Traditional research and development (R&D) on biomedical materials depends heavily on the trial and error process, thereby leading to huge economic and time burden. Most recently, materials genome technology (MGT) has been recognized as an effective approach to addressing this problem. In this paper, the basic concepts involved in the MGT are introduced, and the applications of MGT in the R&D of metallic, inorganic non-metallic, polymeric, and composite biomedical materials are summarized; in view of the existing limitations of MGT for R&D of biomedical materials, potential strategies are proposed on the establishment and management of material databases, the upgrading of high-throughput experimental technology, the construction of data mining prediction platforms, and the training of relevant materials talents. In the end, future trend of MGT for R&D of biomedical materials is proposed. As a dynamic and fast-growing branch of materials science, biomedical materials are used to diagnose and treat physiological diseases, repair or replace biological tissues or organs to enhance or restore their functions. Biomedical materials have been extensively applied in clinical practice in forms of various medical devices including sutures, scaffolds, dentures, artificial bones, and even artificial hearts, etc. The research and development (R&D) of innovative biomedical materials involves the breakthrough in a wide range of knowledge including materials science, engineering, medicine, and life science, etc.The utilization of biomedical materials dates back to 3500 B.C. Since the first use of horsehair as suture, the fast-growing developments in life science and materials science have led to extensive applications of biomedical materials. However, the tissues or organs are extremely complex, the ability of biomedical materials to precisely regulate the growth, regeneration, and repair is far from satisfaction. The growing curiosity on the structure–property relationship of biomedical materials as well as the interactions between biomedical materials and cells/tissues/organs may lead to the investigation of these topics to foster the R&D of new biomedical materials. It is often achieved by development of novel chemical structure, combination of materials, or fusion of materials with living cells, etc.Traditionally, most biomedical materials are developed via the trial-and-error method. In detail, different material components and synthetic techniques could be explored based on existing theories or experiences to achieve desired material properties. During this process, repeated experiments are usually required to validate the design or formulation, which would inevitably lead to the sacrifice and waste of material/time. Such trial-and-error approach may be effective at small scale, but would greatly hinder the innovation of materials and the development of related industries in the case of complex tasks or large scale. In terms of economic and time costs, there is an urgent need for a new method to overcome the drawbacks of traditional trial-and-error method in the R&D of biomedical materials ,2,3,4.Materials genome technology (MGT) is a superior tool of materials research to the traditional trial-and-error method. MGT utilizes high-throughput experimental technique while adding data management and computational tools. The data are analyzed using computational tools to explore potential links between material parameters and material properties. In this way, the ideal material can be discovered more efficiently. This can improve experimental efficiency, reduce costs, and perhaps reduce experimental errors.This review presents the recent progress of the application of MGT in the R&D of biomedical materials to halve their development cycle and cost. Core concepts of biomedical materials and MGT are briefly introduced, followed by the application of MGT in the R&D of metallic, inorganic non-metallic, polymeric, and composite biomedical materials. Finally, future trends in the MGT empowered R&D of innovative biomedical materials are proposed.As the first program on materials genomic study, the Materials Genome Initiative (MGI) was launched in 2011 and includes three major aspects covering database establishment, experimental techniques, and means of material calculation b 5,6,7,,7,6,7,8.Database: It is hard to find valid and high-quality data from the massive amount of data when data are the basis for materials research, and the creation of databases becomes even more important. Ideal material database should be able to store large amount of data, manage the data in a standardized way, and be retrieved and stored easily by users.Famous material information databases have been established, such as Materials Project, AFLOW, and OQMD, etc. In China, efforts have been devoted for the establishment of various large-scale general material databases since the ,11 data High-throughput experimental tools: As the essential part of the MGT, high-throughput synthesis and characterization of materials refers to the preparation and characterization of samples with different structures or components in parallel and in large quantities in a relatively shorter time . UsuallyMaterials calculation methods: Materials calculation methods usually refers to various types of materials computing software and algorithmic models. Facing the complex potential connections between material components, structures, processes, and properties, which usually cannot be discovered directly by researchers, the help of some material computational means is urgently required. Although high-throughput first-principles calculations and density functional theory have achieved appreciable success in predicting and optimizing new materials, the huge amount of calculation makes it impossible to obtain ideal results quickly when the structure is more complex or the material search space is larger . BecauseBecause of the large volume of computational tasks and the automatic processing of computational results, it is extremely challenging to make full use of the huge and complex data and to reveal potential connections between relevant parameters and performance of materials. Computational tools, including various software and algorithm models, could be harnessed to solve the challenges in the processing of large amounts of data.Regression, classification, or clustering tasks are usually employed in the processing of biomaterial data. Regression tasks mainly deal with continuous or real number, while classification or clustering tasks result in discrete outcome by inputting data with or without label. Both regression and classification aim at discovering the relationship between data points through a predictive model, and achieve reliable predicted outcome; for these purposes, some algorithms, such as support vector machines (SVM), random forests, and Bayesian neural networks, etc., can be used for both regression and classification tasks in case of biomedical materials data .Back propagation neural network (BPNN)  is charaRadial basis function neural network (RBFNN) is a single hidden layer, function approximation-based feedforward neural network . After sProbabilistic neural networks (PNN) is a simple structured neural network based on Bayesian decision theory, which is often used for pattern classification; PNN can also be regarded as a branch of RBFNN, it combines density function estimation and Bayesian decision theory . The uniSVM is a binary classification model, which aims to find a line or plane with the largest geometric interval to classify the samples . In caseRandom forest (RF) was proposed as a machine learning algorithm for classification and regression . The “foFor some unlabeled sample data, only the similarity between the data can be used to group the data. For example, the unlabeled sample data with high similarity form a cluster, which is called clustering . K-meansInspired by Hubel’s research on cat visual cortex cells, the convolutional neural network (CNN) was proposed . The comAlthough CNN does not require manual feature selection, which reduces human intervention, the question on what features is automatically extracted remains unanswered for the time being. In addition, CNN requires a large number of samples for model tuning, and usually requires GPU for model training. The puzzling functions and uncertain working principle of CNN have been questioned, but the performance of convolutional neural networks has been greatly improved over other methods.The above-mentioned algorithm models have been widely used in processing biomedical data, and improvements have been extensively proposed.Metals, especially alloys, have excellent mechanical properties, fatigue resistance, processability, and appreciable biocompatibility, and are widely used in the fabrication of implantable medical devices for the treatment of orthopedics, dentistry, and cardiovascular diseases. However, metallic materials are susceptible to the physiological environment and may lead to a series of problems such as degradation/corrosion, toxicity, and fatigue failure ,99,100.Amorphous alloys possess good strength, hardness, wear resistance, corrosion, and soft magnetic properties, which are not available in traditional alloys and therefore have broad biomedical applications ,102. AltPure titanium metal is known for not only its superior mechanical performances but also the reactivity under certain biochemical environment, thus it is not suitable for the fabrication of implantable medical devices; titanium alloys with improved resistance to corrosion and better biocompatibility could be a substitution to the pure titanium metal in the manufacturing of clinical implant devices. The participation of artificial intelligence is helpful to the innovation of titanium alloy ,107,108.High entropy alloy (HEA), as a rapidly developing new metallic material, is a class of alloy with high strength, wear, and corrosion resistance, and may have wide clinical application . HoweverIt is important to distinguish the phases of high-entropy alloys for material design. Ouyang optimized feature variables and used SVM model for phase distinction. It was found that the difference in elastic energy and atomic size had a significant effect on the formation of different phases. Importantly, machine learning  showed its powerful role in the prediction of alloy phases .The demand of polymeric biomaterials, either natural or synthetic, has become increasingly urgent in recent years. Most polymeric materials including polyethylene, poly(methyl methacrylate), silicone rubber, cellulose, gelatin, and chitosan are known for their good biocompatibility. However, most of these polymers suffer from insufficient mechanical strength and mismatch between material degradation and tissue regeneration ,114,115.Chitosan nanoparticles have been widely used as drug delivery matrix due to their unique biocompatibility, degradability, and antimicrobial activity. Amani analyzed the effect of four parametric variables in preparation of chitosan nanoparticles on the nanoparticle size, drug loading, and cytotoxicity using artificial neural networks, and ranked the influential degree of the variables on the dependent variable and optimized the nanoparticles . In anotAlexander and co-workers investigated the preparation drug release matrix through 3D printing of 253 ink formulations in a high-throughput manner, and the functional properties including the release of paroxetine, cytotoxicity, printability as well as mechanical properties are screened .After implantation of biomedical materials, the adsorption of protein and the attachment of cells are the main determinants of the applicability of medical implant materials, especially those applications involving tissue regeneration. Both the surface chemistry and physics of polymeric implant could affect the protein adsorption; in this term, the surface chemistry and physics of polymers are complex and a fingerprint profile could be developed as a characteristic representation of polymers in order to enable a reasonable discovery of new materials for specific applications. Machine learning models can be then trained to quickly predict the properties of new polymer formulations and provide uncertainty in the predictions . In addiPoly(lactic acid)/ploylactide (PLA)-based composites are ideal materials in bone repair, but PLA suffers from low cell adhesion on the material surface, poor mechanical properties, and high cost, which greatly limit its clinical applications . Rojek iInorganic materials are known for their high melting point, hardness, and resistance to oxidation as well as potential biocompatibility in clinical use. The dissolution of metal ions from metallic implant may cause toxicity to host tissue, oxide films on the surface of metallic implant could be used to address this issue; it was found that both the formation and the thickness of oxide films may significantly affect the surface properties and biocompatibility of metallic implant, but the effect of process parameters on the film thickness is far from being elucidated and the general linear fitting methods cannot meet the needs in modeling such processes. To visually examine the quality of oxide film on the surface of magnesium alloy, Yang used genetic algorithm (GA) to optimize the initial weights and thresholds of the BPNN to construct a film thickness prediction model (GA-BP). The GA-BP model was found to have better prediction accuracy than the BPNN model .2) nanotube arrays have been found to promote cell adhesion, proliferation, and differentiation, and can strongly bind to titanium substrate; such characteristics of titanium dioxide nanotube arrays could be harnessed to improve the biocompatibility of titanium/titanium alloy implants and have attracted the attention of biomaterial researchers. Mou fabricated gradient TiO2 nanotubes micro-patterned films on the surface of titanium to facilitate the high-throughput screening of protein adsorption, platelet adhesion, bacterial adhesion, and the effect of octacalcium phosphate membrane layer construction. The gradient TiO2 nanotube micropatterning proved to be an effective tool in high-throughput screening for biomedical applications [Titanium dioxide  achieved better results in terms of prediction accuracy .Composites are materials made by combining two or more materials with different properties in order to effectively make up for the deficiencies in biological and physicochemical properties of a single material, and further improve the applicability of the material in clinical applications ,123,124.Nano-emulsions have been utilized as the carrier for oral drugs, but the cytotoxicity and low stability hinder their wide application. The artificial neural network analysis revealed that the concentration of surfactant is the main determinant of stability without causing dose-dependent cytotoxicity. Such findings paved the way for the preparation of nano-emulsions with optimized cytotoxicity and stability . The natTo better predict and optimize the performance of the carrier, the neural network using other algorithms have been explored. Varshosaz combined genetic algorithm and artificial neural network to optimize and simulate the synthetic process of agar nanosphere from agar, calcium chloride, hydroypropyl-β-cyclodextrin, and bupropione hydrochloride. Satisfactory consistence was achieved between the predicted and actual values of the ANN model . Wu and Composite materials based on chitosan has good biocompatibility and biodegradability, so the composite material with chitosan as one of the components surpasses the traditional materials to a certain extent for potential clinical use ,129. FouMaterials genome technologies have changed the traditional material R&D paradigm; however, tremendous efforts on the following topics are required to meet the fast-growing needs and challenges in the R&D of biomedical materials. Mapping the relationship between the components, structures, and properties of biomedical materials is complex and challenging. This challenge comes mainly from the difficulty in obtaining adequate data of biomedical materials, which are generally small sample data sets. In this regards, either the development of high-throughput experimental tools or data enhancement would be highly desirable ,132. In As an important foundation in the data-driven material R&D, the present biomedical material data are characterized by different sources, diverse types, and complexity, which to some extent hinder the rapid development of the perfect material data standard system and the establishment of data import template are prerequisite to deal with a variety of data types and formats as well as the systematic management and storage of data. My SQL database, which is small in size and low in cost, is a good option for the establishment of open material database. Artificial intelligence can also be used to automatically collect and classify the latest literature data. In addition, the experimental parameters have a huge impact on the performance and structure of the material. Relevant experimental conditions of the data should be supplemented and refreshed in the database to validate the simulation results.In addition, the parameters in animal experiments should also be considered. This is unique and critical data for biomedical materials.Large-scale automation of the experiment and calculation process may significantly accelerate the establishment of the database. At this point, high-throughput techniques can be used to synthesize and characterize materials with high efficiency and precision. The use of high-throughput equipment is of great significance. It may not only solve the defects of manual experiments but also can strengthen the combination of high-throughput equipment with databases and calculation methods, and consequently improve the level of material development, production, and application. In addition, biomedical materials with nanometers and microns in size also require a significant reduction in experimental error.The simulation and prediction ability of algorithm model is essentially important for the R&D of biomedical materials. Animal models are commonly used in the pre-clinical investigation of biomedical material. However, the inevitable inconsistency between the physiological/pathological environments of the animals and humans would lead to confused results during the clinical translation. New algorithm models are needed to simulate as much as possible the real human body environment and the situation of biomedical materials in physiological tissue/organ. In addition, the relatively smaller data set derived from open databases or high-throughput synthesis/screening of biomedical materials does not meet the requirement of general machine learning and deep learning. It would be highly necessary to develop algorithms suitable for small data sets to obtain material data analysis results with higher accuracy.The majority of current efforts on the MGT for biomedical materials have been devoted to the basic research; however, the ultimate outcome or performance of biomedical materials strongly depend on the processing and manufacturing parameters, and the involvement of industry is far from satisfactory. One would foresee that the MGT may add emphasis to its application in R&D of biomedical materials by receiving more input from the industry.MGT has strongly accelerated the R&D of materials, including predicting rapidly and screening materials, optimizing the properties of biomedical materials. Meanwhile, the application of MGT in biomedical materials has also promoted the innovation and development of science and industrial technology, basic theories, key technologies, and equipment. In the future, the development opportunities of MGT may be harnessed to facilitate the R&D of biomedical material, and work out the bottlenecks and difficulties in related fields.


Posterior Cerebral Artery (PCA) strokes cause the restriction of blood flow to multiple areas of the brain including the occipital lobe, the thalamus, the inferomedial temporal lobe, the upper part of the brainstem and the midbrain. This results in a panoply of possible symptomatology (including psychiatric manifestations) that increases the difficulty in diagnosis.We aimed to present and discuss atypical presentations of cerebrovascular disease that often results in misdiagnosis in an emergency context.A non-systematic review of the topic was conducted, and a case report is presented.An 86-year-old male patient, previously autonomous and cognitively intact, presents with periods of confusion and incoherent speech, visual hallucinations, incongruity of affect with pathological laughter, insomnia and increased aggressive behaviour, which began suddenly and worsened in the period of a week. The symptoms motivated several recurrences to the emergency department and numerous diagnostic exams performed, including CT scans and an EEG. Neurological examination showed no focal neurological deficits. The patient was admitted to a psychiatric ward for further diagnostics work-up. Due to increasingly altered status of consciousness, an MRI was performed, which found ischemic left occipital lesions compatible with PCA stroke. The patient was afterwards transferred to a neurology ward for continuing medical care.This case exemplifies how atypical symptoms such as visual hallucinations and changes in behaviour can be the only clues to diagnosing a PCA infarction, particularly in the absence of other focal neurological deficits. PCA strokes most commonly present with homonymous hemianopia, unilateral limb weakness, gait ataxia and vertigo. However, several other studies and case reports have found that this is not always the case and a minutious approach should be preferred in patients with a sudden onset of sensory and perceptual alterations and oscillating state of consciousness and disorientation, especially when discussing elderly people. Often these patients are admitted in psychiatric wards which may hinder the appropriate care they must receive.None Declared


Technical limits were carefully assessed, and strategies to enhance the reliability of real-time imaging were accordingly proposed. Results: Pre-IOUS allowed us to localize the lesion accurately in all of the cases . In 10 deeply located lesions, IOUS with hyperechoic marker, eventually coupled with neuronavigation, was useful to plan the surgical route. In seven cases, the administration of contrast ensured a better definition of the vascular pattern of the tumor. Post-IOUS allowed the evaluation of EOR reliably in small lesions (<2 cm). In large lesions (>2 cm) assessing EOR is hindered by the collapsed surgical cavity, especially when the ventricular system is opened, and by artifacts that may simulate or hide residual tumors. The main strategies to overcome the former limit are inflation of the surgical cavity through pressure irrigation while insonating, and closure of the ventricular opening with Gelfoam before insonating. The strategies to overcome the latter are avoiding the use of hemostatic agents before IOUS and insonating through normal adjacent brain instead of corticotomy. These technical nuances enhanced the reliability of post-IOUS, with a total concordance to postoperative MRI. Indeed, the surgical plan was changed in about 30% of cases, as IOUS showed a residual tumor that was left behind. Conclusion: IOUS ensures reliable real-time imaging in the surgery of space-occupying brain lesions. Limits may be overcome with technical nuances and proper training.Introduction: Intraoperative ultrasound (IOUS) may aid the resection of space-occupying brain lesions, though technical limits may hinder its reliability. Methods: IOUS (MyLabTwice Intraoperative US (IOUS) can be a prompt, effective, low-cost, and reliable adjunct in the surgical resection of space-occupying lesions of the brain. The technology takes advantage of a piezoelectric transducer that produces sound waves starting from electrical signals. These waves are transmitted to the tissues where they are absorbed, reflected, or scattered, based on the acoustic features of the different components of the tissue. The reflected waves are then detected by the same transducer and converted back to electrical signals, which are consequently processed to create the images.The standard required equipment is quite essential. The technique involves the utilization of a single machine equipped with a transducer probe(s), processing unit, control panel, and a monitor to visualize the images.Indeed, the IOUS technology can be easily integrated into an existing surgical workflow and is not significantly affected by the type of medical infrastructure, as opposed to more logistically complex and expensive methods, such as intraoperative MRI.However, ultrasound has been perceived as difficult to learn and standardize. The obtained images have been often considered of low quality, and their consequent interpretation thus can be challenging. Moreover, the intraoperative setting is significantly characterized by certain peculiarities that make the US findings unique. The rate of artifacts is relatively high and may further limit the potential of the technique. However, IOUS has dramatically evolved over the last decade, with vast improvements in image quality and the increasing availability of well-integrated navigation tools.IOUS has the potential to help surgeons in different ways. First of all, this tool may aid in the localization of intracranial lesions. After the skull opening, the ultrasound probe can be placed onto the dura mater or even directly in contact with the brain to analyze the structures underneath that are not visible. In addition to visualizing the lesion, the surgeon can select and optimize the best surgical corridor to target the lesion for the specific patient, minimizing, for example, the distance from a deep-seated tumor. Moreover, the implementation of different assessment techniques, such as Doppler ultrasonography, enhances the data delivered to the surgeon.Furthermore, after lesion resection, IOUS may help to assess the extent of resection (EOR), thus detecting residual pathology and reducing the risk of second-look surgery. The surgeon can assess the surgical cavity after the resection is deemed complete and examine its walls looking for, as an example, nodular findings suspicious of residual pathology. However, the IOUS evaluation of the surgical cavity is often limited by the presence of surgical debris and artifacts. In particular, the collapsed surgical cavity can greatly reduce the accuracy of IOUS. Furthermore, IOUS parameters to define surgical margins as disease-free are not clearly stated in the current literature. Most of the studies on IOUS focus on the standard B-mode  and suggDespite these obvious advantages, the use of IOUS is partly limited by the quality of US imaging, which is commonly perceived as poor, although modern machines offer improved-quality images compared to the recent past. Another drawback is represented by the lack of overall orientation with respect to anatomic features.We reviewed our experience with IOUS in the surgery of pediatric supratentorial space-occupying lesions, aiming to focus on the technical limits of this tool and propose strategies and technical nuances to overcome them.IOUS  with a CA1123 curved array microconvex probe was utilized in 45 consecutive pediatric cases with supratentorial space-occupying lesions. This system allows one to also perform neuronavigated ultrasound thanks to a magnetic coregistration of preoperative MR and IOUS. The probe with a 14 mm ray of curvature offers a trapezoidal field of view, wider at depth and narrow at the surface, but allows one to electronically vary the focus to adjust the resolution of insonation over a range of depths, thus combining the advantage of linear and phased-array probes.A disposable sterile transducer probe cover was routinely used along with sterile transmission gel placed on the probe footprint inside the cover.IOUS is performed before opening the dura mater to assess the lesion site and its features (pre-IOUS). Brain parenchyma is insonated on planes, which could simplify the comparison with preoperative MR, thus aiding the surgeon’s interpretation of IOUS images.In deep-seated lesions, IOUS is also used to guide the surgical trajectory.After the resection of the lesion with microsurgical technique, IOUS is repeated to assess the extent of resection (EOR) on the same planes explored before the resection (post-IOUS).Contrast agent  was administered routinely in pre-IOUS and repeated after surgical resection only in tumor cases.A single surgeon (PF) acquired all of the IOUS.Results and technical limits were carefully assessed along with strategies to enhance the reliability of real-time imaging.IOUS was successfully performed in all of the cases . The microconvex probe ensured the possibility of performing IOUS in all cases, allowing us to access also minimally invasive craniotomic approaches . The avePre-IOUS allowed localizing the lesion accurately in all cases, regardless of the type of pathology  . In 10 dIn seven cases, the administration of contrast ensured a better definition of the vascular pattern of the tumor, while in two cases, it provided a precise definition of the vascular encasement of the vessels of the Willis circle . In thisIn post-IOUS, assessing EOR may be hindered by artifacts that may simulate or hide residual tumors. The main strategies to overcome the former limit are avoiding the use of hemostatic agents before IOUS and insonating through the normal adjacent brain instead of corticotomy.An additional drawback was noted in 21 cases of large lesions (>2cm). Indeed, the collapsed surgical cavity, especially when the ventricular system is opened, may further complicate the assessment of EOR. This effect is particularly evident in deep-seated lesions, thus affecting the interpretation of IOUS.On these grounds, we propose to close the ventricular opening, if present, with Gelfoam before insonating. Additionally, we conceived a technical nuance, that we named dynamic IOUS (d-IOUS), to continuously inflate the surgical cavity through pressure irrigation while insonating.The probe is kept on the brain’s cortical surface, aiming to occlude the corticotomy. The tip of a 14-gauge plastic Abbocath needle  is placed under the US probe into the corticotomy. The Abbocath needle is connected to a syringe filled with 5 mL body-temperature saline. The surgical cavity is irrigated with gentle pressure, thus inflating the surgical cavity and stretching its margins.This "dynamic" assessment of the surgical cavity allows the reduction of artifacts, in particular of the cavity walls.Indeed, if hyperechoic nodular images or thickening along the surgical margins that are detected before inflating the cavity are confirmed during the dynamic IOUS, then microsurgical exploration is performed. If hyperechoic nodular images or thickening change to linear hyperechoic images, these may be considered physiological margins of resection without residual tumor .Thus, this technique enhanced the accuracy of IOUS after lesion resection. There were no procedure-related complications.In summary, these strategies and technical nuances significantly enhanced the reliability of IOUS. This led to a change of the surgical plan in 30% of cases, as IOUS showed a residual tumor that was left behind, thus avoiding second-look surgery . MoreoveOverall, a total concordance of post-IOUS to postoperative MRI was noted. Indeed, the EOR assessed by MR was consistent with the initial surgical plan and EOR assessed by IOUS. In particular, gross total resection was obtained in 40 cases (89%) and subtotal resection in the remaining five cases due to residual tumor in eloquent region, as highlighted by intraoperative neurophysiological monitoring.An intraoperative adjunct may be defined as a tool aiding achievement of the maximal safe resection. Indeed, these tools may answer different surgical needs. Neuronavigation is considered the most valid to localize the lesion and delineate a straightforward surgical trajectory. Additionally, the visualization of the lesion could be enhanced by adjuncts, such as fluorescence ,3,4,5. FObviously, it is essential to know the advantages and drawbacks of each surgical adjunct in order to confidently rely on its use. Intraoperative MR (IOMR) is considered the gold standard in intraoperative neuroimaging ,14,15,16Additionally, IOUS is a reliable, fast, repeatable, and low-cost technique, thus explaining why its application in neurosurgery has become more common over the last few years ,26,27. INotwithstanding the several advantages of IOUS, there are some drawbacks that could be overcome with some technical nuances and tricks . NeurosuHowever, the real-time interpretation of the IOUS images can still be a challenge. For this reason, we think that this technique should become an integral part of neurosurgical training, so that, after a relatively short learning curve, this tool can be employed in the daily surgical routine as a quick and reliable resource.The role of IOUS in the location of deep-seated lesions is obvious, but even more significant is the aid in locating superficial but not recognizable lesions that are not distinguishable from normal brain parenchyma . In this context, we prefer to couple the use of IOUS with a 3D reconstruction of FLAIR MR images. This rapid technique offers a reliable image of the brain surface that could easily aid intraoperative orientation also in minimally invasive access .The use of ultrasound contrast agents (UCAs) could improve the definition of the vascular pattern of the tumor. This could eventually correlate with preoperative perfusion MR and grading of the tumor ,33, thouFurthermore, IOUS after contrast administration may delineate the relationship of the lesion with normal vessels, providing images that could be more easily interpreted compared to echo-color-Doppler mode.These dyes are by now widespread in adults but are still “off-label” for non-liver applications in children , despiteLocalization and definition of the lesion are only a part of the game, in particular when the lesion has a deep location. In this context, the surgical adjunct should ideally guide the surgical route. Neuronavigation is the most widely used tool for this purpose, despite obvious intrinsic limitations. Indeed, neuronavigation is by definition reliable at the start of the procedure, but its reliability may decrease after opening the dura mater due to CSF loss and subsequent brain shift. Retraction of the brain parenchyma to approach deep-seated lesions may further affect neuronavigation. Contrarily, IOUS may provide reliable real-time imaging while advancing through the brain parenchyma. Coupling IOUS with neuronavigation, as warranted by hybrid systems, aids the interpretation of IOUS images and affords the possibility of correcting brain shift using some constant anatomical structures as a spatial reference . Saß B. et al. recently reported their experience with navigated 3D IOUS in glioblastoma surgery. They described the benefits of the technique, highlighting the reliability not only in estimating the EOR, but also in quantifying the brain shift and brain distortion as well as the registration accuracy. The comparison between IOUS images and postoperative MRI underpins the potential of ultrasound to drive the surgical strategy, as seen in one out of five patients for which IOUS detected residual tumor after the resection was initially considered complete, thus leading the surgeon to extend the procedure .Additionally, an echogenic marker, such as Cottonoid patties or Gelfoam, may provide truly real-time anatomical orientation throughout the surgery and delineate the exact surgical trajectory . As the Finally, IOUS may assess the EOR, though several artifacts can hinder the interpretation of the US images, their theoretical reasons being thoroughly described by Selbekk et al. . To reduA commonly encountered artifact is produced by the passage of the US waves through materials with very different attenuation coefficients. Unsgård et al. reported their experience with a new coupling fluid with the same US attenuation coefficient as the brain. This fluid, avoiding the enhanced brightness given by the saline filling the surgical cavity, could improve the interpretation of the US images after tumor resection, compared to Ringer’s solution . These sThe use of ultrasound contrast agents (UCAs) could improve the sensitivity for residual tumor volume. However, UCAs do not help in assessing the EOR if the lesions do not show contrast enhancement at the IOUS before resection, and they may produce a false negative in case of surgical devascularization of the tumor before UCA administration ,41,42.Moreover, IOUS features that define surgical margins as disease-free are unclear to date. A 5 mm rim of hyperechoic tissue on IOUS has been proposed as a reliable predictor of residue . HoweverIn our experience, the dIOUS is a simple and effective technique that allows distending the cavity walls, thus reducing the artifacts and enhancing the accuracy of IOUS to assess the surgical cavity when it collapses. As a consequence, the IOUS sensitivity and specificity in assessing the EOR is increased in our experience and shows a total concordance with postoperative MRI.IOUS ensures reliable real-time imaging in the surgery of space-occupying brain lesions. Limits may be overcome with technical nuances and proper training.Although further studies are needed to better validate these strategies in current neurosurgical practice, more widespread adoption of this tool is advisable.


The development of eco-friendly products to protect the environment has become a topical subject in the research and industrial communities. This is a result of strict environmental regulations necessitating the development of novel strategies to reduce our reliance on petroleum-based products, which exert a negative effect on our ecosystem. Bast-fibre-based hybrids have been extensively studied for various applications due to their eco-friendliness and cost effectiveness. There is a very limited number of review articles covering the properties and preparation of bast-fibre-based hybrid composites. This review is designed to provide an overview of the preparation and application of bast-fibre-based hybrid composites. It covers the thermal properties, mechanical properties, moisture absorption and flame-retardant properties of bast hybrid composites. This review not only summarises recent advances on the use and preparation of bast hybrid composites, it also presents a future outlook. Renewable materials are a new class of materials with huge potential to replace traditional petroleum-based materials in some applications ,2,3. Natviz., 95% volume, the combination of glass fibres with natural fibres  has attes  and other natural fibres have been hybridised with bast fibres to develop hybrid composite materials that not only address the limitations of bast fibres, but also with the aim of developing complete composite materials with balanced overall properties . Most puhttps://wits.worldbank.org/trade/comtrade/en/country/ALL/year/2021/tradeflow/Exports/partner/WLD/product/530310, accessed on the 9 September 2022). The global export increased by ~27% from USD 39 million in 2017 to USD 48 million in 2019. This indicates the interest in using these fibres across multiple sectors. The recent activity in different sectors regarding the modification of bast fibres to overcome their moisture absorption in order to broaden their application in transportation and sport equipment indicates that bast fibres play a critical role in empowering and alleviating poverty, especially for farmers from developing countries  . The light weight and mechanical performance of bast fibres have been the most important properties considered regarding their application in various sectors. Despite these fibres mostly being used in textile applications, the current trend has seen their transition to being one of the best reinforcing agents among polymer composites.Bast fibres can be obtain all around the world, and grow very quickly when compared to traditional natural fibres, e.g., wood. Thus, these fibres have been employed since ancient times, mostly as a replacement for wood. Trade for bast fibres has increased rapidly over the years. India is the highest exporter, followed by Tanzania see  , was found to enhance fibre–polymer interaction ,27. ThisThe secondary modification of silane-treated fibres can drastically compromise the interaction between the fibres and the host polymeric material . Li et aBiological treatments are recognised for their eco-friendly and energy-saving characteristics . AngelinThere are several factors, such as fibre loading, the effect of the treatment applied to the fibres, and the stacking of the fibres, that play an important role in the resultant properties of the bast hybrid composites ,31. SincMelt compounding is commonly employed for thermoplastic polymers, since they can be melted and moulded into the desired shape/structure ,38,39,40The thermoset resins most often used for manufacturing hybrid composites are epoxies ,47,48,49Summary: Other process, such as the solvent evaporation method, have not been utilised to prepare hybrid composites. Regardless of whether long or short fibres are utilised as reinforcing agents in hybrid manufacturing, pretreatment is crucial to the resultant properties. The preparation methods are often chosen with the aim of achieving the desired properties at a relatively low cost. The sensitivity of the natural fibres to long exposure to high heat limits the number of polymers that can be used for the preparation of thermoplastic-based hybrid composites via melt compounding techniques. The limitations of thermosets include recyclability, due to the three-dimensional network formed due to the curing process.D is the Fick coefficient, mM is the maximum moisture content at equilibrium, h is the thickness of the composite, and k is the initial slope of the moisture content (M(t)) as a function of the square root of time (t1/2), as expressed by Equation (2).Moisture absorption by natural-fibre-based polymer composites (NFBPC) is one of the most common concerns or drawbacks affecting the mechanical and physical properties of the composite for high-end or outdoor applications. The hydrophilic nature of natural fibres causes weakness in the interfacial adhesion between the fibres and the polymer matrix in the composite. The adsorption of moisture by the composites relies on various factors, which include the humidity and temperature, the fibre type, the matrix, the reaction between the matrix and water, the volume fraction of the fibre, voids, and the difference in the water distribution within the composites ,54,55,56cM) by the composite is determined on the basis of Equation (3) [TS) or the dimensional stability due to the absorption of water molecules is determined using Equation (4) [tM is the weight of the sample at time t and M0 is the initial weight of the sample,T0 and hT are the thickness of the sample in dry and wet states, respectively, at a given time.In addition to Fickian diffusion, water absorption tests in the literature for NFBPC are commonly performed according to ASTM 570-98, whereby the percentage of moisture absorption (tion (3) ,66,67,68tion (4) ,51.(3)MVarious studies in the literature in the form of reviews ,66 and rTezara et al.  examinedTherefore, one option to enhance the performance of jute fibre is to hybridise it with fibres that have greater mechanical qualities (such as ramie fibre), as jute has poor mechanical properties. This could yield superior results compared to processes in which the natural fibres are chemically modified. It was further concluded that employing the proper stacking sequence (R-J-R-J-R) is an essential factor in defining the quality of the hybrid composite in terms of attaining maximum mechanical strength.On the other hand, at elevated temperatures, the moisture uptake of the resultant hybrid specimen does not exhibit Fickian diffusion behaviour, unlike at room temperature. This is due to the development of micro-cracks on the surface and inside of the hybrid as a result of the high temperature environment and the moisture . TherefoBast fibres can be combined with other fibres, e.g., synthetic or natural fibres, as well as fillers, to subsequently reinforce the polymeric matrix in order to develop hybrid composite. Hybridisation describes the use of optimal combinations of fibres and fillers to improve the properties of the resulting hybrid materials. This balances the advantages and disadvantages of the reinforcements, as well as their cost and performance, which can be determined using an appropriate experimental design. The properties of hybrid composites depend on various factors, including fibre dimensions, fibre loading, distribution of fibres in polymer matrix, and interfacial adhesion between fibres and polymers. The optimum results are attained when the fibres are extremely strain compatible .The incorporation of fibres into hybrid composites can positively and negatively influence the overall mechanical performance of the material or not influence it at all, especially when low loadings are incorporated. Prior to the fabrication of hybridised composite materials, the mechanical performance, density and morphological properties of each individual fibre and/or bulk fibre should be investigated in order to determine which fibres have greater levels of influence than the others. Natural fibres are isolated from different parts of the plants, i.e., leaf, stem, stalk, seeds, fruit, bast, etc., and offer different properties. This provides a platform from which to tailor the overall mechanical perfomance of the resulting hybridised materials. For instance, the mechanical properties of individual fibres (ramie and borassus) and bulk fibres were examined and compared by Sarasini et al. . The resAs previously mentioned, bast fibres have been widely used in hybridisation processes to improve the overall performance of the resulting materials. Despite their usefulness in hybrid applications, there are some inherent drawbacks. These drawbacks include inherent polar and hydrophilic nature, low detectable defibrillation, which causes non-uniform dispersion within the polymer matrix, and a smooth surface, which leads to slippery fibre, resulting in fibre pullout and debonding, which can be attributed to the poor interfacial adhesion between fibres and polymers. This therefore leads to the resulting hybrid material possessing undesirable properties. For instance, Jawaid and coworkers  developeIn order to mitigate the aforementioned shortcomings of bast fibres, one of the major strategies is the chemical treatment of fibres in order to enhance their dispersion within the polymer and improve the interaction between them. The treatment of bast fibres is usually achieved by silane, alkaline, grafting, and acetylation. Alkali treatment using sodium hydroxide has been widely employed for treating bast fibres. The treated fibres were subsequently reinforced with hybrid composites with the aim of improving their interfacial adhesion and mechanical properties. Numerous researchers ,85,86,87This increased their surface area, thus allowing the polymer to penetrate between the individual fibres. Therefore, this resulted in a strong interaction between the fibres and the polymeric matrix, leading to an enhancement of the overall mechanical performance of the hybrid. The incorporation of the alkaline-treated ramie fibres into the polycaprolactone (PCL) hybrid composite containing borassus fibres resulted in a notable increase in both tensile strength and Young’s modulus, whereas ductility behaviour decreased. In fact, this is in agreement with the hypothesis that the tensile properties of composites improve when reinforced with fibres possessing a high aspect ratio. This increment is caused by good stress transfer from the polymeric matrix to the fibres, and the fibres are able to withstand stress. It has also been reported that the incorporation of treated ramie fibres does not influence the hardness of the ensuing composite samples. Other researchers have investigated the impact of treating kenaf and pineapple fibres with silane on the tensile characteristics of epoxy hybrid composite materials . The silIslam et al.  reportedThe incorporation of fibres has been reported to improve the tensile properties of the resulting hybrid materials ,44,89,90However, a significant improvement was noticeable when jute loading was increased from 20 to 80 wt.%. Similar findings have been reported in other studies ,91,92,93g), which is attained on the basis of damping behaviour, defines the temperature range in which the polymeric material transforms from a glassy to a rubbery state [Dynamic Mechanical Analysis (DMA) is the most effective technique for determining the viscoelastic properties (stiffness and damping behaviour) of polymeric materials such as hybrid materials . DMA monry state . Comparary state ,95,96,97g was unaffected by the fibre’s addition to PLA. Jawaid et al. [In an intriguing work by Pappu et al. , the visd et al.  obtainedd et al. .g of the composite shifted to higher temperatures, as depicted in Other researchers ,91,96 hag compared to neat epoxy and epoxy reinforced with sisal fibres alone. This improvement became apparent with increased jute fibre loading. Additionally, the improvement of the viscoelastic properties of the hybrid composite materials became evident when the frequency was increased from 1 Hz to 10 Hz.In another study, the effects of frequency on the viscoelastic behaviour of epoxy hybrid materials reinforced with sisal and jute fibres were investigated . HybridsIn-depth thermal properties analyses of bast-fibre-based hybrids have been performed previously ,101,102.The effect of fibre treatment on the thermal stability of hybrid composites has also been investigated ,100,101.m), melting enthalpy (Hm), crystallisation enthalpy (Hc), crystallisation temperature (Tc), and degree of crystallinity (Xc) were determined via analysis in order to fully understand the thermal properties. In these aforementioned studies, it was reported that the incorporation of bast fibres into hybrids influences their melting and crystallisation behaviour. For instance, Aisyah et al. [m and Tc of the hybrid. This was caused by the inclusion of weaved kenaf, which reduced the amount of total energy needed to be absorbed to break polymer chains. Sarasini et al. [m and Tc, while the crystallisation enthalpy (∆Hc) and melting enthalpy (∆Hm) had lower values. However, it is worth mentioning that there were no significant changes in crystallinity, Tm or Tc when fibre loading further was increased from 10 to 30 wt.%. The influence of chemical treatment on the thermal behaviour of hybrid materials has also been studied [g when compared to hybrid reinforced with untreated fibres, while the endothermic peak decreased in hybrids reinforced with both untreated and treated fibres.Few studies have investigated the melting and crystallisation behaviour of hybrid composites ,101,102.h et al.  reportedi et al.  indicate2P), total heat release (THR), and smoke production rate (SPR). For instance, pHRR provides essential data based on the intensity of the fire, viz., higher pHRR values indicate a major fire hazard. Owing to the high flammability of polymeric materials and natural fibres, different additional fillers can be incorporated to improve their flame-retardant properties [Most hybrid composite applications require them to meet certain fire regulatory criteria in order to ensure public safety ,105,106.operties ,108,109.Silane treatment of bast fibres in flame-retardant hybrid systems has been reported in the literature ,26. A coModification of the secondary filler rather than the bast fibres can also be adopted in order to improve the overall flame-retardant property of the resulting hybrid composites ,111. The−2 (PP/RF) to 547 kWm−2 (PP/RF/FR), and THR decreased from 96 MJm−2 to 84 MJm−2, respectively. It was concluded that the FR on the surface of the fibres degraded, creating a continuous char residue that protected the fibres from the heat source. Elsewhere, both melamine pyrophosphate (MPP) and aluminium hypophosphite (AP) were introduced into BF/PP composites at a mass ratio of 2:1 [In situ synthesis of phosphorus- and nitrogen-containing FR on the surface of ramie fibres was carried using condensation reaction by Du et al. . The hybo of 2:1 . The add2) on the flame retardance of PP/flax composite materials with PP-g-MAH employed as a compatibilising agent. It was pointed out that despite the samples failing to satisfy the lowest UL rating, the samples exhibited a prolonged burning process without signs of dripping. This was ascribed to low content of Mg(OH)2 , since 50–60% is required to achieve the desired flame-retardant properties. In addition, a recyclability study on this composite indicated that an increase in the number of recycling cycles led to a reduction in flame resistance performance by almost 5%. The preparation method plays a critical role in the dispersion of the fillers, and thus the resultant properties. Zhang et al. [Metallic hydroxides are known for their flame-retardant properties, which result from a cooling effect due to endothermic reactions from their degradation . The incg et al.  preparedg et al. .The incorporation of FR into bast-based composites can drastically improve the flame resistance performance of the resulting hybrid composite materials . The useSynthetic fibres play a critical role in the resulting properties of bast hybrid composites ,20. The On the other hand, the light weight of bast fibres has been explored for automotive applications, such as door panels, armrests, seat backs, etc., as depicted in The use of biodegradable polymers  opens doors for the application of hybrid composites in biomedical applications . SarasinThe unique features of natural fibres, such as their light weight, inexpensiveness, and sustainability, have led them to be explored as alternative fillers for composite materials to be used in aircraft components . AircrafThe moisture absorption of bast-fibre-reinforced composites is often a limiting factor in water-related applications. The moisture absorption of bast-fibre-reinforced composites can be solved through hybridisation with synthetic fibres, such as glass or carbon fibres. Fiore et al.  demonstrGreat strides have been made in recent years with regard to the preparation and characterisation of bast hybrid composites. This is a result of strict regulations necessitating the design of products that are eco-friendly and sustainable. In addition, the resulting properties are comparable to those of conventional synthetic hybrid composites; thus, they can be used in a variety of applications . Bast fibres can be exploited as suitable natural fibres to reduce the amount of synthetic fibres often incorporated into traditional synthetic-based hybrid composites. Their combination with synthetic fibres lowers the total cost of the final product and improves the overall performance of the resulting composite materials. Despite the fact that the use of other natural fibres as secondary fillers in bast hybrid composites has been reported to improve the overall resulting properties, the modification of these fibres is essential to promote adhesion while decreasing the moisture absorption of the resulting products. In future, some of the modifications that can serve as flame retardants while improving hydrophobicity will revolutionise the use of natural fibres as reinforcing agents in composite products. Synthetic flame retardants are commonly employed as fillers to improve the flame resistance performance of bast-based hybrid composite products. In future, the use of natural-based FRs should be explored for the development of highly flame-retardant eco-friendly materials.This review’s main focus was on the production of bast hybrid composites using various processing techniques. It is worth mentioning that short or long fibres can be employed, depending on the host matrix and the processing technique used. Treatment of the fibres prior to composite preparation is often performed to increase fibre roughness to facilitate interfacial interlocking with the polymeric materials. Alkali treatment is a commonly used treatment for bast fibres. The resulting properties of the hybrid composite products is directly influenced by the preparation method, the fibre treatment, the fibre dimensions, the fibre type, the alignment of the fibres within the system, and the content of the fibres. We also focused on the use of FRs as a secondary filler to improve the flame-retardant properties of the resulting bast hybrid composites. It was deduced that these FRs can be used as a form of treatment for the fibres, and thus optimisation is often required to achieve the desired flame-retardant properties. In the case of applications, the bast hybrid composites have a huge potential to replace traditional materials  in some applications. Despite other properties  being important for widening the application of hybrid composites, the most frequently investigated feature is the mechanical properties, followed by moisture absorption. This effect is due to the potential for using natural fibres in some applications rather than the commonly used synthetic carbon and glass fibres. There are very few studies centred on employing these methods to explore the impact of hybridisation, despite the rich information that other analytical techniques such as XRD, and FTIR may give with relation to the desired application. The majority of studies employ these techniques when bast fibre and/or polymer modification has been performed to increase interfacial adhesion between composite components. Therefore, more studies on other properties are still required to understand the overall factors influencing the resulting hybrid bast-fibre-based composites. The use of biological treatment is often limited to the removal of other constituent fibres. Studies based on the hybridisation of such fibres are also needed in order to understand the influence of such treatments on the properties of the resultant hybrid composites.This review covered the preparation and characterisation of bast-fibre-based hybrid composites. It can be concluded that bast hybrid composites can be utilised in different applications, opening new platforms for the development of novel products that can compete with traditional hybrid composites. Different polymeric materials and processing techniques have been used to manufacture bast hybrid composites with attractive properties, such as renewability, low density, and cost effectiveness. In most cases, the fibres were chemical modified in order to improve their adhesion with the host polymeric materials. With various developing countries producing the majority of bast fibres, their use serves as a suitable alternative for achieving socio-economic empowerment. Studies using techniques other than traditional mechanical, thermal and moisture absorption are required to obtain insights on the influence of the hybridisation of bast fibres.


The human body is home to trillions of microorganisms, collectively known as microbiota, which play a crucial role in maintaining health and well-being. Recent research has revealed that the gut microbiome in particular can significantly affect the development and progression of cancer. In this edition, we will present state-of-the art articles on the current understanding of the link between microbiota and cancer, with a specific focus on lung and colorectal cancer.Lung cancer is the leading cause of cancer death worldwide, and non-small-cell lung cancer (NSCLC) is the most common form of the disease. Recent studies have found that the gut microbiome is altered in lung cancer patients, with specific changes in microbial composition and function.Chen et al.). Interestingly, gut microbiota and serum metabolic profiles have been closely related, providing new biomarkers for the diagnosis of early-stage NSCLC .The two studies included in this edition investigate the important links between lung cancer and the gut microbiome, which is altered significantly in lung cancer patients compared to healthy individuals . Importantly, Fusobacterium nucleatum (Fn) seems to play a critical role in the development of CRC . As discussed, one might hypothesize that prevention and treatment based on the relationship between Fn and CRC might be possible. Additionally, not only does the composition of the microbiome seem to play a critical role, but also metabolites produced by the intestinal microbiota influence colorectal cancer. Specifically, sodium butyrate can positively affect the immune system, intestinal barrier, anti-cancer treatment efficiency, and reduce mucositis induced by chemotherapy, making it a promising option for colorectal cancer patients . Similarly, fecal metabolites not only seem to play a role in colorectal cancer, but they might also facilitate the diagnosis of gastritis. Interestingly, heptadecanoic acid and pentadecanoic acid in crosstalk with gut microbiota Erysipelotrichaceae_UCG-003 and Haemophilus correlate with chronic atrophic gastritis and could serve as novel biomarkers in the future .Colorectal cancer (CRC) is one of the most common forms of cancer worldwide, and the gut microbiome is known to play a vital role in its etiology. The articles published in this edition analyze specific functions of the microbiome in CRC and their effect on CRC-related miRNA production, as well as the role of several bacteria including Fusobacterium nucleatum, Escherichia coli, Bacteroides fragilis, and Faecalibacterium prausnitzii .Furthermore, research on the microbiome has not only gained a foothold in gastrointestinal and pulmonary oncology, but also in studies on breast and cervical cancer. In this regard, a review included in this special issue illustrates the unique microbial composition in breast tissue and tumors, which could help develop novel therapeutic drugs (https://www.ncbi.nlm.nih.gov/pubmed/30638582). In this edition, an article investigates how HPV screening can detect cervical cancer . In addition, the impact of male HPV infection on both male and female HPV-associated cancers must not be overlooked .Cervical cancer is a disease caused by the abnormal growth of cells in the cervix and is probably the best example of how the microbiome affects tumor biology. The well-established link between the human papilloma virus, cervical cancer, and the now-available vaccine is an excellent example of how microbiome research can lead to changes in real-world tumor therapy and outcomes (This edition of Frontiers in Cellular and Infection Microbiology serves to underline the importance of the microbiome in cancer and seeks to help increase our knowledge about this pivotal topic.The author confirms being the sole contributor of this work and has approved it for publication.


The extension of lymph node dissection in the treatment of early-stage non-small cell lung cancer (NSCLC) is currently a controversial argument in the scientific community. There are few studies that look at the role of lymphadenectomy in exclusively stage I NSCLC, and in them the lymph node evaluation method is not standardized, avoiding the comparison between different studies. The future perspectives on this issue will need to focus on the necessity of carrying out more precise investigations into the propagation of micrometastases in lung cancer and the application of the latest available techniques for their detection, resulting in a reduction in both local and distant recurrence.Lung cancer remains the leading cause of cancer-related death worldwide. The involvement of lymph nodes by the tumor has a strong impact on survival of patients. For this reason, lymphadenectomy plays a crucial role in the staging and prognosis of NSCLC, to define the most appropriate therapeutic strategies concerning the stage of the disease. To date, the benefit, in terms of survival, of the different extents of lymphadenectomy remains controversial in the scientific community. It is recognized that metastatic involvement of mediastinal lymph nodes in lung cancer is one of the most significant prognostic factors, in terms of survival, and it is therefore mandatory to identify patients with lymph node metastases who may benefit from adjuvant therapies, to prevent distant disease and local recurrences. The purpose of this review is to evaluate the role of lymphadenectomy in early-stage NSCLC in terms of efficacy and accuracy, comparing systematic, sampling, and lobe-specific lymph node dissection and analyzing the existing critical issue, through a search of the most relevant articles published in the last decades. Lung cancer is recognized as one of the leading causes of cancer-related death worldwide .Lobectomy with lymph node dissection is the gold standard treatment for patients with resectable NSCLC, as demonstrated by RJ Ginsberg in 1995 .The execution of an adequate lymphadenectomy is essential in lung cancer surgery to obtain an accurate staging and consequently identify patients who could benefit from adjuvant therapies . To dateIn addition, in lung cancer, the minimum number of lymph nodes necessary to consider a lymphadenectomy as complete is not clearly defined. According to NCCN guidelines , a minimRecently, given the development of the ninth edition TNM staging system, the members of the N-Descriptors Subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee have reviewed the literature on the different factors to categorize lymph node metastatic involvement, currently based only on anatomical criteria, such as counting lymph nodes, lymph node stations, or lymph node zones, analyzing the pros and cons .To date, the choice of performing lymphadenectomy with an extension influenced by the stage of NSCLC is controversial. There is a critical aspect in clinical practice concerning the assessment of N-status: the necessity of systematic lymph node assessment in early-stage NSCLC.This review aims to analyze the changes taking place in the execution of lymphadenectomy that could have prognostic implications in the treatment of NSCLC.In recent decades, given the high incidence of lung cancer, screening programs have been proposed for high-risk patients , resultiAs already mentioned, international guidelines define lobectomy with hilum-mediastinal lymphadenectomy as the gold standard treatment for resectable NSCLC. Instead, the extension of lymphadenectomy in early-stage NSCLC is still controversial.This section summarizes the main results observed in the treatment of early-stage NSCLC with different types of lymphadenectomy, discussing the impact that improved diagnostic-staging pathways are having on the type of treatment needed. We proceeded to a revision of the Medline PUBMED English literature (from January 1994 to May 2023), and we grouped the most relevant studies found according to the design , intending to verify the impact of the extension of lymphadenectomy on survival of early-stage NSCLC patients.In recent years, with the increasing finding of early-stage NSCLC, many surgeons have reported their experience on the proper type of lymph node dissection to achieve the greatest benefits in terms of survival and recurrence. When analyzing the existing literature on studies of a retrospective nature, a targeted search was conducted for articles that only considered early clinical or pathological NSCLC stages, excluding those that also analyzed locally advanced ones i.e., , to creaSince 2003, Wu et al.  have proTo understand whether complete lymphadenectomy is always necessary for the early stages is essential to identify the possible tumor risk factors associated with lymph node involvement. Veronesi et al.  demonstrIn recent studies on the role of lymph node dissection in early-stage NSCLC, the use of the preoperative stage was evaluated as a more appropriate factor for clinical practice management. Takizawa et al. published a retrospective study  on the eStage I NSCLC, according to the eighth edition TNM staging system , currentMore recently, lobe-specific lymphadenectomy has been introduced, motivated by the infrequent detection of mediastinal nodal metastasis in early-stage NSCLC  and by tIn the following years, several prospective non-randomized and randomized clinical trials have evaluated the role of different types of lymphadenectomy in the treatment of early-stage NSCLC .The first controlled prospective clinical trial on the effectiveness of systematic mediastinal lymphadenectomy compared with lymph node sampling in the treatment of resectable NSCLC (cI-IIIA) was published by Izbicki et al.  in 1998.In contrast, a further prospective randomized clinical trial was published by Sugi et al.  a few moSubsequently, Wu et al.  conducteThe more recent ACOSOG Z0030 Trial  was a prTo investigate the efficacy of lobe-specific lymphadenectomy compared with complete lymphadenectomy, Okada et al.  performeAnother prospective non-randomized study investigating the role of selective lymph node dissection has been conducted , compariTo date, only one prospective randomized clinical trial has been concluded on the comparison between systematic and lobe-specific lymphadenectomy in patients with stage T1aN0M0 (<2 cm) NSCLC . This stIn January 2017, a randomized Phase III trial was designed by the Japan Clinical Oncology Group-Lung Cancer Surgical Study Group (JCOG-LCSSG) to evaluate the clinical benefit in terms of survival non-inferiority and less invasiveness of lobe-specific lymphadenectomy, compared with systematic nodal dissection, in patients with clinical Stage I–II NSCLC , and we The principal reviews and meta-analyses conducted, over the years, on the role of hilar-mediastinal lymphadenectomy in the treatment of early-stage NSCLC have provided controversial and sometimes inconclusive results .On the comparison between systematic mediastinal lymph node dissection and mediastinal lymph node sampling in the treatment of pathological stage I NSCLC, Dong et al.  performeIn the same year, Huang et al.  publisheIn 2017, Mokhles et al.  conducteSince the benefits of different types of lymph node dissection in the treatment of early-stage NSCLC were unclear, a further systematic review and meta-analysis was published, in 2016 , on the In conclusion, in 2021, Luo et al.  publisheAlthough it is widely acknowledged that lymph node assessment is essential for accurate staging in the treatment of resectable NSCLC, the extent of lymph node dissection and its impact on survival are controversial. The international guidelines give conflicting indications on the number of mediastinal lymph nodes necessary to remove and on the most suitable type of lymphadenectomy to perform concerning the stage ,6,7,8,9.Systematic lymphadenectomy has been considered the gold standard treatment since 1951, when Cahan reported: “that some patients experienced long-term survival when the positive regional lymph nodes also were removed” . HoweverWith the increasing detection of clinical stage I NSCLC, thanks to the screening programs and the improvement of diagnostic-staging pathways ,11,12, tTo date, with this narrative review, it does not seem possible to conclude the appropriate type of lymph node evaluation in this subgroup of patients.The most relevant studies on the role of lymphadenectomy in the early-stage NSCLC exposed in this narrative review have several critical limitations, which could account for such conflicting results on this topic. The previously published studies, even the most recent ones, include indeed heterogeneous samples, in terms of stages and lymphadenectomy technique, that are difficult to compare, making the evaluation of the results and the conclusions complex.First, the surgical methodology of lymphadenectomy, in its existing variants, is not standardized , therefoIn addition, to not being standardized, the lymphadenectomy techniques proposed in some studies have created several criticisms, as happened in the ACOSOG Z0030 randomized trial . SystemaMany authors instead have included sublobar anatomical resections and atypical resections in the sample, which have different survival rates compared to lobectomy, producing bias in the results ,35,43.Another factor that emerges from the analysis of the literature is that many articles do not include only the early stages, i.e., stage I, but also locally advanced ones ,34,35,39Precise preoperative clinical staging of patients with non-small cell lung cancer is essential to define the appropriate treatment strategy. The preoperative lymph nodal evaluation was based on CT scan in several studies published before the introduction of PET in clinical practice ,33,34,38Finally, two systematic reviews and meta-analyses criticize that different papers do not mention the use of postoperative adjuvant chemotherapy ,43, whic-Inclusion of unique clinical stage I NSCLC;-Adequate preoperative staging, based on the most recent guidelines;-Define lymphadenectomy criteria that can be reproduced easily in subsequent studies, such as the number of lymph nodes removed and the corresponding lymph node stations, rather than the type of lymphadenectomy;-Homogenize the sample by the type of lung resection.It is necessary to conduct future prospective randomized trials that meet certain criteria to define scientific recommendations, which could guide clinical practice in the management of early-stage lymphadenectomy:While surgical treatment in the early stage is considered the treatment of choice, 30% of patients manifest recurrence, mainly distant ones . A possiIt has long been widely recognized that N status is the most significant prognostic factor impacting survival in NSCLC  and, to Occult lymph node micrometastases are defined as lymph nodes with metastatic cells that previously resulted negative at the preoperative staging and conventional histopathological methods; their presence is considered a marker for primary tumors with high metastatic potential ,55,56. AImproving the detection of occult lymph node micrometastases, especially N2, could have an important prognostic role in lung cancer staging, guiding the treatment pathway. To date, several molecular biology methods are available for the detection of micrometastases in NSCLC : the polPCR is widely used in molecular biology  and the IHC is a widespread method for detecting lymph node micrometastases based on antigen-antibody responders and a low CDH1/CDH2 ratio has recently been shown to be associated with lung cancer micrometastases .The OSNA method detects CK19 RNA copy number and has been shown to be more sensitive than hematoxylin-eosin staining in detecting lymph node micrometastases in NSCLC . Several studies recommend carrying out the frozen-section evaluation of the lymph nodes  or T intFinally, the detection of circulating tumor cell DNA (ctDNA) for the presence of early NSCLC in liquid biopsy has been shown to be effective and associated with several biomarkers, but there are still gaps in the study of related biomarkers for lymph node micrometastases. It is necessary to direct research towards the detection of highly specific and sensitive tumor markers of micrometastases, to achieve a more accurate pathological staging and to define future perspectives.The major limit for precise pathological nodal staging is represented by the surgeon who decides not to perform lymphadenectomy ,42. ProbIf we want to reduce the incidence of recurrences, without performing unnecessary at-risk procedures in the early stages, we need to establish the strategies for an adequate lymphadenectomy, to give an easier option for the surgeon that guarantees positive results in a subset of patients.Today, there is no standardization on reproducible lymphadenectomy and most of the studies conducted do not include only stage I NSCLC.It is advisable to proceed with studies on the intrinsic characteristics of the tumor and on the mechanism of its dissemination, to investigate the risk factors related to lymph node metastatic involvement and clarify this issue.Prospective randomized studies including only clinical stage I NSCLC are required to establish the outcomes stratified by the characteristics of the tumor. Furthermore, an evaluation of the risk factors related to possible worse oncological outcomes of incomplete lymphadenectomy is necessary, to consequently make recommendations on the lymph node assessment in early-stage patients.


The authors explain that using causal loop diagrams can visualize retrospectively the unintended negative consequences of COVID-19 related policies on maternal health and has potential to be used prospectively to foster decision-making to prevent those consequences. Causal loop diagrams can highlight and visualize complex behaviors, pinpointing vital leverage points for effective interventions in response to public health crises. Additionally, their use promotes a mutual understanding among policymakers, managers, and service providers about the depth of the crisis and the resulting response.We used a causal loop diagram to visualize how the COVID-19 pandemic and its response disrupted maternal health services in Islamabad, Pakistan.We argue that given the complexity of the response to the COVID-19 pandemic and the pre-existing vulnerabilities of Pakistan's maternal health system, systems thinking approaches, such as causal loop diagrams, should have been at the center of the pandemic preparedness and response to consider and prevent unintended consequences. On February 26, 2020, Pakistan reported its first travel-associated confirmed case of COVID-19 in Islamabad. Shortly after, on March 23, 2020, the Government of Pakistan declared a nationwide lockdown, encompassing Islamabad and Rawalpindi. The absence of full-fledged isolation centers in Islamabad led to the implementation of a home-based isolation strategy, accompanied by a 2-week cordoning of the entire area.Even before the emergence of the COVID-19 pandemic, Pakistan's health system grappled with barriers that disproportionately impacted marginalized groups and women. These challenges were fueled by inadequate quality of care and a dearth of essential commodities and services.Regrettably, the COVID-19 crisis exacerbated the deterioration of existing health indicators, particularly in the domain of maternal health. The Ministry of Health of Pakistan estimated a reduction of 19% in facility-led births during 2020 due to the impact of the COVID-19 pandemic on health care access and quality.In this commentary, we use a causal loop diagram (CLD)—a systems thinking tool—to illuminate the complex interplay of factors that collectively contributed to the erosion of access and quality in maternal health services across Islamabad during the first months of the pandemic in 2020.We use a causal loop diagram to illuminate the complex interplay of contributors to the erosion of access and quality in maternal health services across Islamabad early in the pandemic.We aim to showcase how CLDs, if applied at the right time, can serve as a tool for health managers to avert the adverse outcomes arising from isolated interventions within the realm of public health.To develop the CLD, the authors—a group of international researchers, managers, and service providers from the Pakistani health system—held discussions on maternal health care and the impact of COVID-19. The 3 authors from Islamabad had work experience in the maternal health system and used this to orientate the development of the CLD. The resulting diagram, shown in the During the first months of the pandemic in 2020, the surge in COVID-19 cases, coupled with infections among health professionals, rapidly overwhelmed public health facilities.The inclusion of the maternal wards' closure policy within the lockdown measures resulted in a number of unintended consequences, surpassing the intended reduction in hospital transmissions. Many pregnant women were left with the only option to seek care in private hospitals. The financial constraint loop (B4) shows that for women of lower socioeconomic status, the financial burden of private services was restrictive, resulting in their exclusion from critical services such as antenatal care and skilled birth attendance.On the other hand, approximately 85% of all health services were provided by private health facilities even before the pandemic.The lockdown measures also resulted in a series of unintended consequences on the demand side among pregnant women and mothers. A protocol was introduced that required COVID-19 screening before any intervention. This approach excluded COVID-19-positive patients, including pregnant women, from receiving adequate treatment in public facilities.As the pandemic raged on, the demand for health care professionals in maternal care services began to directly compete with the urgent needs of COVID-19-focused responses, as outlined in the resources competition loop (R4). This tug-of-war for health care workers and resources highlighted a crucial imbalance. The very policies aiming to curtail the spread of COVID-19 inadvertently catalyzed more maternal complications, increased the need for emergency care, led to a dwindling availability of health care workers, and exerted greater strain on an already stretched health system.Policies to curtail the spread of COVID-19 inadvertently catalyzed more maternal complications and exerted greater strain on an already stretched health system.Overall, lockdown policies, implemented with the primary intention of curbing the spread of COVID-19, had inadvertently resulted in a series of unintended consequences on maternal health. While these policies were critical in managing the immediate threat of the pandemic, the subsequent disruptions in maternal care services became a significant collateral issue. The unintended impacts on maternal health serve as a poignant reminder of the delicate balance required in health system responses during global crises.The application of a CLD stands as a promising means to bolster the capacities of decision-makers in preparing for forthcoming crises. In the example previously mentioned, we have visualized retrospectively how the lockdown and ward closure policies led to unintended consequences, including severe effects on maternal health. However, the real potential of a CLD lies in its prospective use, which, when combined with real-time surveillance data, can be crucial.This tool has the potential to serve as a dynamic framework that fosters proactive strategies through enhanced stakeholder collaboration.Of course, such a proposition would necessitate that decision-makers possess a literacy in the language of CLDs or collaborate with those that do , along with an understanding of the participatory approaches that render CLDs effective. The authors' engagement with district health managers in Pakistan during the pandemic was geared toward this very objective. In our experience, which we described elsewhere,Although the benefits of employing CLDs in crisis response are evident, the practical implementation may encounter hurdles when attempting to engage all stakeholders and facilitate in-depth discussions. Balancing the need for comprehensive insights with the exigencies of timely decision-making remains a delicate challenge, underscoring the nuanced interplay between the potential strengths and limitations of this approach.The aftermath of COVID-19 has generated unprecedented challenges while unmasking the vulnerabilities inherent within maternal health care systems worldwide.When designing public health interventions and policies specifically for maternal health, and especially within the response to pandemics, decision-makers must consider the different needs of populations, as well as how single interventions can have effects on other seemingly “disconnected” areas. Had policymakers foreseen these unintended consequences, they might have designed policies that prevent disruption to maternal care. Hence, we advocate for the integration of systems thinking approaches in shaping interventions and policies, not only as a response to past crises like COVID-19 but also as a foundation for enhancing emergency preparedness and response to future outbreaks.Finally, embracing a holistic understanding of the health system and beyond must be accompanied by acknowledging and addressing the varied experiences of individuals. COVID-19 is reinforcing and multiplying existing structures of discrimination, and, at the same time, it is showing that no one will be safe until all are.


However, these approaches often focus on the properties of the compound, missing the broader chemical-biological interaction perspective. Currently, the lack of comprehensive molecular characterization of the in vitro test system results in limited real-world representation and contextualization of the toxicological effect under study. Leveraging omics data strengthens the understanding of the responses of different biological systems, emphasizing holistic chemical-biological interactions when developing in vitro methods. Here, we discuss the relevance of meticulous test system characterization on two safety assessment relevant scenarios and how omics-based, data-driven approaches can improve the future generation of alternative methods.Assessing chemical safety is essential to evaluate the potential risks of chemical exposure to human health and the environment. Traditional methods relying on animal testing are being replaced by 3R  principle-based alternatives, mainly depending on  Despite this advancement, NAMs still face a challenge in providing a structured framework for linking molecular events to adverse health and ecotoxicological outcomes. The Adverse Outcome Pathway (AOP) concept was introduced to address this gap. Adverse Outcome Pathways (AOPs) establish a coherent link between molecular initiating events (MIEs) and adverse outcomes (AOs), enhancing our understanding and prediction of toxicity mechanisms  has resulted in an increased understanding of how chemical substances induce their effects in biological systems . Charact of NAMs . These eDespite the concerns and limitations  of integRecently, Carnesecchi et al.  introduc,in vitro tests from the OECD-approved list are performed for each key event (KE).In a typical safety assessment scenario, the evaluation of chemicals often begins with their physicochemical characterizationin vitro tests covering relevant mechanisms associated with thyroid hormone system disruption , for example, by exploiting the recent curation and annotation of genes and biological systems to KEs and AOPs . On the contrary, more apical events, closer to the Adverse Outcome (AO), may require a higher degree of organismal complexity, such as those provided by tissues or organs   . In the function , it becofunction .This complexity also affects the throughput of the test method to various chemicals. Early molecular events can be shared in the response of many compounds, therefore being the starting or intermediate steps toward multiple AOs. Ideally, high-throughput screening of a variety of compounds would be made in these settings. On the other hand, more complex test systems, such as organs-on-chips, may capture apical and specific endpoints very well , being tin vitro and in vivo settings, and across different systems  effect of the substance but also result in better prediction of phenotype variability and contribution to multiple adverse outcomes.in vitro assays and omics profiles must be ensured. Implementing Good Laboratory Practice (GLP) principles for omics data generation can boost transparency, reproducibility, and reliability while ensuring standardization of the experimental planning and reporting. (To stably implement the use of omics data derived information, the robustness and generalizability of porting. .in vitro test systems to prioritize them for diverse KEs. Such prioritization can delineate the biological applicability domain of the AOP, which encompasses a collection of in vitro systems viable for AOP testing. This knowledge could guide researchers in selecting the most pertinent system for their study and facilitating the design of more efficacious integrated test batteries.Overall, a compelling necessity exists to strategically leverage the molecular machinery insight of By meticulously addressing these facets, we propel the advancement of NAMs and significantly streamline and enhance the accuracy of risk assessment within regulatory processes.