Epilepsy affects around 50 million people across the globe and is the third most common chronic brain disorder. It is a non-communicable disease of the brain that affects people of all ages. It is accompanied by depression, anxiety, and substantially increased morbidity and mortality. A large number of third-generation anti-epileptic drugs are available, but they have multiple side-effects causing a decline in the quality of life. The inheritance and etiology of epilepsy are complex with multiple underlying genetic and epigenetic mechanisms. Different neurotransmitters play intricate functions to maintain the normal physiology of various neurons. If there is any dysregulation of neurotransmission due to aberrant transmitter levels or their receptor biology, it can result in seizures. In this review, we have discussed the roles played by various neurotransmitters and their receptors in the pathophysiology of epilepsy. Drug-resistant epilepsy (DRE) has remained one of the forefront areas of epilepsy research for a long time. Understanding the mechanisms underlying DRE is of utmost importance because of its high incidence rate among epilepsy patients and increased risks of psychosocial problems and premature death. Here we have enumerated various hypotheses of DRE. Further, we have discussed different non-conventional therapeutic strategies, including combination therapy and non-drug treatment. The recent studies supporting the modern approaches for the treatment of epilepsy have been deliberated with particular reference to the mTOR pathway, breakdown of the blood-brain barrier, and inflammatory pathways. Epilepsy is a group of chronic non-communicable neurological disorders categorized by spontaneous recurrent seizures ,2. TheseDuring the last 30 years, there has been a huge advancement in the treatment of many types of seizures due to the introduction of over 15 third-generation anti-epileptic drugs (AEDs) . Around FMR1 gene is responsible for causing Fragile X Syndrome. Fragile X syndrome is one of the abnormalities associated with epilepsy and is characterized by intellectual dysfunction and abnormal behavior. According to the OMIM database , there are about 536 genes responsible for causing associated diseases of epilepsy [The newly emerging genetic technology has played a significant role in the discovery of a variety of genes that are associated with epilepsy. A list of the few genes related to epilepsy is summarized in epilepsy ,13.One crucial feature of epilepsy is cognitive dysfunction. Deregulation of cognitive dysfunction is linked to activity-dependent transcription, which is essential for the transition of neuronal plasticity to long-term from short-term . TherefoRecent studies show epigenetics playing essential roles in temporal lobe epilepsy . TherefoEpigenetic modifications are also responsible for many of the pathological changes that take place during epileptogenesis. Many changes have been shown to occur in the central nervous system cells that alter the gene expression due to DNA methylation and histone acetylation and methylation ,21. MoreVarious processes like histone modifications that involve either adding up or eliminating the acetyl or methyl groups are suggested to be associated with epileptogenesis. According to the hypothesis of DNA methylation implicated in epileptogenesis, seizures can induce epigenetic modifications and can exaggerate the process of epileptogenesis. DNA hypermethylation, along with the amplified activity of DNA methylating enzymes has been implicated in the development of experimental and human epilepsy . During Histone modification is one of the epigenetic mechanisms that have the considerable potential to alter the neuronal expression of genes by exerting their additive effects in a correlated manner . The priDNA methylation is dependent on several biochemical enzymatic reactions. One such reaction pathway is the S-adenosylmethionine-dependent transmethylation pathway, which is controlled by glycine and adenosine under the regulation of adenosine kinase (ADK). In chronic epilepsy, it is observed that there is an increase in the ADK and a resulting decline in adenosine, which leads to elevated DNA methylation in the brain. Thus, interference with methylation of DNA gives the new conceptual prospect to control and prevent epilepsy. Glycine modifying therapies can also be regarded as an alternative opportunity that affects the process of DNA methylation and, ultimately, the process of epileptogenesis. Therefore, understanding the epigenetics of epileptogenesis might help in the discovery and development of therapeutic interventions ,26. Keto+-dependent transporters remove the glutamate from the extracellular space and synaptic cleft. Reduced expression of the glutamate transporters can induce seizures. Genetic manipulations related to the functioning of the glutamate receptor proteins in rodent models can enhance the threshold of seizures [Glutamate is an excitatory neurotransmitter responsible for stimulating an increase in calcium and sodium conduction through ligand-gated ion channels . A wide seizures .– permeable GABAA receptors can exhibit both seizure-repressing and -stimulating activity [A receptors in the human epileptic hippocampus tissue [Various pieces of evidence from several clinical and experimental data underline the role of GABA in the mechanism and management of epilepsy . The synactivity . GABAergs tissue . Many res tissue . Effectis tissue . Drugs ls tissue .The structural and functional diversity of the neuronal nicotinic acetylcholine receptors (nAChRs) perform modulatory functions throughout the mammalian brain . Nicotin+ current. It is shown that in cortical neurons, 5-HT2a/c receptor activation is reduced via rapidly inactivating Na+ currents by reducing the maximal current amplitude and shifting fast inactivation voltage dependence. 5-HT2a/c receptor stimulation also reduced the amplitude of persistent Na+ current without altering its activation voltage dependence. This modulation is mediated by a PKC-dependent mechanism and further reduces the dendritic excitability. Seizure susceptibility may be enhanced by the loss of inhibition of Na+ channel currents in 5HT2c receptor [Serotonergic neurotransmission has been shown to have a potential role in epilepsy . Serotonreceptor ,46.Drug-resistant epilepsy (DRE) is also known as refractory epilepsy or pharmaco-resistant epilepsy. It can be defined as a failure of two or more sufficient trials of tolerated, chosen, and appropriately used AEDs regimens, which can be administered as monotherapies or in combination to get relief from seizures. Around one out of four patients with seizures develop DRE . DRE pat2 subunit of the neuronal Na+ channel, which is encoded by the SCN2A gene, has been found to be related to anti-epileptic drug resistance [This hypothesis states that sensitivity to the treatment is decreased due to the alterations in the cellular targets of the drugs. The αsistance . Howeversistance ,52.This transporter hypothesis postulates that at the epileptic target, drug resistance may apply to the overexpression of the multidrug efflux transporters. P-glycoprotein is the most widely researched efflux transporter whose primary function is to maintain the integrity of the blood–brain barrier by decreasing the cerebral build-up of the substrate drugs . Up-reguPresently, the primary usage of the AEDs is only to prevent seizures rather than focusing on the pathogenic processes that are causing the disease. Autoantibodies to the ion channels that are associated with neuronal inhibition and excitation, including voltage-gated ion channels and NMDA and GABA receptors, have been identified in patients with seizures. Such cases have been seen predominantly in multiple circumstances of encephalitis and occult cancer. However, these patients usually are unable to respond to conventional anti-epileptic drugs ,54,55.The available AEDs control the generating tendency of seizures and are effective in about 60% of individuals. Additionally, most of the existing medications have adverse drug reactions and hypersensitivity issues. It further aggravates by the increased incidence of mental health problems, depression, anxiety, and suicidal tendencies . In suchIt is the phenomenon in which the seizures persevere because the fundamental disorder has not been adequately treated. So, it is imperative to rule out or correct the underlying disorder before the drug treatment can be considered to have failed. There can be several situations in which misdiagnosis of epilepsy can take place. Cardiac arrhythmia, vasovagal syncope, and other neurological disorders such as migraine and transient ischemic attacks are some of the conditions that imitate epileptic seizures ,57. The According to many studies and research data, the combination of drugs helps in controlling the disease. The same drugs at differential dosages have been seen to suit different patients. This may be due to the fact that at any instance, separate pathophysiological mechanisms can occur in the same individual. Such a situation would warrant the usage of different therapeutic strategies at different levels for better results. Various natural or herbal-based drugs like Cicuta virosa and Nux vomica have been shown to be effective in reducing seizure activity and other physiological parameters in animal models of epilepsy ,59. SevePatients who are suffering from DRE have surgery as an alternative method for treatment, mainly if they have a surgically remedial disease like unilateral hippocampal sclerosis or other curable lesions. Therefore, depending on the indication, a number of surgical procedures can be performed to treat and control epilepsy after the deliberation of further trials of anti-epileptic drugs . In chilApproved AEDs for the treatment of epilepsy work by various mechanisms that mainly include the modulation of voltage-dependent ion channels, activation of GABA, and inhibition of glutamate receptors. Several capable pathways including shared ones with neurodegenerative disorders  and poteThis signaling pathway is the mammalian target of rapamycin, which is responsible for regulating cell growth, cell proliferation, cell differentiation, and cell metabolism in the brain. Many studies have shown that dysregulation of mTOR is responsible for the pathogenesis of acquired forms of epilepsy, such as temporal lobe epilepsy . TherefoVarious studies and researches have shown shreds of evidence, which states that inflammatory mediators that are released by cells of the brain and peripheral immune cells are implicated in the foundation of seizures and the process of epileptogenesis . Data anIrrespective of their etiology, dysfunction of the blood-brain barrier is a characteristic of epileptogenic injuries of the brain. Any harm to the blood-brain barrier microvasculature during the brain injury leads to the leakage of the serum albumin into the micro-environment of the cerebral cortex, which induces a signaling cascade in astrocytes, which results in local inflammation by activating the transforming growth factor β receptor (TGFβR) . DysfuncSeveral applicable models are available to study and understand the process of epileptogenesis . However


Coronary artery disease (CAD) represents one of the most important causes of death around the world. Multimodality imaging plays a fundamental role in both diagnosis and risk stratification of acute and chronic CAD. For example, the role of Coronary Computed Tomography Angiography (CCTA) has become increasingly important to rule out CAD according to the latest guidelines. These changes and others will likely increase the request for appropriate imaging tests in the future. In this setting, artificial intelligence (AI) will play a pivotal role in echocardiography, CCTA, cardiac magnetic resonance and nuclear imaging, making multimodality imaging more efficient and reliable for clinicians, as well as more sustainable for healthcare systems. Furthermore, AI can assist clinicians in identifying early predictors of adverse outcome that human eyes cannot see in the fog of “big data.” AI algorithms applied to multimodality imaging will play a fundamental role in the management of patients with suspected or established CAD. This study aims to provide a comprehensive overview of current and future AI applications to the field of multimodality imaging of ischemic heart disease. Cardiovascular disease represents one of the leading causes of morbidity and mortality in the world . In 2017This highlights the need of an effective and efficient diagnostic-therapeutic path for the diagnosis and risk stratification of CAD patients.CAD management has dramatically changed over the past few decades. Currently, invasive coronary angiography remains the gold standard for patients with a high risk of CAD allowing for both the diagnosis and potential for therapeutic intervention. However, this strategy is time consuming and prone to intra- or periprocedural risks  and thus is typically not recommended as a first line strategy for patients at low-to-intermediate risk for CAD.In this category of patients, multimodality imaging is assuming an increasingly important role, as outlined in the latest ESC guidelines on the management of chronic coronary syndromes (CCS) , with thWith the increasing availability of powerful computers and large datasets, the implementation of artificial intelligence (AI) in the current workflow of multimodality imaging for CAD diagnosis appears a promising tool in aiding cardiologists and radiologists in the growing demand of cardiovascular imaging examinations.In this review, we will explore the current AI applications of multimodality imaging applied to CAD management, highlighting the great potential and possible pitfalls of this new frontier in CAD management.The term AI outlines the ambitious attempt to replicate with a machine the most distinctive feature of the human being, its ability to think. In order to simulate the characteristics of human thought, an AI algorithm must be able to perform tasks considered distinctive of a human being: to understand a language, to recognize images, to identify known objects, to solve problems, and to learn from its own mistakes.The concept of AI was first mentioned in 1956 . At thatAI algorithms can be developed with the increasing availability of large amounts of data (“big-data”) and powerful computational machines.AI applications are based on two main methods: machine learning (ML) and deep learning (DL).ML is a technique that provides AI algorithms the ability to learn when exposed to large datasets of correctly classified features. Beyond the quality of the algorithm itself, the quality of the characterization of the data and their heterogeneity are crucial factors for the real-world application of the algorithm. For this reason, ML applications are first developed on training and validation datasets and then tested in an independent dataset to verify their adaptability for use outside the domain in which they were developed.Two main models of ML have been developed to date: supervised and unsupervised learning. The main difference between these two methods resides in the presence or absence of a prefixed outcome. In supervised learning the AI model navigates the dataset to find the best combination of features that fits with the prefixed outcome; while in unsupervised learning the algorithm simply tries to discover any potential consistent pattern concealed in the dataset .Examples of ML supervised learning methods are regression analysis, support vector machines (SVM) and random forests (RF); while unsupervised learning is funded on principal component and cluster analysis approaches. A more detailed explanation of these concepts goes beyond the scope of this review .DL can be considered a particular subset of ML that uses multiple artificial neural networks to directly interrogate datasets to make predictions. In the medical imaging context, the most widely DL network is represented by Convoluted Neural Network (CNN), a network of multiple interconnected layers that roughly mimics the functioning of the visual human cortex . In the Early-stage AI applications were deployed to automate time-consuming medical tasks to reduce workload ; more recently their development has been focused to more complex duties, such as to perform autonomous diagnoses and risk-stratification .In this context, in recent years a new technique called radiomics has emerged as a new tool to combine with traditional AI applications to dig deep into the images to identify possible risk predictors or unearth features that can lead to early diagnoses. Radiomics is able to convert every voxel of a digital medical image in a high amount of quantitative mathematical imaging data that can be later analyzed by high-performance computers and AI algorithms , 10. ThiThe most recent ESC guidelines on CCS base the choice of the diagnostic tool for CAD detection on the pre-test individual clinical likelihood of disease, in order to select the most appropriate invasive or non-invasive diagnostic test to perform, according to individual patient characteristics .The last ESC Guidelines base the definition of the pre-test individual likelihood of CAD from a pooled analysis of clinical and demographic characteristics  of 15,815 patients symptomatic for chest pain . Many clIn addition, imaging parameters such as coronary artery calcium (CAC) score and epicardial adipose tissue (EAT) quantification are assuming a role of increasing importance in the quantification of cardiovascular risk.In this paragraph, we will summarize the principal AI applications developed for the automatic quantification of CAC and EAT .CAC score is a well-established predictor of obstructive CAD, particularly useful in identifying patients with high CV risk, independent of clinical risk assessment scores.CAC scoring requires dedicated software for semi-automatic image segmentation and time demanding manual measurement by trained experts on a dedicated ECG-gated cardiac CT. This time-consuming approach is not feasible for everyday clinical practice and hinders the application of CAC score on non-targeted routine chest CT, despite the demonstration of its good reliability on non-targeted CT exams , thus lir = 0.935 for Agatston score assessment between the two methods). Similarly, Wolterink et al.  performed for lung cancer screening , 13.k correlation for all test= 0.9).Based on the demonstration that AI applications were reliable in quantifying CAC on CT scans not targeted for that scope, Van Velzen et al.  demonstrp = 0.544).Recently, a study by Zeleznik et al.  confirmeAI powered CAC score has the potential to become a fundamental tool for risk stratification of patients with suspected acute or chronic CAD, helping the clinician in correctly defining the cardiovascular risk profile of each individual patient.Interest has grown toward the correct quantification and analysis of the epicardial adipose tissue (EAT), namely the fat layer located between the myocardium and the visceral pericardium , due to In physiological conditions it is fundamental in maintaining the homeostasis of the vascular wall; while when dysfunctional  it plays a key role in atherogenesis by the production of pro-inflammatory cytokines.Various cardiac imaging modalities are capable of quantifying EAT, ranging from traditional echocardiography to CMR and cardiac computed tomography. The latter has recently become the key modality in this field due to its ability not only to visualize and precisely quantify EAT, but also to assess the coronary arteries and the PCAT simultaneously.via an imaging biomarker called “fat attenuation index (FAI).” The authors showed that PCAT signal attenuation was a biomarker of adipose tissue inflammation and also demonstrated that FAI correlated with the presence of CAD and was associated with stenosis >50%.A paper by Antonopoulos et al.  demonstrAI applications have been developed to automate the processes of EAT and PCAT quantification and characterization.Since conventional EAT measurement by semi-automated software can be time-consuming, several AI applications have been developed to shorten this process , 23, 24,In 2020, two studies demonstrated the ability of AI powered solutions to improve patients cardiovascular risk stratification with the implementation of information regarding EAT in the analysis of non-contrast cardiac CT.Commandeur et al.  created Similarly, Eisenberg et al.  confirmeFinally, two other studies used a combined AI powered radiomics approach to demonstrate the incremental value of assessing PCAT attenuation over traditional CCTA based cardiovascular risk prediction tools , 26.AI-powered detection of imaging biomarkers shows the potential to impact individual cardiovascular risk stratification, a fundamental process to guide the selection of the most appropriate invasive or non-invasive diagnostic testing for CAD patients.Functional non-invasive ischemia testing is recommended in patients with high PTP  or known CAD; according to the last ESC Guidelines, non-invasive functional imaging should be primarily used to detect ischemia .Myocardial ischemia can be detected through rest or stress induced wall motion abnormalities (RWMA) with stress echocardiograph and areas of reduced myocardial perfusion with stress cardiac magnetic resonance (S-CMR) and with nuclear radiology techniques.In this section, we will summarize the principal AI applications developed for functional imaging.Echocardiography is the most available imaging tool for the management of CAD patients. As aforementioned, stress echocardiography is recommended as one of the functional non-invasive imaging tests of choice for the detection of new onset coronary artery disease in the follow-up of CCS patients .The impact of AI applications in echocardiography has been steadily growing: first applications served to improve image quality; gradually, the focus shifted to automatic diagnostic echocardiographic window classification and measures assessment .AI solutions have mainly focused in reducing the high inter-observer variability in the evaluation of regional wall motion abnormalities (RWMA) with rest and stress echocardiography .The detection of RWMA on rest echocardiograms was initially attempted using ML methods, which demonstrated high levels of accuracy in distinguishing between normal and infarcted echocardiographic images by correctly identifying the presence of RWMAs , 33.p = 0.15) and significantly outperformed the ability of resident physicians .Kusunose et al.  demonstrInitial attempts to apply AI to stress echocardiography were made using techniques of supervised ML. The first examples date back to 2008 and 2011, when Mansor et al.  used a HOmar et al.  comparedAI applications (both with ML and DL) to rest and stress echocardiography have shown good results in detecting RWMAs for CAD diagnosis. In particular, they demonstrated high accuracy both with rest and stress images, improving on the high inter-observer variability experienced in human evaluation. Further developments and test cohorts are required for the wide-spread clinical implementation of AI in real-life echocardiographic workflow for CAD diagnosis.S-CMR is a powerful diagnostic tool that allows a comprehensive evaluation of known or suspected CAD patients.Different from other techniques, S-CMR combines the evaluation of global cardiac function with an accurate and reproducible definition of regional myocardial viability by combining information on cardiac muscle function, tissue characterization, persistent and inducible ischemia .Below, we will summarize AI applications to S-CMR for the assessment of cardiac function, tissue characterization and rest and stress myocardial perfusion .The first AI applications to S-CMR were focused on semi-automated myocardial segmentation on cine CMR images, in order to speed-up the manual time-consuming process of endo-and epicardial border definition. Many applications have sought to automate the analysis of cine CMR images , 48.Although highly accurate, the majority of these applications were tested on small training datasets, thus limiting their real-life applicability. Bai et al.  overcameThe correct identification and quantification of the areas of late gadolinium enhancement (LGE) on CMR images portends a well-established prognostic role in CAD patients .Some authors have successfully applied DL algorithms to perform automated LGE quantification .Xu et al.  proposedTwo other authors developed different DL algorithms, both obtaining high DICE similarity coefficients in LGE quantification when compared to manual segmentation. In the first case, Moccia et al.  successfAlbeit promising, these studies are still based on small cohorts, thus limiting the applicability in the routine S-CMR workflow.p = 0.38), in the mean per-patient scar area (p = 0.27), and in the percentage of damaged myocardial tissue (p = 0.17). If confirmed on larger sample sizes, the ability of an AI model to correctly quantify myocardial LGE on unenhanced cine CMR images paves the way to the possibility to perform tissue characterization in patients with end stage renal disease on dialysis, which represents a contraindication to perform contrast enhanced CMR.Zhang et al.  successfOther authors developed AI applications capable of assessing myocardial viability and scar area without the use of LGE with the combination of traditional AI models and radiomics. In two consecutive studies Larroza et al.  demonstrSimilarly, Baessler et al.  used a MA recent study by Ma et al.  has alsoFinally, Kotu et al.  providedAlbeit deeply interesting, radiomics studies applied to CMR are still based on small datasets and currently does not appear feasible for large-scale routine use. Further investigations on larger CMR datasets are needed to broaden the spectrum of use.S-CMR can detect hemodynamically significant CAD through the assessment of myocardial ischemia through the evaluation of perfusion defects. In routine clinical practice, the analysis of S-CMR images is performed qualitatively, through the visual assessment of S-CMR images by an expert reporting physician.First pass gadolinium enhanced CMR perfusion imaging has shown the potential to delineate a fully quantitative assessment of myocardial blood flow (MBF). Fully automatic MBF maps have been validated against gold standard perfusion techniques, such as positron emission tomography .Albeit highly accurate in CAD diagnosis , quantitIn recent years, innovative AI applications have been developed to allow fully automated perfusion mapping approaches to enter clinical practice.Preliminary work by Scannell et al.  successfp = 0.92). The same group of authors demonstrated  and positron emission tomography (PET) represent the two main tools of nuclear imaging applied to cardiology.Despite its relative low cost and discrete accuracy in detecting CAD, the detection of ischemia by SPECT analysis mostly relies on qualitative methods and appears prone to possible CAD underestimation, especially in patients with non-obstructive multivessel coronary artery disease. PET is able to provide robust quantitative analysis of myocardial blood flow and can detect microvascular ischemia. However, the utilization of PET analysis is limited by its high technical complexity and high costs .Apart from those aimed at image pre-processing and segmentation , the majIn 2013, Arsanjani et al. published two different studies on relatively large populations. The first one  demonstrMore recently, Betancur et al.  introducFinally, Otaki et al.  recentlyML and DL models have also been applied to myocardial perfusion SPECT to improve its prognostic value.Arsanjani et al.  demonstrRecently, Hu et al.  providedFinally, Betancur et al.  developeInitial applications of CCTA in CAD management were on the anatomical detection or exclusion of obstructive CAD, with CCTA progressively assuming the role of gatekeeper to unnecessary ICAs. Due to its high negative predictive power, CCTA has been indicated as the preferred test to rule out CAD in low to intermediate clinical PTP patients by the most recent ESC Guidelines on the management of CCS .However, CCTA has rapidly advanced beyond the qualitative anatomical assessment of the presence of obstructive CAD and is now capable of offering a complete anatomical and functional characterization of CAD, thus providing important diagnostic and prognostic  informatIn this section, we will review the principal AI applications developed for the anatomical and functional assessment of CAD with CCTA .The degree of luminal stenosis and the localization of CAD with CCTA has a defined prognostic role . AI applIn 2011, Kelm et al.  developeLater, Kang et al.  used a dr = 0.984 for MLA; r = 0.957 for DS; and r = 0.975 for CDD, p < 0.001 for all).In 2019, Hong et al. , validatRecently, Muscogiuri, et al.  demonstrAn alternative approach for assessing the presence of hemodynamically significant coronary artery stenosis is the one proposed by Zreik et al. , who demOne of the key advantages of CCTA for the assessment of CAD is the ability to fully characterize coronary plaque phenotype.Not all coronary lesions imply the same cardiovascular risk. In particular, the detection of prevalent fibrotic composition and other specific plaque features at CCTA  have beeAI applications have been developed to automate this process, in order to provide the clinician a full set of information to guide patient management.One of the first AI approaches demonstrated the ability of an automated algorithm to correctly classify calcified and non-calcified lesions compared to expert manual quantification .p = 0.001).Masuda et al.  applied Another feature correlated with high risk of cardiovascular events is rapid plaque progression (RPP), defined as an annual progression of percentage atheroma volume ≥1.0%. The study by Han et al.  providedThis and other ML integrated clinical and CCTA parameter risk scores have shown the potential to clearly outperform traditional CCTA risk score evaluations , 84 whenIn the future, the application of these AI empowered risk scores will enhance risk prediction in CAD patients, ultimately boosting the power of CCTA and other imaging exams.Zreik et al.  developeRecently also Choi et al.  (CIT) prAnother innovative approach to coronary plaque characterization has been represented by the combination of radiomics with AI applications, which has shown the potential to provide useful information on high-risk coronary plaque features.Kolossvary et al.  detectedThe same authors expanded the previous observation by demonstrating that CCTA radiomics could identify invasive and radionuclide imaging markers of plaque vulnerability significantly better than traditional quantitative and qualitative CT parameters .Traditional CCTA techniques only provide anatomical assessment of CAD. In cases of coronary atherosclerosis of uncertain hemodynamic significance, current guidelines support the use of an ischemia test to assess the need for revascularization .In recent years, the development of a non-invasive method to calculate CT-derived fractional flow reserve has permitted the evaluation of the anatomical and functional hemodynamic significance of coronary artery lesions –90. ThisCT was feasible with a conclusive result in >90% of patients. Among those who deferred ICA, there were no major adverse cardiac events. A high proportion of those who underwent ICA were revascularized, resulting in higher diagnostic ICA yield and more efficient utilization of catheterization lab resources.Importantly, Rabbat et al.  studied Multiple AI applications have been developed in recent years to automate the assessment of CT-FFR , 95.Notably, the application of ML to CT-FFR has been clinically validated in a retrospective trial called MACHINE Registry that involved five different centers in Europe, USA and Asia. The ML based computation of CT-FFR outperformed CCTA in terms of diagnostic accuracy; when compared to invasive FFR, ML CT-FFR showed 78% accuracy in comparison to the 58% accuracy of visual CTA alone and the AUC for the detection of hemodynamically significant coronary artery stenosis favored the ML CT-FFR approach . ML CT-FFR was capable of correctly reclassifying 73% false-positive CTA results.The ML application to CT-FFR in the MACHINE registry were later confirmed in multiple sub-studies that investigated their reproducibility in different clinical scenarios: in particular, ML CT-FFR proved its feasibility in the presence of heavy coronary calcifications ; in patiPoor image quality and high heart rate represent potential limitations to CT-FFR .The study of myocardial perfusion through cardiac CT is a powerful and promising tool, since it can provide combined anatomical and functional information for every coronary territory with a single test. CT perfusion (CTP) is able to detect obstructive CAD better than CCTA alone  and is nDespite the great potential of this technique, to date only a few examples of AI applications to CTP exist in the literature and are based on the ML algorithm's ability to assess defects of myocardial perfusion from CTA images acquired at rest , 100.In the future, AI applications have the potential to dramatically impact the field of CTP with applications focused on automatic myocardium segmentation and perfusion defect identification. A particular advantage of this algorithm will be the possibility to directly correlate the presence of anatomically detectable obstructive CAD with the functional evaluation of specific lesions with CTP sequences.This approach has particular potential in complex CCTAs analysis, for example in the presence of previously revascularized vessels.The implementation of AI applications to the multimodality imaging applied for the diagnosis and risk stratification of CAD patients represents a new frontier in cardiology. The implementation of AI in the clinical workflow will impact different aspects of the routine clinical workflow.First, it will offer the possibility to shorten reporting time and to provide pre-reading evaluation of normal exams, to save radiologists and cardiologists time only pathological examinations.Secondly, it will reduce inter-observer variability in the evaluation of exams. Moreover, it will provide more accurate models of prognostication , giving To spread the application of AI models in real-world clinical practice, however, some potential limitations, pitfalls and ethical considerations need to be considered .As a first limitation, we must acknowledge the vast majority of AI applications have been validated in single-center studies with a limited number of cases and is therefore still restricted to research settings. As aforementioned, in fact, a fundamental principle of AI models is represented by the availability of huge sets of high-quality data for the algorithms to be developed, trained and tested.In the field of cardiovascular imaging, the availability of large datasets from different centers is particularly crucial to overcome the biases currently present in the development of AI applications.A first bias is represented by the great variability in terms of exams quality and interpretation (for example in the field of echocardiography) and in the lack in homogeneity in acquisition protocols and machine vendors (for example in the field of cardiac MRI). Therefore, a crucial step to assure AI algorithms generalizability is to perform their development on datasets containing information from machines from multiple vendors and obtained with different acquisition protocols, as in the case of cardiac MRI.Secondly, in view of the great interobserver variability in some methods such as echocardiography, it is particularly important that the implementation of the training datasets and the quality control process, although time-consuming and costly, is not carried out by a single operator, but by teams of experienced cardiologists, if possible, from different centers. In fact, the risk is that the implementation of quality control by a single operator may lead to the unconscious introduction of new biases into the algorithm, making it usable only within the research group in which it was developed.Future collaboration among different research groups and hardware vendors will constitute the basis for the development of more generalizable algorithms.A further possible bias that can limit the general application of AI algorithms is the prevalence of certain ethnic or gender groups within the datasets on which AI applications are developed.Thinking of a future world in which the use of AI should become routine, it is certainly necessary to ensure that this technology is equally available for all people, independent of gender, social class and ethnic origin. In order to make this possible, several obstacles must be overcome.First, for AI algorithms to work homogeneously on people of different genders and ethnicities, they would have to be trained on heterogeneous datasets, including different ethnic groups and an equal number of people of both genders. At present, however, women and people from ethnic minorities have been consistently underrepresented in large trial databases .This must be avoided, as it could lead to the exclusion of entire sections of the population from access to the most advanced medical care, thus exacerbating the inequalities already present today. In fact, even though AI applications are in most cases still at an early stage of development, examples have already been reported in the literature of discrimination between different ethnic or economic groups by some AI applications .In order to overcome this possible bias, it is necessary for regulatory agencies to enforce fair inclusion in AI application development databases of patients of different gender and ethnic origin.Secondly, given the high development costs and the great need of medical records, AI applications will mainly be implemented in high-income countries, based on the organizational needs of their national health systems. This could lead to a substantial inapplicability of AI algorithms in poorer countries, making advanced care even more inaccessible to their citizens.This could be avoided by devoting some of the public resources allocated to the development of AI algorithms in richer countries to the implementation of applications that improve the quality of care in low-income countries.Once obtained, robust AI applications will also require validation in large clinical trials to prove benefits in patient care, the economic sustainability and safety of their implementation in routine clinical workflow.AI application validation in clinical trials will in fact help in overcoming a further issue, which is represented by the medical-legal aspect. In the future doctors will probably base their decisions on risk score algorithms and diagnostic tools powered by AI applications. In this scenario, who will be considered responsible, in the case of a wrong decision made on the basis of incorrect information?This issue seems even more important if we consider that the majority of AI applications are characterized by a lack of transparency of their intermedium processes: the human operator knows the input data and the result of the elaboration, but can hardly understand the internal algorithm processes.To overcome this possible pitfall there will be a need to act on two fronts.On one side, national and transnational medical regulatory authorities will need to further regulate laws and protocols in perspective of a large-scale use of AI algorithms in everyday clinical workflow.The European Commission on medical AI  publisheOn the other side, AI developers will need to work on algorithms' self-explicability and internal transparency, to produce so-called explainable AI applications, namely AI software able to provide justification for every stage of their choices, in order to provide the physician all the information needed for thoughtful clinical decision making.The medical management of patients with coronary artery disease, one of the most prevalent diseases in the world, is rapidly progressing with the implementation of multimodality imaging in diagnostic and prognostic routine workflows.AI applications have proven the ability to significantly improve the detection of coronary artery disease with both an anatomical and a functional imaging approach.Thus, the application of AI to multimodality imaging will continue to play a prominent role in every stage of the diagnostic, risk-stratification and follow-up of patients affected by coronary artery disease. Larger clinical validation and research on safety need to be implemented before large-scale adoption in routine clinical practice.All authors made a substantial contribution to the conception, design of this review paper, including drafting and revisions, and granted their approval for all aspects of the manuscript and its submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This review examines various studies on reducing tensile stresses generated in a polymer matrix composite without increasing the mass or dimension of the material. The sources of residual stresses and their impacts on the developed composite were identified, and the different techniques used in limiting residual stresses were also discussed. Furthermore, the review elaborates on fibre-prestressing techniques based on elastically (EPPMC) and viscoelastically (VPPMC) prestressed polymer matrix composites, while advantages and limitations associated with EPPMC and VPPMC methods are also explained. The report shows that tensile residual stresses are induced in a polymer matrix composite during production as a result of unequal expansion, moisture absorption and chemical shrinkage; their manifestations have detrimental effects on the mechanical properties of the polymer composite. Both EPPMC and VPPMC have great influence in reducing residual stresses in the polymer matrix and thereby improving the mechanical properties of composite materials. The reports from this study provide some basis for selecting a suitable technique for prestressing as well as measuring residual stresses in composite materials. Composite materials are developed by combining materials offering unique properties that cannot be achieved individually by the constituent materials. Because of their excellent strength to weight ratio, they have increasingly been used as engineering materials for many applications, that include automotive and aerospace parts, construction materials, electrical parts and other consumer products . The groTo produce a fibre-reinforced polymer composite, fibres of various configurations and stiffness are embedded into a polymer matrix of lower stiffness. While the fibre is responsible for carrying the load and offering much needed strength and stiffness, the polymer matrix is responsible for the mobility of the load to other parts of the fibre by providing the required binding forces . The matBoth tensile and compressive stresses are generated in polymer composite structures during the manufacturing process, and their occurrence in a composite can result from differences in physical and mechanical properties, a contraction of the polymer matrices before curing, manufacturing techniques and moisture absorption from the environment . HoweverThis review explores the state-of-the-art fibre-prestressing techniques used in reducing residual stress in FRP composites. Moreover, the mechanism and methods used for improving the mechanical properties of FRP composites are examined.In the absence of external forces, residual stresses are forms of stress that bring about the deformation of a composite material . There aMany techniques have reportedly been used to reduce the effect of residual stresses in polymer composites. Process optimisation of cure cycle parameters such as dwell time, dwell temperature, dwell cycle and cooling rate can minimise residual stress during production ,14,15. SSimilarly, the electron beam curing technique composite can also reduce stress concentration . The tecDespite their positive influences, electron beam cured composites cannot replicate some of the characteristics of thermally cured composites (high fracture toughness and inter-laminar shear strength) . SimilarThere has been growing interest in improving the mechanical performance of FRP composites by minimising the induced stress without increasing the mass or dimension of the composite . Since iFibre-prestressing can be achieved elastically or viscoelastically. The elastically prestressed polymer matrix composite (EPPMC) is achieved by subjecting the fibre material to the applied load and maintaining the load throughout the curing cycle of the polymer composite ,29. The The fibres are prestressed by subjecting them to a force lower than the elastic limit of the fibre and maintaining this force throughout the curing cycle of the composite. After curing, the force is removed, and the fibres tend to return to their original states. Compressive stresses are developed within the solidified matrix due to the bonding of the prestressed fibre with the polymer matrix . VariousThe deadweight prestressing method  was firsThe V-slot consists of an aluminium plate with V-shaped slots at the two ends . Unlike The Jack prestress rig method was presented by Abdullah and Hassan . They stIn this technique, fibres roving are pulled with a known amount of load over a liquid resin bath and then warped on a mandrel to produce a composite material . ComposiJevons, Fernando and Kalsi  studied Zhao and Cameron,  utilisedMotahhari and Cameron  reportedTuttle, Koehler and Keren  proposedKrishnamurthy  prestresFibre misalignments were identified close to the edge of the laminates due to the temperature variation between the hot press cure edge of the laminates and the remaining parts that were being cured in an autoclave . The resThe technique involves using polymeric fibres to generate compressive stress in a composite material through the viscoelastic recovery process ,48. The Cui et al.  studied Širvaitienė et al.  also repFurthermore, high-performance synthetic polymer fibres are designed to resist a wide range of thermal, chemical and physical stress . Nylon aUnlike the EPPMC, in which the fibre-prestressing and curing operations are designed and carried out with the same assembly, VPPMC fibre stretching and moulding operations are decoupled therefore there is more flexibility in the fibre orientation (both continuous and short fibre can be used), distribution and material production. Many studies on VPPMC carried out fibre-prestressing using bespoke vertical stretching rigs . The creCompared to other enhancing techniques, both of the two prestressing methods have shown their significance in improving the mechanical performance of composite material without increasing the mass or section dimension. The continuous advancement in the development of composite materials has drawn more attention to prediction and measuring the distribution and sizes of residual stresses because the behaviour of composite materials is greatly influenced by these factors ,73. ResiThe measurement of residual stresses in the composite material can be achieved by modelling the entire production process or through the observation and measurement of the phenomena resulting in residual stress generation in a material. The latter method can be achieved through destructive and non-destructive testing. The layer removal method is an established method for measuring residual stresses by subjecting the material to deformation on one surface while the layers of the materials are removed from the other surface . The surProposed by Mathar , hole drThe hole-drilling method is divided into incremental hole drilling (IHD) and deep hole drilling (DHD). Incremental hole drilling is commonly used to measure residual stresses at varying degrees of thickness through an incremental depth drilling of the material . On the Similarly, the ring-core method works the same way as the hole-drilling method. However, as opposed to drilling a hole, an annular groove is created, with a strain gauge rosette inserted in the middle of the groove to determine the elastic behaviour of the material . The rinOne of the main drawbacks of the ring-core method is that it is more difficult to implement, especially when strain gauges are used, since the central wire gets in the way of the slot cutting process. Moreover, this technique has been limited to homogenous and isotropic materials . The rinThe contour method is distinct among other methods used in measuring residual stresses by a relaxation mechanism because it offers detailed two-dimensional residual stress profiles that act on a plane of the material. To determine residual stresses using the contour method, the material is cut through the cross-sectional area by employing a wire Electro-Discharge Machining (EDM), and then the height maps of the cut surfaces are measured by using a laser profilometer or coordinate measuring machine. By cutting the material along the surface, residual stresses are released, resulting in deformation. The initially existent residual stresses parallel to the surface may be estimated using finite element analysis by evaluating the stresses necessary to restore the altered surface shape to a flat plane. The surface deformations are very small, and thus the EDM cutting and the surface height map measuring must be performed with very high accuracy. Furthermore, to prevent any asymmetry impacts, it is ideal to estimate the surfaces on both sides of the cut and to utilise the average surface height map. It is also feasible to make more cuts on perpendicular planes to acquire maps of the normal residual stresses along the planes. This method has been employed for measuring residual stresses in metal alloy melts , ion excThe slitting method is another destructive testing method employed in measuring residual stresses. In several studies, this is also referred to as incremental slitting , crack cIt is standard practice in the microelectronics industry to employ Micro-Raman Spectroscopy to identify regions of mechanical stress in silicon circuit board components . ChemicaFurthermore, the X-ray diffraction method is another important technique used in measuring residual stresses in materials. This method can measure the residual stresses at the material surfaces up to a depth of 30 microns . HoweverIn addition, neutron diffraction (ND) is a method that uses neutron beam diffraction to identify deep-seated residual stresses in materials. As with X-ray diffraction, neutron diffracted beams follow Bragg’s Law, allowing stress-induced variations in atomic lattice spacing to be detected. As a result, the relative spacing differences are calibrated using a stress-free material sample to compute actual stress values. In comparison to X-rays, neutrons have the benefit of measuring residual stresses in materials at high depth and precision. The Synchrotron X-ray Method operates with the same principle as the XRD and ND discussed above.It is a common phenomenon to employ ultrasound waves in the detection of faults in engineering materials , but theFibre-reinforced materials are used for many engineering applications where high mechanical properties are required. The use of carbon-fibre-reinforced polymer composites may reduce the weight of the materials up to 70% compared to steel . TherefoCrashworthiness is an automobile’s capacity to protect its occupants from severe injury or death in the event of a given number of collisions. It is a quantitative assessment of a structure’s ability to protect its passengers in survivable crashes . It is aThe present article reviews some of the studies related to the techniques associated with fibre-prestressing in polymer matrix development. The presence of tensile residual stresses during the manufacturing process has a detrimental effect on composite materials’ performance, especially when subjected to an external load. Fibre-prestressing offers the advantage of minimising residual stress without increasing the mass or section dimension in composite materials. It involves generating compressive residual stresses in a fibre–polymer matrix interface to minimise the effect of tensile residual stresses. While fibre-prestressing can be achieved both elastically (EPPMC) and viscoelastically (VPPMC), several equipment designs have reportedly been used to achieve prestressing. Despite some limitations associated with these techniques, the influence of fibre-prestressing on polymer composite structural properties has been positive. Previous studies on prestressed composites have reported up to 60% increase in the tensile modulus, 62% increase in impact strength, 140% increase in tensile strength, 50% in the flexural modulus, 9% increase in compressive strength and an increase of more than 150% in fatigue life compare to their unprestressed composite counterparts.Moreover, various methods have been reported for measuring residual stresses in materials. These are generally grouped into destructive and non-destructive methods. The destructive methods measure residual stresses by monitoring the response of a material to deformation, while non-destructive methods monitor the change in material structures when under the influence of residual stresses. The selection of the right method depends on the type of material , material structure , states of stresses, speed and measurement accuracy. Out of these methods, the hole-drilling method has been widely used due to its versatility and the availability of scientific standards for measuring residual stresses in various materials.


With the launch of the UK Academy of Pharmaceutical Sciences Advanced Therapy Medicinal Products Focus Group in late 2020, a webinar series reviewing the current and emerging trends in cell and gene therapy was held virtually in May 2021. This webinar series was timely given the recent withdrawal of the United Kingdom from the European Union and the global COVID-19 pandemic impacting all sectors of the pharmaceutical sciences research landscape globally and in the UK. Delegates from the academic, industry, regulatory and NHS sectors attended the session where challenges and opportunities in the development and clinical implementation of cell and gene therapies were discussed. Globally, the cell and gene therapy market has reached a value of 4.3 billion dollars in 2020, having increased at a compound annual growth rate of 25.5% since 2015. This webinar series captured all the major developments in this rapidly evolving area and highlighted emerging concepts warranting cross-sector efforts from across the community in the future. The Academy of Pharmaceutical Sciences  hosted a virtual webinar series in May 2021 on the topic of cell and gene therapy, holistically combining concepts from bench discovery to their clinical implementation. This was a flagship event for the Advanced Therapy Medicinal Products (ATMP) Focus Group which was launched in fall 2020. The session was attended by delegates representing the academic, pharmaceutical industry, pharmacy practice and regulatory sectors; a diversity which was reflected in the speaker line-up and panel discussion. The global ATMP market is a rapidly growing sector, reaching a market worth of 7.9 billion dollars in 2020 . The majEx vivo strategies for genetic alteration include cell therapies with a rapidly growing global market predicted to reach 45.4 billion dollars by 2028 [In vivo ATMPs include the use of alternative gene delivery systems that may be viral  or non-viral  in composition. Targeting of specific tissues is required for the successful delivery of genetic materials with in vivo therapies . Since t®, Juno/Bristol Myers Squibb , 2021) [Chris van der Walle  opened the presentations with a talk entitled ‘Formulation considerations for T-Cell Therapies’. Dr van der Walle presented an outline of the autologous chimeric antigen receptor (CAR) T cell therapy landscape. The challenges to CAR/TCR T-cell treatment of solid tumours arise from their heterogeneous antigen expression, poor infiltration, immunosuppressive microenvironment and limited persistence . While t), 2021)  broke co), 2021) . Lentivi), 2021) . Signifi), 2021) . It alsoCentral to the presentation was the concept of a ‘vein-to-vein time’ that, for the autologous T cell process, begins with apheresis of a patient’s peripheral blood mononuclear cells and ends with infusion of the DP. It was noted that the cost of goods (COGs) for cell and gene therapies is a topic of hot debate, wherein the Chemistry, Manufacturing and Controls (CMC) of T cell therapies contributes almost 50% to the external project expenditure (costs minus staffing) and over 40% of internal project expenditure. The major contributor is the so-called ‘patient COGS’, followed by process development for vector and T cell, including their technology transfer to a CMO, plasmids and cell banks .With the focus of the presentation being formulation, specific references were made to cryopreservation agents and freezing. The former universally remains dimethyl sulfoxide (DMSO) for T cells entering the clinic and the latter generally involves the use of a liquid nitrogen-controlled rate freezer, prior to long term storage in vapour phase liquid nitrogen (−150 °C) or liquid nitrogen (−196 °C).With regard to the lentiviral vector starting material, its fill-finish into either cryogenic vials or bags likely depends on the compatibility of these primary containers with the intended expansion system for the T cell drug substance, e.g., a closed process for T cell expansion may demand aseptic welding of a bag containing the lentiviral vector material.The T cell formulation must maintain a drug product that is practically free of visible particulates prior to freezing and storage. Promising methods are currently under development for reporting subvisible particulates that may one day find application pending their qualification  With theArpan Desai  presented on advances in the biological understanding of lipid nanoparticle delivery for mRNA therapeutics. He discussed the biological barriers to the systemic delivery of non-viral drug delivery systems ,16. SubsChristine Dufes  discussed challenges in the design of novel gene therapies in oncology drug development. Her presentation focused on the implementation of dendrimers and dendrimer-based vesicles (dendrisomes) ,20,21 wiThe second webinar session included a presentation on the UK manufacture landscape for cell and gene therapies and was followed by an interactive panel discussion with the presenters from across all three webinar sessions covering the manufacture considerations for the rapidly growing complex medicines landscape.Julie Kerby  delivered a presentation introducing the CGT and its remit in the UK cell and gene therapy manufacture landscape. The CGT was set up in 2012 by the UK government and is a part of a network of catapults with the remit to bridge the academic and industry sector translational gap by embedding technologies and innovations in the UK ATMP landscape. The UK is largest CGT cluster outside the US with 26 manufacturing facilities supporting early to large-scale manufacture of ATMPs and >90 innovator companies. The UK hosts 12% of all global ATMP clinical trials. She discussed the industry challenges of developing complex cell and gene therapies using autologous cell therapies and gene therapies as examples. Some of these were attributed to variable starting materials in terms of the genetic variability, clinical treatment history and the supply chain elements of developing these therapies. There is a fast turnaround time involved required and novel analytical methods are required for rapid release tests to accelerate the timelines involved in their development and release to patients.She then discussed the challenges commonly encountered with gene therapy based technologies were described as supply chain issues associated with the fill-finish steps. The variability in the viral gene therapy analytical space was cited as a driver for increasing the cost and size of batch. The scale-up costs for early clinical campaigns drives the costs associated with developing novel gene therapies. The CGT supports the analytical and manufacturing challenges encountered by companies and academia to accelerate the commercial translation and technology-readiness of these products. During the pandemic, the CGT has been actively involved in the delivery of the COVID-19 vaccine. Dr Kerby then presented the partners and facility sites  for the CGT in the UK, discussing the non-competitive space that has contributed to key developments in tackling challenges with fill-finish steps. Her presentation concluded with futureproofing expansion of the CGT industry, where she referred to a survey conducted by the CGT of the UK ATMP workforce studying staff numbers and skilled workforce requirements.In response to the survey, the CGT launched an apprenticeship scheme with >10 programmes developed across a range of technical skill areas and competencies which was the first apprentice programme of its own type. This scheme has led to over 130 apprentices being recruited and employed into the CGT industry sector  Figure .The final webinar session in the series covered Chemistry, Manufacturing and Control (CMC) and regulatory considerations for the development of in vivo gene therapies and the implementation of ATMPs in the clinic setting.® and Luxturna® drug product features as commercially available drug products. Dr Broadhead then discussed the challenges in analytical method development for in vivo gene therapies, citing the heterogeneity of packaged DNA and the potential for fragment annealing and extension that may contribute to efficacy. She then presented some of the typical critical quality attributes (CQAs) for AAV drug products and key analytical considerations at the DNA, capsid and drug product levels Adeno-associated virus (AAV) vectors have now been investigated in >140 clinical trials with over ten years follow-up data available on their safety and efficacy. Dr Joanne Broadhead  discussed regulatory and CMC challenges encountered in the development of recombinant AAV gene therapy vectors from an analytical and formulation perspective. She provided a market overview of in vivo gene therapies, describing the key ZolgensmaViral vector delivery systems have historically been formulated in surfactant-containing  buffers and stored at low temperatures . The cost of goods associated with developing viral gene therapies has limited the range of formulation studies and investigation of more sophisticated formulation options .Dr Broadhead then discussed the challenges associated with drug substance (DS) manufacture, which include process complexity, reliance on multiple starting materials, multiple processing steps and control of process parameters are known to influence product CQAs . A deepeReference samples for quality assurance should be of sufficient size to allow the performance of at least two full analytical measurements on the batch though the feasibility of this due to scarcity of material in small scale production has been acknowledged by regulatory bodies. In line with sample consumption requirements, container closure integrity (CCI) testing of vials containing buffer has been accepted by regulators as sufficient for clinical trial materials .Dr Broadhead then discussed the regulatory challenges and opportunities in the development of in vivo gene therapies. One of the key regulatory hurdles was the ever-evolving regulatory landscape for ATMPs as a deeper product understanding is being developed over time. However, with this evolution platform approaches can be leveraged to deliver various genes of interest across multiple areas of clinical need. Data from existing products can be used to support the development of new products for other disease targets or clinical indications, provided that the same platform is used . The FDA and EMA have issued guidance documents on the CMC considerations for human gene therapy investigational new drug applications  and qualSome of the current hot topics in AAV manufacture were cited as empty/full ratio, where the number of empty capsids is quantified, with regulators raising questions around the impact of empty capsids on safety and efficacy. Many manufacture processes are currently under development to remove empty capsids from the DS during manufacture. Dosing assays to ensure accuracy and reproducibility of the product dosage are key to ensure efficacy. Digital droplet PCR is increasingly being used, which does not require the use of a standard. There is also increasing scrutiny of in vitro potency assays as the most meaningful indicator of in vivo efficacy.Alice Tam  discussed the clinical application of cell and gene therapies (CGT) within the hospital setting. She presented the distribution of CGTs across therapeutic areas, with over 35% of all CGTs under clinical trial investigation being deployed in the oncology category [In addition to governance requirements for the implementation of ATMPs in the clinical setting, infrastructure requirements include aseptic facilities, appropriate cold-chain storage, and due to the acute toxicities of ATMPs an ITU facility is required onsite for some ATMPs. In addition to drug product handling infrastructure, clinical staff involved in the handling of ATMPs are required to receive training on the complex handling requirements for ATMPs and the management of unique acute toxicity (cytokine release syndrome- CRS and immune effector cell-associated neurotoxicity- ICANS) in patients that often results from ATMP treatment . CRS is She continued the presentation with a clinical scenario of a CAR-T patient journey and stages involved in CAR-T therapy .The talk was concluded with a discussion on additional governance structures in terms of organizational policies and requirements, quality systems, and local procedures within the healthcare system.The number of innovator ATMPs under development and clinical investigation is rapidly increasing, creating new opportunities for the management of unmet clinical need. The presentations and panel discussions at the Academy of Pharmaceutical Sciences Advanced Therapy Medicinal Products (ATMP) Focus Group symposium provided an insight into the latest developments within the landscape. These included the challenges and opportunities in the development of new cell and gene-based therapies. With the rapid expansion of ATMP research, development and clinical applications there is a clear need for a multidisciplinary and multisector approach in which clinicians interact with scientists in academia, the pharmaceutical industry and regulatory bodies. In the UK, a number of government organizations such as the Cell and Gene Therapy Catapult and professional bodies including the Royal Pharmaceutical Society and Academy of Pharmaceutical Sciences have initiated a portfolio of activities to support the futureproofing of the UK workforce in meeting the demands associated with ATMP implementation and introducing key infrastructure that will support the rapid development and scale-up of emerging innovator products.


The surgical treatment of gynecological malignancies is, except for tumors diagnosed at the earliest stages and patients’ desire for fertility preservation, not limited to only the affected organ. In cases of metastatic iliac lymph nodes, gynecological tumors or recurrences located near the pelvic sidewall, oncogynecologists should dissect tissues in that region. Moreover, surgery of deep infiltrating endometriosis, e.g., within the sacral plexus, or oncological procedures, such as a laterally extended endoplevic resection or a laterally extended parametrectomy, often require a dissection of the pelvic sidewall. Dissection should be meticulous, and detailed knowledge of anatomy is mandatory. There are many controversies among authors regarding the terminology in the pelvic sidewall. In particular, several imprecise or confusing definitions exist in regard to the region located medially to the psoas major muscle. Therefore, after discussing the anatomy of the pelvic sidewall and the commonly used terminology, we define a new term and boundaries of a potential avascular space, the medial psoas space. Contrary to the variety of earlier definitions, the proposed boundaries relate to a truly avascular space and could help surgeons to avoid complications resulting from misleading anatomical descriptions. Additionally, describing the clear boundaries of and possible anatomical variations in the medial psoas space may urge oncogynecologists to consider different approaches during surgery. The purpose of the present study is to describe the anatomy of the pelvic sidewall and the applications of the medial psoas space in gynecologic oncology. The surgical treatment of gynecological malignancies is, except for tumors diagnosed at the earliest stages and patients’ desire for fertility preservation, not limited to only the affected organ . The lymThe description and reevaluation of the surgical anatomy, as well as the standardization of the surgical technique, were based on the retrospective analysis of 25 surgical procedures performed at the Department of Gynecology, University Hospital “Saint Anna” Varna. MPS and PSW dissections were performed in 25 gynecological cancer patients between February 2016 and December 2019. Sixteen patients had stage I and stage II cervical cancer. A lateral extended parametrectomy (LER) with selective pelvic lymphadenectomy was performed in 11 of them. The other five patients underwent pelvic lymphadenectomy (level one) followed by radical hysterectomy. For the remaining nine patients, six underwent pelvic lymphadenectomy followed by total abdominal hysterectomy, three of them for non-endometrioid endometrial cancer, and the other half for pelvic bulky lymph nodes due to ovarian cancer. The MPS was also accessed for one patient with undifferentiated uterine sarcoma adherent to the PSW. Extraperitoneal open internal iliac artery ligation after MPS dissection was performed in two patients with locally advanced cervical cancer and severe vaginal bleeding.We performed the following surgical procedures and separated the PSW during surgery into three regions (compartments), consisting of the avascular compartment, vascular compartment and nerve compartment . The accSuperiorly: the peritoneum covering the external iliac vessels and psoas major muscle.Inferiorly: the pelvic floor muscles, namely the piriformis, coccygeus, and iliococcygeus muscles.Ventrally: inguinal ligament.Dorsally: sacrum.Laterally: superiorly by the medial aspect of the psoas major muscle and inferiorly by the obturator internus muscle.Medially: superiorly by the external iliac vessels and inferiorly by the sacral spine ,11,12,13The anatomical limits of the PSW region are: The limits of the PSW regions are shown in The technique of PSW and MPS dissection is described in three steps.A vertical midline skin incision is performed below the umbilicus to the symphysis pubis. The subcutaneous fat, rectus adbominis muscle aponeurosis, transversalis fascia and visceral peritoneum are dissected and cut, whilst the rectus abdominis muscles are preserved. Pelvic intraabdominal organs are exposed. The ipsilateral ovary and fallopian tube are retracted medially for better exposure of the ovarian vessels. The round ligament is the key for the initial dissection of the MPS. The ligament is cut and ligated close to the PSW and laterally to the external iliac vascular system . The posAccess to the vascular regions is made by an initial avascular region dissection. Obturator vessels and the majority of the parietal and visceral branches of the internal iliac artery and vein, which lie below the obturator nerve, are visualized below the external iliac vessels. The origin and draining patterns of superior gluteal, inferior gluteal, and internal pudendal vessels are identified. The parietal fatty tissue and the lymph nodes overlying these vessels are dissected. The vascular regions are delimited superiorly by the obturator nerve, inferiorly by the sacral plexus, laterally by the obturator internus muscle, and medially by the internal iliac artery. The limits of vascular region are shown in Development of the lateral paravesical step and the lateral pararectal space (Latzko’s space) as well as the identification of the ureter could be performed, though not a necessary step. However, controlling iatrogenic injury is better achieved after the development of more avascular spaces and the visualization of the ureter.We gain access to the nerve region after the dissection of the vascular region. The internal iliac vessels and the majority of their branches are ligated and divided. The internal iliac artery is ligated and divided at the site of branching off from the common iliac artery. Thereafter, the superior gluteal, interior gluteal, pudendal arteries and additional parietal branches were isolated, ligated and divided. The ligation of the internal iliac venous system started from the peripheral to the central, as Nishikimi et al. noticed that ligation and division from the main central trunk leads to the congestion and swelling of the peripheral internal iliac veins. Central to peripheral ligation may cause ligature slippage or the splitting of the peripheral internal iliac vein . The divAvascular region: The avascular region and MPS were dissected in all 25 patients. Only the MPS was encountered in eight patients who underwent pelvic lymphadenectomy (level one), five patients with cervical cancer and three women with non-endometrioid endometrial cancer.Vascular region: Further dissection of the vascular region was performed in 17 patients, 11 with cervical cancer that underwent LER, three patients with ovarian cancer and bulky lymph nodes, one patient with uterine undifferentiated uterine sarcoma, and two patients with internal iliac artery ligation.Nerve region: After the dissection of the vascular region the nerve region was encountered, but further dissection was not performed in this study.The term “spaces” is considered to be areas delimited by at least two independent fasciae, which are filled with areolar connective tissue. These spaces are developed by separating two independent fascia along their cleavage plane . This deSuperior: peritoneum covering the psoas major muscle and external iliac vessels.Inferior: obturator nerve.Ventral: deep circumflex iliac vein.Dorsal: common iliac artery bifurcation.Lateral: fascia iliacus covering the psoas major muscle, genitofemoral nerve.Medial: external iliac artery and vein.In the avascular regions of the PSW, a new term and boundaries of a potential avascular surgical space could be defined by using the medial psoas approach. Many authors described this space by using different terms. Denis Querleu clarified it as “laterovascular space” . Marc PoThe MPS is a surgical avascular space, as only the lateral border is covered with fascia, iliacus fascia. Fascia covering the obturator internus muscle are not a part of the MPS as the muscle is located just below the obturator nerve .The MPS could be dissected during pelvic lymphadenectomy for gynecological cancers. After encountering the MPS, the obturator nerve is identified. The obturator lymph nodes are dissected from the PSW and obturator nerve in a lateromedial direction. Then, the common iliac and external iliac lymph nodes are dissected in a caudocranial direction to the level of the deep circumflex artery. Finally, the lymph nodes located medial to the external iliac vessels and obturator nerve are dissected in a lateromedial direction to the medial border shaped by the internal iliac artery and obliterated umbilical artery; all pelvic lymph nodes are removed “en bloc”. This is level I pelvic lymphadenectomy according to the Cibula and Abu-Rustum classification . AccordiIn cases of bulky lymph nodes over the external iliac vessels extending to the psoas major muscle, the MPS could be dissected in order to identify the obturator nerve and provide a safe plane of dissection . Here, tMoreover, the MPS could be encountered in cases of positive external and obturator sentinel lymph nodes, as these lymph nodes are most commonly affected in cervical cancer patients with FIGO stages IB1 to IIB. The removal of SLN in the external iliac, interiliac, and obturator area enables the evaluation of more than 80% of all SLN in patients with cervical cancer ,24.The medial psoas space will be dissected together with the lateral pararectal space (Latzko’s space) during therapeutic or prophylactic internal iliac artery ligation for severe vaginal bleeding. We developed both spaces during two cases of extraperitoneal open internal iliac artery ligation. The dissection of both spaces provides an adequate control for possible iatrogenic injury of the internal iliac vein. Controlling pelvic hemorrhage is easier and safer when all potential spaces near the surgical field are encountered before different types of oncogynecological procedures.The MPS could be developed to gain access to the vascular and nerve regions of the PSW.These cases are often considered as inoperable as a complete resection or optimal cytoreduction cannot be achieved. Moreover, such tumors may invade the internal iliac vessel system. However, en bloc resection of the tumors along with the entire internal iliac vessel system to achieve optimal cytoreduction is feasible if the tumor does not involve the lumbosacral plexus or proximal sciatic nerve ,5,6. NisIn 1941, Mibayashi introduced “super-radical hysterectomy” for locally advanced cervical cancers. The procedure included the extended dissection of the cardinal ligament and the removal of the entire internal iliac vessel system . Since tConversely to LEP, the LEER procedure is still indicated in patients with cervical cancer (T4N0M0) and PSW recurrences. The tumor should not be larger than 5 cm and the recurrence-free interval should be longer than 5 months. Achieving lateral-free margins is feasible if the tumor does not involve the sacral plexus. For patients with PSW recurrences after adjuvant treatment, the development of the MPS and vascular region is the preferable approach. The dissection of the MPS gives better access to the PSW in cases of lateral tumor fixation to the obturator internus, coccygeus, or iliococcygeus muscles ,7,26.As mentioned above, the dissection of the nerve region was not performed during the surgeries reported in the present article. However, the nerve region could be observed for deep infiltrating endometriosis and pelvic nerve tumors  located on the sacral plexus, obturator, pudendal or sciatic nerve ,18,27. PThe iliolumbar vein (ILV) drains the venous blood from the iliac fossa, psoas major and iliacus muscle, and terminates into the common iliac vein. The ascending lumbar vein (ALV) joins in the anastomotic venous system, which is formed by the inferior vena cava and the superior vena cava. The caudal part of the ALV drains into the cephalic border of the common iliac vein ,13. LoliOncogynecologists should also be aware of the variations in the external and internal iliac system ,14.In rare cases, an additional muscular branch from the external iliac artery descending laterally to the artery could be observed .Knowledge of the PSW anatomy is of the utmost importance during some oncogynecological procedures. The division of the PSW into three regions will better delineate the anatomy and technique of surgical procedures in that region. Emphasizing new insights concerning a potential avascular space may decrease morbidity during oncogynecological procedures in the PSW. The space gives better access to the obturator fossa and anatomical structures located below the obturator nerve in cases of metastatic lymph nodes or tumors to the PSW. Describing the clear boundaries of and possible anatomical variations in the MPS may urge oncogynecologists to consider different approaches during surgery.


Ultrasonic waves are nowadays used for multiple purposes in many different fields from the non-destructive inspection of materials to sonochemical synthesis of materials and welding. Usually, ultrasonic applications are divided into low intensity/high frequency ultrasound and high intensity/low frequency ultrasound. Low intensity ultrasound transmits energy through the medium in order to obtain the information about the medium or to convey information through the medium . It is sUltrasound for Material Characterization and Processing collects eleven papers, one review and ten research papers, with the aim to present recent advances in ultrasonic wave propagation applied for the characterization or the processing of materials. Both fundamental science and applications of ultrasound in the field of material characterization and material processing have been gathered.The Special Issue Ultrasonic liquid penetration measurement in thin sheets—physical mechanisms and interpretation”, give an overview on the three possible mechanisms for ultrasonic liquid penetration (ULP) measurements for the characterization of intrinsic properties of porous sheets. The review discusses the interpretation of ULP results, which are complex, as the ultrasound signal can be affected by several mechanisms. Then, it describes the individual physical mechanisms leading to different shapes of the ultrasound intensity curves, and provides measurements confirming that the measured ultrasound intensity is linked to the liquid penetration regime into the structure.As regards low intensity ultrasound, Waldner et al.  in theirUltrasound Axicon: systematic approach to optimize focusing resolution through human skull bone” propose a numerical approach for designing axicon lenses for many high-resolution applications, such as mapping or detection. The aim is to generate a focused ultrasound field by plane transducer using axicon lens, which can be suitable for focused ultrasound through human skull bone. The numerical simulations help to find the optimized parameters for the proposed system design. The sound field testing using hydrophone shows the performance of the proposed method by comparing the cases with and without a human skull phantom.Acquaticci et al.  in the pEffects of loading and boundary conditions on the performance of ultrasound compressional viscoelastography: a computational simulation study to guide experimental design” present a finite element analysis of compressional viscoelastography. This ultrasonic imaging technique is used for measuring the viscoelastic properties of biomaterials and tissues and it is based on the analysis of the creep behavior of a material under an external mechanical compression. The authors demonstrate that loading conditions  and boundary conditions (the fixation method used to stabilize the sample) can severely affect the measurement accuracy of the viscoelastic properties of materials.Lin et al.  in the pTopology optimization-based damage identification using visualized ultrasonic wave propagation” present a new damage identification method in structures based on topology optimization in combination with visualized ultrasonic wave propagation. The proposed method is applied to an aluminum plate with an artificial crack and the estimated damage state and the sensitivity of the objective function were compared with numerical predictions.Ryuzono et al.  in the pOut-of-plane permeability evaluation of carbon fiber preforms by ultrasonic wave propagation” present a novel experimental set-up, based on ultrasonic wave propagation, for the determination of the out-of-plane permeability of carbon fiber reinforcements, which is the dominant property in the infusion of large and flat panels with a high thickness. An accurate characterization of the reinforcement permeability is fundamental in order to estimate the optimum process parameters for manufacturing high-quality components. The experimental results, obtained in unsteady conditions, have been compared with those obtained in steady conditions by a traditional gravimetric method and validated by some analytical models. The work demonstrates the feasibility and potential of the proposed set-up for permeability measurements thanks to its non-invasive character and the one-side access.Lionetto et al.  in the pNumerical study of concrete mesostructure effect on lamb wave propagation” analyze the propagation of guided wave in concrete plates accounting for the heterogeneous structure of concrete. The influence of aggregate ratio and particle size on dispersion curves representing Lamb wave modes is analyzed by several concrete models with randomly distributed aggregates, generated by means of the Monte Carlo method. The study shows that Lamb wave propagates with different velocities in homogeneous and heterogeneous models and the difference increases with aggregate ratio and particle size. This result demonstrates the potential of the method for the monitoring of concrete structures.In the area of structural mechanics, concrete structures and nondestructive testing Zima et al.  in the pMonitoring the Setting Process of Cementitious Materials Using Guided Waves in Thin Rods” demonstrate the reliability of an ultrasonic method based on embedded guided waves to monitor the early-age properties of mortar and concrete samples through continuous attenuation monitoring. The technique is able to eliminate the effects of coarse aggregates, which makes it of great potential to be directly applied in situ to the fresh concrete. The method has the potential to be used when additives are added to concrete, thus changing its rheological properties.Wang et al.  in the pDisassembly study of ultrasonically welded thermoplastic composite joints via resistance heating”, demonstrate a novel concept in the disassembly of ultrasonically welded thermoplastic composite joints. The recycling of thermoplastic composite joints is realized by resistance heating via a nanocomposite film located at the welded interface. This electrically conductive film, containing multi-walled carbon nanotubes, is able to promote joint disassembly through a combination of nanocomposite and matrix melting and weakened fiber–matrix interface.Concerning the applications of high intensity ultrasound, Frederick et al. , in the Building of longitudinal ultrasonic assisted turning system and its cutting simulation study on bulk metallic glass”, present an experimental-numerical study on a novel machining technology, longitudinal ultrasonic assisted turning. After presenting this technology, they establish a two-dimensional finite element model of the ultrasonic assisted turning, aimed at studying the effect of ultrasonic vibration on cutting force under different cutting speeds on bulk metallic glasses. The latter are a new kind of material, which are made by rapid condensation of alloy with excellent properties such as high strength, high hardness and corrosion resistance, but they are hard to be machined. The results demonstrate that longitudinal ultrasonic vibration can significantly reduce the average cutting force as well as the von Mises stress when the turning speed is below the critical turning speed.Shan et al. , in the Effects of ultrasonic bending vibration introduced by an L-shaped ultrasonic rod on the microstructure and properties of a 1060 aluminum alloy strip formed by twin-roll casting”, present a new type of ultrasonic generator to assist the process of continuous casting and rolling of aluminum alloy. A novel L-shaped ultrasonic rod is designed to introduce an ultrasonic bending vibration into the aluminum melt. The ultrasonic bending vibration improves the microstructure of the 1060 aluminum alloy cast rolling strip, characterized by grain refinement, and consequently its properties.Shi et al. , in the Effect of ultrasonic bending vibration introduced by the L-shaped ultrasonic rod on solidification structure and segregation of large 2A14 ingots”, propose a new design of L- shaped ceramic ultrasonic wave guide rod for the introduction of ultrasonic bending vibration during the solidification of the 2A14 aluminum alloy. The authors demonstrate the advantages in terms of grain refinement, deagglomeration of the secondary phase, and improving the ingot macrostructure.Shi et al. , in the


Estimated glomerular filtration rate (EGFR)-sensitive mutations are extremely important for targeted treatment strategies in lung cancer. Osimertinib can effectively inhibit the activity of EGFR-sensitive mutations, including the T790M mutation. However, the efficiency of osimertinib for rare mutation types of T790 is unclear. Here, we report the case of a Chinese patient with lung adenocarcinoma (LADC) harboring a T790I mutation who achieved significant benefits from osimertinib treatment. Estimated glomerular filtration rate (EGFR)-tyrosine kinase inhibitors (TKIs) are a standard treatment option for patients harboring activating EGFR mutations, and several TKIs that specifically target EGFR have been approved by the FDA . HoweverThis study was approved by the institutional review board and conducted following the tenets of the Declaration of Helsinki. Informed consent was obtained from the patient. Formalin-fixed paraffin-embedded (FFPE) tumors and matched blood samples from a 61-year-old Chinese male with LADC were collected and transferred to OrigiMed  for genetic alteration detection.Genomic DNA of tumor samples and white blood cells from matched blood was extracted from the FFPE tumor and blood samples using the QIAamp DNA FFPE Tissue Kit and QIAamp DNA Blood Midi Kit  according to the manufacturer’s instructions. The testing was carried out in a laboratory certified by the College of American Pathologists and Clinical Laboratory Improvement Amendments.The patient was a 61-year-old Chinese man without a history of smoking or family history of lung cancer. He had been receiving systemic treatment for coronary heart disease for 13 years. This patient was admitted with a 2-month history of chest tightness and asthmatic and irregular coughing in June 2017. Chest computed tomography (CT) revealed a space-occupying lesion in the upper lobe of the right lung, which invaded the mediastinal and right hilar lymph nodes and right supraclavicular region  can be found in the article/supplementary material.The studies involving human participants were reviewed and approved by the ethics committee of Shandong Provincial Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.WD and YW had full access to all of the data in the manuscript and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: all authors. Acquisition, analysis, and interpretation of data: all authors. Manuscript drafting: WD and YW. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: YW and AF. Supervision: WD. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China (81802282) and the Jinan Science and Technology Development Program (201907112).Author HL, JH and KW were employed by the OrigiMed Inc.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: This study aimed to report a case of vitrectomy with peeling the internal limiting membrane for the treatment of macular hole (MH) following ruptured retinal arterial macroaneurysm (RAMA).Case Presentation: A 65-year-old woman noticed a sudden decrease in vision in the left eye. She had no other ocular problems apart from a mild cataract in both eyes before. Her best-corrected visual acuity (BCVA) was 20/33 in the right eye, and 6/100 in the left eye. Fluorescein angiography (FFA) showed a retinal arterial macroaneurysm with telangiectatic retinal vascular changes in the inferior temporal macular region. Optical coherence tomography (OCT) examination demonstrated the presence of subretinal hemorrhage extending into the foveal area and incomplete posterior vitreous detachment. Because of the presence of submacular hemorrhage, some medicine was administrated and the patient was followed up. Then, 5 months later, the hemorrhage was absorbed. OCT examination exhibited a full-thickness MH with a macular epiretinal membrane. The size of the MH was 722 μm in diameter. She was then given a standard three-port pars plana vitrectomy (PPV), along with peeling of the internal limiting membrane (ILM) and filling the vitreous cavity with air. Anatomic closure of the MH was achieved after 4 weeks of the surgery by the examination of OCT. The BCVA was improved to 15/100.Conclusions: This case expanded our knowledge of the association of MH secondary to ruptured RAMA. We reported a case with successful surgical closure of the MH and improvement of BCVA. Macular holes (MHs) are usually idiopathic and occur most commonly in healthy, middle-aged women. In rare cases, MHs have been associated with retinal vascular diseases such as proliferative diabetic retinopathy , hyperteSeveral studies have reported the efficacy of autologous transplantation of ILM , 11 and A 65-year-old woman with a longstanding history of hypertension noticed a sudden decrease in vision in her left eye. She had no other ocular problems apart from a mild cataract in both eyes before. Her best-corrected visual acuity was 20/33 in her right eye, and 6/100 in her left eye. Fluorescein angiography showed a retinal arterial macroaneurysm with telangiectatic retinal vascular changes in the inferior temporal macular region . OpticalPars plana vitrectomy (PPV) method:Standard three-port vitrectomy was performed, followed by surgical separation of the posterior cortical vitreous from the optic nerve and posterior retina. About 1% indocyanine green (ICG) was injected over the macula region after temporarily stopping the infusion. The ILM with 2 disk diameters of the fovea was removed. The vitreous cavity was filled with air. The patient was asked to remain face down for a week following the surgery.The formation of MH following a ruptured RAMA is not entirely uncommon. Colucciello and Nachbar  reportedIn conclusion, this case expanded our knowledge of the association of MHs secondary to ruptured RAMA. We reported a case with successful surgical closure of the MH and improvement of BCVA. Large-scale, randomized, comparative, and prospective studies are needed to further warrant this method.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by the Ethics Committee of Jinan Aier Eye Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.ZL contributed to writing the manuscript. YW and SW contributed to the literature research and preparation of the manuscript and figures. AM and BZ are responsible for the design of the case report. All authors read and approved the final manuscript.This work was supported by Shandong Natural Foundation, China to BZ and AM (ZR2019MH111 and ZR2017MH021).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.