Coronavirus disease 2019 (COVID-19) is an on-going pandemic disease infecting millions of people across the globe. Recent reports of reduction in antibody levels and the re-emergence of the disease in recovered patients necessitated the understanding of the pandemic at the core level. The cases of multiple organ failures emphasized the consideration of different organ systems while managing the disease. The present study employed RNA sequencing data to determine the disease associated differentially regulated genes and their related protein interactions in several organ systems. It signified the importance of early diagnosis and treatment of the disease. A map of protein interactions of multiple organ systems was built and uncovered CAV1 and CTNNB1 as the top degree nodes. A core interactions sub-network was analyzed to identify different modules of functional significance. AR, CTNNB1, CAV1, and PIK3R1 proteins were unfolded as bridging nodes interconnecting different modules for the information flow across several pathways. The present study also highlighted some of the druggable targets to analyze in drug re-purposing strategies against the COVID-19 pandemic. Therefore, the protein interactions map and the modular interactions of the differentially regulated genes in the multiple organ systems would incline the scientists and researchers to investigate in novel therapeutics for the COVID-19 pandemic expeditiously. The disease cases are further escalating causing human sufferings. Currently, several vaccines are being evaluated at various clinical stages [Coronavirus disease 2019 (COVID-19) is a pandemic disease caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . As on 11 August 2020, it reported to infect more than 78 million and decease over 1.7 million people around the world  were retrieved from the Database of Interacting Proteins (DIP) database . From thThe largest component in the protein interactions map was unwrapped as a core interactions sub-network. The core interactions sub-network was processed through edge betweenness clustering algorithm  to prediTotal drug protein interactions were retrieved from the MATADOR database . The druIGF2, ITM2C, MAPT, and PPP1R1A genes which were up-regulated in bowel, heart, jejunum, kidney and lung and ABCA3, SFTPA1, SFTPA2, SFTPB, and SLC34A2 genes which were down-regulated in all the organ systems except lung. Some genes were observed to be differently regulated such as ANK2 and CLU both of which were up-regulated in bowel and jejunum but down-regulated in marrow and placenta. A heatmap of organ-wise averaged read counts of genes differentially regulated in more than seven organ systems can be visualized in the The distribution of log2 fold change values relative to the mean of DESeq2 normalized counts can be visualized in the The DIP database constituted 6,729 experimentally verified human PPIs. The significant up or down-regulated gene products were detected to engage in 608 PPIs. Of these PPIs, two were specifically observed in bowel, four in heart, five in liver, 36 in marrow, and five in placenta. One hundred and ten PPIs were observed as cross-organ protein interactions where a protein of a specific organ system interacts with a protein of another organ system. Four hundred and forty-six PPIs were observed as multi-organ protein interactions where proteins of multiple organ systems interact with proteins of other organ systems. The involvement of large number of multi-organ protein interactions suggests that the COVID-19 pandemic affects several organ systems to reach its severe pathological state; therefore, early diagnosis and treatment of the pandemic could prevent patient decompensation and thus make easy recovery. A protein interaction map can be visualized in the The largest connected component of the protein interactions map was interpreted as the core interactions sub-network and it constituted 306 edges among 265 nodes. The core interactions sub-network can be visualized in the The number of interacting proteins mapped to MATADOR databases was 222. This indicates that the protein interactions map of COVID-19 is enriched with several significant targets with known drug candidates. Therefore, proteins of the interactions map can be further investigated for drug re-purposing strategies. The


Food and Drug Administration (FDA) for emergency use. Hundreds of relevant clinical trials are ongoing worldwide. Therapeutic antibody therapies have been a very active and crucial part of COVID-19 treatment. In this review, we focus on the progress of therapeutic COVID-19 antibody development and application, discuss corresponding problems and challenges, suggesting new strategies and solutions.The pandemic of Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome 2 coronavirus (SARS-CoV-2) continues to be a global health crisis. Fundamental studies at genome, transcriptome, proteome, and interactome levels have revealed many viral and host targets for therapeutic interventions. Hundreds of antibodies for treating COVID-19 have been developed at preclinical and clinical stages in the format of polyclonal antibodies, monoclonal antibodies, and cocktail antibodies. Four products,  The Coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by the severe acute respiratory syndrome 2 coronavirus (SARS-CoV-2) i.e., nonstructural, structural, and accessory. The nonstructural gene ORF1ab occupies about 2/3 of the genome at the 5′ end, encoding polypeptides pp1a and pp1ab . The proteolytic cleavage of pp1a and pp1ab produces a series of nonstructural proteins (namely nsp1-16), which are essential for viral transcription and replication etcGenomics studies have shown SARS-CoV-2 is a novel member of the genus betacoronavirus. It has a positive-sense, single-stranded RNA genome about 30kb long Transcriptomics, proteomics, and interactomics studies have further revealed many other potential drug targets for COVID-19 therapeutics development A lot of studies on chemical drug design or repurposing for the treatment of COVID-19 have been done Therapeutic polyclonal antibodies have been applied to treat infectious diseases since the 1890s. In 1901, Emil Behring received the first Nobel Prize in Physiology or Medicine for his work on serum therapy, especially its application against diphtheria. Later on, convalescent sera or plasma therapies have been applied to various infectious diseases. Due to the increasing number of SARS-CoV-2 infections and the lack of effective therapies, convalescent plasma therapy has become very popular currently.According to data from ClinicalTrials.gov, there are at least 176 registered clinical trials using convalescent plasma for treating COVID-19 patients. Although most of these clinical trials are still ongoing, there are 26 completed studies. Some early results show convalescent plasma therapy is not only safe but also may help eliminate the virus and improve clinical symptoms A meta-analysis on 20 studies  concluded that the benefits of convalescent plasma for people admitted to hospital with COVID-19 were uncertain More and more positive results however have also been reported recently. In a retrospective, propensity score-matched, case-control study, the effectiveness of convalescent plasma therapy in 39 patients with severe or life-threatening COVID-19 at the Mount Sinai Hospital in New York City was assessed. The median time between admission and transfusion was 4 days. Both oxygen requirements and survival were improved in plasma recipients Taking the seemingly contradictory results from clinical trials together, it becomes clear that the use of convalescent plasma with high anti-RBD IgG levels at the early stage (preferably within 3 days from the onset of symptoms) can reduce mortality and progression of COVID-19 i.e., Ortho VITROS SARS-CoV-2 IgG tested with signal-to-cutoff ratio ≥12). Furthermore, the optimal dose and time point, as well as the most proper patients, still need further investigations, especially in the situation where the supply of convalescent plasma is tenuous compared to a large number of patients. Thirdly, the risk of infecting unknown blood-borne infectious diseases exists, though strict screen is performed before the collection of plasma. Besides, convalescent plasma is not easy to store and deploy compared with other drugs.The major problem with convalescent plasma therapy is quality control and standardization. For example, the antibody titer of plasma is highly variable, but no measurement for neutralizing antibodies is widely available or generally accepted, though FDA has set a standard to define high titer convalescent plasma  has also been proposed to treat COVID-19 Therapeutic monoclonal antibodies have been applied to treat human diseases since 1986 when muromonab-CD3 was approved by FDA for treating acute rejection after a kidney transplant in vitro and in vivo experiments have been done in the preclinical researches to study epitopes, structures, efficacy, and mechanisms of anti-spike monoclonal antibodies As described previously, the spike protein of SARS-CoV-2 mediates the virus entry and the effect of convalescent plasma therapy is dependent on the titer of neutralizing anti-spike antibodies. It is therefore only natural that the main target of anti-virus antibodies is the spike protein. In the last year, a lot of research groups have isolated many monoclonal antibodies against the spike protein of SARS-CoV-2, especially against its receptor-binding domain Host factors involved in the life cycle of SARS-CoV-2 or the pathogenesis of COVID-19 are also potent targets for therapeutic monoclonal antibody development. For example, neuropilin-1 (NRP1) significantly increases SARS-CoV-2 infectivity and mAb3, a monoclonal blocking antibody against NRP1 can block this effect in cell culture Taking the two categories together, there are hundreds of therapeutic monoclonal antibodies at the different stages of development. The community does need a special database that can aggregate and store COVID-19 antibody data together, and most importantly, easily follow the progress of relevant projects. In March 2020, the Chinese Antibody Society launched the “COVID-19 Antibody Therapeutics Tracker” project to track the therapeutic antibodies for COVID-19 treatment in preclinical and clinical development worldwide Compared with therapeutic polyclonal antibodies such as convalescent plasma which is highly variable and heterogeneous, a monoclonal antibody drug is composed of totally identical antibodies. The monoclonal antibody usually has only one drug target and recognizes only one epitope. It can be precisely engineered and optimized to serve specific treatment purposes. Therefore, it is usually safer and more effective than polyclonal antibodies. Furthermore, the quality of monoclonal antibody is easier to control, the manufacture of monoclonal antibody is scalable and independent of donors, and the effect of monoclonal antibody is highly reproducible. However, therapeutic polyclonal antibodies are more robust and resistant to SARS-Cov-2 mutations and variants, because they have multiple drug targets and bind even more epitopes. Thus, a new format that combines the advantages of both therapeutic polyclonal antibodies and therapeutic monoclonal antibodies is urgently needed.Therapeutic cocktail antibodies are combinations of two or more monoclonal antibodies. As all its components are clearly identified and characterized, an antibody cocktail holds all advantages of monoclonal antibodies. Moreover, it targets more than one epitope or even binds multiple antigens like polyclonal antibodies. The synergism and complementarity of each monoclonal antibody make a cocktail a better choice for treating varying infectious diseases Therapeutic cocktail antibodies have become the frontiers of COVID-19 treatment. Some primary data show that cocktail treatment is superior to monotherapy. Bamlanivimab has shown promising interim results in the phase 2 trial and has been approved by the FDA for emergency use. Nevertheless, the viral load reduction of the bamlanivimab monotherapy is not significantly different from the placebo group in a randomized clinical trial. However, a statistically significant reduction in SARS-CoV-2 viral load at day 11 is observed when nonhospitalized patients with mild to moderate COVID-19 are treated with the combination of bamlanivimab and etesevimab REGN-COV2 is a cocktail of two potent neutralizing antibodies (REGN10933/Casirivimab and REGN10987/Imdevimab). As shown in Figure Indeed, when two epitopes are not overlapping, relevant antibodies complement rather than compete with each other At present, several other monoclonal antibody cocktails such as BRII (BRII-196 and BRII-198) and ADM03820  are in clinical trials. As shown in Table in vitro assays and in vivo models for ADE risk evaluation are expecting to be built. As monoclonal antibodies are easy to be engineered, quite a few strategies such as Fc engineering and antibody cocktails may bypass or inhibit ADE.Antibody-dependent enhancement (ADE) is an unexpected phenomenon that happened after vaccination or antibody therapies, where the production or presence of specific antibodies may enhance rather than inhibit viral infection in vitro passaging in the presence of individual antibodies, resulting in loss of neutralization The second challenge comes from SARS-CoV-2 variants e.g. the PDB database. As the information mentioned above is essential for antibody analysis and evaluation, a more comprehensive database for therapeutic antibodies against COVID-19 is needed. Facing hundreds and even thousands of antibody candidates, better and more bioinformatics tools for evaluating the antibody developability are also needed to accelerate the speed of antibody development The third challenge is how to survive drowning in the sea of COVID-19 data and papers i.e. convalescent plasma, bamlanivimab, REGN-Cov2, and the combination of bamlanivimab and etesevimab. Currently, hundreds of therapeutic antibodies against COVID-19 are at the preclinical stage or in clinical trials, making therapeutic antibodies an important complement to interventions such as chemical drugs and vaccines.The available therapeutic antibodies for COVID-19 treatment can be divided into three categories: polyclonal, monoclonal, and cocktail antibodies. Four products have received EUA from the FDA, in vitro and in vivo during the development or quality control process. Fc engineering and antibody cocktails are two suitable strategies to deal with the ADE problem. Future studies should also track SARS-CoV-2 variants, especially antibody-resistant variants. Developing monoclonal antibodies with more diverse targets and formulating cocktail antibodies more flexibly may be proper strategies. In addition, future studies should keep an eye on the development of a special COVID-19 therapeutics antibody database with more comprehensive data fields and better bioinformatics tools for the evaluation of antibody developability. We believe therapeutic antibodies against COVID-19 will play an even more important role in the fight against the catastrophic pandemic in the future.The development of antibody therapeutics for COVID-19 is challenged by the risk of antibody-dependent enhancement, SARS-CoV-2 variants, and information overload. Future studies should pay more attention to the evaluation of ADE


Timely discovery of COVID-19 could aid in formulating a suitable treatment plan for disease mitigation and containment decisions. The widely used COVID-19 test necessitates a regular method and has a low sensitivity value. Computed tomography and chest X-ray are also other methods utilized by numerous studies for detecting COVID-19. In this article, we propose a CNN called depthwise separable convolution network with wavelet multiresolution analysis module (WMR-DepthwiseNet) that is robust to automatically learn details from both spatialwise and channelwise for COVID-19 identification with a limited radiograph dataset, which is critical due to the rapid growth of COVID-19. This model utilizes an effective strategy to prevent loss of spatial details, which is a prevalent issue in traditional convolutional neural network, and second, the depthwise separable connectivity framework ensures reusability of feature maps by directly connecting previous layer to all subsequent layers for extracting feature representations from few datasets. We evaluate the proposed model by utilizing a public domain dataset of COVID-19 confirmed case and other pneumonia illness. The proposed method achieves 98.63% accuracy, 98.46% sensitivity, 97.99% specificity, and 98.69% precision on chest X-ray dataset, whereas using the computed tomography dataset, the model achieves 96.83% accuracy, 97.78% sensitivity, 96.22% specificity, and 97.02% precision. According to the results of our experiments, our model achieves up-to-date accuracy with only a few training cases available, which is useful for COVID-19 screening. This latest paradigm is expected to contribute significantly in the battle against COVID-19 and other life-threatening diseases. The global COVID-19 epidemic has infected 347 millions of people around the globe and over 5.5 million deaths confirmed by the World Health Organization (WHO) as of 25 January 2022 ,7,8, andCT has been successfully used as a supportive method for COVID-19 condition evaluation, despite the fact that it is not approved as a primal diagnostic means . The mosThe application of DL frameworks to diagnose COVID-19 from CT images has shown promise results in several studies ,11,12. CA range of medical biomarkers and abnormalities have also been investigated as indicators of disease development in research, and there are some indications that imaging data could supplement these models ,20,21. WThe aim of this research is to establish a conceptual depthwise separable convolution network with wavelet multiresolution analysis module for COVID-19 screening from chest X-ray (CXR) and computed tomography (CT). In consideration of a novel medical predicament such as COVID-19, obtaining adequately accessible compilation of medical image dataset for training deep learning (DL) algorithms is difficult due to the time and resources required to collect and mark images.Medical image mining is a time-consuming and costly procedure that necessitates the involvement of radiologists and researchers . FurtherIn view to alleviate this drawback, we proposed a novel depthwise separable convolution network with wavelet multiresolution analysis module that optimizes the downsampling operation without losing spatial details for COVID-19 classification. The contributions of this work include: (1) Magnify the feature extraction robustness of the network by replacing the max-pooling layers with discrete wavelet transform (DWT) pooling for the loss reduction of spatial details and to achieve reduction in dimension without losing positional details by employing scaling and wavelet functions. (2) The depthwise separable connectivity framework ensures reusability of feature maps by directly connecting previous layer to all subsequent layers for extracting feature representations from few dataset. This enables the model to learn the spatial details for effective classification. (3) This paper is the first work that introduces a depthwise separable convolution network with wavelet multiresolution analysis module for feature extraction from radiograph images. The proposed model is an end-to-end learning techniques for COVID-19 classification that achieves much higher diagnosis accuracy.The subsequent sections of this article is coordinated as follows. In COVID-19 investigations based on DL algorithms have been on the rise in most research articles at present. The ImageNet weights were pretrained on 18-layer custom ResNet architecture against 100 COVID-19 and 1431 pneumonia instances of CXR dataset as proposed in .According to Lu et al. , who adoNneji et al.  suggesteA ResNet-50 transfer learning based CNN algorithm was proposed in  to identML approach was proposed in  to tacklIn summary, most studies, including those that have utilized CXR and CT imaging, rely on an insufficient number of COVID-19 images from various sources with no standardized protocols. They appear to be simple applications of existing AI-based algorithms leading to minimal AI innovation and clinical utility. The high data discrepancy associated with various studies causes comparison perplexity despite the fact that all models performed admirably . GeneralNotwithstanding, a few models utilize10 COVID-19 test instances, and at least one model utilizes external validation attributed to data scarcity. As a consequence, they may or may not be applicable to other contexts. A system that uses less data and attains high significant achievement in accuracy with less training instances is required. This will permit to a greater extent the inclusion of uncommon data class in the testing set. The objective of this article is to formulate a scheme that can help to enhance previous models and achieve state-of-the-art results.Artificial intelligence (AI) has achieved a remarkable reputation in the field of clinical research. In the face of the current pandemic ravaging our world, AI can assist healthcare workers in the process of disease detection, boosting the accuracy of identification methods at fast rate and perhaps saving lives. The scarcity of appropriate data is perhaps the most significant barrier facing AI-based approaches. Since AI-based approaches are data-driven, a large amount of data is needed. The process of data collection is quite tedious, as there are many ethics concerns from experts. Bearing this view in mind, we resorted to well-known and validated dataset repositories for the collection and compilation of the dataset. In this article, we collected CXR data of different pneumonia related illnesses from three different open sources ,46,47,48In this article, we proposed a deep convolutional neural network called the depthwise separable convolution network with wavelet multiresolution analysis module (WMR-DepthwiseNet) for the classification of COVID-19, healthy, and other pneumonia cases. As depicted in Consequently, a pointwise convolution layer is introduced to accomplish subsampling. The pointwise convolution layer consists of The overall strucure of the WMR-DepthwiseNet employs Depthwise separable convolution module is a factorized form a conventional convolution that consists of depthwise convolution and a pointwise layer of The d indexes the depthwise separable convolution layers and depicts the output of the dth depthwise separable convolution layers as dth depthwise separable convolution layer receives the feature maps of all the subsequent depthwise separable convolution layers, The first depthwise separable convolutional module consists of three To enhance the performance of identification without delineating infection lungs areas manually, a conventional approach is that if the model can unaidedly focus on infection areas without losing spatial information, the model would enhance its ability to differentiate the interclass discrepancies between COVID-19 and other pneumonia which will automatically enhance the classification accuracy. Conventional CNNs mainly adopts pooling layers for downsampling operation to achieve reduction in dimensionality, which usually lead to loss of spatial information. Some advanced CNNs have adopted channel and spatial attention mechanisms to strengthen the network’s critical information adaptability for aggregating and unaidedly recalibrating feature maps through spatialwise and channelwise approaches. Several attention schemes have been proposed such as squeeze-and-excitation , bottlenEquation . Figure The integral of the square of Equation (3)∫−∞∞ψEquation  explicitt is 1, the normalization on the right hand side of Equation =1Our proposed scheme allows us to connect depthwise separable convolution with wavelet multiresolution analysis to achieve filtering and downsampling. The wavelet multiresolution analysis algorithm formulates pointwise convolution and pooling into depthwise separable convolutional neural network as filtering and downsizing. The proposed scheme executes pooling operation to pool features by carrying out four-level decomposition of two-dimensional discrete wavelet transform as depicted in Subsequently, the fourth-order sub-band is used to recapture the image characteristics after conducting the fourth-order decomposition. With the utilization of the inverse WT, which is based on the inverse DWT (IDWT), the image characteristics is pooled by a factor of 2 as depicted in Equation (8)Wψk,mThe WMR-DepthwiseNet is composed of two segments; the first segment is the depthwise separable convolution block with each layer of depthwise separable convolution module densely connected. The second segment is the wavelet multiresolution analysis module connected to the depthwise separable convolution block with concatenation channel connection to link subsequent layer with all the prior layers in order to avoid the loss of information about the input and positional details as the information moves along the network. Many state-of-the-art models have adopted similar technique such as ResNet and residual models and achieved good results in several machine vision problems, but a great amount of computational resources is needed due to the huge amount of parameters.WMR-DepthwiseNet processes the input image through depthwise separable convolution layers. Precisely, the multiresolution analysis decomposes the input image via the low-pass and high-pass filters and concatenate the decomposed images into the depthwise separable convolution block channel-wise. The connection channels are executed using To investigate the performance of our proposed model on screening COVID-19, we collected public dataset of both CXR and CT images from three open sources ,46,47,48However, viral pneumonia dataset consist of 2983 scans of CXR, which is relatively the smallest when compared to the other CXR categories. As a result, we selected 2000 scans from each category for this study, bringing to a total of 24,000 CXR images as presented in i denote the distribution of the class which is 12 categories, i denote the distribution of the class which is 2 categories, We utilized a dropout of 0.5 to avoid overfitting. An Adam optimizer with a learning rate of quations  and 10)1×104 is In this section, we presents an ablation study of the structural configuration of our proposed model with different depthwise bottleneck modules. We selected a few pretrained models and compared them with our proposed network in terms of classification performance using the same dataset. we only fine-tuned the last layer to correspond to the number of classes in our dataset. Another study was conducted to compare our proposed network with several state-of-the-art COVID-19 imaged-based screening methods.In order to verify the effectiveness of our proposed model, we compared our designed WMR-DepthwiseNet with up-to-date models. For fair comparison, we run four state-of-the-art COVID-19 methods on the same dataset. From all indications, our proposed model outperforms the up-to-date methods and the deep learning pretrained models with a promising performance. The evaluation criterion adopted as the metric to evaluate the diagnosis performance of our proposed WMR-DepthwiseNet is as follows: accuracy (ACC), precision (PRE), sensitivity (SEN), specificity (SPE), area under curve (AUC), and F1-Score.Firstly, we performed ablation study on different configurations of our proposed WMR-DepthwiseNet with different depthwise separable convolution bottlenecks. Particularly, we made comparison on the following architectures.WMR-DepthwiseNet-A: WMR-DepthwiseNet-B: WMR-DepthwiseNet-C: WMR-DepthwiseNet-D: The experimental results of the ablation study are summarized in From all indications, the WMR-DepthwiseNet-D with We compare the findings of our proposed model with well-known CNN pre-trained models and up-to-date COVID-19 screening methods. According to As several attempts at COVID-19 classification have been made, we are now comparing the findings of our proposed WMR-DepthwiseNet with previous up-to-date COVID-19 screening methods. In detecting COVID-19 from CT exams, Chen et al.  uses CNNIn separating COVID-19 from other viral pneumonia, Xu et al.  and WangIn another experiment, we compared the formulated WMR-DepthwiseNet with four selected COVID-19 models using the same dataset for fairness. Cov-Net  and DeCoThe proposed WMR-DepthwiseNet has competitive classification efficiency for COVID-19 recognition. The underlying explanation may be that the proposed WMR-DepthwiseNet can better utilize the extracted features of high-level discriminative representation. It is worth noting that the the deptwise separable convolution network with wavelet multiresolution analysis module can handle small-scale data while using less computing power than conventional deep-learning-based approaches. To further examine the performance of the suggested scheme with different hyper-parameter tuning, we presented a statistical report in Despite the outstanding results record by the proposed model, we also presented cross-dataset evaluation to investigate if there is any discrepancy regarding the results obtained. We study the influence of training a model in one data distribution and evaluating it in another in this experiment. This situation is more realistic because training a model with images from all available sensors, environments, and persons is nearly impossible. We maintain same manner of data split of training, validation and test with 50%, 25%, and 25%, respectively, as shown in Although we emphasize that the training images used to train the model and the test images are drawn from different distributions. Other test designs were also investigated, such as employing the COVID-CXR training partition as a test and combining both COVID-CXR partitions as a bigger test set See . We emplWhen we examine cross-dataset assessment to intra-dataset evaluation, the model performance did not change that much which indicates that there is no significant bias in the results reported using the intra-dataset. It is important to make some remark about the proposed depthwise separable convolution network with wavelet multiresolution analysis module. Manual detection of COVID-19 by an expert utilizing CXR and CT can have a high sensitivity but a low specificity of 25%. This inadequate specificity leads to false positive predictions, which leads to ineffective therapy and wasted money. Our proposed WMR-DepthwiseNet has a high specificity of 96.22%, which can be used to help expert radiologists reduce the number of false positive instances reported.More importantly, the stated result in terms of Receiver Operating Characteristic (ROC) can aid expert radiologist in achieving a trade-off between specificity and sensitivity by telling the overall accuracy as illustrated in More interestingly, the precision–recall curve also shows that our proposed WMR-DepthwiseNet outweighs the other models with an average precision of 98.69% on CXR dataset and 97.02% on CT dataset. The precision-recall graph demonstrates the trade-off between precision and sensitivity. It is obvious that the model performs better than the other up-to-date COVID-19 models as shown in Furthermore, some comments on WMR-DepthwiseNet computational cost and model complexity are necessary. We combined depthwise separable convolution network with wavelet multi-resolution analysis module for feature extraction. We adopted wavelet pooling instead of the usual max-pooling operator for down-sizing operation which reduced model complexity and computation time. Another intriguing feature of our WMR-DepthwiseNet is its capacity to preserve high-level features without loss of spatial details. In terms of computing cost, the formulated algorithm was trained on an NVIDIA GTX 1080 and implementation on Keras framework. In comparison to earlier up-to-date models, the complexity of the proposed scheme is much reduced with fewer parameters as a result of the wavelet pooling strategy adopted. In all the assessment metrics, the proposed WMR-DepthwiseNet outperforms their counterparts as depicted in We propose a CNN called depthwise separable convolution network with wavelet multiresolution analysis module (WMR-DepthwiseNet) in this paper with the objective of addressing the issue of low performance in COVID-19 screening from radiograph (CXR and CT) images as well as loss of spatial details during feature extraction. We implemented a depthwise separable convolution network with wavelet multi-resolution analysis and a discrete wavelet transform (DWT) pooling to replace the conventional max-pooling operation as a strategy to avoid loss of spatial details and to preserve high-level feature and learn the distinctive representations for COVID-19 classification. We have demonstrated that our proposed model is effective and converges very fast with better classification performance. By a broad margin, our proposed approach outshone previous up-to-date COVID-19 diagnostic strategies. The limitation of our work is that we did not consider imbalance problem which happens to be the case for newly discovered diseases due to lack of sufficient data which usually leads to uneven class distribution. In our future work, we will also focus on imbalance class problem. We belief that graph-based convolutional neural network can improve the quality of the result. Therefore, part of our future work will take into consideration the possibility of implementing graph depthwise separable convolutional network.


The medical screening practices for blood donor eligibility after vaccination against several conventional infectious agents are well known to blood transfusion centres worldwide. Classically, blood donations are contraindicated for four weeks after vaccination with a live attenuated virus vaccine. For other types of vaccines, no postponement is necessary as there is no proven infectious risk. But for the COVID-19 vaccine, besides the classic platforms for the vaccine, two new types of vaccine platforms have been developed and based on viral vectors vaccines and vaccines from viral genetic material. Thus, blood establishments could be worried that these COVID-19 vaccine production platforms can pose any particular safety concerns for recipients of blood or blood products from vaccinated subjects. Our work aims to provide professionals in blood transfusion centres with all the available information to clarify any confusion relating to the need or not to defer donors who have received a COVID-19 vaccination. So in this paper, we provide an international review of the data available to date about the recommendations of international scientific societies about blood donation after COVID-19 vaccination, all types of COVID-19 vaccines included. We also present some experiences of blood transfusion establishments worldwide concerning this topic and among them our institution, the Moroccan National Centre for Blood Transfusion and Haematology. Since the beginning of the COVID-19 pandemic, blood establishments worldwide have continuously updated the eligibility criteria for donating blood based on the evolution of the international epidemiological situation with the SARS-CoV-2 virus and according to the development of scientific knowledge concerning this new coronavirus. With the start of COVID-19 vaccination campaigns, questions arise about the duration of exclusion (or the lack of exclusion) of blood donors who have received the COVID-19 vaccine. In this context, it´s essential to know that making an inappropriate decision to defer people vaccinated with the COVID-19 vaccine could exclude a large part of the population from blood donation for several weeks and possibly compromise self-sufficiency in labile blood products. The decision to defer a donor after COVID-19 vaccination should be based essentially on the reel risk of transmission of a potentially dangerous infectious agent to recipients of blood products [The medical screening practices for blood donor eligibility after vaccination against several conventional infectious agents are well known to blood transfusion centers worldwide. For classic infectious agents, blood donation is contraindicated four weeks after injection of a live attenuated vaccine. Other types of vaccines  do not entail any risk of infection and do not justify any postponement . For thest December 2020 to 31st April 2021, we searched data about the eligibility criteria for blood donation after receiving the COVID-19 vaccine. For this, we consulted several websites such as PubMed Central, Hinari, Web of Sciences, Google Scholar, Google, World Health Organization (WHO) website, European Centre of Disease Control (ECDC) website, Food and Drug Administration (FDA) website, International Society of Blood Transfusion (ISBT) website, American Association of Blood Banks (AABB) website, the Centre for Disease Control (CDC) website, the High Council for Public Health (HCPH) website. We also consulted websites of blood establishments worldwide like American Red Cross, Australian Red Cross, Scottish National Blood Transfusion Service, Canadian blood services. We used several key search terms such as blood donation after COVID-19 vaccine; eligibility criteria and COVID-19 vaccination; the impact of COVID-19 vaccination on blood donation; blood donor´s deferral after COVD-19 vaccine; technical platforms of production of COVID-19 vaccines; COVID-19 vaccines production; COVID-19 vaccines and blood donation screening. All the data collected was analysed and synthesized into relevant information reported in our article.From 1Brief overview of the new vaccine platforms used for the production of the COVID-19 vaccine: in the context of emerging pathologies, it appeared desirable to have platforms that can easily be used to rapidly develop vaccines capable of inducing humoral and cellular responses without requiring large doses of vaccine [ vaccine . Vaccine vaccine . There a vaccine . The vir vaccine . They in vaccine . For the vaccine . For SAR vaccine . It´s ex vaccine . Like vi vaccine .Escherichia coli (E.coli) and therefore contain the elements promoting their production in this bacterium [The first DNA vaccines were developed about 30 years ago. To produce these vaccines, they use a bacterial plasmid into which they insert a eukaryotic expression cassette encoding the vaccine antigen, which comprises a CMV promoter and a 3'-polyadenylation signal encoding the vaccine antigen. The plasmids are then amplified in acterium ,2. Deoxyacterium ,2. Ribonacterium ,2. At thacterium . The COVacterium . We presData from international scientific societies: the European Centre for Disease Prevention and Control (ECDC), on its second technical update published on December 10th 2020, stipulated that after vaccination with attenuated viruses (e.g. virus vector-based or live-attenuated virus vaccines), donors must be deferred for four weeks [th 2020, reported that the potential for a growing number of donor deferrals for investigational COVID-19 vaccines could pose another challenge to the blood supply [th 2020, in response to the AABB summary about donation of blood components following COVID-19 vaccines, FDA confirmed that it would be reasonable to have no donor deferral following mRNA COVID-19 vaccines and offered that a 14-day deferral is appropriate following a live-attenuated vaccine [rd 2020, AABB confirmed all recommendations cited previously and insisted on noting that a 12-month deferral is needed for recipients of unlicensed vaccines, subject to review by the medical director [ur weeks . Individur weeks . If infour weeks . Given tur weeks . In addiur weeks . A reguld supply . In respd supply . The FDAd supply . On Dece vaccine . Also, a vaccine . On its director .th 2021 notice, the FDA insisted on the same criteria already mentioned in its previous reports and reported that individuals uncertain about which COVID-19 vaccine was administered refrain from donating for a short waiting period (e.g. 14 days) [th 2021, the High Council of Public Health (HCPH) gave a provisional response on donors vaccinated with messenger RNA vaccines in use in France [nd 2021, the HCPH published a report relating to the exclusion criteria for donors of products from the human body who have been vaccinated against SARS-CoV-2 [This review allows a medical director the discretion to define a deferral period of less than 12 months, such as those described above, based on information received from the FDA . In the 14 days) . On JanuSome recent experiences from blood transfusion establishments at the international level: blood transfusion centres have already updated the eligibility criteria for blood donation after the COVID-19 vaccination. The American Red Cross (AmRC), following the FDA blood donation eligibility guidance, has updated its donor criteria eligibility and stipulates that deferral times may vary depending on the type of vaccine received [th 2020, COVID-19 update, stipulated no deferral need after receiving Pfizer or Moderna COVID-19 vaccines [st 2020, stipulated that blood donors how had the vaccine as part of the UK vaccination program can give blood seven days after the jab [vaccines . The Sco the jab . The blo the jab . The Sin the jab . For thi the jab . Donors  the jab . For ina the jab , and if  the jab . Accordi the jab . The blo the jab . For The the jab . This wa the jab . The AsR the jab .th 2020, the Canadian blood services, in its COVID-19 update, stipulated that for the COVID-19 vaccine, there is no deferral period post-vaccination [On December 16cination . India'scination . The Indcination . Some excination . These Icination . They alcination . The Indcination .The Moroccan National Blood Transfusion Centre experience: the Moroccan blood transfusion system includes one National Centre of Blood Transfusion and Hematology, 18 regional blood transfusion centres, 14 blood banks, and 24 blood transfusion units (antenna). The Moroccan National Centre for Blood Transfusion and Hematology (MNCBTH) is a scientific reference on a national scale. He is responsible for implementing the Moroccan Ministry of Health policy in the field of blood transfusion. Since the outbreak of the SARS-CoV-2 pandemic, he ensured health epidemiological and scientific watch to ensure good management of this health crisis. The MNCBTH has made several recommendations to provide, on the one hand, adequate technical support for regional blood transfusion centres and, on the other hand, the availability and safety of blood products [th January 2021 new eligibility criteria for donating blood following COVID-19 vaccination. The MNCBTH advises that blood donors must provide all the necessary information about their vaccination: the date of vaccination, the type of vaccine received, and any side effects developed after the COVID-19 vaccination. All Moroccan Regional Blood Transfusion Centres and blood banks have to consider the new criteria adopted by the MNCBTH to determine eligibility for donating blood after vaccination against COVID-19 from the official launch of the COVID-19 vaccination campaign in Morocco in January 28th 2021. The MNCBTH new eligibility criteria are presented in products . The MorCOVID-19 vaccines containing viral subunits, non-replicating viruses, inactivated viruses, or protein subunits are technologies that cannot be expected to include any element potentially harmful to a recipient of a blood product from a vaccinated donor. No exclusion for blood donation should apply to blood donors who have received this type of COVID-19 vaccine. Measures taken by some blood transfusion centres to observe a period of deferment of donors for 3 days or more in the event of secondary effects after COVID-19 vaccination are preventive measures based on the principle that blood donors must feel well in good health on the day of donation. COVID-19 live attenuated vaccines or replicative vectors vaccines are in the initial phase of clinical trials and not yet available for use. Those vaccines could justify a temporary exclusion of blood donors ranging from 2 to 4 weeks.The medical screening practices for blood donor eligibility after vaccination against several conventional infectious agents are well known to blood transfusion centres worldwide;For classic infectious agents, blood donation is contraindicated four weeks after a live attenuated vaccine injection;Other types of vaccines  do not entail any risk of infection and do not justify any postponement.Several candidate vaccines against SARS-CoV-2, responsible for the current COVID-19 pandemic, are produced using eight different technological platforms, including DNA and RNA platforms that have never been the source of vaccines yet marketed in humans;At this stage of information, we know that for COVID-19, no DNA-based vaccine, live attenuated vaccine, or replicative vector vaccine has yet been marketed in the world; the COVID-19 vaccines now available worldwide are not expected to pose any particular safety concerns for recipients of blood products from vaccinated subjects;COVID-19 live attenuated vaccines or replicative vectors vaccines could justify a blood donor deferral of up to one month; COVID-19 vaccines containing viral subunits, non-replicating viruses, inactivated viruses, or protein sub-units do not require blood donation deferral.


With the current outbreak caused by SARS-CoV-2, vaccination is acclaimed as a public health care priority. Rapid genetic sequencing of SARS-CoV-2 has triggered the scientific community to search for effective vaccines. Collaborative approaches from research institutes and biotech companies have acknowledged the use of viral proteins as potential vaccine candidates against COVID-19. Nucleic acid (DNA or RNA) vaccines are considered the next generation vaccines as they can be rapidly designed to encode any desirable viral sequence including the highly conserved antigen sequences. RNA vaccines being less prone to host genome integration (cons of DNA vaccines) and anti-vector immunity  offer great potential as front-runners for universal COVID-19 vaccine. The proof of concept for RNA-based vaccines has already been proven in humans, and the prospects for commercialization are very encouraging as well. With the emergence of COVID-19, mRNA-1273, an mRNA vaccine developed by Moderna, Inc. was the first to enter human trials, with the first volunteer receiving the dose within 10 weeks after SARS-CoV-2 genetic sequencing. The recent interest in mRNA vaccines has been fueled by the state of the art technologies that enhance mRNA stability and improve vaccine delivery. Interestingly, as per the “Draft landscape of COVID-19 candidate vaccines” published by the World Health Organization (WHO) on December 29, 2020, seven potential RNA based COVID-19 vaccines are in different stages of clinical trials; of them, two candidates already received emergency use authorization, and another 22 potential candidates are undergoing pre-clinical investigations. This review will shed light on the rationality of RNA as a platform for vaccine development against COVID-19, highlighting the possible pros and cons, lessons learned from the past, and the future prospects. Vaccination has had an enormous global impact on the prevention of morbidity and mortality associated with infectious diseases, since the discovery of the smallpox vaccine by Edward Jenner in the 18th century . Immuniz0 of 2–3), and the predisposition of severe disease complications in aged patients and comorbid conditions . Later, on January 30, 2020, the WHO declared this outbreak a Public Health Emergency of International Concern . The pannditions . Given tnditions , the clinditions  to severnditions . Intensinditions . Elevatenditions . As reponditions . Other rnditions . The facnditions , furtherin vivo in lower doses because of their inherent immuno-stimulatory properties  on January 11, 2020 , which further contribute to the inflammatory conditions. The subsequent inflammatory response imparts immediate immunity through the activation of interferon (IFN) pathways by up-regulating the production of pro-inflammatory cytokines like interleukin 6 (IL-6), which results in neutrophil recruitment and initiate SARS-CoV-2-specific adaptive responses  by the pattern-recognition receptors (PRRs) . The viresponses . It is eesponses . For insesponses . Severe esponses . Those Iesponses . The up-esponses .It is believed that the production of neutralizing antibodies against SARS-CoV-2 is vital for the development of a successful human vaccine . Most of+ cells to cytolytic effectors to destroy the virus-infected cells. Similarly, activation of T helper 1 (Th1) cells through HLA class II presentation further augments the CD8+ cell-mediated response. On the other hand, HLA class II restricted Th2 and follicular helper cells trigger the production of virus specific antibodies. Thus, effective viral clearance involves a combined effect of CD8+ and CD4+ cell-mediated B-cell and T-cell responses  present the SARS-CoV-2 epitopes via human leukocyte antigen (HLA) class I, which differentiates the naive CD8esponses . Biopsy esponses . Evidentesponses , indicatesponses , which spatients . This bipatients . Therefoin vivo through various gene targets like reporter genes (+ and CD8+) mediated immune responses along with functional immunity were evident from these studies. Nevertheless, until recently, the nucleic acid-based immunization has been dominated by the experimental plasmid DNA vaccines, as plasmids have been regarded as the highly stable form of nucleic acid, and are comparatively faster and easier to produce. Although the initial success of gene-based immunization, particularly with DNA in small animals, has generated a high level of expectations, insufficient efficacy in higher animals as well as in humans led to the waning of the enthusiasm  mRNA mixing with a complexing agent  Conventional or non-amplifying type mRNA, and 2) RNA replicons engineered from viruses with positive-stranded RNA . These Rin vitro transcription. Once mRNA enters a cell, it utilizes the host cell machinery to translate mRNA in vivo to produce the corresponding antigen, and the final cellular location of the protein synthesis can be either intrinsic to the natural gene sequences or engineered to guide the gene to the desired site  at low (nanogram) doses. Importantly, this strategy offers significant advantages, particularly in manufacturability, increased safety, and ease of optimization as compared with conventional replicons. The use of two separate RNAs also avoids the risk of transferring viral glycoproteins to the extracellular vesicles and other host cells. The trans-amplifying mRNA strategy permits the incorporation of shorter RNA for the scaled-up manufacturing process, which is a challenging issue for the conventional longer self-amplifying RNAs. However, the production of two RNAs and the efficient delivery of them into the cell remain a big challenge  vaccines are based on the engineered RNA molecules (∼10 kb) that encode for the replicative factors required for RNA amplification within the host cell . These rived RNA . Moreoveived RNA . Generalived RNA . The potived RNA . On the ived RNA . The in hallenge . Considehallenge . Neverth4+ cells . Notably4+ cells . Althoug4+ cells . Usuallyhaustion . It is eesponses . Therefoesponses . Other pesponses . Anotheresponses . It has  in vivo . Further in vivo .de novo elicitation of antigen-specific immunity was reported on multiple administration of lipoMERIT  have been undergoing clinical development . For exaipoMERIT . In anotAlthough pandemics wane over time, a sporadic wave of clusters may manifest. As the potential threat from the SARS-CoV-2 virus is likely to be continued, the development of an effective vaccine through intense global efforts is the only way to contain the ongoing infections as well as possible sporadic waves. Previous data from MERS-CoV and SARS-CoV pandemic led to a renaissance in vaccine development against SAR-CoV-2, right after the declaration of the outbreak . The majTo curtail the spread of SARS-CoV-2 infection, unprecedented investment has been made in COVID-19 vaccine development and subsequent scale up for large production. Following this, the WHO periodically provides revised and updated details on the current landscape of vaccine candidates against COVID-19 . As of D+ cell-mediated responses were observed in 25 and 100 μg doses with a lower CD8+ cell response following the second dose of 100 μg  is currently assessing the immunogenicity, safety, and possible adverse reactions of mRNA-1273. In these dose-confirmation study, the participants were divided into total of eight groups depending on the dose and age either receiving vaccine or placebo (NCT04405076). A phase III randomized trial (NCT04470427) incorporating quadruple blinding study was initiated by July 2020 to assess the efficacy of 100 μg dose  of the vaccine . ModernaBioNTech, a German-based company in collaboration with an American company, Pfizer and Fosun Pharma has developed four mRNA-based vaccines , comprising separate mRNA genes encoding for different antigens . ParticuCVnCoV is an mRNA vaccine against COVID-19 being developed by CureVac with support from the German federal government. The vaccine is designed to provide a robust and balanced immune response by using non-chemically modified nucleotides in the mRNA . Data frLNP-nCoVsaRNA is a self-amplifying RNA vaccine candidate developed by the Imperial College London within 14 days of first genetic sequencing. LNP-nCoVsaRNA consists of purified synthetic mRNA, which can mimic the viral S protein. Presently, a phase I/II, controlled, randomized trial (COVAC1) is ongoing in 320 healthy volunteers between 18–45 years  and 18–75 years of age (for expanded safety study) (ISRCTN17072692), with a plan for efficacy trial involving about 6,000 subjects. An initiative, called VacEquity Global Health was established by Imperial College London in collaboration with the Morningside Ventures to achieve equity in supply. LNP-nCoVsaRNA is being supported by the United Kingdom Secretary of State for Business, Energy and Industrial Strategy, and the United Kingdom Secretary of State for Health .+ cell-mediated and Th1/Th2-mediated immunity  is developing a potential vaccine named ARCT-021, which consists of Arcturus’ self-replicating RNA within a nanoparticle-based formulation capable of inducing CD8immunity . A randoimmunity .Another mRNA (unnamed) is being developed and investigated by the Academy of Military Science of the Chinese People's Liberation Army (PLA) in collaboration with Walvax Biotechnology Co., Ltd., Yunnan and Abogen Biosciences Co., Ltd., Suzhou. A phase I trial is being carried out to determine the immunogenicity, safety, and tolerability of three different doses  of the vaccine in subjects aged 18–60 years and above .Although evidence suggests several advantages of RNA-based vaccines, challenges exist in both research and development and policy-making for determining the precautionary and preparatory stages in the development and immunization against SARS-CoV-2. For instance, recent reports of rare cases of moderate to severe reactions for potential mRNA vaccines have raised concerns over immunogenicity and safety, including the primary findings of the mRNA-1273 phase I trial . Therefoin vivo targeting of APCs. Over the past years, there exists a large knowledge gap on the in vivo behavior of mRNA, both for naked mRNA and nanoparticle formulations designed for various routes , an adverse event associated with Th2 response. It has been observed that non-RBD-directed antibodies mainly characterize the ADE; thus, it is conceivable that the optimal use of RBDs as vaccine antigens will reduce the risk for ADE. Yet, it remains unclear whether RBD alone will elicit neutralizing antibodies or not (in vitro assays, could assist in efficient vaccine development. Likewise, the neutralization antibody titer to RBD and the ratio of RBD-directed antibody responses to the full-length S protein can also be considered as suitable surrogates. From a safety perspective, vaccine development must undergo a time-consuming and complicated process, from the early-stage till the marketing of the vaccine. As the traditional vaccine development approaches involving a novel virus target, novel vaccine platforms, and novel development paradigms are likely to be tedious and risky, accelerating the pace in the pandemic era while maintaining the safety concern is still a critical issue to resolve. As mentioned above, the utilization of alternative surrogates for the testing of immunogenicity should be incorporated in the guidelines for vaccine development. Furthermore, approval of the phase 0 trial, if found to be devoid of severe adverse-events in primate immunization, may embolden the innovation of new vaccine development (Pre-clinical experiences with potential vaccine candidates against MERS and SARS have raised issues about worsening the lung conditions, either directly or s or not . Furthers or not . Ultimatelopment . Neverthelopment .in vivo mRNA delivery, RNA has presented itself as a versatile and promising platform for vaccine development. During the COVID-19 pandemic, several biotech companies have started working on the RNA molecule for clinical translation. The RNA-based platform technology prompts rapid refinement with nearly limitless combinations in terms of antigen optimization to a simple and robust manufacturing process. Considering the typical RNA approaches, viz. conventional and self-replicating constructs, many quality attributes to improvise the efficiency and stability of protein expression remain an intense area of development. It is well-known that cytoplasmic mRNA delivery is essential to induce a robust and durable immune response. The self-amplifying and trans-amplifying RNA vaccines are capable of providing augmented and prolonged in vivo antigen production along with potent intrinsic innate immune-stimulatory functions, and dose-sparing property to meet the demand for a suitable vaccine. Accordingly, significant advances have been made with an emphasis on the novel lipid formulation techniques and the next generation delivery approaches. Overall, progress to date in the RNA engineering, delivery, and construction have represented an RNA platform for further development of a novel vaccine against COVID-19 as the probable first-ever approved RNA vaccine. Although it is conceivable that the majority of the vaccine candidates will fail in the clinical trials, one effective vaccine for the ongoing pandemic would be enough to halt further progress. The preliminary success of mRNA-1273 is a beacon of hope in the present scenario. Given the drastic short time being allocated to the pre-clinical vaccine development, a higher proportion of the potential RNA candidates are expected to fail in the pre-clinical as well as in the clinical stages. On the other hand, if the pandemic disappears abruptly before the vaccines are available for clinical use, developers should continue to stockpile the most promising RNA vaccine candidates and keep them ready for further trials and emergency use authorization as a critical element of future preparedness for similar outbreaks. Nevertheless, the global COVID-19 vaccine development efforts should be guided by ethics, speed of manufacturing, deployment at scale, fairness in allocation, and equity in global supply.Since the first publication on


Hemostasis is a finely tuned process of which dysregulation can lead either to bleeding or thrombotic complications. The latter is often caused by the hypercoagulable state as it is also seen in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, i.e., in COVID-19 patients. COVID-19 patients requiring hospitalization often suffer from thrombotic events that could not be predicted using routine coagulation assays. Recently, several studies have reported ROtational ThromboElastoMetry (ROTEM) as a promising tool to predict outcomes in COVID-19 patients. In this review we give an overview of ROTEM with a particular focus on the interpretation of the symmetrical clot formation curve in relation to coagulopathy in COVID-19 patients. Furthermore, we have introduced new parameters that might help to better distinguish between COVID-19 patients and outcomes. Hemostasis is the orchestrated process of platelet reactivity and activated coagulation leading towards a stable platelet/fibrin plug formation to stop bleeding upon vascular damage. Traditionally, the process is divided into primary  and secondary hemostasis (coagulation), although various interactions between the two pathways exist.Upon vascular damage, subendothelial collagen is exposed to blood and can capture and activate circulating platelets with the involvement of various receptors ,2. StablSecondary hemostasis encompasses the process of the formation of a fibrin clot. Upon injury of the vascular wall due to trauma, or in the case of a rupture or erosion of an atherosclerotic plaque, the subendothelial tissue factor (TF) is exposed to blood and interacts with the circulating factor VII (FVII) thereby forming a catalytic complex . In a caAfter the initial fibrin formation, the amplification of thrombin generation occurs as a result of positive feedback mechanisms. Therefore, more than 95% of thrombin occurs after the initial fibrin formation. Ultimately, thrombin also downregulates the coagulation cascade by the activation of the protein C pathway. Thrombin binds to thrombomodulin on endothelial cells which enhances the activation of protein C bound to the endothelial protein C receptor (EPCR), thereby generating the anticoagulant-activated protein C (APC) . APC cleFollowing fibrin formation, the process of fibrinolysis regulates the fibrin network degradation to prevent unnecessary fibrin deposition. This is a serine protease-mediated process wherein the main fibrinolytic protease is plasmin that is cleaved from circulating plasminogen by either the tissue-type plasminogen activator (tPA) or by the urokinase-type plasminogen activator (uPA). Plasmin then cleaves fibrin, fibrinogen, FV, FVIII and other proteins and the proteolytic breakdown of the fibrin network can be monitored by measuring its degradation products such as D-dimer or fibrin degradation products. Plasmin generation is enhanced in the presence of fibrin and can be inhibited by natural serine protease inhibitors  such as plasminogen activator inhibitor-1 (PAI-1), α2-antiplasmin or α2-macroglobulin or by a non-serpin inhibitor, the thrombin activated fibrinolysis inhibitor (TAFI) ,12.Classic hemostasis assays focus on one part of the process, thereby neglecting the complex interaction between coagulation proteases, platelets, and other cells including leukocytes and red blood cells. Coagulation assays such as the prothrombin time (PT) or activated partial thromboplastin time (aPTT) are based on the time till the first fibrin fibers are formed and detected upon the activation of the system. Due to the relative high level of activation, these assays are mainly suitable for detecting deficiencies or the presence of anticoagulants , but not for hypercoagulability or thrombosis risk ,15. The To overcome the limitations of focused assays, laboratory methods have been developed to incorporate the almost complete coagulation cascade such as in plasma thrombin generation methods or overall methods that include all blood cells and measure the elasticity of the thrombus formed. Of the latter type, the two main methods are ThromboElastoGraphy (TEG) and ROtational ThromboElastoMetry (ROTEM) in which a pin is suspended in a cup with whole blood. Rotation is involved in both methods with the main difference that in TEG the cup rotates and in ROTEM the cup is fixed with a rotating pin ,19. IrreIn a ROTEM assay, the coagulation activity can be triggered by various factors, e.g., through the addition of tissue factor for the extrinsic route (EXTEM) or by an activator of factor XII for the intrinsic pathway (INTEM). Alternatively, the method can be modified to be dependent on the endogenous activators (NATEM) or independent of the platelets (FIBTEM) ,21.A typical ROTEM graph is depicted in Coronavirus disease 2019 (COVID-19) is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection associated with severe inflammatory and thrombotic conditions. The prediction of COVID-19-associated thrombotic events, however, is challenging as routine coagulation assays cannot recognize COVID-19 patients at risk for thrombotic complications ,25. For Strikingly, thromboembolism occurs in spite of the administration of anticoagulant medication (mainly (low molecular weight) heparins), which raised questions regarding the optimal management of these patients . NotablyElevated levels of D-dimer have been reported as strong prognostic factors for poor outcomes in COVID-19 patients ,48. HoweThe ROTEM outcome is markedly different in a COVID-19 patient when it is compared with the results of a healthy volunteer , as indiDespite the entirely different appearance of the ROTEM results as seen in COVID-19 patients , the ROTComparing the slope-CFT and slope-MCF-t in whole blood samples with or without additional spiking of fibrinogen and/or heparins, it appeared that both the slope-CFT and slope-MCF-t were significantly higher upon fibrinogen spiking . These iAfter characterizing the data from the in vitro spiking experiments, the new calculations for CFI were also applied on COVID-19 data to see whether the COVID-19 patient results were comparable to the fibrinogen-spiked samples of healthy volunteers. Applying the new parameters on COVID-19 samples revealed that slope-CFT was only slightly increased compared with the healthy volunteers A, while While hypercoagulability has received much attention recently due to its profound role in COVID-19, it has also been long associated with several other cardiovascular pathologies  but it has also been associated with non-cardiovascular pathologies such as malignancies . ROTEM aCOVID-19 is highly associated with thrombotic complications that are unpredictable in terms of occurrence and severity. This poses a major clinical problem as regular thromboprophylaxis fails to sufficiently protect COVID-19 patients with a persistent rate of venous thromboembolism by up to 25% in the most severely affected patients. While conventional, coagulation assays, such as prothrombin time (PT) or activated partial thromboplastin time (aPTT) do not correlate with the COVID-19 outcome, ROTEM has been shown to be a promising approach for this purpose ,41. The advantage of ROTEM is that it incorporates whole blood and depending on the trigger, different aspects of coagulation activity can be studied. The classical parameters of ROTEM  have been shown to be associated with the outcome of COVID-19 to some extent; however, it does not reflect well on the increase in clot firmness (CFI) ,32,33,34Interestingly, the maximum clot firmness in COVID-19 patients was comparable to that of the fibrinogen-spiked samples of healthy volunteers, while the growth of the clot firmness (CFI) was not comparable to that of the fibrinogen-spiked samples of healthy volunteers. Therefore, other components must account for this phenomenon, or the combination of several components could influence the CFI. There are some possible explanations: (1) maybe the heparin had some effect in the COVID-19 patients, stalling the fibrin formation; (2) fibrinolysis might also have been triggered in COVID-19 patients, more than in the spiked samples, breaking down the fibrin constantly, while simultaneously there was enough fibrinogen and thrombin present to build up new fibrinogen as well; (3) the high concentration of D-dimers in the COVID-19 samples triggered coagulation starting the clot formation simultaneously with the lysis of the clots. However, these speculations require testing in further research.More in-depth knowledge about the clot formation in COVID-19 samples could provide solutions in treatment of hypercoagulability and hyperfibrinolysis, for example, in COVID-19 patients. New parameters describing CFI and slope-CFT might give more meaning to the CFT, and the slope-MCF-t could provide a better understanding of the MCF as it describes the rate of the clot formation. Further validation of these novel parameters is required to fully elucidate their importance.


P > 0.050). The scores on the BMQ-S of the unremitted group were significantly lower than those of the remitted group (P < 0.001). The HAMD scores were significantly reduced in both groups after the eight-week treatment (P < 0.001). There was no significant difference in the BMQ-S scores before and after the treatment (P > 0.050). The medication beliefs of the unremitted inpatients after the treatment were still lower than those of the remitted inpatients (P < 0.001). Logistic-regression analysis showed that low BMQ-S scores at the baseline were an independent risk factor for antidepressant efficacy. Beliefs about medication at baseline may be correlated with the therapeutic efficacy in inpatients with first-diagnosed depression under supervised therapeutic compliance.The aim of the present study was to explore the effect of baseline beliefs about medication on therapeutic outcomes of antidepressants in inpatients with first-diagnosed depression under supervised therapeutic compliance. Ninety-seven inpatients with first-diagnosed depression were included to collect their baseline demographic data to evaluate the Hamilton depression rating scale (HAMD) scores and the beliefs about medicine questionnaire-specific (BMQ-S) scores at baseline and the end of the eight-week treatment. Additionally, we explored the relationship between inpatients’ medication beliefs and therapeutic effect of antidepressants. The inpatients were divided into remitted depression and unremitted depression groups according to outcomes at the end of the eight-week treatment. There was no significant difference in the baseline HAMD between the two groups ( Depression is one of the most common, harmful, and burdensome mental illnesses. Approximately 5–12% of males and 9–26% of females will experience at least one depressive episode in their lifetime, and approximately 50% of depressed patients will experience a second depressive episode . PatientPoor medication adherence is one of the factors influencing the progression to treat-resistant depression –13. CompStandard drug treatment for patients with first-diagnosed depression is the main therapeutic measure for reducing the recurrence rate of depression and preventing progression to treatment-resistant depression . EffectsPatients with first-diagnosed depression were individually recruited by experienced psychiatrists from outpatient and inpatient department of Psychology, Suzhou Psychiatric Hospital in Jiangsu Province from January 2018 to December 2019. The inclusion criteria for patients were as follows: (1) met the diagnostic criteria for depression listed in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) published by the American Psychiatric Association; (2) scores > 17 on the 17-item Hamilton depression rating scale (HAMD-17); (3) ages from 18 to 60 years old; (4) patients were not treated for antidepressants before hospitalization and regularly taking medication under the supervision of the nurse for eight weeks. (5) signed the informed consent. The exclusion criteria of this study were as follows for the candidate patients: (1) depression caused by other diseases, such as bipolar depression; (2) depression accompanied by severe organic brain disorder; (3) severe physical illness; (4) other psychiatric disorders; (5) high risk for suicide (≥ 3 suicide score on HAMD-17); or (6) pregnancy or lactation. The 17-item HAMD scores and beliefs about medicine questionnaire-specific (BMQ-S) scores at the baseline and the end of the eight-week treatment were examined and divided into the remitted group (Remitted) and Non-remitted group(Non-Remitted) groups according to the therapeutic outcomes. This study included a total of 97 patients with first-diagnosed depression, including 39 males and 58 females, with their ages ranging from 18–60 years old (mean age: 39.00 ± 12.29 years). The study was approved by the Ethics Committees of the Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, and all participants signed an informed consent form. All study procedures were in accordance with the Declaration of Helsinki.Self-rated survey questionnaires were used to collect the basic clinical data of the participants, such as age, sex, disease course, years of education, marital status, economic condition and previous medication. Married or cohabiting for more than 6 months means in marital status, otherwise unmarried. Economic status poverty refers to the family per capita annual income of less than 3,000 yuan (RMB), or higher income. Previous medication history was divided into: 0, no medication; 1, sleeping pills; 2, other drugs ; 3, 1 and 2.The HAMD-17 was used to evaluate the severity of depression. Most of the items in the scale were evaluated using a five-point scale (0–4 scores), and some individual items were evaluated using a three-point scale (0–2 scores). The total score was the sum of all items in the scale. Patients were divided into two groups based on the total score of the HAMD-17, including the severe-depression group  and the mild-to-moderate depression group .The BMQ-S, established by Horne in 1999, is mainly used to assess the beliefs about medication  and const-tests or analyses of variance and are presented as mean ± standard deviation P < 0.05 was considered as a statistically significant difference.SPSS24.0 software  was used for statistical analysis in this study. The normally distributed data were analyzed by All participants gave written informed consent and ethical approval was obtained from the Ethics Committee of Suzhou Guangji Hospital (2017-036).The dataset used and analysed during the current study are available from the corresponding author on reasonable request.P > 0.05). The patients with non-remitted had significantly lower BMQ-S scores than those of the patients with remitted , the main effect of time , and mutual effect between groups and time . Pairwise comparisons showed that there was no significant difference in HAMD scores between groups before the treatment  but that there was a significant difference in HAMD scores between groups after the treatment . A significant difference in the HAMD score was found within each group before and after antidepressant treatment ; however, there were no significant differences in the main effect of time  or in the mutual effect between groups and time . Pairwise comparisons showed significant differences in BMQ-S scores between groups before and after antidepressant treatment . No significant difference in BMQ-S scores was found within each group before or after antidepressant treatment  were considered as dependent variables, and the age, sex, disease course, years of education, marital status, economic conditions, previous medication, HAMD scores and BMQ-S scores at baseline were considered as independent variables. The variable screening was performed by the Enter method. Multivariable logistic regression analysis showed that the BMQ-S scores at baseline were independently and negatively correlated with the treatment outcomes (OR: 0.386, In patients with first-diagnosed depression, the initial beliefs about medication were the only contributing factor to the short-term therapeutic efficacy of antidepressants. This result indicated that non-remitted patients had stronger concern beliefs than necessity beliefs prior to treatment. Antidepressants alleviated the depressive symptoms of the patients but did not change the patients’ beliefs about medication.Depressed patients with stronger medication beliefs at baseline were more likely to obtain symptomatic relief after antidepressant treatment but non-remitted patients with weaker medication beliefs at baseline less likely to be relieved, suggesting that the therapeutic outcomes of depressed patients were highly correlated with their initial beliefs about medication. Depressed patients with suicidal attempt have weaker baseline necessity beliefs, and suicidal patients reporting hopelessness during follow-up have relatively strong concern beliefs . Weak neOur study showed that the severity of depression in patients was improved after antidepressant treatment, but patients’ beliefs about medication were not changed following treatment. Previous studies have rarely reported the effects of antidepressant treatment on patients’ medication beliefs, and the factors affecting beliefs about medication are poorly understood. Lesén et al.  have shoThe present study showed that beliefs about medication were the only influencing factor affecting the short-term therapeutic outcomes in patients with first-diagnosed depression. No similar reports were published in previous depression-related studies. Zayed et al.  have shoThe present study has certain limitations. Firstly, this is a retrospective in hospital investigation. Selection bias may result from outpatients’ intention to be hospitalized. The results need to be interpreted with caution. Secondly, this study didn’t analyze the correlation between beliefs of necessity or concern and the treatment outcome, and therefore could not determine the specific role of each factor on the prognosis. Previous papers have examined the effects of the two factors on compliance and prognosis respectively, and this study has examined the integrated impact of patients’ medication belief on treatment outcome. Therefore, the results of this study have important complementary value to previous studies. Thirdly, the study didn’t perform hierarchical analysis of the patient’s initial antidepressants, and differences in the effects of variant antidepressants may affect the prognosis of patients. Fourthly, the mechanism by which medication beliefs influence short-term prognosis of depression independently of compliance remains to be clarified. These unmet clinical needs need to be addressed in future large-scale clinical studies. Nevertheless, the medication regimen of this study follows the treatment guideline, the 8-week hospitalization period not only ensures the patient’s medication compliance, but also provides a reliable medical record for judging the effect. The clear results of this study deepen the understanding of the influence of medication belief on the prognosis of patients with depression.This study confirms the significant effect of medication belief on the outcome of antidepressant treatment. For the first time, this study raises the possibility that the effect of medication belief on the antidepressant outcome may have additional mechanism independent of therapeutic compliance. The results of this study warrant further studies on excavating the potential value of the scale for developing new strategies to treat depression.


Impairment of social cognition (SC) skills such as recognition and attribution of intentions and affective states of others  has been evidenced in Alzheimer’s Disease (AD). This study investigated the neuropsychological, neuroanatomical and brain-functional underpinnings of SC processing to obtain an understanding of the social neurophenotype in early probable AD. Forty-six patients with mild cognitive impairment and mild probable AD underwent SC assessment including emotion recognition (Ekman-60-faces task) and cognitive and affective ToM (Reading-the-Mind-in-the-Eyes test and Story-based Empathy task). Linear models tested the association between SC scores and neuropsychological measures, grey matter maps and large-scale functional networks activity. The executive domain had the most predominant association with SC scores in the cognitive profile. Grey matter volume of the anterior cingulate, orbitofrontal, temporoparietal junction (TPJ), superior temporal, and cerebellar cortices were associated with ToM. Social cognition scores were associated with lower connectivity of the default-mode network with the prefrontal cortex. The right fronto-parietal network displayed higher inter-network connectivity in the right TPJ and insula while the salience network showed lower inter-network connectivity with the left TPJ and insula. Connectivity coupling alterations of executive-attentional networks may support default mode social-cognitive-associated decline through the recruitment of frontal executive mechanisms. Theory of Mind (ToM) is defined as self-originating inferences about other people’s intentions, beliefs and emotions that guide decision making and modulate behaviour in accordance with established social standards . ToM canImpairment of ToM has been evidenced in Alzheimer’s disease (AD) , and mayThe most prevalent behavioural framework posits that detriments of ToM and social cognition in AD are a by-product of cognitive dysfunction, particularly in the executive domain . Based oEarly dysfunction of the DMN is a distinguishable pathophysiological hallmark of early stage AD, even at the prodromal Mild Cognitive Impairment (MCI) stage . As a reThe present study aimed thus to test the association between ToM and associated social cognition abilities and behavioural, structural and functional outcomes in order to provide an integrative social brain/neurocognitive profile across the prodromal to mild AD continuum and expand the limited data available in the current literature on this population. To our knowledge, this is the first comprehensive study to investigate domain-specific cognitive and affective ToM correlates in early-AD individuals through multi-task social cognition assessment and multi-modality neuroimaging acquisition.In the context of the above-mentioned findings on normal individuals and AD patients, we hypothesised that ToM abilities in early-AD would be associated with volumetric integrity of fronto-parietal and limbic structures that represent the territory where the DMN is expressed. We also hypothesised that social cognition and complex ToM performance, at a functional level, would be supported by executive and attentional networks (and associated cognitive functions) in the presence of a vulnerable DMN.n = 37, MMSE range 24–30) , following the National Institute on Ageing criteria   or mild criteria . InitialA sample of 34 healthy controls  matched for demographic characteristics and who did not meet any of the exclusion criteria set for the study was also included for comparison of patients’ neuropsychological and neuroimaging profiles. This sample of healthy participants was not involved in the social cognition experiments and was included for the sole purpose of demonstrating that the patterns of cognitive deficits and neuroimaging abnormalities of patients were typical of early AD.Main exclusion criteria for all study participants were set as follows, and were used to rule out the interfering effects of other types of neurological conditions: presence of cognitive fluctuations or neuropsychiatric symptoms compatible with types of neurodegenerative dementia diagnosis other than Alzheimer’s disease, acute/chronic cerebrovascular disease or history of transient ischaemic attacks, uncontrolled brain seizures or history of epilepsy, peripheral neuropathy disorders, neuropsychiatric or other neural conditions not compatible with our study as detected by MRI, cardiovascular and gastroenterological conditions such as sick-sinus syndrome or peptic ulcer, metabolic disorders such as abnormal levels of B12, folates or thyroid-stimulating hormone, pharmacological interventions such as pre-recruitment treatment with memantine/cholinesterase inhibitors, psychotropic medication, pharmacological components displaying important organic adverse effects or medications used in other research protocols and presence of major disabilities that could impact negatively on cognitive or everyday life functions. All participants undergoing chronic treatment for other severe non-neurological diseases were on stable dosage during data acquisition.Ethical approval was granted by the Regional Ethics Committee (Protocol number 2014.08). Written informed consent was obtained from all participants.Ekman 60 Faces (Ek-60F) test quantifies the participant’s ability to recognise six basic human emotions from faces: happiness, sadness, anger, disgust, fear and surprise. The assessment consists of 60 black-and-white trials taken from the Picture and Facial Affect series (The t series . One poit series . This tet series .Reading the Mind in the Eyes Test (RMET) consists of 36 close-up photographs of the eye region  consists of non-verbal cartoon-vignettes designed to assess the ability to attribute intentions  or emotional states  to others. SET-IA and SET-EA performance sub-scores were used as proxies of cognitive and affective ToM, respectively. A third sub-section of this test serves as a control condition. The task is composed by a total of 18 story trials, 6 for each sub-task, and the instructions are to choose the most suitable epilogue for each story. The global score (SET-GS) is calculated by summing up all sub-scores  served as an overall indicator of cognitive performance. Memory functioning was assessed with the Prose Memory test  and with the Rey-Osterrieth Complex Figure  for verbal and visuo-spatial long-term memory, respectively. The Category Fluency test  was used as test of semantic memory. The Verbal Paired Associates Learning test was also administered as an additional measure of verbal memory assessing the interplay between episodic and semantic processing. Semantic processing was further explored via the administration of the WAIS-Similarities sub-test, and lexical recall was assessed with the Confrontation Naming test. The Digit Span test (forward and backward) was then administered to assess short-term and working memory, respectively. Executive functions were examined through the Stroop test to assess inhibition and attention, the Letter Fluency test to assess cognitive control in lexical access and the Raven’s Coloured Progressive Matrices to assess abstract reasoning. The copy of the Rey-Osterrieth Complex Figure was used as a measure of visuo-constructive abilities. Finally, the Token test and the Digit Cancellation test were used as measures of language comprehension and visual selective attention, respectively. The selected cognitive battery had been validated in the local memory clinic, showing to be particularly sensitive to the impairment reflective of the early stages of AD .3; repetition time 7.4 ms; echo delay time 3.4 ms; flip angle 8°; field of view 250 mm; matrix size 256 × 256 × 124. Functional resting-state Echo-planar images were acquired with the following parameters: Voxel size: 3.28 × 3.28 × 6.00 mm3; repetition time 2 s; echo delay time 50 ms; flip angle 90°; field of view 230 mm; matrix size 64 × 64. Two hundred and forty volumes were acquired, preceded by 10 dummy scans to allow the scanner to reach equilibrium; each volume consisted of 20 slices acquired axially and contiguously, in ascending order.Neuroanatomical T1-weighted Turbo Field Echo images were acquired with a Philips Achieva 1.5 T scanner with the following parameters: Voxel size: 1.1 × 1.1 × 0.6 mm1 to calculate total intracranial volumes and thus account for overall head size variability  analysis was carried out with the most updated standard VBM procedures available in Statistical Parametric Mapping (SPM) 12 software . Firstly, scans were reoriented and segmented into grey matter, white matter and cerebrospinal fluid tissue density maps. Secondly, images were normalised to the Montreal Neurological Institute (MNI) space and modulated. Lastly, images were smoothed with an 8-mm full-width at half maximum Gaussian kernel. Quantification of global tissue map volumes was carried out with the get_totals scriptiability . Hippocad images .3); temporal filtering (0.01 – 0.1 Hz) to reduce artefact-related signal not associated with neural activity; and, finally, a 6-mm Gaussian kernel smoothing to maximise signal-to-noise ratio. Images were then elaborated with an independent component analysis (ICA) to extract functional connectivity patterns reflecting major large-scale brain networks (3) was used for this purpose. The Infomax optimisation algorithm was chosen and the number of components to be extracted was set to 20, as a reliable amount that typically allows the extraction of the fundamental resting-state human connectivity networks , the posterior DMN (pDMN), the left and right fronto-parietal networks and the salience network, due to their established involvement in cognitive functioning . ComponeDemographics, social cognition and basic neuropsychological scores were analysed with IBM SPSS Statistics 24 software for Windows . The Shapiro-Wilk test for normality performed on the residuals of the outcome variables of interest showed non-normal distributions for most of the models. Firstly, Mann-Whitney U statistics was used to compare the neuropsychological profile of our sample and that of the healthy matched control group. A non-parametric correlation model was run to establish the degree of association among the various social sub-scores and quantify inter-test reliability. Subsequently, a non-parametric partial correlation analysis was carried out between social cognition and basic neuropsychological scores. Significance was set at a Bonferroni-corrected p (0.05/15) = 0.003.t-test analysis was carried out between the scans of the patient sample and those of the sample of healthy matched controls. Voxel-based multiple regression statistical models were then carried out testing the association between social cognition indices and cerebral grey-matter maps. An uncorrected cluster-forming threshold of p < 0.005 was used and clusters surviving a Family Wise Error (FWE) corrected threshold of p < 0.05 were retained as significant. Peak region coordinates were transformed from MNI space to Talairach stereotactic space with the Talairach client software and Lancaster transformation method  showed smaller grey matter volumes in bilateral medial temporal cortices, supportive of a probable AD aetiology  and the Ek-60F tests . The RMET also correlated with performance on the Letter Fluency test , Category Fluency test , Digit Cancellation test , Raven’s Coloured Progressive Matrices , WAIS Similarities test , the Digit Span Backward  and the Confrontation Naming test . The Ek-60F test was positively correlated with the Letter Fluency test , Digit Cancellation test , Digit Span Backward  and with the Token test . Finally, none of the SET scores showed significant correlations with scores on neuropsychological tests.All social cognition scores were correlated among each other . AssociaA positive association between RMET scores and grey matter volume was found in the left anterior cingulate cortex (ACC), orbitofrontal cortex (OFC) (BA11), middle temporal gyrus, middle occipital gyrus, thalamus, caudate and cerebellum; in the right inferior lateral frontal cortex, inferior and middle temporal gyri, temporoparietal junction (BA39), superior occipital gyrus; and in the bilateral superior temporal sulcus (BA21/22) . While nOutcomes from the multiple regression models between large-scale network connectivity maps and social cognition scores are displayed in Firstly, the Ek-60F test showed a significant positive association with strength of functional connectivity of the right fronto-parietal network (r-FPN) in the right insula (BA13) and TPJ (BA39/40). In contrast, this test displayed a negative association with connectivity of the salience network in the left TPJ (BA40) and of the pDMN in the left precentral gyrus (BA6) and anterior prefrontal cortex (BA10). Similarly, a negative association was found between the RMET and functional connectivity of the aDMN in the right anterior prefrontal cortex (BA9/10) and of the salience network in the left precentral gyrus (BA6), claustrum and insula (BA13).This study established the neuropsychological, structural and functional connectivity associations of social cognition and ToM abilities in the prodromal to mild stages of probable AD.Significant positive associations were found between neuropsychological profiles and the Ek-60F and RMET, proxies measures of recognition and processing of affective mental states . PerformPerformance on the Ek-60F was also correlated with verbal comprehension, while the RMET showed associations with proxies of semantic memory, language and executive functions. Semantic memory mechanisms are essential for recognising and attributing mental states in unfamiliar environments . The assOur data provide support to the premise that executive functions are closely linked to social cognition in AD . FirstlyThe significant findings that emerged from the model of affective ToM scores (RMET) showed consistency with known neuroanatomical ToM core regions .Emerged as a crucial region associated with performance on the RMET, the left ACC shows higher functional task-based activation during ToM performance in MCI individuals compared to controls . SimilarThe right TPJ displayed the largest association with affective ToM in the present study, an area considered essential for ToM abilities . IntegriPrefrontal and parietal areas may contribute, conjointly, to the processes of self-perspective inhibition , and of affective recognition by integrating inferential representations and creating attribution of others’ beliefs (that would be instead sustained by the TPJ) . In thisAssociations with the occipital cortex have been evidenced during ToM performance , and thePatterns of resting-state connectivity showed associations with affective recognition and processing in the main large-scale networks supportive of cognition: DMN, r-FPN  and salience network . In earlFirstly, scores of emotion recognition and processing (Ek-60F and RMET) were negatively correlated with strength of functional connectivity of the anterior and posterior DMN in the left and right dorsomedial prefrontal cortex, respectively. In this context, social cognition impairment has been found in patients with mPFC lesions . In earlSecondly, functional connectivity within the salience network showed a negative association with emotion recognition and processing (Ek-60F and RMET) in the left TPJ, left precentral gyrus and insula. In this context, previous research has shown that the left TPJ displays less connectivity during processing of salient stimuli . AdditioLastly, connectivity strength within the r-FPN showed a positive association with emotion recognition (Ek-60F) in the right TPJ and right insula. Increased bilateral activation of these regions has been linked to affective and facial recognition , in addiA possible limitation may arise from the choice of combining patients with different disease severity levels. To account for differences in disease severity, a correction factor was included in the analyses to control for the influence of severity of neurodegeneration, i.e., a proxy of hippocampal integrity. A second potential limitation may be our decision to implement three different social cognitive measures that might not rely on shared neural substrates. The presence of variable results across the three instruments, however, may reflect the heterogeneous nature of affective abilities and ToM, whereby the outcome of the assessments is complementary rather than capturing a single construct.In summary, our results support a modular “social cognitive network” that relies on multiple-network intercommunication while engaging in social-cognitive tasks . Based oDifferences in brain laterality, evidenced in regions associated with affective social processing , demonstThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Health and Care Research Wales (HCRW) Committee. The patients/participants provided their written informed consent to participate in this study.JMVB contributed to data extraction and curation, data analyses, result interpretation, and writing of the initial draft of the manuscript. MDM contributed to data collection, result interpretation, and critical revision of the manuscript. MM contributed to data collection and critical revision of manuscript. CC contributed to study conception, result interpretation, and critical revision of manuscript. AD contributed to critical revision of manuscript. AV contributed to study conception, clinical assessment and diagnosis, and revising and finalising of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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