The larynx is an organ of the upper airway that participates in breathing, glutition, voice production, and airway protection. These complex functions depend on vocal fold (VF) movement, facilitated in turn by the action of the intrinsic laryngeal muscles (ILM). The necessary precise and near-instantaneous modulation of each ILM contraction relies on proprioceptive innervation of the larynx. Dysfunctional laryngeal proprioception likely contributes to disorders such as laryngeal dystonia, dysphagia, vocal fold paresis, and paralysis. While the proprioceptive system in skeletal muscle derived from somites is well described, the proprioceptive circuitry that governs head and neck structures such as VF has not been so well characterized. For over two centuries, researchers have investigated the question of whether canonical proprioceptive organs, muscle spindles, and Golgi tendon organs, exist in the ILM, with variable findings. The present work is a state-of-the-art review of the peripheral component of laryngeal proprioception, including current knowledge of canonical and possible alternative proprioceptive circuitry elements in the larynx. Posteriorly the intermediate layer of the lamina propria attaches to the vocal process of the arytenoid via a tendon-like structure  to the lower respiratory tract . In humans, these muscles are the thyroarytenoid muscle (TA), lateral cricoarytenoid, posterior cricoarytenoid, interarytenoid, and cricothyroid muscles . Other sThe larynx is innervated primarily by two nerves, the superior (SLN) and the recurrent laryngeal nerve RLN; . Both coAdapted to the tasks of the VF, the ILM is among the fastest contracting muscles yet require near instantaneous, constant adjustment  and Golgi tendon organs (GTO), provide sensory input. MuSp are embedded in the muscle body while GTO are found in muscle tendons. MuSp and GTO collect information about muscle length and tension. This information is relayed to the central nervous system by afferent Group Ia, Ib, and II sensory nerve fibers. Subsequently, the efferent arm is activated with alpha motor neurons activating muscle movement while gamma motor neurons set the gain of the MuSp  in the ILM is unclear. In particular, despite exploration since the 1960s, evidence of laryngeal MuSp remains controversial .In the 1960s electrophysiological studies posited the presence of mechanoreceptors within the ILM. Most of these studies were performed in cats where investigators recorded afferent discharges of the SLN and RLN in the setting of various stimuli to the VF and surrounding laryngeal structures  and immunohistochemistry of the ILM to visualize the proprioceptive organs. These studies have been performed across multiple species including human, dog, nonhuman primates, and guinea pig. These studies have specifically focused on identifying MuSp and demonstrated interspecies and intraspecies variation regarding whether MuSp exist in the ILM. For instance, investigators have reported histological evidence of MuSp in the ILM of humans, guinea pigs, and marmosets, but not in the ILM of dogs Keene, .There is particular controversy over MuSp in the human ILM. Specifically, studies have yielded conflicting findings regarding whether MuSp exist and in what distribution. The most studied of the ILM is the TA. The history of this investigation through 1998 is expertly described by Sanders et al Extraocular muscles: MuSp are present in the extraocular muscles of some mammals  yet absent in others Facial mimetic muscles and the superior pharyngeal constrictor: MuSp have been identified in neither the facial mimetic muscles nor the superior pharyngeal constrictor (Stål et al., The human larynx contains three paired encapsulated joints: the cricothyroid, cricoarytenoid, and arytenocorniculate joints (McHanwell, Studies investigating the source of sensory innervation to the laryngeal joints show the encapsulated joints receive input from the internal branch of the SLN, and the cricothyroid joint may also receive input from the RLN (Kirchner and Wyke, Many afferent receptors are present in the laryngeal mucosa (Adzaku and Wyke, Mechanoreceptors are not uniformly distributed throughout the laryngeal mucosa and are focused in and around the vibratory and mobile elements of the larynx. Electrophysiological studies in cats and rabbits demonstrate that mechanoreceptors are concentrated in the laryngeal mucosa in the glottal area above and below the vocal folds. Some are sensitive to vibration from the VF and others to changes in pressure from airflow (Sampson and Eyzaguirre, Authors also find evidence these mucosal receptors play a role in the laryngeal adductor response. Specifically, Andreatta et al. show that mucosal mechanoreceptors play an important role in the laryngeal adductor response, which is diminished when the larynx is stripped of mucosa (Mårtensson, The study of laryngeal proprioception is fragmented in method and species. Nevertheless, a few unifying conclusions can be drawn from the current knowledge. First, canonical proprioceptive organs are rarely expressed in the ILM, aside from the interarytenoid muscle. Second, this is consistent with the finding that other cranial muscles, such as extraocular and facial mimetic muscles, lack MuSp but demonstrate evidence of non-canonical proprioceptive organs. Third, given the lack of canonical elements in ILM, an alternative proprioceptive mechanism may govern the coordination of laryngeal movement, and this requires further study.IH-M and VY: conceptualization, formal analysis, and writing—original draft. IH-M, VY, and MP: writing—review and editing. IH-M: visualization. MP: supervision, project administration, and funding acquisition. All authors contributed to the article and approved the submitted version.


Lung transplantation has a high risk of haemodynamic complications in a highly vulnerable patient population. The effects on the cardiovascular system of the various underlying end-stage lung diseases also contribute to this risk. Following a literature review and based on our own experience, this review article summarises the current trends and their evidence for intraoperative circulatory support in lung transplantation. Identifiable and partly modifiable risk factors are mentioned and corresponding strategies for treatment are discussed. The approach of first identifying risk factors and then developing an adjusted strategy is presented as the ERSAS (early risk stratification and strategy) concept. Typical haemodynamic complications discussed here include right ventricular failure, diastolic dysfunction caused by left ventricular deconditioning, and reperfusion injury to the transplanted lung. Pre- and intra-operatively detectable risk factors for the occurrence of haemodynamic complications are rare, and the therapeutic strategies applied differ considerably between centres. However, all the mentioned risk factors and treatment strategies can be integrated into clinical treatment algorithms and can influence patient outcome in terms of both mortality and morbidity. Since it was first performed in 1963, lung transplantation has remained a multidisciplinary challenge, especially in the intraoperative setting ,3,4. ThuIrrespective of the clearly differing approaches to circulatory support between individual lung transplant centres, it can make sense to develop strategies for the management of lung transplantation on a patient-specific basis, depending on the risk for certain pathologies, and to define them at an early stage of treatment. Such an approach, for example within the framework of so-called ERSAS concepts (early risk stratification and strategy), aims at identifying possible risk factors for the occurrence of complications and the corresponding strategies and therapies to avoid these complications . This isThis review article therefore aims to summarise the current trends of non-mechanical and mechanical circulatory support (MCS) during lung transplantation in an accentuated manner and to reflect the current status of the respective evidence. Focusing on the exemplary but also frequent complications of right ventricular failure (RVF), impairment of left ventricular function (left ventricular failure (LVF)) and RI, the pathophysiology, frequency of occurrence, and known risk factors are first discussed ,13. ThisIn the context of lung transplantation, the occurrence of various haemodynamic complications is possible. These include RVF, LVF, or left ventricular diastolic dysfunction and RI associated with reperfusion oedema, increased pulmonary vascular resistance, and sterile inflammation ,12,15.For none of these entities is there currently a validated scoring system for risk stratification, as is established, for example, in the preoperative risk assessments for the occurrence of cardiac complications in perioperative medicine ,17. ThisThe following sections therefore focus on the risk factors that are associated with the occurrence of the respective complications, regardless of chosen therapy strategies see .In general, RVF is associated with decreased cardiac output and increased right ventricular filling pressures due to systolic or diastolic dysfunction. In the setting of lung transplantation, pulmonary hypertension is the most important cause of RVF. Other causes, such as pulmonary embolism, myocardial ischaemia, or secondary RVF in left heart failure, are more secondary ,21.In patients scheduled for lung transplantation, the incidence of PAH is up to 40–50% . In abouPathophysiologically, right heart failure is characterised by dilatation and remodelling of the right ventricle (RV), triggered by an increased right ventricular afterload. Changes in ventricular geometry towards a spherical shape, with displacement of the interventricular septum towards the left ventricle, increased wall stress, and reduced myocardial contractility, are also consequences of the increase in afterload and contribute to the reduction in cardiac output (CO). The decrease in CO is exacerbated by tricuspid regurgitation with corresponding regurgitation volume. Due to reduced left ventricular (LV) filling, ventricular dyssynchrony, and septal kinetic disturbances, the LV is also affected. In advanced stages, end-organ damage such as renal failure, hepatic failure, and intestinal motility disorders can be observed ,21. The Predicting the occurrence of acute or acute-on-chronic right heart failure in the setting of lung transplantation is challenging. To our knowledge, no prediction scores exist. Based purely on the intraoperative course of lung transplantation, exacerbation or recurrence of right heart failure is to be expected, primarily before reperfusion of the transplanted lung. Especially in patients with intermediate or severe PAH, immediate positive haemodynamic effects are seen after transplantation. Systolic PAP, mean PAP, and right ventricular end-diastolic volume rapidly decrease. Patients who do not experience these effects are at increased risk for primary graft dysfunction and worse outcomes . Given tIn summary, no clear specific parameters exist to predict RVF during lung transplantation. Patients at particular risk appear to be those who already have severe or intermediate pulmonary hypertension, have pulmonary fibrosis, or do not show recovery of right ventricular function after transplantation.In 2021, the international consensus recommendations for anaesthesiologic and intensive care management in lung transplantation were published . It was The previously described frequent right ventricular dysfunction in patients with chronic lung disease who are scheduled for transplantation results in a decreased left ventricular preload. If prolonged, this results in atrophy of left ventricular cardiomyocytes, which may be associated with both diastolic dysfunction and a reduction in myocardial contractility . This alPorteous et al. investigated the relationship between diastolic left ventricular dysfunction and primary graft dysfunction (PGD) . For theFor the risk stratification of patients, not only the right ventricular but also the left ventricular function should be assessed, especially regarding diastolic dysfunction, already at the time of listing and preoperatively. The diastolic dysfunction can be excellently detected by echocardiography and also monitored intra- and post-operatively ,31.A specific evaluation of this pathology is not mentioned in the international recommendations. A cardiac assessment according to the recommendations of the American College of Cardiology (ACC) and the European Society of Cardiology (ESC) is recommended. This generally advises echocardiographic examinations including assessment of diastolic function in high-risk interventions and patients with evidence of clinically relevant cardiac disease, which includes the patient population in lung transplantation ,16,17.Post lung transplant oedema was described early as a complication after transplantation . There i2 during reperfusion, need for transfusion, and use of the heart-lung machine are noted to increase the risk for RI as intraoperative factors [Risk factors for the occurrence of RI with PGD and thus also reperfusion oedema can be divided into donor- and recipient-related factors. Nicotine abuse was found to be the most important donor risk factor. In addition, pre-mortem hypoxaemia, hypotension, aspiration, and prolonged mechanical ventilation are also known risk factors. Race, gender, and age also play a role. Recipient body mass index (BMI) and size mismatch are two of the most important receiver-related risk factors. In addition, high FiO factors .The consensus-based recommendations highlight the role of anaesthesiologists in the perioperative setting to avoid PGD, including reperfusion oedema. A general identification of modifiable risk factors that may influence the outcome after lung transplantation is recommended. Specific assessments for the identification of risk factors for PGD are not mentioned .In general, the strategy chosen for perioperative care in lung transplant patients varies greatly between the centres performing the operation. This is the result of an international survey conducted by Subramaniam et al. . In our Intraoperative monitoring is the basis of every patient care strategy. New problems are detected and can be diagnosed. This section will focus on those aspects of monitoring that are relevant to circulatory support. Monitoring of anaesthesia depth, bronchoscopy, muscle relaxation, etc., are not included.pO2), and central venous pressure (CVP). Due to the frequent use of VA ECMO, cannulation of the right radial artery or the right brachial artery is recommended for this purpose [2) could play a role, as a reduction in cerebral blood flow can occur in the case of accidentally low CO2 levels under VA ECMO and mechanical ventilation. Especially in patients with permanently shifted CO2 partial pressures and chronic hypoxaemia, such as in advanced COPD, pathological changes in the autoregulation of cerebral blood flow are discussed [In principle, extended haemodynamic monitoring is recommended for the performance of lung transplantation. This includes an invasive blood pressure measurement in addition to the electrocardiogram (ECG), peripheral oxygen saturation  is another important component for assessing haemodynamics. It is one of the few types of monitoring that usually also allow a direct diagnosis of the underlying disease ,50. ThisNon-mechanical circulatory support can be divided into three main aspects: modulation of preload, myocardial contractility, and afterload.In the perioperative care of patients undergoing high-risk interventions, there are various possibilities to enable targeted volume therapy. The assessment of the indication and the necessary amount for correct volume therapy can vary greatly between anaesthetists. Therefore, target-based treatment algorithms are generally recommended . In prinVarious classes of drugs exist to increase the myocardial contractility. Among the typically used catecholamines, which exert their effect through the stimulation of ß-receptors, no drug could be shown to be clearly superior ,59. EvenTo avoid systemic hypotension and the associated inadequate filling of the left ventricle in RVF, norepinephrine and vasopressin are the drugs of choice when used in the correct dose . VasopreInhaled nitric oxide (iNO) or prostacyclin are commonly used to reduce right ventricular afterload . IntraveOriginally, CPB was used for mechanical circulatory support during lung transplantation . In receIn view of the positive effects of ECMO as compared to CPB and the pathophysiological consideration of gradually adapting the deconditioned left ventricle to normal CO values, strategies have also been described for using VA ECMO in 100% of cases of lung transplantation. Hoetzenecker et al. were able to achieve the lowest rates of PGD after lung transplantation to date with this regimen ,8. Here,The question of the ideal cannulation strategy cannot be answered so simply. Of course, this has to be based on the patient’s individual requirements. Classically, an attempt is made to establish peripheral cannulation via the femoral vessels. The advantages here are the low invasiveness and easy removal. However, there are also disadvantages of this access. Perfusion of the leg is limited or must be ensured by an additional cannula in the femoral artery. If the oxygenation capacity of the perfused lung is limited, there is a risk of cerebral oxygen deficiency in the context of the occurrence of an ECMO watershed . This caOverall, the use of VA ECMO is superior to CPB in most cases. Especially in severely pre-diseased patients, the use of VA ECMO is more advantageous as compared to a CPB approach or even non-mechanical circulatory support. However, this also requires a consistent ECMO weaning programme and concept to prevent long ventilation times and longer ICU stays.This article summarises potential options for intraoperative circulatory support in lung transplantation. We have reviewed risk factors for three exemplary but frequent haemodynamic complications as well as possibilities for all types of circulatory support.Pre-existing intermediate and severe PAH and idiopathic pulmonary fibrosis are particular risk factors for the occurrence of RVF preoperatively ,12,85. IAfter recognising risk factors , it is crucial to develop an appropriate therapeutic strategy for the best possible circulatory support with the least complications. The consensus-based recommendations for anaesthesiologic and intensive care management in lung transplantation emphasise the role of the anaesthesiologist as an integral member of the multidisciplinary team caring for those patients. After appropriate screening for risk factors related to very different complications, jointly developed management is also recommended .Assessment of sufficiency of non-mechanical circulatory support is crucial in the perioperative phase. Using various monitoring methods, it is important to avoid both hyper- and hypo-volaemia . The meaUltimately, the question must be asked whether the implementation of an early risk stratification and strategy (ERSAS, see In this context, the data from an international survey on lung transplant management are interesting . Here, lFinally, only selected literature can be reproduced in such an article. Thus, selection bias and centre-based views are notable limitations. The quantity and quality of data on the management of lung transplantation are also limited by the small number of performing centres and the rarity of the procedure.


Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is increasingly recognized as the consequence of a pathological reparative response of the developing lung to both antenatal and postnatal injury. According to this view, the pathogenesis of BPD is multifactorial and heterogeneous with different patterns of antenatal stress (endotypes) that combine with varying postnatal insults and might distinctively damage the development of airways, lung parenchyma, interstitium, lymphatic system, and pulmonary vasculature. This results in different clinical phenotypes of BPD. There is no clear consensus on which are the endotypes of prematurity but the combination of clinical information with placental and bacteriological data enables the identification of two main pathways leading to birth before 32 weeks of gestation: (1) infection/inflammation and (2) dysfunctional placentation. Regarding BPD phenotypes, the following have been proposed: parenchymal, peripheral airway, central airway, interstitial, congestive, vascular, and mixed phenotype. In line with the approach of personalized medicine, endotyping prematurity and phenotyping BPD will facilitate the design of more targeted therapeutic and prognostic approaches. Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is one of the most common complications of very and extremely preterm births ,2,3,4,5.BPD is increasingly recognized as the consequence of a pathological reparative response of the developing lung to both antenatal and postnatal injury ,4. PreclThe evolution of perinatal care over the past few decades has affected premature birth and its complications, including BPD. When BPD was first described by Northway in 1967 , the maiAdvances of prenatal and neonatal care, such as antenatal corticosteroids , surfactDuring the past decade, less invasive forms of non-invasive respiratory support have been implemented for preterm infants . These dAlthough trying to take into consideration the changing times, all the BPD definitions that have been coined over the years are hampered by several pitfalls. The major limitation is the fact that all definitions are based on the need for a therapy  instead of on etiopathogenesis. Moreover, oxygen therapy is highly inconsistent among institutions and even clinicians. The lack of standardization of saturation targets, especially in ex-preterm infants approaching corrected term ,20, resuBesides the poor ability in providing reliable rates of the disease, oxygen need at 36 weeks PMA may not predict long-term outcomes. The need for ventilatory support has been proposed as a better way to correctly foresee death or severe respiratory morbidity regardless of the supplemental oxygen use . Among iAside from the type of support chosen to define BPD and its severity, the time point at diagnosis is another unsolved issue. Isayama et al. explored different time-points to diagnose BPD and predict respiratory outcomes . The neeThe term endotype refers to “a subtype of a condition, which is defined by a distinct functional or pathophysiological mechanism.” . EndotypThere is no clear consensus on which are the endotypes of prematurity but the combination of clinical information with placental and bacteriological data enables the identification of two main pathways leading to birth before 32 weeks of gestation: (1) infection/inflammation and (2) dysfunctional placentation. The first group include chorioamnionitis, pre-labor premature rupture of membranes, placental abruption, and cervical insufficiency . The secThe environment to which the developing lung is exposed varies greatly between the two endotypes of prematurity. The possible mechanisms by which infection and dysfunctional placentation can interfere with lung development have been extensively explored in preclinical studies ,35,36. AUreaplasma spp. has received particular attention. Ureaplasma infection of the developing lung has been studied primarily in sheep and non-human primates [Ureaplasma [Ureaplasma urealyticum led to severe bronchiolitis and interstitial pneumonitis in fetal baboons [Ureaplasma pulmonary colonization demonstrated early improvement in lung function [Ureaplasma parvum increased surfactant production but induced a mild acute inflammatory response that altered lung deposition of elastin and α-smooth muscle actin [Ureaplasma can modulate the innate immune system and prime the immature lung to be more vulnerable to inflammatory stimuli after birth [Among the prenatal infectious/inflammatory stimuli, the one mediated by primates ,43,44. I baboons . Interesfunction . ExposurRegarding placental dysfunction, it has been suggested that both the fetal lung and the placenta have similar responses to alterations in the intrauterine environment ,45. ThisAlthough it is a common understanding among neonatologists that the pathophysiological condition triggering preterm birth plays a major role in the clinical picture and the development of complications, a persistent conundrum is which part of these complications are due to prematurity and which part are due to the pathological changes induced by the endotype. Comparing how different pathological conditions affect the same outcome can provide insight into the relationship between endotype and phenotype.Very recently, we conducted two meta-analyses on the association between endotypes of prematurity and BPD ,48. In tOur studies also confirmed that key factors for the development of BPD are distributed differently in the chorioamnionitis, HDP, and SGA/IUGR groups ,48. WhenTaken together, the data from these two meta-analyses suggest that chorioamnionitis  has a greater overall impact on the risk of developing BPD as it is the most frequent endotype in the lower and more vulnerable GA . HoweverIn addition to differences in GA, our meta-analyses also showed that chorioamnionitis was associated with higher rates of antenatal corticosteroids  and thatBPD is an umbrella term that may encompass different forms of lung injury, caused by various mechanisms and characterized by specific molecular pathways. These mechanisms may affect, in a relatively specific way, airways, alveoli, vessels, interstitiums, and lymphatic systems , giving The approach to BPD classification according to the phenotype hypothesis may carry important clinical consequences. Future BPD classifications, according to the endotypes and phenotypes of the disease, may guide specific diagnostic approaches and consequent plausible treatments. Below is a tentative description of the BPD phenotypes that may require tailored approaches during either the evolving or the established phase of the condition . This deThe parenchymal phenotype of BPD is mainly characterized by the arrest of development in the alveolar portion of the lung, which results in larger and fewer alveoli and reduced alveolar surface area leading to impaired gas exchange . These fThe small airways component of BPD, consisting of structural remodeling, bronchoconstriction, and hyperreactivity, manifests similarly to asthma . HoweverTracheomalacia, subglottic stenosis, bronchomalacia, and bronchial stenosis are the clinical manifestations of the central airway diseases phenotype of BPD . CentralInterstitial disorders, such as an increase in fibrotic tissue and widening of the interstitial spaces, are frequently observed in ex-preterm infants suffering from BPD and undergoing lung biopsy during childhood ,87. ThisInfants with BPD are prone to pulmonary edema, presumably due to immature and inadequate pulmonary lymphatic drainage. Pulmonary edema may be exacerbated by the presence of a patent ductus arteriosus with left to right shunt or by inflammation resulting in capillary leak . ExcessiThe vascular hallmark of BPD is a dysmorphic capillary bed with dysregulation of pulmonary vascular development characterized by vascular growth arrest, reduced distribution of pulmonary capillaries, and altered pattern of vascular organization ,98,99. ARetrospective studies show that late pulmonary hypertension may occur in up to 17–43% of infants with BPD ,103,104 During pulmonary development, there is a constant interaction between the different lung compartments. The most conspicuous example is the interaction between the processes of alveologenesis and vasculogenesis ,112. In Changing the approach from a definition based on signs and symptoms to a causal definition of BPD, based on the chain of events that underlie the disease, would substantially change the way BPD is diagnosed . MoreoveThe field probably demands a composite assessment so that the predictive ability of a definition is reasonable, cost-effective, and easy to use. Easily available biomarkers and bedside testing combined with safe, non-invasive, radiation-free, accessible instrumental tools are needed to account for BPD phenotypes longitudinally from birth into further childhood. Point of care markers such as pro-BNP have been used in the assessment of the progression of pulmonary hypertension, although they may be influenced by other variables such as PDA . The impA phenotype-based definition of BPD should take into account the different pathophysiological pathways and may lead to more specific treatments that not only decrease symptoms, but also change the course of the disease . The posInfants with a predominant small airway BPD phenotype may have variable responses to bronchodilator and anti-inflammatory drugs, depending on the degree of fixed and reactive components of airway obstruction. Infants with a parenchymal emphysematous phenotype, who are unlikely to respond to bronchodilator therapies, as well as infants with a fixed small airways component of BPD may be candidates for future trials investigating novel therapies. The possibility of an early distinction between these phenotypes would allow the early start of anti-inflammatory or bronchodilator therapy . In addiInfants suffering from pulmonary hypertension associated to BPD  often present with recurrent cyanotic episodes, have prolonged initial hospital admissions, and require extra oxygen supplement or higher levels of respiratory support even after discharge compared with infants with isolated BPD . In the www.clinicaltrials.gov (accessed on 11 April 2022), we found that only four of the 91 ongoing studies referred to a BPD phenotype. This was always the vascular phenotype represented by BPD-associated pulmonary hypertension. Similarly, of the approximately 80 studies on BPD completed in the last 10 years, only five took into account a possible phenotype, which was again the vascular phenotype.Classification and definition of prematurity endotypes and BPD phenotypes may improve the design of clinical and translational studies . This woIn addition, the connection between endotypes of prematurity and phenotypes of BPD should also be investigated in the preclinical setting. The most frequently used animal models of BPD are based on the hyperoxic insult ,116. TheCOVID-19 is generally a mild disease in children. However, a proportion of infants that test positive for SARS-CoV-2 require admission to the hospital . Among hBesides the effect of the viral infection on patients with BPD, the changes in lifestyle pose these infants at high risk for a worsening of their condition and quality of life. The fear of contagion can influence infants’ life in many ways. Patients with chronic lung disease will be at particular risk considering that they may experience stigmas related to their respiratory symptoms such as chronic cough and being at risk of isolation by their peers . MoreoveClassifying and defining the endotypes of extreme prematurity and the phenotypes of BPD requires the close collaboration of obstetricians, neonatologists, pulmonologists, cardiologists, radiologists, pathologists, and epidemiologists. All this collaborative knowledge should result in a tailored approach to BPD diagnosis and therapy. In order to achieve this objective, it is also necessary to develop machine learning algorithms and artificial intelligence technologies that are capable of bringing together clinical, functional, imaging, and biomarker data.


In recent decades, accumulating evidence has shown that the biomechanical traits of fibrosis play important roles in cardiac fibrosis initiation, progression and treatment. In this review, we summarize the four main distinct biomechanical traits  and categorize them into two different types , mainly consulting the unique characteristic of the heart. Moreover, we also provide a comprehensive overview of the effect of different biomechanical traits on cardiac fibrosis, their transduction mechanisms, and  Cardiac fibrosis, also known as myocardial fibrosis, is a common pathology in cardiovascular disease, whose mortality has been regarded as the leading cause of death globally and attracted considerable attention . Cardiacin vivo   exceeds ECM is a common meshwork structure that is an important organizer of cell microenvironment. Structural features of the ECM can have profound effects on cell behaviors, which are closely related to the performances and functions of tissues. Cardiac ECM mainly consists of fibrillar collagen, fibronectin, glycosaminoglycans, and proteoglycans, which together provide a stabilized structure and viscoelasticity for cells. Pore size and density of cardiac ECM structure determine the available space and provide a physically confined microenvironment for cell growth . FollowiThe ECM architecture can be rapidly and profoundly regulated by cross-linking reactions enzymatically or non-enzymatically, which can further alter cellular responses and drive disease progression. Collagen cross-linking is a main factor that influences collagen deposition and insolubility of ECM architecture . FirstlyCell microenvironment regulates cellular mechanical responses by providing reaction forces to balance intracellular traction. The change of cell microenvironment will lead to the change of association mode and binding strength between cell-cell and cell-ECM, and thus change the cell function and phenotype  D'Urso . The inc2+ in cardiac cells  channels enable cells to convert mechanical signals into chemical signals to accommodate the microarchitecture of the fibrous collagen matrix through myosin contractility during myocardial remodeling . Componeac cells . The accfibrosis , for exafibrosis . Anotherfibrosis . Integrifibrosis .1R) and Smad7 , has recently been identified as a key molecular during cardiovascular fibrosis and tissue stiffening  or three-dimension (3D) to study the specific mechanism during the progression of cardiac fibrosis. These models can provide strong support for the studies of prevention and treatment of cardiac fibrosis .in vitro models are widely used to study the mechanism of cardiac fibrosis, as well as drug screening. Recently, the role of matrix stiffness in inducing myofibroblast activation can be studied by culturing cardiac fibroblasts with mechanically adjustable gelatin hydrogels  signals, thus promoting cardiac fibrosis  to construct biomimetic 3D s models . For exas models . This coin vitro cardiac fibrosis models can better simulate natural myocardial tissue in vivo, and also can better mimic complex interactions of cell-cell and cell-ECM, complex mechanical traits and chemical signals  and ignored the changes in viscosity, which adversely affect the understanding of the mechanism of cardiac fibrosis. Noteworthy, for the whole heart, the myocardial tissue is arranged in a spiral shape relative to the ventricular axis, and the forces on cells in different parts of the ventricular wall are anisotropic. The biomechanical behaviors of cardiac tissues at the macroscale are tightly coupled with cellular activities at the microscale, such as cardiac cell perception of external physical signals and subsequent dynamic regulation of cell-ECM interactions downstream of mechanotransduction events . Moreovein vitro simulating the process of fibrosis have been a crucial support for the study of effective anti-fibrosis therapy (in vitro may help to explore specific drugs for treating fibrosis. For example, in vitro models have broad prospects in studying the physiological and pathological mechanisms of cardiac fibrosis, as well as screening pro-fibrotic and anti-fibrotic drugs. Maybe we can have deeper research on the physiology and pathology of cardiac fibrosis and other diseases in the human body in the future.Despite the remarkable progress so far, the comprehensive mechano-regulatory mechanisms of cardiac fibrosis remain elusive, which creates a great need to study cardiac fibrosis further. And finding effective anti-fibrosis therapy will make a significant contribution to the treatment of cardiac fibrosis as well as countless other fibrotic diseases. Because the cardiovascular system is constantly subjected to mechanical forces, increasing researchers have been taking the impact of changes in cardiac biomechanics on cardiac fibrosis seriously . Cardiac therapy , simulatUnderstanding the origin and consequences of the biomechanical characteristics of cardiac fibrosis is a key principle that is critical to improving treatment. Many of the concepts involved are non-intuitive and require a deep and broad understanding of the characteristics and biomechanics of fibrosis. In conclusion, the complexity of biomechanics in the cardiac fibrosis microenvironments requires further exploration using groundbreaking technologies for the exquisite recapitulation of mechanical crosstalk during fibrosis progression and prediction. We believe understanding these dynamic and static biomechanical traits should pave the way for effective anti-fibrosis strategies for clinical therapy.


Cooperative perception, as a critical technology of intelligent connected vehicles, aims to use wireless communication technology to interact and fuse environmental information obtained by edge nodes with local perception information, which can improve vehicle perception accuracy, reduce latency, and eliminate perception blind spots. It has become a current research hotspot. Based on the analysis of the related literature on the Internet of vehicles (IoV), this paper summarizes the multi-sensor information fusion method, information sharing strategy, and communication technology of autonomous driving cooperative perception technology in the IoV environment. Firstly, cooperative perception information fusion methods, such as image fusion, point cloud fusion, and image–point cloud fusion, are summarized and compared according to the approaches of sensor information fusion. Secondly, recent research on communication technology and the sharing strategies of cooperative perception technology is summarized and analyzed in detail. Simultaneously, combined with the practical application of V2X, the influence of network communication performance on cooperative perception is analyzed, considering factors such as latency, packet loss rate, and channel congestion, and the existing research methods are discussed. Finally, based on the summary and analysis of the above studies, future research issues on cooperative perception are proposed, and the development trend of cooperative perception technology is forecast to help researchers in this field quickly understand the research status, hotspots, and prospects of cooperative perception technology. Autonomous driving technology means that the vehicle utilizes sensors to collect information about its surroundings and process it in real-time to gain a better understanding of it. At the same time, the combination of location and mapping, path planning, decision-making, and vehicle control modules enables autonomous vehicles to drive on the road safely and efficiently without anyone taking over . The impInsufficient environmental perception information. The perception module of autonomous vehicles primarily relies on numerous onboard sensors, such as LiDAR, cameras, millimeter-wave radar, etc. . HoweverIt is difficult for in-vehicle computing systems to process a large amount of multisource heterogeneous sensor data in real-time. There is no unified format for various sensor data types, and the fusion processing is complicated. In addition, for the object recognition network of an RGB camera, if the image resolution is 320 × 320 KB and the frequency of generating data is 50 Hz, the amount of data, in this case, will reach 14 MB/S . The curThe Society of Automotive Engineers (SAE) introduced the J3016 “Levels of Driving Automation” standard for consumers. The J3016 standard defines the six distinct levels of driving automation, including level 0 (no driving automation), level 1 (driver assistance), level 2 , level 3 , level 4 (high driving automation), and level 5 (full driving automation) [In order to make up for the insufficiency of autonomous driving perception capability and data calculation above level 3, advanced sensing technology, edge computing, communication, and other technologies need to be combined to build an autonomous driving cooperative perception system in the IoV environment, enhancing perception accuracy, improving the perception range, and reducing delay. Furthermore, this will provide more accurate and rich environmental information for autonomous vehicles in real-time and lay the foundation for the realization of autonomous driving above level 3 ,11. SimuIn the entire IoV cooperative perception system, this mainly includes the fusion, processing, and sharing of cooperative perception data. Among these, the multi-sensor information fusion method, information sharing strategies, and communication technology are the keys to realizing the cooperative perception of autonomous driving in the IoV environment. Multi-sensor information fusion is a prerequisite for cooperative perception. Compared to single-vehicle information fusion, cooperative perception multi-sensor fusion in the IoV environment has more abundant information sources, wider viewing angles, stronger adaptability, and can achieve higher perception accuracy and range ,12. MachThe paper is organized as follows. Some breakthroughs have been made in the research of autonomous vehicle multi-sensor fusion methods, including image fusion, point cloud fusion, and image–point cloud fusion ,16,17,18From the perspective of vehicle–road cooperative perception information fusion, this section summarizes the existing research on image fusion, point cloud fusion, and image–point cloud information fusion at different locations and from multiple perspectives. This section also briefly summarizes its existing challenges. Research on cooperative perception based on image information in the IoV environment started early and is relatively mature because the images have the advantages of high resolution and a good target classification effect, the research and applications of visual sensors are older, and the price is cheap. Image data is a common type of shared data between autonomous vehicles and other perception nodes.The amount of raw video data collected by the camera is large among all kinds of environmental perception information, and the transmission of each video frame will cause the network to be overloaded, increase the transmission latency, and affect the timeliness of cooperative perception. In order to reduce the heavy network load caused by the amount of data, traditional image compression , deep leIn addition, many scholars have studied the existing image fusion strategies for limitations and blind spots in the perceived field of view and range. Xiao et al.  used a dThe fusion of point cloud data from various angles and viewpoints has distinct advantages over the fusion of picture data in terms of the perception of the surrounding environment. LiDAR has the advantages of high spatial resolution, a wide detection range, and little influence from light. It plays an important role in the application of target recognition, ranging, and positioning in autonomous driving. This subsection describes and evaluates the available research in accordance with data-level, feature-level, and decision-level fusion categories  and focuData-level fusion research started early, with high precision but a large amount of data. This fusion method does not require any preprocessing of the data, and the heterogeneity of different data processing algorithms will not affect the accuracy of data being shared between vehicles. Chen et al.  were theFeature-level fusion refers to extracting feature information from original data and then performing fusion, which is currently the most studied and widely used fusion method, considering that the original point cloud data sharing will be limited by the bandwidth and delay of the wireless communication network. Based on a previous study , Chen etDecision-level fusion refers to extracting the detected objects from each individual sensor and fusing the detection results. The fusion speed is fast and it is more suitable for data sharing, but there are few studies on it at present. Arnold et al.  proposedIn short, the multi-sensor data fusion method has a great impact on the timeliness and accuracy of cooperative perception. For example, sharing the original point cloud data has high sensing accuracy, but it will increase the detection time and transmission load, which cannot meet the low-latency requirements of cooperative perception. However, sharing the processed point cloud data can reduce the data transmission time, but the perceived accuracy will be reduced. Therefore, balancing the accuracy and real-time performance of perception is crucial to the effectiveness of cooperative perception. Single-modal multi-sensor data fusion is always limited by intrinsic and extrinsic conditions. For example, the camera has a difficult time detecting the target depth information and is greatly affected by adverse weather and light. LiDAR has poor perception effects, low resolution, and a high cost for long-distance small targets. Millimeter-wave radars have strong antijamming capabilities but low resolution and a limited field of view. This subsection summarizes and analyzes the current sensor data fusion methods and challenges for single-vehicle autonomous driving ,36 and pImage–point cloud information fusion is the mainstream method of autonomous driving cooperative perception in the current IoV environment. Common fusion methods include data fusion estimation methods, based on the Kalman filter; the Bayesian-based distributed fusion method; and the neural network-based method . Jiang eIn addition, some studies have compared the perception effects of different sensor combinations and found that the data fusion of cameras and LiDARs has richer environmental information and better target detection performance. However, due to the difference in the number of wire bundles and the detection distance, the amount of environmental information data collected by LiDAR is very different, which will have a certain negative impact on the timeliness of cooperative perception and the accuracy of target recognition. Satio et al.  proposedIn addition, the spatial and temporal alignment of sensors is a prerequisite for information fusion in the sensor information fusion process. Spatial alignment considers the coordinate transformation of the targets of sensor data from different sources. In contrast, temporal alignment mainly focuses on how to solve the problem of the time difference between sensing information collected from edge nodes and received by other vehicles. Spatial alignment is often based on a constant turn rate and acceleration motion model. Temporal alignment typically transforms object coordinates using unscented transformations. Based on these two key problems, research on spatial and temporal alignment in multi-sensor fusion is equally important ,56,57. ABased on the existing literature, this section summarizes the current research status of cooperative perception technology for autonomous driving in the IoV environment from the perspective of cooperative perception information fusion methods, focusing on summarizing image fusion, point cloud fusion, and image–point cloud fusion methods. By comparison, we found that the fusion of image point clouds under multimodality and multi-view perspectives is the best method for cooperative perception  between vehicles and edge nodes requires a certain bandwidth and has strict delay constraints, which sets higher requirements for network performance. Vehicle mobility and market penetration have a great negative impact on cooperative perception effectiveness and network communication quality. In addition, a reasonable CPM-sharing strategy is also very important, which defines how often vehicles share perception data and which perception data to share. Therefore, reasonable network communication technology and sharing strategies are necessary. Usually, it is necessary to select an appropriate communication network and set a reasonable sharing strategy according to different communication and traffic scenarios.Currently, there are two main V2X communication technologies, including dedicated short-range communication (DSRC) and cellular vehicle-to-everything (C-V2X) . Among tOne of the keys to enabling wireless communication technology standards designed specifically for vehicular communication is DSRC . The DSRC-V2X was standardized by the 3rd Generation Partnership Project (3GPP), which includes long-term evolution (LTE)-V2X and 5G-V2X (NR) technologies and is gradually enhanced through the evolution stages shown in At present, there are obvious limitations for a single V2X technology to achieve efficient and reliable cooperative perception in the IoV environment, such as the insufficient penetration rate of smart devices, network switching caused by vehicle mobility, and limited network bandwidth. To this end, some researchers have proposed that a hybrid solution using DSRC and C-V2X technology is more feasible for actual deployment at this stage, as shown in In practical application scenarios, to solve the problems of high network transmission latency and reduced reliability in cases of highspeed vehicle driving, Zhu et al.  proposedAt present, the penetration rate of intelligent networked vehicles is low, and the deployment of intelligent equipment and infrastructure construction still need continuous efforts. Therefore, market penetration is an important factor that cannot be ignored for synergistic perception effects and communication quality. When the penetration rate is too low, the communication link supporting data transmission may be unstable due to the distance, and it may even be difficult to match a suitable edge node. Radovan et al.  analyzedWang et al.  analyzedTo sum up, the cooperative perception sharing network is crucial for improving the perception capability of intelligent connected vehicles. The deployment and application testing of wireless communication technology at this stage have achieved preliminary results. Vehicle mobility and market penetration have a great impact on the effectiveness of cooperative perception and the quality of network communication at this stage. When the penetration rate is too low, the communication link supporting data transmission may be unstable due to the distance, and it may even be difficult to match a suitable edge node. At the same time, the problems of high network transmission delay and reduced reliability caused by highspeed vehicles are also the focus of our attention.The cooperative perception information-sharing strategy plays a key role in alleviating network load and enhancing the cooperative perception effect. If the cooperative sensing information is shared too frequently, the wireless channel will be overburdened, resulting in channel congestion. It will lead to the perception information age being too old, reducing the accuracy of perception. Similarly, sharing all sensory data will result in information redundancy, leading to wasted computing and communication resources. If part of the perception information is shared, the perception will be incomplete, and the accuracy and integrity of the perception will be reduced. Therefore, a reasonable sharing strategy is particularly important for autonomous driving cooperative perception, including how often vehicles share perception data, which perception data to share, and the format of the shared data.Its absolute position has changed by more than 4 m since the last time its information was included in a CPM.Its absolute speed has changed by more than 0.5 m/s since the last time its information was included in a CPM.The last time the detected object was included in a CPM was one or more seconds ago.For research on perception information-sharing strategy, the ETSI recently approved a technical report, which is the first proposal to standardize the CPM and the CPM generation rules . The CPMThandavarayan et al. ,85 compaTo undertake cooperative perception comparisons and investigate the relationship between communication bandwidth and the amount of transmitted data, Kim et al.  used rawFurthermore, many scholars define CPM-sharing strategies according to the value of CPM ,89. HiguWith the continuous development of intelligent roadside equipment, the interaction of information between the vehicle and the roadside is equally important to enhance the cooperative perception effect. The RSU is usually located in a fixed location and supports the deployment of edge computing devices, so it can better support the perception data processing capability of autonomous driving. By analyzing the advantages and applications of existing V2I communication systems, Malik et al.  pointed The realization of cooperative perception relies on the interaction between V2X communication and the perception information of the surrounding environment, which will significantly increase the amount of information exchanged by vehicles. At the same time, problems such as unstable communication quality and channel congestion are prone to occur in the process of information exchange, resulting in a series of negative effects such as high transmission latency and packet loss, which reduce the effectiveness of cooperative perception. In fact, the loss and latency of data packets in the real driving environment are inevitable, and cooperative perception also often uses latency and PLR as evaluation indicators for the application of cooperative perception technology. We compare the impact of PLR, latency, and channel congestion on cooperative perception in this subsection, summarizing and analyzing relevant research in recent years.Latency in V2X cooperative perception includes task offloading latency, data fusion calculation latency, and result feedback latency. The size of the computing task, the bandwidth of the wireless channel, and the computing power of the edge server or mobile device all have a certain impact on latency.The PLR is the ratio of the data packets lost by the target node to the data packets sent by the application layer of the source node. Data integrity is very important for the effectiveness of cooperative perception in the process of data transmission. In fact, under the interference of multiple factors, such as unfavorable weather, illumination, and communication quality, it is difficult to avoid the loss of perception data during transmission. If the data loss is serious, it will reduce the reliability of perception results and even lead to the failure of cooperative perception.The decentralized congestion control (DCC) mainly focuses on solving the problem of channel congestion in cooperative perception information sharing and improving the timeliness and accuracy of cooperative perception information. Currently, DCC technology mainly reduces the congestion of the communication channel by adjusting the generation strategy of cooperative sensing information and controlling the transmission parameters. Among these, adjusting the generation strategy of cooperative perception information mainly reduces the redundancy of cooperative perception information by optimizing the message generation rules. The most common control parameters are transmission rate control, transmission power, and transmission data rate control .The safety-critical application of autonomous driving has strict constraints on the delay, and the time interval delay between the generation and transmission of cooperative perception cannot exceed 100 ms . The proXu et al.  used perIn addition, the performance of V2X communication is highly affected by the communication load, and high channel load levels increase the risk of packet collisions. The vehicle network integrates congestion control algorithms to control the channel load and avoid congestion, mainly including reactive and adaptive methods . These pSepulcre et al.  first exTo sum up, the share network and information-sharing strategies are key elements in realizing the cooperative perception of autonomous driving in the environment of the IoV. In terms of network communication, DSRC and C-V2X are the key communication methods to realize the cooperative perception of the IoV environment. At this stage, the hybrid network architecture of DSRC and C-V2X can be used to support the diversified needs of IoV applications. Advanced vehicle applications requiring high reliability, low latency, and high throughput will be better supported as communication technology continues to enhance. For the cooperative perception information-sharing strategy, the generation and design of cooperative perception information are further optimized according to the importance and relevance of CPM through the analysis and improvement of standard CPM rules. In addition, factors such as traffic flow, market penetration, communication distance, etc. may cause a series of negative effects, such as long transmission times of cooperative perception information, packet loss, and channel congestion, reducing the effectiveness of cooperative perception. At present, the evaluation indicators of the effectiveness of communication technology and sharing strategies for cooperative perception have not been perfected. In the future, the impact of vehicle mobility and market penetration on communication performance should be fully considered, and a more reasonable CPM-sharing strategy and a more complete evaluation system should be designed.Autonomous driving cooperative perception technology in the IoV environment greatly solves the current problems of single autonomous vehicles, such as limited perception range and the perception of blind spots. At the same time, the transmission delay is reduced through a new generation of wireless communication technology to ensure the end-to-end timeliness of autonomous driving, from perception to decision-making. However, the particularities of autonomous driving and the maturity of communication technology still pose many problems for cooperative perception. Combined with the existing research and analysis on cooperative perception technology and communication technology, this section further proposes research trends and problems to be solved in V2X and autonomous driving cooperative perception.The existing image–image, point cloud–point cloud, and image–point cloud perception information fusion methods coexist, and it has been found that multimodal and multi-view image–point cloud fusion cooperative perception is best. The stages of information fusion and sharing are different, which have an important impact on computing speed and perception accuracy. The fusion of processed data can reduce the amount of transmitted data and significantly reduce the network communication load while the fusion of raw sensor data has a better cooperative perception effect, but it will increase the communication burden and has a certain negative impact on the cooperative perception results. Therefore, under the premise of ensuring the performance of target detection, the transmission of low-value data should be reduced as much as possible, and the accuracy and real-time performance of cooperative perception results should be improved. In addition, the dataset construction of vehicle–road collaboration will be a key factor to ensure the research and evaluation of vehicle–road cooperation algorithms.Most of the existing cooperative perception information-sharing strategies are implemented in the form of broadcasting . As oppoThe communication resources of the vehicle network are very precious, so it is necessary to carry out reasonable task scheduling and resource allocation to the edge nodes. Through the reasonable optimization of the CPM-sharing strategy, the information in the area of interest of the vehicle is selectively shared, and the redundancy of data is minimized under the requirements of timeliness and accuracy. At the same time, the deployment of reasonable network technology will effectively reduce the waste of communication resources and realize the sharing of perception information between autonomous vehicles under the constraints of limited communication resources according to different traffic flow, environmental complexity, and vehicle dynamics. Therefore, a reasonable information-sharing strategy will be the focus of future research on cooperative perception.The mobility of vehicles is a major problem in the cooperative perception between edge nodes and autonomous vehicles. The highspeed movement of vehicles will lead to the fast movement of communication nodes, frequent changes in network topology, and unstable communication link times, resulting in the frequent connection and disconnection of communication links. Eventually, the link established between V2I and V2V fails, causing the transmission of communication and computing tasks to fail. Secondly, the rapid movement of vehicles will cause rapid changes in the surrounding environment, resulting in varying degrees of interference in the communication between edge nodes and autonomous vehicles. This leads to changes in data transmission efficiency and transmission quality, the degradation of communication quality, and difficulty in ensuring data integrity. In addition, the mission will fail if the vehicle is out of communication range while data uploading or message reception is in progress. At present, the communication quality problem caused by vehicle mobility cannot be effectively avoided. However, the interference of vehicle mobility on communication quality should be minimized to ensure the effectiveness and timeliness of cooperative perception. Zhu et al.  considerThe mobility of edge nodes and the dynamics of network topology bring new challenges to the security and confidentiality of vehicle networks. Cooperative perception in the IoV environment mainly solves the information interaction between edge nodes and autonomous vehicles. However, edge nodes, including vehicles, RSUs, and edge servers, are deployed in a distributed manner, resulting in low single-point protection capabilities and attacks by malicious users. When a malicious node sends false environmental information to other vehicles, it sends a large number of computing tasks to the RSU to occupy computing resources and network bandwidth, and the autonomous vehicle that receives the computing tasks will not execute them. The reliability of network services will be destroyed, and the safety of autonomous vehicles will be greatly threatened. Therefore, the realization of autonomous driving cooperative perception in the IoV environment not only needs to consider the trust issue between nodes but also needs to pay attention to the security of the system network. For example, Zhang et al.  used ellCooperative perception technology in the IoV environment plays a crucial role in solving the problems of limited perception range and insufficient computing resources for autonomous vehicles, and through wireless communication technology, it further guarantees the real-time requirements of autonomous driving. This paper introduces the current cooperative perception information fusion methods and cooperative perception information-sharing strategies and sorts out the research methods of cooperative perception information in the process of data transmission under unstable communication conditions. Combined with existing research results, we found that future research on cooperative perception technology should focus on more complex fusion algorithm designs, lightweight models, and V2X applications supported by 5G communication technology. In addition, there are still severe challenges to grasping the balance point of perception–communication–fusion, improving the perception performance of autonomous driving by cooperative perception, and realizing the optimization and balance between V2I and V2V. This paper summarizes the research ideas and analysis methods through a review of the research on autonomous driving cooperative perception in the IoV environment, helping researchers in this field quickly understand the research status of autonomous driving cooperative perception technology in the IoV environment and providing future research directions.


African Swine Fever (ASF) is a contagious viral disease of domestic and wild pigs, listed as notifiable by the World Organization for Animal Health (OIE). It causes substantial economic losses to pig farming in the affected countries, with consequent enormous damage to livestock production due to mortality of the animals, and to the restrictions on national and international trade in pigs and derivative products that the presence of the infection implies. To prevent or reduce the risk of ASF introduction, the World Trade Organization (WTO) and the OIE recommend preventive and control measures, such as the ban of live swine and their products traded from ASF-affected to ASF-free countries or zones. The current spread of ASF into Europe poses a serious risk to the industrialized and small-scale pig sector, as demonstrated by observed cases in different EU areas. In this paper the authors discuss the impact of the COVID-19 pandemic on ASF, and the indirect effects including the impact on animal health and disease management. They suggest that the COVID-19 pandemic has severely affected animal disease surveillance control. ASF requires rapid responses and continuous monitoring to identify outbreaks and prevent their spread, and both aspects may have been greatly reduced during the COVID-19 pandemic. African Swine Fever (ASF) is a contagious hemorrhagic viral disease of domestic and wild swine, causing substantial economic losses to pig farming in the affected countries. ASF can be transmitted either via direct animal contact with infected animals (wild or domestic swine), via ingestion of contaminated food , or through indirect contact with fomites  or soft ticks bites . The movEarly detection, prevention, and reporting are crucial to controlling the disease. The prevention in countries free of the disease depends on: the application of appropriate import policies (ensuring that neither infected live pigs nor pork products are introduced into areas free of ASF); strict biosecurity measures ; and improved husbandry practices and production systems.The current spread of ASF in the European Union (EU) and its recent incursion into some areas of Italy, Poland and Slovakia constitutes a serious risk to EU pig producers. To combat the risks associated with the spread of the disease in a proactive manner, EU areas affected by this disease are listed as restricted zones. Based on the current epidemiological situation of ASF in the Union, new restricted zones of a sufficient size are defined, such as for Poland and Slovakia, as laid down in Regulation (EU) 2022/136 [Based on the current situation in EU countries, the objective of this paper was to analyze if and how the COVID-19 pandemic has had an indirect impact on the spread of ASF in the EU.ASF is not considered a new disease; in fact, it has been around for decades and has made its way to several continents, including Europe . In 1978During the COVID-19 pandemic, which broke out in December 2019, an increased incidence of African swine fever cases was observed. A summary of the ASF situation by world region during the COVID-19 pandemic (2020–2022) is reported in The EU area affected by ASF has progressively expanded since 2019 and so far, several countries continue to be affected. The EU Animal Disease Information System (ADIS) that is administered by the European Commission documents the situation of important infectious animal diseases in each EU country, and shows that ASF cases in wild boar specifically have been on a steep increase.Data demonstrate that during 2020 in Europe 11,027 infected wild boar were found . More reThe most outbreaks were observed in Poland (521), followed by Germany (254), Bulgaria (201), and Romania (180). Additionally, cases were registered in January in Bulgaria, Estonia, Hungary, Italy, Latvia, Lithuania, Slovakia, and Ukraine. Relating to outbreaks among domestic pigs, Romania accounts for 63, Serbia for 11, Bulgaria for 2, and Republic of North Macedonia, Italy, Moldova, Slovakia and Ukraine for 1 each.Relating to outbreaks of ASF in domestic pigs, cases have not increased .The situation varies between the member states, due to the structure of domestic pig production , and also geographical conditions and the characteristics of the wild boar population.Although Italy was free from ASF, excluding the island of Sardinia where the disease (ASF genotype 1) has been endemic since 1978 as abovementioned, new outbreaks have recently been reported. At the start of January 2022, the first case of ASF genotype 2 was found in a wild boar carcass in the Municipality of Ovada  in northern Italy. That case was confirmed by the National Reference Center for Swine Fever of the Experimental Zooprophylactic Institute of Umbria and Marche. Further cases were found in neighboring areas, in the province of Genoa (Liguria Region) and in Alessandria (Piedmont Region). Accordingly, the Ministry invited regions of Piedmont and Liguria to suspend hunting in all municipalities falling within the infected area, and it gave regions 30 days to implement a series of measures to contain and eradicate the disease. In the southern region of Campania, preparations are also underway for the protection of native breeds such as black Casertana pigs.This situation confirms that ASF continues to spread in several countries with serious impacts on the pig production system, animal health and welfare, as well as on national food safety and international trade.Pulmonary infection (COVID-19) caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged with the first cases in China in late 2019 and was declared a global pandemic on 11 March 2020 by the World Health Organization’, has disrupted the social fabric and lifestyle causing severe repercussions on health systems and the global economy. However, the COVID-19 pandemic may have affected several aspects of the entry pathways for ASFV into ASF-free countries. Since December 2019, ASF has continued to spread to new areas because of the diffusive nature of the virus. This further spread may have been facilitated by difficulties in animal disease prevention and control due to the various lockdowns of COVID-19. Measures taken to mitigate the pandemic have restricted the movement of people, causing an indirect economic crisis. The latter, exacerbated by a high demand for laboratory supplies for human COVID-19 diagnosis and research, probably also affected the ability of veterinary laboratories to fulfill their mandates. In addition, official international reporting of the ASF may have been disrupted due to logistical issues and constraints faced by countries. Timely and accurate reporting allows the prevention of ASFV entry from affected areas. Thus, a lack of knowledge about the health status of animals in some areas may have increased the risk of virus entry through legally imported swine products/subproducts. In contrast, the risk of entry should be reduced considering that the COVID-19 pandemic negatively affected the global meat trade with a decline in meat imports and a decrease in meat prices. Similarly, the risk of ASFV entry through smuggling pork in passenger luggage may have decreased due to the reduction in the number of people traveling. However, the number of import/export inspectors has decreased worldwide, so border controls may have been compromised. Restrictions at ports and borders, curfews, and limitations on social distance have led to reduced quality, productivity, and competitiveness in key productive sectors. Restrictions have hit the livestock sector hard by disrupting the feed supply chain, reducing livestock services, limiting animal health services including delays in disease diagnosis and treatment, limiting access to markets and consumers, and reducing labor force participation. In summary, the closures and restrictions on local and international trade triggered by the COVID-19 have affected food production, animal production, and animal health and welfare ,15.ASF is a major crisis due to its high mortality rate, affecting rural and swine industries worldwide. Therefore, in 2019, the Food and Agriculture Organization (FAO) and OIE declared ASF a global priority. As a result, these entities included ASF in the Global Framework for the Progressive Control of Transboundary Animal Diseases (GF-TAD) to resist massive disease burdens, especially at the onset of the COVID-19 pandemic. ASF has had a significant impact on affected countries’ livestock producers, communities, and economies. At the same time, it induces trade restrictions due to the lack of approved treatments or vaccines. As a result of this restriction, the depopulation of all affected and exposed pig farms remains the only means of preventing the disease. During the pandemic, restrictive regulations and closures have worsened trade and consumption in the swine industries. Many industries, particularly those related to pharmaceutical manufacturing and grain markets, were adversely affected by ASF disease even before the emergence of COVID-19. However, the trade and day-to-day operations of these sectors deteriorated during the COVID-19 pandemic for several reasons: global efforts to prevent the disease postponed more than 30% of their field activities and measures; the ability of veterinary services to detect the disease early decreased because of movement and trade restrictions between regions; and the focus of many health care professionals shifted away from PSA to help combat COVID-19. Thus, fewer precautions and protective measures have been employed and adhered to.Additional emerging infectious disease outbreaks are a significant concern, as the medical, diagnostic, and supply infrastructure has been severely stressed by the urgent needs of these two pandemics. National veterinary and animal health services have assisted in the diagnosis of SARS-CoV-2, severely limiting the ability to diagnose zoonotic and endemic diseases in animals. Thus, an outbreak may go undiagnosed or be underdiagnosed, hampering control efforts. Highlighting the reality of this risk, avian influenza outbreaks were reported in Australia, Taiwan, Hungary, Poland, and the United States during COVID-19. In the literature, it has been reported that changes in human behavior during the pandemic led to a record number of salmonella outbreaks (from backyard chicken farming) and a fear of increased cases of Lyme disease (attributed to increased outdoor activities amidst a climate pattern that favors tick populations) . Social Limiting movement, an effective measure to prevent transmission of COVID-19, affected activities related to animal health and disease management of farm animals. Some of the veterinary activities, such as prophylactic disease controls, provided their services by working at a reduced intensity, or were suppressed during the pandemic. This, combined with increased wildlife–livestock contacts and longer livestock stays on farms, resulted in an impact on the spread and incidence of communicable animal diseases . In factThe COVID-19 pandemic has inevitably had a lasting impact on both people and animals. Although it is too early for a full assessment, we suggest that the COVID-19 pandemic and the subsequent economic crisis will severely affect animal health in several ways . In the In conclusion, this study aims to highlight the strong connection between ASFV-affected countries in Europe during the COVID-19 pandemic. The results presented are not intended to provide an estimate of ASFV risk, but they highlight important aspects to consider during a global public health emergency. The long-term consequences of this pandemic on countries’ abilities to control and prevent ASFV are still unclear. However, it remains critical to ensure that the risk of ASF is not underestimated. Finally, an increased surveillance effort at the borders of each European country is needed to ensure early detection of ASFV and rapid response.


A scoping review of systematic reviews was carried out to identify evidence of efficacy, effectiveness, and cost-effectiveness of universal and selective suicide prevention programs among university students worldwide. Five databases were reviewed using terms in English, Spanish, and Portuguese. The following were the inclusion criteria: systematic review or meta-analysis or meta-synthesis, suicide prevention in college students, evaluation of the efficacy, effectiveness and/or cost-effectiveness of interventions, and peer-reviewed studies. The quality of reviews was assessed. The field of study features three decades of publication in high-income countries. The strategy used, the components of the program, and the target audience to which they are delivered interfere with efficacy. In the psychoeducation strategy, the experiential and didactic components are more efficacious in the knowledge about suicide. And the motivational enhancement component promotes greater self-efficacy in suicide prevention. Programs that take a multimodal approach are effective in increasing short-term attitudes related to suicide and reducing rates of completed suicide. The gatekeeper strategy delivered to peer counselors is the most effective one in the outcomes, including short-term and long-term knowledge about suicide and its prevention and self-efficacy in suicide prevention. A greater number of evaluated studies of gatekeeper interventions were identified, indicating a trend in this research field. No review addressed the effects on subgroups that were classified based on sex, racial or sexual minorities, and special (indigenous) populations. Only one study addressed cost-effectiveness, pointing out that the psychoeducation and gatekeeper strategies have relevant net benefit rates, but the gatekeeper strategy has a higher cost–benefit ratio compared to the psychoeducation strategy. The findings indicate that psychoeducation and gatekeeper interventions tend to be more efficacious when they combine education and skills training to intervene in suicidal behavior. The components of the intervention and the target audience to which it is delivered influence efficacy. Multimodal interventions evaluate completed suicide outcomes, but require greater implementation efforts, in terms of human and financial resources and more time for the evaluation.The online version contains supplementary material available at 10.1186/s41155-022-00227-x. Suicide is the second leading cause of death among young people aged 15 to 29 years worldwide  investigate which components of suicide prevention programs are predictors of efficacy, effectiveness, and cost-effectiveness in suicide prevention; (b) identify whether factors of the target population can influence the efficacy and/or effectiveness of the programs; (c) evaluate the quality of systematic literature reviews found; (d) demonstrate the number and origin of suicide prevention programs for university students published worldwide; and (e) investigate whether there are suicide prevention programs with an evaluation of efficacy, effectiveness, and/or cost-effectiveness in Latin American countries. It is expected that these data can support decision-making for researchers, managers, and health professionals interested in designing and offering suicide prevention programs for young university students.The methodology used was scoping review , Cochrane Library, ERIC, PubMed, and SciELO in January 2020. The SciELO database was consulted because it is the main digital library in Latin America, as most journals are indexed there. As the objective was to access all available literature, no time and language limits were applied. The review article filter was applied (in databases that had this resource).The articles were located in two stages. In the first stage, searches were performed in electronic databases: BVS (suicide OR suicidio AND (prevention OR prevencao OR intervention OR program OR treatment OR therapy OR strategy OR suicide prevention) AND (college OR university OR campi OR school OR campus OR university OR universidade OR universitary OR student OR estudante OR school-based OR university-based OR faculty) AND (eficacia OR eficácia OR efficacy OR efetividade OR effectiveness OR cost-effect)))]. The search strategy was designed and refined by two experienced librarians at the University of Brasília.The search terms in English, Portuguese, and Spanish were used with the following search strategy: [In the second stage, searches were performed in the bibliographic reference lists of the articles retrieved in the previous stage, with the objective of maximizing the reach of available published studies. The search took place in the references that had the term “review” and “suicide” in the title. The complete database is available upon request from the first author of this research.The inclusion criteria used were as follows: (a) studies that presented results of systematic review, meta-analysis, or meta-synthesis on interventions for suicide prevention among university students; (b) studies that presented data on the efficacy, effectiveness, and/or cost-effectiveness of interventions; and (c) peer-reviewed studies. The exclusion criteria were as follows: (a) studies that addressed the impact of news about university students’ suicide and (b) studies that addressed indicated prevention, treatment, and intervention in suicidal crisis. These studies were excluded because they focus on major media news, which universities have no control of, and which cannot be targeted by suicide prevention programs in the educational environment. And because in cases of indicated prevention, treatment, and crisis intervention, universities tend to refer to the health network, given the complexity of the case.In study cases with very specific themes, such as the use of the Internet or work with indigenous populations, the study was only included if the results of suicide prevention programs in university students could be observed separately. Three reviewers completed these tasks independently in duplicate after the training. Disagreements were resolved through consultation with a fourth author.In the search and screening stages, 335 publications were identified, distributed in the databases as follows: BVS (38), Cochrane Library (26), ERIC (42), PubMed 217), SciELO (12). Fourteen articles are added to this number, located based on the references of the retrieved studies, constituting a sample of 349 publications. After eliminating 20 duplicate studies, a total of 329 references remained. The databases were searched based on their respective start dates until January 2020. After reading the title and abstracts of the articles, and applying the inclusion and exclusion criteria, 289 studies were discarded, and 40 studies were kept for analysis of the full text. After analysis of the full text, literature reviews in which data from university students were indistinguishable from data from other samples were eliminated, totaling 8 studies selected and included in this scoping review, as shown in the flow diagram according to oriented in Peters et al.  7, SciELOA data mapping form was jointly developed by two reviewers to determine which variables to extract. A reviewer independently mapped the data, discussed it with the group, and continually updated the form in an iterative process. Microsoft Excel software, which allows creating and editing spreadsheets, was used.The following information was extracted: country and period of publication, quality of systematic literature review, strategy or approach , type of assessment , intervention characteristics, delivery mode (face-to-face or online), characteristics of the target population, outcome measures, and gaps in the studies.The quality of knowledge synthesis methods was evaluated using the AMSTAR (Assessment of Multiple Systematic Reviews) tool. This tool was created and validated to assess the methodological quality of systematic reviews , as detailed in Additional file The term effectiveness was used differently from the literature in three studies. Kutcher et al. , YonemotOnly two reviews performed meta-analysis and presented the interventions effect size , ALIVE, CampusConnect, and SafeTALK. Efforts to adapt these programs to the local reality or the previous needs of the institution and the target audience were not mentioned.Most studies were delivered in person. Only a few multimodal programs had online screening and primary care, and a psychoeducation program was delivered online. There were no studies found that used screening as the only type of strategy. One study carried out a cost-effectiveness evaluation comparing the psychoeducation strategy with the gatekeeper one. Given the specifics of each strategy, they will be addressed separately, with outcomes and characteristics.Psychoeducational interventions had the following short-term results: increased knowledge about suicide, increased knowledge of suicide prevention, and small increase in suicide prevention self-efficacy. Long-term evaluations were not described.The interventions used at least one of these components: didactic , experiential (modeling and dramatization of suicide prevention situations), and motivational enhancement .Sensitivity analyses concluded that components mentioned influenced the effect rates on some outcomes  was associated to better outcomes compared to involuntary participation  and the other on peer support (gatekeeper), for university students  and peer support (gatekeeper) programs to prevent suicide , the authors concluded that the implementation of both programs in all Florida universities would result in net benefits of US$ 21 million for the general education program (psychoeducation) and US$ 32 million for the peer support program (gatekeeper). This demonstrates that the implementation of these programs provides net positive benefits to society. The study did not calculate additional costs related to the support that family and friends may need after the loss of a loved one. These may involve the increased use of mental health resources and the need to take time from work or school, implying in costs for public policies and a decrease in productivity and/or school performance.The study did not present the characteristics of the target population, such as gender proportion in the groups, marital status of the participants, social class, and the presence or absence of ethnic minorities. The age of the target audience for the interventions was between 18 and 24 years old.The findings of this scoping review indicate that components and participants interventions impact its efficacy. Psychoeducation and gatekeeper interventions tend to be more efficacious when they combine education and training to intervene in suicidal behavior. Members of the university community (such as faculty members and student leaders or volunteers) are important institutional resources that should be considered. However, the results are not sustainable in the long term and therefore actions must be implemented to encourage the maintenance of the outcomes. These strategies demonstrate good results in terms of cost-benefit, but the results cannot be generalized, since only one study was found. Multimodal interventions, on the other hand, did not evaluate the same outcomes as psychoeducation and gatekeeper interventions, making it impossible to compare these strategies.Gatekeeper training proved to be the strategy with the highest number of published studies, a finding that coincides with another literature review that covered programs in schools and universities  and final outcomes (reduction of completed suicide). Similar results were found in another literature review . The multimodal interventions presented a challenge in terms of evaluation, in terms of measuring the effects of each strategy, as they are applied jointly and over the same time frame. These interventions can have cascading effects that increase when they reach the next level  were implemented in the psychoeducation and multimodal programs. The personalized feedback implemented in a multimodal program delivered online stands out. This reiterates findings about customized interventions being more advantageous than generalist ones, as they provide more identification, attention, and retention , and tests to assess homogeneity of the combined studies. In addition, the reviews did not seek to evaluate other aspects that may have contributed to the effectiveness of the interventions, such as the theoretical approach used and consulting the stakeholders. Some reviews used the term effectiveness in situations where the term efficaciousness would be more appropriate.The effects of interventions have not been measured over the long term and it is not known whether they hold. It was not possible to evaluate the effect of psychoeducation and gatekeeper interventions on suicide attempts, threats, or ideation or help-seeking behavior. Few studies have evaluated the effect of using technologies in online screening and counseling. Studies have not reported the capacity of the health system in the territory to meet the mental health demands of university students. Only two meta-analysis studies were found, and only one of them reported the intervention effect size.There is a lack of diversity in the populations of origin, as only undergraduate Psychology students participated in psychoeducation programs, which can lead to outcome bias, as these students may have been more avid, trained or attentive to intervention, leading to more positive effects on outcomes related to suicide prevention  evaluate outcomes at specific times, that is, immediately before starting the intervention, immediately after completion of the intervention, and at a follow-up time to determine how well the changes are maintained; and (e) consistently report key variables of interest that could theoretically impact outcomes  use specific designs such as randomized clinical trials and quasi-experimental designs; (b) use psychometric tools that are consistent across studies to assess core domains; (c) publish complete descriptive statistics of the studies, such as Since the programs that used the gatekeeper strategy did not maintain long-term results, future research should assess this care in order to maintain the effects. These are as follows: offer support networks and the possibility of connecting with other gatekeepers; customize the training considering the level of knowledge of each subpopulation ; and use technologies to provide gatekeepers with up-to-date information on local health services, reminders, ongoing feedback, follow-up materials, and summaries of the intervention  , populations from resource-poor contexts, and/or traditional populations (such as indigenous and quilombolas).The main limitation of this study is the restriction in studies covered by systematic literature reviews. We are aware that existing systematic reviews and meta-analyses may be subject to misinterpretations of primary studies, omission of important primary studies, and inclusion of low-quality primary studies by review authors. Our objective is to alleviate this bias by evaluating the quality of systematic literature reviews.The findings of this scoping review indicate a lack of studies on the effectiveness and vast production on the efficacy of suicide prevention programs for university students. Evidence on cost-effectiveness is still limited to a just one study with restricted scope for generalizability. However, heterogeneous efficacy results have been observed depending on the strategy used, to which public it is delivered, the analyzed outcome, and the time to measure the results. Current approaches to suicide prevention in the university setting emphasize knowledge and attitudes about mental illness, the development of skills to provide help, and treatment options. However, the basis of evidence for these approaches needs to be significantly strengthened. Furthermore, new approaches must be explored because individual-focused issues such as knowledge and attitudes may not be the main barriers for many students who do not seek help. Ecological and systemic approaches could help to focus on other factors that go beyond the personal and interpersonal dimension, but that consider the influences of the organization, the community, and society in which the individual is inserted, and the social and constructed environment, such as availability and quality of services offered. The context must be observed, especially in low- and middle-income countries, since in these locations there may be less access to health services by some sections of the population.Additional file 1: Table 1. Evaluation of systematic literature reviews according to the AMSTAR criteria.Additional file 2.


The idea of treating brain disorders with non-invasive stimulation (NIBS) techniques dates back several centuries and nowadays is among the main therapeutical prospects of modern neurology and psychiatry . Among the different possible mechanisms of action, the authors focus their attention on the activation of the locus coeruleus (LC), which results in catecholamines release in the hippocampus and neocortex, with a subsequent enhancement of synaptic plasticity and reduction of inflammatory signaling. Indeed, loss of noradrenergic LC projection neurons that mediate attention, memory, and arousal has been observed in AD patients, with the number of this noradrenergic neurons also associated with increased postmortem neuropathological findings , firstly approved by FDA in 1997 for treating epilepsy and later for depression, suffers from some safety issues that paved the way for the development of transcutaneous VNS (tVNS), that instead can be applied through locations on the ear (auricular) or the neck  , Tourette's syndrome, autism spectrum disorders (ASD), depression, and schizophrenia. Moreover, the use of prosthetics and brain-computer interfaces plays a major role in rehabilitation. However, the authors highlight that the use of brain augmentation techniques to promote brain function beyond the normal health status opens important ethical issues. Thus, they conclude that the safety and efficacy of brain stimulation techniques for the treatment of neurological and neuropsychiatric disorders deserves to be further explored by well-designed clinical trials in the future.In recent years, NIBS has also been associated with the possibility to increase human mental capacities, namely neuroenhancement, a challenge with a long tradition in science . The ASSRs are scalp-recorded signals reflecting the capability of the auditory system to follow the timing patterns of acoustic stimuli that stay constant over time, and they are considered translational EEG biomarker of the brain's ability to process sensory information , and altered neural synchronization plays a key role in many cortico-cortical processing Singer, . DiffereQuinn et al. investigate the use of anodal transcranial direct current stimulation (tDCS) as a therapeutical tool to ameliorate pathophysiological processes contributing to persistent posttraumatic symptoms (PPS) after a mild-moderate traumatic brain injury (mmTBI). In a cohort of 34 subjects with mmTBI, 10 anodal tDCS sessions over the left dorsolateral prefrontal cortex (DLPFC) resulted in an improved working memory reaction time after 1 month. Moreover, the authors observed that the reaction time improvement correlated with a reduced functional connectivity between the right DLPFC and the left anterior insula, with hyperconnectivity suggested to be a chronic compensatory state  in wild-type mice, focusing on structural neuroplasticity and behavior. Though in humans rTMS over PFC is known to modulate emotions, cognition, and depressive symptoms, the underlying mechanisms of action are still far from being clear. The authors report here that, after a 5-days high-frequency rTMS protocol, mice displayed a decreased depressive-like behavior, associated with increased spine density in layer II/III and layer V of PFC apical and basal dendrites. This increase in the number of spines goes in parallel with an increased complexity in the neural arborization within the same region, suggesting a structural remodeling of the medial PFC. This area is known to be key for the modulation of various abnormal behaviors (Chini and Hanganu-Opatz, Emotional behavior is managed in the paper by This collection of articles highlights the significance of a better understanding of the mechanisms underlying the effects associated to NIBS techniques, for not only neuroscientists but also neurologists, psychiatrists and physiotherapists.MCa wrote the first draft. MCo, SD, SC, and MB provided critical comments and editorial suggestions for revisions. All the authors agreed on the submitted version.