Stroke leads to significant impairment in upper limb (UL) function. The goal of rehabilitation is the reestablishment of pre-stroke motor stroke skills by stimulating neuroplasticity. Among several rehabilitation approaches, functional electrical stimulation (FES) is highlighted in stroke rehabilitation guidelines as a supplementary therapy alongside the standard care modalities. The aim of this study is to present a comprehensive review regarding the usability of FES in post-stroke UL rehabilitation. Specifically, the factors related to UL rehabilitation that should be considered in FES usability, as well a critical review of the outcomes used to assess FES usability, are presented. This review reinforces the FES as a promising tool to induce neuroplastic modifications in post-stroke rehabilitation by enabling the possibility of delivering intensive periods of treatment with comparatively less demand on human resources. However, the lack of studies evaluating FES usability through motor control outcomes, specifically movement quality indicators, combined with user satisfaction limits the definition of FES optimal therapeutical window for different UL functional tasks. FES systems capable of integrating postural control muscles involving other anatomic regions, such as the trunk, during reaching tasks are required to improve UL function in post-stroke patients. Stroke is the major cause of disability ,2. It waIt is expected that stroke will continue to be the main cause of disability-adjusted life years until 2030. Consequently, rehabilitation care will continue to represent an important and growing burden for the global health system difficulting the ideal of personalized rehabilitation based on a ratio of one therapist for one patient ,16,17. TPrevious systematic reviews with meta-analysis have demonstrated the positive effects of FES on ADL outcomes ,20,22. TThe aim of this study is to present a comprehensive review regarding the usability of FES in UL rehabilitation of post-stroke subjects. Specifically, the factors related to post-stroke UL rehabilitation that should be considered in FES usability, as well a critical review of the outcomes used to assess FES usability, are presented. Accordingly, this review is divided into four sections. In the present section, the epidemiological data that sustain the need of exploring strategies to improve UL function in post-stroke patients is presented. The second section presents an overview of the particularities of UL rehabilitation in post-stroke subjects and its implications in FES usability. Section three is focused on FES usability and gathering and discussing the available measures to assess UL movement quality indicators. This section presents a critical review of the outcomes to be considered to assess FES effectiveness. Finally, the last section reports the final considerations of this review. The goal of rehabilitation is the reestablishment of pre-stroke motor stroke skills by stimulating neuroplasticity , a complNeuromuscular electrical stimulation (NMES) has emerged as an efficient tool to induce activity-dependent plasticity in neural circuits in stroke patients ,29,30. NBased on the arguments presented in A wide body of evidence supports the ability of FES in improving motor control ,41,42. TBased on the exposure and considering that the motor learning is specific and depends on the repetition of the motor task, its novelty and concurrent volitional effort, the FES must provide the execution of the movement for functional tasks performance with precision and efficiency . In factAs mentioned in During reaching tasks, each UL movement is preceded  and accompanied  by anticipatory adjustments that must also occur in the contralateral side to movement execution ,59,60,61It is known that square or rectangular biphasic pulse shape is more efficient for nerve stimulation due to an instantaneous increase in current to the maximal level . The pulApart from the limitations previously mentioned, technological advances were made to improve muscle recruitment selectivity. From these, the development of the multifield electrode system enhances the generation of a localized electric field that increases the selectivity in motor units recruitment with reduced discomfort and fatigue , comparethe possibility of desynchronized activation of different portions of the muscle ;the possibility of individual adjustment of the stimulation location ;the possibility of varying the stimulation parameters and patterns of stimulation, namely frequency, amplitude, pulse duration and stimulation channel, to recruit the more adequated synergy .The performance of functional movements resulting from the selective and synergistic activation of muscle groups associated with multifield FES depends on the adequate positioning and calibration of the electrodes, namely in terms of amplitude, pulse width and frequency ,77. MultPrevious studies concerning FES multifield systems have demonstrated the stimulation zones and related parameters that lead to selective activation of the common extensor of the fingers, extensor digiti minimi, cubital extensor, radial extensor of the carpus, abductor pollicis longus, extensor pollicis brevis and extensor pollicis longus ,77. The Concerning technological devices developed for people with limitations in activity and participation, such as post-stroke patients, the usability tests become an essential tool to ensure that a product has the desired impact. To evaluate FES usability, the quality of the user’s experience in terms of satisfaction and effectiveness should be considered . UsabiliSatisfaction is the users’ comfort with and positive attitudes towards the use of a system . The SysEffectiveness is the accuracy and completeness with which users achieve certain goals. Indicators of effectiveness include quality of solution and error rates .To analyze FES effectiveness, clinical measures related to ADL, functional recovery measures and muscle-related outcomes were considered  19,20,2,220,22. When analyzing the results provided by the tools presented in Laboratory measures allow an accurate and objective assessment of FES effectiveness regarding the selectivity and quality of UL movement. Some authors ,93,94,95Quality of movement can be accurately evaluated by kinematic analysis. In fact, in the last decade, the kinematics of the ULs of neurological patients, mostly after stroke, were studied in order to quantify movement objectively . AccordiFor this purpose, the most widely used type of motion capture system is the optoelectronic system with passive markers , which iThe motor tasks generally used to study the function of ULs can be categorized into functional movements (reaching movements and path drawing) and ADL ,98,102, Numerous kinematic metrics were used in the evaluation of UL movement in post-stroke patients ,107, whiThe interpretation of kinematic variables is unclear. Subramanian et al.  suggesteFES seems to be a promising tool for improving UL function in post-stroke patients. However, the lack of studies evaluating motor control variables, specifically movement quality indicators, combined with user’s satisfaction, limits the establishment of conclusions regarding its usability. This lack of information compromises the establishment of the optimal therapeutical window for different UL functional tasks for post-stroke patients. Besides considering the stimulation parameters that best assist the desired movement, the optimal therapeutical window should also consider the muscle synergy that needs to be recruited. FES systems capable of integrating postural control muscles involving other anatomic regions, such as the trunk and ipsilesional side, are required to improve UL function in post-stroke patients.


The current SARS-CoV-2 pandemic has exacerbated the rapid diagnosis of infectious diseases outbreaks to take suitable epidemiological measures to minimize negative impacts , for instance , carried by high-risk clone ST277 isolated from urban rivers. The authors observed a common resistome and virulome between clinical and environmental SPM-1-producing P. aeruginosa strains endemic from Brazil. Additionally, the SNP-based phylogenomics showed a high similarity between clinical and environmental genomes, suggesting that these clones could be disseminated onto water bodies from hospital settings.Hospital wastewaters represent a broad reservoir of antibiotic-resistant bacteria (ARB) and ARGs, which include extended-spectrum β-lactamases (ESBLs) and carbapenemase-producing Perry et al. analyzed the influence of different hospital clinical activities on the abundance of ARGs in hospital wastewater in Scotland, highlighting the advantages of shotgun metagenomics to identify a full range of ARGs that could be used to guide environmental policies about AMR. Additionally, the article of Guo et al., using a high-throughput sequencing-based metagenomic approach, investigated the composition of bacteria and ARGs in wastewater from hospitals in China, suggesting a correlation between the abundance of ARGs and specific bacterial genera and remarking that it is necessary to complement their study including physicochemical analysis for the raw wastewater. Both articles show interesting results and note the necessity to develop an integrative framework that would include omics, physicochemical and epidemiological research to enhance the evaluation of ARGs pollution in environmental sources.One of the current outstanding questions about the analysis of AMR in the environment is the standardization of genomic and metagenomic assays that could minimize the spatiotemporal variability, the allochthonous ARG levels, the environmental resistome complexity, and the biases about genomic extraction, sequencing, and genomic analyses  E. coli isolated from influents of a WWTP. This study suggests that these isolates could be disseminated into the outgoing river from WWTP. The sewage could act as a potential spreader of ARGs, including emerging carbapenemase genes like blaNDM−5. In South Africa, Mbanga et al. characterized isolates of Enterococcus spp. from a WWTP and their receiving water bodies that serve as a water source for domestic, agricultural, and recreational purposes. Those isolates harbor a wide plethora of ARGs and virulence factors, showing that the effluents of the WWTP could act as a dissemination vector of multidrug-resistant (MDR) microorganisms. This Research Topic includes a review paper by Uluseker et al. that extensively reviews the current knowledge on sources, spread, and removal mechanisms of ARGs in microbial communities of wastewaters, WWTPs, and downstream recipients. This review includes the basis of antibiotic resistance, an explanation about the dynamics of AMR and antibiotics in WWTPs, and suggestions to be considered for the operation, regulation, and design of WWTPs. These studies suggest the urgent need for regular surveillance and management of water bodies to limit the spread of these isolates.Several papers of this special issue analyzed the influence of WWTPs and their discharges on AMR dissemination: In South Korea, Singh et al. analyzed Escherichia coli from the river Yamuna (India), a highly polluted river that receives an intense anthropogenic influence from urban and animal origin. Their results showed high AMR profiles, highlighting the presence of CTX-M-15 type ESBLs and the occurrence of class I integrons in their isolates. In Ireland, Sala-Comorera et al. demonstrated the strong impact of different watercourses discharges onto the levels of AMR in both bacterial and bacteriophage fractions in marine bathing waters, which may expose the users to fecal pollution and therefore could increase the probability to be exposed to ARGs. Another outstanding question about AMR in the environment is to demonstrate which levels of AMR are necessary to represent a real environmental danger. Finally, Pallares-Vega et al., shown by in vitro assays the role of ecological factors that could hamper conjugative plasmid transfer from gut bacteria once discharged into the environment. Their findings highlight the possibility that the fecal organisms may transfer plasmids in aquatic ecosystems, despite the variable conditions that could occur environmentally.Montero et al. analyzed ESBL producing E. coli isolated from irrigation waters, vegetables, and fruits in Ecuador. These authors detected that the allelic variants of the blaMCTX− gene found in irrigation channels and vegetables were the same as those observed in commensal E. coli from domestic animals, and commensal and pathogenic E. coli from humans, suggesting a connection between these different sources. In addition, the article of Cheng et al. analyzed sediments from aquaculture farms in China by constructing network plots based on 16S rRNA metagenomics, physicochemical analysis, and quantification of ARGs. Their results provide evidence for understanding the environmental risks associated with aquaculture practices. On the other hand, Ye et al. showed in Edwardsiella tarda, an important pathogen in aquaculture, that reactive oxygen species (ROS) play a role in bacterial resistance and sensitivity to ceftazidime. They saw a lower ROS production in ceftazidime-resistant E. tarda than in a sensitive strain related to the inactivation of the pyruvate cycle. Additionally, their study reveals a new mechanism that increases ROS production, the activation of the pyruvate cycle by Fe3+. These findings provide tools and knowledge for future new strategies to fight MDR pathogens.The food supply chain connects environmental sources of bacteria with humans and represents another outstanding field in the One Health perspective for understanding the dissemination and evolution of AMR. The article of Zeballos-Gross et al. comprehensively reviewed the potential role of gulls as reservoirs and vectors of AMR in the environment, highlighting the current knowledge about related research, the phenotypic and molecular characterization of AMR, limitations about the existing methodologies, and suggestions for improving the derived results.In summary, this Research Topic provides an excellent update of the role of aquatic ecosystems on the evolution and dissemination of AMR worldwide. Therefore, the editors encourage the scientific community to consider the results and challenges of this special issue.WC-C, JO-P, LR-R, and EM contributed to analyzing the reviewed articles and preparing the manuscript. All authors contributed to the article and approved the submitted version.LR-R is a Serra Húnter Lecturer.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Monocytes and macrophages play essential roles in all stages of atherosclerosis – from early precursor lesions to advanced stages of the disease. Intima-resident macrophages are among the first cells to be confronted with the influx and retention of apolipoprotein B-containing lipoproteins at the onset of hypercholesterolemia and atherosclerosis development. In this review, we outline the trafficking of monocytes and macrophages in and out of the healthy aorta, as well as the adaptation of their migratory behaviour during hypercholesterolemia. Furthermore, we discuss the functional and ontogenetic composition of the aortic pool of mononuclear phagocytes and its link to the atherosclerotic disease process. The development of mouse models of atherosclerosis regression in recent years, has enabled scientists to investigate the behaviour of monocytes and macrophages during the resolution of atherosclerosis. Herein, we describe the dynamics of these mononuclear phagocytes upon cessation of hypercholesterolemia and how they contribute to the restoration of tissue homeostasis. The aim of this review is to provide an insight into the trafficking, fate and disease-relevant dynamics of monocytes and macrophages during atherosclerosis, and to highlight remaining questions. We focus on the results of rodent studies, as analysis of cellular fates requires experimental manipulations that cannot be performed in humans but point out findings that could be replicated in human tissues. Understanding of the biology of macrophages in atherosclerosis provides an important basis for the development of therapeutic strategies to limit lesion formation and promote plaque regression. Atherosclerosis is characterised by a chronic, low-grade inflammation in the arterial wall. As the underlying pathology for myocardial infarction and stroke, it is the leading cause of death worldwide . The infResident arterial macrophages play a crucial role in tissue homeostasis and serve as immune sentinels within the tissue. Adventitial macrophages, for instance, are important regulators of collagen production and the arterial tone . At areaSince the description of the Mononuclear Phagocyte System, the prevailing paradigm was that tissue resident macrophages are continuously seeded from circulating monocytes. In recent years, however, it has become obvious that under homeostasis the tissue macrophage pool is mainly maintained through local proliferation and does not solely depend on monocyte influx –25. MonoIn this Review we address the knowns and unknowns of the trafficking, dynamics and fates of vascular monocytes and macrophages in the healthy and atherosclerotic aorta. Analysing these properties in human tissues is complicated by the availability of human material and models. Therefore, we will focus primarily on results from the mouse as a model organism but put these results into human context where possible at the end of this Review.The development and broad accessibility of novel high-dimensional analysis techniques, such as multi-parameter flow cytometry, single-cell RNA sequencing (scRNA-seq) and cytometry by time of flight, has enabled scientists to obtain a clearer picture of leukocyte diversity in the healthy mouse aorta. These studies revealed that myeloid cells, and in particular macrophages, are the dominant immune cell type in the healthy arterial wall , 42, 43.Cre  interferon inducible, (IV) resident-like and (V) cavity macrophages. These five subsets can be found both in the atherosclerotic and healthy aorta, although the complexity of macrophage phenotypes increases in atherosclerotic aortas , which might have detrimental effects on tissue repair or repetitive insults  interferon inducible, (IV) resident-like and (V) cavity macrophages   , 121. Fuof CD11c , similarof CD11c , 101. Inof CD11c , 125. Evunctions . It is iS and BM , 71, 125S and BM . These m disease . The ideial wall . Similarial wall , residenial wall , 70, 121e repair –129. The+ cell subset, which resemble foamy macrophages, has been shown to be actively migrating within the plaque. These results warrant further investigation on the trafficking of adventitial macrophages and macrophages of different ontogenies during the various stages of atherosclerosis development.Even though resident adventitial macrophages constitute 90% of the aortic macrophages and are the only arterial subset originating from EMPs, their involvement in the atherosclerotic disease process is unclear. The role of adventitial macrophage subsets, including the YS EMP-derived adventitial macrophages, warrants further investigation. As described above, EMP-derived adventitial macrophages show a distinct transcriptional signature of anti-inflammatory and efferocytic functions, that is preserved during chronic arterial inflammation . FailingAtherosclerosis is characterised by a failure to resolve the inflammatory response. The continuous influx and retention of apoB-containing lipoproteins represents a persistent inflammatory stimulus. The lowering of blood lipid levels, in particular cholesterol levels , allows Traditional mouse models of atherosclerosis, like the LDL receptor and apolipoprotein E knockout mouse, have greatly contributed to our understanding of the atherosclerotic disease process. These models, however, lack the ability to normalise hypercholesterolemia and induce regression. Fortunately, in recent years several mouse models of atherosclerosis regression were developed –138. Thevia afferent lymphatics or reverse transendothelial migration aids the host defence by presenting antigens to the adaptive immune system , which is known to induce type 2 or reparatory immune responses  non-classical CD14dimCD16+, aligning with the murine Ly6Clow subset, and (III) intermediate CD14+CD16+ monocytes  resident-like and (IV) interferon-inducible macrophages . This study was supported by the DFG, SFB 1123 project A07 to CS.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: As public awareness of family caregiving has grown, adults likely anticipate the role they may play as a caregiver for an aging loved one. Although anticipatory planning for caregiving has been studied, no measure of multiple dimensions of the anticipated caregiving experience exists. The purpose of the present study is to develop and validate the Anticipatory Caregiving Scale (ACS), an assessment of adult children’s attitudes toward and level of expectation surrounding their potential role as an informal caregiver to a parent or parent-in-law. Method: The ACS consists of six subscales that assess multiple factors that may influence willingness to or expectations about taking on a caregiving role: affect surrounding future caregiving, anticipated lifestyle interference, self-efficacy surrounding future caregiving, anticipated caregiving resources, endorsement of norms of family care which influence anticipated caregiving, and the relationship quality, current and anticipated, with the potential care recipient. A sample of 540 adults aged 18 and over recruited online completed the ACS, along with scales to assess convergent, discriminant, and concurrent validity. Results: Overall, the ACS and its subscales demonstrated good reliability and validity, established through internal consistency, and convergent, discriminant, and concurrent validity. Discussion: The ACS fills a gap in the current literature by providing a comprehensive, multidimensional assessment examining expectations about one’s potential caregiving experience, specific to the adult child-parent dyad. Future studies should examine the psychometric properties of the ACS in a more diverse population of adults across different settings and assess the temporal stability and criterion validity of the scale.


Identify types, characteristics and anatomic location of physical signs in elder abuse.Physical signs in elder abuse are most common bruises and anatomically predominantly located on the head, face/maxillofacial area, neck, upper extremities and torso.Increase knowledge on physical signs in elder abuse so as to enhance timely detection and intervention.The online version contains supplementary material available at 10.1007/s41999-021-00550-z. Elder abuse is a worldwide problem with serious consequences for individuals and society. The recognition of elder abuse is complex due to a lack of awareness and knowledge. In this systematic review, types, characteristics and anatomic location of physical signs in elder abuse were identified.Databases of MEDLINE, COCHRANE, EMBASE and CINAHL were searched. The publication dates ranged from March 2005 to July 2020. In addition to the electronic searches, the reference lists and citing of included articles were hand-searched to identify additional relevant studies. The quality of descriptive and mixed-methods studies was assessed.The most commonly described physical signs in elder abuse were bruises. The characteristics of physical signs can be categorized into size, shape and distribution. Physical signs were anatomically predominantly located on the head, face/maxillofacial area , neck, upper extremities and torso . Physical signs related to sexual elder abuse were mostly located in the genital and perianal area and often accompanied by a significant amount of injury to non-genital parts of the body, especially the area of the head, arms and medial aspect of the thigh.Most common types, characteristics and anatomic location of physical signs in elder abuse were identified. To enhance (early) detection of physical signs in elder abuse, it is necessary to invest in (more) in-depth education and to include expertise from a forensic physician or forensic nurse in multidisciplinary team consultations.The online version contains supplementary material available at 10.1007/s41999-021-00550-z. Elder abuse is a worldwide problem with serious consequences for individuals and society, due to increased morbidity, mortality and use of healthcare resources, especially emergency services –3. The dThere is complexity in the recognition of elder abuse. The level of awareness and knowledge on elder abuse in healthcare professionals is still poor and there is a strong need for education and specific training on recognition , 7. On tDifferent types of elder abuse, such as physical abuse, sexual abuse and neglect, can cause physical injuries. The detection and recognition of physical signs related to elder abuse may be complicated because it is not always easy to discriminate from signs of underlying diseases. For example, age-related changes or certain medication can make the skin more vulnerable to injury, which makes it difficult to assess whether skin bruising is either of an accidental or of a non-accidental nature. Furthermore, there are no known pathognomonic physical signs of elder abuse described, unlike in certain cases of child abuse –13.In this systematic review, we aimed to identify the types , characteristics  and anatomic location of physical signs in elder abuse to increase the awareness and recognition on injury (patterns) by clinical geriatricians and other healthcare professionals.A systematic review of the literature was performed according to the steps of the Cochrane Handbook for Systematic Reviews of Interventions , and repCochrane review on Interventions for preventing abuse in the elderly [The databases of MEDLINE, COCHRANE, EMBASE and CINAHL were searched. The publication dates ranged from March 2005 to July 2020. In addition to the electronic searches, the reference lists and citing of included articles were hand-searched to identify additional relevant studies. The search strategy was partly based on available MeSH terms from the search strategy protocol of the  elderly . Further elderly . The fulAll types of reviews, quantitative and qualitative study designs were included, with the limitation of studies published in the Dutch, German, French and English language. The inclusion criteria were: studies containing a description of types of physical signs (related to elder abuse) with regard to their characteristics and/or anatomic location of physical signs. Excluded were: conference proceedings, editorials, or other personal communications and studies that focused on the prevalence of elder abuse, or legislation and education in elder abuse not related to physical injuries. Furthermore, studies on suicide, homicide, histological examination, use of restraints from a professional perspective or self-neglect of older persons were excluded. All articles were screened on title and abstract by two independent reviewers . In case of doubt, a third reviewer (LV) was asked to make a final decision. In addition, reference lists and citing of included articles were screened  and potentially relevant new publications were screened in a similar way . Outcomes extracted were:Due to the paucity of original studies, we analyzed and synthesized all studies, by scrutinizing and categorizing data. The case report data from the mixed methods studies were considered as original data and were therefore analyzed as case report studies. The primary outcomes were based on descriptive studies. Additionally, information from other study designs was added. First, studies were categorized according to their design or publication form. Second, three themes based on the taxonomy for visible intentional and unintentional acute injuries by Rosen et al.  were modSkull/brain/maxillofacial/dental/neck.Chest/abdomen/back.Extremities (upper/lower).Pelvis/gluteal.Extragenital in sexual elder abuse.Miscellaneous.The following anatomic locations were chosen to categorize the physical signs:The initial search identified 5629 unique records, after the selection procedure 24 studies were included see Fig. .The design of the included studies concerned eight descriptive studies , 21–27, n = 8) showed moderate to good quality [Most of the descriptive studies  showed low quality [Most of the mixed methods studies , neck, upper extremities and torso . Other anatomic locations mentioned to be associated with elder abuse included the lower extremities, abdomen, lumbar area and gluteal/genital/rectal area, the latter location often mentioned as being associated with the presence of sexual elder abuse or neglect  , 35–39.Some studies described physical signs due to elder abuse to be specifically located on the left respectively right side of the body , 38, 39.Additional outcomes of elder abuse were diverse and involved wounds and unexplainable injuries, combinations of injuries, mechanism of injuries, sexual elder abuse and neglect in victims. Additional characteristics of physical signs were deep and/or foul-smelling necrotic aspects of ulcers, bilateral or parallel and irregular injuries, multiple and clustered injuries, circular bruising, splash marks from hot water and traumatic/irregular patches of alopecia. Although the color of bruises was stated not reliable for the dating of bruises, bruises with differing colors may point at recurrent abuse , 37, 41.The most commonly described physical signs in elder abuse were bruises. Characteristics of physical signs could be categorized into size, shape and distribution. Physical signs were anatomically predominantly located on the head, face/maxillofacial area , neck, upper extremities and torso . Physical signs related to sexual elder abuse were mostly located in vestibular and vaginal tissues, the labia minora and majora, posterior fourchette and the perianal area. Victims of sexual elder abuse were furthermore described to have a significant amount of injury located at non-genital parts of their body, especially on their head and arms and the medial aspect of the thigh. Unfortunately, with regard to the characteristics and anatomical location of physical signs in sexual elder abuse in older males, information was absent.https://www.government.nl/topics/domestic-violence/domestic-violence-and-child-abuse-protocol). In the Netherlands, elder abuse is categorized as a form of domestic violence and thus in case of elder abuse the mandatory reporting code in case of (suspected) domestic violence and child abuse is followed. Cases of elder abuse as a result of abuse by healthcare professionals are primarily reported to the healthcare inspectorate.This is the first systematic review on the state-of-the-art knowledge on physical signs in elder abuse where a quality analysis of observational studies was performed and additional findings of other designs were included. Furthermore, physical signs were described and classified along the lines of the taxonomy instrument for visible intentional and unintentional acute injuries based on the study by Rosen et al. . By idenThe reporting code offers a five-step plan detailing the best course of action and helps healthcare professionals in and outside  geriatric care to decide whether or not to report the situation to the Adult Protective Services (APS). In addition, within each hospital or institutional setting caring for older persons, it would be advisable to appoint a case manager on domestic violence and elder abuse, to coordinate and guide compliance with the follow-up of the reporting code and to support and advise the healthcare professional in the recognition and care for victims of elder abuse. The installation of an additional Multidisciplinary Elder Abuse Team (MEAT), where cases of elder abuse victims are (anonymously) discussed and course of action is evaluated, could further enhance a multidisciplinary approach to elder abuse investigation. Participants should at minimum include clinical geriatric and emergency medicine experts (nurses and physicians), a case manager on domestic violence and elder abuse, a social worker and a representative of the regional Adult Protective Services. With regard to the recognition of physical signs in elder abuse, it would be advisory not only to include forensic expertise from a forensic physician or a forensic trained nurse in the multidisciplinary elder abuse team, but also to incorporate them as a consultant in the acute setting. They can help recognize and safeguard forensic evidence during the assessment process. Finally, thorough reporting and transfer to healthcare professionals during discharge/care transition is essential in this process.A key limitation of this systematic review is that the primary data studies had moderate methodological quality and included only a limited number of studies with a (matched) control group. Furthermore, the narrative reviews mainly summarized the included observational descriptive studies. However, with this review, a contribution and an incentive to achieve higher methodological research quality in the field of elder abuse have been made, as pitfalls in existing knowledge on physical signs of elder abuse have been identified. More research regarding for example pathognomic injuries in elder abuse could eventually provide healthcare professionals with (more) practical knowledge on adequate and timely recognition of physical signs in elder abuse.The most commonly described physical signs in elder abuse are bruises.Older persons are more likely to have physical signs of elder abuse located on the head, face/maxillofacial area , neck, upper extremities and torso .Physical signs related to sexual elder abuse are mostly located in the genital and perianal area and are often accompanied by a significant amount of injury to non-genital parts of their body, especially to the area of the head, arms and the medial aspect of the thigh.The characteristics and anatomical location of physical signs in sexual elder abuse in males needs to be explored in future research.Knowledge regarding the most common types, characteristics and anatomic location of physical signs in elder abuse is useful to increase the awareness and recognition of elder abuse by clinical geriatricians and other healthcare professionals.There is a need for education on physical signs in elder abuse; furthermore, this topic should be included in clinical curricula at different levels : not only in bachelor and master programs for professionals such as clinical geriatricians and emergency physicians, but also for nursing and other healthcare professionals.Supplementary file1 (DOCX 17 KB)Below is the link to the electronic supplementary material.


Whilst initial anatomical studies of frontotemporal dementia focussed on cortical involvement, the relevance of subcortical structures to the pathophysiology of frontotemporal dementia has been increasingly recognized over recent years. Key structures affected include the caudate, putamen, nucleus accumbens, and globus pallidus within the basal ganglia, the hippocampus and amygdala within the medial temporal lobe, the basal forebrain, and the diencephalon structures of the thalamus, hypothalamus and habenula. At the most posterior aspect of the brain, focal involvement of brainstem and cerebellum has recently also been shown in certain subtypes of frontotemporal dementia. Many of the neuroimaging studies on subcortical structures in frontotemporal dementia have been performed in clinically defined sporadic cases. However, investigations of genetically- and pathologically-confirmed forms of frontotemporal dementia are increasingly common and provide molecular specificity to the changes observed. Furthermore, detailed analyses of sub-nuclei and subregions within each subcortical structure are being added to the literature, allowing refinement of the patterns of subcortical involvement. This review focuses on the existing literature on structural imaging and neuropathological studies of subcortical anatomy across the spectrum of frontotemporal dementia, along with investigations of brain–behaviour correlates that examine the cognitive sequelae of specific subcortical involvement: it aims to ‘look beneath the surface’ and summarize the patterns of subcortical involvement have been described in frontotemporal dementia. in vivo imaging and post mortem studies to discuss how neurodegenerative processes in these structures can lead to the heterogenous symptoms of frontotemporal dementia.Bocchetta et al. provide an overview of the subcortical structure involvement in the clinical, genetic and pathological forms of frontotemporal dementia. Their anatomy is described with   MAPT), progranulin (GRN) or chromosome 9 open reading frame 72 (C9orf72) genes.,Frontotemporal dementia (FTD) is a common cause of early onset dementia, approximately equal in frequency to Alzheimer’s disease in people under the age of 65. It is clinically heterogeneous with symptoms, including behavioural, language, cognitive and motor deficits. Behavioural variant FTD (bvFTD) is the most common presentation, with impaired social conduct and personality changes,Anatomically, FTD has traditionally been characterized as a cortical dementia with atrophy predominantly of the frontal and temporal lobes, hence its name. However, imaging and neuropathological studies have identified not only other cortical areas (including the insula and anterior cingulate) but also subcortical structures as key areas of FTD-related degeneration,Behavioural studies have highlighted the relevance of subcortical structures in the development of the typical symptoms of FTD. Subcortical structures contribute to functional and structural brain networks that are affected in FTD. For example, a reward network related to the limbic systemThis review aims to provide a comprehensive overview of the involvement of subcortical structures in the FTD spectrum , identifin vivo in their volume or morphology within the genetic, clinical and pathological forms of FTD (‘Neuroimaging’). This is followed by the description of which studies have reported abnormal findings at post mortem examination (‘Neuropathology’), and then finally, in the ‘Symptomatology’ section, we discuss how such structural changes contribute to the behavioural and cognitive deficits seen in people with FTD.For each of the structures, we first describe their anatomy and structural connections (‘Anatomy’), and then report the MRI studies that have investigated changes The striatum consists of dorsal and ventral regions. The dorsal striatum comprises the caudate and putamen and is primarily associated with sensorimotor functions, whilst the ventral striatum includes the nucleus accumbens and is a component of the limbic circuit, which modulates behaviour and memory.,motor circuit and oculomotor circuit, the putamen and the caudate receive input from the primary motor, somatosensory, premotor, supplementary motor and posterior parietal cortex, together with the frontal eye fields. They then send their output to the supplementary motor cortex and frontal eye fields, via the globus pallidus , substantia nigra (pars reticulata) and thalamus .,dorsolateral prefrontal circuit is associated with executive function. The dorsolateral prefrontal cortex, together with the posterior parietal and premotor cortex, is connected to the dorsolateral head of the caudate, to the globus pallidus and substantia nigra, and to the thalamus . The lateral orbitofrontal circuit regulates inhibition and impulses. It is connected to the ventral anterior and mediodorsal nuclei of the thalamus via the ventromedial head of the caudate  and the globus pallidus and substantia nigra. In the anterior cingulate circuit, the nucleus accumbens and ventromedial caudate receive input from the anterior cingulate, and limbic and paralimbic regions  with output via the globus pallidus and substantia nigra to the mediodorsal thalamus. This is the crucial pathway controlling motivation.,The striatum has multiple parallel connections with the prefrontal cortex, anterior cingulate cortex, orbitofrontal cortex, insula, inferior and middle temporal gyrus, and thalamus.The nucleus accumbens additionally projects to the basal forebrain and the lateral preoptic area and lateral hypothalamus.,,,,,,,,Clinically, the caudate is affected in both behavioural and language phenotypes of FTD. Compared to controls, the caudate is 11–25% smaller in bvFTD, 21% smaller in nfvPPA (worse on the left) and 8% smaller in svPPA (worse on the left).GRN mutation carriers in particular have shown involvement of the dorsal striatum.,GRN mutations show especially severe atrophy in the caudate (56% reduction versus controls), while putamen atrophy is similar to sporadic cases (27% reduction versus controls).GRN group showed smaller volumes in the putamen (17% difference versus controls) and caudate (5%) only when they were fully symptomatic, but not at earlier stages.C9orf72 expansion carriers were found to have smaller putaminal volumes in asymptomatic and prodromal stages (1–6%) through to fully symptomatic stages (17%), while MAPT mutation carriers were only abnormal at a fully symptomatic stage (17%).Among the genetic forms of FTD, ,Including pathologically confirmed cases, an early investigation showed no volumetric differences in any brain region comparing tau and TDP-43 cases.,,,,MAPT mutation carriers showed smaller volumes in the nucleus accumbens (11%).The ventral striatum, in the form of the nucleus accumbens, has been less studied than the dorsal region. However, atrophy in this region occurs in both bvFTD and svPPA, with volumes from 30% to 50% smaller than controls.post mortem striatal volume loss,Several studies have characterized GRN mutations,Studies focussing on genetic forms of FTD confirm the abnormalities of the basal ganglia, with prevalent involvement of the caudate in cases with Patients with both tau and TDP-43 pathology show neuron loss, astrogliosis and focal microvacuolation in the ventral striatum, accompanied by tau or TDP-43 immunoreactive neuronal cytoplasmic inclusions and dystrophic neurites. In particular, svPPA patients with TDP-43 type C show abundant and focal neuronal cytoplasmic inclusions in the accumbens.,,Striatal degeneration determines diverse symptoms of FTD, directly and indirectly via the striatal projections to other regions. For example, striatal lesions are associated with decreased globus pallidus inhibition which leads to enhanced thalamic inhibition and reduced cortical activation. Striatal atrophy is therefore associated with disinhibition,,,,,,,The role of the dorsal striatum and its connectivity with the frontal lobe is mirrored between FTD and other lesions to the dorsal fronto-striatal network, with executive dysfunction and behavioural impairment in FTD. In particular, dysexecutive syndromes are also associated with atrophy of the regions connected to the dorsolateral prefrontal cortex . On the other hand, neuropathology in the ventromedial head of the caudate and its connections to the orbitofrontal cortex leads to loss of socially appropriate behaviours, abnormal reward-seeking and disinhibited or impulsive behaviours.C9orf72-associated FTD.C9orf72-associated FTD.GRN- and MAPT-associated FTD, striatal atrophy is related to impaired social cognition.In genetic FTD, impairment of negative, as well as positive, outcome representations may account for the association of striatal atrophy with abnormal pain perception in Another important nucleus of the basal ganglia is the globus pallidus, which has been closely associated with motor symptoms and signs, but which also mediate cognitive functions.,,MAPT and GRN mutation carriers showed smaller volumes compared to controls (12–14%), while C9orf72 expansion carriers showed reduced volumes (6%) even at a prodromal stage, reaching 16% volumetric difference when fully symptomatic.In bvFTD, the globus pallidus has been shown to be approximately 10% smaller than controls.MAPT showed tau positive inclusions in the pallidus, together with gliosis and neuronal loss.In a study on pathologically confirmed cases of FTLD, only few TDP-43 inclusions were found in the globus pallidus and ventral pallidus, compared to other basal ganglia structures.,,,,The pallidus plays an important role in response inhibition, reducing thalamocortical output and consequently the activation in the motor cortex.The basal ganglia include the substantia nigra and subthalamic nucleus. The substantia nigra is connected via the subthalamic nucleus to the globus pallidus in the cortico-striato-pallido-thalamic-cortical circuits, regulating motor, reward and executive functions.post mortem 7 T MRI study found a significant increase of iron deposition in the subthalamic nucleus of the FTLD-FUS, FTLD-TDP-43 and pure ALS groups, but not in the FTD-tau, while there was no difference in the substantia nigra from controls.Given the relatively small size of these nuclei, there are very few studies looking at volumetric differences in the substantia nigra and subthalamic nucleus in the FTD spectrum, and the main ones are related to parkinsonian syndromes. One study investigating the iron content in a cohort of bvFTD and PPA patients failed to find any difference in the substantia nigra,A case of bvFTD with confirmed TDP-43 type C showed severe neuronal loss and gliosis without TDP-43 inclusions in the subthalamic nucleus, while the substantia nigra was spared.MAPT, GRN and C9orf72. Specifically, in GRN mutation carriers, the parkinsonism correlates with the degeneration and neural inclusions in the substantia nigra.,Nigrostriatal neurons from the substantia nigra pars compacta regulate the subcortical–cortical loops for motor, oculomotor and cognitive control, through their terminations to the striatum. Neurodegeneration of this structure and reduced level of dopamine in the substantia nigra is typically associated with parkinsonian syndromes.,,,,,The hippocampus is a key component of the medial temporal lobe, involved in the formation of new memories and associated with learning and emotion.,episodic memory network ; an emotional–social anterior network ; a sensory processing and integration system ; and a network for familiarity signalling and retrieval processing, with extensive connection between the hippocampus, the prefrontal cortex and the thalamus.The hippocampus is composed of different cytoarchitectonic subfields, mainly part of the allocortex, which have specialized functions and distinctive connections.,The principal efferents of the hippocampus are the subiculum and CA1, except for the basal forebrain and nucleus accumbens, which are mainly connected with CA3.,,,,,Hippocampal atrophy has traditionally been described as particularly characteristic of Alzheimer’s disease, but many studies over the past 20 years have shown its involvement in some forms of FTD.MAPT mutation carriers compared with C9orf72 and GRN mutation carriers.MAPT mutation carriers,,Looking at the genetic forms of FTD, the hippocampus is particularly atrophic in MAPT mutations: 43%) and TDP-43 type C cases . Other pathologies have involvement to a lesser extent: FUS (31%), TDP-43 type A (23%) and CBD (14%).In patients with pathologically confirmed FTD, the hippocampus has been shown to be significantly smaller in Pick's disease (33% volume difference from controls) as well as in FTDP-17 (i.e. MAPT mutation carriers showed a 24–27% volumetric difference in the hippocampus proper (formed by the CA subfields), whilst C9orf72 expansion carriers showed most atrophy in the dentate gyrus and CA1/4 (8–11%), and GRN mutation carriers were most affected in the subiculum and presubiculum (10–14%).MAPT  and C9orf72 groups , and in the presubiculum (8%) in the prodromal stages of GRN mutation carriers.Hippocampal subfields have also been investigated in FTD. In svPPA, both the CA1 and subiculum regions were significantly smaller in svPPA than controls .post mortem, the hippocampus shows mild to severe neuronal loss, with 48% of cases showing hippocampal sclerosis  and 64% showing the classic ubiquitinated inclusions in the dentate gyrus.,,,At in vivo imaging of the genetic groups: tau deposition is extensively found in the hippocampus and other limbic structures in MAPT mutationsC9orf72; while TDP-43 accumulates in the hippocampus and the cortex in GRN.Pathological studies in general are consistent with ,The hippocampus is central to memory. Although significant episodic memory impairment is an exclusion criterion under current diagnostic criteria for bvFTD, improving the distinction from other causes of dementia, episodic memory can be affected in FTD. Indeed, several of Pick’s original cases had prominent memory symptoms, and one study reported amnesia in the initial clinical evaluation of 10% of pathologically confirmed cases.MAPT mutation carriers, with the greater involvement of the anterior and central regions of the hippocampus which form part of the limbic system: this is associated with the difficulties seen in these patients in regulating emotion and goal-directed behaviour.Hippocampal deficits are relevant to more than memory domains in FTD, as this structure is involved in emotion modulation and evaluation of facial emotion.,The amygdala is a limbic structure, composed of several subnuclei with different connections to the rest of the brain.,The nuclei of the amygdala are heterogeneous in composition, connections and roles.,,,,,,,,Amygdalar atrophy is common in bvFTD with prior studies reporting a 19–33% volume loss on the right and 22–41% on the left.MAPT mutation carriers,,MAPT mutation carriers showed smaller volumes particularly in the superficial and accessory basal regions (44%), which were 2–4% smaller even at an asymptomatic stage.GRN mutation carriers only showed smaller volumes than controls when fully symptomatic, C9orf72 expansion carriers showed reduced volumes in all amygdalar regions even at the asymptomatic and prodromal stages, with the main reduction being in superior-medial regions.Studies of genetic FTD have shown that the amygdala is particularly affected in MAPT mutation carriers) and TDP-43 type C ,,,,,,In pathologically confirmed cohorts, amygdalar atrophy is most marked in cases with FTDP-17  are consistent with the loss of function of the amygdala, and are regularly seen with all types of FTD-related pathology.,,,,,Atrophy and hypometabolism of the amygdala relate to deficits in the emotion processing and recognition, and social interaction insight.,The basal forebrain is a collection of cholinergic nuclei, including the diagonal band of Broca, the medial septal nucleus and the nucleus basalis of Meynert.MAPT mutation carriers showed significantly smaller basal forebrain volumes than controls (15–18%) and both GRN and C9orf72 groups (14–17%).,Basal forebrain volume is reduced in both svPPA and nfvPPA as compared to controls, mainly in the posterior part of the nucleus basalis.In one study, TDP-43 inclusions have been found in the basal forebrain .,,,,Atrophy and pathology of the basal forebrain can lead to diverse symptoms in FTD, but a unifying framework for these effects is outstanding. The cholinergic system plays a key role in cognitive processing, and the cholinergic dysfunction seen in bvFTD and PPA arise from the degeneration of the nucleus basalis. For example, language impairment in PPA has been partially attributed to the cholinergic deficits from the basal forebrain pathology.The thalamus is the relay station of the brain, and it is connected to the majority of other regions. It is composed of several nuclei, each of them with specific connections and functional specialization.,,,Thalamic atrophy is a common feature across all clinical, genetic and pathological forms of FTD,C9orf72 expansion carriers have been considered to be the ones where the thalamus was particularly affected, even presymptomatically,GRN and MAPT mutation carriers, with atrophy mainly localized in the medial dorsal, midline and laterodorsal nuclei (22–31%), while the lateral geniculate nucleus was spared in both groups, but atrophic in C9orf72.Among the genetic groups, the Post mortem volume analysis of svPPA confirmed 27% loss of volume in the anterior thalamusThe heterogeneity of thalamic nuclei and their position within parallel cortico-striato-thalamo-cortical loops for cognition and motor control means that the thalamic pathology in FTD gives rise to diverse symptoms and signs. However, there is ongoing work looking at the specificity of the thalamic origin of the FTD symptoms, trying to accurately localize the thalamic nucleus involved for each clinical phenotypes and genetic forms. It is also challenging to dissociate the direct effects of pathology of the thalamic nuclei, from changes in their afferent and efferent connections,C9orf72 expansion carriers the pulvinar pathology is consistent with impairment of limbic functions and intramodality integration of sensory information,The symptomatology of thalamic changes in FTD follows the functional anatomical circuits discussed above. For example, in ,,The hypothalamus plays an important role in food intake, reward and perception of satiety. It also regulates the homeostasis of neuroendocrine, behavioural, and autonomic processes, including circadian rhythm, stress response, sexual and defensive behaviours and thermoregulation.In a study of eighteen people with bvFTD, hypothalamic volume was reduced 17% compared with controls, with the main differences localized to the superior parts of the anterior and tuberal regions and the posterior region, which regulate appetite.MAPT mutation carriers (in superior and posterior areas), but not in those with C9orf72 expansions. In particular, the posterior part of the hypothalamus was the most affected area, including the mamillary bodies, which are connected to the amygdala and hippocampus, both structures known to be particularly atrophic in MAPT mutation carriers.C9orf72 and GRN), with MAPT symptomatic carriers showing up to 29% smaller volumes in the posterior and anterior regions. However, the only group showing smaller volumes before symptom onset was C9orf72, especially in the superior anterior and tuberal regions.In a small study which included those with genetic FTD, atrophy was significantly more severe than controls in post mortem study of 19 cases with TDP-43 pathology, inclusions were found in the lateral hypothalamic area, tuberomammillary nucleus, lateral tuberal nucleus, preoptic area, ventromedial and dorsomedial nuclear groups, and in the posterior hypothalamic area. No inclusions were seen in other hypothalamic regions.Multiple pathologies have shown involvement of the hypothalamus. For example, one study showed a volume reduction of 41% in bvFTD and TDP-43 pathology cases when compared to controls.,The key role of the hypothalamus in appetite, food-reward and the perception of satiety is reflected in the symptoms associated with its degeneration in FTD. Abnormal eating behaviours are present in up to 60% of patients with FTD, and particularly prominent in patients with bvFTD and svPPA.,Structural and functional alterations of the hypothalamus are associated with autonomic deficits in bvFTD, such as lower baseline skin conductance levels.,The habenula is a small but key nucleus within the reward network.Only one small study has reported the habenula changes in FTD, showing a 29% lower volume in bvFTD compared with controls.There are currently no studies reporting the presence of pathology or neurodegeneration in the habenula in FTD.,,The habenula mediates the processing of negative and aversive information, and suppresses actions when it is anticipated that these will not produce a reward or avoid a negative feedback.The brainstem is divided into the midbrain, pons and medulla oblongata. The midbrain is associated with vision, hearing, sleep and motor control, and it also forms part of a network that regulates emotion perception with the thalamus and amygdala.,GRN mutation carriers, who typically show TDP-43 pathology.GRN mutation carriers, 9% smaller midbrain volumes in MAPT mutation carriers, but no difference in C9orf72 expansion carriers, nor in any presymptomatic carriers.Few imaging studies have focussed on the brainstem in FTD, perhaps because of the exclusion of the brainstem from early imaging atlases of grey matter. However, brainstem changes are typical of other tauopathies, and in particular CBS and PSP, with PSP showing marked atrophy in the midbrain and superior cerebellar peduncle.,TDP-43 pathology and neuronal loss has been found previously in several nuclei of the midbrain and pons in cases with bvFTD, bvFTD and ALS, and PPA variants.MAPT mutation carriers. The brainstem reticular activating system and its projections to the cerebrum are critical for arousal, and its neurodegeneration is associated with apathy in FTD.Despite the name ‘frontotemporal dementia’, brainstem pathology is commonly associated with functional impairment in FTD. Functional networks responding to salient events and enabling adaptive behaviour include brainstem nuclei, and they are impaired in FTD.post mortem and imaging studies.,,Beyond behavioural symptoms, the clinical overlap between FTD, PSP and other forms of parkinsonism also consists in motor symptoms, which are underpinned by brainstem degeneration, as identified by ,Brainstem nuclei are the main sources of the principal modulatory neurotransmitter systems, including serotonergic, dopaminergic and noradrenergic innervation of the forebrain. FTD affects the serotonergic projections from the raphe nuclei, the dopaminergic projections from the ventral tegmental area and the noradrenergic projections from the locus coeruleus.,,,,,Traditionally, cerebellar function has been associated only with the coordination of movement, but recent studies have found that the cerebellum is important in cognitive and emotional processing.,,Differential involvement of the cerebellum has been shown in FTD, as also highlighted in a recent metanalysis of neuroimaging studies.C9orf72 expansion carriers has been well characterized,,,,,GRN mutations, and localized to the vermis in MAPT mutation carriers, the ‘limbic cerebellum’ involved in the modulation of emotions and social behaviours, as already mentioned.,MAPT group, but reported 8–13% smaller volumes in lobules VIIa-Crus II, VIIb and VIIIa in fully symptomatic GRN mutation carriers.The involvement of the cerebellum in C9orf72 expansion carriers, are found throughout the cerebellum, in case with or without ALS phenotype.,,Post mortem examination of two siblings with bvFTD showed massive abnormal tau deposition in astrocytes in the cerebellum.Interestingly, dipeptide repeat proteins, the characteristic pathology of C9orf72 expansions.,The cerebellum has long been associated with motor control, and its lesions with ataxia. Although uncommon, ataxia has been described in patients with Beyond motor control and movement, cerebellar functions extend to all areas of cognition, including affective, social and executive domains. Its role in cognitive and emotional processing in FTD is now emerging. For example, in bvFTD, Tan et al.,,,C9orf72, structural changes in the cerebello-thalamic-cortical network are seen early presymptomatically, and by the time C9orf72 expansion carriers reach the symptomatic stage, they have disturbances of body schema and related neuropsychiatric symptoms related to cerebellar disease.Changes in cerebellar connections have been linked with loss of episodic memory, attention, working memory, visuospatial, executive function and emotion in bvFTD; with working memory, language and emotion in svPPA; and with attention, language, executive function, working memory, visuospatial and emotion in nfvPPA.MAPT mutations as well as Pick’s disease, while the basal ganglia are mainly involved in those with GRN mutations and FUS pathology. C9orf72 expansion carriers have a particular involvement in the pulvinar nucleus of the thalamus and the cerebellum, forming part of a cerebello-thalamic-cortical network related to neuropsychiatric symptoms in this group. Further studies are needed to explore and fully understand the role of these nuclei in all the forms of FTD, and in particular how their place within wider networks is lost as connections are broken down with disease progression.Existing studies reveal extensive involvement of subcortical structures in the clinical, genetic and pathological forms of FTD. As summarized in post mortem investigations. Initiatives like the harmonization of hippocampal subfields The studies included in this review differ in a number of characteristics, including the imaging techniques used , the sample size, the inclusion criteria for patients, the quality of MR images and the covariates included in the comparisons . Therefore, results are not always directly comparable, or amenable to meta-analysis. Collaborative studies investigating multiple structures at the same time on large cohorts will be better able to provide a clearer picture of subcortical changes in FTD, including disease progression and variants. Adequately powered longitudinal studies, including sample size estimates, are essential to understand the variability of subcortical structures, especially small but critical structures, such as the habenula and subthalamic nucleus. These are difficult to identify using automated methods or from clinical-grade images. The anatomical definition of the boundaries of some of these structures is also a relevant source of heterogeneity, not only across neuroimaging studies, but also With this review, we draw attention to the important role that the subcortical structures play in the spectrum of FTD, which has often been overlooked in the past. These regions are affected differently across the FTD disorders, and show clear early changes in the disease process.The Dementia Research Centre is supported by Alzheimer's Research UK, Brain Research Trust and The Wolfson Foundation. This work was supported by the National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility as well as an Alzheimer's Society grant (AS-PG-16-007). MB is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). MB’s work is also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council (MRC), Alzheimer’s Society and Alzheimer’s Research UK. JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). JBR and MM were supported by the Cambridge University Centre for Parkinson-Plus, the Medical Research Council (SUAG/051 G101400) and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.The authors report no competing interests.Data sharing is not applicable to this review article as no new data were generated or analysed in this study. Source study data may be available from the authors cited.


Essential oils (EOs) are extracted from plants and contain active components with therapeutic effects. Evidence shows that various types of EOs have a wide range of health benefits. In our previous studies, the potential of lavender EO for prevention and even treatment of depression and anxiety symptoms was demonstrated. The favourable outcomes may be due to multiple mechanisms, including the regulation of monoamine level, the induction of neurotrophic factor expression, the regulation of the endocrine system and the promotion of neurogenesis. The molecules of EOs may reach the brain and exert an effect through two distinctive pathways, namely, the olfactory system and the respiratory system. After inhalation, the molecules of the EOs would either act directly on the olfactory mucosa or pass into the respiratory tract. These two delivery pathways suggest different underlying mechanisms of action. Different sets of responses would be triggered, such as increased neurogenesis, regulation of hormonal levels, activation of different brain regions, and alteration in blood biochemistry, which would ultimately affect both mood and emotion. In this review, we will discuss the clinical effects of EOs on mood regulation and emotional disturbances as well as the cellular and molecular mechanisms of action. Emphasis will be put on the interaction between the respiratory and central nervous system and the involved potential mechanisms. Further evidence is needed to support the use of EOs in the clinical treatment of mood disturbances. Exploration of the underlying mechanisms may provide insight into the future therapeutic use of EO components treatment of psychiatric and physical symptoms. Essential oil (EO), as the main component used in inhalation therapy, has been widely investigated for its therapeutic effects. Evidence indicates that EOs can successfully reduce anxiety and relieve pain when combined with conventional treatment ,2. EOs cWhile the clinical effectiveness of EOs on depression and mood disturbances has already been proven, the underlying mechanisms of the therapeutic effects still remain elusive. In this review, we will discuss the biological routes of the volatile EO molecules upon entering the body and the possible cellular and molecular mechanisms underlying their therapeutic effects.Our previous studies have shown EOs to be effective in alleviating symptoms of depression, anxiety, and stress in adults both below and over 60 years of age, respectively ,10. TablMoreover, EOs have the potential to relieve depression and secondary depressive symptoms arising from different types of chronic conditions, like anxiety disorders and dementia ,14,15,16The therapeutic effects of EOs have also been proven in animal studies . BehavioAnimal studies have helped in the investigation of the underlying mechanisms of EOs. The anxiolytic effects of EOs were found to be associated with increasing serotonin (5-HT) level or dopamine (DA) level ,32,34, wAlthough most of the EOs can interact with a range of neurotransmitter pathways, such as noradrenergic, 5-HTergic, γ-aminobutyric acid (GABA)-ergic and DAergic systems , the effEOs are composed of a variety of volatile chemical constituents. To facilitate the absorption of EOs, a novel administrative method utilising nanotechnology has been developed. By encapsulating EOs into nanoparticles, the uptake and effect of them can be enhanced. The inhaled EO molecules will be delivered to the brain region via different pathways according to their molecular sizes. The possible inhalation delivery pathway involves both the olfactory and respiratory systems . The olfThere are three potential basic mechanisms enabling EOs to influence brain functioning. The first mechanism involves the activation of nasal olfactory chemoreceptors and the subsequent effect of olfactory signals on the brain. The olfactory system is unique among the sensory systems for having direct anatomical and functional links with the limbic system. Thus, olfactory stimuli can have a strong effect on mood. The second putative mechanism of action is direct penetration of EO molecules via the olfactory nerve into connected brain areas and the induction of cellular and molecular events. The third potential pathway is the alveolar absorption of EO molecules into the blood circulation, crossing the blood–brain barrier (BBB) to interact with specific brain regions.The key in identifying odour and triggering the corresponding effect lies in the olfactory sensory neurons (OSN). Humans have around 400 functional genes coding for OSN receptors, with each OSN expressing a specific type of odorant receptor ,49. ElecSome neurophysiological studies have examined the olfactory cortex in relation to brain mapping to identify the specific function of the activated brain region ,53. The On the other hand, several odorants evoke electrical signal to modulate the specific physiological effects relating to mood and behavioural responses ,60. OlfaApart from olfactory signal transmission, EOs can also exert an effect on mood through intra and extracellular transport. After being inhaled into the nasal cavity, the small volatile compounds may pass through the neuronal network of the olfactory system and directly arrive at the brain ,63. IntrAnother form of transport is extracellular transport in which the molecular compound passes through the paracellular cleft between the supporting cell and OSN to get into the lamina propria (connective tissues) via fluid movement ,65. AfteFurthermore, the EO molecule is able to interact with the neurotransmitter receptor in such a way that the transient receptor potential channels (TRP), GABA, 5-HT, and DA receptors produce an anxiolytic or antidepressant effect.Some studies have proposed that EOs could be absorbed through the respiratory system ,67,68. TBreathing is an automatic response controlled by the vegetative nervous system of the brain. Meanwhile, respiration can be altered by exposure to stress, which would activate the limbic system and trigger physiological responses. Physiological responses can represent emotional responses . Thus, rIn this section, the potential molecular and cellular mechanisms underlying the therapeutic effect of different EOs in both human and animal studies are discussed. Unlike humans, animals cannot express subjective emotional states. Whereas in human studies the severity of depression and anxiety can be assessed via questionnaires or interviews , the exaAccording to the 5-HT hypothesis of depression , the sigThe effect of EOs on the 5-HTergic system has been demonstrated in various studies. In one clinical study, community-dwelling older adults were involved in therapeutic massage/inhalation treatment combining lavender, sweet orange, and bergamot EOs for 8 weeks. After the treatment, depressive symptoms decreased compared to the baseline assessment, as measured by the geriatric depression scale and the patient health questionnaire-9. The decrease of symptoms was associated with an increase of plasma 5-HT in the EO-treated group . In anotBergamot EO (BEO), which has shown to have both anxiolytic and antidepressant effects, is a typical choice adopted in the management of depression . In an aYlang-ylang EO (YYO) is another commonly used EO for relaxation, depression, and anxiety disorders . ExposurAlthough the 5-HT hypothesis is the dominant hypothesis in terms of the pathology of depression, the roles of other monoamines, in particular DA, have also been proven. Anhedonia, a core symptom of mood disorder characterised by lack of interest, is closely linked to the mesolimbic DAergic system ,85. ThisIn the past two decades, the speculation that depression is caused by a deficiency in neurogenesis was widespread . This spNeurotrophins are a class of growth factors that promote the development of neurons and enhance neuroplasticity . Among tIn a clinical study, women whose children were diagnosed with attention deficit and hyperactivity disorder were recruited, assuming that this particular population suffered from considerable stress affecting their mental health . After aIt is believed that regulation of hormonal levels is a potential underlying mechanism explaining the effect of EOs, for instance, in the treatment of premenstrual syndrome  and menoAnimal studies provide cues on the alteration of the HPA axis resulting from exposure to EOs. Acute inhalation of bergamot EO attenuated the rise of corticosterone level response to stress induced by exposure to EPM test, which implies an effect of bergamot on the HPA axis . InhalatInterestingly, the effect of EOs on depression-like and anxiety-like behaviour has been linked to genetic predisposition of temperament in sheep . Upon exThe growing understanding of the pathophysiology of depression and anxiety disorders allows us to link certain effects of EOs to mood and emotion. Oxidative stress, which is brought about by reactive oxygen species (ROS), has an important role in neurodegeneration . Due to To facilitate the use of EOs in clinical practice when treating depression and anxiety disorders, further large-scale clinical trials are required to confirm the effectiveness and efficacy of them. Although various studies have illustrated that certain EOs possess antidepressant and anxiolytic effects ,118, theUp till now, mechanistic studies exploring the molecular signalling pathways of EOs remain scarce. From a pharmacological perspective, the active components of EOs should be identified for elucidation of the background mechanisms. For instance, linalool has been identified as the major component in lavender EO . The ideIn this review, we have discussed the antidepressant and anxiolytic effects of EOs in both human clinical and animal studies. The interplay between the respiratory system and CNS was also touched upon. Through the interconnection of the two systems, EO molecules exert an effect on mood disturbances via different possible routes. Cellular and molecular events, including alteration of monoamines, neurotrophic factors and neurogenesis are potential mechanisms underlying the therapeutic effects of EOs . In futu


The influence of microbiota on host health and disease has attracted adequate attention, and gut microbiota components and microbiota-derived metabolites affect host immune homeostasis locally and systematically. Some studies have found that gut dysbiosis, disturbance of the structure and function of the gut microbiome, disrupts pulmonary immune homeostasis, thus leading to increased disease susceptibility; the gut-lung axis is the primary cross-talk for this communication. Gut dysbiosis is involved in carcinogenesis and the progression of lung cancer through genotoxicity, systemic inflammation, and defective immunosurveillance. In addition, the gut microbiome harbors the potential to be a novel biomarker for predicting sensitivity and adverse reactions to immunotherapy in patients with lung cancer. Probiotics and fecal microbiota transplantation (FMT) can enhance the efficacy and depress the toxicity of immune checkpoint inhibitors by regulating the gut microbiota. Although current studies have found that gut microbiota closely participates in the development and immunotherapy of lung cancer, the mechanisms require further investigation. Therefore, this review aims to discuss the underlying mechanisms of gut microbiota influencing carcinogenesis and immunotherapy in lung cancer and to provide new strategies for governing gut microbiota to enhance the prevention and treatment of lung cancer. The influence of gut microbiota on hosts has aroused intensive research interest. Microorganisms in the human gastrointestinal tract, counting more than 10 times the number of total host cells, with millions of whole, nonredundant genes, shape a dynamically balanced and healthy microenvironment within the body  and inflFirmicobacteria and Bacteroidetes increased the risk of lung cancer  was discovered in children with allergic asthma, which means that R. gnavus could be a biomarker for airway allergies. In addition, mice presented with airway hyperresponsiveness and had histologic evidence of respiratory inflammation after treatment with purified R. gnavus ], with the result of activating dendritic cells and type 2 innate lymphoid cells to boost differentiation of T-helper 2 cells and production of their cytokines , which cause infiltration of the lung parenchyma by mast cells and eosinophils -producing bacteria as associated metabolic pathways, and a high pulmonary tuberculosis rate -sensitized cytokine secretion from lung cells in an airway inflammation model . They then activate immune cells and immune factors locally, which migrate through the lymphatic circulation and blood circulation and can act directly on lung target cells or continue to stimulate other immune cells. In addition, bacterial products or living bacteria from the gut can also travel through the blood or lymphatics to the lungs and stimulate the lung immune system. Thus, depending on tissue prestimulation, type of stimulation, and local and overall immune status, the gut-lung axis can effectively remove bacteria or anti-inflammatory activity, produce an excessive immune response, promote further tissue damage and disrupt pulmonary homeostasis  differed remarkably between patients and controls, while the microbial diversity  showed insignificant decline in lung cancer patients  functional annotation, especially those that participated in RNA processing and modification and chromatin structure and dynamics  demonstrated that the functional abundance spectrum was broadly similar in lung cancer compared to healthy controls, while the microbiome exhibited less frequency in pathways involved in ABC-type (ATP-binding cassette type) transport and energy metabolism in lung cancer patients , such as cytolethal distending toxin (CDT) , 59, cytvia gut-lung axis communication  and pathogen-associated molecular patterns (PAMPs) that can be recognized by nucleoside binding receptors (NODs) and Toll-like receptors (TLRs) on host cells. Direct contact with the lumen of TLRs exists not only in intestinal epithelial cells (IECs) but also in immune cells in the lamina propria, such as stromal cells, dendritic cells, macrophages, B cells and T cells. Microorganisms and their products entering the intestinal mucosa activate TLRs to produce inflammatory mediators and inflammatory factors, which participate in the pulmonary inflammatory process through lymphatic and blood circulation (ammation . Similarammation .Enterobacter and Escherichia-Shigella were found to be significantly associated with serum neutrophil-to-lymphocyte ratio (NLR) levels, while Dialister was negatively associated with serum NLR and platelet-to-lymphocyte ratio (PLR) levels. Furthermore, serum CTLA-4 and IL-12 levels were correlated with Dialister , and weakened leukocyte trafficking into the tumor, followed by a lower population of activated and effective CD8n tumors . In addin tumors . Shikha n tumors .Bifidobacterium longum, Alistipes putredinis and Prevotella copri was associated with better ICI efficacy  T cells in the tumor beds; thus, they alone exhibited antitumor capacity to the same degree as PD-L1 inhibitor, and combination treatment almost eliminated tumor outgrowth , especially when used in combination. Studies have issued that the incidence of irAEs, including diarrhea, colitis, fatigue, rash/itching, mucositis and pneumonia, ranges from 15 to 90%, with estimates of severe irAEs ranging from 0.5 to 13% . Yun-bina phylum .In addition, researchers suggest that antibiotic-induced imbalance of the gut microbiota may affect the clinical benefit of ICIs in NSCLC patients –102. A mIn general, gut microbiota may affect the efficacy of lung cancer immunotherapy and immunorelated toxicity and side effects to a certain extent; thus, artificial intervention of intestinal flora is likely to improve the efficacy and attenuate the toxicity of immunotherapy. In addition, we should be careful to use antibiotics to avoid affecting the efficacy of immunotherapy for lung cancer.via gut-lung crosstalk. Lactobacillus plantarum CIRM653 alleviated the lung inflammatory response in mouse models infected with Klebsiella pneumoniae by reducing the counts of lung innate immune cells, such as macrophages and neutrophils, and cytokines, including mouse keratinocyte-derived chemokines TNF-α and IL-6, as well as triggering an immunosuppressive Treg cell response in the lungs  or emphysema are part of the recognized risk factors for the development of lung cancer. Recent studies have suggested that gut microbiota may influence the susceptibility to malignancy and clinical immunotherapy response. Therefore, we hypothesize that the gut microbiota may be involved in the development of lung cancer and the effectiveness of immunotherapy. Recent efforts to explore the important role of the gut-lung axis in lung disease have also revealed the correlation between specific components of the gut microbiota and their derived metabolites and carcinogenesis and metastasis of lung cancer, as well as lung immunotherapy response. These interactions include gene instability caused by intestinal flora and metabolites, chronic systemic inflammation, disruption of immune homeostasis, and deficiency of immune surveillance. Recent studies have shown that gut microbiota affects the efficacy of ICIs in lung cancer patients and have also demonstrated that probiotics and FMT may be one of the methods to increase the efficacy and reduce the toxicity of immunotherapy. In addition, the use of antibiotics before or during immunotherapy can lead to gut dysbiosis, which in turn affects the efficacy of immunotherapy.Because of the widespread use of NGS and 16S RNA, most studies have focused on the bacterial components of the gut microbiome. However, the gut microbiome is a large and complex library of microbial signals. The roles of fungi, protozoa, worms, viruses, and bacteriophages may be equally important. Fungi and viruses may also influence pulmonary homeostasis through the gut-lung axis, but little is known about this. In addition, although some studies have shown that certain microorganisms and derivatives can affect and regulate the development of lung cancer and the ICI curative effect, some of the flora were not advantageous bacterial groups. In other words, the content is relatively too small, the effect is still questionable, and separate microbiota may be observed with the change of environment and show different biological function. The present study is only at the qualitative level, and thus more research is necessary to reach a quantitative breakthrough. A better analysis of the association between gut microbiome composition, efficacy and toxicity of antibiotic therapy and ICIs, as well as dynamic monitoring of gut microbiome evolution, can lead to this conclusion and support the use of probiotics or microbial agents to regulate the gut microbiome to improve the prevention and treatment of lung cancer.XJL was mainly responsible for writing conception, literature searching, and drafting of the manuscript. YC participated in the collection of literatures and revision of article. DZ, MZ, XHL and DL were responsible for the revision of the manuscript. BG, HZ, JS, XH and ML provided professional revision for the article. JC participated in the conception and revision of the article. All authors contributed to the article and approved the submitted version.This work was supported by the Chinese Society of Clinical Oncology (CSCO) Research Foundation (Nos. Y-JS2019-034).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Premature ovarian insufficiency (POI) is a complex endocrine disease that severely affects the physiological and reproductive functions of females. The current conventional clinical treatment methods for POI are characterized by several side effects, and most do not effectively restore the physiological functions of the ovaries. Transplantation of mesenchymal stem cells (MSCs) is a promising regenerative medicine approach, which has received significant attention in the management of POI with high efficacy. Associated pre-clinical and clinical trials are also proceeding orderly. However, the therapeutic mechanisms underlying the MSCs-based treatment are complex and have not been fully elucidated. In brief, proliferation, apoptosis, immunization, autophagy, oxidative stress, and fibrosis of ovarian cells are modulated through paracrine effects after migration of MSCs to the injured ovary. This review summarizes therapeutic mechanisms of MSCs-based treatments in POI and explores their therapeutic potential in clinical practice. Therefore, this review will provide a theoretical basis for further research and clinical application of MSCs in POI. Premature ovarian insufficiency (POI) is a complex endocrine disease common in women aged below 40 years with global incidence of 1% . In mostin vivo transplantation, MSCs migrate to damaged ovaries where they potentially inhibit release of inflammation-related cytokines, target immune cells to exert immunomodulatory activities, and target damaged tissue cells to regulate proliferation, autophagy, oxidative stress, and fibrosis.Mesenchymal stem cell (MSC) is a kind of multipotent non-hematopoietic stem cell with low immunogenicity . MSCs haUnderstanding the molecular and cellular mechanisms underlying MSCs-based treatment of POI is the first step in ensuring safety and efficacy in clinical application of MSCs and for improving quality of MSCs products. Although studies on MSCs-related therapy for POI have explored some internal therapeutic mechanisms, there is no clear correlation between these studies, and the mechanisms presented are disorganized. In addition, a well-conducted systematic and comprehensive summary of these mechanisms is not available. This review will summarize relevant studies on therapeutic mechanism involved in MSCs-mediated treatment of POI, and report limitations in the current studies in this field and provides a basis for future application of MSCs in clinical practice.The ovary is the most critical female reproductive organ and it performs gametogenic and secretory functions . A healtAlthough the cause of POI is unclear in most cases, accelerated apoptosis of GCs and oocytes, blocked follicle maturation, and abnormalities in follicle activation resulting in dysfunction or depletion of ovarian follicles are potential molecular mechanisms of POI . Therefoin vitro activation of follicles  was approved for treatment of osteoarthritis, and this novel product is safe and effective  through intravenous route and reported that they mainly migrated to the ovarian hilum and medulla, only a few migrated to the cortex, and none migrated to the follicle . The finin vivo. MSCs convey several cell adhesion molecules and receptors including CXCL12 and integrin family, and they can induce migration of MSCs to target tissues , which plays a role in restoring ovarian function . These bA previous study reported that MSCs improved ovarian function and structure of ovarian damaged rabbits by secretion of VEGF, which promoted the proliferation of oocytes and GCs . In addiThese findings indicate that paracrine effects of MSCs are beneficial in restoration of ovarian function in POI. In addition, independent use of growth factors is a potential new therapeutic method for POI patients. Research has also revealed that secretions of MSCs potentially modify the ovarian microenvironment. Although migration and secretion characteristics of MSCs promote their curative actions, further studies should be conducted to explore more precise mechanisms. Specifically, the regulation of proliferation, apoptosis, immunization, and oxidative stress of ovarian cells by the paracrine effects of MSCs needs further exploration.As mentioned above, high apoptosis rates of GCs and oocytes are correlated with ovarian dysfunction and follicle reduction, which are the critical pathogenesis mechanisms of POI . TherefoA previous study reported that UCMSCs restored ovarian functionality by reducing apoptosis of GCs and increasing more oocyte-containing follicles . A recenRegulation of expression of related genes, which modulates apoptosis of cells, is an important mechanism for inhibition of apoptosis of GCs and oocytes. Human MSCs increase GCs proliferation, and inhibit their apoptosis by inhibiting expression of Gadd45b protein, which is involved in cell apoptosis . SimilarMoreover, MSCs can regulate the vitality of oocytes and GCs through various proliferation-related signaling pathways. For instance, hUCMSCs reduced the apoptosis of ovarian cells through regulation of NGF/TrkA signaling pathway . Similar+/CD105+ human amniotic fluid MSCs (hAFCs) to the ovaries of POI mice  cytokines ratio and modulation of number of natural killer cells . In addiThe autoimmune factor is a common etiology of POI, and the immune-regulating effect of MSCs makes them an effective and promising treatment option for immune-mediated POI. Therefore, future studies should explore the specific mechanisms of immunomodulatory activities of MSCs in POI.Autophagy is a cellular degradation process, implicated in elimination of damaged organelles to preserve the normal function of cells . It is aFibrosis of the ovary is a major pathological change in POI . The TGFin vitro and in vivo  are major paracrine effectors derived from MSCs, and have been widely explored in the field of biology and medicine over the past decade . EVs plaarticles . These cin vitro. The finding implied that delivering miR-10a is a potential therapy for the preservation of oocytes and GCs in follicles. Therefore, the delivery of exRNA from MSCs-EVs is a potential approach to manage female POI patients.Several studies demonstrated that MSCs-derived EVs comprising biologically active molecules can restore ovarian biological activity and show similar therapeutic effect as transplantation of MSCs. Moreover, the relevant mechanisms of EVs in POI also have been investigated. A recent study demonstrated that EVs could gather around the damaged GCs, and inhibit their apoptosis to restore ovarian secretory function . Liu et These findings indicate the potential therapeutic value of MSCs-derived EVs in prompting ovarian function recovery of POI, making the cell-free therapeutic method an advanced approach for clinical application. However, most of the complicated functions and the specific therapeutic mechanism of EVs are unknown. It is imperative to ensure safe usage of this approach in clinical applications to avoid side effects and elucidate the precise mechanisms of ovarian functional recovery.in vitro or in vivo. Materials such as collagen scaffold can reinforce stem cell attachment, survival, and proliferation. Moreover, MSCs are developed into a 3D-culture model that increases their long-term survival in injured ovaries (Tissue engineering is an emerging biotechnology technique that combines cell biology and material science to construct tissues or organs  ovaries . In this ovaries . Without ovaries . In addi ovaries . Therefo ovaries . A previ ovaries . The fin ovaries . The fin ovaries .Therefore, combination of tissue engineering material and MSCs for transplantation represents a promising advanced approach for POI treatment with excellent therapeutic potential . HoweverOn the basis of previous investigations and basic mechanistic studies, significant advances in the treatment of ovarian dysfunction can be achieved through clinical trial studies. Application of MSCs in clinical practice was initially used to address osteogenesis imperfecta of children, which showed satisfactory outcomes . Moreovein situ enhances ovarian reserve (Selection of appropriate approaches for application of MSCs in clinical is fundamental for an effective cell-based therapy. Previous studies report that administration of MSCs  reserve . Intrave reserve .in vitro (Although significant advances in MSCs-based treatment for various diseases have been achieved over the past decades, practical application of MSCs still has several challenges. For instance, it is important to verify the safety of transplanting MSCs into ovaries. Fortunately, the safety of administration and application of MSCs gains the highest level of attention. Ensuring safety is a prerequisite for human cell-based therapy. The possible risk of MSCs-based treatment can be attributed to the characteristic of MSCs to suppress immune function and enhance tumor growth . A consein vitro . Meanwhiin vitro . HencefoDifferent studies propose distinct methods of isolation, culture, and identification of MSCs for treatment . This leFurthermore, several successful laboratory-based investigations and positive pre-clinical or clinical findings of MSCs-mediated treatment have been reported. An appropriate example is the good therapeutic outcome for complex perianal fistulas of Crohn’s disease using ADSCs , which wMesenchymal stem cells are widely used stem cells and studies report that they have great potential for alleviating POI in laboratory-based investigations and pre-clinical or clinical studies in the last decade. Transplantation of MSCs is a great option for fundamental POI treatment owing to their low immunogenicity, broad sources, and availability. Therapeutic effect of MSCs is not modulated by a single factor but comprises a complex biological regulation. Proliferation, apoptosis, immunization, autophagy, oxidative stress, and fibrosis of ovarian cells are modulated through paracrine effects after migration of MSCs to the injured ovary. Tissue engineering and extracellular vesicles are new techniques from MSCs for improving treatment efficacy in POI patients. Developing systematic standards of MSCs from culture to application can improve the safety of MSCs-based applications and avoid side-effects. In summary, MSCs-mediated therapy has promising potential for fundamental restoration of ovarian function in POI patients.ZL and XH were responsible for the concept of the review. ZL was responsible for writing the first draft of the manuscript. ZL and QL made all the figures in this manuscript. YT revised the manuscript critically. XH and MZ were responsible for the critical review of the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.