To address practical challenges in establishing and maintaining robust wireless connectivity such as multi-path effects, low latency, size reduction, and high data rate, we have deployed the digital beamformer, as a spatial filter, by using the hybrid antenna array at an operating frequency of 10 GHz. The proposed digital beamformer utilizes a combination of the two well-established beamforming techniques of minimum variance distortionless response (MVDR) and linearly constrained minimum variance (LCMV). In this case, the MVDR beamforming method updates weight vectors on the FPGA board, while the LCMV beamforming technique performs nullsteering in directions of interference signals in the real environment. The most well-established machine learning technique of support vector machine (SVM) for the Direction of Arrival (DoA) estimation is limited to problems with linearly-separable datasets. To overcome the aforementioned constraint, the quadratic surface support vector machine (QS-SVM) classifier with a small regularizer has been used in the proposed beamformer for the DoA estimation in addition to the two beamforming techniques of LCMV and MVDR. In this work, we have assumed that five hybrid array antennas and three sources are available, at which one of the sources transmits the signal of interest. The QS-SVM-based beamformer has been deployed on the FPGA board for spatially filtering two signals from undesired directions and passing only one of the signals from the desired direction. The simulation results have verified the strong performance of the QS-SVM-based beamformer in suppressing interference signals, which are accompanied by placing deep nulls with powers less than −10 dB in directions of interference signals, and transferring the desired signal. Furthermore, we have verified that the performance of the QS-SVM-based beamformer yields other advantages including average latency time in the order of milliseconds, performance efficiency of more than 90%, and throughput of nearly 100%. Adaptive digital beamformers have recently received substantial attention in a variety of applications such as MIMO wireless communications , fault dBeamforming techniques can perform using any type of optimization method, or one of two well-established techniques of MVDR and LCMV, or a combination of the aforementioned techniques. Although the MVDR beamforming technique is capable of determining optimal weight vectors for its beamsteering performance, its nullsteering performance remains unsatisfactory. However, the LCMV beamforming technique can reduce interference signals without losing the information strength. Compared to the MVDR beamforming technique, the LCMV beamforming method offers several different advantages of (1) better performance in suppressing interference signals, (2) a significant reduction in side lobe level, and (3) a drastic increase in signal-to-interference noise ratio (SINR). Hence, in this work, the beamforming functionality has been fulfilled using a combination of the LCMV and MVDR techniques to take advantage of both beamforming techniques and thereby achieve more robustness and stability in the performance of the proposed digital beamformer. The LCMV beamforming technique in the real environment has been performed for suppressing interference signals or improving the nullsteering functionality while the MVDR beamforming technique updates weight vectors for the beamsteering on the FPGA board.Therefore, in this case, the LCMV beamformer is capable of providing a higher directivity and lower sidelobe level in addition to determining optimal weight vectors.The DoA estimation has been fulfilled based on the QS-SVM method with a small regularizer. The practical implications of kernel-based classifier techniques, such as the SVM methods, are mostly limited only to supporting linearly-separable datasets. However, almost all practical problems have inherent non-linear characteristics. To address this limitation, feasible methods for practical applications have to be capable of supporting non-linearly separable datasets without performing a mapping to a larger feature space. In other words, we are interested in developing feasible techniques, which include non-linear classifiers in the original spaces of their own datasets. The QS-SVM model  employs Maximizing SINR values is dependent on not only an increase in the gain in the directions of desired signals but also an enhancement in the spatial distribution of a radiation pattern of the antenna array. Hence, to further improve the beamforming performance, the antenna array has to be capable of having the horizontal and vertical spatial distribution of nulls of the radiation pattern to obtain an additional degree of freedom for suppressing interference. Indeed, beamforming techniques have been used as a spatial filter for reception and transmission by the antenna array.As described in details in , the hybRecent FPGA technology has programmable logic and the capability of algorithm parallelization for further enhancing power consumption, flexibility, and accuracy.Recent advances in the FPGA architectures include a higher storage density, a drastic reduction in power consumption and cost, a large number of gates, and a high-performance processor.Recent FPGA software and high-level optimizations have to be accompanied by architectural changes in the FPGA board in order to satisfy drastic computations of SVM-based applications. Advances in FPGA technology have rigorously presented high-level software tools to be easily adjusted to the FPGA hardware.FPGA technology has recently received tremendous attention as it offers several advantages over other available embedded processors, such as digital signal processing (DSP) and specific application integrated circuit (ASIC) devices ,9:RecentFurthermore, FPGAs have evolved over the past several years into more heterogeneous devices integrated with various types of “hard IP” blocks, such as PCIe solid-state drives (SSDs), floating-point DSPs, etc. Hard blocks can also be implemented in FPGAs to address specific applications.In this work, we have presented the implementation setup of the digital beamforming on the FPGA platform when performing the QS-SVM modeling for the DoA estimation using the proposed hybrid antenna array with bowtie elements. The deployment set-up of the proposed digital beamformer on the FPGA board consists of the software and hardware implementations. The software implementation involves the LCMV beamformer technique for performing nullsteering of the hybrid antenna array in a real environment, while the hardware deployment involves implementing a quadrature programming solver for the QS-SVM technique with a regularizer, weight updating using the MVDR technique, and inner multiplications of the QS-SVM on the FPGA platform.For the first time, the QS-SVM-based beamformer has been implemented using the hybrid antenna array with bowtie elements on an FPGA board.For the first time, this work presents an implementation of the proposed digital beamformer in both the real environment and hardware board.The implementation of the QS-SVM optimization method for the DoA estimation on an FPGA board has been rigorously demonstrated for the first time.We have achieved a superior performance of the digital QS-SVM-based beamformer in terms of beamforming, nullsteering, and beamsteering.A performance evaluation of the QS-SVM-based beamformer has been fulfilled in terms of throughput, latency, and performance efficiency. Consequently, in addition to the introduction section, this work is organized into the seven following sections:In summary, the novel research contributions of this work are as follows:The performance of deploying a digital beamforming technique is significantly affected by the hardware platform, hardware design, and system architecture of a beamformer, and the involved optimization methods. Hence, the discussion of this section presents a brief review of the technical literature on implementing digital beamforming on FPGA accelerated hardware platforms.Dick et al. in  have proThe implementation of an adaptive digital beamforming technique using the conventional least mean squared (LMS) method on the FPGA hardware for massive antenna arrays has been proposed in . A majorThe Cholesky decomposition or factorization has been performed on the input covariance matrix and results have shown a good performance under the computational complexity in . HoweverXin et al. in  implemenThe framework of array signal processing refers to spatial signal processing, which is composed of designing an appropriate configuration of the antenna array for steering the main lobe of its radiation pattern in an arbitrary direction of space, and then implementing beamforming techniques for placing nulls of its radiation pattern towards interference signals while steering (or producing) the main lobe of its radiation pattern towards targets (or users) based on the measured weight vectors. Therefore, in the following work, we have demonstrated the proposed configuration of the antenna array, and then, described the proposed beamforming techniques.The configuration of any antenna array drastically affects the characteristics of the main lobe of its radiation pattern. Hence, the preliminary stage of any beamforming technique includes choosing an appropriate antenna array. Each of antenna arrays has its own constraints and advantage, as discussed in detail in . A unifoAlthough the circular antenna array does not have any edge elements, its radiation pattern includes grating lobes and sidelobes. Moreover, since the radiation pattern of the circular antenna array does not include any null in the azimuth planes, it has a weak nullsteering performance.In this work, we have proposed the hybrid antenna array with bowtie elements, whose radiation pattern includes horizontal and vertical nulls and a narrower main lobe compared to the other available antenna arrays . Hence, In the previous section, we proposed the hybrid antenna array with bowtie elements due to its superior performance in terms of a very directive radiation pattern, the SINR values, and the antenna efficiency, as demonstrated in . DiscussThe digital beamformer is also capable of performing the QS-SVM optimization method for the DoA estimation of the measured outputs of bowtie elements of the hybrid array antennas, In the real environment, we assumed that the available sources emit sinusoidal signals. Data modeling is the process of producing data based on assumptions of the real environment to generate signal sources. In this study, we have employed the MATLAB programming platform to provide raw data. Since Mathworks functions of the MATLAB programming platform have been extensively tested, evaluated, and verified based on IEEE standards and criteria, our obtained simulation results through MATLAB provide a very high level of realistic accuracy. In the preliminary stage of producing data, a sinusoidal function is considered as an available signal. In this scenario, the available signal is significantly affected by environmental noise, the coupling effect, and communication channel conditions. In this study, conditions of the communication channel are supposed to be the Ricean fading channel, line of sight (LoS), and equal correlation matrices, as described in detail in .collectPlaneWave exerts the plane wave condition to the simulated signal or incoming signal to the hybrid antenna array, which has experienced the AWGN noise and channel conditions. In this work, the white Gaussian noise has a variance of In addition, the additive white Gaussian noise (AWGN) is added to the simulated signal by the standard Mathworks’ function of AWGN. Afterward, the standard Mathworks function of Signal measurements at the outputs of array elements of the hybrid antenna array are modeled by random vectors. Ultimately, a beamforming model consists of parameters, such as the source power and covariance of the noise power. As demonstrated in nth array elements. Here, position vectors are assumed to be in a two-dimensional plane of nth element.The beamforming technique is employed for calculating the scalar product between the measured data at outputs of array elements and the steering vector in the following equation,array in  is obtaiarray in ,(3)hn to (16).ng form,I={xi,yic f(x)=0,f(x):12(xectively . In othe f(x)=0,f(x):12  45∘, butThe proposed beamformer technique for the real environment is very sensitive to multi-path effects, which is an inherent property of wireless communication channels. Therefore, in this section, a further enhancement in the performance of the QS-SVM-based beamformer has been achieved by the hardware implementation. All MATLAB codes of the proposed QS-SVM-based beamformer, including data collection codes, the LCMV, and MVDR beamforming codes, the proposed hybrid antenna array codes, and codes of the QS-SVM optimization method, have to be efficiently programmed into a hardware description language (HDL) in the format of arithmetic operations, such as multiplications and/or additions. Three main parts of the hardware implementation of the QS-SVM-based digital beamformer on the FPGA platform, including quadrature programming solver, weight updating, and SVM inner multiplications, have been rigorously demonstrated in Quadrature Programming Solver: The SVM algorithm allows for estimating a function, which maps the input data to a finite set of output labels [L refers to the loss function.t labels ,6 as disWe have employed the approach of Q-less QR decomposition with a forgetting factor to deploy the QS-SVM-based beamformer on the FPGA hardware. In the preliminary stage, the integral of a continuous function, based on quadrature programming, has been expended in terms of a superposition of the weighted loss function at available data points, as represented in the right-hand sight of Equation . As demon detail ,20. WhenWeight Updating: Parameters of a wireless communication channel have to vary quickly, thereby weight updating should be performed at a higher rate than a statistic scenario. An alternative solution for updating the weight vector consists of directly computing the inverse of the correlation matrix using the MVDR algorithm. The primary goal of the MVDR beamforming technique is to minimize SINR expressed by the following formula [n-th entry of  formula ,22,(23)SVM Inner Product: Hadamard multiplication (or element-wise multiplication) refers to the multiplication of array objects, which includes both of the Hadamard product of Hence, the minimum SINR is achieved by the MVDR beamforming technique when the following conditions are satisfied:essed asw(MVDR)=αThe tree sum with distributed pipelining takes a sequence of tasks in which each sequence includes its own steps and overlaps with other steps with different tasks in the execution time. The practical implementation of synchronizing the pipeline distributions can provide limitations, however performing a parallel merging on trees, as demonstrated in Null steering for undesired signals by replacing nulls of the radiation pattern of the proposed hybrid antenna array in the detected directions of undesired signals. Hence, we can weaken significantly or eliminate undesired signals.Keeping the desired signal unchanged by exerting power with the 0dB level in the detected direction of the desired signal. We should neither strengthen nor weaken the desired signal, due to the following two reasons: (1) since the desired signals may include noise, jamming, interference, and other unwanted signals, any amplification in the desired signal results in magnifying noise and other unwanted signals, and (2) any reduction in the desired signal is not of practical interest.In this section, the proposed architecture for the setup and implementation includes the FPGA board, as the hardware unit, integrated with the MATLAB environment, as the processing unit or software unit. The proposed hybrid antenna array with bowtie elements  has beenThe discussion in the previous section focused on comprehensively demonstrating the deployment and setup of the digital beamformer. In the following section, we aim to evaluate and validate the digital beamformer performance. In this scenario, results-based monitoring allows for providing a framework to assess and evaluate the proposed digital beamformer performance in terms of (1) throughput evaluation, (2) average latency time, and (3) performance efficiency.The Euclidean distance refers to the most well-known distance metric for deep learning as well as the classification process in machine learning. The Euclidean distance metric allows for measuring the distance between paired examples in the high-dimensional feature space. However, the utilization of Euclidean distance results in neither preserving the correlation of pairs nor enhancing the robustness of pairs. To overcome the aforementioned limitations, Tongtong Yuan and his research group in  have rigLatency allows for measuring the average time for processing a fixed-point dataset in different sizes of a batch. In the supervised ML, a batch size refers to the length of the training dataset in each iteration. In an ideal scenario, in which the FPGA integrated with a processor is working at speed, an average latency time is around or below 50 microseconds. The kernel-free classifier of QS-SVM can effectively support non-linearly separable datasets without mapping them to any larger feature space in the DoA estimation. In addition, adding an extra regularizer to the objective function has promoted the capability of the QS-SVM technique for linearly-separable datasets of the DoA estimation. The MVDR beamforming technique is capable of updating weight vectors efficiently, but it has the weak performance innullsteering. We have demonstrated that the nullsteering performance has been strongly improved by performing an additional beamforming technique of LCMV, producing deep nulls with powers less than −10 dB in the directions of the two undesired signals.The configuration of the antenna array, which has been employed for the proposed beamformer, can significantly affect the performance and functionality of the DoA estimation and beamforming techniques. The spatial distribution of the hybrid antenna array in the horizontal and vertical directions and the specific characteristics of its radiation pattern have significantly enhanced its capability in controlling the reception of desired signals. In the following, the software and hardware implementations of the QS-SVM-based beamformer have been fulfilled in the Mathworks’ Simulink visual programming environment and FPGA board, respectively. Details of the hardware implementation on the FPGA board have been fully demonstrated. The proposed optimization techniques incorporated by the hybrid array antenna arrays have resulted in a very strong beamformer with superior capabilities of nullsteering, a high throughput of about 100%, a low average latency, and a high-performance efficiency of more than 90%.


There are 330 million people suffering from cardiovascular diseases (CVD) in China, and two out of every five deaths were due to CVD. CVD has become the main disease burden in China. Vascular health management can detect subclinical vascular diseases such as endothelial dysfunction. Through controlling risk factors, vascular function, such as endothelial function, can be improved and cardiovascular events can be prevented from the upstream. Peking University Shougang hospital is the first practitioner of life-long vascular health management since 2010 in China. The established Beijing Vascular Health Stratification (BVHS) focuses on the comprehensive evaluation of vascular health function and structure and explores the application of information technology and artificial intelligence in vascular health management. The life-long vascular health management and tertiary hospital–primary hospital–family service model guided by BVHS can better realize the prophylaxis of CVD. The prevention and control strategy of CVD based on information technology and vascular health, especially endothelial function management, can help to implement the “healthy China 2030” plan. In this review, we focus on advances in the clinical assessment of vascular endothelial function, including the evaluation of endothelial function, the evaluation of arteriosclerosis, new potential biological markers to provide new possible therapeutic targets, and BVHS, a comprehensive vascular aging assessment system. Strengthening the assessment of cardiovascular health and endothelial function is of great significance for the occurrence of cardiovascular diseases in risk groups and the occurrence of adverse events in patients with cardiovascular diseases. Systemic and pulmonary circulations constitute a complex organ that serves multiple important biological functions. Consequently, any pathological processing affecting the vasculature can have profound systemic ramifications. Endothelial and smooth muscle are the two principal cell types composing blood vessels. Critically, endothelial proliferation and migration are central to the formation and expansion of the vasculature, both during embryonic development and in adult tissues. Endothelial populations are quite heterogeneous and are both vasculature type- and organ-specific. There are profound molecular, functional, and phenotypic differences between the arterial, venular, and capillary endothelial cells and the endothelial cells in different organs. Given this endothelial cell population diversity, it has been challenging to determine the origin of endothelial cells responsible for the angiogenic expansion of the vasculature. Recent technical advances, such as precise cell fate mapping, time-lapse imaging, genome editing, and single-cell RNA sequencing, have shed new light on the role of venous endothelial cells in angiogenesis under both normal and pathological conditions. Emerging data indicate that venous endothelial cells are unique in their ability to serve as the primary source of endothelial cellular mass during both developmental and pathological angiogenesis and CVD management .Prevalent cases of total CVD nearly doubled from 271 million in 1990 to 523 million in 2019, and the number of CVD deaths steadily increased from 12.1 million in 1990, reaching 18.6 million in 2019. The global trends for disability-adjusted life years (DALYs) and years of life lost also increased significantly, and years lived with disability doubled from 17.7 million to 34.4 million over that period -induced Notchl activation upregulated the BMP2-Smad1/5/9 pathway, resulting in cell calcification. Notchl activation also induced the translocation of nuclear factor-kappa B (NF-kappa B) accompanied by OPN overexpression and elevated inflammatory cytokines production. Lp(a) is a potential novel therapeutic target for vascular calcification .Elevated blood homocysteine (Hcy) levels are strongly associated with endothelial dysfunction. Nanoscale selenium inhibits Hcy-induced mitochondrial oxidative damage and apoptosis by inhibiting the downregulation of glutathione peroxidase enzyme 1 and 4  in vascular endothelial cells, and it can serve as a new strategy for the treatment of Hcy-mediated vascular dysfunction .Human umbilical vein endothelial cells (HUVEC) can improve the cell survival, wound healing, migration, and angiogenesis of high-sugar-damaged HUVEC through paracrine signaling, with great potential in repairing diabetic vascular endothelial injury, but more research is needed .The overexpression of miR-145 in an acute coronary syndrome rat model may improve the endothelial injury and abnormal inflammation through targeting FOXO1, suggesting it may be a therapeutic target . MoreoveArteriosclerosis is one of the markers of endothelial dysfunction, not the patent of modern people, as it existed earlier than modern civilization, and its risk factors and traditional risk factors are only part of the influencing factors of arteriosclerosis, and genetic factors also play an important part. Atherosclerosis is essentially age-based and begins after birth and progresses with age. Genes and environment play an important role in the occurrence and development of atherosclerosis, whereby genes create the vulnerability to atherosclerosis, and whether or when clinical atherosclerosis occurs is determined by environmental factors .In 2006, the first application guideline of vascular lesion detection technology in China was released. In 2011, the guideline was updated to add some new detection methods to comprehensively evaluate the structure and function of blood vessels from different aspects, such as biomarkers, imaging indicators, and noninvasive arteriosclerosis evaluation indicators. The comprehensive evaluation system of vascular senescence added the BVHS proposed by us in July 2015 :Grade I is normal: normal structure and function;Grade II is arterial endothelial dysfunction: no radiographically proven atherosclerosis, FMD < 10%;Grade III is arterial stiffness stage: no imaging confirmed atherosclerosis, CF-PWV > 9 m/s, CAVI > 9;The early stage of grade IV is structural vascular disease: atherosclerotic lumen stenosis confirmed by imaging < 50%;Grade IVa: atherosclerotic plaque formation, elastic normal ;Grade IVb: atheromatous plaque formation and decreased elasticity ;Grade V is structural vascular lesions;Grade Va: atherosclerosis, lumen stenosis of 50%~75%, elastic normal ;Grade Vb: atherosclerosis, lumen stenosis of 50%~75%, reduced elasticity ;Advanced stage VI is structural vascular lesions: lumen stenosis > 75% ;Stage VII is a clinical vascular event stage : sudden vascular death, acute coronary syndrome, cerebrovascular accident, and lower limb artery occlusion.BVHS integrates different evaluation and grading strategies, from vascular function to structure and from the early stage to the late stage of disease and carries out individualized intervention and management for people with different grades. Structural and functional indicators of vascular injury, which reflect the long-term cumulative effects of traditional and unidentified cardiovascular risk factors, can be considered as alternative endpoints for target organ injury before and even after clinical vascular events .The BVHS grading standard and its subsequent revision supplement the endothelial function was reflected by the RHI. Based on traditional risk factors, vascular structure and function indicators are combined, and blood vessels are directly used as evaluation targets, and the whole life cycle of the population is graded according to different vascular aging conditions . BVHS haBVHS focuses not only on vascular structural changes, such as stenosis or occlusion, but also on vascular function, such as elasticity and endothelial function, for comprehensive assessment. For people with vascular stenosis, subgroup management was further carried out. For those with vascular stenosis, the arterial elastic function was re-evaluated, and differentiated intervention strategies were adopted according to the elastic function status. Comprehensive evaluation of vascular senescence needs to integrate a variety of reliable vascular detection indicators. Given the focus on vascular structure and vascular function, the risk of cardiovascular and cerebrovascular events in patients with good vascular elasticity was lower. Various vascular structure and function indicators were used to manage vascular health by grades. Intervention strategies were different for different grades of people. No matter whether in clinical application or scientific research, attention should be paid to vascular aging as an evaluation target, and effective intervention measures should be taken before the occurrence of cardiovascular and cerebrovascular diseases. Promote vascular medicine and the management concept of the whole life cycle, and evaluate the health and aging of blood vessels as a whole. Vascular lesions at a certain site may be one of the signals of cardiovascular and cerebrovascular events, so attention should be paid. The application of the new BVHS standard provides different levels of population management and the practical implementation of the precision medicine model.Recently, we carried out the first large-scale multicenter clinical trial, the Endothelial Function Guided Therapy, in patients with nonobstructive coronary artery disease in the world (EndoFIND Study) . The rate, intensity, and long-term compliance of secondary preventive drug therapy, mainly based on the clinical practice of many cardiovascular patients, have always been unsatisfactory. Whether the introduction of noninvasive endothelial function testing into clinical diagnosis and treatment can increase doctors’ and patients’ attention to secondary prevention, thus improving the drug treatment rate, dose, and compliance of secondary prevention, and further reducing the risk of major adverse cardiovascular events, there is still no relevant clinical research evidence. In this study, patients with nonobstructive coronary artery disease were selected as subjects in the multicenter, randomized, blind, parallel controlled, two-stage clinical trial. The first stage was to evaluate whether the intervention significantly increased the prescribing rate of secondary prevention drugs. Phase II will further look at whether interventions can affect the risk of major adverse cardiovascular events based on the results of the phase I trial. Vascular or arterial disease is both the cause and the result. Therefore, effective, early and comprehensive assessment of vascular health status and the degree of vascular disease is of great significance for the occurrence of cardiovascular and cerebrovascular diseases in risk groups and the recurrence of acute adverse events in patients with cardiovascular and cerebrovascular diseases .The Outline of the Healthy China 2030 Programme (the Platform) sets out the goal of achieving the effective control of major health risk factors by 2030. With vascular health management as the focus, people at risk of cardiovascular disease can be identified early and the risk of early intervention can be more conducive to the improvement of risk factors, thus helping to achieve the goal of controlling the main health risk factors.The program aims to study and explore new technologies, methods, and strategies for the prevention and treatment of cardiovascular and cerebrovascular diseases in China based on vascular health management and vascular aging evaluation and information construction. Through the quality and efficient integration of existing health resources, it seeks to explore new types of medical and health service systems in combination with pension modes and implement the cardiovascular disease prevention and control of front moved forward, which will help to achieve “to the highest average life expectancy at 79.0 years old, 2030, a major chronic disease premature mortality 30% lower than in 2015”, the goal of the project.Vascular senescence is the main cause of morbidity and mortality in the elderly population. It is necessary to understand the molecular and functional processes of vascular lesions to explore new effective measures to inhibit abnormal vascular aging. Pathophysiology associated with cellular and molecular mechanisms of the vascular system that accompanies the aging process, including oxidative stress, mitochondrial dysfunction, and molecular stressor response Decreased resistance, development of chronic low-level inflammation, genomic instability, cellular senescence, epigenetic alterations, loss of protein homeostasis, dystrophic induction disorders and stem cell dysfunction. The above-mentioned aging-related changes are the pathological basis of microvascular and macrovascular diseases ,77. It iIn China, the incidence of cardiovascular, brain, and LEAD is still increasing year-by-year, and even in recent years, the trend is becoming younger. Many people without obvious clinical symptoms, or young people who have not been diagnosed with cardiovascular and cerebrovascular diseases, also suffer from adverse cardiovascular events or even sudden death. Facing the severe situation of cardiovascular and cerebrovascular diseases, all health works in China have gradually shifted from focusing on disease treatment to disease prevention, disease rehabilitation, and life-cycle management. At present, there are many clinical studies related to blood vessels in foreign countries, while those in China are mostly basic, lacking large samples of high-quality clinical research data in the field of blood vessels, which needs to be further improved.Diabetes mellitus is associated with endothelial dysfunction that leads to cardiovascular complications. SGLT2 inhibitors improve endothelial dysfunction by increasing NO and vasodilation, reducing inflammation, oxidative stress, and arterial stiffness, improving vascular remodeling, and inhibiting endothelial aging . DistincTraditionally, a single measure of endothelial function has played a role in the management of cardiac and vascular health. Identifying new biomarkers related to cardiac and vascular diseases and applying a more scientific, comprehensive, and prospective cardiovascular health assessment system are of great significance for the early detection and intervention of diseases. The comprehensive assessment of all parameters of endothelial function, including FMD, RHI, PWV, CAVI, AI, genetic factors, and biomarkers, will contribute to full-cycle vascular health management.


Risk factors such as hypertension, diabetes, and aging, contribute to the development of IS, and patients with these risk factors face heavier therapeutic burden and worse prognosis. Microbiota–gut–brain axis describes the crosstalk between the gut flora, intestine, and center nervous system, which conduct homeostatic effects through the bacterial metabolites, the regulation of immune activity, also the contact with enteric nerve ends and vagus nerve. Nowadays, more studies have paid attention to the important roles that microbiota–gut–brain axis played in the risk factors of IS. In the current article, we will review the recent works focusing on the bi-directional impacts of gut dysbiosis and the pathogenic process of IS-related risk factors, for the purpose to summarize some novel findings in this area, and try to understand how probiotics could limit the development of IS  Ischemic stroke (IS) is one of the most common neurologic disorders in industrialized and developing countries  from de-oxygenized cells. DAMPs lead to direct death of neurons, injury of blood–brain barrier, alteration of endocrine system, and overreacted inflammation , and following dampened inhibition of oxidation of butyrate and reduce energy supply of epithelium  is derived from the dietary choline and L-carnitine with assistance of gut microbiota. In this nested case–control study, hypertensive patients with higher level of TMAO had a 34% higher risk of stroke onset, compared to patients with lower level of TMAO -Toll-like receptor 4 (TLR-4) pathway, and the infiltration of Tregs in the vasculature , rostral ventrolateral medulla (RVLM) and nucleus tractus solitaries (NTS), Another mechanism that gut microbiota helps to control hypertension is by changing the pharmacokinetics of antihypertensive drugs. Amlodipine, a member of calcium channel blocker, decreased and its metabolites increased when incubated with human and rat feces, and systemic exposure to amlodipine was elevated in rats treated with antibiotics, suggesting the reduced drug metabolic rate after the damage to normal flora  in the drinking water, successfully reduced the daily food intake of mice. They also found higher expression of genes encoding fatty acid oxidation in the gut microbiome, and reduced infiltration of monocytes/macrophages into liver , thus helps to maintain a normal gut–brain axis  inhibitors like statins are widely used for the treatment of hyperlipidemia. Statin treatment was found associated with lower prevalence of gut dysbiosis identified as lower Bact2 enterotype , led to raised insulin release, and upregulated the gene expression of type-4 glucose transporter. Interestingly, according to some studies, the microbiota composition of the offspring of patients with gestational diabetes was also changed, and early stage oligosaccharide consumption was positively correlated with the abundance of infant Ruminococcus, indicating the existence of a maternal microbial imprinting along glucose intake  and nitric oxide (NO), and the prevention of the reduction of mitochondrial fusion gene expression , Spychala et al. demonstrated increased Lactobacillus and 5 Enterococcus strains was able to prevent leaky gut and inflammation in older mice  had global alterations of gut microbiome, including the overgrowth of Streptococcus was demonstrated in the CE group, while the similar change was not seen in LAA group, compared to normal control. The functional and metabolic changes in patients with CE stroke were studied, for the microbial genes related to membrane transport and glycolipid metabolism showed increase, while the genes related to vitamin and glycan synthesis, as well as amino sugar and nucleotide sugar metabolism  stroke had higher level of TMAO than patients with large artery atherosclerotic (LAA) stroke and healthy controls, suggesting a different metabolism pattern for stroke patients with cardiac origin (Xu et al., Cardiomyopathy predisposes to thrombus formation, and patients with cardiomyopathy had much higher incidences for IS occurrence (Crawford et al., Gut microbiota also contributes to the metabolic process of some cardiac drugs, thus indirectly affecting the process of cardiac disorders and the formation of thrombosis. Erythromycin and tetracycline treatment before and concurrent with digoxin could lead to reduced excretion of digoxin reduction products in urine and stool, followed by a two-fold increase of serum digoxin, which might induce cardiac arrhythmia (Lindenbaum et al., Firmicutes, Rothia and less Prevotella, and Neisseria. Maternal nicotine exposure via lactating showed decreased Bacteroidetes, increased Firmicultes and Actinobacteria in the feces of the offspring, indicating long-lasting effects of nicotine to change offspring's microbiota and eating behavior, which might predict extra calories intake and diabetes/obesity development (Rodrigues et al., Tobacco use contributes to the negative change of the immune system through damage of gut microbiota. Shanahan et al.  discoverNicotine not only causes tissue damage of lung itself, but also further breaks the integrity of intestine. Mis-homing of dendritic cells and T cells from injured lung to the intestinal epithelium, together with extra circulating IL-6, IL-13, and TNF-α, drives cross-organ inflammation (Gui et al., via ENS and the vagus nerve, a healthy gut flora plays essential roles in the homeostatic maintenance in various risk factors of IS. Chronic metabolic diseases like hypertension and diabetes are tightly linked to gut dysbiosis by the reasons of nutrition and lifestyle. Probiotic treatment not only just change the microenvironment that limit the pathologic progress of these risk factors, but also conduct supplementary effect by facilitating the pharmaceutical treatment like calcium channel blocker and statin (all above mechanisms are briefly illustrated in In the current review, we summarized some recent findings relating to the crosstalk between the gut flora, the brain, and the risk factors of IS. Microbiota–gut–brain axis conducts multisystemic modulatory functions to attenuate the negative impacts of these risk factors had on the body. Through the degradation of extra oxidative substances, protection of intestinal epithelium, releasing SCFAs, metabolism of TMAO, inhibition of overwhelming immune injury, and transmission of signals YuL, JD, and YW participated in idea conceptualization. YuL, ZZ, and YiL participated in the preparation of the manuscript. YuL participated in the editing of the manuscripts. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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.


These inequalities may lead to reduced access to appropriate health care services, and consequently, poorer health outcomes. Furthermore, research focusing on health outcomes of racial minorities is vastly lacking. In an effort to address the need for research on racial inequality, eClinicalMedicine launched part 1 of an online collection entitled “Racial Inequity in Health” in June 2021.We have now curated part 2 of the collection, which forms part of The Lancet's strategy to address racial inequity in health care. The papers in this collection highlight racial and ethnic inequality across global healthcare settings, and emphasise that without targeted action, such inequalities are maintained and reinforced. The collection will therefore provide a platform for the dissemination of relevant research on racial disparities in chronic kidney disease (CKD) cardiovascular disease and maternal outcomes, amongst others. This Editorial will discuss several of the papers available in the collection.Health-care systems worldwide are fraught with inequalities that have a disproportionate impact on minoritised ethnic and The Netherlands and the US, respectively. Huisman and colleagues showed that the estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR), which are two parameters used for the classification and prognosis evaluation of CKD, are higher among minoritised ethnic groups compared with individuals of Dutch origin. High eGFR values may precede the development of CKD. The authors suggest that current screening tools based on these parameters may therefore have important limitations in multiethnic populations and a more personalised approach is therefore required. In a similar vein, Tsai and colleagues reported that that removal of race correction from equations used to obtain the eGFR, which systematically inflate the eGFR for Black patients, would increase the percentage of Black patients diagnosed with CKD and those who are referred to specialty care and transplantation in the US.Previous studies have shown that not only is the prevalence of CKD higher in minoritised ethnic groups, but also that it has a faster progression to end-stage renal disease in these patients compared with the majority ethnic group. Two papers in the collection explore racial and ethnic disparities in CKD in cardiovascular death and vascular dysfunction, respectively. Kist and colleagues quantified the sex-specific cardiovascular death rates stratified by ethnicity and socioeconomic factors in an urban population with a universal healthcare system in The Netherlands. Large health disparities in cardiovascular age-standardised death rates were observed across ethnic and socioeconomic subgroups. The authors suggest that the identification of these high-risk subgroups as well as tailored preventative efforts may improve cardiovascular health equity within communities. In another study from The Netherlands, Hayfron-Benjamin and colleagues investigated the associations of three inflammatory biomarkers  with aortic stiffness, coronary artery disease, and peripheral artery disease in different ethnic groups. After adjusting for conventional cardiometabolic risk factors, the authors noted ethnic differences in the associations of low-grade inflammation and vascular dysfunction. This could potentially aid vascular disease prevention, diagnosis, and treatment strategies in different ethnic groups.Ethnicity has been established as an independent risk factor for cardiovascular death, alongside other risk factors such as smoking, age, blood pressure, sex, and hyperlipidaemia. Two further studies in the collection have investigated racial and ethnic disparities in high- low- and middle-income settings. Knight and colleagues described factors associated with women who died in the UK during or up to a year after the end of pregnancy, and compared the quality of care received by women from different ethnic groups to identify any structural or cultural biases or discrimination that affected their care. While the authors found no major differences in the causes of death among women from different ethnic groups, multiple areas of bias were identified in the care women received, including a lack of nuanced care, microaggressions, and differences in clinical, social and cultural factors. In Latin America, Rios-Quituizaca and colleagues showed that Ecuadorian women who self-identified as Indigenous had a lower prevalence of modern contraceptive use, antenatal care, skilled birth attendance, and institutional delivery compared with the majority ethnic group in the country. The authors stress that while gaps in care have recently narrowed, Indigenous people are still subjected to structural racism and can have limited access to health care interventions.In addition to documenting the racial and ethnic inequity in chronic diseases, the collection also demonstrates that such disparities are seen in maternal morbidity and mortality in both As evidenced above, the collection covers a breadth of medical specialties indicating that racial disparities are pervasive throughout the health-care landscape. Furthermore, the studies emphasise that minoritised ethnic groups still bear the brunt of health-care challenges. By assembling these studies in an open-access collection, we hope to empower policy makers and health-care workers to prioritise health inequalities among minoritised ethnic groups at research, clinical, and governmental levels. Commitment and systemic change are required to ensure that the health-care needs of minoritised ethnic and racial groups are met and to overcome the long-standing effects of racism.


The COVID-19 pandemic has caused remarkable psychological overwhelming and an increase in stressors that may trigger suicidal behaviors. However, its impact on the rate of suicidal behaviors has been poorly reported. We conducted a population-based retrospective analysis of all suicidal behaviors attended in healthcare centers of Catalonia  between January 2017 and June 2022 . We retrieved data from this period, including an assessment of suicide risk and individuals’ socioeconomic as well as clinical characteristics. Data were summarized yearly and for the periods before and after the onset of the COVID-19 pandemic in Spain in March 2020. The analysis included 26,458 episodes of suicidal behavior ; of these, 16,414 (62.0%) were suicide attempts. The monthly moving average ranged between 300 and 400 episodes until July 2020, and progressively increased to over 600 episodes monthly. In the postpandemic period, suicidal ideation increased at the expense of suicidal attempts. Cases showed a lower suicide risk; the percentage of females and younger individuals increased, whereas the prevalence of classical risk factors, such as living alone, lacking a family network, and a history of psychiatric diagnosis, decreased. In summary, suicidal behaviors have increased during the COVID-19 pandemic, with more episodes of suicidal ideation without attempts in addition to younger and lower risk profiles. Soon after the first case of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, the virus spread rapidly all around the globe, leading to an unprecedented global health crisis. Aside from the direct effects of coronavirus disease 2019 (COVID-19), the pandemic has had other important impacts derived from the measures implemented for limiting the spread of SARS-CoV-2. These measures, primarily based on quarantines , social distancing, and the banning of gatherings ,4,5. AsiBeing overwhelmed, experiencing disaster, and a sense of isolation are among the triggers of suicidal behaviors, particularly among individuals with underlying mental disorders, such as depression, schizophrenia, or alcohol abuse, among others . In 2019To date, various authors have reported changes in the incidence and lethality of suicidal behaviors associated with the COVID-19 pandemic ,13,14,15This was a retrospective analysis of electronic health records of Catalonia, an area with 7.5 million people in northeast Spain. The Catalan Health Service (CHS) provides public, universal healthcare to the entire population of Catalonia. Exclusive private care is scarcely used, particularly in emergency settings; hence, the CHS holds the majority of the health information of Catalan individuals, and nearly all cases of admissions to emergency rooms. Although information systems are fragmented into various datasets, by hospital, primary care, and mental health, among others, the unique identification numbers used for insurance purposes allow for the integration of information across the entire system. In Catalonia, the COVID-19 pandemic started in early March 2020, and a state of emergency was declared by 14 March 2020, with strict lockdown measures that lasted until 21 June 2020. Measures to contain viral transmission, such as curfews, limited mobility across the territory, social restrictions in public spaces, and mandatory face masks, were applied in the following two years with different degrees of intensity according to the needs of six successive epidemic waves. Measures taken during the first lockdown period reduced healthcare activity, which later recovered. Background information regarding mental health outpatient activity and hospital activity during this period is provided in In 2014, the CHS launched the Suicide Risk Code, a secondary prevention program aimed at reducing mortality due to suicide, increasing survival among individuals attended to because of suicidal behaviors, and preventing repeated suicidal attempts in patients with risk factors . One of The study protocol was approved by the independent ethics committee of the Consortium Corporació Sanitària Parc Taulí of Sabadell, which waived the collection of informed consent for the secondary use of health data collected during routine care . The study was conducted according to the General Data Protection Regulation 2016/679 on data protection and privacy for all individuals within the European Union in addition to the local regulatory framework regarding data protection.The characteristics of suicidal behavior episodes and risk factors recorded at the times of episodes were retrieved from the Suicide Risk Code dataset. The type of suicidal behavior episode was classified as either active suicidal ideation without an attempt or a suicide attempt, defined as engaging in self-directed injury with the specific intent to die. In patients with a suicide attempt, the method used in the attempt was recorded. The following variables were recorded during the visit that triggered an entry in the Suicide Risk Code registry: family history of suicide, severe or painful systemic disease, abuse of alcohol or drugs, recent economic or personal stressors, lack of family or social network, living alone, and recent feelings of hopelessness. We also collected the suicide risk level, rated based on the 6-item suicidality module of the Mini International Neuropsychiatric Interview (MINI). The MINI scale has been validated in relation to the Structured Clinical Interview for DSM-III-R and the Composite International Diagnostic Interview (CIDI) for the International Statistical Classification of Disease (ICD)-10 . The suiThe CHS identification numbers were used to retrieve demographic characteristics  and psychiatric disorders diagnosed before or up to one month following the suicidal behavior episodes, including the following: schizophrenia and schizoaffective disorders, eating disorders, anxiety, depression (including recurrent or persistent mood (affective) disorders), disorders of personality and behavior, sleep disorders, Alzheimer’s disease, and psychoactive substance use. The International Classification of Diseases version 10—Clinical Modification (ICD-10-CM) codes are listed in Finally, we collected data on socioeconomic status based on the pharmaceutical co-payment classification of the CHS, which stratifies the population into four socioeconomic groups based on the pharmaceutical co-payment: very low , low , moderate , and high . During the 2020–2021 period, the criteria for very low and low groups changed to widen the coverage of the very low group; therefore, for the purpose of this work, we grouped these two categories.The progression of suicidal behavior episodes throughout the investigated period was plotted in terms of monthly incidence (observed and moving average). The time series of the observed incidences were decomposed into trend, seasonal, and random components. The moving average, used to smooth out short-term fluctuations in the time series and to highlight longer-term trends and cycles, was calculated as an average value of data points covering 12 months, using a symmetric window with equal weights. The seasonal component was computed by removing the trend component from the time series and averaging, for each time unit, over all periods. The random component was determined by removing the trend and seasonal components from the original time series. The monthly incidence was determined for the entire sample and for age, sex, and socioeconomic groups of interest. Data on the Catalan population were retrieved from the Statistical Institute of Catalonia for incidence estimates . The chaBetween January 2017 and June 2022, the Suicide Risk Code registered 26,458 episodes of suicidal behavior in 21,920 individuals. The monthly rate of suicidal behavior events dropped by to an extreme extent during the two months of nationwide lockdown, and the overall trend remarkably increased afterwards a. OveralThe subgroup analysis according to gender and age confirmed females under 18 years old as the primary contributors to the overall increase in suicidal behaviors in the general population a. The anThe analysis of the underlying social and clinical characteristics of the cases throughout the investigated period revealed an increase in the percentage of younger individuals and females in the years following the onset of the pandemic . AdditioThe average values before and after the onset of the pandemic confirmed the trends observed in the yearly analysis . In bothThe most remarkable change in individual profiles was the lower frequency of mental disorders after the onset of the pandemic, evidenced in all psychiatric diagnoses, particularly in regard to schizophrenia and schizoaffective disorders b. DepresIn this population-based, retrospective analysis of suicidal behaviors among a population of 7.5 million, 21,920 cases of suicidal behavior were identified through the population-based Suicide Risk Code registry between January 2017 and June 2022. In this study population, we found that the COVID-19 crisis led to a remarkable increase in the rate of suicidal behavior episodes, primarily explained by an increase in incidence among young females. The turning point in the trend of suicidal behaviors was pervasive after June 2020, four months after the onset of the outbreak in our country. We also found changes in the profiles of individuals with suicidal behaviors, who presented with a lower prevalence of classical risk factors for suicide and suicidal behaviors, such as alcohol/drug abuse or underlying psychiatric disorders.The overall increase in suicidal behaviors observed in our population is consistent with that described by other authors. Reif-Leonhard et al. found a lower rate of suicide attempts reported at the Frankfurt program to prevent suicides in 2020 compared to 2019 . SimilarThere is a scarcity of studies investigating the impact of COVID-19 on suicidal behaviors that provide information on the characteristics of cases. As in our analysis, Yoshioka et al. observed a shift towards younger and female individuals . HoweverOur study has several limitations that must be considered when interpreting its results. First, our findings should be constrained to the setting of suicidal behaviors, which may not necessarily reflect trend changes in suicide rate or changes in the characteristics of suicide completers during the pandemic. However, since previous suicidal behaviors are one of the strongest risk factors for death by suicide , our finOur population-based, specific assessment of suicidal behaviors in our area provides robust data on the alarming increase in suicidal behaviors within the years following the onset of the COVID-19 pandemic, which continues growing by the end of the investigated period. This increase is primarily explained by a higher incidence of suicidal behaviors among young women. Although we do not know whether these findings are also translated to suicide deaths in our area, the consistency of our results supports actions to be taken to revert this trend. It is worth highlighting that, owing to the younger profiles of the individuals committing suicide, the potential years of life lost due to suicide may overtake those due to COVID-19. The notable gender and socioeconomic effects, as well as the shift in the clinical profiles of individuals with suicidal behaviors, described in our study suggest that policies for preventing suicide in the pandemic and postpandemic contexts should focus on addressing these changes.


Monkeypox, a viral zoonosis caused by an Orthopoxvirus, is clinically characterized by fever, headache, lymphadenopathy, myalgia, rash and burdened by some complications that can be severe and life threatening. Monkeypox, endemic in some central and west African countries, in tropical areas near equator, rose to the headlines following its recent outbreak in non-endemic countries of Europe and the USA. Thus, the World Health Organization, worried about the growing dimension of the problem, declared monkeypox a global public health emergency. Now, after months of careful observation, the western scientific research is drawing conclusion that African endemic countries represent a reserve pool able to feed, through travelers and sexual networks, the outbreak in non-endemic countries in which high-risk communities such as gay and bisexual men are the most affected. Prevention through vaccination and early diagnosis are the core to breaking the chain of diffusion of this epidemic. Particular attention should be paid to avoid the spread from endemic countries, also implementing the economic investments in their public health system. Information campaigns and assistance to high-risk classes in non-endemic countries are important priorities, however, assuming that specific treatments for this disease are still tentative. Monkeypox, a double-stranded DNA virus , has been known to belong to the Orthopoxvirus genus of the Poxviridae family since 1958 when, after two outbreaks of a generalized vesicular-pustular rash illness in colonies of Cynomolgus monkeys, it was identified at the Statens Serum Institute of Copenhagen  , but both have evolved independently of their common ancestor and the possibility of one becoming transformed into the other has been excluded, although they are closely related ,6.The presence of human monkeypox was first ascertained in September 1970 in a 9-month-old child in Basankusu district, on Equateur Region, in the Republic Democratic of the Congo ,9.Clinically, human monkeypox has similar but milder features than those of smallpox; surely it has a different epidemiology . Initial-the rapid spread of the virus to many countries never seen before and the new modes of transmission, largely unknown, meeting the International Health Regulations criteria.-the risk for human health and its potential implication with the international traffic;-the high risk in the European regions and the moderate risk worldwide.Although the WHO in 2018 still considered the monkeypox a rare viral zoonotic disease of remote areas of central and West Africa, near tropical rainforests , on 23 JIn the light of this, to avoid misinformation and unjustified public concern  this revMonkeypox is a rare infectious zoonotic disease which is endemic in central and western Africa areas  that are characterized by high mean annual precipitations and low altitude ,18. FromIn the Democratic Republic of the Congo in 1996–1997 and in 2003, the first outbreaks of human monkeypox have occurred in which it was observed that transmission of monkeypox virus took place from person to person [In particular, during the 1996–1997 epidemic, the interhuman mode of transmission continued for two years in large areas of the Katako-Kombe and Lodja health-care zones [On May 2003 there was the first documented human monkeypox case outside of Africa, in a 3-year-old girl from central Wisconsin in the USA . An inteInterestingly, it was noted that the outbreak occurred in the USA was strictly related to the domestic use of exotic wildlife which pushed the Food and Drug Administration to ban the import of all rodents from Africa and the sale, distribution, transport, and release into the environment of prairie dogs and six African rodent species . HoweverThe analysis of another outbreak of monkeypox that began in South Sudan in 2005, confirmed the role of importation into the area from a place where monkeypox is endemic (the Congo) both through infected animals and humans entering in that area, thus supporting the hypothesis of person-to-person transmission .However, a different epidemiology distinguished the African from the American outbreak.Indeed, in Africa, human monkeypox primarily affected children younger than 10 years (80% of cases) that were part of rural populations (residents of villages of less than 1000 people), and the transmission was both via contact with infected small mammals obtained for food or through infected animal bites and person-to-person contact (28% of cases) with a case fatality ranging from 10% to 17% . In the today, 70% of the world population and 75% of young individual have never received the smallpox vaccine resulting unimmunized against the monkeypox virus;re-emergence of monkeypox in Africa  due to endemicity favored by climate change, rain forest exploitation, geopolitical and armed conflicts, without neglecting the possibility of intrafamilial infections;travel-associated monkeypox (case worldwide).Some conditions make possible the epidemic outbreak of monkeypox ,29,30,31It has become clear that Monkeypox may spread from human to human through close contact with skin lesions or lesions on internal mucosal surfaces, body fluids and respiratory droplets, but cases of airborne transmission were not reported ,33. An iRecently, in the course of the monkeypox epidemic in Nigeria in 2017–2018, the sexual transmission in several patients with genital ulcers was also hypothesized .Travel associated monkeypox was reported in 2018 in men who returned from Nigeria to Israel, Singapore and United Kingdom ,37,38,39They were also the first-time international travelers implicated in the spread of monkeypox outside of an outbreak setting .Coming to the present day, the Democratic Republic of the Congo would be the greatest responsible for epidemic resurgence, with 1356 cases of monkeypox and 64 deaths from January to July 2022 ,42.In the first months of the current year, the sudden appearance of the monkeypox virus in non-endemic areas and the high risk of human-to-human transmission attracted the attention of the scientific and institutional world. This led to increase the amount of research and number of publications on this matter.From January 2022 to June, a great number of cases of monkeypox have been reported also in several non-endemic countries of Europe, in the United Kingdom, USA, ASIA  Australia and Republic of China (Taiwan) .Important research across 16 countries showed that gay or bisexual men represented the 98% of the persons affected by monkeypox, 75% of whom were White, and 41% with human immunodeficiency virus infection .Sexual transmission was re-proposed as an important way of infection precisely because the lesions were mostly located in genital and perianal sites, most patients were men who had had sex with men or multiple sexual partners who travelled to festivals or did not use the condom . The comFurthermore, even in the USA the transmission of monkeypox was prevalent in communities of gay, bisexual, and other men who have sex with men and in racial and ethnic minority groups, as well .Physical contact, sexual transmission in men who have sex with men, or transmission via fomites were the infection routes indicated in a prospective cross-sectional study performed by experienced dermatologists in multiple medical facilities during the monkeypox epidemic in Spain in the 2022 outbreak .Person-to-person transmission of monkeypox within the United Kingdom was also demonstrated in a retrospective observational analysis of patients between May and July 2022 in a south London High Consequence Infectious Diseases Centre .Even in Germany, France and Portugal the analysis of the first monkeypox outbreak showed a clear human-to-human transmission among a susceptible demographic group  ,50,51. AThe absence of connection between the current monkeypox outbreak and travels in the endemic areas strengthens the impression of an undetected spread of monkeypox virus in Europe through human-to-human transmission .Indeed, the hypothesis of a mutation in the monkeypox virus able to explain the recent outbreak worldwide has been denied by the absence of major mutations in the viral genome .Today, it is believed that the community transmission of monkeypox is becoming the main cause of contracting the disease rather than travels to monkeypox-endemic countries ,55.0) ranging from 1.4 to 1.8, but less than 2.13 observed in the monkeypox epidemic in the Democratic Republic of the Congo in 1980–1984 [0 is higher than 1, in high-risk subjects, an expansion of epidemic is expected [An interesting study evaluating the disease transmissibility for the current monkeypox epidemic within populations of men who have sex with men, detected a high reproduction number  was hospitalized and 4% (95% CI 1–9%) had fatal outcomes . No fataAn interesting report highlighted that in the USA most of hospitalized patients with monkeypox were black men with HIV infection of which 21% died despite oral or intravenous tecovirimat administration, vaccinia immune globulin intravenous, intravenous cidofovir and intensive care unit-level care .On the contrary during the current monkeypox epidemic, some studies showed lower percentages of hospitalization than previous reports and no deaths: 6% in France , 8.3% inVarious practical preventive measures should be taken and, among them, interrupting the virus transmission from animals to humans might greatly hamper the monkeypox epidemic from spreading . For exaclose physical contact  with persons affected by monkeypox rash;contact with body fluids of infected animals;bites of infected animals;processed meat from infected animals;become in touch with fomites.However, since as previously said, the human-to-human transmission is the prevalent route during this epidemic, it is essential to avoid :close phContact tracing is a desirable measure to identify exposed persons, isolate them and prevent further cases. However, it should be remembered that previous smallpox vaccination may give false positive results .Since men who had sex with men, bisexual and also ethnic and racial minority groups are affected by monkeypox, the efforts of public health should, rather, be focused on these groups for infection prevention and testing .Furthermore, it would be important to give medical staff any information such as to pay close attention to hand hygiene, ensure a proper cleaning of contaminated surfaces and, in addition, provide them with protective devices for full safety of health  ,67.News on vaccination coverage in Europe are lacking but it is known that there is no substantial difference between European countries in relation to the degree of complete vaccination against smallpox except for UK that has a low coverage [. There are, however, significant differences between zones within the same country which depend on some reasons such as demographic changes and different past vaccination strategies against smallpox [.Due to the cessation of smallpox vaccination for people born after 1980 and the poor immunity to monkeypox in younger individuals who live in non-endemic countries, vaccination program is of special importance in this context to reduce spread and severity of monkeypox disease and break the chain of transmission . News oncoverage . There asmallpox .According to some guidelines, people at risk of monkeypox, especially healthcare workers, should be given vaccinia .The first next-generation smallpox vaccine is Dryvax vaccine administered via skin scarification. It was discontinued as it causes severe side effects such as Stevens-Johnson syndrome, acute vaccinia syndrome  and myocarditis .The second next-generation vaccine is ACAM2000, a single-dose vaccine delivered via skin scarification, requiring four weeks after vaccination to give immune protection . UnfortuBrand name: Imvamune and Imvanex in the European Union and Canada, approved from the European Medicines Agency on 22 July 2022)”, a live but attenuated non-replicating MVA strain [The third next-generation smallpox vaccine is “MVA-BN  epithelial cells and fibroblasts, which follows the spread of extracellular enveloped virions to lymph nodes and finally the viremia that favors the viral spread to other organ systems and, once again, the skin cells [During this period, the virus produces two infectious forms: extracellular enveloped virions and intracellular mature virions. A good protection against the infection depends on the ability of vaccines and antibodies to target these antigens .The pathogenesis of human monkeypox includes an incubation period ranging from 5 to 21 days where some steps occur. in cells ,77,78. DInterestingly, it was hypothesized that this virus can gain access to the central nervous system both via the olfactory epithelium and infected circulatory monocytes/macrophages .Bearing in mind that the clinical presentation of vaccinated and unvaccinated individuals is similar , flu-likThe rash develops on the face and even oral mucosa and then spreads centrifugally to the trunk and extremities having the potential to involve other zones such as the genitalia . The lesThe rash starts with a macular shape which subsequently becomes papular, vesicular, and pustular before crusts are formed ,84.The time period from rash onset to desquamation is between 14–21 days . In this-patients without prodromal period (appearance of rash before the onset of signs and symptoms)-patients with a modest size rash-patients without rash but with anal pain and bleeding-patients with rash present only in the genital or perineal/perianal skin area-patients with rash at different stages of developmentAtypical features have also been reported :-patientInfrequently, complications such as encephalitis, pneumonitis, digestive involvement, ocular diseases leading to loss of visual acuity, kidney injury, skin and soft tissue infections and abscesses may occur over the first 5–28 days of illness  50,86,8,886,87. Babies, children, individuals with underlying immune deficiencies and pregnant women may develop severe disease . There aDeath is a possible event, especially in this latter cluster of people ,84.The diagnosis may be difficult since it may be hard to distinguish Monkeypox from other exanthematous viruses, particularly varicella and variola.The diagnosis of monkeypox takes advantage of clinical and laboratory findings . The cliThe main laboratory test includes the execution of nucleic acid amplification testing, with real time polymerase chain reaction (PCR), of the exudate of the skin lesions, pharyngeal swabs and seminal fluid of the patient ,90. AccoSome laboratory findings are of little help. Although, frequently, hypoalbuminemia, high transaminase levels, low values of blood urea nitrogen can be found .Tests for antigens or antibodies research may also be used to diagnose monkeypox but, due to crossreactivity with other orthopoxviruses, they have low sensitivity and specificity . HoweverThe analysis of cerebrospinal fluid initially may prevalently show a polymorphonuclear pleocytosis, with normal glucose and protein levels. However, within 5–6 days, there may be a change as pleocytosis can become mainly of lymphocytic type ,91.Cerebral Magnetic Resonance imaging may show diffuse edema, meningeal enhancement, and increased signal in the thalamus and parietal cortex on fluid-attenuated inversion recovery sequences, whereas slow waves can be observed on electroencephalogram .Histology is unhelpful due to overlapping histologic features with those of viruses such as herpes , vaccinia and cowpox.Instead, immunohistochemistry permits to distinguish herpes from pox virus. Indeed, monoclonal antibodies are available that may detect orthopox antigen and monkeypox virus .No specific Food and Drug Administration (FDA) approved treatment exists for monkeypox disease, but some recommendations should be followed, especially with the aim to prevent or better manage the development of possible complications .The symptomatic management of fever and respiratory distress, with antipiretics and supplemental oxygen, is desirable where necessary .Encephalitis accompanying monkeypox, depending on symptoms and causes, needs to be treated with intravenous fluids, supplemental oxygen, steroids, antiseizure medicine, antiviral or antibiotics.Secondary bacterial infections  should be treated with empirical oral or parenteral cephalosporins or beta-lactam antibiotics .No FDA approved antivirals exist to treat monkeypox, although tecovirimat is FDA approved for treating smallpox, being able to prevent viral release from cells via inhibition of the viral envelope protein p37. However, even if current studies have not proven the effectiveness of tecovirimat in human monkeypox, a recent report supports the continued recourse to treatment with tecovirimat in the current monkeypox outbreak, also taking into account that it is generally well tolerated . MoreoveAlthough the use of monoclonal antibodies is approved to treat severe cases of monkeypox and subjects affected by T cell lymphopenia, divergent views exist on their safety. Indeed, they are burdened with some problems in the production methods, including the one of being exposed to the risk of contamination with blood-borne infectious agents ,94.COVID-19 epidemic is one of those unexpected and inscrutable events hard to manage since we had to deal with the appearance of a completely new virus capable of causing the death of over 15 million people worldwide .-being an RNA virus, the mechanisms of mutation repair are less effective and allow the formation of new more contagious strains more easily-the easy dissemination to animals in which new and more dangerous mutations may occur that make the COVID-19 even more difficult to combat once it is reintroduced in mankind-the possibility that it can be transmitted to others during the incubation period of the infected subject-the airborne transmission through aerosol inhalation-the ease of contagion between people-after healing from the acute phase, the prolongation of the disease in a chronic phase .-the possible increased risk of developing over the years other diseases .Some features have made COVID-19 very insidious, such as ,96,97:-bThe availability of vaccines and drugs, as well as the acquired immunity among people allowed to reduce the number of deaths to more acceptable levels. However, uncertainty remains on the possible new appearance of a COVID strain resistant to human immune system.At present, this makes it difficult to see the definitive outcome of this pandemic phase until a new vaccine can provide protection against all potential COVID strains.Human monkeypox, previously classified as a rare zoonotic disease, raised awareness within the worldwide public health because of its rapid growth in non-endemic nations in which it may possibly create life threatening situations ,98 depenAccording to some researchers, during the current outbreak, the isolated clade of monkeypox could cause in the majority of cases a mild self-limiting disease, whereas only some of them were hospitalized, mainly for pain . HoweverThe lack of resources, diagnostic equipment (adequate laboratory infrastructure), procedures (weak disease surveillance systems) and adequate knowledge of this disease in African countries, with the result of not having uniform health controls of people, (as it was in the most developed countries) was also crucial to favor the worldwide transmission through the international traffic .A few months ago, the WHO expressed serious concern regarding the epidemiological situation in Europe, classifying it to be at high risk due to the spreading of the monkeypox in 30 European countries, where it infected more than 6000 subjects . From JaHowever, the latest reports of the WHO show that the total number of monkeypox cases reported in the European regions and in the Americas it is decreasing, with the American regions that continue to hold the highest cumulative proportion of monkeypox cases reported globally .In order to better contain the expansion of the monkeypox outbreak preventing it from continuing to spread throughout the world, early recognition planning screening protocols adapted to local settings, prompt that isolation and immediate hygiene measures should be adopted without hesitation in endemic countries.Moreover, the vaccination should be recommended as it is considered to be an effective countermeasure to break the chain of transmission and/or to prevent the serious form of the disease .Indeed, previous trials demonstrated that smallpox vaccine is highly effective in preventing monkeypox disease, not losing efficacy also after a few years by protecting subjects against the occurrence of a severe illness ,103.It is of fundamental importance to implement the investments in public health of endemic African countries and launch information campaign to promote appropriate health behaviors that may help stop the disease.To this purpose, it is crucial to prioritize high-risk populations, such as communities of men who have sexual contact with a new or multiple male partners. Due to their intense relations also through sexual networks, these communities represent the most affected category in this epidemic in non-endemic countries ,105. The


The anatomy of the cortico-bulbar tract that drives voluntary movements of mimic muscles is well described. Some cases of facial palsy with inverse automatic-voluntary dissociation  are reported in the literature. These cases suggested a completely independent path of the fibers whose lesion results in EFP. We aimed to review the clinical reports of EFP available in the literature to characterize the anatomical aspect of the fibers whose lesion results in the isolated impairment of spontaneous smiling. Cortico-pontine fibers that control spontaneous smiling arise from the medial surface of the prefrontal cortex and descend through the anterior limb of the internal capsule, thalamus, and brain steam, independently from those that control voluntary movement. The mesial temporal lobe, particularly the amygdala, plays a crucial role in the network driving emotionally evoked facial expressions. We would highlight the relevance of an unusual and rarely explored neurological sign that could be added to clinical examination in ruling out focal brain pathology, such as stroke, tumors, or multiple sclerosis. Emotional facial paresis (EFP) is a rare condition characterized by the weakness of emotionally evoked facial movements. The clinical picture consists of a supranuclear hemifacial paresis exclusively in spontaneous smiling (inverse automatic-voluntary dissociation) .Automatic-voluntary dissociation has been widely reported in stroke patients with damage to different motor areas . LesionsThese findings suggest an independent “limbic” pathway that mediates emotionally evoked facial movements.Patients with ischemic damage involving the midcingulate cortex can make a voluntary smile, whereas they show the weakness of emotionally evoked facial movements. The emotional movements are controlled by the continuous inhibition of the voluntary motor centers, probably through the pyramidal fibers . When a Here, we aimed to review the clinical reports of EFP available in the literature to characterize the anatomical aspect of the fibers whose lesion results in the isolated impairment of spontaneous smiling.EFP is often described as a sign of anterolateral thalamic infarction, secondarily to tubero-thalamic artery ischemia . More raMoreover, lesions in deep frontal white matter, most tumors, sparing medial frontal cortex and thalamus result in EFP. The anterior and posterior parts of the thalamus are connected with the basal-temporal and frontal portion of the brain, and the presented clinical evidence suggests that these connections belong to the network that mediates emotionally evocated facial expression.Trosch and colleagues  reportedFurthermore, the EFP was found in the presence of brainstem lesions, even though more rarely –9. TumorClassically, a rostral lesion in the center of the upper pons causes a contralateral facial  supranuclear paresis, whereas the ipsilateral paresis of the infranuclear type derives from lesions of the inferolateral pons (VII nucleus).Terao  and collCurrier has suggested that the facial corticobulbar tract fibers leave the pyramidal tract at the pontomedullary junction and descend caudally, crossing to the opposite facial nucleus at the middle medullary level . The intTherefore, the typical supranuclear facial paresis  could be associated with the involvement of these descending pathways. Conversely, the involvement of the ascending fibers could be associated with central facial palsy homolateral to the side of the lesion.In this regard, the only available report that described EFP due to lower brainstem lesion reported a case of EFP due to infarct in the territory of the anteroinferior cerebellar artery homolateral to the facial deficit . The autFurther, the results of Terao  and collThe occurrence of an ipsilaterally EFP and an ischemic lesion in the territory of the lower anterior cerebellar artery, as in the case of Khurana and colleagues , may be In conclusion, cortico-pontine fibers that control spontaneous smiling arise from the medial surface of the prefrontal cortex and descend through the anterior limb of the internal capsule, thalamus, and brain steam, independently from those that control voluntary movement. The mesial temporal lobe, particularly the amygdala, plays a crucial role in the network driving emotionally evoked facial expressions. Therefore, EFP should be considered an unusual and rarely explored neurological sign that could be added to clinical examination in ruling out focal brain pathology, such as stroke, tumors, or multiple sclerosis.