Economic evaluations of public health interventions to prevent malaria should consider the adoption of wider perspectives and the inclusion of non-health impacts, particularly economic development outcomes, such as education. This is especially relevant in malaria elimination settings and in the context of the current SARS-CoV-2 pandemic. P. falciparum vaccine RTS,S/AS01 has been recently recommended for broad use in children in regions with moderate to high transmission, and initiatives are ongoing to support its rollout in Sub-Saharan African settings. The use of the preventive public health toolbox can aim at either reducing malaria incidence to a locally acceptable level (control) or interrupting local transmission in a defined geographic area (elimination).Malaria prevention relies on vector control strategies such as indoor residual spraying and the use of insecticide-treated nets, on preventive chemotherapies such as intermittent preventive treatment in infants and pregnant women, and seasonal malaria chemoprevention in children. In addition, the long-time craved first 1.In disease control settings, the introduction of safe and efficacious malaria preventive interventions on top of malaria case management activities has typically represented a cost-effective use of health care resources. The same applies when new preventive activities are introduced to complement or replace existing ones, or when these are intensified for improving efficacy: at adequate levels of coverage and adherence, the incremental health impact outweighs the incremental cost2, inability to pay for the full or even partial cost of the intervention, or difficulties in accessing the preventive activities. Furthermore, when the correct information is lacking, fallacious beliefs based on misleading signals may lead to suboptimal health care choices. For example, in absence of information on treatment, the disappearance of symptoms may cause the interruption of the therapy before its completion, leading to a likely reduction in the preventive effects (i.e. transmission containment) of antimalarial drugs.However, even if preventive tools and strategies are proven to be efficacious in disease modelling exercises or clinical trial settings, their implementation does not always lead to a full realisation of the expected health impacts in real-world settings. Such a gap between efficacy and effectiveness is attributable to both demand- and supply-related factors. Demand-side factors include, for example, lack of awareness of the community benefits of individual preventive choices3 and, more generally, funds shortage4. Of note, by unfairly affecting access to health care, these barriers to the realisation of the full expected impacts on health may potentially generate health inequities, too.Supply-side barriers encompass issues at different levels of the healthcare system such as, for example, products stockouts; poor labour organisation and performance;5 or micro-loans6 in search of a balance between ensuring universal ownership and incentivising actual usage. To increase adherence to antimalarial treatment, simple packaging messages have been employed to explain the importance of completing the whole therapeutic course7. Most of these strategies are more expensive for the health provider, but have been proven to positively impact health and to be cost-effective. Notably, most of these strategies are also able to improve health equity, by granting access to those that would be otherwise left behind.Innovative mechanisms of delivery and acquisition of preventive tools and strategies of information dissemination have been designed to address at least some of these issues. For example, to improve the coverage of malaria prevention programmes, community health workers and volunteers have been involved in the promotion and distribution of preventive chemotherapies. To improve the coverage and actual use of bed nets, various forms of distribution have been adopted, ranging from free provision, to provision based on cost-sharingIn elimination settings, maximising the effectiveness of public health actions to prevent malaria becomes even more critical. This is because the interruption of local transmission requires extra efforts in terms of intensifying and expanding the range of interventions currently implemented. Such “last mile” activities are characterised by high costs, uncertainty and risk of failure. Sources of uncertainty and risk of failure are multiple, such as the lack of political coordination and the difficulties in providing continuous sustained support to policies with a potentially decreasing community demand for prevention in settings where malaria incidence approximates zero. Furthermore, on the path towards elimination, the incremental health impacts decrease. Therefore, if only focused on direct impacts on health and health care costs, cost-effectiveness analysis may discourage investing in elimination policies. For example, non-routine public health interventions, such as mass drug administration (MDA) and reactive focal MDA, together with strengthened surveillance may be essential to achieve and sustain elimination, but economic analyses may indicate that the incremental costs are not compensated by the incremental health benefits in the short-term.10. However, such evidence is seldom considered in economic evaluations.For economic evaluation to be better aligned with decision-making needs and priorities in elimination settings, particular attention should be devoted to two aspects: the consideration of the long-term effects of the policies and their impacts beyond health. To fully reflect the benefits of malaria elimination, it would be necessary to estimate the long-term benefits of a scenario with no malaria. These encompass not only the consequent health benefits and cost savings for the health system, but also the spillovers beyond health and health care. Notably, thanks to the use of robust quasi-experimental methods applied to observational data, malaria public health interventions have been proven to cause, in most of the settings explored, a non-negligible long-term impact on education, labour, income, fertility and, more in general, on economic growth and development11. Moreover, the magnitude of such impacts has been mainly based on assumptions rather than on estimates from robust impact evaluations. For example, the impact on schooling and education outcomes, or more generally on human capital accumulation, has never been explicitly considered in the economic evaluation of public health malaria interventions conducted within the healthcare sector. Such an approach may potentially misrepresent the full impact of malaria prevention interventions12. Of note, even if an intervention is deemed cost-effective or cost-beneficial from a narrow health care perspective, the inclusion of potential impacts beyond health in the economic evaluation would provide useful information to decision-makers across different sectors.To the best of our knowledge, only selected non-health impacts have been included in economic evaluations, specifically in cost-benefit analyses, such as the value of enhanced work productivity or extended productive lifespan and increased revenues from tourism13, the lack of consideration of outcomes falling on sectors other than health may still lead to a subotpimal allocation of resources and to underfunding of key health care interventions for economic development. The adoption of broader perspectives in economic evaluations or the consideration of economic development indicators could lead to policy recommendations that better reflect the wide impact of malaria preventive activities. Even though the measurement of the impact of elimination/eradication of neglected and low transmission diseases beyond health could be challenging, benefits have already been identified relative to education, food security, and happiness16.While substantial efforts have been made to improve the methods for economic evaluation in the context of disease elimination17.The SARS-CoV-2 pandemic has disrupted malaria healthcare services. According to the latest World Malaria Report, about two-thirds of the 69,000 additional malaria deaths in 2020 compared to 2019 were linked to disruptions in the provision of malaria prevention, diagnosis and treatment during the pandemic18. Nevertheless, once available, data will have to be interpreted with caution as reported cases of malaria are likely to have dropped over the year 2020 due to a generalised reduction in the use of healthcare services by the population, as a consequence of governmental recommendation to seek treatment only for the most essential health needs and because of the fear of contracting SARS-CoV-2 infection at the health care facilities.In settings where elimination activities are being carried out either as part of the national health programmes or as research projects, elimination activities were withdrawn for most of the year 2020. This is the case, for example, in the South of Mozambique where elimination projects, in place since 2015, were interrupted because of mobility restrictions and diversion of healthcare resources from malaria programs to SARS-CoV-2 related activities. For example, community health workers who were meant to be employed in reactive focal MDA were reallocated to address other healthcare priorities. Even if no evidence is yet available for most of the elimination settings, including Southern Mozambique, the interruption of malaria elimination activities is likely to have compromised the fragile health gains in terms of the malaria incidence reduction obtained in the pre-pandemic periodIn addition to the plausible increase in malaria burden, the aftermath of the SARS-CoV-2 pandemic is likely to affect not only health, but also economic development factors. Of particular concern is the impact on education. As in most countries worldwide, schools remained shut for most of 2020 also in Sub-Saharan Africa, with extreme cases such as Uganda, where classes were suspended for almost two years. In malaria endemic settings, school outcomes are likely to have been hit by a double negative shock: school closure and malaria resurgence. The pandemic-induced repercussion of such double negative shock on school outcomes will soon emerge, probably with substantial consequences. School closures are expected to impact education both in the short-term, due to higher absenteeism and lower performance once schools are reopened, and in the long-term, due to definitive school drop-out.19. On the other hand, as a consequence of the protective effect of elimination campaigns over malaria, improved health in elimination areas may have driven a higher share of children towards the labour market during school closures20.Nevertheless, in endemic areas where elimination activities were successfully carried out before the onset of the pandemic, the decline in short-term school outcomes may be lower than in areas with similar epidemiological and socio-economic conditions, but no malaria elimination activities. In other words, elimination efforts in the pre-pandemic period may have exerted a protective effect against malaria resurgence, and consequently mitigated the worsening of short-term school outcomes. However, in the context of interrupted elimination activities paired with school closures due to SARS-CoV-2, there are potential threats to such mitigation claims. On the one hand, children born in the malaria elimination pre-pandemic years may be at risk of low immunity formation and thus be particularly hit by the potential resurgence of malaria if control/elimination activities are not quickly resumedIn the near future, it will be fundamental to identify and measure the impact of malaria elimination activities disruption due to the pandemic on education outcomes. This evidence could inform economic evaluations conducted from broader perspectives that could assist decisions on whether, how, and when to resume malaria elimination activities after the SARS-CoV-2 emergency. The generation of such information calls for collaborations across different research fields, including public health, economics, development, and education.Further information on research design is available in the Reporting summary


Current techniques are available to assess the mechanical characteristics of the cornea in vivo. Accordingly, various attempts have been expended to obtain the relevant mechanical parameters from different perspectives, using the air-puff method, ultrasound, optical techniques, and finite element analyses. However, a measurement technique that can comprehensively reflect the full mechanical characteristics of the cornea (gold standard) has not yet been developed. We review herein the in vivo measurement techniques used to assess corneal biomechanics, and discuss their advantages and limitations to provide a comprehensive introduction to the current state of technical development to support more accurate clinical decisions.In early corneal examinations, the relationships between the morphological and biomechanical features of the cornea were unclear. Although consistent links have been demonstrated between the two in certain cases, these are not valid in many diseased states. An accurate assessment of the corneal biomechanical properties is essential for understanding the condition of the cornea. Studies on corneal biomechanics  Mechanical characteristics are important features of the cornea. These are dependent on the distribution of collagen fibers in the stroma, the thickest layer of the cornea. The alignment of these internal collagen fibers is directly related to the biomechanical properties and  to the morphology of the cornea, which further influence its optical properties. Parameters determining corneal biomechanical characteristics can be used to reflect the states of corneal diseases.A broader and deeper knowledge of corneal biomechanics could promote the evaluation of corneal ectasia patients  and faciin vivo is of immense importance in clinical practice. At present, various instruments based on different inherent principles are employed to evaluate the cornea based on different biomechanical parameters.Various parameters are currently used to quantify the corneal biomechanical properties. The longitudinal, shear, and Young’s moduli are the three main classical mechanical parameters that are used. Though different machines gave various terms for the description of corneal biomechanics, they can almost all be related to these three biomechanical features. This review explains the differences between them and their clinical implications. The shear modulus is often used to describe the rigidity of a material and is also referred to as the rigidity modulus. The Young’s modulus, on the other hand, reflects the stiffness of the material . In dynaIn vivo biomechanical measurements of the cornea are still in the nascent stage. The tonometer, which measures corneal rigidity using contact technology, has been available since the early 1900s [ly 1900s . Earlierly 1900s . Less dely 1900s  and ultrly 1900s ,17, werely 1900s , and thely 1900s   and corneal resistance factor (CRF). The former of these quantifies the corneal viscoelastic properties and the latter is an indicator of the overall corneal resistance, reflecting the corneal elastic characteristics ,14. ThesAlthough CH and CRF can reflect the corneal biomechanical properties, it is difficult to distinguish between the biomechanical properties of different areas of the cornea according to their principle and function . The matTo overcome these limitations, several new studies have defined additional parameters ,30. ThesCorneal visualization Scheimpflug technology (Corvis ST) was developed as an improvement of the ORA via the addition of an ultrafast Scheimpflug camera that allows direct monitoring of corneal deformation ,32,33. Bin vivo have recently been proposed [Corvis ST reports two parameters, namely, the corneal biomechanical index (CBI) and the total biomechanical index (TBI). Both are new parameters based on a linear regression analysis combining corneal morphology and stiffness parameters, which can improve the detection rate of conical corneas . Other pproposed . Figure However, Corvis ST cannot be used to analyze the corneal mechanical behavior in a specific direction. Furthermore, its results are also affected by factors such as the IOP . Repeatein vivo. It uses tomography for nondestructive estimation of the material properties of the cornea [Optical coherence tomography (OCT) is a technique used to examine the microscopic structures in biological tissues. The study that first reported it did not target ocular components . Opticale cornea . The evae cornea  in ordere cornea ,44,45. Te cornea .in vivo measurements in humans [in vitro testing phase and in vivo measurements have not yet been achieved.Some studies have quantified the corneal biomechanical properties after CXL treatment in rabbit eyes using OCE , and havn humans . A numben humans . Air-pufn humans . Similarn humans . Addition humans . Shear-wn humans . The resn humans . Pulsed n humans  and acoun humans  utilize n humans . The tecMechanical waves can be used in perturbation techniques to induce slight tissue displacement. These techniques can reflect the biomechanical properties of the cornea based on propagation analyses of mechanical waves induced in the corneal tissue, thus serving as a new noninvasive technique type used to assess corneal biomechanical properties.in vivo studies.Supersonic shear-wave imaging (SSWI) is a novel ultrasound technique that can provide real-time and quantitative mapping of the corneal viscoelasticity in noninvasive conditions to objectively assess soft-tissue stiffness ,55. A coin vivo [in vivo measurements of corneal biomechanics [SSWI can be used to quantify the corneal elastic anisotropy in vivo , quantitin vivo . SSWI hain vivo ,58. Thisechanics ,60,61.in vivo examinations of corneas recently [Ultrasound surface wave elastometry (USWE) uses an ultrasound probe to measure the time of wave propagation between two transducers set at a fixed distance; the propagation time can be used to determine the corneal elasticity. This technique reflects the local mechanical properties of the cornea and compares the stiffness values in the central, radial, and other directions . This terecently .USWE has been applied to the determination of corneal biomechanics in CXL studies . HoweverUnlike perturbation-based measurements, non-perturbation-based measurements do not rely on corneal deformation. These techniques usually involve direct corneal biomechanical assessments based on the inherent structural properties of the corneal tissue. The acquisition of the intrinsic corneal tissue parameters can be currently achieved using techniques such as optical or computational simulations.Brillouin microscopy (BM) uses the Brillouin shift between Stokes and anti-Stokes scattering to measure the longitudinal or bulk modulus in order to describe the mechanical compressibility of tissue. BM imaging techniques can be used to obtain volumetric images of the elastic characteristics of the cornea . A low-pBM observations can describe the local biomechanical characteristics of the cornea and reflect its three-dimensional spatial heterogeneity. The downsides are the narrow measurement range and the long acquisition time, which limits the large-scale use of BM approaches ,65. As fin vivo corneal measurements [Many clinical studies have utilized BM for urements , detectiurements , and othurements . This teurements .Phase-decorrelation OCT (PhD-OCT) is a new technique used to characterize corneal biomechanics by combining OCT and BM. Unlike BM, which uses Brillouin scattering, PhD-OCT uses dynamic light scattering of particles in a fluid to obtain the relevant parameters. After scanning, the attenuation constant of the particles, which is related to the viscoelasticity of the material, is calculated using the Fourier transform .PhD-OCT can reflect the corneal spatial heterogeneity in three dimensions . Moreovein silico technique that can mimic real-world physical or mathematical problems by discretizing the complex geometry into a finite number of small volumes with regular shapes, the so-called elements. Regarding the corneal assessment applications, the cornea and its surrounding structures can be represented as a large number of brick or pyramid elements, which are connected through nodes and defined with specific material properties that are ideally derived from patient-specific measurements. The responses to changes in the simulated structure are then obtained by calculating the stiffness matrix. For large deformation analyses, calculation iterations are needed until a converged solution of the entire structure is obtained [The finite element method is an obtained .The finite element method has been used extensively in several studies of the cornea, and many techniques based on these models have been developed for evaluating corneal biomechanical properties ,72.Stress–strain index mapping is an emerging approach used to assess the biomechanics of corneal materials. This method is based on material model simulations using the finite element method  and can The SSI map is a comprehensive analysis of the local SSI values obtained via Corvis ST, using the geometric information and collagen distribution principles to derive the final stress–strain index map. In view of the nonlinear nature of the stress–strain behavior of the cornea, SSI maps can provide more accurate measurements of biomechanical parameters. Before exporting the SSI maps, it is necessary to diagnose the presence and type of corneal ectasia to select the appropriate model for computational analysis. In the case of a healthy cornea, the derived SSI maps show only slight fluctuations in the SSI values across the corneal surface, whereas keratoconus shows great disparities in the SSI value over some areas . Two-dimThe SSI mapping technique has evolved very rapidly and is now in clinical trials. Recent studies have evaluated the progression of keratoconus using SSI maps  and demoin vitro in keratoconus and to map the two-dimensional distribution of Young’s modulus showed that the Young’s modulus in the central conical region was much lower than that in healthy corneas [The concern about corneal biomechanics stems directly from clinical problems. The corneal stroma is essentially a thin tissue made up of multiple layers of interwoven fibers, so any disruption of the corneal structure will alter the biomechanical properties of the cornea . One of  corneas . Such co corneas . To redu corneas . CXL tre corneas . It has  corneas .Outside the field of refraction, glaucoma is also associated with the corneal biomechanical properties. The measurement of IOP is inextricably linked to corneal viscoelasticity . Furtherin vivo evaluation of biomechanical characteristics of the cornea, among which ORA  and Corvis ST  are already in commercial production. Both commercially available devices enable noninvasive, more accurate measurements of biomechanical properties by analyzing the process of corneal large-amplitude deformation. However, the large-amplitude deformation of the cornea shows a nonlinear character, and IOP and CCT can affect the accuracy of the measurement. The analysis method is also based on ultrafast photographic equipment that precludes the possibility of spatially resolved measurements. In response to these problems, measurement techniques such as SSI, USWE, and OCE have been developed. These low-perturbation, low-amplitude techniques enable two-dimensional and even three-dimensional spatial measurements, reflecting variability in the biomechanical properties of different regions of the cornea and improving the safety of detection. It should be noted that these devices still measure based on the perturbation principle, which makes it difficult to avoid sources of interference such as IOP, CCT, eye movements, etc. In view of the unavoidable measurement inaccuracies associated with perturbations, techniques such as BM and SSI mapping have subsequently emerged to assess the biomechanical properties of the cornea, based on optical principles or finite element modeling of the internal structures of the eye. These techniques allow for high-accuracy measurements of the cornea and provide a more comprehensive picture of various corneal biomechanical properties. However, these techniques are still in the early stages of research: BM allows detection in three dimensions, but it has considerable limitation of range and takes a long time to evaluate; while SSI maps are currently only available in two dimensions and need to be modeled separately for multiple diseases and different types of corneas, which is costly. These features limit the use of these devices in clinical applications, such as the early diagnosis of corneal ectasia and incision selection for refractive surgery.In recent years, the field of corneal biomechanics has been an area of focus owing to the continuous development of refractive surgery techniques. These assessment techniques are being developed and have the potential to enable noncontact, noninvasive clinical examinations, and to provide real-time, three-dimensional, high-resolution maps of the distribution of corneal biomechanical parameters. These measurements will provide more accurate clinical tools for issues such as early screening of keratoconus or risk assessment for refractive surgery, and improve the understanding of corneal diseases.


The placenta is a vital organ for fetal development, providing the fetus with nutrients, oxygen, and other important factors. Placenta is rich in blood vessels. Abnormal placental vascular function and blood circulation may lead to insufficient blood supply to the fetus in the uterus, leading to serious consequences such as pregnancy complications, fetal distress and even stillbirth. Pregnancy-induced hypertension (PIH) and gestational diabetes mellitus (GDM) are common complications of pregnancy. Recent studies report that pregnancy complications are often accompanied by changes in placental vascular structure and function. What are the physiological characteristics of human placental blood vessels? What are the pathological changes in the state of PIH and GDM? What are the relationships between these pathological changes and the occurrence of these pregnancy complications? Answers to these questions not only increase the understanding of placental vascular characteristics, but also provide important information for revealing the pathological mechanism of PIH and GDM. This article will summarize the research on the pathological changes of placental blood vessels in PIH and GDM, hoping to further unravel the physiological and pathological characteristics of placental blood vessels in the state of PIH and GDM, provide information for guiding clinical treatment for PIH and GDM. Human placenta is a combination of embryo/fetus and maternal tissue to which the fetus is connected by an umbilical cord. Human placental villi begin to appear from 7 to 8 days after fertilization, and form a complete placenta at 3 months of pregnancy, and gradually grow with increased gestation. Placenta is a vascular organ and constitutes the active interface between the maternal and fetal blood circulation. Its normal blood supply is the key to fetal development and maternal health. The complete placental vascular bed is rich in a large number of blood vessels, which includes the chorionic plate  artery and its branches, villi and veins. Placenta is a low resistance vascular system, and plays a key role in maintaining adequate blood flow and blood volume with the placenta. Regulation of placental vascular tension is controlled by molecules brought by the blood supply, because of lack of sympathetic innervation in placental vessels . VasoactInsufficient blood supply to the placenta is closely related to the occurrence of pregnancy complications . PregnanGDM has traditionally been defined as any degree of glucose intolerance first identified during pregnancy . In 2018Previous reports on placental ischemia in pregnancy complications tended to focus on the hypoperfusion of the spiral artery between the uterus and placenta, ignoring the role of the placental vascular function in the blood supply of the placenta. What are the physiological characteristics of human placental blood vessels and the pathological changes in the state of PIH and GDM? In this review, we will summarize the previous studies in this area, hoping to provide important information for understanding the morphological and functional changes of placental blood vessels and the management of such pregnancy complications.Uterine spiral arteries between the uterus and placenta are extensively remodeled during placentation to ensure sufficient delivery of maternal blood to the developing fetus. A considerable amount of research has indicated that PIH is associated with poor placentation, shallow remodeling of the uteroplacental spiral arteries . The spiRegarding GDM, Soma Saha, et al. observed that the placentas of mothers with diabetes were significantly bigger in size, weight, volume, area, diameter, thickness, and circumference than those of mothers without diabetes . GDM plaAs we mention above, vasoactive substances  in placental tissue and surrounding blood circulation play a crucial role in controlling placental vascular function and blood circulation . In thisProstanoids are composed of prostaglandin (PG), thromboxane (TX) and prostacyclin (PGI2), and play an important role in the control of the umbilical-placental circulation . PG and In studies of PIH and normal pregnancies, Robinson, et al. found that the content of PG in the PIH placenta was significantly lower than that in the normal placenta , while HCompared with normal pregnancy, the content and activity of PGI2 in the PIH placental vascular tissue was significantly reduced ; while YIn a study of GDM and normal pregnancy, Saldeen et al. found no significant difference in umbilical vascular PGI2 or TxA2 production between the GDM and the control group . HoweverEndothelin-1 (ET-1) produced in endothelial cells is the most effective and long-lasting vasoconstrictor. In vascular tissue, ET-1 mediates vasoconstriction through type A (ETA) and type B receptors (ETB) . ET-1 isCurrently, the results of research on the reactivity of placental blood vessels to ET-1 are limited. Only two studies reported that there is no significant difference in ET-1-mediated placental perfusion and vasoconstriction between normal pregnancy and PIH placenta . Serum EHistamine (HA) has a clear role in non-placental blood vessels, which differs depending on the type of blood vessel. Generally, HA can mediate the vasoconstriction of the mesenteric and cerebral arteries , while iThe balance between HA and DAO seems to be crucial for an uncomplicated pregnancy . HA has Serotonin, also known as 5-hydroxytryptamine (5-HT), plays a crucial part in placentogenesis and fetal development . As a stCurrently, there are controversies about the results of studies on the response of PIH placental blood vessels to 5-HT. For example, Cruz and Ezimokhai, et al. showed that compared with the normal placenta, the sensitivity of the PIH placental chorionic plate artery and venous rings to 5-HT is significantly enhanced . Other sThe Renin-Angiotensin-System (RAS) plays an important role in the pathogenesis of hypertension . Human pExtensive studies have been done to determine the circulating and placental Ang II in normal and PIH pregnancies. Some studies indicated that the level of Ang II was increased, whereas others showed it unchanged or decreased in PIH . In the It has been shown that the circulating RAS is activated during normal pregnancy, but little is known about RAS in pregnancies complicated by GDM. Nogueira, et al. reported that levels of Ang I, Ang II and Ang-(1-7) were higher in pregnant women, but showed a different pattern in the GDM group, in which reduced Ang-(1-7) circulating levels were found . This obOxytocin is widely used clinically. Oxytocin and its receptors are abundant in human placental tissues . As a vaIn reviewing the research about GDM, some studies indicated that oxytocin was involved in the deterioration of glucose tolerance in GDM . Gu, et By reviewing previous studies on the placenta and its blood vessels in PIH and GDM, the following conclusions can be drawn: 1) Compared with non-placental blood vessels, placental blood vessels show their own unique contraction characteristics. 2) Although controversy still exists, the ability of placenta to secrete vasoactive substances and the vasoconstriction sensitivity of placental blood vessels were changed under PIH or GDM pathological conditions. A major reason for the controversial conclusions regarding the pathological changes of PIH and GDM placentas may be the small sample size. Due to the huge differences in human genetics, environment, lifestyle, etc., the number of experimental samples in many studies was too small , which is not enough to draw reliable conclusions on the physiological and pathological characteristics of the placenta. The other main reason for the controversial conclusions is gestational week. Compared with normal pregnancy, the gestational week of PIH and GDM is generally smaller. This confounder may be an important reason for the conflicting results of previous studies. Furthermore, the influence of maternal age and other potential co-morbidities such as obesity cannot be ignored. Although most studies attempted to exclude these confounders as much as possible, the lack of samples made some conflicting results unavoidable. The impacts of these difference are unknowable. In addition, the impact of complications such as multiple births, abnormal amniotic fluid volume and abnormal umbilical cord has not been explained by related studies. In short, future research is urgently needed to address these controversies.Currently, agents or drugs associated with these endogenous vasoconstrictors were reported to have the therapeutic potential to PIH or GDM. For example, ET-1 receptor antagonists may have potential for the treatment of PIH . AT1R ag


A total of 1000 mice were included, with 864 animals being heavily manipulated and 136 being handled for routine husbandry procedures only. Traumatic osteoarticular lesions were found in 61 heavily manipulated mice, and in a single unmanipulated mouse, showing a highly significant association between the presence of traumatic osteoarticular lesions and heavy handling of mice. We discuss the need for intentional training of research personnel on appropriate mouse handling and restraint techniques, which could help reduce the lesion frequency and the impact on animal wellbeing as well as study reproducibility.Any routine manipulation and handling of mice for husbandry and/or experimental needs can cause physical harm. Besides being an ethical concern, trauma from manipulation and handling is a possible confounding effect on research outcomes. Specific pathologic effects of routine manipulations and handling are poorly documented and largely ignored by investigators. Our study provides a comprehensive post mortem overview of the main pathological changes associated with routine interventions  of laboratory mice with an emphasis on presumed traumatic osteoarticular lesions. A total of 1000 mice from various studies were included, with 864 animals being heavily manipulated and 136 being handled for routine husbandry procedures only. The most common lesions observed were associated with blood collection or intraperitoneal injections, as well as a series of traumatic osteoarticular lesions likely resulting from restraint. Osteoarticular lesions were found in 62 animals  with rib fractures and avulsion of the dens of the axis being over-represented. Histopathology and micro-CT confirmed the traumatic nature of the rib fractures. While these lesions might be unavoidable if mice are manipulated according to the current standards, intentional training of research personnel on appropriate mouse handling and restraint techniques could help reduce their frequency and the impact on animal wellbeing as well as study reproducibility.Routine handling and manipulation of laboratory mice are integral components of most preclinical studies. Any type of handling and manipulation may cause stress and result in physical harm to mice, potentially leading to unintended consequences of experimental outcomes. Nevertheless, the pathological effects of these interventions are poorly documented and assumed to have a negligible effect on experimental variables. In that context, we provide a comprehensive  Mice have been used in biomedical research for centuries, with the first reports of scientific experiments using mice dating to the 17th century . This ispost mortem overview of the main pathologic changes associated with routine handling and restraint techniques for experimental interventions in laboratory mice with an emphasis on traumatic osteoarticular lesions. The application of a rigorous and comprehensive protocol for post mortem analysis of experimental mice across different studies  has been critical to defining many of these manipulation-induced lesions. While some lesions are expected based on the type of manipulations , this study also reveals unique traumatic osteoarticular lesions that are unexpectedly associated with standard handling/restraining techniques.The present study provides a comprehensive 2 inhalation, and exsanguination via cardiac blood collection served as a secondary method of euthanasia. Complete necropsy with macroscopic post mortem examination was then performed and the following organs/tissues were sampled and fixed in 10% neutral buffered formalin (NBF) for histopathological examination: head and brain, spine with spinal cord , skin from the dorsal region, pinnae, quadriceps femoris, sternum, salivary glands, larynx and trachea, esophagus, lungs, heart, gastrointestinal tract, mesenteric ligament, pancreas, liver and gall bladder, gonads and reproductive tract, kidneys, urinary bladder, and any organ/tissue showing macroscopic lesion/s. The weights of liver, spleen, right and left kidneys, and heart were recorded before fixation. Formalin-fixed tissue samples were trimmed according to the RITA guidelines  . The association between heavy manipulation and the presence of osteoarticular lesions was statistically highly significant . To better characterize the extent of the trauma, a correlative micro-CT study was performed on mice with macroscopically identifiable rib lesions. The micro-CT confirmed the presence of complete transverse rib fractures with callus formation . The effect of the genetic background was assessed in the NSG and C57BL/6J groups as enough mice from multiple studies were available for these strains only. Mice from these two strains underwent similar types of experimental interventions. In this context, the frequency of osteoarticular lesions was significantly higher in mice on a C57BL/6J background as compared to NSG mice . When mice were grouped and compared based on the type of experimental manipulation, no significant differences were seen between mice undergoing retro-orbital or facial/maxillary vein bleeding, and IV or IP injections . While an overall trend towards increased traumatic osteoarticular lesion frequency in older animals was observed, statistical significance was not reached, even after stratification based on strain and sex  penetrating trauma to the ocular/periocular region  and (2) penetrating trauma to the facial and maxillary regions . The former was seen in 133 mice out of 317 with confirmed RO blood collection and ranged from mild inflammatory cell infiltrates in the limbal conjunctiva and episclera, to extensive necrotizing and suppurative retro-orbital cellulitis with destruction of the Harderian gland, or well-defined retro-bulbar abscesses. Penetration of the sclera with secondary panophthalmitis and occasion . Foreignoccasion . ExposurSimilarly, 39 out of 164 mice that underwent blood collection by puncture of the maxillary, or another branch of the facial vein, exhibited pathologic changes in the region. The changes ranged from minor venous non-occlusive mural thrombi  to extenn = 3) (n = 13)  . In most(n = 13) . These l(n = 13) .n = 82) or hemoabdomen (n = 21), puncture of visceral organs (n = 16), and necrosis and inflammation of the mammary fat pad (n = 6). In the cases of peritonitis, the inflammation was frequently associated with the introduction of foreign material  and bacteria, or with the injection of lipid-rich vehicles, resulting in a granulomatous inflammatory process with intralesional lipid droplets. The puncture of visceral organs, including the gastrointestinal or reproductive tracts, the kidneys or the liver commonly resulted in a localized inflammatory reaction with linear tracts of necrosis and/or granulation tissue in the parenchyma, and introduction of foreign material   . In two  origin) .Mice have been used in biomedical research for centuries . BecauseThis study presents obvious limitations due to the retrospective nature of the data. In particular, the nonuniform dataset, including undetailed experimental intervention history for some of the animals, prevented a more granular assessment of the relative contribution of different variables to the development of the reported lesions. Nonetheless, we believe the sheer number of animals included in this study and the statistically significant correlation between forced physical restraint and specific types of traumatic osteoarticular lesions support our hypothesis of handling-induced pathogenesis.A multitude of methods have been described for handling and restraint of mice. Those practices are essential for the safety of the animals as well as the handler . NeverthThe distribution of these traumatic lesions, as well as the highly significant association with repeated restraint, supports the notion that forced handling is the critical determining factor in their development. Male mice and mice on a C57BL/6J background were significantly more likely to present osteoarticular lesions. The exact reason for these correlations remains unclear. Mice on a C57BL/6 background are not classically considered as being more aggressive , which rAdissu et al. described sternal lesions in C57BL/6N mice in the context of an extensive phenotyping program with frequent handling and restraint of animals. The lesions consisted of dislocation of the 4th sternebra and were seen with a higher prevalence in males. They hypothesized a possible traumatic pathogenesis caused by the frequent neck scruffing and subsequent increased constraint on the sternum . InteresBlood collection is a crucial part of most scientific investigations and can be performed in several ways, all of which require adequate and specific training . TechniqPeritoneal injections are an integral part of research and are performed for various reasons, whether for injection of experimental drugs, for injections of medications such as tamoxifen, busulfan, anesthetics, or for orthotopic implantation of neoplastic cells. When performed appropriately, these manipulations typically result in minimal changes. However, our data showed the development of significant pathological changes of the peritoneal cavity and/or abdominal wall in almost 20% of the mice receiving IP injection(s). In some cases, such as with the injection of lipid-rich vehicles, the changes were anticipated. In others, they are suspected to be due to poor technique with the introduction of foreign material or bacteria, and puncture of visceral organs.Although we were not able to detect a statistically significant correlation between the different blood collection techniques, the IV and IP injections, and the presence of traumatic osteoarticular lesions, the vast majority of the manipulated animals included in this study underwent either all or a combination of these experimental interventions. The relative contribution of each individual manipulation to the overall spectrum of osteoarticular traumatic changes is therefore difficult to ascertain.While most of the pathological changes associated with blood collection and IP injections have been reported in the literature and studied extensively in regard to animal welfare, the osteoarticular lesions we report, and their potential effects on research outcomes are not known, and likely not taken into consideration by investigators. The consequences of pain and analgesia on several physiologic and pathologic conditions has been extensively investigated, with effects ranging from suppression of specific immune functions ,35, moduThe pain generated by bone fractures is well-studied in the context of fracture repair research . ImportaA recent survey of 185 laboratory animal veterinarians identified that the training of researchers performing procedures on animals was the number one area that would benefit from continued evaluation in order to increase mouse welfare in research as well as experimental reproducibility . IntentiIn conclusion, our results establish a very compelling causative link between specific routine manipulations and clinically significant lesions in laboratory mice. Therefore, we believe that the outcomes of our study are important to inform the refinement of best practices for routine mouse handling/restraining, blood collection, and IP injection with the ultimate goals of minimizing animal discomfort/pain and improving experimental reproducibility.


In recent years, myoelectric control systems have emerged for upper limb wearable robotic exoskeletons to provide movement assistance and/or to restore motor functions in people with motor disabilities and to augment human performance in able-bodied individuals. In myoelectric control, electromyographic (EMG) signals from muscles are utilized to implement control strategies in exoskeletons and exosuits, improving adaptability and human–robot interactions during various motion tasks. This paper reviews the state-of-the-art myoelectric control systems designed for upper-limb wearable robotic exoskeletons and exosuits, and highlights the key focus areas for future research directions. Here, different modalities of existing myoelectric control systems were described in detail, and their advantages and disadvantages were summarized. Furthermore, key design aspects  and the type of experiments conducted to validate the efficacy of the proposed myoelectric controllers were also discussed. Finally, the challenges and limitations of current myoelectric control systems were analyzed, and future research directions were suggested. The demand for wearable robotic exoskeletons, more specifically upper limb rigid wearable robotic exoskeletons and soft wearable robotic exosuits, has substantially grown over the past few decades due to their promising applications across industry, and the medical and military sectors. The exoskeletons contain rigid links and joints attached to the user’s body, while exosuits use soft, flexible materials (such as fabric or soft polymer) to interface with the user’s body . The intThe myoelectric control systems of upper limb exoskeletons are based on surface electromyography (EMG) signals, which are the electric potentials directly measured from skeletal muscles and that are generated from motor unit activation . The genThe early stages of myoelectric control modalities for upper limb exoskeletons were based on on-off/finite state control and proportional control ,9. AlthoGiven the growing demand for exoskeletons, the number of publications on myoelectric control systems for upper limb exoskeletons and exosuits has rapidly increased over the past decade. It is therefore imperative to understand the latest trends and developments of myoelectric control systems for upper limb exoskeletons and exosuits, and to analyze their advantages and limitations in order to pinpoint the future directions for advancing this field. However, to the best of our knowledge, there has not been any comprehensive review that specifically focuses on the myoelectric control systems of upper limb exoskeletons and exosuits. Therefore, this review provides a comprehensive overview that will serve as a guidance for researchers and developers working in this field to address the challenges and limitations of existing myoelectric control systems, which in turn will enhance the utility and practicality of this technology and boost its real-world transition.This review includes articles published in IEEE Xplore, Web of Science, and PubMed. Because the search result indicates that 194 out of 228 research articles were published between 2011 and 2021, this review will only focus on the research articles published during this duration. This review particularly focuses on the state-of-the-art myoelectric control systems designed for upper limb exoskeletons successfully implemented on a physical platform, i.e., exoskeleton/exosuit prototypes, and validated experimentally. The rest of the paper is organized as follows: The method used to search and to identify key literature pertaining to myoelectric control systems on upper limb exoskeletons are described in this section. This process was guided by the PRISMA method  for condThe eligibility criteria of this survey include articles: (i) written in English, (ii) published between 2011 and 2021, (iii) using s-EMG signals as inputs to control the upper limb wearable robotic exoskeleton, and (iv) implementing the controller on a physical model and conducting an experimental validation on human subjects. The time frame selected for this survey (criteria (ii)) was to capture the most recent advancements in myoelectric control systems for upper limb wearable robotic exoskeletons within the past 11 years. In addition, criterion (iv) was set to preclude studies in which myoelectric controllers were realized only in computational models or through simulation, since they cannot capture some uncertainties and nonlinearities present in the human–robot interface in the real world ,14.The research articles reviewed in this paper were collected from three databases: IEEE Xplore, Web of Science, and PubMed, which are the database for the world’s highest quality technical literature in engineering and technology (IEEE Xplore), the world’s oldest, most widely used, and authoritative database of research publications and citations (Web of Science), and the world’s largest free MEDLINE database for life sciences and biomedical literature (PubMed).All three databases accepted similar search queries and keywords with small variations . The keyhttps://www.overleaf.com/project, (accessed on 12 September 2022) process of searching, screening, filtering, and the selection of articles to be included [The search query resulted in 180 articles, among which 90 were counted twice, as they appeared from more than one database. In addition, based on criteria (iv), i.e., the implementation and validation of the proposed myoelectric control system on a physical model, 30 articles were excluded. Finally, 60 articles were selected and reviewed in this survey. This result section contains the description and analysis of the included research articles. A narrative style is adopted to present our results. The results are presented based on four aspects: (i) a general description of information sources, (ii) different types of myoelectric control systems, (iii) key design characteristics of the device , and (iv) types of experiments conducted to evaluate the efficacy of the proposed controller.A summary of the relevant characteristics of the 60 articles included in this literature review is organized in In addition, we conducted a bibliometric analysis of the selected articles and plot  to preseThe myoelectric control system is designed to detect the movement intention of the user by deciphering the EMG signals generated in skeletal muscles. Among the reviewed literature, different modalities of myoelectric control systems for upper limb exoskeletons were identified , then uses it as a control input to assist the user in performing a specific movement  used biomechanical model-based myoelectric control systems, and most were intended for power augmentation. The first implementation of Hill’s Muscle Model in the myoelectric control system was presented by  to contrThe authors in  also impOne limitation of Hill’s Muscle Model is that there are situations when it cannot yield an accurate detection of the user’s motion intention . For exaTo reduce the setup time and to use fewer numbers of muscle segments for the shoulder joint muscle, ref. ,29 used pared to , which rpared to ,29 only pared to ,29 signipared to , the resThe research articles mentioned above use Hill’s Muscle Model to estimate the joint torque; however, it can also be used in the myoelectric control system for other purposes. For example, ref.  developeFurthermore, ref.  used theAs validated in many studies ,59,63,72The machine learning approach has been employed in upper limb exoskeletons to predict the movement pattern from EMG signals using various modalities. Such modalities of the myoelectric control system use the statistical features of the preprocessed EMG signals, such as root mean square (RMS), wave length (WL), and mean absolute value (MAV)  as input1Pattern recognition or classification-based myoelectric controlIn the myoelectric control system, the classification model can detect the type of movement corresponding to the input EMG signal. For example, ref.  implemen2Regression-based Myoelectric ControlThe regression model represents the relationship between input and output data as a function that is trained with a pre-collected dataset. Compared to the classification model, which can only detect discrete motions, the regression model can output continuous variables with the statistical feature of the EMG signal as input, such as joint angle and joint torque. The regression models can be constructed using different approaches, such as linear regression, ANN , and KalAmong the included articles, ref.  implemen3Reinforcement Learning-based Myoelectric ControlIn addition to the classification and regression model, the reinforcement learning model was also used in the myoelectric control system in the reviewed articles. Unlike the classification and regression models, the reinforcement learning model is trained with a reinforcement learning algorithm that uses a smart agent to learn the optimal policy while interacting with an environment. During the process of reinforcement learning, the smart agent exerts an action on the environment, based on its observation of the environment (state) as feedback, and then the environment returns a score to evaluate the agent’s action (reward). Based on the reward returned from the environment, the agent optimizes its policy toward the direction of greater reward .In the field of wearable robotics, reinforcement learning has been used in prosthetic control , lower As mentioned above, the ML-based myoelectric control schemes show promising results in increasing the accuracy and reliability of myoelectric control of an upper limb wearable robotic exoskeleton. However, some limitations exist in the ML-based myoelectric controls, such as a limited implementation in multi-DOF upper limb wearable robotic exoskeletons , poor peThe neural-fuzzy-based myoelectric control system is another scheme for controlling an upper limb exoskeleton-type exoskeleton. According to the theory of modern artificial intelligence, neural fuzzy is defined as the combination of a neural network and fuzzy logic . The fuzJosé et al. ,93 firstTo improve the compatibility of the neuro-fuzzy myoelectric control system for higher DOF exoskeletons, a different type of fuzzy logic was implemented on a 7-DOF upper-limb exoskeleton , which rThis section presents the literature research for the design aspects of upper limb exoskeletons that are equipped with the myoelectric control system, which include degrees of freedom, portability, and the application of upper limb exoskeletons.As shown in Among the reviewed literature, 63% (37 articles) of studies developed upper limb exoskeletons with portable structures, while the remaining ones presented fixed upper limb robots , assistive use , and human augmentation  (as shown in About 30% (18 articles) of the reviewed literature developed assistive upper limb wearable robotic exoskeletons  of the reviewed exoskeletons were developed for potential application in human performance augmentation ,39,50,71Among the reviewed literature, nine studies tested their prototypes on subjects with neuro-muscular impairment (either stroke or SCI patients) ,54,64,65The controller performance was tested in many studies using kinematic evaluation, where the most commonly used outcome measures identified were trajectory tracking performance  and velocity ,62,65,67Only one study  performeIn this review, myoelectric control systems designed, implemented, and validated on upper limb exoskeletons, especially the rigid-link exoskeleton and exosuit, were classified into threshold-based, proportional, biomechanical model-based, machine learning-based, and neural-fuzzy myoelectric control systems. In addition, each control modality provided details on the control methods, performance, and limitations. These existing myoelectric control systems show promising outcomes, demonstrating enhanced human–robot interactions, robot intelligence, and adaptiveness to the user, task, and environment compared to traditional control systems without using electromyography. However, several challenges and limitations are commonly discussed and explored in the articles associated with myoelectric control systems applied to upper limb wearable robots. The limitations and challenges extracted from the included research articles suggest that future studies of myoelectric control systems for upper limb exoskeletons should focus on narrowing the gap between laboratory studies and clinical applications. Further studies are needed to investigate the myoelectric control system of upper limb exoskeletons in clinical environment. This chapter discusses the research questions and tasks for future research works to narrow the gap between laboratory studies and clinical applications, which include (1) the robustness of machine learning-based myoelectric control, (2) the calibration procedure of the biomechanical model-based myoelectric control system, (3) the implementation of myoelectric control systems to a high degree-of-freedom wearable exoskeleton, (4) the incorporation of safety requirements in myoelectric control systems, (5) a clinical assessment of assistive and rehabilitative wearable exoskeletons based on myoelectric control systems, and (6) the incorporation of human-centered myoelectric control. These are crucial barriers to the effective use of myoelectric controls on upper limb wearable exoskeletons, warranting further research.The robustness of the myoelectric control system relates to its capability to resist disturbance from and within the environment on electromyography signal ; such a Within the reviewed research articles that implemented machine-learning-based myoelectric control systems in this review, commonly reported issues include varying characteristics of EMG signals between different physiological conditions, noise/artifacts, and muscle fatigue that cause variants in the EMG signal, and electrode shifts during or between sessions. However, none of the research articles included in this review specifically addressed these issues. Existing studies on the myoelectric control of prosthetics, teleoperate robotic arms, and the pattern recognition of EMG signals have already investigated such issues. For example,  exploredIn addition to the above mentioned research fields, future research should also explore the implementation of sensor fusion methods and their contributions to improving the robustness of machine learning-based myoelectric control systems. The sensor fusion of myoelectric control systems refers to the combination of sensors different from the EMG sensors to achieve a better accuracy and a better inference on the user’s movement intention. In this review, some research articles implemented sensor fusion methods to improve the accuracy of the myoelectric control system ,30,45,52The parameters of the human musculoskeletal models implemented in myoelectric control systems vary between users. Therefore, repetitive customization and calibration are required before each use, significantly affecting the practicality of wearable exoskeletons using biomechanical model-based control, and limiting their translation from in-lab assessment to real-world applications. The calibration of the musculoskeletal model needs additional experiments before its use as the anatomical model of the limb. For example, in , a motioAlthough the included articles have made many efforts to simplify the calibration procedure ,47 and sMost papers have explored only a single DoF control scheme, rather than the simultaneous control of multiple DoFs, due to its relative simplicity, while a multiple DoF system could render the enhanced adaptability of the robot. Compared to a single DoF actuation control, the simultaneous control of multiple DoF is challenging in practice. Having more than a single DoF requires the exoskeleton joint motion controller to properly coordinate the desired limb motion. During complex motions, including cyclic tasks , the frequencies of different joint movement trajectories must be synchronized to produce the robot’s desired periodic motion. However, in the conventional EMG-based control methods, e.g., where a single (or a pair of) muscle activity is mapped to a single DoF actuation, joints with only a few DoF can be controlled because of their low motion complexity. Similarly, a fuzzy controller’s rules would become convoluted with an increased number of DoF and/or periodic motions. For the more involved and higher DoF movements, such as that of the hand, a machine learning-based myoelectric muscle motion pattern recognition has proven to be a reliable method due to its characteristics previously detailed in To provide effective assistance in ADLs, an upper limb wearable exoskeleton must have a high number of DoFs, and a controller to coordinate those motions while requiring the user to put in a minimum of effort. Therefore, dimensionally reducing the control problem can be a possible approach. In one study, to dimensionally reduce the essential control inputs, a 10-DoF (independently actuated) whole-hand exoskeleton took advantage of kinematic synergies—a collection of relatively independent degrees of freedom behaving as one functional unit —enablingFinally, the number of actuators increases with the number of DoFs, causing limitations in wearability and portability as it increases the weight, cost, and size. Therefore, reducing the number of DoFs; for example, mechanically coupling a few joints with small ranges of motions or requiring low actuation forces, can make the device simpler and more lightweight. One drawback of this solution is that it can limit the flexibility and possible motion patterns of the system. Another possible solution can be having fewer actuators than the number of DoFs, which is known as the under actuation strategy .Safety is a critical requirement for upper limb exoskeletons, particularly for active powered systems. For assistive and rehabilitative applications, it is essential to ensure the safety of the patients so that these robots will not cause a risk of injury during use. Existing exoskeletons in the literature mainly focus on implementing safety measures in mechanical design, such as installing mechanical stops, rotation limits, or force limits to guarantee that there is no excessive range of motion movements or excessive force applied to the user .However, such mechanisms cannot always fully warrant the safety of the user in the presence of unknown large parameter variances, hardware failures, or actuator defects . TherefoFor machine learning- or deep learning-based myoelectric control systems, implementing post-processing techniques, such as multiwindow smoothing and confidence estimation, may also improve the reliability of the controller . MultiwiThe myoelectric control systems reviewed in the literature were tested in laboratory settings, mostly on able-bodied users. Although many studies showed good preliminary results with healthy subjects, to transition from laboratory to real-world assistive and rehabilitative applications, these prototypes need to be further tested on large-scale clinical populations to address inter- and intra-subject variability issues. Because the voluntary muscle contraction level and muscle fatigue endurance may vary between healthy and neurologically impaired subjects; thus, it might impact on the efficacy of the proposed control method in assisting the intended motion/task of subjects with motor disabilities with high accuracy and reliability, despite achieving desired results with healthy users. For example, in , the ovearly, in , the avearly, in ), particExperimental validation methods for rehabilitative exoskeletons in the reviewed literature have mostly been limited to evaluating trajectory tracking performance, movement execution velocity, user’s effort, and joint torque estimation for one session of lab assessment. Although these outcome measures may indicate the functionality of the physical model and the efficacy of the control system in assisting the user in performing a certain movement or task, it might not completely reflect the effectiveness of the robot-assisted training in improving the motor function of subjects with neuro-muscular disorders. Since clinical validation studies of myoelectric control systems for upper limb exoskeletons are still in their infancy, the focus should be given to performing experimental validation with control groups at least, to provide stronger evidence for the effectiveness of robot-assisted training. In addition, there is a possibility that the classification accuracy of ML-based myoelectric control might not be strongly associated with the training effectiveness. For example, in , the reaClinical assessment tests are useful in evaluating the efficacy of myoelectric control-based exoskeletons in achieving desired outcomes among neurologically impaired patients. For example, in , the SolThe research literature included in this systematic review has shown innovative ideas for using EMG signals to control an upper limb wearable robot. However, the presented control modalities can be broadly categorized as using a machine learning model or a musculoskeletal model, using EMG for the continuous control of assistive torque , and starting the assistance of a wearable robot if the EMG signal satisfies certain conditions . Despite these articles demonstrating promising results, these myoelectric control systems are developed to map the user’s movement intention from the EMG signal to a specific task, and then to control the wearable robot to complete this task. The wearable robots controlled by such types of myoelectric control systems only focus on finishing the assigned tasks, and are unable to perceive the feedback of the user. However, the wearable robot and human physically interact in a bidirectional approach; therefore, understanding the feedback of the human by developing a human-based myoelectric control system can improve adaption and synchrony between the human and the wearable robot.Different from the existing literature, the human-based myoelectric control system should focus on fulfilling the human’s motion intention, which can be achieved by minimizing human effort . For example, when controlling an upper limb wearable robot to help the human to lift a heavy load, the myoelectric control system should no longer estimate the load from the EMG signal and control the robot to output the corresponding assistive force to compensate for the gravitational load. Instead, the myoelectric control system will control the wearable robot to output a proper amount of assistive force to minimize the amplitude of the human’s EMG signal. Compared to the conventional control approach, the human-based myoelectric control system is adaptive to the variant of EMG signal, which reduces the dependency on calibration. As a matter of fact, such an approach has been introduced by  to contrThe myoelectric control systems have shown their efficacy for use in the upper limb exoskeletons to enhance human–robot dynamics and interactions. This review focused on identifying and categorizing key control strategies employed in myoelectric control systems implemented on upper limb exoskeletons. The overview of each myoelectric control system was presented, highlighting their control performance and accuracy, as well as their limitations and challenges. Some future research directions are proposed: improving adaptiveness across different users, tasks, and environments, myoelectric control systems for multi-joints and/or bilateral arm assistance, improving robustness against the disturbance in the real-world application, developing a human-centered myoelectric control system, and improving its safety features through a human subject evaluation process. It was noted that comparably less work has been performed to exploit a human-centered myoelectric control system, and fewer validated models exist in the literature. This warrants further research to assess the applicability of a human-centered myoelectric control system to control upper limb wearable exoskeletons. Further, all myoelectric control systems discussed in this review were evaluated in laboratory settings, and mostly on healthy able-bodied individuals, limiting their implications on clinical applications. Nevertheless, the rapid evolution and the many variations of myoelectric control systems observed in recent years suggest that it is the most promising strategy for the intelligent, adaptive, robust, and human-in-loop control of upper limb exoskeletons.