cloxacillin treatment significantly reduced the bactericidal concentration of the antibiotic, irrespective of the biomass density of the biofilm or the AMR pattern of the non-S. aureus isolates.This Research Topic also focuses on how to prevent and control AMR. Natural product extracts are increasingly being recognized as alternative antimicrobials for the treatment of infectious diseases in animals. Kim et al. collected 2010–2021 pathogen and AMR data from >600 farms in the United States to conduct AMR time series analyses using machine learning. They established three machine learning-based time series analyses to predict the future AMR rate. They found that the seasonal auto-regressive integrated moving average (SARIMA) approach had low root mean square error compared to other approaches, and it worked even for highly dynamic time series.Rapid detection of AMR and prediction of future AMR burden and trends are crucial for implementing appropriate interventions to mitigate AMR. Several studies have used various machine learning algorithms to predict AMR rates using data on phenotypes and genotypes. Zhou et al. found that 87.85% of E. coli isolates from chicken and pigs had MDR (the main MDR pattern was AMP-SPT-TET-FFC-SF-SXT) and there were 65 sequence types (STs) among the E. coli isolates. Yang et al. screened a total 921 samples from pigs and humans in China for the plasmid-encoded tet(X4) ARG . They isolated two tet(X4)-positive strains, and conjugation experiments showed that the two tet(X4)-encoding plasmids could be transferred from K. pneumoniae to E. coli.Whole-genome sequencing plays an extremely important role in AMR research, and it has provided insights into AMR mechanisms, pathogen evolution, and population dynamics in global pathogen surveillance. In conclusion, we believe that the data collected in the aforementioned studies and reviews can provide physicians, veterinarians, environmental scientists, public health professionals, wildlife experts, and many others with a toolkit for use within the One Health framework.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Molecular representations are of fundamental importance for the modeling and analysing molecular systems. The successes in drug design and materials discovery have been greatly contributed by molecular representation models. In this paper, we present a computational framework for molecular representation that is mathematically rigorous and based on the persistent Dirac operator. The properties of the discrete weighted and unweighted Dirac matrix are systematically discussed, and the biological meanings of both homological and non-homological eigenvectors are studied. We also evaluate the impact of various weighting schemes on the weighted Dirac matrix. Additionally, a set of physical persistent attributes that characterize the persistence and variation of spectrum properties of Dirac matrices during a filtration process is proposed to be molecular fingerprints. Our persistent attributes are used to classify molecular configurations of nine different types of organic-inorganic halide perovskites. The combination of persistent attributes with gradient boosting tree model has achieved great success in molecular solvation free energy prediction. The results show that our model is effective in characterizing the molecular structures, demonstrating the power of our molecular representation and featurization approach. Different molecular fingerprints have also been proposed for machine learning and deep learning models to predict molecular functions and properties8. Despite significant advances, the development of highly efficient descriptors remains a major challenge for QSAR/QSPR and learning models in the analysis of molecular data in the fields of materials, chemistry, and biology2.Molecular representation and featurization play an essential role in physical as well as in data-driven learning models. The relationship between the structure and function of molecules is complex, and a comprehensive understanding of the structural properties is crucial to extract functional information. To establish explicit linear or nonlinear relationships between molecular structure and function, various quantitative structure-activity/property relationship (QSAR/QSPR) models have been developed18 are arguably the most widely used tools for molecular representations in molecular dynamics simulation, coarse-grained models, elastic network models, QSAR/QSPR, graph neural networks, etc. In general, a molecule (or a molecular complex) is modeled as a graph with each vertex representing an atom, an amino acid, a domain, or an entire molecule, and edge representing covalent-bond, non-covalent-bond, or more general interaction. However, graphs are designed for the characterization of pairwise interactions. To capture higher-order interactions, topological representations, such as multilayer networks19, simplicial complexes22, hypergraphs24, etc, should be considered. Among them, multilayer networks have been used in the characterization of higher-order dynamics28 and synchronization dynamics31. As a generalization of graphs, simplicial complexes are made not only of 0-simplices (nodes) and 1-simplices (edges), but also of higher-dimensional simplices, such as 2-simplices (triangles), 3-simplices (tetrahedron), etc. Note that higher-order networks and simplicial complexes can describe the many-body interactions beyond pairwise interactions. Hypergraphs are a further generalization of simplicial complexes. An hypergraph is composed of hyperedges, which are formed by a set of vertices. Recently, simplicial complexes and hypergraphs have been used in molecular representations and have allowed improved performance of drug design algorithms, in particular, in the protein-ligand binding affinity prediction.Graph models33 and combinatorial Hodge theory-based molecular descriptors has had a significant impact on drug design. These models have been successful in various stages of drug design, such as predicting protein-ligand binding affinity39, protein stability changes resulting from mutations41, toxicity42, solvation free energy44, partition coefficient and aqueous solubility45, and identifying binding pockets46. In comparison to traditional molecular representations, these models have demonstrated superior performance in the D3R Grand Challenge48. TDA’s fundamental mathematical concept involves using persistent homology to extract topological information, tracking the change of homology generators of simplicial complexes over a filtration process. In particular, the topological invariant Betti numbers can be obtained from the kernel of combinatorial Hodge Laplacian (HL) matrix. Interestingly, the Forman Ricci curvature can be obtained via the Bochner–Weitzenböck decomposition of HL matrix6. The great success of TDA and combinatorial Hodge theory based molecular descriptors in learning models is due to their characterization of structures with intrinsic invariants, including Betti numbers and Ricci curvatures. These intrinsic descriptors are well defined mathematical observables that characterize fundamental topological and geometrical properties of real datasets, thus they have an excellent transferability for learning models.Based on topological representations, molecular descriptors or fingerprints can be generated and further used as features for learning models. The recent emergence of topological data analysis (TDA)55 is a first-order differential operator which can be interpreted as the square root of Hodge Laplace operator. This operator has been developed on graphs and simplicial complexes and used in TDA and for investigating dynamics of topological signals58. Moreover, the persistent Dirac model can be used in the quantum algorithm of persistent homology59. Here we present a rigorous mathematical theory for persistent Dirac through the commutative diagram of discrete Dirac operator over a filtration process. The commutative diagram is similar to the ones in persistent spectral graph60, persistent Hodge Laplacian61, and persistent sheaf Laplacian62. Further, we develop a series of persistent attributes from persistent Dirac, and use them as descriptors to characterize molecular structures.Inspired by the success of Hodge Laplacian matrix in molecular sciences, here we propose the persistent Dirac based molecular representation and fingerprint. The discrete Dirac operator63 is carefully defined. In particular, we analyse the influence of weighting schemes on the spectral properties of molecular structures. The persistent Dirac is then introduced and is employed for the clustering of molecular configurations from the molecular dynamic simulations of nine types of organic-inorganic halide perovskites (OIHP). By the comparison with several existing models, we show that our model is highly efficient in clustering the structure configurations. Further, the combination of persistent attributes with gradient boosting tree model has achieved great success in molecular solvation free energy prediction. This demonstrates the great potential of our persistent Dirac-based fingerprints in molecular representation and featurization.Our work starts with a systematic study of the spectrum of the discrete Dirac matrix. In particular, we identify the geometric and topological properties of both non-homology and homology eigenvectors for molecular structures. We generalize these results to weighted simplicial complexes on top of which the weighted Dirac operatorThe paper is organized as follows. Section “In this section, we discuss the discrete Dirac models, including discrete Dirac matrices and weighted Dirac matrices for biomolecular structure representation and characterization. Different from previous graph-based models, molecular structures are represented based on simplicial complexes, and algebraic tools from chain groups, homology groups, boundary operators and Dirac matrices, are used to reveal deeper geometric and topological properties.p-dimensional simplicial complex is formed by simplices of dimension up to p. Every p dimensional simplex consists of a set of Generally speaking, a simplicial complex can be viewed as a higher-dimensional generalization of graphs. A p-simplices belonging to the simplicial complex 64.Here and in the following we indicate with p-dimensional simplices (i)(ii)If either condition is satisfied, but both conditions do not hold at the same time, Two p-dimensional oriented simplex In homology, a p-dimensional chain group p-simplices in p-simplex p-dimensional chains p-chain p and the boundary of p-simplex is made of p-dimensional simplices For an oriented simplicial complex p-th cycle group p-th boundary group p-th homology group is defined as p-th Betti number that satisfiesThe p-dimensional weighted Hodge Laplacian The Computationally, the information for weighted boundary operators acting from finite dimensional chain groups p-simplices respectively in a simplicial complex i-th j-th p-simplex More specifically, let Since the unweighted boundary operator It is important to observe that Since 0-simplices have no lower adjacent neighbors, any two 0-simplices Hence, the matrix elements of the Hodge Laplacian pth Betti number as follows,65   \documen63:p-simplex For the rest of the paper, the metric matrices With the weighted Dirac matrix 70z occurs when Previously, a general Dirac matrix has been defined asp-simplices in 70 isFor a simplicial complex Figure mentclass2pt{minimNote that by taking the square of Recall that Let v if and only ifEssentially, the above shows that the Dirac operator of a simplicial complex satisfies v (ii)It is easy to derive the above cases by considering w. This implies that Now, we consider the relationship between the eigenspectrum of since by , either mentclasspt{minimaw. This implies that Similarly, if mentclasspt{minimav is a vector consisting of block vectors This leads us to the following relations connecting Hence, the kernel of k-th homology and k-th non-homology information within the structural data for all Therefore, the eigenvectors of Mathematically, the eigenvectors corresponding to the zero eigenvalues are known as homology generators while those from non-zero eigenvalues are the non-homology generators. Both of them can be used in structural clustering. More specifically, the homology generators can be used for clustering structures based on their loop or circle components, while non-homology generators are related to the spectral clustering, in which communities and clusters are based on their distances. Figure Figure entclass1pt{minimaFigure entclass1pt{minimaThe weighted Dirac matrix has different spectral properties based on the different weighting schemes. Figure ed using . The disIn general, the weight of a simplex has an inverse effect on the corresponding element of the homology eigenvectors . When the simplex has a smaller weight, the corresponding element of the homology eigenvectors has larger magnitude. Similar patterns also appear in non-homology generators. Fig. 62. Their essential idea is to explore the persistence of spectral information during the filtration process. Here we develop the rigorous mathematical framework for persistent Dirac.Recently, persistent Laplacian and persistent sheaf Laplacians have been developedp-chains in Let Let p-dimensional boundary matrices Notice that The persistent Dirac operator p-th persistent Hodge Laplacian can be defined asp-th persistent lower and upper Hodge Laplacians p-th persistent Dirac operator equals to the rank of k-th persistent Betti numbers, where a, b)-persistent homology groups. The -persistent homology groups characterizes the homology generators that are born at time a and survive to time b.Further, the Based on , the folFigure 69,m-th spectral moments of Dirac matrices and For any Dirac matrix, its non-zero eigenvalues come in pairs. Each pair contains one negative eigenvalue and one positive counterpart. For the set of all its positive eigenvalues, a Dirac Zeta function can be defined as followsq-Dirac complexity of a simplicial complex 70. k-simplices and Furthermore, the 1, can be written asUsing Eq. , \docume(i)(ii)(iii)(iv)Standard Deviation(v)Laplacian Graph Energy (vi)(Signless) Euler–Poincaré Number  (vii)Generalised Mean Graph Energy (viii)Spectral 2nd Moment (ix)(x)Quasi-Wiener Index (xi)Spanning Tree Number In addition to the 11 statistical attributes, we also consider the persistent multiplicity of zero eigenvalues. (xii)Persistent Multiplicity of zero eigenvalues.Figure k-th persistent Betti numbers for To summarize, we consolidate and consider 11 statistical and combinatorial attributes as molecular descriptors for each given set of positive eigenvalues At the very start of the filtration, there are 16 isolated atoms which means that there are 16 connected components. Hence, the persistent multiplicity of sing Eq. , the perf increases, the size of As filtration parameter p-simplex. When this happens, the size of At filtration size 4.7Å, a complete simplicial complex is achieved, i.e., any sing Eq. , the per71. They have consistently outperformed traditional graph-based models in various tasks of drug design. Here we study the representation capability of Persistent Dirac in molecular data analysis.Recently, a series of persistent models, including persistent homology, persistent spectral, persistent Ricci curvature, and persistent Laplacian, have demonstrated their great power in molecular representationsWe consider the organic-inorganic halide perovskite (OIHP) dataset. More specifically, three kinds of Methylammonium lead halides .Computationally, our persistent Dirac is generated based on Alpha complex and the filtration parameter is the circumradius. More specifically, for each frame, an Alpha complex is constructed based on Delauney triangulation and circumradius of the simplex. The Dirac matrices Figure 72. The FreeSolv database contains 643 SMILES sequences for small molecules and their solvation free energy values in water73. The FreeSolv database is also one of the physical chemistry benchmark tasks in MoleculeNet74. Recently, structural information has been generated from 643 SMILES sequences and applied in graph-based methods to improve overall solvation energy predictions7. Using the structural information, we consider three atom subsets, i.e. (A): all atoms, (B): all atoms except hydrogen, and (C): all atoms except hydrogen and carbon, for our persistent Dirac model. For (A), we generate the discrete Dirac matrices 74, we apply the random 80/10/10 split and our persistent Dirac features act as input features for a XGBoost model. Specifically, the XGBoost model is used with hyperparameters: n_estimators=20000, eta=0.1, max_depth=7, subsample=0.4, colsample_bytree=0.8. After repeating the training process 50 times and taking the mean value of the root mean squared error (RMSE) from the test predictions, our results showed that the persistent Dirac features with XGBoost achieved mean RMSE of 74 as shown in Fig. In order to further validate the capabilities of persistent Dirac models, we perform a preliminary test of our persistent Dirac model on the Free Solvation (FreeSolv) databaseFurthermore, we consider a specially-designed persistent weighted Dirac model. We define the weight of each 0-simplex (or atom) as the magnitude of electrostatic charge of the atom, weight of each 1-simplex (edge) as the Euclidean distance (in Å) between the two connected atoms and the weight of each 2-simplex (triangle) as the area of the triangle . This work could open new perspectives for the use of persistent Dirac-based molecular fingerprints. We hope that this can inspire future interdisciplinary work between Dirac operators and machine learning along OIHPs or other relevant research directions. An interesting direction for further exploration would be the use of non-symmetric persistent Dirac features in predicting biological, chemical and physical properties in biomolecular data. For instance, further exploration in the use of non-symmetric persistent Dirac features can be considered in the prediction of energy bandgap and other material properties in OIHPsSupplementary Information.


Vibrio vulnificus is a gram-negative, opportunistic pathogen common to warm waters worldwide. Human V. vulnificus infection is rare and typically affects those residing in coastal areas during the summer months, but it causes rapid deterioration and is fatal.V. vulnificus infection who were treated at the First Affiliated Hospital of Ningbo University from 2020 to 2022 were retrospectively reviewed. The patient demographics, clinical symptoms, laboratory test results, treatments, and outcomes are summarized.The medical records of six patients with sepsis caused by Vibrio vulnificus infection was confirmed by blood or pus culture, 16S ribosomal DNA sequencing, and metagenomic next-generation sequencing. All six patients were male with pre-existing liver diseases and two reported consuming seafood before the onset of symptoms. Of the six patients, four succumbed to the disease, two recovered, and one underwent leg amputation.Vibrio vulnificus infection progresses rapidly and is highly fatal, thus prompt and aggressive treatment is necessary. Vibrio vulnificus infection should be considered in older (>40 years) patients with a history of liver disease and recent consumption of seafood or exposure to seawater, especially those residing in coastal areas during the summer months. Patient demographics, clinical symptoms, laboratory test results, antimicrobial therapies, and clinical outcomes were retrieved from electronic medical records.The medical records of six patients diagnosed with 2.2.C-reactive protein, procalcitonin, prothrombin time, international normalized ratio, activated partial thromboplastin time, D-dimer, cardiac troponin I, routine blood examinations, and biochemical parameters were assessed with standard equipment and commercial kits.2.3.Vibrio vulnificus isolates were identified in pus or blood samples by pathogen culture, sequencing of 16S ribosomal DNA (rDNA), and/or metagenomic next-generation sequencing (mNGS).2.3.1.Clinical specimens of blood and pus were cultured on Columbia blood agar medium at 35°C and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry .2.3.2.Sequences of 16S rDNA are highly conserved within the same genus but vary among genera and species. Therefore, 16S rDNA sequencing can be used to accurately identify bacterial isolates and discover novel strains . In this2.3.3.mNGS of gene fragments is a highly efficient, rapid, and unbiased high-throughput technology for detection of pathogens in clinical samples . In this3.3.1.V. vulnificus infections were diagnosed and treated at the First Affiliated Hospital of Ningbo University from 2020 to 2022. All patients were male with a median age of 57  years and all had symptoms of sepsis on admission. In the cases of six patients, none of these patients reported contact with seawater. However, it is noteworthy that one patient had a history of exposure to tilapia before admission. One patient presented with fever and reported eating raw mud snails (Bullacta exarate) 5 days before admission and one was admitted after consuming seafood, while the other three reported no knowledge of the mode of V. vulnificus infection. All patients resided in Ningbo, a major port city with a local culinary tradition of seafood consumption. Notably, all six patients had pre-existing hepatic disease, including viral hepatitis B cirrhosis and/or alcoholic cirrhosis, and two had diabetes . Antimicrobial susceptibility testing was performed using the microdilution method with a VITEK® 2 Compact system (bioMérieux), and the results are shown in Vibrio vulnificus was confirmed in the blood or pus specimens of five patients by 16S rDNA sequencing and one blood sample by mNGS.Standard microbiological methods  were used to confirm the presence of 3.4.V. vulnificus infection is quite rapid. For instance, a 66-year-old patient with alcoholic cirrhosis was admitted to the intensive care unit (ICU) with a diagnosis of severe sepsis shock, which was treated with cefoperazone-sulbactam and furacilin, but yet died at 24 h after admission.All patients had an underlying liver disease and, although all received antibiotic therapy on admission, four died of septic shock, as the onset of V. vulnificus infection, including one with alcoholic cirrhosis who consumed raw mud snails 5 days before admission. Vibrio vulnificus infection was highly suspected based on clinical presentation before confirmation by pathogen culture. The second surviving patient, aged 41 years, with hepatitis B developed acute myocardial infarction while hospitalized elsewhere. The patient had a history of exposure to tilapia before admission. He was transferred to our hospital and underwent right upper limb amputation for V. vulnificus infection  (nfection . Patienty sepsis . Interes0 years) , 2020. TVibrio vulnificus infections are characterized by rapid onset of symptoms that can develop into fatal systemic infections within days. The devastating nature of these infections suggests that the pathogenicity is a multifactorial and complex phenomenon involving many virulence factors, such as capsular polysaccharides, lipopolysaccharide (LPS), multifunctional auto-processing repeats-in-toxin, phospholipase A2, hemolysin/cytolysin, and iron acquisition systems , fluoroquinolone , and trimethoprim-sulfamethoxazole plus aminoglycosides  patients with a history of liver disease and recent consumption of seafood or exposure to seawater, especially those residing in coastal areas during the summer months. Prompt and aggressive antibiotic therapy, intensive treatment of shock and symptoms of multi-organ dysfunction, surgical debridement, incision, and drainage of abscesses, and even amputation may be necessary.In conclusion, The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: NCBI – OQ975991-OQ975995.The studies involving human participants were reviewed and approved by The Ethics Committee of Ningbo First Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.JW, XW, YW, QX, YL, and YM contributed to the study conception and design. Material preparation, data collection, and analysis were performed by JW and YM. The first draft of the manuscript was written by JW and all authors commented on previous versions. All authors contributed to the article and approved the submitted version.This work was financially supported by a grant from the Zhejiang Province Basic Public Welfare Research Program Project (grant no. LGC21H200002).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


EMM Scientific Editors and Editor‐in‐Chief announce that the scope of articles considered will expand, with the goal to enhance our commitment to precision medicine. The scope expansion will cover three major areas: environmental health, clinical studies and case reports, and biomedical technologies EMBO Molecular Medicine (EMM) has been at the forefront of publishing research at the interface between clinical studies and basic life sciences. Following a discussion with the editorial advisory board, EMM Scientific Editors and Editor‐in‐Chief would like to announce that the scope of articles considered will expand, with the primary goal to enhance our commitment to precision medicine. The EMM scope expansion will accordingly encompass three major areas: environmental health, clinical studies and case reports, and biomedical technologies.Since its launch in 2009, th century, a central public health paradigm switch was marked by a transition in the major causes of mortality from infections and acute malnutrition to chronic conditions such as cardiovascular, metabolic, neurodegenerative diseases, and cancer. The formidable increase in life expectancy, and hence the global aging of the population, has consolidated this transition. In this new paradigm, the health‐disease balance relies on a triad: genetics, lifestyle, and environment. EMBO Molecular Medicine has traditionally focused on covering the genetic and molecular basis of these chronic diseases. On occasion, papers would take lifestyle into account, but the emerging field of “environmental health and medicine” remained overall poorly covered. Given the climate and environmental changes upon us, EMM will strongly engage with this emerging field, focusing on molecular aspects. Particular attention will be brought on the crosstalk between the human “exposome” and the host physiology, and its impact on disease development. The scope expansion will also include microbiome sciences, especially those that provide perspective of the human microbiome as a sensor, integrator, and effector of environmental changes. EMBO Molecular Medicine will embrace environmental medicine in its functional and mechanistic aspects including exposome studies, toxicology, biomarkers, modeling, and interventions .In the course of the 20EMBO Molecular Medicine will also continue welcoming case reports that support hypothesis‐driven research on the disease of investigation .Since the first modern randomized controlled trials, clinical trials have undergone astonishing progress. Although the evolution of clinical trials has not reached its end point, the COVID‐19 pandemic led to considerable methodological changes and revealed the need for novel adaptive trial designs. In this evolving landscape, EMM will now consider human clinical studies that provide decisive molecular and mechanistic insight into a given disease . Precision medicine  cannot be dissociated from molecular medicine. Its development relies on technologies of high molecular resolution for diagnostic and high precision for individualized treatments. In this context, EMM will consider studies that present innovative methods, materials, tools, devices, and technologies with direct translational potential and applicability. This includes, but is not limited to: imaging techniques, drug delivery systems, tissue engineering, and computational/AI‐based technologies.With this announcement, we encourage authors not to hesitate to contact the EMM editors to discuss the suitability of their manuscript in this new context. As always, we will be delighted to provide advice and assistance before submission just as much as during peer review and revision.EMBO Molecular Medicine remains “molecular,” but in a more holistic sense!As we implement these changes, we leave you with one strong final message to our readership:


This study aimed to explore research topic trends on turnover intention among Korean hospital nurses by analyzing the keywords and topics of related articles. Methods: This text-mining study collected, processed, and analyzed text data from 390 nursing articles published between 1 January 2010 and 30 June 2021 that were collected via search engines. The collected unstructured text data were preprocessed, and the NetMiner program was used to perform keyword analysis and topic modeling. Results: The word with the highest degree centrality was “job satisfaction”, the word with the highest betweenness centrality was “job satisfaction”, and the word with the highest closeness centrality and frequency was “job stress”. The top 10 keywords in both the frequency analysis and the 3 centrality analyses included “job stress”, “burnout”, “organizational commitment”, “emotional labor”, “job”, and “job embeddedness”. The 676 preprocessed key words were categorized into five topics: “job”, “burnout”, “workplace bullying”, “job stress”, and “emotional labor”. Since many individual-level factors have already been thoroughly investigated, future research should concentrate on enabling successful organizational interventions that extend beyond the microsystem. Because of population aging, the rise in patients with chronic diseases, and modifications to healthcare delivery systems, there is an increased demand for nurses. The coronavirus disease 2019 (COVID-19) pandemic has also drawn particular attention to nurse staffing. The shortage of nurses is a global issue, and the World Health Organization (WHO) estimates that the globe would require 9 million more nurses and midwives by 2030 [To address the global shortage of nurses, the WHO recommended increasing the number of nursing graduates by 8% each year until 2030 . RepubliNurse turnover rates vary among countries, ranging from 15.1% in Australia  to 27.65Lee and Kang  conducteTo effectively manage the nursing workforce, it is essential to develop human, physical, and institutional strategies in a multifaceted approach that allow nurses to stay in the field for longer periods of time, rather than simply increasing nurse staffing. In addition, multi-level approaches at individual, unit, organization, and nation levels should be considered. Studies on nurse turnover intention conducted so far have been focused on identifying the phenomenon, such as investigating the influencing factors and classifying the factors through systematic research ,11. ThesText network analysis is a method of analyzing the structure of words, their communication mechanisms, and their relationships in text data collected for research purposes, and building a network is useful for visualizing texts’ overall structure and understanding them holistically . Topic mThis descriptive study employed text network analysis and topic modeling to extract keywords and topics from titles, abstracts, and author keywords of studies related to nurse turnover in Republic of Korea, facilitating the identification of research topic trends.The study subjects included the titles, abstracts, and author keywords of research papers on the turnover and turnover intention of Korean nurses published in domestic and international journals. Letters to the editor, conference presentation papers, and dissertations that did not go through editorial or peer review processes were excluded.Based on the previous study, research papers published from January 2010 to June 2021 were collected to identify research topic trends over the past decade . ResearcA flow chart depicting the research process is presented in Latent Dirichlet allocation (LDA)-based topic modeling was performed to extract topics and identify keywords with a high allocation probability by topic. LDA-based topic modeling analyzes unstructured text to find meaningful and important topics, allowing context-related topics to be inferred from vast unstructured texts . This anCentrality analysis was conducted through one-mode network analysis to identify the influence of keywords. Degree centrality, betweenness centrality, closeness centrality, and the frequencies of occurrence were analyzed. Degree centrality shows how many nodes in a network are connected, betweenness centrality reflects the degree to which a word plays a mediating role in a network, and closeness centrality shows how close a word is to other words .Eight articles were published in 2010 and 16 in 2011, which was an increase of 100%. Since then, more than 20 articles have been published each year, with 50 articles published in 2020. However, there was a temporary drop in the number of articles published in 2021 through June .In this study, topic modeling was performed using 676 words from the analysis. The number of topics with the most appropriate mutual independence of research topics was determined to be five. The researchers named each topic considering the associations among major keywords with a high probability of assignment for each research topic . The labThe word with the highest degree centrality was “job satisfaction”, the word with the highest betweenness centrality was “job satisfaction”, and the word with the highest closeness centrality and frequency was “job stress”. The following words were among the top 10 in the frequency analysis and all three centrality analyses: “job stress”, “burnout”, “organizational commitment”, “emotional labor”, “job”, and “job embeddedness” .As a result of classifying the keywords included in This study utilized topic modeling to examine the words in the abstracts, author keywords, and titles of 390 articles associated with turnover among Korean nurses published in the last 10 years. The analysis yielded important keywords associated with turnover and provided insights into major research topic trends. Based on the findings, we propose directions for future research that can assist in the establishment of strategies to reduce nurse turnover.Through topic modeling, we identified five major topics, which were then ranked in descending order based on their likelihood of occurrence: “job”, “burnout”, “workplace bullying”, “job stress”, and “emotional labor”. According to the topics “burnout”, “workplace bullying”, “job stress”, and “emotional labor”, previous research has mostly concentrated on exploring factors that increase the likelihood of turnover or turnover intention. The topic “burnout” included keywords such as “organizational commitment”, “professionalism”, “shift”, and “role conflict”. “Job stress” included “stress”, “support”, “fatigue”, and “perception”. “Emotional labor” included “management”, “conflict”, “environment”, and “emotional intelligence”. The word that mediated between the topics “job stress” and “emotional labor” was found to be “role”. “Emotional labor” was not discovered in studies aimed at nurses in other countries ,19, but This study also differed from a meta-analysis of nurses in 12 countries, in which job-related factors such as “team cohesion”, “recognition”, and “work–family conflict” were found to be predictors of turnover intention . This su“Role conflict” was a noteworthy keyword that was pertinent to the three areas of “burnout”, “work stress”, and “emotional labor”, and it had a substantial effect on the intention of Korean nurses to leave their jobs . Only 6 The topic of “workplace bullying” included keywords such as “violence”, “workplace”, “patient”, and “empowerment”. “Violence” has been identified as a factor that promotes turnover intention ,11. “WorThe topic of “job” included keywords such as “job embeddedness”, “work environment”, “career”, and “health”, providing strategic directions to assist nurses in staying on the job. Other topics, such as “emotional labor”, “job stress”, “workplace bullying”, and “burnout”, focus on finding the reasons and associated factors of turnover intention and belong to negative concepts. These topics demonstrate the substantial advancement in the field that academics have been researching for the past ten years. In the study of nurse turnover in the US from 2010 to 2020 , “job emUsing comparable keywords to those found in the “job” topic of this study, Nurdiana and Hariyati  proposed“Job stress”, “burnout”, “organizational commitment”, “job embeddedness”, “stress”, “workplace bullying”, “conflict”, “professionalism”, “organizational culture”, “role conflict”, and “fatigue” were among the top 30 keywords in terms of frequency and all three types of centrality. “Job satisfaction”, “work”, “experience”, “satisfaction”, and “work–family” were among the top 30 keywords for all three categories of centrality but did not rank among the top 30 in terms of frequency.Following that, we investigated “job satisfaction”, “organizational culture”, and “work–family” without relying on the topic modeling keywords. “Job satisfaction” is strongly related to turnover intentions and patient care quality, but because the factors influencing it can vary widely, it is necessary to identify the most influential factors . FurtherWe classified the turnover-associated keywords according to the Ecological Systems Theory, and most of the keywords were included in the microsystem including at the individual level. However, strategic initiatives, such as Nursing Law, and national nursing leadership positions in the exosystem and macrosystem should be prioritized to address them, and the related factors should be explored accordingly. Furthermore, since most studies to date have focused on identifying factors, future studies should focus on uncovering causes and leading to interventions. To create a new nursing paradigm, we need to make efforts such as restructuring the job system for nurses’ career development. We should also undertake various intervention studies, such as expanding internships, orientation, and transition programs, to reduce turnover among new nurses, who account for the majority of turnover.In this study, abstracts, author keywords, and titles of publications acquired through search engines were analyzed among research papers published in the last decade, with the caveat that the published studies may be biased. When topic modeling is conducted, the possibility cannot be ruled out that subjective criteria based on the researcher’s assessment are reflected in the refinement process of the keywords and post-analysis interpretation process, leading to an arbitrary interpretation . TherefoThis study examined 300 papers on the turnover intention of Korean nurses published in the recent decade and discovered that the studies were mostly conducted at the individual and ward levels. Unstructured text keywords taken from abstracts, author keywords, and paper titles were refined and grouped using topic modeling into “job”, “burnout”, “workplace bullying”, “job stress”, and “emotional labor” in this study. The fact that topics such as “emotional labor” or “workplace bullying” were derived implies that the social environment has a large influence on the turnover of Korean nurses. Based on the Ecological Systems Theory, we discovered that research interest was concentrated on microsystems. Since many individual-level factors have already been thoroughly investigated, future research should focus on eliminating bullying and improving social awareness to facilitate more successful interventions on the derived issues.


Therefore, it is of interest to document the molecular docking analysis of beta-lactamase fromSalmonella species with eicosane. Hence, we document the molecular docking analysis data of beta-lactamase from Salmonella species with eicosane. Several serovars of Salmonella enterica subspecies enterica cause salmonellosis in humans. Food is a large global reservoir of Salmonella. Salmonella is the 2nd top known bacteria that cause human gastero intestinal outbreaks especially with the species ofSalmonella enteritidis and Salmonella typhimurium. Salmonella is the primary cause of infection in about half of the 1500 cumulative food borne infections that occurs in France every year. Salmonellosis is caused by non-typhoid Salmonella resulting in acutegastroenteritis. It is seen in 95% of cases by the intake of contaminated food specifically fresh fruit juices, meet and egg. It is also present in fresh products like fruits and vegetables which are contaminated by animal faeces .ESBL deThe protein sequence of beta-lactamase  was used for domain analysis using PFAM (https://pfam.xfam.org/). Then, the sequence was used for homology modelling server using Swiss Model (https://swissmodel.expasy.org/). The modelled protein 3Dstructure was validated using ProCheck server (https://saves.mbi.ucla.edu/) and viewed with the molecular visualization Software, Discovery Studio Software.We used metronidazole, (CID: 4173) retrieved from NCBI –PubChem (https://pubchem.ncbi.nlm.nih.gov/) and data for the GC–MS instrument test compound, eicosane (CID: 8222) to perform molecular drug docking analysis. The 2D drug like compounds was convertedinto the 3D structure using Cheminformatics protocols.Molecular drug docking studies were performed using an automated molecular drug docking server, PatchDock (https://bioinfo3d.cs.tau.ac.il/PatchDock/). We docked the control drug (metronidazole) with beta-lactamase from Salmonella Sp and the test compound(eicosane) with beta-lactamase from Salmonella Species in order to compare the molecular binding affinities between the chemical molecules and the protein target.The selected protein target was retrieved from NCBI database in FASTA format. The length of the Nucleotide sequence is 861 nt and corresponding amino acids sequence is 286 aa. The 3D structure of the target protein was developed using an automated homologymodelling server named Swiss-Model. SWISS-MODEL server -16 conveFigure 7(see PDF) shows the 2D structure of metronidazole and Figure 8 represents the 3D structure of the metronidazole. Similarly, we show the 2D and 3D structure of eicosane in Figure 9 and 10, respectively. The conversion of 2D to 3D structure is one ofthe primary steps in drug docking procedure. We used Discovery Studio Software to perform automated 2D to 3D conversion for molecular docking using PatchDock. We ranked the remaining candidates as per a geometric shape complementarity score – 20. ThWe document the molecular docking of beta-lactamase from Salmonella species with eicosane compared to metronidazole for further consideration.


Kaposi’s sarcoma (KS) is the most common malignancy in people living with HIV. The reported incidence of AIDS-related KS has been dramatically decreased with the introduction of antiretroviral therapy (ART). Systemic treatment with ART is indicated for patients with AIDS-related KS; however, some patients may develop KS-related immune reconstitution inflammatory syndrome characterized by sudden rapid progression of new or pre-existing KS within the initiation of ART. Here, we present a case of rapidly disseminated KS with widespread visceral involvement despite ART initiation in a 27-year-old African American man with advanced HIV/AIDS. Kaposi’s sarcoma (KS) is a low-grade vascular tumor caused by human herpesvirus 8 (HHV-8) . It is tMr. DD is a 27-year-old African American man who was diagnosed with AIDS and cryptococcal meningitis at the age of 14 years. His clinical course was complicated by difficulties with adherence and engagement in care due to his mental state, polysubstance use disorder, and poor social support. He was diagnosed with biopsy-proven cutaneous KS in late 2021, two months prior to admission to our institution. At that time, Mr. DD’s CD4 count was 12 cells/μL and his HIV viral load was 100,000 copies/mL. He was initiated on bictegravir/emtricitabine/tenofovir alafenamide as well as monthly inhaled pentamidine. He was previously on suppressive trimethoprim/sulfamethoxazole, but this was discontinued in the setting of thrombocytopenia. He was previously on outpatient suppressive fluconazole for his prior history of cryptococcal meningitis, recently held due to transaminitis. Finally, Mr. DD was on valganciclovir for cytomegalovirus (CMV)-induced esophagitis.He was admitted to our institution with a three-week history of sharp, constant, and severe abdominal pain with radiation to the back, associated with nausea/vomiting and poor oral intake. His vital signs on arrival included a blood pressure of 133/90 mmHg, heart rate of 100 beats per minute, a body temperature of 98.5°F, respiratory rate of 18 breaths per minute, and oxygen saturation (SpO2) of 98% on room air. Physical examination was remarkable for icteric sclera, moderate right upper quadrant abdominal pain, and lesions consistent with KS on the right anterior shoulder  was pursued for his cholestatic picture. The MRCP showed cholelithiasis and biliary sludge but no biliary ductal dilatation; there was no excretion into the normal caliber bile ducts on the MRCP . Hepatobiliary iminodiacetic acid showed hepatic dysfunction with retention of the radiopharmaceutical. A percutaneous cholecystostomy tube was placed. Nonetheless, hyperbilirubinemia and alkaline phosphatemia continued to rise. He underwent endoscopic retrograde cholangiopancreatography and sphincterotomy for possible AIDS cholangiopathy.A review of his outpatient records disclosed that his CD4 count and HIV viral load had improved to 116 cells/μL and 70,000 copies/mL, respectively, one month prior to admission, and his HIV viral load further improved to 40,000 copies/mL at the time of admission. His CD4 count at admission was unchanged. His white blood cell count was 4.62 K/μL, hemoglobin was 9.2 g/dL, and platelets count was 208 K/μL. Additional labs included total bilirubin at 9.2 mg/dL, direct bilirubin at 7.2 mg/dL, alkaline phosphatase at 1132 U/L, aspartate aminotransferase at 394 U/L, alanine aminotransferase at 250 U/L, albumin at 2.4 g/dL, lipase at 17 U/L, and international normalized ratio of 1.2. Infectious workup, including tuberculin skin test, serum cryptococcal antigen, urine histoplasma antigen, stool Pneumocystis jirovecii pneumonia (PJP) was negative. Our pulmonary service performed a bronchoscopy with gross findings of diffuse, impressive, and patchy mucosal abnormalities with cobblestoning and hyperemia, consistent with KS. Given the potential for bleeding, biopsies were not taken. Bronchoalveolar lavage showed pale yellow fluid with white blood cells of 197 cells/uL , while polymerase chain reaction, bacterial, fungal, and acid-fast testing were also negative.A month into his hospital course, Mr. DD then developed a new onset nonproductive cough, wheezing, and dyspnea. CT of the chest showed consolidation of the lower lung fields concerning for pulmonary KS. Sputum sampling for Enterococcus faecalis. He initially received empiric vancomycin plus piperacillin-tazobactam, which later was tailored to ampicillin based on culture results. After repeat blood cultures were cleared, a mediport was placed for doxorubicin administration. Unfortunately, Mr. DD developed recurrent fever post-chemotherapy, and blood cultures showed Escherichia coli. Piperacillin-tazobactam was started. CT of the abdomen/pelvis did not show an infectious process, and the cholecystostomy tube was removed.Throughout his hospitalization, the patient was maintained on his ART regimen. He developed two new violaceous patches over the abdomen while inpatient , presumably more KS Figure  decline  were negative. Two days later, the patient was found in asystole, and he was pronounced dead.Cryptosporidium parvum, Enterocytozoon bieneusi, Isospora, Cyclospora, Mycobacterium avium complex, Cryptococcus, and PJP [Overall, the clinical picture of our patient was consistent with rapidly disseminated KS despite the initiation of ART, concerning for KS-IRIS. Diagnosis of disseminated KS can be challenging due to overlapping symptoms and findings with other opportunistic infections in advanced HIV/AIDS patients. His initial presentation with abdominal pain and cholestatic transaminitis was suspicious for AIDS cholangiopathy, which can be caused by several different opportunistic infections, including KS-associated herpesvirus, CMV, as well as  and PJP . Targeti and PJP ,11. WhilMycobacterium avium complex, Cryptococcus, or PJP with pulmonary involvement. Bronchoscopy was performed on this patient, which showed both blood and pus. Perhaps our patient had diffuse alveolar hemorrhage secondary to KS or any other infection; pus would raise suspicion for the additional bacterial process. He was also at high risk for PJP given the inability to properly prophylax in the setting of hepatic dysfunction; also, he was at risk for typical and atypical community or hospital-acquired pneumonia as well as fungal infections.The cornerstone for the treatment of AIDS-related KS is ART, but the response to ART differs greatly . The regSystemic steroid therapy was considered for the possibility of IRIS but held as steroids are associated with increased KS mortality ,17. PatiAlthough the development of improved ART has done much to reduce the incidence and improve the overall survival in patients with AIDS-related KS, our patient’s AIDS-related KS rapidly disseminated, with widespread visceral involvement despite ART and systemic chemotherapy initiation. There is an unmet need for new and effective treatments targeting AIDS-related KS.


Antimicrobial resistance (AMR) genes are found to be ubiquitous within the microbiome, even when antimicrobial usage is absent. To identify the AMR phenotype, the most common method is to use a laboratory-based assay. Yet, when dealing with samples from the microbiome, many species are difficult to culture within the laboratory. The vast quantity of strains would be time-consuming to culture. To avoid this, a computational approach may be a more favourable choice. AMR gene finder tools are efficient at determining the AMR genotype. Despite this, how a genotype relates to the AMR phenotype is still an open question.To evaluate the relationship between the AMR phenotype and the AMR genotype, 16 950 genomes from BV-BRC which had corresponding MIC values were analysed. Using Weka’s J48 decision tree model, the relationship between the AMR phenotype and the AMR genotype was analysed. The role of accessory genes in relation to the AMR phenotype was analysed in the same way.The J48 models could predict the AMR phenotype accurately using AMR genes and accessory genes; the average accuracy was 91.7% and 92.2%, respectively. The results found that gene co-occurrence, presence and absence of genes are key factors to analyse when identifying the AMR phenotype from genomic data. These factors are not evaluated by commonly used AMR gene finder tools, which could miss vital information to determine the correct phenotype.Our results highlight why we should continue to research the relationship between the AMR phenotype and genomic data.


Nanofibers morphology was evaluated by scanning electron microscopy. Thermal and spectroscopic analyses were performed to characterize the state of MEL in the scaffolds. MEL release profiles were observed under simulated physiological conditions . The swelling behavior was evaluated by a gravimetric method. The results confirmed that submicron-sized nanofibrous structures were obtained with MEL in the amorphous state. Different MEL release rates were achieved depending on the nature of the polymer. Fast (20 min) and complete release was observed for the PVA-based samples, unlike the PLA polymer, which provided slow and controlled MEL release. The addition of Tween® 80 affected the swelling properties of the fibrous structures. Overall, the results suggest that membranes could be an attractive vehicle as a potential alternative to liquid formulations for ocular administration of MEL.The poor ocular bioavailability of melatonin (MEL) limits the therapeutic action the molecule could exert in the treatment of ocular diseases. To date, no study has explored the use of nanofiber-based inserts to prolong ocular surface contact time and improve MEL delivery. Here, the electrospinning technique was proposed to prepare poly  (PVA) and poly (lactic acid) (PLA) nanofiber inserts. Both nanofibers were produced with different concentrations of MEL and with or without the addition of Tween Oxidative cellular stress is one of the main risk factors in the onset of neurodegenerative ocular diseases. The inflammatory processes that occur as a result of an oxidative insult trigger a series of events such as protein modifications, DNA damage and induction of apoptosis, which ultimately cause the death of neurons . These pThe enormous advantages of biodegradable polymers combined with those of electrospun nanofibers make nanofiber-based inserts promising ocular drug delivery systems. The positioning of the scaffolds in the conjunctival sac bypasses the precorneal barriers  typically associated with topical instillation of eye drops . The sofw/w). Tween® 80 as permeation enhancer was investigated for all nanofibers to observe variations in the final properties of the nanosystems compared to the ones obtained without the permeation enhancer. The structural characterization of formulated fibrous inserts was in the focus of this work. Differential Scanning Calorimetry (DSC) and Fourier-transform Infrared Spectroscopy (FT-IR) were performed to characterize the solid-state samples. The morphology of the composite nanofibers was investigated by scanning electron microscope (SEM). Release profiles were measured under simulated physiological conditions  at pH 7.4, 37 °C). The swelling degree (%SD) of the produced nanofibers was also analyzed.The aim of this study was to formulate and characterize for the first time MEL-loaded nanofibers for potential ocular administration. Hydrophobic PLA and hydrophilic PVA polymers were selected to develop electrospun nanofibers. Both nanosystems were loaded with different concentrations of MEL , polylactic acid, chloroform  and N,N-dimethylformamide  were obtained from Sigma-Aldrich . Ethanol 96%, Polysorbatum 80 (Tween® 80), potassium dihydrogen phosphate and sodium hydroxide were purchased from Molar Chemicals . Materials were used without additional purification and deionized water was of analytical grade.Melatonin (powder <98% (TLC), Cas number: 73-31-4, Mw: 232.28), polyvinyl alcohol  PLA polymer concentration, using binary solvent system to solubilize the hydrophobic polymer. Briefly, PLA polymer was dissolved in Chl:DMF in a 6:1 mass ratio and stirred under magnetic stirring until a clear and viscous solution was obtained. To produce empty-PLA nanofibers, electrospinning processes studies were conducted at different voltages and flow rates. Voltages were varied from 10 to 15 kV, while the flow rates were investigated from 0.2 to 0.5 µL/s. All the fibers were collected on aluminum foil, and the distance between the needle and the collector was fixed at 20 cm. To obtain drug-loaded PLA nanofibers, different concentration of MEL  were blended into PLA polymer solution with 7% (w/w) PLA concentration with and without Tween® 80 (0.5% w/w). The composition of the PLA-based nanofiber samples and the amounts of the components applied are described in The electrospinning process was performed at 7% (The mixtures were stirred at room temperature until a clear viscous solution was obtained. The appropriate flow rate for electrospinning the drug blended PLA polymer solutions was set at 0.5 µL/s and the voltage was adjusted ~11 kV. w/w) was used to obtain empty-PVA nanofibers. To improve the solubility in distilled water and to disrupt the strong intra- and interchain bonding of PVA polymer, the PVA solutions were stirred on a magnetic plate and heated to about 80 °C. When a clear viscous solution was obtained the polymeric solution was electrospun at a flow rate 0.1 µL/sec and applied voltage was 15–20 kV. The nanofibers were obtained using the eSpin Cube machine , and were collected in aluminum foil placed at a fixed distance between the needle and the collector of 12.5 cm. The fabrication of MEL-loaded PVA nanofibers was conducted as described below. A water/ethanol solution  was used to promote MEL solubilization. MEL-loaded PVA nanofibers were obtained by adding MEL solution at different concentration  into the PVA polymer solution with 12% w/w PVA concentration, in presence or absence of permeation enhancer Tween® 80 (0.5% w/w). The composition and quantity of the components applied for the preparation of the PVA-based nanofiber samples are listed in A PVA polymer concentration of 12% . SEM images were taken with JEOL JSM-6380LA scanning electron microscope . The measurements were performed at an acceleration voltage of 15 kV and a working distance of 10 mm. Diameters of 100 individual fibers were measured with ImageJ software . From the data collected, the average diameter, the standard deviation (SD) and the nanofibers diameter distribution were calculated.® 80 and of the raw materials were evaluated by differential scanning calorimetry using a thermal analysis instrument model DSC1 Star System  provided of a Poly-Science thermoregulator . The detection system consisted of high-sensitivity HSS8 and FRS56 ceramic detectors with 120 and 56 thermocouples respectively. For the DSC analysis, 5 mg samples were weighed and sealed with a sealing machine in 40 μL aluminum crucible. The samples were heated in a temperature range of 20–250 °C with a scanning speed of 5 °C/min. Mettler STARe Evaluation system software installed on DELL Optiplex3020 was used for data collection.The thermal properties of the empty and MEL-loaded nanofibers with and without Tween® 80, physical mixture (PhM) between MEL and pure polymer (MEL + PVA and MEL + PLA) and all nanofiber samples were analyzed using a Jasco FT/IR-4200 spectrophotometer. The instrument was equipped with single reflection accessory (Jasco ATR PRO470-H) detector. The measurements were detected in absorbance mode and background was acquired before of each measure. For each spectrum, 100 scans were collected over the range of 4000 and 500 cm−1, at a resolution of 4 cm−1 at room temperature. Spectra Manager-II software  was used for data acquisition.Pure MEL, pure polymers, Tween® 80 was evaluated in PBS at pH 7.4. Nanofibers samples removed from the aluminum foil were coiled on a magnetic stirrer and placed in a 4 mm-diameter steel coil to keep them at the bottom of the beaker (inner diameter 23 mm). To detect a concentration of 3 µg/mL, 30, 10 and 6 mg were weighed from the samples containing 0.1, 0.3 and 0.5% (w/w) of MEL, respectively. The temperature of the medium was adjusted at 37 ± 0.5 °C, and 10 mL of medium was added to the sample which was stirred at 100 rpm. An in-line probe was immersed in the beaker and MEL release profile was monitored at a λmax of 278 nm through spectrophotometry (Jasco-V-750 UV-VIS spectrophotometer) until complete dissolution of the nanofibers. The amount of MEL dissolved was determined by a calibration curve according to a partially validated spectrophotometric method. Release study was performed in triplicate for each formulation. The release curve was obtained from the mean and SD of 3 different batches.The dissolution test was performed by modifying a previously described technique based on the basket method reported by Pharmacopoeia Hungarica (Ph.Hg. VIII) . The in t and M∞ indicate the amount of drug released at time t and the maximum amount of drug released respectively. The parameters t0 and τd indicate the lag time and average dissolution time. The shape parameter, denoted as β, characterizes the type of release curve. In detail β = 1 outlines first-order kinetics with an exponential curve, β > 1 shows a sigmoidal curvature, and β < 1 denotes a parabolic curve [To explore the release kinetics of MEL, the Weibull model was fitted to the dissolution curves according to the following equation:ic curve .s is the weight of the sample after swelling and Wd represents the initial dry weight of the nanofibers. Each experiment was performed in triplicate and the results represent the mean ± SD.The swelling behavior of nanofibers was performed using a gravimetric method at room temperature. 10 mg of sample was placed in an aqueous medium (PBS pH 5.5 and 7.4). After 24 h, nanofibrous inserts were removed from the medium, rinsed with distilled water and the excess water was wiped off with paper towels before weighing the samples. The swelling degree (%SD) was calculated according to following equation:® 80 were prepared by electrospinning to obtain the above samples (PLA and PVA nanofibers with different concentrations of MEL and with or without the addition of Tween samples .w/w) improved the stability of the Taylor cone and produced smooth, uniform and bead-free fibres [PVA is a hydrophilic semi-crystalline polymer that possesses properties of high mechanical strength and excellent electroconductivity. The hydroxyl groups on the side chains of PVA allow the polymer to self-crosslink in aqueous solutions to form soft, flexible but at the same time resistant hydrogels. Due to these unique properties and the recognized biodegradability and biocompatibility, PVA hydrogels have been widely used to produce nanofibers by electrospinning . PVA pole fibres .w/w) and the use of a solvent mixture system such as Chl:DMF (in a 6:1 mass ratio) could result in continuous and bead-free nanofibrous structures [® 80 was investigated.PLA polymer is synthesized from renewable sources and possesses attractive manufacturing properties . Its higructures . To furt® 80.The morphological properties of the prepared nanofibers were observed by SEM analysis. The SEM images and fiber diameter distribution graph of the electrospun PLA and PVA nanofibers are shown in g), the second exothermic-type event at 85 °C consisted of the crystallization phase, and finally the melting peak (Tm) at 150 °C [g of the polymer shifted to slightly higher values (69 °C), and the melting peak decreased about 15 °C. Regarding the thermograms of all PLA-based nanofibrous scaffolds, no characteristic MEL peak was observed, suggesting that the drug was in amorphous phase within the electrospun nanofibers. The reason could be attributed to rapid solvent evaporation during the electrospinning process, which could prevent the drug molecules to form crystalline lattices [To investigate the thermal behavior of the nanofibers, DSC measurements were carried out. The heating curves of the electrospun samples and starting materials are shown in t 150 °C . In the lattices .® into the structure modified the crystallinity conditions of the nanofibers. The scaffolds producing with surfactant  showed a 10 °C reduction in both the Tg (from 85 to 75 °C) and the crystallization phase of the polymer (from 64 to 54 °C). This reduction could be attributed to the plasticizing effect of the permeation enhancer, which would increase the free volume within the polymer matrix, improve the mobility of the polymer chains that could lead to higher scaffold elasticity [Furthermore, it was observed that the incorporation of the surfactant Tween 80asticity ,38.g and Tm, respectively. In the PhM between PVA and MEL (curve b), the peaks of the individual constituents were present. All the curves of the PVA-based nanofibers, empty and loaded with MEL, with and without the surfactant, showed a similar trend. Again, the MEL peak was not observed in any of the thermograms, confirming the presence of the drug in the amorphous state, while the polymer peaks were observed at higher temperatures, specifically the Tg was shifted from 45 to 65 °C and the Tm from 188 to 193 °C. The higher heat demand required to melt the nanofibers could suggest that the electrospinning process promoted a more ordered and confined orientation of the polymer chains.Regarding the graph in −1, respectively, the vibration peak for C=O amidic carbonyl group was identified at 1617 cm−1 and the characteristic stretching signals for C–N group were detected at 1210 and 1040 cm−1 [−1, the peaks in the 3000–2800 cm−1 region were attributed to the CH2 alkyl groups, the stretching peak assigned for C=O was identified at 1731 cm−1, the peaks at 1026 and 1089 cm−1 represented the C–O stretching vibration and the C–H bending and deformations were identified in the finger print region (900–500 cm−1). Similar results were reported by other authors [−1, the peak at 1746 cm−1 was assigned to C=O stretching, the C–H alkane groups bending vibrations were observed at 1450 and 1356 cm−1 and the bands identified between 1210 and 1040 cm−1 were assigned to C–O stretching vibration [® 80 the broad band at 3500 cm−1 was attributed to the O–H stretching vibration, the absorption band between 2921 and 2857 cm−1 reflected the C–H stretching of the methylene groups, the stretching band for C=O was observed at 1735 cm−1 and the narrow peak at 1092 cm−1 was related to C–O–C stretching. Concerning the spectrum of PhM between MEL and PVA, the high-frequency regions were similar to the MEL scan, with a narrow peak at 3275 cm−1 for N–H stretching and the region between 3000–2800 cm−1 identified for CH2 alkyl groups. The low-frequency region was similar to pure PVA polymer, with bands attributable to C=O stretching (1731 cm−1) and C–O stretching (1000–1200 cm−1). Similar results were observed for PhM containing the PLA polymer, in which the low-frequency region showed an absorption peak at 1747 cm−1 for carbonyl C=O and C–O stretching vibrations between 1210 and 1040 cm−1. No difference was observed for all PVA nanofibers scans . In detail, the spectra showed no peak attributable to MEL, but rather similarities with the spectrum of neat polymer. The absorption band between 3500–3200 cm−1 appeared broader compared to PVA alone, the C=O carbonyl group stretching, and the C–O stretching bands were detected at a higher intensity of both polymer and PhM. Also, for the PLA nanofibers, no differences were found between the spectra, all of which showed an overlapping trend with the absence of the typical absorption peaks of MEL. Similarly, for the bands attributable to the C=O and C–O groups observed in all samples and representing the characteristic peaks of the PLA polymer, more intense absorption peaks were identified compared to the PhM and the raw polymer. The higher intensity that was observed for C=O and C–O stretches in both types of nanofibers could suggest the formation of hydrogen bonds that probably occurred during the polymer dissolution phase. It has been demonstrated that polymer solubility in polar solvents is dominated by interactions such as hydrogen bonds. The results of FT-IR analysis proved that PVA and PLA nanofibers were successfully fabricated.Pure components, physical mixtures and electrospun nanofibers were investigated by FT-IR spectroscopy to assess potential molecular interactions and to confirm the chemical composition of the composite nanofibers . MEL sho040 cm−1 . PVA pol authors . The FT-ibration . For TweThe two nanofibers showed different release profiles according to their nature.® 80 showed substantial differences , respectively. In contrast, nanofibers produced in the absence of Tween® 80 showed sustained release; after 12 h percentages of melatonin between 40 and 55% were released from the scaffolds.The PLA-based nanofibers exhibited slow drug release, and the saturation curves of scaffolds prepared with and without Tweenferences . The nan® 80 showed overlapping curves.In contrast, nanofibers composed of PVA released the entire MEL load within 20 min ; the relThe faster release from PVA nanofibers could be explained by the interaction of the hydrophilic polymer with the water molecules in the release medium . The int® 80 could presumably be attributed to the porosity of the nanofibers prepared with the addition of permeation enhancer. In fact, Tween® 80 could result in the formation of fibers with a more open structure that speeds up melatonin release compared with fibers obtained without the surfactant.The remarkable difference in the release profiles of PLA fibers with or without TweenThe Weibull model was employed to characterize the release kinetics of MEL from nanofibrous samples. The release kinetic parameters of the examined scaffolds are listed in All correlation coefficients of the linear regression analysis showed values >0.9, suggesting a satisfactory fit of the collected data to the Weibull model.The swelling behavior of nanofiber was determined at pH 5.5 and 7.4 within 24 h. Pictures of the samples in the dry state, after medium addition (time 0), after 30 min and at the end of the experiment (24 h) were collected and shown in According to the results of the in vitro release test, the hydrophilic PVA-based nanofibers showed complete dissolution in the aqueous medium within 30 min. For these samples, the experiment was stopped at this time and %SD data, although experimentally observed were not reported. Concerning the different aqueous media %SD was higher in pH 7.4 than in pH 5.5 of all the studied samples. Swelling of samples decreased from 160% to 117% and from 8% to 6% in pH 7.4 and 5.5, respectively. The degradation of PLA is strongly influenced by pH and acidic conditions compared to physiological levels resulted in a slower degradation rate ,48.® 80 addition in PLA-based nanofibers provided a faster dissolution, a complete release profile and an approximately 20-fold increase in swelling properties, suggesting a probable structural improvement of nanofibrous inserts. Based on the obtained results, the formulated MEL-loaded nanofibers could represent a promising vehicle with improved biopharmaceutical characteristics for the ocular delivery of MEL. Further in vivo studies are required to approve the biological activity of the absorbed melatonin.In this study, the electrospinning technique was successfully used to produce MEL-loaded nanofibers. SEM studies confirmed the nanofibrous structure, while thermal and spectroscopic characterization of the samples confirmed that the neat crystalline MEL was in the amorphous form in the scaffolds. According to the Weibull model, the release kinetics followed a sigmoidal pattern, suggesting diffusive processes for MEL. Although, drug release profiles from nanofibers indicated different dissolution rates according to the nature of the polymer. Hydrophilic PVA nanofibers showed an immediate within 20 min and complete MEL releases in contrast to the hydrophobic PLA ones. An interesting finding was that Tween