Tibetan medicinal materials play a significant role in Tibetan culture. However, some types of Tibetan medicinal materials share similar shapes and colors, but possess different medicinal properties and functions. The incorrect use of such medicinal materials may lead to poisoning, delayed treatment, and potentially severe consequences for patients. Historically, the identification of ellipsoid-like herbaceous Tibetan medicinal materials has relied on manual identification methods, including observation, touching, tasting, and nasal smell, which heavily rely on the technicians’ accumulated experience and are prone to errors. In this paper, we propose an image-recognition method for ellipsoid-like herbaceous Tibetan medicinal materials that combines texture feature extraction and a deep-learning network. We created an image dataset consisting of 3200 images of 18 types of ellipsoid-like Tibetan medicinal materials. Due to the complex background and high similarity in the shape and color of the ellipsoid-like herbaceous Tibetan medicinal materials in the images, we conducted a multi-feature fusion experiment on the shape, color, and texture features of these materials. To leverage the importance of texture features, we utilized an improved LBP  algorithm to encode the texture features extracted by the Gabor algorithm. We inputted the final features into the DenseNet network to recognize the images of the ellipsoid-like herbaceous Tibetan medicinal materials. Our approach focuses on extracting important texture information while ignoring irrelevant information such as background clutter to eliminate interference and improve recognition performance. The experimental results show that our proposed method achieved a recognition accuracy of 93.67% on the original dataset and 95.11% on the augmented dataset. In conclusion, our proposed method could aid in the identification and authentication of ellipsoid-like herbaceous Tibetan medicinal materials, reducing errors and ensuring the safe use of Tibetan medicinal materials in healthcare. As the material basis of medical theory, Tibetan medicinal materials serve to achieve the purposes of disease prevention and healthcare, acting as a bridge between medical theory and clinical practice . The corWe verified the key role of texture features in recognizing ellipsoid-like herbaceous Tibetan medicinal materials by conducting multi-feature fusion experiments on a constructed ellipsoid-like herbaceous Tibetan medicinal material dataset.We used data enhancement to increase the number of images and validated its effectiveness in the recognition of ellipsoid-like herbaceous Tibetan medicinal materials.We proposed the use of an improved LBP algorithm to encode texture features of ellipsoid-like herbaceous Tibetan medicinal materials and demonstrated its effectiveness at improving the recognition accuracy on an additional complex test set.We evaluated our proposed method against existing herbal methods on the constructed dataset, and our results show that our method achieved better recognition for ellipsoid-like herbaceous Tibetan medicinal materials on a complex background.To address these challenges, we built a standard dataset of ellipsoid-like herbaceous Tibetan medicinal materials with complex backgrounds. We combined a Gabor wavelet transform and improved local binary patterns to extract the texture features of images, and used the DenseNet network with an added attention mechanism to identify ellipsoid-like herbaceous Tibetan medicine images. The experimental results show that our method can achieve a 93.67% recognition accuracy on our dataset. To sum up, the main contributions of this paper are as follows:The remainder of this paper is organized as follows: Achievements have been made in the computer-based recognition of herbal medicines with similar shapes. Earlier works have relied on the underlying features of a single image, such as the color ,7,8,9, tBy reviewing the Encyclopedia of Tibetan Medicinal Materials in China, we selected 18 types of ellipsoid-like herbaceous Tibetan medicinal materials, including Lu Lu Tong, soapberry, and You Ma Zhong. We leveraged Python 3.8  to searcThe color features of the images were less sensitive to size and orientation and had clear, intuitive, and easily described physical properties . The RGB follows :(1)H=θ,BThe histogram of oriented gradient (HOG) algorithm is widely used for the shape feature extraction of images. The image is first normalized, and then gamma compression is applied to the color image to reduce the effects of shadows and illumination variations. Then, the gradient calculation is performed on the normalized color image to obtain the horizontal and vertical gradient components,  follows :(4)Gx=maThe local binary pattern (LBP) texture analysis operator was first proposed by Ojala et al. . This ala, b, and c represent the weight coefficients of each feature, respectively.Ellipsoid-like herbaceous Tibetan medicinal materials have a high similarity in terms of shape and color. Conducting multi-feature fusion experiments on the extracted features can verify the importance of color, shape, and texture features in image representation. We allocated different weights to different features for feature fusion . The totImproved local binary patterns: The basic LBP operator assigns the gray value of all pixels smaller than the central gray value to 0 when extracting the image texture . It doesIn addition, comparing only the grayscale values of the peripheral pixels with the central grayscale value suffers from the influence of the central grayscale value and is not very stable . TherefoThe improved LBP algorithm, which uses the gray average of 8 neighborhoods instead of the central gray value when calculating the binary sequence and considers the variance of the neighborhoods, reduces the influence of the central gray value on the LBP operator and can extract the texture features of the image more effectively.Algorithm 1: ILBP encoded Gabor feature Algorithm.The process of ILBP-encoded Gabor feature extraction is as follows: the Gabor wavelet can reduce the interference of external factors and extract feature information from multiple angles and scales of the target image, while the LBP algorithm can better present the local feature information of the image, extract clearer local texture features, and reduce the feature dimension of the image . CombiniThe attention mechanism was originally inspired by the human brain’s signal-processing mechanism for vision. When the brain receives information from the external world, it selectively processes only the important information while filtering out the distracting information, thus enhancing the efficiency of information processing . In cognTo construct a recognition model for ellipsoid-like herbaceous Tibetan medicinal materials, we used the DenseNet proposed by Huang et al.  in 2017 To verify the effectiveness of our method, we conducted experiments on the dataset of ellipsoid-like herbaceous Tibetan medicinal material images with complex backgrounds. We first inputted the image features into the DenseNet network with the attention mechanism after multi-feature fusion, and obtained the optimal feature weights for different features in multi-feature fusion by experimentally comparing the recognition accuracy of images with different weights. We then verified the performance of the network when using a single LBP or Gabor algorithm, LBP-encoded Gabor, ILBP-encoded Gabor, and an attention mechanism. The accuracy of each model was compared and analyzed. We used the adaptive momentum stochastic optimization algorithm to update the weights and biases in the network model. The parameters in the experiment were set as follows: the network learning rate was set to 0.001 and the batch size was set to 16. In the experiment, the stochastic gradient descent method was used for network training, the number of network iterations (Epoch) was set to 50, and focal loss was used as the loss function. We set the hyperparameters a, b, and c represent the color, shape, and texture features, respectively. The highest accuracy and macro-F1 score for the recognition of complex background ellipsoid-like herbaceous Tibetan medicinal material images were achieved when a = 0.1, b = 0.1, and c = 0.8. Although the color and shape features played a role in classifying and recognizing different types of ellipsoid-like herbaceous Tibetan medicinal materials, they were easily influenced by background interference. The complexity of the texture structure of these materials made texture characteristics crucial for their identification. The weights of different features indicated that texture features play a key role in expressing the image content information. An analysis of the weights of different features concluded that texture features in ellipsoid-like herbaceous Tibetan medicinal material images play a key role in expressing the content information of the images.The results of the ablation experiment shown in  demonstrTo verify the effectiveness of data augmentation, the model was trained using the original data and the data-augmented dataset, and then the experimental results were obtained afterwards using the original data images for testing. The experimental results using our method for the original dataset and the augmented dataset are shown in Dilated convolution  is able In this section, the proposed model is compared with existing methods for identifying traditional Chinese medicines with similar shapes. The model was trained using both the original dataset and the dataset after data augmentation, and then tested using the original dataset images. The experimental results are shown in The color moment + SVM model  had the The recognition performance of various models on the complex test set is presented in In this paper, based on the established ellipsoid-like herbaceous Tibetan medicinal material dataset, we first verified the criticality of texture features for distinguishing different medicinal material images by multi-feature fusion experiments. We proposed DenseNet models with attention and LBP-encoded Gabor features to recognize ellipsoid-like herbaceous Tibetan medicinal materials on complex backgrounds, and proposed an improved LBP algorithm for texture feature extraction. We discussed the effectiveness of data augmentation for this paper’s research through experiments, and the experimental results prove that data augmentation can effectively improve the recognition accuracy of the experimental results. Our method achieved 93.67% accuracy on the original dataset and 95.11% accuracy on the augmented dataset. We additionally selected images with backgrounds more similar to the medicinal materials as a complex test set, and showed that our proposed method obtained a higher accuracy on this test set compared to other methods. Yet, the secondary recognition of misidentified ellipsoid-like herbaceous Tibetan medicinal materials still needs to be performed manually to ensure the safety of medication. The number of images in the dataset of this experiment was smaller than the standard public dataset CIFAR-10. Although the proposed model has achieved improvements in accuracy, there is still much room for improvement compared with the ideal case of Chinese medicinal material recognition. In the next work, the finished Tibetan medicinal material dataset constructed in this paper will be further expanded and unsupervised or semi-supervised methods will be used to solve the annotation problem of a high-cost, large-scale, ellipsoid-like herbaceous Tibetan medicinal material dataset.


Infectious keratitis is a vision threatening disease. Bacterial and fungal keratitis are often confused in the early stages, so right diagnosis and optimized treatment for causative organisms is crucial. Antibacterial and antifungal medications are completely different, and the prognosis for fungal keratitis is even much worse. Since the identification of microorganisms takes a long time, empirical treatment must be started according to the appearance of the lesion before an accurate diagnosis. Thus, we developed an automated deep learning (DL) based diagnostic system of bacterial and fungal keratitis based on the anterior segment photographs using two proposed modules, Lesion Guiding Module (LGM) and Mask Adjusting Module (MAM).We used 684 anterior segment photographs from 107 patients confirmed as bacterial or fungal keratitis by corneal scraping culture. Both broad- and slit-beam images were included in the analysis. We set baseline classifier as ResNet-50. The LGM was designed to learn the location information of lesions annotated by ophthalmologists and the slit-beam MAM was applied to extract the correct feature points from two different images (broad- and slit-beam) during the training phase. Our algorithm was then externally validated using 98 images from Google image search and ophthalmology textbooks.A total of 594 images from 88 patients were used for training, and 90 images from 19 patients were used for test. Compared to the diagnostic accuracy of baseline network ResNet-50, the proposed method with LGM and MAM showed significantly higher accuracy (81.1 vs. 87.8%). We further observed that the model achieved significant improvement on diagnostic performance using open-source dataset (64.2 vs. 71.4%). LGM and MAM module showed positive effect on an ablation study.This study demonstrated that the potential of a novel DL based diagnostic algorithm for bacterial and fungal keratitis using two types of anterior segment photographs. The proposed network containing LGM and slit-beam MAM is robust in improving the diagnostic accuracy and overcoming the limitations of small training data and multi type of images. Acanthamoeba) occur annually in South Korea, where bacteria still dominate as the causative organisms of the disease  network that classifies and diagnoses bacterial and fungal keratitis combining with two novel modules which can improve keratitis diagnosis accuracy and predict more accurate lesion areas than conventional models.This study was performed at Samsung Medical Center (SMC) and Korea Advanced Institute of Science and Technology (KAIST) according to the tenets of the Declaration of Helsinki. The Institutional Review Board of SMC  approved this study (SMC 2019-01-014).A retrospective analysis of the medical records of patients who had been diagnosed and treated for infectious keratitis  at the SMC between January 1, 2002, and December 31, 2018, was conducted. All the patients underwent corneal scraping and culture; other forms of keratitis, such as viral or acanthamoeba keratitis, were excluded in this study.Anterior segment image dataset, called the SMC dataset, is a set of anterior segment images collected from 107 patients. It consists of broad-beam and slit-beam anterior segment images  16). A . A 16). To verify the performance of the proposed network, we made the open source dataset consisted of 98 anterior segment images which were collected from Google image search and ophthalmology textbooks –19, and The distribution of the images is shown in An overview of the entire study design and the proposed network framework is shown in nLGMs are inserted between the layers, as shown in Lesion Guiding Module is designed for deep learning-based diagnostic systems to learn the location information of lesions annotated by ophthalmologists in the anterior segment image. In a classifier with convolutional layers, the In contrast to LGM learning information about areas to be focused on, the slit-beam MAM learns information about areas that should not be focused on. By using MAM in a training phase, the single network can efficiently learn slit-beam images and broad-beam images without paying attention to the slit-beam portion of the slit-beam image . In addiDetails of the proposed network and training procedure are provided in the We compared the diagnostic performance of our deep learning network system with that of the baseline classifier, ResNet-50. To evaluate the accuracy of the diagnosis, the simple accuracy when the cause had the higher probability score was assumed as the final decision and areas under the receiver operating characteristic curve (AUC) were calculated. In addition, the accuracy of the detected lesion location during the diagnosis process was measured using the intersection over union (IOU) metric. The IOU is the ratio of the overlap between the predicted bounding box and the ophthalmologist’s manually labeled bounding box. The closer the IOU value is to 1, the more accurate is the location of the detected lesion. We also visualized the spatial attention map of LGM. To verify the individual effects of the proposed modules on diagnostic accuracy, we conducted an ablation study.Details of the performance of baseline (ResNet-50) and the proposed method are shown in By inferencing the two datasets, we obtained the diagnostic accuracy, as shown in In contrast, the network with the proposed modules showed an approximately 8% increase in the SMC dataset and 7% in the open source dataset on diagnostic accuracy compared to those of the baseline network trained with both a broad-beam and slit-beam images.We developed a novel deep learning algorithm that specializes in diagnosing bacterial and fungal keratitis by analyzing anterior segment images. A representative convolutional neural network (CNN), ResNet-50, was used as the backbone of the algorithm with the two proposed modules, LGM and MAM, resulting in high performance in distinguishing the images with bacterial keratitis from those with fungal keratitis.The early and accurate diagnosis of infectious keratitis is essential for resolving the infection and minimizing corneal damage . GeneralA deep-learning approach was used to analyze a variety of medical images. Recent advances in deep learning technology in the ophthalmic field have also allowed rapid and accurate diagnosis of several ocular diseases , 25. HowIn this study, we utilized a deep learning CAD network system for the differential diagnosis of bacterial and fungal keratitis based on the different shapes of corneal lesions. There are two major challenges in diagnosing the cause of keratitis by using anterior segment images. First, because of the corneal aspheric shape, the depth and extent of the infiltration lesions that were seen in the actual slit-lamp examination are not clearly visible in the image, and small lesions are often not represented in the image. Additional information such as trauma  or past medical history of the patient are very important for diagnosis. Furthermore, the appearance differs depending on the light source; therefore, keratitis is often misdiagnosed. Therefore, for an accurate diagnostic network, the knowledge of experienced ophthalmologists who can distinguish the lesion related to the diagnosis from other anatomical parts should be transferred to the diagnostic network. Second, it is difficult to obtain a large number of anterior segment images of keratitis from the various aspects of each pathogen. It is also problematic that anterior segment images can be captured in different ways. These diverse features make it difficult to learn a diagnosis network with a finite number of weights, reducing diagnostic accuracy. To solve these problems, a method for learning the features regardless of the type of anterior segment image is required. We propose two modules to solve these two challenges.The two proposed modules, LGM and MAM, were combined with the main classifier. In the feature extraction process, LGM attends to a suspicious area related to diagnosis. Because its output has the form of a heat map, the detected lesion location can be obtained. The slit-beam MAM is used only in the training stage; it generates an optimal mask pointing to the slit-beam and small parts that have less impact on diagnosis. The unnoticed part of the actual diagnosis process is also suppressed in the learning process of the network so that the anterior segment images with and without the slit-beam can be effectively learned together. Through training a network using this module in the proposed procedure, the network can learn different types of anterior segment image (broad-beam and slit-beam) efficiently, and we obtained a high diagnostic accuracy for infectious keratitis using different types of images.Similar to our deep learning model, some recent other studies have applied deep learning models to distinguish patients with fungal keratitis from those with bacterial keratitis using anterior segment images. The algorithms by Hung et al.  based onThis study had several limitations. First, we only distinguished between bacterial and fungal keratitis. Indeed, the causes of infectious keratitis are diverse, and it is difficult to discriminate non-infectious immune keratitis in the early stages. Through subsequent studies, we need to develop a system to discriminate between the various types of keratitis. Second, the training process of LGM requires a hand-labeled bounding box annotation by specialists who are experienced in keratitis diagnosis. Therefore, a significant amount of time and resources are required to train the model. In MAM, a sophisticated pixel-level slit-beam mask is required for learning. Relatively less expertise is required than for lesion annotation, but it is also difficult to obtain masks in large quantities because of the higher accuracy required for pixel-level labeling than for bounding boxes. The expensive work required to obtain resources for learning can be a deterrent preventing the proposed network from being used in practice. Third, the usability of LGM is limited. The broad-beam anterior segment images with and without the slit-beam used in this experiment had a relatively high similarity to each other compared to other types (scatter and stain images). Therefore, by applying LGM to the original and image-level modified image, effective learning of the diagnostic system could be achieved regardless of the presence of the slit-beam in this study. However, to apply a similar mechanism to all types of anterior segment images, a method of dividing image features into parts having diagnostic information at the feature level and parts that are unnecessary for diagnosis is required. Fourth, although the LGM technique of our study allowed us to distinguish between bacterial keratitis and fungal keratitis by first accurately finding the lesion and looking at the characteristics of the lesion, exactly which part of the lesion was used to distinguish between bacterial and fungal keratitis is unknown with the results. However, LGM can identify the pathologic areas accurately by focusing only on lesions without any other noise than the Grad-Cam in the heatmaps. Finally, we combined our two modules with ResNet-50. Because some previous deep learning algorithms tend to show higher performance in other CNNs, not on ResNet-50, further studies comparing different CNNs applying our modules are required to enhance the diagnostic accuracy of infectious keratitis.In conclusion, our deep-learning framework for the diagnosis of infectious keratitis was successfully developed and validated. LGM is presented for an accurate diagnosis by emphasizing the lesions associated with the diagnosis. To prevent the less-informative part from affecting the diagnostic result and to efficiently learn two different types of anterior segment images in a single network, we designed a new learning procedure using a masking module, MAM, to control masking in the training phase. The results showed that our proposed module had a meaningful effect in enhancing the diagnostic performance of bacterial and fungal keratitis on different anterior segment image datasets.wyk900105@hanmail.net.The data analyzed in this study is subject to the following licenses/restrictions: The approval process from research data review committee is required and the dataset is not open to the public. Requests to access these datasets should be directed to YW, This study was performed at Samsung Medical Center (SMC) and Korea Advanced Institute of Science and Technology (KAIST) according to the tenets of the Declaration of Helsinki. The Institutional Review Board of SMC  approved this study (SMC 2019-01-014).DL and YR designed the study, reviewed the design and results, and submitted the draft. YK, T-YC, and DL annotated lesions on images related to the diagnosis of keratitis. YW, HL, YK, and GH analyzed and interpreted the clinical data. YW and HL drafted the submitted manuscript draft. All authors have read and approved the final manuscript.


Omics technologies have triggered a transformation in the field of clinical genetics and molecular biology. The evaluation of the whole genome in terms of genomic variations, transcriptome, epigenome and regulome , also down to the single-cell level, has provided unprecedented insights for our comprehension of human health and disease complexity.Colin et al., Colin et al., and McConkey et al.) highlight the value of integrating multi-omics approaches to solve challenging diagnostic cases with rare genetic diseases. The findings of Colin et al. and McConkey et al. additionally emphasize the significance of genomic DNA methylation studies in combination with sequencing technologies to achieve a molecular diagnosis.These omics approaches have been particularly instrumental in the field of genetics, especially for the understanding of neurodevelopmental disorders (NDDs) . NDDs enParenti et al. and Kampmeier et al. utilize the genotype-first strategy to refine the clinical spectrum of NDDs linked to specific genes  and emphasize the importance of timely molecular diagnosis and genetic counseling for appropriate patient management.Besides improving the diagnostic success rate, omics technologies offer valuable support for genotype-first approaches. Such strategies consist in assembling patients’ cohorts based on their genomic variants rather than their phenotypic features. When combined with an in-depth phenotyping, the genotype-first approach enables a less biased and therefore more comprehensive understanding of the phenotypic range associated with different genetic alterations in a given gene. In their studies, Schmidt et al. employed deep sequencing analyses and performed expression studies using organoids from patient-derived iPSCs to characterize STAG2 mosaicism and to reveal the essential role of STAG2 in early brain development. Ahmed et al. shed light on the specific cellular and molecular alterations in cholinergic interneurons and their potential role in the pathogenesis of autism spectrum disorder through the investigation of developmental alterations of striatal interneurons in the Cntnap2 knockout mouse model. The review by Di Fede et al. further focuses on animal models that mimic human genetic conditions, highlighting the shared abnormalities and clinical manifestations between these models and human patients.Despite the indisputable advances, the employment of omics technologies comes along with new challenges, like the increasing number of detected variants of uncertain significance (VUS). In this context, cellular models, such as patient-derived induced pluripotent stem cells (iPSCs) and organoids as well as various animal models can indeed facilitate the interpretation of the clinical significance of these variants and the identification of the underlying mechanisms of NDDs. As an example, Kampmeier et al. took advantage of the AI-based GestaltMatcher database -based methods offer valuable tools for the analysis of omics data and interpretation of VUSs at both the phenotypic and molecular levels . For insdatabase  to categ(i) Which strategies can aid the interpretation of VUSs? The identification of VUSs still leaves patients without genetic diagnoses and optimal clinical care. Assessing the functional impact of these variants individually using cellular or animal models is both resource-intensive and time-consuming. Consequently, only a fraction of genetic variants has been functionally characterized in the last decades. A promising method to improve VUS interpretation emerged with the development of Multiplexed Assays of Variant Effects (MAVEs). These assays enable the simultaneous assessment of thousands of variants within a single experiment, yielding variant effect maps for entire genes. These maps can additionally be used to train AI-based variant effect predictors. International collaborations like the Variant Effect Atlas Alliance aim to maximize the utility of genomics for diagnosing and treating diseases by providing and enhancing MAVE related resources and tools such as MaveDB .(ii) Which omics technologies should become part of the routine diagnostic process? NGS is currently the most employed diagnostic method. However, the content of our Research Topic attests how variants could be missed when only a single omics technology is applied. Whether or not the combination of two or more technologies will represent a time- and cost-effective option as a first-tier analysis still needs to be determined , but the(iii) Can we translate the new knowledge into therapies? Omics technologies bear the potential to shed light on the pathomechanism responsible for the disease-onset and on the molecules that are altered in the disease-state, which could conceivably represent future therapeutic targets or biomarkers.On the other side, the growing amount of data generated with omics technologies also raises new questions:In summary, the integration of omics technologies and the adoption of genotype-first approaches, as shown in the studies of this Research Topic, are enabling substantial progress in the diagnosis as well as in the clinical and molecular characterization of NDDs. Addressing the aforementioned questions could offer substantial benefits to patients in terms of enhanced diagnostic precision, development of personalized treatment approaches, and better management.


Following the development of the PCR and the internet in the early 80’s, the molecular revolution took off in the 90’s and by the new millennium most research was utilizing some variation of the technique and platform. Subsequently, the amount of information grew exponentially allowing the scientific community to speed up discovery and it has continued ever since. However, in the last decade the application of new technologies and bioinformatic approaches has again enhanced the creation of data and allowed sharing to a magnitude never seen before.in silico modeling and prediction before moving into the lab, cutting costs and times significantly. Due to the exponential gain of knowledge on viral pathogenesis, we are on the verge of a new therapeutics’ revolution.At present the focus is on approaches that have moved research from the genomics to the transcriptomics, proteomics, metabolomics, etc., allowing for a better understanding of pathophysiologic processes but also permitting the steep acceleration in drug discovery by permitting In recent years, we have seen the emergence of new viral infections such as SARS-CoV-2 and the re-emergence of known diseases such as Dengue or the continuous occurrence of spillover events of Influenza in different parts of the world. Globalization of human travel and encroachment into natural environments have increased opportunities for spillover viruses to travel around the globe.Shen et al.) potential SARS-COV-2 antiviral targets (Park and Moon), elucidate the viral pathogenesis  or applied to viral diseases of veterinary importance .Some of the works listed in this editorial depict ways in which some of the newer approaches are being applied to a broad variety of topics, from viral association in human cancer  the transcriptome analysis of dairy calves experimentally challenged with Bovine Herpes Virus type 1 (BoHV-1) and compared the gene expression results with Bovine Respiratory Syncytial Virus (BRSV). Their genetics analysis identified Differentially Expressed Genes (DEGs) in infected and control animals that could identify potential therapeutic targets for bovine respiratory infection and also could assist in a selective breeding program in order to reduce disease susceptibility. The magnitude of data being generated by these approaches, as well as the data that can easily be additionally retrieved through the use of tools such as Gene Ontology is so vast that most studies have to select the top 3 or 5 DEGs and deposit the rest of the information on some supplementary file to maybe be investigated at a later time. The use of pathway enrichment analysis has permitted further understanding of the processes involved and the prediction of key network regulators, potential biomarkers and drug targets.From the initial attachment to the final release of viruses from infected cells, there is an active cross-talk between viral and host factors that determine the pathogenicity of viral infection. Al-Kubati et al. the researchers used immunoinformatics, machine learning, and artificial intelligence, to predict the virulence and immunogenicity of Bovine Viral Diarrhea Virus (BVDV) proteins, and they proposed to use this approach for developing novel diagnostic assays and vaccines. Similarly, Shen et al. used bioinformatics analysis to identify potential molecular biomarkers involved in EBV positive peripheral T cell lymphoma including transcription factors (TF), microRNAs (miRNAs) and Long Noncoding RNA (lncRNA). These studies present the recent interest in regulating molecules such as TF-mRNA, lncRNA-miRNA-mRNA, EBV-encoded miRNA-mRNA; how these can be from either from host or pathogen origin and how some of these regulatory functions may be used to inhibit viral replication or control cancer cells.In the work by Liu et al. employed a Mendelian randomization method. This method is widely used to examine the potential causal relationship between exposure and disease outcome. In this case, they explored the causality of myocardial injury in COVID-19 patients. They used single nucleotide polymorphisms (SNPs) as instrumental variables of exposure, finding that SARS-CoV-2 infection may exacerbate cardiac injury in these patients. Similarly, Jiang et al. described the use of a two-sample bidirectional Mendelian method and a genome-wide genetic correlation analysis based on the summary-level data of two large genome-wide association studies (GWAS). Their findings did not support the causal role of genetically predicted shorter leukocyte telomere length in the increased risk of COVID-19 phenotypes. Consequently, their study found no support for leukocyte telomere length as a biomarker for predicting COVID-19 outcomes.In relation to the new pandemic caused by SARS-CoV-2, Park and Moon identified 3′ of UTR mutations in the Alpha, Beta, Gamma, Delta SARS-CoV-2 variants that rarely occur as persistent mutations. It was revealed that the binding sites of the five miRNAs with antiviral effect were mostly conserved, even in newly occurring SARS-CoV-2 variants, so these miRNAs could be appropriate antiviral treatment despite the emergence of new variants.Finally, Consequently, this Research Topic highlights the importance of genetic studies as versatile tools for analyzing viral pathogenesis and predicting the zoonotic potential of new viral strains. Moreover, such studies can determine the viral cellular pathogenesis and identify new treatments or preventive strategies against viral infection routes.in vitro, in vivo or in silico genetic studies must focus on trying to be prepared for the next pandemic viral strain. The increasing computer power together with the more recent implementation of artificial intelligence (AI) is revolutionizing this area of research. It is imperative that we prepare for the resulting products of such efforts and that we keep an overview on the whole process.The threat of new viral infections continues and thus,


The treatment of central nervous system (CNS) tumors is complicated by high rates of recurrence and treatment resistance that contribute to high morbidity and mortality . One of the challenges of treating these tumors is the limited permeability of the blood brain barrier (BBB). Early pharmacologic treatments worked to overcome the BBB by targeting vulnerabilities in the tumor cell replication process directly through alkylating agents like temozolomide. However, as advancements have been made options have expanded to include immunologic targets through the use of monoclonal antibodies. In the future, treatment will likely continue to focus on the use of immunotherapies, as well as emerging technology like the use of low-intensity focused ultrasound (LIFU). Ultimately, this paper serves as an introductory overview of current therapeutic options for post-resection primary brain tumors, as well as a look towards future work and emerging treatment options. While treatment advancements in neurosurgery, chemotherapy, and radiation for primary central nervous system (CNS) tumors have improved, there are still high rates of recurrence and treatment resistance . The chaPrimary CNS tumors are organized into glial and non-glial cell tumors. The glial tumors include astrocytoma, oligodendroglioma, and ependymoma. Glioblastoma multiforme (GBM), a subtype of astrocytoma, is the most common and aggressive malignant tumor found in the adult CNS . Non-gliCurrently, the most common chemotherapeutics used for post-resection brain tumors are alkylating agents. The path to the creation of alkylating agents began when it was discovered that chemicals being used as military weapons caused bone marrow suppression and lymphoid aplasia . InnovatTemozolomide is the most commonly used alkylating agent. One of its current applications is as an adjunct to radiotherapy for post-resection GBM, known as the Stupp protocol . The useMonoclonal antibodies are promising in the field of oncology to treat tumors outside the CNS as antibodies serve as tumor-specific treatments . InitialThe path to applying monoclonal antibody use to brain tumor treatment was paved through an evaluation of how tumor-mediated damage to the BBB contributes to pathogenesis. High grade gliomas, such as glioblastoma, have high amounts of VEGF. The high expression of VEGF leads to a highly vascularized, disorganized, and leaky BBB. As the BBB serves as a protective mechanism for the brain, the damage to the structure that results from high levels of VEGF leads to vasogenic edema . This suThe first study evaluating the preclinical efficacy of an anti-VEGF agent for brain tumors was published in 2000 by Rubenstein et al. . It demoBevacizumab, a monoclonal antibody that inhibits VEGF, demonstrated success in the treatment of other highly vascular tumors such as colorectal . Thus, iNaxitamab-gqgk is a monoclonal antibody that targets disialoganglioside GD-2 . It was Dinutiximab differs from naxitamab because dinutuximab has a murine protein. Murine antibodies are less favored as they may trigger stronger immunologic responses and lead to allergic reactions. They also are known to lead to the development of human anti-mouse antibodies (HAMA). This feature of murine antibodies leads to an accelerated clearance of the antibody and less therapeutic impact on tumors . SeveralCurrently, the mainstay of FDA-approved combination chemotherapy options for the treatment of brain tumors is composed of procarbazine hydrochloride, lomustine, and vincristine sulfate (PCV). The mechanism of action of each component is outlined in PCV was initially favored for the treatment of brain tumors such as anaplastic oligodendrogliomas prior to the introduction of temozolomide. However, since the introduction of temozolomide, the use of PCV has begun to fall out of favor due to the toxicity. The toxicities include severe weight loss, fatigue, neuropathy, and paralytic ileus . The dosData on PCV was measured in TTP. One study isolated PCV and temozolomide treatment in patients with 1p19q co-deletions as co-deleted anaplastic oligodendrogliomas are typically treated with chemotherapy alone. The study found that in cases with co-deletions PCV only treatment had a longer TTP of 7.6 years when compared to temozolomide alone .In their study, Lassman et al.  note theTyrosine kinase inhibitors are a type of targeted treatment that works by modifying the signals of tyrosine kinase . The recOptions in pharmacologic intervention are further expanding with the emergence of molecular subclassifications and advancements in immunotherapy. Exploring the field of molecular markers allows scientists to better understand the tumor microenvironment, though this environment has proven to be diversely complex. Subtyping tumors based on the presence or absence of integral cell signaling molecules has led to advancements in targeted immunotherapy. A number of these therapies are being studied in the preclinical setting. For example, the ataxia-telangiectasia mutated (ATM) protein directs cell response to double-strand DNA breaks that are induced by radiation. Ablation or pharmacologic inhibition of this protein results in tumor cell hypersensitivity to radiation in the monkey brain . An oralAn area of interest currently undergoing further study is the use of cytotoxic T lymphocytes (T cells). These cells can be extracted from a patient and modified to express a chimeric antigen receptor (CAR) specific to an identified tumor antigen . This prIn addition, to work in chemotherapeutics there is also promising work being done outside of pharmacology in order to overcome the BBB. Recently, this barrier has been overcome with the utilization of LIFU in combination with intravenous- administered oscillating microbubbles (MBs) . High-inWhile the advancements in the treatment of primary CNS tumors are promising and have success in improving survival rates. They also show promise in applications beyond tumor treatment with potential applications to the treatment of Parkinsonian and Essential tremors. However, the limited treatment options also represent the relatively neoteric domain of tumor pharmacology. Moving towards the future, our understanding of the BBB will need to continue to be explored in order to better understand how to navigate its intricacies in order to more optimally and effectively treat patients.


This study presents a series of shock-tube tests conducted on structural panels using ammonium nitrate fuel oil (ANFO) as the explosive. The characteristics of the blast waves propagating through the shock tube were analyzed by measuring the pressure generated at specific locations inside the shock tube. The extent of differences in blast pressure generated in a confined space, such as the shock tube, was compared to that predicted by the proposed method in the Unified Facilities Criteria 3-340-02 report. The target specimens of this study were plain reinforced concrete (RC), high-performance fiber-reinforced cementitious composites (HPFRCCs), and composite panels. Polyurea-coated RC panels and steel plate grid structure-attached RC panels were used as composite panels to evaluate the effectiveness of the coating and structural damping methods on the enhancement of structural blast resistance. The tests were conducted with different ANFO charges, and the crack patterns and lengths on the rear surface of each panel were measured. Based on the measured results, discussions regarding the blast resistance capacities of each panel type are provided. With increasing concerns regarding explosion incidents, such as bomb attacks, improvement of the blast resistance of concrete structures has become an important factor to be considered in structural design. When concrete structures are subjected to extreme loads of high amplitudes and short durations, considerable amounts of debris and fragments are generated on the rear face of the concrete structures owing to the brittle characteristics of concrete. Because this phenomenon can result in secondary damage to facilities and human lives inside protective structures, various reinforcement methods have been developed to compensate for the inherent drawbacks of concrete. To improve material performance, different fibers have been introduced in various cement-based composite materials that have high energy absorption and ductility properties; some of them are ultrahigh-performance concrete (UHPC) and high-performance fiber-reinforced cement composites (HPFRCCs) ,2,3,4. FMany studies have investigated the blast-resistance performance of structures using improved cement-based materials. Li et al.  manufactIn addition to the development of cement-based materials to improve material properties, many studies have focused on enhancing structural performance by applying various reinforcing materials to the interior or exterior of structures. Ha et al.  conducteSeveral experimental studies have been conducted to evaluate the resistance performance of structures subjected to blast loads; however, their results were mostly obtained from field tests resulting in large variations and a lack of reproducibility . Therefo3 was introduced into the cementitious matrix to compensate for the insufficient flowability owing to the low water-to-binder ratio (W/B). A glycol-based shrinkage-reducing admixture (SRA) was used to mitigate the potential for shrinkage cracks during production. Straight steel fibers with a 2% volume fraction were added to the HPFRCC mixtures, and the aspect ratio  were installed 11 m, 13.5 m, and 14.85 m away from the ANFO source to identify the superposition of blast load within the shock tube, as shown in W) and the ground distance (R). In this study, the TNT equivalent of ANFO was set to 0.74, incident pressures were calculated based on the graphs provided in [The measured pressures in the shock tube and the calculated pressures were obtained from the procedure proposed in the Unified Facilities Criteria (UFC) 3-340-02 report . The incvided in , and freThe experimental results for each specimen obtained by performing the shock-tube test, including the acceleration, reflected pressure, duration, and crack length at the rear face, are summarized in The total crack lengths on the rear faces of the specimens were measured using an image-processing program after objectification by preprocessing all the images to the same pixel and scale. Based on the measured crack length, the resistance capacities of the specimens against the blast wave were compared, and the experimental results according to the ANFO charge weight are presented in As shown in Several peaks were observed in the pressure–time curve owing to reflection by the mass concrete block located at the back end of the shock tube. The time difference between the first and second peaks decreased with the distance from the explosion source, and the pressure was significantly amplified owing to the overlap of the first and second pressure peaks at the Free 3 location;The blast pressure was amplified owing to multiple reflections of the pressure within the shock tube as the generated pressure passed through it. Thus, the measured pressure in the shock tube was significantly different from the pressure predicted by the method proposed in the UFC report;Among the specimens considered in this study, the HPFRCC panels demonstrated the best performance against blast pressure even for the thinner specimen. This was attributed to the improved material properties and the inclusion of steel fiber to restrain crack propagation;Polyurea can be effectively used to reinforce the tensile behavior of concrete structures and prevent the scattering of fragments;Energy-absorbing panels used in this study were found to be ineffective with regard to their energy absorption capacity. To increase the energy absorption capacity, the stiffness of the energy-absorbing panels should be reduced to allow deformation of the panel to dissipate the blast energy.This study investigated the characteristics of blast waves in a shock tube with an ANFO explosive and compared the blast resistance capacities of the considered specimens. By adopting plain reinforced concrete panel as the control specimen, the application of polyurea, an energy-absorbing panel, and HPFRCC were considered as variables. The following conclusions were drawn from the shock-tube tests:


An abdominal aortic aneurysm (AAA) is a life-threatening condition that affects millions of people worldwide. It remains hidden and unnoticed during most of its development but ultimately results in the patient’s death. AAA-related mortality remains significantly high, with its prevalence estimated to be around 1.1 million in the United States ,3. A rupThe early detection and proper management of AAAs is critical to preventing serious consequences. However, despite its devastating impact, it remains under-diagnosed and under-researched, largely due to its silent nature. The current diagnostic options for AAA are limited, with ultrasound being the most widely used method for detection. In many cases, an AAA is discovered accidentally, only when patients present with symptoms of rupture. This highlights the need for improved diagnostic methods for AAA, which could lead to earlier detection and improved outcomes for patients ,8.International Journal of Molecular Sciences, we bring together leading researchers from around the world to present the latest findings on AAAs. From exploring the genetics of AAAs to understanding the molecular basis of its progression, this issue provides a comprehensive overview of the current state of the field.Advances in molecular research have shed new light on the underlying mechanisms of AAAs and opened up new avenues for diagnosis and treatment. In this Special Issue of the The authors in this Special Issue explore innovative approaches to addressing the challenges posed by AAAs. By incorporating cutting-edge technologies and innovative research methods, they are working towards a better understanding of the underlying mechanisms of AAAs and the development of new and more effective diagnostic and treatment options. Through their contributions, these authors are leading the way in the fight against AAAs and providing hope for those affected by this devastating condition.The authors in this Special Issue present state-of-the-art approaches to addressing the challenges posed by AAAs. For example, Fukuhara et al. developed a polymeric micelle loaded with a statin drug for treating AAAs in rat models. Polymeric micelles are nanomedicines that selectively deliver drugs to disease sites, potentially improving the therapeutic efficacy. The study found that micelles prevented aortic aneurysm expansion in a dose-dependent manner and decreased macrophage infiltration and matrix metalloproteinase-9 (MMP-9) activity in cases of an AAA. This research presents a promising approach to developing systemically injectable drugs for treating AAAs with improved bioavailability [Yoshimura et al. developed a novel drug delivery system for inhibiting aortic wall degeneration and aneurysm exclusion failure after endovascular aneurysm repair with a stent graft. The system involved a targeted graft labeled with a small target molecule and a target-recognizing nanocarrier containing suitable drugs. The researchers successfully demonstrated that the nanocarriers could bind to the targeted graft both in vitro and in blood vessels of live mice. The drug released from the system reduced the expression of MMP-9 in mouse aortas, representing a promising adjuvant therapy to improve the long-term outcomes of endovascular aneurysm repair .Plana et al. investigated dysregulated microRNAs (miRNAs) in plasma and tissue samples of patients with an AAA. The study found that miR-27b-3p and miR-221-3p were overexpressed in the plasma of patients with an AAA, while six miRNAs were underexpressed and four miRNAs were overexpressed in AAA tissue. Thrombospondin-2 was identified as a potential target of miR-195-5p in AAA tissue. These findings suggest that miRNAs may play a role in AAA pathogenesis and could be potential therapeutic targets .Hayashi-Hori et al. investigated the effectiveness of rapamycin, an mTOR inhibitor, in preventing and suppressing aortic dissection (AD) in a mouse model. Rapamycin was found to be effective in preventing AD development and suppressing its progression by suppressing cell cycle-related genes, inducing muscle development-related genes, and maintaining the contractile phenotype of aortic smooth muscle cells. These findings suggest that the mTOR pathway plays a crucial role in AD pathogenesis and that rapamycin may be a potential treatment option for AD in clinical practice .Krishna et al. reviewed the current literature on mouse models of AAAs to study the factors that influence AAA rupture, such as the aortic wall structure and strength, biomechanical forces, and the cellular and proteolytic composition of the AAA wall. AAA rupture, which is a major cause of death in older adults, occurs when the stress on the aneurysm wall exceeds the wall strength. Mouse models offer a unique opportunity to study these factors and develop surrogate markers of AAA rupture in patients. However, the review also highlights the limitations of mouse models and suggests innovative approaches to generate clinically relevant results in future experimental AAA studies .Gurung et al. analyzed the current literature on the genetic and epigenetic mechanisms involved in the role of smooth muscle cells (SMCs) in AAA formation. An AAA is characterized by thinning of the media and adventitia of the aortic wall, which leads to aortic rupture and high mortality if left untreated. This review highlighted the importance of SMC plasticity, which is characterized by phenotypic modulation towards de-differentiation and a proliferative state that is associated with extracellular matrix remodeling, cell senescence, and inflammation in the pathogenesis of AAAs. While the evidence from mouse models is convincing, the authors emphasized the urgent need to apply this knowledge to human biology using modern experimental technology .In addition to the latest findings in molecular research on AAAs presented in this Special Issue, our understanding of the pathophysiology of AAAs continues to expand. Aneurysmal degeneration of the aortic wall is caused by the degeneration of elastin in the aortic wall . Our labPrevious research from our group has established that cigarette smoking is a significant risk factor for AAAs, and a better understanding of the effect of cigarette smoke on AAAs has the potential to reveal new therapeutic targets . Our groInternational Journal of Molecular Sciences thus provides a comprehensive overview of the current state of molecular research on AAAs, highlighting the importance of continued investigation into the underlying mechanisms of this life-threatening condition. From exploring the genetics of AAAs to understanding the molecular basis of its progression, this issue demonstrates the potential for further advancements in the diagnosis and treatment of AAAs. The collection of ground-breaking research presented in this issue provides a valuable resource for researchers, clinicians, and other professionals working in the field of AAAs. It also provides insights into the future directions of the field, inspiring further research and collaboration towards better outcomes for patients with AAAs.This Special Issue of the


In 2018, within the Horizon 2020 program, RECOVER-E project activities were initiated in Montenegro. During the years 2019 and 2020 Community mental health team (CMHT) within the Special Psychiatric Hospital Kotor was established. This team became responsible for management of treatment of a group of users with severe mental health illnesses, based on the principles of „Flexible Assertive Community Treatment (FACT – A Dutch model).The main objective of this research was to establish whether there were substantial differences regarding the use of seclusions, restraints and forced medication during the hospital readmissions in the group of patients treated by the CMHT, compared to usual mental health care in Montenegro.A sample of 202 users of mental health services from Kotor and surrounding municipalities were recruited. Patients were randomized into two similar-sized groups - intervention group, whose treatment was managed by the multidisciplinary CMHT, and control group where treatment as usual was continued .To estimate and follow-up the frequency of application of coercive measures in this research, hospital documentation was used.Patients in the intervention group had statistically significant less coercive intervention  during the study. There were no significant differences in the number of hospital days and readmission rates.This study showed that CMHT care could reduce some of the coercive measures during the treatment of severe mental illnesses.None Declared


Cholangiocarcinoma (CCA) is a rare cancer originating from the biliary epithelium and accounts for about 3% of all gastrointestinal malignancies. Unfortunately, the majority of patients are not eligible for surgical resection at the time of diagnosis, because of the locally advanced stage or metastatic disease. The overall survival time of unresectable CCA is generally less than 1 year, despite current chemotherapy regimens. Biliary drainage is often required as a palliative treatment for patients with unresectable CCA. Recurrent jaundice and cholangitis tend to occur because of reobstruction of the biliary stents. This not only jeopardizes the efficacy of chemotherapy, but also causes significant morbidity and mortality. Effective control of tumor growth is crucial for prolonging stent patency and consequently patient survival. Recently, endobiliary radiofrequency ablation (ERFA) has been experimented as a treatment modality to reduce tumor mass, and delay tumor growth, extending stent patency. Ablation is accomplished by means of high-frequency alternating current which is released from the active electrode of an endobiliary probe placed in a biliary stricture. It has been shown that tumor necrosis releases intracellular particles which are highly immunogenic and activate antigen-presenting cells, enhancing local immunity directed against the tumor. This immunogenic response could potentially enhance tumor suppression and be responsible for improved survival of patients with unresectable CCA who undergo ERFA. Several studies have demonstrated that ERFA is associated with an increased median survival of approximately 6 months in patients with unresectable CCA. Furthermore, recent data support the hypothesis that ERFA could ameliorate the efficacy of chemotherapy administered to patients with unresectable CCA, without increasing the risk of complications. This narrative review discusses the results of the studies published in recent years and focuses on the impact that ERFA could have on overall survival of patients with unresectable cholangiocarcinoma. Cholangiocarcinoma (CCA) is a rare cancer originating from the biliary epithelium and accounts for about 3% of all gastrointestinal malignancies , 2. The Since the majority of patients with unresectable CCA present with malignant biliary obstruction, biliary drainage is a crucial palliative treatment for patients with hilar or distal CCA. This can be obtained either by means of ERCP (Endoscopic Retrograde ColangioPancreatography) or PTC (Percutaneous Transhepatic Colangiography), placing one or more biliary stents  which relieve jaundice, without changing patients prognosis , 6. UnfoRecently, endobiliary radiofrequency ablation (ERFA) has been experimented as a treatment modality to reduce the tumor mass and delay tumor growth, extending stent patency –12. SeveThis narrative review summarizes the results of the studies published in recent years and focuses on the impact that ERFA could have on the overall survival of patients with unresectable cholangiocarcinoma.Endobiliary therapy of the tumor complementing chemotherapy for treatment of patients with unresectable CCA is appealing and it has been evaluated in clinical practice. The majority of patients with unresectable CCA require biliary drainage because of obstructive jaundice. Biliary stenting improves the quality of life but does not extend overall survival of these patients . At the IRE is a non-thermal tumor ablation technique which is mainly indicated for the treatment of locally advanced pancreatic cancer . IRE genEndobiliary PDT requires the administration of an intravenous photosensitizing agent (porfimer sodium) which concentrates in malignant biliary cells and is activated by a laser light of a specific wavelength delivered by a laser fiber placed into the biliary tree at the level of the stricture by means of ERCP or PTC . SubsequAfter preliminary experimental studies, in 2011 Steel et al. published the first report of a pilot study which evaluated feasibility, efficacy and safety of ERFA for the treatment of patients with malignant biliary obstruction (MBO) . The resERFA is accomplished by means of a high-frequency alternating current which is released from an active electrode located in the middle portion of an endobiliary probe. This is placed inside the biliary stricture where the subsequent emission of thermal energy causes coagulative necrosis and cellular death when the temperature exceeds 50°C , 12. It Radiofrequency ablation (RFA) has been shown to induce antigen-presenting cell infiltration and enhance systemic antitumor T-cell immune response as well as tumor regression in hepatocellular carcinoma . The tumTo date, there are two ERFA catheters which have been approved for clinical use Table 2.ERFA can be performed at the time of ERCP or PTC before biliary drainage in patients with MBO and strictures due to different neoplastic etiologies , 47, 48.The therapeutic efficacy of ERFA could be affected by the morphology of the biliary stricture and its location , 47. SinAnatomic characteristics of the intrahepatic and hilar biliary ducts might affect the efficacy of ERFA and/or increase the risk of complications. Bile ducts angulation in the hilum can impair ERFA treatment because straight and rigid endobliary catheters may not pass the angulations and/or the tip of the probe may not mantain the required tight contact with the target tissue . Hilar aSeveral possible solutions to the above mentioned technical issues have been proposed. A preoperative road map with abdominal MRI (magnetic resonance imaging) and MRCP (magnetic resonance cholangiopancreatography) is recommended to accurately assess the tumor surroundings and evaluate the relationship of the target biliary stricture with the surrounding vascular and biliary structures, especially for the treatment of hilar and intrahepatic stenosis . Before The major advantages of ERFA are simplicity and low cost, without many major adverse events and very few controindications. The latter include the presence of cardiac devices, coagulation disorders, and ascites, as well as pregnancy , 63. TheStrict patient-selection and ablation with customized settings (according to the location of the biliary stricture and the comorbidity of the patient) have been proposed to reduce the incidence of severe complications . CarefulPatients with unresectable CCA have an overall survival of approximately 10 months if they undergo chemotherapy and about 4 months if they receive best supportive care (BSC) . The mosAmong endobiliary therapies ERFA is the best option for its semplicity, low cost and relatively few serious side effects , 25, 31.Maintaining the patency of biliary stents guarantees the administration of chemotherapy without interruption. Despite the use of biliary SEMS, recurrent jaundice and cholangitis tend to occur because of reobstruction of the biliary stents due to tumor growth , 8. SeveThe most valuable effect of ERFA is its impact on the overall survival of patients with unresectable CCA undergoing biliary drainage and stent placement. The above mentioned comparative studies as well as the cited meta-analysis investigated the impact of ERFA on overall survival and improved functional status of patients , 68, 70.It has been postulated that the thermal cell injury induced by ERFA could increase the cytotoxic effect of chemotherapy, especially in the case of intrahepatic CCA where the endobiliary ablation is often sublethal . MoreoveAvailable literature data support the role of ERFA as adjuvant therapy which increases both stent patency and overall survival in patients with unresectable CCA. These beneficial effects could add up to those of chemotherapy, with a cumulative impact of combination therapy on functional status, PFS and overall survival of patients with unresectable CCA. In the light of its potential benefit, ERFA could become part of the management of patients with locally advanced unresectable CCA, Bismuth type I-III, with a prognosis of at least 6 months Figure 2EDG and MDB managed the overall project and prepared the first draft. LT, FF, AO and AB reviewed the first draft. All other authors reviewed the manuscript and contributed to the final version of the article. EDG and MDB finalized the article on the basis of comments from the other authors. All authors contributed to the article and approved the submitted version.


COVID-19 had a significant impact on the mental health of the affected population. Such multifactorial risk for a deterioration of mental health suggests the need to identify groups of patients with psychiatric vulnerability and to establish strategies of intervention based on scientific evidence.The aim of the study was to identify psychiatric outcomes one year after recovery and possible associations between these and the clinical, anamnestic, and sociodemographic variables.The Mini International Neuropsychiatric Interview was employed to assess current and lifetime mental illness in a cohort of 100 patients discharged between March and April 2020 from COVID-19 wards of the San Paolo Hospital in Milan, Italy. The Kendall rank correlation coefficient was administered to measure the ordinal association between clinical-demographic variables and the psychiatric diagnoses of patients. Bivariate correlation was used to explore the association between psychiatric outcomes and the sample characteristics.Almost one third of subjects screened positive for a diagnosis of a new psychiatric disorder, and a novel onset of psychiatric morbidity did not differ significantly in patients with and without a positive history of mental illness (42 and 58%). New psychiatric disorders were grouped into stress reactions, anxiety-group disorders and mood disorders. Concerning demographic characteristics, advanced age represented a protective factor against the onset of new psychiatric disorders . Despite a lower risk of contracting the infection, women in our cohort were more vulnerable to psychiatric post-Covid symptoms . The correlation between the onset of new psychiatric disorders and some pre-admission vulnerability factors, such as an overweight condition  and a positive medical history for cigarette smoking , were statistically significant. Moreover, subjects who reported taking a therapy to control the infection prior to hospitalization were more likely to receive a new psychiatric diagnose . Of note, variables related to the severity of hospitalization such as oxygenation intensity, days of hospitalization, or requirement of intensive car were not associated with new psychiatric diagnoses.The onset of psychiatric disorders shows a relevant frequency in patients hospitalized for COVID-19, suggesting that mental health services should structure adequate screening and diagnosis methods. Three levels of intervention can also be expected to reduce the overall risk and burden of psychiatric morbidity: increasing awareness regarding modifiable risk factors; guaranteeing a minimal level of mental health support to patients hospitalized for COVID-19; providing personalized interventions with respect to gender and age groups.None Declared


Advances in flow-diversion devices for cerebral aneurysms” with Pervinder Bhogal and Alexander Sirakov. The material of this Research Topic has published cutting-edge research on this subject from all over the world, including clinical application research of new flow-diversion devices (FDs), FD treatment of distal aneurysms, ruptured and unruptured dissecting aneurysms, bifurcation aneurysm, antiplatelet therapy and hemodynamic study of FDs.I am honored to co-edit the topic “In the past 60 years, great success has been achieved in endovascular surgery of cerebral aneurysms. From the iron-acrylic compound , electroThe concept of FD is derived from the experiences and lessons learned in the development of stent-assisted coiling, which provides the denser coil filling, better angiographic and clinical results. Stent-assisted coiling directly interrupts the blood flow from the parent artery into the aneurysm and leads to the thrombosis in the aneurysm sac. The concept FD is based on two principles: (1) placing woven mesh device in the parent artery changes the blood flow away from the aneurysm sac and (2) the device structure provides a scaffold for the growth of endothelial cells. This process of “new endothelialization” separates the aneurysm from the circulation and allows the gradual thrombosis of the aneurysm . The advAs the first FDA certified FD, the pipeline embolization device  is still the most popular FD at present. Its safety and effectiveness of the off-label use have been widely published. Its clinical use has expanded from unruptured internal carotid artery aneurysms to the most cerebral aneurysms, such as anterior cerebral artery, middle cerebral artery and posterior circulation aneurysms . All FDA-approved FDs consist of Nitinol or Co-Cr alloy. If the clinical scenario requires, the endovascular neurosurgeon must be proficient in at least one or two of them as well as maintain a certain understanding and familiarity with the advantages/limitations of these devices.There are many other FDs with different designs , such asThe main limitation of FD is ischemic stroke associated with intra-stent thrombosis, which requires dual antiplatelet therapy or GP IIb/IIIa inhibitors . TherefoWith the increase in the off-label use of FDs in a broader clinical scenario , it is nFinally, we thank all the authors and endovascular centers who have contributed to this topic and congratulate their great success in the use of FDs. This topic will undoubtedly continue to arouse the enthusiasm of the research, development and clinical use of FDs, and pursuit of excellent endovascular surgery results of cerebral aneurysms.The author confirms being the sole contributor of this work and has approved it for publication.


Fibrodysplasia ossificans progressiva (FOP) is an exceptionally rare genetic disorder characterized by the progressive formation of heterotopic bone in soft tissues. Here, we present the radiological findings of an 18-year-old female diagnosed with FOP who had severe spinal and right-upper-limb abnormalities. Her SF-36 scores suggested significant impairment in physical function, affecting work and other regular daily activities. Radiographic evaluation with X-rays and CT scans revealed scoliosis and total fusion of almost all levels of the spine, with only a few disc spaces spared. A large mass of heterotopic bone was observed, corresponding to the location of the paraspinal muscles in the lumbar region, branching upwards and fusing with the scapulae on both sides. On the right side, this exuberant heterotopic bone mass fused with the humerus, resulting in a fixed right shoulder, while the rest of the upper and lower limbs are spared and have a range of motion. Our report highlights the extensive ossification that can manifest in patients with FOP, resulting in restricted mobility and a poor quality of life. While there is no definite treatment that can reverse the effects of the disease, preventing injuries and minimizing iatrogenic harm is of critical importance in this patient as inflammation is known to play a key role in triggering heterotopic bone. Meanwhile, ongoing research into therapeutic strategies holds the key to unlocking a potential cure for FOP in the future.


The incidence of stroke plays the foremost role in the genesis of central neuropathic pain. Central post-stroke pain (CPSP) is a central pain arising from a vascular lesion in the central nervous system that elicits somatosensory deficits, often contralateral to stroke lesions. It is expressed as continuous or intermittent pain accompanied by sensory abnormalities like dysesthesia and allodynia. CPSP remains de-emphasized due to the variation in onset and diversity in symptoms, besides the difficulty of distinguishing it from other post-stroke pains, often referred to as a diagnosis of exclusion. Spinothalamic dysfunction, disinhibition of the medial thalamus, and neuronal hyperexcitability combined with deafferentation in thalamocortical regions are the mechanisms underlying central pain, which play a significant role in the pathogenesis of CPSP. The treatment regimen for CPSP seems to be perplexed in nature; however, based on available studies, amitriptyline and lamotrigine are denoted as first-line medications and non-pharmacological choices may be accounted for cases intractable to pharmacotherapy. This review attempts to provide an overview of the mechanisms, existing management approaches, and emerging targets of CPSP. A profound understanding of CPSP aids in optimizing the quality of life among stroke sufferers and facilitates further research to develop newer therapeutic agents for managing CPSP. A nerve injury or dysfunction in the central nervous system (CNS) may evolve into central neuropathic pain . NeuropaThe complexity in distinguishing CPSP from other peripheral pain arising post-stroke de-emphasizes it among post-stroke pains. Though management of CPSP seems challenging, the use of appropriate diagnostic methods and analyzing the right therapeutic methods depending on the state of the patient may help in achieving progress in the state of pain . There aCentral post-stroke pain (CPSP) is a neuropathic pain originating from a lesion in the CNS, which occurs as an impact of cerebrovascular diseases like stroke . It may Prevalence of CPSP after stroke exhibits a varying nature and is estimated as 1 to 35% , given tPain symptoms initiate with dysesthesia that might be spontaneous or evoked  and whicDiagnosis of CPSP probably presents a demanding task due to varying clinical symptoms and coexisting poststroke pains. As clear-cut diagnosis of CPSP is difficult, it may be based on integrating the patient’s history along with clinical examination, sensory tests, and neuroimaging of lesions in the CNS. CPSP is indicated contralateral to the affected cerebral hemisphere as stated by the International Association for the Study of Pain (IASP) guidelines. Somatosensory examinations will also serve as a tool in the prognosis of CPSP. The appearance of dysesthesia or allodynia and the absence or decreased sensation of a needle or cold stimulus can also augment the possibility of central pain after the stroke ,18,19,20The pathway of pain involves various sites of the CNS, like the cerebral cortex, midbrain, and spinal cord. Pain inputs sent by nociceptors are received by the dorsal horn (DH) of the spinal cord  and are The periaqueductal gray (PAG), situated in the midbrain, plays an integral role in pain transmission as a receiver point for ascending feed from the dorsal horn as well as incorporating the inputs from higher centers like the hypothalamus, amygdala, and frontal lobe. The descending circuit in the relay of pain access PAG is connected to the dorsolateral pontine tegmentum (DLPT) and rostral ventral medulla (RVM) via projection neurons for regulating the output from the spinal cord. Marked presence of neurotransmitters like noradrenaline (NA) and 5-hydroxy tryptamine(5-HT) have been identified in the PAG/RVM pathways apart from the endogenous opioid system .Injury to CNS in the form of vascular lesions, trauma, or infections leads to nerve impairment or damage in nerves of the somatosensory system and results in central neuropathic pain. In general, the proper transmission of pain signals to CNS is the balance of inhibitory and facilitatory influence in coordination with sensory inputs between the brain stem nuclei  and spinothalamic tract along with thalamocortical circuits. Any disturbance to this balance can be put forward as mechanisms underlying the central pain.Abnormalities in the central pain pathway have been denoted by the dysfunction of the spinothalamic tract, which is an integral part of the sensory pathway for somatic pain and thermal and touch sensations. Damaged nerves in the spinothalamic tract initiate complex reactions accompanied by neuronal hyperexcitability, eventually leading to hypersensitivity to cold and pinprick stimuli, which are common findings among CPSP patients rather than stroke patients without central pain . HyperseDisinhibition theory, proposed by Head and Holmes in 1911 , states Disproportion in the excitation inhibition facilitates a rise in neuronal excitability in the thalamus or cortex due to increased binding of glutamate with NMDA receptors, leading to spontaneous pain due to a rise in intracellular calcium, constituting the central sensitization; Pain transmission is influenced by the neurotransmitters in the central nervous system and facilitated in deriving the theories behind central neuropathic pain. A balance between excitatory and inhibitory neurotransmitters in the neuronal tracts of the somatosensory system determines the proper transmission of pain. Neurotransmitters that are inhibitory in action, like glycine, GABA (Gamma amino butyric acid) along with monoamines , and endogenous opioids, are found to inhibit the spinothalamic tract. Hyperexcitability of neurons arises from the release of the excitatory neurotransmitter glutamate at the site of nerve injury . InteresKnowledge regarding the pathophysiology of this neuropathic pain arising post-stroke is limited, though advances in functional imaging studies of the brain and factors that precipitate central pain have led to the perception of several aspects that may lead to the onset of CPSP. The thalamus is believed to play a significant role in mechanisms contributing to central pain and CPSP. Recent studies reveal the presence of lesions in the ventral posterolateral nucleus (VPL) or ventral posterior medial nucleus (VPM) of the thalamus among CPSP patients. A study conducted using modern techniques like magnetic resonance imaging (MRI) and digital radiographic atlases in thalamic stroke patients with CPSP found the presence of lesions in the VPL nucleus, specifically posterolateral and inferior parts, to a greater extent, unlike the smaller presence in the VPM nucleus . At the Furthermore, the study of Treister and colleagues states that the probability of CPSP is 81 times more if the thalamic lesions happen to be in the meeting point of ventral posterior nuclei and pulvinar nucleus . As sympConvincingly, CPSP patients on magnetic resonance imaging (MRI) studies revealed the presence of distinctive patterns of cortical atrophy in various cortical regions like, insular, secondary somatosensory, ventrolateral prefrontal, including nucleus accumbens. Sensory deficits and abnormalities in affective pain may be explained by the anatomical changes observed within these regions . FurtherCPSP can be described and agreed on with ‘disinhibition theory’ and was confirmed with a study conducted in hyperpathic CPSP patients using single photon emission computerized tomography (SPECT), which presented thalamus hyperactivity when a pain stimulus was given on the hemiparetic side. Interestingly, this effect was not retrieved in the other three patients with the absence of hyperpathia. So, CPSP can arise from lesions in the thalamus, mostly the lateral thalamus ,22. PainHaroutounian and colleagues in 2018 suggested that the origin of pain in CPSP need not be from ectopic CNS activity but could be from the afferent signals that mediate CNS sensitization. The prospective study conducted among eight CPSP patients by blocking the sensory signals from the peripheral pain field using ultrasound-guided block using lidocaine reduced pain to half the intensity in half an hour. The study results elucidate pain impulses derived from the peripheral sensory inputs and may be misconceived as CNS origin, contrasting with the hypothesis that central pain may be emerging within the CNS . Central− concentration across the membrane, which turns down the hyperpolarizing effects of GABA and also directs to the disinhibition of the medial thalamus mediated from the inhibitory signals from the lateral thalamus. On treating CPSP rats with TrkB-Fc, the BDNF blocker drug manifested a reduction in a neuronal burst in the medial thalamus and attenuated mechanical allodynia. Therefore, the influence of inflammatory mediators contributing to neuropathic pain is implicated in CPSP  diprenorphine) to analyze the OR binding was conducted on 5 chronic CPSP patients and 12 healthy subjects. The outcome of the study displayed reduced OR ligand binding on significant pain-processing regions in the thalamus and different cortical regions among CPSP patients. In addition, former PET studies conducted on CPSP subjects have shown an augmented activity in most of these structures. The study findings aid in correlating the reports that stated therapeutic response failure after intake of opioids in CPSP patients, though opioids have been used in various neuropathic conditions due to their property to increase the threshold of pain sensitization. Furthermore, it supports a better understanding of the neurochemical properties of the structures in the pain circuit, though it could not derive the entire role of opioids in CPSP. Thus, further research is needed to reveal the perplexed role of opioids in the pathophysiology of CPSP -benzoic acid (t-AUCB) . FurtherChronic pain has been greatly attributed to the release of proinflammatory cytokines, especially tumor necrosis factor-ά (TNF-ά), which is strongly associated with neuropathic pain . Stroke 2AR) antagonist SCH5826 is capable of inhibiting the neurotoxic effects of glutamate, thereby offering remarkable neuroprotection in the early stage of postischemic injury. Moreover, studies have shown impairment in immune cell infiltration and neuroinflammation on A2 agonist CGS21680 treatment after a week of stroke, owing to minimized damage in the brain [Reports suggest that adenosine (Ahe brain . ModulatIt is common to experience post-stroke pains after the incidence of a stroke. The effective management of CPSP relies on recognizing and characterizing it from coexisting poststroke pains. The interval in observing the symptoms of CPSP makes it unrecorded during a medical examination in the acute period of post-stroke. The differences in the study groups and diagnostic measures used make the prevalence of CPSP low among stroke patients and are reported with variance in results. Though the thalamus is widely studied among CPSP patients, research also discloses the association of lesions in extra thalamic sites. Apparently, understanding central pain mechanisms that correlate with the pathophysiology of CPSP may aid in the early identification of central neuropathic pain induced by stroke. Amitriptyline and gabapentinoids are considered first-line and second-line agents in the treatment of CPSP, respectively. Monotherapy in treating CPSP might not be sufficient to provide optimum results. The combination of antidepressants with gabapentinoids used in clinical practice is found to be more effective with reduced drug doses. Non-invasive approaches could be considered for patients refractory to pharmacotherapy. Therapeutic options in CPSP are limited, and there is an urge to focus on new drug targets to optimize efficacy along with minimizing side effects. The negative impact of CPSP on the psychological well-being of the patients may lead to anxiety, depression, and sleep disturbances. Also, the extent of recovery from the pain symptoms seems to be moderate. Hence, cognizance of CPSP unquestionably helps in creating awareness among healthcare providers for early prognosis and timely management of CPSP.